Patulous Subarachnoid Space of the Optic Nerve Associated with X-Linked Hypophosphatemic Rickets.

PubMed

Galvez-Ruiz, Alberto; Chaudhry, Imtiaz

2013-01-01

Although the deficiency forms are the most common manifestations of rickets, there are other forms of rickets that are resistant to vitamin D. Of these, the most common is X-linked hypophosphatemic rickets. Rickets represents a group of multiple cranial bone disorders-craniosynostosis and the presence of Chari I malformation being the most notable-that explain the increase in intracranial pressure. We present a 4-year-old patient with an unusual association of X-linked hypophosphataemic rickets, bilateral proptosis, and prominent bilateral widening of the optic nerve sheaths. Although the association between intracranial hypertension and rickets is known, to the best of our knowledge, such a prominent distention of the subarachnoid space of the optic nerve without papilloedema has not been previously described.

Vitamin D receptor gene polymorphisms and the risk of rickets among Asians: a meta-analysis.

PubMed

Mao, Song; Huang, Songming

2014-03-01

To evaluate the association between vitamin D receptor (VDR) gene polymorphisms and the risk of rickets among Asians. Eligible studies were included in our meta-analysis by searching PubMed, Embase, Cochrane and China National Knowledge Infrastructure databases according to a predefined criteria. A random effects model was used to calculate the combined ORs and its corresponding 95% CI. 16 studies were recruited for the analysis of the association between VDR BsmI (rs1544410), TaqI (rs731236), FokI (rs2228570) and ApaI (rs7975232) gene polymorphisms and the risk of rickets among Asians, most of whom were from China. B allele/BB genotype was associated with the susceptibility of rickets (p=0.017 and 0.044, respectively), and bb genotype was associated with lower risk of rickets (p=0.033). F allele/FF genotype was associated with the susceptibility of rickets (p<10(-4)), and ff genotype was associated with lower risk of rickets (p<10(-4)). AA genotype was associated with the onset of rickets (p=0.044). No significant association was observed between TaqI polymorphism the risk of rickets. A allele/aa genotype was not associated with the risk of rickets. No evidence of publication bias was observed. B allele/BB genotype at the BsmI site, F allele/FF genotype at the FokI site and AA genotype at the ApaI site may be risk factors for the onset of rickets among Asians; bb genotype at the BsmI site and ff genotype at the FokI site may be protective factors against the risk of rickets among Asians.

The effect of nutritional rickets on bone mineral density.

PubMed

Thacher, Tom D; Fischer, Philip R; Pettifor, John M

2014-11-01

Nutritional rickets is caused by impaired mineralization of growing bone. The effect of nutritional rickets on areal bone mineral density (aBMD) has not been established. Our objective was to determine if aBMD is lower in children with active rickets than in healthy control children. We expected that the reduction in aBMD would vary between the radial and ulnar metaphyses near the growth plates and the proximal diaphyses. Case-control study. Primary care outpatient department of a teaching hospital in Jos, Nigeria. Nigerian children with radiographically-confirmed rickets were compared with a reference group of control children without rickets from the same community. Forearm bone density measurements were performed in all children with pDXA. Age, sex, and height-adjusted bone density parameters were compared between children with rickets and control subjects. A total of 264 children with active rickets (ages 13-120 months) and 660 control children (ages 11-123 months) were included. In multivariate analyses controlling for height, age, and gender, rickets was associated with a 4% greater bone area and 7% lower aBMD of the radial and ulnar metaphyses compared with controls (P < .001). The effects of rickets on the diaphyses of the radius and ulna were more pronounced with an 11% greater bone area, 21% lower aBMD, and 24% lower bone mineral apparent density than controls (P < .001). In children with rickets, aBMD values were unrelated to dairy product intake or serum calcium, phosphorus, alkaline phosphatase, or 25-hydroxyvitamin D. Metaphyseal aBMD was positively associated with radiographic severity score, attributed to bone edge detection artifact by densitometry in active rickets. Rickets results in increased bone area and reduced aBMD, which are more pronounced in the diaphyseal than in the metaphyseal regions of the radius and ulna, consistent with secondary hyperparathyroidism, generalized osteoid expansion and impaired mineralization.

Pseudovitamin D deficiency rickets—a report from the Indian subcontinent

PubMed Central

Zargar, A. H.; Mithal, A.; Wani, A. I.; Laway, B. A.; Masoodi, S. R.; Bashir, M. I.; Ganie, M. A.

2000-01-01

Pseudovitamin D deficiency rickets (also called vitamin D dependent rickets type I) is one of the types of inherited rickets and is caused by a deficit in renal 25-hydroxyvitamin D 1α-hydroxylase. This form of rickets has not been reported from the Indian subcontinent. Three patients with this disorder are presented. These patients were all females aged 3-20 years and presented with growth failure and skeletal deformities. All had florid clinical and radiological rickets. The biochemical abnormalities seen included hypocalcaemia, hypophosphataemia, and hyperphosphatasia. All patients had grossly raised 25-hydroxyvitamin D concentrations and markedly low to undetectable concentrations of 1,25-dihydroxyvitamin D. A disturbing feature of this study was the late referral of the patients.


Keywords: 1α-hydroxylase; calcitriol; inherited rickets; vitamin D dependent rickets PMID:10824056

Renal rickets-practical approach

PubMed Central

Sahay, Manisha; Sahay, Rakesh

2013-01-01

Rickets/osteomalacia is an important problem in a tropical country. Many cases are due to poor vitamin D intake or calcium deficient diets and can be corrected by administration of calcium and vitamin D. However, some cases are refractory to vitamin D therapy and are related to renal defects. These include rickets of renal tubular acidosis (RTA), hypophosphatemic rickets, and vitamin D dependent rickets (VDDR). The latter is due to impaired action of 1α-hydroxylase in renal tubule. These varieties need proper diagnosis and specific treatment. PMID:24251212

Two cases of rickets presenting with poor growth, hypotonia, and respiratory problems.

PubMed

Wouters, E; Wojciechowski, M; de Vries, E

2015-06-01

Rickets is a rare disease in developed countries. In children, it is a disease which affects growing bone. Depending on the severity, it can present with a wide variety of symptoms. Because it is such a rare disease in developed countries, symptoms suggesting rickets are often not easily recognized. This can cause a delay in diagnosing and treating rickets. Often unnecessary and sometimes invasive investigations are performed. First leading clues to rickets on physical examination are poor growth, especially length, thickening of wrists, bow legs, and craniotabes. At further examination, special attention should be paid to osteopenia and cupping and fraying at the metaphyses on X-rays. Laboratory results suggestive for rickets are elevated alkaline phosphatase and disturbances in calcium and phosphate homeostasis. In this report, we present two cases presenting with poor growth, severe pain, and respiratory problems secondary to calcipenic rickets.

Relationship of calcium absorption with 25(OH)D and calcium intake in children with rickets

USDA-ARS?s Scientific Manuscript database

Nutritional rickets has long been considered a disease caused by vitamin D deficiency, but recent data indicate that inadequate dietary calcium intake is an important cause of rickets, particularly in tropical countries. Children with rickets due to calcium deficiency do not have very low 25(OH) D c...

Celiac disease presenting as rickets in Saudi children.

PubMed

Assiri, Asaad; Saeed, Anjum; AlSarkhy, Ahmed; El Mouzan, Mohammed Issa; El Matary, Wael

2013-01-01

Rickets is commonly seen as a sign of malabsorption like celiac disease if it is not treated appropriately with vitamin D and calcium supplements. The aim of this study was to examine the frequency of diagnosis of celiac disease among children with unexplained rickets in Saudi children at a tertiary hospital setting. Retrospective review of records of patients referred over 10 years to a pediatric gastroenterology and hepatology unit. The study included all patients referred for evaluation of unexplained rickets and osteomalacia and screened for celiac disease. The diagnosis of rickets was made on the basis of history, physical examination, biochemical and radiological investigations. The diagnosis of celiac disease was made based on the ESPGHAN (European Society for Pediatric Gastroenterology, Hepatology, and Nutrition) criteria. Twenty-six children with a mean (SD) age of 9.5 (4.6) years (5 males, range 1-15 years) were referred for evaluation of unexplained rickets and were screened for celiac disease. The diagnosis of celiac disease based on small bowel biopsy findings was confirmed in 10 (38.4%) patients with rickets. Serological markers for celiac disease including antiendomyseal antibodies and antitissue transglutaminase antibodies were positive in all ten children. Rickets is not an uncommon presentation of celiac disease in Saudi children and pediatricians should consider celiac disease as an underlying cause for rickets.

Using data from a multi-hospital clinical network to explore prevalence of pediatric rickets in Kenya

PubMed Central

Karuri, Stella W.; Murithi, Maureen K.; Irimu, Grace; English, Mike

2017-01-01

Background: Nutritional rickets is a public health concern in developing countries despite tropical climates and a re-emerging issue in developed countries. In this study, we reviewed pediatric admission data from the Clinical Information Network (CIN) to help determine hospital and region based prevalence of rickets in three regions of Kenya (Central Kenya, Western Kenya and Nairobi County). We also examine the association of rickets with other diagnosis, such as malnutrition and pneumonia, and study the effect of rickets on regional hospital stays. Methods: We analyzed discharge records for children aged 1 month to 5 years from county (formerly district) hospitals in the CIN, with admissions from February 1 st 2014 to February 28 th 2015. The strength of the association between rickets and key demographic factors, as well as with malnutrition and pneumonia, was assessed using odds ratios. The Fisher exact test was used to test the significance of the estimated odd ratios. Kaplan-Meier curves were used to analyze length of hospital stays. Results: There was a marked difference in prevalence across the three regions, with Nairobi having the highest number of cases of rickets at a proportion of 4.01%, followed by Central Region at 0.92%. Out of 9756 admissions in the Western Region, there was only one diagnosis of rickets. Malnutrition was associated with rickets; this association varied regionally. Pneumonia was found to be associated with rickets in Central Kenya. Children diagnosed with rickets had longer hospital stays, even when cases of malnutrition and pneumonia were excluded in the analysis. Conclusion: There was marked regional variation in hospital based prevalence of rickets, but in some regions it is a common clinical diagnosis suggesting the need for targeted public health interventions. Factors such as maternal and child nutrition, urbanization and cultural practices might explain these differences. PMID:29062911

Hereditary rickets. How genetic alterations explain the biochemical and clinical phenotypes.

PubMed

Papadopoulou, Anna; Gole, Evaggelia; Nicolaidou, Polyxeni

2013-12-01

The reemergence of vitamin D deficiency in the industrialized countries resurrects the "threat" of nutritional rickets, especially among pediatric populations, a fact that may lead to underdiagnosis of hereditary rickets. Today, hereditary rickets may be subdivided into two main groups according to their biochemical profile: the one associated with defects in vitamin D synthesis and action and the second associated with abnormal phosphorus metabolism. The classification of the patients in a particular group of hereditary rickets is determinative of the treatment to follow. This review, through the recent advances on vitamin D and P metabolism, discusses the molecular and biochemical defects associated to each group of inherited rickets, as well as the clinical phenotypes and the recommended therapeutic approaches.

Iron Supplementation Associated With Loss of Phenotype in Autosomal Dominant Hypophosphatemic Rickets.

PubMed

Kapelari, Klaus; Köhle, Julia; Kotzot, Dieter; Högler, Wolfgang

2015-09-01

Autosomal dominant hypophosphatemic rickets (ADHR) is the only hereditary disorder of renal phosphate wasting in which patients may regain the ability to conserve phosphate. Low iron status plays a role in the pathophysiology of ADHR. This study reports of a girl with ADHR, iron deficiency, and a paternal history of hypophosphatemic rickets that resolved without treatment. The girl's biochemical phenotype resolved with iron supplementation. A 26-month-old girl presented with typical features of hypophosphatemic rickets, short stature (79 cm; -2.82 SDS), and iron deficiency. Treatment with elemental phosphorus and calcitriol improved her biochemical profile and resolved the rickets. The girl's father had presented with rickets at age 11 months but never received medication. His final height was reduced (154.3 cm; -3.51 SDS), he had undergone corrective leg surgery and had an adult normal phosphate, fibroblast growth factor 23, and iron status. Father and daughter were found to have a heterozygous mutation in exon 3 of the FGF23 gene (c.536G>A, p.Arg179Gln), confirming ADHR. Withdrawal of rickets medication was attempted off and on iron supplementation. Withdrawal of rickets medication in the girl was unsuccessful in the presence of low-normal serum iron levels at age 5.6 years but was later successful in the presence of high-normal serum iron levels following high-dose iron supplementation. We report an association between iron supplementation and a complete loss of biochemical ADHR phenotype, allowing withdrawal of rickets medication. Experience from this case suggests that reduction and withdrawal of rickets medication should be attempted only after iron status has been optimized.

Vitamin D/dietary calcium deficiency rickets and pseudo-vitamin D deficiency rickets

PubMed Central

Glorieux, Francis H; Pettifor, John M

2014-01-01

This review describes the pathogenesis, clinical presentation and biochemical perturbations found in privational (nutritional) rickets and pseudo-vitamin D deficiency rickets (PDDR), an autosomal recessive condition with loss of function mutations in CYP27B1. It may seem strange to combine a discussion on privational rickets and PDDR as a single topic, but privational rickets and PDDR present with similar clinical signs and symptoms and with similar perturbations in bone and mineral metabolism. Of interest is the characteristic lack of features of rickets at birth in infants with PDDR, a finding which has also been reported in infants born to vitamin D-deficient mothers. This highlights the independence of the fetus and neonate from the need for vitamin D to maintain calcium homeostasis during this period. The variable roles of vitamin D deficiency and dietary calcium deficiency in the pathogenesis of privational rickets are discussed and the associated alterations in vitamin D metabolism highlighted. Although PDDR is a rare autosomal recessive disorder, results of long-term follow-up are now available on the effect of treatment with calcitriol, and these are discussed. Areas of uncertainty, such as should affected mothers breastfeed their infants, are emphasized. PMID:24818008

Clinical and morphological investigations on the incidence of forms of rickets and their association with other pathological states in broiler chickens.

PubMed

Dinev, I

2012-04-01

The purpose of investigations was to determine, by means of pathomorphological methods, the incidence of different rickets forms and their role for the occurrence of other illnesses in broiler chickens in Bulgaria. Clinical, blood biochemical, gross anatomy and histological investigations were carried out in broiler chickens with signs of rickets. The studies were performed in 12 broiler flocks in 4 farms located in different regions of the country. Based on macro- and microscopic lesions, alterations specific for hypocalcaemic rickets were observed in two farms, whereas signs of hypophosphataemic rickets - in the other two. The rickets diagnosis was confirmed by analysis of blood serum calcium, magnesium and inorganic phosphate concentrations. At the age of 30-35 days, various pathological states were observed in the same farms. The presented results suggested that existing problems in studied flocks were associated with an earlier occurrence of rickets. Copyright © 2011 Elsevier Ltd. All rights reserved.

Rickets: Part I.

PubMed

Shore, Richard M; Chesney, Russell W

2013-01-01

Rickets is characterized by impaired mineralization and ossification of the growth plates of growing children caused by a variety of disorders, the most frequent of which is nutritional deficiency of vitamin D. Despite ample knowledge of its etiology and the availability of cost-effective methods of preventing it, vitamin D deficiency rickets remains a significant problem in developing and developed countries. This two-part review covers the history, etiology, pathophysiology and clinical and radiographical findings of vitamin D deficiency rickets. Other less frequent causes of rickets and some of the disorders entering into the differential diagnoses of rickets are also considered. Controversial issues surrounding vitamin D deficiency include determination of what constitutes vitamin D sufficiency and the potential relationship between low levels of vitamin D metabolites in many individuals and unexplained fractures in infants.

[Vitamin D-deficiency rickets: a case report from Burkina Faso].

PubMed

Sagna, Y; Ouédraogo, D-D; Dao, F; Diallo, O; Tiéno, H; Guira, O; Traoré, L O; Yanogo, A R D; Drabo, Y J

2013-01-01

Deficiency rickets results from a deficiency of vitamin D that is responsible for deficient calcium absorption, leading to failure of bone mineralization and cartilage bone growth, especially in children. We report the case of a 9-year-old girl who shows signs of rickets. Her family history, which includes similar malformations in several family members, led us to suggest vitamin D-resistant rickets, but all laboratory tests and response to treatment indicated deficiency rickets. Prophylaxis, at least for some very poor people, should be proposed for certain populations at risk, even in tropical zones.

The relationship of maternal bone density with nutritional rickets in Nigerian children.

PubMed

Hsu, Jennifer; Fischer, Philip R; Pettifor, John M; Thacher, Tom D

2017-04-01

Factors that affect maternal bone mineral density may be related to the risk of nutritional rickets in their offspring. Our aim was to determine the relationship between maternal areal bone mineral density (aBMD) and rickets in Nigerian children. Using a case-control design, we measured forearm aBMD in 56 and 135 mothers of children with and without nutritional rickets, respectively. Active rickets was confirmed or excluded in all children radiographically. Using logistic regression, we assessed the association of maternal aBMD, adjusted for parity, pregnancy and lactation status, duration of most recent completed lactation, age of menarche, height, body mass index, and maternal age with nutritional rickets. The median (range) age of all mothers was 30years (17-47years), and parity was 4 (1-12). A total of 36 (19%) were pregnant and 55 (29%) were currently breast feeding. Mean (±SD) metaphyseal forearm aBMDs were 0.321±0.057 and 0.316±0.053g/cm 2 in mothers of children with and without rickets, respectively (P=0.60). Diaphyseal forearm aBMDs were 0.719±0.071 and 0.715±0.072g/cm 2 , respectively (P=0.69). In an adjusted analysis, maternal forearm aBMD, bone mineral content and bone area at metaphyseal and diaphyseal sites were not associated with rickets in the child. In the adjusted analysis, rickets was associated with shorter duration of most recently completed lactation (aOR 0.91 for each additional month; 95% CI 0.83-0.99), older maternal age (aOR 1.07 for each additional year; 1.00-1.14), and less frequent maternal use of lead-containing eye cosmetics (aOR 0.20; 95% CI 0.05-0.64), without any difference in maternal blood lead levels. Maternal age, parity, age of menarche, height, and body mass index were not associated with having had a child with rickets in multivariate analysis. Nutritional rickets in Nigerian children was not associated with maternal forearm aBMD. Other unidentified maternal characteristics and practices likely contribute to the risk of rickets in Nigerian children. Copyright © 2017 Elsevier Inc. All rights reserved.

Nutritional rickets in Norway: a nationwide register-based cohort study.

PubMed

Meyer, Haakon E; Skram, Kristina; Berge, Ingvill Almås; Madar, Ahmed A; Bjørndalen, Hilde Johanne

2017-05-29

Poor vitamin D status has been reported to be highly prevalent in many non-western immigrant groups living in Norway and other western countries. However, data on rickets are scarce, and the aim of the current study was to identify new cases of nutritional rickets in Norway in the period 2008-2012 among children under the age of 5 years. Register-based cohort study. The Norwegian population from 2008 to 2012. Children with nutritional rickets under the age of 5 years. Nutritional rickets. Patients with ICD10 (International Statistical Classification of Diseases and Related Health Problems, 10th revision) diagnosis code E55.0 (active rickets) treated at all Norwegian hospitals were identified in the Norwegian Patient Registry. We were able to review 85% of the medical records for diagnosis confirmation. In addition, we identified patients with the diagnoses E55.9, E64.3 and E83.3 to identify individuals with rickets who had been given other diagnoses. Nutritional rickets was confirmed in 39 children aged 0-4 years with the diagnosis of E55.0. In addition, three patients with the diagnosis of unspecified vitamin D deficiency (E55.9) were classified as having nutritional rickets, giving a total of 42 patients. Mean age at diagnosis was 1.40 years (range 0.1-3.5 years), and 93% had a non-western immigrant background. The incidence rate of rickets was estimated to be 0.3 per 10 000 person-years in the total Norwegian child population under the age of 5 years and 3.1 per 10 000 person-years in those with an immigrant background from Asia or Africa. The number of children with nutritional rickets in Norway remained low in the period 2008-2012. Nearly all children had a non-western immigrant background. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Increasing incidence of nutritional rickets: a population-based study in Olmsted County, Minnesota.

PubMed

Thacher, Tom D; Fischer, Philip R; Tebben, Peter J; Singh, Ravinder J; Cha, Stephen S; Maxson, Julie A; Yawn, Barbara P

2013-02-01

To determine temporal trends in incidence and risk factors of nutritional rickets in a community-based population. Rochester Epidemiology Project data were used to identify all children (aged <18 years) residing in Olmsted County, Minnesota, between January 1, 1970, and December 31, 2009, with diagnostic codes corresponding to rickets, vitamin D deficiency, hypovitaminosis D, rachitis, osteomalacia, genu varum, genu valgum, craniotabes, hypocalcemia, hypocalcemic seizure, and tetany. Record abstraction was performed to select individuals with radiographic confirmation of rickets. Age- and sex-matched controls were identified for the evaluation of risk factors. The main outcome measure was radiographic evidence of rickets without identifiable inherited, genetic, or nonnutritional causes. Incidence rates were calculated using Rochester Epidemiology Project census data. Of 768 children with eligible diagnostic codes, 23 had radiographic evidence of rickets; of these, 17 children had nutritional rickets. All 17 children were younger than 3 years, and 13 (76%) were of nonwhite race/ethnicity. Clinical presentation included poor growth (n=12), leg deformity (n=8), motor delay (n=5), leg pain (n=3), weakness (n=3), and hypocalcemia or tetany (n=2). The incidence of nutritional rickets in children younger than 3 years was 0, 2.2, 3.7, and 24.1 per 100,000 for the decades beginning in 1970, 1980, 1990, and 2000, respectively (P=.003 for incidence trend). Nutritional rickets was associated with black race, breast-feeding, low birth weight, and stunted growth (P<.05 for all). Four of 13 patients (31%) who underwent 25-hydroxyvitamin D testing had values less than 10 ng/mL. Nutritional rickets remains rare, but its incidence has dramatically increased since 2000. Not all cases of rickets can be attributed to vitamin D deficiency. Copyright © 2013 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

Nutritional rickets in Norway: a nationwide register-based cohort study

PubMed Central

Meyer, Haakon E; Skram, Kristina; Berge, Ingvill Almås; Madar, Ahmed A; Bjørndalen, Hilde Johanne

2017-01-01

Objectives Poor vitamin D status has been reported to be highly prevalent in many non-western immigrant groups living in Norway and other western countries. However, data on rickets are scarce, and the aim of the current study was to identify new cases of nutritional rickets in Norway in the period 2008–2012 among children under the age of 5 years. Design Register-based cohort study. Setting The Norwegian population from 2008 to 2012. Participants Children with nutritional rickets under the age of 5 years. Main outcome measure Nutritional rickets. Patients with ICD10 (International Statistical Classification of Diseases and Related Health Problems, 10th revision) diagnosis code E55.0 (active rickets) treated at all Norwegian hospitals were identified in the Norwegian Patient Registry. We were able to review 85% of the medical records for diagnosis confirmation. In addition, we identified patients with the diagnoses E55.9, E64.3 and E83.3 to identify individuals with rickets who had been given other diagnoses. Results Nutritional rickets was confirmed in 39 children aged 0–4 years with the diagnosis of E55.0. In addition, three patients with the diagnosis of unspecified vitamin D deficiency (E55.9) were classified as having nutritional rickets, giving a total of 42 patients. Mean age at diagnosis was 1.40 years (range 0.1–3.5 years), and 93% had a non-western immigrant background. The incidence rate of rickets was estimated to be 0.3 per 10 000 person-years in the total Norwegian child population under the age of 5 years and 3.1 per 10 000 person-years in those with an immigrant background from Asia or Africa. Conclusion The number of children with nutritional rickets in Norway remained low in the period 2008–2012. Nearly all children had a non-western immigrant background. PMID:28554929

The impact of rickets on growth and morbidity during recovery among children with complicated severe acute malnutrition in Kenya: A cohort study

PubMed Central

Thitiri, Johnstone; Mwalekwa, Laura; Timbwa, Molline; Iversen, Per Ole; Fegan, Greg W.; Berkley, James A.

2017-01-01

Abstract The effects of rickets on children recovery from severe acute malnutrition (SAM) are unknown. Rickets may affect both growth and susceptibility to infectious diseases. We investigated the associations of clinically diagnosed rickets with life‐threatening events and anthropometric recovery during 1 year following inpatient treatment for complicated SAM. This was a secondary analysis of clinical trial data among non‐human immunodeficiency virus‐infected Kenyan children with complicated SAM (2–59 months) followed for 1 year posthospital discharge (ClinicalTrials.gov ID NCT00934492). The outcomes were mortality, hospital readmissions, and growth during 12 months. The main exposure was clinically diagnosed rickets at baseline. Of 1,778 children recruited, 230 (12.9%, 95% CI [11.4, 14 .6]) had clinical signs of rickets at baseline. Enrolment at an urban site, height‐for‐age and head circumference‐for‐age z scores were associated with rickets. Rickets at study enrolment was associated with increased mortality (adjusted Hazard Ratio [aHR] 1.61, 95% CI [1.14, 2.27]), any readmission (aHR 1.37, 95% CI [1.09, 1.72]), readmission for severe pneumonia (aHR 1.37, 95% CI [1.05, 1.79]), but not readmission with diarrhoea (aHR 1.05, 95% CI [0.73, 1.51]). Rickets was associated with increased height gain (centimetres), adjusted regression coefficient 0.19 (95% CI [0.10, 0.28]), but not changes in head circumference, mid‐upper arm circumference, or weight. Rickets was common among children with SAM at urban sites and associated with increased risks of severe pneumonia and death. Increased height gain may have resulted from vitamin D and calcium treatment. Future work should explore possibility of other concurrent micronutrient deficiencies and optimal treatment of rickets in this high‐risk population. PMID:29178404

Increasing Incidence of Nutritional Rickets: A Population-Based Study in Olmsted County, Minnesota

PubMed Central

Thacher, Tom D.; Fischer, Philip R.; Tebben, Peter J.; Singh, Ravinder J.; Cha, Stephen S.; Maxson, Julie A.; Yawn, Barbara P.

2013-01-01

Objective To determine temporal trends in incidence and risk factors of nutritional rickets in a community-based population. Patients and Methods Rochester Epidemiology Project (REP) data were used to identify all children (<18 years) residing in Olmsted County, Minnesota between January 1, 1970 and December 31, 2009 with diagnostic codes corresponding to rickets, vitamin D deficiency, hypovitaminosis D, rachitis, osteomalacia, genu varum, genu valgum, craniotabes, hypocalcemia, hypocalcemic seizure, and tetany. Record abstraction was performed to select subjects with radiographic confirmation of rickets. Age- and gender-matched controls were identified for evaluation of risk factors. The main outcome measure was radiographic rickets without identifiable inherited, genetic, or non-nutritional causes. Incidence rates were calculated using REP census data. Results Of 768 children with eligible diagnostic codes, 23 had radiographic evidence of rickets; of these, 17 children had nutritional rickets. All were younger than 3 years and 13 (76%) were nonwhite. Clinical presentation included poor growth (n=12), leg deformity (n=8), motor delay (n=5), leg pain (n=3), weakness (n=3), and hypocalcemia or tetany (n=2). The incidence of nutritional rickets in children under 3 years was 0, 2.2, 3.7, and 24.1 per 100,000 for the decades beginning in 1970, 1980, 1990, and 2000, respectively (P=.003 for incidence trend). Nutritional rickets was associated with black race, breastfeeding, low birth weight, and stunted growth (P<.05 for all). Four of 13 (31%) who underwent 25-hydroxyvitamin D testing had values less than 10 ng/mL (25 nmol/L). Conclusion Nutritional rickets remains rare, but the incidence has dramatically increased after 2000. Not all cases can be attributed to vitamin D deficiency. PMID:23374621

Genetics Home Reference: hereditary hypophosphatemic rickets

MedlinePlus

... noticeable of these abnormalities are bowed legs or knock knees (a condition in which the lower legs ... Information & Resources MedlinePlus (4 links) Encyclopedia: Bowlegs Encyclopedia: Knock Knees Encyclopedia: Rickets Health Topic: Rickets Genetic and ...

Hypophosphatemic rickets and craniosynostosis: a multicenter case series.

PubMed

Vega, Rafael A; Opalak, Charles; Harshbarger, Raymond J; Fearon, Jeffrey A; Ritter, Ann M; Collins, John J; Rhodes, Jennifer L

2016-06-01

OBJECTIVE This study examines a series of patients with hypophosphatemic rickets and craniosynostosis to characterize the clinical course and associated craniofacial anomalies. METHODS A 20-year retrospective review identified patients with hypophosphatemic rickets and secondary craniosynostosis at 3 major craniofacial centers. Parameters examined included sex, age at diagnosis of head shape anomaly, affected sutures, etiology of rickets, presenting symptoms, number and type of surgical interventions, and associated diagnoses. A review of the literature was performed to optimize treatment recommendations. RESULTS Ten patients were identified (8 males, 2 females). Age at presentation ranged from 1 to 9 years. The most commonly affected suture was the sagittal (6/10 patients). Etiologies included antacid-induced rickets, autosomal dominant hypophosphatemic rickets, and X-linked hypophosphatemic (XLH) rickets. Nine patients had undergone at least 1 cranial vault remodeling (CVR) surgery. Three patients underwent subsequent surgeries in later years. Four patients underwent formal intracranial pressure (ICP) monitoring, 3 of which revealed elevated ICP. Three patients were diagnosed with a Chiari Type I malformation. CONCLUSIONS Secondary craniosynostosis develops postnatally due to metabolic or mechanical factors. The most common metabolic cause is hypophosphatemic rickets, which has a variety of etiologies. Head shape changes occur later and with a more heterogeneous presentation compared with that of primary craniosynostosis. CVR may be required to prevent or relieve elevated ICP and abnormalities of the cranial vault. Children with hypophosphatemic rickets who develop head shape abnormalities should be promptly referred to a craniofacial specialist.

Early animal models of rickets and proof of a nutritional deficiency hypothesis.

PubMed

Chesney, Russell W

2012-03-01

In the period between 1880 and 1930, the role of nutrition and nutritional deficiency as a cause of rickets was established based upon the results from 6 animal models of rickets. This greatly prevalent condition (60%-90% in some locales) in children of the industrialized world was an important clinical research topic. What had to be reconciled was that rickets was associated with infections, crowding, and living in northern latitudes, and cod liver oil was observed to prevent or cure the disease. Several brilliant insights opened up a new pathway to discovery using animal models of rickets. Studies in lion cubs, dogs, and rats showed the importance of cod liver oil and an antirachitic substance later termed vitamin D. They showed that fats in the diet were required, that vitamin D had a secosteroid structure and was different from vitamin A, and that ultraviolet irradiation could prevent or cure rickets. Several of these experiments had elements of serendipity in that certain dietary components and the presence or absence of sunshine or ultraviolet irradiation could critically change the course of rickets. Nonetheless, at the end of these studies, a nutritional deficiency of vitamin D resulting from a poor diet or lack of adequate sunshine was firmly established as a cause of rickets.

"English Disease": Historical Notes on Rickets, the Bone-Lung Link and Child Neglect Issues.

PubMed

Zhang, Mingyong; Shen, Fan; Petryk, Anna; Tang, Jingfeng; Chen, Xingzhen; Sergi, Consolato

2016-11-15

Nutritional or classical rickets (here labeled as "rickets") is a worldwide disease involving mostly infants and young children having inadequate sunlight exposure, often associated with a low dietary intake of Vitamin D. Rickets targets all layers of society independently of economic status with historical information spanning more than two millennia. Vitamin D is critical for the absorption of calcium and prevention of rickets in children as well as osteomalacia in adults. The initial and misleading paradigm of the 19th and 20th centuries that rickets may have been the consequence of infection has been, indeed, reversed following the identification of the Vitamin D molecule's important role in the function of the immune system. Although traditionally considered limited to osteopathology, Vitamin D deficiency is now known to be linked to infection, inflammation, and carcinogenesis. In this review, we consider the key historical (Whistler, pre-Whistler and post-Whistler descriptors) and social facts around rickets; highlight the osteo-pathological features of rickets and the pathology of the upper and lower respiratory tract, stressing the fact that lungs remain the main secondary organ affected by Vitamin D deficiency; and emphasize the public health role in identifying the cases of child neglect or abuse based on the evaluation of the costochondral region.

X-linked hypophosphatemic rickets and sagittal craniosynostosis: three patients requiring operative cranial expansion: case series and literature review.

PubMed

Jaszczuk, Phillip; Rogers, Gary F; Guzman, Raphael; Proctor, Mark R

2016-05-01

A defect in a phosphate-regulating gene leads to the most common form of rickets: X-linked hypophosphatemic rickets (XLH) or vitamin D-resistant rickets (VDDR). XLH has been associated with craniosynostosis, the sagittal suture being the most commonly involved. We present three patients with rickets and symptomatic sagittal suture craniosynostosis all of whom presented late (>2 years of age). Two had a severe phenotype and papilledema, while the third presented with an osseous bulging near the anterior fontanel and experienced chronic headaches. All underwent successful cranial vault expansion. Rachitic patients with scaphocephaly should be screened for craniosynostosis.

Prevalence of vitamin D deficiency and rickets in children with cholestasis in Iran.

PubMed

Mohammadi, Bahram; Najafi, Mehri; Farahmand, Fateme; Motamed, Farzaneh; Ghajarzadeh, Mahsa; Mohammadi, Jamshid; Eshagh Roze, Mohammad

2012-01-01

This study was aimed to determine prevalence of vitamin D deficiency and rickets in children with cholestatic liver diseases. Forty eight children with established cholestatic liver disease who referred to gastrointestinal clinic of Children Medical Center (Tehran, Iran) between April 2010 and March 2011 were enrolled in a cross-sectional study. Laboratory analysis including calcium, phosphate, albumin, total and direct bilirubin, aminotransferases, alkalinephosphatase (ALP), prothrombin time (PT), parathyroid hormone (PTH), total protein determined by routine laboratory techniques. Mean age of participants was 299.1 ± 676.8 days (range 2-3600 days) whereas twenty one were female (43.8%) and 27 (56.3%) were male. Twenty two (45.8%) had evidences of rickets in X-ray evaluation. Three children with rickets and two with normal X-ray had vitamin D deficiency while ten in rickets group and 16 in normal group had vitamin D insufficiency. The main underlying diseases were anatomical biliary atresia in cases with rickets and idiopathic in other group. Rickets and vitamin D deficiency should be considered in chronic cholestatic children.

Pathogenesis and diagnostic criteria for rickets and osteomalacia - proposal by an expert panel supported by Ministry of Health, Labour and Welfare, Japan, The Japanese Society for Bone and Mineral Research and The Japan Endocrine Society.

PubMed

Fukumoto, Seiji; Ozono, Keiichi; Michigami, Toshimi; Minagawa, Masanori; Okazaki, Ryo; Sugimoto, Toshitsugu; Takeuchi, Yasuhiro; Matsumoto, Toshio

2015-01-01

Rickets and osteomalacia are diseases characterized by impaired mineralization of bone matrix. Recent investigations revealed that the causes for rickets and osteomalacia are quite variable. While these diseases can severely impair the quality of life of the affected patients, rickets and osteomalacia can be completely cured or at least respond to treatment when properly diagnosed and treated according to the specific causes. On the other hand, there are no standard criteria to diagnose rickets or osteomalacia nationally and internationally. Therefore, we summarize the definition and pathogenesis of rickets and osteomalacia, and propose the diagnostic criteria and a flowchart for the differential diagnosis of various causes for these diseases. We hope that these criteria and flowchart are clinically useful for the proper diagnosis and management of patients with these diseases.

Pathogenesis and diagnostic criteria for rickets and osteomalacia--proposal by an expert panel supported by the Ministry of Health, Labour and Welfare, Japan, the Japanese Society for Bone and Mineral Research, and the Japan Endocrine Society.

PubMed

Fukumoto, Seiji; Ozono, Keiichi; Michigami, Toshimi; Minagawa, Masanori; Okazaki, Ryo; Sugimoto, Toshitsugu; Takeuchi, Yasuhiro; Matsumoto, Toshio

2015-09-01

Rickets and osteomalacia are diseases characterized by impaired mineralization of bone matrix. Recent investigations have revealed that the causes of rickets and osteomalacia are quite variable. Although these diseases can severely impair the quality of life of affected patients, rickets and osteomalacia can be completely cured or at least respond to treatment when properly diagnosed and treated according to the specific causes. On the other hand, there are no standard criteria to diagnose rickets or osteomalacia nationally and internationally. Therefore, we summarize the definition and pathogenesis of rickets and osteomalacia, and propose diagnostic criteria and a flowchart for the differential diagnosis of various causes of these diseases. We hope that these criteria and the flowchart are clinically useful for the proper diagnosis and management of these diseases.

A reliable and cost effective approach for radiographic monitoring in nutritional rickets.

PubMed

Chatterjee, D; Gupta, V; Sharma, V; Sinha, B; Samanta, S

2014-04-01

Radiological scoring is particularly useful in rickets, where pre-treatment radiographical findings can reflect the disease severity and can be used to monitor the improvement. However, there is only a single radiographic scoring system for rickets developed by Thacher and, to the best of our knowledge, no study has evaluated radiographic changes in rickets based on this scoring system apart from the one done by Thacher himself. The main objective of this study is to compare and analyse the pre-treatment and post-treatment radiographic parameters in nutritional rickets with the help of Thacher's scoring technique. 176 patients with nutritional rickets were given a single intramuscular injection of vitamin D (600 000 IU) along with oral calcium (50 mg kg(-1)) and vitamin D (400 IU per day) until radiological resolution and followed for 1 year. Pre- and post-treatment radiological parameters were compared and analysed statistically based on Thacher's scoring system. Radiological resolution was complete by 6 months. Time for radiological resolution and initial radiological score were linearly associated on regression analysis. The distal ulna was the last to heal in most cases except when the initial score was 10, when distal femur was the last to heal. Thacher's scoring system can effectively monitor nutritional rickets. The formula derived through linear regression has prognostic significance. The distal femur is a better indicator in radiologically severe rickets and when resolution is delayed. Thacher's scoring is very useful for monitoring of rickets. The formula derived through linear regression can predict the expected time for radiological resolution.

Nutritional Rickets among Children in a Sun Rich Country

PubMed Central

Bener, Abdulbari; Hoffmann, Georg F.

2010-01-01

Objective. This study describes the magnitude and characteristics of nutritional rickets and associated risk factors among children in Qatar. Subjects. A consecutive sample of 730 healthy subjects who visited the primay health care clinics were approached and 540 (73.9%) subjects gave consent. Mehods. Nutritional rickets diagnosis was based on clinical radiologic and biochemical parameters and normalization of alkaline phosphatase level after 6 weeks course of daily vitamin D therapy. Results. The study revealed that 23.9% of the studied children had nutritional rickets. The mean ± SD age of those with rickets (3.76 years ± 1.51) was slightly higher than those without rickets (3.57 years ± 1.45). Family history of vitamin D deficiency (44.2%; P = .001) and diabetes mellitus (53.5%; P = .002) were significantly higher in rachitic children than in nonrachitic children. The children with rickets spent a significantly shorter average duration (26.86 minutes ± 19.94) under the sun than those without rickets (30.59 minutes ± 15.72; P < .001). A significantly larger proportion of rachitic children was afflicted with vitamin D deficiency (75.2% versus 62.2%; P < .001), secondary hypothyroidism (100% versus 7.5%; P = .009) and muscular weakness (56.6% versus 26.3%; P < .001). Conclusion. The most important risk factors were low vitamin D and calcium intakes, lack of exposure to sunlight, prolonged breast feeding without supplementation of vitamin D. PMID:21048925

Nutritional rickets around the world.

PubMed

Prentice, Ann

2013-07-01

Nutritional rickets is a major public health problem in many countries of the world. The disease is characterized by deformities of the long bones, enlargement of the wrists and costochondral junctions, hypotonia and, in infants, craniotabes and delayed fontanelle closure. Predominantly caused by severe vitamin D deficiency, rickets can also be associated with hypocalcemic seizures and cardiac failure. First presentation is typically at 6-24 months of age, although hypocalcemia may be evident in younger infants. In many affluent industrialized countries, the prevalence of rickets in the general population diminished after the introduction of clean-air legislation and dietary supplementation. However, in such countries, vitamin-D deficiency rickets has re-emerged in recent years, particularly among groups with limited exposure to UVB-containing sunshine. Infants at risk of rickets tend to be those whose mothers had poor vitamin D status during pregnancy and those exclusively breast-fed for a prolonged period with little skin exposure to UVB. In other countries of the world, the prevalence of rickets can be high, even in regions with abundant year-round UVB-containing sunshine. In general, this is also due to vitamin D deficiency related to limited sun exposure. However, reports from Africa and Asia suggest that there may be other etiological factors involved. Studies in South Africa, Nigeria, The Gambia and Bangladesh have identified rickets in children, typically 3-5 years old at first presentation, in whom plasma 25-hydroxyvitamin D concentrations are higher than those characteristic of primary vitamin D deficiency. Calcium deficiency has been implicated, and in some, but not all, disturbances of phosphate metabolism, renal compromise and iron deficiency may also be involved. Continuing studies of the etiology of nutritional rickets will provide evidence to underpin guidelines for the prevention and treatment of rickets world-wide. This article is part of a Special Issue entitled 'Vitamin D Workshop'. Copyright © 2012 Elsevier Ltd. All rights reserved.

Rickets or abuse? A histologic comparison of rickets and child abuse-related fractures.

PubMed

Kepron, Charis; Pollanen, Michael S

2015-03-01

The bone changes of vitamin D deficiency rickets have been invoked as an alternate explanation for child-abuse related fractures identified through medical imaging. The lack of modern histopathologic comparisons between these two entities limits the abilities of the forensic pathologist to address this differential diagnosis, both in their autopsy reports and on the witness stand. We report a comparison of the histologic appearance of the bones in a two year old child with vitamin D deficiency rickets with fractures occurring in three young children with child abuse. In the case of rickets, there was marked architectural disorganization of endochondral ossification at the costochondral junctions and growth plates of long bones. The child abuse-related fractures showed osteochondral callus at different stages of healing, either centered on a discrete fracture line or at metaphyses (e.g. classical metaphyseal lesions). In many instances, the healing fractures disrupted the line of endochondral ossification. In none of the child abuse-related fractures was there any similarity to the histologic appearance of rickets. The maturation disturbance in the growth plate that occurs in rickets is a distinctive entity that cannot be confused histologically with healing fractures, including the classical metaphyseal lesion.

A reliable and cost effective approach for radiographic monitoring in nutritional rickets

PubMed Central

Gupta, V; Sharma, V; Sinha, B; Samanta, S

2014-01-01

Objective: Radiological scoring is particularly useful in rickets, where pre-treatment radiographical findings can reflect the disease severity and can be used to monitor the improvement. However, there is only a single radiographic scoring system for rickets developed by Thacher and, to the best of our knowledge, no study has evaluated radiographic changes in rickets based on this scoring system apart from the one done by Thacher himself. The main objective of this study is to compare and analyse the pre-treatment and post-treatment radiographic parameters in nutritional rickets with the help of Thacher's scoring technique. Methods: 176 patients with nutritional rickets were given a single intramuscular injection of vitamin D (600 000 IU) along with oral calcium (50 mg kg−1) and vitamin D (400 IU per day) until radiological resolution and followed for 1 year. Pre- and post-treatment radiological parameters were compared and analysed statistically based on Thacher's scoring system. Results: Radiological resolution was complete by 6 months. Time for radiological resolution and initial radiological score were linearly associated on regression analysis. The distal ulna was the last to heal in most cases except when the initial score was 10, when distal femur was the last to heal. Conclusion: Thacher's scoring system can effectively monitor nutritional rickets. The formula derived through linear regression has prognostic significance. Advances in knowledge: The distal femur is a better indicator in radiologically severe rickets and when resolution is delayed. Thacher's scoring is very useful for monitoring of rickets. The formula derived through linear regression can predict the expected time for radiological resolution. PMID:24593231

[Updates on rickets and osteomalacia. dental diseases in rickets].

PubMed

Kubota, Takuo

2013-10-01

Rickets is characterized by mineralization defect in bone and cartilage. X-linked hypophosphatemic rickets (XLH) is the most common form of inherited rickets. Mineralization defect is observed in dentin as well as in bone and cartilage in XLH. The dominant feature is the occurrence of infectious periradicular abscesses on deciduous and permanent teeth, not associated with trauma or decay. Dental care including the maintenance of good oral hygiene and periodical examinations should be performed. A preventive sealing of occlusal surfaces can be considered. Endodontic treatment or extraction are carried out in the presence of periradicular abscesses. Further studies are necessary for elucidating mechanisms of dentin mineralization defect and the occurrence of periradicular abscesses and for developing preventive and curative measures in XLH.

Nutritional Rickets and Osteomalacia in the Twenty-first Century: Revised Concepts, Public Health, and Prevention Strategies.

PubMed

Uday, Suma; Högler, Wolfgang

2017-08-01

Nutritional rickets and osteomalacia are common in dark-skinned and migrant populations. Their global incidence is rising due to changing population demographics, failing prevention policies and missing implementation strategies. The calcium deprivation spectrum has hypocalcaemic (seizures, tetany and dilated cardiomyopathy) and late hypophosphataemic (rickets, osteomalacia and muscle weakness) complications. This article reviews sustainable prevention strategies and identifies areas for future research. The global rickets consensus recognises the equal contribution of vitamin D and dietary calcium in the causation of calcium deprivation and provides a three stage categorisation for sufficiency, insufficiency and deficiency. For rickets prevention, 400 IU daily is recommended for all infants from birth and 600 IU in pregnancy, alongside monitoring in antenatal and child health surveillance programmes. High-risk populations require lifelong supplementation and food fortification with vitamin D or calcium. Future research should identify the true prevalence of rickets and osteomalacia, their role in bone fragility and infant mortality, and best screening and public health prevention tools.

Evaluation of Stature Development During Childhood and Adolescence in Individuals with Familial Hypophosphatemic Rickets

PubMed Central

Borghi, Mauro M.S.; Coates, Veronica; Omar, Hatim A.

2005-01-01

This review was conducted to study the diagnosis, treatment, and growth progression in infants and adolescents with familial hypophosphatemic rickets. The bibliographic search was carried out utilizing the electronic databases MEDLINE, OVID, and LILACS and by direct research within the last 15 years using the keywords rickets, familial hypophosphatemia, vitamin D deficiency, stature growth, childhood, and adolescence. Article selection was done by comparing the evaluation of the growth in patients with familial hypophosphatemic rickets, including the variables that might affect them, for possible future therapeutic proposals. It is concluded that the most significant fact in the treatment of familial hypophosphatemic rickets in infancy was the magnitude of the final stature. The use of growth hormone can be helpful in these patients. However, research reporting treatments with the use of the growth hormone for rickets are controversial. The majority of the authors agree that treatment using vitamin D and phosphate enables some statural growth in cases of early diagnosis, reflecting a better prognosis. PMID:16244755

Effects of early vitamin D deficiency rickets on bone and dental health, growth and immunity.

PubMed

Zerofsky, Melissa; Ryder, Mark; Bhatia, Suruchi; Stephensen, Charles B; King, Janet; Fung, Ellen B

2016-10-01

Vitamin D deficiency is associated with adverse health outcomes, including impaired bone growth, gingival inflammation and increased risk for autoimmune disease, but the relationship between vitamin D deficiency rickets in childhood and long-term health has not been studied. In this study, we assessed the effect of early vitamin D deficiency on growth, bone density, dental health and immune function in later childhood to determine if children previously diagnosed with rickets were at greater risk of adverse health outcomes compared with healthy children. We measured serum 25-hydroxyvitamin D, calcium, parathyroid hormone, bone mineral density, anthropometric measures, dietary habits, dental health, general health history, and markers of inflammation in 14 previously diagnosed rickets case children at Children's Hospital Oakland Research Center. We compared the findings in the rickets cases with 11 healthy children selected from the population of CHO staff families. Fourteen mothers of the rickets cases, five siblings of the rickets cases, and seven mothers of healthy children also participated. Children diagnosed with vitamin D deficiency rickets had a greater risk of fracture, greater prevalence of asthma, and more dental enamel defects compared with healthy children. Given the widespread actions of vitamin D, it is likely that early-life vitamin D deficiency may increase the risk of disease later in childhood. Further assessment of the long-term health effects of early deficiency is necessary to make appropriate dietary recommendations for infants at risk of deficiency. © 2015 John Wiley & Sons Ltd.

Global Consensus Recommendations on Prevention and Management of Nutritional Rickets.

PubMed

Munns, Craig F; Shaw, Nick; Kiely, Mairead; Specker, Bonny L; Thacher, Tom D; Ozono, Keiichi; Michigami, Toshimi; Tiosano, Dov; Mughal, M Zulf; Mäkitie, Outi; Ramos-Abad, Lorna; Ward, Leanne; DiMeglio, Linda A; Atapattu, Navoda; Cassinelli, Hamilton; Braegger, Christian; Pettifor, John M; Seth, Anju; Idris, Hafsatu Wasagu; Bhatia, Vijayalakshmi; Fu, Junfen; Goldberg, Gail; Sävendahl, Lars; Khadgawat, Rajesh; Pludowski, Pawel; Maddock, Jane; Hyppönen, Elina; Oduwole, Abiola; Frew, Emma; Aguiar, Magda; Tulchinsky, Ted; Butler, Gary; Högler, Wolfgang

2016-02-01

Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of infants, children, and adolescents; the consequences can be lethal or can last into adulthood. The goals of this evidence-based consensus document are to provide health care professionals with guidance for prevention, diagnosis, and management of nutritional rickets and to provide policy makers with a framework to work toward its eradication. A systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describe the strength of the recommendation and the quality of supporting evidence. Thirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within five working groups. The consensus group, representing 11 international scientific organizations, participated in a multiday conference in May 2014 to reach a global evidence-based consensus. This consensus document defines nutritional rickets and its diagnostic criteria and describes the clinical management of rickets and osteomalacia. Risk factors, particularly in mothers and infants, are ranked, and specific prevention recommendations including food fortification and supplementation are offered for both the clinical and public health contexts. Rickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents. Implementation of international rickets prevention programs, including supplementation and food fortification, is urgently required.

Effects of early vitamin D deficiency rickets on bone and dental health, growth and immunity

PubMed Central

Zerofsky, Melissa; Ryder, Mark; Bhatia, Suruchi; Stephensen, Charles B.; King, Janet; Fung, Ellen B.

2015-01-01

Vitamin D deficiency is associated with adverse health outcomes, including impaired bone growth, gingival inflammation and increased risk for autoimmune disease, but the relationship between vitamin D deficiency rickets in childhood and long-term health has not been studied. In this study, we assessed the effect of early vitamin D deficiency on growth, bone density, dental health and immune function in later childhood to determine if children previously diagnosed with rickets were at greater risk of adverse health outcomes compared with healthy children. We measured serum 25-hydroxyvitamin D, calcium, parathyroid hormone, bone mineral density, anthropometric measures, dietary habits, dental health, general health history, and markers of inflammation in 14 previously diagnosed rickets case children at Children’s Hospital Oakland Research Center. We compared the findings in the rickets cases with 11 healthy children selected from the population of CHO staff families. Fourteen mothers of the rickets cases, five siblings of the rickets cases, and seven mothers of healthy children also participated. Children diagnosed with vitamin D deficiency rickets had a greater risk of fracture, greater prevalence of asthma, and more dental enamel defects compared with healthy children. Given the widespread actions of vitamin D, it is likely that early-life vitamin D deficiency may increase the risk of disease later in childhood. Further assessment of the long-term health effects of early deficiency is necessary to make appropriate dietary recommendations for infants at risk of deficiency. PMID:25850574

High frequencies of elevated alkaline phosphatase activity and rickets exist in extremely low birth weight infants despite current nutritional support

PubMed Central

Mitchell, Shannon M; Rogers, Stefanie P; Hicks, Penni D; Hawthorne, Keli M; Parker, Bruce R; Abrams, Steven A

2009-01-01

Background Osteopenia and rickets are common among extremely low birth weight infants (ELBW, <1000 g birth weight) despite current practices of vitamin and mineral supplementation. Few data are available evaluating the usual course of markers of mineral status in this population. Our objectives in this study were to determine the relationship between birth weight (BW) and peak serum alkaline phosphatase activity (P-APA) in ELBW infants and evaluate our experience with the diagnosis of rickets in these infants. Methods We evaluated all ELBW infants admitted to Texas Children's Hospital NICU in 2006 and 2007. Of 211 admissions, we excluded 98 patients who were admitted at >30 days of age or did not survive/stay for >6 weeks. Bone radiographs obtained in 32 infants were reviewed by a radiologist masked to laboratory values. Results In this cohort of 113 infants, P-APA was found to have a significant inverse relationship with BW, gestational age and serum phosphorus. In paired comparisons, P-APA of infants <600 g (957 ± 346 IU/L, n = 20) and infants 600–800 g (808 ± 323 IU/L, n = 43) were both significantly higher than P-APA of infants 800–1000 g (615 ± 252 IU/L, n = 50), p < 0.01. Thirty-two patients had radiographic evaluation for evidence of rickets, based on P-APA greater than 800 IU/L, parenteral nutrition greater than 3 to 4 weeks, or clinical suspicion. Of these, 18 showed radiologic rickets and 14 showed osteopenia without rickets. Infants with BW <600 g were more likely to have radiologic rickets (10/20 infants) compared to those with BW 600–800 g (6/43 infants) and BW 800–1000 g (2/50 infants), p < 0.01 for each. P-APA was not significantly higher in infants with radiologic rickets (1078 ± 356 IU/L) compared to those without radiologic evidence of rickets (943 ± 346, p = 0.18). Conclusion Elevation of P-APA >600 IU/L was very common in ELBW infants. BW was significantly inversely related to both P-APA and radiologic rickets. No single value of P-APA was related to radiological findings of rickets. Given the very high risk of osteopenia and rickets among ELBW infants, we recommend consideration of early screening and early mineral supplementation, especially among infants <600 g BW. PMID:19640269

Calcium absorption, kinetics, bone density, and bone structure in patients with hereditary vitamin D-resistant rickets

USDA-ARS?s Scientific Manuscript database

Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) is caused by mutations in the vitamin D receptor gene. Children with HVDRR suffer from severe hypocalcemia and rickets that are treatable with extremely high-dose calcium supplements. Surprisingly, spontaneous recovery of calcium metabolis...

Systems of Systems: Scaling Up the Development Process

DTIC Science & Technology

2006-08-01

many organizations are using the TSP and growing evidence sup- ports its efficacy [Davis 03, Grojeans 05, McAndrews 00, Pracchia 04, Rickets 05...January 2004. http://www.stsc.hill.af.mil/Crosstalk/2004/01 /0401Pracchia.html. [ Rickets 05] Rickets , Chris A. “A TSP Software Maintenance Life Cycle

Systems of Systems: Scaling up the Development Program

DTIC Science & Technology

2006-08-01

many organizations are using the TSP and growing evidence sup- ports its efficacy [Davis 03, Grojeans 05, McAndrews 00, Pracchia 04, Rickets 05...January 2004. http://www.stsc.hill.af.mil/Crosstalk/2004/01 /0401Pracchia.html. [ Rickets 05] Rickets , Chris A. “A TSP Software Maintenance Life Cycle

[Severe nutritional rickets in young children: Resurgence of an old disease].

PubMed

Estrade, S; Majorel, C; Tahhan, N; Dulac, Y; Baunin, C; Gennero, I; Chaix, Y; Salles, J-P; Edouard, T

2017-08-01

Nutritional rickets remains a significant public health issue for children worldwide. Although it has almost disappeared in industrialized countries following routine vitamin D supplementation, recent evidence suggests an increasing incidence, especially in young children. In addition to the classical clinical consequences on bone and the growth plate, rickets may also be associated with life-threatening neurological and cardiac complications in the most severe forms. Consequently, early screening and treatment are required. Here, we report the case of a 2-year-old child who presented with severe nutritional rickets associated with seizure and cardiomyopathy. Family screening revealed rickets in all the siblings. This case report emphasizes the importance of being aware of this disease, notably in population with sociocultural risk factors. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

“English Disease”: Historical Notes on Rickets, the Bone–Lung Link and Child Neglect Issues

PubMed Central

Zhang, Mingyong; Shen, Fan; Petryk, Anna; Tang, Jingfeng; Chen, Xingzhen; Sergi, Consolato

2016-01-01

Nutritional or classical rickets (here labeled as “rickets”) is a worldwide disease involving mostly infants and young children having inadequate sunlight exposure, often associated with a low dietary intake of Vitamin D. Rickets targets all layers of society independently of economic status with historical information spanning more than two millennia. Vitamin D is critical for the absorption of calcium and prevention of rickets in children as well as osteomalacia in adults. The initial and misleading paradigm of the 19th and 20th centuries that rickets may have been the consequence of infection has been, indeed, reversed following the identification of the Vitamin D molecule’s important role in the function of the immune system. Although traditionally considered limited to osteopathology, Vitamin D deficiency is now known to be linked to infection, inflammation, and carcinogenesis. In this review, we consider the key historical (Whistler, pre-Whistler and post-Whistler descriptors) and social facts around rickets; highlight the osteo-pathological features of rickets and the pathology of the upper and lower respiratory tract, stressing the fact that lungs remain the main secondary organ affected by Vitamin D deficiency; and emphasize the public health role in identifying the cases of child neglect or abuse based on the evaluation of the costochondral region. PMID:27854286

Global Consensus Recommendations on Prevention and Management of Nutritional Rickets.

PubMed

Munns, Craig F; Shaw, Nick; Kiely, Mairead; Specker, Bonny L; Thacher, Tom D; Ozono, Keiichi; Michigami, Toshimi; Tiosano, Dov; Mughal, M Zulf; Mäkitie, Outi; Ramos-Abad, Lorna; Ward, Leanne; DiMeglio, Linda A; Atapattu, Navoda; Cassinelli, Hamilton; Braegger, Christian; Pettifor, John M; Seth, Anju; Idris, Hafsatu Wasagu; Bhatia, Vijayalakshmi; Fu, Junfen; Goldberg, Gail; Sävendahl, Lars; Khadgawat, Rajesh; Pludowski, Pawel; Maddock, Jane; Hyppönen, Elina; Oduwole, Abiola; Frew, Emma; Aguiar, Magda; Tulchinsky, Ted; Butler, Gary; Högler, Wolfgang

2016-01-01

Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of infants, children, and adolescents; the consequences can be lethal or can last into adulthood. The goals of this evidence-based consensus document are to provide health care professionals with guidance for prevention, diagnosis, and management of nutritional rickets and to provide policy makers with a framework to work toward its eradication. A systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describes the strength of the recommendation and the quality of supporting evidence. Thirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within five working groups. The consensus group, representing 11 international scientific organizations, participated in a multiday conference in May 2014 to reach a global evidence-based consensus. This consensus document defines nutritional rickets and its diagnostic criteria and describes the clinical management of rickets and osteomalacia. Risk factors, particularly in mothers and infants, are ranked, and specific prevention recommendations including food fortification and supplementation are offered for both the clinical and public health contexts. Rickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents. Implementation of international rickets prevention programs, including supplementation and food fortification, is urgently required. © 2016 S. Karger AG, Basel and The Endocrine Society.

Global Consensus Recommendations on Prevention and Management of Nutritional Rickets

PubMed Central

Munns, Craig F.; Shaw, Nick; Kiely, Mairead; Specker, Bonny L.; Thacher, Tom D.; Ozono, Keiichi; Michigami, Toshimi; Tiosano, Dov; Mughal, M. Zulf; Mäkitie, Outi; Ramos-Abad, Lorna; Ward, Leanne; DiMeglio, Linda A.; Atapattu, Navoda; Cassinelli, Hamilton; Braegger, Christian; Pettifor, John M.; Seth, Anju; Idris, Hafsatu Wasagu; Bhatia, Vijayalakshmi; Fu, Junfen; Goldberg, Gail; Sävendahl, Lars; Khadgawat, Rajesh; Pludowski, Pawel; Maddock, Jane; Hyppönen, Elina; Oduwole, Abiola; Frew, Emma; Aguiar, Magda; Tulchinsky, Ted; Butler, Gary

2016-01-01

Background: Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of infants, children, and adolescents; the consequences can be lethal or can last into adulthood. The goals of this evidence-based consensus document are to provide health care professionals with guidance for prevention, diagnosis, and management of nutritional rickets and to provide policy makers with a framework to work toward its eradication. Evidence: A systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describe the strength of the recommendation and the quality of supporting evidence. Process: Thirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within five working groups. The consensus group, representing 11 international scientific organizations, participated in a multiday conference in May 2014 to reach a global evidence-based consensus. Results: This consensus document defines nutritional rickets and its diagnostic criteria and describes the clinical management of rickets and osteomalacia. Risk factors, particularly in mothers and infants, are ranked, and specific prevention recommendations including food fortification and supplementation are offered for both the clinical and public health contexts. Conclusion: Rickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents. Implementation of international rickets prevention programs, including supplementation and food fortification, is urgently required. PMID:26745253

Rickets and osteopenia are more common in infants <600g birth weight than those 600-1000g

USDA-ARS?s Scientific Manuscript database

Osteopenia and rickets are common among extremely low birth weight infants (ELBW, <1000g birth weight) despite current nutritional practices. To determine the incidence of osteopenia and rickets in ELBW infants. We evaluated all ELBW infants admitted to Texas Children's Hospital NICU in 2006 and 200...

Infantile osteopetrosis with superimposed rickets.

PubMed

Gonen, Korcan Aysun; Yazici, Zeynep; Gokalp, Gokhan; Ucar, Ayse Kalyoncu

2013-01-01

Rickets is a complication of infantile osteopetrosis and pre-treatment recognition of this complication is important. To describe four children with infantile osteopetrosis complicated by rickets (osteopetrorickets) and review the relevant literature. Retrospective chart analysis of four infants with osteopetrorickets and a systematic review of the relevant literature. We saw five children with infantile osteopetrosis, of whom four had superimposed rickets, for a period of 12 years. The review of the literature (including the current four children), yielded 20 children with infantile osteopetrorickets. The children ranged in age from 2 months to 12 months. In all children, hepatosplenomegaly was found. Sixteen (80%) children had visual impairments and eight (40%) children had hearing impairments. Serum calcium-phosphorus product was less than 30 in 18 children (90%). Twelve children (60%) were hypocalcemic and 18 (90%) were hypophosphatemic. In all children, the radiological examination demonstrated diffuse bony sclerosis and metaphyseal splaying and fraying of long bones. Five children (25%) had pathological fracture of extremities and 15 (75%) had rachitic rosary. Rickets as a complication to infantile osteopetrosis is not uncommon. Skeletal roentgenograms are of critical importance in the diagnosis of both osteopetrosis and superimposed rickets.

Nutritional rickets: pathogenesis and prevention.

PubMed

Pettifor, John M

2013-06-01

Nutritional rickets remains a public health concern in many areas of the world despite cheap and effective means of preventing the disease. The roles of vitamin D deficiency, low dietary calcium intakes and the interrelationships between the two in the pathogenesis of the disease are discussed. It is now recognized that vitamin D deficiency in the pregnant and lactating mother predisposes to the development of rickets in the breastfed infant, and that cultural and social factors are important in the pathogenesis of the disease during the adolescent growth spurt. Prevention of rickets is dependent on the awareness of the medical profession and the general public of the need to ensure adequate intakes of vitamin D in at-risk populations, and of the importance of increasing dietary intakes of calcium using locally available and inexpensive foods in communities in which dietary calcium deficiency rickets is prevalent.

Role of calcium deficiency in development of nutritional rickets in Indian children: a case control study.

PubMed

Aggarwal, Varun; Seth, Anju; Aneja, Satinder; Sharma, Bhawna; Sonkar, Pitamber; Singh, Satveer; Marwaha, Raman K

2012-10-01

Nutritional rickets is usually attributed to vitamin D deficiency. Studies from some tropical countries have postulated low dietary intake of calcium as the cause of nutritional rickets. Both vitamin D and dietary calcium deficiency are highly prevalent in India. Information on their relative contribution in the development of rickets in Indian children is limited. The aim was to study the role of calcium and vitamin D deficiency in causation of nutritional rickets in young Indian children. In a case-control study, 67 children with nutritional rickets and 68 age- and sex-matched healthy controls were compared for demographic factors, nutritional status, sun exposure (UV score), dietary calcium and phytate intake (for subjects not breast-fed at presentation), and biochemical parameters [serum calcium, inorganic phosphate, alkaline phosphatase, 25-hydroxyvitamin D (25OHD), and PTH]. Mean intake of calcium (204±129 vs. 453±234 mg/d; P<0.001) and proportion of calcium from dairy sources (41.7 vs. 88.6%; P<0.001) were significantly lower in cases vs. controls. The dietary intake of phytate was also significantly higher in cases (P=0.01). Median serum 25OHD level (interquartile range) in both cases and controls was in the range of deficiency [13.7 (10; 17.9) and 19.4 (12.3; 24.6) ng/ml, respectively]. There was no significant difference in the serum 25OHD level (P=0.08) or sun exposure as measured by UV score (P=0.39) among the cases and controls. In cases with rickets, significant negative correlations were seen between dietary calcium intake and radiological score (r=-0.28; P=0.03) and PTH (r=-0.26; P=0.02). No correlation was found between serum 25OHD level and radiological score or biochemical parameters of rickets. Rickets develops when low dietary calcium intake coexists with a low or borderline vitamin D nutrition status.

Incidence and characteristics of vitamin D deficiency rickets in New Zealand children: a New Zealand Paediatric Surveillance Unit study.

PubMed

Wheeler, Benjamin J; Dickson, Nigel P; Houghton, Lisa A; Ward, Leanne M; Taylor, Barry J

2015-08-01

To investigate the incidence and characteristics of vitamin D deficiency rickets in New Zealand (NZ). Prospective surveillance among paediatricians of Vitamin D Deficiency Rickets was conducted by the New Zealand Paediatric Surveillance Unit (NZPSU) for 36 months, from July 2010 to June 2013, inclusive. Inclusion criteria were: children and adolescents <15 years of age with vitamin D deficiency rickets (defined by low serum 25-hydroxyvitamin D and elevated alkaline phosphatase levels, and/or radiological rickets). Fifty-eight children with confirmed vitamin D deficiency rickets were identified. Median age was 1.4 (range 0.3-11) years, 47% were male, and 95% of the children were born in NZ; however, the majority of the mothers (68%) were born outside NZ. Overall annual incidence of rickets in children aged <15 years was 2.2/100,000 (95%CI 1.4-3.5); with incidence in those <3 years being 10.5/100,000 (95%CI 6.7-16.6). Skeletal abnormalities, poor growth and motor delay were the most common presenting features, with hypocalcaemic convulsion in 16% of children. Key risk factors identified were: darker skin pigment, Indian and African ethnicity, age <3 years, exclusive breast feeding, and southern latitude, particularly when combined with season (winter/spring). Of the patients reported, none had received appropriate vitamin D supplementation. Vitamin D deficiency rickets remains a problem for NZ children. Key risk factors remain similar to those identified in the international literature. Preventative targeted vitamin D supplementation, as per existing national guidelines, was lacking in all cases reported. Vitamin D deficiency rickets is the most significant manifestation of vitamin D deficiency in growing children. To reduce the incidence of this disease among those at high risk, increasing awareness and implementation of current public health policies for targeted maternal, infant and child supplementation are required. © 2015 Public Health Association of Australia.

Rickets in Tehran. Study of 200 cases.

PubMed Central

Salimpour, R

1975-01-01

Radiologically diagnosed rickets was found to be common in children of the poorer classes in Tehran. It was frequently associated with gastroenteritis or bronchopneumonia and a large proportion of the children were severely underweight for their age. In children below the age of 1 year malnutrition tended to mask the signs of rickets. Convulsions were much less frequent in the malnourished children; the concentration of calcium in the serum was higher and that of alkaline phosphatase was lower than in those who were well nourished. Biochemistry is of little value in the diagnosis of rickets in the presence of malnutrition. PMID:1124945

Dilated cardiomyopathy secondary to rickets-related hypocalcaemia: eight case reports and a review of the literature.

PubMed

Yilmaz, Osman; Olgun, Hasim; Ciftel, Murat; Kilic, Omer; Kartal, Ibrahim; Iskenderoglu, Nebahat Y; Laloglu, Fuat; Ceviz, Naci

2015-02-01

Dilated cardiomyopathy is usually idiopathic and may arise secondary to infections or metabolic or genetic causes. Another rare cause is hypocalcaemia. Owing to the fact that calcium plays an essential role in excitation and contraction of myocardial muscle, myocardial contractility may decline in patients with hypocalcaemia. Patients with symptoms of congestive heart failure and rickets-related hypocalcaemia were assessed clinically and by echocardiography in a paediatric cardiology clinic. Echocardiography was performed for all patients. Rickets was diagnosed according to the clinical, laboratory, and radiologic findings. Maternal lifestyle and living conditions were investigated, and the maternal 25-OH vitamin D3 blood level was measured. We evaluated eight patients who developed heart failure as a result of severe hypocalcaemia associated with rickets between August, 1999 and June, 2012. The age distribution of the patients was 3-12 months. Laboratory results were consistent with advanced-stage rickets. Severe hypocalcaemia was detected in all patients. The maternal 25-OH vitamin D3 levels were low. Echocardiography revealed increased pre-treatment left ventricle end-systolic and end-diastolic diameters for age and reduced ejection fraction and fractional shortening. After clinical improvement, the patients were discharged. Severe hypocalcaemia associated with rickets must always be kept in mind among the causes of dilated cardiomyopathy and impaired cardiac function in infants. If diagnosed and treated in time, dilated cardiomyopathy and severe heart failure related to rickets respond well.

Radiology of Osteogenesis Imperfecta, Rickets and Other Bony Fragility States.

PubMed

Calder, Alistair D

2015-01-01

This section gives an overview of radiological findings in bony fragility states, with a special focus on osteogenesis imperfecta (OI) and rickets. Conventional radiological assessment of bone density is inaccurate and imprecise and only reliably detects severe osteopaenia. However, other aspects of bone structure and morphology can be assessed, and it is possible to distinguish between osteopaenic and osteomalacic states. OI is a heterogeneous group of disorders of type 1 collagen formation and processing that are characterised by varying degrees of bony fragility, with presentations varying from perinatal lethality to asymptomatic. Radiological diagnosis of severe forms is usually straightforward, but that of milder disease may be challenging because specific features are often absent. However, a multidisciplinary approach is usually successful. Features of OI, including Wormian bones, skull base deformities, vertebral involvement and long bone fractures and deformities, are reviewed in this section. Rickets is best defined as a disorder of the growth plate characterised by the impaired apoptosis of hypertrophied chondrocytes. Vitamin D deficiency is a common cause of rickets. The patho-anatomical basis of radiological findings in rickets is reviewed and illustrated. Rickets is frequently accompanied by hyperparathyroidism and osteomalacia. Rickets used to be classified as calciopaenic or phosphopaenic but is now referred to as parathyroid hormone or fibroblast growth factor 23 mediated, respectively [1]. The radiological features of the two forms are reviewed. © 2015 S. Karger AG, Basel.

Vitamin D deficiency causes rickets in an urban informal settlement in Kenya and is associated with malnutrition

PubMed Central

Hachmeister, C. Ulrich; Khasira, Maureen; Cox, Lorna; Schoenmakers, Inez; Munyi, Caroline; Nassir, H. Samira; Hünten‐Kirsch, Barbara; Prentice, Ann; Berkley, James A.

2017-01-01

Abstract The commonest cause of rickets worldwide is vitamin D deficiency, but studies from sub‐Saharan Africa describe an endemic vitamin D‐independent form that responds to dietary calcium enrichment. The extent to which calcium‐deficiency rickets is the dominant form across sub‐Saharan Africa and in other low‐latitude areas is unknown. We aimed to characterise the clinical and biochemical features of young children with rickets in a densely populated urban informal settlement in Kenya. Because malnutrition may mask the clinical features of rickets, we also looked for biochemical indices of risk in children with varying degrees of acute malnutrition. Twenty one children with rickets, aged 3 to 24 months, were identified on the basis of clinical and radiologic features, along with 22 community controls, and 41 children with either severe or moderate acute malnutrition. Most children with rickets had wrist widening (100%) and rachitic rosary (90%), as opposed to lower limb features (19%). Developmental delay (52%), acute malnutrition (71%), and stunting (62%) were common. Compared to controls, there were no differences in calcium intake, but most (71%) had serum 25‐hydroxyvitamin D levels below 30 nmol/L. These results suggest that rickets in young children in urban Kenya is usually driven by vitamin D deficiency, and vitamin D supplementation is likely to be required for full recovery. Wasting was associated with lower calcium (p = .001), phosphate (p < .001), 25‐hydroxyvitamin D (p = .049), and 1,25‐dihydroxyvitamin D (p = 0.022) levels, the clinical significance of which remain unclear. PMID:28470840

Vitamin D deficiency causes rickets in an urban informal settlement in Kenya and is associated with malnutrition.

PubMed

Jones, Kelsey D J; Hachmeister, C Ulrich; Khasira, Maureen; Cox, Lorna; Schoenmakers, Inez; Munyi, Caroline; Nassir, H Samira; Hünten-Kirsch, Barbara; Prentice, Ann; Berkley, James A

2018-01-01

The commonest cause of rickets worldwide is vitamin D deficiency, but studies from sub-Saharan Africa describe an endemic vitamin D-independent form that responds to dietary calcium enrichment. The extent to which calcium-deficiency rickets is the dominant form across sub-Saharan Africa and in other low-latitude areas is unknown. We aimed to characterise the clinical and biochemical features of young children with rickets in a densely populated urban informal settlement in Kenya. Because malnutrition may mask the clinical features of rickets, we also looked for biochemical indices of risk in children with varying degrees of acute malnutrition. Twenty one children with rickets, aged 3 to 24 months, were identified on the basis of clinical and radiologic features, along with 22 community controls, and 41 children with either severe or moderate acute malnutrition. Most children with rickets had wrist widening (100%) and rachitic rosary (90%), as opposed to lower limb features (19%). Developmental delay (52%), acute malnutrition (71%), and stunting (62%) were common. Compared to controls, there were no differences in calcium intake, but most (71%) had serum 25-hydroxyvitamin D levels below 30 nmol/L. These results suggest that rickets in young children in urban Kenya is usually driven by vitamin D deficiency, and vitamin D supplementation is likely to be required for full recovery. Wasting was associated with lower calcium (p = .001), phosphate (p < .001), 25-hydroxyvitamin D (p = .049), and 1,25-dihydroxyvitamin D (p = 0.022) levels, the clinical significance of which remain unclear. © 2017 The Authors Maternal & Child Nutrition Published by John Wiley & Sons Ltd.

The presentation of rickets to orthopaedic clinics: return of the English disease.

PubMed

Naseem, Haris; Wall, Alun P; Sangster, Marshall; Paton, Robin W

2011-04-01

Rickets is a potentially treatable disease of the bone that is most commonly due to deficiency of vitamin D and is increasing in incidence in developed countries. Risk factors include dietary factors, the practice of covering up and darker skin pigmentation. This small retrospective case study set out to examine all cases of rickets presenting to the Paediatric Orthopaedic clinic over a 15-month period. Rickets presented in a bimodal fashion in the 6 cases identified: in males and females aged 3 or less and female adolescents aged 10 and above. This is in keeping with what is known regarding the rapid phases of growth during development. Five cases were from ethnic minority groups. Both female adolescents presented with genu valgum. Rickets can present primarily to Orthopaedic clinics with vague musculoskeletal symptoms. We recommend that biochemical screening be performed on patients from ethnic minorities who may be 'at risk'.

Studies on Typhus and Spotted Fever

DTIC Science & Technology

1979-02-01

thawing caused no detectaule loss of ricket - tsial infectivity. Accordingly, the longterm survival of typhus organisms at -700 C in these and other...or even qualitative,differentiation between a specific action on intracellular ricket - tsiae and selective cytotoxicity directed against infected...study of the cell envelopes of Rickettsia prowazekii, Rickettsia ricket ii, and Rickettsia tsutsugamushi. Infect. Immun. 21: 1020-1uZ3 (1978). 8

[Updates on rickets and osteomalacia: vitamin D dependency].

PubMed

Kitanaka, Sachiko

2013-10-01

Vitamin D dependency was first termed for patients resembling vitamin D-deficiency but require high doses of vitamin D administration. Now this disease is known to be caused by defective conversion of 25OHD to 1,25 (OH) 2D, which is termed vitamin D-dependent rickets type 1 or 1α-hydroxylase deficiency, or by end-organ unresponsiveness to 1,25 (OH) 2D, which is called vitamin D-dependent rickets type 2 or hereditary vitamin D-resistant rickets. Recent advance in the molecular analysis of these diseases revealed variety in the presentation and in the inheritance patterns. Molecular diagnosis would be preferable for some atypical cases for adequate therapy.

Congenital rickets presenting as refractory respiratory distress at birth.

PubMed

Tiwari, Soumya; Kumar, Rajesh; Singla, Shilpy; Dudeja, Ajay; Nangia, Sushma; Saili, Arvind

2014-08-01

Congenital rickets is a very rare entity in the spectrum of metabolic bone disease in children. The authors report an as yet unreported case of congenital rickets presenting with respiratory distress at birth. The radiographs of long bones and wrist showed generalized osteopenia with cupping and fraying of epiphyseal ends in the second week of life. The patient was managed with very high doses of vitamin D which led to clinico-radiological and biochemical improvement. More than being interesting for its extreme rarity, this report assumes importance as it brings forth the possibility of congenital rickets being a differential diagnosis for a newborn with respiratory distress.

Pathologic femur fracture due to a brown tumor in a patient with secondary hyperparathyroidism and vitamin D-resistant rickets.

PubMed

Wallace, Eric; Day, Matthew; Fadare, Oluwole; Schaefer, Heidi

2013-02-01

Vitamin D-resistant rickets is the common clinical outcome of multiple genetic mutations that alter the regulation of phosphorus and vitamin D metabolism, mainly through their effects on fibroblast growth factor 23 (FGF-23). These diseases typically present in childhood with the classic physical examination finding of nutritional rickets, such as genu varum/valgum and rachitic rosary. Treatment, which is aimed at improving severe bone disease with vitamin D and phosphorus supplementation, can cause secondary hyperparathyroidism and/or kidney failure from nephrocalcinosis over the life of the patient. Although FGF-23 has been shown to downregulate parathyroid hormone in vitro, its effect on parathyroid secretion in disease states such as chronic kidney disease and X-linked hypophosphatemic rickets is unclear because elevations in FGF-23 and parathyroid hormone levels characterize both of these disease states. We describe a case of vitamin D-resistant rickets that presented with a femur fracture through a brown tumor. Radiographs show the combination of severe bony abnormalities associated with both long-standing hyperparathyroidism and vitamin D-resistant rickets. Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Preventable but neglected: rickets in an informal settlement, Nairobi, Kenya

PubMed Central

Thiongó, A.; Van den Bergh, R.; Kizito, W.; Kosgei, R. J.; Sobry, A.; Vandenbulcke, A.; Zuniga, I.; Reid, A. J.

2014-01-01

Setting: The primary care clinics of Médecins Sans Frontières within the informal settlement of Kibera, Nairobi, Kenya. Objective: To describe the demographic and clinical characteristics of children clinically diagnosed with rickets from September 2012 to October 2013. Design: Descriptive retrospective case review of diagnosis and treatment course with vitamin D and calcium using routine programme data. Results: Of the 82 children who met the clinical diagnosis of rickets, 57% were male, with a median age of 12 months and 14 months for females. Children with rickets were found to have ⩽3 hours/week sunlight exposure for 71% of the children and malnutrition in 39%. Clinical findings on presentation revealed gross motor developmental delays in 44%. The loss to follow-up rate during treatment was 40%. Conclusions: This study found that rickets is a common clinical presentation among children living in the informal settlement of Kibera and that there are likely multiple factors within that environment contributing to this condition. As rickets is a simply and inexpensively preventable non-communicable disease, we suggest that routine vitamin D supplementation be formally recommended by the World Health Organization for well-child care in Africa, especially in the contexts of informal settlements. PMID:26399212

EXPERIMENTAL RICKETS IN RATS

PubMed Central

Pappenheimer, A. M.; McCann, G. F.; Zucker, T. F.

1922-01-01

1. Casein phosphorus does not completely prevent the development of rickets when substituted in Diet 84 in amount equivalent to a protective dose of basic potassium phosphate. 2. The protection given by lecithin is equivalent to its phosphorus content. 3. The protection given by yeast is at least proportional to its phosphorus content. An amount carrying sufficient vitamine B to promote growth, but insufficient to provide adequate phosphorus, does not prevent rickets. 4. Vitamine A, in the form of butter or butter fat to the amount of 10 per cent of the diet, neither prevents nor cures rickets. 5. The substitution of 10 per cent of egg albumin in Diet 84 improves the nutrition, but does not prevent rickets. 6. The addition of meat to Diet 84, thereby supplying an abundance of phosphorus, promotes normal growth and normal bone formation. A diet consisting solely of meat and flour is inadequate for proper growth, and leads to changes in the bones comparable with those observed on a diet low in calcium, but rich in phosphorus. 7. A diet has been found which contains the necessary food elements for approximately normal growth, and in which the only known deficiency is phosphorus. This leads regularly to the production of rickets. PMID:19868618

Changes in bone structure of Corriedale sheep with inherited rickets: a peripheral quantitative computed tomography assessment.

PubMed

Dittmer, Keren E; Firth, Elwyn C; Thompson, Keith G; Marshall, Jonathan C; Blair, Hugh T

2011-03-01

An inherited skeletal disease with gross and microscopic features of rickets has been diagnosed in Corriedale sheep in New Zealand. The aim of this study was to quantify the changes present in tibia from sheep with inherited rickets using peripheral quantitative computed tomography. In affected sheep, scans in the proximal tibia, where metaphysis becomes diaphysis, showed significantly greater trabecular bone mineral content (BMC) and bone mineral density (BMD). The sheep with inherited rickets had significantly greater BMC and bone area in the mid-diaphysis of the proximal tibia compared to control sheep. However, BMD in the mid-diaphysis was significantly less in affected sheep than in controls, due to the greater cortical area and lower voxel density values in affected sheep. From this it was concluded that the increased strain on under-mineralised bone in sheep with inherited rickets led to increased bone mass in an attempt to improve bone strength. Copyright © 2010 Elsevier Ltd. All rights reserved.

Subclinical nutritional rickets among adolescents in Kaghan Valley.

PubMed

Shah, Tanveer Hussain; Hassan, Mukhtiar; Siddiqui, Tahir Saeed

2014-09-01

To determine the occurrence of subclinical rickets and its causing factors among adolescent students of schools in Kaghan Valley, Pakistan. Observation cross-sectional study. Department of Biochemistry and Health Sciences, Hazara University, Mansehra, Ayub Medical College and Teaching Hospital, Abbottabad, from March to April 2012. Sixty seven students (34 boys and 33 girls) age between 11 - 16 years included in the study from different schools of Kaghan Valley, Pakistan. Characteristic, serum biochemical and nutritional status were measured for all the participants. On the basis of biochemical finding the boys and girls students were divided in to two groups, normal subjects and subclinical rickets (absent symptoms with altered biochemistry). Twenty six participants, 19 (73%) girls and 07 (27%) boys had biochemical abnormality but no clinical signs and symptoms of rickets. Low vitamin D and high alkaline phosphatase level were observed in 26 (100%), 21 (81%), low calcium in 17 (65%) and low phosphorus 7 (27%) subjects with subclinical rickets. None had high parathormone level above normal range. Nutritional intake of calcium, phosphorus and vitamin D was found less than the recommended daily intake in all the participants. Subclinical rickets is common problem among adolescent students especially in girls which is due to low nutritional intakes and avoidance of sunshine due to environmental and traditional impacts.

Nutritional rickets among children in the United States: review of cases reported between 1986 and 2003.

PubMed

Weisberg, Pamela; Scanlon, Kelley S; Li, Ruowei; Cogswell, Mary E

2004-12-01

Reports of hypovitaminosis D among adults in the United States have drawn attention to the vitamin D status of children. National data on hypovitaminosis D among children are not yet available. Reports from 2000 and 2001 of rickets among children living in North Carolina, Texas, Georgia, and the mid-Atlantic region, however, confirmed the presence of vitamin D deficiency among some US children and prompted new clinical guidelines to prevent its occurrence. We reviewed reports of nutritional rickets among US children <18 y of age that were published between 1986 and 2003. We identified 166 cases of rickets in 22 published studies. Patients were 4-54 mo of age, although in 17 studies the maximal age was <30 mo. Approximately 83% of children with rickets were described as African American or black, and 96% were breast-fed. Among children who were breast-fed, only 5% of records indicated vitamin D supplementation during breast-feeding. The American Academy of Pediatrics (AAP) recently recommended a minimal intake of 200 IU/d vitamin D for all infants, beginning in the first 2 mo of life. AAP recommends a vitamin D supplement for breast-fed infants who do not consume at least 500 mL of a vitamin D-fortified beverage. Given our finding of a disproportionate number of rickets cases among young, breast-fed, black children, we recommend that education regarding AAP guidelines emphasize the higher risk of rickets among these children. Education should also emphasize the importance of weaning children to a diet adequate in both vitamin D and calcium.

Screening for nutritional rickets in a community.

PubMed

Pettifor, John M

2016-11-01

Concern has been expressed about the rising incidence of nutritional rickets with its associated long-term sequelae in children globally. In order to address the condition worldwide, it is imperative that accurate figures of its incidence are available particularly in at-risk communities. In order to obtain these figures, various screening tools and diagnostic criteria have been used with no standardization of methodologies, resulting in varying prevalences which may under- or over-estimate the prevalence depending of the techniques used. This review discusses the advantages and disadvantages of various screening tests used to diagnose rickets in communities. Clinical signs characteristic of rachitic deformities have been used extensively, but are likely to over-estimate the prevalence and are dependent on the clinical skills of the observer. Biochemical tests such as alkaline phosphatase and 25-hydroxyvitamin D have also been proposed. There is no consensus on the usefulness of alkaline phosphatase as a screening tool, while there is general agreement that the measurement of vitamin D status is unhelpful in screening for rickets. Finally, the confirmation of the presence of active rickets in suspected infants and children is dependent on radiographic findings, although these may be less helpful in adolescents whose growth plates might be closed or nearly so. In order to obtain uniformity in screening for rickets globally, the is a need for consensus among public health specialists, paediatric endocrinologists and those interested in paediatric bone disease as to the best methods to be employed to determine the prevalence of rickets, particularly in communities with limited resources. Copyright © 2015 Elsevier Ltd. All rights reserved.

Ergocalciferol

MedlinePlus

... body does not produce enough parathyroid hormone), refractory rickets (softening and weakening of bones that does not respond to treatment), and familial hypophosphatemia (rickets or osteomalacia caused by an inherited condition with ...

Interventions for the prevention of nutritional rickets in term born children.

PubMed

Lerch, C; Meissner, T

2007-10-17

Nutritional rickets is a disease of growing children leading to bone deformities, bone pain, convulsions or delayed motor development. Today, high-incidence of nutritional rickets is mainly found in low-income countries. To assess the effects of various interventions on the prevention of nutritional rickets in term born children. Studies were obtained from computerised searches of The Cochrane Library, MEDLINE, EMBASE, LILACS and reference lists of relevant articles. We contacted authors of studies or reviews to obtain further studies. Studies were included if they were randomised controlled clinical trials, controlled clinical trials or prospective cohort studies comparing any intervention for the prevention of nutritional rickets in term born children with placebo or no intervention. Minimum duration of the intervention was three months for children under 12 months or six months for children over 12 months. Two authors independently extracted data and assessed study quality. Authors of studies were contacted to obtain missing information. Four studies enrolled approximately 1700 participants. Trials lasted between nine months to two years. Three studies were randomised controlled trials, two of which showed a cluster randomised design; one trial probably was a controlled trial with researcher controlled group assignment. In children up to three years of age in Turkey, Vitamin D compared to no intervention showed a relative risk of 0.04 (95% confidence interval (CI) 0 to 0.71). Despite a marked non-compliance, a Chinese trial in children up to three years of age comparing a combined intervention of supplementation of vitamin D, calcium and nutritional counseling showed a relative risk of 0.76 (95% CI 0.61 to 0.95) compared to no intervention. In two studies conducted in older children in China and in France no rickets occurred in both the intervention and control group. There a only few studies on the prevention of nutritional rickets in term born children. Until new data become available, it appears sound to offer preventive measures (vitamin D or calcium) to groups of high risk, like infants and toddlers; children living in Africa, Asia or the Middle East or migrated children from these regions into areas where rickets is not frequent. Due to a marked clinical heterogeneity and the scarcity of data, the main and adverse effects of preventive measures against nutritional rickets should be investigated in different countries, different age groups and in children of different ethnic origin.

Genetics

MedlinePlus

... One of these is hypophosphatemic rickets , also called vitamin D -resistant rickets. CHROMOSOMAL DISORDERS In chromosomal disorders, the defect is due to either an excess or lack of the genes contained in a ...

A novel CYP27B1 mutation causes a feline vitamin D-dependent rickets type IA.

PubMed

Grahn, Robert A; Ellis, Melanie R; Grahn, Jennifer C; Lyons, Leslie A

2012-08-01

A 12-week-old domestic cat presented at a local veterinary clinic with hypocalcemia and skeletal abnormalities suggestive of rickets. Osteomalacia (rickets) is a disease caused by impaired bone mineralization leading to an increased prevalence of fractures and deformity. Described in a variety of species, rickets is most commonly caused by vitamin D or calcium deficiencies owing to both environmental and or genetic abnormalities. Vitamin D-dependent rickets type 1A (VDDR-1A) is a result of the enzymatic pathway defect caused by mutations in the 25-hydroxyvitamin D(3)-1-alpha-hydroxylase gene [cytochrome P27 B1 (CYP27B1)]. Calcitriol, the active form of vitamin D(3), regulates calcium homeostasis, which requires sufficient dietary calcium availability and correct hormonal function for proper bone growth and maintenance. Patient calcitriol concentrations were low while calcidiol levels were normal suggestive of VDDR-1A. The entire DNA coding sequencing of CYP27B1 was evaluated. The affected cat was wild type for previously identified VDDR-1A causative mutations. However, six novel mutations were identified, one of which was a nonsense mutation at G637T in exon 4. The exon 4 G637T nonsense mutation results in a premature protein truncation, changing a glutamic acid to a stop codon, E213X, likely causing the clinical presentation of rickets. The previously documented genetic mutation resulting in feline VDDR-1A rickets, as well as the case presented in this research, result from novel exon 4 CYP27B1 mutations, thus exon 4 should be the initial focus of future sequencing efforts.

Prevention of nutritional rickets in Nigerian children with dietary calcium supplementation.

PubMed

Thacher, Tom D; Fischer, Philip R; Isichei, Christian O; Zoakah, Ayuba I; Pettifor, John M

2012-05-01

Nutritional rickets in Nigerian children usually results from dietary calcium insufficiency. Typical dietary calcium intakes in African children are about 200mg daily (approximately 20-28% of US RDAs for age). We sought to determine if rickets could be prevented with supplemental calcium or with an indigenous food rich in calcium. We enrolled Nigerian children aged 12 to 18months from three urban communities. Two communities were assigned calcium, either as calcium carbonate (400mg) or ground fish (529±109mg) daily, while children in all three communities received vitamin A (2500IU) daily as placebo. Serum markers of mineral homeostasis and forearm bone density (pDEXA) were measured and radiographs were obtained at enrollment and after 18months of supplementation. The overall prevalence of radiographic rickets at baseline was 1.2% and of vitamin D deficiency [serum 25(OH)D<12ng/ml] 5.4%. Of 647 children enrolled, 390 completed the 18-month follow-up. Rickets developed in 1, 1, and 2 children assigned to the calcium tablet, ground fish, and control groups, respectively (approximate incidence 6.4/1000 children/year between 1 and 3years of age). Children who developed rickets in the calcium-supplemented groups had less than 50% adherence. Compared with the group that received no calcium supplementation, the groups that received calcium had a greater increase in areal bone density of the distal and proximal 1/3 radius and ulna over time (P<0.04). We conclude that calcium supplementation increased areal bone density at the radius and ulna, but a larger sample size would be required to determine its effect on the incidence of rickets. Copyright © 2012 Elsevier Inc. All rights reserved.

Multiple unexplained fractures in infants and child physical abuse.

PubMed

Cannell, John Jacob; Holick, Michael F

2018-01-01

When an infant presents with X-rays showing multiple unexplained fractures in various stages of healing (MUFVSH), the child is usually diagnosed with child abuse based on criteria of the Academy of Pediatrics' Committee on Child Abuse and Neglect (AAPCCAAN). Almost always, the infant is subsequently removed from the home and civil or criminal proceeding commence. It may be that healing infantile rickets or other poorly understood metabolic bone disorders of infancy are responsible for these x-rays. Activated vitamin D is a seco-steroid hormone, whose mechanism of action is genetic regulation. Lack of it can result in musculoskeletal defects known as rickets. Low calcium can also cause rickets. However, it is clear that experts for the state believe that the x-rays in these cases are so definitive as to be pathognomonic for child abuse. Therefore, if the caregivers deny abusing their infants, experts following American Academy of Pediatric's Committee on Child Abuse and Neglect. guidelines are essentially claiming that x-rays showing multiple unexplained fractures in various stages of healing are lie detector tests. However, it is not widely appreciated that the gold standard for the diagnosis of rickets is a bone biopsy, not x-rays, as radiologists miss biopsy proven rickets 80% of the time; that is, 4 out of 5 infants with rickets will have normal x-rays. In this article we provide reports of two cases and their outcomes. We discuss information about healing infantile rickets and an example of common sense medical conclusions in these cases. This information could lead to a significant reduction in the number of innocent parents having their infant removed or sent to prison. Copyright © 2016 Elsevier Ltd. All rights reserved.

How TSPSM Implementation has Evolved at AV-8B

DTIC Science & Technology

2008-05-01

How TSPSM Implementation Has Evolved at AV-8B Chris Rickets AV-8B Joint Systems/Software Support Activity (JSSA) Brad Hodgins NAVAIR Systems...members need to be involved) NAVAIR Software/Systems Support Center (NSSC) Slide 40 Contact Information • Chris Rickets (AV-8B Sr. Software Engr...phone: (760) 939-5838 – e-mail: chris rickets @navy mil . . • Brad Hodgins (NAVAIR TSP Coach supporting AV-8B ) – phone: (760) 939-0666/4446 – e

Dental Aspect of Distal Tubular Renal Acidosis with Genu Valgum Secondary to Rickets: A Case Report

PubMed Central

Bahadure, Rakesh N.; Thosar, Nilima; Kriplani, Ritika; Baliga, Sudhindra; Fulzele, Punit

2012-01-01

Distal renal tubular acidosis is a disease that occurs when the kidneys do not remove acid properly into the urine, leaving the blood too acidic (called acidosis). Distal renal tubular acidosis (type I RTA) is caused by a defect in the kidney tubes that causes acid to build up in the bloodstream. It ultimately results rickets which include chronic skeletal pain, in skeletal deformities, skeletal fractures. Rickets is among the most frequent childhood diseases in many developing countries. Dental problems in rickets include delayed eruption of permanent teeth, premature fall of deciduous teeth, defects in structure of teeth, enamel defects in permanent teeth (hypoplastic), pulp defects, intraglobular dentine, and caries tooth. Herewith, reported a case of distal tubular renal acidosis with genu valgum secondary to rickets, with pain and extraoral swelling associated with right and left mandibular 1st permanent molars. Teeth were infected with pulp without being involved with caries. Radiographically cracks in enamel and dentin were observed. Pulp revascularization with 46 and root canal treatment was done for 36 with followup of 1 year. PMID:22567455

Resurrection of vitamin D deficiency and rickets

PubMed Central

Holick, Michael F.

2006-01-01

The epidemic scourge of rickets in the 19th century was caused by vitamin D deficiency due to inadequate sun exposure and resulted in growth retardation, muscle weakness, skeletal deformities, hypocalcemia, tetany, and seizures. The encouragement of sensible sun exposure and the fortification of milk with vitamin D resulted in almost complete eradication of the disease. Vitamin D (where D represents D2 or D3) is biologically inert and metabolized in the liver to 25-hydroxyvitamin D [25(OH)D], the major circulating form of vitamin D that is used to determine vitamin D status. 25(OH)D is activated in the kidneys to 1,25-dihydroxyvitamin D [1,25(OH)2D], which regulates calcium, phosphorus, and bone metabolism. Vitamin D deficiency has again become an epidemic in children, and rickets has become a global health issue. In addition to vitamin D deficiency, calcium deficiency and acquired and inherited disorders of vitamin D, calcium, and phosphorus metabolism cause rickets. This review summarizes the role of vitamin D in the prevention of rickets and its importance in the overall health and welfare of infants and children. PMID:16886050

Rickets

MedlinePlus

... can increase a child's risk of rickets include: Dark skin. Dark skin doesn't react as strongly to sunshine ... near midday is enough. However, if you're dark-skinned, if it's winter or if you live ...

[Updates on rickets and osteomalacia: etiology and pathophysiology of osteomalacia].

PubMed

Suzuki, Hisanori; Takeuchi, Yasuhiro

2013-10-01

Impairment of bone mineralization causes rickets and osteomalacia. Rickets develops with impaired mineralization of bone prior to epiphyseal closure, and so does osteomalacia after the closure of epiphyses. Pain in lower extremities and back and bone pain are usually observed in patients with osteomalacia. Chronic hypophosphatemia and/or impairment of vitamin D action are involved in the development of osteomalacia. It is of great importance to suspect osteomalacia from clinical symptoms and laboratory data, such as hypophosphatemia and/or high serum alkaline phosphatase level.

Afebrile seizures and electrocardiography abnormality: an unusual presentation of nutritional rickets.

PubMed

Gad, Kg; Khan, Ma; Mahmood, K

2014-08-01

Nutritional rickets is not uncommon in the western world and has been reported widely. Occasionally, children have presented to paediatrics with afebrile seizures secondary to hypocalcaemia due to hypovitaminosis D. However, association of nutritional rickets with electrocardiography changes and prolonged QT interval is not well documented. It is a rare, potentially serious and yet easy-to-treat complication as shown in our case. Our case also highlights the importance of awareness and education of both parents and clinicians regarding this relatively common but easily treatable condition. We report a case of undiagnosed nutritional rickets presenting as 'Afebrile' seizure in a seven-month-old Somali girl. Her initial blood work-up showed low ionised calcium (0.8 mmol/l) on blood gas sampling, confirmed by laboratory result (adjusted 1.49 mmol/l). She had prolonged QTc on electrocardiography which reverted to normal with treatment. She was treated with intravenous as well as oral calcium after which she had no further seizures. We present a unique case of nutritional rickets-associated hypocalcaemia. This case highlights the resurgence of nutritional rickets in western societies. We need to keep this disease in our list of diagnoses as it is a potentially serious and yet easily treatable disease. We should be more vigilant for screening ethnic minorities as alarmingly high rates of hypovitaminosis D have been found in ethnic minorities living in Great Britain. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Detecting rickets in premature infants and treating them with calcitriol: experience from two cases.

PubMed

Chen, Hung-Yi; Chiu, Li-Chien; Yek, Yung-Lee; Chen, Yi-Ling

2012-08-01

A premature infant is a baby born before 37 weeks of gestation. Rickets is a bone disease characterized by growth retardation due to the expansion of the hypertrophic chondrocyte layer of the growth plate and a failure to mineralize bone. Consequently, the bone is soft and permits marked bending and distortion. Although the incidence of rickets in preterm infants is lower due to improvements in health care and nutrition, there are still infants at high risk for this disease. However, few reports are available regarding the treatment of rickets in premature infants. Furthermore, published case studies on experiences with using calcitriol as a potential therapeutic for rickets in premature infants are very rare. Herein, we describe the detection of rickets in premature infants and our experience with calcitriol treatment in two premature infants. We recommended the use of oral calcitriol at a dose of 0.03-0.125 μg/kg/day, in addition to an appropriate formula that provides an adequate amount of calcium and phosphate intake. One patient was prescribed calcitriol for 40 days and the other for 37 days. The two infants gradually recovered and were discharged without any obvious side effects. It is recommended that alkaline phosphatase levels be monitored within 1 month after birth in premature infants with a birth weight of <1000 g. Infants presenting with high alkaline phosphatase levels are candidates for a long bone survey. Copyright © 2012. Published by Elsevier B.V.

Relationship between polymorphisms in vitamin D metabolism-related genes and the risk of rickets in Han Chinese children.

PubMed

Zhang, Yuling; Yang, Shufen; Liu, Ye; Ren, Lihong

2013-09-30

Vitamin D deficiency rickets is common in China. Genetic factors may play an important role in the susceptibility to rickets. Our study aimed to identify the relationship between three vitamin D-related genes (group specific component [GC], cytochrome P450, family 2, subfamily R, polypeptide 1 (CYP2R1), and 7-dehydrocholesterol reductase/nicotinamide-adenine dinucleotide synthetase 1 (DHCR7/NADSYN1) and rickets in Han Chinese children from northeastern China. A total of 506 Han children from northeastern China were enrolled in the current study. Twelve SNPs in three candidate genes were genotyped using the SNaPshot assay. Linear regression was used to examine the effect of 12 single-nucleotide polymorphisms (SNPs) on the risk of rickets. In our case-control cohort, six alleles of the 12 SNPs conferred a significantly increased risk of rickets in GC (rs4588 C, P = 0.003, OR: 0.583, 95% CI: 0.412-0.836; rs222020 C, P = 0.009, OR: 1.526, 95% CI: 1.117-2.0985; rs2282679 A, P = 0.010, OR: 0.636, 95% CI: 0.449-0.900; and rs2298849 C, P = 0.001, OR: 1.709, 95% CI: 1.250-2.338) and in CYP2R1 (rs10741657 G, P = 0.019, OR: 1.467, 95% CI: 1.070-2.011; and rs2060793 G, P = 0.023, OR: 0.689, 95% CI: 0.502-0.944). The results remained significant after adjustment for sex and body mass index. We further analyzed the effect of genotypes under three different genetic models. After using Bonferroni's method for multiple corrections, rs4588, rs2282679, and rs2298849 of the GC gene were significantly associated with rickets under the dominant (P =0.003 for rs4588, P =0.024 for rs2282679, and P =0.005 for rs2298849) and additive models (P = 0.006 for rs4588, P = 0.024 for rs2282679, and P = 0.005 for rs2298849). Haplotype analysis showed that the CAT haplotype of the GC gene (P = 0.005) and the GAA haplotype of the CYP2R1 gene (P = 0.026) were associated with susceptibility to rickets. This case-control study confirmed the strong effect of GC and CYP2R1 loci on rickets in Han children from northeastern China.

Relationship between polymorphisms in vitamin D metabolism-related genes and the risk of rickets in Han Chinese children

PubMed Central

2013-01-01

Background Vitamin D deficiency rickets is common in China. Genetic factors may play an important role in the susceptibility to rickets. Our study aimed to identify the relationship between three vitamin D-related genes (group specific component [GC], cytochrome P450, family 2, subfamily R, polypeptide 1 (CYP2R1), and 7-dehydrocholesterol reductase/nicotinamide-adenine dinucleotide synthetase 1 (DHCR7/NADSYN1) and rickets in Han Chinese children from northeastern China. Methods A total of 506 Han children from northeastern China were enrolled in the current study. Twelve SNPs in three candidate genes were genotyped using the SNaPshot assay. Linear regression was used to examine the effect of 12 single-nucleotide polymorphisms (SNPs) on the risk of rickets. Results In our case–control cohort, six alleles of the 12 SNPs conferred a significantly increased risk of rickets in GC (rs4588 C, P = 0.003, OR: 0.583, 95% CI: 0.412-0.836; rs222020 C, P = 0.009, OR: 1.526, 95% CI: 1.117-2.0985; rs2282679 A, P = 0.010, OR: 0.636, 95% CI: 0.449-0.900; and rs2298849 C, P = 0.001, OR: 1.709, 95% CI: 1.250-2.338) and in CYP2R1 (rs10741657 G, P = 0.019, OR: 1.467, 95% CI: 1.070-2.011; and rs2060793 G, P = 0.023, OR: 0.689, 95% CI: 0.502-0.944). The results remained significant after adjustment for sex and body mass index. We further analyzed the effect of genotypes under three different genetic models. After using Bonferroni’s method for multiple corrections, rs4588, rs2282679, and rs2298849 of the GC gene were significantly associated with rickets under the dominant (P =0.003 for rs4588, P =0.024 for rs2282679, and P =0.005 for rs2298849) and additive models (P = 0.006 for rs4588, P = 0.024 for rs2282679, and P = 0.005 for rs2298849). Haplotype analysis showed that the CAT haplotype of the GC gene (P = 0.005) and the GAA haplotype of the CYP2R1 gene (P = 0.026) were associated with susceptibility to rickets. Conclusions This case–control study confirmed the strong effect of GC and CYP2R1 loci on rickets in Han children from northeastern China. PMID:24073854

Tumor-associated FGF-23-induced hypophosphatemic rickets in children: a case report and review of the literature.

PubMed

Burckhardt, Marie-Anne; Schifferli, Alexandra; Krieg, Andreas H; Baumhoer, Daniel; Szinnai, Gabor; Rudin, Christoph

2015-01-01

Tumor-associated fibroblast growth factor 23 (FGF-23)-induced hypophosphatemic rickets is a rare but known pediatric entity first described in 1959. It results from local production of phosphatonins by benign and malignant mesenchymal tumors. We report an 8-year-old boy with tumor-associated hypophosphatemic rickets due to paraneoplastic FGF-23 secretion from a benign mesenchymal pelvic-bone tumor. Excessive FGF-23 production was visualized by immunohistochemistry in the resected tumor. Phosphate wasting stopped immediately after tumor resection. We reviewed 26 reports of pediatric patients with tumor-induced hypophosphatemic rickets; paraneoplastic FGF-23 secretion was documented in only three of them. All tumors developed inside bone, were benign in 21/26 cases, and were localized in femur/tibia (13/26), radius/ulna/humerus (7/26), pelvis (4/26), rib (1/26), and craniofacial (1/26) bones. Mean interval between onset of signs and/or symptoms and diagnosis was 34 months. In patients with hypophosphatemic rickets acquired beyond infancy, radiologic investigations for bone tumors need to be performed rapidly. In contrast to biochemical screening for increased circulating FGF-23 levels, immunohistochemical confirmation of FGF-23 production in resected tumor tissue can be regarded as being well established.

Prevalence of rickets-like bone deformities in rural Gambian children.

PubMed

Jones, Helen L; Jammeh, Lamin; Owens, Stephen; Fulford, Anthony J; Moore, Sophie E; Pettifor, John M; Prentice, Ann

2015-08-01

The aim of this study was to estimate the burden of childhood rickets-like bone deformity in a rural region of West Africa where rickets has been reported in association with a low calcium intake. A population-based survey of children aged 0.5-17.9 years living in the province of West Kiang, The Gambia was conducted in 2007. 6221 children, 92% of those recorded in a recent census, were screened for physical signs of rickets by a trained survey team with clinical referral of suspected cases. Several objective measures were tested as potential screening tools. The prevalence of bone deformity in children <18.0 years was 3.3%. The prevalence was greater in males (M = 4.3%, F = 2.3%, p < 0.001) and in children <5.0 years (5.7%, M = 8.3%, F = 2.9%). Knock-knee was more common (58%) than bow-leg (31%) or windswept deformity (9%). Of the 196 examined clinically, 36 were confirmed to have a deformity outside normal variation (47% knock-knee, 53% bow-leg), resulting in more conservative prevalence estimates of bone deformity: 0.6% for children <18.0 years (M = 0.9%, F = 0.2%), 1.5% for children < 5.0 years (M = 2.3%, F = 0.6%). Three of these children (9% of those with clinically-confirmed deformity, 0.05% of those screened) had active rickets on X-ray at the time of medical examination. This emphasises the difficulties in comparing prevalence estimates of rickets-like bone deformities from population surveys and clinic-based studies. Interpopliteal distance showed promise as an objective screening measure for bow-leg deformity. In conclusion, this population survey in a rural region of West Africa with a low calcium diet has demonstrated a significant burden of rickets-like bone deformity, whether based on physical signs under survey conditions or after clinical examination, especially in boys < 5.0 years. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Management of nutritional rickets in Indian children: a randomized controlled trial.

PubMed

Aggarwal, Varun; Seth, Anju; Marwaha, Raman K; Sharma, Bhavna; Sonkar, Pitamber; Singh, Satveer; Aneja, Satinder

2013-04-01

Rickets is usually attributed to vitamin D deficiency. However, recent studies have implicated dietary calcium deficiency in its etiology. Information on relative efficacy of calcium, vitamin D or both together in healing of rickets is limited. To study effect of treatment with calcium, vitamin D or a combination of these two on healing of nutritional rickets in young children. Randomized controlled trial. Sixty-seven cases of nutritional rickets in the age group of 6 months to 5 years were randomly allocated to receive vitamin D (600 000 IU single intramuscular dose), calcium (75 mg/kg/day elemental calcium orally) or a combination of the above two for a period of 12 weeks. The demographic parameters, nutritional status, dietary calcium and phytate intake were assessed for all. Radiographs (wrist and knee) and biochemical parameters (serum calcium, inorganic phosphate, alkaline phosphatase, 25-hydroxycholecalciferol and parathyroid hormone) were evaluated at baseline, 6 and 12 weeks for evidence of healing. Mean dietary intake of calcium in all cases was low (204 ± 129 mg/day). Mean serum 25-hydroxycholecalciferol D level was 15.9 ± 12.4 ng/ml, and 82.1% of patients had serum vitamin D levels <20 ng/ml, indicative of vitamin D deficiency. After 6 and 12 weeks of treatment, radiological and biochemical evidence of healing rickets was observed in all treatment groups, albeit to a variable extent. The combined end point of normal serum alkaline phosphatase and complete radiological healing at 12 weeks was observed in 50% subjects on combination therapy as compared with 15.7% subjects on vitamin D alone and 11.7% on calcium alone. Children with rickets had a low serum vitamin D level and a low dietary calcium intake. The best therapeutic response was seen with a combination of vitamin D and calcium than either of them given alone. CTRI/2010/091/000448.

Follow-up study of Gambian children with rickets-like bone deformities and elevated plasma FGF23: possible aetiological factors.

PubMed

Braithwaite, Vickie; Jarjou, Landing M A; Goldberg, Gail R; Jones, Helen; Pettifor, John M; Prentice, Ann

2012-01-01

We have previously reported on a case-series of children (n=46) with suspected calcium-deficiency rickets who presented in The Gambia with rickets-like bone deformities. Biochemical analyses discounted vitamin D-deficiency as an aetiological factor but indicated a perturbation of Ca-P metabolism involving low plasma phosphate and high circulating fibroblast growth factor-23 (FGF23) concentrations. A follow-up study was conducted 5 years after presentation to investigate possible associated factors and characterise recovery. 35 children were investigated at follow-up (RFU). Clinical assessment of bone deformities, overnight fasted 2 h urine and blood samples, 2-day weighed dietary records and 24 h urine collections were obtained. Age- and season-matched data from children from the local community (LC) were used to calculate standard deviation scores (SDS) for RFU children. None of the RFU children had radiological signs of active rickets. However, over half had residual leg deformities consistent with rickets. Dietary Ca intake (SDS-Ca=-0.52 (0.98) p=0.04), dietary Ca/P ratio (SDS-Ca/P=-0.80 (0.82) p=0.0008) and TmP:GFR (SDS-TmP:GFR=-0.48 (0.81) p=0.04) were significantly lower in RFU children compared with LC children and circulating FGF23 concentration was elevated in 19% of RFU children. Furthermore an inverse relationship was seen between haemoglobin and FGF23 (R(2)=25.8, p=0.004). This study has shown differences in biochemical and dietary profiles between Gambian children with a history of rickets-like bone deformities and children from the local community. This study provided evidence in support of the calcium deficiency hypothesis leading to urinary phosphate wasting and rickets and identified glomerular filtration rate and iron status as possible modulators of FGF23 metabolic pathways. Copyright © 2011 Elsevier Inc. All rights reserved.

Rickets in lion cubs at the London Zoo in 1889: some new insights.

PubMed

Chesney, Russell W; Hedberg, Gail

2009-05-01

In 1889, when Dr John Bland-Sutton, a prominent surgeon in London, England, was consulted concerning fatal rickets in more than 20 successive litters of lion cubs at the London Zoo, he evaluated the role of diet relative to the development of rickets. He prescribed goat meat and bones and cod-liver oil to be added to the lean horse-meat diet of the cubs and their mothers. Rickets reversed, the cubs survived, and litters were reared successfully. In classic controlled studies conducted in puppies and young rats 3 decades later, the crucial role of calcium, phosphate, and vitamin D in both prevention and therapy of rickets was elucidated. Later studies led to the identification of the structural features of vitamin D. Although the Bland-Sutton interventional diet obviously provides calcium and phosphate from bones and vitamin D from cod-liver oil, other benefits of this diet were not initially recognized. Chewing bones promotes tooth and gum health and removes bacteria-laden tartar. Cod-liver oil also contains vitamin A, which is essential for the prevention of infection and for epithelial cell health. Taurine-conjugated bile salts are also necessary for the intestinal absorption of fat-soluble vitamins, including A and D. Moreover, unlike dogs and rats, all feline species are unable to synthesize taurine yet can only conjugate bile acids with taurine. This sulfur-containing beta-amino acid must be provided in the carnivorous diet of a large cat. Taurine-conjugated bile salts were provided in the oil cold-pressed from cod liver. The now famous Bland-Sutton "experiment of nature," namely, fatal rickets in lion cubs, was cured by the addition of minerals and vitamin D. However, gum health and the presence of taurine-conjugated bile salts undoubtedly permitted absorption of vitamin A and D, the latter promoting the cure of rickets.

Severe rickets in a young girl caused by celiac disease: the tragedy of delayed diagnosis: a case report.

PubMed

Al-Sharafi, Butheinah A; Al-Imad, Shafiq A; Shamshair, Amani M; Al-Faqeeh, Derhim H

2014-10-08

Celiac disease is a systemic immune mediated disease which usually presents with gastrointestinal symptoms, but it may present with extra gastrointestinal manifestations such as metabolic bone disease and failure to thrive. This may lead to a delay in the diagnosis. We present a 13 year old female from the middle east with an 8 year history of severe rickets causing multiple bone deformities leaving the child crippled with bowing of both of her arms and legs. The patient was also found to have growth failure, anemia and on further workup she was found to have celiac disease. We are presenting this case because it shows a severe case of rickets after malabsorption for many years. Celiac disease should be kept in mind as a cause of rickets in patients not responding to usual forms of treatment or when associated with other manifestations of malabsorption.

Treatment of hypophosphatemic rickets in generalized arterial calcification of infancy (GACI) without worsening of vascular calcification.

PubMed

Ferreira, Carlos R; Ziegler, Shira G; Gupta, Ashutosh; Groden, Catherine; Hsu, Kevin S; Gahl, William A

2016-05-01

Patients with generalized arterial calcification of infancy (GACI) develop vascular calcifications early in life. About half of them die within the first 6 months despite optimal medical care. A subset of those who survive eventually develop hypophosphatemic rickets. Since hypophosphatemia and hyperphosphaturia have been previously associated with increased survival in GACI patients, physicians often avoid phosphate repletion as treatment for rickets. As a consequence, GACI patients develop severe rachitic complications such as short stature and skeletal deformities. It appears that the recognition of hypophosphatemia later in life in some GACI patients is a consequence of having survived the first few months of life, and not the cause of their survival per se. Here, we report the long-term follow-up of a GACI patient who was phosphate-repleted for his rickets for more than 7 years without worsening of vascular calcification. © 2016 Wiley Periodicals, Inc.

Congenital rickets due to vitamin D deficiency in the mothers.

PubMed

Paterson, Colin R; Ayoub, David

2015-10-01

We wished to review all published reports of congenital rickets to identify the causes and characteristics. 25 cases were identified in 19 published reports in which there was radiological and/or histological evidence of rickets in the first two weeks after birth. Cases of rickets associated with maternal renal failure were excluded as were infants born at less than 32 weeks gestation. There was evidence of maternal deficiency in 24 of these cases. In 16 cases the diagnosis of the rickets led to the identification of symptomatic osteomalacia in the mothers. Of the 12 mothers who had assays for serum 25-hydroxyvitamin D (25OHD) 11 had values less than 10 ng/mL. Presentations in the infants included craniotabes, wide skull sutures, rachitic rosaries, enlargement of the wrists, tetany and convulsions. In two cases rickets had been suspected from antenatal X-rays. In five cases fractures were found at the time of initial presentation. Of the 16 infants with serum calcium assays 15 had values lower than 8.8 mg/dL. Of 13 infants who had serum alkaline phosphatase assays 12 had abnormally high levels. Of the seven infants in whom serum 25OHD was measured before treatment, all had values less than 10 ng/mL. These reports provide strong support for the view that maternal deficiency leads to overt bone disease from before birth. Maternal deficiency probably also leads to impairment of bone quality in postnatal life. The importance of ensuring adequate vitamin D nutrition in pregnancy is emphasised. Copyright © 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

RICKETS IN RURAL KENYAN PRESCHOOL CHILDREN: CASE REPORT.

PubMed

Bwibo, N O; Nyawade, S; Neumann, C G

2013-03-01

Clinical rickets has not been reported previously in Embu district, Kenya. Baseline clinical assessments performed for a nutrition intervention study in preschool children (n=324) identified 28 cases of rickets (8.6% of study sample). Clinical characteristics included: delays of sitting, walking, and teething; bone and chest deformities; widened wrists and ankles; and bowed lower extremities. Risk factors identified were short duration of breastfeeding with feeding of cereal-based supplements with little or no milk, low calcium intake, limited sunlight exposure. Vitamin D and calcium deficiencies likely contributed to these cases. Treatment with Vitamin D3 and milk resulted in clinical improvement.

Spatial distribution of calcium in food, water and soil and its possible influence on rickets disease in Northern Nigeria.

PubMed

Hartmann, Lena; Sponholz, Barbara

2012-08-01

Since the 1990s, children of the Gbagyi tribe in Northern Nigeria have been suffering severe rickets with an incidence of up to 40% in the children's generation. The disease seems to be prevalent in an area of approximately 100 km(2) south-east of Kaduna. According to broad medical studies in that area, there is no evidence for a genetic disposition but for a nutritional cause of the disease. A lack of calcium was found in blood and was calculated to originate from diet. We therefore checked parent material, soil, maize cobs (Zea mays) and drinking water for their specific Ca contents from a region with rickets problem (study area A) and compared the results to Ca amounts in similar samples from a region where rickets is unknown among the Gbagyi population (study area B). It thereby became apparent that there are no differences in mineralogical composition of the parent material between the study areas, but that Ca contents in soil, maize cobs and drinking water are 47.6%, 26.6%, respectively, 79.1% lower in study area A compared to study area B. This result suggests that there may indeed be a nutritionally and/or environmentally influence on rickets disease. Nevertheless, further research on this topic is required.

Description and evaluation of operative deformity correction in calcium-deficiency rickets in Kaduna, northern Nigeria.

PubMed

Wesselsky, Viktor; Kitz, Christa; Jakob, Franz; Eulert, Jochen; Raab, Peter

2016-04-01

Rickets is a recurrent disease worldwide, especially in countries with limited resources (Nield et al Am Fam Physician 74(4):619-626, 2006; Thacher et al Ann Trop Paediatr 26(1):1-16, 2006). Medical therapy including orally administered calcium substitution is shown to improve a patients clinical symptoms and positively impact bone deformities, especially in the lower extremity. Even though orthopaedic intervention is necessary in a significant percentage of patients, few reports exist about operative deformity correction in patients wtih rickets. We describe our concept of operative treatment by single-stage, three-dimensional closing-wedge osteotomies on 45 deformed legs in 27 patients from the rural area of Kaduna, North Nigeria, with calcium-deficiency rickets and evaluate the early results in a 1.5-year follow-up. We found a significant improvement in parameters of quality of life, functionality, clinical and radiological angulation and angles following the definition of Paley et al., with a complication rate of 4 % under 88 osteotomies (Paley et al Orthop Clin North Am 25(3):425-65, 1994). The described operative therapy shows to be sufficient and with satisfactory results in correcting rickets-related leg deformities under rural circumstances with low availability of medical resources.

Magnetic Resonance Imaging Features as Surrogate Markers of X-Linked Hypophosphatemic Rickets Activity.

PubMed

Lempicki, Marta; Rothenbuhler, Anya; Merzoug, Valérie; Franchi-Abella, Stéphanie; Chaussain, Catherine; Adamsbaum, Catherine; Linglart, Agnès

2017-01-01

X-linked hypophosphatemic rickets (XLH) is the most common form of inheritable rickets. Rickets treatment is monitored by assessing alkaline phosphatase (ALP) levels, clinical features, and radiographs. Our objectives were to describe the magnetic resonance imaging (MRI) features of XLH and to assess correlations with disease activity. Twenty-seven XLH patients (median age 9.2 years) were included in this prospective single-center observational study. XLH activity was assessed using height, leg bowing, dental abscess history, and serum ALP levels. We looked for correlations between MRI features and markers of disease activity. On MRI, the median maximum width of the physis was 5.6 mm (range 4.8-7.8; normal <1.5), being >1.5 mm in all of the patients. The appearance of the zone of provisional calcification was abnormal on 21 MRI images (78%), Harris lines were present on 24 (89%), and bone marrow signal abnormalities were present on 16 (59%). ALP levels correlated with the maximum physeal widening and with the transverse extent of the widening. MRI of the knee provides precise rickets patterns that are correlated with ALP, an established biochemical marker of the disease, avoiding X-ray exposure and providing surrogate quantitative markers of disease activity. © 2017 S. Karger AG, Basel.

Genetic Testing Confirmed the Early Diagnosis of X-Linked Hypophosphatemic Rickets in a 7-Month-Old Infant

PubMed Central

Poon, Kok Siong; Sng, Andrew Anjian; Ho, Cindy Weili; Koay, Evelyn Siew-Chuan

2015-01-01

Loss-of-function mutations in the phosphate regulating gene with homologies to endopeptidases on the X-chromosome (PHEX) have been causally associated with X-linked hypophosphatemic rickets (XLHR). The early diagnosis of XLHR in infants is challenging when it is based solely on clinical features and biochemical findings. We report a 7-month-old boy with a family history of hypophosphatemic rickets., who demonstrated early clinical evidence of rickets, although serial biochemical findings could not definitively confirm rickets. A sequencing assay targeting the PHEX gene was first performed on the mother’s DNA to screen for mutations in the 5′UTR, 22 coding exons, and the exon-intron junctions. Targeted mutation analysis and mRNA studies were subsequently performed on the boys’ DNA to investigate the pathogenicity of the identified mutation. Genetic screening of the PHEX gene revealed a novel mutation, c.1080-2A>C, at the splice acceptor site in intron 9. The detection of an aberrant mRNA transcript with skipped (loss of) exon 10 establishes its pathogenicity and confirms the diagnosis of XLHR in this infant. Genetic testing of the PHEX gene resulted in early diagnosis of XLHR, thus enabling initiation of therapy and prevention of progressive rachitic changes in the infant. PMID:26904698

Effect of intramuscular cholecalciferol megadose in children with nutritional rickets.

PubMed

Bothra, Meenakshi; Gupta, Nandita; Jain, Vandana

2016-06-01

The treatment practices for vitamin D deficiency rickets are highly variable. Though a single intramuscular (IM) megadose of vitamin D is economical, and ensures good compliance, it poses the risk of hypervitaminosis D. This observational study was conducted to assess the duration of effect and safety of single IM megadose of cholecalciferol in the treatment of vitamin D deficiency rickets. Children younger than 14 years with rickets were enrolled. Baseline investigations included radiograph of wrists and estimation of serum calcium, phosphate, alkaline phosphatase (ALP), 25(OH) vitamin D and parathormone (PTH) levels. All children received a single IM megadose of vitamin D3. Biochemical parameters were re-evaluated at 1.5, 3 and 6 months after the megadose and the values were compared to the baseline. We enrolled 21 children, out of which nine remained under active follow-up till 6 months. Radiological evidence of rickets was present in all 21 children, 14 had hypocalcemia at the time of presentation. After IM cholecalciferol megadose, median 25 hydroxy vitamin D [25(OH)D] level remained significantly more than the baseline till 6 months after the megadose. At 1.5 months after the vitamin D megadose, three (30%) of the children were found to develop toxic levels of vitamin D (>150 ng/mL), although none had hypercalcemia or any clinical manifestation of vitamin D toxicity. At 3 months and 6 months after the megadose, 25(OH)D levels remained in the sufficient range (20-100 ng/mL) in seven out of the eight children who came for follow-up. A single IM megadose of vitamin D may be effective in significantly increasing the 25(OH)D levels for at least 6 months in children with rickets, but elevation of 25(OH)D to toxic range raises concern regarding its safety.

Incidence of vitamin D deficiency rickets among Australian children: an Australian Paediatric Surveillance Unit study.

PubMed

Munns, Craig F; Simm, Peter J; Rodda, Christine P; Garnett, Sarah P; Zacharin, Margaret R; Ward, Leanne M; Geddes, Janet; Cherian, Sarah; Zurynski, Yvonne; Cowell, Christopher T

2012-04-16

To determine the incidence of and factors associated with vitamin D deficiency rickets in Australian children. 18-month questionnaire-based prospective observational study, using Australian Paediatric Surveillance Unit (APSU) data. Australian paediatricians and child health workers, January 2006 - July 2007. Children aged ≤ 15 years with vitamin D deficiency rickets (25-hydroxyvitamin D [25OHD] ≤ 50 nmol/L, and elevated alkaline phosphatase levels [> 229 IU/L] and/or radiological rickets). Incidence of vitamin D deficiency rickets. Description of demographics, clinical presentation, identification and further analysis of overrepresented groups, and treatment regimens compared with best-practice guidelines. We identified 398 children with vitamin D deficiency (55% male; median age, 6.3 years [range, 0.2-15 years]). The overall incidence in children ≤ 15 years of age in Australia was 4.9/100 000/year. All had a low 25OHD level (median, 28 nmol/L [range, 5-50 nmol]) and an elevated alkaline phosphatase level (median, 407 IU/L [range, 229-5443 IU/L]), and 48 (12%) were hypocalcaemic. Ninety-five children had wrist x-rays, of whom 67 (71%) had rachitic changes. Most (98%) had dark or intermediate skin colour and 18% of girls were partially or completely veiled. Most children were born in Africa (252; 63%) and 75% of children were refugees. Duration of exclusive breastfeeding was inversely related to serum vitamin D levels in children < 3 years of age. Empirical vitamin D treatment was given to 4% of children before diagnosis. Vitamin D deficiency rickets is a significant problem in Australia among known high-risk groups. Public health campaigns to prevent, identify and tre@vitamin D deficiency, especially in high-risk groups, are essential.

Dental complications of rickets in early childhood: case report on 2 young girls.

PubMed

Davit-Béal, Tiphaine; Gabay, Julie; Antoniolli, Pauline; Masle-Farquhar, Jeanne; Wolikow, Maryse

2014-04-01

Vitamin D is an essential hormone for calcium gut absorption. It is also involved in child growth, cancer prevention, immune system responses, and tooth formation. Due to inadequate vitamin D intake and/or decreased sunlight exposure, vitamin D deficiency has resurfaced in developed countries despite known inexpensive and effective preventive methods. Vitamin D deficiency is a common cause of rickets, a condition that affects bone development in children and that can have serious dental complications. Deficiency during pregnancy can cause enamel hypoplasia of primary teeth. Enamel regeneration is currently impossible; hypoplasia is therefore irreversible, and once affected, teeth are prone to fast caries development. Deficiency during early childhood can affect permanent teeth and ensuing caries can sometimes lead to tooth loss at a young age. Oral manifestations of rickets should be diagnosed early by both physicians and dentists to prevent severe dental complications. This case study presents 2 young girls with rickets in early childhood who suffered from subsequent serious tooth decay.

[Familial hypercalcemia and hypophosphatemia: importance in differential diagnosis of disorders in calcium-phosphate metabolism].

PubMed

Zofková, I

2010-05-01

Hypercalcemia and hypophosphatemia are symptoms of two relatively rare hereditary diseases and are extraordinarily important from the standpoint of the differential diagnosis. Mutation in calcium sensing receptor gene (CaSR) clinically manifests as familial hypocalciuric hypercalcemia (FHH) or as the much more serious neonatal hyperparathyreosis. Hypercalciuric hypocalcemia is extremely rare. Prognosis for the most frequent mutations in the CaSR gene FHH is considered benign; nevertheless, if overlooked it can lead to an incorrect diagnosis of primary hyperparathyreosis, which has a fundamentally different prognosis and treatment. Familial hypophosphatemia sometimes occurs as hereditary rickets, which is a consequence of insufficient production of vitamin D-hormone or abnormal function of vitamin D receptors (VDR). The disease manifests as X-linked dominant hypophosphatemic rickets or autosomal dominant hypophosphatemic rickets. Autosomal recessive form is very rare. Oncogenic hypophosphatemia should be excluded in differential diagnosis. In this review the issues of pathogenesis, differential diagnosis and treatment of FHH and hypophosphatemic rickets are discussed.

Follow-up study of Gambian children with rickets-like bone deformities and elevated plasma FGF23: Possible aetiological factors☆☆☆

PubMed Central

Braithwaite, Vickie; Jarjou, Landing M.A.; Goldberg, Gail R.; Jones, Helen; Pettifor, John M.; Prentice, Ann

2012-01-01

We have previously reported on a case-series of children (n = 46) with suspected calcium-deficiency rickets who presented in The Gambia with rickets-like bone deformities. Biochemical analyses discounted vitamin D-deficiency as an aetiological factor but indicated a perturbation of Ca–P metabolism involving low plasma phosphate and high circulating fibroblast growth factor-23 (FGF23) concentrations. A follow-up study was conducted 5 years after presentation to investigate possible associated factors and characterise recovery. 35 children were investigated at follow-up (RFU). Clinical assessment of bone deformities, overnight fasted 2 h urine and blood samples, 2-day weighed dietary records and 24 h urine collections were obtained. Age- and season-matched data from children from the local community (LC) were used to calculate standard deviation scores (SDS) for RFU children. None of the RFU children had radiological signs of active rickets. However, over half had residual leg deformities consistent with rickets. Dietary Ca intake (SDS-Ca = − 0.52 (0.98) p = 0.04), dietary Ca/P ratio (SDS-Ca/P = − 0.80 (0.82) p = 0.0008) and TmP:GFR (SDS-TmP:GFR = − 0.48 (0.81) p = 0.04) were significantly lower in RFU children compared with LC children and circulating FGF23 concentration was elevated in 19% of RFU children. Furthermore an inverse relationship was seen between haemoglobin and FGF23 (R2 = 25.8, p = 0.004). This study has shown differences in biochemical and dietary profiles between Gambian children with a history of rickets-like bone deformities and children from the local community. This study provided evidence in support of the calcium deficiency hypothesis leading to urinary phosphate wasting and rickets and identified glomerular filtration rate and iron status as possible modulators of FGF23 metabolic pathways. PMID:22023931

Prevalence of rickets-like bone deformities in rural Gambian children

PubMed Central

Jones, Helen L.; Jammeh, Lamin; Owens, Stephen; Fulford, Anthony J.; Moore, Sophie E.; Pettifor, John M.; Prentice, Ann

2015-01-01

The aim of this study was to estimate the burden of childhood rickets-like bone deformity in a rural region of West Africa where rickets has been reported in association with a low calcium intake. A population-based survey of children aged 0.5–17.9 years living in the province of West Kiang, The Gambia was conducted in 2007. 6221 children, 92% of those recorded in a recent census, were screened for physical signs of rickets by a trained survey team with clinical referral of suspected cases. Several objective measures were tested as potential screening tools. The prevalence of bone deformity in children < 18.0 years was 3.3%. The prevalence was greater in males (M = 4.3%, F = 2.3%, p < 0.001) and in children < 5.0 years (5.7%, M = 8.3%, F = 2.9%). Knock-knee was more common (58%) than bow-leg (31%) or windswept deformity (9%). Of the 196 examined clinically, 36 were confirmed to have a deformity outside normal variation (47% knock-knee, 53% bow-leg), resulting in more conservative prevalence estimates of bone deformity: 0.6% for children < 18.0 years (M = 0.9%, F = 0.2%), 1.5% for children < 5.0 years (M = 2.3%, F = 0.6%). Three of these children (9% of those with clinically-confirmed deformity, 0.05% of those screened) had active rickets on X-ray at the time of medical examination. This emphasises the difficulties in comparing prevalence estimates of rickets-like bone deformities from population surveys and clinic-based studies. Interpopliteal distance showed promise as an objective screening measure for bow-leg deformity. In conclusion, this population survey in a rural region of West Africa with a low calcium diet has demonstrated a significant burden of rickets-like bone deformity, whether based on physical signs under survey conditions or after clinical examination, especially in boys < 5.0 years. PMID:25871880

[Long term follow up of a patient with type I vitamin D-dependent rickets].

PubMed

Velásquez-Jones, Luis; Medeiros, Mara; Valverde-Rosas, Saúl; Jiménez-Triana, Clímaco; Del Moral-Espinosa, Irma; Romo-Vázquez, José Carlos; Franco-Alvarez, Isidro

Vitamin D dependent rickets type I is a rare hereditary disease due to a mutation in CYP27B1 encoding the 1α-hydroxylase gene. Clinically, the condition is characterized by hypocalcemic rickets in early infancy due to a deficit in the production of the vitamin D active metabolite 1,25-dihydroxy-vitamin D 3 . We report the case of a patient diagnosed at 11 months with follow-up until 9 years of age. The pathophysiology of the disease and the relevance of early diagnosis and management are discussed. Copyright © 2015. Publicado por Masson Doyma México S.A.

Twin troubles--rickets causing myelofibrosis.

PubMed

Kamien, Benjamin; Harris, Linda

2007-01-01

Myelofibrosis is an uncommon condition that causes anaemia, failure to thrive and massive splenomegaly. This case report describes migrant Sudanese twins who developed myelofibrosis secondary to severe rickets from a combination of poor diet, inadequate sun exposure, and a breastfeeding mother who wore hijab and was also vitamin D deficient.

Adaptation of calcium absorption during treatment of nutritional rickets in Nigerian children

USDA-ARS?s Scientific Manuscript database

Nutritional rickets in Nigerian children has been effectively treated with Ca supplementation. High values of Ca absorption efficiency have been observed in untreated children, but whether Ca absorption efficiency changes during treatment with Ca is unknown. Our objective in conducting this study wa...

Absence of rickets in infants with fatal abusive head trauma and classic metaphyseal lesions.

PubMed

Perez-Rossello, Jeannette M; McDonald, Anna G; Rosenberg, Andrew E; Tsai, Andy; Kleinman, Paul K

2015-06-01

To determine if rickets is present in cases of infant homicide with classic metaphyseal lesions (CMLs) and other skeletal injuries. This study was exempt from the institutional human subjects board review because all infants were deceased. An archival review (1984-2012) was performed of the radiologic and histopathologic findings of 46 consecutive infant fatalities referred from the state medical examiner's office for the evaluation of possible child abuse. Thirty infants with distal femoral histologic material were identified. Additional inclusion criteria were as follows: (a) The medical examiner determined that the infant had sustained a head injury and that the manner of death was a homicide, (b) at least one CML was evident at skeletal survey, (c) CMLs were confirmed at autopsy, and (d) non-CML fractures were also present. Nine infants (mean age, 3.9 months; age range, 1-9 months) were identified. Two pediatric radiologists independently reviewed the skeletal surveys for rachitic changes at the wrists and knees. A bone and soft tissue pathologist reviewed the distal femoral histologic slices for rickets. There were no radiographic or pathologic features of rickets in the cohort. The findings provide no support for the view that the CML is due to rickets. Rather, they strengthen a robust literature that states that the CML is a traumatic injury commonly encountered in physically abused infants. RSNA, 2015

Rickets: case series and diagnostic review of hypovitaminosis D in swine.

PubMed

Madson, Darin M; Ensley, Steve M; Gauger, Phil C; Schwartz, Kent J; Stevenson, Greg W; Cooper, Vickie L; Janke, Bruce H; Burrough, Eric R; Goff, Jesse P; Horst, Ronald L

2012-11-01

Rickets can be attributed to nutritional, genetic, hormonal, or toxic disturbances and is classified as a metabolic bone disease. Rickets is most often associated with inappropriate dietary levels of calcium, phosphorus, and/or vitamin D. During a 27-month period (January 2010 through March 2012), the Iowa State University Veterinary Diagnostic Laboratory investigated causes of sudden, unexpected death and lameness in growing pigs throughout the Midwestern United States. Clinical observations from 17 growing pig cases included weakness, lameness, reluctance to move, muscle fasciculations and/or tremors, tetany, and death. Ribs were weak, soft, and bent prior to breaking; rachitic lesions were apparent at costochondral junctions in multiple cases. Acute and/or chronic bone fractures were also noted in multiple bones. Failure of endochondral ossification, expanded physes, infractions, thin trabeculae, and increased osteoclasts were noted microscopically. Decreased bone ash and serum 25(OH)D(3), combined with clinical and microscopic evaluation, confirmed a diagnosis of vitamin D-dependent rickets in all cases. In 3 cases, disease was linked to a specific nutrient supplier that ultimately resulted in a voluntary feed recall; however, most cases in the current investigation were not associated with a particular feed company. The present report describes vitamin D-associated rickets and its importance as a potential cause of weakness, lameness, muscle fasciculations, recumbency or sudden unexpected death in swine, and describes appropriate samples and tests for disease diagnosis.

Meals and dephytinization affect calcium and zinc absorption in Nigerian children with rickets

USDA-ARS?s Scientific Manuscript database

Nutritional rickets resulting from calcium insufficiency is common in Nigeria, and high dietary phytate is thought to inhibit calcium and zinc absorption. We compared the effects of a high-phytate meal and enzymatic dephytinization on calcium and zinc absorption in Nigerian children with and without...

Theobald Palm and His Remarkable Observation: How the Sunshine Vitamin Came to Be Recognized

PubMed Central

Chesney, Russell W.

2012-01-01

The seminal discovery that sunlight was important in the prevention of nutritional rickets was made in 1890 by Theobald A. Palm, a medical missionary who contrasted the prevalence of rickets in northern European urban areas with similar areas in Japan and other tropical countries. He surmised that exposure to sunlight prevented rickets. Over the next 40 years his observation led to an understanding of ultraviolet irradiation and its role in vitamin D synthesis. This opened a new era of appreciation for the curative powers of the sun and “the sunshine vitamin”. While Palm’s observations were in some ways obscure, they had a potent effect on the development of photobiology. PMID:22347617

A Bibliography of the Personal Software Process (PSP) and the Team Software Process (TSP)

DTIC Science & Technology

2009-10-01

Postmortem.‖ Proceedings of the TSP Symposium (September 2007). http://www.sei.cmu.edu/tspsymposium/ Rickets , Chris; Lindeman, Robert; & Hodgins, Brad... Rickets , Chris A. ―A TSP Software Maintenance Life Cycle.‖ CrossTalk (March 2005). Rozanc, I. & Mahnic, V. ―Teaching Software Quality with Emphasis on PSP

Resurgence of nutritional rickets associated with breast-feeding and special dietary practices.

PubMed

Edidin, D V; Levitsky, L L; Schey, W; Dumbovic, N; Campos, A

1980-02-01

Ten cases of nutritional rickets seen over a 10-month period are reviewed. The salient clinical features are summarized, and the striking association with unsupplemented breast-feeding, fad diets, and lack of immunizations is discussed. The importance of recognizing such associated practices for purposes of early diagnosis and intervention is stressed.

Early onset hearing loss in autosomal recessive hypophosphatemic rickets caused by loss of function mutation in ENPP1.

PubMed

Steichen-Gersdorf, Elisabeth; Lorenz-Depiereux, Bettina; Strom, Tim Matthias; Shaw, Nicholas J

2015-07-01

Autosomal recessive hypophosphatemic rickets 2 (ARHR2) is a rare form of renal tubular phosphate wasting disorder. Loss of function mutations of the ecto-nucleotide pyrophosphatase/pyrophosphodiesterase 1 gene (ENPP1) causes a wide spectrum of phenotypes, ranging from lethal generalized arterial calcification of infancy to hypophosphatemic rickets with hypertension. Hearing loss was not previously thought to be one of the features of the disease entities and was merely regarded as a complication rather than a part of the disease. We report two children who presented in mid to late childhood with progressive varus deformity of their legs due to hypophosphatemic rickets caused by mutations in the ENPP1 gene. Both children had evidence of progressive hearing loss requiring the use of hearing aids. This report of two unrelated infants with compound heterozygous mutations in ENPP1 and previously published cases confirms that mild to moderate hearing loss is frequently associated with ARHR2. Early onset conductive hearing loss may further distinguish the autosomal recessive ENPP1 related type from other types of hypophosphatemia.

Identification of a novel PHEX mutation in a Chinese family with X-linked hypophosphatemic rickets using exome sequencing.

PubMed

Yuan, Lamei; Wu, Song; Xu, Hongbo; Xiao, Jingjing; Yang, Zhijian; Xia, Hong; Liu, An; Hu, Pengzhi; Lu, Anjie; Chen, Yulan; Xu, Fengping; Deng, Hao

2015-01-01

Familial hypophosphatemic rickets (HR), the most common inherited form of rickets, is a group of inherited renal phosphate wasting disorders characterized by growth retardation, rickets with bone deformities, osteomalacia, poor dental development, and hypophosphatemia. The purpose of this study was to identify the genetic defect responsible for familial HR in a four-generation Chinese Han pedigree by exome sequencing and Sanger sequencing. Clinical features include skeletal deformities, teeth abnormalities, hearing impairments and variable serum phosphate level in patients of this family. A novel deletion mutation, c.1553delT (p.F518Sfs*4), was identified in the X-linked phosphate regulating endopeptidase homolog gene (PHEX). The mutation is predicted to result in prematurely truncated and loss-of-function PHEX protein. Our data suggest that exome sequencing is a powerful tool to discover mutation(s) in HR, a disorder with genetic and clinical heterogeneity. The findings may also provide new insights into the cause and diagnosis of HR, and have implications for genetic counseling and clinical management.

Idiopathic Fanconi's syndrome with nephrogenic diabetes insipidus in a child who presented as vitamin D resistant rickets--a case report and review of literature.

PubMed

Patra, Soumya; Nadri, Gulnaz; Chowdhary, Harish; Pemde, Harish K; Singh, Varinder; Chandra, Jagdish

2011-01-01

Fanconi's syndrome is a complex of multiple tubular dysfunctions of proximal tubular cells occurring alone or in association with a variety of inherited (primary) or acquired (secondary) disorders. It is characterized by aminoaciduria, normoglycemic glycosuria, tubular proteinuria without hematuria, metabolic acidosis without anion gap and excessive urinary excretion of phosphorous, calcium, uric acid, bicarbonate, sodium, potassium and magnesium. Diabetes insipidus is a disease of collecting tubules and a child mainly presents with dehydration and hypernatremia. We report the first case of idiopathic Fanconi's syndrome along with nephrogenic diabetes insipidus (NDI) in a child who presented to us as resistant rickets. Medline search did not reveal any case of nephrogenic diabetes insipidus associated with idiopathic Fanconi's syndrome. We hypothesized that the NDI may be due to severe hypokalemia induced tubular dysfunction. The child was treated for hypophosphatemic rickets with severe metabolic acidosis and the treatment for NDI was also given. Now he has healed rickets and normal blood pH, sodium and osmolarity.

Hypocalcemic rachitic cardiomyopathy in infants

PubMed Central

Elidrissy, Abdelwahab T.H.; Munawarah, Medinah; Alharbi, Khalid M.

2012-01-01

Hypocalcemic cardiomyopathy in infants is characterized by heart failure in a previously normal infant with hypocalcemia without organic cardiac lesion. Vitamin D deficiency rickets is increasing in Middle East. In a six month study 136 cases of rickets were diagnosed in the main Children’s Hospital in Almadinah but none of them showed evidence of cardiomyopathy. Concerned of missing this serious complication of rickets we searched pub med and present this review article. Results 61 cases of hypocalcemic cardiomyopathy were reported as case reports with two series of 16 and 15 cases from London and Delhi, respectively. The major features of these cases: the age ranged from one month to 15 months with a mean age of 5 months. All presented with heart failure and hypocalcemia. There was a minor feature of rickets in a few of the cases. All had high alkaline phosphatase. Echocardiology evidence of cardiomyopathy was found in all. Most of them responded to calcium, vitamin D and cardiotonic and diuretics. Discussion We concentrated on pathogenesis of this hypocalcemic cardiomyopathy and reviewed the literature. The evidence available supports that the most likely cause of cardiomyopathy is hypocalcemia. Hypovitamin D also contributes but hyperparathyroidism might have a protective role as we did not detect any evidence of cardiomyopathy with hyperparathyroidism and florid features of rickets. Conclusion We need to look out for cardiomyopathy among infants with hypocalcemia. For prevention maternal supplementation during pregnancy and lactation with up to 2000 units of vitamin D and 400 units for their infants. PMID:24174842

SLC34A3 Intronic Deletion in an Iranian Kindred with Hereditary Hypophosphatemic Rickets with Hypercalciuria and Review of Reported Cases.

PubMed

Hasani-Ranjbar, Shirin; Ejtahed, Hanieh Sadat; Amoli, Mahsa M; Bitarafan, Fatemeh; Qorbani, Mostafa; Soltani, Akbar; Yarjoo, Bahareh

2018-05-29

Hereditary Hypophosphatemic Rickets with Hypercalciuria (HHRH) is a very rare inheritable hypophosphatemic rickets/osteomalacia characterized by decreased renal phosphate reabsorption, hypophosphatemia, vitamin D refractory rickets, hyperphosphaturia, hypercalciuria, elevated circulating 1, 25-dihydroxy vitamin D levels and low serum parathyroid hormone (PTH) levels, leading to growth retardation, limb deformities, bone pain, muscle weakness, rickets and osteomalacia. Biallelic mutations in SLC34A3/NPT2c gene are responsible for the occurrence of the disease. In this paper we describe the clinical examination, biochemical profile and gene analysis of Iranian kindred with a 101bp deletion in SLC34A3 gene. 12 members of a family of previously reported patient with HHRH (3 homozygote and 7 heterozygote) and 10 healthy controls were evaluated. All patients had significantly increased risk of kidney stone formation, bone deformities and short stature compared with unrelated healthy controls. The heterozygous patients displayed milder clinical symptoms compared with homozygous patients. These patients displayed mild or no hypophosphatemia and they did not develop skeletal deformities. Recurrent renal stones and hypercalciuria were the main presentations of heterozygous patients which could be confused with familial hypercalciuria. In addition, biochemical analysis showed significantly low serum sodium level and elevated alkaline phosphatase in patients. Genetic counseling and screening for SLC34A3 mutations can be helpful in adult onset phenotype with unexplained osteoporosis, bone deformities and especial recurrent renal stones. In subjects with vitamin D deficiency the results should be interpreted cautiously.

The Rachitic Tooth

PubMed Central

Nociti, Francisco H.; Somerman, Martha J.

2014-01-01

Teeth are mineralized organs composed of three unique hard tissues, enamel, dentin, and cementum, and supported by the surrounding alveolar bone. Although odontogenesis differs from osteogenesis in several respects, tooth mineralization is susceptible to similar developmental failures as bone. Here we discuss conditions fitting under the umbrella of rickets, which traditionally referred to skeletal disease associated with vitamin D deficiency but has been more recently expanded to include newly identified factors involved in endocrine regulation of vitamin D, phosphate, and calcium, including phosphate-regulating endopeptidase homolog, X-linked, fibroblast growth factor 23, and dentin matrix protein 1. Systemic mineral metabolism intersects with local regulation of mineralization, and factors including tissue nonspecific alkaline phosphatase are necessary for proper mineralization, where rickets can result from loss of activity of tissue nonspecific alkaline phosphatase. Individuals suffering from rickets often bear the additional burden of a defective dentition, and transgenic mouse models have aided in understanding the nature and mechanisms involved in tooth defects, which may or may not parallel rachitic bone defects. This report reviews dental effects of the range of rachitic disorders, including discussion of etiologies of hereditary forms of rickets, a survey of resulting bone and tooth mineralization disorders, and a discussion of mechanisms, known and hypothesized, involved in the observed dental pathologies. Descriptions of human pathology are augmented by analysis of transgenic mouse models, and new interpretations are brought to bear on questions of how teeth are affected under conditions of rickets. In short, the rachitic tooth will be revealed. PMID:23939820

Optimal Dose of Calcium for Treatment of Nutritional Rickets: A Randomized Controlled Trial.

PubMed

Thacher, Tom D; Smith, Lauren; Fischer, Philip R; Isichei, Christian O; Cha, Stephen S; Pettifor, John M

2016-11-01

Calcium supplementation is indicated for the treatment of nutritional rickets. Our aim was to determine the optimal dose of calcium for treatment of children with rickets. Sixty-five Nigerian children with radiographically confirmed rickets were randomized to daily supplemental calcium intake of 500 mg (n = 21), 1000 mg (n = 23), or 2000 mg (n = 21). Venous blood, radiographs, and forearm areal bone density (aBMD) were obtained at baseline and at 8, 16, and 24 weeks after enrollment. The primary outcome was radiographic healing, using a 10-point radiographic severity score. The radiographic severity scores improved in all three groups, but the rate of radiographic healing (points per month) was significantly more rapid in the 1000-mg (-0.29; 95% confidence interval [CI] -0.13 to -0.45) and 2000-mg (-0.36; 95% CI -0.19 to -0.53) supplementation groups relative to the 500-mg group. The 2000-mg group did not heal more rapidly than the 1000-mg group. Of those who completed treatment for 24 weeks, 12 (67%), 20 (87%), and 14 (67%) in the 2000-mg, 1000-mg, and 500-mg groups, respectively, had achieved a radiographic score of 1.5 or less (p = 0.21). Serum alkaline phosphatase decreased and calcium increased similarly in all groups. Forearm diaphyseal aBMD improved significantly more rapidly in the 2000-mg group than in the 500-mg and 1000-mg groups (p < 0.001). Daily calcium intakes of 1000 mg or 2000 mg produced more rapid radiographic healing of rickets than 500 mg, but 2000 mg did not have greater benefit than 1000 mg. Some children require longer than 24 weeks for complete healing of nutritional rickets. © 2016 American Society for Bone and Mineral Research. © 2016 American Society for Bone and Mineral Research.

A Novel Nonsense Mutation in the DMP1 Gene Identified by a Genome-Wide Association Study Is Responsible for Inherited Rickets in Corriedale Sheep

PubMed Central

Blair, Hugh T.; Thompson, Keith G.; Rothschild, Max F.; Garrick, Dorian J.

2011-01-01

Inherited rickets of Corriedale sheep is characterized by decreased growth rate, thoracic lordosis and angular limb deformities. Previous outcross and backcross studies implicate inheritance as a simple autosomal recessive disorder. A genome wide association study was conducted using the Illumina OvineSNP50 BeadChip on 20 related sheep comprising 17 affected and 3 carriers. A homozygous region of 125 consecutive single-nucleotide polymorphism (SNP) loci was identified in all affected sheep, covering a region of 6 Mb on ovine chromosome 6. Among 35 candidate genes in this region, the dentin matrix protein 1 gene (DMP1) was sequenced to reveal a nonsense mutation 250C/T on exon 6. This mutation introduced a stop codon (R145X) and could truncate C-terminal amino acids. Genotyping by PCR-RFLP for this mutation showed all 17 affected sheep were “T T” genotypes; the 3 carriers were “C T”; 24 phenotypically normal related sheep were either “C T” or “C C”; and 46 unrelated normal control sheep from other breeds were all “C C”. The other SNPs in DMP1 were not concordant with the disease and can all be ruled out as candidates. Previous research has shown that mutations in the DMP1 gene are responsible for autosomal recessive hypophosphatemic rickets in humans. Dmp1_knockout mice exhibit rickets phenotypes. We believe the R145X mutation to be responsible for the inherited rickets found in Corriedale sheep. A simple diagnostic test can be designed to identify carriers with the defective “T” allele. Affected sheep could be used as animal models for this form of human rickets, and for further investigation of the role of DMP1 in phosphate homeostasis. PMID:21747952

High frequencies of elevated alkaline phosphatase activity and rickets exist in extremely low birth weight infants despite current nutritional support

USDA-ARS?s Scientific Manuscript database

Osteopenia and rickets are common among extremely low birth weight infants (ELBW, <1000 g birth weight) despite current practices of vitamin and mineral supplementation. Few data are available evaluating the usual course of markers of mineral status in this population. Our objectives in this study w...

The effect of vitamin D2 and vitamin D3 on intestinal calcium absorption in Nigerian children with rickets

USDA-ARS?s Scientific Manuscript database

Children with calcium-deficiency rickets have high 1,25-dihydroxyvitamin D values. The objective of the study was to determine whether vitamin D increased calcium absorption. This was an experimental study. The study was conducted at a teaching hospital. Participants included 17 children with nutrit...

Biochemical Response of Late Rickets and Osteomalacia to a Chupatty-free Diet

PubMed Central

Ford, J. A.; Colhoun, E. M.; McIntosh, W. B.; Dunnigan, M. G.

1972-01-01

Eight Pakistani children with late rickets and two Pakistani women with osteomalacia were given a chupatty-free diet for seven weeks, substituting leavened bread of lower extraction. On this diet serum calcium levels rose to normal or near normal, levels of serum inorganic phosphorus rose slightly but significantly, and serum alkaline phosphatase levels showed a definite rise indicative of healing bone disease. It is concluded that the high phytate content of unleavened bread is the major cause of late rickets and osteomalacia in Pakistani and Indian communities in the United Kingdom. The simplest prophylactic measure seems to be the additional fortification with calcium carbonate of the high extraction flour used in preparing unleavened bread. PMID:5069221

Vitamin D deficiency rickets in an adolescent with severe atopic dermatitis.

PubMed

Borzutzky, Arturo; Grob, Francisca; Camargo, Carlos A; Martinez-Aguayo, Alejandro

2014-02-01

Atopic dermatitis (AD) affects 10% to 20% of children worldwide. Its severity may be inversely correlated with 25-hydroxyvitamin D (25OHD) levels. Although low levels of vitamin D (VD) can cause rickets in infants, VD deficiency rickets is an unusual presentation in teenagers. We report the case of a 14-year-old girl with severe AD and fish allergy since early childhood. She lived at high latitude (with less sun exposure) and, because of her atopic disorders, avoided sunlight and fish. Laboratory studies showed elevated alkaline phosphatase and parathyroid hormone levels and low serum calcium; her serum 25OHD level was <12 nmol/L. A radiograph of the wrist showed a radiolucent band in the distal metaphysis of the radius with marginal sclerosis. She was diagnosed as having hypocalcemic rickets due to VD deficiency. Treatment with VD increased her 25OHD level to 44 nmol/L, with normalization of alkaline phosphatase, parathyroid hormone, and calcium. Moreover, we observed a dramatic improvement in her AD severity with VD treatment. This case demonstrates the complex interaction between VD deficiency, AD, and food allergy. We advise a high index of suspicion of VD deficiency rickets in children of all ages with AD, particularly during accelerated growth periods and in the presence of other risk factors such as darker skin, living at high latitude, sun avoidance, and low intake of VD-rich foods. The concomitant improvement in bone-related parameters and AD severity may reflect a double benefit of VD treatment, a possibility that warrants research on VD as potential treatment for AD.

Presence of a deletion mutation (c.716delA) in the ligand binding domain of the vitamin D receptor in an Indian patient with vitamin D-dependent rickets type II.

PubMed

Kanakamani, Jeyaraman; Tomar, Neeraj; Kaushal, Esha; Tandon, Nikhil; Goswami, Ravinder

2010-01-01

Vitamin D-dependent rickets type II (VDDR-type II) is a rare disorder caused by mutations in the vitamin D receptor (VDR) gene. Here, we describe a patient with VDDR-type II with severe alopecia and rickets. She had hypocalcemia, hypophosphatemia, secondary hyperparathyroidism, and elevated serum alkaline phosphatase and 1,25-dihydroxyvitamin D(3). Sequence analysis of the lymphocyte VDR cDNA revealed deletion mutation c.716delA. Sequence analysis of her genomic DNA fragment amplified from exon 6 of the VDR gene incorporating this mutation confirmed the presence of the mutation in homozygous form. This frameshift mutation in the ligand binding domain (LBD) resulted in premature termination (p.Lys240Argfs) of the VDR protein. The mutant protein contained 246 amino acids, with 239 normal amino acids at the N terminus, followed by seven changed amino acids resulting in complete loss of its LBD. The mutant VDR protein showed evidence of 50% reduced binding with VDR response elements on electrophoretic mobility assay in comparison to the wild-type VDR protein. She was treated with high-dose calcium infusion and oral phosphate. After 18 months of treatment, she gained 6 cm of height, serum calcium and phosphorus improved, alkaline phosphatase levels decreased, and intact PTH normalized. Radiologically, there were signs of healing of rickets. Her parents and one of her siblings had the same c.716delA mutation in heterozygous form. Despite the complete absence of LBD, the rickets showed signs of healing with intravenous calcium.

A Case of Vitamin-D-Dependent Rickets Type 1A with Normal 1,25-Dihydroxyvitamin D Caused by Two Novel Mutations of the CYP27B1 Gene.

PubMed

Giannakopoulos, Aris; Efthymiadou, Alexandra; Chrysis, Dionisios

2017-01-01

Vitamin-D-dependent rickets 1A (VDDR-1A) is caused by mutations of the renal CYP27B1 gene and is a rare form of rickets. Herein, we report a 20-month-old toddler who presented with inability to walk and failure to thrive. The clinical, biochemical and radiological findings were consistent with a diagnosis of rickets, specifically of the genetic type due to increased 25-OH vitamin D stores. Our patient was a compound heterozygote with 2 novel mutations: c.242G>A(p.Gly81Glu) and c.1144C>G (p.Pro382Ala) in the CYP27B1 gene. Analysis of both mutations with in silico models predicted a deleterious effect on 25-OH vitamin D 1α-hydroxylase function. Interestingly, the levels of 1,25-(OH)2 vitamin D were within normal limits. Our patient was initiated on 1α-hydroxyvitamin D (alfacalcidol) and supplemental calcium. Monitoring of bone metabolism showed a normalization of all bone metabolism serum indices after 3 months of therapy and, thereafter, only alfacalcidol was given at a maintenance dose. The clinical follow-up showed a dramatic improvement in musculoskeletal activity, and the patient regained acceleration in height and weight appropriate for his age. This rare case report of VDDR-1A with normal levels of 1,25-(OH)2 vitamin D enhances our awareness for this type of rickets in clinical practice. © 2016 S. Karger AG, Basel.

A Randomized controlled trial on safety and efficacy of single intramuscular versus staggered oral dose of 600 000IU Vitamin D in treatment of nutritional rickets.

PubMed

Mondal, Krishanu; Seth, Anju; Marwaha, Raman K; Dhanwal, Dinesh; Aneja, Satinder; Singh, Ritu; Sonkar, Pitambar

2014-06-01

Comparison of efficacy and safety of two different regimens of vitamin D-600 000 IU as a single intramuscular dose, and 60 000IU orally once a week for 10 weeks-in treatment of nutritional rickets. Children with nutritional rickets (age: 0.5-5 years, n = 61) were randomized to receive either 60 000IU vitamin D orally once a week for 10 weeks or 600 000IU single intramuscular injection. Serum calcium, phosphate, alkaline phosphatase, urinary calcium/creatinine ratio, serum 25 hydroxy vitamin D and radiological score were compared at 12-week follow-up. No difference was found in efficacy of the two regimens on comparing biochemical and radiological parameters. Serum 25 hydroxy vitamin D >100 ng/ml was found in two children in the oral group and one child in the intramuscular group. No child developed hypercalcemia or hypercalciuria after starting treatment. Staggered oral and one-time intramuscular administrations of 600 000IU vitamin D are equally effective and safe in treatment of nutritional rickets. © The Author [2014]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Prevention and treatment of nutritional rickets.

PubMed

Shaw, N J

2016-11-01

Nutritional rickets continues to be a significant health problem for children worldwide with recent evidence of increasing incidence in many developed countries. It is due to vitamin D deficiency and/or inadequate dietary calcium intake with variation in the relative contributions of each of these dependant on environmental factors such a dietary intake and sunlight exposure. Key to the prevention of rickets is ensuring that pregnant women and their infants receive vitamin D supplementation with good evidence from randomised controlled trials that infants who receive 400iu daily can achieve levels of 25 hydroxyvitamin D of >50nmol/l. However, public health implementation of daily supplementation is more challenging with a need to revisit food fortification strategies to ensure optimal vitamin D status of the population. Treatment of nutritional rickets has traditionally been with vitamin D2 or D3, often given as a daily oral dose for several weeks until biochemical and radiological evidence of healing. However, other treatment regimes with single or intermittent high doses have also proved to be effective. It is now recognised that oral calcium either as dietary intake or supplements should be routinely used in conjunction with vitamin D for treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes.

PubMed

Sabbagh, Yves; Carpenter, Thomas O; Demay, Marie B

2005-07-05

Rickets is seen in association with vitamin D deficiency and in several genetic disorders associated with abnormal mineral ion homeostasis. Studies in vitamin D receptor (VDR)-null mice have demonstrated that expansion of the late hypertrophic chondrocyte layer, characteristic of rickets, is secondary to impaired apoptosis of these cells. The observation that normalization of mineral ion homeostasis in the VDR-null mice prevents rachitic changes suggests that rickets is secondary to hypocalcemia, hypophosphatemia, or hyperparathyroidism, rather than impaired VDR action. To determine which of these abnormalities is responsible for impaired chondrocyte apoptosis and subsequent rachitic changes, two additional models were examined: diet-induced hypophosphatemia/hypercalcemia and hypophosphatemia secondary to mutations in the Phex gene. The former model is associated with suppressed parathyroid hormone levels as a consequence of hypercalcemia. The latter model demonstrates normal calcium and parathyroid hormone levels, but 1,25-dihydroxyvitamin D levels that are inappropriately low for the degree of hypophosphatemia. Our studies demonstrate that normal phosphorus levels are required for growth plate maturation and implicate a critical role for phosphate-regulated apoptosis of hypertrophic chondrocytes via activation of the caspase-9-mediated mitochondrial pathway.

Patients with FGF23-related hypophosphatemic rickets/osteomalacia do not present with left ventricular hypertrophy.

PubMed

Takashi, Yuichi; Kinoshita, Yuka; Hori, Michiko; Ito, Nobuaki; Taguchi, Manabu; Fukumoto, Seiji

2017-05-01

Fibroblast growth factor 23 (FGF23) is a hormone regulating phosphate metabolism. Excessive actions of FGF23 cause several types of FGF23-related hypophosphatemic rickets/osteomalacia. Recently, it was reported that FGF23 levels were independently correlated with left ventricular hypertrophy (LVH) in patients with chronic kidney disease (CKD). In addition, FGF23 was also shown to cause cardiac hypertrophy directly acting on cardiomyocytes. However, there is no study indicating the correlation between FGF23 and LVH in adult patients with FGF23-related hypophosphatemic rickets/osteomalacia. Therefore, we examined the existence of LVH in these patients. We recruited consecutive 24 patients with FGF23-related hypophosphatemic diseases. Their serum intact FGF23 levels and the parameters associated with LVH, including left ventricular mass index (LVMI), relative wall thickness (RWT), Sokolow-Lyon voltage, and Cornell product, were measured. The correlations between FGF23 and these parameters were examined. The participants did not show LVH on the whole. In addition, no significant correlation was observed by these examinations. It seems unlikely that FGF23 levels are the apparent determinant of the cardiac mass in patients with FGF23-related hypophosphatemic rickets/osteomalacia.

Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism

PubMed Central

Feng, Jian Q; Ward, Leanne M; Liu, Shiguang; Lu, Yongbo; Xie, Yixia; Yuan, Baozhi; Yu, Xijie; Rauch, Frank; Davis, Siobhan I; Zhang, Shubin; Rios, Hector; Drezner, Marc K; Quarles, L Darryl; Bonewald, Lynda F; White, Kenneth E

2007-01-01

The osteocyte, a terminally differentiated cell comprising 90%–95% of all bone cells1,2, may have multiple functions, including acting as a mechanosensor in bone (re)modeling3. Dentin matrix protein 1 (encoded by DMP1) is highly expressed in osteocytes4 and, when deleted in mice, results in a hypomineralized bone phenotype5. We investigated the potential for this gene not only to direct skeletal mineralization but also to regulate phosphate (Pi) homeostasis. Both Dmp1- null mice and individuals with a newly identified disorder, autosomal recessive hypophosphatemic rickets, manifest rickets and osteomalacia with isolated renal phosphate-wasting associated with elevated fibroblast growth factor 23 (FGF23) levels and normocalciuria. Mutational analyses showed that autosomal recessive hypophosphatemic rickets family carried a mutation affecting the DMP1 start codon, and a second family carried a 7-bp deletion disrupting the highly conserved DMP1 C terminus. Mechanistic studies using Dmp1-null mice demonstrated that absence of DMP1 results in defective osteocyte maturation and increased FGF23 expression, leading to pathological changes in bone mineralization. Our findings suggest a bone-renal axis that is central to guiding proper mineral metabolism. PMID:17033621

FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type IIa.

PubMed

Shimada, Takashi; Urakawa, Itaru; Yamazaki, Yuji; Hasegawa, Hisashi; Hino, Rieko; Yoneya, Takashi; Takeuchi, Yasuhiro; Fujita, Toshiro; Fukumoto, Seiji; Yamashita, Takeyoshi

2004-02-06

Fibroblast growth factor (FGF)-23 was identified as a causative factor of tumor-induced osteomalacia and also as a responsible gene for autosomal dominant hypophosphatemic rickets. To clarify the pathophysiological roles of FGF-23 in these diseases, we generated its transgenic mice. The transgenic mice expressing human FGF-23 reproduced the common clinical features of these diseases such as hypophosphatemia probably due to increased renal phosphate wasting, inappropriately low serum 1,25-dihydroxyvitamin D level, and rachitic bone. The renal phosphate wasting in the transgenic mice was accompanied by the reduced expression of sodium phosphate cotransporter type IIa in renal proximal tubules. These results reinforce the notion that the excessive action of FGF-23 plays a causative role in the development of several hypophosphatemic rickets/osteomalacia.

Autosomal-Recessive Hypophosphatemic Rickets Is Associated with an Inactivation Mutation in the ENPP1 Gene

PubMed Central

Levy-Litan, Varda; Hershkovitz, Eli; Avizov, Luba; Leventhal, Neta; Bercovich, Dani; Chalifa-Caspi, Vered; Manor, Esther; Buriakovsky, Sophia; Hadad, Yair; Goding, James; Parvari, Ruti

2010-01-01

Human disorders of phosphate (Pi) handling and hypophosphatemic rickets have been shown to result from mutations in PHEX, FGF23, and DMP1, presenting as X-linked recessive, autosomal-dominant, and autosomal-recessive patterns, respectively. We present the identification of an inactivating mutation in the ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene causing autosomal-recessive hypophosphatemic rickets (ARHR) with phosphaturia by positional cloning. ENPP1 generates inorganic pyrophosphate (PPi), an essential physiologic inhibitor of calcification, and previously described inactivating mutations in this gene were shown to cause aberrant ectopic calcification disorders, whereas no aberrant calcifications were present in our patients. Our surprising result suggests a different pathway involved in the generation of ARHR and possible additional functions for ENPP1. PMID:20137772

The aetiology of rickets-like lower limb deformities in Malawian children.

PubMed

Braithwaite, V S; Freeman, R; Greenwood, C L; Summers, D M; Nigdikar, S; Lavy, C B D; Offiah, A C; Bishop, N J; Cashman, J; Prentice, A

2016-07-01

Debilitating rickets-like lower limb deformities are common in children throughout the world, particularly in Malawi, Africa where the causes are unknown. We have identified that Blount disease and calcium deficiency rickets are the likely causes of these deformities and propose calcium supplementation as a potential treatment of Malawian rickets. Surgical correction of rickets-like lower limb deformities is the most common paediatric operation performed at Beit Cure Orthopaedic Hospital, Malawi. The aim of this study was to investigate the aetiology of these deformities. Children with a tibio-femoral angle of deformity >20° were enrolled (n = 42, 3.0-15.0 years). Anthropometric and early life and well-being data were collected. Early morning serum and urine samples were collected on the morning of the operation for markers of calcium and phosphate homeostasis. Knee radiographs were obtained, and the children were diagnosed with either Blount (BD, n = 22) or evidence of rickets disease (RD, n = 20). As BD is a mechanical rather than metabolic disease, BD were assumed to be biochemically representative of the local population and thus used as a local reference for RD. There were no differences in anthropometry or early life experiences between BD and RD. Parathyroid hormone (PTH), 1,25-dihydroxyvitamin D, total alkaline phosphatase and urinary phosphate were significantly higher and serum phosphate, 25-hydroxyvitamin D (25OHD) and tubular maximal reabsorption of phosphate significantly lower in RD than BD. There was no difference in serum calcium, fibroblast growth factor 23 or markers of iron status between groups. All children had 25OHD > 25 nmol/L. Vitamin D deficiency is not implicated in the aetiology of RD or BD in Malawian children. The cause of RD in Malawi is likely to be dietary calcium deficiency leading to elevated PTH resulting in increased losses of phosphate from the bone and glomerular filtrate. The causes of BD remain unclear; there was no evidence in support of previously suggested risk factors such as being overweight or starting to walk early. Prior to surgical intervention, supplementation with calcium should be considered for children with RD.

Threshold levels of 25-hydroxyvitamin D and parathyroid hormone for impaired bone health in children with congenital ichthyosis and type IV and V skin.

PubMed

Sethuraman, G; Sreenivas, V; Yenamandra, V K; Gupta, N; Sharma, V K; Marwaha, R K; Bhari, N; Irshad, M; Kabra, M; Thulkar, S

2015-01-01

Patients with congenital ichthyosis, especially those with darker skin types, are at increased risk of developing vitamin D deficiency and rickets. The relationships between 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH) and bone health have not been studied previously, in ichthyosis. To determine the threshold levels of 25(OH)D and PTH for impaired bone health in children with congenital ichthyosis. In this cross-sectional study, 119 children with ichthyosis and 168 controls were recruited. Serum 25(OH)D, PTH, calcium, phosphate and alkaline phosphatase (ALP) were measured. Radiological screening for rickets was carried out only in children with ichthyosis. Forty-seven children with ichthyosis had either clinical or radiological evidence of rickets. The correlation between serum 25(OH)D and PTH showed that a serum level of 25(OH)D 8 ng mL(-1) was associated with a significant increase in PTH. The correlation between PTH and ALP showed that a serum PTH level of 75 pg mL(-1) was associated with a significant increase in ALP levels. Of the different clinical phenotypes of ichthyosis, both autosomal recessive congenital ichthyosis (ARCI) and epidermolytic ichthyosis (EI) were found to have significantly increased PTH, ALP and radiological rickets scores compared with common ichthyosis. Serum levels of 25(OH)D ≤ 8 ng mL(-1) and PTH ≥ 75 pg mL(-1) significantly increases the risk for development of rickets [odds ratio (OR) 2·8; 95% confidence interval (CI) 1·05-7·40; P = 0·04] in ichthyosis. Among the different types, patients with ARCI (OR 4·83; 95% CI 1·74-13·45; P < 0·01) and EI (OR 5·71; 95% CI 1·74-18·79; P < 0·01) are at an increased risk of developing rickets. © 2014 British Association of Dermatologists.

Tumor-induced rickets in a child with a central giant cell granuloma: a case report.

PubMed

Fernández-Cooke, Elisa; Cruz-Rojo, Jaime; Gallego, Carmen; Romance, Ana Isabel; Mosqueda-Peña, Rocio; Almaden, Yolanda; Sánchez del Pozo, Jaime

2015-06-01

Tumor-induced osteomalacia/rickets is a rare paraneoplastic disorder associated with a tumor-producing fibroblast growth factor 23 (FGF23). We present a child with symptoms of rickets as the first clinical sign of a central giant cell granuloma (CGCG) with high serum levels of FGF23, a hormone associated with decreased phosphate resorption. A 3-year-old boy presented with a limp and 6 months later with painless growth of the jaw. On examination gingival hypertrophy and genu varum were observed. Investigations revealed hypophosphatemia, normal 1,25 and 25 (OH) vitamin D, and high alkaline phosphatase. An MRI showed an osteolytic lesion of the maxilla. Radiographs revealed typical rachitic findings. Incisional biopsy of the tumor revealed a CGCG with mesenchymal matrix. The CGCG was initially treated with calcitonin, but the lesions continued to grow, making it necessary to perform tracheostomy and gastrostomy. One year after onset the hyperphosphaturia worsened, necessitating increasing oral phosphate supplements up to 100 mg/kg per day of elemental phosphorus. FGF23 levels were extremely high. Total removal of the tumor was impossible, and partial reduction was achieved after percutaneous computed tomography-guided radiofrequency, local instillation of triamcinolone, and oral propranolol. Compassionate use of cinacalcet was unsuccessful in preventing phosphaturia. The tumor slowly regressed after the third year of disease; phosphaturia improved, allowing the tapering of phosphate supplements, and FGF23 levels normalized. Tumor-induced osteomalacia/rickets is uncommon in children and is challenging for physicians to diagnose. It should be suspected in patients with intractable osteomalacia or rickets. A tumor should be ruled out if FGF23 levels are high. Copyright © 2015 by the American Academy of Pediatrics.

Comparison of Limestone and Ground Fish for Treatment of Nutritional Rickets in Children in Nigeria.

PubMed

Thacher, Tom D; Bommersbach, Tanner J; Pettifor, John M; Isichei, Christian O; Fischer, Philip R

2015-07-01

To determine whether children with calcium-deficiency rickets respond better to treatment with calcium as limestone or as ground fish. Nigerian children with active rickets (n = 96) were randomized to receive calcium as powdered limestone (920 mg of elemental calcium) or ground fish (952 mg of elemental calcium) daily for 24 weeks. Radiographic healing was defined as achieving a score of 1.5 or less on a 10-point scale. The median (range) age of enrolled children was 35 (6-151) months. Of the 88 children who completed the study, 29 (66%) in the ground fish group and 24 (55%) in the limestone group achieved the primary outcome of a radiographic score of 1.5 or less within 6 months (P = .39). The mean radiographic score improved from 6.2 ± 2.4 to 1.8 ± 2.2 in the ground fish group and from 6.3 ± 2.2 to 2.1 ± 2.4 in the limestone group (P = .68 for group comparison). In an intention to treat analysis adjusted for baseline radiographic score, age, milk calcium intake, and serum 25-hydroxyvitamin D concentration, the response to treatment did not differ between the 2 groups (P = .39). Younger age was associated with more complete radiographic healing in the adjusted model (aOR 0.74 [95% CI 0.57-0.92]). After 24 weeks of treatment, serum alkaline phosphatase had decreased, calcium and 25-hydroxyvitamin D increased, and bone mineral density increased in both groups, without significant differences between treatment groups. In children with calcium-deficiency rickets, treatment with calcium as either ground fish or limestone for 6 months healed rickets in the majority of children. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

QUALITY OF LIFE OF CHILDREN WITH RICKETS IN YOUNG AGE IN ARMENIA.

PubMed

Dunamalyan, R; Mardiyan, M; Danielyan, L; Mkrtchyan, S; Chopikyan, A

2017-02-01

Quality of Life (QL) currently is one of the most important criteria for evaluating a child's function. The main characteristics of QL in pediatrics are the psychological, physical and social functioning of the body. Integral characteristics of QOL based on the subjective perception of the components of the child and his parents. As a result of the official statistics and our research it turned out that children in this age-group more often suffer from intestinal infections, anemia, hypertrophy, rickets, skin and subcutaneous fiber disease, deficiencies occurring in prenatal period. The aim of the research is to evaluate the peculiarities of QL criteria change in case of rickets. So far in Armenia there were no tools of QL assessment of children of an early age, thereby the most acceptable questionnaire of QUALIN was used to create Armenian version on its basis. We cooperated with MAPI institute and the authors of QUALIN(Qualite de vie du Nourisson) questionnaire (Manificat S., Dazord A,) and got MAPI's permission to apply the questionnaire in the Republic of Armenia. The questionnaire QUALIN was selected for studying children's QL. The results show that the QL of children with rickets is lower than the QL of the ones who are healthy. The difference is more vividly expressed in the following parameters of QL: neuropsychological development and physical health, the ability to stay alone. In this case the pediatricians have given lower mark of QL than parents. We think that one of the possible motives of such diversity is the professional approach of doctors who estimated the QL more strictly than parents did. So QUALIN international questionnaire can be applied to estimate the peculiarities of QL criteria change of children with rickets at an early age.

A compound heterozygous mutation in SLC34A3 causes hereditary hypophosphatemic rickets with hypercalciuria in a Chinese patient.

PubMed

Chi, Yue; Zhao, Zhen; He, Xiaodong; Sun, Yue; Jiang, Yan; Li, Mei; Wang, Ou; Xing, Xiaoping; Sun, Andrew Y; Zhou, Xueying; Meng, Xunwu; Xia, Weibo

2014-02-01

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare metabolic disorder inherited in an autosomal recessive fashion and characterized by hypophosphatemia, short stature, rickets and/or osteomalacia, and secondary absorptive hypercalciuria. HHRH was recently mapped to chromosome 9q34, which contains the gene SLC34A3 which encodes the renal proximal tubular sodium-phosphate cotransporter NaPi-IIc. Here we describe a 29-year-old man with a history of childhood rickets who presented with increased renal phosphate clearance leading to hypophosphatemia, hypercalciuria, low serum parathyroid hormone (PTH), elevated serum 1,25-dihydroxyvitamin D (1,25(OH)2D) and recurrent nephrolithiasis. We performed a mutation analysis of SLC34A3 (exons and adjacent introns) of the proband and his parents to determine if there was a genetic contribution. The proband proved to be compound heterozygous for two missense mutations in SLC34A3: one novel mutation in exon 7 c.571G>C (p.G191R) and one previously identified mutation in exon 13 c.1402C>T (p.R468W). His parents were both asymptomatic heterozygous carriers of one of these two mutations. We also performed an oral phosphate loading test and compared serum phosphate, intact PTH, and intact fibroblast growth factor 23 (iFGF23) in this patient versus patients with other forms of hypophosphatemic rickets, the results of which further revealed that the mechanism of hypophosphatemia in HHRH is independent of FGF23. This is the first report of HHRH in the Chinese population. Our findings of the novel mutation in exon 7 add to the list of more than 20 reported mutations of SLC34A3. Copyright © 2013 Elsevier Inc. All rights reserved.

Novel SLC34A3 mutation causing hereditary hypophosphataemic rickets with hypercalciuria in a Gambian family.

PubMed

Braithwaite, Vickie; Pettifor, John M; Prentice, Ann

2013-03-01

Three siblings, aged 12, 4 and 2 years, presented at a Gambian clinic with bone deformities. Radiographs of knees and wrists confirmed the presence of florid rickets. The family (including 2 unaffected siblings and the mother) were investigated for hereditary rickets. The three affected siblings had biochemical features of hereditary hypophosphataemic rickets with hypercalciuria (HHRH) with normal plasma calcium and 25-hydroxyvitamin D concentrations, elevated 1,25-dihydroxyvitamin D, hypophosphataemia, hyperphosphaturia and hypercalciuria. At presentation, two of the three affected siblings had an elevated fibroblast growth factor-23 (FGF23) concentration. The mother and clinically unaffected siblings had largely normal biochemistry. Genetic analysis of the SLC34A3 gene, encoding the type IIc sodium-phosphate cotransporter, in DNA samples from the siblings and their mother was conducted. Three single nucleotide polymorphisms (SNPs) S168F, E513V and L599L were identified. E513V and L599L had been previously identified as benign polymorphisms. S168F however, is a previously unreported variant. In silico mutation evaluation predicted that the S168F mutation causes changes in the protein product which are damaging to its function. In addition, the three clinically affected siblings were homozygous in the S168F variant whereas the unaffected family members were carriers. This study describes a biochemical profile and complementary gene data consistent with a rare genetic hypophosphataemic rickets disease in a family from rural Gambia. To our knowledge, this study reports the first cases of HHRH in Africa and describes a novel causal mutation within the SLC34A3 gene. Copyright © 2012 Elsevier Inc. All rights reserved.

Serum fibroblast growth factor 23 is a useful marker to distinguish vitamin D-deficient rickets from hypophosphatemic rickets.

PubMed

Kubota, Takuo; Kitaoka, Taichi; Miura, Kohji; Fujiwara, Makoto; Ohata, Yasuhisa; Miyoshi, Yoko; Yamamoto, Keiko; Takeyari, Shinji; Yamamoto, Takehisa; Namba, Noriyuki; Ozono, Keiichi

2014-01-01

Vitamin D-deficient rickets (DR) has recently re-emerged among developed countries. Vitamin D deficiency can influence biochemical results of patients with fibroblast growth factor 23 (FGF23)-related hereditary hypophosphatemic rickets (HR), making differential diagnosis difficult. In the present study we evaluated the utility of serum FGF23 levels in the diagnosis of DR and during its treatment. The study group comprised 24 children with DR and 8 children with HR. Serum FGF23 levels and bone metabolism-related measurements were assessed. Serum FGF23 levels in patients with DR were less than 19 pg/ml, while those in patients with HR were more than 57 pg/ml. There were significant differences in serum levels of calcium, phosphate, parathyroid hormone, and 1,25-dihydroxyvitamin D, as well as tubular maximum phosphate reabsorption per glomerular filtration rate between patients with DR and HR, but these values were not fully mutually exclusive. In addition, serum FGF23 and phosphate levels were increased following treatment. Serum FGF23 level is the most critical biochemical marker for distinguishing DR from HR and might be a good indicator of biochemical response to the intervention. Serum FGF23 levels show utility for the diagnosis of DR and in the assessment of its response to treatment.

Familial hypophosphataemic rickets affecting a father and his two daughters: a case report.

PubMed

Ekpebegh, C O; Blanco-Blanco, E

2010-01-01

Hypophosphataemic rickets (HR) is a rare cause of short stature associated with limb deformities. To report the clinical and laboratory features of HR in two siblings and their father. Following the diagnosis of HR in a 4-year-old girl, her siblings and parents were screened using clinical, laboratory, and radiological parameters. Short stature, lower limb deformities, frontal bossing and hypophosphataemia were present in all three patients. Serum alkaline phosphatase (ALP) was markedly elevated in both siblings who were aged two and 11 years but only minimally raised in their 43-year-old father. While spontaneous mutation is the presumed aetiology in the father, X linked dominant inheritance is the likely cause in both daughters. Hypophosphataemic rickets should be considered in the differential diagnosis of short stature associated with limb deformities regardless of a family history of HR. Serum ALP may not be remarkably elevated when the diagnosis is made in adulthood.

Familial cleidocranial dysplasia misdiagnosed as rickets over three generations.

PubMed

Franceschi, Roberto; Maines, Evelina; Fedrizzi, Michela; Piemontese, Maria Rosaria; De Bonis, Patrizia; Agarwal, Nivedita; Bellizzi, Maria; Di Palma, Annunziata

2015-10-01

Cleidocranial dysplasia (CCD) is a rare autosomal dominant skeletal dysplasia characterized by hypoplastic clavicles, late closure of the fontanels, dental problems and other skeletal features. CCD is caused by mutations, deletions or duplications in runt-related transcription factor 2 (RUNX2), which encodes for a protein essential for osteoblast differentiation and chondrocyte maturation. We describe three familial cases of CCD, misdiagnosed as rickets over three generations. No mutations were detected on standard DNA sequencing of RUNX2, but a novel deletion was identified on quantitative polymerase chain reaction (qPCR) and multiple ligation-dependent probe amplification (MLPA). The present cases indicate that CCD could be misdiagnosed as rickets, leading to inappropriate treatment, and confirm that mutations in RUNX2 are not able to be identified on standard DNA sequencing in all CCD patients, but can be identified on qPCR and MLPA. © 2015 Japan Pediatric Society.

An Ethyl-Nitrosourea-Induced Point Mutation in Phex Causes Exon Skipping, X-Linked Hypophosphatemia, and Rickets

PubMed Central

Carpinelli, Marina R.; Wicks, Ian P.; Sims, Natalie A.; O’Donnell, Kristy; Hanzinikolas, Katherine; Burt, Rachel; Foote, Simon J.; Bahlo, Melanie; Alexander, Warren S.; Hilton, Douglas J.

2002-01-01

We describe the clinical, genetic, biochemical, and molecular characterization of a mouse that arose in the first generation (G1) of a random mutagenesis screen with the chemical mutagen ethyl-nitrosourea. The mouse was observed to have skeletal abnormalities inherited with an X-linked dominant pattern of inheritance. The causative mutation, named Skeletal abnormality 1 (Ska1), was shown to be a single base pair mutation in a splice donor site immediately following exon 8 of the Phex (phosphate-regulating gene with homologies to endopeptidases located on the X-chromosome) gene. This point mutation caused skipping of exon 8 from Phex mRNA, hypophosphatemia, and features of rickets. This experimentally induced phenotype mirrors the human condition X-linked hypophosphatemia; directly confirms the role of Phex in phosphate homeostasis, normal skeletal development, and rickets; and illustrates the power of mutagenesis in exploring animal models of human disease. PMID:12414538

Exome sequencing reveals FAM20c mutations associated with fibroblast growth factor 23-related hypophosphatemia, dental anomalies, and ectopic calcification.

PubMed

Rafaelsen, Silje Hjorth; Raeder, Helge; Fagerheim, Anne Kristine; Knappskog, Per; Carpenter, Thomas O; Johansson, Stefan; Bjerknes, Robert

2013-06-01

Fibroblast growth factor 23 (FGF23) plays a crucial role in renal phosphate regulation, exemplified by the causal role of PHEX and DMP1 mutations in X-linked hypophosphatemic rickets and autosomal recessive rickets type 1, respectively. Using whole exome sequencing we identified compound heterozygous mutations in family with sequence similarity 20, member C (FAM20C) in two siblings referred for hypophosphatemia and severe dental demineralization disease. FAM20C mutations were not found in other undiagnosed probands of a national Norwegian population of familial hypophosphatemia. Our results demonstrate that mutations in FAM20C provide a putative new mechanism in human subjects leading to dysregulated FGF23 levels, hypophosphatemia, hyperphosphaturia, dental anomalies, intracerebral calcifications and osteosclerosis of the long bones in the absence of rickets. Copyright © 2013 American Society for Bone and Mineral Research.

An ethyl-nitrosourea-induced point mutation in phex causes exon skipping, x-linked hypophosphatemia, and rickets.

PubMed

Carpinelli, Marina R; Wicks, Ian P; Sims, Natalie A; O'Donnell, Kristy; Hanzinikolas, Katherine; Burt, Rachel; Foote, Simon J; Bahlo, Melanie; Alexander, Warren S; Hilton, Douglas J

2002-11-01

We describe the clinical, genetic, biochemical, and molecular characterization of a mouse that arose in the first generation (G(1)) of a random mutagenesis screen with the chemical mutagen ethyl-nitrosourea. The mouse was observed to have skeletal abnormalities inherited with an X-linked dominant pattern of inheritance. The causative mutation, named Skeletal abnormality 1 (Ska1), was shown to be a single base pair mutation in a splice donor site immediately following exon 8 of the Phex (phosphate-regulating gene with homologies to endopeptidases located on the X-chromosome) gene. This point mutation caused skipping of exon 8 from Phex mRNA, hypophosphatemia, and features of rickets. This experimentally induced phenotype mirrors the human condition X-linked hypophosphatemia; directly confirms the role of Phex in phosphate homeostasis, normal skeletal development, and rickets; and illustrates the power of mutagenesis in exploring animal models of human disease.

Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene.

PubMed

Levy-Litan, Varda; Hershkovitz, Eli; Avizov, Luba; Leventhal, Neta; Bercovich, Dani; Chalifa-Caspi, Vered; Manor, Esther; Buriakovsky, Sophia; Hadad, Yair; Goding, James; Parvari, Ruti

2010-02-12

Human disorders of phosphate (Pi) handling and hypophosphatemic rickets have been shown to result from mutations in PHEX, FGF23, and DMP1, presenting as X-linked recessive, autosomal-dominant, and autosomal-recessive patterns, respectively. We present the identification of an inactivating mutation in the ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene causing autosomal-recessive hypophosphatemic rickets (ARHR) with phosphaturia by positional cloning. ENPP1 generates inorganic pyrophosphate (PPi), an essential physiologic inhibitor of calcification, and previously described inactivating mutations in this gene were shown to cause aberrant ectopic calcification disorders, whereas no aberrant calcifications were present in our patients. Our surprising result suggests a different pathway involved in the generation of ARHR and possible additional functions for ENPP1. Copyright (c) 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

CYP2R1 mutations causing vitamin D-deficiency rickets.

PubMed

Thacher, Tom D; Levine, Michael A

2017-10-01

CYP2R1 is the principal hepatic 25-hydroxylase responsible for the hydroxylation of parent vitamin D to 25-hydroxyvitamin D [25(OH)D]. Serum concentrations of 25(OH)D reflect vitamin D status, because 25(OH)D is the major circulating metabolite of vitamin D. The 1α-hydroxylation of 25(OH)D in the kidney by CYP27B1 generates the fully active vitamin D metabolite, 1,25-dihydroxyvitamin D (1,25(OH) 2 D). The human CYP2R1 gene, located at 11p15.2, has five exons, coding for an enzyme with 501 amino acids. In Cyp2r1-/- knockout mice, serum 25(OH)D levels were reduced by more than 50% compared wild-type mice. Genetic polymorphisms of CYP2R1 account for some of the individual variability of circulating 25(OH)D values in the population. We review the evidence that inactivating mutations in CYP2R1 can lead to a novel form of vitamin D-deficiency rickets resulting from impaired 25-hydroxylation of vitamin D. We sequenced the promoter, exons and intron-exon flanking regions of the CYP2R1 gene in members of 12 Nigerian families with rickets in more than one family member. We found missense mutations (L99P and K242N) in affected members of 2 of 12 families. The L99P mutation had previously been reported as a homozygous defect in an unrelated child of Nigerian origin with rickets. In silico analyses predicted impaired CYP2R1 folding or reduced interaction with substrate vitamin D by L99P and K242N mutations, respectively. In vitro studies of the mutant CYP2R1 proteins in HEK293 cells confirmed normal expression levels but completely absent or markedly reduced 25-hydroxylase activity by the L99P and K242N mutations, respectively. Heterozygous subjects had more moderate biochemical and clinical features of vitamin D deficiency than homozygous subjects. After an oral bolus dose of 50,000 IU of vitamin D 2 or vitamin D 3 , heterozygous subjects had lower increases in serum 25(OH)D than control subjects, and homozygous subjects had minimal increases, supporting a semidominant inheritance of these mutations. No CYP2R1 mutations were found in 27 Nigerian children with sporadic rickets, a cohort of 50 unrelated Nigerian subjects, or in 628 unrelated subjects in the 1000 Genomes Project. We conclude that mutations in CYP2R1 are responsible for an atypical form of vitamin D-deficiency rickets, which has been classified as vitamin D dependent rickets type 1B (VDDR1B, MIM 600081). Copyright © 2016 Elsevier Ltd. All rights reserved.

Anticonvulsant-induced rickets and nephrocalcinosis

PubMed Central

Lau, Keith K; Papneja, Koyelle

2012-01-01

Reported here is the case of a severely disabled young girl who developed Fanconi syndrome secondary to long-term valproic acid administration, ultimately leading to hypophosphatemic rickets. Although nephrocalcinosis is not a common feature in patients with proximal tubulopathy, the patient presented also with this condition, and the concomitant use of another anticonvulsant might have potentiated this condition. The purpose of this report is to increase awareness among healthcare providers of such rare but significant complications associated with anticonvulsants. PMID:22665570

Nutritional rickets: vitamin D, calcium, and the genetic make-up.

PubMed

El Kholy, Mohamed; Elsedfy, Heba; Fernández-Cancio, Monica; Hamza, Rasha Tarif; Amr, Nermine Hussein; Ahmed, Alaa Youssef; Toaima, Nadin Nabil; Audí, Laura

2017-02-01

The prevalence of vitamin D (vitD) deficiency presenting as rickets is increasing worldwide. Insufficient sun exposure, vitD administration, and/or calcium intake are the main causes. However, vitD system-related genes may also have a role. Prospective study: 109 rachitic children completed a 6-mo study period or until rachitic manifestations disappeared. Thirty children were selected as controls. Clinical and biochemical data were evaluated at baseline in patients and controls and biochemistry re-evaluated at radiological healing. Therapy was stratified in three different protocols. Fifty-four single-nucleotide polymorphisms (SNPs) of five vitD system genes (VDR, CP2R1, CYP27B1, CYP24A1, and GC) were genotyped and their association with clinical and biochemcial data was analyzed. Therapy response was similar in terms of radiological healing although it was not so in terms of biochemical normalization. Only VDR gene (promoter, start-codon, and intronic genotypes) was rickets-associated in terms of serum 25-OH-D, calcium, radiological severity and time needed to heal. Eight patients with sufficient calcium intake and 25-OH-D levels carried a VDR genotype lacking minor allele homozygous genotypes at SNPs spread along the gene. Although patients presented epidemiologic factors strongly contributing to rickets, genetic modulation affecting predisposition, severity, and clinical course is exerted, at least in part, by VDR gene polymorphic variation.

Identification of two novel mutations in the PHEX gene in Chinese patients with hypophosphatemic rickets/osteomalacia.

PubMed

Yue, Hua; Yu, Jin-bo; He, Jin-wei; Zhang, Zeng; Fu, Wen-zhen; Zhang, Hao; Wang, Chun; Hu, Wei-wei; Gu, Jie-mei; Hu, Yun-qiu; Li, Miao; Liu, Yu-juan; Zhang, Zhen-Lin

2014-01-01

X-linked dominant hypophosphatemia (XLH) is the most prevalent form of inherited rickets/osteomalacia in humans. The aim of this study was to identify PHEX gene mutations and describe the clinical features observed in 6 unrelated Chinese families and 3 sporadic patients with hypophosphatemic rickets/osteomalacia. For this study, 45 individuals from 9 unrelated families of Chinese Han ethnicity (including 16 patients and 29 normal phenotype subjects), and 250 healthy donors were recruited. All 22 exons and exon-intron boundaries of the PHEX gene were amplified by polymerase chain reaction (PCR) and directly sequenced. The PHEX mutations were detected in 6 familial and 3 sporadic hypophosphatemic rickets/osteomalacia. Altogether, 2 novel mutations were detected: 1 missense mutation c.1183G>C in exon 11, resulting in p.Gly395Arg and 1 missense mutation c.1751A>C in exon 17, resulting in p.His584Pro. No mutations were found in the 250 healthy controls. Our study increases knowledge of the PHEX gene mutation types and clinical phenotypes found in Chinese patients with XLH, which is important for understanding the genetic basis of XLH. The molecular diagnosis of a PHEX genetic mutation is of great importance for confirming the clinical diagnosis of XLH, conducting genetic counseling, and facilitating prenatal intervention, especially in the case of sporadic patients.

RICKETS AT THE MEDICI COURT OF FLORENCE: THE CASE OF DON FILIPPINO (1577-1582).

PubMed

Castagna, Maura; Giuffra, Valentina; Fattori, Silvia; Vitiello, Angelica; Caramella, Davide; Giustini, Davide; Fornaciari, Gino

2014-01-01

Among the children found in the crypt of the Grand Duke Giangastone in S. Lorenzo Basilica (Florence), the skeletal remains of a 5-year-old child still wearing his fine high social status clothing were recovered. This child of the Medici family was identified as Don Filippino (1577-1582), son of the Grand Duke Francesco I (1541-1587) and Giovanna from Austria (1547 - 1578). The prince showed several pathological deformities of the cranial and post-cranial skeleton, including enlargement of the cranium, thinning of the cranial vault bones (craniotabes), platybasia and marked bending of femora, tibiae and fibulae. Differential diagnosis suggests that Don Filippino was affected by rickets. The occurrence of this metabolic disease related to vitamin D deficiency in a Renaissance high social class individual can be explained by the practice of very prolonged breast-feeding, up until two years of age. Maternal milk contains insufficient vitamin D ratios and retarded weaning severely exposes children to a higher risk of developing rickets, especially if dietary habits are combined with inadequate exposure to sunlight. Historical sources describe Don Filippino as frail and sickly, with frequent illnesses and persistent slight fevers, and it can be supposed that the child was frequently confined indoors, especially in the cold season. Integration of osteoarchaeological evidence with historical documentation suggests that bone lesions observed in the skeletal remains of Don Filippino are compatible with a diagnosis of rickets, caused by the custom of prolonged breast-feeding associated with inadequate sunlight exposure to sunlight. Historical sources describe Don Filippino as frail and sickly, with frequent illnesses and persistent slight fevers, and it can be supposed that the child was frequently confined indoors, especially in the cold season. Integration of osteoarchaeological evidence with historical documentation suggests that bone lesions observed in the skeletal remains of Don Filippino are compatible with a diagnosis of rickets, caused by the custom of prolonged breast-feeding associated with inadequate sunlight exposure.

[Radiated drugs, the way of health].

PubMed

Raynal, Cécile

2011-04-01

During the inter-war years, the word "radiated" did not only suggest radioactivity, but it was also used to indicate exposure to others radiations, such as ultraviolets. The actinotherapy, a new therapy in vogue, was applied to many pathologies and tried on many substances. "Radiated drugs" result of those experimentations. Their therapeutical characteristics were found during searches on rickets. Our study relates the story of fight against rickets in France, from the use of cod liver oil to the synthesis of Vitamine D.

A paradoxical presentation of rickets and secondary osteomyelitis of the jaw in Type II autosomal dominant osteopetrosis: Rare case reports.

PubMed

Jayachandran, S; Kumar, M Suresh

2016-01-01

Osteopetrosis is a rare genetic bone disorder arising due to a defect in the differentiation or function of osteoclast which results in a generalized increase in bone mass. Osteomyelitis is one of the most common complications because of decreased bone marrow function and compromised blood supply. Radiologist plays a vital role in diagnosing osteopetrosis. Here, we present two cases of autosomal dominant osteopetrosis Type II (ADO II) with secondary osteomyelitis changes which were reported to our department. One of these two cases presented with secondary osteomyelitis in both maxilla and mandible and features of rickets, which is very rarely seen in ADO II. To the best of our knowledge, the presentation of rickets with ADO is the first of its kind to be reported. In this paper, we describe the clinical and radiological features leading to the diagnosis of ADO in these two patients. Further, a review of the literature regarding ADO is discussed.

Hereditary hypophosphatemic rickets with hypercalciuria and nephrolithiasis-identification of a novel SLC34A3/NaPi-IIc mutation.

PubMed

Phulwani, Priya; Bergwitz, Clemens; Jaureguiberry, Graciana; Rasoulpour, Majjid; Estrada, Elizabeth

2011-03-01

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is characterized by rickets, hyperphosphaturia, hypophosphatemia, elevated 1,25-dihydroxyvitamin-D, increased gastrointestinal calcium absorption and hypercalciuria. Serum calcium, 25-hydroxyvitamin-D and PTH levels are normal. Here we describe a boy with HHRH, nephrolithiasis, and compound heterozygosity for one previously described mutation (g.4225_50del) and a novel splice mutation (g.1226G>A) in SLC34A3, the gene encoding the renal sodium-phosphate co-transporter NaPi-IIc. The patient's mother and grandmother are carriers of g.4225_50del, and both have a history of nephrolithiasis associated with hypercalciuria and elevated 1,25-dihydroxyvitamin-D. His three siblings (2-6 years old), who are also carriers of g.4225_50del, have hypercalciuria but so far their renal ultrasounds are normal. Thus, SLC34A3/NaPi-IIc mutations appear to be associated with variable phenotypic changes at presentation, which can include recurrent nephrolithiasis. Copyright © 2011 Wiley-Liss, Inc.

Hereditary Hypophosphatemic Rickets With Hypercalciuria and Nephrolithiasis—Identification of a Novel SLC34A3/NaPi-IIc Mutation

PubMed Central

Phulwani, Priya; Bergwitz, Clemens; Jaureguiberry, Graciana; Rasoulpour, Majjid; Estrada, Elizabeth

2015-01-01

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is characterized by rickets, hyperphosphaturia, hypophosphatemia, elevated 1,25-dihydroxyvitamin-D, increased gastrointestinal calcium absorption and hypercalciuria. Serum calcium, 25-hydroxyvitamin-D and PTH levels are normal. Here we describe a boy with HHRH, nephrolithiasis, and compound heterozygosity for one previously described mutation (g.4225_50del) and a novel splice mutation (g.1226G>A) in SLC34A3, the gene encoding the renal sodium-phosphate co-transporter NaPi-IIc. The patient’s mother and grandmother are carriers of g.4225_50del, and both have a history of nephrolithiasis associated with hypercalciuria and elevated 1,25-dihydroxyvitamin-D. His three siblings (2–6 years old), who are also carriers of g.4225_50del, have hypercalciuria but so far their renal ultrasounds are normal. Thus, SLC34A3/NaPi-IIc mutations appear to be associated with variable phenotypic changes at presentation, which can include recurrent nephrolithiasis. PMID:21344632

Cross-talk between Msx/Dlx homeobox genes and vitamin D during tooth mineralization.

PubMed

Lézot, F; Descroix, V; Mesbah, M; Hotton, D; Blin, C; Papagerakis, P; Mauro, N; Kato, S; MacDougall, M; Sharpe, P; Berdal, A

2002-01-01

Rickets is associated with site-specific disorders of enamel and dentin formation, which may reflect the impact of vitamin D on a morphogenetic pathway. This study is devoted to potential cross-talk between vitamin D and Msx/Dlx transcription factors. We raised the question of a potential link between tooth defects seen in mice with rickets and Msx2 gene misexpression, using mutant mice lacking the nuclear vitamin D receptor as an animal model. Our data showed a modulation of Msx2 expression. In order to search for a functional impact of this Msx2 misexpression secondary to rickets, we focused our attention on osteocalcin as a target gene for both vitamin D and Msx2. Combining Msx2 overexpression and vitamin D addition in vitro, we showed an inhibitory effect on osteocalcin expression in immortalized MO6-G3 odontoblasts. Finally, in the same cells, such combinations appeared to modulate VDR expression outlining the existence of complex cross-regulations between vitamin D and Msx/Dix pathways.

Prevalence of skeletal deformity due to nutritional rickets in children between 1 and 18 years in tea garden community.

PubMed

Chabra, Tarun; Tahbildar, Pranjal; Sharma, Ayush; Boruah, Sushanta; Mahajan, Rajat; Raje, Amrut

2016-01-01

The present study was undertaken to find out the prevalence of skeletal deformity due to nutritional rickets in children aged 1-18 years in tea garden community in Dibrugarh District of Assam. It was a cross-sectional study and two-stage cluster sampling was used. In the selected tea gardens, all the children aged 1-18 years were screened for skeletal deformity by house-to-house visit. The overall prevalence of skeletal deformity was 2.7 per thousand. Majority of children with deformities (57.27%) were between 7 and 12 years of age. Widening of wrists and ankle was the most frequent symptom (53.8%). Most of the children with deformity had moderate malnutrition (77.27%). Most of the children with skeletal deformity belong to lower (v) (45.45%) grade of Kuppuswamy's grading scale. Bilateral genu valgus deformity (54.54%) and bilateral genu varum (25.92%) deformity were the most common deformities. Widening of wrists and ankle was the most frequent symptom (61.66%). Of the 16,274 tea garden children included in our study (male and female) in the age group 1-18 years, 44 had skeletal deformity due to nutritional rickets. The prevalence of skeletal deformity due to nutritional rickets was found to be 2.7 per thousand children, which are significantly higher when compared with the only other such study, which was on general population in Bangladesh.

Craniometaphyseal dysplasia with obvious biochemical abnormality and rickets-like features.

PubMed

Wu, Bo; Jiang, Yan; Wang, Ou; Li, Mei; Xing, Xiao-Ping; Xia, Wei-Bo

2016-05-01

Craniometaphyseal dysplasia (CMD) is a rare genetic disorder that is characterized by progressive sclerosis of the craniofacial bones and metaphyseal widening of long bones, and biochemical indexes were mostly normal. To further the understanding of the disease from a biochemical perspective, we reported a CMD case with obviously abnormal biochemical indexes. A 1-year-old boy was referred to our clinic. Biochemical test showed obviously increased alkaline phosphatase (ALP) and parathyroid hormone (PTH), mild hypocalcemia and hypophosphatemia. Moreover, significant elevated receptor activator of nuclear factor kappa-B ligand (RANKL) level, but normal β-C-terminal telopeptide of type I collagen (β-CTX) concentration were revealed. He was initially suspected of rickets, because the radiological examination also showed broadened epiphysis in his long bones. Supplementation with calcium and calcitriol alleviated biochemical abnormality. However, the patient gradually developed osteosclerosis which was inconformity with rickets. Considering that he was also presented with facial paralysis and nasal obstruction symptom, the diagnosis of craniometaphyseal dysplasia was suspected, and then was confirmed by the mutation analysis of ANKH of the proband and his family, which showed a de novo heterozygous mutation (C1124-1126delCCT) on exon 9. Our study revealed that obvious biochemical abnormality and rickets-like features might present as uncommon characteristics in CMD patients, and the calcium and calcitriol supplementation could alleviate biochemical abnormalities. Furthermore, although early osteoclast differentiation factor was excited in CMD patient, activity of osteoclast was still inert. Copyright © 2016. Published by Elsevier B.V.

Sclerostin Antibody (Scl-Ab) Improves Osteomalacia Phenotype in Dentin Matrix Protein 1(Dmp1) Knockout Mice with Little Impact on Serum Levels of Phosphorus and FGF23

PubMed Central

Ren, Yinshi; Han, Xianglong; Jing, Yan; Yuan, Baozhi; Ke, Huazhu; Liu, Min; Feng, Jian Q.

2016-01-01

Unlike treatments for most rickets, the treatment using 1,25-(OH)2 vitamin D3 has little efficacy on patients with hypophosphatemic rickets, a set of rare genetic diseases. Thus, understanding the local cause for osteomalacia in hypophosphatemic rickets and developing an effective treatment to restore mineralization in this rare disease has been a longstanding goal in medicine. Here, we used Dmp1 knockout (KO) mice (whose mutations led to the same type of autosomal recessive hypophosphatemic rickets in humans) as the model in which the monoclonal antibody of sclerostin (Scl-Ab) was tested in two age groups for 8 weeks: the prevention group (starting at age 4 weeks) and the treatment group (starting at age 12 weeks). Applications of Scl-Ab greatly improved the osteomalacia phenotype (>15%) and the biomechanical properties (3-point bending, ~60%) in the treated long-bone group. Our studies not only showed improvement of the osteomalacia in the alveolar bone, which has the highest bone metabolism rate, as well as the long bone phenotypes in treated mice. All these improvements attributed to the use of Scl-Ab are independent of the change in serum levels of phosphorus and FGF23, since Scl-Ab had little efficacy on those parameters. Finally, we propose a model to explain how Scl-Ab can improve the Dmp1 KO osteomalacia phenotype, in which the sclerostin level is already low. PMID:26721590

[Vitamin-resistant rickets cured by removal of a bone tumor. Review of the literature].

PubMed

François, S; Lefort, G; Poli-Merol, M L; Gaillard, D; Roussel, B; Sulmont, V; Daoud, S

1997-01-01

Rickets secondary to bone or soft tissue tumors are rare in children. Majority of the reported cases occurred in adults older than thirty. This entity can be cured after tumor removal. The authors present a case in a ten year boy and literature review. A ten year boy complained of diffuse bone and muscle weakness for two years. A diagnosis of arthritis was made but the patient continued to complain. Serum calcium level was normal (2.33 mmol/l), phosphorus was very low (0.43 mmol/l), serum alkaline phosphatase was high, parathyroid hormone and vitamin D level were normal. Urinalysis showed abnormal phosphate excretion. The absence of malabsorption, no family history of rickets or hypophosphatermy presence of a marked excess of urinary phosphate, very low serum phosphate and normal serum calcium, vitamin D and parathyroid hormone levels led us to consider a diagnosis of tumor induced osteomalacia. Radiographs showed a large round radiolucent lesion in the left superior pubic ramus and generalized demineralisation. We performed a complete tumor resection and the space was filled with bone graft. On histopathologic examination it was a benign mesenchymal tumor. Rapid reversal of biochemical anomalies, radiographs anomalies and clinical manifestation were observed after complete tumor resection. The authors have described the tumor, the osteomalacia and the pathogenesis of tumor rickets. Histologically the most common causative tumors were vascular tumors, mesenchymal tumors and non ossifying tumors. The tumor were of bone or soft tissue origin. Clinical symptoms were muscular weakness, bone and muscle pain. Biochemically there is a very low phosphate level, a normal serum calcium level as well as a normal vitamin D and PTH level. There is a significant high level of urinal phosphate. The mechanism proposed to explain oncogenic osteomalacia includes tumor secretion of phosphaturic substance other than PTH and calcitonin. Another hypothesis is a substance interfering with normal vitamin D metabolism. The pathogenesis is not clearly defined. Regardless to the mechanism of osteomalacia, complete removal of the tumor will cure the patient. A diligent search for tumors should be done in patients with vitamin D resistant rickets.

Digital Paper Prints as Replacement for LASER Films: A Study of Intra-Observer Agreement for Wrist Radiographic Findings in Rickets

PubMed Central

Jain, Abhinav; Anand, Surinder Pal Singh; Dang, Archana

2016-01-01

Introduction Replacement of conventional LASER films with digital paper prints as supplement to radiology reports may serve as an economical and environment friendly method. However, it is essential that such a change does not compromise patient’s intended diagnostic outcome. Aim The aim of this study was to assess the reliability and acceptability of digital paper prints for the radiographic images by the treating physicians and radiologists. Materials and Methods This observational analytical study was done at a tertiary care hospital of New Delhi, India. A total of 58 consecutively ordered wrist radiographs of paediatric patients (6 months to 12 years of age) for ruling out rickets were retrieved from the PACS (Picture Archiving and Communication System). These 58 radiographs, out of which 21 (36.2%) had radiological evidence of rickets over PACS were printed on two different media i.e., LASER films and glossy photographic paper. An objective scoring for the severity of rickets was done on both LASER films and paper prints by six observers independently. Overall comfort level with paper prints was rated on a 1-5 point Likert scale. Data was analysed using STATA 14.0 (Stata Corp, College Station, TX). Results Intra-observer percentage agreement and value of Cohen’s kappa for PACS vs. LASER films and PACS vs. paper prints was equal i.e., 98.3% and 0.97, respectively. Intra-observer agreement between LASER films and paper prints for all six observers was excellent, ranging from 0.92 to 1.00; percentage agreement ranging from 94.8% to 100%. Fracture of ulna/radius present in 4 sets of the X-rays was well demonstrated in both LASER films and paper prints. Comfort level with paper prints was rated as 5 out of 5 by all due to no requirement of any special illuminated view box and dark room. Conclusion This study concludes that the use of paper prints may serve as a reliable alternative to LASER films to communicate the report of wrist radiographs for the treating physicians without any compromise over diagnostic information in cases of rickets. PMID:27656525

Somatic and germline mosaicism for a mutation of the PHEX gene can lead to genetic transmission of X-linked hypophosphatemic rickets that mimics an autosomal dominant trait.

PubMed

Goji, Katsumi; Ozaki, Kayo; Sadewa, Ahmad H; Nishio, Hisahide; Matsuo, Masafumi

2006-02-01

Familial hypophosphatemic rickets is usually transmitted as an X-linked dominant disorder (XLH), although autosomal dominant forms have also been observed. Genetic studies of these disorders have identified mutations in PHEX and FGF23 as the causes of X-linked dominant disorder and autosomal dominant forms, respectively. The objective of the study was to describe the molecular genetic findings in a family affected by hypophosphatemic rickets with presumed autosomal dominant inheritance. We studied a family in which the father and the elder of his two daughters, but not the second daughter, were affected by hypophosphatemic rickets. The pedigree interpretation of the family suggested that genetic transmission of the disorder occurred as an autosomal dominant trait. Direct nucleotide sequencing of FGF23 and PHEX revealed that the elder daughter was heterozygous for an R567X mutation in PHEX, rather than FGF23, suggesting that the genetic transmission occurred as an X-linked dominant trait. Unexpectedly, the father was heterozygous for this mutation. Single-nucleotide primer extension and denaturing HPLC analysis of the father using DNA from single hair roots revealed that he was a somatic mosaic for the mutation. Haplotype analysis confirmed that the father transmitted the genotypes for 18 markers on the X chromosome equally to his two daughters. The fact that the father transmitted the mutation to only one of his two daughters indicated that he was a germline mosaic for the mutation. Somatic and germline mosaicism for an X-linked dominant mutation in PHEX may mimic autosomal dominant inheritance.

Safety and Efficacy of Stosstherapy in Nutritional Rickets.

PubMed

Chatterjee, Daipayan; Swamy, Mathad K S; Gupta, Vikas; Sharma, Vasu; Sharma, Akshat; Chatterjee, Krishti

2017-03-01

Stosstherapy has been used since early 19 th century for treating nutritional rickets. However, there are no clear cut guidelines for the biochemical monitoring of this treatment. Repeated blood tests at short intervals increase the cost of therapy and noncompliance. A prospective study was conducted on 191 cases of nutritional rickets below 10 years of age to evaluate the effectivity of stosstherapy. All cases were treated with a single intramuscular injection of vitamin D (600.000 IU) along with oral calcium (50 mg/kg) and vitamin D (400 IU per day) until radiological resolution. Dietary modifications and adequate sunlight exposure were also recommended. The mean age of presentation was 2 years 9 months. Mean sunlight exposure was 17 minutes/week with 90% having low sunlight exposure (<30 minutes/week). Prolonged breast feeding (>6 months) was found in 93.7% of the cases. With treatment, the clinical features started resolving by 1 month with complete resolution of most of the features over a period of 1 year. By 6 months, all the study subjects had complete radiological resolution. Serum levels of calcium and alkaline phosphatase (ALP) were restored by 6 months in most cases while phosphate and vitamin D levels normalized by 6 weeks. Stosstherapy is a safe, cheap and effective method of treating nutritional rickets. Biochemical tests at initial presentation followed by vitamin D assay at 6 weeks and calcium, phosphate and ALP assays at 6 months is recommended in the monitoring of these patients. For regular monitoring, only ALP assay is recommended, provided one abstains from repeat injection of vitamin D based on high ALP levels.

Rickets: concerns over the worldwide increase.

PubMed

Lowdon, Jacqui

2011-01-01

Rickets is a childhood disease that causes a softening of the bones, potentially leading to fractures and deformity. Eighty years ago it was thought to have largely been eradicated from the U.K. However a recent increase in cases of rickets, not just in Britain but around the world, has proven this isn't the case. Today the disease affects children from all types of socio-economic backgrounds, not just the poorer ones, and it is primarily caused by low levels of vitamin D and certain foods. In January 2011 the government's chief medical officer Dame Sally Davies recommended all children aged six months to five should be given vitamin D supplements, particularly during winter months when natural sunshine is limited. The irony is that the advice in recent years for children to wear a high factor sunscreen and remain covered up while playing outdoors are partly felt to be behind the reason for its re-emergence. Parents and health professionals alike were shocked when it was revealed that a school girl living on the Isle of Wight developed rickets precisely because of her mother's vigilance at following sun safety rules. NICE, in their latest report (Jan 2011) stated that: "Exposure to the sun has a number of benefits. For example, it increases people's sense of wellbeing, allows them to synthesise vitamin D and provides opportunities for physical activity". A tendency for children to stay indoors and watch TV or play on computer games, rather than play outside when the sun is shining, is arguably also another contributing factor.

Ideology and disease identity: the politics of rickets, 1929-1982.

PubMed

Bivins, Roberta

2014-06-01

How can we assess the reciprocal impacts of politics and medicine in the contemporary period? Using the example of rickets in twentieth century Britain, I will explore the ways in which a preventable, curable non-infectious disease came to have enormous political significance, first as a symbol of socioeconomic inequality, then as evidence of racial and ethnic health disparities. Between the 1920s and 1980s, clinicians, researchers, health workers, members of Parliament and later Britain's growing South Asian ethnic communities repeatedly confronted the British state with evidence of persistent nutritional deficiency among the British poor and British Asians. Drawing on bitter memories of the 'Hungry Thirties', postwar rickets-so often described as a 'Victorian' disease-became a high-profile sign of what was variously constructed as a failure of the Welfare State; or of the political parties charged with its protection; or of ethnically Asian migrants and their descendants to adapt to British life and norms. Here I will argue that rickets prompted such consternation not because of its severity, the cost of its treatment, or even its prevalence; but because of the ease with which it was politicised. I will explore the ways in which this condition was envisioned, defined and addressed as Britain moved from the postwar consensus to Thatcherism, and as Britain's diverse South Asian communities developed from migrant enclaves to settled multigenerational ethnic communities. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Radiological and biochemical resolution of nutritional rickets with calcium

PubMed Central

Oginni, L; Sharp, C; Badru, O; Risteli, J; Davie, M; Worsfold, M; Fischer, P; Oginni, L; Badru, O; Sharp, C; Davie, M; Worsfold, M; Risteli, J

2003-01-01

Aims: To determine the response to oral calcium in Nigerian children with rickets. Methods: In a teaching hospital in Western Nigeria, 26 children (13 boys, 13 girls, aged 2–5 years) with confirmed rickets received calcium lactate (2.7 g/day). Results: Within one month of treatment leg pain was relieved and the children were more active. The mean x ray score improved from 3.3 at baseline to 1.7 at three months and 0.9 at six months (arbitrary scoring system, 0–6). Twelve cases were healed radiologically after six months, 11 others improved considerably, two showed no significant improvement, and a non-compliant patient was worse. There was progressive reversal of biochemical features. Median plasma alkaline phosphatase fell from 519 (range 178–1078) to 283 (209–443) IU/l (p = 0.04) in four months, while mean 1,25-dihydroxyvitamin D fell from 473 (251–1057) to 281 (155–481) pmol/l (p = 0.04), and mean plasma calcium increased from 2.26 (1.63–2.54) to 2.37 (2.06–2.54) mmol/l (p = 0.13). Parathyroid hormone fell from 5.3 (0.4–21.5) to 1.7 (0.45–7.4) pmol/l. Type I collagen carboxy terminal cross linked telopeptide was very high at baseline (20 (7.2–103) to 14 (11–24) µg/l) (p = 0.03) and fell promptly to normal. Conclusion: Calcium supplementation alone effected healing of rickets in most of these Nigerian children and may provide sufficient treatment in this environment. PMID:12937108

Sclerostin antibody (Scl-Ab) improves osteomalacia phenotype in dentin matrix protein 1(Dmp1) knockout mice with little impact on serum levels of phosphorus and FGF23.

PubMed

Ren, Yinshi; Han, Xianglong; Jing, Yan; Yuan, Baozhi; Ke, Huazhu; Liu, Min; Feng, Jian Q

2016-01-01

Unlike treatments for most rickets, the treatment using 1,25-(OH)2 vitamin D3 has little efficacy on patients with hypophosphatemic rickets, a set of rare genetic diseases. Thus, understanding the local cause for osteomalacia in hypophosphatemic rickets and developing an effective treatment to restore mineralization in this rare disease has been a longstanding goal in medicine. Here, we used Dmp1 knockout (KO) mice (whose mutations led to the same type of autosomal recessive hypophosphatemic rickets in humans) as the model in which the monoclonal antibody of sclerostin (Scl-Ab) was tested in two age groups for 8weeks: the prevention group (starting at age 4weeks) and the treatment group (starting at age 12weeks). Applications of Scl-Ab greatly improved the osteomalacia phenotype (>15%) and the biomechanical properties (3-point bending, ~60%) in the treated long-bone group. Our studies not only showed improvement of the osteomalacia in the alveolar bone, which has the highest bone metabolism rate, as well as the long bone phenotypes in treated mice. All these improvements attributed to the use of Scl-Ab are independent of the change in serum levels of phosphorus and FGF23, since Scl-Ab had little efficacy on those parameters. Finally, we propose a model to explain how Scl-Ab can improve the Dmp1 KO osteomalacia phenotype, in which the sclerostin level is already low. Copyright © 2016 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.

Vitamin D and skeletal health in infancy and childhood

PubMed Central

Moon, Rebecca J; Harvey, Nicholas C; Davies, Justin H; Cooper, Cyrus

2014-01-01

During growth, severe vitamin D deficiency in childhood can result in symptomatic hypocalcaemia and rickets. Despite the suggestion from some studies of a secular increase in the incidence of rickets, this observation may be driven more by changes in population demographics than a true alteration to age, sex and ethnicity-specific incidence rates; indeed rickets remains uncommon overall and is rarely seen in fair-skinned children. Additionally, the impact of less severe vitamin D deficiency and insufficiency has received much interest in recent years, and in this review we consider the evidence relating vitamin D status to fracture risk and bone mineral density (BMD) in childhood and adolescence. We conclude that there is insufficient evidence to support the suggestion that low serum 25-hydroxyvitamin D [25(OH)D] increases childhood fracture risk. Overall, the relationship between 25(OH)D and BMD is inconsistent across studies and across skeletal sites within the same study; however there is evidence to suggest that vitamin D supplementation in children with the lowest levels of 25(OH)D might improve BMD. High quality randomised trials are now required to confirm this benefit. PMID:25138259

A novel Phex mutation with defective glycosylation causes hypophosphatemia and rickets in mice.

PubMed

Xiong, Xiwen; Qi, Xin; Ge, Xiaomei; Gu, Pengyu; Zhao, Jing; Zhao, Qingshun; Gao, Xiang

2008-01-01

N-ethyl-N-nitrosourea (ENU) mutagenesis is a phenotype-driven approach with potential to assign function to every locus in the mouse genome. In this article, we describe a new mutation, Pug, as a mouse model for X-linked hypophosphatemic rickets (XLH) in human. Mice carrying the Pug mutation exhibit abnormal phenotypes including growth retardation, hypophosphatemia and decreased bone mineral density (BMD). The new mutation was mapped to X-chromosome between 65.4 cM and 66.6 cM, where Phex gene resides. Sequence analysis revealed a unique T-to-C transition mutation resulting in Phe-to-Ser substitution at amino acid 80 of PHEX protein. In vitro studies of Pug mutation demonstrated that PHEX(pug) was incompletely glycosylated and sequestrated in the endoplasmic reticulum region of cell, whereas wild-type PHEX could be fully glycosylated and transported to the plasma membrane to exert its function as an endopeptidase. Taken together, the Pug mutant directly confirms the role of Phex in phosphate homeostasis and normal skeletal development and may serves as a new disease model of human hypophosphatemic rickets.

Prevalence of classic signs and symptoms of rickets and vitamin D deficiency in Mongolian children and women.

PubMed

Uush, Tserendolgor

2013-07-01

In order to assess the current nutrition status of Mongolian population, including rickets and vitamin D deficiency of children and women, the Fourth National Nutrition Cross-Sectional Survey was conducted in 21 aimags (provinces) of 4 economic regions of the country and capital city Ulaanbaatar in 2010. Children of age under five years, and non-pregnant women of reproductive age were used as subjects for assessing rickets and vitamin D deficiency. A total of 400 households were randomly selected from each of 4 economic regions and Ulaanbaatar city. Clinical examinations were performed on 706 children of age under five years. Interviews were used to assess vitamin D supplement use. The serum level of 25-hydroxyvitamin D was measured in 524 children aged 6-59 months and in 867 women of reproductive age. This survey found that 21.8% of children had vitamin D deficiency, 20.6% had low vitamin D reserve, and 30.0% of women had vitamin D deficiency and 22.2% had low vitamin D reserve. The prevalence of vitamin D deficiency in children (35.0%, 95% CI, 24.7-47.0) and women (54.9%, 95% CI 45.5-64.0) in the Eastern Region was (35.0%, 95% CI, 24.7-47.0) significantly higher than in the Western, Khangai, Central Regions, and Ulaanbaatar. Further it was found that 27.4% of children under-two years had received vitamin D supplementation. The proportion of children, who did not receive vitamin D supplementation had a higher prevalence of vitamin D deficiency than that of the children of the Eastern Region. None of the women who were involved in this survey had received vitamin D supplementation; 10.2% of them had delivered in the past 12 months, and 22.5% were breastfeeding. The prevalence of classic signs and symptoms of rickets were commonly reported among children of age under five, and skeletal abnormalities more commonly reported in children aged 12-47 months. In conclusion, there is a high prevalence of classic signs and symptoms of rickets in children of age under five years. Vitamin D supplementation in adequate doses for the prevention and treatment of rickets in children is insufficient. Thus, a trial survey is needed to assess the safe and effective doses of vitamin D supplementation necessary for the maintenance of normal serum 25-hydroxyvitamin D concentrations in Mongolian children, and women. In addition, a vitamin D food fortification program is required. This article is part of a Special Issue entitled 'Vitamin D Workshop'. Copyright © 2012 Elsevier Ltd. All rights reserved.

Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) caused by a VDR mutation: A novel mechanism of dominant inheritance.

PubMed

Isojima, Tsuyoshi; Ishizawa, Michiyasu; Yoshimura, Kazuko; Tamura, Mayuko; Hirose, Shinichi; Makishima, Makoto; Kitanaka, Sachiko

2015-06-01

Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) is caused by mutations in the VDR gene, and its inheritance is autosomal recessive. In this report, we aimed to confirm whether HVDRR is occasionally inherited as a dominant trait. An 18-month-old Japanese boy was evaluated for short stature and bowlegs. His father had been treated for rickets during childhood, and his paternal grandfather had bowlegs. We diagnosed him with HVDRR based on laboratory data and radiographic evidence of rickets. Sequence analyses of VDR were performed, and the functional consequences of the detected mutations were analyzed for transcriptional activity, ligand binding, and interaction with the retinoid X receptor, cofactors, and the vitamin D response element (VDRE). A novel mutation (Q400LfsX7) and a reported variant (R370H) were identified in the patient. Heterozygous Q400LfsX7 was detected in his father, and heterozygous R370H was detected in his healthy mother. Functional studies revealed that the transcriptional activity of Q400LfsX7-VDR was markedly disturbed. The mutant had a dominant-negative effect on wild-type-VDR, and the ligand binding affinity of Q400LfsX7-VDR was completely impaired. Interestingly, Q400LfsX7-VDR had a strong interaction with corepressor NCoR and could interact with VDRE without the ligand. R370H-VDR was functionally similar to wild-type-VDR. In conclusion, we found a dominant-negative mutant of VDR causing dominantly inherited HVDRR through a constitutive corepressor interaction, a mechanism similar to that in dominantly inherited thyroid hormone receptor mutations. Our report together with a reported pedigree suggested a distinct inheritance of HVDRR and enriched our understanding of VDR abnormalities.

Effect of calcium and vitamin D on growth, rickets and Kashin-Beck disease in 0- to 5-year-old children in a rural area of central Tibet.

PubMed

Rooze, Shancy; Mathieu, Françoise; Claus, William; Yangzom, Tashi; Yangzom, Dikki; Goyens, Philippe; de Maertelaer, Viviane

2016-06-01

To evaluate the effect of calcium (15 mmol/day) and vitamin D (625 μg/month), as single supplement or in combination, vs. no supplement on growth, clinical signs of rickets and Kashin-Beck disease (KBD) and dental health. Prospective controlled trial involving children aged 0-5 years living in four groups of villages in a KBD-endemic rural area of central Tibet who received either calcium and/or vitamin D or no supplement. The cohort was followed over 3 years. Primary outcome was the impact of the different supplementation regimes on KBD, rickets and growth; secondary outcomes were impact on urinary levels of calcium and phosphorus, biomarkers of bone and cartilage turnover, and dental health. No difference was observed between the four groups with regard to anthropometric data, rickets, KBD, urinary levels of CrossLaps(®) and CartiLaps(®) . Weight for height or age, mid-upper arm circumference and skinfold thickness decreased in the four groups. Height for age increased and the prevalence of KBD fell in the four groups. Dental health was better in the group receiving calcium and vitamin D. Urinary calcium levels increased after 3 years of follow-up in all groups; the group receiving vitamin D had a higher increase (P-value: 0.044). The same global increase was observed for urinary phosphorus levels; the group receiving calcium had a higher increase (P-value: 0.01). Calcium and vitamin D failed to improve growth and bone metabolism of children living in a KBD-endemic rural area. Calcium and vitamin D supplementation improved dental health. © 2016 John Wiley & Sons Ltd.

Novel PHEX nonsense mutation in a patient with X-linked hypophosphatemic rickets and review of current therapeutic regimens.

PubMed

Kienitz, T; Ventz, M; Kaminsky, E; Quinkler, M

2011-07-01

The most common form of familial hypophosphatemic rickets is X-linked. PHEX has been identified as the gene defective in this phosphate wasting disorder leading to decreased renal phosphate reabsorption, hypophosphatemia and inappropriate concentrations of 1,25-dihydroxyvitamin D in regard to hypophosphatemia. Clinical manifestation are skeletal deformities, short stature, osteomalacia, dental abscesses, bone pain, and loss of hearing. We report 3 cases of hypophosphatemic rickets with genetic mutational analysis of the PHEX gene. In 1 male patient an unknown nonsense mutation was found in exon 7, codon 245 (c.735T>G, Tyr245Term, Y245X). In both female patients known mutations were found: c.682delTC (exon 6, codon 228) and c.1952G>C (exon 19, codon 651, R651P). Age at diagnosis ranged from early childhood to the age of 35 years. Clinical complications were hip replacement in 1 patient, mild nephrocalcinosis in 2 patients and loss of hearing in 1 patient. All 3 patients have been treated with phosphate supplements and receive 1,25-dihydroxyvitamin D. Under this regimen all patients show stable biochemical markers with slight hyperparathyreoidism. In all patients at least one family member is affected by rickets, as well. We report a novel nonsense mutation of PHEX that has not been identified so far. The recent discovery of FGF23 and MEPE has changed our understanding of the kidney-bone metabolism, but also raises concerns about the efficacy of current therapeutic regimens that are reviewed in this context. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.

Life and death in a civitas capital: metabolic disease and trauma in the children from late Roman Dorchester, Dorset.

PubMed

Lewis, Mary E

2010-07-01

The impact that "Romanization" and the development of urban centers had on the health of the Romano-British population is little understood. A re-examination of the skeletal remains of 364 nonadults from the civitas capital at Roman Dorchester (Durnovaria) in Dorset was carried out to measure the health of the children living in this small urban area. The cemetery population was divided into two groups; the first buried their dead organized within an east-west alignment with possible Christian-style graves, and the second with more varied "pagan" graves, aligned north-south. A higher prevalence of malnutrition and trauma was evident in the children from Dorchester than in any other published Romano-British group, with levels similar to those seen in postmedieval industrial communities. Cribra orbitalia was present in 38.5% of the children, with rickets and/or scurvy at 11.2%. Twelve children displayed fractures of the ribs, with 50% of cases associated with rickets and/or scurvy, suggesting that rib fractures should be considered during the diagnosis of these conditions. The high prevalence of anemia, rickets, and scurvy in the Poundbury children, and especially the infants, indicates that this community may have adopted child-rearing practices that involved fasting the newborn, a poor quality weaning diet, and swaddling, leading to general malnutrition and inadequate exposure to sunlight. The Pagan group showed no evidence of scurvy or rib fractures, indicating difference in religious and child-rearing practices but that both burial groups were equally susceptible to rickets and anemia suggests a shared poor standard of living in this urban environment. (c) 2009 Wiley-Liss, Inc.

Molecular bases of diseases characterized by hypophosphatemia and phosphaturia: new understanding.

PubMed

Ozono, Keiichi; Michigami, Toshimi; Namba, Noriyuki; Nakajima, Shigeo; Yamamoto, Takehisa

2006-01-01

Serum phosphate levels are regulated in both calcium-dependent and -independent fashions. Active vitamin D increases while PTH decreases serum phosphate levels in association with the elevation of serum calcium. On the other hand, a calcium-independent phosphaturic factor, historically called phosphatonin is believed to exert a physiological function based on findings in hereditary and tumor-induced diseases characterized by hypophosphatemia with normocalcemia. Among them, autosomal dominant hypophosphatemic rickets (ADHR) has contributed greatly to its elucidation because the gene responsible for ADHR encodes fibroblast growth factor 23 (FGF23) that has been found to have a phosphaturic effect. In addition, FGF23 has been proved to be involved in most cases of oncogenic osteomalacia and X-linked hypophosphatemic rickets that are also characterized by hypophosphatemia and normocalcemia. Moreover, familial tumoral calcinosis, which represents the metabolic mirror image of hypophosphatemic conditions, is caused by a loss-of-function mutation in the FGF23 gene in some patients. Very recently, hereditary hypophosphatemic rickets with hypercalciuria has been found to be caused by mutations in the SLC34A1 gene which encodes a type of sodium phosphate cotransporter. These findings may provide new strategies for treating patients with abnormal phosphate metabolism.

[Homozygous ectonucleotide pyrophosphatase/phosphodiesterase 1 variants in a girl with hypophosphatemic rickets and literature review].

PubMed

Liu, Z Q; Chen, X B; Song, F Y; Gao, K; Qiu, M F; Qian, Y; Du, M

2017-11-02

Objective: To investigate the clinical features and genetic characteristics of patients with ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene variants. Method: The clinical data of a patient with ENPP1 homozygous variants from Capital Institute of Pediatrics was collected, the related literature was searched from China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, National Center from Biotechnology Information and PubMed by using search term "ENPP1" , "hypophosphatemic rickets" . The literature retrieval was confined from 1980 to February 2017. The clinical manifestations, bone metabolism examinations, X-RAY and genotypes were reviewed. Result: Our patient was an 11 years old girl, with 7 years history of lower limb malformation. She showed significant valgus deformity of the knee (genu valgum). Metabolic examination revealed reduced level of plasma phosphate (0.86 mmol/L), a normal level of plasma calcium (2.30 mmol/L) and an elevated alkaline phosphatase level of 688 IU/L. The calcium-phosphorus product was 25.9. A homozygous nonsense variants of ENPP1 gene, c.783C>G (p.Tyr261X) in exon 7 was identified in the patient. Both parents were heterozygous carriers. Literature review identified 3 Chinese patients from one publication and 17 cases from twenty one publications around the world. None of the patients was found PHEX variants which is the most common variants among hypophosphatemic rickets patients. The disease onset age was 11 months to 10 years. Eight patients had short stature, five patients had the history of generalized arterial calcification of infancy. Four suffered from deafness, three showed localized calcifications of arteries, three patients manifested pseudoxanthoma elasticum and two suffered from ossification of posterior longitudinal ligament. Nine missense variants, six splicing variants and 4 nonsense variants were reported among these twenty patients. c.783C>G was found in two Chinese patients. Conclusion: ENPP1 gene mutation was a cause of patient with hypophosphatemic rickets. Comorbid features included generalized arterial calcification of infancy, early onset hearing loss, pseudoxanthoma and ossification of posterior longitudinal ligament. ENPP1 gene testing should be performed on hypophosphatemic rickets patients without PHEX gene variants. Long-term follow up is recommended. The most common types of ENPP1 gene variants were nonsense/splicing variants. The gene c.783C>G was the most common variants in Chinese patients.

Fontanelles - excessively large

MedlinePlus

... Hydrocephalus Intrauterine growth retardation (IUGR) Premature birth Rarer causes: Achondroplasia Apert syndrome Cleidocranial dysostosis Congenital rubella Neonatal hypothyroidism Osteogenesis imperfecta Rickets When to Contact a Medical ...

Novel de novo nonsense mutation of the PHEX gene (p.Lys50Ter) in a Chinese patient with hypophosphatemic rickets.

PubMed

Huang, Yanru; Mei, Libin; Pan, Qian; Tan, Hu; Quan, Yi; Gui, Baoheng; Chang, Jiazhen; Ma, Ruiyu; Peng, Ying; Yang, Pu; Liang, Desheng; Wu, Lingqian

2015-07-01

X-linked hypophosphatemic rickets (XLHR), the most common form of inherited rickets, is a dominant disorder characterized by hypophosphatemia, abnormal bone mineralization, and short stature. Mutations in the PHEX gene are major causes of XLHR. Herein, we clinically characterized four unrelated families with hypophosphatemia, bone abnormalities, short stature, and dentin malformation. Mutational analysis of the PHEX gene using Sanger sequencing revealed three recurrent mutations (c.2197T>C, c.1646G>C, and c.2198G>A) and a de novo nonsense mutation (c.148A>T). The novel mutation was not found in any of the unaffected family members or in the 100 healthy controls and was predicted to produce a truncated protein (p.K50X), a truncated form of the PHEX protein caused by nonsense mutations has been frequently detected in XLHR individuals. Thus, our work indicated that the c.148A>T (p.K50X) mutation was the likely pathogenic mutation in individual III-2 in family 2, and that PHEX gene mutations were responsible for XLHR in these Chinese families. These findings expand the mutation spectrum of PHEX and may help us to understand the molecular basis of XLHR in order to facilitate genetic counseling. Copyright © 2015 Elsevier B.V. All rights reserved.

Hereditary vitamin D resistant rickets: identification of a novel splice site mutation in the vitamin D receptor gene and successful treatment with oral calcium therapy.

PubMed

Ma, Nina S; Malloy, Peter J; Pitukcheewanont, Pisit; Dreimane, Daina; Geffner, Mitchell E; Feldman, David

2009-10-01

To study the vitamin D receptor (VDR) gene in a young girl with severe rickets and clinical features of hereditary vitamin D resistant rickets, including hypocalcemia, hypophosphatemia, partial alopecia, and elevated serum levels of 1,25-dihydroxyvitamin D. We amplified and sequenced DNA samples from blood from the patient, her mother, and the patient's two siblings. We also amplified and sequenced the VDR cDNA from RNA isolated from the patient's blood. DNA sequence analyses of the VDR gene showed that the patient was homozygous for a novel guanine to thymine substitution in the 5'-splice site in the exon 8-intron J junction. Analysis of the VDR cDNA using reverse transcriptase-polymerase chain reaction showed that exons 7 and 9 were fused, and that exon 8 was skipped. The mother was heterozygous for the mutation and the two siblings were unaffected. A novel splice site mutation was identified in the VDR gene that caused exon 8 to be skipped. The mutation deleted amino acids 303-341 in the VDR ligand-binding domain, which is expected to render the VDR non-functional. Nevertheless, successful outpatient treatment was achieved with frequent high doses of oral calcium.

Skeletal deformities associated with nutritional congenital rickets in newborn lambs.

PubMed

Dittmer, K E; Morley, R E; Smith, R L

2017-01-01

A group of 545 pregnant rising 2-year-old Coopdale ewes on a Southland sheep farm were grazed over winter on a fodder beet (Beta vulgaris) crop. Subsequently, 45 out of approximately 750 lambs were born with a variety of skeletal deformities, including shortened limbs, varus and valgus angular limb deformities, palmar grade stance and cranial bowing of the carpus. Analysis of the crop showed the fodder beet contained a low percentage of phosphorus. In addition, 60 out of 460 rising 2-year-old ewes that had been grazed on the fodder beet crop as 1-year-olds had incisor abnormalities and malocclusion. Two affected lambs (1-day-old and 3-days-old) with representative clinical signs examined postmortem were found to have markedly enlarged costochondral junctions, and noticeably enlarged long bone metaphyses. In addition, one lamb had a dense band of metaphyseal sclerosis beneath the physes of all long bones examined. Histopathological findings included small islands and columns of chondrocytes and eosinophilic cartilage matrix present in the metaphysis. Metaphyseal trabeculae were disorganised and often lined by accumulations of pale pink osteoid; similar pale pink osteoid was also present in the cortices. Unerupted molar teeth in the affected lambs lacked a layer of enamel, and the dentine was irregular with globular basophilia. The gross and histopathological lesions were consistent with a diagnosis of rickets. Nutritional congenital rickets has not been previously diagnosed in sheep, but is a recognised disease of human infants with vitamin D deficient mothers. The rickets in affected lambs was most likely associated with phosphorus deficiency as a result of the pregnant ewes grazing fodder beet during gestation. While vitamin D deficiency was not definitively ruled out in these cases, practitioners are alerted to the possible effects of feeding phosphorus-deficient fodder beet to ewes for long periods during gestation and to 1-year-old sheep during important growth periods.

Rickets

MedlinePlus

... information applies to you and to get more information on this subject. Featured ContentSecondary DrowningRead Article >>Secondary DrowningSensory Processing Disorder (SPD)Read Article >>Sensory Processing Disorder (SPD) ...

Rickets: An Overview and Future Directions, with Special Reference to Bangladesh

PubMed Central

Craviari, Thierry; Pettifor, John M.; Thacher, Tom D.; Meisner, Craig; Arnaud, Josiane; Fischer, Philip R.

2008-01-01

Rickets has emerged as a public-health problem in Bangladesh during the past two decades, with up to 8% of children clinically affected in some areas. Insufficiency of dietary calcium is thought to be the underlying cause, and treatment with calcium (350–1,000 mg elemental calcium daily) is curative. Despite this apparently simple treatment, little is known about the most appropriate management of bone deformities of affected children, and further studies are needed to determine the details of dosing and duration of calcium therapy, the role of bracing, and specific indications for surgical intervention. Effective preventive measures that can feasibly reach entire communities are needed, and these may differ between various affected regions. PMID:18637536

Osteopenia - premature infants

MedlinePlus

Neonatal rickets; Brittle bones - premature infants; Weak bones - premature infants; Osteopenia of prematurity ... of calcium and phosphorus needed to form strong bones. While in the womb, fetal activity increases during ...

Is vitamin D hypothesis for schizophrenia valid? Independent segregation of psychosis in a family with vitamin-D-dependent rickets type IIA.

PubMed

Ozer, Suzan; Uluşahin, Aylin; Ulusoy, Semra; Okur, Hamza; Coşkun, Turgay; Tuncali, Timur; Göğüş, Ahmet; Akarsu, A Nurten

2004-03-01

The vitamin D hypothesis of schizophrenia is a recent concept bringing together old observations on environmental risk factors and new findings on the neurodevelopmental effects of vitamin D. Candidate genes related to the vitamin D endocrine system have not yet been fully explored for this purpose. The coexistence of vitamin-D-dependent-rickets type II with alopecia (VDDR IIA) and different forms of psychosis in the same inbred family has provided us with an opportunity to investigate the presumed relationship between vitamin D deficiency and psychosis. Psychiatric examination and molecular genetic studies were performed in this family overloaded with psychotic disorders and VDDR IIA. Forty members were evaluated in order to describe their phenotypic features. The family was tested for a linkage to the chromosome 12q12-q14 region where the vitamin D receptor (VDR) gene is located. Psychosis was the common phenotype in the 18 psychiatrically affected members. Pedigree analysis did not show a cosegregation of psychosis and rickets. Lod scores were not significant to prove a linkage between psychosis and VDR locus. The authors concluded that (1) the neurodevelopmental consequences of vitamin D deficiency do not play a causative role in psychotic disorders, (2) these two syndromes are inherited independently, and (3) vitamin D deficiency does not act as a risk factor in subjects susceptible to psychosis.

Diagnostic dilemma: osteopetrosis with superimposed rickets causing neonatal hypocalcemia.

PubMed

Olgaç, Asburçe; Tümer, Leyla; Boyunağa, Öznur; Kızılkaya, Metehan; Hasanoğlu, Alev

2015-04-01

Osteopetrosis is a rare genetic condition of reduced osteoclastic bone resorption which causes defective bone remodeling and skeletal sclerosis during growth, having effects on many organs and tissues. Mutation of T-cell immune regulator 1 (TCRG1) gene is the most common genetic defect leading to osteopetrosis, with poor prognosis. The autosomal recessive form presents in the infantile period (also known as malignant infantile osteopetrosis--MIOP), and is characterized by fractures, short stature, hepatosplenomegaly, compressive neuropathies, hypocalcemia and pancytopenia. Being a rare disease with non-specific clinical manifestations, the diagnosis is difficult and usually delayed. Rickets is a characteristic feature of MIOP which results from the defect in osteoclasts to provide a normal Ca/P balance resulting in the poor mineralization of the osteoid. Various treatment options have been suggested for osteopetrosis, but hematopoietic stem cell transplantation still remains the only curative treatment option presently. The authors report the case of a 46-day-old girl with late-onset neonatal hypocalcemia and rickets that was later diagnosed as osteopetrosis. This case report emphasizes that infantile osteopetrosis is an important cause of neonatal hypocalcemia. As irreversible complications develop within the first months of life, immediate diagnosis and early intervention are crucial and may be life-saving. © The Author [2015]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Changes in bone metabolic parameters following oral calcium supplementation in an adult patient with vitamin D-dependent rickets type 2A.

PubMed

Kinoshita, Yuka; Ito, Nobuaki; Makita, Noriko; Nangaku, Masaomi; Fukumoto, Seiji

2017-06-29

Vitamin D-dependent rickets type 2A (VDDR2A) is a rare inherited disorder with decreased tissue responsiveness to 1,25-dihydroxyvitamin D [1,25(OH) 2 D], caused by loss of function mutations in the vitamin D receptor (VDR) gene. Approximately 50 types of mutations have been identified so far that change amino acids in either the N-terminal DNA binding domain (DBD) or the C-terminal ligand binding domain (LBD) of the VDR protein. The degree of responsiveness to 1,25(OH) 2 D varies between patients with VDDR2A, which may depend on their residual VDR function. In this report, we describe a female patient with VDDR2A caused by an early stop codon (R30X) in the VDR gene that resulted in a severely truncated VDR protein. She developed alopecia and bowed legs within a year after birth and was diagnosed with rickets at the age of 2. She had been treated with active vitamin D and oral calcium supplementation until 22 years of age, when she developed secondary hyperparathyroidism and high bone turnover. The genetic diagnosis of VDDR2A promoted the discontinuation of active vitamin D treatment in favor of monotherapy with oral calcium supplementation. We observed amelioration of the secondary hyperparathyroidism and normalization of bone metabolic parameters within 6 years.

Ideology and disease identity: the politics of rickets, 1929–1982

PubMed Central

Bivins, Roberta

2014-01-01

How can we assess the reciprocal impacts of politics and medicine in the contemporary period? Using the example of rickets in twentieth century Britain, I will explore the ways in which a preventable, curable non-infectious disease came to have enormous political significance, first as a symbol of socioeconomic inequality, then as evidence of racial and ethnic health disparities. Between the 1920s and 1980s, clinicians, researchers, health workers, members of Parliament and later Britain's growing South Asian ethnic communities repeatedly confronted the British state with evidence of persistent nutritional deficiency among the British poor and British Asians. Drawing on bitter memories of the ‘Hungry Thirties’, postwar rickets—so often described as a ‘Victorian’ disease—became a high-profile sign of what was variously constructed as a failure of the Welfare State; or of the political parties charged with its protection; or of ethnically Asian migrants and their descendants to adapt to British life and norms. Here I will argue that rickets prompted such consternation not because of its severity, the cost of its treatment, or even its prevalence; but because of the ease with which it was politicised. I will explore the ways in which this condition was envisioned, defined and addressed as Britain moved from the postwar consensus to Thatcherism, and as Britain's diverse South Asian communities developed from migrant enclaves to settled multigenerational ethnic communities. PMID:23918817

[Familial hypophosphatemic rickets].

PubMed

Reusz, G

2001-12-02

Familiar hypophosphatemic rickets (FHR) is characterized by isolated defect of renal phosphate reabsorption, hypophosphataemia, rickets and poor growth. In untreated cases parathyroid hormone and calcitriol levels are normal. FHR is caused by mutations of the PHEX gene encoding a zinc-binding metalloprotease enzyme. PHEX is expressed in bones and the parathyroid gland but not in the kidney. The gene product is involved in the inactivation of a phosphate regulating hormone (phosphatonin). The presence of this hormone through unknown mechanisms decreases the sodium-dependent phosphate cotransporter in the kidney resulting in impaired phosphate transport. In addition the PHEX gene product exerts autocrine and paracrine effects on the bone. Despite recent advances in the understanding of the pathomechanism, treatment of FHR is still symptomatic. It consists of active vitamin D analogues and oral phosphate supplementation. Nephrocalcinosis is a well-known, usually non-progressive side effect of the conventional therapy. As shown by pilot studies, poorly growing children with FHR may benefit from the positive effect of human recombinant growth hormone (rhGH). However, rhGH treatment could aggravate the already existing tendency to disproportionate growth resulting in the overgrowth of the trunk. The disturbed phosphate homeostasis persists during the whole life span of the FHR patients. It is therefore essential to provide lifelong care, to prevent late skeletal and dental consequences or to treat them if already established. That care should be done by the teamwork of the pediatrician, internist, orthopedist, dentist and the psychologist.

Clinical presentation and etiology of osteomalacia/rickets in adolescents.

PubMed

Hazzazi, Mohammad A; Alzeer, Ibrahim; Tamimi, Waleed; Al Atawi, Mohsen; Al Alwan, Ibrahim

2013-09-01

This study was conducted to determine the causes and clinical presentations of osteomalacia/rickets in adolescents seen at the King Abdulaziz Medical City (KAMC), Riyadh. Because osteomalacia and rickets constitute the same entity, the term osteomalacia will be used for future discussion. A retrospective file review was performed on all adolescents (10-16 years) with osteomalacia, defined as alkaline phosphatase levels ≥500 IU/L, seen at the KAMC, Riyadh, from 2000 to 2006. We recorded the signs and symptoms, dietary history and amount of sun exposure at presentation. A total of 135 patients were found to fit the inclusion criteria for the study. Of them, 57 had nutritional causes, with a mean age of 13.2 years, and included 32 females. At diagnosis, 22 patients were found to have bone pain, 10 had bone deformities, eight had pathological fractures and 17 were asymptomatic. Secondary causes for osteomalacia were found in 59 cases who had liver and renal disease and in 19 other patients who were on medications such as anticonvulsants and steroids, which are known to cause osteomalacia. Our study indicates that osteomalacia is a significant health burden that deserves special attention. Bone pain is the most common presenting symptom at diagnosis. Because of the high risk of osteomalacia associated with the use of anticonvulsants and steroids, it is advised that all patients on these drugs should be routinely screened for secondary osteomalacia.

Rickets

MedlinePlus

... or produced by the skin when exposed to sunlight. Lack of vitamin D production by the skin ... who: Live in climates with little exposure to sunlight Must stay indoors Work indoors during the daylight ...

Rickets

MedlinePlus

... usually occurs when they do not get enough vitamin D, which helps growing bones absorb the minerals calcium ... too low. Your child might not get enough vitamin D if he or she Has dark skin Spends ...

Bone x-ray

MedlinePlus

... different views of the bone may be uncomfortable. Why the Test is Performed A bone x-ray ... neoplasia (MEN) II Multiple myeloma Osgood-Schlatter disease Osteogenesis imperfecta Osteomalacia Paget's disease Primary hyperparathyroidism Rickets Risks There ...

Calcium - ionized

MedlinePlus

... diuretics Thrombocytosis (high platelet count) Tumors Vitamin A excess Vitamin D excess Lower-than-normal levels may be due to: Hypoparathyroidism Malabsorption Osteomalacia Pancreatitis Renal failure Rickets Vitamin D deficiency Alternative Names Free calcium; Ionized calcium ...

Case report of 5 siblings: malnutrition? Rickets? DiGeorge syndrome? Developmental delay?

PubMed

Cundiff, David K; Harris, William

2006-01-16

Parents of six children are facing a trial on charges of aggravated manslaughter in the care a 5 1/2 month old infant who died suddenly and neglect of their four older children for causing them to be malnourished by feeding them all an exclusively raw foods vegan diet. Both parents declined plea bargains and plan to defend themselves in court. The fifth child born to a married couple was breast-fed until 2 1/2 months. Subsequently, the parents fed the baby an exclusively raw foods diet prepared in a blender at home. The four older children, ages 18 months-6 1/2 years also ate an exclusively raw foods vegan diet. None of the four older children had significant previous injuries or serious illnesses. At autopsy, the infant weighed 3180 mg (6.99 pounds) and appeared emaciated. The thymus gland was absent and parathyroid glands were not located. The lungs were "congested." DiGeorge anomaly cannot be ruled out from these findings. Although, the coroner ruled that "malnutrition" was the sole cause of death, malnutrition, according to the World Health Organization definition, cannot be diagnosed in this infant. Compared with standard growth charts, the older children fell 2.1-4.1 standard deviations below the mean for North American children in height and weight. Labs were normal except for a low cholesterol level in all and a low prealbumin in one of three children tested. Therefore, malnutrition cannot be diagnosed in these children. The pediatrician diagnosed rickets in the four-year-old. However, chest x-rays were normal in all and long bone x-rays showed minimal changes in one child--no sign of rickets. The clinical diagnosis of rickets was not confirmed by the Center for Disease Control's criteria. A psychologist diagnosed the 18-month-old as developmentally delayed to the level of a 15-month-old, but this diagnosis is questionable. The raw foods vegan diet and possibly inherited small stature from the father's side account for their relatively low heights and weights. Catch-up growth will probably occur on the standard American diet but would have also been expected if they had remained on a vegan diet.

Can Subclinical Rickets Cause SCFE? A Prospective, Pilot Study.

PubMed

Arkader, Alexandre; Woon, Regina P; Gilsanz, Vicente

2015-01-01

Slipped capital femoral epiphysis (SCFE) is a common disorder of the growing hip; however, its etiology remains unknown. Vitamin D (25-OH) is a major regulator of bone homeostasis and calcium metabolism. Vitamin D deficiency is one of the major causes of rickets, and rickets has been associated with SCFE. Increased body mass index (BMI) has been linked to SCFE and obese children are known to have lower vitamin D levels. Therefore, we hypothesize that children who develop SCFE may have subclinical rickets predisposing them to the development of physeal disease. This was a pilot, prospective study designed to determine the relationship between vitamin D, bone, muscle, and fat in patients with SCFE. We enrolled 20 consecutive patients with idiopathic SCFE aged 9 to 14 years. Upon diagnosis, vitamin D, PTH, T4, and thyroid-stimulating hormone blood levels were obtained. A single-slice computed tomography was used to measure cortical bone density (CBD) of the femur. Demographics, BMI, and the results obtained were compared to generate a relationship between vitamin D levels and SCFE. Twenty patients were enrolled, 13 males and 7 females, at an average age of 12 years (range, 9 to 14 y), and mean BMI% was 93.9 (range, 81.3 to 99.5). There were 15 stable and 5 unstable SCFE. Overall, mean and SD values for vitamin D, 25-OH were within the normal range (43.9 ± 13.5). We found no difference in values in vitamin D between nonobese (BMI < 95%) and obese (BMI ≥ 95%) subjects (34.8 ± 16.8 vs. 51.6 ± 22.4, P = 0.144). Moreover, we found no difference in CBD between these 2 groups (1126 ± 33.1 vs. 1147 ± 41.2, P = 0.333). There was no relation between blood values of vitamin D and measures of CBD. Although obese children are known to have lower levels of vitamin D and a higher prevalence of SCFE, we found no correlation between low vitamin D and the development of SCFE in this subset of patients.

Vitamin D treatment in calcium-deficiency rickets: a randomised controlled trial.

PubMed

Thacher, Tom D; Fischer, Philip R; Pettifor, John M

2014-09-01

To determine whether children with calcium-deficiency rickets have a better response to treatment with vitamin D and calcium than with calcium alone. Randomised controlled trial. Jos University Teaching Hospital, Jos, Nigeria. Nigerian children with active rickets treated with calcium carbonate as limestone (approximately 938 mg elemental calcium twice daily) were, in addition, randomised to receive either oral vitamin D2 50,000 IU (Ca+D, n=44) or placebo (Ca, n=28) monthly for 24 weeks. Achievement of a 10-point radiographic severity score ≤1.5 and serum alkaline phosphatase ≤350 U/L. The median (range) age of enrolled children was 46 (15-102) months, and baseline characteristics were similar in the two groups. Mean (±SD) 25-hydroxyvitamin D (25(OH)D) was 30.2±13.2 nmol/L at baseline, and 29 (43%) had values <30 nmol/L. Baseline alkaline phosphatase and radiographic scores were unrelated to vitamin D status. Of the 68 children (94% of original cohort) who completed 24 weeks of treatment, 29 (67%) in the Ca+D group and 11 (44%) in the Ca group achieved the primary outcome (p=0.06). Baseline 25(OH)D did not alter treatment group effects (p=0.99 for interaction). At the end of 24 weeks, 25(OH)D values were 55.4±17.0 nmol/L and 37.9±20.0 nmol/L in the Ca+D and Ca groups, respectively, (p<0.001). In the Ca+D and Ca groups, the final 25(OH)D concentration was greater in those who achieved the primary outcome (56.4±17.2 nmol/L) than in those who did not (37.7±18.5 nmol/L, p<0.001). In children with calcium-deficiency rickets, there is a trend for vitamin D to improve the response to treatment with calcium carbonate as limestone, independent of baseline 25(OH)D concentrations. ClinicalTrials.gov NCT00949832. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Resolution of severe, adolescent-onset hypophosphatemic rickets following resection of an FGF-23-producing tumour of the distal ulna.

PubMed

Ward, L M; Rauch, F; White, K E; Filler, G; Matzinger, M A; Letts, M; Travers, R; Econs, M J; Glorieux, F H

2004-05-01

Oncogenic hypophosphatemic osteomalacia (OHO) is an uncommon hypophosphatemic syndrome characterized by bone pain, proximal muscle weakness and rickets. It has been postulated that OHO results from overproduction of a humoral phosphaturic factor by an occult tumour. Recently, some OHO tumours have been shown to elaborate fibroblast growth factor-23 (FGF-23), which causes renal phosphate wasting when administered to mice. The purpose of this study was to undertake detailed investigations to confirm the diagnosis of OHO in a pediatric patient and to document the biochemical, radiographic and bone histological phenotype before and after tumour removal. We describe an 11-year-old, previously healthy girl with significant pain and functional disability associated with hypophosphatemic rickets. Circulating 1,25-(OH)(2) vitamin D was very low (14 pM; N: 40-140) while the FGF-23 serum level was markedly elevated [359.5 reference units (RU)/ml, N: 33-105]. An iliac bone biopsy revealed severe osteomalacia, but periosteocytic lesions, as are typical for X-linked hypophosphatemic rickets, were not seen. Sequence analyses of the PHEX and FGF23 genes were normal. A radiographic skeletal survey revealed a small exostosis of the left, distal ulnar metaphysis. A tumour was subsequently removed from this site and the pathology was consistent with benign, fibro-osseous tissue. Serum FGF-23 was normal when measured at 7 h post-operatively, while serum phosphate reached the low-normal range at 16 days following surgery. An iliac bone biopsy taken 5 months after the operation showed improvement, but not yet resolution, of the osteomalacia. Biochemical parameters of bone and mineral metabolism suggested that complete resolution of the osteomalacia was not achieved until 12 months following surgery. One year after tumour removal, the patient was pain-free and had resumed a normal level of activity. The rapid normalization of FGF-23 levels following removal of a benign tumour and the subsequent improvement in the biochemical and histological parameters of bone and mineral metabolism suggest that FGF-23 played a key role in this girl's disease.

Disease and Evolution.

ERIC Educational Resources Information Center

Wells, Calvin

1978-01-01

Discusses disease and genetic disorders as evolutionary mechanisms. Emphasizes the archeological evidence from past human populations and societies, mentioning albinism, scurvy, sleeping sickness, bone conditions, various host-parasite relationships, rickets, sickle-cell anemia, diabetes, and influenza. (CS)

Genetics Home Reference: vitamin D-dependent rickets

MedlinePlus

... body. The VDR protein is also involved in hair growth through a process that does not require calcitriol ... Certain abnormalities in the VDR protein also impair hair growth, causing alopecia in some people with VDDR2A. Learn ...

Mutational Survey of the PHEX Gene in Patients with X-linked Hypophosphatemic Rickets

PubMed Central

Ichikawa, Shoji; Traxler, Elizabeth A.; Estwick, Selina A.; Curry, Leah R.; Johnson, Michelle L.; Sorenson, Andrea H.; Imel, Erik A.; Econs, Michael J.

2008-01-01

X-linked hypophosphatemic rickets (XLH) is a dominantly inherited disorder characterized by renal phosphate wasting, aberrant vitamin D metabolism, and abnormal bone mineralization. XLH is caused by inactivating mutations in PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome). In this study, we sequenced the PHEX gene in subjects from 26 kindreds who were clinically diagnosed with XLH. Sequencing revealed 18 different mutations, of which thirteen have not been reported previously. In addition to deletions, splice site mutations, and missense and nonsense mutations, a rare point mutation in the 3’-untranslated region (3’-UTR) was identified as a novel cause of XLH. In summary, we identified a wide spectrum of mutations in the PHEX gene. Our data, in accord with those of others, indicate that there is no single predominant PHEX mutation responsible for XLH. PMID:18625346

Hypophosphatemic rickets with hypocalciuria following long-term treatment with aluminum-containing antacid.

PubMed

Foldes, J; Balena, R; Ho, A; Parfitt, A M; Kleerekoper, M

1991-01-01

We present what we believe is the first case of rickets following prolonged treatment with aluminum containing antacids that bind phosphate, in an 18-year-old mentally retarded boy with cerebral palsy and spastic quadriplegia. As expected, serum calcitriol was increased and urinary phosphate excretion was very low. However, in contrast to all published cases of antacid induced hypophosphatemic osteomalacia in adults, despite a substantial increase in bone resorption reflected by urinary total hydroxyproline excretion, urinary calcium excretion was low rather than high, and significant hypocalcemia occurred after antacids were ceased and a phosphate salt administered. We suggest that the skeleton was so under-mineralized because of growth during prolonged phosphate deficiency, possibly augmented by anticonvulsant administration and immobilization, that increased bone resorption did not release enough calcium to cause hypercalciuria, or to prevent hypocalcemia during resumption of normal mineralization.

A case report of nephrogenic diabetes insipidus with idiopathic Fanconi syndrome in a child who presented with vitamin D resistant rickets.

PubMed

Patra, Soumya; Nadri, Gulnaz; Chowdhary, Harish; Pemde, Harish K; Singh, Varinder; Chandra, Jagdish

2014-05-01

Fanconi syndrome is a complex of multiple tubular dysfunctions of proximal tubular cells, occurring alone or in association with a variety of inherited (primary) or acquired (secondary) disorders. It is characterized by aminoaciduria, normoglycemic glycosuria, tubular proteinuria without hematuria, metabolic acidosis without anion gap and excessive urinary excretion of phosphorous, calcium, uric acid, bicarbonate, sodium, potassium and magnesium. Diabetes insipidus is a disease of collecting tubules and children mainly present with dehydration and hypernatremia. We are reporting the first case of idiopathic Fanconi's syndrome along with nephrogenic diabetes insipidus in a child who presented to us with vitamin D resistant rickets. Medline search did not reveal any case of nephrogenic diabetes insipidus (NDI) associated with idiopathic Fanconi syndrome. We hypothesized that the NDI may be due to to severe hypokalemia induced tubular dysfunction.

Nephrogenic diabetes insipidus with idiopathic Fanconi's syndrome in a child who presented as vitamin D resistant rickets.

PubMed

Patra, Soumya; Nadri, Gulnaz; Chowdhary, Harish; Pemde, Harish K; Singh, Varinder; Chandra, Jagdish

2011-10-01

Fanconi's syndrome is a complex of multiple tubular dysfunctions of proximal tubular cells occurring alone or in association with a variety of inherited (primary) or acquired (secondary) disorders. It is characterized by aminoaciduria, normoglycaemic glycosuria, tubular proteinuria without hematuria, metabolic acidosis without anion gap and excessive urinary excretion of phosphorous, calcium, uric acid, bicarbonate, sodium, potassium, and magnesium. Whereas diabetes insipidus is a disease of collecting tubules and child mainly presents with dehydration and hypernatremia. Though all the cases published till date were secondary to drugs, myeloma, hematological disorders, etc., we are reporting the first case of idiopathic Fanconi's syndrome along with nephrogenic diabetes insipidus in a child who presented to us as resistant rickets. Medline search did not reveal any case of nephrogenic diabetes insipidus associated with idiopathic Fanconi syndrome. We hypothesized that the NDI may be due to of severe hypokalemia induced tubular dysfunction.

Therapeutics Targeting FGF Signaling Network in Human Diseases.

PubMed

Katoh, Masaru

2016-12-01

Fibroblast growth factor (FGF) signaling through its receptors, FGFR1, FGFR2, FGFR3, or FGFR4, regulates cell fate, angiogenesis, immunity, and metabolism. Dysregulated FGF signaling causes human diseases, such as breast cancer, chondrodysplasia, gastric cancer, lung cancer, and X-linked hypophosphatemic rickets. Recombinant FGFs are pro-FGF signaling therapeutics for tissue and/or wound repair, whereas FGF analogs and gene therapy are under development for the treatment of cardiovascular disease, diabetes, and osteoarthritis. FGF traps, anti-FGF/FGFR monoclonal antibodies (mAbs), and small-molecule FGFR inhibitors are anti-FGF signaling therapeutics under development for the treatment of cancer, chondrodysplasia, and rickets. Here, I discuss the benefit-risk and cost-effectiveness issues of precision medicine targeting FGFRs, ALK, EGFR, and FLT3. FGFR-targeted therapy should be optimized for cancer treatment, focusing on genomic tests and recurrence. Copyright © 2016 Elsevier Ltd. All rights reserved.

Coupling fibroblast growth factor 23 production and cleavage: iron deficiency, rickets, and kidney disease.

PubMed

Wolf, Myles; White, Kenneth E

2014-07-01

High levels of fibroblast growth factor 23 (FGF23) cause the rare disorders of hypophosphatemic rickets and are a risk factor for cardiovascular disease and death in patients with chronic kidney disease (CKD). Despite major advances in understanding FGF23 biology, fundamental aspects of FGF23 regulation in health and in CKD remain mostly unknown. Autosomal dominant hypophosphatemic rickets (ADHR) is caused by gain-of-function mutations in FGF23 that prevent its proteolytic cleavage, but affected individuals experience a waxing and waning course of phosphate wasting. This led to the discovery that iron deficiency is an environmental trigger that stimulates FGF23 expression and hypophosphatemia in ADHR. Unlike osteocytes in ADHR, normal osteocytes couple increased FGF23 production with commensurately increased FGF23 cleavage to ensure that normal phosphate homeostasis is maintained in the event of iron deficiency. Simultaneous measurement of FGF23 by intact and C-terminal assays supported these breakthroughs by providing minimally invasive insight into FGF23 production and cleavage in bone. These findings also suggest a novel mechanism of FGF23 elevation in patients with CKD, who are often iron deficient and demonstrate increased FGF23 production and decreased FGF23 cleavage, consistent with an acquired state that mimics the molecular pathophysiology of ADHR. Iron deficiency stimulates FGF23 production, but normal osteocytes couple increased FGF23 production with increased cleavage to maintain normal circulating levels of biologically active hormone. These findings uncover a second level of FGF23 regulation within osteocytes, failure of which culminates in elevated levels of biologically active FGF23 in ADHR and perhaps CKD.

Intronic deletions in the SLC34A3 gene: A cautionary tale for mutation analysis of hereditary hypophosphatemic rickets with hypercalciuria

PubMed Central

Ichikawa, Shoji; Tuchman, Shamir; Padgett, Leah R.; Gray, Amie K.; Baluarte, H. Jorge; Econs, Michael J.

2013-01-01

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare metabolic disorder, characterized by hypophosphatemia, variable degrees of rickets/osteomalacia, and hypercalciuria secondary to increased serum 1,25-dihydroxyvitamin D [1,25(OH)2D] levels. HHRH is caused by mutations in the SLC34A3 gene, which encodes sodium-phosphate co-transporter type IIc. A 6 ½-year-old female presented with a history of nephrolithiasis. Her metabolic evaluation revealed increased 24- hour urine calcium excretion with high serum calcium, low intact parathyroid hormone (PTH) levels, and elevated 1,25(OH)2D level. In addition, the patient had low to low-normal serum phosphorus with high urine phosphorus. The patient had normal stature; without rachitic or boney deformities or a history of fractures. Genetic analysis of SLC34A3 revealed the patient to be a compound heterozygote for a novel single base pair deletion in exon 12 (c.1304delG) and 30-base pair deletion in intron 6 (g.1440–1469del). The single-base pair mutation causes a frameshift, which results in premature stop codon. The intronic deletion is likely caused by misalignment of the 4-basepair homologous repeats and results in the truncation of an already small intron to 63 bp, which would impair proper RNA splicing of the intron. This is the fourth unique intronic deletion identified in patients with HHRH, suggesting the frequent occurrence of sequence misalignments in SLC34A3 and the importance of screening introns in patients with HHRH. PMID:24176905

Intronic deletions in the SLC34A3 gene: a cautionary tale for mutation analysis of hereditary hypophosphatemic rickets with hypercalciuria.

PubMed

Ichikawa, Shoji; Tuchman, Shamir; Padgett, Leah R; Gray, Amie K; Baluarte, H Jorge; Econs, Michael J

2014-02-01

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare metabolic disorder, characterized by hypophosphatemia, variable degrees of rickets/osteomalacia, and hypercalciuria secondary to increased serum 1,25-dihydroxyvitamin D [1,25(OH)2D] levels. HHRH is caused by mutations in the SLC34A3 gene, which encodes sodium-phosphate co-transporter type IIc. A 6-1/2-year-old female presented with a history of nephrolithiasis. Her metabolic evaluation revealed increased 24-hour urine calcium excretion with high serum calcium, low intact parathyroid hormone (PTH), and elevated 1,25(OH)2D. In addition, the patient had low to low-normal serum phosphorus with high urine phosphorus. The patient had normal stature; without rachitic or boney deformities or a history of fractures. Genetic analysis of SLC34A3 revealed the patient to be a compound heterozygote for a novel single base pair deletion in exon 12 (c.1304delG) and 30-base pair deletion in intron 6 (g.1440-1469del). The single-base pair mutation causes a frameshift, which results in premature stop codon. The intronic deletion is likely caused by misalignment of the 4-basepair homologous repeats and results in the truncation of an already small intron to 63bp, which would impair proper RNA splicing of the intron. This is the fourth unique intronic deletion identified in patients with HHRH, suggesting the frequent occurrence of sequence misalignments in SLC34A3 and the importance of screening introns in patients with HHRH. © 2013.

Prenatal diagnosis for a novel splice mutation of PHEX gene in a large Han Chinese family affected with X-linked hypophosphatemic rickets.

PubMed

Qiu, Guangrong; Liu, Caixia; Zhou, Jingyi; Liu, Peiyan; Wang, Jun; Jiang, Hongkun; Hou, Zhiyan; Zhao, Yanyan; Sun, Kailai; Li-Ling, Jesse

2010-06-01

X-linked hypophosphatemia (XLH) is the most common form of heritable rickets characterized by X-linked dominant inheritance, renal phosphate wasting, hypophosphatemia, and defective bone mineralization. Inactivating mutations of the PHEX gene located at Xp22.1 have been linked with this disease. Ethnic distribution of such mutations seems widespread but only a few mutations in the Chinese population have been reported to date. We report on a large Han Chinese family affected with XLH rickets, which included 13 patients from four generations. Polymerase chain reaction and direct sequencing were performed for all exons and intron-exon boundaries of the PHEX gene. The effect of nucleotide changes was analyzed using bioinformatic software. Prenatal diagnosis was performed on umbilical cord blood at the 20th gestational week. A novel G-->A splice mutation in intron 7 (c.849+1G>A) was identified in all patients from the family. As confirmed by reverse-transcription (RT)-polymerase chain reaction (PCR), the mutation has rendered loss of a normal splice donor site (c.849+1G) while activating a cryptic one at c.849+519G, which resulted in addition of 518 nucleotides to the mature RNA. Prenatal diagnosis had excluded the fetus for carrying the same mutation. A healthy boy was born later. A novel splice mutation c.849+1G>A in the PHEX gene is responsible for XLH in the studied family. Further studies may enhance our understanding of the role of this mutation in the pathogenesis of XLH.

Pharmacological inhibition of fibroblast growth factor (FGF) receptor signaling ameliorates FGF23-mediated hypophosphatemic rickets.

PubMed

Wöhrle, Simon; Henninger, Christine; Bonny, Olivier; Thuery, Anne; Beluch, Noemie; Hynes, Nancy E; Guagnano, Vito; Sellers, William R; Hofmann, Francesco; Kneissel, Michaela; Graus Porta, Diana

2013-04-01

Fibroblast growth factor 23 (FGF23) is a circulating factor secreted by osteocytes that is essential for phosphate homeostasis. In kidney proximal tubular cells FGF23 inhibits phosphate reabsorption and leads to decreased synthesis and enhanced catabolism of 1,25-dihydroxyvitamin D3 (1,25[OH]2 D3 ). Excess levels of FGF23 cause renal phosphate wasting and suppression of circulating 1,25(OH)2 D3 levels and are associated with several hereditary hypophosphatemic disorders with skeletal abnormalities, including X-linked hypophosphatemic rickets (XLH) and autosomal recessive hypophosphatemic rickets (ARHR). Currently, therapeutic approaches to these diseases are limited to treatment with activated vitamin D analogues and phosphate supplementation, often merely resulting in partial correction of the skeletal aberrations. In this study, we evaluate the use of FGFR inhibitors for the treatment of FGF23-mediated hypophosphatemic disorders using NVP-BGJ398, a novel selective, pan-specific FGFR inhibitor currently in Phase I clinical trials for cancer therapy. In two different hypophosphatemic mouse models, Hyp and Dmp1-null mice, resembling the human diseases XLH and ARHR, we find that pharmacological inhibition of FGFRs efficiently abrogates aberrant FGF23 signaling and normalizes the hypophosphatemic and hypocalcemic conditions of these mice. Correspondingly, long-term FGFR inhibition in Hyp mice leads to enhanced bone growth, increased mineralization, and reorganization of the disturbed growth plate structure. We therefore propose NVP-BGJ398 treatment as a novel approach for the therapy of FGF23-mediated hypophosphatemic diseases. Copyright © 2013 American Society for Bone and Mineral Research.

Case report of 5 siblings: malnutrition? Rickets? DiGeorge syndrome? Developmental delay?

PubMed Central

Cundiff, David K; Harris, William

2006-01-01

Background Parents of six children are facing a trial on charges of aggravated manslaughter in the care a 5 1/2 month old infant who died suddenly and neglect of their four older children for causing them to be malnourished by feeding them all an exclusively raw foods vegan diet. Both parents declined plea bargains and plan to defend themselves in court. Case presentation The fifth child born to a married couple was breast-fed until 2 1/2 months. Subsequently, the parents fed the baby an exclusively raw foods diet prepared in a blender at home. The four older children, ages 18 months – 6 1/2 years also ate an exclusively raw foods vegan diet. None of the four older children had significant previous injuries or serious illnesses. At autopsy, the infant weighed 3180 mg (6.99 pounds) and appeared emaciated. The thymus gland was absent and parathyroid glands were not located. The lungs were "congested." DiGeorge anomaly cannot be ruled out from these findings. Although, the coroner ruled that "malnutrition" was the sole cause of death, malnutrition, according to the World Health Organization definition, cannot be diagnosed in this infant. Compared with standard growth charts, the older children fell 2.1–4.1 standard deviations below the mean for North American children in height and weight. Labs were normal except for a low cholesterol level in all and a low prealbumin in one of three children tested. Therefore, malnutrition cannot be diagnosed in these children. The pediatrician diagnosed rickets in the four-year-old. However, chest x-rays were normal in all and long bone x-rays showed minimal changes in one child – no sign of rickets. The clinical diagnosis of rickets was not confirmed by the Center for Disease Control's criteria. A psychologist diagnosed the 18-month-old as developmentally delayed to the level of a 15-month-old, but this diagnosis is questionable. Conclusion The raw foods vegan diet and possibly inherited small stature from the father's side account for their relatively low heights and weights. Catch-up growth will probably occur on the standard American diet but would have also been expected if they had remained on a vegan diet. PMID:16412249

SPR4-peptide Alters Bone Metabolism of Normal and HYP Mice

PubMed Central

Zelenchuk, Lesya V; Hedge, Anne-Marie; Rowe, Peter S N

2015-01-01

Context ASARM-peptides are substrates and ligands for PHEX, the gene responsible for X-linked hypophosphatemic rickets (HYP). PHEX binds to the DMP1-ASARM-motif to form a trimeric-complex with α5β3-integrin on the osteocyte surface and this suppresses FGF23 expression. ASARM-peptide disruption of this complex increases FGF23 expression. We used a 4.2 kDa peptide (SPR4) that binds to ASARM-peptide and ASARM-motif to study DMP1-PHEX interactions and to assess SPR4 for treating inherited hypophosphatemic rickets. Design Subcutaneously transplanted osmotic pumps were used to infuse SPR4-peptide or vehicle into wild-type mice (WT) and HYP-mice for 4 weeks. Results Asymmetrically distributed mineralization defects occurred with WT-SPR4 femurs. Specifically, SPR4 induced negative effects on trabecular bone and increased bone volume and mineralization in cortical-bone. Markedly increased sclerostin and reduced active β-catenin occurred with HYP mice. SPR4-infusion suppressed sclerostin and increased active β-catenin in WT and HYP mice and improved HYP-mice trabecular mineralization defects but not cortical mineralization defects. Conclusions SPR4-peptide has bimodal activity and acts by: (1) preventing DMP1 binding to PHEX and (2) sequestering an inhibitor of DMP1-PHEX binding, ASARM-peptide. In PHEX defective HYP-mice the second pathway predominates. Although SPR4-peptide improved trabecular calcification defects, decreased sclerostin and increased active β-catenin it did not correct HYP-mice cortical mineralization defects on a normal phosphate diet. Thus, for inherited hypophosphatemic rickets patients on a normal phosphate diet, SPR4-peptide is not a useful therapeutic. PMID:25460577

Osteocyte regulation of phosphate homeostasis and bone mineralization underlies the pathophysiology of the heritable disorders of rickets and osteomalacia

PubMed Central

Feng, Jian Q.; Clinkenbeard, Erica L.; Yuan, Baozhi; White, Kenneth E.; Drezner, Marc K.

2013-01-01

Although recent studies have established that osteocytes function as secretory cells that regulate phosphate metabolism, the biomolecular mechanism(s) underlying these effects remain incompletely defined. However, investigations focusing on the pathogenesis of X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets (ADHR), and autosomal recessive hypophosphatemic rickets (ARHR), heritable disorders characterized by abnormal renal phosphate wasting and bone mineralization, have clearly implicated FGF23 as a central factor in osteocytes underlying renal phosphate wasting, documented new molecular pathways regulating FGF23 production, and revealed complementary abnormalities in osteocytes that regulate bone mineralization. The seminal observations leading to these discoveries were the following: 1) mutations in FGF23 cause ADHR by limiting cleavage of the bioactive intact molecule, at a subtilisin-like protein convertase (SPC) site, resulting in increased circulating FGF23 levels and hypophosphatemia; 2) mutations in DMP1 cause ARHR, not only by increasing serum FGF23, albeit by enhanced production and not limited cleavage, but also by limiting production of the active DMP1 component, the C-terminal fragment, resulting in dysregulated production of DKK1 and β-catenin, which contributes to impaired bone mineralization; and 3) mutations in PHEX cause XLH both by altering FGF23 proteolysis and production and causing dysregulated production of DKK1 and β-catenin, similar to abnormalities in ADHR and ARHR, but secondary to different central pathophysiological events. These discoveries indicate that ADHR, XLH, and ARHR represent three related heritable hypophosphatemic diseases that arise from mutations in, or dysregulation of, a single common gene product, FGF23 and, in ARHR and XLH, complimentary DMP1 and PHEX directed events that contribute to abnormal bone mineralization. PMID:23403405

Hypophosphatemic Rickets with Hypercalciuria due to Mutation in SLC34A3/NaPi-IIc can be Masked by Vitamin D Deficiency and can be Associated with Renal Calcifications

PubMed Central

Kremke, B.; Bergwitz, C.; Ahrens, W.; Schütt, S.; Schumacher, M.; Wagner, V.; Holterhus, P.-M.; Jüppner, H.; Hiort, O.

2015-01-01

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is caused by mutations in SLC34A3, the gene encoding the renal sodium-phosphate co-transporter NaPi-IIc. Despite increased urinary calcium excretion, HHRH is typically not associated with kidney stones prior to treatment. However, here we describe two sisters, who displayed nephrolithiasis or nephrocalcinosis upon presentation. The index patient, II-4, presented with short stature, bone pain, and knee X-rays suggestive of mild rickets at age 8.5 years. Laboratory evaluation showed hypophosphatemia, elevated 1,25(OH) 2 vitamin D levels, and hypercalciuria, later also developing vitamin D deficiency. Her sister, II-6, had a low normal serum phosphorous level, biochemically vitamin D deficiency and no evidence for osteomalacia, but had undergone left nephro-ureterectomy at age 17 because of ureteral stricture secondary to renal calculi. Nucleotide sequence analysis of DNA from II-4 and II-6 revealed a homozygous missense mutation c.586G>A (p.G196R) in SLC34A3/NaPi-IIc. Ultrasonographic examinations prior to treatment showed grade I nephrocalcinosis for II-4, while II-6 had grade I-II nephrocalcinosis in her remaining kidney. Four siblings and the mother were heterozygous carriers of the mutation, but showed no biochemical abnormalities. With oral phosphate supplements, hypophosphatemia and hypercalciuria improved in both homozygous individuals. Renal calcifications that are presumably due to increased urinary calcium excretion can be the presenting finding in homozygous carriers of G196R in SLC34A3/NaPi-IIc, and some or all laboratory features of HHRH may be masked by vitamin D deficiency. PMID:18523928

A novel Phex mutation in a new mouse model of hypophosphatemic rickets.

PubMed

Owen, Celeste; Chen, Frieda; Flenniken, Ann M; Osborne, Lucy R; Ichikawa, Shoji; Adamson, S Lee; Rossant, Janet; Aubin, Jane E

2012-07-01

X-linked hypophosphatemic rickets (XLH) is a dominantly inherited disease characterized by renal phosphate wasting, aberrant vitamin D metabolism, and defective bone mineralization. It is known that XLH in humans and in certain mouse models is caused by inactivating mutations in PHEX/Phex (phosphate-regulating gene with homologies to endopeptidases on the X chromosome). By a genome-wide N-ethyl-N-nitrosourea (ENU)-induced mutagenesis screen in mice, we identified a dominant mouse mutation that exhibits the classic clinical manifestations of XLH, including growth retardation, skeletal abnormalities (rickets/osteomalacia), hypophosphatemia, and increased serum alkaline phosphatase (ALP) levels. Mapping and sequencing revealed that these mice carry a point mutation in exon 14 of the Phex gene that introduces a stop codon at amino acid 496 of the coding sequence (Phex(Jrt) also published as Phex(K496X) [Ichikawa et al., 2012]). Fgf23 mRNA expression as well as that of osteocalcin, bone sialoprotein, and matrix extracellular phosphoglycoprotein was upregulated in male mutant long bone, but that of sclerostin was unaffected. Although Phex mRNA is expressed in bone from mutant hemizygous male mice (Phex(Jrt)/Y mice), no Phex protein was detected in immunoblots of femoral bone protein. Stromal cultures from mutant bone marrow were indistinguishable from those of wild-type mice with respect to differentiation and mineralization. The ability of Phex(Jrt)/Y osteoblasts to mineralize and the altered expression levels of matrix proteins compared with the well-studied Hyp mice makes it a unique model with which to further explore the clinical manifestations of XLH and its link to FGF23 as well as to evaluate potential new therapeutic strategies. Copyright © 2012 Wiley Periodicals, Inc.

Hypophosphatemic rickets with hypercalciuria due to mutation in SLC34A3/NaPi-IIc can be masked by vitamin D deficiency and can be associated with renal calcifications.

PubMed

Kremke, B; Bergwitz, C; Ahrens, W; Schütt, S; Schumacher, M; Wagner, V; Holterhus, P-M; Jüppner, H; Hiort, O

2009-02-01

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is caused by mutations in SLC34A3, the gene encoding the renal sodium-phosphate co-transporter NaPi-IIc. Despite increased urinary calcium excretion, HHRH is typically not associated with kidney stones prior to treatment. However, here we describe two sisters, who displayed nephrolithiasis or nephrocalcinosis upon presentation. The index patient, II-4, presented with short stature, bone pain, and knee X-rays suggestive of mild rickets at age 8.5 years. Laboratory evaluation showed hypophosphatemia, elevated 1,25(OH) (2) vitamin D levels, and hypercalciuria, later also developing vitamin D deficiency. Her sister, II-6, had a low normal serum phosphorous level, biochemically vitamin D deficiency and no evidence for osteomalacia, but had undergone left nephro-ureterectomy at age 17 because of ureteral stricture secondary to renal calculi. Nucleotide sequence analysis of DNA from II-4 and II-6 revealed a homozygous missense mutation c.586G>A (p.G196R) in SLC34A3/NaPi-IIc. Ultrasonographic examinations prior to treatment showed grade I nephrocalcinosis for II-4, while II-6 had grade I-II nephrocalcinosis in her remaining kidney. Four siblings and the mother were heterozygous carriers of the mutation, but showed no biochemical abnormalities. With oral phosphate supplements, hypophosphatemia and hypercalciuria improved in both homozygous individuals. Renal calcifications that are presumably due to increased urinary calcium excretion can be the presenting finding in homozygous carriers of G196R in SLC34A3/NaPi-IIc, and some or all laboratory features of HHRH may be masked by vitamin D deficiency.

Late-onset hereditary hypophosphatemic rickets with hypercalciuria (HHRH) due to mutation of SLC34A3/NPT2c.

PubMed

Dhir, Gauri; Li, Dong; Hakonarson, Hakon; Levine, Michael A

2017-04-01

To identify a genetic basis for markedly reduced bone density and multiple fractures in an adult patient with hypophosphatemia and hypercalciuria. A 54-year-old Vietnamese man, his unaffected two daughters and wife. We performed biochemical studies and sequenced the SLC34A3 gene using genomic DNA from peripheral blood mononuclear cells. Biochemical evaluation of the proband revealed hypophosphatemia with increased renal phosphate wasting, hypercalciuria, low serum parathyroid hormone (PTH) and an elevated serum 1,25(OH) 2 D level. Mutation analysis of SLC34A3 gene revealed that the patient was a compound heterozygote for two nonsynonymous nucleotide substitutions: a novel c.571G>A (p.G191S) damaging mutation and the previously reported c.200G>A (p.R67H) polymorphism, consistent with the clinical diagnosis of late-onset hereditary hypophosphatemic rickets with hypercalciuria (HHRH). His wife and older daughter both carried the p.R67H polymorphism, while his younger daughter was compound heterozygous for p.R67H and p.G191S. HHRH is an uncommon autosomal recessive disease that generally manifests in childhood as rickets or nephrolithiasis, but an adult onset phenotype may occur in heterozygous carriers of SLC34A3 mutations. The severe presentation of this proband in adulthood with marked nephrolithiasis, multiple fractures and low bone density emphasizes the importance of measuring the serum phosphorus level in patients with suspected but unexplained osteoporosis and/or recurrent renal stones. The recognition of late-onset HHRH facilitates timely institution of appropriate therapy. Copyright © 2016 Elsevier Inc. All rights reserved.

HYPOPHOSPHATEMIC RICKETS: CASE REPORT.

PubMed

Maia, Marta Liliane de Almeida; Abreu, Ana Lucia Santos; Nogueira, Paulo Cesar Koch; Val, Maria Luiza Dautro Moreira do; Carvalhaes, João Tomas de Abreu; Andrade, Maria Cristina de

2018-03-29

Early diagnosis and immediate treatment of hypophosphatemic rickets is of utmost importance as it may prevent subsequent sequelae. This report aims at warning pediatricians to consider the presence of the disease. Description of the metabolic profile, creatinine clearance, nutritional status, weight and body structure of a patient who presented the clinical-laboratorial characteristics of hypophosphatemic rickets and was followed in an outpatient clinic for tubulopathies over the period of 12 months. The patient had been bedridden for some time, was dependent on mechanical ventilation and presented an altered metabolic bone condition. Treatment was phosphate (initial: 65 mg/kg/day and final: 24,2 mg/kg/day), calcium (initial: 127 mg/kg/day, final: 48,4 mg/kg/day) and calcitriol (initial: 0.06 mcg/kg/day, final: 0.03 mcg/kg/day). The patient improved, evolving into spontaneous breathing and walking unaided. Laboratory results: calcium (mg/dL) initial 7.1, final 10.1; phosphate (mg/dL) initial 1.7 final 3.2; magnesium (mg/dL) initial 1.5 final 2.1, parathyroid hormone (pg/l) initial 85.8, final 52.7, alkaline phosphatase (UI/l) initial 12660, final 938; there was also improvement in weight/structural development (Z score: H/A initial: -6.05, final -3.64; W/A: initial -2.92, final -1.57) with presence of transitory gallstones. Creatinine clearance (mL/min/1.73m2bsa) was constant. The medication improved his laboratory results and nutritional status, but the patient did not return for two years for follow-up and, during this period, his condition has noticeably deteriorated. Early diagnosis and follow-up are essential in dealing with this pathology.

Hypovitaminosis D in the Middle East and North Africa

PubMed Central

Bassil, Darina; Rahme, Maya; Hoteit, Maha; Fuleihan, Ghada El-Hajj

2013-01-01

Background: The Middle East and North Africa (MENA) region registers some of the highest rates of hypovitaminosis D worldwide.   Aim: We systematically reviewed the prevalence of hypovitaminosis D, rickets and osteomalacia, their predictors and impact on major outcomes, in the region. Methods: Medline, Pubmed and Embase search engines, entering keywords and concepts, combined with individual countries of interest, were used. Search was limited years 2000–2012; and review articles were used for the period preceding year 2000. Results: Rickets and osteomalacia still occur in this sunny region. Hypovitaminosis D prevails, with rates varying 30–90%, considering a desirable serum 25 hydroxy-vitamin D [25(OH)D] of 20 ng/ml. Advancing age, female gender, multi-parity, clothing style, season, socio-economic status and urban living are recognized predictors of hypovitaminosis D in adults. Prolonged breastfeeding without vitamin D supplementation and low dietary calcium intake are the recognized risk factors for rickets and hypovitaminosis D in children.. Associations with pain score and disease activity in rheumatologic disorders, viral load and interleukins in hepatitis C, BMI, lipids and insulin sensitivity, blood pressure, heart failure and mortality are described. Sun exposure in adults decreased prevalence of metabolic syndrome in one study. Few randomized vitamin D trials revealed that the majority of mothers or children failed to achieve a desirable 25(OH)D level, even with doses by far exceeding current recommendations. A trial in adolescent girls reveals substantial bone and lean mass increments. Conclusion: Hypovitaminosis D is prevalent in MENA. The lack of populations based studies, gaps in studies in infants, pre-pubertal children and pregnant women, hinder the development of region specific guidelines and constitute a major obstacle to impact this chronic and most often subclinical disease. PMID:24194968

Neurofibromatosis, pathological fracture and hypervitaminosis-D.

PubMed

Mondal, Rakesh; Nandi, Madhumita; Chandra, P K

2010-10-01

Pathologic fractures in children may be due to various causes. Rarely, it may be the presenting symptom of neurofibromatosis. A misdiagnosis of Rickets and Vitamin D supplementation in such a case may wreak havoc in the form of iatrogenic hypervitaminosis D. We report one such case.

Localization of a renal sodium-phosphate cotransporter gene to human chromosome 5q35

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kos, C.H.; Tenenhouse, H.S.; Tihy, F.

1994-01-01

Several Mendelian disorders of renal phosphate reabsorption, associated with hypophosphatemia and bone disease, have been described. These include X-linked hypophosphatemia (XLH), hereditary hypophosphatemic rickets with hypercalciuria, hypophosphatemic bone disease, and autosomal dominant and autosomal recessive hypophosphatemic rickets. The underlying mechanisms for renal phosphate wasting in these disorders remain unknown. The proximal tubule is the major site of renal phosphate reabsorption. Thus, mutations in genes that participate in the transepithelial transport of phosphate in this segment of the nephron may be responsible for these disorders. Recently, a cDNA encoding a renal proximal tubular, brush-border membrane Na[sup +]-phosphate cotransporter (NaP[sub i]-3) wasmore » cloned from human kidney cortex. As a first step in establishing whether mutations in the NaP[sub i]-3 gene are the cause of inherited disorders in phosphate homeostasis, the authors sought to determine its chromosomal localization. 9 refs., 1 fig.« less

Mosaic NRAS Q61R mutation in a child with giant congenital melanocytic naevus, epidermal naevus syndrome and hypophosphataemic rickets.

PubMed

Ramesh, R; Shaw, N; Miles, E K; Richard, B; Colmenero, I; Moss, C

2017-01-01

The association of hypophosphataemic rickets with verrucous epidermal naevus (EN) and elevated fibroblast growth factor 23 levels is known as cutaneous-skeletal hypophosphataemia syndrome (CSHS), and can be caused by somatic activating mutations in RAS genes. We report a unique patient with CSHS associated with giant congenital melanocytic naevus (CMN), neurocutaneous melanosis and EN syndrome, manifesting as facial linear sebaceous naevus, developmental delay and ocular dermoids. An activating mutation Q61R in the NRAS gene was found in affected skin and ocular tissue but not blood, implying that the disparate manifestations are due to a multilineage activating mutation (mosaic RASopathy). We speculate on the apparently rare association of CSHS with CMN compared with EN. We also report the favourable outcome of this patient at the age of 8 years after extensive neonatal curettage of the giant CMN and use of vitamin D and phosphate supplementation. © 2016 British Association of Dermatologists.

Primary hyperparathyroidism may masquerade as rickets-osteomalacia in vitamin D replete children.

PubMed

Ganie, Mohd Ashraf; Raizada, Nishant; Chawla, Himika; Singh, Arun Kumar; Aggarwala, Sandeep; Bal, Chandra Sekhar

2016-10-01

Primary hyperparathyroidism, typically a disease of the middle aged and the old, is less commonly seen in children. In children the disease has a bimodal age distribution with calcium sensing receptor mutation presenting in infancy as hypercalcemic crises and parathyroid adenoma or hyperplasia presenting later in childhood with bone disease. The childhood parathyroid adenomas are often familial with multiglandular disease and manifest with severe bone disease unlike adults. We report a series of four male patients with juvenile primary hyperparathyroidism, three of whom presented with bone disease masquerading as rickets-osteomalacia. One patient had asymptomatic hypercalcemia with short stature. Parathyroid adenoma was detected in all the four cases and all of them underwent resection of parathyroid adenomas confirmed on histopathology. Post-surgery all the cases had initial hypocalcaemia followed by normocalcemia. One case developed pancreatitis after surgery even after achieving normocalcemia. We conclude that parathyroid adenomas, although uncommon in children, are an important cause of skeletal disease that may initially be confused with hypovitaminosis D.

Sir Edward Mellanby (1884-1955) GBE KCB FRCP FRS: nutrition scientist and medical research mandarin.

PubMed

Hawgood, Barbara J

2010-08-01

Edward Mellanby used the experimental method to investigate medical problems. In 1918, working at King's College for Women, London, he provided conclusive evidence that rickets is a dietary deficiency disease due to lack of a fat-soluble vitamin [D]. In Sheffield he demonstrated that cereals, in an unbalanced diet, produced rickets due to the phytic acid content reducing the availability of calcium. Mellanby became Secretary of the Medical Research Council (1933-49) but continued his research by working at weekends. In the 1930s he campaigned for the results of nutritional research to be used for the benefit of public health. During World War II he acted as a scientific adviser to the War Cabinet and had a strong influence on the food policy which maintained successfully the nutrition of the population during the shipping blockade. Mellanby was a formidable person but with sagacity he promoted new research and guided the expansion of the organization.

Multiple fractures in infants who have Ehlers-Danlos/hypermobility syndrome and or vitamin D deficiency: A case series of 72 infants whose parents were accused of child abuse and neglect

PubMed Central

Hossein-Nezhad, A.; Tabatabaei, F.

2017-01-01

ABSTRACT Objective: To increase the level of awareness that Ehlers-Danlos/hypermobility syndrome (EDS) and vitamin D deficiency are associated with infantile fragility fractures and radiologic features that may be mistakenly reported to be caused by non-accidental trauma due to Child Abuse and Neglect (CAN). Patients and Methods: We constructed a case series, the largest to date, of infants with EDS who were vitamin D sufficient, insufficient and deficient and infants without EDS but with documented vitamin D deficiency and radiologic evidence of rickets who presented with multiple fractures originally diagnosed as being non-accidental and caused by child abuse. These infants were referred to the outpatient Bone Health Care Clinic at Boston University Medical Campus over a 6-year (2010–2015) period. We also present 6 index cases in which the court concluded that there was no convincing evidence of child abuse and the infants were returned to their parents. Institutional Review Board (IRB) approval was obtained. Results: We present 72 cases of infants with multiple fractures diagnosed to be caused by non-accidental trauma. All infants were younger than one year of age. Among them, 93%(67) had clinical evidence of EDS and/or a family history with a confirmed clinical diagnosis of at least one parent having EDS and the other 7%(5) without evidence of EDS had vitamin D deficiency/infantile rickets. Three of the EDS infants were diagnosed as osteogenesis imperfecta (OI)/EDS overlap syndrome. The most common fractures noted at diagnosis were ribs and extremity fractures (including classic metaphyseal lesions). Serum levels of 25-hydroxyvitamin D [25(OH)D] were reported in 48 infants (18.0 ± 8.5 ng/ml) and in 30 mothers (21.3 ± 11.7 ng/ml). Sixty-three percent (27) of the EDS infants who had their serum 25(OH)D measured were vitamin D deficient 25(OH)D<20 ng/ml and 5 were vitamin D sufficient 25(OH)D>30 ng/ml. The mean serum level for infants with vitamin D deficiency/rickets was (10.2 ± 3.0 ng/ml) Conclusion: EDS, OI/EDS and vitamin D deficiency/infantile rickets are associated with fragility fractures in infants that can be misinterpreted as caused by non-accidental trauma due to child abuse. PMID:29511428

The Determination of Vitamin D-Dependent Calcium Binding Protein in Chick Intesting: An Undergraduate Biochemistry Laboratory Experiment.

ERIC Educational Resources Information Center

Lessard, George M.

1980-01-01

Described is an experiment used in an undergraduate biochemistry laboratory involving inducing rickets in chicks and correlating the disease to a reduction in vitamin D-dependent calcium binding protein. Techniques involved are hormone induction, protein isolation, and radioisotope methodology. (Author/DS)

Lights, Windows, Color: Elements of the School Environment.

ERIC Educational Resources Information Center

Hathaway, Warren E.

Recent research indicates there are a great many nonvisual effects of light on people. The control of rickets and the suntan effect are well understood. Less well known effects include synchronization of a number of physiological rhythms and prevention and control of infantile jaundice. Physiological and psychological effects also vary with the…

What Ails Public Health?

ERIC Educational Resources Information Center

Alcabes, Philip

2007-01-01

Public health, once the gem of American social programs, has turned to dross. During the 20th century, the public-health sector wiped smallpox and polio off the U.S. map; virtually eliminated rickets, rubella, and goiter; stopped epidemic typhoid and yellow fever; and brought tuberculosis--once the leading cause of death in U.S. cities--under…

CRISPR/Cas9-mediated mutation of PHEX in rabbit recapitulates human X-linked hypophosphatemia (XLH).

PubMed

Sui, Tingting; Yuan, Lin; Liu, Huan; Chen, Mao; Deng, Jichao; Wang, Yong; Li, Zhanjun; Lai, Liangxue

2016-07-01

X-linked hypophosphatemia (XLH) is the most common cause of inheritable rickets, with an incidence of 1/20 000 in humans. Inactivation or mutation of the gene PHEX, a phosphate-regulating endopeptidase, leads to hypophosphatemia and defective bone mineralization in XLH patients. Presently, there is no adequate animal model for safety assessments of physiotherapies and drug screening for XLH rickets. In this study, an XLH model was generated via PHEX gene knockout (KO) through coinjection of clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9)/sgRNA mRNA into rabbit zygotes. The typical phenotypes of growth retardation, hypophosphatemia, elevated serum FGF23 and bone mineralization were observed in the PHEX KO rabbits but not in normal controls. In summary, for the first time, we have successfully obtained PHEX KO rabbits and recapitulated human XLH using the CRISPR/Cas9 system. This novel XLH rabbit model could be utilized as a drug screening model for XLH prevention and preclinical therapy. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Kbus/Idr, a mutant mouse strain with skeletal abnormalities and hypophosphatemia: identification as an allele of 'Hyp'.

PubMed

Moriyama, Kenji; Hanai, Atsuko; Mekada, Kazuyuki; Yoshiki, Atsushi; Ogiwara, Katsueki; Kimura, Atsushi; Takahashi, Takayuki

2011-08-20

The endopeptidase encoded by Phex (phosphate-regulating gene with homologies to endopeptidases linked to the X chromosome) is critical for regulation of bone matrix mineralization and phosphate homeostasis. PHEX has been identified from analyses of human X-linked hypophosphatemic rickets and Hyp mutant mouse models. We here demonstrated a newly established dwarfism-like Kbus/Idr mouse line to be a novel Hyp model. Histopathological and X-ray examination with cross experiments were performed to characterize Kbus/Idr. RT-PCR-based and exon-directed PCR screening performed to identify the presence of genetic alteration. Biochemical assays were also performed to evaluate activity of alkaline phosphatase. Kbus/Idr, characterized by bone mineralization defects, was found to be inherited in an X chromosome-linked dominant manner. RT-PCR experiments showed that a novel mutation spanning exon 16 and 18 causing hypophosphatemic rickets. Alkaline phosphatase activity, as an osteoblast marker, demonstrated raised levels in the bone marrow of Kbus/Idr independent of the age. Kbus mice should serve as a useful research tool exploring molecular mechanisms underlying aberrant Phex-associated pathophysiological phenomena.

Vitamin D-Dependent Rickets Type II with Alopecia: A Rare Case Report.

PubMed

Vupperla, Divya; Lunge, Snehal Balvant; Elaprolu, Praveen

2018-01-01

Vitamin D-dependent rickets type II is a rare hereditary disorder. It occurs due to mutations in the gene chr. 12q12-q14, which codes for vitamin D receptor. End-organ resistance to 1,25-(OH) 2 vitamin D3 and alopecia in severe cases are the characteristic features. We report a case of a 4-year-old boy with loss of hair over the scalp and body - first observed after 1 month of birth. The boy also developed difficulty in walking at the age of 2 year. On analysis, reduced serum calcium level (7.5 mg/dL) and elevated alkaline phosphatase level (625 IU/L) were reported. Initially, the treatment included intramuscularly administered single dose of 600,000 IU vitamin D, followed by 400 IU of vitamin D along with 1 g of supplemental calcium every day. Periodic follow-up was conducted for 2 months. Improvement was observed in the biochemical parameters and X-rays of the distal radial and ulnar metaphyses, although no improvement was observed in alopecia.

Regulation of gene expression by dietary Ca2+ in kidneys of 25-hydroxyvitamin D3-1 alpha-hydroxylase knockout mice.

PubMed

Hoenderop, Joost G J; Chon, Helena; Gkika, Dimitra; Bluyssen, Hans A R; Holstege, Frank C P; St-Arnaud, Rene; Braam, Branko; Bindels, Rene J M

2004-02-01

Pseudovitamin D deficiency rickets (PDDR) is an autosomal disease, characterized by undetectable levels of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), rickets and secondary hyperparathyroidism. Mice in which the 25-hydroxyvitamin D3-1 alpha-hydroxylase (1 alpha-OHase) gene was inactivated, presented the same clinical phenotype as patients with PDDR. cDNA Microarray technology was used on kidneys of 1 alpha-OHase knockout mice to study the expression profile of renal genes in this Ca2+-related disorder. Genome wide molecular events that occur during the rescue of these mice by high dietary Ca2+ intake were studied by the use of 15K cDNA microarray chips. 1 alpha-OHase knockout mice fed a normal Ca2+ diet developed severe hypocalcemia, rickets and died with an average life span of 12 +/- 2 weeks. Intriguingly, 1 alpha-OHase-/- mice supplemented with an enriched Ca2+ diet were normocalcemic and not significantly different from wild-type mice. Inactivation of the 1 alpha-OHase gene resulted in a significant regulation of +/- 1000 genes, whereas dietary Ca2+ supplementation of the 1 alpha-OHase-/- mice revealed +/- 2000 controlled genes. Interestingly, 557 transcripts were regulated in both situations implicating the involvement in the dietary Ca2+-mediated rescue mechanism of the 1 alpha-OHase-/- mice. Conspicuous regulated genes encoded for signaling molecules like the PDZ-domain containing protein channel interacting protein, FK binding protein type 4, kinases, and importantly Ca2+ transporting proteins including the Na+-Ca2+ exchanger, calbindin-D28K and the Ca2+ sensor calmodulin. Dietary Ca2+ intake normalized disturbances in the Ca2+ homeostasis due to vitamin D deficiency that were accompanied by the regulation of a subset of renal genes, including well-known renal Ca2+ transport protein genes, but also genes not previously identified as playing a role in renal Ca2+ handling.

Prevention and Treatment of Vitamin D and Calcium Deficiency in Children and Adolescents: Indian Academy of Pediatrics (IAP) Guidelines.

PubMed

Khadilkar, Anuradha; Khadilkar, Vaman; Chinnappa, Jagdish; Rathi, Narendra; Khadgawat, Rajesh; Balasubramanian, S; Parekh, Bakul; Jog, Pramod

2017-07-15

Vitamin D deficiency (VDD) is being increasingly reported from India from all age-groups. Reports suggest that VDD affects all age groups, from neonates to adolescents. Further, habitually low calcium intakes are also reported in Indian children. Given the multiple guidelines, peculiarities of Indian circumstances, changing lifestyles, and lack of fortification, the Indian Academy of Pediatrics (IAP) felt the need for a Practice Guideline for Pediatricians for the prevention and treatment of vitamin D and calcium deficiency in children and adolescents. The 'Guideline for Vitamin D and Calcium in Children' committee was formed by the IAP in September 2016. A consultative committee meeting was held in November 2016 in Mumbai. Evidence from Indian and international studies and other previous published recommendations, which were pertinent to the Indian circumstances, were collated for the preparation of these guidelines. To present a practice guideline for pediatricians for the prevention and treatment of deficiency of vitamin D and calcium in the Indian context. For the prevention of rickets in premature infants, 400 IU of vitamin D and 150-220 mg/kg of calcium, and in neonates, 400 IU of vitamin D and 200 mg of calcium are recommended daily. For prevention of rickets and hypocalcemia in infants (after neonatal period) upto 1 year of age, and from 1-18 years, 400 IU and 600 IU vitamin D/day and 250-500 mg/day and 600-800 mg/day of calcium, respectively, are recommended. For treatment of rickets in premature neonates, infants upto 1 year and from 1-18 years, 1000 IU, 2000 IU and 3000-6000 IU of vitamin D daily, respectively, and elemental calcium of 70-80 mg/kg/day in premature neonates and 500-800 mg daily for all children over that age are recommended. Larger doses of vitamin D may be given from 3 months to 18 years of age as 60,000 IU/week for 6 weeks.

A Case of Vitamin D-Dependent Rickets Type 1A with a Novel Mutation in the Uzbek Population.

PubMed

Özcabı, Bahar; Tahmiscioğlu Bucak, Feride; Jaferova, Sevinç; Oruç, Çiğdem; Adrovic, Amra; Ceylaner, Serdar; Ercan, Oya; Evliyaoğlu, Olcay

2016-12-01

Vitamin D-dependent rickets type 1A (VDDR-1A) (Online Mendelian Inheritance in Man #264700) is a rare, autosomal recessively inherited disorder due to inactivating mutations in CYP27B1. It is characterized by early onset of rickets with hypocalcemia. We aimed to describe the clinical and laboratory findings in a VDDR-1A case and to report a novel homozygote truncating mutation NM_000785.3 c.403C>T (p.Q135*) in CYP27B1 which to our knowledge is the first described mutation in the Uzbek population. The patient was admitted with tetany at the age of 12 months. He was a healthy Uzbek boy until 9 months of age when he had a seizure due to hypocalcemia. Vitamin D treatment was given orally in Turkmenistan (no data available for dose and duration). The patient was the product of a consanguineous marriage. His brother had died with hypocalcemia and pneumonia. At physical examination, anthropometric measurements were within normal limits; he had caput quadratum, enlarged wrists, and carpopedal spasm. Blood calcium, phosphorus, alkaline phosphatase, and parathormone (PTH) levels were 5.9 mg/dL, 3.5 mg/dL, 987 IU/L, and 182.8 pg/mL (12-72), respectively. Radiological findings included cupping and fraying of the radial and ulnar metaphyses. Renal ultrasound revealed nephrocalcinosis (grade 1). Despite high serum PTH and 25-hydroxyvitamin D3 levels, 1,25-dihydroxyvitamin D3 level was low, suggesting a diagnosis of VDDR-1A. The patient was treated with calcium carbonate and calcitriol. DNA sequencing revealed a novel homozygous mutation of NM_000785.3 c.403C>T (p.Q135*) in CYP27B1. VDDR-1A is a rare disorder which needs to be considered even in countries where nutritional vitamin D deficiency is still common.

300,000 IU or 600,000 IU of oral vitamin D3 for treatment of nutritional rickets: a randomized controlled trial.

PubMed

Mittal, Hema; Rai, Sunita; Shah, Dheeraj; Madhu, S V; Mehrotra, Gopesh; Malhotra, Rajeev Kumar; Gupta, Piyush

2014-04-01

To evaluate the non-inferiority of a lower therapeutic dose (300,000 IU) in comparison to standard dose (600,000) IU of Vitamin D for increasing serum 25(OH) D levels and achieving radiological recovery in nutritional rickets. Randomized, open-labeled, controlled trial. Tertiary care hospital. 76 children (median age 12 mo) with clinical and radiologically confirmed rickets. Oral vitamin D3 as 300,000 IU (Group 1; n=38) or 600,000 IU (Group 2; n=38) in a single day. Primary: Serum 25(OH)D, 12 weeks after administration of vitamin D3; Secondary: Radiological healing and serum parathormone at 12 weeks; and clinical and biochemical adverse effects. Serum 25(OH)D levels [geometric mean (95% CI)] increased significantly from baseline to 12 weeks after therapy in both the groups [Group 1: 7.58 (5.50–10.44) to 16.06 (12.71– 20.29) ng/mL, P<0.001]; Group 2: 6.57 (4.66–9.25) to 17.60 (13.71–22.60, P<0.001]. The adjusted ratio of geometric mean serum 25(OH)D levels at 12 weeks between the groups (taking baseline value as co-variate) was 0.91 (95% CI: 0.65–1.29). Radiological healing occurred in all children by 12 weeks. Both groups demonstrated significant (P<0.05) and comparable fall in the serum parathormone and alkaline phosphatase levels at 12 weeks. Relative change [ratio of geometric mean (95% CI)] in serum PTH and alkaline phosphatase, 12 weeks after therapy, were 0.98 (0.7–1.47) and 0.92 (0.72–1.19), respectively. The serum 25(OH)D levels were deficient (<20 ng/mL) in 63% (38/60) children after 12 weeks of intervention [Group 1: 20/32 (62.5%); Group 2: 18/28 (64.3%)]. No major clinical adverse effects were noticed in any of the children. Hypercalcemia was documented in 2 children at 4 weeks (1 in each Group) and 3 children at 12 weeks (1 in Group 1 and 2 in Group 2). None of the participants had hypercalciuria or hypervitaminosis D. A dose of 300,000 IU of vitamin D3 is comparable to 600,000 IU, administered orally, over a single day, for treating rickets in under-five children although there is an unacceptably high risk of hypercalcemia in both groups. None of the regime is effective in normalization of vitamin D status in majority of patients, 3 months after administering the therapeutic dose.

The Role of VDR in Phosphorylation in Vitamin D-Induced Apoptosis

DTIC Science & Technology

2001-07-01

nuclear pellet was resuspended in Buffer A, Cytometer (Coulter Corp., Miami, FL) equipped with an argon laser . sonicated 2 x 10 s, and stored at -80 ’C...rickets type II with alopecia . Proc Natl Acad Sci [45] Mezzetti G, Barbiroli B, Oka T. 1,25-Dihydroxycholecalciferol re- USA 1997;94:9831-5. ceptor

CALCIUM AND PHOSPHORUS METABOLISM IN OSTEOMALACIA

PubMed Central

Miles, Lee Monroe; Feng, Chih-Tung

1925-01-01

Osteomalacia is a diet deficiency disease of the same category as rickets. The deficiency is principally in the fat-soluble vitamine content of the diet, though there may be a calcium deficiency at the same time. The disease may be prevented by providing a diet rich in the fat-soluble vitamine content, and may be cured by adding the same to the diet. PMID:19868970

Does taurine deficiency cause metabolic bone disease and rickets in polar bear cubs raised in captivity?

PubMed

Chesney, Russell W; Hedberg, Gail E; Rogers, Quinton R; Dierenfeld, Ellen S; Hollis, Bruce E; Derocher, Andrew; Andersen, Magnus

2009-01-01

Rickets and fractures have been reported in captive polar bears. Taurine (TAU) is key for the conjugation of ursodeoxycholic acid (UDCA), a bile acid unique to bears. Since TAU-conjugated UDCA optimizes fat and fat-soluble vitamin absorption, we asked if TAU deficiency could cause vitamin D malabsorption and lead to metabolic bone disease in captive polar bears. We measured TAU levels in plasma (P) and whole blood (WB) from captive and free-ranging cubs and adults, and vitamin D3 and TAU concentrations in milk samples from lactating sows. Plasma and WB TAU levels were significantly higher in cubs vs captive and free-ranging adult bears. Vitamin D in polar bear milk was 649.2 +/- 569.2 IU/L, similar to that found in formula. The amount of TAU in polar bear milk is 3166.4 +/- 771 nmol/ml, 26-fold higher than in formula. Levels of vitamin D in bear milk and formula as well as in plasma do not indicate classical nutritional vitamin D deficiency. Higher dietary intake of TAU by free-ranging cubs may influence bile acid conjugation and improve vitamin D absorption.

[Gene mutation analysis of X-linked hypophosphatemic rickets].

PubMed

Song, Ying; Ma, Hong-Wei; Li, Fang; Hu, Man; Ren, Shuang; Yu, Ya-Fen; Zhao, Gui-Jie

2013-11-01

To investigate the frequency and type of PHEX gene mutations in children with X-linked hypophosphatemic rickets (XLH), the possible presence of mutational hot spots, and the relationship between genotype and clinical phenotype. Clinical data of 10 children with XLH was retrospectively reviewed. The relationship between gene mutation type and severity of XLH was evaluated. PHEX gene mutations were detected in all 10 children with XLH, including 6 cases of missense mutation, 2 cases of splice site mutation, 1 case of frameshift mutation, and 1 case of nonsense mutation. Two new mutations, c.2048T>C and IVS14+1delAG, were found. The type of PHEX gene mutation was not associated with the degree of short stature and leg deformity (P=0.571 and 0.467), and the mutation site was also not associated with the degree of short stature and leg deformity (P=0.400 and 1.000). Missense mutation is the most common type of PHEX gene mutation in children with XLH, and c.2048T>C and IVS14+1delAG are two new PHEX gene mutations. The type and site of PHEX gene mutation are not associated with the severity of XLH.

[Anemia and limping in a vegetarian adolescent].

PubMed

Chiron, R; Dabadie, A; Gandemer-Delignieres, V; Balençon, M; Legall, E; Roussey, M

2001-01-01

A vegan diet in the child and adolescent can induce severe bone sequelae by rickets and osteomalacia and megaloblastic anemia by cobalamin deficiency. A 15-year-old adolescent was hospitalized because of lameness and pallor. The lameness was explained by femoral epiphysiolysis caused by rickets with severe hypocalcemia. The pallor, jaundice and splenomegalia were due to cobalamin-deficiency megaloblastic anemia. A prolonged supplemental diet with calcium, vitamins D and B12 as well as orthopedic treatment stabilized the bone lesions. The megaloblastic anemia was cured by parenteral cobalamin. The adolescent and his brother were victims of a diet imposed by a cult and a lack of care due to their parents refusing that a vegan diet was the cause of the deficient pathology. Penal proceedings led to the incarceration of the parents and to the placement of the children. Deficiencies in calcium and vitamins D and B12 may be severe in a child's development with a vegan diet. This case report reveals the social and legal problems of an inappropriate diet in infancy imposed by parents who are followers of a fundamentalist church. Beyond the management of children in cults, health professionals have to prevent, screen and supplement the deficient diet.

Burosumab Therapy in Children with X-Linked Hypophosphatemia.

PubMed

Carpenter, Thomas O; Whyte, Michael P; Imel, Erik A; Boot, Annemieke M; Högler, Wolfgang; Linglart, Agnès; Padidela, Raja; Van't Hoff, William; Mao, Meng; Chen, Chao-Yin; Skrinar, Alison; Kakkis, Emil; San Martin, Javier; Portale, Anthony A

2018-05-24

X-linked hypophosphatemia is characterized by increased secretion of fibroblast growth factor 23 (FGF-23), which leads to hypophosphatemia and consequently rickets, osteomalacia, and skeletal deformities. We investigated burosumab, a monoclonal antibody that targets FGF-23, in patients with X-linked hypophosphatemia. In an open-label, phase 2 trial, we randomly assigned 52 children with X-linked hypophosphatemia, in a 1:1 ratio, to receive subcutaneous burosumab either every 2 weeks or every 4 weeks; the dose was adjusted to achieve a serum phosphorus level at the low end of the normal range. The primary end point was the change from baseline to weeks 40 and 64 in the Thacher rickets severity total score (ranging from 0 to 10, with higher scores indicating greater disease severity). In addition, the Radiographic Global Impression of Change was used to evaluate rachitic changes from baseline to week 40 and to week 64. Additional end points were changes in pharmacodynamic markers, linear growth, physical ability, and patient-reported outcomes and the incidence of adverse events. The mean Thacher rickets severity total score decreased from 1.9 at baseline to 0.8 at week 40 with every-2-week dosing and from 1.7 at baseline to 1.1 at week 40 with every-4-week dosing (P<0.001 for both comparisons); these improvements persisted at week 64. The mean serum phosphorus level increased after the first dose in both groups, and more than half the patients in both groups had levels within the normal range (3.2 to 6.1 mg per deciliter [1.0 to 2.0 mmol per liter]) by week 6. Stable serum phosphorus levels were maintained through week 64 with every-2-week dosing. Renal tubular phosphate reabsorption increased from baseline in both groups, with an overall mean increase of 0.98 mg per deciliter (0.32 mmol per liter). The mean dose of burosumab at week 40 was 0.98 mg per kilogram of body weight with every-2-week dosing and 1.50 mg per kilogram with every-4-week dosing. Across both groups, the mean serum alkaline phosphatase level decreased from 459 U per liter at baseline to 369 U per liter at week 64. The mean standing-height z score increased in both groups, with greater improvement seen at all time points with every-2-week dosing (an increase from baseline of 0.19 at week 64) than with every-4-week dosing (an increase from baseline of 0.12 at week 64). Physical ability improved and pain decreased. Nearly all the adverse events were mild or moderate in severity. In children with X-linked hypophosphatemia, treatment with burosumab improved renal tubular phosphate reabsorption, serum phosphorus levels, linear growth, and physical function and reduced pain and the severity of rickets. (Funded by Ultragenyx Pharmaceutical and Kyowa Hakko Kirin; ClinicalTrials.gov number, NCT02163577 ; EudraCT number, 2014-000406-35 ).

[Genetic basis for skeletal disease. Dental management of patients with bone diseases].

PubMed

Shintani, Seikou; Ooshima, Takashi

2010-08-01

Malformation of teeth can be found in patients with bone diseases, which was induced when the disease occurred during the tooth formation. The tooth malformation shows typical manifestations of the disease, which may demonstrate the occurrence of the bone disease. In this article, dental management of the patients with bone diseases such as X-linked hypophosphatemic rickets, osteogenesis imperfecta, and hypophosphatasia was presented.

Can Stoss Therapy Be Used in Children with Vitamin D Deficiency or Insufficiency without Rickets?

PubMed

Koçyiğit, Cemil; Çatlı, Gönül; İnce, Gülberat; Özkan, Elif Büşra; Dündar, Bumin Nuri

2017-06-01

Stoss vitamin D treatment has been recommended for its non-skeletal benefits in adults, but there is a lack of data on the optimal dose of vitamin D stoss therapy in children with vitamin D deficiency/insufficiency without rickets. This study aimed to compare efficiency/side effects of two different stoss therapy regimens (10 000 IU/kg and 300 000 IU vitamin D3) administered in children with vitamin D deficiency/insufficiency without rickets. Sixty-four children who had vitamin D deficiency/insufficiency were studied. A serum 25-hydroxyvitamin-D (25-OH-D) level of 15-20 ng/mL was considered as vitamin D insufficient and <15 ng/mL was considered as vitamin D deficient. The patients were divided into two groups according to the stoss therapy doses they received. Serum calcium, phosphate, alkaline phosphatase, 25-OH-D, parathyroid hormone levels, and spot urine calcium/creatinine ratios before/after treatment were recorded. Wrist radiography and renal ultrasonography were performed. The mean age of the subjects was 10.6±4.4 years. Thirty-two children were treated with a single vitamin D3 dose of 10 000 IU/kg and 32 patients received 300 000 IU. No difference was found in 25-OH-D levels between the two groups at presentation. The mean level of 25-OH-D was higher in the 10 000 IU/kg group at the second week of therapy. There was no difference between the groups at post-treatment weeks 4 and 12. The 25-OH-D was found to be below optimal levels (≥30 ng/mL) in 66.5% and <20 ng/mL in 21.8% of patients at the third month in both groups. None developed hypercalcemia and/or hypercalciuria. Nephrolithiasis was not detected in any patient. This study showed that both doses of stoss therapy used in the treatment of vitamin D insufficiency/deficiency are effective and safe. However, an optimal level of 25-OH-D cannot be maintained for more than three months.

The international biological program/human adaptability studies among the Skolt Sami in Finland (1966-1970).

PubMed

Forsius, Henrik; Eriksson, Aldur W; Fellman, Johan

2012-04-16

The population is increasingly lighter pigmented moving in a northward direction in Europe until reaching the Arctic Circle, where the Samis (Lapps) are clearly more pigmented. In 1966-1970, we investigated a total of 689 subjects in the villages of Sevettijärvi and Nellim, including persons with mixed Sami and Finnish heritage; of these, 487 (242 males, 245 females) had both parents classified as Skolt Sami. For estimation of the colour of the iris and hair, international scales were used. For translucency of the iris, pigmentation of the fundus was estimated in 3 different shades. The length and type of eyelashes were classified into 3 categories. To our knowledge, a simultaneous study of the pigmentation of eyebrows, eyelashes and eye fundus at different ages has not previously been published. The age differences of iris colour were highly significant. Iris colour in children varied markedly, and they generally had lighter colours than later in life. Age and sex effects on the translucency of irises were found. Male irises were more translucent. Fundus pigmentation was scanty in the youngest age groups, with full pigmentation being reached at 20 years. Among young individuals hair colour darkens with increasing age. Eyebrow colour was slightly lighter for both sexes in the youngest age groups that in older cohorts. Women had longer eyelashes than males. The main factor of the lighter skin is a higher ability to synthesize vitamin D, providing superior protection against rickets. The Skolt Samis are more pigmented than other Nordic people. In earlier times they had problems with rickets but our studies did not show any essential symptoms of rickets today. Visual acuity among Skolt Samis was good. They had lower prevalence of myopia compared to Finns. The stronger pigmentation of Skolt Samis is probably due to their origin from darker Eastern populations. Since our investigations were made, the Skolt Samis have been to a great part mixed with neighbouring populations and scattered throughout Finland. Even their old language is nowadays used mainly for traditional purposes. Therefore similar studies could not be performed anymore.

The international biological program/human adaptability studies among the Skolt Sami in Finland (1966-1970).

PubMed

Forsius, Henrik; Eriksson, AldurW; Fellman, Johan

2012-01-01

The population is increasingly lighter pigmented moving in a northward direction in Europe until reaching the Arctic Circle, where the Samis (Lapps) are clearly more pigmented. In 1966-1970, we investigated a total of 689 subjects in the villages of Sevettijärvi and Nellim, including persons with mixed Sami and Finnish heritage; of these, 487 (242 males, 245 females) had both parents classified as Skolt Sami. For estimation of the colour of the iris and hair, international scales were used. For translucency of the iris, pigmentation of the fundus was estimated in 3 different shades. The length and type of eyelashes were classified into 3 categories. To our knowledge, a simultaneous study of the pigmentation of eyebrows, eyelashes and eye fundus at different ages has not previously been published. The age differences of iris colour were highly significant. Iris colour in children varied markedly, and they generally had lighter colours than later in life. Age and sex effects on the translucency of irises were found. Male irises were more translucent. Fundus pigmentation was scanty in the youngest age groups, with full pigmentation being reached at 20 years. Among young individuals hair colour darkens with increasing age. Eyebrow colour was slightly lighter for both sexes in the youngest age groups that in older cohorts. Women had longer eyelashes than males. The main factor of the lighter skin is a higher ability to synthesize vitamin D, providing superior protection against rickets. The Skolt Samis are more pigmented than other Nordic people. In earlier times they had problems with rickets but our studies did not show any essential symptoms of rickets today. Visual acuity among Skolt Samis was good. They had lower prevalence of myopia compared to Finns. The stronger pigmentation of Skolt Samis is probably due to their origin from darker Eastern populations. Since our investigations were made, the Skolt Samis have been to a great part mixed with neighbouring populations and scattered throughout Finland. Even their old language is nowadays used mainly for traditional purposes. Therefore similar studies could not be performed anymore.

The Kinetics of Bainitic Transformation of Roll Steel 75Kh3MF

NASA Astrophysics Data System (ADS)

Kletsova, O. A.; Krylova, S. E.; Priymak, E. Yu.; Gryzunov, V. I.; Kamantsev, S. V.

2018-01-01

The critical points of steel 75Kh3MF and the temperature of the start of martensitic transformation are determined by a dilatometric method. The thermokinetic and isothermal diagrams of decomposition of supercooled austenite are plotted. The microstructure and microhardness of steel specimens cooled at different rates are studied. The kinetics of the occurrence of bainitic transformation in the steel is calculated using the Austin-Ricket equation.

The Geology of Yemen: An Annotated Bibliography of Yemen’s Geology, Geography and Earth Science

DTIC Science & Technology

2012-01-01

pneumonia by improving maternal nutrition , health education, promoting breastfeeding, and preventing rickets and nutritional anaemia among the...Monitoring, Modeling, and Management. Merida, Yucatan , Mexico. Bauman, Paul, Sallomy, Janan, Lyness, Lucien, et al. 1996. “The Exploration for a Deep...shopping must also be educated on health and nutrition matters. Due to the traditional segregation of the sexes, this training will have to be

Clinical Phenotype in a Toddler with a Novel Heterozygous Mutation of the Vitamin D Receptor.

PubMed

Brar, Preneet Cheema; Dingle, Elena; Pappas, John; Raisingani, Manish

2017-01-01

We present the clinical phenotype of a toddler who presented with vitamin D-resistant rickets, with one of the highest initial levels of alkaline phosphatase and parathyroid hormone (PTH) levels reported in the literature. The toddler had novel compound heterozygous mutations in the ligand-binding site of the vitamin D receptor and had an excellent response to calcitriol (1,25(OH)2D).

Breast-feeding and Vitamin D Supplementation Rates in the Ochsner Health System

PubMed Central

Ponnapakkam, Tulasi; Ravichandran, Anisha; Bradford, Elease; Tobin, Gregory; Gensure, Robert

2008-01-01

Breast-feeding imparts many benefits to both mothers and infants. Because of these numerous recognized benefits, there has been an effort to increase breast-feeding rates nationwide; increasing breast-feeding rates was one of the goals of the U.S. Department of Health and Human Services' Healthy People 2010 initiative. This study examined the breast-feeding rate at the Ochsner Clinic Foundation by conducting a retrospective chart review of patients aged 0–12 months who visited any branch of the Ochsner hospital system. Our results indicate that the rate of initiation of breast-feeding for children followed at the Ochsner Clinic Foundation is 66.3%. However, as breast-feeding rates rise, there is concern that there may be a resurgence of rickets, a disease caused by the deficiency of vitamin D. Currently the American Academy of Pediatrics recommends that exclusively breast-fed infants receive vitamin D supplementation starting within the first 2 months of life. We have therefore initiated a clinical trial to determine whether vitamin D supplementation is required to prevent rickets in breast-fed children. In the course of conducting this study, we have gathered additional data regarding the patterns of breast-feeding and of vitamin D supplementation for babies born at Ochsner. PMID:21603467

Normal growth and muscle dysfunction in X-linked hypophosphatemic rickets associated with a novel mutation in the PHEX gene.

PubMed

Makras, Polyzois; Hamdy, Neveen A T; Kant, Sarina G; Papapoulos, Socrates E

2008-04-01

X-linked hypophosphatemic rickets (XLH) is characterized by hypophosphatemia and growth retardation. Early diagnosis and treatment improve growth. Our objective was to describe long-term observations of a family with XLH due to a novel mutation of the PHEX gene with unusual clinical features, including normal growth. The mother and her two sons were followed in the same institution for nearly 30 yr. The mother had hypophosphatemia and normal height (Z score, -0.6) without ever receiving any treatment. Her two sons achieved final heights of 183.7 cm (Z score, -0.01) and 182.7 cm (Z score, -0.18), respectively, despite late initiation of treatment with phosphate and low serum phosphate levels. In addition, they had reversible proximal myopathy that took about 7 yr to resolve in one of them. Direct sequencing of the PHEX gene revealed a new splice site mutation in intron 4 of the gene (IVS4+6T-->C) resulting in skipping of exon 4. Three members of a family with XLH due to a novel mutation of the PHEX gene had a normal growth pattern despite late diagnosis and treatment of the two boys and no treatment at all of their mother. The pathophysiological basis of this phenotype-genotype association warrants further investigation.

A novel nonsense mutation in the DMP1 gene in a Japanese family with autosomal recessive hypophosphatemic rickets.

PubMed

Koshida, Ryusuke; Yamaguchi, Hideki; Yamasaki, Koji; Tsuchimochi, Wakaba; Yonekawa, Tadato; Nakazato, Masamitsu

2010-09-01

Autosomal recessive hypophosphatemic rickets (ARHR) is an extremely rare disorder of autosomal recessive inheritance, characterized by hypophosphatemia resulting from renal phosphate wasting. Dentin matrix protein 1 (DMP1), a noncollagenous extracellular protein, plays critical roles in bone mineralization and phosphate homeostasis. Recently, loss-of-function mutations in DMP1 gene have been identified as the molecular cause of ARHR. Here, we describe a Japanese family that includes two ARHR-affected siblings carrying a novel mutation of the DMP1 gene. The patients were a 53-year-old woman and a 50-year-old man with short stature and skeletal deformities who were the offspring of a first-cousin marriage. Biochemical examination revealed hypophosphatemia with renal phosphate excretion and low levels of 1,25(OH)(2)D. Serum calcium, parathyroid hormone, and urinary calcium excretion were within the normal range, leading to clinical diagnosis of ARHR. Sequence analysis of peripheral leukocytes from the patients revealed that they carried a novel homozygous nonsense mutation in the DMP1 gene (98G>A, W33X), which leads to a truncated DMP protein with no putative biological function. Unaffected family members were heterozygous for the mutation. This is the first report of a Japanese family with ARHR carrying a novel mutation of the DMP1 gene.

Cutaneous skeletal hypophosphatemia syndrome (CSHS) is a multilineage somatic mosaic RASopathy.

PubMed

Lim, Young H; Ovejero, Diana; Derrick, Kristina M; Collins, Michael T; Choate, Keith A

2016-08-01

We recently demonstrated multilineage somatic mosaicism in cutaneous skeletal hypophosphatemia syndrome (CSHS), which features epidermal or melanocytic nevi, elevated fibroblast growth factor (FGF)-23, and hypophosphatemia, finding identical RAS mutations in affected skin and bone. We sought to: (1) provide an updated overview of CSHS; (2) review its pathobiology; (3) present a new patient with CSHS; and (4) discuss treatment modalities. We searched PubMed for "nevus AND rickets," and "nevus AND hypophosphatemia," identifying cases of nevi with hypophosphatemic rickets or elevated serum FGF-23. For our additional patient with CSHS, we performed histopathologic and radiographic surveys of skin and skeletal lesions, respectively. Sequencing was performed for HRAS, KRAS, and NRAS to determine causative mutations. Our new case harbored somatic activating HRAS p.G13 R mutation in affected tissue, consistent with previous findings. Although the mechanism of FGF-23 dysregulation is unknown in CSHS, interaction between FGF and MAPK pathways may provide insight into pathobiology. Anti-FGF-23 antibody KRN-23 may be useful in managing CSHS. Multilineage RAS mutation in CSHS was recently identified; further studies on mechanism are unavailable. Patients with nevi in association with skeletal disease should be evaluated for serum phosphate and FGF-23. Further studies investigating the role of RAS in FGF-23 regulation are needed. Published by Elsevier Inc.

Linkage disequilibrium analysis in young populations: Pseudo-vitamin D-deficiency rickets and the founder effect in French Canadians

DOE Office of Scientific and Technical Information (OSTI.GOV)

Labuda, M.; Glorieux, F.H.; Labuda, D.

1996-09-01

Pseudo-vitamin D-deficiency rickets (PDDR) was mapped close to D12S90 and between proximal D12S312 and distal (D12S305, D12S104) microsatellites that were subsequently found on a single YAC clone. Analysis of a complex haplotype in linkage disequilibrium (LD) with the disease discriminated among distinct founder effects in French Canadian populations in Acadia and in Charlevoix-Saguenay-Lac-Saint-Jean (Ch-SLSJ), as well as an earlier one in precolonial Europe. A simple demographic model suggested the historical age of the founder effect in Ch-SLSJ to be {approximately}12 generations. The corresponding LD data are consistent with this figure when they are analyzed within the framework of Luria-Delbruck model,more » which takes into account the population growth. Population sampling due to a limited number of first settlers and the rapid demographic expansion appear to have played a major role in the founding of PDDR in Ch-SLSJ and, presumably, other genetic disorders endemic to French Canada. Similarly, the founder effect in Ashkenazim, coinciding with their early settlement in medieval Poland and subsequent expansion eastward, could explain the origin of frequent genetic diseases in this population. 48 refs., 5 figs., 2 tabs.« less

Breast-feeding and Vitamin D Supplementation Rates in the Ochsner Health System.

PubMed

Ponnapakkam, Tulasi; Ravichandran, Anisha; Bradford, Elease; Tobin, Gregory; Gensure, Robert

2008-01-01

Breast-feeding imparts many benefits to both mothers and infants. Because of these numerous recognized benefits, there has been an effort to increase breast-feeding rates nationwide; increasing breast-feeding rates was one of the goals of the U.S. Department of Health and Human Services' Healthy People 2010 initiative. This study examined the breast-feeding rate at the Ochsner Clinic Foundation by conducting a retrospective chart review of patients aged 0-12 months who visited any branch of the Ochsner hospital system. Our results indicate that the rate of initiation of breast-feeding for children followed at the Ochsner Clinic Foundation is 66.3%. However, as breast-feeding rates rise, there is concern that there may be a resurgence of rickets, a disease caused by the deficiency of vitamin D. Currently the American Academy of Pediatrics recommends that exclusively breast-fed infants receive vitamin D supplementation starting within the first 2 months of life. We have therefore initiated a clinical trial to determine whether vitamin D supplementation is required to prevent rickets in breast-fed children. In the course of conducting this study, we have gathered additional data regarding the patterns of breast-feeding and of vitamin D supplementation for babies born at Ochsner.

Clinical Phenotype in a Toddler with a Novel Heterozygous Mutation of the Vitamin D Receptor

PubMed Central

Dingle, Elena

2017-01-01

We present the clinical phenotype of a toddler who presented with vitamin D-resistant rickets, with one of the highest initial levels of alkaline phosphatase and parathyroid hormone (PTH) levels reported in the literature. The toddler had novel compound heterozygous mutations in the ligand-binding site of the vitamin D receptor and had an excellent response to calcitriol (1,25(OH)2D). PMID:28620554

Vitamin D-Dependent Rickets Type 1B (25-Hydroxylase Deficiency): A Rare Condition or a Misdiagnosed Condition?

PubMed

Molin, Arnaud; Wiedemann, Arnaud; Demers, Nick; Kaufmann, Martin; Do Cao, Jérémy; Mainard, Laurent; Dousset, Brigitte; Journeau, Pierre; Abeguile, Geneviève; Coudray, Nadia; Mittre, Hervé; Richard, Nicolas; Weryha, Georges; Sorlin, Arthur; Jones, Glenville; Kottler, Marie-Laure; Feillet, Francois

2017-09-01

Vitamin D requires a two-step activation by hydroxylation: The first step is catalyzed by hepatic 25-hydroxylase (CYP2R1, 11p15.2) and the second one is catalyzed by renal 1α-hydroxylase (CYP27B1, 12q13.1), which produces the active hormonal form of 1,25-(OH) 2 D. Mutations of CYP2R1 have been associated with vitamin D-dependent rickets type 1B (VDDR1B), a very rare condition that has only been reported to affect 4 families to date. We describe 7 patients from 2 unrelated families who presented with homozygous loss-of-function mutations of CYP2R1. Heterozygous mutations were present in their normal parents. We identified a new c.124_138delinsCGG (p.Gly42_Leu46delinsArg) variation and the previously published c.296T>C (p.Leu99Pro) mutation. Functional in vitro studies confirmed loss-of-function enzymatic activity in both cases. We discuss the difficulties in establishing the correct diagnosis and the specific biochemical pattern, namely, very low 25-OH-D suggestive of classical vitamin D deficiency, in the face of normal/high concentrations of 1,25-(OH) 2 D. Siblings exhibited the three stages of rickets based on biochemical and radiographic findings. Interestingly, adult patients were able to maintain normal mineral metabolism without vitamin D supplementation. One index case presented with a partial improvement with 1alfa-hydroxyvitamin D 3 or alfacalcidol (1α-OH-D 3 ) treatment, and we observed a dramatic increase in the 1,25-(OH) 2 D serum concentration, which indicated the role of accessory 25-hydroxylase enzymes. Lastly, in patients who received calcifediol (25-OH-D 3 ), we documented normal 24-hydroxylase activity (CYP24A1). For the first time, and according to the concept of personalized medicine, we demonstrate dramatic improvements in patients who were given 25-OH-D therapy (clinical symptoms, biochemical data, and bone densitometry). In conclusion, the current study further expands the CYP2R1 mutation spectrum. We note that VDDR1B could be easily mistaken for classical vitamin D deficiency. © 2017 American Society for Bone and Mineral Research. © 2017 American Society for Bone and Mineral Research.

Recent developments in metabolic bone diseases: a gnathic perspective.

PubMed

Raubenheimer, Erich J; Noffke, Claudia E; Hendrik, Hilde D

2014-12-01

Metabolic bone diseases often are asymptomatic and progress sub clinically. Many patients present at a late stage with catastrophic skeletal and extra skeletal complications. In this article, we provide an overview of normal bone remodeling and a synopsis of recent developments in the following conditions: osteoporosis, rickets/osteomalacia, endocrine-induced bone disease, chronic kidney disease-mineral bone disorder and Paget's disease of bone. Our discussion will emphasize the clinical and microscopic manifestations of these diseases in the jaws.

Development and application of an instrument for analysis of bone structure on radiographs.

PubMed

Xu, S; Liu, S; Bao, K

1997-01-01

An instrument used for quantitative assessment of trabecular structure of radius on radiograph including trabecular number and trabecular width was developed using a microdensitometer and a single-chip microcomputer. The device is characterized by its high sensitivity, good reproducibility, convenience and economy. The results obtained with the instrument were significantly correlated to actual bone mineral content. This device can be used for the diagnosis of osteoporosis, fluorosis, rickets and bone damages caused by cadmium.

Osteosclerosis, hyperostosis, and related disorders

DOE Office of Scientific and Technical Information (OSTI.GOV)

Frame, B.; Honasoge, M.; Kottamasu, S.R.

1987-01-01

This book will assist physicians in the evaluation of patients where osteosclerosis and hyperostosis are the predominant radiographic features. This volume also covers disorders with lesser degrees of osteosclerosis and hyperostosis, and those which exhibit ligamentous calcifications and/or ossifications such as: fluorosis, hypervitaminosis, hypoparathyroidism, and hypophosphatemic rickets. Discussed and reviewed are the salient clinical and radiographic features as well as the pathophysiology of these conditions. In addition, many chapters contain experimental data that facilitates understanding of the pathogenesis of the disease.

Distribution of mutations in the PEX gene in families with X-linked hypophosphataemic rickets (HYP).

PubMed

Rowe, P S; Oudet, C L; Francis, F; Sinding, C; Pannetier, S; Econs, M J; Strom, T M; Meitinger, T; Garabedian, M; David, A; Macher, M A; Questiaux, E; Popowska, E; Pronicka, E; Read, A P; Mokrzycki, A; Glorieux, F H; Drezner, M K; Hanauer, A; Lehrach, H; Goulding, J N; O'Riordan, J L

1997-04-01

Mutations in the PEX gene at Xp22.1 (phosphate-regulating gene with homologies to endopeptidases, on the X-chromosome), are responsible for X-linked hypophosphataemic rickets (HYP). Homology of PEX to the M13 family of Zn2+ metallopeptidases which include neprilysin (NEP) as prototype, has raised important questions regarding PEX function at the molecular level. The aim of this study was to analyse 99 HYP families for PEX gene mutations, and to correlate predicted changes in the protein structure with Zn2+ metallopeptidase gene function. Primers flanking 22 characterised exons were used to amplify DNA by PCR, and SSCP was then used to screen for mutations. Deletions, insertions, nonsense mutations, stop codons and splice mutations occurred in 83% of families screened for in all 22 exons, and 51% of a separate set of families screened in 17 PEX gene exons. Missense mutations in four regions of the gene were informative regarding function, with one mutation in the Zn2+-binding site predicted to alter substrate enzyme interaction and catalysis. Computer analysis of the remaining mutations predicted changes in secondary structure, N-glycosylation, protein phosphorylation and catalytic site molecular structure. The wide range of mutations that align with regions required for protease activity in NEP suggests that PEX also functions as a protease, and may act by processing factor(s) involved in bone mineral metabolism.

Cutaneous-Skeletal Hypophosphatemia Syndrome is a Multilineage Somatic Mosaic RASopathy

PubMed Central

Lim, Young H.; Ovejero, Diana; Derrick, Kristina M.; Collins, Michael T.; Choate, Keith A.

2016-01-01

Background We recently demonstrated multilineage somatic mosaicism in cutaneous-skeletal hypophosphatemia syndrome (CSHS), which features epidermal or melanocytic nevi, elevated fibroblast growth factor-23 (FGF23) and hypophosphatemia, finding identical RAS mutations in affected skin and bone. Objective 1) To provide an updated overview of CSHS; 2) To review its pathobiology; 3) To present a new CSHS patient; and 4) To discuss treatment modalities. Methods We searched PubMed for “nevus AND rickets,” and “nevus AND hypophosphatemia,” identifying cases of nevi with hypophosphatemic rickets or elevated serum FGF23. For our additional CSHS patient, we performed histopathologic and radiographic surveys of skin and skeletal lesions, respectively. Sequencing was performed for HRAS, KRAS, and NRAS to determine causative mutations. Results Our new case harbored somatic activating HRAS p.G13R mutation in affected tissue, consistent with previous findings. While the mechanism of FGF23 dysregulation is unknown in CSHS, interaction between FGF and MAPK pathways may provide insight into pathobiology. Anti-FGF23 antibody KRN23 may be useful in managing CSHS. Limitations Multilineage RAS mutation in CSHS was recently identified; further studies on mechanism are unavailable. Conclusion Patients with nevi in association with skeletal disease should be evaluated for serum phosphate and FGF23. Further studies investigating the role of RAS in FGF23 regulation are needed. PMID:27444071

Effect of GH replacement therapy in two male siblings with combined X-linked hypophosphatemia and partial GH deficiency.

PubMed

Schütt, Snjezana M; Schumacher, Marius; Holterhus, Paul M; Felgenhauer, Stefanie; Hiort, Olaf

2003-10-01

X-linked hypophosphatemia (XLH) is characterized by low serum phosphorus, relative 1,25-dihydroxyvitamin D(3) deficiency and rickets. It is caused by mutations in the phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX). The conventional treatment of XLH includes the administration of phosphate and calcitriol; however, treated patients usually present with a short stature. Therefore, additional coexistent defects, such as GH deficiency, are under debate. Two male siblings presented with a disproportionate growth failure and rickets. Investigation of calcium and phosphate metabolism, molecular genetic analysis of the PHEX gene and GH function tests were initiated. Both patients showed typical clinical and biochemical signs of XLH. Molecular genetic analysis revealed a 747 CGA (Arg)-TGA (End) mutation in exon 22 of the PHEX gene, confirming XLH. Since treatment with phosphate and calcitriol alone failed to improve growth in both patients, the GH axis was examined and a partial GH deficiency was diagnosed in both cases. Almost 3 Years of additional therapy with recombinant human GH (rhGH) led to a significant improvement of height standard deviation scores (HtSDS). Poor growth in XLH may, in at least some patients, be aggravated by GH deficiency. Hence, GH deficiency should be considered in extremely poorly growing patients with XLH, because these patients are likely to benefit from rhGH therapy.

Role of prostaglandins in the pathogenesis of X-linked hypophosphatemia.

PubMed

Baum, Michel; Syal, Ashu; Quigley, Raymond; Seikaly, Mouin

2006-08-01

X-linked hypophosphatemia is an X-linked dominant disorder resulting from a mutation in the PHEX gene. PHEX stands for phosphate-regulating gene with endopeptidase activity, which is located on the X chromosome. Patients with X-linked hypophosphatemia have hypophosphatemia due to renal phosphate wasting and low or inappropriately normal levels of 1,25-dihydroxyvitamin D. The renal phosphate wasting is not intrinsic to the kidney but likely due to an increase in serum levels of fibroblast growth factor-23 (FGF-23), and perhaps other phosphate-wasting peptides previously known as phosphatonins. Patients with X-linked hypophosphatemia have short stature, rickets, bone pain and dental abscesses. Current therapy is oral phosphate and vitamin D which effectively treats the rickets and bone pain but does not adequately improve short stature. In this review, we describe recent observations using Hyp mice; mice with the same mutation as patients with X-linked hypophosphatemia. We have recently found that Hyp mice have abnormal renal prostaglandin production, which may be an important factor in the pathogenesis of this disorder. Administration of FGF-23 in vivo results in phosphaturia and an increase in prostaglandin excretion, and FGF-23 increases proximal tubule prostaglandin production in vitro. In Hyp mice, indomethacin improves the phosphate transport defect in vitro and in vivo. Whether indomethacin has the same effect in patients with X-linked hypophosphatemia is unknown.

Enzyme replacement prevents enamel defects in hypophosphatasia mice

PubMed Central

Yadav, Manisha C.; de Oliveira, Rodrigo Cardoso; Foster, Brian L.; Fong, Hanson; Cory, Esther; Narisawa, Sonoko; Sah, Robert L.; Somerman, Martha; Whyte, Michael P.; Millán, José Luis

2012-01-01

Hypophosphatasia (HPP) is the inborn error of metabolism characterized by deficiency of alkaline phosphatase activity leading to rickets or osteomalacia and to dental defects. HPP occurs from loss-of-function mutations within the gene that encodes the tissue-nonspecific isozyme of alkaline phosphatase (TNAP). TNAP knockout (Alpl−/−, a.k.a. Akp2−/−) mice closely phenocopy infantile HPP, including the rickets, vitamin B6-responsive seizures, improper dentin mineralization, and lack of acellular cementum. Here, we report that lack of TNAP in Alpl−/− mice also causes severe enamel defects, which are preventable by enzyme replacement with mineral-targeted TNAP (ENB-0040). Immunohistochemistry was used to map the spatiotemporal expression of TNAP in the tissues of the developing enamel organ of healthy mouse molars and incisors. We found strong, stage-specific expression of TNAP in ameloblasts. In the Alpl−/− mice, histological, μCT, and scanning electron microscopy analysis showed reduced mineralization and disrupted organization of the rods and inter-rod structures in enamel of both the molars and incisors. All of these abnormalities were prevented in mice receiving from birth daily subcutaneous injections of mineral-targeting, human TNAP (sALP-FcD10, a.k.a. ENB-0040) at 8.2 mg/kg/day for up to 44 days. These data reveal an important role for TNAP in enamel mineralization, and demonstrate the efficacy of mineral-targeted TNAP to prevent enamel defects in HPP. PMID:22461224

The Changing Face of Hypophosphatemic Disorders in the FGF-23 Era

PubMed Central

Lee, Janet Y.; Imel, Erik A.

2014-01-01

In the past decade, research in genetic disorders of hypophosphatemia has significantly expanded our understanding of phosphate metabolism. X-linked hypophosphatemia (XLH) is the most common inherited form of rickets due to renal phosphate wasting. Recent understanding of the mechanisms of disease and role of fibroblast growth factor 23 (FGF-23) in XLH and other hypophosphatemic disorders have opened new potential therapeutic avenues. We will discuss the current standard of treatment for XLH as well as promising future directions under study. PMID:23858620

The Role of Vitamin D Stimulation of Mullerian Inhibiting Substance (MIS) in Prostate Cancer Therapy

DTIC Science & Technology

2008-12-01

calcitriol for 6 hr and cross -linked by addition of 1% formaldehyde. Chromatin was prepared and digested with micrococcal nuclease for 12 min at 37...immunoprecipitates eluted with ChIP elution buffer. The cross -links were reversed by incubation at 65°C for 30 min. Proteinase K was added and incubated at 65°C...coactivator interaction and causes hereditary 1,25-dihydroxyvitamin D-resistant rickets without alopecia. Mol Endocrinol 16:2538-2546 26. Dresser DW

Fanconi-Bickel syndrome: GLUT2 mutations associated with a mild phenotype.

PubMed

Grünert, Sarah Catharina; Schwab, Karl Otfried; Pohl, Martin; Sass, Jörn Oliver; Santer, René

2012-03-01

Fanconi-Bickel syndrome (FBS, OMIM #227810), a congenital disorder of carbohydrate metabolism, is caused by mutations in GLUT2 (SLC2A2), the gene encoding the glucose transporter protein-2. The typical clinical picture is characterized by hepatorenal glycogen accumulation resulting in hepato- and nephromegaly, impaired utilization of glucose and galactose, proximal tubular nephropathy, rickets, and severe short stature. We report on two siblings with FBS and an unusually mild clinical course. A 9.5-year-old boy with failure to thrive was diagnosed at the age of 9 months, his younger sister (4.5 years) was investigated in the first months of life and also diagnosed with FBS. Both patients were found to be compound heterozygous for the novel GLUT2 (SLC2A2) mutations c.457_462delCTTATA (p.153_4delLI) and c.1250C>G (p.P417R). On a diet restricted in free glucose and galactose, both children showed normal growth. Hepatomegaly, nephromegaly and hypophosphatemic rickets have never been observed. Glucosuria and tubular proteinuria were only mild compared to previously reported patients with FBS. This report describes an unusually mild phenotype of FBS expanding the spectrum of this disease. Some clinical signs that have been considered hallmarks of FBS like hepatomegaly and short stature may be absent in this condition. As a consequence, clinicians will have to look for GLUT2 mutations even in patients with isolated glucosuria. Copyright © 2011 Elsevier Inc. All rights reserved.

A de novo mosaic mutation of PHEX in a boy with hypophosphatemic rickets.

PubMed

Weng, Chen; Chen, Jiao; Sun, Li; Zhou, Zhong-Wei; Feng, Xue; Sun, Jun-Hui; Lu, Ling-Ping; Yu, Ping; Qi, Ming

2016-03-01

X-linked dominant hypophosphatemic rickets (XLHR), is characterized mainly by renal phosphate wasting with hypophosphatemia, short stature and abnormal bone mineralization. PHEX, located at Xp22.1-p22.2, is the gene causing XLHR. We aim to characterize the pathogenesis of a Chinese boy who is apparently 'heterozygous' in PHEX gene. Direct sequencing showed two peaks: one was a wild-type 'G' and the other was one base substitution to 'A', though the patient was a male. TA clone assay clearly showed each sequences and the ratios. The mutation effect was predicted via bioinformatics and validated by exon-trapping assay. Real-time PCR was applied to determine the copy number of PHEX. TA clone assay showed the frequency of normal (G) to mutant allele (A) as 19:13. Normal karyotype and real-time PCR results indicate the normal copy number of PHEX. This splice site mutation leads to 4 bp of exon 18 skipping out causing frame shift p.Gly590Glufs*28 that ends up with a loss of active site and Zn(2+)-binding site of PHEX, which probably interfere with renal phosphate reabsorption and bone mineralization. In conclusion, mutation at conserved splice acceptor site resulted in aberrant splicing, ending up with a damaged protein product. This novel mutation is de novo in mosaic pattern that may be induced during early postzygotic period. Taking mosaic somatic mutation of PHEX into consideration is strongly suggested in genetic counseling and etiology research for XLHR.

A novel auditory ossicles membrane and the development of conductive hearing loss in Dmp1-null mice.

PubMed

Lv, Kun; Huang, Haiyang; Yi, Xing; Chertoff, Mark E; Li, Chaoyuan; Yuan, Baozhi; Hinton, Robert J; Feng, Jian Q

2017-10-01

Genetic mouse models are widely used for understanding human diseases but we know much less about the anatomical structure of the auditory ossicles in the mouse than we do about human ossicles. Furthermore, current studies have mainly focused on disease conditions such as osteomalacia and rickets in patients with hypophosphatemia rickets, although the reason that these patients develop late-onset hearing loss is unknown. In this study, we first analyzed Dmp1 lac Z knock-in auditory ossicles (in which the blue reporter is used to trace DMP1 expression in osteocytes) using X-gal staining and discovered a novel bony membrane surrounding the mouse malleus. This finding was further confirmed by 3-D micro-CT, X-ray, and alizarin red stained images. We speculate that this unique structure amplifies and facilitates sound wave transmissions in two ways: increasing the contact surface between the eardrum and malleus and accelerating the sound transmission due to its mineral content. Next, we documented a progressive deterioration in the Dmp1-null auditory ossicle structures using multiple imaging techniques. The auditory brainstem response test demonstrated a conductive hearing loss in the adult Dmp1-null mice. This finding may help to explain in part why patients with DMP1 mutations develop late-onset hearing loss, and supports the critical role of DMP1 in maintaining the integrity of the auditory ossicles and its bony membrane. Copyright © 2017 Elsevier Inc. All rights reserved.

[Clinical follow up of Chilean patients with tyrosinemia type 1 treated with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-ciclohexanedione (NTBC)].

PubMed

Raimann, Erna; Cornejo, Verónica; Arias, Carolina; Cabello, Juan Francisco; Castro, Gabriela; Fernández, Eloina; de la Parra, Alicia

2012-02-01

Tyrosinemia type I is an inborn error of metabolism due to deficiency of fumarilacetoacetase. Acute presentation is with liver failure, hypophosphatemic rickets and peripheral neuropathy. Chronic presentation is with visceromegaly and subclinical rickets. The most severe complications are hepatic cancer and acute neurological crises. Without treatment, tyrosinemia type 1 is fatal. In 1992 treatment for tyrosinemia type 1 with 2-(2-nitro-4-trifluoromethybenzoyl)-1,3-ciclohexanedione (NTBC) was proposed. A clinical response was reported in 90% of patients. In cases that did not respond, a successful liver transplantation was performed, reducing mortality to 5%. To report the follow up of 12 patients treated with NTBC. Review of clinical records of 12 Chilean cases treated with NTBC at the Instituto de Nutrición y Tecnología de los Alimentos (INTA) from January 2004 until June 2010. In all patients, a rapid metabolic control was achieved. Two patients developed hepatocarcinoma. One of these patients died and one was successfully treated with liver transplantation. One patient died after receiving a liver transplantation. Nine patients have at present good liver function, but 2 had peripheral neuropathy due to late diagnosis and discontinuing NTBC treatment. Treatment with NTBC allows metabolic normalization in tyrosinemia type 1, prevents liver cirrhosis and hepatic cancer, improving survival rates and quality of life in the patients. Neonatal screening is essential for the early diagnosis of this treatable disease, that otherwise may be lethal.

Renal tubular function in children with tyrosinaemia type I treated with nitisinone.

PubMed

Santra, S; Preece, M A; Hulton, S-A; McKiernan, P J

2008-06-01

Tyrosinaemia type I (TTI) is an inherited deficiency in the enzyme fumarylacetoacetate hydrolase and is frequently complicated by renal tubular dysfunction which may persist in some patients after hepatic transplantation. Nitisinone has revolutionized the management of TTI but its effect on renal tubular dysfunction has not been described in a large cohort of patients. To document the incidence and progression of renal tubular dysfunction in children with TTI treated with nitisinone at a single centre. Twenty-one patients with TTI from a single centre were treated with nitisinone for at least 12 months. Median age at first treatment was 17 weeks (range 1 week to 27 months). Nine patients (43%) presented in acute liver failure, seven (33%) had a chronic presentation and five (24%) were detected pre-clinically. A retrospective case analysis of plasma phosphate, urinary protein/creatinine ratio and tubular reabsorption of phosphate was performed for all patients as markers of tubular function. Renal ultrasounds were examined for evidence of nephrocalcinosis and where available, skeletal radiographs for rickets. All patients had biochemical evidence of renal tubular dysfunction at presentation. After nitisinone and dietary treatment were started, all three markers normalized within one year. Four children had clinical rickets at presentation (which improved), of whom one had nephrocalcinosis, which did not reverse on nitisinone. No child redeveloped tubular dysfunction after commencing nitisinone. All patients with TTI had evidence of tubular dysfunction at presentation and in all cases this resolved with nitisinone and dietary control. The tubulopathy associated with TTI is reversible.

Dent Disease in Chinese Children and Findings from Heterozygous Mothers: Phenotypic Heterogeneity, Fetal Growth, and 10 Novel Mutations.

PubMed

Li, Fucheng; Yue, Zhihui; Xu, Tingting; Chen, Minghui; Zhong, Liangying; Liu, Ting; Jing, Xiangyi; Deng, Jia; Hu, Bin; Liu, Yuling; Wang, Haiyan; Lai, Kar N; Sun, Liangzhong; Liu, Jinsong; Maxwell, Patrick H; Wang, Yiming

2016-07-01

To characterize the phenotypes of Dent disease in Chinese children and their heterozygous mothers and to establish genetic diagnoses. Using a modified protocol, we screened 1288 individuals with proteinuria. A diagnosis of Dent disease was established in 19 boys from 16 families by the presence of loss of function/deleterious mutations in CLCN5 or OCRL1. We also analyzed 16 available patients' mothers and examined their pregnancy records. We detected 14 loss of function/deleterious mutations of CLCN5 in 15 boys and 2 mutations of OCRL1 in 4 boys. Of the patients, 16 of 19 had been wrongly diagnosed with other diseases and 11 of 19 had incorrect or unnecessary treatment. None of the patients, but 6 of 14 mothers, had nephrocalcinosis or nephrolithiasis at diagnosis. Of the patients, 8 of 14 with Dent disease 1 were large for gestational age (>90th percentile); 8 of 15 (53.3%) had rickets. We also present predicted structural changes for 4 mutant proteins. Pediatric Dent disease often is misdiagnosed; genetic testing achieves a correct diagnosis. Nephrocalcinosis or nephrolithiasis may not be sensitive diagnostic criteria. We identified 10 novel mutations in CLCN5 and OCRL1. The possibility that altered CLCN5 function could affect fetal growth and a possible link between a high rate of rickets and low calcium intake are discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

Molecular Analysis of DMP1 Mutants Causing Autosomal Recessive Hypophosphatemic Rickets

PubMed Central

Farrow, Emily G.; Davis, Siobhan I.; Ward, Leanne M.; Summers, Lelia J.; Bubbear, Judith S.; Keen, Richard; Stamp, Trevor C.B.; Baker, Laurence R. I.; Bonewald, Lynda F.; White, Kenneth E.

2009-01-01

We previously demonstrated that the mutations Met1Val (M1V) and the deletion of nucleotides 1484-1490 (1484-1490del) in Dentin matrix protein-1 (DMP1) cause the novel disorder autosomal recessive hypophosphatemic rickets (ARHR), which is associated with elevated Fibroblast growth factor-23 (FGF23). To further understand the role of DMP1 in ARHR, we undertook molecular genetic and in vitro expression studies. First, we examined a kindred with a severe hypophosphatemic rickets phenotype and recessive inheritance. Analyses of this family demonstrated that the affected members had elevated serum FGF23 and carried a large, biallelic deletion that removed the majority of DMP1. At a minimum, this deletion encompassed 49 kb between DMP1 exon 3 and an intergenic region 5′ to the next telomeric gene, integrin-binding sialoprotein (IBSP). We next performed immunofluorescent studies in cells to understand the effects of the known ARHR mutations on DMP1 cellular processing. These analyses showed that the M1V DMP1 mutant was not sorted to the trans-Golgi network (TGN) and secretory pathway, but filled the entire cytoplasm. In contrast, the 1484-1490del mutant localized to the TGN and was secreted, similar to wild type DMP1. The 1484-1490del mutation replaces the DMP1 18 C-terminal amino acids with 33 non-native residues. Truncation of wild type DMP1 by these native 18 residues followed by Western blot and confocal microscopic analyses demonstrated a wild type expression pattern when compared with the 1484-1490del mutant, indicating that the last 18 residues are not critical for cellular trafficking, but that the 33 additional residues arising from the 1484-1490del mutation likely compromise DMP1 processing. The relationship between DMP1 and FGF23 is unclear. To test endogenous DMP1 response to serum metabolites that also regulate FGF23, UMR-106 cells were treated with 1,25(OH)2 vitamin D (1×10−7M) and showed a 12-fold increase in DMP1 mRNA and protein at 24 hr. In summary, we have identified a novel DMP1 deletion as the cause of ARHR, as well as demonstrated that the ARHR mutations alter DMP1 cellular processing, and that DMP1 can be regulated by vitamin D. Taken together, this work expands our understanding of the genetic and molecular mechanisms associated with DMP1 alterations causing ARHR. PMID:19007919

Urban-rural differences in Roman Dorset, England: A bioarchaeological perspective on Roman settlements.

PubMed

Redfern, Rebecca C; DeWitte, Sharon N; Pearce, John; Hamlin, Christine; Dinwiddy, Kirsten Egging

2015-05-01

In the Roman period, urban and rural ways of living were differentiated philosophically and legally, and this is the first regional study of these contrasting life-ways. Focusing on frailty and mortality risk, we investigated how these differed by age, sex, and status, using coffin type as a proxy for social status. We employed skeletal data from 344 individuals: 150 rural and 194 urban (1st-5th centuries A.D.) from Dorset, England. Frailty and mortality risk were examined using indicators of stress (cribra orbitalia, porotic hyperostosis, nonspecific periostitis, and enamel hypoplastic defects), specific metabolic and infectious diseases (rickets, scurvy, and tuberculosis), and dental health (carious lesions and calculus). These variables were studied using Chi-square, Siler model of mortality, Kaplan-Meier analysis, and the Gompertz model of adult mortality. Our study found that overall, mortality risk and survivorship did not differ between cemetery types but when the data were examined by age, mortality risk was only significantly higher for urban subadults. Demographic differences were found, with urban cemeteries having more 0-10 and >35 year olds, and for health, urban cemeteries had significantly higher frequencies of enamel hypoplastic defects, carious lesions, and rickets. Interestingly, no significant difference in status was observed between rural and urban cemeteries. The most significant finding was the influence of the skeletal and funerary data from the Poundbury sites, which had different demographic profiles, significantly higher frequencies of the indicators of stress and dental health variables. In conclusion, there are significant health, demographic, and mortality differences between rural and urban populations in Roman Britain. © 2015 Wiley Periodicals, Inc.

Acute Phosphate Restriction Leads to Impaired Fracture Healing and Resistance to BMP-2

PubMed Central

Wigner, Nathan A; Luderer, Hilary F; Cox, Megan K; Sooy, Karen; Gerstenfeld, Louis C; Demay, Marie B

2010-01-01

Hypophosphatemia leads to rickets and osteomalacia, the latter of which results in decreased biomechanical integrity of bones, accompanied by poor fracture healing. Impaired phosphate-dependent apoptosis of hypertrophic chondrocytes is the molecular basis for rickets. However, the underlying pathophysiology of impaired fracture healing has not been characterized previously. To address the role of phosphate in fracture repair, mice were placed on a phosphate-restricted diet 2 days prior to or 3 days after induction of a mid-diaphyseal femoral fracture to assess the effects of phosphate deficiency on the initial recruitment of mesenchymal stem cells and their subsequent differentiation. Histologic and micro-computed tomographic (µCT) analyses demonstrated that both phosphate restriction models dramatically impaired fracture healing primarily owing to a defect in differentiation along the chondrogenic lineage. Based on Sox9 and Sox5 mRNA levels, neither the initial recruitment of cells to the callus nor their lineage commitment was effected by hypophosphatemia. However, differentiation of these cells was impaired in association with impaired bone morphogenetic protein (BMP) signaling. In vivo ectopic bone-formation assays and in vitro investigations in ST2 stromal cells confirmed that phosphate restriction leads to BMP-2 resistance. Marrow ablation studies demonstrate that hypophosphatemia has different effects on injury-induced intramembranous bone formation compared with endochondral bone formation. Thus phosphate plays an important role in the skeleton that extends beyond mineralized matrix formation and growth plate maturation and is critical for endochondral bone repair. © 2010 American Society for Bone and Mineral Research. PMID:19839770

Food insecurity and malnutrition in Chinese elementary school students.

PubMed

Shen, Xiuhua; Gao, Xiang; Tang, Wenjing; Mao, Xuanxia; Huang, Jingyan; Cai, Wei

2015-09-28

It has been shown that food insecurity is associated with poor diet quality and unfavourable health outcomes. However, little is known about the potential effects of food insecurity on the overall malnutrition status among children. In this study, we investigated the prevalence of food insecurity among 1583 elementary school students, aged 6-14 years, living in Chinese rural areas and examined its association with four malnutrition signs, including rickets sequelae, anaemia, stunting and wasting. Information on food security was collected via questionnaires. Rickets sequelae were assessed by an experienced paediatrician during the interview. Anaemia was determined by the WHO Hb thresholds adjusted by the local altitude. Weight and height were measured during the interview. Stunting and wasting were then evaluated according to WHO child growth standards (2007). We examined the association between food insecurity and the number of malnutrition signs (total number = 4), and the likelihood of having severe malnutrition (presence of 3+ signs), after adjusting for potential confounders, such as age, social-economic status and dietary intakes. During the previous 12 months, the overall prevalence of food insecurity was 6.1% in the entire studied population and 16.3% in participants with severe malnutrition. Participants with food insecurity had a slightly higher number of malnutrition signs (1.14 v. 0.96; P=0.043) relative to those who were food secure, after adjusting for potential confounders. Food insecurity was also associated with increased likelihood of having severe malnutrition (adjusted OR 3.08; 95% CI 1.47, 6.46; P=0.003). In conclusion, food insecurity is significantly associated with malnutrition among Chinese children in this community.

Evidence for an Intrinsic Renal Tubular Defect in Mice with Genetic Hypophosphatemic Rickets

PubMed Central

Cowgill, Larry D.; Goldfarb, Stanley; Lau, Kai; Slatopolsky, Eduardo; Agus, Zalman S.

1979-01-01

To investigate the role of parathyroid hormone (PTH) and(or) an intrinsic renal tubular reabsorptive defect for phosphate in mice with hereditary hypophosphatemic rickets, we performed clearance and micropuncture studies in hypophosphatemic mutants and nonaffected littermate controls. Increased fractional excretion of phosphate in mutants (47.2±4 vs. 30.8±2% in controls) was associated with reduced fractional and absolute reabsorption in the proximal convoluted tubule and more distal sites. Acute thyropara-thyroidectomy (TPTX) increased phosphate reabsorption in both mutants and controls with a fall in fractional phosphate excretion to ≅7.5% in both groups indicating that PTH modified the degree of phosphaturia in the intact mutants. Absolute reabsorption in the proximal tubule and beyond remained reduced in the mutants, however, possibly because of the reduced filtered load. Serum PTH levels were the same in intact mutants and normals as was renal cortical adenylate cyclase activity both before and after PTH stimulation. To evaluate the possibility that the phosphate wasting was caused by an intrinsic tubular defect that was masked by TPTX, glomerular fluid phosphate concentration was raised by phosphate infusion in TPTX mutants to levels approaching those of control mice. Phosphate excretion rose markedly and fractional reabsorption fell, but there was no change in absolute phosphate reabsorption in either the proximal tubule or beyond, indicating a persistent reabsorptive defect in the absence of PTH. We conclude that hereditary hypophosphatemia in the mouse is associated with a renal tubular defect in phosphate reabsorption, which is independent of PTH and therefore represents a specific intrinsic abnormality of phosphate transport. PMID:221535

Hypophosphatasia - pathophysiology and treatment.

PubMed

Millán, José Luis; Plotkin, Horacio

2012-09-01

Hypophosphatasia (HPP) is the inborn-error-of-metabolism caused by loss-of-function mutation(s) in the gene that encodes the tissue-nonspecific isozyme of alkaline phosphatase (TNAP). The disease has been classified according to patient age when the first signs and symptoms manifest; i.e., perinatal, infantile, childhood, adult HPP. Other types include odonto HPP and perinatal benign. Babies with the perinatal/infantile forms of HPP often die with severe rickets and respiratory insufficiency and sometimes hypercalcemia and vitamin B 6 -responsive seizures. The primary biochemical defect in HPP is a deficiency of TNAP activity that leads to elevated circulating levels of substrates, in particular inorganic pyrophosphate (PP i ), a potent calcification inhibitor. To-date, the management of HPP has been essentially symptomatic or orthopedic. However, enzyme replacement therapy with mineral-targeting TNAP (sALP-FcD 10 , also known as ENB-0040 or asfotase alfa) has shown promising results in a mouse model of HPP ( Alpl -/- mice). Administration of mineral-targeting TNAP from birth increased survival and prevented the seizures, rickets, as well as all the tooth abnormalities, including dentin, acellular cementum, and enamel defects in this model of severe HPP. Clinical trials using mineral-targeting TNAP in children 3 years of age or younger with life-threatening HPP was associated with healing of the skeletal manifestations of HPP as well as improved respiratory and motor function. Improvement is still being observed in the patients receiving continued asfotase alfa therapy, with more than 3 years of treatment in some children. Enzyme replacement therapy with asfotase alfa has to-date been successful in patients with life-threatening HPP.

Hypophosphatasia - pathophysiology and treatment

PubMed Central

Millán, José Luis; Plotkin, Horacio

2013-01-01

English Summary Hypophosphatasia (HPP) is the inborn-error-of-metabolism caused by loss-of-function mutation(s) in the gene that encodes the tissue-nonspecific isozyme of alkaline phosphatase (TNAP). The disease has been classified according to patient age when the first signs and symptoms manifest; i.e., perinatal, infantile, childhood, adult HPP. Other types include odonto HPP and perinatal benign. Babies with the perinatal/infantile forms of HPP often die with severe rickets and respiratory insufficiency and sometimes hypercalcemia and vitamin B6-responsive seizures. The primary biochemical defect in HPP is a deficiency of TNAP activity that leads to elevated circulating levels of substrates, in particular inorganic pyrophosphate (PPi), a potent calcification inhibitor. To-date, the management of HPP has been essentially symptomatic or orthopedic. However, enzyme replacement therapy with mineral-targeting TNAP (sALP-FcD10, also known as ENB-0040 or asfotase alfa) has shown promising results in a mouse model of HPP (Alpl−/− mice). Administration of mineral-targeting TNAP from birth increased survival and prevented the seizures, rickets, as well as all the tooth abnormalities, including dentin, acellular cementum, and enamel defects in this model of severe HPP. Clinical trials using mineral-targeting TNAP in children 3 years of age or younger with life-threatening HPP was associated with healing of the skeletal manifestations of HPP as well as improved respiratory and motor function. Improvement is still being observed in the patients receiving continued asfotase alfa therapy, with more than 3 years of treatment in some children. Enzyme replacement therapy with asfotase alfa has to-date been successful in patients with life-threatening HPP. PMID:25254037

[Cystinosis : Diagnosis, cystine-depleting therapy, and transition].

PubMed

Kaufeld, Jessica; Weber, Lutz T; Kurschat, Christine; Canaan-Kuehl, Sima; Brand, Eva; Oh, Jun; Pape, Lars

2018-04-18

This article presents a case of cystinosis in a young man. Diagnosis of the disease and the problem of transition to adult care are described. Cystinosis is a rare lysosomal storage disease with first manifestation in early childhood presenting as renal Fanconi syndrome. Without treatment, the disease leads to severe health impairment. Due to the rarity of the disease, a correct diagnosis is often delayed. Without treatment, cystinosis often leads to end-stage renal failure, blindness, hypothyroidism, diabetes mellitus, and rickets. Cystine-depleting therapy with cysteamine significantly improves mortality and quality of life.

Three novel PHEX gene mutations in four Chinese families with X-linked dominant hypophosphatemic rickets

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kang, Qing-lin; Xu, Jia; Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233

2012-07-13

Highlights: Black-Right-Pointing-Pointer In our study, all of the patients were of Han Chinese ethnicity, which were rarely reported. Black-Right-Pointing-Pointer We identified three novel PHEX gene mutations in four unrelated families with XLH. Black-Right-Pointing-Pointer We found that the relationship between the phenotype and genotype of the PHEX gene was not invariant. Black-Right-Pointing-Pointer We found that two PHEX gene sites, p.534 and p.731, were conserved. -- Abstract: Background: X-linked hypophosphatemia (XLH), the most common form of inherited rickets, is a dominant disorder that is characterized by renal phosphate wasting with hypophosphatemia, abnormal bone mineralization, short stature, and rachitic manifestations. The related genemore » with inactivating mutations associated with XLH has been identified as PHEX, which is a phosphate-regulating gene with homologies to endopeptidases on the X chromosome. In this study, a variety of PHEX mutations were identified in four Chinese families with XLH. Methods: We investigated four unrelated Chinese families who exhibited typical features of XLH by using PCR to analyze mutations that were then sequenced. The laboratory and radiological investigations were conducted simultaneously. Results: Three novel mutations were found in these four families: one frameshift mutation, c.2033dupT in exon 20, resulting in p.T679H; one nonsense mutation, c.1294A > T in exon 11, resulting in p.K432X; and one missense mutation, c.2192T > C in exon 22, resulting in p.F731S. Conclusions: We found that the PHEX gene mutations were responsible for XLH in these Chinese families. Our findings are useful for understanding the genetic basis of Chinese patients with XLH.« less

Pathophysiology of hypophosphatasia and the potential role of asfotase alfa.

PubMed

Orimo, Hideo

2016-01-01

Hypophosphatasia (HPP) is an inherited systemic bone disease that is characterized by bone hypomineralization. HPP is classified into six forms according to the age of onset and severity as perinatal (lethal), perinatal benign, infantile, childhood, adult, and odontohypophosphatasia. The causative gene of the disease is the ALPL gene that encodes tissue-nonspecific alkaline phosphatase (TNAP). TNAP is expressed ubiquitously, and its physiological role is apparent in bone mineralization. A defect in bone mineralization can manifest in several ways, including rickets or osteomalacia in HPP patients. Patients with severe forms suffer from respiratory failure because of hypoplastic chest, which is the main cause of death. They sometimes present with seizures due to a defect in vitamin B6 metabolism resulting from the lack of alkaline phosphatase activity in neuronal cells, which is also lethal. Patients with a mild form of the disease exhibit rickets or osteomalacia and a functional defect of exercise. Odontohypophosphatasia shows only dental manifestations. To date, 302 mutations in the ALPL gene have been reported, mainly single-nucleotide substitutions, and the relationships between phenotype and genotype have been partially elucidated. An established treatment for HPP was not available until the recent development of enzyme replacement therapy. The first successful enzyme replacement therapy in model mice using a modified human TNAP protein (asfotase alfa) was reported in 2008, and subsequently success in patients with severe form of the disease was reported in 2012. In 2015, asfotase alfa was approved in Japan in July, followed by in the EU and Canada in August, and then by the US Food and Drug Administration in the USA in October. It is expected that therapy with asfotase alfa will drastically change treatments and prognosis of HPP.

A Mutation in the Dmp1 Gene Alters Phosphate Responsiveness in Mice

PubMed Central

Gerard-O'Riley, Rita L.; Acton, Dena; McQueen, Amie K.; Strobel, Isabel E.; Witcher, Phillip C.; Feng, Jian Q.; Econs, Michael J.

2017-01-01

Mutations in the dentin matrix protein 1 (DMP1) gene cause autosomal recessive hypophosphatemic rickets (ARHR). Hypophosphatemia in ARHR results from increased circulating levels of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). Similarly, elevated FGF23, caused by mutations in the PHEX gene, is responsible for the hypophosphatemia in X-linked hypophosphatemic rickets (XLH). Previously, we demonstrated that a Phex mutation in mice creates a lower set point for extracellular phosphate, where an increment in phosphorus further stimulates Fgf23 production to maintain low serum phosphorus levels. To test the presence of the similar set point defect in ARHR, we generated 4- and 12-week-old Dmp1/Galnt3 double knockout mice and controls, including Dmp1 knockout mice (a murine model of ARHR), Galnt3 knockout mice (a murine model of familial tumoral calcinosis), and phenotypically normal double heterozygous mice. Galnt3 knockout mice had increased proteolytic cleavage of Fgf23, leading to low circulating intact Fgf23 levels with consequent hyperphosphatemia. In contrast, Dmp1 knockout mice had little Fgf23 cleavage and increased femoral Fgf23 expression, resulting in hypophosphatemia and low femoral bone mineral density (BMD). However, introduction of the Galnt3 null allele to Dmp1 knockout mice resulted in a significant increase in serum phosphorus and normalization of BMD. This increased serum phosphorus was accompanied by markedly elevated Fgf23 expression and circulating Fgf23 levels, an attempt to reduce serum phosphorus in the face of improving phosphorus levels. These data indicate that a Dmp1 mutation creates a lower set point for extracellular phosphate and maintains it through the regulation of Fgf23 cleavage and expression. PMID:28005411

Hereditary hypophosphatemia in Norway: a retrospective population-based study of genotypes, phenotypes, and treatment complications

PubMed Central

Rafaelsen, Silje; Johansson, Stefan; Ræder, Helge; Bjerknes, Robert

2015-01-01

Objective Hereditary hypophosphatemias (HH) are rare monogenic conditions characterized by decreased renal tubular phosphate reabsorption. The aim of this study was to explore the prevalence, genotypes, phenotypic spectrum, treatment response, and complications of treatment in the Norwegian population of children with HH. Design Retrospective national cohort study. Methods Sanger sequencing and multiplex ligand-dependent probe amplification analysis of PHEX and Sanger sequencing of FGF23, DMP1, ENPP1KL, and FAM20C were performed to assess genotype in patients with HH with or without rickets in all pediatric hospital departments across Norway. Patients with hypercalcuria were screened for SLC34A3 mutations. In one family, exome sequencing was performed. Information from the patients' medical records was collected for the evaluation of phenotype. Results Twety-eight patients with HH (18 females and ten males) from 19 different families were identified. X-linked dominant hypophosphatemic rickets (XLHR) was confirmed in 21 children from 13 families. The total number of inhabitants in Norway aged 18 or below by 1st January 2010 was 1 109 156, giving an XLHR prevalence of ∼1 in 60 000 Norwegian children. FAM20C mutations were found in two brothers and SLC34A3 mutations in one patient. In XLHR, growth was compromised in spite of treatment with oral phosphate and active vitamin D compounds, with males tending to be more affected than females. Nephrocalcinosis tended to be slightly more common in patients starting treatment before 1 year of age, and was associated with higher average treatment doses of phosphate. However, none of these differences reached statistical significance. Conclusions We present the first national cohort of HH in children. The prevalence of XLHR seems to be lower in Norwegian children than reported earlier. PMID:26543054

A patient with hypophosphatemia, a femoral fracture, and recurrent kidney stones: report of a novel mutation in SLC34A3.

PubMed

Page, Kathleen; Bergwitz, Clemens; Jaureguiberry, Graciana; Harinarayan, Chittari V; Insogna, Karl

2008-10-01

To determine if there was a genetic contribution to our patient's unusual clinical presentation of nephrolithiasis and nonhealing stress fracture. We describe a 31-year-old man who had rickets as a child and developed a femur insufficiency fracture and recurrent nephrolithiasis as an adult after moving to the United States from India. The patient's clinical course and results from radiographic and biochemical analyses are described. Analysis of the SLC34A3 gene was performed using genomic DNA samples from the patient and his family members. Before referral to the Yale Bone Center, the patient was treated with calcitriol, ergocalciferol, and phosphate. Changing therapy to phosphate alone led to clinical improvement. Genetic analysis revealed that the patient is a compound heterozygote for mutations in the SLC34A3 gene. On 1 allele, he has a previously described missense mutation in exon 7: c.575C>T (p.Ser192Leu). The other allele carries a novel nonsense mutation in exon 3: c.145C>T (p.Gln49X). One unaffected sibling is a carrier of the missense mutation and 1 sister with a history of flank pain is a carrier of the novel mutation. Hereditary hypophosphatemic rickets with hypercalciuria is a rare metabolic disorder associated with mutations in SLC34A3, the gene that encodes the renal sodium phosphate cotransporter NaPi-IIc. Although hypercalciuria is a distinguishing feature of the disease, nephrolithiasis is rarely described. The patient's atypical clinical presentation illustrates that both environmental and genetic factors potentially affect phenotypic expression of SLC34A3 mutations.

A Mutation in the Dmp1 Gene Alters Phosphate Responsiveness in Mice.

PubMed

Ichikawa, Shoji; Gerard-O'Riley, Rita L; Acton, Dena; McQueen, Amie K; Strobel, Isabel E; Witcher, Phillip C; Feng, Jian Q; Econs, Michael J

2017-03-01

Mutations in the dentin matrix protein 1 (DMP1) gene cause autosomal recessive hypophosphatemic rickets (ARHR). Hypophosphatemia in ARHR results from increased circulating levels of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). Similarly, elevated FGF23, caused by mutations in the PHEX gene, is responsible for the hypophosphatemia in X-linked hypophosphatemic rickets (XLH). Previously, we demonstrated that a Phex mutation in mice creates a lower set point for extracellular phosphate, where an increment in phosphorus further stimulates Fgf23 production to maintain low serum phosphorus levels. To test the presence of the similar set point defect in ARHR, we generated 4- and 12-week-old Dmp1/Galnt3 double knockout mice and controls, including Dmp1 knockout mice (a murine model of ARHR), Galnt3 knockout mice (a murine model of familial tumoral calcinosis), and phenotypically normal double heterozygous mice. Galnt3 knockout mice had increased proteolytic cleavage of Fgf23, leading to low circulating intact Fgf23 levels with consequent hyperphosphatemia. In contrast, Dmp1 knockout mice had little Fgf23 cleavage and increased femoral Fgf23 expression, resulting in hypophosphatemia and low femoral bone mineral density (BMD). However, introduction of the Galnt3 null allele to Dmp1 knockout mice resulted in a significant increase in serum phosphorus and normalization of BMD. This increased serum phosphorus was accompanied by markedly elevated Fgf23 expression and circulating Fgf23 levels, an attempt to reduce serum phosphorus in the face of improving phosphorus levels. These data indicate that a Dmp1 mutation creates a lower set point for extracellular phosphate and maintains it through the regulation of Fgf23 cleavage and expression. Copyright © 2017 by the Endocrine Society.

FGF23 AND SYNDROMES OF ABNORMAL RENAL PHOSPHATE HANDLING

PubMed Central

Bergwitz, Clemens; Jüppner, Harald

2016-01-01

Fibroblast growth factor 23 (FGF23) is part of a previously unrecognized hormonal bone-parathyroid-kidney axis, which is modulated by 1,25(OH)2-vitamin D (1,25(OH)2D), dietary and circulating phosphate and possibly PTH. FGF23 was discovered as the humoral factor in tumors that causes hypophosphatemia and osteomalacia and through the identification of a mutant form of FGF23 that leads to autosomal dominant hypophosphatemic rickets (ADHR), a rare genetic disorder. FGF23 appears to be mainly secreted by osteocytes where its expression is up-regulated by 1,25(OH)2D and probably by increased serum phosphate levels. Its synthesis and secretion is reduced through yet unknown mechanisms that involve the phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX), dentin matrix protein 1 (DMP1) and ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). Consequently, loss-of-function mutations in these genes underlie hypophosphatemic disorders that are either X-linked or autosomal recessive. Impaired O-glycosylation of FGF23 due to the lack of UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyl-transferase 3 (GALNT3) or due to certain homozygous FGF23 mutations results in reduced secretion of intact FGF23 and leads to familial hypophosphatemic tumoral calcinosis. FGF23 acts through FGF-receptors and the coreceptor Klotho to reduce 1,25(OH)2D synthesis in the kidney and probably the synthesis of parathyroid hormone (PTH) by the parathyroid glands. It furthermore synergizes with PTH to increase renal phosphate excretion by reducing expression of the sodium-phosphate cotransporters NaPi-IIa and NaPi-IIc in the proximal tubules. Loss-of-function mutations in these two transporters lead to autosomal recessive Fanconi syndrome or to hereditary hypophosphatemic rickets with hypercalciuria, respectively. PMID:22396161

Effect of 1,25-dihydroxyvitamin D3 on plasma concentrations of calcium-binding protein in normal and rachitic (vitamin D-dependent rickets type I) pigs.

PubMed

Maunder, E M; Pillay, A V; Care, A D

1987-10-01

An i.v. injection of calcitriol (1,25-(OH)2D3) had no effect within 2.5 h on plasma concentrations of calbindin-D9K (vitamin D-induced calcium-binding protein; CaBP) in hypocalcaemic pigs with inherited vitamin D-dependent rickets type I or in their normocalcaemic siblings or half-siblings. Three days later the plasma concentration of CaBP had doubled in the hypocalcaemic pigs, but was unaltered in the normocalcaemic siblings and half-siblings. Following daily i.v. injections of 1,25-(OH)2D3 for a further 5 days (days 4-8) plasma concentrations of CaBP increased in both the hypocalcaemic (days 4-8) and normocalcaemic (day 8) pigs, the effect being more rapid and greater in the hypocalcaemic 1,25-(OH)2D3-deficient animals. An i.v. injection of 1,25-(OH)2D3 to pure Yucatan pigs also had no effect on plasma concentrations of CaBP within 1.5 h, but in the following 1 h there was some indication of an increase in plasma CaBP levels. In contrast to the normal pigs, insulin-induced hypoglycaemia did not lead to a peak in plasma CaBP concentrations in the hypocalcaemic pigs. There was also no change in the plasma concentrations of 1,25-(OH)2D3 associated with the peak in plasma CaBP following insulin-induced hypoglycaemia in normocalcaemic pigs. These results suggest that changes in plasma concentrations of 1,25-(OH)2D3 are not directly involved in mediating the increase in plasma CaBP which follows hypoglycaemia induced by insulin in normal pigs, although 1,25-(OH)2D3 probably plays a permissive role.

Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia.

PubMed

Shimada, T; Mizutani, S; Muto, T; Yoneya, T; Hino, R; Takeda, S; Takeuchi, Y; Fujita, T; Fukumoto, S; Yamashita, T

2001-05-22

Tumor-induced osteomalacia (TIO) is one of the paraneoplastic diseases characterized by hypophosphatemia caused by renal phosphate wasting. Because removal of responsible tumors normalizes phosphate metabolism, an unidentified humoral phosphaturic factor is believed to be responsible for this syndrome. To identify the causative factor of TIO, we obtained cDNA clones that were abundantly expressed only in a tumor causing TIO and constructed tumor-specific cDNA contigs. Based on the sequence of one major contig, we cloned 2,270-bp cDNA, which turned out to encode fibroblast growth factor 23 (FGF23). Administration of recombinant FGF23 decreased serum phosphate in mice within 12 h. When Chinese hamster ovary cells stably expressing FGF23 were s.c. implanted into nude mice, hypophosphatemia with increased renal phosphate clearance was observed. In addition, a high level of serum alkaline phosphatase, low 1,25-dihydroxyvitamin D, deformity of bone, and impairment of body weight gain became evident. Histological examination showed marked increase of osteoid and widening of growth plate. Thus, continuous production of FGF23 reproduced clinical, biochemical, and histological features of TIO in vivo. Analyses for recombinant FGF23 products produced by Chinese hamster ovary cells indicated proteolytic cleavage of FGF23 at the RXXR motif. Recent genetic study indicates that missense mutations in this RXXR motif of FGF23 are responsible for autosomal dominant hypophosphatemic rickets, another hypophosphatemic disease with similar features to TIO. We conclude that overproduction of FGF23 causes TIO, whereas mutations in the FGF23 gene result in autosomal dominant hypophosphatemic rickets possibly by preventing proteolytic cleavage and enhancing biological activity of FGF23.

Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia

PubMed Central

Shimada, Takashi; Mizutani, Satoru; Muto, Takanori; Yoneya, Takashi; Hino, Rieko; Takeda, Shu; Takeuchi, Yasuhiro; Fujita, Toshiro; Fukumoto, Seiji; Yamashita, Takeyoshi

2001-01-01

Tumor-induced osteomalacia (TIO) is one of the paraneoplastic diseases characterized by hypophosphatemia caused by renal phosphate wasting. Because removal of responsible tumors normalizes phosphate metabolism, an unidentified humoral phosphaturic factor is believed to be responsible for this syndrome. To identify the causative factor of TIO, we obtained cDNA clones that were abundantly expressed only in a tumor causing TIO and constructed tumor-specific cDNA contigs. Based on the sequence of one major contig, we cloned 2,270-bp cDNA, which turned out to encode fibroblast growth factor 23 (FGF23). Administration of recombinant FGF23 decreased serum phosphate in mice within 12 h. When Chinese hamster ovary cells stably expressing FGF23 were s.c. implanted into nude mice, hypophosphatemia with increased renal phosphate clearance was observed. In addition, a high level of serum alkaline phosphatase, low 1,25-dihydroxyvitamin D, deformity of bone, and impairment of body weight gain became evident. Histological examination showed marked increase of osteoid and widening of growth plate. Thus, continuous production of FGF23 reproduced clinical, biochemical, and histological features of TIO in vivo. Analyses for recombinant FGF23 products produced by Chinese hamster ovary cells indicated proteolytic cleavage of FGF23 at the RXXR motif. Recent genetic study indicates that missense mutations in this RXXR motif of FGF23 are responsible for autosomal dominant hypophosphatemic rickets, another hypophosphatemic disease with similar features to TIO. We conclude that overproduction of FGF23 causes TIO, whereas mutations in the FGF23 gene result in autosomal dominant hypophosphatemic rickets possibly by preventing proteolytic cleavage and enhancing biological activity of FGF23. PMID:11344269

Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo.

PubMed

Shimada, Takashi; Muto, Takanori; Urakawa, Itaru; Yoneya, Takashi; Yamazaki, Yuji; Okawa, Katsuya; Takeuchi, Yasuhiro; Fujita, Toshiro; Fukumoto, Seiji; Yamashita, Takeyoshi

2002-08-01

FGF-23 is involved in the pathogenesis of two similar hypophosphatemic diseases, autosomal dominant hypophosphatemic rickets/osteomalacia (ADHR) and tumor-induced osteomalacia (TIO). We have shown that the overproduction of FGF-23 by tumors causes TIO. In contrast, ADHR derives from missense mutations in FGF-23 gene. However, it has been unclear how those mutations affect phosphate metabolism. Therefore, we produced mutant as well as wild-type FGF-23 proteins and examined their biological activity. Western blot analysis using site-specific antibodies showed that wild-type FGF-23 secreted into conditioned media was partially cleaved between Arg(179) and Ser(180). In addition, further processing of the cleaved N-terminal portion was observed. In constrast, mutant FGF-23 proteins found in ADHR were resistant to the cleavage. In order to clarify which molecule has the biological activity to induce hypophosphatemia, we separated full-length protein, the N-terminal and C-terminal fragments of wild-type FGF-23. When the activity of each fraction was examined in vivo, only the full-length FGF-23 decreased serum phosphate. Mutant FGF-23 protein that was resistant to the cleavage also retained the activity to induce hypophosphatemia. The extent of hypophosphatemia induced by the single administration of either wild-type or the mutant full-length FGF-23 protein was similar. In addition, implantation of CHO cells expressing the mutant FGF-23 protein caused hypophosphatemia and the decrease of bone mineral content. We conclude that ADHR is caused by hypophosphatemic action of mutant full-length FGF-23 proteins that are resistant to the cleavage between Arg(179) and Ser(180).

[Plasma vitamin D levels in native and immigrant children under the age of 6 years of different ethnic origins].

PubMed

Sánchez Muro, J M; Yeste Fernández, D; Marín Muñoz, A; Fernández Cancio, M; Audí Parera, L; Carrascosa Lezcano, A

2015-05-01

Nutritional rickets is an emergent disease in Spain, and occurs particularly in black and dark-skinned infants and children from immigrant populations. The aim of this work was to ascertain the vitamin D reserve in a population of native and immigrant children under the age of 6 years. A prospective study was conducted at a Primary Healthcare Centre in Salt (Girona). 307 children with the following origin and race distribution: Caucasian (n=85; 28%), Sub-Saharan (n=101; 32.5%); Maghrebí (n=87, 28.0%); Central-American (n=20; 6.4%) and Indo-Pakistani (n=14; 4.5%). The biochemistry blood parameters studied were: calcium, phosphorus, alkaline phosphatase, 25-hydroxivitamin D, and parathormone. A nutritional survey was used to estimate calcium and vitamin D intake and degree of sun exposure. Vitamin D deficiency (<20 ng/ml) was detected in Caucasians (8%), Sub-Saharans (18%), Central-Americans (20%), Maghrebís (34.5%), and Indo-Pakistanis (64%). Of the children studied (n=9), 2.9% had serious vitamin D deficiency (< 10 ng/ml); only one child of Sub-Saharan origin met the biochemical criteria for classical rickets. The prevalence of vitamin D deficiency was significantly higher in children not receiving vitamin D supplements in the first year of life. Plasma vitamin D concentrations were deficient in 22.5% of children under the age of six, being more prevalent in children of Indo-Pakistani and Maghrebí origin. Copyright © 2014 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.

Hypophosphatemic osteomalacia and bone sclerosis caused by a novel homozygous mutation of the FAM20C gene in an elderly man with a mild variant of Raine syndrome.

PubMed

Takeyari, Shinji; Yamamoto, Takehisa; Kinoshita, Yuka; Fukumoto, Seiji; Glorieux, Francis H; Michigami, Toshimi; Hasegawa, Kosei; Kitaoka, Taichi; Kubota, Takuo; Imanishi, Yasuo; Shimotsuji, Tsunesuke; Ozono, Keiichi

2014-10-01

Hypophosphatemia and increased serum fibroblast growth factor 23 (FGF23) levels have been reported in young brothers with compound heterozygous mutations for the FAM20C gene; however, rickets was not observed in these cases. We report an adult case of Raine syndrome accompanying hypophosphatemic osteomalacia with a homozygous FAM20C mutation (R408W) associated with increased periosteal bone formation in the long bones and an increase in bone mineral density in the femoral neck. The patient, a 61-year-old man, was born from a cousin-to-cousin marriage. A short stature and severe dental demineralization were reported at an elementary school age. Hypophosphatemia was noted inadvertently at 27years old, at which time he started to take an active vitamin D metabolite (alphacalcidol) and phosphate. He also manifested ossification of the posterior longitudinal ligament. On bone biopsy performed at the age of 41years, we found severe osteomalacia surrounding osteocytes, which appeared to be an advanced form of periosteocytic hypomineralized lesions compared to those reported in patients with X-linked hypophosphatemic rickets. Laboratory data at 61years of age revealed markedly increased serum intact-FGF23 levels, which were likely to be the cause of hypophosphatemia and the decreased level of 1,25(OH)2D. We recently identified a homozygous FAM20C mutation, which was R408W, in this patient. When expressed in HEK293 cells, the R408W mutant protein exhibited impaired kinase activity and secretion. Our findings suggest that certain homozygous FAM20C mutations can cause FGF23-related hypophosphatemic osteomalacia and indicate the multiple roles of FAM20C in bone. Copyright © 2014 Elsevier Inc. All rights reserved.

Enzyme replacement therapy for murine hypophosphatasia.

PubMed

Millán, José Luis; Narisawa, Sonoko; Lemire, Isabelle; Loisel, Thomas P; Boileau, Guy; Leonard, Pierre; Gramatikova, Svetlana; Terkeltaub, Robert; Camacho, Nancy Pleshko; McKee, Marc D; Crine, Philippe; Whyte, Michael P

2008-06-01

Hypophosphatasia (HPP) is the inborn error of metabolism that features rickets or osteomalacia caused by loss-of-function mutation(s) within the gene that encodes the tissue-nonspecific isozyme of alkaline phosphatase (TNALP). Consequently, natural substrates for this ectoenzyme accumulate extracellulary including inorganic pyrophosphate (PPi), an inhibitor of mineralization, and pyridoxal 5'-phosphate (PLP), a co-factor form of vitamin B6. Babies with the infantile form of HPP often die with severe rickets and sometimes hypercalcemia and vitamin B6-dependent seizures. There is no established medical treatment. Human TNALP was bioengineered with the C terminus extended by the Fc region of human IgG for one-step purification and a deca-aspartate sequence (D10) for targeting to mineralizing tissue (sALP-FcD10). TNALP-null mice (Akp2-/-), an excellent model for infantile HPP, were treated from birth using sALP-FcD10. Short-term and long-term efficacy studies consisted of once daily subcutaneous injections of 1, 2, or 8.2 mg/kg sALP-FcD10 for 15, 19, and 15 or 52 days, respectively. We assessed survival and growth rates, circulating levels of sALP-FcD10 activity, calcium, PPi, and pyridoxal, as well as skeletal and dental manifestations using radiography, microCT, and histomorphometry. Akp2-/- mice receiving high-dose sALP-FcD10 grew normally and appeared well without skeletal or dental disease or epilepsy. Plasma calcium, PPi, and pyridoxal concentrations remained in their normal ranges. We found no evidence of significant skeletal or dental disease. Enzyme replacement using a bone-targeted, recombinant form of human TNALP prevents infantile HPP in Akp2-/- mice.

Enzyme Replacement Therapy for Murine Hypophosphatasia*

PubMed Central

Millán, José Luis; Narisawa, Sonoko; Lemire, Isabelle; Loisel, Thomas P; Boileau, Guy; Leonard, Pierre; Gramatikova, Svetlana; Terkeltaub, Robert; Camacho, Nancy Pleshko; McKee, Marc D; Crine, Philippe; Whyte, Michael P

2008-01-01

Introduction Hypophosphatasia (HPP) is the inborn error of metabolism that features rickets or osteomalacia caused by loss-of-function mutation(s) within the gene that encodes the tissue-nonspecific isozyme of alkaline phosphatase (TNALP). Consequently, natural substrates for this ectoenzyme accumulate extracellulary including inorganic pyrophosphate (PPi), an inhibitor of mineralization, and pyridoxal 5`-phosphate (PLP), a co-factor form of vitamin B6. Babies with the infantile form of HPP often die with severe rickets and sometimes hypercalcemia and vitamin B6-dependent seizures. There is no established medical treatment. Materials and Methods Human TNALP was bioengineered with the C terminus extended by the Fc region of human IgG for one-step purification and a deca-aspartate sequence (D10) for targeting to mineralizing tissue (sALP-FcD10). TNALP-null mice (Akp2−/−), an excellent model for infantile HPP, were treated from birth using sALP-FcD10. Short-term and long-term efficacy studies consisted of once daily subcutaneous injections of 1, 2, or 8.2 mg/kg sALP-FcD10 for 15, 19, and 15 or 52 days, respectively. We assessed survival and growth rates, circulating levels of sALP-FcD10 activity, calcium, PPi, and pyridoxal, as well as skeletal and dental manifestations using radiography, μCT, and histomorphometry. Results Akp2−/− mice receiving high-dose sALP-FcD10 grew normally and appeared well without skeletal or dental disease or epilepsy. Plasma calcium, PPi, and pyridoxal concentrations remained in their normal ranges. We found no evidence of significant skeletal or dental disease. Conclusions Enzyme replacement using a bone-targeted, recombinant form of human TNALP prevents infantile HPP in Akp2−/− mice. PMID:18086009

CYP24 inhibition as a therapeutic target in FGF23-mediated renal phosphate wasting disorders

PubMed Central

Bai, Xiuying; Miao, Dengshun; Xiao, Sophia; Qiu, Dinghong; St-Arnaud, René; Petkovich, Martin; Gupta, Ajay; Goltzman, David; Karaplis, Andrew C.

2016-01-01

CYP24A1 (hereafter referred to as CYP24) enzymatic activity is pivotal in the inactivation of vitamin D metabolites. Basal renal and extrarenal CYP24 is usually low but is highly induced by its substrate 1,25-dihydroxyvitamin D. Unbalanced high and/or long-lasting CYP24 expression has been proposed to underlie diseases like chronic kidney disease, cancers, and psoriasis that otherwise should favorably respond to supplemental vitamin D. Using genetically modified mice, we have shown that renal phosphate wasting hypophosphatemic states arising from high levels of fibroblast growth factor 23 (FGF23) are also associated with increased renal Cyp24 expression, suggesting that elevated CYP24 activity is pivotal to the pathophysiology of these disorders. We therefore crossed 2 mouse strains, each with distinct etiology for high levels of circulating FGF23, onto a Cyp24-null background. Specifically, we evaluated Cyp24 deficiency in Hyp mice, the murine homolog of X-linked dominant hypophosphatemic rickets, and transgenic mice that overexpress a mutant FGF23 (FGF23R176Q) that is associated with the autosomal dominant form of hypophosphatemic rickets. Loss of Cyp24 in these murine models of human disease resulted in near-complete recovery of rachitic/osteomalacic bony abnormalities in the absence of any improvement in the serum biochemical profile. Moreover, treatment of Hyp and FGF23R1760-transgenic mice with the CYP24 inhibitor CTA102 also ameliorated their rachitic bones. Our results link CYP24 activity to the pathophysiology of FGF23-dependent renal phosphate wasting states and implicate pharmacologic CYP24 inhibition as a therapeutic adjunct for their treatment. PMID:26784541

Biological Effects Of Full-Spectrum Lighting

NASA Astrophysics Data System (ADS)

Bickford, Elwood D.

1980-10-01

Humans and other living organisms have evolved various known and unknown photoreceptors and responses under full-spectrum optical radiation of sun and sky at the earth's surface. The trend to indoor living over the past 100 years has produced a self-exile from this radiation environment resulting in the disease conditions of rickets and erythema. Concerns for these diseases have pointed attention to the delicate balance between the beneficial and detrimental effects of full-spectrum optical radiation and has confounded the concepts of illumination and radiation safety criteria. Further knowledge has to be obtained to better evaluate the known and unknown effects of full-spectrum optical radiation in a modern society.

Vegetarian diets and children.

PubMed

Sanders, T A

1995-08-01

Although the general health and development of vegan and vegetarian children seem to be normal, there may be subtle differences compared with omnivores. They are at increased risk of iron deficiency, and impaired psychomotor development associated with iron deficiency has been reported in macrobiotic infants. Fortunately, this impairment is not permanent, and follow-up studies have reported higher-than-average intelligence quotients among older macrobiotic children. Several other hazards of vegetarian diets have been identified, including vitamin B12 deficiency, rickets, and a bulky diet that can restrict energy intake in the first few years of life; however, these pitfalls can be avoided easily, and children can be successfully reared on vegetarian diets.

[Mutation analysis of FAH gene in patients with tyrosinemia type 1].

PubMed

Dou, Li-Min; Fang, Ling-Juan; Wang, Xiao-Hong; Lu, Wei; Chen, Rui; Li, Li-Ting; Zhao, Jing; Wang, Jian-She

2013-04-01

To investigate the clinical features and mutations of the FAH gene. Clinical records of two cases were collected, and diagnosis was made according to the diagnostic criteria of the International Organization for Rare Disorders (NORD). Genomic DNA was extracted from peripheral blood leukocytes with QIAamp DNA Mini Kit. The DNA extracts were subjected to direct sequencing for 14 exons together with adjacent fragments of FAH gene using ABI Prism 3730 Genetic Analyzer (Applied Biosystems, Foster City, CA) after PCR based on genomic DNA. The mutation source was verified by analyzing parents' exons corresponding to patients' mutation exons. The homology between human FAH enzyme and that of other species was surveyed using software Clustal X(European Bioinformatics Institute, Hinxton, Saffron Walde, UK). Polyphen (Polymorphism Phenotyping), available online, were used to predict possible impact of an amino acid substitution on structure and function of FAH enzyme. Polyphen calculates position-specific independent counts (PISC) scores for two amino acid variants in polymorphic position. A PISC scores that differ by > 2 were regarded as indicating the probability of damaging variants. Patient 1 was a 5 months and 21 days-old boy who suffered from persistent diarrhea, hepatomegaly, ascites; Alpha-fetoprotein > 1210 µg/L, levels of tyrosine in blood and succinylacetone in urine were 110.8 µmol/L and 83.7 µmol/L. His sister suffered from tyrosinemia type 1. Direct sequencing showed a G to A transition in CDS position 455 and 1027. He was compound heterozygous for the mutation c.455G > A/c.1027G > A, which predicts a change from tryptophan to a stop codon (TGG > TAG) at position 152 (W152X) and a change from glycine to arginine (GGG > AGG) at position 343 respectively. Patient 2 was a 6 year and 1 month-old girl with late-onset rickets who had signs of hepatosplenomegaly, rachitic rosary, windswept knees. Hypophosphatemia and alkaline phosphatase 1620 IU/L were detected. Alpha-fetoprotein 412.8 µg/L, levels of tyrosine in blood and succinylacetone in urine were 835.8 µmol/L and 27.48 µmol/L. Rickets did not improve after administration of calcium and vitamine D3. She is homozygous for the mutation c.1027G > A/c.1027G > A, which predicts G343R. The parents were mutation carriers. Analysis by Clustal X on the alignment of amino acids residual reservation among different species showed that the locative amino acid was highly conserved. Polyphen software predicted G343R was probably damaging (PISC score 3.235). Children with tyrosinemia type 1 can have manifestations of persistent diarrhea or late-onset rickets. Physical examination can reveal hepatosplenomegaly, laboratory tests indicate markedly elevated serum concentration of alpha-fetoprotein and alkaline phosphatase in plasma and succinylacetone in urine, other members in family may have tyrosinemias or parents are consanguineous. Mutations c.455G > A and c.1027G > A can be detected in FAH gene of Chinese children.

Regulation of bone-renal mineral and energy metabolism: the PHEX, FGF23, DMP1, MEPE ASARM pathway.

PubMed

Rowe, Peter S N

2012-01-01

More than 300 million years ago, vertebrates emerged from the vast oceans to conquer gravity and the dry land. With this transition, new adaptations occurred that included ingenious changes in reproduction, waste secretion, and bone physiology. One new innovation, the egg shell, contained an ancestral protein (ovocleidin-116) that likely first appeared with the dinosaurs and was preserved through the theropod lineage in modern birds and reptiles. Ovocleidin-116 is an avian homolog of matrix extracellular phosphoglycoprotein (MEPE) and belongs to a group of proteins called short integrin-binding ligand-interacting glycoproteins (SIBLINGs). These proteins are all localized to a defined region on chromosome 5q in mice and chromosome 4q in humans. A unifying feature of SIBLING proteins is an acidic serine aspartate-rich MEPE-associated motif (ASARM). Recent research has shown that the ASARM motif and the released ASARM peptide have regulatory roles in mineralization (bone and teeth), phosphate regulation, vascularization, soft-tissue calcification, osteoclastogenesis, mechanotransduction, and fat energy metabolism. The MEPE ASARM motif and peptide are physiological substrates for PHEX, a zinc metalloendopeptidase. Defects in PHEX are responsible for X-linked hypophosphatemic rickets (HYP). There is evidence that PHEX interacts with another ASARM motif containing SIBLING protein, dentin matrix protein-1 (DMP1). DMP1 mutations cause bone and renal defects that are identical with the defects caused by a loss of PHEX function. This results in autosomal recessive hypophosphatemic rickets (ARHR). In both HYP and ARHR, increased FGF23 expression plays a major role in the disease and in autosomal dominant hypophosphatemic rickets (ADHR), FGF23 half-life is increased by activating mutations. ASARM peptide administration in vitro and in vivo also induces increased FGF23 expression. FGF23 is a member of the fibroblast growth factor (FGF) family of cytokines, which surfaced 500 million years ago with the boney fish (i.e., teleosts) that do not contain SIBLING proteins. In terrestrial vertebrates, FGF23, like SIBLING proteins, is expressed in the osteocyte. The boney fish, however, are an-osteocytic, so a physiological bone-renal link with FGF23 and the SIBLINGs was cemented when life ventured from the oceans to the land during the Triassic period, approximately 300 million years ago. This link has been revealed by recent research that indicates a competitive displacement of a PHEX-DMP1 interaction by an ASARM peptide that leads to increased FGF23 expression. This review discusses the new discoveries that reveal a novel PHEX, DMP1, MEPE, ASARM peptide, and FGF23 bone-renal pathway. This pathway impacts not only bone formation, bone-renal mineralization, and renal phosphate homeostasis but also energy metabolism. The study of this new pathway is relevant for developing therapies for several diseases: bone-teeth mineral loss disorders, renal osteodystrophy, chronic kidney disease and bone mineralization disorders (CKD-MBD), end-stage renal diseases, ectopic arterial-calcification, cardiovascular disease renal calcification, diabetes, and obesity.

Bartter syndrome associated with nephropathic cystinosis

PubMed Central

Sanosi, Ali Al

2016-01-01

Bartter syndrome is a rare inherited defect in the thick ascending limb of the loop of Henle. It is characterized by low potassium levels (hypokalaemia), increased blood pH (alkalosis) and normal to low blood pressure. There are three types of Bartter syndrome: neonatal, the classic type and Gitelman syndrome. Nephropathic cystinosis is an autosomal recessive disorder characterized by accumulation of free cystine in lysosomes due to disorder of lysosomal transport that can lead to end stage renal failure within 10 years and multiorgan impairment. We report a 5 year 9 month old child with Bartter syndrome associated with nephropathic cystinosis, hypothyroidism and rickets. Hitherto, only a handful of similar cases have been reported in the literature. PMID:28096565

Bartter syndrome associated with nephropathic cystinosis.

PubMed

Osman, Nader M; Sanosi, Ali Al

2016-01-01

Bartter syndrome is a rare inherited defect in the thick ascending limb of the loop of Henle. It is characterized by low potassium levels (hypokalaemia), increased blood pH (alkalosis) and normal to low blood pressure. There are three types of Bartter syndrome: neonatal, the classic type and Gitelman syndrome. Nephropathic cystinosis is an autosomal recessive disorder characterized by accumulation of free cystine in lysosomes due to disorder of lysosomal transport that can lead to end stage renal failure within 10 years and multiorgan impairment. We report a 5 year 9 month old child with Bartter syndrome associated with nephropathic cystinosis, hypothyroidism and rickets. Hitherto, only a handful of similar cases have been reported in the literature.

Functions of key residues in the ligand-binding pocket of vitamin D receptor: Fragment molecular orbital interfragment interaction energy analysis

NASA Astrophysics Data System (ADS)

Yamagishi, Kenji; Yamamoto, Keiko; Yamada, Sachiko; Tokiwa, Hiroaki

2006-03-01

Fragment molecular orbital-interfragment interaction energy calculations of the vitamin D receptor (VDR)/1α,25-dihydroxyvitamin D 3 complex were utilized to assign functions of key residues of the VDR. Only one residue forms a significant interaction with the corresponding hydroxy group of the ligand, although two residues are located around each hydroxy group. The degradation of binding affinity for derivatives upon removal of a hydroxy group is closely related to the trend in the strength of the hydrogen bonds. Type II hereditary rickets due to an Arg274 point mutation is caused by the lack of the strongest hydrogen bond.

[Epidemiology of FGF23-related hypophosophatemic diseases].

PubMed

Endo, Itsuro

2016-02-01

Through the studies of patients with hypophosphatemic rickets/osteomalacia, fibroblast growth factor 23(FGF23)has emerged as a humoral factor that reduces serum phosphate. Discovery of FGF23 as an essential regulator of phosphate homeostasis has markedly improved our understanding of phosphate homeostasis and hypophosphatemic or hyperphosphatemic disorders. A nationwide epidemiologic survey of FGF23-related hypophosphatemic diseases indicated that the patients showed FGF23 levels of above 30 pg/mL by intact assay in the presence of hypophosphatemia. The survey also showed that prevalence and biochemical data before and after treatment of the diseases. Novel therapeutic methods for these disorders may be developed by elucidation of the mechanism of action of FGF23.

Air Force Officer Qualifying Test (AFOQT) Form P: Test Manual

DTIC Science & Technology

1990-04-01

103 59.19 14.20 58.75 13.99 Navigator-Technical 131 77.10 18.63 75.96 18.26 Academic Aptitude 75 46.79 12.89 46.56 13.01 Verbal 39 24.17 7.26 24.46 7.44...and even extrate rrestrial in tiraction such as nn)1tVi), inrid grai% iLttIo)ni 6)frces. ’Ihe earth, in actuality, is aI large rock V-A i n .I stU it i...E polymers. 3. Lack of iodine is often related to which of the following diseases? 3-A Beriberi 3-B Scurvy 3-C Rickets 3-D Goiter 3-E Asthma 4. The

Tumor-induced Osteomalacia in a 3-Year-Old With Unresectable Central Giant Cell Lesions.

PubMed

Crossen, Stephanie S; Zambrano, Eduardo; Newman, Beverley; Bernstein, Jonathan A; Messner, Anna H; Bachrach, Laura K; Twist, Clare J

2017-01-01

Tumor-induced osteomalacia (TIO) is a rare cause of hypophosphatemia involving overproduction of fibroblast growth factor 23. TIO has been described largely in adults with small mesenchymal tumors. We report a case of TIO in a child who presented with knee pain and radiographic findings concerning for rickets, and was found to have maxillomandibular giant cell lesions. The patient was treated with oral phosphorus and calcitriol, surgical debulking, and intralesional corticosteroids, which resulted in tumor regression and normalization of serum fibroblast growth factor 23 and phosphorus. This case illustrates the occurrence of this rare paraneoplastic syndrome in children and adds to our knowledge about clinical manifestations and pathologic findings associated with pediatric TIO.

Transgenic Expression of the Vitamin D Receptor Restricted to the Ileum, Cecum, and Colon of Vitamin D Receptor Knockout Mice Rescues Vitamin D Receptor-Dependent Rickets.

PubMed

Dhawan, Puneet; Veldurthy, Vaishali; Yehia, Ghassan; Hsaio, Connie; Porta, Angela; Kim, Ki-In; Patel, Nishant; Lieben, Liesbet; Verlinden, Lieve; Carmeliet, Geert; Christakos, Sylvia

2017-11-01

Although the intestine plays the major role in 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] action on calcium homeostasis, the mechanisms involved remain incompletely understood. The established model of 1,25(OH)2D3-regulated intestinal calcium absorption postulates a critical role for the duodenum. However, the distal intestine is where 70% to 80% of ingested calcium is absorbed. To test directly the role of 1,25(OH)2D3 and the vitamin D receptor (VDR) in the distal intestine, three independent knockout (KO)/transgenic (TG) lines expressing VDR exclusively in the ileum, cecum, and colon were generated by breeding VDR KO mice with TG mice expressing human VDR (hVDR) under the control of the 9.5-kb caudal type homeobox 2 promoter. Mice from one TG line (KO/TG3) showed low VDR expression in the distal intestine (<50% of the levels observed in KO/TG1, KO/TG2, and wild-type mice). In the KO/TG mice, hVDR was not expressed in the duodenum, jejunum, kidney, or other tissues. Growth arrest, elevated parathyroid hormone level, and hypocalcemia of the VDR KO mice were prevented in mice from KO/TG lines 1 and 2. Microcomputed tomography analysis revealed that the expression of hVDR in the distal intestine of KO/TG1 and KO/TG2 mice rescued the bone defects associated with systemic VDR deficiency, including growth plate abnormalities and altered trabecular and cortical parameters. KO/TG3 mice showed rickets, but less severely than VDR KO mice. These findings show that expression of VDR exclusively in the distal intestine can prevent abnormalities in calcium homeostasis and bone mineralization associated with systemic VDR deficiency. Copyright © 2017 Endocrine Society.

Iron Modifies Plasma FGF23 Differently in Autosomal Dominant Hypophosphatemic Rickets and Healthy Humans

PubMed Central

Peacock, Munro; Gray, Amie K.; Padgett, Leah R.; Hui, Siu L.; Econs, Michael J.

2011-01-01

Context: In autosomal dominant hypophosphatemic rickets (ADHR), fibroblast growth factor 23 (FGF23) resists cleavage, causing increased plasma FGF23 levels. The clinical phenotype includes variable onset during childhood or adulthood and waxing/waning of hypophosphatemia. Delayed onset after puberty in females suggests iron status may be important. Objective: Studies were performed to test the hypothesis that plasma C-terminal and intact FGF23 concentrations are related to serum iron concentrations in ADHR. Design and Setting: Cross-sectional and longitudinal studies of ADHR and a cross-sectional study in healthy subjects were conducted at an academic medical center. Participants: Participants included 37 subjects with ADHR mutations from four kindreds and 158 healthy adult controls. Main Outcome Measure: The relationships of serum iron concentrations with plasma C-terminal and intact FGF23 concentrations were evaluated. Results: Serum phosphate and 1,25-dihydroxyvitamin D correlated negatively with C-terminal FGF23 and intact FGF23 in ADHR but not in controls. Serum iron was negatively correlated to both C-terminal FGF23 (r = −0.386; P < 0.05) and intact FGF23 (r = −0.602; P < 0.0001) in ADHR. However, control subjects also demonstrated a negative relationship of serum iron with C-terminal FGF23 (r = −0.276; P < 0.001) but no relationship with intact FGF23. Longitudinally in ADHR subjects, C-terminal FGF23 and intact FGF23 concentrations changed negatively with iron concentrations (P < 0.001 and P = 0.055, respectively), serum phosphate changed negatively with C-terminal FGF23 and intact FGF23 (P < 0.001), and there was a positive relationship between serum iron and phosphate (P < 0.001). Conclusions: Low serum iron is associated with elevated FGF23 in ADHR. However, in controls, low serum iron was also associated with elevated C-terminal FGF23, but not intact FGF23, suggesting cleavage maintains homeostasis despite increased FGF23 expression. PMID:21880793

Iron modifies plasma FGF23 differently in autosomal dominant hypophosphatemic rickets and healthy humans.

PubMed

Imel, Erik A; Peacock, Munro; Gray, Amie K; Padgett, Leah R; Hui, Siu L; Econs, Michael J

2011-11-01

In autosomal dominant hypophosphatemic rickets (ADHR), fibroblast growth factor 23 (FGF23) resists cleavage, causing increased plasma FGF23 levels. The clinical phenotype includes variable onset during childhood or adulthood and waxing/waning of hypophosphatemia. Delayed onset after puberty in females suggests iron status may be important. Studies were performed to test the hypothesis that plasma C-terminal and intact FGF23 concentrations are related to serum iron concentrations in ADHR. Cross-sectional and longitudinal studies of ADHR and a cross-sectional study in healthy subjects were conducted at an academic medical center. Participants included 37 subjects with ADHR mutations from four kindreds and 158 healthy adult controls. The relationships of serum iron concentrations with plasma C-terminal and intact FGF23 concentrations were evaluated. Serum phosphate and 1,25-dihydroxyvitamin D correlated negatively with C-terminal FGF23 and intact FGF23 in ADHR but not in controls. Serum iron was negatively correlated to both C-terminal FGF23 (r = -0.386; P < 0.05) and intact FGF23 (r = -0.602; P < 0.0001) in ADHR. However, control subjects also demonstrated a negative relationship of serum iron with C-terminal FGF23 (r = -0.276; P < 0.001) but no relationship with intact FGF23. Longitudinally in ADHR subjects, C-terminal FGF23 and intact FGF23 concentrations changed negatively with iron concentrations (P < 0.001 and P = 0.055, respectively), serum phosphate changed negatively with C-terminal FGF23 and intact FGF23 (P < 0.001), and there was a positive relationship between serum iron and phosphate (P < 0.001). Low serum iron is associated with elevated FGF23 in ADHR. However, in controls, low serum iron was also associated with elevated C-terminal FGF23, but not intact FGF23, suggesting cleavage maintains homeostasis despite increased FGF23 expression.

Unexpected widespread hypophosphatemia and bone disease associated with elemental formula use in infants and children.

PubMed

Gonzalez Ballesteros, Luisa F; Ma, Nina S; Gordon, Rebecca J; Ward, Leanne; Backeljauw, Philippe; Wasserman, Halley; Weber, David R; DiMeglio, Linda A; Gagne, Julie; Stein, Robert; Cody, Declan; Simmons, Kimber; Zimakas, Paul; Topor, Lisa Swartz; Agrawal, Sungeeta; Calabria, Andrew; Tebben, Peter; Faircloth, Ruth; Imel, Erik A; Casey, Linda; Carpenter, Thomas O

2017-04-01

Hypophosphatemia occurs with inadequate dietary intake, malabsorption, increased renal excretion, or shifts between intracellular and extracellular compartments. We noticed the common finding of amino-acid based elemental formula [EF] use in an unexpected number of cases of idiopathic hypophosphatemia occurring in infants and children evaluated for skeletal disease. We aimed to fully characterize the clinical profiles in these cases. A retrospective chart review of children with unexplained hypophosphatemia was performed as cases accumulated from various centres in North America and Ireland. Data were analyzed to explore any relationships between feeding and biochemical or clinical features, effects of treatment, and to identify a potential mechanism. Fifty-one children were identified at 17 institutions with EF-associated hypophosphatemia. Most children had complex illnesses and had been solely fed Neocate® formula products for variable periods of time prior to presentation. Feeding methods varied. Hypophosphatemia was detected during evaluation of fractures or rickets. Increased alkaline phosphatase activity and appropriate renal conservation of phosphate were documented in nearly all cases. Skeletal radiographs demonstrated fractures, undermineralization, or rickets in 94% of the cases. Although the skeletal disease had often been attributed to underlying disease, most all improved with addition of supplemental phosphate or change to a different formula product. The observed biochemical profiles indicated a deficient dietary supply or severe malabsorption of phosphate, despite adequate formula composition. When transition to an alternate formula was possible, biochemical status improved shortly after introduction to the alternate formula, with eventual improvement of skeletal abnormalities. These observations strongly implicate that bioavailability of formula phosphorus may be impaired in certain clinical settings. The widespread nature of the findings lead us to strongly recommend careful monitoring of mineral metabolism in children fed EF. Transition to alternative formula use or implementation of phosphate supplementation should be performed cautiously with as severe hypocalcemia may develop. Copyright © 2017 Elsevier Inc. All rights reserved.

Vitamin D Assays and the Definition of Hypovitaminosis D: Results from the 1st International Conference on Controversies in Vitamin D.

PubMed

Sempos, Christopher T; Heijboer, Annemieke C; Bikle, Daniel D; Bollerslev, Jens; Bouillon, Roger; Brannon, Patsy M; DeLuca, Hector F; Jones, Glenville; Munns, Craig F; Bilezikian, John P; Giustina, Andrea; Binkley, Neil

2018-05-31

The 1st International Conference on Controversies in Vitamin D was held in Pisa, Italy June 14-16, 2017. The meeting's purpose was to address controversies in vitamin D research, review data available to help resolve them and suggest a research agenda to clarify areas of uncertainty. Serum 25-hydroxyvitamin D (25 (OH)D) concentration, i.e., the sum of 25 (OH)D 3 and 25 (OH)D 2 , remains the critical measurement for defining vitamin D status. Assay variation for 25 (OH) D has contributed to the current chaos surrounding efforts to define hypovitaminosis D. An essential requirement to develop consensus on vitamin D status is that measurement of 25 (OH) D and, in the future, other potential vitamin D biomarkers, e.g., 1α,25 (OH) 2 D 3 , 3-epi-25 (OH) D, 24,25 (OH) 2 D 3, vitamin D binding protein (DBP), free/bioavailable 25 (OH) D and parathyroid hormone be standardized/harmonized, to allow pooling of research data. Vitamin D Standardization Program (VDSP) tools are described and recommended for standardizing 25 (OH) D measurement in research. In the future, similar methodology, based on National Institute for Standards and Technology (NIST) Standard Reference Materials, must be developed for other candidate markers of vitamin D status. Failure to standardize/harmonize vitamin D metabolite measurements is destined to promulgate continued chaos. At this time, 25 (OH) D values below 12 ng/mL (30 nmol/L) should be considered to be associated with an increased risk of rickets/osteomalacia while 25 (OH) D concentrations between 20-50 ng/mL (50-125 nmol/L) appear to be safe and sufficient in the general population for skeletal health. In an effort to bridge knowledge gaps in defining hypovitaminosis D, an international study on rickets as a multifactorial disease is proposed. This article is protected by copyright. All rights reserved.

The effect of season and latitude on in vitro vitamin D formation by sunlight in South Africa.

PubMed

Pettifor, J M; Moodley, G P; Hough, F S; Koch, H; Chen, T; Lu, Z; Holick, M F

1996-10-01

To assess the effect of season and latitude on the in vitro formation of previtamin D3 and vitamin D3 from 7-dehydrocholesterol (7-DHC) by sunlight in two cities in South Africa, Cape Town and Johannesburg. An in vitro study utilising vials containing 7-DHC, which were exposed to sunlight for a period of 1 hour between 8:00 and 17:00 on 1 day a month for a year. Previtamin D3 and vitamin D3 were separated from 7-DHC by high-performance liquid chromatography, and the amounts formed were calculated with the use of external standards. A marked seasonal variation in vitamin D3 production was noted in Cape Town, with very little being formed during the winter months of April through September. In Johannesburg, in vitro formation changed little throughout the year, and was similar to that found in Cape Town during the summer. During sunlit hours, vitamin D3 production was maximal at midday and small quantities were still being formed between 8:00 and 9:00, and between 16:00 and 17:00 during the summer. During winter in Cape Town, peak formation at midday was less than one-third of that in Johannesburg, and negligible amounts were formed before 10:00 and after 15:00. The previously documented seasonal variation in serum 25-hydroxyvitamin D recorded in patients in Johannesburg is probably a consequence of the increased clothing worn and the decreased time spent out of doors during winter, rather than decreased ultraviolet radiation reaching the earth. The limited in vitro formation of vitamin D3 during winter in Cape Town may have clinical implications insofar as the management of metabolic bone diseases like rickets and osteoporosis is concerned. Breast-fed infants resident in the area are likely to suffer from vitamin D deficiency rickets unless vitamin D supplements are provided, or the mothers are encouraged to take their children out of doors.

Oral Supplementation of Parturient Mothers with Vitamin D and Its Effect on 25OHD Status of Exclusively Breastfed Infants at 6 Months of Age: A Double-Blind Randomized Placebo Controlled Trial.

PubMed

Naik, Prasanna; Faridi, M M A; Batra, Prerna; Madhu, S V

2017-12-01

Exclusively breastfed infants are at increased risk of vitamin D deficiency and many lactating mothers have been found deficient in 25OHD stores. To compare serum vitamin D levels in exclusively breastfed infants at 6 months of age with or without oral supplementation of 600,000 IU of vitamin D3 to mothers in early postpartum period. Exclusively breastfeeding term parturient mothers were randomized 24-48 hours following delivery to receive either 600,000 IU of vitamin D3 (Cholecalciferol) over 10 days in a dose of 60,000 IU/day or placebo. 25OHD levels were measured by Radio Immuno Assay method at recruitment and after 6 months in all mothers and their infants. Urinary calcium and creatinine ratio was measured to monitor adverse effects of vitamin D3 in both mothers and infants at 14 weeks and 6 months of age. X-ray of both wrists in anteroposterior view and serum alkaline phosphatase of infants were done in both groups at 6 months of age to look for evidence of rickets. Maternal profile was similar in intervention (A) and control (B) groups. Mothers' serum 25OHD levels at recruitment were also similar being 16.2 ± 9.3 ng/mL in group A and 14.1 ± 7.1 ng/mL in group B. After 6 months, 25OHD levels were 40.3 ± 21.6 and 22.9 ± 20.1 ng/mL in group A and group B mothers (p ≤ 0.00), respectively. The serum 25OHD levels in cord blood were 9.9 ± 5.7 and 8.9 ± 5.1 ng/mL, respectively, in infants born to mothers in intervention and control groups (p = 0.433). At 6 months of age, the serum 25OHD levels significantly (p < 0.00) raised to 29.1 ± 14.6 ng/mL in infants of group A compared to those of group B (15.7 ± 17.7 ng/mL). Four infants developed radiological rickets at 6 months of age, two infants each in intervention group and study group. As against 10 infants in the control group (16.94%), no infant in the study group had biochemical rickets. Urinary calcium and creatinine ratio in mothers and infants at 14 weeks and 6 months of age in both intervention and study group was within normal limits, indicating there was no adverse effects of oral administration of 600,000 IU of vitamin D3. Serum 25OHD levels of exclusively breastfed infants significantly rise at 6 months of age when their mothers are orally supplemented with 60,000 IU of vitamin D3 daily for 10 days in the early postpartum period in comparison to infants of vitamin D3 unsupplemented mothers.

Novel mutation of OCRL1 in Lowe syndrome.

PubMed

Liu, Ting; Yue, Zhihui; Wang, Haiyan; Tong, Huajuan; Sun, Liangzhong

2015-01-01

Lowe syndrome is a rare, X-linked recessive genetic disease with multi-organ involvement. The pathogenic gene is OCRL1. The authors analyzed the OCRL1 mutation and summarized the clinical features of a Chinese child with Lowe syndrome. The patient is a 3 year 7 mo-old boy. He presented with hypotonia at birth and gradually presented with bilateral congenital cataracts, psychomotor retardation, hypophosphatemic rickets and renal tubular function disorder. Sequence analysis of OCRL1 revealed a novel insertion mutation, c.2367insA (p. Ala813X), in exon 22. This mutation was suspected to cause a premature stop codon of OCRL1 and truncation of the OCRL1 protein. His mother, who carried a heterozygous mutation, had no sign of abnormality.

[Genetic hypophosphatemia: recent advances in physiopathogenic concept].

PubMed

Beraud, G; Perimenis, P; Velayoudom, Fr-L; Wemeau, J-L; Vantyghem, M-Chr

2005-04-01

Renal proximal tubular reabsorption of phosphate and intestinal absorption both regulate phosphate homeostasis. Brush-border membrane Npt2a cotransporter is the key element in proximal tubular P (i) reabsorption. Inactivating mutations of Npt2a cause bone demineralisation and urolithiasis. An excess of a phosphaturic factor, called "Phosphatonin", could modulate phosphate reabsorption by inhibition on Npt2a. Inactivating mutation of PHEX, an endopeptidase-membrane coding gene, is responsible for X-linked Hypophosphatemia (XLH), because of an impaired degradation of phosphatonine by PHEX product. Autosomic Dominant Hypophosphatemic Rickets (ADHR) is explained by a mutation preventing FGF23 (one of the best identified phosphatonines) from cleavage. According recent data, FGF23, MEPE (Matrix Extracellular Phosphoglycoprotein) et FRP4 (frizzled related protein-4) are 3 putative "phosphatonines".

A CLINICIAN'S GUIDE TO X-LINKED HYPOPHOSPHATEMIA

PubMed Central

Carpenter, Thomas O.; Imel, Erik A.; Holm, Ingrid A.; Jan de Beur, Suzanne M.; Insogna, Karl L.

2011-01-01

X-linked hypophosphatemia (XLH) is the prototypic disorder of renal phosphate wasting, and the most common form of heritable rickets. Physicians, patients, and XLH support groups have all expressed concerns about the dearth of information about this disease and the lack of treatment guidelines which frequently lead to missed diagnoses or mismanagement. This perspective addresses the recommendation by conferees for the dissemination of concise and accessible treatment guidelines for clinicians arising from the “Advances in Rare Bone Diseases Scientific Conference,” held at the National Institutes of Health in October 2008. We briefly review the clinical and pathophysiologic features of the disorder, and offer this guide in response to the conference recommendation, base on our collective accumulated experience in the management of this complex disorder. PMID:21538511

Vegetarian diets and children.

PubMed

Sanders, T A; Reddy, S

1994-05-01

The diets and growth of children reared on vegetarian diets are reviewed. Excessive bulk combined with low energy density can be a problem for children aged < or = 5 y and can lead to imparied growth. Diets that have a high content of phytate and other modifiers of mineral absorption are associated with an increased prevalence of rickets and iron-deficiency anemia. Vitamin B-12 deficiency is a real hazard in unsupplemented or unfortified vegan and vegetarian diets. It is suggested that vegans and vegetarians should use oils with a low ratio of linoleic to linolenic acid in view of the recently recognized role of docosahexaenoic acid in visual functioning. If known pitfalls are avoided, the growth and development of children reared on both vegan and vegetarian diets appears normal.

Northern infant syndrome: a deficiency state?

PubMed

Godel, J C; Hart, A G

1984-08-01

A syndrome is described that affected 16 Indian and Inuit infants roughly 3 months old, most of whom were born in settlements in the Canadian Arctic. The infants presented with a clinical picture that included hepatitis, hemolytic anemia, rickets and respiratory distress, a combination that resembled a syndrome first described in malnourished infants at the turn of the century by von Jaksch and Luzet. The clinical course was self-limited, and all the infants survived without sequelae. The cause of the syndrome was not determined; no infectious agents were discovered. However, low levels of vitamins A, C, D and E were found in a few infants in whom assays were done. The implications of these findings and their relation to the possible cause of this "northern infant syndrome" are discussed.

[Is bone biopsy necessary for the diagnosis of metabolic bone diseases? Necessity of bone biopsy].

PubMed

Ito, Akemi; Yajima, Aiji

2011-09-01

Histological analysis of undecalcified bone biopsy specimens is a valuable clinical and research tool for studying the etiology, pathogenesis and treatment of metabolic bone diseases. In case of osteoporosis, bone biopsy is not usually required for the diagnosis ; however, bone histomorphometry may be useful in rare cases with unusual skeletal fragility. Bone histomorphometry also provides valuable information on the mechanism of action, safety and efficacy of new anti-osteoporosis drugs. Bone histomorphometry is useful for the diagnosis and the assessment of treatment response in rickets/osteomalacia and in CKD-MBD (chronic kidney disease-mineral and bone disorders) . In Japan, bone biopsy is often performed to establish the diagnosis of Paget's disease of bone, especially to differentiate it from metastatic bone disease.

Contemporary Medical and Surgical Management of X-linked Hypophosphatemic Rickets.

PubMed

Sharkey, Melinda S; Grunseich, Karl; Carpenter, Thomas O

2015-07-01

X-linked hypophosphatemia is an inheritable disorder of renal phosphate wasting that clinically manifests with rachitic bone pathology. X-linked hypophosphatemia is frequently misdiagnosed and mismanaged. Optimized medical therapy is the cornerstone of treatment. Even with ideal medical management, progressive bony deformity may develop in some children and adults. Medical treatment is paramount to the success of orthopaedic surgical procedures in both children and adults with X-linked hypophosphatemia. Successful correction of complex, multiapical bone deformities found in patients with X-linked hypophosphatemia is possible with careful surgical planning and exacting surgical technique. Multiple methods of deformity correction are used, including acute and gradual correction. Treatment of some pediatric bony deformity with guided growth techniques may be possible. Copyright 2015 by the American Academy of Orthopaedic Surgeons.

Calcium and Bone Metabolism Indices.

PubMed

Song, Lu

2017-01-01

Calcium and inorganic phosphate are of critical importance for many body functions, thus the regulations of their plasma concentrations are tightly controlled by the concerted actions of reabsorption/excretion in the kidney, absorption in the intestines, and exchange from bone, the major reservoir for calcium and phosphate in the body. Parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D (1,25(OH) 2 D) control calcium homeostasis, whereas PTH, 1,25(OH) 2 D, and bone-derived fibroblast growth factor 23 (FGF 23) control phosphate homeostasis. Hypoparathyroidism can cause hypocalcemia and hyperphosphatemia, whereas deficient vitamin D actions can cause osteomalacia in adults and rickets in children. Hyperparathyroidism, alternatively, can cause hypercalcemia and hypophosphatemia. Laboratory tests of calcium, phosphate, PTH, and 25-hydroxyvitamin D are very useful in the diagnosis of abnormalities associated with calcium and/or phosphate metabolisms. Bone is constantly remodeled throughout life in response to mechanical stress and a need for calcium in extracellular fluids. Metabolic bone diseases such as osteoporosis, osteomalacia in adults or rickets in children, and renal osteodystrophy develop when bone resorption exceeds bone formation. Bone turnover markers (BTM) such as serum N-terminal propeptide of type I procollagen (P1NP) and C-terminal collagen cross-link (CTX) may be useful in predicting future fracture risk or monitoring the response to anti-resorptive therapy. There is a need to standardize sample collection protocols because certain BTMs exhibit large circadian variations and tend to be influenced by food intakes. In the United States, a project to standardize BTM sample collection protocols and to establish the reference intervals for serum P1NP and serum CTX is ongoing. We anticipate the outcome of this project to shine lights on the standardization of BTM assays, sample collection protocols, reference intervals in relation to age, sex, and ethnic origins, and clinical utilities of BTMs. This review will briefly discuss the regulations of calcium and phosphate homeostasis, laboratory's role in the diagnosis, and monitoring of bone and calcium metabolism, as well as the usefulness and controversies of the utilities of BTMs in the diagnosis and monitoring of metabolic bone diseases. © 2017 Elsevier Inc. All rights reserved.

Tissue-nonspecific Alkaline Phosphatase Deficiency Causes Abnormal Craniofacial Bone Development in the Alpl−/− Mouse Model of Infantile Hypophosphatasia

PubMed Central

Liu, Jin; Nam, Hwa Kyung; Campbell, Cassie; Gasque, Kellen Cristina da Silva; Millán, José Luis; Hatch, Nan E.

2014-01-01

Tissue-nonspecific alkaline phosphatase (TNAP) is an enzyme present on the surface of mineralizing cells and their derived matrix vesicles that promotes hydroxyapatite crystal growth. Hypophosphatasia (HPP) is an inborn-error-of-metabolism that, dependent upon age of onset, features rickets or osteomalacia due to loss-of function mutations in the gene (Alpl) encoding TNAP. Craniosynostosis is prevalent in infants with HPP and other forms of rachitic disease but how craniosynostosis develops in these disorders is unknown. Objectives: Because craniosynostosis carries high morbidity, we are investigating craniofacial skeletal abnormalities in Alpl−/− mice to establish these mice as a model of HPP-associated craniosynostosis and determine mechanisms by which TNAP influences craniofacial skeletal development. Methods: Cranial bone, cranial suture and cranial base abnormalities were analyzed by micro-CT and histology. Craniofacial shape abnormalities were quantified using digital calipers. TNAP expression was suppressed in MC3T3E1(C4) calvarial cells by TNAP-specific shRNA. Cells were analyzed for changes in mineralization, gene expression, proliferation, apoptosis, matrix deposition and cell adhesion. Results: Alpl−/− mice feature craniofacial shape abnormalities suggestive of limited anterior-posterior growth. Craniosynostosis in the form of bony coronal suture fusion is present by three weeks after birth. Alpl−/− mice also exhibit marked histologic abnormalities of calvarial bones and the cranial base involving growth plates, cortical and trabecular bone within two weeks of birth. Analysis of calvarial cells in which TNAP expression was suppressed by shRNA indicates that TNAP deficiency promotes aberrant osteoblastic gene expression, diminished matrix deposition, diminished proliferation, increased apoptosis and increased cell adhesion. Conclusions: These findings demonstrate that Alpl−/− mice exhibit a craniofacial skeletal phenotype similar to that seen in infants with HPP, including true bony craniosynostosis in the context of severely diminished bone mineralization. Future studies will be required to determine if TNAP deficiency and other forms of rickets promote craniosynostosis directly through abnormal calvarial cell behavior, or indirectly due to deficient growth of the cranial base. PMID:25014884

A novel inverse association between cord 25-hydroxyvitamin D and leg length in boys up to three years. An Odense Child Cohort study.

PubMed

Christensen, Mathilde Egelund; Beck-Nielsen, Signe Sparre; Dalgård, Christine; Larsen, Søs Dragsbæk; Lykkedegn, Sine; Kyhl, Henriette Boye; Husby, Steffen; Christesen, Henrik Thybo

2018-01-01

Long standing vitamin D deficiency in children causes rickets with growth impairment. We investigated whether sub-ischial leg length (SLL) is shorter, and cephalo-caudal length:length (CCL:L) ratio and sitting height:height (SH:H) ratio larger, with lower cord s-25-hydroxyvitamin D (25OHD) in the population-based prospective Odense Child Cohort, Denmark. We included healthy singletons born to term with available measures of cord 25OHD and anthropometrics up to three years' age. Linear regression was stratified by sex a priori and adjusted for maternal ethnicity, pre-pregnancy body mass index and smoking during pregnancy, season of blood sampling and child age. Median (IQR) cord 25OHD was 48.0 (34.0-62.4) nmol/L. At mean age 19.1 months, n = 504, mean (SD) SLL was 31.7 (1.7) cm; CCL:L-ratio 0.62 (0.01). At 36.3 months, n = 956, mean SLL was 42.9 (2.0) cm; SH:H-ratio 0.56 (0.01). No participants had rickets. In adjusted analyses, 19-months-old boys had 0.1 cm shorter SLL (p = 0.009) and 0.1% higher CCL:L-ratio (p = 0.04) with every 10 nmol/L increase in cord 25OHD. Similar findings were seen for late pregnancy 25OHD. In the highest cord 25OHD quartile (>60.7 nmol/L), SLL was 0.8 cm shorter (95% C.I.: 1.36;-0.29, linear trend, p = 0.004), and CCL:L-ratio 0.8% higher (95% C.I. 8.0x10-05;0.01, linear trend, p = 0.01), compared to lowest quartile (<30.7 nmol/L). Similar associations with cord 25OHD were observed in 3-year-old boys. No consistent associations between 25OHD and anthropometrics were seen in girls at either age. No leg shortening was found with decreasing cord s-25OHD in a healthy population of infants. A small, yet significant inverse association between cord 25OHD and SLL in boys 1½-3 years warrants further investigations.

Genetic diagnosis of X-linked dominant hypophosphatemic rickets in a cohort study: Tubular reabsorption of phosphate and 1,25(OH)2D serum levels are associated with PHEX mutation type

PubMed Central

2011-01-01

Background Genetic Hypophosphatemic Rickets (HR) is a group of diseases characterized by renal phosphate wasting with inappropriately low or normal 1,25-dihydroxyvitamin D3 (1,25(OH)2D) serum levels. The most common form of HR is X-linked dominant HR (XLHR) which is caused by inactivating mutations in the PHEX gene. The purpose of this study was to perform genetic diagnosis in a cohort of patients with clinical diagnosis of HR, to perform genotype-phenotype correlations of those patients and to compare our data with other HR cohort studies. Methods Forty three affected individuals from 36 non related families were analyzed. For the genetic analysis, the PHEX gene was sequenced in all of the patients and in 13 cases the study was complemented by mRNA sequencing and Multiple Ligation Probe Assay. For the genotype-phenotype correlation study, the clinical and biochemical phenotype of the patients was compared with the type of mutation, which was grouped into clearly deleterious or likely causative, using the Mann-Whitney and Fisher's exact test. Results Mutations in the PHEX gene were identified in all the patients thus confirming an XLHR. Thirty four different mutations were found distributed throughout the gene with higher density at the 3' end. The majority of the mutations were novel (69.4%), most of them resulted in a truncated PHEX protein (83.3%) and were family specific (88.9%). Tubular reabsorption of phosphate (TRP) and 1,25(OH)2D serum levels were significantly lower in patients carrying clearly deleterious mutations than in patients carrying likely causative ones (61.39 ± 19.76 vs. 80.14 ± 8.80%, p = 0.028 and 40.93 ± 30.73 vs. 78.46 ± 36.27 pg/ml, p = 0.013). Conclusions PHEX gene mutations were found in all the HR cases analyzed, which was in contrast with other cohort studies. Patients with clearly deleterious PHEX mutations had lower TRP and 1,25(OH)2D levels suggesting that the PHEX type of mutation might predict the XLHR phenotype severity. PMID:21902834

Early neonatal special care units and their scientific achievements.

PubMed

Obladen, Michael

2012-01-01

Treatment of sick neonates originated in maternity and foundling hospitals in the 19th century. Nosocomial infections and difficult logistics of wet-nursing prevented admission of neonates in most children's hospitals well into the 20th century. In this article, 31 hospitals are described, all located in large cities, in which preterm and sick neonates were treated before the Great Depression. Even though mostly initiated by private charity, these institutions performed research right from the start. Topics included warming and feeding preterm infants, collecting and distributing human milk, developing and storing breast milk substitutes, prevention of rickets and nosocomial infections, maternal and public education regarding infection control, pathoanatomic characterisation of diseases and malformations and epidemiologic studies of infant mortality. These pioneering hospitals, their founding dates, researchers and classic publications are presented in a table. Copyright © 2012 S. Karger AG, Basel.

Dwarfism in Alaskan malamutes: a disease resembling metaphyseal dysplasia in human beings.

PubMed Central

Sande, R. D.; Alexander, J. E.; Spencer, G. R.; Padgett, G. A.; Davis, W. C.

1982-01-01

In a study of 300 Alaskan Malamutes, dwarfism was shown to be an autosomal recessive inherited disease with complete penetrance that resulted in disturbed endochondral bone formation. Osseous growth disturbance was manifest at the metaphyses of tubular bones. Clinical and radiographic changes were very similar to those of rickets, although appositional bone formation rates were normal. Serum calcium, phosphorus, and alkaline phosphatase were within normal limits. Urinary excretion of calcium, phosphate, and amino acids were normal. Excess matrix was formed in the zone of cartilage cell proliferation, and the matrix persisted in the growth plate. Normal stresses resulted in microfractures in the metaphyses with subsequent interference of vascular penetration into the zone of degenerated cartilage cells. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 PMID:7065114

Hypophosphatemic rickets: Revealing Novel Control Points for Phosphate Homeostasis

PubMed Central

White, Kenneth E.; Hum, Julia M.; Econs, Michael J.

2014-01-01

Rapid and somewhat surprising advances have recently been made towards understanding the molecular mechanisms causing heritable disorders of hypophosphatemia. The results of clinical, genetic, and translational studies have interwoven novel concepts underlying the endocrine control of phosphate metabolism, with far-reaching implications for treatment of both rare, Mendelian diseases as well as common disorders of blood phosphate excess such as chronic kidney disease (CKD). In particular, diseases caused by changes in the expression and proteolytic control of the phosphaturic hormone Fibroblast growth factor-23 (FGF23) have come to the forefront in terms of directing new models explaining mineral metabolism. These hypophosphatemic disorders, as well as others resulting from independent defects in phosphate transport or metabolism, will be reviewed herein, and implications for emerging therapeutic strategies based upon these new findings will be discussed. PMID:24980542

Evaluation of hypophosphatemia: lessons from patients with genetic disorders

PubMed Central

Bacchetta, Justine; Salusky, Isidro B

2014-01-01

Phosphate is a key element for several physiological pathways, such as skeletal development, bone mineralization, membrane composition, nucleotide structure, maintenance of plasma pH, and cellular signaling. The kidneys have a key role in phosphate homeostasis with three hormones playing important roles in renal phosphate handling (i.e., parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and 1-25 dihydroxy-vitamin D). Independently of the genetic diseases affecting the FGF23 pathway (such as hypophosphatemic rickets), hypophosphatemia is a frequent condition in daily practice, and untreated severe hypophosphatemia can induce hemolysis, rhabdomyolysis, respiratory failure, cardiac dysfunction and neurological impairment, thus requiring a rapid correction to avoid severe complications. The aims of this case report are to summarize the etiologies and the biological evaluation of hypophosphatemia in adults, and to provide an overview of our current understanding of phosphate metabolism. PMID:22075221

Hypovitaminosis D and severe hypocalcaemia: the rebirth of an old disease

PubMed Central

Pedrosa, Cristina; Ferraria, Nélia; Limbert, Catarina; Lopes, Lurdes

2013-01-01

Vitamin D deficiency, once thought to be eradicated, is becoming a frequent occurence in children, caused mainly by dietary insufficiency. The classical manifestation is rickets, but in infants severe hypocalcaemia may present as stridor, tetany, seizures or, rarely, heart disease. Here, we describe four infants who presented with complications of severe hypocalcaemia secondary to nutritional vitamin D deficiency. (1) Female, 4 months old, several spasms. (2) Male, 8 days old, generalised tonic-clonic seizure. (3) Male, 9 months old, tetany. (4) Male, 4 months old, cardiogenic shock. The cases highlight the importance of child vitamin D supplementation from birth and throughout childhood. We also note that the vitamin D state should be evaluated by the 25(OH)-D value and not the 1,25(OH)2-D. PMID:23729699

Relationship between vitamin D during perinatal development and health.

PubMed

Kaludjerovic, Jovana; Vieth, Reinhold

2010-01-01

Vitamin D deficiency is a highly prevalent condition that is present in 40% to 80% of pregnant women. There is emerging evidence that vitamin D deficiency may be a risk modifying factor for many chronic diseases, including osteomalacia, rickets, multiple sclerosis, schizophrenia, heart disease, type 1 diabetes, and cancer. Heightened susceptibility to these diseases may originate in early life during the development of tissue structure and function. It is suspected that biologic mechanisms can "memorize" the metabolic effects of early nutritional environment through fetal and neonatal imprinting. Inadequate vitamin D nutrition during perinatal life may establish a poor foundation that may produce long-term threats to human health. This review summarizes the risks of vitamin D deficiency for human health and provides the current vitamin D recommendations for mothers and their newborns. Copyright © 2010 American College of Nurse-Midwives. Published by Elsevier Inc. All rights reserved.

Osteomalacia with low alkaline phosphatase: a not so rare condition with important consequences.

PubMed

Belkhouribchia, Jamal; Bravenboer, Bert; Meuwissen, Marije; Velkeniers, Brigitte

2016-01-28

Hypophosphatasia is a genetic disorder, characterised by a dysfunctional tissue-non-specific isoenzyme of alkaline phosphatase that impacts bone metabolism and predisposes to osteomalacia or rickets. The clinical presentation is very diverse, depending on the age of onset and the severity of the disease. Several forms of hypophosphatasia are recognised. We present a case of a 50-year-old woman with low impact fractures and loss of teeth at a young age. She also had a low alkaline phosphatase and was diagnosed with adult hypophosphatasia. Although the severe forms of hypophosphatasia are rather rare, the adult form is thought to occur quite frequently. As this condition is not well known by healthcare professionals, the time to diagnosis and initiation of adequate treatment is often postponed. When encountering a patient with low alkaline phosphatase, low bone density or a history of bone fractures, the possibility of hypophosphatasia should be considered. 2016 BMJ Publishing Group Ltd.

[Anti-FGF23 antibody therapy for patients with tumor-induced osteomalacia].

PubMed

Kinoshita, Yuka; Fukumoto, Seiji

2014-08-01

Tumor-induced osteomalacia (TIO) is a disease caused by fibroblast growth factor 23 (FGF23) secreted from the causative tumor. This disease is cured by complete surgical removal of the tumor. However, there are several difficult cases in which the responsible tumors cannot be found, are incompletely removed, or relapse after the surgery. Anti-FGF23 antibody is being studied as a novel therapy for FGF23-related hypophosphatemic diseases. The efficacy of anti-FGF23 antibodies were confirmed using a murine model of X-linked hypophosphatemic rickets (XLHR) , which is the most common heritable form of FGF23-related hypophosphatemic disease. In addition, results of phase I study of single injection of humanized anti-FGF23 antibody for adult patients with XLHR were recently published and the safety and effectiveness of this antibody was shown. This antibody therapy may be useful for patients with TIO with similar pathogenesis to that of XLHR.

Metaphyseal chondrodysplasia.

PubMed Central

Spranger, J. W.

1977-01-01

Any review of the metaphyseal chondrodysplasias is complicated by their variety and mainly unknown pathogenesis. The more familiar types display considerable clinical and radiological diversity: even more so the rarer disorders which still require complete definition, but differences in their mode of inheritance make diagnostic precision mandatory. These dysplasias present in infancy or in childhood, when the patient, usually dwarfed, may be proportionate, so that some forms may be confused with rickets or other lesions. Mental retardation is unusual, but the skin, hair, nails and facies provide valuable diagnostic features. Radiological abnormalities mainly affect the metaphyses of the shortened limb bones, less often the skull, vertebrae, pelvis, ribs and extremities, and sometimes their distribution may indicate the specific type of dysplasia. In a further complex group multiple systems are involved, notably the pancreas, intestine and lympho-reticular, causing malabsorption and haematological or immunological disorders. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 PMID:335375

Pediatric endocrine diseases in pre-Hispanic Aztecs.

PubMed

Calzada León, Raúl

2003-01-01

Aztec medical and religious knowledge derived from Olmecs (800 BC), Teotihuacans (100 BC) and Toltecs (1100-1521 AC); however, there is no unique source that accurately presents Aztec medicine. Sahagfin combines naturalism and religion but not magic ("First Memorials", "Matritense Codex", "Florentine Codex" and "General History of New Spain"); Hernández gives a naturalistic image but is full of mistakes ("Natural History of the New Spain"); Badiano tries to match Aztecs with contemporary Europeans and with the first century medicine of the Romans ("Badiano Codex"), and Ruiz de Alarcón contains plenty of magical concepts ("Book of Superstition"). For the Aztecs, surveillance of growth was very important and represented a balance between body and soul. They described the different steps of pubertal development. They had specific treatments for thyroid disease in children, mainly hypothyroidism and goiter. There are no references to rickets, nor to type 1 or 2 diabetes mellitus.

The design and statistical analysis of animal experiments: introduction to this issue.

PubMed

Festing, Michael F W; Nevalainen, Timo

2014-01-01

Animal research has made major contributions to the health and welfare of humans and domestic animals. Immunization, first developed against rabies and anthrax by Pasteur using dogs, sheep, and rabbits, is now used to control many infectious diseases. The first drug, Salvarsan, was developed by Ehrlich using rabbits infected with the organism causing syphilis. This was the forerunner of the many drugs developed by the pharmaceutical industry today. The discovery of vitamins using rats has almost eliminated diseases such as scurvy and rickets; and hormones, such as insulin discovered following work in dogs, have helped to control many metabolic diseases. These and many other advances have enabled physicians to treat a wide range of human diseases. But many diseases continue to cause suffering. © The Author 2014. Published by Oxford University Press on behalf of the Institute for Laboratory Animal Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Cortical Matrix Mineral Density Measured Non-invasively in Pre- and Postmenopausal Women and a Woman with Vitamin D Dependent Rickets.

PubMed

Chiang, Cherie Y; Zebaze, Roger; Wang, Xiao-Fang; Ghasem-Zadeh, Ali; Zajac, Jeffrey D; Seeman, Ego

2018-02-28

Reduced bone mineral density (BMD) may be due to reduced mineralized bone matrix volume, incomplete secondary mineralization or reduced primary mineralization. As bone biopsy is invasive, we hypothesized that non-invasive image acquisition at high resolution can accurately quantify matrix mineral density (MMD). Quantification of MMD was confined to voxels attenuation photons above 80% of that produced by fully mineralized bone matrix because attenuation at this level is due to variation in mineralization not porosity. To assess accuracy, 9 cadaveric distal radii were imaged at a voxel size of 82 microns using high resolution peripheral quantitative computed tomography (HR-pQCT, XtremeCT, Scanco Medical AG, Switzerland) and compared with VivaCT 40 (µCT) at 19 microns voxel size. Associations between MMD and porosity were studied in 94 heathy vitamin D replete pre-menopausal, 77 post-menopausal women, and in a 27 year-old woman with vitamin-D Dependent Rickets (VDDR). Microstructure and MMD were quantified using StrAx (StraxCorp, Melbourne, Australia). MMD measured by HR-pQCT and µCT correlated (R = 0.87; p <0.0001). The precision error for MMD was 2.43%. Cortical porosity and MMD were associated with age (r 2  = 0.5 and - 0.4 respectively) and correlated inversely in pre- and post-menopausal women (both r 2  = 0.9, all p < 0.001). Porosity was higher, and MMD was lower, in post- than in pre-menopausal women (porosity 40.3% ± 7.0 versus 34.7% ± 3.5 respectively, MMD 65.4% ± 1.8 versus 66.6% ± 1.4 respectively, both p < 0.001). In the woman with VDDR, MMD was 5.6 SD lower, and porosity was 5.6 SD higher, than the respective trait means in premenopausal women. BMD was reduced (Z scores femoral neck - 4.3 SD, lumbar spine - 3.8 SD). Low radiation HR-pQCT may facilitate non-invasive quantification of bone's MMD and microstructure in health, disease and during treatment. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Skeletal Muscle, but not Cardiovascular Function, Is Altered in a Mouse Model of Autosomal Recessive Hypophosphatemic Rickets.

PubMed

Wacker, Michael J; Touchberry, Chad D; Silswal, Neerupma; Brotto, Leticia; Elmore, Chris J; Bonewald, Lynda F; Andresen, Jon; Brotto, Marco

2016-01-01

Autosomal recessive hypophosphatemic rickets (ARHR) is a heritable disorder characterized by hypophosphatemia, osteomalacia, and poor bone development. ARHR results from inactivating mutations in the DMP1 gene with the human phenotype being recapitulated in the Dmp1 null mouse model which displays elevated plasma fibroblast growth factor 23. While the bone phenotype has been well-characterized, it is not known what effects ARHR may also have on skeletal, cardiac, or vascular smooth muscle function, which is critical to understand in order to treat patients suffering from this condition. In this study, the extensor digitorum longus (EDL-fast-twitch muscle), soleus (SOL-slow-twitch muscle), heart, and aorta were removed from Dmp1 null mice and ex-vivo functional tests were simultaneously performed in collaboration by three different laboratories. Dmp1 null EDL and SOL muscles produced less force than wildtype muscles after normalization for physiological cross sectional area of the muscles. Both EDL and SOL muscles from Dmp1 null mice also produced less force after the addition of caffeine (which releases calcium from the sarcoplasmic reticulum) which may indicate problems in excitation contraction coupling in these mice. While the body weights of the Dmp1 null were smaller than wildtype, the heart weight to body weight ratio was higher. However, there were no differences in pathological hypertrophic gene expression compared to wildtype and maximal force of contraction was not different indicating that there may not be cardiac pathology under the tested conditions. We did observe a decrease in the rate of force development generated by cardiac muscle in the Dmp1 null which may be related to some of the deficits observed in skeletal muscle. There were no differences observed in aortic contractions induced by PGF2α or 5-HT or in endothelium-mediated acetylcholine-induced relaxations or endothelium-independent sodium nitroprusside-induced relaxations. In summary, these results indicate that there are deficiencies in both fast twitch and slow twitch muscle fiber type contractions in this model of ARHR, while there was less of a phenotype observed in cardiac muscle, and no differences observed in aortic function. These results may help explain skeletal muscle weakness reported by some patients with osteomalacia and need to be further investigated.

Skeletal Muscle, but not Cardiovascular Function, Is Altered in a Mouse Model of Autosomal Recessive Hypophosphatemic Rickets

PubMed Central

Wacker, Michael J.; Touchberry, Chad D.; Silswal, Neerupma; Brotto, Leticia; Elmore, Chris J.; Bonewald, Lynda F.; Andresen, Jon; Brotto, Marco

2016-01-01

Autosomal recessive hypophosphatemic rickets (ARHR) is a heritable disorder characterized by hypophosphatemia, osteomalacia, and poor bone development. ARHR results from inactivating mutations in the DMP1 gene with the human phenotype being recapitulated in the Dmp1 null mouse model which displays elevated plasma fibroblast growth factor 23. While the bone phenotype has been well-characterized, it is not known what effects ARHR may also have on skeletal, cardiac, or vascular smooth muscle function, which is critical to understand in order to treat patients suffering from this condition. In this study, the extensor digitorum longus (EDL-fast-twitch muscle), soleus (SOL–slow-twitch muscle), heart, and aorta were removed from Dmp1 null mice and ex-vivo functional tests were simultaneously performed in collaboration by three different laboratories. Dmp1 null EDL and SOL muscles produced less force than wildtype muscles after normalization for physiological cross sectional area of the muscles. Both EDL and SOL muscles from Dmp1 null mice also produced less force after the addition of caffeine (which releases calcium from the sarcoplasmic reticulum) which may indicate problems in excitation contraction coupling in these mice. While the body weights of the Dmp1 null were smaller than wildtype, the heart weight to body weight ratio was higher. However, there were no differences in pathological hypertrophic gene expression compared to wildtype and maximal force of contraction was not different indicating that there may not be cardiac pathology under the tested conditions. We did observe a decrease in the rate of force development generated by cardiac muscle in the Dmp1 null which may be related to some of the deficits observed in skeletal muscle. There were no differences observed in aortic contractions induced by PGF2α or 5-HT or in endothelium-mediated acetylcholine-induced relaxations or endothelium-independent sodium nitroprusside-induced relaxations. In summary, these results indicate that there are deficiencies in both fast twitch and slow twitch muscle fiber type contractions in this model of ARHR, while there was less of a phenotype observed in cardiac muscle, and no differences observed in aortic function. These results may help explain skeletal muscle weakness reported by some patients with osteomalacia and need to be further investigated. PMID:27242547

PHEX Mimetic (SPR4-Peptide) Corrects and Improves HYP and Wild Type Mice Energy-Metabolism

PubMed Central

Zelenchuk, Lesya V.; Hedge, Anne-Marie; Rowe, Peter S. N.

2014-01-01

Context PHEX or DMP1 mutations cause hypophosphatemic-rickets and altered energy metabolism. PHEX binds to DMP1-ASARM-motif to form a complex with α5β3 integrin that suppresses FGF23 expression. ASARM-peptides increase FGF23 by disrupting the PHEX-DMP1-Integrin complex. We used a 4.2 kDa peptide (SPR4) that binds to ASARM-peptide/motif to study the DMP1-PHEX interaction and to assess SPR4 for the treatment of energy metabolism defects in HYP and potentially other bone-mineral disorders. Design Subcutaneously transplanted osmotic pumps were used to infuse SPR4-peptide or vehicle (VE) into wild-type mice (WT) and HYP-mice (PHEX mutation) for 4 weeks. Results SPR4 partially corrected HYP mice hypophosphatemia and increased serum 1.25(OH)2D3. Serum FGF23 remained high and PTH was unaffected. WT-SPR4 mice developed hypophosphatemia and hypercalcemia with increased PTH, FGF23 and 1.25(OH)2D3. SPR4 increased GAPDH HYP-bone expression 60× and corrected HYP-mice hyperglycemia and hypoinsulinemia. HYP-VE serum uric-acid (UA) levels were reduced and SPR4 infusion suppressed UA levels in WT-mice but not HYP-mice. SPR4 altered leptin, adiponectin, and sympathetic-tone and increased the fat mass/weight ratio for HYP and WT mice. Expression of perlipin-2 a gene involved in obesity was reduced in HYP-VE and WT-SPR4 mice but increased in HYP-SPR4 mice. Also, increased expression of two genes that inhibit insulin-signaling, ENPP1 and ESP, occurred with HYP-VE mice. In contrast, SPR4 reduced expression of both ENPP1 and ESP in WT mice and suppressed ENPP1 in HYP mice. Increased expression of FAM20C and sclerostin occurred with HYP-VE mice. SPR4 suppressed expression of FAM20C and sclerostin in HYP and WT mice. Conclusions ASARM peptides and motifs are physiological substrates for PHEX and modulate osteocyte PHEX-DMP1-α5β3-integrin interactions and thereby FGF23 expression. These interactions also provide a nexus that regulates bone and energy metabolism. SPR4 suppression of sclerostin and/or sequestration of ASARM-peptides improves energy metabolism and may have utility for treating familial rickets, osteoporosis, obesity and diabetes. PMID:24839967

First 25-hydroxyvitamin D assay for general chemistry analyzers.

PubMed

Saida, Fakhri B; Chen, Xiaoru; Tran, Kiet; Dou, Chao; Yuan, Chong

2015-03-01

25-Hydroxyvitamin D [25(OH)D], the predominant circulating form of vitamin D, is an accurate indicator of the general vitamin D status of an individual. Because vitamin D deficiencies have been linked to several pathologies (including osteoporosis and rickets), accurate monitoring of 25(OH)D levels is becoming increasingly important in clinical settings. Current 25(OH)D assays are either chromatographic or immunoassay-based assays. These assays include HPLC, liquid chromatography-tandem mass spectrometry (LC-MS/MS), enzyme-immunosorbent, immunochemiluminescence, immunofluorescence and radioimmunoassay. All these assays use heterogeneous formats that require phase separation and special instrumentations. In this article, we present an overview of these assays and introduce the first homogeneous assay of 25(OH)D for use on general chemistry analyzers. A special emphasis is put on the unique challenges posed by the 25(OH)D analyte. These challenges include a low detection limit, the dissociation of the analyte from its serum transporter and the inactivation of various binding proteins without phase separation steps.

Metabolic syndrome: A review of the role of vitamin D in mediating susceptibility and outcome

PubMed Central

Strange, Richard C; Shipman, Kate E; Ramachandran, Sudarshan

2015-01-01

Despite the well-recognised role of vitamin D in a wide range of physiological processes, hypovitaminosis is common worldwide (prevalence 30%-50%) presumably arising from inadequate exposure to ultraviolet radiation and insufficient consumption. While generally not at the very low levels associated with rickets, hypovitaminosis D has been implicated in various very different, pathophysiological processes. These include putative effects on the pathogenesis of neoplastic change, inflammatory and demyelinating conditions, cardiovascular disease (CVD) and diabetes. This review focuses on the association between hypovitaminosis D and the metabolic syndrome as well as its component characteristics which are central obesity, glucose homeostasis, insulin resistance, hypertension and atherogenic dyslipidaemia. We also consider the effects of hypovitaminosis D on outcomes associated with the metabolic syndrome such as CVD, diabetes and non-alcoholic fatty liver disease. We structure this review into 3 distinct sections; the metabolic syndrome, vitamin D biochemistry and the putative association between hypovitaminosis D, the metabolic syndrome and cardiovascular risk. PMID:26185598

Markers of bone turnover in patients with epilepsy and their relationship to management of bone diseases induced by antiepileptic drugs.

PubMed

Hamed, Sherifa A

2016-01-01

Data from cross-sectional and prospective studies revealed that patients with epilepsy and on long-term treatment with antiepileptic drugs (AEDs) are at increased risk for metabolic bone diseases. Bone diseases were reported in about 50% of patients on AEDs. Low bone mineral density, osteopenia/osteoporosis, osteomalacia, rickets, altered concentration of bone turnover markers and fractures were reported with phenobarbital, phenytoin, carbamazepine, valproate, oxcarbazepine and lamotrigine. The mechanisms for AEDs-induced bone diseases are heterogeneous and include hypovitaminosis D, hypocalcemia and direct acceleration of bone loss and/or reduction of bone formation. This article reviews the evidence, predictors and mechanisms of AEDs-induced bone abnormalities and its clinical implications. For patients on AEDs, regular monitoring of bone health is recommended. Prophylactic administration of calcium and vitamin D is recommended for all patients. Treatment doses of calcium and vitamin D and even anti-resorptive drug therapy are reserved for patients at high risk of pathological fracture.

French law: what about a reasoned reimbursement of serum vitamin D assays?

PubMed

Souberbielle, Jean-Claude; Benhamou, Claude Laurent; Cortet, Bernard; Rousière, Mickael; Roux, Christian; Abitbol, Vered; Annweiler, Cédric; Audran, Maurice; Bacchetta, Justine; Bataille, Pierre; Beauchet, Olivier; Bardet, Rémi; Benachi, Alexandra; Berenbaum, Francis; Blain, Hubert; Borson-Chazot, Françoise; Breuil, Véronique; Briot, Karine; Brunet, Philippe; Carel, Jean-Claude; Caron, Philippe; Chabre, Olivier; Chanson, Philippe; Chapurlat, Roland; Cochat, Pierre; Coutant, Régis; Christin-Maitre, Sophie; Cohen-Solal, Martine; Combe, Christian; Cormier, Catherine; Courbebaisse, Marie; Debrus, Grégory; Delemer, Brigitte; Deschenes, Georges; Duquenne, Marc; Duval, Guillaume; Fardellone, Patrice; Fouque, Denis; Friedlander, Gérard; Gauvain, Jean-Bernard; Groussin, Lionel; Guggenbuhl, Pascal; Houillier, Pascal; Hannedouche, Thierry; Jacot, William; Javier, Rose-Marie; Jean, Guillaume; Jeandel, Claude; Joly, Dominique; Kamenicky, Peter; Knebelmann, Bertrand; Lafage-Proust, Marie-Hélène; LeBouc, Yves; Legrand, Erick; Levy-Weil, Florence; Linglart, Agnès; Machet, Laurent; Maheu, Emmanuel; Mallet, Eric; Marcelli, Christian; Marès, Pierre; Mariat, Christophe; Maruani, Gérard; Maugars, Yves; Montagnon, France; Moulin, Bruno; Orcel, Philippe; Partouche, Henri; Personne, Virginie; Pierrot-Deseilligny, Charles; Polak, Michel; Pouteil-Noble, Claire; Prié, Dominique; Raynaud-Simon, Agathe; Rolland, Yves; Sadoul, Jean-Louis; Salle, Bernard; Sault, Corinne; Schott, Anne-Marie; Sermet-Gaudelus, Isabelle; Soubrier, Martin; Tack, Ivan; Thervet, Eric; Tostivint, Isabelle; Touraine, Philippe; Tremollières, Florence; Urena-Torres, Pablo; Viard, Jean-Paul; Wemeau, Jean-Louis; Weryha, Georges; Winer, Norbert; Young, Jacques; Thomas, Thierry

2016-12-01

The number of serum 25-hydroxyvitamin D (25OHD) assays has increased tenfold in France in less than 10 years, sometimes for invalidated reasons. In 2013, the French National Authority for Health (Haute autorité de santé, or HAS) limited the indications for serum 25OHD measurements to rickets/osteomalacia, older adults with recurrent falls, monitoring of kidney transplant in adults, and surgical treatment of obesity in adults. Our aim here was to note that other indications for serum 25OHD measurements are supported by previous literature and by a number of national and international recommendations, in particular the following: any situation of bone fragility, any chronic renal failure <45 mL/min/1.73m 2 , any situation of malabsorption, clinical signs consistent with vitamin D deficiency or vitamin D overload, and calcium phosphorus evaluation. We suggest that the measurement of serum 25OHD concentration should remain reimbursed as part of these extended indications.

De novo mutation of PHEX in a type 1 diabetes patient.

PubMed

Fang, Chen; Li, Hui; Li, Xiaozhen; Xiao, Wenjin; Huang, Yun; Cai, Wu; Yang, Yi; Hu, Ji

2016-05-01

A new missense mutation on the X chromosome (PHEX) at exon 4(c.442C>T) in a 4-generation Chinese Han pedigree is reported. The proband and four family members were clinically identified as the X-linked hypophosphatemic rickets (XLH) which is a dominant inherited disorder characterized by renal phosphate wasting, aberrant vitamin D metabolism, and abnormal bone mineralization. The proband is identified as hemizygous with the four female family members to be heterozygous genotypes. The discovery was made through the complete sequencing of the exons and the intron-exon boundaries of the PHEX gene of this family. The mutation caused the S141 residue to change to Phe from Ser which is perfectly conserved among humans, mice, rats, cows and chickens. PolyPhen-2 software analysis of the mutation indicated it was probably damaging. The proband was also diagnosed with type 1 diabetes (T1D) and the relationship between XLH and diabetes phenotypes was discussed in the paper.

Vitamine--vitamin. The early years of discovery.

PubMed

Rosenfeld, L

1997-04-01

In 1905, Cornelius Adrianus Pekelharing found that animals fed purified proteins, carbohydrates, fats, inorganic salts, and water would thrive only if small amounts of milk were added to the diet. He concluded that the milk contained some unrecognized substance that in very small quantities was necessary for normal growth and maintenance. In 1911, Casimir Funk isolated a concentrate from rice polishings that cured polyneuritis in pigeons. He named the concentrate "vitamine" because it appeared to be vital to life and because it was probably an amine. Although the concentrate and other "accessory food substances" were not amines, the name stuck, but the final "e" was dropped. In 1913 two groups discovered a "fat-soluble" accessory food substance. Initially believed to be a single vitamin, two separate factors were involved. One, effective against xerophthalmia, was named vitamin A; the other, effective against rickets, was named vitamin D. The factor that prevented scurvy was isolated in 1928. Known as "water-soluble C," it was renamed ascorbic acid.

Solar radiation and human health

NASA Astrophysics Data System (ADS)

Juzeniene, Asta; Brekke, Pål; Dahlback, Arne; Andersson-Engels, Stefan; Reichrath, Jörg; Moan, Kristin; Holick, Michael F.; Grant, William B.; Moan, Johan

2011-06-01

The Sun has played a major role in the development of life on Earth. In Western culture, people are warned against Sun exposure because of its adverse effects: erythema, photoimmunosuppression, photoageing, photocarcinogenesis, cataracts and photokeratitis. However, Sun exposure is also beneficial, since moderate doses give beneficial physiological effects: vitamin D synthesis, reduction of blood pressure and mental health. Shortage of Sun exposure may be even more dangerous to human health than excessive exposure. Avoiding Sun exposure leads to vitamin D deficiency which is associated not only with rickets and osteomalacia, but also with increased risk of cardiovascular disease, multiple sclerosis, rheumatoid arthritis, diabetes, influenza, many types of cancer and adverse pregnancy outcomes. Solar radiation induces nitric oxide release in tissue and immediate pigment darkening which certainly play important roles, although these are still unknown. Action spectra relevant for health are described. We will also review what is known about spectral and intensity variations of terrestrial solar radiation as well as its penetration through the atmosphere and into human skin and tissue.

Metabolic bone disease in the preterm infant: Current state and future directions

PubMed Central

Rehman, Moghis Ur; Narchi, Hassib

2015-01-01

Neonatal osteopenia is an important area of interest for neonatologists due to continuing increased survival of preterm infants. It can occur in high-risk infants such as preterm infants, infants on long-term diuretics or corticosteroids, and those with neuromuscular disorders. Complications such as rickets, pathological fractures, impaired respiratory function and poor growth in childhood can develop and may be the first clinical evidence of the condition. It is important for neonatologists managing such high-risk patients to regularly monitor biochemical markers for evidence of abnormal bone turnover and inadequate mineral intake in order to detect the early phases of impaired bone mineralization. Dual-energy X-ray absorptiometry has become an increasingly used research tool for assessing bone mineral density in children and neonates, but more studies are still needed before it can be used as a useful clinical tool. Prevention and early detection of osteopenia are key to the successful management of this condition and oral phosphate supplements should be started as soon as is feasible. PMID:26413483

Phosphate homeostasis and its role in bone health.

PubMed

Penido, Maria Goretti M G; Alon, Uri S

2012-11-01

Phosphate is one of the most abundant minerals in the body, and its serum levels are regulated by a complex set of processes occurring in the intestine, skeleton, and kidneys. The currently known main regulators of phosphate homeostasis include parathyroid hormone (PTH), calcitriol, and a number of peptides collectively known as the "phosphatonins" of which fibroblast growth factor-23 (FGF-23) has been best defined. Maintenance of extracellular and intracellular phosphate levels within a narrow range is important for many biological processes, including energy metabolism, cell signaling, regulation of protein synthesis, skeletal development, and bone integrity. The presence of adequate amounts of phosphate is critical for the process of apoptosis of mature chondrocytes in the growth plate. Without the presence of this mineral in high enough quantities, chondrocytes will not go into apoptosis, and the normal physiological chain of events that includes invasion of blood vessels and the generation of new bone will be blocked, resulting in rickets and delayed growth. In the rest of the skeleton, hypophosphatemia will result in osteomalacia due to an insufficient formation of hydroxyapatite. This review will address phosphate metabolism and its role in bone health.

[The Base of the Skull. Rudolf Virchow between Pathology and Anthropology].

PubMed

Seemann, Sophie

2016-01-01

Throughout his scientific career, the pathologist and anthropologist Rudolf Virchow (1821-1902) examined countless skulls, gradually changing his perspective on this object of research. Initially, he was mainly concerned with pathologically deformed skulls. From the 1850s onwards, he gradually developed a more anthropological approach, and anthropology increasingly came to dominate his scientific interest. This article shows how different influences became central for the establishment of his specific and dynamic model of the human skull development and its successful application in anthropology. Crucial for this process were Virchow's collaboration with his teacher Robert Froriep (1804-1861) in the department of pathology of the Charité, his research on cretinism and rickets, as well as his description of the base of the skull as the center of skull development. His research work was attended by and showed a reciprocal interaction with the buildup of large skull collections. This article uses Virchow's original publications on skull pathology as well as his still preserved skull specimens from the collection of the Berlin Museum of Medical History at the Charité for an integrated text and object based analysis.

Health Risks of Hypovitaminosis D: A Review of New Molecular Insights

PubMed Central

Ricca, Sergio; Currò, Monica; Ientile, Riccardo

2018-01-01

Hypovitaminosis D has become a pandemic, being observed in all ethnicities and age groups worldwide. Environmental factors, such as increased air pollution and reduced ultraviolet B (UVB) irradiation, as well as lifestyle factors, i.e., decreased outdoor activities and/or poor intake of vitamin D-rich food, are likely involved in the etiology of a dramatic reduction of vitamin D circulating levels. The insufficiency/deficiency of vitamin D has long been known for its association with osteoporosis and rickets. However, in the last few decades it has become a serious public health concern since it has been shown to be independently associated with various chronic pathological conditions such as cancer, coronary heart disease, neurological diseases, type II diabetes, autoimmune diseases, depression, with various inflammatory disorders, and with increased risk for all-cause mortality in the general population. Prevention strategies for these disorders have recently involved supplementation with either vitamin D2 or vitamin D3 or their analogs at required daily doses and tolerable upper-limit levels. This review will focus on the emerging evidence about non-classical biological functions of vitamin D in various disorders. PMID:29562608

Health Risks of Hypovitaminosis D: A Review of New Molecular Insights.

PubMed

Caccamo, Daniela; Ricca, Sergio; Currò, Monica; Ientile, Riccardo

2018-03-17

Hypovitaminosis D has become a pandemic, being observed in all ethnicities and age groups worldwide. Environmental factors, such as increased air pollution and reduced ultraviolet B (UVB) irradiation, as well as lifestyle factors, i.e., decreased outdoor activities and/or poor intake of vitamin D-rich food, are likely involved in the etiology of a dramatic reduction of vitamin D circulating levels. The insufficiency/deficiency of vitamin D has long been known for its association with osteoporosis and rickets. However, in the last few decades it has become a serious public health concern since it has been shown to be independently associated with various chronic pathological conditions such as cancer, coronary heart disease, neurological diseases, type II diabetes, autoimmune diseases, depression, with various inflammatory disorders, and with increased risk for all-cause mortality in the general population. Prevention strategies for these disorders have recently involved supplementation with either vitamin D2 or vitamin D3 or their analogs at required daily doses and tolerable upper-limit levels. This review will focus on the emerging evidence about non-classical biological functions of vitamin D in various disorders.

Hospital admissions for vitamin D related conditions and subsequent immune-mediated disease: record-linkage studies

PubMed Central

2013-01-01

Background Previous studies have suggested that there may be an association between vitamin D deficiency and the risk of developing immune-mediated diseases. Methods We analyzed a database of linked statistical records of hospital admissions and death registrations for the whole of England (from 1999 to 2011). Rate ratios for immune-mediated disease were determined, comparing vitamin D deficient cohorts (individuals admitted for vitamin D deficiency or markers of vitamin D deficiency) with comparison cohorts. Results After hospital admission for either vitamin D deficiency, osteomalacia or rickets, there were significantly elevated rates of Addison’s disease, ankylosing spondylitis, autoimmune hemolytic anemia, chronic active hepatitis, celiac disease, Crohn’s disease, diabetes mellitus, pemphigoid, pernicious anemia, primary biliary cirrhosis, rheumatoid arthritis, Sjogren’s syndrome, systemic lupus erythematosus, thyrotoxicosis, and significantly reduced risks for asthma and myxoedema. Conclusions This study shows that patients with vitamin D deficiency may have an increased risk of developing some immune-mediated diseases, although we cannot rule out reverse causality or confounding. Further study of these associations is warranted and these data may aid further public health studies. PMID:23885887

CT and MR imaging features in phosphaturic mesenchymal tumor-mixed connective tissue: A case report

PubMed Central

Shi, Zhenshan; Deng, Yiqiong; Li, Xiumei; Li, Yueming; Cao, Dairong; Coossa, Vikash Sahadeo

2018-01-01

Phosphaturic mesenchymal tumor-mixed connective tissue (PMT-MCT) is rare and usually benign and slow-growing. The majority of these tumors is associated with sporadic tumor-induced osteomalacia (TIO) or rickets, affect middle-aged individuals and are located in the extremities. Previous imaging studies often focused on seeking the causative tumors of TIO, not on the radiological features of these tumors, especially magnetic resonance imaging (MRI) features. PMT-MCT remains a largely misdiagnosed, ignored or unknown entity by most radiologists and clinicians. In the present case report, a review of the known literature of PMT-MCT was conducted and the CT and MRI findings from three patient cases were described for diagnosing the small subcutaneous tumor. Typical MRI appearances of PMT-MCT were isointense relative to the muscles on T1-weighted imaging, and markedly hyperintense on T2-weighted imaging containing variably flow voids, with markedly heterogeneous/homogenous enhancement on post contrast T1-weighted fat-suppression imaging. Short time inversion recovery was demonstrated to be the optimal sequence in localizing the tumor. PMID:29552133

CT and MR imaging features in phosphaturic mesenchymal tumor-mixed connective tissue: A case report.

PubMed

Shi, Zhenshan; Deng, Yiqiong; Li, Xiumei; Li, Yueming; Cao, Dairong; Coossa, Vikash Sahadeo

2018-04-01

Phosphaturic mesenchymal tumor-mixed connective tissue (PMT-MCT) is rare and usually benign and slow-growing. The majority of these tumors is associated with sporadic tumor-induced osteomalacia (TIO) or rickets, affect middle-aged individuals and are located in the extremities. Previous imaging studies often focused on seeking the causative tumors of TIO, not on the radiological features of these tumors, especially magnetic resonance imaging (MRI) features. PMT-MCT remains a largely misdiagnosed, ignored or unknown entity by most radiologists and clinicians. In the present case report, a review of the known literature of PMT-MCT was conducted and the CT and MRI findings from three patient cases were described for diagnosing the small subcutaneous tumor. Typical MRI appearances of PMT-MCT were isointense relative to the muscles on T1-weighted imaging, and markedly hyperintense on T2-weighted imaging containing variably flow voids, with markedly heterogeneous/homogenous enhancement on post contrast T1-weighted fat-suppression imaging. Short time inversion recovery was demonstrated to be the optimal sequence in localizing the tumor.

TRPV5-mediated Ca2+ Reabsorption and Hypercalciuria

NASA Astrophysics Data System (ADS)

Renkema, Kirsten Y.; Hoenderop, Joost G. J.; Bindels, René J. M.

2007-04-01

The concerted action of the intestine, kidney and bone results in the maintenance of a normal Ca2+ balance, a mechanism that is tightly controlled by the calciotropic hormones vitamin D, parathyroid hormone and calcitonin. Disturbances in the Ca2+ balance have been linked to diverse pathophysiological disorders like urolithiasis, hypertension, electroencephalogram abnormalities and rickets. Importantly, the final amount of Ca2+ that is released from the body is determined in the distal part of the nephron, where active Ca2+ reabsorption occurs. Here, Transient Receptor Potential Vanilloid member 5 (TRPV5), a highly Ca2+-selective channel, has been recognized as the gatekeeper of active Ca2+ reabsorption. The in vivo relevance of TRPV5 has been further investigated by the characterization of TRPV5 knockout (TRPV5-/-) mice, which exhibit severe disturbances in renal Ca2+ handling, such as profound hypercalciuria, intestinal Ca2+ hyperabsorption and reduced bone thickness. Hypercalciuria increases the risk of kidney stone formation in these mice. This review highlights our current knowledge about TRPV5-mediated Ca2+ reabsorption and emphasizes the physiological relevance and the clinical implications related to the TRPV5-/- mice model.

Abnormal bone formation induced by implantation of osteosarcoma-derived bone-inducing substance in the X-linked hypophosphatemic mouse

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yoshikawa, H.; Masuhara, K.; Takaoka, K.

1985-01-01

The X-linked hypophosphatemic mouse (Hyp) has been proposed as a model for the human familial hypophosphatemia (the most common form of vitamin D-resistant rickets). An osteosarcoma-derived bone-inducing substance was subcutaneously implanted into the Hyp mouse. The implant was consistently replaced by cartilage tissue at 2 weeks after implantation. The cartilage matrix seemed to be normal, according to the histological examination, and 35sulphur (TVS) uptake was also normal. Up to 4 weeks after implantation the cartilage matrix was completely replaced by unmineralized bone matrix and hematopoietic bone marrow. Osteoid tissue arising from the implantation of bone inducing substance in the Hypmore » mouse showed no radiologic or histologic sign of calcification. These findings suggest that the abnormalities of endochondral ossification in the Hyp mouse might be characterized by the failure of mineralization in cartilage and bone matrix. Analysis of the effects of bone-inducing substance on the Hyp mouse may help to give greater insight into the mechanism and treatment of human familial hypophosphatemia.« less

X-linked hypophosphataemia: a homologous disorder in humans and mice.

PubMed

Tenenhouse, H S

1999-02-01

X-linked hypophosphatemia is an inherited disorder of phosphate (Pi) homeostasis characterized by growth retardation, rickets and osteomalacia, hypophosphataemia, and aberrant renal Pi reabsorption and vitamin D metabolism. Studies in murine Hyp and Gy homologues have identified a specific defect in Na+-Pi cotransport at the brush border membrane, abnormal regulation of 1,25-dihydroxyvitamin D3 (1,25(OH)2D) synthesis and degradation, and an intrinsic defect in bone mineralization. The mutant gene has been identified in XLH patients, by positional cloning, and in Hyp and Gy mice, and was designated PHEX/Phex to signify a PHosphate-regulating gene with homology to Endopeptidases on the X chromosome. PHEX/Phex is expressed in bones and teeth but not in kidney and efforts are under way to elucidate how loss of PHEX/Phex function elicits the mutant phenotype. Based on its homology to endopeptidases, it is postulated that PHEX/Phex is involved in the activation or inactivation of a peptide hormone(s) which plays a key role in the regulation of bone mineralization, renal Pi handling and vitamin D metabolism.

Rheumatic disorders in Sub-saharan Africa.

PubMed

McGill, P E; Oyoo, G O

2002-04-01

To review prevalence of rheumatic disorders in Sub-saharan Africa and in the context of current medical practice in the region assess the need for service and educational provision. Medline, (English, French). Pre-Medline literature review from the 1950's (Current contents). Various conference reports including attendance at all three AFLAR (African League Against Rheumatism) congresses in the 1990's. Author's personal database. All cited references read in full. The evidence shows rheumatoid arthritis and systemic lupus erythematosus to be increasing in frequency in the indigenous populations of East, Central and South Africa but remaining rare in West Africans. Gout is now more prevalent than ever throughout the subcontinent. HIV has spawned a variety of previously rare spondyloarthropathies (reactive arthritis, psoriatic arthritis, enthesopathy) and changed the epidemiology of pyomyositis and osteomyelitis. Osteoarthritis is a universal problem. Juvenile chronic arthritis is not rare and rheumatic fever is common. Acute and chronic locomotor problems associated with diverse entities such as leprosy, brucellosis, meningococcus, alpha viruses, parasites, fluorosis, rickets and haemoglobinopathies enhance diagnostic diversity and therapeutic and educational requirements. Suggestions made to address the challenge posed by the burden of rheumatic disorders.

Coping strategies and nutritional health in rural Niger: recommendations for consumption of wild plant foods in the Sahel.

PubMed

Glew, Robert S; Vanderjagt, Dorothy

2006-01-01

People who live in food and water deficit regions of Sahelien West Africa employ various coping strategies as they attempt to meet their food and water needs. In this paper we discuss various coping strategies employed by rural Nigeriens living in the Tanout and Mirriya administrative regions of central Niger. In rural Niger people often harvest or buy wild plant foods to eat. Laboratory studies of the nutritional content of these plants indicate that there are benefits to eating wild plant foods. In this study we summarize the results of field research conducted during the summer of 2002 on the use of wild plant foods in three regions of rural central Niger. Comparing local use of various wild plant foods with major nutrition-related health problems including protein deficiency, essential fatty acid deficiency, iron deficiency and iron deficiency anemia, calcium deficiency rickets, and zinc deficiency, suggests potential recommendations for consumption of these plants. However, further research on the bioavailability of these nutrients is needed to confirm the potential benefits of these plants.

The historical evolution of thought regarding multiple micronutrient nutrition.

PubMed

Semba, Richard D

2012-01-01

Multiple micronutrient nutrition is an idea that originated in the 1940s and exemplifies the iterative nutritional paradigm. In the first four decades of the 20th century, scientists sought to separate and characterize the vitamins that were responsible for xerophthalmia, rickets, pellagra, scurvy, and beriberi. The dietary requirements of the different micronutrients began to be established in the early 1940s. Surveys showed that multiple micronutrient deficiencies were widespread in industrialized countries, and the problem was addressed by use of cod-liver oil, iodized salt, fortified margarine, and flour fortification with multiple micronutrients, and, with rising living standards, the increased availability and consumption of animal source foods. After World War II, surveys showed that multiple micronutrient deficiencies were widespread in developing countries. Approaches to the elimination of multiple micronutrient deficiencies include periodic vitamin A supplementation, iodized salt, targeted iron/folate supplementation, fortified flour, other fortified foods, home fortification with micronutrient powders, and homestead food production. The prevention of multiple micronutrient malnutrition is a key factor in achieving the Millennium Development Goals, given the important effects of micronutrients on health and survival.

Analysis of nutritional disease in prehistory: The search for scurvy in antiquity and today.

PubMed

Armelagos, George J; Sirak, Kendra; Werkema, Taylor; Turner, Bethany L

2014-06-01

In this paper, we discuss the issues surrounding the study of scurvy, or vitamin C deficiency, in paleopathology, and highlight the work of Donald Ortner in advancing this area of research. This micronutrient deficiency impacts collagen formation and results in damage to a variety of bodily tissues. While clinical manifestations are observed routinely, the lack of specific signatures on bone makes paleopathological diagnosis difficult. Rapid growth in infants, children, and subadults provides abundant remodeled tissue and an increase in vascularization that makes identification possible in younger segments of the population. However, diagnosis of scurvy in adults remains problematic, given that diagnostic lesions are strikingly similar to those associated with rickets, osteomalacia, and other conditions. We argue that this confounding factor underscores the need for a broader anthropological approach to scurvy research that expands beyond differential diagnosis to include more accurate reconstruction of diets and available resources, greater consideration of the possibility - even likelihood - of multiple nutrient deficiencies simultaneously affecting an individual, and the patterning of these deficiencies along lines of status, sex, and age. Copyright © 2013 Elsevier Inc. All rights reserved.

Vitamin D Insufficiency

PubMed Central

Thacher, Tom D.; Clarke, Bart L.

2011-01-01

Vitamin D deficiency, which classically manifests as bone disease (either rickets or osteomalacia), is characterized by impaired bone mineralization. More recently, the term vitamin D insufficiency has been used to describe low levels of serum 25-hydroxyvitamin D that may be associated with other disease outcomes. Reliance on a single cutoff value to define vitamin D deficiency or insufficiency is problematic because of the wide individual variability of the functional effects of vitamin D and interaction with calcium intakes. In adults, vitamin D supplementation reduces the risk of fractures and falls. The evidence for other purported beneficial effects of vitamin D is primarily based on observational studies. We selected studies with the strongest level of evidence for clinical decision making related to vitamin D and health outcomes from our personal libraries of the vitamin D literature and from a search of the PubMed database using the term vitamin D in combination with the following terms related to the potential nonskeletal benefits of vitamin D: mortality, cardiovascular, diabetes mellitus, cancer, multiple sclerosis, allergy, asthma, infection, depression, psychiatric, and pain. Conclusive demonstration of these benefits awaits the outcome of controlled clinical trials. PMID:21193656

Extrahepatic biliary atresia in a border collie.

PubMed

Schulze, C; Rothuizen, J; van Sluijs, F J; Hazewinkel, H A; van den Ingh, T S

2000-01-01

Progressive lameness and leg pain were the predominant clinical signs in a 17-week-old male border collie presented for examination. On clinical investigation, extrahepatic cholestasis in association with rickets due to inadequate vitamin D resorption was diagnosed. The dog was treated parenterally with vitamin D and a cholecystoduodenostomy was performed. At 25 days postsurgery the lameness had resolved and bone structure was radiographically normal. However, at six weeks postsurgery, the dog's condition deteriorated rapidly and euthanasia was finally performed at eight weeks postsurgery. At postmortem examination, Toxocara canis nematodes were found to have invaded the biliary system via the anastomosis between the gallbladder and duodenum, causing biliary and hepatic toxocariasis. The cause of the primary extrahepatic cholestasis was atresia of the common bile duct at the hepatic end. The liver tissue showed microscopic lesions of chronic extrahepatic cholestasis as well as acute inflammation associated with the nematode invasion. There was no postmortem evidence of bone lesions. Extrahepatic biliary atresia is extremely rare in animals and has not been described before in dogs. In contrast, it represents the most common cause of congenital cholestasis in children, occurring in approximately one per 10,000 to 15,000 live births.

UV radiation, vitamin D, and cancer: how to measure the vitamin D synthetic capacity of UV sources?

NASA Astrophysics Data System (ADS)

Terenetskaya, Irina; Orlova, Tatiana

2005-09-01

UV irradiation is widely used in phototherapy. Regardless of the fact that UV overexposure is liable to cause adverse health effect, in appropriate doses UV radiation initiates synthesis of vitamin D in skin that is absolutely essential for human health. As it proved, most people in northern industrial countries have a level of vitamin D in their bodies that is insufficient for optimum health, especially in winter. These low levels of vitamin D are now known to be associated with a wide spectrum of serious disease much of which leads on to premature death. The diseases associated with D deficiency involve more than a dozen types of cancer including colon, breast and prostate, as well as the classic bone diseases: rickets, osteoporosis and osteomalacia. Irradiation with artificial UV sources can prevent the vitamin D deficiency. However, in view of different irradiation spectra of UV lamps, their ability to initiate vitamin D synthesis is different. The reliable method based on an in vitro model of vitamin D synthesis has been developed for direct measurement in situ of the vitamin D synthetic capacity of artificial UV sources during a phototherapeutic procedure

Human skin pigmentation, migration and disease susceptibility

PubMed Central

Jablonski, Nina G.; Chaplin, George

2012-01-01

Human skin pigmentation evolved as a compromise between the conflicting physiological demands of protection against the deleterious effects of ultraviolet radiation (UVR) and photosynthesis of UVB-dependent vitamin D3. Living under high UVR near the equator, ancestral Homo sapiens had skin rich in protective eumelanin. Dispersals outside of the tropics were associated with positive selection for depigmentation to maximize cutaneous biosynthesis of pre-vitamin D3 under low and highly seasonal UVB conditions. In recent centuries, migrations and high-speed transportation have brought many people into UVR regimes different from those experienced by their ancestors and, accordingly, exposed them to new disease risks. These have been increased by urbanization and changes in diet and lifestyle. Three examples—nutritional rickets, multiple sclerosis (MS) and cutaneous malignant melanoma (CMM)—are chosen to illustrate the serious health effects of mismatches between skin pigmentation and UVR. The aetiology of MS in particular provides insight into complex and contingent interactions of genetic and environmental factors necessary to trigger lethal disease states. Low UVB levels and vitamin D deficiencies produced by changes in location and lifestyle pose some of the most serious disease risks of the twenty-first century. PMID:22312045

Rare bone diseases and their dental, oral, and craniofacial manifestations.

PubMed

Foster, B L; Ramnitz, M S; Gafni, R I; Burke, A B; Boyce, A M; Lee, J S; Wright, J T; Akintoye, S O; Somerman, M J; Collins, M T

2014-07-01

Hereditary diseases affecting the skeleton are heterogeneous in etiology and severity. Though many of these conditions are individually rare, the total number of people affected is great. These disorders often include dental-oral-craniofacial (DOC) manifestations, but the combination of the rarity and lack of in-depth reporting often limit our understanding and ability to diagnose and treat affected individuals. In this review, we focus on dental, oral, and craniofacial manifestations of rare bone diseases. Discussed are defects in 4 key physiologic processes in bone/tooth formation that serve as models for the understanding of other diseases in the skeleton and DOC complex: progenitor cell differentiation (fibrous dysplasia), extracellular matrix production (osteogenesis imperfecta), mineralization (familial tumoral calcinosis/hyperostosis hyperphosphatemia syndrome, hypophosphatemic rickets, and hypophosphatasia), and bone resorption (Gorham-Stout disease). For each condition, we highlight causative mutations (when known), etiopathology in the skeleton and DOC complex, and treatments. By understanding how these 4 foci are subverted to cause disease, we aim to improve the identification of genetic, molecular, and/or biologic causes, diagnoses, and treatment of these and other rare bone conditions that may share underlying mechanisms of disease. © International & American Associations for Dental Research.

Bone Disease in the Common Marmoset: Radiographic and Histological Findings.

PubMed

Olson, E J; Shaw, G C; Hutchinson, E K; Schultz-Darken, N; Bolton, I D; Parker, J B; Morrison, J M; Baxter, V K; Pate, K A Metcalf; Mankowski, J L; Carlson, C S

2015-09-01

The common marmoset (Callithrix jacchus) is a New World primate that is used in biomedical research due to its small size and relative ease of handling compared with larger primates. Although bone disease in common marmosets is well recognized, there are very few detailed descriptions in the literature that cover the range of lesions seen in these animals. For all animals used to model human disease, it is important to be aware of background lesions that may affect the interpretation of study findings. This retrospective study details bone diseases encountered in marmoset breeding colonies at 2 different institutions. Affected marmosets at Johns Hopkins University had lesions compatible with diagnoses of rickets, fibrous osteodystrophy and osteopenia. Affected marmosets at the Wisconsin National Primate Research Center exhibited severe lesions of osteoclastic bone resorption and remodeling that had an unusual distribution and were not easily categorized into a known disease entity. The purpose of this report is to document these naturally occurring skeletal lesions of common marmosets and suggest an approach to evaluating skeletal disease in prospective studies of these animals that will allow the most accurate diagnoses. © The Author(s) 2015.

Vitamin D in North-East Asian clinical nutrition practice.

PubMed

Wahlqvist, Mark L

2013-01-01

Sound clinical nutrition practice is grounded in evidence and stimulated by research. Yet, there are unanswered questions about food-health relationships. Clinical nutrition involves the identification of nutritional disorders and the motivation to rectify them with all required care. Vitamin D health exemplifies the biomedical, societal and environmental dimensions of clinical nutrition, its science and practice. It depends most of all on access to sunshine and food and probably represents a paradigm in human health which is still at its beginning. Nevertheless, the problem of its deficiency is much more widespread and common than has been thought since it was first identified as a cause of rickets and osteomalacia. It is now known to spare no body organ or system. The problem in North-East Asia is comparable to much of the rest of the world, but the risk profile for it is exaggerated by atmospheric pollution, cultures with sun-avoidance on account of skin colour and potentially mitigated by foodstuffs like fish, eggs, organ meats and mushrooms which can partially offset sunshine-deficiency. Diagnosis requires a high index of suspicion and confirmation by biochemistry which may not be affordable. Therefore a close working relationship between public health and clinical nutritionist is essential.

Tooth dentin defects reflect genetic disorders affecting bone mineralization

PubMed Central

Vital, S. Opsahl; Gaucher, C.; Bardet, C.; Rowe, P.S.; George, A.; Linglart, A.; Chaussain, C.

2012-01-01

Several genetic disorders affecting bone mineralization may manifest during dentin mineralization. Dentin and bone are similar in several aspects, especially pertaining to the composition of the extracellular matrix (ECM) which is secreted by well-differentiated odontoblasts and osteoblasts, respectively. However, unlike bone, dentin is not remodelled and is not involved in the regulation of calcium and phosphate metabolism. In contrast to bone, teeth are accessible tissues with the shedding of deciduous teeth and the extractions of premolars and third molars for orthodontic treatment. The feasibility of obtaining dentin makes this a good model to study biomineralization in physiological and pathological conditions. In this review, we focus on two genetic diseases that disrupt both bone and dentin mineralization. Hypophosphatemic rickets is related to abnormal secretory proteins involved in the ECM organization of both bone and dentin, as well as in the calcium and phosphate metabolism. Osteogenesis imperfecta affects proteins involved in the local organization of the ECM. In addition, dentin examination permits evaluation of the effects of the systemic treatment prescribed to hypophosphatemic patients during growth. In conclusion, dentin constitutes a valuable tool for better understanding of the pathological processes affecting biomineralization. PMID:22296718

Rare Bone Diseases and Their Dental, Oral, and Craniofacial Manifestations

PubMed Central

Foster, B.L.; Ramnitz, M.S.; Gafni, R.I.; Burke, A.B.; Boyce, A.M.; Lee, J.S.; Wright, J.T.; Akintoye, S.O.; Somerman, M.J.; Collins, M.T.

2014-01-01

Hereditary diseases affecting the skeleton are heterogeneous in etiology and severity. Though many of these conditions are individually rare, the total number of people affected is great. These disorders often include dental-oral-craniofacial (DOC) manifestations, but the combination of the rarity and lack of in-depth reporting often limit our understanding and ability to diagnose and treat affected individuals. In this review, we focus on dental, oral, and craniofacial manifestations of rare bone diseases. Discussed are defects in 4 key physiologic processes in bone/tooth formation that serve as models for the understanding of other diseases in the skeleton and DOC complex: progenitor cell differentiation (fibrous dysplasia), extracellular matrix production (osteogenesis imperfecta), mineralization (familial tumoral calcinosis/hyperostosis hyperphosphatemia syndrome, hypophosphatemic rickets, and hypophosphatasia), and bone resorption (Gorham-Stout disease). For each condition, we highlight causative mutations (when known), etiopathology in the skeleton and DOC complex, and treatments. By understanding how these 4 foci are subverted to cause disease, we aim to improve the identification of genetic, molecular, and/or biologic causes, diagnoses, and treatment of these and other rare bone conditions that may share underlying mechanisms of disease. PMID:24700690

Severe lateral tibial bowing with short stature in two siblings--a provisionally novel syndrome.

PubMed

Zitano, Lia; Loder, Randall T; Cohen, Mervyn D; Weaver, David D

2012-09-01

In this report, we describe two siblings with short stature and severe lateral tibial bowing. In the younger sibling, the bowing was bilateral, while in the older sib, it was unilateral. However, both showed bilateral abnormalities of the distal tibial epiphyses and growth plates. Pseudoarthrosis of the left distal tibial metaphysis and subsequent spontaneous resolution of the abnormality occurred in the younger sibling. The fibulas of both children were of normal diameter and were straight, except for the distal ends. Surgery has almost completely corrected the lower leg bowing in both patients. The type of tibial bowing seen in these children can be associated with a number of syndromes, such as neurofibromatosis type I, Weismann-Netter syndrome, and a variety of environmental caused disorders, such as vitamin D deficient rickets. However, the severity of the bowing present in our patients and the absence of other clinical features differentiates this condition from those reported in the literature. We posit that the condition in the children presented here represents an as yet undescribed syndrome, which is likely to be of genetic origin. Copyright © 2012 Wiley Periodicals, Inc.

A computationally identified compound antagonizes excess FGF-23 signaling in renal tubules and a mouse model of hypophosphatemia

DOE PAGES

Xiao, Zhousheng; Riccardi, Demian; Velazquez, Hector A.; ...

2016-11-22

Fibroblast growth factor–23 (FGF-23) interacts with a binary receptor complex composed of α-Klotho (α-KL) and FGF receptors (FGFRs) to regulate phosphate and vitamin D metabolism in the kidney. Excess FGF-23 production, which causes hypophosphatemia, is genetically inherited or occurs with chronic kidney disease. Among other symptoms, hypophosphatemia causes vitamin D deficiency and the bone-softening disorder rickets. Current therapeutics that target the receptor complex have limited utility clinically. In this paper, using a computationally driven, structure-based, ensemble docking and virtual high-throughput screening approach, we identified four novel compounds predicted to selectively inhibit FGF-23–induced activation of the FGFR/α-KL complex. Additional modeling andmore » functional analysis found that Zinc13407541 bound to FGF-23 and disrupted its interaction with the FGFR1/α-KL complex; experiments in a heterologous cell expression system showed that Zinc13407541 selectivity inhibited α-KL–dependent FGF-23 signaling. Zinc13407541 also inhibited FGF-23 signaling in isolated renal tubules ex vivo and partially reversed the hypophosphatemic effects of excess FGF-23 in a mouse model. Finally, these chemical probes provide a platform to develop lead compounds to treat disorders caused by excess FGF-23.« less

Maternal supplementation for prevention and treatment of vitamin D deficiency in exclusively breastfed infants.

PubMed

Haggerty, Linda L

2011-06-01

Current research links newborn and infant vitamin D deficiency with various clinical outcomes, including rickets, failure to thrive, type 1 diabetes, and other immune-related diseases. Breastfed infants are often at a greater risk of developing deficiency due to their mothers' low vitamin D status. Human milk reflects the vitamin D status of the mother and often contains inadequate levels of 25-hydroxyvitamin D for infant nutrition. In 2008 the American Academy of Pediatrics (AAP) recommended 400 IU of vitamin D supplementation of all infants. However, research has indicated low levels of compliance of vitamin D supplementation of breastfed infants and a high incidence of vitamin D deficiency in the United States. Many breastfeeding advocates believe that the AAP's recommendations undermine breastfeeding, implying that human milk is inadequate for infant nutrition. Lactating mothers are also reluctant to add any supplements to their breastmilk. The literature review will examine the effectiveness and safety of maternal vitamin D supplementation for prevention and/or treatment of vitamin D deficiency in breastfed infants and lactating mothers. This method of prevention and intervention provides pediatric providers and certified lactation consultants with an alternative approach for education, counseling, promotion of breastfeeding, and treatment to improve maternal and infant health.

Physical therapy management of infants and children with hypophosphatasia.

PubMed

Phillips, Dawn; Case, Laura E; Griffin, Donna; Hamilton, Kim; Lara, Sergio Lerma; Leiro, Beth; Monfreda, Jessica; Westlake, Elaine; Kishnani, Priya S

2016-09-01

Hypophosphatasia (HPP) is a rare inborn error of metabolism resulting in undermineralization of bone and subsequent skeletal abnormalities. The natural history of HPP is characterized by rickets and osteomalacia, increased propensity for bone fracture, early loss of teeth in childhood, and muscle weakness. There is a wide heterogeneity in disease presentation, and the functional impact of the disease can vary from perinatal death to gait abnormalities. Recent clinical trials of enzyme replacement therapy have begun to offer an opportunity for improvement in survival and function. The role of physical therapy in the treatment of the underlying musculoskeletal dysfunction in HPP is underrecognized. It is important for physical therapists to understand the disease characteristics of the natural history of a rare disease like HPP and how the impairment and activity limitations may change in response to medical interventions. An understanding of when and how to intervene is also important in order to optimally impact body function, lessen structural impairment, and facilitate increased functional independence in mobility and activities of daily living. Individualizing treatment to the child's needs, medical fragility, and setting (home/school/hospital), while educating parents, caregivers, and school staff regarding approved activities and therapy frequency, may improve function and development in children with HPP. Copyright © 2016 Elsevier Inc. All rights reserved.

Cod liver oil supplement consumption and health: cross-sectional results from the EPIC-Norfolk cohort study.

PubMed

Lentjes, Marleen A H; Welch, Ailsa A; Mulligan, Angela A; Luben, Robert N; Wareham, Nicholas J; Khaw, Kay-Tee

2014-10-16

Supplement users (SU) make healthy lifestyle choices; on the other hand, SU report more medical conditions. We hypothesised that cod liver oil (CLO) consumers are similar to non-supplement users, since CLO use might originate from historical motives, i.e., rickets prevention, and not health consciousness. CLO consumers were studied in order to identify possible confounders, such as confounding by indication. The European Prospective Investigation into Cancer (EPIC) investigates causes of chronic disease. The participants were 25,639 men and women, aged 40-79 years, recruited from general practices in Norfolk, East-Anglia (UK). Participants completed questionnaires and a health examination between 1993 and 1998. Supplement use was measured using 7-day diet diaries. CLO was the most common supplement used, more prevalent among women and associated with not smoking, higher physical activity level and more favourable eating habits. SU had a higher occurrence of benign growths and bone-related diseases, but CLO was negatively associated with cardiovascular-related conditions. Although the results of SU characteristics in EPIC-Norfolk are comparable with studies worldwide, the CLO group is different from SU in general. Confounding by indication takes place and will need to be taken into account when analysing prospective associations of CLO use with fracture risk and cardiovascular diseases.

FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting

PubMed Central

Riminucci, Mara; Collins, Michael T.; Fedarko, Neal S.; Cherman, Natasha; Corsi, Alessandro; White, Kenneth E.; Waguespack, Steven; Gupta, Anurag; Hannon, Tamara; Econs, Michael J.; Bianco, Paolo; Gehron Robey, Pamela

2003-01-01

FGF-23, a novel member of the FGF family, is the product of the gene mutated in autosomal dominant hypophosphatemic rickets (ADHR). FGF-23 has been proposed as a circulating factor causing renal phosphate wasting not only in ADHR (as a result of inadequate degradation), but also in tumor-induced osteomalacia (as a result of excess synthesis by tumor cells). Renal phosphate wasting occurs in approximately 50% of patients with McCune-Albright syndrome (MAS) and fibrous dysplasia of bone (FD), which result from postzygotic mutations of the GNAS1 gene. We found that FGF-23 is produced by normal and FD osteoprogenitors and bone-forming cells in vivo and in vitro. In situ hybridization analysis of FGF-23 mRNA expression identified “fibrous” cells, osteogenic cells, and cells associated with microvascular walls as specific cellular sources of FGF-23 in FD. Serum levels of FGF-23 were increased in FD/MAS patients compared with normal age-matched controls and significantly higher in FD/MAS patients with renal phosphate wasting compared with those without, and correlated with disease burden bone turnover markers commonly used to assess disease activity. Production of FGF-23 by FD tissue may play an important role in the renal phosphate–wasting syndrome associated with FD/MAS. PMID:12952917

A computationally identified compound antagonizes excess FGF-23 signaling in renal tubules and a mouse model of hypophosphatemia.

PubMed

Xiao, Zhousheng; Riccardi, Demian; Velazquez, Hector A; Chin, Ai L; Yates, Charles R; Carrick, Jesse D; Smith, Jeremy C; Baudry, Jerome; Quarles, L Darryl

2016-11-22

Fibroblast growth factor-23 (FGF-23) interacts with a binary receptor complex composed of α-Klotho (α-KL) and FGF receptors (FGFRs) to regulate phosphate and vitamin D metabolism in the kidney. Excess FGF-23 production, which causes hypophosphatemia, is genetically inherited or occurs with chronic kidney disease. Among other symptoms, hypophosphatemia causes vitamin D deficiency and the bone-softening disorder rickets. Current therapeutics that target the receptor complex have limited utility clinically. Using a computationally driven, structure-based, ensemble docking and virtual high-throughput screening approach, we identified four novel compounds predicted to selectively inhibit FGF-23-induced activation of the FGFR/α-KL complex. Additional modeling and functional analysis found that Zinc13407541 bound to FGF-23 and disrupted its interaction with the FGFR1/α-KL complex; experiments in a heterologous cell expression system showed that Zinc13407541 selectivity inhibited α-KL-dependent FGF-23 signaling. Zinc13407541 also inhibited FGF-23 signaling in isolated renal tubules ex vivo and partially reversed the hypophosphatemic effects of excess FGF-23 in a mouse model. These chemical probes provide a platform to develop lead compounds to treat disorders caused by excess FGF-23. Copyright © 2016, American Association for the Advancement of Science.

Approach to treatment of hypophosphatemia.

PubMed

Felsenfeld, Arnold J; Levine, Barton S

2012-10-01

Hypophosphatemia can be acute or chronic. Acute hypophosphatemia with phosphate depletion is common in the hospital setting and results in significant morbidity and mortality. Chronic hypophosphatemia, often associated with genetic or acquired renal phosphate-wasting disorders, usually produces abnormal growth and rickets in children and osteomalacia in adults. Acute hypophosphatemia may be mild (phosphorus level, 2-2.5 mg/dL), moderate (1-1.9 mg/dL), or severe (<1 mg/dL) and commonly occurs in clinical settings such as refeeding, alcoholism, diabetic ketoacidosis, malnutrition/starvation, and after surgery (particularly after partial hepatectomy) and in the intensive care unit. Phosphate replacement can be given either orally, intravenously, intradialytically, or in total parenteral nutrition solutions. The rate and amount of replacement are empirically determined, and several algorithms are available. Treatment is tailored to symptoms, severity, anticipated duration of illness, and presence of comorbid conditions, such as kidney failure, volume overload, hypo- or hypercalcemia, hypo- or hyperkalemia, and acid-base status. Mild/moderate acute hypophosphatemia usually can be corrected with increased dietary phosphate or oral supplementation, but intravenous replacement generally is needed when significant comorbid conditions or severe hypophosphatemia with phosphate depletion exist. In chronic hypophosphatemia, standard treatment includes oral phosphate supplementation and active vitamin D. Future treatment for specific disorders associated with chronic hypophosphatemia may include cinacalcet, calcitonin, or dypyrimadole. Published by Elsevier Inc.

Vitamin D Deficiency in India: Prevalence, Causalities and Interventions

PubMed Central

G, Ritu; Gupta, Ajay

2014-01-01

Vitamin D deficiency prevails in epidemic proportions all over the Indian subcontinent, with a prevalence of 70%–100% in the general population. In India, widely consumed food items such as dairy products are rarely fortified with vitamin D. Indian socioreligious and cultural practices do not facilitate adequate sun exposure, thereby negating potential benefits of plentiful sunshine. Consequently, subclinical vitamin D deficiency is highly prevalent in both urban and rural settings, and across all socioeconomic and geographic strata. Vitamin D deficiency is likely to play an important role in the very high prevalence of rickets, osteoporosis, cardiovascular diseases, diabetes, cancer and infections such as tuberculosis in India. Fortification of staple foods with vitamin D is the most viable population based strategy to achieve vitamin D sufficiency. Unfortunately, even in advanced countries like USA and Canada, food fortification strategies with vitamin D have been only partially effective and have largely failed to attain vitamin D sufficiency. This article reviews the status of vitamin D nutrition in the Indian subcontinent and also the underlying causes for this epidemic. Implementation of population based educational and interventional strategies to combat this scourge require recognition of vitamin D deficiency as a public health problem by the governing bodies so that healthcare funds can be allocated appropriately. PMID:24566435

A computationally identified compound antagonizes excess FGF-23 signaling in renal tubules and a mouse model of hypophosphatemia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xiao, Zhousheng; Riccardi, Demian; Velazquez, Hector A.

Fibroblast growth factor–23 (FGF-23) interacts with a binary receptor complex composed of α-Klotho (α-KL) and FGF receptors (FGFRs) to regulate phosphate and vitamin D metabolism in the kidney. Excess FGF-23 production, which causes hypophosphatemia, is genetically inherited or occurs with chronic kidney disease. Among other symptoms, hypophosphatemia causes vitamin D deficiency and the bone-softening disorder rickets. Current therapeutics that target the receptor complex have limited utility clinically. In this paper, using a computationally driven, structure-based, ensemble docking and virtual high-throughput screening approach, we identified four novel compounds predicted to selectively inhibit FGF-23–induced activation of the FGFR/α-KL complex. Additional modeling andmore » functional analysis found that Zinc13407541 bound to FGF-23 and disrupted its interaction with the FGFR1/α-KL complex; experiments in a heterologous cell expression system showed that Zinc13407541 selectivity inhibited α-KL–dependent FGF-23 signaling. Zinc13407541 also inhibited FGF-23 signaling in isolated renal tubules ex vivo and partially reversed the hypophosphatemic effects of excess FGF-23 in a mouse model. Finally, these chemical probes provide a platform to develop lead compounds to treat disorders caused by excess FGF-23.« less

Vitamin D in European children-statement from the European Academy of Paediatrics (EAP).

PubMed

Grossman, Zachi; Hadjipanayis, Adamos; Stiris, Tom; Del Torso, Stefano; Mercier, Jean-Christophe; Valiulis, Arunas; Shamir, Raanan

2017-06-01

Vitamin D is synthesized in human skin upon sun exposure and is also a nutrient. It regulates calcium and phosphate metabolism and is essential for the maintenance of bone health. Vitamin D supplementation during infancy, in order to prevent rickets, is universally accepted. Many human cell types carry vitamin D receptor, this being a drive for conducting studies on the possible association between vitamin D status and other diseases. Studies have affirmed that a considerable number of healthy European children may be vitamin D deficient, especially in high-risk groups (darker pigmented skin, living in areas with reduced sun exposure and other disorders). However, the definition of deficiency is unclear due to inter assay differences and due to a lack of consensus as to what is an "adequate" 25(OH)D level. Therefore, there is no justification for routine screening for vitamin D deficiency in healthy children. An evaluation of vitamin D status is justified in children belonging to high-risk groups. All infants up to 1 year of age should receive an oral supplementation of 400 IU/day of vitamin D. Beyond this age, seasonal variation of sunlight should be taken into account when considering a national policy of supplementation or fortification.

Immune Modulation by Vitamin D: Special Emphasis on Its Role in Prevention and Treatment of Cancer.

PubMed

Pandolfi, Franco; Franza, Laura; Mandolini, Claudia; Conti, Pio

2017-05-01

Vitamin D has been known to be involved in mineral and bone homeostasis for many years. In the past its main use was in treating osteoporosis and rickets. In recent years it was found that vitamin D is an immune-modulating agent and may also have a role in several diseases, including autoimmune diseases. The immune-modulating effects appear to be mediated by vitamin D interaction with the vitamin D receptor (VDR) that has transcriptional effects and is expressed on various cell types, especially those of the immune system. Immunologic and rheumatologic diseases were the first to be studied, but at the moment the spotlight is on the interactions between tumor cells and vitamin D. This review focuses on four forms of cancer that apparently benefit from a vitamin D supplementation during treatment: prostate, breast, and colorectal cancers and melanoma. Several studies reported that differences exist between white and black patients, which we discuss in the review. We systematically searched PubMed for studies published in English. The search terms included vitamin D, cancer, breast, colorectal, prostate, and melanoma. Our findings show that vitamin D has the potential to become a valid coadjuvant in the treatment of cancer. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

Holoptelea integrifolia (Roxb.) Planch: A Review of Its Ethnobotany, Pharmacology, and Phytochemistry

PubMed Central

Ganie, Showkat Ahmad; Yadav, Surender Singh

2014-01-01

Holoptelea integrifolia (Ulmaceae) is a versatile medicinal plant used in various indigenous systems of medicine for curing routine healthcare maladies. It is traditionally used in the treatment and prevention of several ailments like leprosy, inflammation, rickets, leucoderma, scabies, rheumatism, ringworm, eczema, malaria, intestinal cancer, and chronic wounds. In vitro and in vivo pharmacological investigations on crude extracts and isolated compounds showed antibacterial, antifungal, analgesic, antioxidant, anti-inflammatory, anthelmintic, antidiabetic, antidiarrhoeal, adaptogenic, anticancer, wound healing, hepatoprotective, larvicidal, antiemetic, CNS depressant, and hypolipidemic activities. Phytochemical analysis showed the presence of terpenoids, sterols, saponins, tannins, proteins, carbohydrates, alkaloids, phenols, flavonoids, glycosides, and quinines. Numerous compounds including Holoptelin-A, Holoptelin-B, friedlin, epifriedlin, β-amyrin, stigmasterol, β-sitosterol, 1, 4-napthalenedione, betulin, betulinic acid, hexacosanol, and octacosanol have been identified and isolated from the plant species. The results of several studies indicated that H. integrifolia may be used as an effective therapeutic remedy in the prevention and treatment of various ailments. However, further studies on chemical constituents and their mechanisms in exhibiting certain biological activities are needed. In addition, study on the toxicity of the crude extracts and the compounds isolated from this plant should be assessed to ensure their eligibility to be used as source of modern medicines. PMID:24949441

Correction of vitamin D deficiency in a cohort of newborn infants using daily 200 IU vitamin D supplementation.

PubMed

Onwuneme, C; Diya, B; Uduma, O; McCarthy, R A; Murphy, N; Kilbane, M T; McKenna, M J; Molloy, E J

2016-08-01

Although the role of vitamin D in the prevention of rickets has long been well established, controversies still exist on the ideal dose of vitamin D supplementation in infants. We assessed serum 25-hydroxyvitamin D (25OHD) status simultaneously in maternal and cord samples and the response to vitamin D3 supplementation in neonates. Serum 25OHD levels were evaluated from maternal, and umbilical cord samples from term normal pregnancies. Repeat 25OHD levels were assessed in neonates with 25OHD below 30 nmol/L following vitamin D3 200 IU daily after 6 weeks. Blood samples were taken including 57 cord samples and 16 follow-up neonatal samples. Maternal and cord serum 25OHD were 43 ± 21 and 29 ± 15 nmol/L, respectively. Infants with 25OHD < 30 nmol/L (19.8 ± 4.7 nmol/L) had a significant increase in serum 25OHD (63.3 ± 14.5 nmol/L) following vitamin D3 200 IU daily after 6 weeks. Healthy Irish infants born at term are at high risk of vitamin D deficiency, but vitamin D3 200 IU daily, rapidly corrects poor vitamin D status.

Temporary brittle bone disease: relationship between clinical findings and judicial outcome

PubMed Central

Paterson, Colin R.; Monk, Elizabeth A.

2011-01-01

There is a wide differential diagnosis for the child with unexplained fractures including non-accidental injury, osteogenesis imperfecta and vitamin D deficiency rickets. Over the last 20 years we and others have described a self-limiting syndrome characterised by fractures in the first year of life. This has been given the provisional name temporary brittle bone disease. This work had proved controversial mostly because the fractures, including rib fractures and metaphyseal fractures, were those previously regarded as typical or even diagnostic of non-accidental injury. Some have asserted that the condition does not exist. Over the years 1985 to 2000 we investigated 87 such cases with fractures with a view to determining the future care of the children. In 85 of these the judiciary was involved. We examined the clinical and radiological findings in the 33 cases in which there was a judicial finding of abuse, the 24 cases in which the parents were exonerated and the 28 cases in which no formal judicial finding was made. The three groups of patients were similar in terms of demographics, age at fracturing and details of the fractures. The clinical similarities between the three groups of patients contrast with the very different results of the judicial process. PMID:22053268

Temporary brittle bone disease: relationship between clinical findings and judicial outcome.

PubMed

Paterson, Colin R; Monk, Elizabeth A

2011-06-30

There is a wide differential diagnosis for the child with unexplained fractures including non-accidental injury, osteogenesis imperfecta and vitamin D deficiency rickets. Over the last 20 years we and others have described a self-limiting syndrome characterised by fractures in the first year of life. This has been given the provisional name temporary brittle bone disease. This work had proved controversial mostly because the fractures, including rib fractures and metaphyseal fractures, were those previously regarded as typical or even diagnostic of non-accidental injury. Some have asserted that the condition does not exist. Over the years 1985 to 2000 we investigated 87 such cases with fractures with a view to determining the future care of the children. In 85 of these the judiciary was involved. We examined the clinical and radiological findings in the 33 cases in which there was a judicial finding of abuse, the 24 cases in which the parents were exonerated and the 28 cases in which no formal judicial finding was made. The three groups of patients were similar in terms of demographics, age at fracturing and details of the fractures. The clinical similarities between the three groups of patients contrast with the very different results of the judicial process.

Interplay of vitamin D, erythropoiesis, and the renin-angiotensin system.

PubMed

Santoro, Domenico; Caccamo, Daniela; Lucisano, Silvia; Buemi, Michele; Sebekova, Katerina; Teta, Daniel; De Nicola, Luca

2015-01-01

For many years deficiency of vitamin D was merely identified and assimilated to the presence of bone rickets. It is now clear that suboptimal vitamin D status may be correlated with several disorders and that the expression of 1-α-hydroxylase in tissues other than the kidney is widespread and of clinical relevance. Recently, evidence has been collected to suggest that, beyond the traditional involvement in mineral metabolism, vitamin D may interact with other kidney hormones such as renin and erythropoietin. This interaction would be responsible for some of the systemic and renal effects evoked for the therapy with vitamin D. The administration of analogues of vitamin D has been associated with an improvement of anaemia and reduction in ESA requirements. Moreover, vitamin D deficiency could contribute to an inappropriately activated or unsuppressed RAS, as a mechanism for progression of CKD and/or cardiovascular disease. Experimental data on the anti-RAS and anti-inflammatory effects treatment with active vitamin D analogues suggest a therapeutic option particularly in proteinuric CKD patients. This option should be considered for those subjects that are intolerant to anti-RAS agents or, as add-on therapy, in those already treated with anti-RAS but not reaching the safe threshold level of proteinuria.

DOES VITAMIN D DEFICIENCY CONTRIBUTE TO THE SEVERITY OF ASTHMA IN CHILDREN AND ADULTS?

PubMed

Ahmed, Syed Zaryab; Jaleel, Anila; Hameed, Kamran; Qazi, Salman; Suleman, Ahsan

2015-01-01

Role of vitamin D in the health of bones has been well established for over decades; It was known that its deficiency caused rickets in children and osteomalacia in adults. Later it was discovered that these can be corrected by giving vitamin D. Researchers discovered that vitamin D can be synthesized by exposure to sun. Hence it was also named "the sunshine vitamin". As time passed it was observed that low levels of vitamin D were associated with multiple diseases. This sparked the interest of the scientific community to further the research on vitamin D which led to the studies that started associating vitamin D with various diseases like cancers (prostate, colon and breast), autoimmune diseases (rheumatoid arthritis), infectious diseases (tuberculosis, hepatitis B, hepatitis C, HIV), cardiovascular diseases, mental illnesses (schizophrenia), diabetes mellitus (type 1, type 2 and gestational) and allergic conditions like asthma. With time, more studies were carried out relating levels of vitamin D to development of asthma, asthma exacerbations and risk factors leading to development of asthma like respiratory tract infections with positive associations. A number of studies were carried out which tried to explain the possible molecular mechanisms relating deficiency of vitamin D in pathogenesis of asthma. This review summarizes the role of vitamin D in development of asthma and probable mechanisms relating vitamin D to the pathogenesis of asthma.

Osteopenia of Prematurity: Are We at Risk?

PubMed

Mannan, M A; Jahan, I; Rahman, M Z; Hasan, Z; Dey, A C; Shahidullah, M

2015-07-01

The continuous advances in intensive care have led to increased survival of premature infants. As a consequence, the problem of less imminent, slowly progressing disorders such as osteopenia of prematurity has been emerging. Osteopenia of prematurity (OOP) also called metabolic bone disease of prematurity (MBD) or rickets of prematurity is characterized by a reduction in bone mineral content usually manifest between 6th to 12th weeks of corrected gestational age. It occurs in up to 55% of infants born with weight <1000gm and 23% of infants weighing <1500gm. Clinical features of osteopenia of prematurity are mostly non-specific often appears as a late symptoms. Several biochemical markers have frequently been used as screening tools and diagnostic markers, but timing of measurements and the levels at which treatment should be initiated vary widely. Dual energy X-ray absorptiometry (DEXA) and Quantitative ultrasnogram are important diagnostic tool. Standard X-ray, a widely accepted but cannot detect osteopenia unless 20% loss of bone mineralization. The treatment of osteopenia includes provision of adequate mineral supplementation. Monitoring of serum and urinary markers are mandatory. The focus on prevention has largely centered on providing adequate intake of phosphorus and calcium but more research is needed. Till date there are neither enough data regarding clinical risk factors, valid biochemical markers which can detect premature babies at risk of osteopenia nor supplementation as well as appropriate timely management protocol is practicing in Bangladesh.

Low Vitamin D Status: Definition, Prevalence, Consequences and Correction

PubMed Central

Binkley, Neil; Ramamurthy, Rekha; Krueger, Diane

2014-01-01

Vitamin D is obtained from cutaneous production when 7-dehydrocholesterol is converted to vitamin D3 (cholecalciferol) by ultraviolet B radiation or by oral intake of vitamin D2 (ergocalciferol) and D3. An individual's vitamin D status is best evaluated by measuring the circulating 25-hydroxyvitamin D [25(OH)D] concentration. Though controversy surrounds the definition of low vitamin D status, there is increasing agreement that the optimal circulating 25(OH)D level should be ~30-32 ng/ml or above. Using this definition, it has been is estimated that approximately three quarters of all adults in the United States are low. Classically, low vitamin D status has skeletal consequences such as osteomalacia/rickets. More recently, associations between low vitamin D status and increased risk for various non-skeletal morbidities have been recognized; whether all of these associations are causally related to low vitamin D status remains to be determined. To achieve optimal vitamin D status, daily intakes of at least 1000 IU or more of vitamin D are required. The risk of toxicity with “high” amounts of vitamin D intake is low. Substantial between-individual variability exists in response to the same administered vitamin D dose. When to monitor 25(OH)D levels has received little attention. Supplementation with vitamin D3 may be preferable to vitamin D2. PMID:20511052

Classical metaphyseal lesions thought to be pathognomonic of child abuse are often artifacts or indicative of metabolic bone disease.

PubMed

Miller, Marvin; Mirkin, L David

2018-06-01

The objective of the present study was to review the histopathology in the original articles by authors Kleinman and Marks that described the specificity of the classical metaphyseal lesion for child abuse and to determine if there were any oversights in the authors' analysis. We reviewed the histopathology of the original studies that equated the classical metaphyseal lesion with child abuse. We compared this with the histopathology of metaphyseal fractures caused by known accidental, severe trauma in children and reviewed the histopathology of artifacts that can sometimes be produced in bone histology preparations. Acute classical metaphyseal lesions showed no hemorrhage, and the chronic classical metaphyseal showed islands of cartilage proliferation at the metaphyses and growth plate, findings consistent with rickets and other metabolic bone disorders. Some of the acute metaphyseal lesions were consistent with artifacts. We believe the original studies that equate the classical metaphyseal lesion with child abuse are flawed. The most compelling observation that challenges the histopathology of the classical metaphyseal lesion as being a fracture is the absence of hemorrhage in the acute classical metaphyseal lesion. We hypothesize that some of the classical metaphyseal lesions were artifacts or represent metabolic bone disorders that were not considered and that these two non-traumatic explanations may have been the basis of the abnormal bone findings. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Time trend investigation of PCBs, PBDEs, and organochlorine pesticides in selected n-3 polyunsaturated fatty acid rich dietary fish oil and vegetable oil supplements; nutritional relevance for human essential n-3 fatty acid requirements.

PubMed

Jacobs, Miriam N; Covaci, Adrian; Gheorghe, Adriana; Schepens, Paul

2004-03-24

In addition to being used in the food and animal feed industry, fish oils have also been used traditionally as dietary supplements. Due to the presence of long-chain n-3 fatty acids, fish oils have therapeutic benefits in the prevention and treatment of cardiovascular, immunological, and arthritic diseases, as well as childhood deficiency diseases such as rickets, because of a high content of vitamin D. However, fish oils are also susceptible to contamination with lipophilic organic chemicals that are now ubiquitous contaminants of marine ecosystems. Many vegetable oils are sources of the shorter chain precursor forms of n-3 fatty acids, and in recent years the specialist dietary supplement market has expanded to include these oils in a variety of different formulations. This paper reports analytical results of selected contaminants, including polychlorinated biphenyls, organochlorine pesticides, and polybrominated diphenyl ethers, for a range of commercially available n-3 fatty acid rich fish and vegetable oil dietary supplements. Using principal component analysis, the values are compared with historic samples to elucidate time trends in contamination profiles. Levels of contaminants are discussed in relation to the nutritional benefits to the consumer of long- and short-chain forms of n-3 fatty acids.

Enzyme Replacement Therapy Prevents Dental Defects in a Model of Hypophosphatasia

PubMed Central

McKee, M.D.; Nakano, Y.; Masica, D.L.; Gray, J.J.; Lemire, I.; Heft, R.; Whyte, M.P.; Crine, P.; Millán, J.L.

2011-01-01

Hypophosphatasia (HPP) occurs from loss-of-function mutation in the tissue-non-specific alkaline phosphatase (TNALP) gene, resulting in extracellular pyrophosphate accumulation that inhibits skeletal and dental mineralization. TNALP-null mice (Akp2-/-) phenocopy human infantile hypophosphatasia; they develop rickets at 1 week of age, and die before being weaned, having severe skeletal and dental hypomineralization and episodes of apnea and vitamin B6-responsive seizures. Delay and defects in dentin mineralization, together with a deficiency in acellular cementum, are characteristic. We report the prevention of these dental abnormalities in Akp2-/- mice receiving treatment from birth with daily injections of a mineral-targeting, human TNALP (sALP-FcD10). sALP-FcD10 prevented hypomineralization of alveolar bone, dentin, and cementum as assessed by micro-computed tomography and histology. Osteopontin – a marker of acellular cementum – was immuno-localized along root surfaces, confirming that acellular cementum, typically missing or reduced in Akp2-/- mice, formed normally. Our findings provide insight concerning how acellular cementum is formed on tooth surfaces to effect periodontal ligament attachment to retain teeth in their osseous alveolar sockets. Furthermore, they provide evidence that this enzyme-replacement therapy, applied early in post-natal life – where the majority of tooth root development occurs, including acellular cementum formation – could prevent the accelerated tooth loss seen in individuals with HPP. PMID:21212313

Enzyme replacement therapy prevents dental defects in a model of hypophosphatasia.

PubMed

McKee, M D; Nakano, Y; Masica, D L; Gray, J J; Lemire, I; Heft, R; Whyte, M P; Crine, P; Millán, J L

2011-04-01

Hypophosphatasia (HPP) occurs from loss-of-function mutation in the tissue-non-specific alkaline phosphatase (TNALP) gene, resulting in extracellular pyrophosphate accumulation that inhibits skeletal and dental mineralization. TNALP-null mice (Akp2(-/-)) phenocopy human infantile hypophosphatasia; they develop rickets at 1 week of age, and die before being weaned, having severe skeletal and dental hypomineralization and episodes of apnea and vitamin B(6)-responsive seizures. Delay and defects in dentin mineralization, together with a deficiency in acellular cementum, are characteristic. We report the prevention of these dental abnormalities in Akp2(-/-) mice receiving treatment from birth with daily injections of a mineral-targeting, human TNALP (sALP-FcD(10)). sALP-FcD(10) prevented hypomineralization of alveolar bone, dentin, and cementum as assessed by micro-computed tomography and histology. Osteopontin--a marker of acellular cementum--was immuno-localized along root surfaces, confirming that acellular cementum, typically missing or reduced in Akp2(-/-) mice, formed normally. Our findings provide insight concerning how acellular cementum is formed on tooth surfaces to effect periodontal ligament attachment to retain teeth in their osseous alveolar sockets. Furthermore, they provide evidence that this enzyme-replacement therapy, applied early in post-natal life--where the majority of tooth root development occurs, including acellular cementum formation--could prevent the accelerated tooth loss seen in individuals with HPP.

Crucial Role of Vitamin D in the Musculoskeletal System

PubMed Central

Wintermeyer, Elke; Ihle, Christoph; Ehnert, Sabrina; Stöckle, Ulrich; Ochs, Gunnar; de Zwart, Peter; Flesch, Ingo; Bahrs, Christian; Nussler, Andreas K.

2016-01-01

Vitamin D is well known to exert multiple functions in bone biology, autoimmune diseases, cell growth, inflammation or neuromuscular and other immune functions. It is a fat-soluble vitamin present in many foods. It can be endogenously produced by ultraviolet rays from sunlight when the skin is exposed to initiate vitamin D synthesis. However, since vitamin D is biologically inert when obtained from sun exposure or diet, it must first be activated in human beings before functioning. The kidney and the liver play here a crucial role by hydroxylation of vitamin D to 25-hydroxyvitamin D in the liver and to 1,25-dihydroxyvitamin D in the kidney. In the past decades, it has been proven that vitamin D deficiency is involved in many diseases. Due to vitamin D’s central role in the musculoskeletal system and consequently the strong negative impact on bone health in cases of vitamin D deficiency, our aim was to underline its importance in bone physiology by summarizing recent findings on the correlation of vitamin D status and rickets, osteomalacia, osteopenia, primary and secondary osteoporosis as well as sarcopenia and musculoskeletal pain. While these diseases all positively correlate with a vitamin D deficiency, there is a great controversy regarding the appropriate vitamin D supplementation as both positive and negative effects on bone mineral density, musculoskeletal pain and incidence of falls are reported. PMID:27258303

Crucial Role of Vitamin D in the Musculoskeletal System.

PubMed

Wintermeyer, Elke; Ihle, Christoph; Ehnert, Sabrina; Stöckle, Ulrich; Ochs, Gunnar; de Zwart, Peter; Flesch, Ingo; Bahrs, Christian; Nussler, Andreas K

2016-06-01

Vitamin D is well known to exert multiple functions in bone biology, autoimmune diseases, cell growth, inflammation or neuromuscular and other immune functions. It is a fat-soluble vitamin present in many foods. It can be endogenously produced by ultraviolet rays from sunlight when the skin is exposed to initiate vitamin D synthesis. However, since vitamin D is biologically inert when obtained from sun exposure or diet, it must first be activated in human beings before functioning. The kidney and the liver play here a crucial role by hydroxylation of vitamin D to 25-hydroxyvitamin D in the liver and to 1,25-dihydroxyvitamin D in the kidney. In the past decades, it has been proven that vitamin D deficiency is involved in many diseases. Due to vitamin D's central role in the musculoskeletal system and consequently the strong negative impact on bone health in cases of vitamin D deficiency, our aim was to underline its importance in bone physiology by summarizing recent findings on the correlation of vitamin D status and rickets, osteomalacia, osteopenia, primary and secondary osteoporosis as well as sarcopenia and musculoskeletal pain. While these diseases all positively correlate with a vitamin D deficiency, there is a great controversy regarding the appropriate vitamin D supplementation as both positive and negative effects on bone mineral density, musculoskeletal pain and incidence of falls are reported.

Fermentation of food and feed: A technology for efficient utilization of macro and trace elements in monogastrics.

PubMed

Humer, Elke; Schedle, Karl

2016-09-01

Mineral deficiencies, especially of iron, zinc, and calcium, respectively, negatively affect human health and may lead to conditions such as iron deficiency anemia, rickets, osteoporosis, and diseases of the immune system. Cereal grains and legumes are of global importance in nutrition of monogastrics (humans and the respective domestic animals) and provide high amounts of several minerals, e.g., iron, zinc, and calcium. Nevertheless, their bioavailability is low. Plants contain phytates, the salts of phytic acid, chemically known as inositol-hexakisphosphate, which interact with several minerals and proteins. However, phytate may be hydrolysed by phytase. This enzyme is naturally present in plants and also widely distributed in microorganisms. Several food processing methods have been reported to enhance phytate hydrolysis, due to the activation of endogenous phytase activity or via the enzyme produced by microbes. In recent years, fermentation for food and feed improvement and preservation, respectively, has gained increasing interest as a promising method to degrade phytate and enhance mineral utilization in monogastrics. Indeed, several in vitro as well as in vivo studies confirm a positive effect on the utilization of minerals, such as P, Ca, Fe and Zn, using sourdough fermentation for baking or fermentation of legumes, mainly soybeans. This review summarizes the current knowledge regarding the potential of fermentation to enhance macro and trace element bioavailability in monogastric species. Copyright © 2016 Elsevier GmbH. All rights reserved.

X-linked hypophosphatemia. A phenotype in search of a cause.

PubMed

Tenenhouse, H S; Scriver, C R

1992-05-01

XLH is an important disease, it is the subject of several classic articles in the medical sciences (Scriver et al., 1991), and it has been an important stimulus to study renal hypophosphatemias and how they are involved in rickets and osteomalacia (Scriver, 1974; Scriver and Tenenhouse, 1991). Renal transport is the major determinant of phosphate homeostasis in mammals and it is unlikely that this important biochemical parameter would have been left by evolution to a single renal transport system. Together physiologists and geneticists found that the mammalian kidney has several gene products dedicated to phosphate transport. That has implications for biochemists in search of a membrane protein to clone and explain XLH, for example. Let us suppose the transporter affected in XLH is cloned. Will it be the product of the XLH (or Hyp or Gy) locus? One will not know until the transporter gene is mapped. There is no question of the X-chromosome locus product being protein kinase C for example, since it maps to autosomes. But where does one start in the search for the X-chromosome locus? With the elusive putative diffusible factor or with the transporter, or perhaps with an enzyme in vitamin D hormone metabolism? Which goes to say that it is necessary to know the phenotype to arrive at the right locus. Or is it? Sufficient physical mapping of region Xp22.31-p21.3 will eventually lead to positional cloning of the Hyp gene. What will it be?(ABSTRACT TRUNCATED AT 250 WORDS)

Bone mineral content measurement in small infants by single-photon absorptiometry: current methodologic issues

DOE Office of Scientific and Technical Information (OSTI.GOV)

Steichen, J.J.; Asch, P.A.; Tsang, R.C.

1988-07-01

Single-photon absorptiometry (SPA), developed in 1963 and adapted for infants by Steichen et al. in 1976, is an important tool to quantitate bone mineralization in infants. Studies of infants in which SPA was used include studies of fetal bone mineralization and postnatal bone mineralization in very low birth weight infants. The SPA technique has also been used as a research tool to investigate longitudinal bone mineralization and to study the effect of nutrition and disease processes such as rickets or osteopenia of prematurity. At present, it has little direct clinical application for diagnosing bone disease in single patients. The bonesmore » most often used to measure bone mineral content (BMC) are the radius, the ulna, and, less often, the humerus. The radius appears to be preferred as a suitable bone to measure BMC in infants. It is easily accessible; anatomic reference points are easily palpated and have a constant relationship to the radial mid-shaft site; soft tissue does not affect either palpation of anatomic reference points or BMC quantitation in vivo. The peripheral location of the radius minimizes body radiation exposure. Trabecular and cortical bone can be measured separately. Extensive background studies exist on radial BMC in small infants. Most important, the radius has a relatively long zone of constant BMC. Finally, SPA for BMC in the radius has a high degree of precision and accuracy. 61 references.« less

Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia

PubMed Central

Lim, Young H.; Ovejero, Diana; Sugarman, Jeffrey S.; DeKlotz, Cynthia M.C.; Maruri, Ann; Eichenfield, Lawrence F.; Kelley, Patrick K.; Jüppner, Harald; Gottschalk, Michael; Tifft, Cynthia J.; Gafni, Rachel I.; Boyce, Alison M.; Cowen, Edward W.; Bhattacharyya, Nisan; Guthrie, Lori C.; Gahl, William A.; Golas, Gretchen; Loring, Erin C.; Overton, John D.; Mane, Shrikant M.; Lifton, Richard P.; Levy, Moise L.; Collins, Michael T.; Choate, Keith A.

2014-01-01

Pathologically elevated serum levels of fibroblast growth factor-23 (FGF23), a bone-derived hormone that regulates phosphorus homeostasis, result in renal phosphate wasting and lead to rickets or osteomalacia. Rarely, elevated serum FGF23 levels are found in association with mosaic cutaneous disorders that affect large proportions of the skin and appear in patterns corresponding to the migration of ectodermal progenitors. The cause and source of elevated serum FGF23 is unknown. In those conditions, such as epidermal and large congenital melanocytic nevi, skin lesions are variably associated with other abnormalities in the eye, brain and vasculature. The wide distribution of involved tissues and the appearance of multiple segmental skin and bone lesions suggest that these conditions result from early embryonic somatic mutations. We report five such cases with elevated serum FGF23 and bone lesions, four with large epidermal nevi and one with a giant congenital melanocytic nevus. Exome sequencing of blood and affected skin tissue identified somatic activating mutations of HRAS or NRAS in each case without recurrent secondary mutation, and we further found that the same mutation is present in dysplastic bone. Our finding of somatic activating RAS mutation in bone, the endogenous source of FGF23, provides the first evidence that elevated serum FGF23 levels, hypophosphatemia and osteomalacia are associated with pathologic Ras activation and may provide insight in the heretofore limited understanding of the regulation of FGF23. PMID:24006476

Developments in rare bone diseases and mineral disorders

PubMed Central

Bacon, Siobhan; Crowley, Rachel

2017-01-01

In the last decade, there have been a number of significant advances made in the field of rare bone diseases. In this review, we discuss the expansion of the classification system for osteogenesis imperfecta (OI) and the resultant increase in therapeutic options available for management of OI. Bisphosphonates remain the most widely used intervention for OI, although the effect on fracture rate reduction is equivocal. We review the other therapies showing promising results, including denosumab, teriparatide, sclerostin, transforming growth factor β inhibition and gene targeted approaches. X-linked hypophosphataemia (XLH) is the most common heritable form of osteomalacia and rickets caused by a mutation in the phosphate regulating endopeptidase gene resulting in elevated serum fibroblast growth factor 23 (FGF23) and decreased renal phosphate reabsorption. The traditional treatment is phosphate replacement. We discuss the development of a human anti-FGF23 antibody (KRN23) as a promising development in the treatment of XLH. The current management of primary hypoparathyroidism is replacement with calcium and active vitamin D. This can be associated with under or over replacement and its inherent complications. We review the use of recombinant parathyroid hormone (1–84), which can significantly reduce the requirements for calcium and vitamin D resulting in greater safety and quality of life for individuals with hypoparathyroidism. The use of receptor activator of nuclear factor κB ligand infusions in the treatment of a particular form of osteopetrosis and enzyme replacement therapy for hypophosphatasia are also discussed. PMID:29344330

Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia.

PubMed

Lim, Young H; Ovejero, Diana; Sugarman, Jeffrey S; Deklotz, Cynthia M C; Maruri, Ann; Eichenfield, Lawrence F; Kelley, Patrick K; Jüppner, Harald; Gottschalk, Michael; Tifft, Cynthia J; Gafni, Rachel I; Boyce, Alison M; Cowen, Edward W; Bhattacharyya, Nisan; Guthrie, Lori C; Gahl, William A; Golas, Gretchen; Loring, Erin C; Overton, John D; Mane, Shrikant M; Lifton, Richard P; Levy, Moise L; Collins, Michael T; Choate, Keith A

2014-01-15

Pathologically elevated serum levels of fibroblast growth factor-23 (FGF23), a bone-derived hormone that regulates phosphorus homeostasis, result in renal phosphate wasting and lead to rickets or osteomalacia. Rarely, elevated serum FGF23 levels are found in association with mosaic cutaneous disorders that affect large proportions of the skin and appear in patterns corresponding to the migration of ectodermal progenitors. The cause and source of elevated serum FGF23 is unknown. In those conditions, such as epidermal and large congenital melanocytic nevi, skin lesions are variably associated with other abnormalities in the eye, brain and vasculature. The wide distribution of involved tissues and the appearance of multiple segmental skin and bone lesions suggest that these conditions result from early embryonic somatic mutations. We report five such cases with elevated serum FGF23 and bone lesions, four with large epidermal nevi and one with a giant congenital melanocytic nevus. Exome sequencing of blood and affected skin tissue identified somatic activating mutations of HRAS or NRAS in each case without recurrent secondary mutation, and we further found that the same mutation is present in dysplastic bone. Our finding of somatic activating RAS mutation in bone, the endogenous source of FGF23, provides the first evidence that elevated serum FGF23 levels, hypophosphatemia and osteomalacia are associated with pathologic Ras activation and may provide insight in the heretofore limited understanding of the regulation of FGF23.

Byler disease: early natural history.

PubMed

Morris, Amy L; Bukauskas, Kathryn; Sada, Rachel E; Shneider, Benjamin L

2015-04-01

Byler disease, originally described in Amish kindred, results from mutations in ATPase Class I Type 8b Member 1 (ATP8b1). Specific clinical reports of Amish Byler disease were last published 40 years ago. These investigations were directed at the present detailed clinical understanding of the early course of hepatic manifestations of Byler disease. This study analyzed routine clinical practice and outcomes of children with Byler disease (defined by homozygous c.923G>T mutation in ATP8b1), who initially presented to Children's Hospital of Pittsburgh of UPMC between January 2007 and October 2014. Data were analyzed to the earlier of 24 months of age or partial external biliary diversion. Six children presented between 1 and 135 days of life: 2 presented with newborn direct hyperbilirubinemia, 2 had complications of coagulopathy, 1 had failure to thrive and rickets, and 1 sibling was identified by newborn genetic testing. Intensive fat-soluble vitamin supplementation was required to prevent insufficiencies in vitamins D, E, and K. Hyperbilirubinemia was variable both over time and between children. Serum bile acid levels were elevated, whereas γ-glutamyltranspeptidase levels were low normal. Scratching behavior (pruritus) was intractable in 4 of 6 children with onset between 6 and 12 months of age. Features of portal hypertension were not observed. Partial external biliary diversion was used during the second year of life in 4 children. Detailed analysis of Byler disease revealed varied disease presentation and course. Nutritional issues and pruritus dominated the clinical picture in the first 2 years of life.

Osteo-Renal Regulation of Systemic Phosphate Metabolism

PubMed Central

Razzaque, Mohammed Shawkat

2011-01-01

Summary Impaired kidney function and subsequent skeletal responses play a critical role in disrupting phosphate balance in chronic kidney disease (CKD) patients with mineral and bone disorder (CKD-MBD). In patients with CKD-MBD, the inability of the kidney to maintain normal mineral ion balance affects bone remodeling to induce skeletal fracture and extraskeletal vascular calcification. In physiological conditions, bone-derived fibroblast growth factor 23 (FGF23) acts on the kidney to reduce serum phosphate and 1,25-dihydroxyvitamin D levels. In humans, increased bioactivity of FGF23 leads to increased urinary phosphate excretion, which induces hypophosphatemic diseases (e.g., rickets/osteomalacia). However, reduced FGF23 activity is associated with hyperphosphatemic diseases (e.g., tumoral calcinosis). In patients with CKD, high serum levels of FGF23 fail to reduce serum phosphate levels and lead to numerous complications, including vascular calcification, one of the important determinants of mortality of CKD-MBD patients. Of particular significance, molecular, biochemical and morphological changes in patients with CKD-MBD are mostly due to osteo-renal dysregulation of mineral ion metabolism. Furthermore, hyperphosphatemia can partly contribute to the development of secondary hyperparathyroidism in patients with CKD-MBD. Relatively new pharmacological agents including sevelamer hydrochloride, calcitriol analogs and cinacalcet hydrochloride are used either alone, or in combination, to minimize hyperphosphatemia and hyperparathyroidism associated complications to improve morbidity and mortality of CKD-MBD patients. This article will briefly summarize how osteo-renal miscommunication can induce phosphate toxicity, resulting in extensive tissue injuries. PMID:21438115

Osteo-renal regulation of systemic phosphate metabolism.

PubMed

Razzaque, Mohammed Shawkat

2011-04-01

Impaired kidney function and subsequent skeletal responses play a critical role in disrupting phosphate balance in chronic kidney disease (CKD) patients with mineral and bone disorder (CKD-MBD). In patients with CKD-MBD, the inability of the kidney to maintain normal mineral ion balance affects bone remodeling to induce skeletal fracture and extraskeletal vascular calcification. In physiological conditions, bone-derived fibroblast growth factor 23 (FGF23) acts on the kidney to reduce serum phosphate and 1,25-dihydroxyvitamin D levels. In humans, increased bioactivity of FGF23 leads to increased urinary phosphate excretion, which induces hypophosphatemic diseases (e.g., rickets/osteomalacia). However, reduced FGF23 activity is associated with hyperphosphatemic diseases (e.g., tumoral calcinosis). In patients with CKD, high serum levels of FGF23 fail to reduce serum phosphate levels and lead to numerous complications, including vascular calcification, one of the important determinants of mortality of CKD-MBD patients. Of particular significance, molecular, biochemical and morphological changes in patients with CKD-MBD are mostly due to osteo-renal dysregulation of mineral ion metabolism. Furthermore, hyperphosphatemia can partly contribute to the development of secondary hyperparathyroidism in patients with CKD-MBD. Relatively new pharmacological agents including sevelamer hydrochloride, calcitriol analogs and cinacalcet hydrochloride are used either alone, or in combination, to minimize hyperphosphatemia and hyperparathyroidism associated complications to improve morbidity and mortality of CKD-MBD patients. This article will briefly summarize how osteo-renal miscommunication can induce phosphate toxicity, resulting in extensive tissue injuries. Copyright © 2011 Wiley Periodicals, Inc.

[Little known activity of the Czestochowa typhus Institute in 1943 and 1944].

PubMed

Aramowicz, P; Fijałek, J; Lutrzykowski, A

1996-01-01

In 1921 Prof. Rudolf Weigl started manufacturing on an industrial scale a typhus vaccine. Until the beginning of World War Two he organised five companies called Weigl Institute. During the Soviet occupation the Lvov plant became the Lvov Sanitary and Bacteriological Institute and after the town was taken over by the German Army on 1st July 1941, Prof. Weigl became a head of research of the Military Typhus Institute. It consisted of four sections for manufacturing the vaccine. All the produce was mainly despatched to the Russian front and only very little reached the civilians. In November and December 1943 the plant was moved to Czestochowa into a main building in Wilsona str. and two four storey others in Jasnogórska str. Its head became a German doctor Mozer (witness test). It is difficult to state numbers the plant employed there being no data left but according to employees still alive there must have been about a hundred lab. staff and two hundred feeders. The plant was divided into "breeding", "preparatory" and "liofilisation" sections. "The breeding" was for feeders and breeding lice. Cages containing about 30,000 lice were fastened to voluntary feeders for each feeding. Next "loaders" covered a so-called key board with 20 insects and infectors introduced and pressurised solution containing live rickets into a louse intestine. After a six or seven day passage, lice ware dried and their intestines prepared to produce liofilizeate all the staff and their families were inoculated. ...

Vitamin D supplementation: we must not fail our children!

PubMed

Drury, Rosalyn; Rehm, Andreas; Johal, Simran; Nadler, Robert

2015-05-01

There is increasing concern that vitamin D deficiency poses a major health problem for children. Deficiency can cause hypocalcemic seizures, growth disturbances, and rickets and may influence diabetes, cardiovascular dysfunction, autoimmune diseases, and attention deficit hyperactivity disorders. Reduced vitamin D levels in children presenting to pediatric orthopedic services are common.In the United Kingdom, recommendations on vitamin D supplementation are set by the Department of Health (DoH) and the National Institute of Health and Clinical Excellence. These state that all children aged 6 months to 5 years ought to receive 7 to 8.5 μg of vitamin D daily.We carried out a survey of 203 parents attending our pediatric and pediatric orthopedic and fracture clinics to evaluate parental awareness of the DoH recommendations on vitamin D supplementation for children and to assess the extent to which children were receiving vitamin D supplements.About 85.71% of parents were not aware of the recommendations. Only 14.29% stated that they were aware of the benefits of vitamin D for their children and just 17.73% of children were receiving vitamin D supplementation; 17 via formula milk and 18 via multivitamin formulations.Parents are generally not aware about vitamin D supplementation because of a lack of information with the high rates of reported suboptimal vitamin D levels amongst children not being addressed resulting in increased health risks to our children. Major improvements are needed in the implementation of supplementation at all points of contact between parents and health-care professionals.

Vitamin D, Cognition and Alzheimer’s Disease: The Therapeutic Benefit is in the D-Tails

PubMed Central

Landel, Véréna; Annweiler, Cédric; Millet, Pascal; Morello, Maria; Féron, François

2016-01-01

Since its discovery during the epidemic of rickets in the early 1920s, the physiological effects of vitamin D on calcium/phosphorus homeostasis have been thoroughly studied. Along with the understanding of its actions on skeletal diseases and advances in cellular and molecular biology, this misnamed vitamin has gained attention as a potential player in a growing number of physiological processes and a variety of diseases. During the last 25 years, vitamin D has emerged as a serious candidate in nervous system development and function and a therapeutic tool in a number of neurological pathologies. More recently, experimental and pre-clinical data suggest a link between vitamin D status and cognitive function. Human studies strongly support a correlation between low levels of circulating 25-hydroxyvitamin D (25(OH)D) and cognitive impairment or dementia in aging populations. In parallel, animal studies show that supplementation with vitamin D is protective against biological processes associated with Alzheimer’s disease (AD) and enhances learning and memory performance in various animal models of aging and AD. These experimental observations support multiple mechanisms by which vitamin D can act against neurodegenerative processes. However, clinical interventional studies are disappointing and fail to associate increased 25(OH)D levels with improved cognitive outcomes. This review collects the current available data from both animal and human studies and discusses the considerations that future studies examining the effects of vitamin D status on neurocognitive function might consider. PMID:27176073

Fortification and health: challenges and opportunities.

PubMed

Dwyer, Johanna T; Wiemer, Kathryn L; Dary, Omar; Keen, Carl L; King, Janet C; Miller, Kevin B; Philbert, Martin A; Tarasuk, Valerie; Taylor, Christine L; Gaine, P Courtney; Jarvis, Ashley B; Bailey, Regan L

2015-01-01

Fortification is the process of adding nutrients or non-nutrient bioactive components to edible products (e.g., food, food constituents, or supplements). Fortification can be used to correct or prevent widespread nutrient intake shortfalls and associated deficiencies, to balance the total nutrient profile of a diet, to restore nutrients lost in processing, or to appeal to consumers looking to supplement their diet. Food fortification could be considered as a public health strategy to enhance nutrient intakes of a population. Over the past century, fortification has been effective at reducing the risk of nutrient deficiency diseases such as beriberi, goiter, pellagra, and rickets. However, the world today is very different from when fortification emerged in the 1920s. Although early fortification programs were designed to eliminate deficiency diseases, current fortification programs are based on low dietary intakes rather than a diagnosable condition. Moving forward, we must be diligent in our approach to achieving effective and responsible fortification practices and policies, including responsible marketing of fortified products. Fortification must be applied prudently, its effects monitored diligently, and the public informed effectively about its benefits through consumer education efforts. Clear lines of authority for establishing fortification guidelines should be developed and should take into account changing population demographics, changes in the food supply, and advances in technology. This article is a summary of a symposium presented at the ASN Scientific Sessions and Annual Meeting at Experimental Biology 2014 on current issues involving fortification focusing primarily on the United States and Canada and recommendations for the development of responsible fortification practices to ensure their safety and effectiveness. © 2015 American Society for Nutrition.

Calcium Deficiency in Bangladesh: Burden and Proposed Solutions for the First 1000 Days

PubMed Central

Bromage, Sabri; Ahmed, Tahmeed; Fawzi, Wafaie W.

2016-01-01

Background Bangladesh incurs among the highest prevalence of stunting and micronutrient deficiencies in the world, despite efforts against diarrheal disease, respiratory infections, and protein energy malnutrition which have led to substantial and continuous reductions in child mortality over the past 35 years. Although programs have generally paid more attention to other micronutrients, the local importance of calcium to health has been less recognized. Objective To synthesize available information on calcium deficiency in Bangladesh in order to inform the design of an effective national calcium program. Methods We searched 3 online databases and a multitude of survey reports to conduct a narrative review of calcium epidemiology in Bangladesh, including population intake, determinants and consequences of deficiency, and tested interventions, with particular reference to young children and women of childbearing age. This was supplemented with secondary analysis of a national household survey in order to map the relative extent of calcium adequacy among different demographics. Results Intake of calcium is low in the general population of Bangladesh, with potentially serious and persistent effects on public health. These effects are especially pertinent to young children and reproductive-age women, by virtue of increased physiologic needs, disproportionately poor access to dietary calcium sources, and a confluence of other local determinants of calcium status in these groups. Conclusion A tablet supplementation program for pregnant women is an appealing approach for the reduction in preeclampsia and preterm birth. Further research is warranted to address the comparative benefit of different promising approaches in children for the prevention of rickets. PMID:27307152

Public Health & Nutrition in the Asia-Pacific: reflections on a quarter century.

PubMed

Cavalli-Sforza, Luca Tommaso

2015-01-01

Some reflections from work in the Asia Pacific Region, mostly with WHO, in the past 25 years, and the changes in nutrition seen in this time are shared. In 1988-89 I helped to start a Centre for Child Nutrition in Chengdu, Sichuan, through the Italian Development Cooperation. The nutritional problems in urban and rural China, 25 years ago, were similar to those elsewhere in the Region. Like China, these countries underwent rapid economic development and changes in health patterns, within two decades. The main problems for child nutrition had to do with infant feeding practices and less breastfeeding: anaemia, protein energy malnutrition and rickets were frequent. How did China and other countries tackle these and other nutrition problems? In the 1990s the global nutrition community started working on a problem-solving framework. In 1992, at the 1st FAO/WHO International Conference on Nutrition, 159 countries agreed to develop national nutrition plans. In 2014, 22 years later, FAO and WHO invited countries to review their national nutrition situation and plans. The epidemiological picture today is profoundly different. Many Asia-Pacific countries have achieved remarkable progress in socio-economic development, including malnutrition reduction. To reach the MDGs and the post-MDG goals being formulated, the remaining under-nutrition problems need to be alleviated, inequalities between sectors of society reduced, and also the growing threat of overweight/obesity and NCDs prevented and controlled. Assessing, monitoring and evaluating programmes to improve progress, now requires focusing not only on biological outcomes, but also on food security, programme process, and the policy environment.

[Classical actions of vitamin D: insights from human genetics and from mouse models on calcium and phosphate homeostasis].

PubMed

Jehan, Frédéric; Voloc, Alexandru

2014-01-01

At the beginning of the 20th century, the discovery of vitamin D by Sir EV McCollum allowed a better comprehension of its origin and its role, and made it possible to cure rickets, a largely prevalent disease at that time. The main role of vitamin D3 is to maintain calcium and phosphate homeostasis through the action of 1,25-dihydroxyvitamin D3, its active form. This underlies physiological functions related to calcium and phosphate, such as bone mineralization or muscle function. Progress in basic research for the last 40 years led to the discovery of the main hydroxylation steps that produce and catabolize the active form of vitamin D. It also uncovered the molecular aspects of vitamin D action, from its nuclear receptor, VDR, to the various target genes of this hormone. Recent progress in human genetics pointed out mutations in genes involved in vitamin D metabolism and 1,25-dihydroxyvitamin D3 actions. It also helped to understand the role of the major actors that control vitamin D production and effects, through 1,25-dihydroxyvitamin D3 actions on phosphate and calcium homeostasis, and on bone biology. Genetical engineering targeting the whole animal or defined tissues or cell types have yielded many mouse models in the past decades. When targeted to tissues important for vitamin D metabolism and activity, these models allowed a more detailed comprehension of vitamin effects on calcium and phosphorus homeostasis. © Société de Biologie, 2014.

The Specific Role of FAM20C in Dentinogenesis

PubMed Central

Wang, X.; Wang, J.; Liu, Y.; Yuan, B.; Ruest, L.B.; Feng, J.Q.

2015-01-01

FAM20C is an evolutionarily reserved molecule highly expressed in mineralized tissues. Previously we demonstrated that Sox2-Cre;Fam20Cfl/fl mice, in which Fam20C was ubiquitously inactivated, had dentin and enamel defects as well as hypophosphatemic rickets. We also showed that K14-Cre;Fam20Cfl/fl mice, in which Fam20C was specifically inactivated in the epithelium, had enamel defects but lacked hypophosphatemia and defects in the bone and dentin. These results indicated that the enamel defects in the Sox2-Cre;Fam20Cfl/fl mice were independent of dentin defects and hypophosphatemia. To determine if the dentin defects in the Sox2-Cre;Fam20Cfl/fl mice were associated with the enamel defects and hypophosphatemia, we crossed Fam20Cfl/fl mice with Wnt1-Cre and Osr2-Cre transgenic mice to inactivate Fam20C in the craniofacial mesenchymal cells that form dentin and alveolar bone. The resulting Wnt1-Cre;Fam20Cfl/fl and Osr2-Cre;Fam20Cfl/fl mice showed remarkable dentin and alveolar bone defects, while their enamel did not show apparent defects. The serum FGF23 levels in these mice were higher than normal but lower than those in the Sox2-Cre;Fam20Cfl/fl mice; they developed a mild type of hypophosphatemia that did not cause major defects in long bones. These results indicate that the dentin defects in the Sox2-Cre;Fam20Cfl/fl mice were independent of the enamel defects. PMID:25515778

Calcium Deficiency in Bangladesh: Burden and Proposed Solutions for the First 1000 Days.

PubMed

Bromage, Sabri; Ahmed, Tahmeed; Fawzi, Wafaie W

2016-12-01

Bangladesh incurs among the highest prevalence of stunting and micronutrient deficiencies in the world, despite efforts against diarrheal disease, respiratory infections, and protein-energy malnutrition which have led to substantial and continuous reductions in child mortality over the past 35 years. Although programs have generally paid more attention to other micronutrients, the local importance of calcium to health has been less recognized. To synthesize available information on calcium deficiency in Bangladesh in order to inform the design of an effective national calcium program. We searched 3 online databases and a multitude of survey reports to conduct a narrative review of calcium epidemiology in Bangladesh, including population intake, determinants and consequences of deficiency, and tested interventions, with particular reference to young children and women of childbearing age. This was supplemented with secondary analysis of a national household survey in order to map the relative extent of calcium adequacy among different demographics. Intake of calcium is low in the general population of Bangladesh, with potentially serious and persistent effects on public health. These effects are especially pertinent to young children and reproductive-age women, by virtue of increased physiologic needs, disproportionately poor access to dietary calcium sources, and a confluence of other local determinants of calcium status in these groups. A tablet supplementation program for pregnant women is an appealing approach for the reduction in preeclampsia and preterm birth. Further research is warranted to address the comparative benefit of different promising approaches in children for the prevention of rickets. © The Author(s) 2016.

Hypophosphataemia among Severely-malnourished Children: Case Series

PubMed Central

Chisti, Mohammod Jobayer; Hossain, Md. Iqbal; Islam, Md. Munirul; Fukushima, Takashi; Wagatsuma, Yukiko; Smith, Jonathan Harvey; Sumazaki, Ryo; Ahmed, Tahmeed

2012-01-01

Phosphorus is an essential substance in our body, and hypophosphataemia (HP) is well-described in rickets, refeeding syndrome, diabetic ketoacidosis (DKA), and in chronic alcohol-abuse. However, to our knowledge, HP among severely-malnourished children has not been studied in detail, and information on prevalence, severity, and treatment is scarce. Currently, there are only a few published case reports of HP. This case series describes three cases of HP that presented to Dhaka Hospital of the International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b). Our first case required mechanical ventilation for respiratory distress associated with severe hypokalaemia (K 1.1 mmol/L) and moderate hypophosphataemia (P 2.1 mg/dL). The second case presented with severe sepsis which was associated with symptomatic hypocalcaemia (Ca 1.68 mmol/L), hypokalaemia (K 1.82 mmol/L), and severe hypophosphataemia (P 0.9 mg/dL). The third case presented with pneumonia and sepsis which were complicated by hypokalaemia (K 2.05 mmol/L) and severe hypophosphataemia (P 1.1 mg/dL). Marked lethargy and severe hypotonia were associated with HP in all of these cases. Manifestations of HP are diverse and can occur in association with other electrolyte imbalances, especially among malnourished children. Malnutrition, combined with sepsis, is one of the major killers of children younger than 5 years of age, and both malnutrition and sepsis can cause HP. It is concluded that the underlying causes of morbidity, including HP, should be actively sought and treated to reduce the mortality of children aged below five years. PMID:23304916

Hypophosphataemia among severely-malnourished children: case series.

PubMed

Yoshimatsu, Shoji; Chisti, Mohammod Jobayer; Hossain, Md Iqbal; Islam, Md Munirul; Fukushima, Takashi; Wagatsuma, Yukiko; Smith, Jonathan Harvey; Sumazaki, Ryo; Ahmed, Tahmeed

2012-12-01

Phosphorus is an essential substance in our body, and hypophosphataemia (HP) is well-described in rickets, refeeding syndrome, diabetic ketoacidosis (DKA), and in chronic alcohol-abuse. However, to our knowledge, HP among severely-malnourished children has not been studied in detail, and information on prevalence, severity, and treatment is scarce. Currently, there are only a few published case reports of HP. This case series describes three cases of HP that presented to Dhaka Hospital of the International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b). Our first case required mechanical ventilation for respiratory distress associated with severe hypokalaemia (K 1.1 mmol/L) and moderate hypophosphataemia (P 2.1 mg/dL). The second case presented with severe sepsis which was associated with symptomatic hypocalcaemia (Ca 1.68 mmol/L), hypokalaemia (K 1.82 mmol/L), and severe hypophosphataemia (P 0.9 mg/dL). The third case presented with pneumonia and sepsis which were complicated by hypokalaemia (K 2.05 mmol/L) and severe hypophosphataemia (P 1.1 mg/dL). Marked lethargy and severe hypotonia were associated with HP in all of these cases. Manifestations of HP are diverse and can occur in association with other electrolyte imbalances, especially among malnourished children. Malnutrition, combined with sepsis, is one of the major killers of children younger than 5 years of age, and both malnutrition and sepsis can cause HP. It is concluded that the underlying causes of morbidity, including HP, should be actively sought and treated to reduce the mortality of children aged below five years.

Survey of the enthesopathy of X-linked hypophosphatemia and its characterization in Hyp mice.

PubMed

Liang, Guoying; Katz, Lee D; Insogna, Karl L; Carpenter, Thomas O; Macica, Carolyn M

2009-09-01

X-linked hypophosphatemia (XLH) is characterized by rickets and osteomalacia as a result of an inactivating mutation of the PHEX (phosphate-regulating gene with homology to endopeptidases on the X chromosome) gene. PHEX encodes an endopeptidase that, when inactivated, results in elevated circulating levels of FGF-23, a novel phosphate-regulating hormone (a phosphatonin), thereby resulting in increased phosphate excretion and impaired bone mineralization. A generalized and severe mineralizing enthesopathy in patients with XLH was first reported in 1985; we likewise report a survey in which we found evidence of enthesopathy in fibrocartilaginous insertion sites, as well as osteophyte formation, in the majority of patients. Nonetheless, there has been very little focus on the progression and pathogenesis underlying the paradoxical heterotopic calcification of tendon and ligament insertion sites. Such studies have been hampered by lack of a model of mineralizing enthesopathy. We therefore characterized the involvement of the most frequently targeted fibrocartilaginous tendon insertion sites in Hyp mice, a murine model of the XLH mutation that phenocopies the human syndrome in every detail including hypophosphatemia and elevated FGF-23. Histological examination of the affected entheses revealed that mineralizing insertion sites, while thought to involve bone spur formation, were not due to bone-forming osteoblasts but instead to a significant expansion of mineralizing fibrocartilage. Our finding that enthesis fibrocartilage cells specifically express fibroblast growth factor receptor 3 (FGFR3)/Klotho suggests that the high circulating levels of FGF-23, characteristic of XLH and Hyp mice, may be part of the biochemical milieu that underlies the expansion of mineralizing enthesis fibrocartilage.

Ca and Sr in the landscapes of the East Transbaikalia

NASA Astrophysics Data System (ADS)

Ermakov, Vadim; Bech, Jaume; Gulyaeva, Ul'yana; Safonov, Vladimir; Kuz'mina, Natal'ya; Roca, Núria

2017-04-01

It is known that Sr is involved in bone formation, but high levels of this trace element in the environment is associated with the risk of manifestation of chondrodystrophia (Urov Kashin-Beck disease), strontium rickets and bone destruction. The aim of this work was comparative assessment of Ca-Sr relationships in the soil-plant complex of the Urov biogeochemical provinces of Eastern Transbaikalia and "control" areas. The basic research landfills located on the territory of the area between the rivers Argun and Shilka. The study territory belongs to the forest-steppe areas of the High-Amur Midlands. Ca and Sr in soils were determined by X-ray fluorescence spectroscopy. The content of this chemical elements in plants (hay harvest) were measured by means of AAS. It was found that the content of Ca in soils, waters and plants of endemic Urov disease territories is approaching the concentrations of this macroelement in the objects of "background" areas. Sr concentrations are increased in the soil-plant complex of the Urov biogeochemical province and characterized by "spotting. It was found that the most frequently occurring ratio of Ca and Sr in the soils of some areas without the manifestation of osteoarticular pathologies in animals and humans varies from 11 to 236 units (53±24). In soils of Eastern Transbaikalia in the areas of distribution Urov Kashin-Beck disease, this ratio varies from 2 to 98 (36±11). The high content of strontium in the soil of the Urov biogeochemical province correlated with the concentration of this trace element in rocks.

Fibroblast growth factor-23 increases mouse PGE2 production in vivo and in vitro.

PubMed

Syal, Ashu; Schiavi, Susan; Chakravarty, Sumana; Dwarakanath, Vangipuram; Quigley, Raymond; Baum, Michel

2006-02-01

Fibroblast growth factor-23 (FGF-23) has been implicated in the renal phosphate wasting in X-linked hypophosphatemia, tumor-induced osteomalacia, and autosomal dominant hypophosphatemic rickets. Recently, we demonstrated that Hyp mice have greater urinary PGE2 levels compared with C57/B6 mice and that indomethacin administration in vivo and in vitro ameliorates the phosphate transport defect in Hyp mice. To determine further whether altered prostaglandin metabolism plays a role in the renal phosphate transport defect in Hyp mice, we incubated renal proximal tubules with arachidonic acid. We find that PGE2 production was higher in Hyp mice than in C57/B6 mice. Incubation of C57/B6 mouse renal proximal tubules with FGF-23R176Q, an active mutant form of FGR23, increased tubular PGE2 production, an effect that was inhibited by 50 microM PD-98059 and 10 microM SB-203580, inhibitors of the MAP kinase pathway. C57/B6 mice injected with FGF-23R176Q had a approximately 10-fold increase in PGE2 excretion 24 h after intraperitoneal injection of FGF-23R176Q compared with vehicle-treated controls. Finally, we show that PGE2 inhibited both phosphate and volume absorption in mouse proximal convoluted tubules perfused in vitro and reduced brush-border membrane vesicle NaPi-2a protein abundance from renal cortex incubated in vitro with PGE2. In conclusion, FGF-23 increases urinary and renal tubular PGE2 production via the MAP kinase pathway and PGE2 inhibits proximal tubule phosphate transport.

Fibroblast growth factor-23 increases mouse PGE2 production in vivo and in vitro

PubMed Central

Syal, Ashu; Schiavi, Susan; Chakravarty, Sumana; Dwarakanath, Vangipuram; Quigley, Raymond; Baum, Michel

2014-01-01

Fibroblast growth factor-23 (FGF-23) has been implicated in the renal phosphate wasting in X-linked hypophosphatemia, tumor-induced osteomalacia, and autosomal dominant hypophosphatemic rickets. Recently, we demonstrated that Hyp mice have greater urinary PGE2 levels compared with C57/B6 mice and that indomethacin administration in vivo and in vitro ameliorates the phosphate transport defect in Hyp mice. To determine further whether altered prostaglandin metabolism plays a role in the renal phosphate transport defect in Hyp mice, we incubated renal proximal tubules with arachidonic acid. We find that PGE2 production was higher in Hyp mice than in C57/B6 mice. Incubation of C57/B6 mouse renal proximal tubules with FGF-23R176Q, an active mutant form of FGR23, increased tubular PGE2 production, an effect that was inhibited by 50 μM PD-98059 and 10 μM SB-203580, inhibitors of the MAP kinase pathway. C57/B6 mice injected with FGF-23R176Q had a ~10-fold increase in PGE2 excretion 24 h after intraperitoneal injection of FGF-23R176Q compared with vehicle-treated controls. Finally, we show that PGE2 inhibited both phosphate and volume absorption in mouse proximal convoluted tubules perfused in vitro and reduced brush-border membrane vesicle NaPi-2a protein abundance from renal cortex incubated in vitro with PGE2. In conclusion, FGF-23 increases urinary and renal tubular PGE2 production via the MAP kinase pathway and PGE2 inhibits proximal tubule phosphate transport. PMID:16144964

Raine Syndrome (OMIM #259775), Caused By FAM20C Mutation, Is Congenital Sclerosing Osteomalacia With Cerebral Calcification (OMIM 259660).

PubMed

Whyte, Michael P; McAlister, William H; Fallon, Michael D; Pierpont, Mary Ella; Bijanki, Vinieth N; Duan, Shenghui; Otaify, Ghada A; Sly, William S; Mumm, Steven

2017-04-01

In 1985, we briefly reported infant sisters with a unique, lethal, autosomal recessive disorder designated congenital sclerosing osteomalacia with cerebral calcification. In 1986, this condition was entered into Mendelian Inheritance In Man (MIM) as osteomalacia, sclerosing, with cerebral calcification (MIM 259660). However, no attestations followed. Instead, in 1989 Raine and colleagues published an affected neonate considering unprecedented the striking clinical and radiographic features. In 1992, "Raine syndrome" entered MIM formally as osteosclerotic bone dysplasia, lethal (MIM #259775). In 2007, the etiology emerged as loss-of-function mutation of FAM20C that encodes family with sequence similarity 20, member C. FAM20C is highly expressed in embryonic calcified tissues and encodes a kinase (dentin matrix protein 4) for most of the secreted phosphoproteome including FGF23, osteopontin, and other regulators of skeletal mineralization. Herein, we detail the clinical, radiological, biochemical, histopathological, and FAM20C findings of our patients. Following premortem tetracycline labeling, the proposita's non-decalcified skeletal histopathology after autopsy indicated no rickets but documented severe osteomalacia. Archival DNA revealed the sisters were compound heterozygotes for a unique missense mutation and a novel deletion in FAM20C. Individuals heterozygous for the missense mutation seemed to prematurely fuse their metopic suture and develop a metopic ridge sometimes including trigonocephaly. Our findings clarify FAM20C's role in hard tissue formation and mineralization, and show that Raine syndrome is congenital sclerosing osteomalacia with cerebral calcification. © 2016 American Society for Bone and Mineral Research. © 2016 American Society for Bone and Mineral Research.

Value of Renal Biopsy in Diagnosing Infantile Nephropathic Cystinosis Associated With Secondary Nephrogenic Diabetes Insipidus.

PubMed

Joyce, Emily; Ho, Jacqueline; El-Gharbawy, Areeg; Salgado, Cláudia M; Ranganathan, Sarangarajan; Reyes-Múgica, Miguel

2017-01-01

Cystinosis is the most common cause of inherited renal Fanconi syndrome in young children, and typically presents with laboratory findings of a proximal tubulopathy and corneal crystals by one year of age. We describe here renal biopsy findings in a 20-month-old patient with an atypical presentation of distal renal tubular acidosis, diabetes insipidus, and the absence of corneal crystals. Although renal biopsy is usually not necessary to establish the diagnosis of cystinosis, when the patient presents with atypical signs and symptoms, a renal biopsy may be extremely valuable. A 20-month-old boy presented with failure to thrive, polyuria, polydipsia, and rickets. He initially showed evidence of a renal tubular acidosis, mild renal insufficiency, and nephrogenic diabetes insipidus. His initial ophthalmologic examination did not demonstrate corneal crystals. His subsequent workup revealed phosphaturia, suggesting a partial proximal tubulopathy. Concomitantly, a renal biopsy revealed prominent podocytes with an immature glomerular appearance, and electron microscopy analysis showed numerous intracellular crystals within tubular epithelial cells. Subsequent laboratory and genetic testing confirmed a diagnosis of infantile nephropathic cystinosis. This case highlights the variability in the clinical presentation of cystinosis, resulting in an uncommon clinical picture of a rare disease. Given that treatment is available to prolong renal function and minimize the extra-renal manifestations of this disorder, early diagnosis is essential. It is important to raise the index of suspicion of cystinosis by recognizing its subtle morphological changes in young patients, and that nephrogenic diabetes insipidus can be secondary to this disorder.

Serum vitamin D levels are not altered after controlled diesel ...

EPA Pesticide Factsheets

Past research has suggested that exposure to urban air pollution may be associated with vitamin D deficiency in human populations. Vitamin D is widely known for its importance in bone growth/remodeling, muscle metabolism, and its ability to promote calcium absorption in the gut; deficiency in vitamin D results in the development of rickets in children and osteomalacia in adults. In the current study, we assessed whether vitamin D levels are altered under controlled exposures to a commonly measured urban air pollutant, diesel. For this study, we exposed 12 healthy volunteers to clean air and diesel exhaust (300 μg/m3) for 2 hours while undergoing intermittent exercise. Venous blood was collected before, 0 hrs post-, and 18 hrs post-exposure, and 25-hydroxyvitamin D [25(OH)D] was measured in the serum. The average baseline value of 25(OH)D (mean ± standard error) was 22.9 ± 2.5 ng/mL. Four subject’s baseline values were vitamin D deficient (30 ng/mL). Additionally, there was no significant change in the baseline values between the clean air and diesel exposures (paired t-test, p = 0.54), suggesting minimal variability in 25(OH)D over the experiment's time course. Small inductions in 25(OH)D were found following clean air exposures (12.5 ± 4.9% and a 7.1 ± 5.0% for 0 hrs post- and 18 hrs post-exposure values compared to baseline, respectively). Minimal changes in 25(OH)D were observed following diesel exhaust exposures 0 hrs (3.5 ± 5.2%) and 18 hrs followin

A new approach to the study of Romanization in Britain: a regional perspective of cultural change in late Iron Age and Roman Dorset using the Siler and Gompertz-Makeham models of mortality

PubMed Central

Redfern, Rebecca C.; DeWitte, Sharon N.

2011-01-01

This is the first study of Romanization to use the Siler and Gompertz-Makeham models of mortality in order to investigate the health consequences of the 43 AD conquest of Britain. The study examined late Iron Age and Romano-British populations (N=518) from Dorset, England, which is the only region of Britain to display continuity in inhumation burial practice and cemetery use throughout the two periods. Skeletal evidence for frailty was assessed using cribra orbitalia, porotic hyperostosis, periosteal lesions, enamel hypoplasia, dental caries, tuberculosis, and rickets. These health variables were chosen for analysis because they are reliable indicators of general health for diachronic comparison (Steckel and Rose 2002) and are associated with the introduction of urbanism in Britain during the Roman period (Redfern 2007; Redfern 2008b; Roberts and Cox 2003). The results show that levels of frailty and mortality were lower in the late Iron Age period, and no sex differences in mortality were present. However, post-conquest, mortality risk increased for children and the elderly, and particularly for males. The latter finding challenges received wisdom concerning the benefits of Romanization and the higher status of the male body in the Roman world. Therefore, we conclude that the consequences of urbanism, changes in diet and increased population heterogeneity negatively impacted health, to the extent that the enhanced cultural buffering of males did not out-weigh underlying sex differences in biology that advantage females. PMID:20925081

Seasonal variation in Internet searches for vitamin D.

PubMed

Moon, Rebecca J; Curtis, Elizabeth M; Davies, Justin H; Cooper, Cyrus; Harvey, Nicholas C

2017-12-01

Internet search rates for "vitamin D" were explored using Google Trends. Search rates increased from 2004 until 2010 and thereafter displayed a seasonal pattern peaking in late winter. This knowledge could help guide the timing of public health interventions aimed at managing vitamin D deficiency. The Internet is an important source of health information. Analysis of Internet search activity rates can provide information on disease epidemiology, health related behaviors and public interest. We explored Internet search rates for vitamin D to determine whether this reflects the increasing scientific interest in this topic. Google Trends is a publically available tool that provides data on Internet searches using Google. Search activity for the term "vitamin D" from 1st January 2004 until 31st October 2016 was obtained. Comparison was made to other bone and nutrition related terms. Worldwide, searches for "vitamin D" increased from 2004 until 2010 and thereafter a statistically significant (p < 0.001) seasonal pattern with a peak in February and nadir in August was observed. This seasonal pattern was evident for searches originating from both the USA (peak in February) and Australia (peak in August); p < 0.001 for both. Searches for the terms "osteoporosis", "rickets", "back pain" or "folic acid" did not display the increase observed for vitamin D or evidence of seasonal variation. Public interest in vitamin D, as assessed by Internet search activity, did increase from 2004 to 2010, likely reflecting the growing scientific interest, but now displays a seasonal pattern with peak interest during late winter. This information could be used to guide public health approaches to managing vitamin D deficiency.

Romanian adoption. The Manitoba experience.

PubMed

Benoit, T C; Jocelyn, L J; Moddemann, D M; Embree, J E

1996-12-01

To study the developmental, behavioral, and medical features in a cohort of Romanian children adopted by Manitoba families. A prospective longitudinal study. The Child Development Clinic, Children's Hospital, Winnipeg, Manitoba, from September 1990 to June 1992. Developmental, behavioral, and medical features were assessed in 22 Romanian children adopted by 18 Manitoba families. Mean (+/- SD) age at adoption was 15.5 +/- 13 months. Mean (+/- SD) age at initial assessment was 19 +/- 12 months and at follow-up, 35 +/- 13 months. Medical complications included 6 children (27%) who were positive for the hepatitis B surface antigen, 5 with intestinal parasites (23%), 1 positive for the human immunodeficiency virus, 1 with rickets (5%), and 1 with monoplegia and cleft palate (5%). Initial growth parameters were less than the fifth percentile for age for head circumference in 10 children (45%), for weight in 8 (36%), and for height in 7 (32%). At follow-up, statistically significant improvement was seen in height and weight. Initial mean (+/- SD) developmental quotients were 82 +/- 20 for gross motor, 83 +/- 23 for fine motor, 83 +/- 19 for cognitive, and 79 +/- 18 for language domains. Follow-up mean developmental quotients improved in all domains (P < .05). Twelve children (55%) displayed abnormal behavior at the initial assessment; behavioral findings persisted in 8 (36%). Initial appropriate activity level and play behavior predicted normal cognitive outcome (P < .05). This longitudinal study of Romanian adoptees delineates improvements in growth and development once the children are placed in a nurturing environment. The persistence of abnormal behavior in some children underscores the importance of further follow-up.

Ethnic disparities in the dietary requirement for vitamin D during pregnancy: considerations for nutrition policy and research.

PubMed

O'Callaghan, Karen M; Kiely, Mairead E

2018-05-01

Despite the inverse association between skin colour and efficiency of cutaneous vitamin D synthesis, in addition to the widely accepted racial disparity in vitamin D status, populations of ethnic minority are understudied in terms of setting target serum 25-hydroxyvitamin D concentrations and corresponding dietary requirements for vitamin D. In minority groups, prevention of vitamin D deficiency on a population basis is challenging due to the lack of clarity surrounding the metabolism and transport of vitamin D. Authoritative agencies have been unable to define pregnancy-specific dietary recommendations for vitamin D, owing to an absence of sufficient evidence to confirm whether nutritional requirements for vitamin D are altered during pregnancy. While the question of setting race- and pregnancy-specific dietary reference values for vitamin D has not been addressed to date, endemic vitamin D deficiency has been reported among gravidae worldwide, specifically among ethnic minorities and white women resident at high latitude. In light of the increased risk of nutritional rickets among infants of ethnic minority, coupled with growing evidence for potential non-skeletal roles of vitamin D in perinatal health, determination of the dietary vitamin D requirement that will prevent deficiency during pregnancy is a research priority. However, systematic approaches to establishing dietary requirements are limited by the quality of the available evidence and the under-representation of minority groups in clinical research. This review considers the evidence for racial differences in vitamin D status and response to vitamin D supplementation, with particular application to pregnancy-specific requirements among ethnic minorities resident at high latitudes.

Incidence rate and characteristics of symptomatic vitamin D deficiency in children: a nationwide survey in Japan.

PubMed

Kubota, Takuo; Nakayama, Hirofumi; Kitaoka, Taichi; Nakamura, Yosikazu; Fukumoto, Seiji; Fujiwara, Ikuma; Hasegawa, Yukihiro; Ihara, Kenji; Kitanaka, Sachiko; Koyama, Satomi; Kusuda, Satoshi; Mizuno, Haruo; Nagasaki, Keisuke; Oba, Koji; Sakamoto, Yuko; Takubo, Noriyuki; Shimizu, Toshiaki; Tanahashi, Yusuke; Hasegawa, Kosei; Tsukahara, Hirokazu; Yorifuji, Tohru; Michigami, Toshimi; Ozono, Keiichi

2018-03-10

There is concern that vitamin D deficiency is prevalent among children in Japan as well as worldwide. We conducted a nationwide epidemiologic survey of symptomatic vitamin D deficiency to observe its incidence rate among Japanese children. A questionnaire inquiring the number of new patients with vitamin D deficiency rickets and/or hypocalcemia for 3 years was sent to 855 randomly selected hospitals with a pediatrics department in Japan. In this survey, we found that 250 children were diagnosed with symptomatic vitamin D deficiency. The estimated number of patients with symptomatic vitamin D deficiency per year was 183 (95% confidence interval (CI): 145-222). The overall annual incidence rate among children under 15 years of age was 1.1 per 100,000 population (95% CI: 0.9-1.4). The second survey has provided detailed information on 89 patients with symptomatic vitamin D deficiency under 5 years of age in hospitals in the current research group. The nationwide and second surveys estimated the overall annual incidence rate of symptomatic vitamin D deficiency in children under 5 years of age to be 3.5 (2.7-4.2) per 100,000 population. The second survey revealed 83% had bowed legs, 88% had exclusive breastfeeding, 49% had a restricted and/or unbalanced diet and 31% had insufficient sun exposure among the 89 patients. This is the first nationwide survey on definitive clinical vitamin D deficiency in children in Japan. Elucidating the frequency and characteristics of symptomatic vitamin D deficiency among children is useful to develop preventative public health strategies.

[Nutrition and individual defense--historical considerations].

PubMed

Schadewaldt, H

1991-03-01

The first scientific understandings on the value of nutrition and the assimilation of food, in the Greek language "metabole" (metabolism), are published in the Corpus Hippocraticum. But the conception of metabolism was introduced in scientific literature not earlier than 1839 by Theodor Schwann (1810-1882) and 1842 by Justus von Liebig (1803-1873). The antique ideas were completed in the 17th century by the theory of ferments, introduced by the iatro-chemist Johann Baptist van Helmont (1577-1644), and the Italian priest Lazzaro Spallanzani (1729-1799) could proof the existence of such processes in the living organism by animal experiments in 1776. Then Schwann could discover in the gastric juice a substance in 1835 which he called "pepsin". In the time of the voyages of discovery new, not yet known malnutritions on the ships were known as scurvy, beriberi and in the northern countries rickets. Then it became clear that not only the three groups of food, but also supplementary materials, known in 1912 as vitamines by Casimir Funk (1884-1967), could develop determined effects. The starvation in the first and the second world war showed clearly, that deterioration of food supply diminished the condition of immunity. Failed food experiments with gelatin, synthetically produced citric acid and the discussions of malnutrition diseases, based on a deficiency of zinc, of toddlers, are discussed as the malnutrition illness kwashiorkor in the third world. In conclusion a citation of the famous American physiologist Graham Lusk (1866-1932) is mentioned from the year 1906, who praised the scientific priority of the German medical research.

Vitamin D status and food security in North-East Asia.

PubMed

Wahlqvist, Mark L

2013-01-01

The functions of vitamin D are pleiotropic affecting all body organs and systems in some way. Its adequacy depends principally on sunshine for UV light to stimulate its synthesis in skin and on foods which contain it, either animal-derived or obtained from fungi or mushrooms, with the UV-responsive substrates dehydrocholesterol for vitamin D-3 or ergosterol for vitamin D-2, respectively. Thus, vitamin D health is very environmentally dependent. With ecosytem degradation, whether by atmospheric pollution or food systems which do not derive UV irradiation, as with fish farming or mushroom processing, then this nutrient input into human biology may falter. Vitamin D deficiency is now common and widespread in North-East Asia as elsewhere. When discovered early in the 20th century it was linked to rickets in children and osteomalacia in adults and, for a generation or so, children were given fish, usually cod, liver oil to prevent bone disease. Now cod as a species and many edible fish are threatened. Over-exposure to sun-light increases the risk of skin cancer. We may tackle this problem by vitamin D supplementation with an alternative to fish liver. But the demographic pressures of population size and ageing (when the skin is less UV responsive) make the clinical and public health decisions and strategies demanding. Vitamin D health has become indicative of food security whose usual indicator is food diversity; such diversity may allow lesser concentrations to be more effective in organ and system function, but we have little evidence to support this at present.

Vitamin D Supplementation: We Must Not Fail Our Children!

PubMed Central

Drury, Rosalyn; Rehm, Andreas; Johal, Simran; Nadler, Robert

2015-01-01

Abstract There is increasing concern that vitamin D deficiency poses a major health problem for children. Deficiency can cause hypocalcemic seizures, growth disturbances, and rickets and may influence diabetes, cardiovascular dysfunction, autoimmune diseases, and attention deficit hyperactivity disorders. Reduced vitamin D levels in children presenting to pediatric orthopedic services are common. In the United Kingdom, recommendations on vitamin D supplementation are set by the Department of Health (DoH) and the National Institute of Health and Clinical Excellence. These state that all children aged 6 months to 5 years ought to receive 7 to 8.5 μgof vitamin D daily. We carried out a survey of 203 parents attending our pediatric and pediatric orthopedic and fracture clinics to evaluate parental awareness of the DoH recommendations on vitamin D supplementation for children and to assess the extent to which children were receiving vitamin D supplements. About 85.71% of parents were not aware of the recommendations. Only 14.29% stated that they were aware of the benefits of vitamin D for their children and just 17.73% of children were receiving vitamin D supplementation; 17 via formula milk and 18 via multivitamin formulations. Parents are generally not aware about vitamin D supplementation because of a lack of information with the high rates of reported suboptimal vitamin D levels amongst children not being addressed resulting in increased health risks to our children. Major improvements are needed in the implementation of supplementation at all points of contact between parents and health-care professionals. PMID:25950689

Proceedings of the Rank Forum on Vitamin D

PubMed Central

Lanham-New, S. A.; Buttriss, J. L.; Miles, L. M.; Ashwell, M.; Berry, J. L.; Boucher, B. J.; Cashman, K. D.; Cooper, C.; Darling, A. L.; Francis, R. M.; Fraser, W. D.; de Groot, C. P. G. M.; Hyppönen, E.; Kiely, M.; Lamberg-Allardt, C.; Macdonald, H. M.; Martineau, A. R.; Masud, T.; Mavroeidi, A.; Nowson, C.; Prentice, A.; Stone, E. M.; Reddy, S.; Vieth, R.; Williams, C. M.

2012-01-01

The Rank Forum on Vitamin D was held on 2nd and 3rd July 2009 at the University of Surrey, Guildford, UK. The workshop consisted of a series of scene-setting presentations to address the current issues and challenges concerning vitamin D and health, and included an open discussion focusing on the identification of the concentrations of serum 25-hydroxyvitamin D (25(OH)D) (a marker of vitamin D status) that may be regarded as optimal, and the implications this process may have in the setting of future dietary reference values for vitamin D in the UK. The Forum was in agreement with the fact that it is desirable for all of the population to have a serum 25(OH)D concentration above 25 nmol/l, but it discussed some uncertainty about the strength of evidence for the need to aim for substantially higher concentrations (25(OH)D concentrations > 75 nmol/l). Any discussion of ‘optimal’ concentration of serum 25(OH)D needs to define ‘optimal’ with care since it is important to consider the normal distribution of requirements and the vitamin D needs for a wide range of outcomes. Current UK reference values concentrate on the requirements of particular subgroups of the population; this differs from the approaches used in other European countries where a wider range of age groups tend to be covered. With the re-emergence of rickets and the public health burden of low vitamin D status being already apparent, there is a need for urgent action from policy makers and risk managers. The Forum highlighted concerns regarding the failure of implementation of existing strategies in the UK for achieving current vitamin D recommendations. PMID:21134331

Vitamin d deficiency in Saudi Arabs.

PubMed

Elsammak, M Y; Al-Wosaibi, A A; Al-Howeish, A; Alsaeed, J

2010-05-01

Vitamin D plays a critical role in bone metabolism and many cellular and immunological processes. Low levels of vitamin D have been associated with various chronic diseases especially rickets in children and osteoporosis in adults. Adequate vitamin D intake is of paramount importance to protect against bone metabolic diseases and prevent the occurrence of complications (e. g., fracture and bone pains). This study aimed at the evaluation of vitamin D levels in a cohort of healthy Saudi Arabs. The comprised 139 healthy subjects coming for regular blood donation. Participants had full clinical examination and evaluation of their calcium and vitamin D intake and the degree of exposure to sunlight. Serum 25-OH vitamin D was determined using Liasion chemiluminescent immunoassay and serum parathormone levels were determined using the Architect 2,000 immunochemiluminescent assay. Our results showed increased prevalence of vitamin D deficiency between Saudi Arabs (both males and females) in the studied group of subjects. Serum parathyroid hormone (PTH) did not correlate with serum vitamin D level in either male or female groups (p<0.01). Our data illustrate a high prevalence of vitamin D deficiency between Saudi Arabs and the importance for screening for vitamin D deficiency (irrespective of PTH level). We hypothesize that the reported vitamin D deficiency in the studied group of Saudi Arabs may reflect a possible inadequacy of the current level of vitamin D fortification of food products. We suggest that higher level of fortification of food products with vitamin D may be needed to compensate for the reduced skin vitamin D synthesis due to poor exposure to sunlight and to reverse this state of vitamin D deficiency in Saudi Arabs. Georg Thieme Verlag KG Stuttgart-New York.

Vitamin D supplementation is associated with higher serum 25OHD in Asian and White infants living in Vancouver, Canada.

PubMed

Green, Tim J; Li, Wangyang; Barr, Susan I; Jahani, Mitra; Chapman, Gwen E

2015-04-01

To prevent rickets, the Health Canada and the American Academy of Pediatrics recommend that breastfed infants receive a daily vitamin D supplement of 10 μg d(-1) . Compliance with this recommendation is variable and its effect on infant vitamin D status is unclear. We measured serum 25-hydroxyvitamin D (25OHD) in Asian immigrant (n=28) and White (n=37) mothers and their infants aged 2-4 months living in Vancouver (49°N). Mothers completed health and demographic questionnaires. All subjects were term infants who were primarily breastfed. Analysis of variance, χ(2) , multiple regression and logistic regression analysis were performed as appropriate. Mean 25OHD of the infants was 31 (95% confidence interval 28-34) ng mL(-1) . Only two infants had a 25OHD concentration indicative of deficiency, <10 ng mL(-1) . Of the infants, 14% (n=9) and 49% (n=32) were vitamin D insufficient based on two commonly used cut-offs of 20 and 30 ng mL(-1) , respectively. Fifty-eight (89%) infants had been given a vitamin D supplement. Mean 25OHD was 9.4 ng mL(-1) higher in infants consuming ≥10 μg d(-1) of vitamin D from supplements vs. those consuming less (P=0.003). Mother's 25OHD, season, skin colour or ethnicity (Asian vs. White) did not influence infant 25OHD. The infants in our study, most of whom received vitamin D supplements, were generally protected against low 25OHD. The study was limited by sample size and the nature of the cross-sectional study design. © 2012 Blackwell Publishing Ltd.

Sunshine is good medicine. The health benefits of ultraviolet-B induced vitamin D production.

PubMed

Grant, W B; Strange, R C; Garland, C F

2003-04-01

Most public health statements regarding exposure to solar ultraviolet radiation (UVR) recommend avoiding it, especially at midday, and using sunscreen. Excess UVR is a primary risk factor for skin cancers, premature photoageing and the development of cataracts. In addition, some people are especially sensitive to UVR, sometimes due to concomitant illness or drug therapy. However, if applied uncritically, these guidelines may actually cause more harm than good. Humans derive most of their serum 25-hydroxycholecalciferol (25(OH)D3) from solar UVB radiation (280-315 nm). Serum 25(OH)D3 metabolite levels are often inadequate for optimal health in many populations, especially those with darker skin pigmentation, those living at high latitudes, those living largely indoors and in urban areas, and during winter in all but the sunniest climates. In the absence of adequate solar UVB exposure or artificial UVB, vitamin D can be obtained from dietary sources or supplements. There is compelling evidence that low vitamin D levels lead to increased risk of developing rickets, osteoporosis and osteomaloma, 16 cancers (including cancers of breast, ovary, prostate and non-Hodgkin's lymphoma), and other chronic diseases such as psoriasis, diabetes mellitus, hypertension, heart disease, myopathy, multiple sclerosis, schizophrenia, hyperparathyroidism and susceptibility to tuberculosis. The health benefits of UVB seem to outweigh the adverse effects. The risks can be minimized by avoiding sunburn, excess UVR exposure and by attention to dietary factors, such as antioxidants and limiting energy and fat consumption. It is anticipated that increasing attention will be paid to the benefits of UVB radiation and vitamin D and that health guidelines will be revised in the near future.

Molecular genetic and biochemical analyses of FGF23 mutations in familial tumoral calcinosis.

PubMed

Garringer, Holly J; Malekpour, Mahdi; Esteghamat, Fatemehsadat; Mortazavi, Seyed M J; Davis, Siobhan I; Farrow, Emily G; Yu, Xijie; Arking, Dan E; Dietz, Harry C; White, Kenneth E

2008-10-01

Fibroblast growth factor 23 (FGF23) is a hormone required for normal renal phosphate reabsorption. FGF23 gain-of-function mutations result in autosomal dominant hypophosphatemic rickets (ADHR), and FGF23 loss-of-function mutations cause familial hyperphosphatemic tumoral calcinosis (TC). In this study, we identified a novel recessive FGF23 TC mutation, a lysine (K) substitution for glutamine (Q) (160 C>A) at residue 54 (Q54K). To understand the molecular consequences of all known FGF23-TC mutants (H41Q, S71G, M96T, S129F, and Q54K), these proteins were stably expressed in vitro. Western analyses revealed minimal amounts of secreted intact protein for all mutants, and ELISA analyses demonstrated high levels of secreted COOH-terminal FGF23 fragments but low amounts of intact protein, consistent with TC patients' FGF23 serum profiles. Mutant protein function was tested and showed residual, yet decreased, bioactivity compared with wild-type protein. In examining the role of the FGF23 COOH-terminal tail (residues 180-251) in protein processing and activity, truncated mutants revealed that the majority of the residues downstream from the known FGF23 SPC protease site ((176)RXXR(179)/S(180)) were not required for protein secretion. However, residues adjacent to the RXXR site (between residues 188 and 202) were required for full bioactivity. In summary, we report a novel TC mutation and demonstrate a common defect of reduced FGF23 stability for all known FGF23-TC mutants. Finally, the majority of the COOH-terminal tail of FGF23 is not required for protein secretion but is required for full bioactivity.

A new approach to the study of Romanization in Britain: a regional perspective of cultural change in late iron age and roman dorset using the siler and gompertz-makeham models of mortality.

PubMed

Redfern, Rebecca C; Dewitte, Sharon N

2011-02-01

This is the first study of health in the Roman Empire to use the Siler and Gompertz-Makeham models of mortality to investigate the health consequences of the 43 AD conquest of Britain. The study examined late Iron Age and Romano-British populations (N = 518) from Dorset, England, which is the only region of Britain to display continuity in inhumation burial practice and cemetery use throughout the two periods. Skeletal evidence for frailty was assessed using cribra orbitalia, porotic hyperostosis, periosteal lesions, enamel hypoplasia, dental caries, tuberculosis, and rickets. These health variables were chosen for analysis because they are reliable indicators of general health for diachronic comparison (Steckel and Rose: The backbone of history: health and nutrition in the western hemisphere (2002)) and are associated with the introduction of urbanism in Britain during the Roman period (Redfern: J Rom Archaeol Supp Series 64 (2007) 171-194; Redfern: Britannia 39 (2008a) 161-191; Roberts and Cox: Health and disease in Britain: from prehistory to the present day (2003)). The results show that levels of frailty and mortality were lower in the late Iron Age period, and no sex differences in mortality was present. However, post-conquest, mortality risk increased for children and the elderly, and particularly for men. The latter finding challenges received wisdom concerning the benefits of incorporation into the Empire and the higher status of the male body in the Roman world. Therefore, we conclude that the consequences of urbanism, changes in diet, and increased population heterogeneity negatively impacted health, to the extent that the enhanced cultural buffering of men did not outweigh underlying sex differences in biology that advantage women. 2010 Wiley-Liss, Inc.

New intragenic deletions in the Phex gene clarify X-linked hypophosphatemia-related abnormalities in mice

PubMed Central

Lorenz-Depiereux, Bettina; Guido, Victoria E.; Johnson, Kenneth R.; Zheng, Qing Yin; Gagnon, Leona H.; Bauschatz, Joiel D.; Davisson, Muriel T.; Washburn, Linda L.; Donahue, Leah Rae; Strom, Tim M.; Eicher, Eva M.

2010-01-01

X-linked hypophosphatemic rickets (XLH) in humans is caused by mutations in the PHEX gene. Previously, three mutations in the mouse Phex gene have been reported: PhexHyp, Gy, and PhexSka1. Here we report analysis of two new spontaneous mutations in the mouse Phex gene, PhexHyp-2J and PhexHyp-Duk. PhexHyp-2J and PhexHyp-Duk involve intragenic deletions of at least 7.3 kb containing exon 15, and 30 kb containing exons 13 and 14, respectively. Both mutations cause similar phenotypes in males, including shortened hind legs and tail, a shortened square trunk, hypophosphatemia, hypocalcemia, and rachitic bone disease. In addition, mice carrying the PhexHyp-Duk mutation exhibit background-dependent variable expression of deafness, circling behavior, and cranial dysmorphology, demonstrating the influence of modifying genes on Phex-related phenotypes. Cochlear cross-sections from PhexHyp-2J/Y and PhexHyp-Duk/Y males reveal a thickening of the temporal bone surrounding the cochlea with the presence of a precipitate in the scala tympani. Evidence of the degeneration of the organ of Corti and spiral ganglion also are present in the hearing-impaired PhexHyp-Duk/Y mice, but not in the normal-hearing PhexHyp-2J/Y mice. Analysis of the phenotypes noted in PhexHyp-Duk/Y an PhexHyp-2J/Y males, together with those noted in PhexSka1/Y and PhexHyp/Y males, now allow XLH-related phenotypes to be separated from non-XLH-related phenotypes, such as those noted in Gy/Y males. Also, identification of the genetic modifiers of hearing and craniofacial dysmorphology in PhexHyp-Duk/Y mice could provide insight into the phenotypic variation of XLH in humans. PMID:15029877

Pharmacokinetics and pharmacodynamics of a human monoclonal anti‐FGF23 antibody (KRN23) in the first multiple ascending‐dose trial treating adults with X‐linked hypophosphatemia

PubMed Central

Imel, Erik A.; Ruppe, Mary D.; Weber, Thomas J.; Klausner, Mark A.; Ito, Takahiro; Vergeire, Maria; Humphrey, Jeffrey; Glorieux, Francis H.; Portale, Anthony A.; Insogna, Karl; Carpenter, Thomas O.; Peacock, Munro

2015-01-01

Abstract In X‐linked hypophosphatemia (XLH), serum fibroblast growth factor 23 (FGF23) is increased and results in reduced renal maximum threshold for phosphate reabsorption (TmP), reduced serum inorganic phosphorus (Pi), and inappropriately low normal serum 1,25 dihydroxyvitamin D (1,25[OH]2D) concentration, with subsequent development of rickets or osteomalacia. KRN23 is a recombinant human IgG1 monoclonal antibody that binds to FGF23 and blocks its activity. Up to 4 doses of KRN23 were administered subcutaneously every 28 days to 28 adults with XLH. Mean ± standard deviation KRN23 doses administered were 0.05, 0.10 ± 0.01, 0.28 ± 0.06, and 0.48 ± 0.16 mg/kg. The mean time to reach maximum serum KRN23 levels was 7.0 to 8.5 days. The mean KRN23 half‐life was 16.4 days. The mean area under the concentration–time curve (AUCn) for each dosing interval increased proportionally with increases in KRN23 dose. The mean intersubject variability in AUCn ranged from 30% to 37%. The area under the effect concentration–time curve (AUECn) for change from baseline in TmP per glomerular filtration rate, serum Pi, 1,25(OH)2D, and bone markers for each dosing interval increased linearly with increases in KRN23 AUCn. Linear correlation between serum KRN23 concentrations and increase in serum Pi support KRN23 dose adjustments based on predose serum Pi concentration. © 2015 The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology PMID:26073451

FGFR Inhibitor Ameliorates Hypophosphatemia and Impaired Engrailed-1/Wnt Signaling in FGF2 High Molecular Weight Isoform Transgenic Mice.

PubMed

Du, Erxia; Xiao, Liping; Hurley, Marja M

2016-09-01

High molecular weight FGF2 transgenic (HMWTg) mouse phenocopies the Hyp mouse, homolog of human X-linked hypophosphatemic rickets with hypophosphatemis, and abnormal FGF23, FGFR, Klotho signaling in kidney. Since abnormal Wnt signaling was reported in Hyp mice we assessed whether Wnt signaling was impaired in HMWTg kidneys and the effect of blocking FGF receptor (FGFR) signaling. Bone mineral density and bone mineral content in female HMWTg mice were significantly reduced. HMWTg mice were gavaged with FGFR inhibitor NVP-BGJ398, or vehicle and were euthanized 24 h post treatment. Serum phosphate was significantly reduced and urine phosphate was significantly increased in HMWTg and was rescued by NVP-BGJ398. Analysis of kidneys revealed a significant reduction in Npt2a mRNA in HMWTg that was significantly increased by NVP-BGJ398. Increased FGFR1, KLOTHO, P-ERK1/2, and decreased NPT2a protein in HMWTg were rescued by NVP-BGJ398. Wnt inhibitor Engrailed-1 mRNA and protein was increased in HMWTg and was decreased by BGJ398. Akt mRNA and protein was decreased in HMWTg and was increased by NVP-BGJ398. The active form of glycogen synthase 3 beta (pGSK3-β) and phosphor-β-catenin were increased in HMWTg and were both decreased by NVP-BGJ398 while decreased active-β-catenin in HMWTg was increased by NVP-BGJ398. We conclude that FGFR blockade rescued hypophosphatemia by regulating FGF and WNT signaling in HMWTg kidneys. J. Cell. Biochem. 117: 1991-2000, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Identification of a novel loss-of-function PHEX mutation, Ala720Ser, in a sporadic case of adult-onset hypophosphatemic osteomalacia.

PubMed

Goljanek-Whysall, Katarzyna; Tridimas, Andreas; McCormick, Rachel; Russell, Nicki-Jayne; Sloman, Melissa; Sorani, Alan; Fraser, William D; Hannan, Fadil M

2018-01-01

Adults presenting with sporadic hypophosphatemia and elevations in circulating fibroblast growth factor-23 (FGF23) concentrations are usually investigated for an acquired disorder of FGF23 excess such as tumor induced osteomalacia (TIO). However, in some cases the underlying tumor is not detected, and such patients may harbor other causes of FGF23 excess. Indeed, coding-region and 3'UTR mutations of phosphate-regulating neutral endopeptidase (PHEX), which encodes a cell-surface protein that regulates circulating FGF23 concentrations, can lead to alterations in phosphate homeostasis, which are not detected until adulthood. Here, we report an adult female who presented with hypophosphatemic osteomalacia and raised serum FGF23 concentrations. The patient and her parents, who were her only first-degree relatives, had no history of rickets. The patient was thus suspected of having TIO. However, no tumor had been identified following extensive localization studies. Mutational analysis of the PHEX coding-region and 3'UTR was undertaken, and this revealed the patient to be heterozygous for a novel germline PHEX mutation (c.2158G>T; p.Ala720Ser). In vitro studies involving the expression of WT and mutant PHEX proteins in HEK293 cells demonstrated the Ala720Ser mutation to impair trafficking of PHEX, with ~20% of the mutant protein being expressed at the cell surface, compared to ~80% cell surface expression for WT PHEX (p<0.05). Thus, our studies have identified a pathogenic PHEX mutation in a sporadic case of adult-onset hypophosphatemic osteomalacia, and these findings highlight a role for PHEX gene analysis in some cases of suspected TIO, particularly when no tumor has been identified. Copyright © 2017 Elsevier Inc. All rights reserved.

New intragenic deletions in the Phex gene clarify X-linked hypophosphatemia-related abnormalities in mice.

PubMed

Lorenz-Depiereux, Bettina; Guido, Victoria E; Johnson, Kenneth R; Zheng, Qing Yin; Gagnon, Leona H; Bauschatz, Joiel D; Davisson, Muriel T; Washburn, Linda L; Donahue, Leah Rae; Strom, Tim M; Eicher, Eva M

2004-03-01

X-linked hypophosphatemic rickets (XLH) in humans is caused by mutation in the PHEX gene. Previously, three mutations in the mouse Phex gene have been reported: Phex(Hyp), Gy, and Phex(Ska1). Here we report analysis of two new spontaneous mutation in the mouse Phex gene, Phex(Hyp-2J) and Phex(Hyp-Duk). Phex(Hyp-2J) and Phex(Hyp-Duk) involve intragenic deletions of at least 7.3 kb containing exon 15, and 30 kb containing exons 13 and 14, respectively. Both mutations cause similar phenotypes in males, including shortened hind legs and tail, a shortened square trunk, hypophosphatemia, hypocalcemia, and rachitic bone disease. In addition, mice carrying the Phex(Hyp-Duk) mutation exhibit background-dependent variable expression of deafness, circling behavior, and cranial dysmorphology, demonstrating the influence of modifying genes on Phex-related phenotypes. Cochlear cross-sections from Phex(Hyp-2J)/Y and Phex(Hyp-Duk)/Y males reveal a thickening of the temporal bones surrounding the cochlea with the presence of a precipitate in the scala tympani. Evidence of the degeneration of the organ of Corti and spiral ganglion also are present in the hearing-impaired Phex(Hyp-Duk)/Y mice, but not in the normal-hearing Phex(Hyp-2J)/Y mice. Analysis of the phenotypes noted in Phex(Hyp-Duk)/Y and Phex(Hyp-2J)/Y males, together with those noted in Phex(Ska1)/Y and Phex(Hyp)/Y males, now allow XLH-related phenotypes to be separated from non-XLH-related phenotypes, such as those noted in Gy/Y males. Also, identification of the genetic modifiers of hearing and craniofacial dysmorphology in Phex(Hyp-Duk)/Y mice could provide insight into the phenotypic variation of XLH in humans.

Long-Term Clinical Outcome and Carrier Phenotype in Autosomal Recessive Hypophosphatemia Caused by a Novel DMP1 Mutation

PubMed Central

Mäkitie, Outi; Pereira, Renata C; Kaitila, Ilkka; Turan, Serap; Bastepe, Murat; Laine, Tero; Kröger, Heikki; Cole, William G; Jüppner, Harald

2010-01-01

Homozygous inactivating mutations in DMP1 (dentin matrix protein 1), the gene encoding a noncollagenous bone matrix protein expressed in osteoblasts and osteocytes, cause autosomal recessive hypophosphatemia (ARHP). Herein we describe a family with ARHP owing to a novel homozygous DMP1 mutation and provide a detailed description of the associated skeletal dysplasia and carrier phenotype. The two adult patients with ARHP, a 78-year-old man and his 66-year-old sister, have suffered from bone pain and lower extremity varus deformities since early childhood. With increasing age, both patients developed severe joint pain, contractures, and complete immobilization of the spine. Radiographs showed short and deformed long bones, significant cranial hyperostosis, enthesopathies, and calcifications of the paraspinal ligaments. Biochemistries were consistent with hypophosphatemia owing to renal phosphate wasting; markers of bone turnover and serum fibroblast growth factor 23 (FGF-23) levels were increased significantly. Nucleotide sequence analysis of DMP1 revealed a novel homozygous mutation at the splice acceptor junction of exon 6 (IVS5-1G > A). Two heterozygous carriers of the mutation also showed mild hypophosphatemia, and bone biopsy in one of these individuals showed focal areas of osteomalacia. In bone, DMP1 expression was absent in the homozygote but normal in the heterozygote, whereas FGF-23 expression was increased in both subjects but higher in the ARHP patient. The clinical and laboratory observations in this family confirm that DMP1 has an important role in normal skeletal development and mineral homeostasis. The skeletal phenotype in ARHP may be significantly more severe than in other forms of hypophosphatemic rickets. © 2010 American Society for Bone and Mineral Research. PMID:20499351

Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel DMP1 mutation.

PubMed

Mäkitie, Outi; Pereira, Renata C; Kaitila, Ilkka; Turan, Serap; Bastepe, Murat; Laine, Tero; Kröger, Heikki; Cole, William G; Jüppner, Harald

2010-10-01

Homozygous inactivating mutations in DMP1 (dentin matrix protein 1), the gene encoding a noncollagenous bone matrix protein expressed in osteoblasts and osteocytes, cause autosomal recessive hypophosphatemia (ARHP). Herein we describe a family with ARHP owing to a novel homozygous DMP1 mutation and provide a detailed description of the associated skeletal dysplasia and carrier phenotype. The two adult patients with ARHP, a 78-year-old man and his 66-year-old sister, have suffered from bone pain and lower extremity varus deformities since early childhood. With increasing age, both patients developed severe joint pain, contractures, and complete immobilization of the spine. Radiographs showed short and deformed long bones, significant cranial hyperostosis, enthesopathies, and calcifications of the paraspinal ligaments. Biochemistries were consistent with hypophosphatemia owing to renal phosphate wasting; markers of bone turnover and serum fibroblast growth factor 23 (FGF-23) levels were increased significantly. Nucleotide sequence analysis of DMP1 revealed a novel homozygous mutation at the splice acceptor junction of exon 6 (IVS5-1G > A). Two heterozygous carriers of the mutation also showed mild hypophosphatemia, and bone biopsy in one of these individuals showed focal areas of osteomalacia. In bone, DMP1 expression was absent in the homozygote but normal in the heterozygote, whereas FGF-23 expression was increased in both subjects but higher in the ARHP patient. The clinical and laboratory observations in this family confirm that DMP1 has an important role in normal skeletal development and mineral homeostasis. The skeletal phenotype in ARHP may be significantly more severe than in other forms of hypophosphatemic rickets.

Nutritional factors affecting poultry bone health.

PubMed

Fleming, Robert H

2008-05-01

Outlined are two main current research concerns relating to skeletal disorders in poultry: (a) osteoporosis in egg-laying hens; (b) leg problems caused by rapid bone growth in broiler chickens. Surveys indicate that 30% of caged laying hens suffer at least one lifetime fracture (a severe welfare issue). Modern hybrids produce one egg per d for 50 weeks. For this period 'normal' bone turnover ceases; only medullary bone (MB) is formed, a woven bone type of limited structural value. MB is resorbed for eggshell formation alongside structural bone, leading to increased fracture risk. Avian osteoporosis is reduced by activity and genetic selection but nutrition is also important. Fluoride and vitamin K are beneficial but the timing of nutritional intervention is important. Ca, inorganic P and vitamin D must be adequate and the form of Ca is critical. Limestone fed as particulates benefits skeletal and eggshell quality. In hens fed particulate limestone compared with flour-fed hens the tibiotarsus breaking strength and radiographic density are increased at 56 weeks of age (P<0.01 and P<0.001 respectively) and the number of tartrate-resistant acid phosphatase-positive stained active osteoclasts (mean number per microscopic field) is decreased (P<0.001). In broiler (meat) chickens selection for rapid growth from approximately 50 g to 3 kg in 42 d has inadvertently produced skeletal disorders such as tibial dyschondroplasia, rickets and associated valgus-varus deformities leading to lameness. The beneficial skeletal effects during growth of increased dietary n-3 PUFA:n-6 PUFA (utilising salmon oil) have been demonstrated. Experiments simulating daylight UVB levels have produced beneficial skeletal effects in Ca- and vitamin D-deficient chicks.

Physiological limit of the daily endogenous cholecalciferol synthesis from UV light in cattle.

PubMed

Hymøller, L; Jensen, S K; Kaas, P; Jakobsen, J

2017-04-01

The link between UV light (sunlight) and endogenous cholecalciferol (vitamin D 3 ) synthesis in the skin of humans has been known for more than a 100 years, since doctors for the first time successfully used UV light to cure rickets in children. Years later, it was shown that UV light also had a significant effect on the cholecalciferol status in the body of cattle. The cholecalciferol status in the body is measured as the plasma concentration of 25-hydroxycholecalciferol, which in cattle and humans is the major circulating metabolite of cholecalciferol. Very little is, however, known about the quantitative efficiency of UV light as a source of cholecalciferol in cattle nutrition and physiology. Hence, the aim of this study was to determine the efficiency of using UV light for increasing the plasma 25-hydroxycholecalciferol concentration in cholecalciferol-deprived cattle. Twelve cows deprived of cholecalciferol for 6 months were divided into three treatment groups and exposed to UV light for 30, 90 or 120 min/day during 28 days. UV-light wavelengths ranged from 280 to 415 nm and 30-min exposure to the UV light was equivalent to 60-min average summer-sunlight exposure at 56 °N. Blood samples were collected every 3-4 days and analysed for 25-hydroxycholecalciferol and cholecalciferol. Results showed that increasing the exposure time from 90-120 min/day did not change the slope of the daily increase in plasma 25-hydroxycholecalciferol. Hence, it appears that cholecalciferol-deprived dairy cattle are able to increase their plasma 25-hydroxycholecalciferol concentration by a maximum of 1 ng/ml/day from UV-light exposure. Journal of Animal Physiology and Animal Nutrition © 2016 Blackwell Verlag GmbH.

Biallelic mutations in CYP24A1 or SLC34A1 as a cause of infantile idiopathic hypercalcemia (IIH) with vitamin D hypersensitivity: molecular study of 11 historical IIH cases.

PubMed

Pronicka, Ewa; Ciara, Elżbieta; Halat, Paulina; Janiec, Agnieszka; Wójcik, Marek; Rowińska, Elżbieta; Rokicki, Dariusz; Płudowski, Paweł; Wojciechowska, Ewa; Wierzbicka, Aldona; Książyk, Janusz B; Jacoszek, Agnieszka; Konrad, Martin; Schlingmann, Karl P; Litwin, Mieczysław

2017-08-01

Idiopathic infantile hypercalcemia (IIH) is a mineral metabolism disorder characterized by severe hypercalcemia, failure to thrive, vomiting, dehydration, and nephrocalcinosis. The periodical increase in incidence of IIH, which occurred in the twentieth century in the United Kingdom, Poland, and West Germany, turned out to be a side effect of rickets over-prophylaxis. It was recently discovered that the condition is linked to two genes, CYP24A1 and SLC34A1. The aim of the study was to search for pathogenic variants of the genes in adult persons who were shortlisted in infancy as IIH caused by "hypersensitivity to vit. D". All persons were found to carry mutations in CYP24A1 or SLC34A1, nine and two persons respectively. The changes were biallelic, with one exception. Incidence of IIH in Polish population estimated on the basis of allele frequency of recurrent p.R396W CYP24A1 variant, is 1:32,465 births. It indicates that at least a thousand homozygotes and compound heterozygotes with risk of IIH live in the country. Differences in mechanism of developing hypercalcemia indicate that its prevention may vary in both IIH defects. Theoretically, vit. D restriction is a first indication for CYP24A1 defect (which disturbs 1,25(OH) 2 D degradation) and phosphate supplementation for SLC34A1 defect (which impairs renal phosphate transport). In conclusion, we suggest that molecular testing for CYP24A1 and SLC34A1 mutations should be performed in each case of idiopathic hypercalcemia/hypercalciuria, both in children and adults, to determine the proper way for acute treatment and complications prevention.

Autism and vitamin D.

PubMed

Cannell, John Jacob

2008-01-01

Any theory of autism's etiology must take into account its strong genetic basis while explaining its striking epidemiology. The apparent increase in the prevalence of autism over the last 20 years corresponds with increasing medical advice to avoid the sun, advice that has probably lowered vitamin D levels and would theoretically greatly lower activated vitamin D (calcitriol) levels in developing brains. Animal data has repeatedly shown that severe vitamin D deficiency during gestation dysregulates dozens of proteins involved in brain development and leads to rat pups with increased brain size and enlarged ventricles, abnormalities similar to those found in autistic children. Children with the Williams Syndrome, who can have greatly elevated calcitriol levels in early infancy, usually have phenotypes that are the opposite of autism. Children with vitamin D deficient rickets have several autistic markers that apparently disappear with high-dose vitamin D treatment. Estrogen and testosterone have very different effects on calcitriol's metabolism, differences that may explain the striking male/female sex ratios in autism. Calcitriol down-regulates production of inflammatory cytokines in the brain, cytokines that have been associated with autism. Consumption of vitamin D containing fish during pregnancy reduces autistic symptoms in offspring. Autism is more common in areas of impaired UVB penetration such as poleward latitudes, urban areas, areas with high air pollution, and areas of high precipitation. Autism is more common in dark-skinned persons and severe maternal vitamin D deficiency is exceptionally common the dark-skinned. simple Gaussian distributions of the enzyme that activates neural calcitriol combined with widespread gestational and/or early childhood vitamin D deficiency may explain both the genetics and epidemiology of autism. If so, much of the disease is iatrogenic, brought on by medical advice to avoid the sun. Several types of studies could easily test the theory.

Nutritional status of school-age children - A scenario of urban slums in India

PubMed Central

2012-01-01

Background One of the greatest problems for India is undernutrition among children. The country is still struggling with this problem. Malnutrition, the condition resulting from faulty nutrition, weakens the immune system and causes significant growth and cognitive delay. Growth assessment is the measurement that best defines the health and nutritional status of children, while also providing an indirect measurement of well-being for the entire population. Methods A cross-sectional study, in which we explored nutritional status in school-age slum children and analyze factors associated with malnutrition with the help of a pre-designed and pre-tested questionnaire, anthropometric measurements and clinical examination from December 2010 to April 2011 in urban slums of Bareilly, Uttar-Pradesh (UP), India. Result The mean height and weight of boys and girls in the study group was lower than the CDC 2000 (Centers for Disease Control and Prevention) standards in all age groups. Regarding nutritional status, prevalence of stunting and underweight was highest in age group 11 yrs to 13 yrs whereas prevalence of wasting was highest in age group 5 yrs to 7 yrs. Except refractive errors all illnesses are more common among girls, but this gender difference is statistically significant only for anemia and rickets. The risk of malnutrition was significantly higher among children living in joint families, children whose mother's education was [less than or equal to] 6th standard and children with working mothers. Conclusions Most of the school-age slum children in our study had a poor nutritional status. Interventions such as skills-based nutrition education, fortification of food items, effective infection control, training of public healthcare workers and delivery of integrated programs are recommended. PMID:22958757

[Importance of the clinical profile in the postmenopausal osteoporosis screening by densitometry].

PubMed

Bigler, J M; Abetel, G; Krieg, M A; Wimpfheimer, C; Burnand, B; Thiébaud, D; Burckhardt, P

1996-08-06

In order to test the impact of a given risk profile on the incidence of osteoporosis which could justify BMD measurement, and that of a low risk profile which could render it unnecessary, BMD was measured in 217 women under 72 in whom menopause had occurred at least 6 years previously and who corresponded to one of the two following profiles: high risk (A, n = 102) = BMI < 27 kg/m2, with no estrogen replacement treatment, and with at least one of the following risk factors: BMI < 20, early menopause, positive family history, no dairy products associated with tobacco consumption (> 10 cigarettes/day for > 20 years and/or alcohol consumption of > 0.5 l wine/day during > 10 years, corticotherapy of > 6 months, rickets, anorexia nervosa. Low risk (B, n = 115) = absence of characteristics of group A, BMI > 27 kg/m2 with (B+, n = 24) or without estrogen therapy (B-, n = 91). BMD was measured by DXA in 4 centers using Lunar or Hologic equipment. Results were expressed in % of the mean of the respective young adult control groups. As expected, BMD was significantly different in these two subgroups of the population. Osteoporosis was diagnosed (BMD < 75% = < -2.5 SD, according to WHO) in 72% of group A, and in 17% (B+) and 19% (B-) respectively of group B. There was no difference between the various risk factors in group A concerning their impact on BMD, but concerning incidence, low BMI and early menopause were the most frequent. The high risk profile of group A seems to justify densitometry, since it leads to the diagnosis of osteoporosis in over 70%. However, the protective profile of group B does not exclude osteoporosis (risk still 20%); only in severe obesity (BMI > 33) does it drop to 1%.

Transplantation of bone marrow-derived mesenchymal stem cells rescues partially rachitic phenotypes induced by 1,25-Dihydroxyvitamin D deficiency in mice

PubMed Central

Zhang, Zengli; Yin, Shaomeng; Xue, Xian; Ji, Ji; Tong, Jian; Goltzman, David; Miao, Dengshun

2016-01-01

To determine whether the transplantation of bone marrow-derived mesenchymal stem cells (BM-MSCs) can improve the 1,25(OH)2D deficiency-induced rachitic phenotype, 2×106 BM-MSCs from wild-type mice or vehicle were transplanted by tail vein injection into mice deficient in 1,25(OH)2D due to targeted deletion of 1α(OH)ase (1α(OH)ase-/-). Our results show that 1α(OH)ase mRNA was expressed in the BM-MSCs derived from wild-type mice, and was detected in long bone, kidney and intestine from BM-MSC-transplanted 1α(OH)ase-/- recipients. Serum calcium, 1,25(OH)2D3 levels and body weight were significantly increased in BM-MSC-transplanted 1α(OH)ase-/- recipients compared to vehicle-treated 1α(OH)ase-/- mice. Skeletal mineralization improved in 1α(OH)ase-/- recipients as demonstrated by BMD measurement, micro-CT analysis and von Kossa staining of undecalcified sections. Expression levels of type I collagen, osteocalcin, bone sialoprotein and vitronectin and the size of calcified nodules were decreased in BM-MSC cultures from 1α(OH)ase-/- mice compared with those from wild-type mice, however, these parameters were increased in those from BM-MSCs-transplanted 1α(OH)ase-/- recipients compared with those from vehicle-treated 1α(OH)ase-/- mice. This study indicates that donor BM-MSCs cells can relocate to multiple tissues where they synthesize 1α(OH)ase and produce 1,25(OH)2D that contributes to the improvement of serum calcium and skeletal mineralization. Results from this study suggest that BM-MSC transplantation may provide a therapeutic approach to treatment of pseudovitamin D-deficiency rickets. PMID:27830022

Transplantation of bone marrow-derived mesenchymal stem cells rescues partially rachitic phenotypes induced by 1,25-Dihydroxyvitamin D deficiency in mice.

PubMed

Zhang, Zengli; Yin, Shaomeng; Xue, Xian; Ji, Ji; Tong, Jian; Goltzman, David; Miao, Dengshun

2016-01-01

To determine whether the transplantation of bone marrow-derived mesenchymal stem cells (BM-MSCs) can improve the 1,25(OH) 2 D deficiency-induced rachitic phenotype, 2×10 6 BM-MSCs from wild-type mice or vehicle were transplanted by tail vein injection into mice deficient in 1,25(OH) 2 D due to targeted deletion of 1α(OH)ase (1α(OH)ase -/- ). Our results show that 1α(OH)ase mRNA was expressed in the BM-MSCs derived from wild-type mice, and was detected in long bone, kidney and intestine from BM-MSC-transplanted 1α(OH)ase -/- recipients. Serum calcium, 1,25(OH) 2 D 3 levels and body weight were significantly increased in BM-MSC-transplanted 1α(OH)ase -/- recipients compared to vehicle-treated 1α(OH)ase -/- mice. Skeletal mineralization improved in 1α(OH)ase -/- recipients as demonstrated by BMD measurement, micro-CT analysis and von Kossa staining of undecalcified sections. Expression levels of type I collagen, osteocalcin, bone sialoprotein and vitronectin and the size of calcified nodules were decreased in BM-MSC cultures from 1α(OH)ase -/- mice compared with those from wild-type mice, however, these parameters were increased in those from BM-MSCs-transplanted 1α(OH)ase -/- recipients compared with those from vehicle-treated 1α(OH)ase -/- mice. This study indicates that donor BM-MSCs cells can relocate to multiple tissues where they synthesize 1α(OH)ase and produce 1,25(OH) 2 D that contributes to the improvement of serum calcium and skeletal mineralization. Results from this study suggest that BM-MSC transplantation may provide a therapeutic approach to treatment of pseudovitamin D-deficiency rickets.

Dose response of bone-targeted enzyme replacement for murine hypophosphatasia.

PubMed

Yadav, Manisha C; Lemire, Isabelle; Leonard, Pierre; Boileau, Guy; Blond, Laurent; Beliveau, Martin; Cory, Esther; Sah, Robert L; Whyte, Michael P; Crine, Philippe; Millán, José Luis

2011-08-01

Hypophosphatasia (HPP) features rickets or osteomalacia from tissue-nonspecific alkaline phosphatase (TNSALP) deficiency due to deactivating mutations within the ALPL gene. Enzyme replacement therapy with a bone-targeted, recombinant TNSALP (sALP-FcD(10), renamed ENB-0040) prevents manifestations of HPP when initiated at birth in TNSALP knockout (Akp2(-/-)) mice. Here, we evaluated the dose-response relationship of ENB-0040 to various phenotypic traits of Akp2(-/-) mice receiving daily subcutaneous (SC) injections of ENB-0040 from birth at 0.5, 2.0, or 8.2mg/kg for 43days. Radiographs, μCT, and histomorphometric analyses documented better bone mineralization with increasing doses of ENB-0040. We found a clear, positive correlation between ENB-0040 dose and prevention of mineralization defects of the feet, rib cage, lower limbs, and jaw bones. According to a dose-response model, the ED(80) (the dose that prevents bone defects in 80% of mice) was 3.2, 2.8 and 2.9mg/kg/day for these sites, respectively. Long bones seemed to respond to lower daily doses of ENB-0040. There was also a positive relationship between ENB-0040 dose and survival. Median survival, body weight, and bone length all improved with increasing doses of ENB-0040. Urinary PP(i) concentrations remained elevated in all treatment groups, indicating that while this parameter is a good biochemical marker for diagnosing HPP in patients, it may not be a good follow up marker for evaluating response to treatment when administering bone-targeted TNSALP to mice. These dose-response relationships strongly support the pharmacological efficacy of ENB-0040 for HPP, and provide the experimental basis for the therapeutic range of ENB-0040 chosen for clinical trials. Copyright © 2011 Elsevier Inc. All rights reserved.

Dose response of bone-targeted enzyme replacement for murine hypophosphatasia

PubMed Central

Yadav, Manisha C.; Lemire, Isabelle; Leonard, Pierre; Boileau, Guy; Blond, Laurent; Beliveau, Martin; Cory, Esther; Sah, Robert L.; Whyte, Michael P.; Crine, Philippe; Millán, José Luis

2011-01-01

Hypophosphatasia (HPP) features rickets or osteomalacia from tissue-nonspecific alkaline phosphatase (TNSALP) deficiency due to deactivating mutations within the ALPL gene. Enzyme replacement therapy with a bone-targeted, recombinant TNSALP (sALP-FcD10, renamed ENB-0040) prevents manifestations of HPP when initiated at birth in TNSALP knockout (Akp2−/−) mice. Here, we evaluated the dose-response relationship of ENB-0040 to various phenotypic traits of Akp2−/− mice receiving daily subcutaneous (SC) injections of ENB-0040 from birth at 0.5, 2.0, or 8.2 mg/kg for 43 days. Radiographs, μCT, and histomorphometric analyses documented better bone mineralization with increasing doses of ENB-0040. We found a clear, positive correlation between ENB-0040 dose and prevention of mineralization defects of the feet, rib cage, lower limbs, and jaw bones. According to a dose-response model, the ED80 (the dose prevents the bone defects in 80% of mice) was 3.2, 2.8 and 2.9 mg/kg/day for these sites, respectively. Long bones seemed to respond to lower daily doses of ENB-0040. There was also a positive relationship between ENB-0040 dose and survival. Median survival, body weight, and bone length all improved with increasing doses of ENB-0040. Urinary PPi concentrations remained elevated in all treatment groups, indicating that while this parameter is a good biochemical marker for diagnosing HPP, it may not be a good follow up marker for evaluating response to treatment when administering bone-targeted TNSALP. These dose-response relationships strongly support the pharmacological efficacy of ENB-0040 for HPP, and provide the experimental basis for the therapeutic range of ENB-0040 chosen for clinical trials. PMID:21458605

Increased Probability of Co-Occurrence of Two Rare Diseases in Consanguineous Families and Resolution of a Complex Phenotype by Next Generation Sequencing

PubMed Central

Lal, Dennis; Neubauer, Bernd A.; Toliat, Mohammad R.; Altmüller, Janine; Thiele, Holger; Nürnberg, Peter; Kamrath, Clemens; Schänzer, Anne; Sander, Thomas; Hahn, Andreas; Nothnagel, Michael

2016-01-01

Massively parallel sequencing of whole genomes and exomes has facilitated a direct assessment of causative genetic variation, now enabling the identification of genetic factors involved in rare diseases (RD) with Mendelian inheritance patterns on an almost routine basis. Here, we describe the illustrative case of a single consanguineous family where this strategy suffered from the difficulty to distinguish between two etiologically distinct disorders, namely the co-occurrence of hereditary hypophosphatemic rickets (HRR) and congenital myopathies (CM), by their phenotypic manifestation alone. We used parametric linkage analysis, homozygosity mapping and whole exome-sequencing to identify mutations underlying HRR and CM. We also present an approximate approach for assessing the probability of co-occurrence of two unlinked recessive RD in a single family as a function of the degree of consanguinity and the frequency of the disease-causing alleles. Linkage analysis and homozygosity mapping yielded elusive results when assuming a single RD, but whole-exome sequencing helped to identify two mutations in two genes, namely SLC34A3 and SEPN1, that segregated independently in this family and that have previously been linked to two etiologically different diseases. We assess the increase in chance co-occurrence of rare diseases due to consanguinity, i.e. under circumstances that generally favor linkage mapping of recessive disease, and show that this probability can increase by several orders of magnitudes. We conclude that such potential co-occurrence represents an underestimated risk when analyzing rare or undefined diseases in consanguineous families and should be given more consideration in the clinical and genetic evaluation. PMID:26789268

Population groups in dietary transition

PubMed Central

Wändell, Per E.

2013-01-01

Background Little is known about the effects of dietary acculturation in minority groups in the Nordic countries, including immigrants from non-Western societies. Methods A search was performed in Medlin33e/PubMed and SweMed+ for articles published in 1990–2011. Results A total of 840 articles were identified, with a final 32 articles used to tabulate results which were included in the primary analysis. High rates of vitamin D deficiency (23 articles) were found in immigrants of non-Western origin; deficiency rates were very high among both pregnant and non-pregnant women, and also among children, with young children of immigrant parents showing 50 times higher risk for rickets when compared to children of indigenous parents. The risk of iron deficiency (two articles) was high among immigrant women, while the results were inconclusive regarding children. High rates of dental caries (seven articles) were found among pre-school and younger school children of immigrant origin, while the risk of caries was not as evident among older children. In a secondary analysis, including 48 articles (results not tabulated), overweight and obesity (14 articles) were seen in many immigrant groups, resulting in a high prevalence of diabetes (2 review articles from a total of 14 original articles) and incidence of coronary heart disease (CHD; seven articles). For hypertension (three articles), dyslipidemia (four articles), and dietary patterns among immigrants (10 articles), the results were contradictory. Conclusions Risk of vitamin D deficiency is alarmingly high in the Nordic countries among immigrants of non-Western origin, especially among women. Dental caries is high among immigrant children aged 0–7 years due to a higher intake of sugary products. Overweight and obesity, associated with a higher risk of diabetes and CHD, are prevalent in many immigrant groups and need further attention. PMID:24106456

In Pursuit of Vitamin D in Plants.

PubMed

Black, Lucinda J; Lucas, Robyn M; Sherriff, Jill L; Björn, Lars Olof; Bornman, Janet F

2017-02-13

Vitamin D deficiency is a global concern. Much research has concentrated on the endogenous synthesis of vitamin D in human skin following exposure to ultraviolet-B radiation (UV-B, 280-315 nm). In many regions of the world there is insufficient UV-B radiation during winter months for adequate vitamin D production, and even when there is sufficient UV-B radiation, lifestyles and concerns about the risks of sun exposure may lead to insufficient exposure and to vitamin D deficiency. In these situations, dietary intake of vitamin D from foods or supplements is important for maintaining optimal vitamin D status. Some foods, such as fatty fish and fish liveroils, certain meats, eggs, mushrooms, dairy, and fortified foods, can provide significant amounts of vitamin D when considered cumulatively across the diet. However, little research has focussed on assessing edible plant foods for potential vitamin D content. The biosynthesis of vitamin D in animals, fungi and yeasts is well established; it is less well known that vitamin D is also biosynthesised in plants. Research dates back to the early 1900s, beginning with in vivo experiments showing the anti-rachitic activity of plants consumed by animals with induced rickets, and in vitro experiments using analytical methods with limited sensitivity. The most sensitive, specific and reliable method for measuring vitamin D and its metabolites is by liquid chromatography tandem mass spectrometry (LC-MS/MS). These assays have only recently been customised to allow measurement in foods, including plant materials. This commentary focuses on the current knowledge and research gaps around vitamin D in plants, and the potential of edible plants as an additional source of vitamin D for humans.

Towards evidence-based vitamin D supplementation in infants: vitamin D intervention in infants (VIDI) - study design and methods of a randomised controlled double-blinded intervention study.

PubMed

Helve, Otto; Viljakainen, Heli; Holmlund-Suila, Elisa; Rosendahl, Jenni; Hauta-Alus, Helena; Enlund-Cerullo, Maria; Valkama, Saara; Heinonen, Kati; Räikkönen, Katri; Hytinantti, Timo; Mäkitie, Outi; Andersson, Sture

2017-03-29

Vitamin D is important for bone mass accrual during growth. Additionally, it is considered a requirement for a multitude of processes associated with, for example, the development of immunity. Many countries apply vitamin D supplementation strategies in infants, but the guidelines are not based on scientific evidence and aim at prevention of rickets. It remains unclear whether the recommended doses are sufficient for the wide array of other effects of vitamin D. The VIDI trial performed in Finland is the first large randomised controlled study for evaluation of the effects of different vitamin D supplemental doses in infancy on: 1. bone strength 2. infections and immunity 3. allergy, atopy and asthma 4. cognitive development 5. genetic regulation of mineral homeostasis METHODS/DESIGN: VIDI, a randomised controlled double-blinded single-centre intervention study is conducted in infants from the age of 2 weeks to 24 months. Participants, recruited at Helsinki Maternity Hospital, are randomised to receive daily either 10 μg (400 IU) or 30 μg (1 200 IU) of vitamin D3 supplementation. Both groups are assessed at 6 months of age for calcium homeostasis, and at 12 and 24 months of age for parameters associated with bone strength, growth, developmental milestones, infections, immunity, atopy-related diseases, and genetic factors involved in these functions. The study enables evaluation of short and long term effects of supplemental vitamin D on growth, immune functions and skeletal and developmental parameters in infants, and the effects of genetic factors therein. The results enable institution of evidence-based guidelines for vitamin D supplementation in infancy. ClinicalTrials.gov, NCT01723852 , registration date 6.11.2012.

Great social benefits.

PubMed

Huang, B

1991-06-01

The Integrated Project (IP), originated by the Japanese Organization for International Cooperation in Family Planning (JOICFP) was started in China in 1984. The 2nd phase covered 210,000 people in 8 townships in Inner Mongolia Autonomous Region, and others in Liaoning, Jiangsu and Shandong Provinces, in 1987-1989. 2 pilot areas, monitored by representatives from IPPF's East and Southeast Asia and Oceania Region in September 1990, showed significant gains in contraceptive prevalence as well as health benefits and community acceptance. The IP consists of integrated family planning, maternal and child health and parasite control for rural areas. In Tumotezuo County, Inner Mongolia, the village of Bashi with 2526 people was mobilized to construct its own health clinic with a delivery room and a maternal and child health unit, where night classes were held for women. Because of antihelminthic treatment, installation of water pipes and toilets, parasites were controlled. Neighboring towns benefited by treatment of common disorders such as anemia and rickets. In the pilot areas there have been no maternal deaths in 3 years, and declines in perinatal mortality from 33.3 to 17.9/1000, and in infant mortality from 35.1 to 21.5/1000. Incidence of roundworm infection fell from 27.8 to 7.6%, Contraceptive prevalence, already high at 91.8%, rose to 93.7% among the Han majority, and from 65.9 to 77.2% in minorities. Family planning was spread by using the "core household" approach. The large household of the village leader, with 13 women of childbearing age, subscribed to several periodicals on family planning and farm and home economics, so people learned how to become well off by raising vegetables and pigs, and how to limit family size with the correct concept of a happy healthy family.

The When, What & How of Measuring Vitamin D Metabolism in Clinical Medicine

PubMed Central

Dirks, Niek F.; Ackermans, Mariëtte T.; Lips, Paul; de Jongh, Renate T.; de Jonge, Robert; Heijboer, Annemieke C.

2018-01-01

We now have the ability to measure a number of different vitamin D metabolites with very accurate methods. The most abundant vitamin D metabolite, 25-hydroxyvitamin D, is currently the best marker for overall vitamin D status and is therefore most commonly measured in clinical medicine. The added value of measuring metabolites beyond 25-hydroxyvitamin D, like 1,25-, and 24,25-dihydroxyvitamin D is not broadly appreciated. Yet, in some more complicated cases, these metabolites may provide just the information needed for a legitimate diagnosis. The problem at present, is knowing when to measure, what to measure and how to measure. For 25-hydroxyvitamin D, the most frequently used automated immunoassays do not meet the requirements of today’s standards for certain patient groups and liquid chromatography-tandem mass spectrometry is the desired method of choice in these individuals. The less frequently measured 1,25-dihydroxyvitamin D metabolite enables us to identify a number of conditions, including 1α-hydroxylase deficiency, hereditary vitamin D-resistant rickets and a number of granulomatous diseases or lymphoproliferative diseases accompanied by hypercalcaemia. Furthermore, it discriminates between the FGF23-mediated and non-FGF23-mediated hypophosphatemic syndromes. The 24,25-dihydroxyvitamin D metabolite has proven its value in the diagnosis of idiopathic infantile hypercalcaemia and has the potential of having value in identifying other diseases. For both metabolites, the understanding of the origin of differences between assays is limited and requires further attention. Nonetheless, in every way, appropriate measurement of vitamin D metabolism in the clinical laboratory hinges eminently on the comprehension of the value of the different metabolites, and the importance of the choice of method. PMID:29652819

Symposium on ‘Nutrition and health in children and adolescents’ Session 1: Nutrition in growth and development

PubMed Central

Prentice, Ann; Schoenmakers, Inez; Laskey, M. Ann; de Bono, Stephanie; Ginty, Fiona; Goldberg, Gail R.

2007-01-01

The growth and development of the human skeleton requires an adequate supply of many different nutritional factors. Classical nutrient deficiencies are associated with stunting (e.g. energy, protein, Zn), rickets (e.g. vitamin D) and other bone abnormalities (e.g. Cu, Zn, vitamin C). In recent years there has been interest in the role nutrition may play in bone growth at intakes above those required to prevent classical deficiencies, particularly in relation to optimising peak bone mass and minimising osteoporosis risk. There is evidence to suggest that peak bone mass and later fracture risk are influenced by the pattern of growth in childhood and by nutritional exposures in utero, in infancy and during childhood and adolescence. Of the individual nutrients, particular attention has been paid to Ca, vitamin D, protein and P. There has also been interest in several food groups, particularly dairy products, fruit and vegetables and foods contributing to acid–base balance. However, it is not possible at the present time to define dietary reference values using bone health as a criterion, and the question of what type of diet constitutes the best support for optimal bone growth and development remains open. Prudent recommendations (Department of Health, 1998; World Health Organization/Food and Agriculture Organization, 2003) are the same as those for adults, i.e. to consume a Ca intake close to the reference nutrient intake, optimise vitamin D status through adequate summer sunshine exposure (and diet supplementation where appropriate), be physically active, have a body weight in the healthy range, restrict salt intake and consume plenty of fruit and vegetables. PMID:17181901

Outdoor exposure and vitamin D levels in urban children with asthma.

PubMed

Bose, Sonali; Breysse, Patrick N; McCormack, Meredith C; Hansel, Nadia N; Rusher, Robert R; Matsui, Elizabeth; Peng, Roger; Curtin-Brosnan, Jean; Diette, Gregory B

2013-06-12

The inner-city pediatric population in the United States has a disproportionate burden of asthma. Recent attention has focused on the immunomodulatory role of vitamin D, which may be protective against disease morbidity. As the primary determinant of vitamin D status in humans is exposure to sunlight, we aimed to determine if 25-OH vitamin D levels in urban preschool children with asthma were low, influenced by time spent outdoors, and associated with asthma morbidity. Serum 25-OH vitamin D levels were measured at baseline in a cohort of 121 inner-city children ages 2-6 years with asthma in Baltimore, MD. Participants were followed longitudinally at 3 and 6 months to assess time spent outdoors, asthma symptoms through questionnaires and daily diaries, and allergic markers. In a predominantly black population of preschool children, the median 25-OH vitamin D level was 28 ng/mL (IQR 21.2-36.9), with 54% of the children below the traditionally sufficient level of 30 ng/mL and 7.4% in the range associated with risk of rickets (< 15 ng/mL). The median time spent outdoors was 3 hours/day (IQR 2-4), and greater time spent outdoors was not associated with higher vitamin D levels. 25-OH vitamin D did not show seasonal variation in our cohort (p = 0.66). Lower 25-OH levels were correlated with higher IgE levels. Urban African-American preschool children with asthma have high rates of vitamin D insufficiency, and increased outdoor exposure is unlikely to correct these low 25-OH vitamin D levels. Repletion in this population may require dietary supplementation.

iPhone-imaged and cell-powered electrophoresis titration chip for the alkaline phosphatase assay in serum by the moving reaction boundary.

PubMed

Cao, Xin-Yu; Kong, Fan-Zhi; Zhang, Qiang; Liu, Wei-Wen; Liu, Xiao-Ping; Li, Guo-Qing; Zhong, Ran; Fan, Liu-Yin; Xiao, Hua; Cao, Cheng-Xi

2018-05-21

As a vital enzyme, alkaline phosphatase (ALP) has great clinical significance in diagnoses of bone or liver cancer, bone metastases, rickets, and extrahepatic biliary obstruction. However, there is still no really portable chip for the ALP assay in blood. Herein, a simple electrophoresis titration (ET) model was developed for ALP detection via a moving reaction boundary (MRB). In the model, ALP catalyzed the dephosphorylation of a 4-methylumbelliferyl phosphate disodium salt (4-MUP) substrate in the cathode well to 4-methylumbelliferone ([4-MU]-) with a negative charge and blue fluorescence under UV excitation. After the catalysis, an electric field was used between the cathode and the anode. Under the electric field, [4-MU]- moved into the channel and neutralized the acidic Tris-HCl buffer, resulting in the quenching of [4-MU]- and creating a MRB. The ET system just had an ET chip, a lithium cell, a UV LED and an iPhone used as a recorder, having no traditional expensive power supply and fluorescence detector. The relevant method was developed, and a series of experiments were conducted via the ET chip. The experiments showed: (i) a MRB could be formed between the [4-MU]- base and the acidic buffer, and the MRB motion had a linear relationship with the ALP activity, validating the ET model; (ii) the ET run was not impacted by many interferences, implying good selectivity; and (iii) the ET chip could be used for portable detection within 10 min, implying an on-site and rapid analysis. In addition, the ET method had a relatively good sensitivity (0.1 U L-1), linearity (V = 0.033A + 3.87, R2 = 0.9980), stability (RSD 2.4-6.8%) and recoveries (101-105%). Finally, the ET method was successfully used for ALP assays in real serum samples. All the results implied that the developed method was simple, rapid and low-cost, and had potential for POCT clinical ALP assays.

Association between mental disorders, cognitive disturbances and vitamin D serum level: Current state.

PubMed

Lerner, Paul P; Sharony, Laura; Miodownik, Chanoch

2018-02-01

Vitamin D deficiency has been identified as a global problem. Approximately 14% of the world population has inadequate vitamin D levels. This vitamin has been usually associated with bone disorders such as rickets, osteomalacia, and osteoporosis. However, these disorders present only a small part of all the disturbances which can be induced by its deficiency. Low serum vitamin D is associated with development of cardiovascular diseases, hypertension, neurodegenerative diseases, diabetes mellitus, metabolic syndrome and even cancer. This vitamin may be an important factor in the development of psychiatric illnesses, therefore clinicians should not leave this serious issue unresolved. The aim of this review is to describe the current data concerning the association between vitamin D serum levels, cognition and mental disorders. We conducted a systematic bibliographical research, of PubMed, MedLine literature and Cochrane database without language restriction to identify all publications concerning this issue from 1995 to the first quarter of 2017. We found 48,937 articles concerning vitamin D, published during the last 22 years and 3 months (1995-2017). We selected only those publications focused on the association between vitamin D serum deficiency and mental disturbances (depression, schizophrenia, cognitive disturbances, attention deficit disorder, and autism). One hundred and sixty-seven papers were found suitable to our selection criteria. Careful evaluation of the relevant literature demonstrates that addition of vitamin D to conventional antidepressive agents can improve antidepressive effect in contrast to placebo. Regarding other mental conditions there are no clear-cut conclusions. An association between low vitamin D serum levels and different mental disorders was found. Yet, nonetheless there is no clear consensus that addition of vitamin D improves or is related to a beneficial effect on mental health. More randomized clinical control trials should be performed in order to reach evidence based conclusions. Copyright © 2017 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.

Neonatal iron deficiency causes abnormal phosphate metabolism by elevating FGF23 in normal and ADHR mice.

PubMed

Clinkenbeard, Erica L; Farrow, Emily G; Summers, Lelia J; Cass, Taryn A; Roberts, Jessica L; Bayt, Christine A; Lahm, Tim; Albrecht, Marjorie; Allen, Matthew R; Peacock, Munro; White, Kenneth E

2014-02-01

Fibroblast growth factor 23 (FGF23) gain of function mutations can lead to autosomal dominant hypophosphatemic rickets (ADHR) disease onset at birth, or delayed onset following puberty or pregnancy. We previously demonstrated that the combination of iron deficiency and a knock-in R176Q FGF23 mutation in mature mice induced FGF23 expression and hypophosphatemia that paralleled the late-onset ADHR phenotype. Because anemia in pregnancy and in premature infants is common, the goal of this study was to test whether iron deficiency alters phosphate handling in neonatal life. Wild-type (WT) and ADHR female breeder mice were provided control or iron-deficient diets during pregnancy and nursing. Iron-deficient breeders were also made iron replete. Iron-deficient WT and ADHR pups were hypophosphatemic, with ADHR pups having significantly lower serum phosphate (p < 0.01) and widened growth plates. Both genotypes increased bone FGF23 mRNA (>50 fold; p < 0.01). WT and ADHR pups receiving low iron had elevated intact serum FGF23; ADHR mice were affected to a greater degree (p < 0.01). Iron-deficient mice also showed increased Cyp24a1 and reduced Cyp27b1, and low serum 1,25-dihydroxyvitamin D (1,25D). Iron repletion normalized most abnormalities. Because iron deficiency can induce tissue hypoxia, oxygen deprivation was tested as a regulator of FGF23, and was shown to stimulate FGF23 mRNA in vitro and serum C-terminal FGF23 in normal rats in vivo. These studies demonstrate that FGF23 is modulated by iron status in young WT and ADHR mice and that hypoxia independently controls FGF23 expression in situations of normal iron. Therefore, disturbed iron and oxygen metabolism in neonatal life may have important effects on skeletal function and structure through FGF23 activity on phosphate regulation. © 2014 American Society for Bone and Mineral Research.

Cutaneous skeletal hypophosphatemia syndrome: clinical spectrum, natural history, and treatment.

PubMed

Ovejero, D; Lim, Y H; Boyce, A M; Gafni, R I; McCarthy, E; Nguyen, T A; Eichenfield, L F; DeKlotz, C M C; Guthrie, L C; Tosi, L L; Thornton, P S; Choate, K A; Collins, M T

2016-12-01

Cutaneous skeletal hypophosphatemia syndrome (CSHS), caused by somatic RAS mutations, features excess fibroblast growth factor-23 (FGF23) and skeletal dysplasia. Records from 56 individuals were reviewed and demonstrated fractures, scoliosis, and non-congenital hypophosphatemia that in some cases were resolved. Phosphate and calcitriol, but not skin lesion removal, were effective at controlling hypophosphatemia. No skeletal malignancies were found. CSHS is a disorder defined by the association of epidermal and/or melanocytic nevi, a mosaic skeletal dysplasia, and an FGF23-mediated hypophosphatemia. To date, somatic RAS mutations have been identified in all patients whose affected tissue has undergone DNA sequencing. However, the clinical spectrum and treatment are poorly defined in CSHS. The purpose of this study is to determine the spectrum of the phenotype, natural history of the disease, and response to treatment of hypophosphatemia. Five CSHS subjects underwent prospective data collection at clinical research centers. A review of the literature identified 45 reports that included a total of 51 additional patients, in whom the findings were compatible with CSHS. Data on nevi subtypes, bone histology, mineral and skeletal disorders, abnormalities in other tissues, and response to treatment of hypophosphatemia were analyzed. Fractures, limb deformities, and scoliosis affected most CSHS subjects. Hypophosphatemia was not present at birth. Histology revealed severe osteomalacia but no other abnormalities. Skeletal dysplasia was reported in all anatomical compartments, though less frequently in the spine; there was no clear correlation between the location of nevi and the skeletal lesions. Phosphate and calcitriol supplementation was the most effective therapy for rickets. Convincing data that nevi removal improved blood phosphate levels was lacking. An age-dependent improvement in mineral abnormalities was observed. A spectrum of extra-osseous/extra-cutaneous manifestations that included both benign and malignant neoplasms was present in many subjects, though osteosarcoma remains unreported. An understanding of the spectrum, natural history, and efficacy of treatment of hypophosphatemia in CSHS may improve the care of these patients.

Ectopic Mineralization and Conductive Hearing Loss in Enpp1asj Mutant Mice, a New Model for Otitis Media and Tympanosclerosis.

PubMed

Tian, Cong; Harris, Belinda S; Johnson, Kenneth R

2016-01-01

Otitis media (OM), inflammation of the middle ear, is a common cause of hearing loss in children and in patients with many different syndromic diseases. Studies of the human population and mouse models have revealed that OM is a multifactorial disease with many environmental and genetic contributing factors. Here, we report on otitis media-related hearing loss in asj (ages with stiffened joints) mutant mice, which bear a point mutation in the Enpp1 gene. Auditory-evoked brainstem response (ABR) measurements revealed that around 90% of the mutant mice (Enpp1asj/asj) tested had moderate to severe hearing impairment in at least one ear. The ABR thresholds were variable and generally elevated with age. We found otitis media with effusion (OME) in all of the hearing-impaired Enpp1asj/asj mice by anatomic and histological examinations. The volume and inflammatory cell content of the effusion varied among the asj mutant mice, but all mutants exhibited a thickened middle ear epithelium with fibrous polyps and more mucin-secreting goblet cells than controls. Other abnormalities observed in the Enpp1 mutant mice include over-ossification at the round window ridge, thickened and over-calcified stapedial artery, fusion of malleus and incus, and white patches on the inside of tympanic membrane, some of which are typical symptoms of tympanosclerosis. An excessive yellow discharge was detected in the outer ear canal of older asj mutant mice, with 100% penetrance by 5 months of age, and contributes to the progressive nature of the hearing loss. This is the first report of hearing loss and ear pathology associated with an Enpp1 mutation in mice. The Enpp1asj mutant mouse provides a new animal model for studying tympanosclerotic otitis and otitis media with effusion, and also provides a specific model for the hearing loss recently reported to be associated with human ENPP1 mutations causing generalized arterial calcification of infancy and hypophosphatemic rickets.

Iron and fibroblast growth factor 23 in X-linked hypophosphatemia

PubMed Central

Imel, Erik A.; Gray, Amie; Padgett, Leah; Econs, Michael J.

2014-01-01

Background Excess fibroblast growth factor 23 (FGF23) causes hypophosphatemia in autosomal dominant hypophosphatemic rickets (ADHR) and X-linked hypophosphatemia (XLH). Iron status influences C-terminal FGF23 (incorporating fragments plus intact FGF23) in ADHR and healthy subjects, and intact FGF23 in ADHR. We hypothesized that in XLH serum iron would inversely correlate to C-terminal FGF23, but not to intact FGF23, mirroring the relationships in normal controls. Methods Subjects included 25 untreated outpatients with XLH at a tertiary medical center and 158 healthy adult controls. Serum iron and plasma intact FGF23 and C-terminal FGF23 were measured in stored samples. Results Intact FGF23 was greater than the control mean in 100% of XLH patients, and >2SD above the control mean in 88%, compared to 71% and 21% respectively for C-terminal FGF23. In XLH, iron correlated negatively to log-C-terminal FGF23 (r= −0.523, p<0.01), with a steeper slope than in controls (p<0.001). Iron was not related to log-intact FGF23 in either group. The log-ratio of intact FGF23 to C-terminal FGF23 was higher in XLH (0.00 ± 0.44) than controls (−0.28 ± 0.21, p<0.01), and correlated positively to serum iron (controls r= 0.276, p<0.001; XLH r= 0.428, p<0.05), with a steeper slope in XLH (p<0.01). Conclusion Like controls, serum iron in XLH is inversely related to C-terminal FGF23 but not intact FGF23. XLH patients are more likely to have elevated intact FGF23 than C-terminal FGF23. The relationships of iron to FGF23 in XLH suggest altered regulation of FGF23 cleaving may contribute to maintaining hypophosphatemia around an abnormal set-point. PMID:24325979

Treatment of X-Linked Hypophosphatemia with Calcitriol and Phosphate Increases Circulating Fibroblast Growth Factor 23 Concentrations

PubMed Central

Imel, Erik A.; DiMeglio, Linda A.; Hui, Siu L.; Carpenter, Thomas O.; Econs, Michael J.

2010-01-01

Context: X-Linked hypophosphatemia (XLH) is characterized by renal phosphate wasting, with inappropriately low or normal serum 1,25-dihydroxyvitamin D concentrations causing rickets and osteomalacia. Mutations in PHEX result in increased fibroblast growth factor 23 (FGF23) expression, elevating circulating FGF23 concentrations. Treating XLH with phosphate and calcitriol may further increase FGF23 concentrations, based on in vitro and in vivo models. Objective: The aim of the study was to investigate whether current standard XLH therapies increase circulating FGF23 concentrations. Design and Setting: We conducted a prospective observational study of XLH subjects during routine clinical management at two tertiary referral centers. Patients: The study included 10 XLH patients (seven children, three adults; age, 2–30 yr) initiating therapy and five XLH patients (age, 18–41 yr) electing not to undergo therapy. Intervention(s): Oral calcitriol and phosphate were administered. Main Outcome Measures: We measured circulating intact FGF23 concentrations. Results: Baseline circulating FGF23 concentrations were elevated in 14 of 15 subjects, increasing after treatment in most subjects. Follow-up was 14.4 ± 11.7 months (treatment cohort) and 25 ± 32 months (nontreatment cohort). FGF23 concentrations increased 132.7 ± 202.4% from pretreatment to peak during therapy but did not change significantly over time in the nontreatment cohort. FGF23 concentrations were related to phosphate doses (P = 0.04) and nonsignificantly to calcitriol doses (P = 0.06). Conclusions: Treating XLH with phosphate and calcitriol was associated with concurrent increases in circulating FGF23 concentrations, which may diminish therapeutic effect or contribute to complications of therapy. Because it is unknown whether the degree of FGF23 elevation correlates with disease severity in XLH, further study is needed to determine whether adjusting therapy to minimize effects on FGF23 concentration is warranted. PMID:20157195

FGF23 Neutralizing Antibody Ameliorates Hypophosphatemia and Impaired FGF Receptor Signaling in Kidneys of HMWFGF2 Transgenic Mice.

PubMed

Du, E; Xiao, L; Hurley, M M

2017-03-01

High molecular weight FGF2 transgenic mice (HMWTg) phenocopy the Hyp mouse, homolog of human X-linked hypophosphatemic rickets with phosphate wasting and abnormal fibroblast growth factor (FGF23), fibroblast growth factor receptor (FGFR), Klotho and mitogen activated protein kinases (MAPK) signaling in kidney. In this study, we assessed whether short-term (24 h) in vivo administration of FGF23 neutralizing antibody (FGF23Ab) could rescue hypophosphatemia and impaired FGFR signaling in kidneys of HMWTg male mice. Bone mineral density and bone mineral content in 1-month-old HMWTg mice were significantly reduced compared with Control/VectorTg mice. Serum FGF23 was significantly increased in HMWTg compared with VectorTg. Serum phosphate was significantly reduced in HMWTg and was rescued by FGF23Ab. Serum parathyroid hormone (PTH) was significantly increased in HMWTg but was not reduced by FGF23Ab. 1, 25(OH) 2 D was inappropriately normal in serum of HMWTg and was significantly increased in both Vector and HMWTg by FGF23Ab. Analysis of HMWTg kidneys revealed significantly increased mRNA expression of the FGF23 co-receptor Klotho, transcription factor mRNAs for early growth response-1 transcription factor (Egr-1), and c-fos were all significantly decreased by FGF23Ab. A significant reduction in the phosphate transporter Npt2a mRNA was also observed in HMWTg kidneys, which was increased by FGF23Ab. FGF23Ab reduced p-FGFR1, p-FGFR3, KLOTHO, p-ERK1/2, C-FOS, and increased NPT2A protein in HMWTg kidneys. We conclude that FGF23 blockade rescued hypophosphatemia by regulating FGF23/FGFR downstream signaling in HMWTg kidneys. Furthermore, HMWFGF2 isoforms regulate PTH expression independent of FGF23/FGFR signaling. J. Cell. Physiol. 232: 610-616, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Altered renal FGF23-mediated activity involving MAPK and Wnt: effects of the Hyp mutation.

PubMed

Farrow, Emily G; Summers, Lelia J; Schiavi, Susan C; McCormick, James A; Ellison, David H; White, Kenneth E

2010-10-01

Fibroblast growth factor-23 (FGF23), a hormone central to renal phosphate handling, is elevated in multiple hypophosphatemic disorders. Initial FGF23-dependent Erk1/2 activity in the kidney localizes to the distal convoluted tubule (DCT) with the co-receptor α-Klotho (KL), distinct from Npt2a in proximal tubules (PT). The Hyp mouse model of X-linked hypophosphatemic rickets (XLH) is characterized by hypophosphatemia with increased Fgf23, and patients with XLH elevate FGF23 following combination therapy of phosphate and calcitriol. The molecular signaling underlying renal FGF23 activity, and whether these pathways are altered in hypophosphatemic disorders, is unknown. To examine Npt2a in vivo, mice were injected with FGF23. Initial p-Erk1/2 activity in the DCT occurred within 10 min; however, Npt2a protein was latently reduced in the PT at 30-60  min, and was independent of Npt2a mRNA changes. KL-null mice had no DCT p-Erk1/2 staining following FGF23 delivery. Under basal conditions in Hyp mice, c-Fos and Egr1, markers of renal Fgf23 activity, were increased; however, KL mRNA was reduced 60% (P<0.05). Despite the prevailing hypophosphatemia and elevated Fgf23, FGF23 injections into Hyp mice activated p-Erk1/2 in the DCT. FGF23 injection also resulted in phospho-β-catenin (p-β-cat) co-localization with KL in wild-type mice, and Hyp mice demonstrated strong p-β-cat staining under basal conditions, indicating potential crosstalk between mitogen-activated protein kinase and Wnt signaling. Collectively, these studies refine the mechanisms for FGF23 bioactivity, and demonstrate novel suppression of Wnt signaling in a KL-dependent DCT-PT axis, which is likely altered in XLH. Finally, the current treatment of phosphate and calcitriol for hypophosphatemic disorders may increase FGF23 activity.

Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice.

PubMed

Sitara, Despina; Razzaque, Mohammed S; Hesse, Martina; Yoganathan, Subbiah; Taguchi, Takashi; Erben, Reinhold G; Jüppner, Harald; Lanske, Beate

2004-11-01

Fibroblast growth factor-23 (FGF-23), a recently identified molecule that is mutated in patients with autosomal dominant hypophosphatemic rickets (ADHR), appears to be involved in the regulation of phosphate homeostasis. Although increased levels of circulating FGF-23 were detected in patients with different phosphate-wasting disorders such as oncogenic osteomalacia (OOM) and X-linked hypophosphatemia (XLH), it is not yet clear whether FGF-23 is directly responsible for the abnormal regulation of mineral ion homeostasis and consequently bone development. To address some of these unresolved questions, we generated a mouse model, in which the entire Fgf-23 gene was replaced with the lacZ gene. Fgf-23 null (Fgf-23-/-) mice showed signs of growth retardation by day 17, developed severe hyperphosphatemia with elevated serum 1,25(OH)2D3 levels, and died by 13 weeks of age. Hyperphosphatemia in Fgf-23-/- mice was accompanied by skeletal abnormalities, as demonstrated by histological, molecular, and various other morphometric analyses. Fgf-23-/-) mice had increased total-body bone mineral content (BMC) but decreased bone mineral density (BMD) of the limbs. Overall, Fgf-23-/- mice exhibited increased mineralization, but also accumulation of unmineralized osteoid leading to marked limb deformities. Moreover, Fgf-23-/- mice showed excessive mineralization in soft tissues, including heart and kidney. To further expand our understanding regarding the role of Fgf-23 in phosphate homeostasis and skeletal mineralization, we crossed Fgf-23-/- animals with Hyp mice, the murine equivalent of XLH. Interestingly, Hyp males lacking both Fgf-23 alleles were indistinguishable from Fgf-23/-/ mice, both in terms of serum phosphate levels and skeletal changes, suggesting that Fgf-23 is upstream of the phosphate regulating gene with homologies to endopeptidases on the X chromosome (Phex) and that the increased plasma Fgf-23 levels in Hyp mice (and in XLH patients) may be at least partially responsible for the phosphate imbalance in this disorder.

Hypervitaminosis D mediates compensatory Ca2+ hyperabsorption in TRPV5 knockout mice.

PubMed

Renkema, Kirsten Y; Nijenhuis, Tom; van der Eerden, Bram C J; van der Kemp, Annemiete W C M; Weinans, Harrie; van Leeuwen, Johannes P T M; Bindels, René J M; Hoenderop, Joost G J

2005-11-01

Vitamin D plays an important role in Ca(2+) homeostasis by controlling Ca(2+) (re)absorption in intestine, kidney, and bone. The epithelial Ca(2+) channel TRPV5 mediates the Ca(2+) entry step in active Ca(2+) reabsorption. TRPV5 knockout (TRPV5(-/-)) mice show impaired Ca(2+) reabsorption, hypercalciuria, hypervitaminosis D, and intestinal hyperabsorption of Ca(2+). Moreover, these mice demonstrate upregulation of intestinal TRPV6 and calbindin-D(9K) expression compared with wild-type mice. For addressing the role of the observed hypervitaminosis D in the maintenance of Ca(2+) homeostasis and the regulation of expression levels of the Ca(2+) transport proteins in kidney and intestine, TRPV5/25-hydroxyvitamin-D(3)-1alpha-hydroxylase double knockout (TRPV5(-/-)/1alpha-OHase(-/-)) mice, which show undetectable serum 1,25(OH)(2)D(3) levels, were generated. TRPV5(-/-)/1alpha-OHase(-/-) mice displayed a significant hypocalcemia compared with wild-type mice (1.10 +/- 0.02 and 2.54 +/- 0.01 mM, respectively; P < 0.05). mRNA levels of renal calbindin-D(28K) (7 +/- 2%), calbindin-D(9K) (32 +/- 4%), Na(+)/Ca(2+) exchanger (12 +/- 2%), and intestinal TRPV6 (40 +/- 8%) and calbindin-D(9K) (26 +/- 4%) expression levels were decreased compared with wild-type mice. Hyperparathyroidism and rickets were present in TRPV5(-/-)/1alpha-OHase(-/-) mice, more pronounced than observed in single TRPV5 or 1alpha-OHase knockout mice. It is interesting that a renal Ca(2+) leak, as demonstrated in TRPV5(-/-) mice, persisted in TRPV5(-/-)/1alpha-OHase(-/-) mice, but a compensatory upregulation of intestinal Ca(2+) transporters was abolished. In conclusion, the elevation of serum 1,25(OH)(2)D(3) levels in TRPV5(-/-) mice is responsible for the upregulation of intestinal Ca(2+) transporters and Ca(2+) hyperabsorption. Hypervitaminosis D, therefore, is of crucial importance to maintain normocalcemia in impaired Ca(2+) reabsorption in TRPV5(-/-) mice.

Hypercalcemic Disorders in Children

PubMed Central

Stokes, Victoria J; Nielsen, Morten F; Hannan, Fadil M

2017-01-01

ABSTRACT Hypercalcemia is defined as a serum calcium concentration that is greater than two standard deviations above the normal mean, which in children may vary with age and sex, reflecting changes in the normal physiology at each developmental stage. Hypercalcemic disorders in children may present with hypotonia, poor feeding, vomiting, constipation, abdominal pain, lethargy, polyuria, dehydration, failure to thrive, and seizures. In severe cases renal failure, pancreatitis and reduced consciousness may also occur and older children and adolescents may present with psychiatric symptoms. The causes of hypercalcemia in children can be classified as parathyroid hormone (PTH)‐dependent or PTH‐independent, and may be congenital or acquired. PTH‐independent hypercalcemia, ie, hypercalcemia associated with a suppressed PTH, is commoner in children than PTH‐dependent hypercalcemia. Acquired causes of PTH‐independent hypercalcemia in children include hypervitaminosis; granulomatous disorders, and endocrinopathies. Congenital syndromes associated with PTH‐independent hypercalcemia include idiopathic infantile hypercalcemia (IIH), William's syndrome, and inborn errors of metabolism. PTH‐dependent hypercalcemia is usually caused by parathyroid tumors, which may give rise to primary hyperparathyroidism (PHPT) or tertiary hyperparathyroidism, which usually arises in association with chronic renal failure and in the treatment of hypophosphatemic rickets. Acquired causes of PTH‐dependent hypercalcemia in neonates include maternal hypocalcemia and extracorporeal membrane oxygenation. PHPT usually occurs as an isolated nonsyndromic and nonhereditary endocrinopathy, but may also occur as a hereditary hypercalcemic disorder such as familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, and familial isolated primary hyperparathyroidism, and less commonly, as part of inherited complex syndromic disorders such as multiple endocrine neoplasia (MEN). Advances in identifying the genetic causes have resulted in increased understanding of the underlying biological pathways and improvements in diagnosis. The management of symptomatic hypercalcemia includes interventions such as fluids, antiresorptive medications, and parathyroid surgery. This article presents a clinical, biochemical, and genetic approach to investigating the causes of pediatric hypercalcemia. © 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc. PMID:28914984

Hypercalcemic Disorders in Children.

PubMed

Stokes, Victoria J; Nielsen, Morten F; Hannan, Fadil M; Thakker, Rajesh V

2017-11-01

Hypercalcemia is defined as a serum calcium concentration that is greater than two standard deviations above the normal mean, which in children may vary with age and sex, reflecting changes in the normal physiology at each developmental stage. Hypercalcemic disorders in children may present with hypotonia, poor feeding, vomiting, constipation, abdominal pain, lethargy, polyuria, dehydration, failure to thrive, and seizures. In severe cases renal failure, pancreatitis and reduced consciousness may also occur and older children and adolescents may present with psychiatric symptoms. The causes of hypercalcemia in children can be classified as parathyroid hormone (PTH)-dependent or PTH-independent, and may be congenital or acquired. PTH-independent hypercalcemia, ie, hypercalcemia associated with a suppressed PTH, is commoner in children than PTH-dependent hypercalcemia. Acquired causes of PTH-independent hypercalcemia in children include hypervitaminosis; granulomatous disorders, and endocrinopathies. Congenital syndromes associated with PTH-independent hypercalcemia include idiopathic infantile hypercalcemia (IIH), William's syndrome, and inborn errors of metabolism. PTH-dependent hypercalcemia is usually caused by parathyroid tumors, which may give rise to primary hyperparathyroidism (PHPT) or tertiary hyperparathyroidism, which usually arises in association with chronic renal failure and in the treatment of hypophosphatemic rickets. Acquired causes of PTH-dependent hypercalcemia in neonates include maternal hypocalcemia and extracorporeal membrane oxygenation. PHPT usually occurs as an isolated nonsyndromic and nonhereditary endocrinopathy, but may also occur as a hereditary hypercalcemic disorder such as familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, and familial isolated primary hyperparathyroidism, and less commonly, as part of inherited complex syndromic disorders such as multiple endocrine neoplasia (MEN). Advances in identifying the genetic causes have resulted in increased understanding of the underlying biological pathways and improvements in diagnosis. The management of symptomatic hypercalcemia includes interventions such as fluids, antiresorptive medications, and parathyroid surgery. This article presents a clinical, biochemical, and genetic approach to investigating the causes of pediatric hypercalcemia. © 2017 American Society for Bone and Mineral Research. © 2017 American Society for Bone and Mineral Research.

Vitamin D levels in children with severe hemophilia A: an underappreciated deficiency.

PubMed

Albayrak, Canan; Albayrak, Davut

2015-04-01

Osteoporosis in hemophilic patients is a significant problem. The causes of osteoporosis in hemophilic patients are lack of adequate exercise, multiple hemorrhage and inflammation, and low vitamin D levels. The aim of this study was to retrospectively determine the frequency of vitamin D deficiency and insufficiency in children with severe hemophilia A. Forty-seven children with severe hemophilia were included in the study. None of the patients had previously received vitamin D supplementation. No patient had clinical or radiologic findings of rickets or seropositivity of hepatitis C virus or HIV. The mean age of the patients was 11.64 ± 5.70 (range, 2-18) years. The mean vitamin D level was 16.35 ± 7.49 ng/ml (range, 3.25-33.80). Vitamin D levels were below 10 ng/ml (severe vitamin D deficiency) in 9 cases (19%), between 10 and 19.99 ng/ml (vitamin D deficiency) in 23 cases (49%), between 20 and 29.99 ng/ml (vitamin D insufficiency) in 13 cases (28%), and above 30 ng/ml (normal vitamin D level) in 2 cases (4%). The mean serum levels of 25-hydroxy vitamin D in the children with hemophilia during winter and autumn were significantly lower than that during summer (P = 0.0028 and P = 0.0091, respectively). A majority of our hemophilic patients (96%) had low vitamin D levels. The study showed that the risk of vitamin D deficiency is the most highest during winter and autumn. Normal lifelong vitamin D levels are especially important in hemophilia because of the possible synergistic effect of vitamin D levels on periarticular and general osteoporosis, which is intrinsic to hemophilic conditions. We advise routine checking of vitamin D levels twice a year and vitamin D supplementation to maintain its level between 30 and 100 ng/ml.

Magnesium, vitamin D status and mortality: results from US National Health and Nutrition Examination Survey (NHANES) 2001 to 2006 and NHANES III

PubMed Central

2013-01-01

Background Magnesium plays an essential role in the synthesis and metabolism of vitamin D and magnesium supplementation substantially reversed the resistance to vitamin D treatment in patients with magnesium-dependent vitamin-D-resistant rickets. We hypothesized that dietary magnesium alone, particularly its interaction with vitamin D intake, contributes to serum 25-hydroxyvitamin D (25(OH)D) levels, and the associations between serum 25(OH)D and risk of mortality may be modified by magnesium intake level. Methods We tested these novel hypotheses utilizing data from the National Health and Nutrition Examination Survey (NHANES) 2001 to 2006, a population-based cross-sectional study, and the NHANES III cohort, a population-based cohort study. Serum 25(OH)D was used to define vitamin D status. Mortality outcomes in the NHANES III cohort were determined by using probabilistic linkage with the National Death Index (NDI). Results High intake of total, dietary or supplemental magnesium was independently associated with significantly reduced risks of vitamin D deficiency and insufficiency respectively. Intake of magnesium significantly interacted with intake of vitamin D in relation to risk of both vitamin D deficiency and insufficiency. Additionally, the inverse association between total magnesium intake and vitamin D insufficiency primarily appeared among populations at high risk of vitamin D insufficiency. Furthermore, the associations of serum 25(OH)D with mortality, particularly due to cardiovascular disease (CVD) and colorectal cancer, were modified by magnesium intake, and the inverse associations were primarily present among those with magnesium intake above the median. Conclusions Our preliminary findings indicate it is possible that magnesium intake alone or its interaction with vitamin D intake may contribute to vitamin D status. The associations between serum 25(OH)D and risk of mortality may be modified by the intake level of magnesium. Future studies, including cohort studies and clinical trials, are necessary to confirm the findings. PMID:23981518

Vitamin D Synthesis by UV Radiation: the Importance of Ozone Monitoring

NASA Astrophysics Data System (ADS)

Olds, W. J.; Moore, M. R.; Kimlin, M. G.

2006-12-01

The majority of humans rely on incidental sun exposure to maintain vitamin D sufficiency. Depending on where thresholds of vitamin D "sufficiency" are defined, it was recently stated that up to one billion people worldwide have suboptimal vitamin D levels (Bouillon, R., University of Leuven). Even in sunny southeast Queensland, the world's skin cancer capital, a 2006 study uncovered deficiency rates of up to 78% (at a threshold of 75 nmol/L of circulating 25-hydroxyvitamin D). Vitamin D regulates calcium absorption and inadequate levels are proven to result in osteomalacia, osteoporosis, rickets, bone pain and general skeletal weakness. Recent evidence also suggests vitamin D plays a preventative role in autoimmune diseases including numerous cancers, diabetes, schizophrenia, coronary heart disease, depression and other disorders. The most promising means of alleviating the worldwide burden of vitamin D deficiency seems to be by increased UV exposure. However, a much more mature understanding of UV exposures encountered in everyday life is required. This understanding is fundamentally founded in geophysics. UV exposures are strongly influenced by season/time of year, time of day, climate, location, pollution, aerosols and, importantly, ozone. In this work, we use computer simulations to obtain daily totals of vitamin D producing UV at numerous latitudes during one year. The ozone concentration is varied from 260 DU to 360 DU to determine the role of ozone variability on the ambient levels of vitamin D UV. Vitamin D synthesis is highly dependent on UVB. In our results, we demonstrate that this has important implications. Namely, vitamin D is strongly affected by ozone variability, since ozone filters UVB more strongly than UVA. Moreover, since erythema (sunburn) can occur at UVA wavelengths, ozone variation will more strongly affect vitamin D synthesis than erythema. Our results highlight that ozone monitoring is essential for understanding appropriate UV exposures for vitamin D health. We finally discuss implications for population health and how geophysics continues to play a vital role in addressing the widespread dilemma of vitamin D deficiency.

A mouse model with postnatal endolymphatic hydrops and hearing loss

PubMed Central

Megerian, Cliff A.; Semaan, Maroun T.; Aftab, Saba; Kisley, Lauren B.; Zheng, Qing Yin; Pawlowski, Karen S.; Wright, Charles G.; Alagramam, Kumar N.

2010-01-01

Endolymphatic hydrops (ELH), hearing loss and neuronal degeneration occur together in a variety of clinically significant disorders, including Meniere’s disease (MD). However, the sequence of these pathological changes and their relationship to each other are not well understood. In this regard, an animal model that spontaneously develops these features postnatally would be useful for research purposes. A search for such a model led us to the PhexHyp-Duk mouse, a mutant allele of the Phex gene causing X-linked hypophosphatemic rickets. The hemizygous male (PhexHyp-Duk/Y) was previously reported to exhibit various abnormalities during adulthood, including thickening of bone, ELH and hearing loss. The reported inner-ear phenotype was suggestive of progressive pathology and spontaneous development of ELH postnatally, but not conclusive. The main focuses of this report are to further characterize the inner ear phenotype in PhexHyp-Duk/Y mice and to test the hypotheses that (a) the PhexHyp-Duk/Y mouse develops ELH and hearing loss postnatally, and (b) the development of ELH in the PhexHyp-Duk/Y mouse is associated with obstruction of the endolymphatic duct (ED) due to thickening of the surrounding bone. Auditory brainstem response (ABR) recordings at various times points and histological analysis of representative temporal bones reveal that PhexHyp-Duk/Y mice typically develop adult onset, asymmetric, progressive hearing loss closely followed by the onset of ELH. ABR and histological data show that functional degeneration precedes structural degeneration. The major degenerative correlate of hearing loss and ELH in the mutants is the primary loss of spiral ganglion cells. Further, PhexHyp-Duk/Y mice develop ELH without evidence of ED obstruction, supporting the idea that ELH can be induced by a mechanism other than the blockade of longitudinal flow of endolymphatic fluid, and occlusion of ED is not a prerequisite for the development of ELH in patients. PMID:18289812

Impact of open manganese mines on the health of children dwelling in the surrounding area

PubMed Central

Duka, Ykateryna D.; Ilchenko, Svetlana I.; Kharytonov, Mykola M.; Vasylyeva, Tetyana L.

2011-01-01

Introduction: Chronic manganese (Mn) exposure is a health hazard associated with the mining and processing of Mn ores. Children living in an area with increased environmental exposure to Mn may have symptoms of chronic toxicity that are different from adults who experience occupational exposure. The aim of the study was to compare health outcomes in a pediatric population living near open Mn mines with a group of children from a reference area and then to develop and implement preventive/rehabilitation measures to protect the children in the mining region. Methods: After environmental assessment, a group of 683 children living in a Mn-rich region of Ukraine were screened by clinical evaluation, detection of sIgA (37 children), micronucleus analysis (56 children), and hair Mn content (166 children). Results: Impaired growth and rickets-like skeletal deformities were observed in 33% of the children. This was a significantly higher percentage than in children in the reference region (15%). The children from the Mn-mining region also had increased salivary levels of immunoglobulin A (104.4±14.2 mcg/ml vs. 49.7±6.1 mcg/ml among the controls (p<0.05), increased serum alpha 1 proteinase inhibitor levels (4.93±0.21 g/l compared with 2.91±0.22 g/l for controls; p<0.001) and greater numbers of micronuclei in the mucous cells of the oral cavity (0.070±0.008 vs. 0.012±0.009, p<0.001). Conclusions: These findings indicate the deleterious health consequences of living in a Mn-mining area. Medical rehabilitation programs were conducted and produced positive results, but further validation of their effectiveness is required. The study provided background information to formulate evidence-based decisions about public health in a region of high Mn exposure. PMID:24149028