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Sample records for hypomaturation amelogenesis imperfecta

  1. Mutations in the Beta Propeller WDR72 Cause Autosomal-Recessive Hypomaturation Amelogenesis Imperfecta

    PubMed Central

    El-Sayed, Walid; Parry, David A.; Shore, Roger C.; Ahmed, Mushtaq; Jafri, Hussain; Rashid, Yasmin; Al-Bahlani, Suhaila; Al Harasi, Sharifa; Kirkham, Jennifer; Inglehearn, Chris F.; Mighell, Alan J.

    2009-01-01

    Healthy dental enamel is the hardest and most highly mineralized human tissue. Though acellular, nonvital, and without capacity for turnover or repair, it can nevertheless last a lifetime. Amelogenesis imperfecta (AI) is a collective term for failure of normal enamel development, covering diverse clinical phenotypes that typically show Mendelian inheritance patterns. One subset, known as hypomaturation AI, is characterised by near-normal volumes of organic enamel matrix but with weak, creamy-brown opaque enamel that fails prematurely after tooth eruption. Mutations in genes critical to enamel matrix formation have been documented, but current understanding of other key events in enamel biomineralization is limited. We investigated autosomal-recessive hypomaturation AI in a consanguineous Pakistani family. A whole-genome SNP autozygosity screen identified a locus on chromosome 15q21.3. Sequencing candidate genes revealed a point mutation in the poorly characterized WDR72 gene. Screening of WDR72 in a panel of nine additional hypomaturation AI families revealed the same mutation in a second, apparently unrelated, Pakistani family and two further nonsense mutations in Omani families. Immunohistochemistry confirmed intracellular localization in maturation-stage ameloblasts. WDR72 function is unknown, but as a putative β propeller is expected to be a scaffold for protein-protein interactions. The nearest homolog, WDR7, is involved in vesicle mobilization and Ca2+-dependent exocytosis at synapses. Vesicle trafficking is important in maturation-stage ameloblasts with respect to secretion into immature enamel and removal of cleaved enamel matrix proteins via endocytosis. This raises the intriguing possibility that WDR72 is critical to ameloblast vesicle turnover during enamel maturation. PMID:19853237

  2. Genetics Home Reference: amelogenesis imperfecta

    MedlinePlus

    ... Amelogenesis imperfecta Encyclopedia: Tooth - Abnormal Colors Health Topic: Tooth Disorders Genetic and Rare Diseases Information Center (1 link) ... amelogenesis imperfecta Merck Manual Consumer Version: Overview of Tooth Disorders Orphanet: Amelogenesis imperfecta School of Dentistry, University of ...

  3. The mineral composition and enamel ultrastructure of hypocalcified amelogenesis imperfecta.

    PubMed

    Wright, J T; Duggal, M S; Robinson, C; Kirkham, J; Shore, R

    1993-01-01

    Hypocalcified amelogenesis imperfecta is characterized clinically by a yellow-brown colored enamel that is prone to severe attrition, often leading to rapid destruction of the crown. While the enamel is thought to be poorly mineralized few studies have evaluated the mineral content, or the histological or microradiographic features of this specific AI type. The purpose of this investigation was to examine teeth affected with autosomal dominant hypocalcified AI histologically using light microscopy (LM), scanning electron microscopy (SEM), and to evaluate the degree of enamel mineralization chemically and with microradiography. Four AI teeth were obtained from an affected individual for comparison with age-matched teeth from normal healthy individuals. Thin sections approximately 100 microns were cut with a diamond disc for examination by LM and microradiography. Using SEM, fractured enamel samples were examined either untreated or after removal of organic material using NaOCl or urea. Normal and AI enamel particles were dissected from thin sections to evaluate the mineral per volume and carbonate content. The enamel was not uniformly affected in all areas of the teeth with the lingual surfaces of the mandibular central incisors appearing clinically and histologically normal. The affected enamel was porous and appeared opaque with LM. Both SEM and LM showed the enamel to be prismatic with relatively normal prism morphology. However, the enamel crystallites were rough and granular compared with those of normal enamel. Extraction to remove organic material did not change the appearance of the crystallites indicating their granular appearance was due to mineral and not residual organic material such as enamel protein. Microradiography showed the enamel was less radiodense and therefore poorly mineralized compared with normal enamel. This was confirmed by chemical determination of the mineral per volume, which showed some areas of the AI enamel had as much as 30% less

  4. Treatment considerations for patient with Amelogenesis Imperfecta: a review

    PubMed Central

    Chen, Chiung-Fen; Hu, Jan CC; Bresciani, Eduardo; Peters, Mathilde C; Estrella, Maria Regina

    2016-01-01

    Objectives Amelogenesis imperfecta (AI) is a group of inherited disorders primary affecting the structural of enamel. Patients with AI experience poor esthetic, excessive tooth sensitivity and compromised chewing function that dental treatments are frequently required at early age. This review describes the non-enamel implications, stage-specific management strategies and outcomes of selected restorative materials based on literature evidence.

  5. Restoring Function and Aesthetics in a Class II Division 1 Patient with Amelogenesis Imperfecta: A Clinical Report

    PubMed Central

    Doruk, Cenk; Ozturk, Firat; Sari, Fatih; Turgut, Mehmet

    2011-01-01

    Amelogenesis imperfecta (AI) encompasses a complicated group of hereditary conditions that cause developmental alterations in the structure of the enamel in the absence of a systemic disorder. AI primarily affects the quality and/or quantity of dental enamel, and it may affect all or only some of the teeth in the primary and/or permanent dentition. This clinical report describes the oral rehabilitation of a 21-year-old man diagnosed with hypomaturation-type AI. He presented with discolored and mutilated teeth. Cephalometrically, the patient has skeletal class II malocclusion due to mandibular deficiency considered as a result of maxillary constriction. The interdisciplinary approach was followed because of the complex needs of the patient. The aim of treatment was to restore aesthetics, improve malocclusion and masticatory function. Aesthetic and functional expectations were met with metal ceramic restorations. In this report, the interdisciplinary approach for a patient with AI and a malocclusion is described. PMID:21494393

  6. Clinical and molecular analysis of the enamelin gene ENAM in Colombian families with autosomal dominant amelogenesis imperfecta

    PubMed Central

    Gutiérrez, Sandra; Torres, Diana; Briceño, Ignacio; Gómez, Ana Maria; Baquero, Eliana

    2012-01-01

    In this study, we analyzed the phenotype, clinical characteristics and presence of mutations in the enamelin gene ENAM in five Colombian families with autosomal dominant amelogenesis imperfecta (ADAI). 22 individuals (15 affected and seven unaffected) belonging to five Colombian families with ADAI and eight individuals (three affected and five unaffected) belonging to three Colombian families with autosomal recessive amelogenesis imperfecta (ARAI) that served as controls for molecular alterations and inheritance patterns were studied. Clinical, radiographic and genetic evaluations were done in all individuals. Eight exons and three intron-exon boundaries were sequenced for mutation analysis. Two of the five families with ADAI had the hypoplasic phenotype, two had the hypocalcified phenotype and one had the hypomaturative phenotype. Anterior open bite and mandibular retrognathism were the most frequent skeletal abnormalities in the families with ADAI. No mutations were found. These findings suggest that ADAI in these Colombian families was unrelated to previously described mutations in the ENAM gene. These results also indicate that other regions not included in this investigation, such as the promoter region, introns and other genes should be considered as potential ADAI candidates. PMID:23055792

  7. Deletion of ameloblastin exon 6 is associated with amelogenesis imperfecta.

    PubMed

    Poulter, James A; Murillo, Gina; Brookes, Steven J; Smith, Claire E L; Parry, David A; Silva, Sandra; Kirkham, Jennifer; Inglehearn, Chris F; Mighell, Alan J

    2014-10-15

    Amelogenesis imperfecta (AI) describes a heterogeneous group of inherited dental enamel defects reflecting failure of normal amelogenesis. Ameloblastin (AMBN) is the second most abundant enamel matrix protein expressed during amelogenesis. The pivotal role of AMBN in amelogenesis has been confirmed experimentally using mouse models. However, no AMBN mutations have been associated with human AI. Using autozygosity mapping and exome sequencing, we identified genomic deletion of AMBN exon 6 in a second cousin consanguineous family with three of the six children having hypoplastic AI. The genomic deletion corresponds to an in-frame deletion of 79 amino acids, shortening the protein from 447 to 368 residues. Exfoliated primary teeth (unmatched to genotype) were available from family members. The most severely affected had thin, aprismatic enamel (similar to that reported in mice homozygous for Ambn lacking exons 5 and 6). Other teeth exhibited thicker but largely aprismatic enamel. One tooth had apparently normal enamel. It has been suggested that AMBN may function in bone development. No clinically obvious bone or other co-segregating health problems were identified in the family investigated. This study confirms for the first time that AMBN mutations cause non-syndromic human AI and that mouse models with disrupted Ambn function are valid. PMID:24858907

  8. Distal renal tubular acidosis and amelogenesis imperfecta: A rare association.

    PubMed

    Ravi, P; Ekambaranath, T S; Arasi, S Ellil; Fernando, E

    2013-11-01

    Renal tubular acidosis (RTA) is characterized by a normal anion gap with hyperchloremic metabolic acidosis. Primary distal RTA (type I) is the most common RTA in children. Childhood presentation of distal RTA includes vomiting, failure to thrive, metabolic acidosis, and hypokalemia. Amelogenesis imperfecta (AI) represents a condition where the dental enamel and oral tissues are affected in an equal manner resulting in the hypoplastic or hypopigmented teeth. We report a 10-year-old girl, previously asymptomatic presented with the hypokalemic paralysis and on work-up found out to have type I RTA. The discoloration of teeth and enamel was diagnosed as AI. PMID:24339526

  9. LAMB3 mutations causing autosomal-dominant amelogenesis imperfecta.

    PubMed

    Kim, J W; Seymen, F; Lee, K E; Ko, J; Yildirim, M; Tuna, E B; Gencay, K; Shin, T J; Kyun, H K; Simmer, J P; Hu, J C-C

    2013-10-01

    Amelogenesis imperfecta (AI) can be either isolated or part of a larger syndrome. Junctional epidermolysis bullosa (JEB) is a collection of autosomal-recessive disorders featuring AI associated with skin fragility and other symptoms. JEB is a recessive syndrome usually caused by mutations in both alleles of COL17A1, LAMA3, LAMB3, or LAMC2. In rare cases, heterozygous carriers in JEB kindreds display enamel malformations in the absence of skin fragility (isolated AI). We recruited two kindreds with autosomal-dominant amelogenesis imperfecta (ADAI) characterized by generalized severe enamel hypoplasia with deep linear grooves and pits. Whole-exome sequencing of both probands identified novel heterozygous mutations in the last exon of LAMB3 that likely truncated the protein. The mutations perfectly segregated with the enamel defects in both families. In Family 1, an 8-bp deletion (c.3446_3453del GACTGGAG) shifted the reading frame (p.Gly 1149Glufs*8). In Family 2, a single nucleotide substitution (c.C3431A) generated an in-frame translation termination codon (p.Ser1144*). We conclude that enamel formation is particularly sensitive to defects in hemidesmosome/basement-membrane complexes and that syndromic and non-syndromic forms of AI can be etiologically related. PMID:23958762

  10. Amelogenesis imperfecta and anterior open bite: Etiological, classification, clinical and management interrelationships

    PubMed Central

    Alachioti, Xanthippi Sofia; Dimopoulou, Eleni; Vlasakidou, Anatoli; Athanasiou, Athanasios E

    2014-01-01

    Although amelogenesis imperfecta is not a common dental pathological condition, its etiological, classification, clinical and management aspects have been addressed extensively in the scientific literature. Of special clinical consideration is the frequent co-existence of amelogenesis imperfecta with the anterior open bite. This paper provides an updated review on amelogenesis imperfecta as well as anterior open bite, in general, and documents the association of these two separate entities, in particular. Diagnosis and treatment of amelogenesis imperfecta patients presenting also with anterior open bite require a lengthy, comprehensive and multidisciplinary approach, which should aim to successfully address all dental, occlusal, developmental, skeletal and soft tissue problems associated with these two serious clinical conditions. PMID:24987656

  11. Occurrence of epidermolysis bullosa along with Amelogenesis imperfecta in female patient of India

    PubMed Central

    Javed, A. P.; Shenai, Prashanth; Chatra, Laxmikanth; Veena, K. M.; Rao, Prasanna Kumar; Prabhu, Rachana

    2013-01-01

    Epidermolysis bullosa (EB) is an inherited disorder, which is characteristically presented as skin blisters developing in response to minor injury. Junctional variety of EB is also associated with enamel hypoplasia. Amelogenesis imperfecta presents with abnormal formation of the enamel both in deciduous and permanent dentition. This article describes a previously unreported case of Amelogenesis imperfecta with complete loss of enamel in a young female patient with EB. PMID:24379873

  12. Clinical findings and long-term managements of patients with amelogenesis imperfecta

    PubMed Central

    Koruyucu, Mine; Bayram, Merve; Tuna, Elif Bahar; Gencay, Koray; Seymen, Figen

    2014-01-01

    The aim of this clinical case series is to present a diagnosis and different treatment methods of patients in different ages with amelogenesis imperfecta (AI) as well as further treatments during a 3-6 years follow-up period. A number of 31 patients (16 female, 15 male with a mean age of 10.77 ± 2.65 years) with AI have been examined for the study group between 2007 and 2010 years. A detailed anamnesis was recorded, followed by a clinical and radiological assessment of oral health. The types of AI classified for each patient according to clinical and radiographic evaluation. The main complaints of patients, presence of dental caries and dental anomalies were noted. Necessary treatments had been planned for the individual cases of AI. A number of 19 patients had hypoplastic (HP) form, and 10 patients showed hypomaturation (HM) form of AI, while one patient showed hypocalcified form of AI and one patient had HM-HP form with taurodontism. Main complaints were chiefly related to dissatisfactory esthetics and dental sensitivity. Caries prevalence index was 93.5%. Mean decayed, missing, filling permanent teeth (DMF) and DMF surface (DMFS) were found as 2.74 ± 1.71 and 6.23 ± 3.99; df (decayed, filling primary teeth) and dfs (decayed, filling primary teeth surface) were found as 3.12 ± 2.85 and 5.24 ± 4.97, respectively. All patients received individual clinical care, including preventive, restorative, and prosthetic treatments. Patients have scheduled for regular follow-up in every 3 months. Composite restorations were used as the most common treatment (25 patients, 80.6%). The treatment plan should be based on patient's age, type of defects and individual needs of the patients. Necessary treatment plan is essential, not only due to functional and aesthetic reasons, but also for the positive psychological impact on young patients. PMID:25512739

  13. Amelogenesis Imperfecta, Facial Esthetics and Snap-On Smile.

    PubMed

    Wilson, Lee; Bradshaw, Jonathan P; Marks, Murray K

    2015-01-01

    Amelogenesis imperfecta is a hereditary enamel protein disorder affecting deciduous and secondary crown formation. The prevalence ranges from 1:700 to 1:14,000 depending on the population. These teeth may be hypoplastic, hypomineralized, or hypermineralized and are often discolored, sensitive and caries vulnerable. Patients often present with psychosocial issues due to appearance. Primary teeth are often treated with stainless steel crowns while secondary teeth are treated with full coverage esthetic crowns. The presenting preteen male here was fitted with Snap-On Smile? (www.snaponsmile.com). This treatment option provided cosmetic enhancement of the patient's appearance besides stabilization without altering the primary and secondary dentition during adolescent development. PMID:26433999

  14. Bilateral nephrocalcinosis and amelogenesis imperfecta: A case report

    PubMed Central

    Patel, Alok; Jagtap, Chetana; Bhat, Chetan; Shah, Rohan

    2015-01-01

    Amelogenesis imperfecta (AI) is a group of hereditary disorders that affect the quality and/or quantity of dental enamel. This paper describes the clinicopathological features of a patient who was born of nonconsanguineous parents and who presented with oral alterations, including yellow and misshapen teeth, intrapulpal calcifications, delayed tooth eruption, and gum enlargement. Scanning electron microscopy of the teeth revealed hypoplastic enamel, and a renal ultrasound detected bilateral nephrocalcinosis, leading to a diagnosis of AI and nephrocalcinosis syndrome. Since nephrocalcinosis is often asymptomatic and can be associated with impaired renal function, dentists who see children with a generalized and thin hypoplastic AI should consider a renal ultrasound scan and referral to a Nephrologist. Children with nephrocalcinosis should also be considered for a dental check. PMID:26097369

  15. Amelogenesis imperfecta - lifelong management. Restorative management of the adult patient.

    PubMed

    Patel, M; McDonnell, S T; Iram, S; Chan, M F W-Y

    2013-11-01

    The biggest challenge restorative dentists face in rehabilitating patients with amelogenesis imperfecta (AI) is trying to restore aesthetics, function and occlusal stability while keeping the treatment as conservative as possible. The goals of treatment should be to prolong the life of the patient's own teeth and avoid or delay the need for extractions and subsequent replacement with conventional fixed, removable or implant retained prostheses. In order to achieve these goals a stepwise approach to treatment planning is required starting with the most conservative but aesthetically acceptable treatment. This article discusses the management of AI and presents the various treatment options available for restoring the adult patient who presents to the dentist with AI. PMID:24201615

  16. Conservative esthetic rehabilitation of a young patient with amelogenesis imperfecta.

    PubMed

    Tunkiwala, Aliasger; Vazifdar, Danesh

    2014-03-01

    Conservative management of young adult patients with amelogenesis imperfecta using contemporary materials and techniques is needed in dentistry. These patients have malformed enamel that tends to wear down at a faster rate than normal and is prone to decay. Conventional management of such patients requires devitalization of all involved teeth, followed by post cores and crown lengthening and preparing them to provide sufficient space to receive full-coverage restorations. This article outlines a minimally invasive method of managing such cases. By increasing the vertical dimension of occlusion and using very minimal or no preparations and fabrication of lithium-disilicate crowns to adhesively bond to the remaining tooth structure, these teeth can be saved from being devitalized, as demonstrated in a case. This allows the structural integrity of the teeth to be maintained, along with their vitality. PMID:24773197

  17. Esthetic and functional rehabilitation of mutilated dentition and loss of vertical dimension due to amelogenesis imperfecta.

    PubMed

    Mittal, Shweta; Tewari, Sanjay; Goel, Rajat

    2014-04-01

    Cases of severe attrition are a common finding. Among the congenital anomalies, amelogenesis imperfecta and dentinogenesis imperfecta are important conditions that may cause accelerated wear of teeth. The following case report describes the complete oral rehabilitation of a patient diagnosed with amelogenesis imperfecta. A detailed treatment plan was chalked out which included proper oral hygiene measures, restoration of carious teeth and endodontic treatment followed by foundation restorations of teeth that were crucial for the final prostheses. Patient was given transitional restorations for about 6 weeks with the aim of regaining the lost vertical dimensions. Final rehabilitation was done by fixed dental prostheses. PMID:25565735

  18. Enamel renal syndrome with associated amelogenesis imperfecta, nephrolithiasis, and hypocitraturia: A case report.

    PubMed

    Bhesania, Dhvani; Arora, Ankit; Kapoor, Sonali

    2015-09-01

    Numerous cases of enamel renal syndrome have been previously reported. Various terms, such as enamel renal syndrome, amelogenesis imperfecta and gingival fibromatosis syndrome, and enamel-renal-gingival syndrome, have been used for patients presenting with the dental phenotype characteristic of this condition, nephrocalcinosis or nephrolithiasis, and gingival findings. This report describes a case of amelogenesis imperfecta of the enamel agenesis variety with nephrolithiasis in a 21-year-old male patient who complained of small teeth. The imaging modalities employed were conventional radiography, cone-beam computed tomography, and renal sonography. Such cases are first encountered by dentists, as other organ or metabolic diseases are generally hidden. Hence, cases of amelogenesis imperfecta should be subjected to advanced diagnostic modalities, incorporating both dental and medical criteria, in order to facilitate comprehensive long-term management. PMID:26389061

  19. Novel ITGB6 mutation in autosomal recessive amelogenesis imperfecta

    PubMed Central

    Seymen, F; Lee, K-E; Koruyucu, M; Gencay, K; Bayram, M; Tuna, EB; Lee, ZH; Kim, J-W

    2015-01-01

    Objective Hereditary defects in tooth enamel formation, amelogenesis imperfecta (AI), can be non-syndromic or syndromic phenotype. Integrins are signaling proteins that mediate cell–cell and cell–extracellular matrix communication, and their involvement in tooth development is well known. The purposes of this study were to identify genetic cause of an AI family and molecular pathogenesis underlying defective enamel formation. Materials and Methods We recruited a Turkish family with isolated AI and performed mutational analyses to clarify the underlying molecular genetic etiology. Results Autozygosity mapping and exome sequencing identified a novel homozygous ITGB6 transversion mutation in exon 4 (c.517G>C, p.Gly173Arg). The glycine at this position in the middle of the βI-domain is conserved among a wide range of vertebrate orthologs and human paralogs. Clinically, the enamel was generally thin and pitted with pigmentation. Thicker enamel was noted at the cervical area of the molars. Conclusions In this study, we identified a novel homozygous ITGB6 mutation causing isolated AI, and this advances the understanding of normal and pathologic enamel development. PMID:25431241

  20. A historical case of amelogenesis imperfecta: Giovanna of Austria, Grand Duchess of Tuscany (1547-1578).

    PubMed

    Giuffra, Valentina; Panetta, Daniele; Salvadori, Piero A; Fornaciari, Gino

    2014-02-01

    The skeletal remains of Giovanna of Austria (1547-1578), daughter of the Emperor Ferdinand I of Habsburg (1503-1564) and first wife of the Grand Duke of Tuscany, Francesco I (1541-1587), exhumed from the Basilica of San Lorenzo in Florence, were submitted to paleopathological study. Examination of the dentition, which was in a good state of preservation, showed maxillary retrognathism, together with a caries lesion, moderate periodontal disease, malposition of the upper second premolars and tooth wear. Furthermore, several horizontal grooves were observed in both the buccal and the lingual crown surfaces of almost all teeth, especially the anterior ones. The orthopantomogram showed hypomineralized enamel and alveolar bone loss. Two third-molar teeth were investigated using micro-computed tomography (micro-CT) analysis, revealing highly irregular enamel caps with reduced average thickness. The observed features suggest a diagnosis of hypoplastic amelogenesis imperfecta, a developmental condition affecting enamel formation. PMID:24405030

  1. Novel ENAM and LAMB3 Mutations in Chinese Families with Hypoplastic Amelogenesis Imperfecta

    PubMed Central

    Wang, Xin; Zhao, Yuming; Yang, Yuan; Qin, Man

    2015-01-01

    Amelogenesis imperfecta is a group of inherited diseases affecting the quality and quantity of dental enamel. To date, mutations in more than ten genes have been associated with non-syndromic amelogenesis imperfecta (AI). Among these, ENAM and LAMB3 mutations are known to be parts of the etiology of hypoplastic AI in human cases. When both alleles of LAMB3 are defective, it could cause junctional epidermolysis bullosa (JEB), while with only one mutant allele in the C-terminus of LAMB3, it could result in severe hypoplastic AI without skin fragility. We enrolled three Chinese families with hypoplastic autosomal-dominant AI. Despite the diagnosis falling into the same type, the characteristics of their enamel hypoplasia were different. Screening of ENAM and LAMB3 genes was performed by direct sequencing of genomic DNA from blood samples. Disease-causing mutations were identified and perfectly segregated with the enamel defects in three families: a 19-bp insertion mutation in the exon 7 of ENAM (c.406_407insTCAAAAAAGCCGACCACAA, p.K136Ifs*16) in Family 1, a single-base deletion mutation in the exon 5 of ENAM (c. 139delA, p. M47Cfs*11) in Family 2, and a LAMB3 nonsense mutation in the last exon (c.3466C>T, p.Q1156X) in Family 3. Our results suggest that heterozygous mutations in ENAM and LAMB3 genes can cause hypoplastic AI with markedly different phenotypes in Chinese patients. And these findings extend the mutation spectrum of both genes and can be used for mutation screening of AI in the Chinese population. PMID:25769099

  2. Rehabilitation of a patient with amelogenesis imperfecta using porcelain veneers and CAD/CAM polymer restorations: A clinical report.

    PubMed

    Saeidi Pour, Reza; Edelhoff, Daniel; Prandtner, Otto; Liebermann, Anja

    2015-01-01

    The complete dental rehabilitation of patients with a vertical dimension loss (VDL) caused by structural enamel deficits associated with amelogenesis imperfecta (AI) represents a difficult challenge for restorative teams. Accurate analysis and treatment planning that includes esthetic and functional evaluations and adequate material selection are important prerequisites for successful results. Long-term provisional restorations play an important role in exploring and elucidating the patients' esthetic demands and functional needs. Restorative treatment options can vary from requiring only oral hygiene instructions to extensive dental restorations that include composite fillings, ceramic veneers, metal-ceramic, or all-ceramic crowns. This case report describes a full-mouth rehabilitation of a patient with amelogenesis imperfecta including the case planning, bite replacement, preparation, and restoration setting steps with an experimental CAD/CAM polymer and porcelain veneers. PMID:26345104

  3. Amelogenesis imperfecta

    MedlinePlus

    ... is low in sugar and practicing very good oral hygiene can reduce the chance of developing cavities. Outlook (Prognosis) Treatment is often successful in protecting the teeth. ... by: Ilona Fotek, DMD, MS, Palm Beach Prosthodontics Dental Associates, West Palm Beach, FL. Review provided by ...

  4. Simple recessive mutation in ENAM is associated with amelogenesis imperfecta in Italian Greyhounds.

    PubMed

    Gandolfi, Barbara; Liu, Hongwei; Griffioen, Layle; Pedersen, Niels C

    2013-08-01

    We report a familial enamel hypoplasia in Italian Greyhounds resembling non-syndromic autosomal recessive amelogenesis imperfecta (AI) of humans. The condition uniformly affects deciduous and permanent teeth and is manifested by enamel roughening/thinning and brownish mottling. Affected teeth are often small and pointed with increased gaps. However, basic tooth structure is usually maintained throughout life, and fractures and dental cavities are not a serious problem as in humans. No tissues or organs other than teeth were affected by this mutation, and there was no relationship between enamel hypoplasia and either autoimmunity or periodontal disease, which also are prevalent in the breed. The enamel hypoplasia was associated with a 5-bp deletion in exon 10 of the enamelin (ENAM) gene. The prevalence of the enamel defect in Italian Greyhounds was 14%, and 30% of dogs with normal teeth were carriers. Genome analyses suggest that the trait is under inadvertent positive selection. Based on the deletion detected in the ENAM gene, a genetic test was developed for identifying mutation carriers, which would enable breeders to manage the trait. PMID:23638899

  5. Aesthetic and functional rehabilitation of the primary dentition affected by amelogenesis imperfecta.

    PubMed

    Marquezin, Maria Carolina Salomé; Zancopé, Bruna Raquel; Pacheco, Larissa Ferreira; Gavião, Maria Beatriz Duarte; Pascon, Fernanda Miori

    2015-01-01

    The objective of this case report was to describe the oral rehabilitation of a five-year-old boy patient diagnosed with amelogenesis imperfecta (AI) in the primary dentition. AI is a group of hereditary disorders that affects the enamel structure. The patient was brought to the dental clinic complaining of tooth hypersensitivity during meals. The medical history and clinical examination were used to arrive at the diagnosis of AI. The treatment was oral rehabilitation of the primary molars with stainless steel crowns and resin-filled celluloid forms. The main objectives of the selected treatment were to enhance the esthetics, restore masticatory function, and eliminate the teeth sensitivity. The child was monitored in the pediatric dentistry clinic at four-month intervals until the mixed dentition stage. Treatment not only restored function and esthetic, but also showed a positive psychological impact and thereby improved perceived quality of life. The preventive, psychological, and curative measures of a young child with AI were successful. This result can encourage the clinicians to seek a cost-effective technique such as stainless steel crowns, and resin-filled celluloid forms to reestablish the oral functions and improve the child's psychosocial development. PMID:25705526

  6. Aesthetic and Functional Rehabilitation of the Primary Dentition Affected by Amelogenesis Imperfecta

    PubMed Central

    Marquezin, Maria Carolina Salomé; Zancopé, Bruna Raquel; Pacheco, Larissa Ferreira; Gavião, Maria Beatriz Duarte; Pascon, Fernanda Miori

    2015-01-01

    The objective of this case report was to describe the oral rehabilitation of a five-year-old boy patient diagnosed with amelogenesis imperfecta (AI) in the primary dentition. AI is a group of hereditary disorders that affects the enamel structure. The patient was brought to the dental clinic complaining of tooth hypersensitivity during meals. The medical history and clinical examination were used to arrive at the diagnosis of AI. The treatment was oral rehabilitation of the primary molars with stainless steel crowns and resin-filled celluloid forms. The main objectives of the selected treatment were to enhance the esthetics, restore masticatory function, and eliminate the teeth sensitivity. The child was monitored in the pediatric dentistry clinic at four-month intervals until the mixed dentition stage. Treatment not only restored function and esthetic, but also showed a positive psychological impact and thereby improved perceived quality of life. The preventive, psychological, and curative measures of a young child with AI were successful. This result can encourage the clinicians to seek a cost-effective technique such as stainless steel crowns, and resin-filled celluloid forms to reestablish the oral functions and improve the child's psychosocial development. PMID:25705526

  7. Amelogenesis Imperfecta: Rehabilitation and Brainstorming on the Treatment Outcome after the First Year.

    PubMed

    İzgi, Ayça Deniz; Kale, Ediz; Niğiz, Remzi

    2015-01-01

    Amelogenesis imperfecta (AI) affects enamel on primary and permanent dentition. This hereditary disorder is characterized by loss of enamel, poor esthetics, and hypersensitivity. Functional and cosmetic rehabilitation is challenging with variety of treatment options. This report presents the treatment of an AI patient using conventional fixed dentures and discusses issues related to posttreatment complications and prosthetic treatment outcome after 1 year of follow-up. A 19-year-old male AI patient with impaired self-esteem presented with hypersensitive, discolored, and mutilated teeth. Clinical examination revealed compromised occlusion and anterior open-bite. After hygiene maintenance full-coverage porcelain-fused-to-metal fixed restorations were indicated and applied. At the end of the treatment acceptable functional and esthetic results could be achieved. However, nearly a year after treatment a gingival inflammation in the esthetic zone complicated the outcome. Insufficient oral hygiene was to be blamed. Tooth sensitivity present from early childhood in these patients may prevent oral hygiene from becoming a habit. The relaxation due to relieve of hypersensitivity after treatment makes oral hygiene learning difficult. Continuous oral hygiene maintenance motivation may be crucial for the success of the treatment of AI patients. Treatment of AI patients should be carefully planned and an acceptable risk-benefit balance should be established. PMID:26783475

  8. Multidisciplinary Approach for Restoring Function and Esthetics in a Patient with Amelogenesis Imperfecta: A Clinical Report

    PubMed Central

    Kamble, Vaibhav D; Parkhedkar, Rambhau D

    2013-01-01

    Amelogenesis Imperfecta (AI) is a genetically determined and enamel mineralization defect reported, depicted as “Hereditary brown teeth.” AI is characterized as a clinical entity and its clinical manifestations, histological appearance, and genetic pattern are characterized by their heterogeneity. The need for prosthodontic management of this group of patients varies. Some patients need oral hygiene instructions only, whereas others need extensive dental treatment that includes composite restorations, metal ceramic crowns, all ceramic crowns, porcelain veneers. A 20-year-old male patient presented with sensitive, discoloured, and mutilated teeth, with a decreased vertical dimension of occlusion. The 4-year recall examination revealed no pathology associated with the full mouth rehabilitation, and the patient’s aesthetic and functional expectations were satisfied. The rehabilitation included all-ceramic crowns on anterior teeth and metal-ceramic crowns on posterior teeth following endodontic treatment and a crown-lengthening procedure for eliminating tooth sensitivity, improving the aesthetics and occlusion, and for restoring function. PMID:24551735

  9. Amelogenesis Imperfecta: Rehabilitation and Brainstorming on the Treatment Outcome after the First Year

    PubMed Central

    İzgi, Ayça Deniz; Kale, Ediz; Niğiz, Remzi

    2015-01-01

    Amelogenesis imperfecta (AI) affects enamel on primary and permanent dentition. This hereditary disorder is characterized by loss of enamel, poor esthetics, and hypersensitivity. Functional and cosmetic rehabilitation is challenging with variety of treatment options. This report presents the treatment of an AI patient using conventional fixed dentures and discusses issues related to posttreatment complications and prosthetic treatment outcome after 1 year of follow-up. A 19-year-old male AI patient with impaired self-esteem presented with hypersensitive, discolored, and mutilated teeth. Clinical examination revealed compromised occlusion and anterior open-bite. After hygiene maintenance full-coverage porcelain-fused-to-metal fixed restorations were indicated and applied. At the end of the treatment acceptable functional and esthetic results could be achieved. However, nearly a year after treatment a gingival inflammation in the esthetic zone complicated the outcome. Insufficient oral hygiene was to be blamed. Tooth sensitivity present from early childhood in these patients may prevent oral hygiene from becoming a habit. The relaxation due to relieve of hypersensitivity after treatment makes oral hygiene learning difficult. Continuous oral hygiene maintenance motivation may be crucial for the success of the treatment of AI patients. Treatment of AI patients should be carefully planned and an acceptable risk-benefit balance should be established. PMID:26783475

  10. Phenotype-Genotype Correlations in Mouse Models of Amelogenesis Imperfecta Caused by Amelx and Enam Mutations

    PubMed Central

    Coxon, Thomas Liam; Brook, Alan Henry; Barron, Martin John; Smith, Richard Nigel

    2012-01-01

    Mutations in human and in mouse orthologous genes Amelx and Enam result in a diverse range of enamel defects. In this study we aimed to investigate the phenotype-genotype correlation between the mutants and the wild-type controls in mouse models of amelogenesis imperfecta using novel measurement approaches. Ten hemi-mandibles and incisors were dissected from each group of AmelxWT, AmelxX/Y64H, AmelxY/Y64H, AmelxY64H/Y64H, and EnamWT, EnamRgsc395 heterozygous and EnamRgsc395 homozygous mice. Their macro-morphology, colour and micro-topography were assessed using bespoke 2D and 3D image analysis systems and customized colour and whiteness algorithms. The novel methods identified significant differences (p ≤ 0.05) between the Amelx groups for mandible and incisor size and enamel colour and between the Enam groups for incisor size and enamel colour. The AmelxWT mice had the largest mandibles and incisors, followed in descending order of size by the AmelxX/Y64H, AmelxY/Y64H and AmelxY64H/Y64H mice. Within the Enam groups the EnamWT incisors were largest and the EnamRgsc395 heterozygous mice were smallest. The effect on tooth morphology was also reflected by the severity of the enamel defects in the colour and whiteness assessment. Amelogenin affected mandible morphology and incisor enamel formation, while enamelin only affected incisors, supporting the multifunctional role of amelogenin. The enamelin mutation was associated with earlier forming enamel defects. The study supported the critical involvement of amelogenin and enamelin in enamel mineralization. PMID:22759786

  11. Abrogation of epithelial BMP2 and BMP4 causes Amelogenesis Imperfecta by reducing MMP20 and KLK4 expression

    PubMed Central

    Xie, Xiaohua; Liu, Chao; Zhang, Hua; Jani, Priyam H.; Lu, Yongbo; Wang, Xiaofang; Zhang, Bin; Qin, Chunlin

    2016-01-01

    Amelogenesis Imperfecta (AI) can be caused by the deficiencies of enamel matrix proteins, molecules responsible for the transportation and secretion of enamel matrix components, and proteases processing enamel matrix proteins. In the present study, we discovered the double deletion of bone morphogenetic protein 2 (Bmp2) and bone morphogenetic protein 4 (Bmp4) in the dental epithelium by K14-cre resulted in hypoplastic enamel and reduced density in X-ray radiography as well as shortened enamel rods under scanning electron microscopy. Such enamel phenotype was consistent with the diagnosis of hypoplastic amelogenesis imperfecta. Histological and molecular analyses revealed that the removal of matrix proteins in the mutant enamel was drastically delayed, which was coincided with the greatly reduced expression of matrix metalloproteinase 20 (MMP20) and kallikrein 4 (KLK4). Although the expression of multiple enamel matrix proteins was down-regulated in the mutant ameloblasts, the cleavage of ameloblastin was drastically impaired. Therefore, we attributed the AI primarily to the reduction of MMP20 and KLK4. Further investigation found that BMP/Smad4 signaling pathway was down-regulated in the K14-cre;Bmp2f/f;Bmp4f/fameloblasts, suggesting that the reduced MMP20 and KLK4 expression may be due to the attenuated epithelial BMP/Smad4 signaling. PMID:27146352

  12. Abrogation of epithelial BMP2 and BMP4 causes Amelogenesis Imperfecta by reducing MMP20 and KLK4 expression.

    PubMed

    Xie, Xiaohua; Liu, Chao; Zhang, Hua; Jani, Priyam H; Lu, Yongbo; Wang, Xiaofang; Zhang, Bin; Qin, Chunlin

    2016-01-01

    Amelogenesis Imperfecta (AI) can be caused by the deficiencies of enamel matrix proteins, molecules responsible for the transportation and secretion of enamel matrix components, and proteases processing enamel matrix proteins. In the present study, we discovered the double deletion of bone morphogenetic protein 2 (Bmp2) and bone morphogenetic protein 4 (Bmp4) in the dental epithelium by K14-cre resulted in hypoplastic enamel and reduced density in X-ray radiography as well as shortened enamel rods under scanning electron microscopy. Such enamel phenotype was consistent with the diagnosis of hypoplastic amelogenesis imperfecta. Histological and molecular analyses revealed that the removal of matrix proteins in the mutant enamel was drastically delayed, which was coincided with the greatly reduced expression of matrix metalloproteinase 20 (MMP20) and kallikrein 4 (KLK4). Although the expression of multiple enamel matrix proteins was down-regulated in the mutant ameloblasts, the cleavage of ameloblastin was drastically impaired. Therefore, we attributed the AI primarily to the reduction of MMP20 and KLK4. Further investigation found that BMP/Smad4 signaling pathway was down-regulated in the K14-cre;Bmp2(f/f);Bmp4(f/f)ameloblasts, suggesting that the reduced MMP20 and KLK4 expression may be due to the attenuated epithelial BMP/Smad4 signaling. PMID:27146352

  13. Interdisciplinary Full Mouth Rehabilitation of a Patient with Amelogenesis Imperfecta: A Case Report with 8 Years Follow-up.

    PubMed

    Sreedevi, S; Sanjeev, R; Ephraim, Rena; Joseph, Mathai

    2014-01-01

    This case report deals with the interdisciplinary approach of a 28-year-old lady with Amelogenesis imperfecta of the hypoplastic kind. The patient came with a chief illness of worn out teeth, unsatisfactory esthetics and severe sensitivity of teeth. Her family history revealed a related situation in her father's brother and her sister. On clinical assessment, the crowns of all teeth were worn out. The plan of the treatment was to protect as much tooth structure, restore the vertical dimension, and improve esthetics and masticatory function. The treatment procedures involved prosthodontic, endodontic, and periodontic interventions. After recording the vertical height, endodontic treatment and crown lengthening were performed with respect to the lower anteriors. The lost vertical height was regained in stages by insertion of full coverage crowns for all the teeth. The patient's esthetic and functional needs were met with systematic and sequential interdisciplinary treatment approach. PMID:25628493

  14. Amelogenin signal peptide mutation: Correlation between mutations in the amelogenin gene (AMGX) and manifestations of X-linked amelogenesis imperfecta

    SciTech Connect

    Lagerstroem-Fermer, M.; Nilsson, M.; Pettersson, U.

    1995-03-01

    Formation of tooth enamel is a poorly understood biological process. In this study the authors describe a 9-bp deletion in exon 2 of the amelogenin gene (AMGX) causing X-linked hypoplastic amelogenesis imperfecta, a disease characterized by defective enamel. The mutation results in the loss of 3 amino acids and exchange of 1 in the signal peptide of the amelogenin protein. This deletion in the signal peptide probably interferes with translocation of the amelogenin protein during synthesis, resulting in the thin enamel observed in affected members of the family. The authors compare this mutation to a previously reported mutation in the amelogenin gene that causes a different disease phenotype. The study illustrates that molecular analysis can help explain the various manifestations of a tooth disorder and thereby provide insights into the mechanisms of tooth enamel formation. 16 refs., 2 figs., 1 tab.

  15. Mutations in the latent TGF-beta binding protein 3 (LTBP3) gene cause brachyolmia with amelogenesis imperfecta.

    PubMed

    Huckert, Mathilde; Stoetzel, Corinne; Morkmued, Supawich; Laugel-Haushalter, Virginie; Geoffroy, Véronique; Muller, Jean; Clauss, François; Prasad, Megana K; Obry, Frédéric; Raymond, Jean Louis; Switala, Marzena; Alembik, Yves; Soskin, Sylvie; Mathieu, Eric; Hemmerlé, Joseph; Weickert, Jean-Luc; Dabovic, Branka Brukner; Rifkin, Daniel B; Dheedene, Annelies; Boudin, Eveline; Caluseriu, Oana; Cholette, Marie-Claude; Mcleod, Ross; Antequera, Reynaldo; Gellé, Marie-Paule; Coeuriot, Jean-Louis; Jacquelin, Louis-Frédéric; Bailleul-Forestier, Isabelle; Manière, Marie-Cécile; Van Hul, Wim; Bertola, Debora; Dollé, Pascal; Verloes, Alain; Mortier, Geert; Dollfus, Hélène; Bloch-Zupan, Agnès

    2015-06-01

    Inherited dental malformations constitute a clinically and genetically heterogeneous group of disorders. Here, we report on four families, three of them consanguineous, with an identical phenotype, characterized by significant short stature with brachyolmia and hypoplastic amelogenesis imperfecta (AI) with almost absent enamel. This phenotype was first described in 1996 by Verloes et al. as an autosomal recessive form of brachyolmia associated with AI. Whole-exome sequencing resulted in the identification of recessive hypomorphic mutations including deletion, nonsense and splice mutations, in the LTBP3 gene, which is involved in the TGF-beta signaling pathway. We further investigated gene expression during mouse development and tooth formation. Differentiated ameloblasts synthesizing enamel matrix proteins and odontoblasts expressed the gene. Study of an available knockout mouse model showed that the mutant mice displayed very thin to absent enamel in both incisors and molars, hereby recapitulating the AI phenotype in the human disorder. PMID:25669657

  16. Mutations in the latent TGF-beta binding protein 3 (LTBP3) gene cause brachyolmia with amelogenesis imperfecta

    PubMed Central

    Huckert, Mathilde; Stoetzel, Corinne; Morkmued, Supawich; Laugel-Haushalter, Virginie; Geoffroy, Véronique; Muller, Jean; Clauss, François; Prasad, Megana K.; Obry, Frédéric; Raymond, Jean Louis; Switala, Marzena; Alembik, Yves; Soskin, Sylvie; Mathieu, Eric; Hemmerlé, Joseph; Weickert, Jean-Luc; Dabovic, Branka Brukner; Rifkin, Daniel B.; Dheedene, Annelies; Boudin, Eveline; Caluseriu, Oana; Cholette, Marie-Claude; Mcleod, Ross; Antequera, Reynaldo; Gellé, Marie-Paule; Coeuriot, Jean-Louis; Jacquelin, Louis-Frédéric; Bailleul-Forestier, Isabelle; Manière, Marie-Cécile; Van Hul, Wim; Bertola, Debora; Dollé, Pascal; Verloes, Alain; Mortier, Geert; Dollfus, Hélène; Bloch-Zupan, Agnès

    2015-01-01

    Inherited dental malformations constitute a clinically and genetically heterogeneous group of disorders. Here, we report on four families, three of them consanguineous, with an identical phenotype, characterized by significant short stature with brachyolmia and hypoplastic amelogenesis imperfecta (AI) with almost absent enamel. This phenotype was first described in 1996 by Verloes et al. as an autosomal recessive form of brachyolmia associated with AI. Whole-exome sequencing resulted in the identification of recessive hypomorphic mutations including deletion, nonsense and splice mutations, in the LTBP3 gene, which is involved in the TGF-beta signaling pathway. We further investigated gene expression during mouse development and tooth formation. Differentiated ameloblasts synthesizing enamel matrix proteins and odontoblasts expressed the gene. Study of an available knockout mouse model showed that the mutant mice displayed very thin to absent enamel in both incisors and molars, hereby recapitulating the AI phenotype in the human disorder. PMID:25669657

  17. Loss of epithelial FAM20A in mice causes amelogenesis imperfecta, tooth eruption delay and gingival overgrowth.

    PubMed

    Li, Li-Li; Liu, Pei-Hong; Xie, Xiao-Hua; Ma, Su; Liu, Chao; Chen, Li; Qin, Chun-Lin

    2016-01-01

    FAM20A has been studied to a very limited extent. Mutations in human FAM20A cause amelogenesis imperfecta, gingival fibromatosis and kidney problems. It would be desirable to systemically analyse the expression of FAM20A in dental tissues and to assess the pathological changes when this molecule is specifically nullified in individual tissues. Recently, we generated mice with a Fam20A-floxed allele containing the beta-galactosidase reporter gene. We analysed FAM20A expression in dental tissues using X-Gal staining, immunohistochemistry and in situ hybridization, which showed that the ameloblasts in the mouse mandibular first molar began to express FAM20A at 1 day after birth, and the reduced enamel epithelium in erupting molars expressed a significant level of FAM20A. By breeding K14-Cre mice with Fam20A(flox/flox) mice, we created K14-Cre;Fam20A(flox/flox) (conditional knock out, cKO) mice, in which Fam20A was inactivated in the epithelium. We analysed the dental tissues of cKO mice using X-ray radiography, histology and immunohistochemistry. The molar enamel matrix in cKO mice was much thinner than normal and was often separated from the dentinoenamel junction. The Fam20A-deficient ameloblasts were non-polarized and disorganized and were detached from the enamel matrix. The enamel abnormality in cKO mice was consistent with the diagnosis of amelogenesis imperfecta. The levels of enamelin and matrix metalloproteinase 20 were lower in the ameloblasts and enamel of cKO mice than the normal mice. The cKO mice had remarkable delays in the eruption of molars and hyperplasia of the gingival epithelium. The findings emphasize the essential roles of FAM20A in the development of dental and oral tissues. PMID:27281036

  18. Loss of epithelial FAM20A in mice causes amelogenesis imperfecta, tooth eruption delay and gingival overgrowth

    PubMed Central

    Li, Li-Li; Liu, Pei-Hong; Xie, Xiao-Hua; Ma, Su; Liu, Chao; Chen, Li; Qin, Chun-Lin

    2016-01-01

    FAM20A has been studied to a very limited extent. Mutations in human FAM20A cause amelogenesis imperfecta, gingival fibromatosis and kidney problems. It would be desirable to systemically analyse the expression of FAM20A in dental tissues and to assess the pathological changes when this molecule is specifically nullified in individual tissues. Recently, we generated mice with a Fam20A-floxed allele containing the beta-galactosidase reporter gene. We analysed FAM20A expression in dental tissues using X-Gal staining, immunohistochemistry and in situ hybridization, which showed that the ameloblasts in the mouse mandibular first molar began to express FAM20A at 1 day after birth, and the reduced enamel epithelium in erupting molars expressed a significant level of FAM20A. By breeding K14-Cre mice with Fam20Aflox/flox mice, we created K14-Cre;Fam20Aflox/flox (conditional knock out, cKO) mice, in which Fam20A was inactivated in the epithelium. We analysed the dental tissues of cKO mice using X-ray radiography, histology and immunohistochemistry. The molar enamel matrix in cKO mice was much thinner than normal and was often separated from the dentinoenamel junction. The Fam20A-deficient ameloblasts were non-polarized and disorganized and were detached from the enamel matrix. The enamel abnormality in cKO mice was consistent with the diagnosis of amelogenesis imperfecta. The levels of enamelin and matrix metalloproteinase 20 were lower in the ameloblasts and enamel of cKO mice than the normal mice. The cKO mice had remarkable delays in the eruption of molars and hyperplasia of the gingival epithelium. The findings emphasize the essential roles of FAM20A in the development of dental and oral tissues. PMID:27281036

  19. Noninvasive and multidisciplinary approach to the functional and esthetic rehabilitation of amelogenesis imperfecta: a pediatric case report.

    PubMed

    de Souza, Juliana Feltrin; Fragelli, Camila Maria Bullio; Paschoal, Marco Aurélio Benini; Campos, Edson Alves; Cunha, Leonardo Fernandes; Losso, Estela Maris; Cordeiro, Rita de Cássia Loiola

    2014-01-01

    Case Report. An 8-year-old girl with amelogenesis imperfecta (AI) reported unsatisfactory aesthetics, difficulty in mastication, and dental hypersensitivity. The intraoral examination observed mixed dentition, malocclusion in anteroposterior relationships, anterior open bite, and dental asymmetry. A hypoplastic form of AI was diagnosed in the permanent dentition. A multidisciplinary planning was performed and divided into preventive, orthopedic, and rehabilitation stages. Initially, preventive treatment was implemented, with fluoride varnish applications, in order to protect the fragile enamel and reduce the dental sensitivity. In the second stage, the patient received an interceptive orthopedic treatment to improve cross-relationship of the arches during six months. Finally, the rehabilitation treatment was executed to establish the vertical dimension. In the posterior teeth, indirect composite resin crowns were performed with minimally invasive dental preparation. Direct composite resin restorations were used to improve the appearance of anterior teeth. Follow-Up. The follow-up was carried out after 3, 6, 12, and 18 months. After 18 months of follow-up, The restoration of integrity, oral hygiene, and patient satisfaction were observed . Conclusion. Successful reduction of the dental hypersensitivity and improvement of the aesthetic and functional aspects as well as quality of life were observed. PMID:25061528

  20. Amelogenesis Imperfecta and Early Restorative Crown Therapy: An Interview Study with Adolescents and Young Adults on Their Experiences.

    PubMed

    Pousette Lundgren, Gunilla; Wickström, Anette; Hasselblad, Tove; Dahllöf, Göran

    2016-01-01

    Patients with Amelogenesis imperfecta (AI) can present with rapid tooth loss or fractures of enamel as well as alterations in enamel thickness, color, and shape; factors that may compromise aesthetic appearance and masticatory function. The aim was to explore the experiences and perceptions of adolescents and young adults living with AI and receiving early prosthetic therapy. Seven patients with severe AI aged 16 to 23 years who underwent porcelain crown therapy participated in one-to-one individual interviews. The interviews followed a topic guide consisting of open-ended questions related to experiences of having AI. Transcripts from the interviews were analyzed using thematic analysis. The analysis process identified three main themes: Disturbances in daily life, Managing disturbances, and Normalization of daily life. These themes explain the experiences of patients living with enamel disturbances caused by AI and receiving early crown therapy. Experiences include severe pain and sensitivity problems, feelings of embarrassment, and dealing with dental staff that lack knowledge and understanding of their condition. The patients described ways to manage their disturbances and to reduce pain when eating or drinking, and strategies for meeting other people. After definitive treatment with porcelain crown therapy, they described feeling like a normal patient. In conclusion the results showed that adolescents and young adults describe a profound effect of AI on several aspects of their daily life. PMID:27359125

  1. Full-mouth adhesive rehabilitation in a case of amelogenesis imperfecta: a 5-year follow-up case report.

    PubMed

    Gerdolle, David; Mortier, Eric; Richard, Adeline; Vailati, Francesca

    2015-01-01

    Amelogenesis imperfecta (AI) is a hereditary disorder caused by mutations of genes primarily involved in the enamel formation. Several different types of AI have been identified, based on the phenotype and on the mode of inheritance. Regardless of the type, the dental treatment tends to be the same, favoring the complete removal of the compromised enamel late in the patient's life. With the new dentistry guidelines that orient clinicians towards minimal invasiveness, it should be mandatory to intercept patients affected by AI earlier, not only to protect the dentition from further degradation but also to help patients improve their self-esteem. This article examines the restorative dentistry performed on a 24-year-old Caucasian female suffering from the hypoplastic type of AI, using only adhesive procedures. Due to the complex needs of the patient, an interdisciplinary approach was followed, involving orthodontics, periodontics, and restorative dentistry. A full-mouth adhesive rehabilitation was achieved by means of direct composite restorations, veneer/onlays and facial/palatal veneers. No elective endodontic therapy was necessary for restorative purposes. The esthetics, mechanics, and biological success were achieved and maintained. The bond to the enamel did not show signs of degradation (eg, discoloration or infiltration) even after 5 years of function. This is encouraging as it shows that adhesive techniques may be a reliable approach even in the presence of a compromised enamel layer. PMID:25625125

  2. Noninvasive and Multidisciplinary Approach to the Functional and Esthetic Rehabilitation of Amelogenesis Imperfecta: A Pediatric Case Report

    PubMed Central

    de Souza, Juliana Feltrin; Fragelli, Camila Maria Bullio; Paschoal, Marco Aurélio Benini; Campos, Edson Alves; Cunha, Leonardo Fernandes; Losso, Estela Maris; Cordeiro, Rita de Cássia Loiola

    2014-01-01

    Case Report. An 8-year-old girl with amelogenesis imperfecta (AI) reported unsatisfactory aesthetics, difficulty in mastication, and dental hypersensitivity. The intraoral examination observed mixed dentition, malocclusion in anteroposterior relationships, anterior open bite, and dental asymmetry. A hypoplastic form of AI was diagnosed in the permanent dentition. A multidisciplinary planning was performed and divided into preventive, orthopedic, and rehabilitation stages. Initially, preventive treatment was implemented, with fluoride varnish applications, in order to protect the fragile enamel and reduce the dental sensitivity. In the second stage, the patient received an interceptive orthopedic treatment to improve cross-relationship of the arches during six months. Finally, the rehabilitation treatment was executed to establish the vertical dimension. In the posterior teeth, indirect composite resin crowns were performed with minimally invasive dental preparation. Direct composite resin restorations were used to improve the appearance of anterior teeth. Follow-Up. The follow-up was carried out after 3, 6, 12, and 18 months. After 18 months of follow-up, The restoration of integrity, oral hygiene, and patient satisfaction were observed . Conclusion. Successful reduction of the dental hypersensitivity and improvement of the aesthetic and functional aspects as well as quality of life were observed. PMID:25061528

  3. Mutations in CNNM4 Cause Jalili Syndrome, Consisting of Autosomal-Recessive Cone-Rod Dystrophy and Amelogenesis Imperfecta

    PubMed Central

    Parry, David A.; Mighell, Alan J.; El-Sayed, Walid; Shore, Roger C.; Jalili, Ismail K.; Dollfus, Hélène; Bloch-Zupan, Agnes; Carlos, Roman; Carr, Ian M.; Downey, Louise M.; Blain, Katharine M.; Mansfield, David C.; Shahrabi, Mehdi; Heidari, Mansour; Aref, Parissa; Abbasi, Mohsen; Michaelides, Michel; Moore, Anthony T.; Kirkham, Jennifer; Inglehearn, Chris F.

    2009-01-01

    The combination of recessively inherited cone-rod dystrophy (CRD) and amelogenesis imperfecta (AI) was first reported by Jalili and Smith in 1988 in a family subsequently linked to a locus on chromosome 2q11, and it has since been reported in a second small family. We have identified five further ethnically diverse families cosegregating CRD and AI. Phenotypic characterization of teeth and visual function in the published and new families reveals a consistent syndrome in all seven families, and all link or are consistent with linkage to 2q11, confirming the existence of a genetically homogenous condition that we now propose to call Jalili syndrome. Using a positional-candidate approach, we have identified mutations in the CNNM4 gene, encoding a putative metal transporter, accounting for the condition in all seven families. Nine mutations are described in all, three missense, three terminations, two large deletions, and a single base insertion. We confirmed expression of Cnnm4 in the neural retina and in ameloblasts in the developing tooth, suggesting a hitherto unknown connection between tooth biomineralization and retinal function. The identification of CNNM4 as the causative gene for Jalili syndrome, characterized by syndromic CRD with AI, has the potential to provide new insights into the roles of metal transport in visual function and biomineralization. PMID:19200525

  4. Amelogenesis Imperfecta and Early Restorative Crown Therapy: An Interview Study with Adolescents and Young Adults on Their Experiences

    PubMed Central

    Wickström, Anette; Hasselblad, Tove; Dahllöf, Göran

    2016-01-01

    Patients with Amelogenesis imperfecta (AI) can present with rapid tooth loss or fractures of enamel as well as alterations in enamel thickness, color, and shape; factors that may compromise aesthetic appearance and masticatory function. The aim was to explore the experiences and perceptions of adolescents and young adults living with AI and receiving early prosthetic therapy. Seven patients with severe AI aged 16 to 23 years who underwent porcelain crown therapy participated in one-to-one individual interviews. The interviews followed a topic guide consisting of open-ended questions related to experiences of having AI. Transcripts from the interviews were analyzed using thematic analysis. The analysis process identified three main themes: Disturbances in daily life, Managing disturbances, and Normalization of daily life. These themes explain the experiences of patients living with enamel disturbances caused by AI and receiving early crown therapy. Experiences include severe pain and sensitivity problems, feelings of embarrassment, and dealing with dental staff that lack knowledge and understanding of their condition. The patients described ways to manage their disturbances and to reduce pain when eating or drinking, and strategies for meeting other people. After definitive treatment with porcelain crown therapy, they described feeling like a normal patient. In conclusion the results showed that adolescents and young adults describe a profound effect of AI on several aspects of their daily life. PMID:27359125

  5. Identification of the first multi-exonic WDR72 deletion in isolated amelogenesis imperfecta, and generation of a WDR72-specific copy number screening tool.

    PubMed

    Hentschel, Julia; Tatun, Dana; Parkhomchuk, Dmitri; Kurth, Ingo; Schimmel, Bettina; Heinrich-Weltzien, Roswitha; Bertzbach, Sabine; Peters, Hartmut; Beetz, Christian

    2016-09-15

    Amelogenesis imperfecta (AI) is a clinically and genetically heterogeneous disorder of tooth development which is due to aberrant deposition or composition of enamel. Both syndromic and isolated forms exist; they may be inherited in an X-linked, autosomal recessive, or autosomal dominant manner. WDR72 is one of ten currently known genes for recessive isolated AI; nine WDR72 mutations affecting single nucleotides have been described to date. Based on whole exome sequencing in a large consanguineous AI pedigree, we obtained evidence for presence of a multi-exonic WDR72 deletion. A home-made multiplex ligation-dependent probe amplification assay was used to confirm the aberration, to narrow its extent, and to identify heterozygous carriers. Our study extends the mutational spectrum for WDR72 to include large deletions, and supports a relevance of the previously proposed loss-of-function mechanism. It also introduces an easy-to-use and highly sensitive tool for detecting WDR72 copy number alterations. PMID:27259663

  6. Improved protocol to purify untagged amelogenin – Application to murine amelogenin containing the equivalent P70→T point mutation observed in human amelogenesis imperfecta

    DOE PAGESBeta

    Buchko, Garry W.; Shaw, Wendy J.

    2014-10-13

    Amelogenin is the predominant extracellular protein responsible for converting carbonated hydroxyapatite into dental enamel, the hardest and most heavily mineralized tissue in vertebrates. Despite much effort, the precise mechanism by which amelogenin regulates enamel formation is not fully understood. To assist efforts aimed at understanding the biochemical mechanism of enamel formation, more facile protocols to purify recombinantly expressed amelogenin, ideally without any tag to assist affinity purification, are advantageous. Here we describe an improved method to purify milligram quantities of amelogenin that exploits its high solubility in 2% glacial acetic acid under conditions of low ionic strength. The method involvesmore » heating the frozen cell pellet for two 15 min periods at ~70 ºC with two minutes of sonication in between, dialysis twice in 2% acetic acid (1:250 v/v), and reverse phase chromatography. A further improvement in yield is obtained by resuspending the frozen cell pellet in 6 M guanidine hydrochloride in the first step. The acetic acid heating method is illustrated with a murine amelogenin containing the corresponding P70→T point mutation observed in an human amelogenin associated with amelogenesis imperfecta (P71T), while the guanidine hydrochloride heating method is illustrated with wild type murine amelogenin (M180). The self-assembly properties of P71T were probed by NMR chemical shift perturbation studies as a function of protein (0.1 to 1.8 mM) and NaCl (0 to 367 mM) concentration. In conclusion, relative to similar studies with wild type murine amelogenin, P71T self-associates at lower protein or salt concentrations with the interactions initiated near the N-terminus.« less

  7. Improved protocol to purify untagged amelogenin – Application to murine amelogenin containing the equivalent P70→T point mutation observed in human amelogenesis imperfecta

    SciTech Connect

    Buchko, Garry W.; Shaw, Wendy J.

    2014-10-13

    Amelogenin is the predominant extracellular protein responsible for converting carbonated hydroxyapatite into dental enamel, the hardest and most heavily mineralized tissue in vertebrates. Despite much effort, the precise mechanism by which amelogenin regulates enamel formation is not fully understood. To assist efforts aimed at understanding the biochemical mechanism of enamel formation, more facile protocols to purify recombinantly expressed amelogenin, ideally without any tag to assist affinity purification, are advantageous. Here we describe an improved method to purify milligram quantities of amelogenin that exploits its high solubility in 2% glacial acetic acid under conditions of low ionic strength. The method involves heating the frozen cell pellet for two 15 min periods at ~70 ºC with two minutes of sonication in between, dialysis twice in 2% acetic acid (1:250 v/v), and reverse phase chromatography. A further improvement in yield is obtained by resuspending the frozen cell pellet in 6 M guanidine hydrochloride in the first step. The acetic acid heating method is illustrated with a murine amelogenin containing the corresponding P70→T point mutation observed in an human amelogenin associated with amelogenesis imperfecta (P71T), while the guanidine hydrochloride heating method is illustrated with wild type murine amelogenin (M180). The self-assembly properties of P71T were probed by NMR chemical shift perturbation studies as a function of protein (0.1 to 1.8 mM) and NaCl (0 to 367 mM) concentration. In conclusion, relative to similar studies with wild type murine amelogenin, P71T self-associates at lower protein or salt concentrations with the interactions initiated near the N-terminus.

  8. Improved protocol to purify untagged amelogenin - Application to murine amelogenin containing the equivalent P70→T point mutation observed in human amelogenesis imperfecta.

    PubMed

    Buchko, Garry W; Shaw, Wendy J

    2015-01-01

    Amelogenin is the predominant extracellular protein responsible for converting carbonated hydroxyapatite into dental enamel, the hardest and most heavily mineralized tissue in vertebrates. Despite much effort, the precise mechanism by which amelogenin regulates enamel formation is not fully understood. To assist efforts aimed at understanding the biochemical mechanism of enamel formation, more facile protocols to purify recombinantly expressed amelogenin, ideally without any tag to assist affinity purification, are advantageous. Here we describe an improved method to purify milligram quantities of amelogenin that exploits its high solubility in 2% glacial acetic acid under conditions of low ionic strength. The method involves heating the frozen cell pellet for two 15min periods at ∼70°C with 2min of sonication in between, dialysis twice in 2% acetic acid (1:250 v/v), and reverse phase chromatography. A further improvement in yield is obtained by resuspending the frozen cell pellet in 6M guanidine hydrochloride in the first step. The acetic acid heating method is illustrated with a murine amelogenin containing the corresponding P70→T point mutation observed in an human amelogenin associated with amelogenesis imperfecta (P71T), while the guanidine hydrochloride heating method is illustrated with wild type murine amelogenin (M180). The self-assembly properties of P71T were probed by NMR chemical shift perturbation studies as a function of protein (0.1-1.8mM) and NaCl (0-367mM) concentration. Relative to similar studies with wild type murine amelogenin, P71T self-associates at lower protein or salt concentrations with the interactions initiated near the N-terminus. PMID:25306873

  9. A mutation in the mouse Amelx tri-tyrosyl domain results in impaired secretion of amelogenin and phenocopies human X-linked amelogenesis imperfecta

    PubMed Central

    Barron, Martin J.; Brookes, Steven J.; Kirkham, Jennifer; Shore, Roger C.; Hunt, Charlotte; Mironov, Aleksandr; Kingswell, Nicola J.; Maycock, Joanne; Shuttleworth, C. Adrian; Dixon, Michael J.

    2010-01-01

    Amelogenesis imperfecta (AI) describes a broad group of clinically and genetically heterogeneous inherited defects of dental enamel bio-mineralization. Despite identification of a number of genetic mutations underlying AI, the precise causal mechanisms have yet to be determined. Using a multi-disciplinary approach, we describe here a mis-sense mutation in the mouse Amelx gene resulting in a Y → H substitution in the tri-tyrosyl domain of the enamel extracellular matrix protein amelogenin. The enamel in affected animals phenocopies human X-linked AI where similar mutations have been reported. Animals affected by the mutation have severe defects of enamel bio-mineralization associated with absence of full-length amelogenin protein in the developing enamel matrix, loss of ameloblast phenotype, increased ameloblast apoptosis and formation of multi-cellular masses. We present evidence to demonstrate that affected ameloblasts express but fail to secrete full-length amelogenin leading to engorgement of the endoplasmic reticulum/Golgi apparatus. Immunohistochemical analysis revealed accumulations of both amelogenin and ameloblastin in affected cells. Co-transfection of Ambn and mutant Amelx in a eukaryotic cell line also revealed intracellular abnormalities and increased cytotoxicity compared with cells singly transfected with wild-type Amelx, mutant Amelx or Ambn or co-transfected with both wild-type Amelx and Ambn. We hypothesize that intracellular protein–protein interactions mediated via the amelogenin tri-tyrosyl motif are a key mechanistic factor underpinning the molecular pathogenesis in this example of AI. This study therefore successfully links phenotype with underlying genetic lesion in a relevant murine model for human AI. PMID:20067920

  10. Improved protocol to purify untagged amelogenin – Application to murine amelogenin containing the equivalent P70→T point mutation observed in human amelogenesis imperfecta

    SciTech Connect

    Buchko, Garry W.; Shaw, Wendy J.

    2015-01-01

    Amelogenin is the predominant extracellular protein responsible for converting carbonated hydroxyapatite into dental enamel, the hardest and most heavily mineralized tissue in vertebrates. Despite much effort, the precise mechanism by which amelogenin regulates enamel formation is not fully understood. To assist efforts aimed at understanding the biochemical mechanism of enamel formation, more facile protocols to purify recombinantly expressed amelogenin, ideally without any tag to assist affinity purification, are advantageous. Here we describe an improved method to purify milligram quantities of amelogenin that exploits its high solubility in 2% glacial acetic acid under conditions of low ionic strength. The method involves heating the frozen cell pellet for two 15 min periods at ~70 ºC with two minutes of sonication in between, dialysis twice in 2% acetic acid (1:250 v/v), and reverse phase chromatography. A further improvement in yield is obtained by resuspending the frozen cell pellet in 6 M guanidine hydrochloride in the first step. The acetic acid heating method is illustrated with a murine amelogenin containing the corresponding P70→T point mutation observed in an human amelogenin associated with amelogenesis imperfecta (P71T), while the guanidine hydrochloride heating method is illustrated with wild type murine amelogenin (M180). The self-assembly properties of P71T were probed by NMR chemical shift perturbation studies as a function of protein (0.1 to 1.8 mM) and NaCl (0 to 367 mM) concentration. Relative to similar studies with wild type murine amelogenin, P71T self-associates at lower protein or salt concentrations with the interactions initiated near the N-terminus.

  11. A Functional Study of Mutations in K+-dependent Na+-Ca2+ Exchangers Associated with Amelogenesis Imperfecta and Non-syndromic Oculocutaneous Albinism.

    PubMed

    Jalloul, Ali H; Rogasevskaia, Tatiana P; Szerencsei, Robert T; Schnetkamp, Paul P M

    2016-06-17

    K(+)-dependent Na(+)/Ca(2+) exchangers belong to the solute carrier 24 (SLC24A1-5) gene family of membrane transporters. Five different gene products (NCKX1-5) have been identified in humans, which play key roles in biological processes including vision, olfaction, and skin pigmentation. NCKXs are bi-directional membrane transporters that transport 1 Ca(2+)+K(+) ions in exchange for 4 Na(+) ions. Recent studies have linked mutations in the SLC24A4 (NCKX4) and SLC24A5 (NCKX5) genes to amylogenesis imperfecta (AI) and non-syndromic oculocutaneous albinism (OCA6), respectively. Here, we introduced mutations found in patients with AI and OCA6 into human SLC24A4 (NCKX4) cDNA leading to single residue substitutions in the mutant NCKX4 proteins. We measured NCKX-mediated Ca(2+) transport activity of WT and mutant NCKX4 proteins expressed in HEK293 cells. Three mutant NCKX4 cDNAs represent mutations found in the SCL24A4 gene and three represent mutations found in the SCL24A5 gene involving residues conserved between NCKX4 and NCKX5. Five mutant proteins had no observable NCKX activity, whereas one mutation resulted in a 78% reduction in transport activity. Total protein expression and trafficking to the plasma membrane (the latter with one exception) were not affected in the HEK293 cell expression system. We also analyzed two mutations in a Drosophila NCKX gene that have been reported to result in an increased susceptibility for seizures, and found that both resulted in mutant proteins with significantly reduced but observable NCKX activity. The data presented here support the genetic analyses that mutations in SLC24A4 and SLC24A5 are responsible for the phenotypic defects observed in human patients. PMID:27129268

  12. Osteogenesis Imperfecta

    MedlinePlus

    ... imperfecta (OI) is a genetic disorder in which bones break easily. Sometimes the bones break for no known reason. OI can also ... you make collagen, a protein that helps make bones strong. OI can range from mild to severe, ...

  13. Osteogenesis imperfecta.

    PubMed

    Forlino, Antonella; Marini, Joan C

    2016-04-16

    Osteogenesis imperfecta is a phenotypically and molecularly heterogeneous group of inherited connective tissue disorders that share similar skeletal abnormalities causing bone fragility and deformity. Previously, the disorder was thought to be an autosomal dominant bone dysplasia caused by defects in type I collagen, but in the past 10 years discoveries of novel (mainly recessive) causative genes have lent support to a predominantly collagen-related pathophysiology and have contributed to an improved understanding of normal bone development. Defects in proteins with very different functions, ranging from structural to enzymatic and from intracellular transport to chaperones, have been described in patients with osteogenesis imperfecta. Knowledge of the specific molecular basis of each form of the disorder will advance clinical diagnosis and potentially stimulate targeted therapeutic approaches. In this Seminar, together with diagnosis, management, and treatment, we describe the defects causing osteogenesis imperfecta and their mechanism and interrelations, and classify them into five groups on the basis of the metabolic pathway compromised, specifically those related to collagen synthesis, structure, and processing; post-translational modification; folding and cross-linking; mineralisation; and osteoblast differentiation. PMID:26542481

  14. Transcriptional Factor DLX3 Promotes the Gene Expression of Enamel Matrix Proteins during Amelogenesis

    PubMed Central

    Zhang, Zhichun; Tian, Hua; Lv, Ping; Wang, Weiping; Jia, Zhuqing; Wang, Sainan; Zhou, Chunyan; Gao, Xuejun

    2015-01-01

    Mutation of distal-less homeobox 3 (DLX3) is responsible for human tricho-dento-osseous syndrome (TDO) with amelogenesis imperfecta, indicating a crucial role of DLX3 in amelogenesis. However, the expression pattern of DLX3 and its specific function in amelogenesis remain largely unknown. The aim of this study was to investigate the effects of DLX3 on enamel matrix protein (EMP) genes. By immunohistochemistry assays of mouse tooth germs, stronger immunostaining of DLX3 protein was identified in ameloblasts in the secretory stage than in the pre-secretory and maturation stages, and the same pattern was found for Dlx3 mRNA using Realtime PCR. In a mouse ameloblast cell lineage, forced expression of DLX3 up-regulated the expression of the EMP genes Amelx, Enam, Klk4, and Odam, whereas knockdown of DLX3 down-regulated these four EMP genes. Further, bioinformatics, chromatin immunoprecipitation, and luciferase assays revealed that DLX3 transactivated Enam, Amelx, and Odam through direct binding to their enhancer regions. Particularly, over-expression of mutant-DLX3 (c.571_574delGGGG, responsible for TDO) inhibited the activation function of DLX3 on expression levels and promoter activities of the Enam, Amelx, and Odam genes. Together, our data show that DLX3 promotes the expression of the EMP genes Amelx, Enam, Klk4, and Odam in amelogenesis, while mutant-DLX3 disrupts this regulatory function, thus providing insights into the molecular mechanisms underlying the enamel defects of TDO disease. PMID:25815730

  15. Transcriptional factor DLX3 promotes the gene expression of enamel matrix proteins during amelogenesis.

    PubMed

    Zhang, Zhichun; Tian, Hua; Lv, Ping; Wang, Weiping; Jia, Zhuqing; Wang, Sainan; Zhou, Chunyan; Gao, Xuejun

    2015-01-01

    Mutation of distal-less homeobox 3 (DLX3) is responsible for human tricho-dento-osseous syndrome (TDO) with amelogenesis imperfecta, indicating a crucial role of DLX3 in amelogenesis. However, the expression pattern of DLX3 and its specific function in amelogenesis remain largely unknown. The aim of this study was to investigate the effects of DLX3 on enamel matrix protein (EMP) genes. By immunohistochemistry assays of mouse tooth germs, stronger immunostaining of DLX3 protein was identified in ameloblasts in the secretory stage than in the pre-secretory and maturation stages, and the same pattern was found for Dlx3 mRNA using Realtime PCR. In a mouse ameloblast cell lineage, forced expression of DLX3 up-regulated the expression of the EMP genes Amelx, Enam, Klk4, and Odam, whereas knockdown of DLX3 down-regulated these four EMP genes. Further, bioinformatics, chromatin immunoprecipitation, and luciferase assays revealed that DLX3 transactivated Enam, Amelx, and Odam through direct binding to their enhancer regions. Particularly, over-expression of mutant-DLX3 (c.571_574delGGGG, responsible for TDO) inhibited the activation function of DLX3 on expression levels and promoter activities of the Enam, Amelx, and Odam genes. Together, our data show that DLX3 promotes the expression of the EMP genes Amelx, Enam, Klk4, and Odam in amelogenesis, while mutant-DLX3 disrupts this regulatory function, thus providing insights into the molecular mechanisms underlying the enamel defects of TDO disease. PMID:25815730

  16. Osteogenesis imperfecta: cesarean deliveries in identical twins.

    PubMed

    Dinges, E; Ortner, C; Bollag, L; Davies, J; Landau, R

    2015-02-01

    Osteogenesis imperfecta is a congenital disorder resulting in multiple fractures and extremely short stature, usually necessitating cesarean delivery. Identical twins with severe osteogenesis imperfecta each of whom underwent a cesarean delivery with different anesthetic modalities are presented. A review of the literature and anesthetic options for cesarean delivery and postoperative analgesia for women with osteogenesis imperfecta are discussed. PMID:25433579

  17. Bmp2 Deletion Causes an Amelogenesis Imperfecta Phenotype Via Regulating Enamel Gene Expression

    PubMed Central

    GUO, FENG; FENG, JUNSHENG; WANG, FENG; LI, WENTONG; GAO, QINGPING; CHEN, ZHUO; SHOFF, LISA; DONLY, KEVIN J.; GLUHAK-HEINRICH, JELICA; CHUN, YONG HEE PATRICIA; HARRIS, STEPHEN E.; MACDOUGALL, MARY; CHEN, SHUO

    2015-01-01

    Although Bmp2 is essential for tooth formation, the role of Bmp2 during enamel formation remains unknown in vivo. In this study, the role of Bmp2 in regulation of enamel formation was investigated by the Bmp2 conditional knock out (Bmp2 cKO) mice. Teeth of Bmp2 cKO mice displayed severe and profound phenotypes with asymmetric and misshaped incisors as well as abrasion of incisors and molars. Scanning electron microscopy analysis showed that the enamel layer was hypoplastic and enamel lacked a typical prismatic pattern. Teeth from null mice were much more brittle as tested by shear and compressive moduli. Expression of enamel matrix protein genes, amelogenin, enamelin, and enamel-processing proteases, Mmp-20 and Klk4 was reduced in the Bmp2 cKO teeth as reflected in a reduced enamel formation. Exogenous Bmp2 up-regulated those gene expressions in mouse enamel organ epithelial cells. This result for the first time indicates Bmp2 signaling is essential for proper enamel development and mineralization in vivo. PMID:25545831

  18. Bmp2 deletion causes an amelogenesis imperfecta phenotype via regulating enamel gene expression.

    PubMed

    Guo, Feng; Feng, Junsheng; Wang, Feng; Li, Wentong; Gao, Qingping; Chen, Zhuo; Shoff, Lisa; Donly, Kevin J; Gluhak-Heinrich, Jelica; Chun, Yong Hee Patricia; Harris, Stephen E; MacDougall, Mary; Chen, Shuo

    2015-08-01

    Although Bmp2 is essential for tooth formation, the role of Bmp2 during enamel formation remains unknown in vivo. In this study, the role of Bmp2 in regulation of enamel formation was investigated by the Bmp2 conditional knock out (Bmp2 cKO) mice. Teeth of Bmp2 cKO mice displayed severe and profound phenotypes with asymmetric and misshaped incisors as well as abrasion of incisors and molars. Scanning electron microscopy analysis showed that the enamel layer was hypoplastic and enamel lacked a typical prismatic pattern. Teeth from null mice were much more brittle as tested by shear and compressive moduli. Expression of enamel matrix protein genes, amelogenin, enamelin, and enamel-processing proteases, Mmp-20 and Klk4 was reduced in the Bmp2 cKO teeth as reflected in a reduced enamel formation. Exogenous Bmp2 up-regulated those gene expressions in mouse enamel organ epithelial cells. This result for the first time indicates Bmp2 signaling is essential for proper enamel development and mineralization in vivo. PMID:25545831

  19. Hereditary dentine disorders: dentinogenesis imperfecta and dentine dysplasia

    PubMed Central

    Barron, Martin J; McDonnell, Sinead T; MacKie, Iain; Dixon, Michael J

    2008-01-01

    The hereditary dentine disorders, dentinogenesis imperfecta (DGI) and dentine dysplasia (DD), comprise a group of autosomal dominant genetic conditions characterised by abnormal dentine structure affecting either the primary or both the primary and secondary dentitions. DGI is reported to have an incidence of 1 in 6,000 to 1 in 8,000, whereas that of DD type 1 is 1 in 100,000. Clinically, the teeth are discoloured and show structural defects such as bulbous crowns and small pulp chambers radiographically. The underlying defect of mineralisation often results in shearing of the overlying enamel leaving exposed weakened dentine which is prone to wear. Currently, three sub-types of DGI and two sub-types of DD are recognised but this categorisation may change when other causative mutations are found. DGI type I is inherited with osteogenesis imperfecta and recent genetic studies have shown that mutations in the genes encoding collagen type 1, COL1A1 and COL1A2, underlie this condition. All other forms of DGI and DD, except DD-1, appear to result from mutations in the gene encoding dentine sialophosphoprotein (DSPP), suggesting that these conditions are allelic. Diagnosis is based on family history, pedigree construction and detailed clinical examination, while genetic diagnosis may become useful in the future once sufficient disease-causing mutations have been discovered. Differential diagnoses include hypocalcified forms of amelogenesis imperfecta, congenital erythropoietic porphyria, conditions leading to early tooth loss (Kostmann's disease, cyclic neutropenia, Chediak-Hegashi syndrome, histiocytosis X, Papillon-Lefevre syndrome), permanent teeth discolouration due to tetracyclines, Vitamin D-dependent and vitamin D-resistant rickets. Treatment involves removal of sources of infection or pain, improvement of aesthetics and protection of the posterior teeth from wear. Beginning in infancy, treatment usually continues into adulthood with a number of options including

  20. Intramedullary rodding in osteogenesis imperfecta.

    PubMed

    Mulpuri, K; Joseph, B

    2000-01-01

    The results of intramedullary rodding of long bones of 16 children with osteogenesis imperfecta, over a 10-year period, were analyzed. Sheffield elongating rods or non-elongating rods were used. The frequency of fractures was dramatically reduced after implantation of either type of rod, and the ambulatory status improved in all instances. The results were significantly better after Sheffield rodding with regard to the frequency of complications requiring reoperations and the longevity of the rods. Migration of the rods, encountered frequently, appears to be related to improper placement of the rods in the bone. It seems likely that if care is taken to ensure precise placement of a rod of appropriate size, several of these complications may be avoided. PMID:10739296

  1. The dynamics of DNA methylation and hydroxymethylation during amelogenesis.

    PubMed

    Yoshioka, Hirotaka; Minamizaki, Tomoko; Yoshiko, Yuji

    2015-11-01

    Amelogenesis is a multistep process that relies on specific temporal and spatial signaling networks between the dental epithelium and mesenchymal tissues. Epigenetic modifications of key developmental genes in this process may be closely linked to a network of molecular events. However, the role of epigenetic regulation in amelogenesis remains unclear. Here, we have uncovered the spatial distributions of 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) to determine epigenetic events in the mandibular incisors of mice. Immunohistochemistry and dot blotting showed that 5-hmC in ameloblasts increased from the secretory stage to the later maturation stage. We also demonstrated the distribution of 5-mC-positive ameloblasts with punctate nuclear labeling from sometime after the initiation of the secretory stage to the later maturation stage; however, dot blotting failed to detect this change. No obvious alteration of 5-mC/5-hmC staining in odontoblasts and dental pulp cells was observed. Concomitant with quantitative expression data, immunohistochemistry showed that maintenance DNA methyltransferase DNMT1 was highly expressed in immature dental epithelial cells and subsequently decreased at later stages of development. Meanwhile, de novo DNA methyltransferase Dnmt3a and Dnmt3b and DNA demethylase Tet family genes were universally expressed, except Tet1 that was highly expressed in immature dental epithelial cells. Thus, DNMT1 may sustain the undifferentiated status of dental epithelial cells through the maintenance of DNA methylation, while the hydroxylation of 5-mC may occur through the whole differentiation process by TET activity. Taken together, these data indicate that the dynamic changes of 5-mC and 5-hmC may be critical for the regulation of amelogenesis. PMID:26209269

  2. New Perspectives on Osteogenesis Imperfecta

    PubMed Central

    Forlino, Antonella; Cabral, Wayne A.; Barnes, Aileen M.; Marini, Joan C.

    2012-01-01

    A new paradigm has emerged for osteogenesis imperfecta (OI) as a collagen-related disorder. The more prevalent autosomal dominant forms of OI are caused by primary defects in type I collagen, while autosomal recessive forms are caused by deficiency of proteins which interact with type I procollagen for post-translational modification and/or folding. Factors contributing to the mechanism of dominant OI include intracellular stress, disruption of interactions between collagen and non-collagenous proteins, compromised matrix structure, abnormal cell-cell and cell-matrix interactions and tissue mineralization. Recessive OI is caused by deficiency of any of the three components of the collagen prolyl 3-hydroxylation complex; absence of 3-hydroxylation is associated with increased modification of the collagen helix, supporting delayed collagen folding. Other causes of recessive OI include deficiency of collagen chaperones, FKBP65 or HSP47. Murine models are crucial to uncovering the common pathways in dominant and recessive OI bone dysplasia. Clinical management of OI is multidiscipinary, encompassing substantial progress in physical rehabilitation and surgical procedures, managment of hearing, dental and pulmonary abnormalities, as well as drugs such as bisphosphonates and rGH. Novel treatments using cell therapy or new drug regimens hold promise for the future. PMID:21670757

  3. Suspect osteogenesis imperfecta in a male kitten.

    PubMed

    Evason, Michelle D; Taylor, Susan M; Bebchuk, Trevor N

    2007-03-01

    A 4.5-month-old, male domestic shorthair was presented with bilateral femoral fractures after falling from a low height. Radiographs revealed reduced radio-opacity and thin cortices of all long bones. A presumptive diagnosis of osteodystrophy, secondary to osteogenesis imperfecta, was made on postmortem examination. PMID:17436908

  4. A rare combination of amniotic constriction band with osteogenesis imperfecta.

    PubMed

    Shah, Krupa Hitesh; Shah, Hitesh

    2015-01-01

    Amniotic constriction bands and osteogenesis imperfecta are disorders arising from a collagen defect. We report a rare association of amniotic bands with osteogenesis imperfecta in a child. The child was born with multiple amniotic bands involving the right leg, both hands and both feet. Multiple fractures of long bones of lower limbs occurred in childhood due to trivial trauma. Deformities of the femur and tibia due to malunion with osteopenia and blue sclerae were present. The patient was treated with z plasty of constriction band of the right tibia and bisphosphonate for osteogenesis imperfecta. This rare association of both collagen diseases may provide further insight for the pathogenesis of these diseases. PMID:26561227

  5. How Do Health Care Providers Diagnose Osteogenesis Imperfecta?

    MedlinePlus

    ... Information Clinical Trials Resources and Publications How do health care providers diagnose osteogenesis imperfecta (OI)? Skip sharing on ... Page Content If OI is moderate or severe, health care providers usually diagnose it during prenatal ultrasound at ...

  6. IFITM5 mutations and osteogenesis imperfecta.

    PubMed

    Hanagata, Nobutaka

    2016-03-01

    Interferon-induced transmembrane protein 5 (IFITM5) is an osteoblast-specific membrane protein that has been shown to be a positive regulatory factor for mineralization in vitro. However, Ifitm5 knockout mice do not exhibit serious bone abnormalities, and thus the function of IFITM5 in vivo remains unclear. Recently, a single point mutation (c.-14C>T) in the 5' untranslated region of IFITM5 was identified in patients with osteogenesis imperfecta type V (OI-V). Furthermore, a single point mutation (c.119C>T) in the coding region of IFITM5 was identified in OI patients with more severe symptoms than patients with OI-V. Although IFITM5 is not directly involved in the formation of bone in vivo, the reason why IFITM5 mutations cause OI remains a major mystery. In this review, the current state of knowledge of OI pathological mechanisms due to IFITM5 mutations will be reviewed. PMID:26031935

  7. [Orthotic management for patients with osteogenesis imperfecta].

    PubMed

    Alguacil Diego, I M; Molina Rueda, F; Gómez Conches, M

    2011-02-01

    Osteogenesis imperfecta (OI) is a disease caused by a genetic defect in the qualitative and quantitative synthesis of type I collagen. There is a wide variation in its clinical signs, characterized by bone fragility, resulting in a bone vulnerable to external and internal forces, determining the occurrence of frequent fractures with minimal or no trauma. The therapeutic objective is directed to improve the functional capacity of the child or adult concerned, adopting those compensatory strategies to optimise their independence. In this sense, the use of different orthoses and assistive technology are important for achieving these objectives. We reviewed the main contributions to this orthotic disease and the evolution of the different devices used in different databases over the last 25 years. PMID:20880764

  8. Clinical manifestations and dental management of dentinogenesis imperfecta associated with osteogenesis imperfecta: Case report.

    PubMed

    Abukabbos, Halima; Al-Sineedi, Faisal

    2013-10-01

    Dentinogenesis imperfecta (DI) associated with osteogenesis imperfecta (OI) is a genetic disorder that affects the connective tissues and results in dentine dysplasia. This case report discusses the systemic and dental manifestations of OI and DI in a 4-year-old child, with moderate presentation of both disorders, who was treated at King Fahd Military Medical Complex in Dhahran. Dental treatment included the use of strip and stainless-steel crowns under local anesthesia, as well as behavior modification techniques. Rigorous home care instructions, including reinforcement of the oral hygiene practice and avoidance of any episode that may lead to bone fracture, were discussed with the parents. The case was reevaluated at 3-month follow-up visits, wherein the medical and dental histories were updated, the child's growth was monitored, periodic clinical and radiographic examinations were performed, and the oral hygiene was evaluated via the debris index score and caries risk assessment. Further treatment of the permanent dentition may be needed in the future. PMID:24371383

  9. Clinical manifestations and dental management of dentinogenesis imperfecta associated with osteogenesis imperfecta: Case report

    PubMed Central

    Abukabbos, Halima; Al-Sineedi, Faisal

    2013-01-01

    Dentinogenesis imperfecta (DI) associated with osteogenesis imperfecta (OI) is a genetic disorder that affects the connective tissues and results in dentine dysplasia. This case report discusses the systemic and dental manifestations of OI and DI in a 4-year-old child, with moderate presentation of both disorders, who was treated at King Fahd Military Medical Complex in Dhahran. Dental treatment included the use of strip and stainless-steel crowns under local anesthesia, as well as behavior modification techniques. Rigorous home care instructions, including reinforcement of the oral hygiene practice and avoidance of any episode that may lead to bone fracture, were discussed with the parents. The case was reevaluated at 3-month follow-up visits, wherein the medical and dental histories were updated, the child’s growth was monitored, periodic clinical and radiographic examinations were performed, and the oral hygiene was evaluated via the debris index score and caries risk assessment. Further treatment of the permanent dentition may be needed in the future. PMID:24371383

  10. Instability of Polymeric Skin Collagen in Osteogenesis Imperfecta

    PubMed Central

    Francis, M. J. O.; Smith, Roger; Bauze, Robert J.

    1974-01-01

    The structural polymeric collagen of the skin of 19 patients with osteogenesis imperfecta has been examined. In those with severe bone disease, who often have white sclerae, this collagen fraction is less resistant to depolymerization than that of age-matched controls, though the total amount is normal. In patients with less severe bone disease, whose sclerae are usually blue, the polymeric collagen may have normal stability but the total amount is reduced. These results suggest defective cross-linking of collagen in severe osteogenesis imperfecta. PMID:4816854

  11. Prenatal diagnosis of lethal osteogenesis imperfecta in twin pregnancy.

    PubMed

    Morin, L R; Herlicoviez, M; Loisel, J C; Jacob, B; Feuilly, C; Stanescu, V

    1991-06-01

    Lethal osteogenesis imperfecta was diagnosed at 27 weeks amenorrea in one fetus of a bichorial twin pregnancy. Sonographic findings included: short-limb dwarfism, hypotrophy and hypoechoic bones. The affected fetus was so translucent that only the normal fetus could be seen on plain in utero radiography. The affected fetus died immediately after birth. Postmortem radiography and histology were typical of lethal osteogenesis imperfecta of type IIA. Aids to the etiological diagnosis of in utero dwarfism are presented. Sonographic features correlated with neonatal death are described. PMID:1863995

  12. A Case of Dentinogenesis Imperfecta Treated with Submerged Root Technique

    PubMed Central

    Chandar, Bhanu; Srilakshmi, J.; Khaitan, Tanya; Babu, B. Balaji

    2015-01-01

    Dentinogenesis imperfecta (DGI), an autosomal dominant trait, is one of the most common hereditary disorders affecting both the formation and mineralization of dentin. Either or both primary and permanent dentition is affected by it. Here, we present a case report of a 13-year-old female patient affected with DGI who had undergone prosthetic rehabilitation with submerged root technique. PMID:26501025

  13. Osteogenesis imperfecta misdiagnosed as child abuse.

    PubMed

    Singh Kocher, Mininder; Dichtel, Laura

    2011-11-01

    The differential diagnosis of child abuse includes osteogenesis imperfecta (OI). Mild phenotypes of OI may be misdiagnosed as child abuse. The purpose of this study was to review the experience of families in which OI was misdiagnosed as child abuse. Sixty-one potential cases of misdiagnosis were identified from a lay support organization. Upon review of the medical records, 33 cases were identified with a confirmed diagnosis of OI (skin biopsy or DNA blood test). Questionnaires were given to families to describe their condition and experiences. There were 19 male and 14 female children. Mean age at presentation was 7.1 months (range: 1-23 months). All patients had fractures and the presenting symptoms included pain (n=14), swelling (n=7), decreased limb movement (n=5), or unusual limb position (n=2). Abnormal radiograph findings consistent with OI were found in 19 of 33 patients (58%), clinical findings of OI were present in 23 of 33 patients (70%), and a family history that could be supportive of OI was present in 18 of 33 families (55%). Children were removed from the family in 70% of cases and older siblings were removed from the family in 62% of cases. The mean age at the time of diagnosis of OI was 10.5 months (range: 3-35 months). The consequences of misdiagnosis of OI as child abuse are devastating to the family. OI should be considered in all cases of suspected child abuse. In children with any clinical, radiographic, or family history features of OI, early involvement of a bone specialist and performance of laboratory testing should be considered to establish a timely and accurate diagnosis. PMID:21716141

  14. A Guide to Education for Children with Osteogenesis Imperfecta. What Is OIF? Care of an Osteogenesis Imperfecta Baby and Child.

    ERIC Educational Resources Information Center

    Ostegenesis Imperfecta Foundation, Inc., Manchester, NH.

    Three pamphlets provide basic information on the care and education of children with osteogenesis imperfecta (OI) a lifelong liability to fractures due to imperfectly formed "brittle bones." The first brochure, a guide to education for children with OI, addresses the importance of attitudes, the value of early education, public school enrollment,…

  15. Isolated dentinogenesis imperfecta and dentin dysplasia: revision of the classification.

    PubMed

    de La Dure-Molla, Muriel; Philippe Fournier, Benjamin; Berdal, Ariane

    2015-04-01

    Dentinogenesis imperfecta is an autosomal dominant disease characterized by severe hypomineralization of dentin and altered dentin structure. Dentin extra cellular matrix is composed of 90% of collagen type I and 10% of non-collagenous proteins among which dentin sialoprotein (DSP), dentin glycoprotein (DGP) and dentin phosphoprotein (DPP) are crucial in dentinogenesis. These proteins are encoded by a single gene: dentin sialophosphoprotein (DSPP) and undergo several post-translational modifications such as glycosylation and phosphorylation to contribute and to control mineralization. Human mutations of this DSPP gene are responsible for three isolated dentinal diseases classified by Shield in 1973: type II and III dentinogenesis imperfecta and type II dentin dysplasia. Shield classification was based on clinical phenotypes observed in patient. Genetics results show now that these three diseases are a severity variation of the same pathology. So this review aims to revise and to propose a new classification of the isolated forms of DI to simplify diagnosis for practitioners. PMID:25118030

  16. Anesthetic Management in a Gravida with Type IV Osteogenesis Imperfecta

    PubMed Central

    Vue, Elizabeth; Davila, Juan

    2016-01-01

    Osteogenesis imperfecta (OI) is an inherited disorder of the connective tissues caused by abnormalities in collagen formation. OI may present many challenges to the anesthesiologist. A literature review reveals a wide range of implications, from basic positioning to management of the difficult airway. We present the anesthetic management of a 25-year-old gravid woman with OI, fetal demise, and possible uterine rupture, admitted for an exploratory laparotomy. PMID:27433164

  17. Infantile-onset glaucoma and anterior megalophthalmos in osteogenesis imperfecta.

    PubMed

    Bohnsack, Brenda L

    2016-04-01

    Osteogenesis imperfecta (OI) is an inherited condition in which defects in type 1 collagen cause abnormalities in many tissues and organs, including bone, teeth, heart valves, and eyes. We describe a 6-month-old boy with OI who presented with anterior megalophthalmos of the right eye and infantile-onset glaucoma of the left eye. To our knowledge, this is the first reported case of these types of congenital eye anomalies in an infant with OI. PMID:26994503

  18. Osteogenesis imperfecta: from diagnosis and multidisciplinary treatment to future perspectives.

    PubMed

    Bregou Bourgeois, Aline; Aubry-Rozier, Bérengère; Bonafé, Luisa; Laurent-Applegate, Lee; Pioletti, Dominique P; Zambelli, Pierre-Yves

    2016-01-01

    Osteogenesis imperfecta is an inherited connective tissue disorder with wide phenotypic and molecular heterogeneity. A common issue associated with the molecular abnormality is a disturbance in bone matrix synthesis and homeostasis inducing bone fragility. In very early life, this can lead to multiple fractures and progressive bone deformities, including long bone bowing and scoliosis. Multidisciplinary management improves quality of life for patients with osteogenesis imperfecta. It consists of physical therapy, medical treatment and orthopaedic surgery as necessary. Medical treatment consists of bone-remodelling drug therapy. Bisphosphonates are widely used in the treatment of moderate to severe osteogenesis imperfecta, from infancy to adulthood. Other more recent drug therapies include teriparatide and denosumab. All these therapies target the symptoms and have effects on the mechanical properties of bone due to modification of bone remodelling, therefore influencing skeletal outcome and orthopaedic surgery. Innovative therapies, such as progenitor and mesenchymal stem cell transplantation, targeting the specific altered pathway rather than the symptoms, are in the process of development. PMID:27346233

  19. Children with Osteogenesis Imperfecta and Their Life Situation. Report and Documentation.

    ERIC Educational Resources Information Center

    Brodin, Jane

    Children with osteogenesis imperfecta form a small and relatively unknown group, with 5 to 10 children diagnosed in Sweden each year and a total of around 200 people under the age of 17 having the condition. A questionnaire was completed by families of 24 Swedish children with osteogenesis imperfecta, and three families were interviewed. The…

  20. Osteogenesis imperfecta due to compound heterozygosity for the LEPRE1 gene.

    PubMed

    Moul, Adrienne; Alladin, Amanda; Navarrete, Cristina; Abdenour, George; Rodriguez, Maria M

    2013-10-01

    Osteogenesis imperfecta is a rare connective tissue disorder characterized by bone fragility and low bone density. Most cases are caused by an autosomal dominant mutation in either COL1A1 or COL1A2 gene encoding type I collagen. However, autosomal recessive forms have been identified. We present a patient with severe respiratory distress due to osteogenesis imperfecta simulating type II, born to a non-consanguineous couple with mixed African-American and African-Hispanic ethnicity. Cultured skin fibroblasts demonstrated compound heterozygosity for mutations in the LEPRE1 gene encoding prolyl 3-hydroxylase 1 confirming the diagnosis of autosomal recessive osteogenesis imperfecta type VIII, perinatal lethal type. PMID:23301918

  1. Perinatal lethal type II osteogenesis imperfecta: a case report

    PubMed Central

    Ayadi, Imene Dahmane; Hamida, Emira Ben; Rebeh, Rania Ben; Chaouachi, Sihem; Marrakchi, Zahra

    2015-01-01

    We report a new case of osteogenesis imperfecta (OI) type II which is a perinatal lethal form. First trimester ultrasound didn't identified abnormalities. Second trimester ultrasound showed incurved limbs, narrow chest, with hypomineralization and multiple fractures of ribs and long bones. Parents refused pregnancy termination; they felt that the diagnosis was late. At birth, the newborn presented immediate respiratory distress. Postnatal examination and bone radiography confirmed the diagnosis of OI type IIA. Death occurred on day 25 of life related to respiratory failure. PMID:26401205

  2. [PREPARATIONS OF PAMIDRONOVIC ACID IN COMPLEX TREATMENT ON OSTEOGENESIS IMPERFECTA].

    PubMed

    Zyma, A M; Guk, Yu M; Magomedov, O M; Gayko, O G; Kincha-Polishchuk, T A

    2015-07-01

    Modern view of drug therapy in the complex treatment of orthopedic manifestations of osteogenesis imperfecta (OI) was submitted. Developed and tested system of drug correction of structural and functional state of bone tissue (BT) using drugs pamidronovic acid, depending on osteoporosis severity and type of disease. Such therapy is appropriate to apply both independently and in conjunction with surgery to correct deformations of long bones of the lower extremities. Effectiveness and feasibility of the proposed methods of drug therapy was proved, most patients resume features walking and support. PMID:26591224

  3. Osteogenesis Imperfecta: A Case Report and Review of Literature

    PubMed Central

    Edelu, BO; Ndu, IK; Asinobi, IN; Obu, HA; Adimora, GN

    2014-01-01

    Osteogenesis imperfecta (OI) is a group of rare inherited disorders of connective tissue with the common feature of excessive fragility of bones caused by mutations in collagen. Diagnosis is mainly based on the clinical features of the disorder. We report, the case of a male neonate delivered to a 33-year-old para 2 female at University of Nigeria Teaching Hospital, Enugu with no family history suggestive of OI. He had clinical features of a type II OI and severe birth asphyxia. Multidisciplinary management was instituted, but he died on the 7th day of life. PMID:25031897

  4. Clinical perspectives on osteogenesis imperfecta versus non-accidental injury.

    PubMed

    Pereira, Elaine Maria

    2015-12-01

    Although non-accidental injuries (NAI) are more common in cases of unexplained fractures than rare disorders such as osteogenesis imperfecta (OI), ruling out OI and other medical causes of fracture is always indicated. The majority of OI patients can be diagnosed with the help of family history, physical examination, and radiographic findings. In particular, there are a few radiological findings which are seen more commonly in NAI than in OI which may help guide clinician considerations regarding the probability of either of these diagnoses. At the same time, molecular testing still merits careful consideration in cases with unexplained fractures without obvious additional signs of abuse. PMID:26492946

  5. Clinical and Molecular Characterization of Osteogenesis Imperfecta Type V

    PubMed Central

    Brizola, Evelise; Mattos, Eduardo P.; Ferrari, Jessica; Freire, Patricia O.A.; Germer, Raquel; Llerena Jr, Juan C.; Félix, Têmis M.

    2015-01-01

    Osteogenesis imperfecta type V (OI-V) has a wide clinical variability, with distinct clinical/radiological features, such as calcification of the interosseous membrane (CIM) between the radius-ulna and/or tibia-fibula, hyperplastic callus (HPC) formation, dislocation of the radial head (DRH), and absence of dentinogenesis imperfecta (DI). Recently, a single heterozygous mutation (c.-14C>T) in the 5′UTR of the IFITM5 gene was identified to be causative for OI-V. Here, we describe 7 individuals from 5 unrelated families that carry the c.-14C>T IFITM5 mutation. The clinical findings in these cases are: absence of DI in all patients, presence of blue sclera in 2 cases, and 4 patients with DRH. Radiographic findings revealed HPC in 3 cases. All patients presented CIM between the radius and ulna, while 4 patients presented additional CIM between the tibia and fibula. Spinal fractures by vertebral compression were observed in all individuals. The proportion of cases identified with this mutation represents 4% of OI cases at our institution. The clinical identification of OI-V is crucial, as this mutation has an autosomal dominant inheritance with variable expressivity. PMID:26648832

  6. Clinical and Molecular Characterization of Osteogenesis Imperfecta Type V.

    PubMed

    Brizola, Evelise; Mattos, Eduardo P; Ferrari, Jessica; Freire, Patricia O A; Germer, Raquel; Llerena, Juan C; Félix, Têmis M

    2015-10-01

    Osteogenesis imperfecta type V (OI-V) has a wide clinical variability, with distinct clinical/radiological features, such as calcification of the interosseous membrane (CIM) between the radius-ulna and/or tibia-fibula, hyperplastic callus (HPC) formation, dislocation of the radial head (DRH), and absence of dentinogenesis imperfecta (DI). Recently, a single heterozygous mutation (c.-14C>T) in the 5'UTR of the IFITM5 gene was identified to be causative for OI-V. Here, we describe 7 individuals from 5 unrelated families that carry the c.-14C>T IFITM5 mutation. The clinical findings in these cases are: absence of DI in all patients, presence of blue sclera in 2 cases, and 4 patients with DRH. Radiographic findings revealed HPC in 3 cases. All patients presented CIM between the radius and ulna, while 4 patients presented additional CIM between the tibia and fibula. Spinal fractures by vertebral compression were observed in all individuals. The proportion of cases identified with this mutation represents 4% of OI cases at our institution. The clinical identification of OI-V is crucial, as this mutation has an autosomal dominant inheritance with variable expressivity. PMID:26648832

  7. Chest compressions in an infant with osteogenesis imperfecta type II: No new rib fractures.

    PubMed

    Sewell, R D; Steinberg, M A

    2000-11-01

    The case report of a newborn female with osteogenesis imperfecta type II who underwent cardiopulmonary resuscitation (CPR) with manual chest compressions for several minutes is presented. Chest radiographs taken before and after the chest compressions were administered were reviewed by several radiologists from 3 different hospitals and demonstrated no new radiographically visible rib fractures. Collagen analysis, the patient's clinical appearance, and clinical course, as well as a consultant's opinion aided in confirmation of the diagnosis of osteogenesis imperfecta type II. A review of 4 previous studies concerning rib fractures and CPR is included. This unique case supports previous articles that have concluded that rib fractures rarely, if ever, result from CPR in pediatrics, even in children with a lethal underlying bone disease, such as osteogenesis imperfecta type II. cardiopulmonary resuscitation, chest compressions, osteogenesis imperfecta, rib fractures, bone disease. PMID:11061808

  8. Osteogenesis imperfecta : current treatment options and future prospects.

    PubMed

    Devogelaer, Jean-Pierre; Coppin, Christine

    2006-01-01

    Osteogenesis imperfecta is a heritable condition characterized by abnormally brittle bones, with an approximate prevalence of 1/20 000 births. Fractures are the main cause of suffering and disability, but owing to the abundance and wide distribution of the defective type I collagen in the body, a variety of symptoms occur. Several types of osteogenesis imperfecta (I-VII) have been described that vary in severity. For many years, therapy consisted of rehabilitation and orthopedic surgery. Presently, pharmacologic therapies aimed at strengthening bone are available, which decrease the pain and fracture rate associated with this condition, and allow more appropriate rehabilitation programs that will hopefully result in a less marked failure to thrive in affected children. In particular, the bisphosphonates, especially pamidronate, have been used for several years. They have been successful in increasing bone mineral density (BMD) and improving bone resistance, leading to a decrease in the fracture rate. Various regimens have been proposed, but it is the therapeutic regimen first used by Glorieux and co-workers in Montreal that has been the most frequently applied.However, as yet there is no definite consensus regarding the indications for therapy, the osteogenesis imperfecta types that are of the greatest concern, the appropriate age at the outset of therapy, and the treatment duration, without yet speaking about the best bisphosphonate regimen for use. The authors have proposed some personal recommendations for the clinical use of bisphosphonates, based on their own experience with the management of patients with this condition; these include the indications for therapy, based on the clinical status, and the treatment duration. These recommendations will certainly not be unanimously endorsed, but they should help to stimulate discussion. Ameliorating BMD is an important step, but will not prevent all fractures because bisphosphonate therapy does not correct the

  9. Cochlear implantation in a child with osteogenesis imperfecta.

    PubMed

    Migirov, Lela; Henkin, Yael; Hildesheimer, Minka; Kronenberg, Jona

    2003-06-01

    Osteogenesis imperfecta (OI) is a hereditary disease of connective tissue and affects bone, dentine, sclera, joint, tendon, blood vessels, heart valves, and skin. Approximately 50% of the adult patients with OI have associated hearing impairment. To date, only three cases of cochlear implantation in adults with OI have been reported, but none in children. We present a case of cochlear implantation in a congenitally deaf 6-year-old boy with OI. The Nucleus 24 Contour device was successfully implanted using the suprameatal approach (SMA). At 6 months post-initial stimulation there was no evidence of non-acoustic nerve excitation (i.e. facial twitching) or discomfort, and significant progress in auditory abilities was manifested by open set word identification. PMID:12745164

  10. Prenatal transplantation of mesenchymal stem cells to treat osteogenesis imperfecta

    PubMed Central

    Chan, Jerry K. Y.; Götherström, Cecilia

    2014-01-01

    Osteogenesis imperfecta (OI) can be a severe disorder that can be diagnosed before birth. Transplantation of mesenchymal stem cells (MSC) has the potential to improve the bone structure, growth, and fracture healing. In this review, we give an introduction to OI and MSC, and the basis for pre- and postnatal transplantation in OI. We also summarize the two patients with OI who have received pre- and postnatal transplantation of MSC. The findings suggest that prenatal transplantation of allogeneic MSC in OI is safe. The cell therapy is of likely clinical benefit with improved linear growth, mobility, and reduced fracture incidence. Unfortunately, the effect is transient. For this reason, postnatal booster infusions using same-donor MSC have been performed with clinical benefit, and without any adverse events. So far there is limited experience in this specific field and proper studies are required to accurately conclude on clinical benefits of MSC transplantation to treat OI. PMID:25346689

  11. Changes in acid-phosphate content in enamel mineral during porcine amelogenesis.

    PubMed

    Shimoda, S; Aoba, T; Moreno, E C

    1991-12-01

    The present study was undertaken to investigate changes in the acid-phosphate content of porcine enamel mineral during its development and to assess separately the HPO4(2-) pools in labile and stable forms. Enamel samples at the secretory and maturing stages of amelogenesis were obtained from the permanent incisors of five- to six-month-old slaughtered piglets. Human enamel from erupted, extracted teeth, synthetic hydroxyapatite, and carbonatoapatite containing acid phosphate were included as references. The acid-phosphate content of each sample was determined chemically through its pyrolytic conversion to pyrophosphate. The assessment of HPO4(2-) in labile forms was made by analysis of samples preequilibrated with solutions containing 3 mmol/L phosphate at pH11 (to de-protonate the HPO4(2-) species on crystal surfaces). The analytical results of porcine enamel samples showed that: (a) the outermost secretory (youngest) enamel contained the highest HPO4(2-), corresponding to about 16% of the total phosphate; (b) the acid-phosphate content decreased gradually to 10% in the inner (older) secretory and to 6% in the maturing tissue; (c) a substantial part of the HPO4(2-) in developing enamel tissue (50-60% of the HPO4(2-) for the secretory enamel) was in labile forms; and (d) the pool of the labile HPO4(2-) decreased with the growth of enamel mineral. In parallel studies with mature human enamel, it was ascertained that the total acid phosphate was only about 3% of the total phosphate, much lower than in developing porcine enamel, and that the labile pool of HPO4(2-) was also small, corresponding to about 15% of the total acid phosphate determined.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1774383

  12. Cesarean delivery and colon resection in a patient with type III osteogenesis imperfecta.

    PubMed

    Fiegel, Matthew J

    2011-09-01

    OBJECTIVE. Osteogenesis imperfecta is a connective tissue disorder that results from the inability to produce normal collagen. Eight types are described; type II is considered the lethal variant. Because of abnormal collagen production, these patients possess many anatomic and functional abnormalities. In addition to the obvious brittle bones, osteogenesis imperfecta patients may also possess respiratory, cardiac, spinal, endocrine, and hematologic abnormalities. These numerous derangements can lead to a challenging perioperative course. CASE REPORT. This report describes a case of a 27-year-old woman, G1P0 with history of type III osteogenesis imperfecta presenting at 31+ weeks with preterm premature rupture of membranes, lower extremity edema, and constipation. Because of progressive labor and cephalopelvic disproportion, an urgent cesarean section was performed under general anesthesia. Intraoperative coagulopathy was noted. After hemostasis was achieved, a colonic mass below the splenic flexure that measured 20 × 10 cm was revealed. General surgery was consulted intraoperatively, and a rectosigmoid resection was performed for a presumed colonic pseudo-obstruction. Patient tolerated the procedure well and was extubated at the completion of the case. The patient was discharged home on postoperative day 5. CLINICAL CHALLENGES. (a) Preoperative assessment of an osteogenesis imperfecta patient, (b) determination of anesthetic type, (c) management of hemorrhage/cardiovascular instability, and (d) management of hyperthermia. CONCLUSIONS. This case report illustrates that, with proper knowledge of this disease state, osteogenesis imperfecta patients can undergo a safe anesthetic during a potentially challenging combined cesarean section/colonic resection. PMID:21813546

  13. Clinical Application of Antenatal Genetic Diagnosis of Osteogenesis Imperfecta Type IV

    PubMed Central

    Yuan, Jing; Li, Song; Xu, YeYe; Cong, Lin

    2015-01-01

    Background Clinical analysis and genetic testing of a family with osteogenesis imperfecta type IV were conducted, aiming to discuss antenatal genetic diagnosis of osteogenesis imperfecta type IV. Material/Methods Preliminary genotyping was performed based on clinical characteristics of the family members and then high-throughput sequencing was applied to rapidly and accurately detect the changes in candidate genes. Results Genetic testing of the III5 fetus and other family members revealed missense mutation in c.2746G>A, pGly916Arg in COL1A2 gene coding region and missense and synonymous mutation in COL1A1 gene coding region. Conclusions Application of antenatal genetic diagnosis provides fast and accurate genetic counseling and eugenics suggestions for patients with osteogenesis imperfecta type IV and their families. PMID:25835785

  14. AB129. Osteogenesis imperfecta: clinical features and bisphosphonate treatment outcome

    PubMed Central

    Can, Ngoc Thi Bich; Vu, Dung Chi; Bui, Thao Phuong; Nguyen, Khanh Ngoc

    2015-01-01

    Background and objective Osteogenesis imperfecta (OI) comprises a group of disorders principally affecting type I collagen which result in increased bone fragility. Children with severe OI suffer recurrent fractures, resulting in severe deformity and growth stunting in many cases, with loss of independent ambulation by the teenage years in over 50% of cases. Recently, cyclical intravenous treatment with pamidronate has proven of benefit to children with severe forms of OI. This article aims to describle clinical features and laboratory manifestations of patient with OI and evaluate outcome of bisphosphonate management. Methods Clinical features, biochemical finding, and management outcome of 104 cases were study. The patients were classified into four major subtypes of Sillience et al. 1979. Patients with severe types were treatment with pamidronate (Aredia) used Rauch protocol 2003. Results Now we have 196 patients (87 females and 109 males) but we studied focus on 104 patients from 98 families (60 males, 44 females) onset at 2.1±3.0 years (median 0.35) with the average fracture bone of 5.9±4.4 times. In there, 17% type I, 8% type II, 63% type III, and 12% type IV. Clinical features include of intrauterine fracture visible on ultrasound 35%, bone deformation after birth 68%, triangle face 76%, long bone deformation 91%, chest deformation 46%, scoliosis 27%, short status 90%, blue sclera 83%, dentinogenesis imperfecta 20%, hearing loss 6%. Thirty patients have been treated with pamidronate at 3.2±3.7 years (4 months to 8 years) during 13±0.8 months (6-30 months). Fourteen patients had fracture bone after 6 months of treatment but no patients had fracture bone after 12 months. Seven patients had been treatment after 1.6±0.5 years, BMD increase from 0.39±0.311 to 0.79±0.105 g/cm2 (P<0.05). One patient had fever reaction after first pamidronate infusion but controlled with standard antipyretic therapy, and do not recur in later treatments. Conclusions OI has

  15. Excessive TGFβ signaling is a common mechanism in Osteogenesis Imperfecta

    PubMed Central

    Grafe, Ingo; Yang, Tao; Alexander, Stefanie; Homan, Erica; Lietman, Caressa; Jiang, Ming Ming; Bertin, Terry; Munivez, Elda; Chen, Yuqing; Dawson, Brian; Ishikawa, Yoshihiro; Weis, Mary Ann; Sampath, T. Kuber; Ambrose, Catherine; Eyre, David; Bächinger, Hans Peter; Lee, Brendan

    2014-01-01

    Osteogenesis Imperfecta (OI) is a heritable disorder of connective tissue characterized by brittle bones, fractures and extraskeletal manifestations1. How structural mutations of type I collagen (dominant OI) or of its post-translational modification machinery (recessive OI) can cause abnormal quality and quantity of bone is poorly understood. Notably, the clinical overlap between dominant and recessive forms of OI suggests common molecular pathomechanisms2. Here, we show that excessive transforming growth factor-beta (TGFβ) signaling is a mechanism of OI in both recessive (Crtap−/−) and dominant (Col1a2tm1.1Mcbr) OI mouse models. In the skeleton, we find higher expression of TGFβ target genes, ratio of pSmad2/Smad2 protein, and in vivo Smad2 reporter activity. Anti-TGFβ treatment using the neutralizing antibody 1D11 corrects the bone phenotype in both forms of OI, and improves the lung abnormalities in Crtap−/− mice. Moreover, type I collagen of Crtap−/− mice shows reduced binding to the small leucine rich proteoglycan decorin, a known regulator of TGFβ activity3–4. Hence, altered TGFβ matrix-cell signaling is a primary mechanism in the pathogenesis of OI, and could be a promising target for the treatment of OI. PMID:24793237

  16. Anisotropic properties of human cortical bone with osteogenesis imperfecta.

    PubMed

    Katti, Kalpana S; Gu, Chunju; Katti, Dinesh R

    2016-02-01

    The heterogeneity of bone shape and size variation is modulated by genetic, mechanical, nutritional, and hormonal patterning throughout its lifetime. Microstructural changes across cross sections are a result of mechanistic optimization that results over the years of evolution while being based on universal, time-invariant ingredients and patterns. Here we report changes across anatomical sections of bone with osteogenesis imperfecta (OI) that undermines the work of evolution through genetic mutation. This work examines the microstructure and molecular composition of different anatomical positions (anterior, medial, posterior, and lateral regions) in the diaphysis of an OI human tibia. The study shows that although there is no significant microstructural difference, molecular changes are observed using FTIR revealing differences in molecular composition of the four anatomical positions. In addition, the nanomechanical properties of anterior section of OI bone seem more heterogeneous. The nanomechanical properties of interstitial lamellae in all these bone samples are consistently greater than those of osteonal lamellae. The nanomechanical properties of bone depend on its anatomical section and on the measurement direction as well. Variations in molecular structure with anatomical positions and also corresponding differences in nanomechanical properties are reported. These are compared to those observed typically in healthy bone illustrating the unique influence of OI on bone multiscale behavior which results from an evolutionary process lasting for many years. PMID:26399513

  17. Recessive Osteogenesis Imperfecta Caused by Missense Mutations in SPARC

    PubMed Central

    Mendoza-Londono, Roberto; Fahiminiya, Somayyeh; Majewski, Jacek; Tétreault, Martine; Nadaf, Javad; Kannu, Peter; Sochett, Etienne; Howard, Andrew; Stimec, Jennifer; Dupuis, Lucie; Roschger, Paul; Klaushofer, Klaus; Palomo, Telma; Ouellet, Jean; Al-Jallad, Hadil; Mort, John S.; Moffatt, Pierre; Boudko, Sergei; Bächinger, Hans-Peter; Rauch, Frank

    2015-01-01

    Secreted protein, acidic, cysteine-rich (SPARC) is a glycoprotein that binds to collagen type I and other proteins in the extracellular matrix. Using whole-exome sequencing to identify the molecular defect in two unrelated girls with severe bone fragility and a clinical diagnosis of osteogenesis imperfecta type IV, we identified two homozygous variants in SPARC (GenBank: NM_003118.3; c.497G>A [p.Arg166His] in individual 1; c.787G>A [p.Glu263Lys] in individual 2). Published modeling and site-directed mutagenesis studies had previously shown that the residues substituted by these mutations form an intramolecular salt bridge in SPARC and are essential for the binding of SPARC to collagen type I. The amount of SPARC secreted by skin fibroblasts was reduced in individual 1 but appeared normal in individual 2. The migration of collagen type I alpha chains produced by these fibroblasts was mildly delayed on SDS-PAGE gel, suggesting some overmodification of collagen during triple helical formation. Pulse-chase experiments showed that collagen type I secretion was mildly delayed in skin fibroblasts from both individuals. Analysis of an iliac bone sample from individual 2 showed that trabecular bone was hypermineralized on the material level. In conclusion, these observations show that homozygous mutations in SPARC can give rise to severe bone fragility in humans. PMID:26027498

  18. Mutations in SERPINF1 Cause Osteogenesis Imperfecta Type VI

    PubMed Central

    Homan, Erica P; Rauch, Frank; Grafe, Ingo; Lietman, Caressa; Doll, Jennifer A; Dawson, Brian; Bertin, Terry; Napierala, Dobrawa; Morello, Roy; Gibbs, Richard; White, Lisa; Miki, Rika; Cohn, Daniel H; Crawford, Susan; Travers, Rose; Glorieux, Francis H; Lee, Brendan

    2011-01-01

    Abstract Osteogenesis imperfecta (OI) is a spectrum of genetic disorders characterized by bone fragility. It is caused by dominant mutations affecting the synthesis and/or structure of type I procollagen or by recessively inherited mutations in genes responsible for the posttranslational processing/trafficking of type I procollagen. Recessive OI type VI is unique among OI types in that it is characterized by an increased amount of unmineralized osteoid, thereby suggesting a distinct disease mechanism. In a large consanguineous family with OI type VI, we performed homozygosity mapping and next-generation sequencing of the candidate gene region to isolate and identify the causative gene. We describe loss of function mutations in serpin peptidase inhibitor, clade F, member 1 (SERPINF 1) in two affected members of this family and in an additional unrelated patient with OI type VI. SERPINF1 encodes pigment epithelium-derived factor. Hence, loss of pigment epithelium-derived factor function constitutes a novel mechanism for OI and shows its involvement in bone mineralization. © 2011 American Society for Bone and Mineral Research PMID:21826736

  19. Cochlear implantation in a patient with osteogenesis imperfecta.

    PubMed

    Makizumi, Yoshimi; Kashio, Akinori; Sakamoto, Takashi; Karino, Shotaro; Kakigi, Akinobu; Iwasaki, Shinichi; Yamasoba, Tatsuya

    2013-10-01

    Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by a deficit in the synthesis of type I collagen. Hearing loss affects 42-58% of OI patients and progresses to deafness in 35-60% of these patients. For OI patients, cochlear implantation (CI) is the only promising treatment option. However, literature on CI in patients with OI is relatively rare. After CI, speech perception is generally good. However, among patients with severe demineralization of the cochlea, most patients are reported to have complications of facial nerve stimulation (FNS), preventing some patients from using the cochlear implant on a daily basis. Here we report a successful CI using a Nucleus CI24 Contour Advance cochlear implant in a patient with OI. Although high-resolution computed tomography (HRCT) showed extensive demineralization of the cochlea, intracochlear electrodes were inserted properly. The use of a modiolus-hugging device and the advance off-stylet technique contributed to the successful implantation, with no complications such as FNS or misplacement of electrodes. Therefore, CI can be used for treating deaf patients with OI. PMID:23219154

  20. Osteogenesis Imperfecta Type VI in Individuals from Northern Canada.

    PubMed

    Ward, Leanne; Bardai, Ghalib; Moffatt, Pierre; Al-Jallad, Hadil; Trejo, Pamela; Glorieux, Francis H; Rauch, Frank

    2016-06-01

    Osteogenesis imperfecta (OI) type VI is a recessively inherited form of OI that is caused by mutations in SERPINF1, the gene coding for pigment-epithelium derived factor (PEDF). Here, we report on two apparently unrelated children with OI type VI who had the same unusual homozygous variant in intron 6 of SERPINF1 (c.787-10C>G). This variant created a novel splice site that led to the in-frame addition of three amino acids to PEDF (p.Lys262_Ile263insLeuSerGln). Western blotting showed that skin fibroblasts with this mutation produced PEDF but failed to secrete it. Both children were treated with intravenous bisphosphonates, but the treatment of Individual 1 was switched to subcutaneous injections of denosumab (dose 1 mg per kg body weight, repeated every 3 months). An iliac bone sample obtained after 5 denosumab injections (and 3 months after the last injection) showed no change in the increased osteoid parameters that are typical of OI type VI, but the number of osteoclasts in trabecular bone was markedly increased. This suggests that the effect of denosumab on osteoclast suppression is of shorter duration in children with OI type VI than what has previously been reported on adults with osteoporosis. PMID:26815784

  1. Osteogenesis imperfecta: Clinical diagnosis, nomenclature and severity assessment

    PubMed Central

    Van Dijk, FS; Sillence, DO

    2014-01-01

    Recently, the genetic heterogeneity in osteogenesis imperfecta (OI), proposed in 1979 by Sillence et al., has been confirmed with molecular genetic studies. At present, 17 genetic causes of OI and closely related disorders have been identified and it is expected that more will follow. Unlike most reviews that have been published in the last decade on the genetic causes and biochemical processes leading to OI, this review focuses on the clinical classification of OI and elaborates on the newly proposed OI classification from 2010, which returned to a descriptive and numerical grouping of five OI syndromic groups. The new OI nomenclature and the pre-and postnatal severity assessment introduced in this review, emphasize the importance of phenotyping in order to diagnose, classify, and assess severity of OI. This will provide patients and their families with insight into the probable course of the disorder and it will allow physicians to evaluate the effect of therapy. A careful clinical description in combination with knowledge of the specific molecular genetic cause is the starting point for development and assessment of therapy in patients with heritable disorders including OI. © 2014 The Authors. American Journal of Medical Genetics Published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution–NonCommercial–NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. PMID:24715559

  2. Osteogenesis Imperfecta and non-accidental injury: problems in diagnosis and management.

    PubMed

    Kasim, M S; Cheah, I; Sameon, H

    1995-06-01

    It has been noted in the literature that Osteogenesis Imperfecta is frequently mistaken for non-accidental injury. This article serves to illustrate the difficulty in differentiating between the two conditions and that they can occur concomitantly in one patient. PMID:7565189

  3. Children with Osteogenesis Imperfecta and Their Daily Living. Handicap Research Group Report No. 4.

    ERIC Educational Resources Information Center

    Brodin, Jane

    The study examined aspects of daily living of Swedish children with osteogenesis imperfecta, a mineral deficiency in the skeleton which results in stunted growth and frequent fractures. A questionnaire was administered to 24 families with children under the age of 18 and 3 families were interviewed. The study found the families in great need of…

  4. Fracture of mandible during yawning in a patient with osteogenesis imperfecta

    PubMed Central

    Ram, Hari; Shadab, Mohammad; Vardaan, Ajay; Aga, Pallavi

    2014-01-01

    Osteogenesis imperfecta is a genetic disorder characterised by fragility and multiple fractures of bones. Clinical signs and symptoms vary depending on the type of disease. Fractures of facial bones are rare compared with load-bearing long bones. We report a case of fracture of the mandible during yawning which was managed by open reduction and internal fixation. PMID:25103485

  5. Traumatic and spontaneous scleral rupture and uveal prolapse in osteogenesis imperfecta.

    PubMed

    Pirouzian, Amir; O'Halloran, Henry; Scher, Colin; Jockin, Yvett; Yaghmai, Reza

    2007-01-01

    Three cases of severe globe injuries due to scleral fragility in osteogenesis imperfecta patients between the ages of 4 and 15 years are reported. Patient 1 had complete loss of vision. Patients 2 and 3 suffered non-sight-threatening scleral perforation. All 3 patients had no previous knowledge of recommendation for eyewear protection. PMID:17913179

  6. CRTAP AND LEPRE1 MUTATIONS IN RECESSIVE OSTEOGENESIS IMPERFECTA

    PubMed Central

    Baldridge, Dustin; Schwarze, Ulrike; Morello, Roy; Lennington, Jennifer; Bertin, Terry K.; Pace, James M.; Pepin, Melanie G.; Weis, MaryAnn; Eyre, David R.; Walsh, Jennifer; Lambert, Deborah; Green, Andrew; Robinson, Haynes; Michelson, Melonie; Houge, Gunnar; Lindman, Carl; Martin, Judith; Ward, Jewell; Lemyre, Emmanuelle; Mitchell, John J.; Krakow, Deborah; Rimoin, David L.; Cohn, Daniel H.; Byers, Peter H.; Lee, Brendan

    2009-01-01

    Autosomal dominant osteogenesis imperfecta (OI) is caused by mutations in the genes (COL1A1 or COL1A2) encoding the chains of type I collagen. Recently, dysregulation of hydroxylation of a single proline residue at position 986 of both the triple-helical domains of type I collagen α1(I) and type II collagen α1(II) chains has been implicated in the pathogenesis of recessive forms of OI. Two proteins, CRTAP, or cartilage-associated protein, and prolyl-3-hydroxylase-1 (P3H1, encoded by the LEPRE1 gene) form a complex that performs the hydroxylation and brings the prolyl cis-trans isomerase cyclophilin-B (CYPB) to the unfolded collagen. In our screen of 78 subjects diagnosed with OI type II or III, we identified three probands with mutations in CRTAP and sixteen with mutations in LEPRE1. The latter group includes a mutation in patients from the Irish Traveller population, a genetically isolated community with increased incidence of OI. The clinical features resulting from CRTAP or LEPRE1 loss of function mutations were difficult to distinguish at birth. Infants in both groups had multiple fractures, decreased bone modeling (affecting especially the femurs), and extremely low bone mineral density. Interestingly, “popcorn” epiphyses may reflect underlying cartilaginous and bone dysplasia in this form of OI. These results expand the range of CRTAP/LEPRE1 mutations that result in recessive OI and emphasize the importance of distinguishing recurrence of severe OI of recessive inheritance from those that result from parental germline mosaicism for COL1A1 or COL1A2 mutations. PMID:18566967

  7. Pamidronate Affects the Mandibular Cortex of Children with Osteogenesis Imperfecta

    PubMed Central

    Apolinário, A.C.; Figueiredo, P.T.; Guimarães, A.T.; Acevedo, A.C.; Castro, L.C.; Paula, A.P.; Paula, L.M.; Melo, N.S.; Leite, A.F.

    2015-01-01

    We hypothesized that mandibular cortical width (MCW) is smaller in children with osteogenesis imperfecta (OI) than in healthy children and that pamidronate can improve the cortical mandibular thickness. The aim of this study was to assess changes in the MCW on dental panoramic radiographs (DPRs) of children with normal bone mineral density (BMD) and with OI. We also compared the MCW of children with different types of OI regarding the number of pamidronate cycles and age at the beginning of treatment. MCW measurements were retrospectively obtained from 197 DPRs of 66 children with OI types I, III, and IV who were in treatment with a comparable dosage of cyclical intravenous pamidronate between 2007 and 2013. The control group had 92 DPRs from normal BMD children. Factorial analysis of variance was used to compare MCW measurements among different age groups and between sexes and also to compare MCW measurements of children with different types of OI among different pamidronate cycles and age at the beginning of treatment. No significant differences in results were found between male and female subjects in both OI and healthy children, so they were evaluated altogether (P > 0.05). There was an increase of MCW values related to aging in all normal BMD and OI children but on a smaller scale in children with OI types I and III. Children with OI presented lower mean MCW values than did children with normal BMD at the beginning of treatment (P < 0.05). A linear model estimated the number of pamidronate cycles necessary to achieve mean MCW values equivalent to those of healthy children. The thinning of the mandibular cortex depended on the number of pamidronate cycles, the type of OI, and the age at the beginning of treatment. DPRs could thus provide a way to identify cyclic pamidronate treatment outcomes in patients with OI. PMID:25608973

  8. Mutations in patients with osteogenesis imperfecta from consanguineous Indian families.

    PubMed

    Stephen, Joshi; Girisha, Katta Mohan; Dalal, Ashwin; Shukla, Anju; Shah, Hitesh; Srivastava, Priyanka; Kornak, Uwe; Phadke, Shubha R

    2015-01-01

    Osteogenesis imperfecta (OI) is a spectrum of genetic disorders with decreased bone density and bone fragility. Most of the cases of OI are inherited in autosomal dominant fashion with mutations in COL1A1 or COL1A2 genes. Over last few years, twelve genes for autosomal recessive OI have been identified. In this study we have evaluated seven patients with OI from consanguineous Indian families. Homozygosity mapping using SNP microarray was done and selected candidate genes were sequenced. Candidate genes were identified in four out of seven patients studied. Four mutations, namely; a homozygous non-sense (p.Q178*) and a deletion (p.F277del) mutations in SERPINF1 gene, a missense mutation (p.M101K) in PPIB gene and a nonsense mutation (p.E45*) in CRTAP gene were identified. In three patients for whom the regions of homozygosity did not reveal any known autosomal recessive OI genes, exome sequencing was performed and we identified a known missense mutation (p.G1012S) in COL1A2 gene in one of the patients. As WNT1 gene was not properly covered in exome sequencing in one patient, the gene was sequenced and a homozygous in-frame deletion of four amino acids (p.Phe176_Leu179del) was identified. In one of the three cases the exome sequencing did not reveal a mutation in any known OI genes, suggesting the possibility of mutations in an unidentified gene. The phenotypes of all the cases are described. This work proves the power of homozygosity mapping followed by candidate gene sequencing approach for clinical application in consanguineous families. PMID:25450603

  9. Osteogenesis imperfecta and clubfoot—a rare combination

    PubMed Central

    Persiani, Pietro; Ranaldi, Filippo Maria; Martini, Lorena; Zambrano, Anna; Celli, Mauro; D’Eufemia, Patrizia; Villani, Ciro

    2016-01-01

    Abstract Background: Osteogenesis imperfecta (OI) is a rare congenital genetic osteodystrophy, which has a prevalence of 1:20,000. OI is caused by the mutation of the COL1A1/COL1A2 genes, leading to a deficit of quality and/or quantity in the synthesis of procollagen-α type 1. Seven different forms of diverse clinical entity have been classified by Sillence and Glorieux, although, recently, up to 11 forms characterized by different genetic mutations have been recognized. Patients with OI suffer from extreme bone fragility and osteoporosis, which often predisposes them to frequent fractures. This paper presents the case of a child with OI type IV who, at birth, was also diagnosed with a severe clubfoot (congenital talipes equinovarus) grade III. Patient's mother also suffers from OI type IV. Methods: The treatment was started by placing femoro-podalic corrective casts, according to the Ponseti method, but some unexpected problems occurred during this treatment. When the patient was 3 months of age, we decided to correct the clubfoot before the time limit planned, performing a bilateral posteromedial surgical release. Results: Three weeks after surgery the casts were removed and replaced with bilateral Spica cast-like braces. On the 6th postoperative week, the patient began wearing Bebax corrective shoes, after 1 year ambidextrous orthopedic shoes. Now, he is 2 years old and has started to walk properly without any orthesis. Conclusion: In the presence of an orthopedic pathology associated with OI, it is recommended to manage the patient according to the underlying pathology, always considering the bone fragility associated with OI. The final surgical treatment to correct the clubfoot can be done earlier, if necessary. In our opinion, this uncommon association between OI and clubfoot is non-syndromic. This means that the two congenital diseases are not necessarily included in a singular uncommon genetic syndrome, but the clubfoot was caused by multifactorial causes

  10. Transgenic mouse model of the mild dominant form of osteogenesis imperfecta.

    PubMed Central

    Bonadio, J; Saunders, T L; Tsai, E; Goldstein, S A; Morris-Wiman, J; Brinkley, L; Dolan, D F; Altschuler, R A; Hawkins, J E; Bateman, J F

    1990-01-01

    Osteogenesis imperfecta type I is a mild, dominantly inherited, connective tissue disorder characterized by bone fragility. Mutations in type I collagen account for all known cases. In Mov-13 mice, integration of a murine retrovirus within the first intron of the alpha 1(I) collagen gene results in a null allele blocked at the level of transcription. This study demonstrates that mutant mice heterozygous for the null allele are a model of osteogenesis imperfecta type I. A defect in type I collagen production is associated with dominant-acting morphological and functional defects in mineralized and nonmineralized connective tissue and with progressive hearing loss. The model provides an opportunity to investigate the effect of a reduced amount of type I collagen on the structure and integrity of extracellular matrix. It also may represent a system in which therapeutic strategies to strengthen connective tissue can be developed. Images PMID:2402497

  11. A rare presentation of a child with osteogenesis imperfecta and congenital laryngomalacia for herniotomy

    PubMed Central

    Chandran, Roshith; Dave, Nandini; Padvi, Amit; Garasia, Madhu

    2011-01-01

    Sometimes anaesthesiologists come across rare congenital anomalies in their practice. The inherent complications associated with the disorder necessitate tailor-made approaches for providing anaesthesia to even seemingly simple surgical interventions. Here, we share our experience of anaesthesia management of an infant with congenital laryngomalacia and recently diagnosed osteogenesis imperfecta type 1 who had presented to us with an acute abdomen for a semi-emergency herniotomy. PMID:22174477

  12. A rare presentation of a child with osteogenesis imperfecta and congenital laryngomalacia for herniotomy.

    PubMed

    Chandran, Roshith; Dave, Nandini; Padvi, Amit; Garasia, Madhu

    2011-09-01

    Sometimes anaesthesiologists come across rare congenital anomalies in their practice. The inherent complications associated with the disorder necessitate tailor-made approaches for providing anaesthesia to even seemingly simple surgical interventions. Here, we share our experience of anaesthesia management of an infant with congenital laryngomalacia and recently diagnosed osteogenesis imperfecta type 1 who had presented to us with an acute abdomen for a semi-emergency herniotomy. PMID:22174477

  13. The epitheliogenesis imperfecta locus maps to equine chromosome 8 in American Saddlebred horses.

    PubMed

    Lieto, L D; Cothran, E G

    2003-01-01

    Epitheliogenesis imperfecta (EI) is a hereditary junctional mechanobullous disease that occurs in newborn American Saddlebred foals. The pathological signs of epitheliogenesis imperfecta closely match a similar disease in humans known as Herlitz junctional epidermolysis bullosa, which is caused by a mutation in one of the genes (LAMA3, LAMB3 and LAMC2) coding for the subunits of the laminin 5 protein (laminin alpha3, laminin beta3 and laminin gamma2). The LAMA3 gene has been assigned to equine chromosome 8 and LAMB3 and LAMC2 have been mapped to equine chromosome 5. Linkage disequilibrium between microsatellite markers that mapped to equine chromosome 5 and equine chromosome 8 and the EI disease locus was tested in American Saddlebred horses. The allele frequencies of microsatellite alleles at 11 loci were determined for both epitheliogenesis imperfecta affected and unaffected populations of American Saddlebred horses by genotyping and direct counting of alleles. These were used to determine fit to Hardy-Weinberg equilibrium for control and EI populations using Chi square analysis. Two microsatellite loci located on equine chromosome 8q, ASB14 and AHT3, were not in Hardy-Weinberg equilibrium in affected American Saddlebred horses. In comparison, all of the microsatellite markers located on equine chromosome 5 were in Hardy-Weinberg equilibrium in affected American Saddlebred horses. This suggested that the EI disease locus was located on equine chromosome 8q, where LAMA3 is also located. PMID:14970704

  14. A cephalometric method to diagnosis the craniovertebral junction abnormalities in osteogenesis imperfecta patients

    PubMed Central

    Ríos-Rodenas, Mercedes; Gutiérrez-Díez, María-Pilar; Feijóo, Gonzalo; Mourelle, Maria-Rosa; Garcilazo, Mario; Ortega-Aranegui, Ricardo

    2015-01-01

    Osteogenesis imperfecta (OI) is a hereditary bone fragility disorder that in most patients is caused by mutations affecting collagen type I. Their typical oral and craneofacial characteristics (Dentinogenesis imperfecta type I and class III malocclusion), involve the dentist in the multidisciplinary team that treat these patients. It is usual to perform lateral skull radiographs for the orthodontic diagnosis. In addition, this radiograph is useful to analyse the junctional area between skull base and spine, that could be damaged in OI. Pathology in the craneovertebral junction (CVJ) is a serious complication of OI with a prevalence ranging from rare to 37%. To diagnosis early skull base anomalies in these patients, previously the neurological symptoms have been appear, we make a simple cephalometric analysis of the CVJ. This method has four measurements and one angle. Once we calculate the values of the OI patient, we compare the result with the mean and the standard deviations of an age-appropriate average in healthy controls. If the patient has a result more than 2,5 SDs above the age-appropriate average in healthy controls, we should to refer the patient to his/her pediatrician or neurologist. These doctors have to consider acquiring another diagnostic images to be used to determine cranial base measurements with more reliability. Thereby, dentists who treat these patients, must be aware of the normal radiological anatomy of the cervical spine on the lateral cephalogram. Key words:Osteogenesis imperfecta, craniovertebral junction, cephalometric. PMID:25810828

  15. A cephalometric method to diagnosis the craniovertebral junction abnormalities in osteogenesis imperfecta patients.

    PubMed

    Ríos-Rodenas, Mercedes; de Nova, Joaquín; Gutiérrez-Díez, María-Pilar; Feijóo, Gonzalo; Mourelle, Maria-Rosa; Garcilazo, Mario; Ortega-Aranegui, Ricardo

    2015-02-01

    Osteogenesis imperfecta (OI) is a hereditary bone fragility disorder that in most patients is caused by mutations affecting collagen type I. Their typical oral and craneofacial characteristics (Dentinogenesis imperfecta type I and class III malocclusion), involve the dentist in the multidisciplinary team that treat these patients. It is usual to perform lateral skull radiographs for the orthodontic diagnosis. In addition, this radiograph is useful to analyse the junctional area between skull base and spine, that could be damaged in OI. Pathology in the craneovertebral junction (CVJ) is a serious complication of OI with a prevalence ranging from rare to 37%. To diagnosis early skull base anomalies in these patients, previously the neurological symptoms have been appear, we make a simple cephalometric analysis of the CVJ. This method has four measurements and one angle. Once we calculate the values of the OI patient, we compare the result with the mean and the standard deviations of an age-appropriate average in healthy controls. If the patient has a result more than 2,5 SDs above the age-appropriate average in healthy controls, we should to refer the patient to his/her pediatrician or neurologist. These doctors have to consider acquiring another diagnostic images to be used to determine cranial base measurements with more reliability. Thereby, dentists who treat these patients, must be aware of the normal radiological anatomy of the cervical spine on the lateral cephalogram. Key words:Osteogenesis imperfecta, craniovertebral junction, cephalometric. PMID:25810828

  16. Evolution of Klk4 and enamel maturation in eutherians.

    PubMed

    Kawasaki, Kazuhiko; Hu, Jan C-C; Simmer, James P

    2014-09-01

    Kallikrein-related peptidase 4 (KLK4) is a secreted serine protease that degrades residual enamel proteins to facilitate their removal by ameloblasts, which increases mineralization and hardens the enamel. Mutations in human KLK4 cause hypomaturation amelogenesis imperfecta. Enamel formed by Klk4 null mice is normal in thickness and prism structure, but the enamel layer retains proteins, is hypomineralized, and undergoes rapid attrition following tooth eruption. We searched multiple databases, retrieved Klk4 and Klk5 from various mammalian genomes, and identified Klk4 in 46 boreoeutherian genomes. In non-Boreoeutheria, Klk4 was detected in only one afrotherian genome (as a pseudogene), and not in the other six afrotherian, two xenarthran, or three marsupial genomes. In contrast, Klk5 was detected in both marsupial and eutherian mammals. Our phylogenetic and mutation rate analyses support the hypothesis that Klk4 arose from Klk5 by gene duplication near the divergence of Afrotheria, Xenarthra and Boreoeutheria, and that functionally-differentiated Klk4 survived only in Boreoeutheria. Afrotherian mammals share the feature of delayed dental eruption relative to boreoeutherian mammals. KLK4 shortens the time required for enamel maturation and could have alleviated negative selection following mutations that resulted in thicker enamel or earlier tooth eruption, without reducing enamel hardness or causing dental attrition. PMID:25153384

  17. Evolution of Klk4 and enamel maturation in eutherians

    PubMed Central

    Kawasaki, Kazuhiko; Hu, Jan C.-C; Simmer, James P.

    2014-01-01

    Kallikrein-related peptidase 4 (KLK4) is a secreted serine protease that degrades residual enamel proteins to facilitate their removal by ameloblasts, which increases mineralization and hardens the enamel. Mutations in human KLK4 cause hypomaturation amelogenesis imperfecta. Enamel formed by Klk4 null mice is normal in thickness and prism structure, but the enamel layer retains proteins, is hypomineralized, and undergoes rapid attrition following tooth eruption. We searched multiple databases, retrieved Klk4 and Klk5 from various mammalian genomes, and identified Klk4 in 47 boreoeutherian genomes. In non-Boreoeutheria, Klk4 was detected in only one afrotherian genome (as a pseudogene), and not in the other six afrotherian, two xenarthran, or three marsupial genomes. In contrast, Klk5 was detected in both marsupial and eutherian mammals. Our phylogenetic and mutation rate analyses support the hypothesis that Klk4 arose from Klk5 by gene duplication near the divergence of Afrotheria, Xenarthra and Boreoeutheria, and that functionally- differentiated Klk4 survived only in Boreoeutheria. Afrotherian mammals share the feature of delayed dental eruption relative to boreoeutherian mammals. KLK4 shortens the time required for enamel maturation and could have alleviated negative selection following mutations that resulted in thicker enamel or earlier tooth eruption, without reducing enamel hardness or causing dental attrition. PMID:25153384

  18. Critical roles for WDR72 in calcium transport and matrix protein removal during enamel maturation

    PubMed Central

    Wang, Shih-Kai; Hu, Yuanyuan; Yang, Jie; Smith, Charles E; Nunez, Stephanie M; Richardson, Amelia S; Pal, Soumya; Samann, Andrew C; Hu, Jan C-C; Simmer, James P

    2015-01-01

    Defects in WDR72 (WD repeat-containing protein 72) cause autosomal recessive hypomaturation amelogenesis imperfecta. We generated and characterized Wdr72-knockout/lacZ-knockin mice to investigate the role of WDR72 in enamel formation. In all analyses, enamel formed by Wdr72 heterozygous mice was indistinguishable from wild-type enamel. Without WDR72, enamel mineral density increased early during the maturation stage but soon arrested. The null enamel layer was only a tenth as hard as wild-type enamel and underwent rapid attrition following eruption. Despite the failure to further mineralize enamel deposited during the secretory stage, ectopic mineral formed on the enamel surface and penetrated into the overlying soft tissue. While the proteins in the enamel matrix were successfully degraded, the digestion products remained inside the enamel. Interactome analysis of WDR72 protein revealed potential interactions with clathrin-associated proteins and involvement in ameloblastic endocytosis. The maturation stage mandibular incisor enamel did not stain with methyl red, indicating that the enamel did not acidify beneath ruffle-ended ameloblasts. Attachment of maturation ameloblasts to the enamel layer was weakened, and SLC24A4, a critical ameloblast calcium transporter, did not localize appropriately along the ameloblast distal membrane. Fewer blood vessels were observed in the papillary layer supporting ameloblasts. Specific WDR72 expression by maturation stage ameloblasts explained the observation that enamel thickness and rod decussation (established during the secretory stage) are normal in the Wdr72 null mice. We conclude that WDR72 serves critical functions specifically during the maturation stage of amelogenesis and is required for both protein removal and enamel mineralization. PMID:26247047

  19. Surgical technique of double valve replacement in a patient with osteogenesis imperfecta.

    PubMed

    Sumi, Mizuki; Ariyoshi, Tsuneo; Matsukuma, Seiji; Nakaji, Shun; Hashizume, Koji; Kinoshita, Naoe; Eishi, Kiyoyuki

    2016-04-01

    Osteogenesis imperfecta (OI) is an inherited connective tissue disorder. Left ventricle dilation and valve insufficiency are complications in patients with OI and such patients are at high risk of mortality and complications related to bleeding and tissue friability during cardiac surgery. Valve dehiscence due to extreme friability of the annulus is a major complication of cardiac valve replacement with OI. We describe OI in a male patient who underwent double valve replacement with mechanical valves using a tissue protective method to prevent valve dehiscence. PMID:25028093

  20. Mandibular lengthening by distraction osteogenesis in the setting of osteogenesis imperfecta.

    PubMed

    Black, Jonathan S; Denny, Arlen D

    2015-01-01

    Osteogenesis imperfecta (OI) is an inherited disorder characterized by bone fragility and deformity. The craniofacial skeleton may be involved either primarily or by result of a concomitant diagnosis. Distraction osteogenesis has emerged as a versatile reconstructive option for many craniofacial deformities. Mandibular lengthening by distraction has not been reported in a patient with OI. We present a patient in whom mandibular lengthening was successfully performed twice for hemifacial microsomia. Bilateral lengthening was initially performed with successful airway improvement. This was followed by transport distraction on the more severely affected side for condylar reconstruction. Successful mandibular lengthening by distraction is possible in the setting of OI. PMID:25565236

  1. Effect of osteogenesis imperfecta mutations in tropocollagen molecule on strength of biomimetic tropocollagen-hydroxyapatite nanocomposites

    NASA Astrophysics Data System (ADS)

    Dubey, Devendra K.; Tomar, Vikas

    2010-01-01

    Osteogenesis Imperfecta (OI) is a genetic disorder that affects cellular synthesis of Type-I collagen fibrils and causes extreme bone fragility. This study reports the effects of OI mutations in Tropocollagen (TC) molecules on strength of model Tropocollagen-Hydroxyapatite biomaterials with two different mineral [hydroxyapatite (HAP)] distributions using three dimensional atomistic simulations. Results show that the effect of TC mutations on the strength of TC-HAP biomaterials is insignificant. Instead, change in mineral distribution showed significant impact on the overall strength of TC-HAP biomaterials. Study suggests that TC mutations manifest themselves by changing the mineral distribution during hydroxyapatite growth and nucleation period.

  2. The role of dual energy x-ray absorptiometry in aiding the diagnosis of pediatric osteogenesis imperfecta.

    PubMed

    Moore, M S; Minch, C M; Kruse, R W; Harcke, H T; Jacobson, L; Taylor, A

    1998-12-01

    The role of dual energy x-ray absorptiometry (DEXA) in the evaluation of the pediatric patient with multiple fractures has not been well established. We retrospectively examined the medical records of 45 patients who had presented to our institution with multiple fractures of unknown cause, who were not known to have osteogenesis imperfecta, and who had obtained DEXA as part of their evaluation. Of these, 26 patients had sufficient clinical data for inclusion in this study. Patients underwent DEXA of the anteroposterior spine and whole body. A z score was calculated to normalize the DEXA values for age. The diagnosis of osteogenesis imperfecta was correlated with the outcome of each DEXA scan to assess the validity of DEXA as a diagnostic tool. The DEXA of the anteroposterior spine had the highest sensitivity at 91.7%, while DEXA of the whole body had the highest specificity at 100.0%. Decreased bone mineral density may be associated with osteogenesis imperfecta, and DEXA is helpful in detecting low bone mineral density that may be missed on plain radiographs of children with milder forms of osteogenesis imperfecta. PMID:9880097

  3. Investigation of the Human Disease Osteogenesis Imperfecta: A Research-Based Introduction to Concepts and Skills in Biomolecular Analysis

    ERIC Educational Resources Information Center

    Mate, Karen; Sim, Alistair; Weidenhofer, Judith; Milward, Liz; Scott, Judith

    2013-01-01

    A blended approach encompassing problem-based learning (PBL) and structured inquiry was used in this laboratory exercise based on the congenital disease Osteogenesis imperfecta (OI), to introduce commonly used techniques in biomolecular analysis within a clinical context. During a series of PBL sessions students were presented with several…

  4. COL1A1 mutation analysis in Lithuanian patients with osteogenesis imperfecta.

    PubMed

    Benusiené, Egle; Kucinskas, Vaidutis

    2003-01-01

    Osteogenesis imperfecta (OI) is a generalised disorder of connective tissue characterised by an increased fragility of bones and also manifested in other tissues containing collagen type I, by blue sclera, hearing loss, dentinogenesis imperfecta, hyperextensible joints, hernias and easy bruising. OI is dominantly inherited and results in >90% OI cases, caused by mutations in one of the two genes COL1A1 or COL1A2 coding for type I procollagen. The Lithuanian OI database comprises 147 case records covering the period of 1980 - 2001. Clinical and genealogical analysis of OI cases/families from Lithuania available for examination revealed 18 familial cases of OI type I and 22 sporadic cases: OI type II (3 cases), OI type III (11 cases) and OI type I (8 cases). As a result of their molecular genetic investigation, 11 mutations were identified in the COL1A1 gene in 13 unrelated patients. Of them, nine mutations (E500X, G481A, c.2046insCTCTCTAG, c.1668delT, c.1667insC, c.4337insC, IVS19+1G > A, IVS20-2A > G, IVS22-1G > T) appeared to be novel, i.e. not yet registered in the Human Type I and Type III Collagen Mutations Database (http://www.le.ac.uk/genetics/collagen). PMID:12590186

  5. Combined Treatment with Laser Sintering and Zirconium: A Case Report of Dentinogenesis Imperfecta

    PubMed Central

    Sahin, Cem; Akgün, Özlem Marti; Basak, Feridun

    2013-01-01

    Osteogenesis imperfecta (OI) is a heterogeneous disorder of connective tissue that manifests mainly as skeletal deformity and bone fragility. Dentinogenesis imperfecta (DI) is sometimes an accompanying symptom of OI. The treatment protocol of these patients varies according to the clinical appearance. The case report here describes complete mouth rehabilitation of an 18-year-old male patient with OI and DI using direct metal laser sintering (DMLS) technique of metal-ceramic restorations and zirconium all-ceramic crowns. DMLS is an additive metal fabrication technology that is simpler, more precise, and healthier than conventional manufacturing and can be remarkably cost effective. Moreover, the technique affords highly accurate production of fixed partial dentures with ideal marginal fit and excellent mechanical properties. The patient was treated using a multidisciplinary strategy that focused on controlling caries, protecting teeth from further wear, obtaining an appropriate vertical dimension, and providing soft tissue support to return the facial profile to a normal appearance using new technology in the field of prosthetics. PMID:23533828

  6. Craniofacial and Dental Defects in the Col1a1Jrt/+ Mouse Model of Osteogenesis Imperfecta.

    PubMed

    Eimar, H; Tamimi, F; Retrouvey, J-M; Rauch, F; Aubin, J E; McKee, M D

    2016-07-01

    Certain mutations in the COL1A1 and COL1A2 genes produce clinical symptoms of both osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS) that include abnormal craniofacial growth, dental malocclusion, and dentinogenesis imperfecta. A mouse model (Col1a1(Jrt)/+) was recently developed that had a skeletal phenotype and other features consistent with moderate-to-severe OI and also with EDS. The craniofacial phenotype of 4- and 20-wk-old Col1a1(Jrt)/+ mice and wild-type littermates was assessed by micro-computed tomography (µCT) and morphometry. Teeth and the periodontal ligament compartment were analyzed by µCT, light microscopy/histomorphometry, and electron microscopy. Over time, at 20 wk, Col1a1(Jrt)/+ mice developed smaller heads, a shortened anterior cranial base, class III occlusion, and a mandibular side shift with shorter morphology in the masticatory region (maxilla and mandible). Col1a1(Jrt)/+ mice also had changes in the periodontal compartment and abnormalities in the dentin matrix and mineralization. These findings validate Col1a1(Jrt)/+ mice as a model for OI and EDS in humans. PMID:26951553

  7. Bulbous epiphysis and popcorn calcification as related to growth plate differentiation in osteogenesis imperfecta

    PubMed Central

    Brizola, Evelise; McCarthy, Edward; Shapiro, Jay Robert

    2015-01-01

    Summary Background Osteogenesis Imperfecta (OI) is an heritable systemic disorder of connective tissue due to different sequence variants in genes affecting both the synthesis of type I collagen and osteoblast function. Dominant and recessive inheritance is recognized. Approximately 90% of the OI cases are due to mutations in COL1A1/A2 genes. We clinically and radiologically describes an adult male with type III osteogenesis imperfecta who presents a rare bone dysplasia termed bulbous epiphyseal deformity in association with popcorn calcifications. Popcorn calcifications may occur with bulbous epiphyseal deformity or independently. Methods Molecular analysis was performed for COL1A1, COL1A2, LEPRE1 and WNT1 genes. Results An uncommon COL1A1 mutation was identified. Clinical and radiological exams confirmed a distinctive bulbous epiphyseal deformity with popcorn calcifications in distal femurs. We have identified four additional OI patients reported in current literature, whose X-rays show bulbous epiphyseal deformity related to mutations in CR-TAP, LEPRE1 and WNT1 genes. Conclusion The mutation identified here had been previously described twice in OI patients and no previous correlation with bulbous epiphyseal deformity was described. The occurrence of this bone dysplasia focuses attention on alterations in normal growth plate differentiation and the subsequent effect on endochondral bone formation in OI. PMID:26604951

  8. How tough is Brittle Bone? Investigating Osteogenesis Imperfecta in Mouse Bone††

    PubMed Central

    Carriero, A.; Zimmermann, E. A.; Paluszny, A.; Tang, S. Y.; Bale, H.; Busse, B.; Alliston, T.; Kazakia, G.

    2015-01-01

    The multiscale hierarchical structure of bone is naturally optimized to resist fractures. In osteogenesis imperfecta, or brittle bone disease, genetic mutations affect the quality and/or quantity of collagen, dramatically increasing bone fracture risk. Here we reveal how the collagen defect results in bone fragility in a mouse model of osteogenesis imperfecta (oim), which has homotrimeric α1(I) collagen. At the molecular level we attribute the loss in toughness to a decrease in the stabilizing enzymatic crosslinks and an increase in non-enzymatic crosslinks, which may break prematurely inhibiting plasticity. At the tissue level, high vascular canal density reduces the stable crack growth, and extensive woven bone limits the crack-deflection toughening during crack growth. This demonstrates how modifications at the bone molecular level have ramifications at larger length scales affecting the overall mechanical integrity of the bone; thus, treatment strategies have to address multiscale properties in order to regain bone toughness. In this regard, findings from the heterozygous oim bone, where defective as well as normal collagen are present, suggest that increasing the quantity of healthy collagen in these bones helps to recover toughness at the multiple length scales. PMID:24420672

  9. Next-generation sequencing of common osteogenesis imperfecta-related genes in clinical practice.

    PubMed

    Árvai, Kristóf; Horváth, Péter; Balla, Bernadett; Tobiás, Bálint; Kató, Karina; Kirschner, Gyöngyi; Klujber, Valéria; Lakatos, Péter; Kósa, János P

    2016-01-01

    Next generation sequencing (NGS) is a rapidly developing area in genetics. Utilizing this technology in the management of disorders with complex genetic background and not recurrent mutation hot spots can be extremely useful. In this study, we applied NGS, namely semiconductor sequencing to determine the most significant osteogenesis imperfecta-related genetic variants in the clinical practice. We selected genes coding collagen type I alpha-1 and-2 (COL1A1, COL1A2) which are responsible for more than 90% of all cases. CRTAP and LEPRE1/P3H1 genes involved in the background of the recessive forms with relatively high frequency (type VII and VIII) represent less than 10% of the disease. In our six patients (1-41 years), we identified 23 different variants. We found a total of 14 single nucleotide variants (SNV) in COL1A1 and COL1A2, 5 in CRTAP and 4 in LEPRE1. Two novel and two already well-established pathogenic SNVs have been identified. Among the newly recognized mutations, one results in an amino acid change and one of them is a stop codon. We have shown that a new full-scale cost-effective NGS method can be developed and utilized to supplement diagnostic process of osteogenesis imperfecta with molecular genetic data in clinical practice. PMID:27335225

  10. Next-generation sequencing of common osteogenesis imperfecta-related genes in clinical practice

    PubMed Central

    Árvai, Kristóf; Horváth, Péter; Balla, Bernadett; Tobiás, Bálint; Kató, Karina; Kirschner, Gyöngyi; Klujber, Valéria; Lakatos, Péter; Kósa, János P.

    2016-01-01

    Next generation sequencing (NGS) is a rapidly developing area in genetics. Utilizing this technology in the management of disorders with complex genetic background and not recurrent mutation hot spots can be extremely useful. In this study, we applied NGS, namely semiconductor sequencing to determine the most significant osteogenesis imperfecta-related genetic variants in the clinical practice. We selected genes coding collagen type I alpha-1 and-2 (COL1A1, COL1A2) which are responsible for more than 90% of all cases. CRTAP and LEPRE1/P3H1 genes involved in the background of the recessive forms with relatively high frequency (type VII and VIII) represent less than 10% of the disease. In our six patients (1–41 years), we identified 23 different variants. We found a total of 14 single nucleotide variants (SNV) in COL1A1 and COL1A2, 5 in CRTAP and 4 in LEPRE1. Two novel and two already well-established pathogenic SNVs have been identified. Among the newly recognized mutations, one results in an amino acid change and one of them is a stop codon. We have shown that a new full-scale cost-effective NGS method can be developed and utilized to supplement diagnostic process of osteogenesis imperfecta with molecular genetic data in clinical practice. PMID:27335225

  11. What every clinical geneticist should know about testing for osteogenesis imperfecta in suspected child abuse cases.

    PubMed

    Pepin, Melanie G; Byers, Peter H

    2015-12-01

    Non-accidental injury (NAI) is a major medical concern in the United States. One of the challenges in evaluation of children with unexplained fractures is that genetic forms of bone fragility are one of the differential diagnoses. Infants who present with fractures with mild forms of osteogenesis imperfecta (OI) (OI type I or OI type IV), the most common genetic form of bone disease leading to fractures might be missed if clinical evaluation alone is used to make the diagnosis. Diagnostic clinical features (blue sclera, dentinogenesis imperfecta, Wormian bones on X-rays or positive family history) may not be present or apparent at the age of evaluation. The evaluating clinician faces the decision about whether genetic testing is necessary in certain NAI cases. In this review, we outline clinical presentations of mild OI and review the history of genetic testing for OI in the NAI versus OI setting. We summarize our data of molecular testing in the Collagen Diagnostic Laboratory (CDL) from 2008 to 2014 where NAI was noted on the request for DNA sequencing of COL1A1 and COL1A2. We provide recommendations for molecular testing in the NAI versus OI setting. First, DNA sequencing of COL1A1, COL1A2, and IFITM5 simultaneously and duplication/deletion testing is recommended. If a causative variant is not identified, in the absence of a pathologic clinical phenotype, no additional gene testing is indicated. If a VUS is found, parental segregation studies are recommended. PMID:26566591

  12. Osteogenesis imperfecta type III in South Africa: Psychosocial challenges.

    PubMed

    Stephen, L X G; Roberts, T; Van Hayden, E; Chetty, M

    2016-01-01

    Individuals with osteogenesis imperfecta type III (OI III) are severely physically disabled due to frequent fracturing. Their disability poses numerous barriers that challenge their social development. Despite these limitations, several affected persons are able to rise above these problems and achieve success in their personal and professional life. This outcome is directly relevant to their psychosocial development.The achievements of five individuals with OI III living in Cape Town are highlighted in this article, as well as the challenges that they have experienced and continue to experience in their daily lives. The authors intend to promulgate understanding of the psychosocial circumstances of affected persons, thereby facilitating the deployment of appropriate efforts and resources to address these challenges. PMID:27245537

  13. [Sliding centro-medullary nailing. Application to the treatment of severe forms of osteogenesis imperfecta].

    PubMed

    Metaizeau, J P

    1987-01-01

    In osteogenesis Imperfecta, the bowing of bones concures to increase their fragility. In order to avoid bowing of bones, Sofield, followed by Bailey have proposed centro medullary nailing. The pins used by Sofield do not expand and repeated changes are necessary. The expanding rods used by Bailey are to large and they can't be used in neonates. The author describe a new technique of bipolar centro medullary pinning. Two bowed K. Wires are introduced in the centromedullary canal, the first one through the proximal epiphysis, the second one through the distal epiphysis. During growth, each pin migrates distally and the osteosynthesis expand regularly. The technique can be used in the neonates and protects their bone from progressive bowing. PMID:3442930

  14. MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta.

    PubMed

    Lindert, Uschi; Cabral, Wayne A; Ausavarat, Surasawadee; Tongkobpetch, Siraprapa; Ludin, Katja; Barnes, Aileen M; Yeetong, Patra; Weis, Maryann; Krabichler, Birgit; Srichomthong, Chalurmpon; Makareeva, Elena N; Janecke, Andreas R; Leikin, Sergey; Röthlisberger, Benno; Rohrbach, Marianne; Kennerknecht, Ingo; Eyre, David R; Suphapeetiporn, Kanya; Giunta, Cecilia; Marini, Joan C; Shotelersuk, Vorasuk

    2016-01-01

    Osteogenesis imperfecta (OI) is a collagen-related bone dysplasia. We identified an X-linked recessive form of OI caused by defects in MBTPS2, which encodes site-2 metalloprotease (S2P). MBTPS2 missense mutations in two independent kindreds with moderate/severe OI cause substitutions at highly conserved S2P residues. Mutant S2P has normal stability, but impaired functioning in regulated intramembrane proteolysis (RIP) of OASIS, ATF6 and SREBP transcription factors, consistent with decreased proband secretion of type I collagen. Further, hydroxylation of the collagen lysine residue (K87) critical for crosslinking is reduced in proband bone tissue, consistent with decreased lysyl hydroxylase 1 in proband osteoblasts. Reduced collagen crosslinks presumptively undermine bone strength. Also, proband osteoblasts have broadly defective differentiation. These mutations provide evidence that RIP plays a fundamental role in normal bone development. PMID:27380894

  15. Identification and in vivo functional characterization of novel compound heterozygous BMP1 variants in osteogenesis imperfecta.

    PubMed

    Cho, Sung Yoon; Asharani, P V; Kim, Ok-Hwa; Iida, Aritoshi; Miyake, Noriko; Matsumoto, Naomichi; Nishimura, Gen; Ki, Chang-Seok; Hong, Geehay; Kim, Su Jin; Sohn, Young Bae; Park, Sung Won; Lee, Jieun; Kwun, Younghee; Carney, Thomas J; Huh, Rimm; Ikegawa, Shiro; Jin, Dong-Kyu

    2015-02-01

    Osteogenesis imperfecta (OI) comprises a heterogeneous group of disorders that are characterized by susceptibility to bone fractures, and range in severity from a subtle increase in fracture frequency to death in the perinatal period. Most patients have defects in type I collagen biosynthesis with autosomal-dominant inheritance, but many autosomal-recessive genes have been reported. We applied whole-exome sequencing to identify mutations in a Korean OI patient who had an umbilical hernia, frequent fractures, a markedly short stature, delayed motor development, scoliosis, and dislocation of the radial head, with a bowed radius and ulna. We identified two novel variants in the BMP1 gene: c.808A>G and c.1297G>T. The former variant caused a missense change p.(Met270Val) and the latter variant caused the skipping of exon 10. The hypofunctional nature of the two variants was demonstrated in a zebrafish assay. PMID:25402547

  16. Bone tissue ultrastructural defects in a mouse model for osteogenesis imperfecta: a Raman spectroscopy study

    NASA Astrophysics Data System (ADS)

    Chen, Tsoching; Kozloff, Kenneth M.; Goldstein, Steven A.; Morris, Michael D.

    2004-07-01

    Osteogenesis imperfecta (OI) is genetic defect in which the genes that code for the α1(I) or α2(I) chains of type I collagen are defective. The defects often result in substitution of a bulky amino acid for glycine, causing formation of collagen that can not form the normal triple helix. Depending on the details of the defects, the outcomes range from controllable to lethal. This study focuses on OI type IV, a more common and moderately severe form of the disease. People with the disease have a substantial increase in the risk and rate of fracture. We examine the spectroscopic consequences of these defects, using a mouse model (BRTL) that mimics OI type IV. We compare Raman images from tibial cortical tissue of wild-type mice and BRTL mice with single copy of mutation and show that both mineral to matrix ratios and collagen inter-fibril cross-links are different in wild-type and mutant mice.

  17. Osteogenesis Imperfecta Diagnosed from Mandibular and Lower Limb Fractures: A Case Report.

    PubMed

    Kobayashi, Yoshikazu; Satoh, Koji; Mizutani, Hideki

    2016-06-01

    Osteogenesis imperfecta (OI) is a congenital disease characterized by bone fragility and low bone mass. Despite the variety of its manifestation and severity, facial fractures occur very infrequently. Here, we report a case of an infant diagnosed with OI after mandibular and lower limb fractures. A boy aged 1 year and 3 months was brought to his neighboring hospital with a complaint of facial injury. He was transferred to our hospital to undergo operation 3 days later. Computed tomography images revealed multiple mandibular fractures including complete fracture in the symphysis and dislocated condylar fracture on the right side. Open reduction and internal fixation with absorbable implants was performed 7 days after injury. He fractured his right lower limb 2 months later. He was diagnosed with OI type IA by an orthopedist. He will be administered bone-modifying agents if he suffers from frequent fractures. PMID:27162570

  18. MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta

    PubMed Central

    Lindert, Uschi; Cabral, Wayne A.; Ausavarat, Surasawadee; Tongkobpetch, Siraprapa; Ludin, Katja; Barnes, Aileen M.; Yeetong, Patra; Weis, Maryann; Krabichler, Birgit; Srichomthong, Chalurmpon; Makareeva, Elena N.; Janecke, Andreas R.; Leikin, Sergey; Röthlisberger, Benno; Rohrbach, Marianne; Kennerknecht, Ingo; Eyre, David R.; Suphapeetiporn, Kanya; Giunta, Cecilia; Marini, Joan C.; Shotelersuk, Vorasuk

    2016-01-01

    Osteogenesis imperfecta (OI) is a collagen-related bone dysplasia. We identified an X-linked recessive form of OI caused by defects in MBTPS2, which encodes site-2 metalloprotease (S2P). MBTPS2 missense mutations in two independent kindreds with moderate/severe OI cause substitutions at highly conserved S2P residues. Mutant S2P has normal stability, but impaired functioning in regulated intramembrane proteolysis (RIP) of OASIS, ATF6 and SREBP transcription factors, consistent with decreased proband secretion of type I collagen. Further, hydroxylation of the collagen lysine residue (K87) critical for crosslinking is reduced in proband bone tissue, consistent with decreased lysyl hydroxylase 1 in proband osteoblasts. Reduced collagen crosslinks presumptively undermine bone strength. Also, proband osteoblasts have broadly defective differentiation. These mutations provide evidence that RIP plays a fundamental role in normal bone development. PMID:27380894

  19. Mutations in FKBP10 Cause Recessive Osteogenesis Imperfecta and Bruck Syndrome

    PubMed Central

    Kelley, Brian P; Malfait, Fransiska; Bonafe, Luisa; Baldridge, Dustin; Homan, Erica; Symoens, Sofie; Willaert, Andy; Elcioglu, Nursel; Van Maldergem, Lionel; Verellen-Dumoulin, Christine; Gillerot, Yves; Napierala, Dobrawa; Krakow, Deborah; Beighton, Peter; Superti-Furga, Andrea; De Paepe, Anne; Lee, Brendan

    2011-01-01

    Osteogenesis imperfecta (OI) is a genetic disorder of connective tissue characterized by bone fragility and alteration in synthesis and posttranslational modification of type I collagen. Autosomal dominant OI is caused by mutations in the genes (COL1A1 or COL1A2) encoding the chains of type I collagen. Bruck syndrome is a recessive disorder featuring congenital contractures in addition to bone fragility; Bruck syndrome type 2 is caused by mutations in PLOD2 encoding collagen lysyl hydroxylase, whereas Bruck syndrome type 1 has been mapped to chromosome 17, with evidence suggesting region 17p12, but the gene has remained elusive so far. Recently, the molecular spectrum of OI has been expanded with the description of the basis of a unique posttranslational modification of type I procollagen, that is, 3-prolyl-hydroxylation. Three proteins, cartilage-associated protein (CRTAP), prolyl-3-hydroxylase-1 (P3H1, encoded by the LEPRE1 gene), and the prolyl cis-trans isomerase cyclophilin-B (PPIB), form a complex that is required for fibrillar collagen 3-prolyl-hydroxylation, and mutations in each gene have been shown to cause recessive forms of OI. Since then, an additional putative collagen chaperone complex, composed of FKBP10 (also known as FKBP65) and SERPINH1 (also known as HSP47), also has been shown to be mutated in recessive OI. Here we describe five families with OI-like bone fragility in association with congenital contractures who all had FKBP10 mutations. Therefore, we conclude that FKBP10 mutations are a cause of recessive osteogenesis imperfecta and Bruck syndrome, possibly Bruck syndrome Type 1 since the location on chromosome 17 has not been definitely localized. © 2011 American Society for Bone and Mineral Research. PMID:20839288

  20. Increased intra-cortical porosity reduces bone stiffness and strength in pediatric patients with osteogenesis imperfecta.

    PubMed

    Vardakastani, V; Saletti, D; Skalli, W; Marry, P; Allain, J M; Adam, C

    2014-12-01

    Osteogenesis imperfecta (OI) is a heritable disease occurring in one out of every 20,000 births. Although it is known that Type I collagen mutation in OI leads to increased bone fragility, the mechanism of this increased susceptibility to fracture is not clear. The aim of this study was to assess the microstructure of cortical bone fragments from patients with osteogenesis imperfecta (OI) using polarized light microscopy, and to correlate microstructural observations with the results of previously performed mechanical compression tests on bone from the same source. Specimens of cortical bone were harvested from the lower limbs of three (3) OI patients at the time of surgery, and were divided into two groups. Group 1 had been subjected to previous micro-mechanical compression testing, while Group 2 had not been subjected to any prior testing. Polarized light microscopy revealed disorganized bone collagen architecture as has been previously observed, as well as a large increase in the areal porosity of the bone compared to typical values for healthy cortical bone, with large (several hundred micron sized), asymmetrical pores. Importantly, the areal porosity of the OI bone samples in Group 1 appears to correlate strongly with their previously measured apparent Young's modulus and compressive strength. Taken together with prior nanoindentation studies on OI bone tissue, the results of this study suggest that increased intra-cortical porosity is responsible for the reduction in macroscopic mechanical properties of OI cortical bone, and therefore that in vivo imaging modalities with resolutions of ~100 μm or less could potentially be used to non-invasively assess bone strength in OI patients. Although the number of subjects in this study is small, these results highlight the importance of further studies in OI bone by groups with access to human OI tissue in order to clarify the relationship between increased porosity and reduced macroscopic mechanical integrity. PMID

  1. Osteogenesis imperfecta: determining the demographics and the predictors of death from an inpatient population.

    PubMed

    Vitale, Michael G; Matsumoto, Hiroko; Kessler, Michael W; Hoffmann, William; Roye, David P

    2007-03-01

    Osteogenesis imperfecta is a heritable disease that may result in bone fragility, increased joint laxity, decreased muscle tone, thinning of the skin, a bluish appearance of the sclerae, and scoliosis in as many as 60% of cases. The purpose of this study was to examine the impact of patient and hospital characteristics on mortality rate during inpatient stays. Data was collected retrospectively from the Healthcare Cost and Utilization Project Kids' Inpatient Database, a resource designed to analyze pediatric hospital usage. Data were collected from 1793 patients in the 27 states. Overall, 3% of this population died during hospitalization. Self-pay patients, patients in hospitals with small bed sizes, patients in non pediatric hospitals, and younger patients all had higher mortality rates than did their counterparts. In addition, black patients were 3.7 times more likely to die than did patients of any other race, and women were more likely to die than did men, although more than half of the number of patients were classified as white and 52% were men. Although these trends suggest that the mortality of younger patients may be reduced by admittance to children's hospitals, the children who are hospitalized younger tend to have more severe forms of the disease and are therefore more deformed and more difficult to treat. Overall, the results of this study indicate that children with osteogenesis imperfecta who need hospitalization may benefit from being referred to a large children's hospital, and that there is further research needed into the significant differences in the mortality of black patients and female patients. PMID:17314652

  2. A rare case of osteogenesis imperfecta combined with complete tooth loss.

    PubMed

    Lu, Yanqin; Zhao, Fei; Ren, Xiuzhi; Li, Zhiliang; Yang, Xiaomeng; Han, Jinxiang

    2014-01-01

    Osteogenesis imperfecta (OI) is a heritable disorder of the connective tissue characterized by blue sclerae, osteoporosis and bone fragility. Dentinogenesis imperfecta type I is commonly seen in OI patients, but other dental impairments, such as tooth agenesis or complete tooth loss, are rarely reported for these patients. Here, we report the case of a 37-year-old female Chinese OI patient who experienced complete tooth loss before puberty. The patient has a family history of OI and her father has a history of tooth loss. She showed obvious OI phenotypes, including a dwarfed stature, blue sclerae, scoliosis, pigeon chest and a history of fractures. Tooth loss began at the age of 6 years and continued until complete tooth loss at 20 years; this occurred in the absence of dental decay, gum disease, accidents or drug usage. Radiological studies revealed osteoporosis of the lower limbs and an underdeveloped scapula. Type I collagen gene analysis identified a known c.2314G>A (p.Gly772Ser) substitution in the COL1A2 gene, which we suggest affects the interaction between type I collagen and extracellular matrix proteins, including cartilage oligomeric matrix protein, phosphophoryn and SPARC (secreted protein acidic and rich in cysteine). In silico prediction indicated a relatively mild effect of the mutation, so it is conceivable that the severity of the clinical phenotype may result from additional mutations in candidate genes responsible for abnormal dental phenotypes in this family. To our knowledge, this is the first report of an OI patient with a phenotype of complete tooth loss at a young age. PMID:23934635

  3. AB069. Effect of osteogenesis imperfecta on children and their families

    PubMed Central

    Dung, Vu Chi; Armstrong, Kate; Ngoc, Can Thi Bich; Thao, Bui Phuong; Khanh, Nguyen Ngoc; Trang, Nguyen Thu; Hoan, Nguyen Thi; Dat, Nguyen Phu; Munns, Craig

    2015-01-01

    Osteogenesis imperfecta (OI) is a heterogeneous genetic disorder, with features that include increased bone fragility, pathological fractures, blue sclera, dentinogenesis imperfecta and conductive or mixed hearing loss. Clinical variability is wide from children with few fractures and normal stature to children with multiple fractures, long bone deformity, scoliosis and extreme short stature. Although there is no curative treatment, there are several therapeutic tools capable of improving the course of the condition and patient quality of life. We aim to evaluate the effect of OI on the well-being of children with the disorder and their families through a family-centered questionnaire. Sixty children with OI from the Vietnam National Hospital of Pediatrics and/or their parent(s), who attended the first annual family support group in 2011, completed a child and parent questionnaire. Sixty patients participated, 26 female and 34 male. The median age was 6.0 years [interquartile range (IQR), 0.25-18 years]. Of these, 36 (60%) had dentinogenesis imperfect and 23 (38.3%) had a scoliosis. The median number of fractures was 6.0 (IQR 0-30) and median number of hospitalizations due to OI was 5.0 (IQR 0-30). Among patients of school age, 9 (15%) could not go to school due to OI. Almost all parents (93.7%) worried about school social communication of the patients. Among these parents, 100% fear of inferiority with friends and 98.3% fear of broken bones. Most parents (76.2%) were significantly concerned about their child’s health. The parents’ themselves reported psychological concerns, with feelings of desperation (58.4%), anxiety (81.7%) and depression (56.7%). OI appeared to have a significant deleterious effect on the life of the patients and their families. These data provide a baseline from which to evaluate the effectiveness of interventions to improve the medical and psychological needs of this cohort and their families.

  4. Reduced diaphyseal strength associated with high intracortical vascular porosity within long bones of children with Osteogenesis Imperfecta

    PubMed Central

    Jameson, John; Smith, Peter; Harris, Gerald

    2015-01-01

    Osteogenesis Imperfecta is a genetic disorder resulting in bone fragility. The mechanisms behind this fragility are not well understood. In addition to characteristic bone mass deficiencies, research suggests that bone material properties are compromised in individuals with this disorder. However, little data exists regarding bone properties beyond the microstructural scale in individuals with this disorder. Specimens were obtained from long bone diaphyses of nine children with osteogenesis imperfecta during routine osteotomy procedures. Small rectangular beams, oriented longitudinally and transversely to the diaphyseal axis, were machined from these specimens and elastic modulus, yield strength, and maximum strength were measured in three-point bending. Intracortical vascular porosity, bone volume fraction, osteocyte lacuna density, and volumetric tissue mineral density were determined by synchrotron micro-computed tomography, and relationships among these mechanical properties and structural parameters were explored. Modulus and strength were on average 64–68% lower in the transverse vs. longitudinal beams (P<0.001, linear mixed model). Vascular porosity ranged between 3–42% of total bone volume. Longitudinal properties were associated negatively with porosity (P≤0.006, linear regressions). Mechanical properties, however, were not associated with osteocyte lacuna density or volumetric tissue mineral density (P≥0.167). Bone properties and structural parameters were not associated significantly with donor age (p≥0.225, linear mixed models). This study presents novel data regarding bone material strength in children with osteogenesis imperfecta. Results confirm that these properties are anisotropic. Elevated vascular porosity was observed in most specimens, and this parameter was associated with reduced bone material strength. These results offer insight towards understanding bone fragility and the role of intracortical porosity on the strength of bone

  5. Reduced diaphyseal strength associated with high intracortical vascular porosity within long bones of children with osteogenesis imperfecta.

    PubMed

    Albert, Carolyne; Jameson, John; Smith, Peter; Harris, Gerald

    2014-09-01

    Osteogenesis imperfecta is a genetic disorder resulting in bone fragility. The mechanisms behind this fragility are not well understood. In addition to characteristic bone mass deficiencies, research suggests that bone material properties are compromised in individuals with this disorder. However, little data exists regarding bone properties beyond the microstructural scale in individuals with this disorder. Specimens were obtained from long bone diaphyses of nine children with osteogenesis imperfecta during routine osteotomy procedures. Small rectangular beams, oriented longitudinally and transversely to the diaphyseal axis, were machined from these specimens and elastic modulus, yield strength, and maximum strength were measured in three-point bending. Intracortical vascular porosity, bone volume fraction, osteocyte lacuna density, and volumetric tissue mineral density were determined by synchrotron micro-computed tomography, and relationships among these mechanical properties and structural parameters were explored. Modulus and strength were on average 64-68% lower in the transverse vs. longitudinal beams (P<0.001, linear mixed model). Vascular porosity ranged between 3 and 42% of total bone volume. Longitudinal properties were associated negatively with porosity (P≤0.006, linear regressions). Mechanical properties, however, were not associated with osteocyte lacuna density or volumetric tissue mineral density (P≥0.167). Bone properties and structural parameters were not associated significantly with donor age (P≥0.225, linear mixed models). This study presents novel data regarding bone material strength in children with osteogenesis imperfecta. Results confirm that these properties are anisotropic. Elevated vascular porosity was observed in most specimens, and this parameter was associated with reduced bone material strength. These results offer insight toward understanding bone fragility and the role of intracortical porosity on the strength of bone

  6. Burnei’s technique of femoral neck variation and valgisation by using the intramedullary rod in Osteogenesis imperfecta

    PubMed Central

    Georgescu, I; Gavriliu, Șt; Nepaliuc, I; Munteanu, L; Țiripa, I; Ghiță, R; Japie, E; Hamei, S; Dughilă, C; Macadon, M

    2014-01-01

    Background: Varus or valgus deviations of the femoral neck in osteogenesis imperfecta have been an ignored chapter because the classic correction procedures were applied in medical practice with unsatisfying results. Until the use of telescopic rods, coronal deviations remained unsolved and the distal configuration of the proximal femoral extremity remained uncorrected or partially corrected, which required an extensive use of the wheel chair or bed immobilization of the patient. The concomitant correction of the complex deformities, coxa vara/valga and femoral integrated configuration, have been a progress which allowed the patients to walk with or without support. Purpose: The purpose of this study is to present the Burnei’s technique, a therapeutic alternative in deformity corrections of the varus or valgus hip in children with osteogenesis imperfecta. Study design: The paper is about a retrospective study done in a single center, which analyses Burnei technique and other procedures described in literature. Patient sample: The content of the article is based on a 12 years experience on a batch of 51 patients with osteogenesis imperfecta from which 10 patients (13 hips) presented frontal plane deviations of the femoral neck. Outcome measures: All the patients with osteogenesis imperfecta who presented coxa vara or valga were submitted to investigations with the purpose of measuring blood loss, the possibility of extending the surgical intervention to the leg, the association of severe deformities of the proximal extremity of the femur and the necessity of postoperative intensive care. Burnei’s technique: The operation was first performed in 2002. A subtrochanteric osteotomy was made in an oblique cut, from the internal side to the external side and from proximal to distal for coxa vara, or by using a cuneiform resection associated with muscular disinsertions. Only telescopic rods were used for osteosynthesis. Discussions: There are a few articles in

  7. Osteogenesis imperfecta

    MedlinePlus

    ... defect in the gene that produces type 1 collagen, an important building block of bone. There are ... fractures Early hearing loss ( deafness ) Because type I collagen is also found in ligaments, people with OI ...

  8. Osteogenesis imperfecta

    MedlinePlus

    ... baby has the condition. However, because so many different mutations can cause OI, some forms cannot be diagnosed with a genetic test. The severe form of type II OI can be seen on ultrasound when the fetus is as young as 16 weeks.

  9. The swaying mouse as a model of osteogenesis imperfecta caused by WNT1 mutations.

    PubMed

    Joeng, Kyu Sang; Lee, Yi-Chien; Jiang, Ming-Ming; Bertin, Terry K; Chen, Yuqing; Abraham, Annie M; Ding, Hao; Bi, Xiaohong; Ambrose, Catherine G; Lee, Brendan H

    2014-08-01

    Osteogenesis imperfecta (OI) is a heritable disorder of connective tissue characterized by bone fragility and low bone mass. Recently, our group and others reported that WNT1 recessive mutations cause OI, whereas WNT1 heterozygous mutations cause early onset osteoporosis. These findings support the hypothesis that WNT1 is an important WNT ligand regulating bone formation and bone homeostasis. While these studies provided strong human genetic and in vitro functional data, an in vivo animal model to study the mechanism of WNT1 function in bone is lacking. Here, we show that Swaying (Wnt1(sw/sw)) mice previously reported to carry a spontaneous mutation in Wnt1 share major features of OI including propensity to fractures and severe osteopenia. In addition, biomechanical and biochemical analyses showed that Wnt1(sw/sw) mice exhibit reduced bone strength with altered levels of mineral and collagen in the bone matrix that is also distinct from the type I collagen-related form of OI. Further histomorphometric analyses and gene expression studies demonstrate that the bone phenotype is associated with defects in osteoblast activity and function. Our study thus provides in vivo evidence that WNT1 mutations contribute to bone fragility in OI patients and demonstrates that the Wnt1(sw/sw) mouse is a murine model of OI caused by WNT1 mutations. PMID:24634143

  10. The swaying mouse as a model of osteogenesis imperfecta caused by WNT1 mutations

    PubMed Central

    Joeng, Kyu Sang; Lee, Yi-Chien; Jiang, Ming-Ming; Bertin, Terry K.; Chen, Yuqing; Abraham, Annie M.; Ding, Hao; Bi, Xiaohong; Ambrose, Catherine G.; Lee, Brendan H.

    2014-01-01

    Osteogenesis imperfecta (OI) is a heritable disorder of connective tissue characterized by bone fragility and low bone mass. Recently, our group and others reported that WNT1 recessive mutations cause OI, whereas WNT1 heterozygous mutations cause early onset osteoporosis. These findings support the hypothesis that WNT1 is an important WNT ligand regulating bone formation and bone homeostasis. While these studies provided strong human genetic and in vitro functional data, an in vivo animal model to study the mechanism of WNT1 function in bone is lacking. Here, we show that Swaying (Wnt1sw/sw) mice previously reported to carry a spontaneous mutation in Wnt1 share major features of OI including propensity to fractures and severe osteopenia. In addition, biomechanical and biochemical analyses showed that Wnt1sw/sw mice exhibit reduced bone strength with altered levels of mineral and collagen in the bone matrix that is also distinct from the type I collagen-related form of OI. Further histomorphometric analyses and gene expression studies demonstrate that the bone phenotype is associated with defects in osteoblast activity and function. Our study thus provides in vivo evidence that WNT1 mutations contribute to bone fragility in OI patients and demonstrates that the Wnt1sw/sw mouse is a murine model of OI caused by WNT1 mutations. PMID:24634143

  11. Multiparametric Classification of Skin from Osteogenesis Imperfecta Patients and Controls by Quantitative Magnetic Resonance Microimaging

    PubMed Central

    Carter, Erin M.; Lin, Ping-Chang; Pleshko, Nancy; Raggio, Cathleen L.; Spencer, Richard G.

    2016-01-01

    The purpose of this study is to evaluate the ability of quantitative magnetic resonance imaging (MRI) to discriminate between skin biopsies from individuals with osteogenesis imperfecta (OI) and skin biopsies from individuals without OI. Skin biopsies from nine controls (unaffected) and nine OI patients were imaged to generate maps of five separate MR parameters, T1, T2, km, MTR and ADC. Parameter values were calculated over the dermal region and used for univariate and multiparametric classification analysis. A substantial degree of overlap of individual MR parameters was observed between control and OI groups, which limited the sensitivity and specificity of univariate classification. Classification accuracies ranging between 39% and 67% were found depending on the variable of investigation, with T2 yielding the best accuracy of 67%. When several MR parameters were considered simultaneously in a multivariate analysis, the classification accuracies improved up to 89% for specific combinations, including the combination of T2 and km. These results indicate that multiparametric classification by quantitative MRI is able to detect differences between the skin of OI patients and of unaffected individuals, which motivates further study of quantitative MRI for the clinical diagnosis of OI. PMID:27416032

  12. Structure-mechanics relationships of collagen fibrils in the osteogenesis imperfecta mouse model.

    PubMed

    Andriotis, O G; Chang, S W; Vanleene, M; Howarth, P H; Davies, D E; Shefelbine, S J; Buehler, M J; Thurner, P J

    2015-10-01

    The collagen molecule, which is the building block of collagen fibrils, is a triple helix of two α1(I) chains and one α2(I) chain. However, in the severe mouse model of osteogenesis imperfecta (OIM), deletion of the COL1A2 gene results in the substitution of the α2(I) chain by one α1(I) chain. As this substitution severely impairs the structure and mechanics of collagen-rich tissues at the tissue and organ level, the main aim of this study was to investigate how the structure and mechanics are altered in OIM collagen fibrils. Comparing results from atomic force microscopy imaging and cantilever-based nanoindentation on collagen fibrils from OIM and wild-type (WT) animals, we found a 33% lower indentation modulus in OIM when air-dried (bound water present) and an almost fivefold higher indentation modulus in OIM collagen fibrils when fully hydrated (bound and unbound water present) in phosphate-buffered saline solution (PBS) compared with WT collagen fibrils. These mechanical changes were accompanied by an impaired swelling upon hydration within PBS. Our experimental and atomistic simulation results show how the structure and mechanics are altered at the individual collagen fibril level as a result of collagen gene mutation in OIM. We envisage that the combination of experimental and modelling approaches could allow mechanical phenotyping at the collagen fibril level of virtually any alteration of collagen structure or chemistry. PMID:26468064

  13. The effect of SERPINF1 in-frame mutations in osteogenesis imperfecta type VI.

    PubMed

    Al-Jallad, Hadil; Palomo, Telma; Roughley, Peter; Glorieux, Francis H; McKee, Marc D; Moffatt, Pierre; Rauch, Frank

    2015-07-01

    Osteogenesis imperfecta type VI is caused by mutations in SERPINF1, which codes for pigment-epithelium derived factor (PEDF). Most of the reported SERPINF1 mutations lead to premature termination codons, but three in-frame insertion or deletion mutations have also been reported. It is not clear how such in-frame mutations lead to OI type VI. In the present study we therefore investigated how SERPINF1 in-frame mutations affect the intracellular localization and secretion of PEDF. Skin fibroblasts affected by SERPINF1 in-frame mutations transcribed SERPINF1 at slightly reduced levels but secretion of PEDF was markedly diminished. Two deletions (p.F277del and the deletion of SERPINF1 exon 5) were associated with retention of PEDF in the endoplasmic reticulum and a stress response in osteoblastic cells. A recurrent in-frame duplication of three amino acids (p.Ala91_Ser93dup) appeared to lead to intracellular degradation but no retention in the endoplasmic reticulum or stress response. Immunofluorescence imaging in transiently transfected osteoblastic MC3T3-E1 cells suggested that PEDF affected by in-frame mutations was not transported along the secretory pathway. MC3T3-E1 osteoblasts stably overexpressing SERPINF1 with the p.Ala91_Ser93dup mutation had decreased collagen type I deposition and mineralization. Thus, the assessed homozygous in-frame deletions or insertions lead to retention or degradation within cellular compartments and thereby interfere with PEDF secretion. PMID:25868797

  14. Structure–mechanics relationships of collagen fibrils in the osteogenesis imperfecta mouse model

    PubMed Central

    Andriotis, O. G.; Chang, S. W.; Vanleene, M.; Howarth, P. H.; Davies, D. E.; Shefelbine, S. J.; Buehler, M. J.; Thurner, P. J.

    2015-01-01

    The collagen molecule, which is the building block of collagen fibrils, is a triple helix of two α1(I) chains and one α2(I) chain. However, in the severe mouse model of osteogenesis imperfecta (OIM), deletion of the COL1A2 gene results in the substitution of the α2(I) chain by one α1(I) chain. As this substitution severely impairs the structure and mechanics of collagen-rich tissues at the tissue and organ level, the main aim of this study was to investigate how the structure and mechanics are altered in OIM collagen fibrils. Comparing results from atomic force microscopy imaging and cantilever-based nanoindentation on collagen fibrils from OIM and wild-type (WT) animals, we found a 33% lower indentation modulus in OIM when air-dried (bound water present) and an almost fivefold higher indentation modulus in OIM collagen fibrils when fully hydrated (bound and unbound water present) in phosphate-buffered saline solution (PBS) compared with WT collagen fibrils. These mechanical changes were accompanied by an impaired swelling upon hydration within PBS. Our experimental and atomistic simulation results show how the structure and mechanics are altered at the individual collagen fibril level as a result of collagen gene mutation in OIM. We envisage that the combination of experimental and modelling approaches could allow mechanical phenotyping at the collagen fibril level of virtually any alteration of collagen structure or chemistry. PMID:26468064

  15. Quantitative changes in human epithelial cancers and osteogenesis imperfecta disease detected using nonlinear multicontrast microscopy

    NASA Astrophysics Data System (ADS)

    Adur, Javier; Pelegati, Vitor B.; de Thomaz, Andre A.; D'Souza-Li, Lilia; Assunção, Maria do Carmo; Bottcher-Luiz, Fátima; Andrade, Liliana A. L. A.; Cesar, Carlos L.

    2012-08-01

    We show that combined multimodal nonlinear optical (NLO) microscopies, including two-photon excitation fluorescence, second-harmonic generation (SHG), third harmonic generation, and fluorescence lifetime imaging microscopy (FLIM) can be used to detect morphological and metabolic changes associated with stroma and epithelial transformation during the progression of cancer and osteogenesis imperfecta (OI) disease. NLO microscopes provide complementary information about tissue microstructure, showing distinctive patterns for different types of human breast cancer, mucinous ovarian tumors, and skin dermis of patients with OI. Using a set of scoring methods (anisotropy, correlation, uniformity, entropy, and lifetime components), we found significant differences in the content, distribution and organization of collagen fibrils in the stroma of breast and ovary as well as in the dermis of skin. We suggest that our results provide a framework for using NLO techniques as a clinical diagnostic tool for human cancer and OI. We further suggest that the SHG and FLIM metrics described could be applied to other connective or epithelial tissue disorders that are characterized by abnormal cells proliferation and collagen assembly.

  16. Homozygous sequence variants in the FKBP10 gene underlie osteogenesis imperfecta in consanguineous families.

    PubMed

    Umair, Muhammad; Hassan, Annum; Jan, Abid; Ahmad, Farooq; Imran, Muhammad; Samman, Muhammad I; Basit, Sulman; Ahmad, Wasim

    2016-03-01

    Osteogenesis imperfecta (OI, MIM 610968) is a genetically and clinically heterogeneous disorder characterized by bone fragility. It is one of the rare forms of skeletal deformity caused by sequence variants in at least 14 different genes, including FKBP10 (MIM 607063) encoding protein FKBP65. Here we present three consanguineous families of Pakistani origin segregating OI in an autosomal-recessive pattern. Genotyping using either single-nucleotide polymorphism markers by Affymetrix GeneChip Human Mapping 250K Nsp array or polymorphic microsatellite markers revealed a homozygous region, containing a candidate gene FKBP10, among affected members on chromosome 17q21.2. Sequencing the FKBP10 gene revealed a homozygous novel nonsense variant (c.1490G>A, p.Trp497*) in the family A and two previously reported variants, including a missense (c.344G>A, p.Arg115Gln), in the family B and duplication of a nucleotide C (c.831dupC, p.Gly278ArgfsX295) in the family C. Our findings further extend the body of evidence that supports the importance of FKBP10 gene in the development of skeletal system. PMID:26538303

  17. Deficiency of CRTAP in non-lethal recessive osteogenesis imperfecta reduces collagen deposition into matrix

    PubMed Central

    Valli, M; Barnes, AM; Gallanti, A; Cabral, WA; Viglio, S; Weis, MA; Makareeva, E; Eyre, D; Leikin, S; Antoniazzi, F; Marini, JC; Mottes, M

    2013-01-01

    Deficiency of any component of the ER-resident collagen prolyl 3-hydroxylation complex causes recessive osteogenesis imperfecta (OI). The complex modifies the α1(I)Pro986 residue and contains cartilage-associated protein (CRTAP), prolyl 3-hydroxylase 1 (P3H1) and cyclophilin B (CyPB). Fibroblasts normally secrete about 10% of CRTAP. Most CRTAP mutations cause a null allele and lethal type VII OI. We identified a 7-year-old Egyptian boy with non-lethal type VII OI and investigated the effects of his null CRTAP mutation on collagen biochemistry, the prolyl 3-hydroxylation complex, and collagen in extracellular matrix. The proband is homozygous for an insertion/deletion in CRTAP (c.118_133del16insTACCC). His dermal fibroblasts synthesize fully overmodified type I collagen, and 3-hydroxylate only 5% of α1(I)Pro986. CRTAP transcripts are 10% of control. CRTAP protein is absent from proband cells, with residual P3H1 and normal CyPB levels. Dermal collagen fibril diameters are significantly increased. By immunofluorescence of long-term cultures, we identified a severe deficiency (10–15% of control) of collagen deposited in extracellular matrix, with disorganization of the minimal fibrillar network. Quantitative pulse-chase experiments corroborate deficiency of matrix deposition, rather than increased matrix turnover. We conclude that defects of extracellular matrix, as well as intracellular defects in collagen modification, contribute to the pathology of type VII OI. PMID:21955071

  18. Muscle force sensitivity of a finite element fracture risk assessment model in osteogenesis imperfecta - biomed 2009.

    PubMed

    Fritz, Jessica M; Guan, Yabo; Wang, Mei; Smith, Peter A; Harris, Geald F

    2009-01-01

    Osteogenesis imperfecta (OI) is a heritable bone fragility disorder characterized by skeletal deformities and increased bone fragility. There is currently no established clinical method for quantifying fracture risk in OI patients. A method for developing a finite element model of the femur to assist in fracture risk assessment of a selected patient with OI type I was created. The material properties were based on nanoindentation testing of OI bone specimens collected during routine surgery. Dynamic data from clinical gait analysis was used to prescribe joint reaction forces and moments in a quasi-static model. Muscle forces were prescribed according to current literature. Von Mises stresses were analyzed across all seven phases of the gait cycle and analyzed for sensitivity to changes in muscle forces. The model showed that the patient with OI was not at current risk for fracture during normal gait. The highest stress levels occurred during mid stance and loading response. Maximum von Mises stresses were most sensitive to the gluteal muscles. Insight provided by the model may be useful for similar clinical applications, more refined model development and an improved ability for fracture prediction. PMID:19369782

  19. Child abuse and osteogenesis imperfecta: how can they be still misdiagnosed? A case report

    PubMed Central

    D’Eufemia, Patrizia; Palombaro, Marta; Lodato, Valentina; Zambrano, Anna; Celli, Mauro; Persiani, Pietro; De Bari, Maria Pia; Sangiorgi, Luca

    2012-01-01

    Summary Osteogenesis imperfecta (OI) is a rare hereditary disease caused by mutations in genes coding for type I collagen, resulting in bone fragility. In literature are described forms lethal in perinatal period, forms which are moderate and slight forms where the only sign of disease is osteopenia. Child abuse is an important social and medical problem. Fractures are the second most common presentation after skin lesions and may present specific patterns. The differential diagnosis between slight-moderate forms of OI and child abuse could be very challenging especially when other signs typical of abuse are absent, since both could present with multiple fractures without reasonable explanations. We report a 20 months-old female with a history of 4 fractures occurred between the age of three and eighteen months, brought to authorities’ attention as a suspected child abuse. However when she came to our department physical examination, biochemical tests, total body X-ray and a molecular analysis of DNA led the diagnosis of OI. Thus, a treatment with bisphosphonate and a physical rehabilitation process, according to Vojta method, were started with improvement in bony mineralization, gross motor skills and absence of new fracture. In conclusion our case demonstrates how in any child presenting fractures efforts should be made to consider, besides child abuse, all the other hypothesis even the rarest as OI. PMID:23289038

  20. Child abuse and osteogenesis imperfecta: how can they be still misdiagnosed? A case report.

    PubMed

    D'Eufemia, Patrizia; Palombaro, Marta; Lodato, Valentina; Zambrano, Anna; Celli, Mauro; Persiani, Pietro; De Bari, Maria Pia; Sangiorgi, Luca

    2012-09-01

    Osteogenesis imperfecta (OI) is a rare hereditary disease caused by mutations in genes coding for type I collagen, resulting in bone fragility. In literature are described forms lethal in perinatal period, forms which are moderate and slight forms where the only sign of disease is osteopenia. Child abuse is an important social and medical problem. Fractures are the second most common presentation after skin lesions and may present specific patterns.The differential diagnosis between slight-moderate forms of OI and child abuse could be very challenging especially when other signs typical of abuse are absent, since both could present with multiple fractures without reasonable explanations. We report a 20 months-old female with a history of 4 fractures occurred between the age of three and eighteen months, brought to authorities' attention as a suspected child abuse.However when she came to our department physical examination, biochemical tests, total body X-ray and a molecular analysis of DNA led the diagnosis of OI.Thus, a treatment with bisphosphonate and a physical rehabilitation process, according to Vojta method, were started with improvement in bony mineralization, gross motor skills and absence of new fracture.In conclusion our case demonstrates how in any child presenting fractures efforts should be made to consider, besides child abuse, all the other hypothesis even the rarest as OI. PMID:23289038

  1. Dentin phosphoprotein gene locus is not associated with dentinogenesis imperfecta types II and III

    SciTech Connect

    MacDougall, M.; Zeichner-David, M.; Davis, A.; Slavkin, H. ); Murray, J. ); Crall, M. )

    1992-01-01

    Dentinogenesis imperfecta (DGI) is an autosomal dominant inherited dental disease which affects dentin production and mineralization. Genetic linkage studies have been performed on several multigeneration informative kindreds. These studies determined linkage between DGI types II and III and group-specific component (vitamin D-binding protein). This gene locus has been localized to the long arm of human chromosome 4 in the region 4q11-q21. Although this disease has been mapped to chromosome 4, the defective gene product is yet to be determined. Biochemical studies have suggested abnormal levels of dentin phosphoprotein (DPP) associated with DGI type II. This highly acidic protein is the major noncollagenous component of dentin, being solely expressed by the ectomesenchymal derived odontoblast cells of the tooth. The purpose of the present study was to establish whether DPP is associated with DGI types II and III, by using molecular biology techniques. The results indicated that DPP is not localized to any region of human chromosome 4, thus suggesting that the DPP gene is not directly associated with DGI type II or DGI type III. The data do not exclude the possibility that other proteins associated with DPP posttranslational modifications might be responsible for this genetic disease.

  2. Gait characteristics and functional assessment of children with type I osteogenesis imperfecta.

    PubMed

    Graf, Adam; Hassani, Sahar; Krzak, Joseph; Caudill, Angela; Flanagan, Ann; Bajorunaite, Ruta; Harris, Gerald; Smith, Peter

    2009-09-01

    The purpose of this study was to improve the evaluation process of children with type I Osteogenesis Imperfecta (OI) by providing a quantitative comparison of gait and selected functional assessments to age-matched controls. A 14-camera Vicon Motion Analysis System was used for gait analysis along with selected functional assessments (Pediatric Outcomes Data Collection Instrument [PODCI], Functional Assessment Questionnaire [FAQ], Faces Pain Scale-Revised [FPS-R]) conducted on 10 subjects with type I OI and 22 age-matched healthy controls. The results of the OI group demonstrated abnormal gait parameters including increased double support, delayed foot off, reduced ankle range of motion and plantarflexion during third rocker, along with greater ankle power absorption during terminal stance and reduced ankle power generation during push off. The functional assessment scores of the OI group were similar to the control group for basic mobility and function, but were lower than their peers in the sports and physical function category. The evaluation of individuals with OI by means of gait analysis and selected functional assessments, along with an accurate biomechanical model of the lower extremities, is proposed to better understand and predict OI disability and improve quality of life. PMID:19242979

  3. Microstructural and Photoacoustic Infrared Spectroscopic Studies of Human Cortical Bone with Osteogenesis Imperfecta

    NASA Astrophysics Data System (ADS)

    Gu, Chunju; Katti, Dinesh R.; Katti, Kalpana S.

    2016-04-01

    The molecular basis of bone disease osteogenesis imperfecta (OI) and the mineralization of hydroxyapatite in OI bone have been of significant research interest. To further investigate the mechanism of OI disease and bone mineralization, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy, and x-ray diffraction (XRD) are used in the present study to describe the structural and compositional differences between OI and healthy bone. OI bone exhibits more porous, fibrous features, abnormal collagen fibrils, and abnormal mineral deposits. Likewise, photoacoustic-FTIR experiments indicate an aberrant collagen structure and an altered mineral structure in OI. In contrast, there is neither significant difference in the non-collagenous proteins (NCPs) composition observed nor apparent change in the crystal structure between OI and healthy bone minerals as shown in XRD and energy-dispersive x-ray spectroscopy (EDS) results. This observation indicates that the biomineralization process is more controlled by the bone cells and non-collagenous phosphorylated proteins. The present study also confirms that there is an orientational influence on the stoichiometry of the mineral in OI bone. Also, a larger volume of the hydrated layer in the transverse plane than the longitudinal plane of the mineral crystal structure is proposed. The appearance of a new C-S band in the FTIR spectra in OI bone suggests the substitution of glycine by cysteine in collagen molecules or/and an increased amount of cysteine-rich osteonectin that relates to mineral nucleation and mineral crystal formation.

  4. Robust physical methods that enrich genomic regions identical by descent for linkage studies: confirmation of a locus for osteogenesis imperfecta

    PubMed Central

    Brooks, Peter; Marcaillou, Charles; Vanpeene, Maud; Saraiva, Jean-Paul; Stockholm, Daniel; Francke, Stephan; Favis, Reyna; Cohen, Nadine; Rousseau, Francis; Tores, Frédéric; Lindenbaum, Pierre; Hager, Jörg; Philippi, Anne

    2009-01-01

    Background The monogenic disease osteogenesis imperfecta (OI) is due to single mutations in either of the collagen genes ColA1 or ColA2, but within the same family a given mutation is accompanied by a wide range of disease severity. Although this phenotypic variability implies the existence of modifier gene variants, genome wide scanning of DNA from OI patients has not been reported. Promising genome wide marker-independent physical methods for identifying disease-related loci have lacked robustness for widespread applicability. Therefore we sought to improve these methods and demonstrate their performance to identify known and novel loci relevant to OI. Results We have improved methods for enriching regions of identity-by-descent (IBD) shared between related, afflicted individuals. The extent of enrichment exceeds 10- to 50-fold for some loci. The efficiency of the new process is shown by confirmation of the identification of the Col1A2 locus in osteogenesis imperfecta patients from Amish families. Moreover the analysis revealed additional candidate linkage loci that may harbour modifier genes for OI; a locus on chromosome 1q includes COX-2, a gene implicated in osteogenesis. Conclusion Technology for physical enrichment of IBD loci is now robust and applicable for finding genes for monogenic diseases and genes for complex diseases. The data support the further investigation of genetic loci other than collagen gene loci to identify genes affecting the clinical expression of osteogenesis imperfecta. The discrimination of IBD mapping will be enhanced when the IBD enrichment procedure is coupled with deep resequencing. PMID:19331686

  5. Deep tissue single cell MSC ablation using a fiber laser source to evaluate therapeutic potential in osteogenesis imperfecta

    NASA Astrophysics Data System (ADS)

    Tehrani, Kayvan F.; Pendleton, Emily G.; Lin, Charles P.; Mortensen, Luke J.

    2016-04-01

    Osteogenesis imperfecta (OI) is a currently uncurable disease where a mutation in collagen type I yields brittle bones. One potential therapy is transplantation of mesenchymal stem cells (MSCs), but controlling and enhancing transplanted cell survival has proven challenging. Therefore, we use a 2- photon imaging system to study individual transplanted cells in the living bone marrow. We ablated cells deep in the bone marrow and observed minimal collateral damage to surrounding tissue. Future work will evaluate the local impact of transplanted MSCs on bone deposition in vivo.

  6. [Early use of BiPAP in the management of respiratory failure in an infant with osteogenesis imperfecta: case report].

    PubMed

    Vega-Briceño, Luis; Contreras, Ilse; Sánchez, Ignacio; Bertrand, Pablo

    2004-07-01

    Osteogenesis imperfecta (OI) is an heterogeneous group of genetic disorders that affect connective tissue integrity. Severe forms cause chest deformities, sometimes associated to alveolar hypoventilation. We report a 4 months old infant with OI type III, who developed respiratory failure (RF) due to a bronchiolitis and required mechanical ventilation. Weaning progressed successfully to a nasal bi-level Positive Airway Pressure (n-BiPAP) device. Clinical follow up showed a normal cognitive development and growth. Respiratory condition, blood gases and ventilation status were in normal ranges. Non invasive ventilation, associated to careful monitoring may avoid tracheostomy and its complications in infants with OI. PMID:15379335

  7. Sclerostin Antibody Treatment Improves the Bone Phenotype of Crtap(-/-) Mice, a Model of Recessive Osteogenesis Imperfecta.

    PubMed

    Grafe, Ingo; Alexander, Stefanie; Yang, Tao; Lietman, Caressa; Homan, Erica P; Munivez, Elda; Chen, Yuqing; Jiang, Ming Ming; Bertin, Terry; Dawson, Brian; Asuncion, Franklin; Ke, Hua Zhu; Ominsky, Michael S; Lee, Brendan

    2016-05-01

    Osteogenesis imperfecta (OI) is characterized by low bone mass, poor bone quality, and fractures. Standard treatment for OI patients is limited to bisphosphonates, which only incompletely correct the bone phenotype, and seem to be less effective in adults. Sclerostin-neutralizing antibodies (Scl-Ab) have been shown to be beneficial in animal models of osteoporosis, and dominant OI resulting from mutations in the genes encoding type I collagen. However, Scl-Ab treatment has not been studied in models of recessive OI. Cartilage-associated protein (CRTAP) is involved in posttranslational type I collagen modification, and its loss of function results in recessive OI. In this study, we treated 1-week-old and 6-week-old Crtap(-/-) mice with Scl-Ab for 6 weeks (25 mg/kg, s.c., twice per week), to determine the effects on the bone phenotype in models of "pediatric" and "young adult" recessive OI. Vehicle-treated Crtap(-/-) and wild-type (WT) mice served as controls. Compared with control Crtap(-/-) mice, micro-computed tomography (μCT) analyses showed significant increases in bone volume and improved trabecular microarchitecture in Scl-Ab-treated Crtap(-/-) mice in both age cohorts, in both vertebrae and femurs. Additionally, Scl-Ab improved femoral cortical parameters in both age cohorts. Biomechanical testing showed that Scl-Ab improved parameters of whole-bone strength in Crtap(-/-) mice, with more robust effects in the week 6 to 12 cohort, but did not affect the increased bone brittleness. Additionally, Scl-Ab normalized the increased osteoclast numbers, stimulated bone formation rate (week 6 to 12 cohort only), but did not affect osteocyte density. Overall, our findings suggest that Scl-Ab treatment may be beneficial in the treatment of recessive OI caused by defects in collagen posttranslational modification. © 2015 American Society for Bone and Mineral Research. PMID:26716893

  8. Raloxifene reduces skeletal fractures in an animal model of osteogenesis imperfecta.

    PubMed

    Berman, Alycia G; Wallace, Joseph M; Bart, Zachary R; Allen, Matthew R

    2016-01-01

    Osteogenesis imperfecta (OI) is a genetic disease of Type I collagen and collagen-associated pathways that results in brittle bone behavior characterized by fracture and reduced mechanical properties. Based on previous work in our laboratory showing that raloxifene (RAL) can significantly improve bone mechanical properties through non-cellular mechanisms, we hypothesized that raloxifene would improve the mechanical properties of OI bone. In experiment 1, tibiae from female wild type (WT) and homozygous oim mice were subjected to in vitro soaking in RAL followed by mechanical tests. RAL soaking resulted in significantly higher post-yield displacement (+75% in WT, +472% in oim; p<0.004), with no effect on ultimate load or stiffness, in both WT and oim animals. In experiment 2, eight-week old WT and oim male mice were treated for eight weeks with saline vehicle (VEH) or RAL. Endpoint measures included assessment of in vivo skeletal fractures, bone density/geometry and mechanical properties. In vivo skeletal fractures of the femora, assessed by micro CT imaging, were significantly lower in oim-RAL (20%) compared to oim-VEH (48%, p=0.047). RAL led to significantly higher DXA-based BMD (p<0.01) and CT-based trabecular BV/TV in both WT and oim animals compared to those treated with VEH. Fracture toughness of the femora was lower in oim mice compared to WT and improved with RAL in both genotypes. These results suggest that raloxifene reduces the incidence of fracture in this mouse model of oim. Furthermore, they suggest that raloxifene's effects may be the result of both cellular (increased bone mass) and non-cellular (presumably changes in hydration) mechanisms, raising the possibility of using raloxifene, or related compounds, as a new approach for treating bone fragility associated with OI. PMID:26707242

  9. Strontium Ranelate Reduces the Fracture Incidence in a Growing Mouse Model of Osteogenesis Imperfecta.

    PubMed

    Shi, Changgui; Hu, Bo; Guo, Lei; Cao, Peng; Tian, Ye; Ma, Jun; Chen, Yuanyuan; Wu, Huiqiao; Hu, Jinquan; Deng, Lianfu; Zhang, Ying; Yuan, Wen

    2016-05-01

    Osteogenesis imperfecta (OI) is a genetic bone dysplasia characterized by brittle bones with increased fracture risk. Although current treatment options to improve bone strength in OI focus on antiresorptive bisphosphonates, controlled clinical trials suggest they have an equivocal effect on reducing fracture risk. Strontium ranelate (SrR) is a promising therapy with a dual mode of action that is capable of simultaneously maintaining bone formation and reducing bone resorption, and may be beneficial for the treatment of OI. In this study, SrR therapy was investigated to assess its effects on fracture frequency and bone mass and strength in an animal model of OI, the oim/oim mouse. Three-week-old oim/oim and wt/wt mice were treated with either SrR or vehicle (Veh) for 11 weeks. After treatment, the average number of fractures sustained by SrR-treated oim/oim mice was significantly reduced compared to Veh-treated oim/oim mice. Micro-computed tomographic (μCT) analyses of femurs showed that both trabecular and cortical bone mass were significantly improved with SrR treatment in both genotypes. SrR significantly inhibited bone resorption, whereas bone formation indices were maintained. Biomechanical testing revealed improved bone structural properties in both oim/oim and wild-type (wt/wt) mice under the treatment, whereas no significant effects on bone brittleness and material quality were observed. In conclusion, SrR was able to effectively reduce fractures in oim/oim mice by improving bone mass and strength and thus represents a potential therapy for the treatment of pediatric OI. © 2015 American Society for Bone and Mineral Research. PMID:26679066

  10. Bone Collagen: New Clues to its Mineralization Mechanism From Recessive Osteogenesis Imperfecta

    PubMed Central

    Eyre, David R.; Ann Weis, Mary

    2013-01-01

    Until 2006 the only mutations known to cause osteogenesis imperfecta (OI) were in the two genes coding for type I collagen chains. These dominant mutations affecting the expression or primary sequence of collagen α1(I) and α2(I) chains account for over 90% of OI cases. Since then a growing list of mutant genes causing the 5–10% of recessive cases has rapidly emerged. They include CRTAP, LEPRE1 and PPIB, which encode three proteins forming the prolyl 3-hydroxylase complex; PLOD2 and FKBP10, which encode respectively lysyl hydroxylase 2 and a foldase required for its activity in forming mature cross-links in bone collagen; SERPIN H1, which encodes the collagen chaperone HSP47; SERPIN F1, which encodes pigment epithelium-derived factor required for osteoid mineralization; and BMP1, which encodes the type I procollagen C-propeptidase. All cause fragile bone in infancy, which can include over-mineralization or under-mineralization defects as well as abnormal collagen post-translational modifications. Consistently both dominant and recessive variants lead to abnormal cross-linking chemistry in bone collagen. These recent discoveries strengthen the potential for a common pathogenic mechanism of misassembled collagen fibrils. Of the new genes identified, eight encode proteins required for collagen post-translational modification, chaperoning of newly synthesized collagen chains into native molecules or transport through the endoplasmic reticulum and Golgi for polymerization, cross-linking and mineralization. In reviewing these findings, we conclude that a common theme is emerging in the pathogenesis of brittle bone disease of mishandled collagen assembly with important insights on post-translational features of bone collagen that have evolved to optimize it as a biomineral template. PMID:23508630

  11. Evidence for a Role for Nanoporosity and Pyridinoline Content in Human Mild Osteogenesis Imperfecta.

    PubMed

    Paschalis, Eleftherios P; Gamsjaeger, Sonja; Fratzl-Zelman, Nadja; Roschger, Paul; Masic, Admir; Brozek, Wolfgang; Hassler, Norbert; Glorieux, Francis H; Rauch, Frank; Klaushofer, Klaus; Fratzl, Peter

    2016-05-01

    Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous connective tissue disorder characterized by bone fragility that arises from decreased bone mass and abnormalities in bone material quality. OI type I represents the milder form of the disease and according to the original Sillence classification is characterized by minimal skeletal deformities and near-normal stature. Raman microspectroscopy is a vibrational spectroscopic technique that allows the determination of bone material properties in bone biopsy blocks with a spatial resolution of ∼1 µm, as a function of tissue age. In the present study, we used Raman microspectroscopy to evaluate bone material quality in transiliac bone biopsies from children with a mild form of OI, either attributable to collagen haploinsufficiency OI type I (OI-Quant; n = 11) or aberrant collagen structure (OI-Qual; n = 5), as a function of tissue age, and compared it against the previously published values established in a cohort of biopsies from healthy children (n = 54, ages 1 to 23 years). The results indicated significant differences in bone material compositional characteristics between OI-Quant patients and healthy controls, whereas fewer were evident in the OI-Qual patients. Differences in both subgroups of OI compared with healthy children were evident for nanoporosity, mineral maturity/crystallinity as determined by maxima of the v1 PO4 Raman band, and pyridinoline (albeit in different direction) content. These alterations in bone material compositional properties most likely contribute to the bone fragility characterizing this disease. © 2016 American Society for Bone and Mineral Research. PMID:26748579

  12. Induced ablation of Bmp1 and Tll1 produces osteogenesis imperfecta in mice

    PubMed Central

    Muir, Alison M.; Ren, Yinshi; Butz, Delana Hopkins; Davis, Nicholas A.; Blank, Robert D.; Birk, David E.; Lee, Se-Jin; Rowe, David; Feng, Jian Q.; Greenspan, Daniel S.

    2014-01-01

    Osteogenesis imperfecta (OI), or brittle bone disease, is most often caused by dominant mutations in the collagen I genes COL1A1/COL1A2, whereas rarer recessive OI is often caused by mutations in genes encoding collagen I-interacting proteins. Recently, mutations in the gene for the proteinase bone morphogenetic 1 (BMP1) were reported in two recessive OI families. BMP1 and the closely related proteinase mammalian tolloid-like 1 (mTLL1) are co-expressed in various tissues, including bone, and have overlapping activities that include biosynthetic processing of procollagen precursors into mature collagen monomers. However, early lethality of Bmp1- and Tll1-null mice has precluded use of such models for careful study of in vivo roles of their protein products. Here we employ novel mouse strains with floxed Bmp1 and Tll1 alleles to induce postnatal, simultaneous ablation of the two genes, thus avoiding barriers of Bmp1−/− and Tll1−/− lethality and issues of functional redundancy. Bones of the conditionally null mice are dramatically weakened and brittle, with spontaneous fractures—defining features of OI. Additional skeletal features include osteomalacia, thinned/porous cortical bone, reduced processing of procollagen and dentin matrix protein 1, remarkably high bone turnover and defective osteocyte maturation that is accompanied by decreased expression of the osteocyte marker and Wnt-signaling inhibitor sclerostin, and by marked induction of canonical Wnt signaling. The novel animal model presented here provides new opportunities for in-depth analyses of in vivo roles of BMP1-like proteinases in bone and other tissues, and for their roles, and for possible therapeutic interventions, in OI. PMID:24419319

  13. Osteogenesis imperfecta caused by PPIB mutation with severe phenotype and congenital hearing loss

    PubMed Central

    Rush, Eric T.; Caldwell, Kathleen S.; Kreikemeier, Rose M.; Lutz, Richard E.; Esposito, Paul W.

    2014-01-01

    Osteogenesis imperfecta (OI) is an inherited disorder of connective tissue typically caused by defects in either COL1A1 or COL1A2. A number of other genes causative of this disorder have been found, including PPIB, which forms one subunit of the prolyl 3-hydroxylase enzyme complex. Patients with homozygous or compound heterozygous mutations in this gene have OI with a trend toward lethal or severe phenotype. We present a Native American female with prenatal diagnosis of OI. Long bones were shortened with significant rhizomelia. At birth, fractures were present in ribs, humerii, and femurs. She had significant respiratory disease at birth, and required oxygen throughout her life. She also had recurrent pneumonias, one of which ultimately caused her death at age 16 mo. She also had significant bilateral sensorineural hearing loss. Molecular testing showed that the patient was homozygous for a single nucleotide substitution in PPIB (c. 136-2A>G). Patients with OI caused by PPIB mutations have had variable disease, but with majority of either with perinatal lethality or progressively deforming severe disease. Patients with OI due to PPIB mutation have shown some differences in phenotype. There appears to be a trend toward rhizomelic shortening and less severe bowing of the extremities, as compared to patients with comparably severe OI caused by COL1A1 or COL1A2 mutation. Congenital hearing loss may be an inconsistent feature of this condition, or may have co-occurred in our patient for unrelated reasons. Still, patients with OI caused by PPIB mutation should have appropriate early and regular management of their hearing.

  14. Mutation and polymorphism spectrum in osteogenesis imperfecta type II: implications for genotype–phenotype relationships

    PubMed Central

    Bodian, Dale L.; Chan, Ting-Fung; Poon, Annie; Schwarze, Ulrike; Yang, Kathleen; Byers, Peter H.; Kwok, Pui-Yan; Klein, Teri E.

    2009-01-01

    Osteogenesis imperfecta (OI), also known as brittle bone disease, is a clinically and genetically heterogeneous disorder primarily characterized by susceptibility to fracture. Although OI generally results from mutations in the type I collagen genes, COL1A1 and COL1A2, the relationship between genotype and phenotype is not yet well understood. To provide additional data for genotype–phenotype analyses and to determine the proportion of mutations in the type I collagen genes among subjects with lethal forms of OI, we sequenced the coding and exon-flanking regions of COL1A1 and COL1A2 in a cohort of 63 subjects with OI type II, the perinatal lethal form of the disease. We identified 61 distinct heterozygous mutations in type I collagen, including five non-synonymous rare variants of unknown significance, of which 43 had not been seen previously. In addition, we found 60 SNPs in COL1A1, of which 17 were not reported previously, and 82 in COL1A2, of which 18 are novel. In three samples without collagen mutations, we found inactivating mutations in CRTAP and LEPRE1, suggesting a frequency of these recessive mutations of ∼5% in OI type II. A computational model that predicts the outcome of substitutions for glycine within the triple helical domain of collagen α1(I) chains predicted lethality with ∼90% accuracy. The results contribute to the understanding of the etiology of OI by providing data to evaluate and refine current models relating genotype to phenotype and by providing an unbiased indication of the relative frequency of mutations in OI-associated genes. PMID:18996919

  15. Quality of life in osteogenesis imperfecta: A mixed-methods systematic review.

    PubMed

    Dahan-Oliel, N; Oliel, S; Tsimicalis, A; Montpetit, K; Rauch, F; Dogba, M J

    2016-01-01

    Clinical interventions and research have mostly focused on the orthopedic, genetic, and pharmacological outcomes of individuals with osteogenesis imperfecta (OI), and although quality of life (QoL) has gained recognition as an important patient-outcome, it has received little attention in individuals with OI. This mixed-methods systematic review of the literature included five search engines and identified a total of 212 articles. Once study eligibility was reviewed, 10 studies met the inclusion criteria and were included in this mixed-methods review (9 quantitative and 1 qualitative). Among the 10 included QoL studies, six reported on children with OI, three on adults with OI, and one on the parents of children with OI. Physical QoL in children and adults with OI appears to be less than that of the general population, with individuals with more severe OI types reporting worse QoL. On the other hand, mental and psychosocial QoL is the same or better in individuals with OI than that of the general population. Pain, scoliosis activity limitations and participation restrictions due to decreased function are associated with lower levels of physical QoL. Researchers must agree on a definition of QoL as it relates to OI and use validated measures appropriate for evaluating QoL in OI. Pediatric studies should consider both the child and the parent's QOL perceptions as these may differ. QoL in the adult population should not be dismissed in order to offer proper client-centered interventions throughout the lifespan. PMID:26365089

  16. Copy number variants in association with type 1 collagenopathy: Atypical osteogenesis imperfecta.

    PubMed

    Balasubramanian, Meena; Cartwright, Ashley; Smith, Kath; Arundel, Paul; Bishop, Nicholas J

    2016-02-01

    We report a sibling-pair and a 4-year old child from two families with an atypical presentation in Osteogenesis imperfecta (OI). In the sib-pair, the older sibling initially came to medical attention due to a fracture history (Patient 1) and she was shown to have a COL1A2 mutation. In addition, she also had developmental delay, facial dysmorphism, and a history of frequent infections which led to a search for an alternate diagnosis. ArrayCGH revealed a 4.3 Mb duplication on chromosome 19q13.42q13.43, which was confirmed by FISH analysis. On further familial analysis, the younger sibling who had no previous fracture history was also found to have the COL1A2 mutation and tested positive for the 19q13.42q13.43 duplication (Patient 2). The 19q13 duplication appears to be the cause of intellectual disability in these siblings but given that this is a chromosomal duplication, it is still possible that there is an as yet unidentified cause that may account for the combined phenotype in this family. Patient 3 was a 4-year old child presenting with a femoral fracture, blue sclerae, developmental delay, and joint hypermobility. Genetic analyses confirmed a COL1A2 mutation but also revealed an 8.8 Mb deletion of 11q24.2q25, confirmed by G-band chromosome analysis. We discuss the differing phenotypes in patients presenting with atypical OI and stress the need to consider ancillary investigations in individuals presenting with heterogeneous phenotypic symptoms, not entirely attributable to OI. PMID:26471105

  17. Echocardiographic Evidence of Early Diastolic Dysfunction in Asymptomatic Children with Osteogenesis Imperfecta

    PubMed Central

    Al-Senaidi, Khalfan S.; Ullah, Irfan; Javad, Hashim; Al-Khabori, Murtadha; Al-Yaarubi, Saif

    2015-01-01

    Objectives: Structural and functional cardiovascular abnormalities have been reported in adults with osteogenesis imperfecta (OI); however, there is a lack of paediatric literature on this topic. This study aimed to investigate cardiovascular abnormalities in children with OI in comparison to a control group. Methods: This case-control study was conducted at the Sultan Qaboos University Hospital in Muscat, Oman, between May 2013 and August 2014. Data from eight patients with OI and 24 healthy controls were compared using conventional and tissue Doppler echocardiography (TDE). Results: The OI group had significantly lower peak early mitral valve flow velocity (P = 0.027), peak a-wave reversal in the pulmonary vein (P = 0.030) and peak early diastolic velocity of the mitral valve and upper septum (P = 0.001 each). The peak late diastolic velocities of the mitral valve (P = 0.002) and the upper septum (P = 0.037) were significantly higher in the OI group; however, the peak early/late diastolic velocity ratios of the mitral valve (P = 0.002) and upper septum (P = 0.001) were significantly lower. Left ventricular dimensions and aortic and pulmonary artery diameters were larger in the OI group when indexed for body surface area. Both groups had normal systolic cardiac function. Conclusion: Children with OI had normal systolic cardiac function. However, changes in myocardial tissue Doppler velocities were suggestive of early diastolic cardiac dysfunction. They also had increased left ventricular dimensions and greater vessel diameters. These findings indicate the need for early and detailed structural and functional echocardiographic assessment and follow-up of young patients with OI. PMID:26629370

  18. Effect of paternal age in achondroplasia, thanatophoric dysplasia, and osteogenesis imperfecta

    SciTech Connect

    Orioli, I.M.; Castilla, E.E.; Scarano, G.; Mastroiacovo, P.

    1995-11-06

    The paternal ages of nonfamilial cases of achondroplasia (AC) (n = 78), thanatophoric dysplasia (TD) (n = 64), and osteogenesis imperfecta (OI) (n = 106), were compared with those of matched controls, from an Italian Indagine Policentrica Italiana sulle Malformazioni Congenite (IPIMC) and a South American Estudio Colaborativo Latinoamericano de Malformaciones Congenitas (ECLAMC) series. The degree of paternal age effect on the origin of these dominant mutations differed among the three conditions. Mean paternal age was highly elevated in AC, 36.30 {plus_minus} 6.74 years in the IPIMC, and 37.19 {plus_minus} 10.53 years in the ECLAMC; less consistently elevated in TD, 33.60 {plus_minus} 7.08 years in the IPIMC, and 36.41 {plus_minus} 9.38 years in the ECLAMC; and only slightly elevated in OI in the ECLAMC, 31.15 {plus_minus} 9.25 years, but not in the IPIMC, 32.26 {plus_minus} 6.07 years. Increased maternal age or birth order in these conditions disappeared when corrected for paternal age. Approximately 50% of AC and TD cases, and only 30% of OI cases, were born to fathers above age 35 years. For AC and TD, the increase in relative incidence with paternal age fitted an exponential curve. The variability of paternal age effect in these new mutations could be due, among other reasons, to the high proportion of germ-line mosaicism in OI parents, or to the localization of the AC gene, mapped to the 4p16.3 region, in the neighborhood of an unstable DNA area. 28 refs., 1 fig., 6 tabs.

  19. Allelic background of LEPRE1 mutations that cause recessive forms of osteogenesis imperfecta in different populations

    PubMed Central

    Pepin, Melanie G; Schwarze, Ulrike; Singh, Virendra; Romana, Marc; Jones-LeCointe, Altheia; Byers, Peter H

    2013-01-01

    Biallelic mutations in LEPRE1 result in recessively inherited forms of osteogenesis imperfecta (OI) that are often lethal in the perinatal period. A mutation (c.1080+1G>T, IVS5+1G>T) in African Americans has a carrier frequency of about 1/240. The mutant allele originated in West Africa in tribes of Ghana and Nigeria where the carrier frequencies are 2% and 5%. By examining 200 samples from an African-derived population in Tobago and reviewing hospital neonatal death records, we determined that the carrier frequency of c.1080+1G>T was about one in 200 and did not contribute to the neonatal deaths recorded over a 3-year period of time in Trinidad. In the course of sequence analysis, we found surprisingly high LEPRE1 allelic diversity in the Tobago DNA samples in which there were 11 alleles distinguished by a single basepair variant in or near exon 5. All the alleles found in the Tobago population that were within the sequence analysis region were found in the African American population in the Exome Variant Project. This diversity appeared to reflect the geographic origin of the original population in Tobago. In 44 individuals with biallelic LEPRE1 mutations identified by clinical diagnostic testing, we found the sequence alterations occurred on seven of the 11 variant alleles. All but one of the mutations identified resulted in mRNA or protein instability for the majority of the transcripts from the altered allele. These findings suggest that the milder end of the clinical spectrum could be due to as yet unidentified missense mutations in LEPRE1. PMID:24498616

  20. Digital stereophotogrammetry as a new technique to quantify truncal deformity: a pilot study in persons with osteogenesis imperfecta.

    PubMed

    Gabor, Lisa R; Chamberlin, Andrew P; Levy, Ellen; Perry, Monique B; Cintas, Holly; Paul, Scott M

    2011-10-01

    The objective of this pilot study was to determine the usability of stereophotogrammetry (SP) as a noninvasive technique for obtaining linear measures and anatomical data of the torso in people with osteogenesis imperfecta in comparison with clinical observations. Ten participants were recruited from subjects enrolled in ongoing institutional review board-approved osteogenesis imperfecta protocols at the National Institute of Child Health and Human Development. Using a Gulick tape measure, anthropometer, and the SP system proprietary software, linear measurements of the torso were taken. In addition, the presence or absence of specific torso deformities was documented from both clinical observation and evaluation of SP images. Measurements of torso diameter and circumference by SP demonstrated strong agreement with the manual measurements (intraclass correlation coefficient = 0.995 and 0.964, respectively). Substantial and statistically significant agreement was present between SP image evaluation and clinical observation for pectus carinatum (κ = 0.52 ± 0.23) and thoracic scoliosis (κ = 0.72 ± 0.12). The kappa values between clinical observation and SP evaluations of other torso deformities were not significant. The strong correlations and P values determined by this study demonstrate the potential value of SP in studying persons with truncal deformities. However, the weak agreement between SP and some clinical observations suggests that further development of SP image analysis tools is required before SP can be used as a standard method of diagnosis or assessment of treatment success. PMID:21862911

  1. X-ray micro-analysis of the mineralization patterns in developing enamel in hamster tooth germs exposed to fluoride in vitro during the secretory phase of amelogenesis

    SciTech Connect

    Lyaruu, D.M.; Blijleven, N.; Hoeben-Schornagel, K.; Bronckers, A.L.; Woeltgens, J.H.

    1989-09-01

    The developing enamel from three-day-old hamster first maxillary (M1) molar tooth germs exposed to fluoride (F-) in vitro was analyzed for its mineral content by means of the energy-dispersive x-ray microanalysis technique. The aim of this study was to obtain semi-quantitative data on the F(-)-induced hypermineralization patterns in the enamel and to confirm that the increase in electron density observed in micrographs of F(-)-treated enamel is indeed due to an increase in mineral content in the fluorotic enamel. The tooth germs were explanted during the early stages of secretory amelogenesis and initially cultured for 24 hr in the presence of 10 ppm F- in the culture medium. The germs were then cultured for another 24 hr without F-. In order to compare the ultrastructural results directly with the microprobe data, we used the same specimens for both investigations. The net calcium counts (measurement minus background counts) in the analyses were used as a measure of the mineral content in the enamel. The aprismatic pre-exposure enamel, deposited in vivo before the onset of culture, was the most hypermineralized region in the fluorotic enamel, i.e., it contained the highest amount of calcium measured. The degree of the F(-)-induced hypermineralization gradually decreased (but was not abolished) in the more mature regions of the enamel. The unmineralized enamel matrix secreted during the initial F- treatment in vitro mineralized during the subsequent culture without F-. The calcium content in this enamel layer was in the same order of magnitude as that recorded for the newly deposited enamel in control tooth germs cultured without F-.

  2. Right ventricular and pulmonary arterial dimensions in adults with osteogenesis imperfecta.

    PubMed

    Radunovic, Zoran; Wekre, Lena L; Steine, Kjetil

    2012-06-15

    We examined right ventricular (RV) and ascending pulmonary artery (PA1) dimensions in adults with osteogenesis imperfecta (OI). The survey included 99 adults with OI divided in 3 clinical types (I, III, and IV) and 52 controls. RV and PA1 dimensions were measured by echocardiography and indexed for body surface area. Scoliosis was registered, and spirometry was performed in 75 patients with OI. All RV dimensions indexed by body surface area were significantly larger in the OI group compared to controls (RV basal dimension 1.9 ± 0.5 vs 1.7 ± 0.3 cm/m(2), p <0.05; RV midcavity dimension 1.7 ± 0.5 vs 1.5 ± 0.3 cm/m(2), p <0.05; RV longitudinal dimension 4.3 ± 1.1 vs 4.0 ± 0.9 cm/m(2), p <0.05). RV outflow tract (RVOT) proximal diameter (1.8 ± 0.4 vs 1.5 ± 0.2 cm/m(2), p <0.05), RVOT distal diameter (1.2 ± 0.2 vs 1.0 ± 0.1 cm/m(2), p <0.05), and PA1 (1.2 ± 0.3 vs 1.0 ± 0.2 cm/m(2), p <0.05) were also significantly larger in the OI group. Furthermore, all RV dimensions and PA1 were significantly larger in patients with OI type III compared to patients with OI types I and IV and controls. There were no differences in RV, RVOT, or PA1 dimensions between patients presenting a restrictive ventilatory pattern (n = 11) and patients a normal ventilatory pattern. Scoliosis was registered in 42 patients. Patients with OI type III had greater RV and PA1 dimensions compared to controls and patients with OI types I and IV. Impaired ventilatory patterns and scoliosis did not have any impact on RV dimensions in these patients. In conclusion, patients with OI had increased RV and PA1 dimensions compared to the control group. PMID:22459302

  3. Thermal stability of type I and type III procollagens from normal human fibroblasts and from a patient with osteogenesis imperfecta.

    PubMed

    Peltonen, L; Palotie, A; Hayashi, T; Prockop, D J

    1980-01-01

    Type I and type III procollagens were isolated from the medium of human fibroblast cultures in amounts adequate for examination by circular dichroism. Type I procollagen had a spectrum similar to that of type I procollagen and collagen from chicken embryos. The human type III procollagen showed a red shift not seen in type III collagen from calf skin. The midpoint (tm) for the helix-to-coil transition for both human procollagens was 40 degrees C. the same tm values were obtained with type I and type III procollagens synthesized by fibroblasts from a patient with osteogenesis imperfecta. Type I procollagen synthesized by the patient's fibroblasts, however, tended to aggregate more readily than type I procollagen from normal human fibroblasts, apparently because of a structural alteration of the protein. PMID:6928611

  4. Microstructure and compressive mechanical properties of cortical bone in children with osteogenesis imperfecta treated with bisphosphonates compared with healthy children.

    PubMed

    Imbert, Laurianne; Aurégan, Jean-Charles; Pernelle, Kélig; Hoc, Thierry

    2015-06-01

    Osteogenesis imperfecta (OI) is a genetic disorder characterized by a change in bone tissue quality, but little data are available to describe the factors involved at the macroscopic scale. To better understand the effect of microstructure alterations on the mechanical properties at the sample scale, we studied the structural and mechanical properties of six cortical bone samples from children with OI treated with bisphosphonates and compared them to the properties of three controls. Scanning electron microscopy, high resolution computed tomography and compression testing were used to assess these properties. More resorption cavities and a higher osteocyte lacunar density were observed in OI bone compared with controls. Moreover, a higher porosity was measured for OI bones along with lower macroscopic Young's modulus, yield stress and ultimate stress. The microstructure was impaired in OI bones; the higher porosity and osteocyte lacunar density negatively impacted the mechanical properties and made the bone more prone to fracture. PMID:25828157

  5. Severe osteogenesis imperfecta Type-III and its challenging treatment in newborn and preschool children. A systematic review.

    PubMed

    Sinikumpu, Juha-Jaakko; Ojaniemi, Marja; Lehenkari, Petri; Serlo, Willy

    2015-08-01

    Osteogenesis imperfecta (OI) is a group of genetic disorders, of which Type III is the most severe among survivors. The disease is characterised in particular by bone fragility, decreased bone mass and increased incidence of fractures. Other usual findings are muscle hypotonia, joint hypermobility and short stature. Fractures and weak bones may consequently cause limb and spinal deformity and chronic physical disability. Bisphosphonates have revolutionised the treatment of newborn children with severe OI type III. Surgery is still needed in most patients due to high frequency of the fractures. In this systematic review we describe the present state-of-art in treating the most severe type of OI in newborn and preschool children with their bone fractures. PMID:25943292

  6. Adaptor Protein Complex 2 (AP-2) Mediated, Clathrin Dependent Endocytosis, And Related Gene Activities, Are A Prominent Feature During Maturation Stage Amelogenesis

    PubMed Central

    LACRUZ, Rodrigo S.; BROOKES, Steven J.; WEN, Xin; JIMENEZ, Jaime M.; VIKMAN, Susanna; HU, Ping; WHITE, Shane N.; LYNGSTADAAS, S. Petter; OKAMOTO, Curtis T.; SMITH, Charles E.; PAINE, Michael L.

    2012-01-01

    Molecular events defining enamel matrix removal during amelogenesis are poorly understood. Early reports have suggested that adaptor proteins (AP) participate in ameloblast-mediated endocytosis. Enamel formation involves the secretory and maturation stages, with an increase in resorptive function during the latter. Here, using real time PCR, we show that the expression of clathrin and adaptor protein subunits are up-regulated in maturation stage rodent enamel organ cells. AP-2 is the most up-regulated of the four distinct adaptor protein complexes. Immunolocalization confirms the presence of AP-2 and clathrin in ameloblasts with strongest reactivity at the apical pole. These data suggest that the resorptive functions of enamel cells involve AP-2 mediated, clathrin dependent endocytosis, thus implying the likelihood of a specific membrane-bound receptor(s) of enamel matrix protein debris. The mRNA expression of other endocytosis-related gene products is also up-regulated during maturation including: lysosomal-associated membrane protein 1 (Lamp1), cluster of differentiation 63 and 68 (Cd63 and Cd68), ATPase, H+ transporting, lysosomal V0 subunit D2 (Atp6v0d2), ATPase, H+ transporting, lysosomal V1 subunit B2 (Atp6v1b2), chloride channel, voltage-sensitive 7 (Clcn7) and cathepsin K (Ctsk). Immunohistological data confirms the expression of a number of these proteins in maturation stage ameloblasts. The enamel of Cd63-null mice was also examined. Despite increased mRNA and protein expression in the enamel organ during maturation, the enamel of Cd63-null mice appeared normal. This may suggest inherent functional redundancies between Cd63 and related gene products, such as Lamp1 and Cd68. Ameloblast-like LS8 cells treated with the enamel matrix protein complex Emdogain® showed up-regulation of AP-2 and clathrin subunits, further supporting the existence of a membrane-bound receptor regulated pathway for the endocytosis of enamel matrix proteins. These data together

  7. Transcriptional Repression of the Dspp Gene Leads to Dentinogenesis Imperfecta Phenotype in Col1a1-Trps1 Transgenic Mice

    PubMed Central

    Napierala, Dobrawa; Sun, Yao; Maciejewska, Izabela; Bertin, Terry K; Dawson, Brian; D'Souza, Rena; Qin, Chunlin; Lee, Brendan

    2012-01-01

    Dentinogenesis imperfecta (DGI) is a hereditary defect of dentin, a calcified tissue that is the most abundant component of teeth. Most commonly, DGI is manifested as a part of osteogenesis imperfecta (OI) or the phenotype is restricted to dental findings only. In the latter case, DGI is caused by mutations in the DSPP gene, which codes for dentin sialoprotein (DSP) and dentin phosphoprotein (DPP). Although these two proteins together constitute the majority of noncollagenous proteins of the dentin, little is known about their transcriptional regulation. Here we demonstrate that mice overexpressing the Trps1 transcription factor (Col1a1-Trps1 mice) in dentin-producing cells, odontoblasts, present with severe defects of dentin formation that resemble DGI. Combined micro–computed tomography (µCT) and histological analyses revealed tooth fragility due to severe hypomineralization of dentin and a diminished dentin layer with irregular mineralization in Col1a1-Trps1 mice. Biochemical analyses of noncollagenous dentin matrix proteins demonstrated decreased levels of both DSP and DPP proteins in Col1a1-Trps1 mice. On the molecular level, we demonstrated that sustained high levels of Trps1 in odontoblasts lead to dramatic decrease of Dspp expression as a result of direct inhibition of the Dspp promoter by Trps1. During tooth development Trps1 is highly expressed in preodontoblasts, but in mature odontoblasts secreting matrix its expression significantly decreases, which suggests a Trps1 role in odontoblast development. In these studies we identified Trps1 as a potent inhibitor of Dspp expression and the subsequent mineralization of dentin. Thus, we provide novel insights into mechanisms of transcriptional dysregulation that leads to DGI. © 2012 American Society for Bone and Mineral Research. PMID:22508542

  8. Current Practices and the Provider Perspectives on Inconclusive Genetic Test Results for Osteogenesis Imperfecta in Children with Unexplained Fractures: ELSI Implications.

    PubMed

    Youngblom, Emily; Murray, Mitzi Leah; Byers, Peter H

    2016-09-01

    Genetic testing can be used to determine if unexplained fractures in children could have resulted from a predisposition to bone fractures, e.g., osteogenesis imperfecta. However, uncertainty is introduced if a variant of unknown significance (VUS) is identified. Proper interpretation of VUS in these situations is critical because of its influence on clinical care and in court rulings. This study sought to understand how VUS are interpreted and used by practitioners when there is a differential diagnosis including both osteogenesis imperfecta and non-accidental injury.A 15-question survey was emailed to physicians who requested analysis of two genes, COL1A1 and COL1A2, from the University of Washington from 2005-2013 for patient cases involving suspicion of child abuse.Among the 89 participants, responses differed about when genetic testing should be ordered for osteogenesis imperfecta, who should be consulted about utilization of VUS test results, follow-up procedures, and who should receive the VUS results.There are no clear guidelines for how to interpret and follow up on VUS. In the legal setting, misinterpreted VUS could lead to unintended consequences and deleterious ramifications for family members. The need for better practice guidelines to help promote more equitable handling of these sensitive legal cases is clear. PMID:27587455

  9. Pigment epithelium-derived factor (PEDF) normalizes matrix defects in iPSCs derived from Osteogenesis imperfecta Type VI.

    PubMed

    Belinsky, Glenn S; Ward, Leanne; Chung, Chuhan

    2016-01-01

    Osteogenesis imperfecta (OI) Type VI is characterized by a defect in bone mineralization, which results in multiple fractures early in life. Null mutations in the PEDF gene, Serpinf1, are the cause of OI VI. Whether PEDF restoration in a murine model of OI Type VI could improve bone mass and function was previously unknown. In Belinsky et al, we provided evidence that PEDF delivery enhanced bone mass and improved parameters of bone function in vivo. Further, we demonstrated that PEDF temporally inhibits Wnt signaling to enhance osteoblast differentiation. Here, we demonstrate that generation of induced pluripotent stem cells (iPSCs) from a PEDF null patient provides additional evidence for PEDF's role in regulating extracellular matrix proteins secreted from osteoblasts. PEDF null iPSCs have marked abnormalities in secreted matrix proteins, capturing a key feature of human OI Type VI, which were normalized by exogenous PEDF. Lastly, we place our recent findings within the broader context of PEDF biology and the developmental signaling pathways that are implicated in its actions. PMID:27579219

  10. An unusual case of atrophic mandible fracture in a patient with osteogenesis imperfecta and on oral bisphosphonate therapy: Case report

    PubMed Central

    Al-Osaimi, Abdulrahman; Samman, Mahmood; Al-Shakhs, Mohammad; Al-Suhaim, Faisal; Ramalingam, Sundar

    2014-01-01

    Fractures of severely atrophic (height < 10 mm) edentulous mandibles are infrequent and challenging to manage. Factors such as sclerotic bone and decreased vascularity combined with systemic diseases complicate the management of such fractures. Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders of type I collagen metabolism. Patients with OI characteristically present with histories of long bone fractures, deformities, blue sclerae, and opalescent dentin. However, fractures of the facial skeleton are rare. Bisphosphonate therapy has been proven to effectively reduce the fracture risk in patients with OI. The purpose of this clinical report is to present an unusual case of spontaneous fracture of the atrophic mandible in a patient with OI. Despite open reduction and internal fixation (ORIF) with miniplate osteosynthesis, the patient developed a second fracture at a screw placement site distal to the first fracture. The patient was successfully treated with ORIF using locking reconstruction plates fixed in the symphyseal and angle regions. Bone healing following ORIF was normal, and no clinical sign of osteonecrosis as a result of bisphosphonate therapy was observed. Patients with OI can present with spontaneous fractures of already weakened mandibles. Although such fractures can be managed with care using established protocols, further research is required to examine the effects of concomitant medication, such as bisphosphonates. PMID:25408599

  11. The Impact of Psycho-Educational Trainingon the Psychosocial Adjustment of Caregivers ofOsteogenesis Imperfecta Patients

    PubMed Central

    Bozkurt, Satı; Arabacı, Leyla Baysan; Vara, Şenay; Özen, Samim; Gökşen, Damla; Darcan, Şükran

    2014-01-01

    Ob­jec­ti­ve: To investigate the impact of a psycho-educational program developed for the caregivers of patients diagnosed with osteogenesis imperfecta (OI). Methods: The participants consisted of 16 caregivers. The study was designed as a quasi-experimental pre-test/post-test type study consisting of 10 semi-structured three-hour training sessions. The data were collected using the “Introductory Information Form” and appropriate scales (Burden Interview, Coping Strategies Scale, Problem-Solving Inventory and Psychosocial Adjustment to Illness Scale). The results were evaluated by descriptive statistics, correlation analysis, one-way variance analysis and Bonferroni analysis. Results: Psychosocial adjustment levels of the caregivers of OI patients before their participation in the educational program were found to be associated with styles of coping with stress, problem-solving skills and care burden. After the psycho-educational training, the majority of the participants reported favorable changes in their lives. Following the offered psycho-education resulted in positive changes in the mean scores of the caregivers (p<0.05). Conclusion: Before the education program, the participants were not able to deal efficiently with many aspects of their caregiver responsibilities and suffered from an emotional burden due to lack of knowledge. The program appears to have provided them both with support to achieve significant psychosocial transformation and with an opportunity to reconsider their lives in multiple dimensions. PMID:24932601

  12. An unusual case of atrophic mandible fracture in a patient with osteogenesis imperfecta and on oral bisphosphonate therapy: Case report.

    PubMed

    Al-Osaimi, Abdulrahman; Samman, Mahmood; Al-Shakhs, Mohammad; Al-Suhaim, Faisal; Ramalingam, Sundar

    2014-04-01

    Fractures of severely atrophic (height < 10 mm) edentulous mandibles are infrequent and challenging to manage. Factors such as sclerotic bone and decreased vascularity combined with systemic diseases complicate the management of such fractures. Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders of type I collagen metabolism. Patients with OI characteristically present with histories of long bone fractures, deformities, blue sclerae, and opalescent dentin. However, fractures of the facial skeleton are rare. Bisphosphonate therapy has been proven to effectively reduce the fracture risk in patients with OI. The purpose of this clinical report is to present an unusual case of spontaneous fracture of the atrophic mandible in a patient with OI. Despite open reduction and internal fixation (ORIF) with miniplate osteosynthesis, the patient developed a second fracture at a screw placement site distal to the first fracture. The patient was successfully treated with ORIF using locking reconstruction plates fixed in the symphyseal and angle regions. Bone healing following ORIF was normal, and no clinical sign of osteonecrosis as a result of bisphosphonate therapy was observed. Patients with OI can present with spontaneous fractures of already weakened mandibles. Although such fractures can be managed with care using established protocols, further research is required to examine the effects of concomitant medication, such as bisphosphonates. PMID:25408599

  13. Osteogenesis Imperfecta Missense Mutations in Collagen: Structural consequences of a glycine to alanine replacement at a highly charged site

    PubMed Central

    Xiao, Jianxi; Cheng, Haiming; Silva, Teresita; Baum, Jean; Brodsky, Barbara

    2011-01-01

    Glycine is required as every third residue in the collagen triple-helix, and a missense mutation leading to the replacement of even one Gly in the repeating (Gly-Xaa-Yaa)n sequence by a larger residue leads to a pathological condition. Gly to Ala missense mutations are highly underrepresented in osteogenesis imperfecta (OI) and other collagen diseases, suggesting that the smallest replacement residue Ala might cause the least structural perturbation and mildest clinical consequences. The relatively small number of Gly to Ala mutation sites that do lead to OI must have some unusual features, such as greater structural disruption due to local sequence environment or location at a biologically important site. Here, peptides are used to model a severe OI case where a Gly to Ala mutation is found within a highly stabilizing Lys-Gly-Asp sequence environment. NMR, CD and DSC studies indicate this Gly to Ala replacement leads to a substantial loss in triple-helix stability and non-equivalence of the Ala residues in the three chains such that only one of the three Ala residues is capable of form a good backbone hydrogen bond. Examination of reported OI Gly to Ala mutations suggests preferential location at known collagen binding sites, and we propose that structural defects due to Ala replacements may lead to pathology when interfering with interactions. PMID:22054507

  14. Delivery by Cesarean Section is not Associated With Decreased at-Birth Fracture Rates in Osteogenesis Imperfecta

    PubMed Central

    Bellur, S; Jain, M; Cuthbertson, D; Krakow, D; Shapiro, JR; Steiner, RD; Smith, PA; Bober, MB; Hart, T; Krischer, J; Mullins, M; Byers, PH; Pepin, M; Durigova, M; Glorieux, FH; Rauch, F; Sutton, VR; Lee, B; Nagamani, SC

    2015-01-01

    Purpose Osteogenesis imperfecta (OI) predisposes to recurrent fractures. The moderate-to-severe forms of OI present with antenatal fractures and the mode of delivery that would be safest for the fetus is not known. Methods We conducted systematic analyses on the largest cohort of individuals (n=540) with OI enrolled to-date in the OI Linked Clinical Research Centers. Self-reported at-birth fracture rates were compared in individuals with OI types I, III, and IV. Multivariate analyses utilizing backward-elimination logistic regression model building were performed to assess the effect of multiple covariates including method of delivery on fracture-related outcomes. Results When accounting for other covariates, at-birth fracture rates did not differ based on whether delivery was by vaginal route or by cesarean section (CS). Increased birth weight conferred higher risk for fractures irrespective of the delivery method. In utero fracture, maternal history of OI, and breech presentation were strong predictors for choosing CS for delivery. Conclusion Our study, the largest to analyze the effect of various factors on at-birth fracture rates in OI shows that delivery by CS is not associated with decreased fracture rate. With the limitation that the fracture data were self-reported in this cohort, these results suggest that CS should be performed only for other maternal or fetal indications, but not for the sole purpose of fracture prevention in OI. PMID:26426884

  15. Administration of soluble activin receptor 2B increases bone and muscle mass in a mouse model of osteogenesis imperfecta

    PubMed Central

    DiGirolamo, Douglas J.; Singhal, Vandana; Chang, Xiaoli; Lee, Se-Jin; Germain-Lee, Emily L.

    2015-01-01

    Osteogenesis imperfecta (OI) comprises a group of heritable connective tissue disorders generally defined by recurrent fractures, low bone mass, short stature and skeletal fragility. Beyond the skeletal complications of OI, many patients also report intolerance to physical activity, fatigue and muscle weakness. Indeed, recent studies have demonstrated that skeletal muscle is also negatively affected by OI, both directly and indirectly. Given the well-established interdependence of bone and skeletal muscle in both physiology and pathophysiology and the observations of skeletal muscle pathology in patients with OI, we investigated the therapeutic potential of simultaneous anabolic targeting of both bone and skeletal muscle using a soluble activin receptor 2B (ACVR2B) in a mouse model of type III OI (oim). Treatment of 12-week-old oim mice with ACVR2B for 4 weeks resulted in significant increases in both bone and muscle that were similar to those observed in healthy, wild-type littermates. This proof of concept study provides encouraging evidence for a holistic approach to treating the deleterious consequences of OI in the musculoskeletal system. PMID:26161291

  16. Pigment epithelium-derived factor (PEDF) normalizes matrix defects in iPSCs derived from Osteogenesis imperfecta Type VI

    PubMed Central

    Belinsky, Glenn S.; Ward, Leanne; Chung, Chuhan

    2016-01-01

    ABSTRACT Osteogenesis imperfecta (OI) Type VI is characterized by a defect in bone mineralization, which results in multiple fractures early in life. Null mutations in the PEDF gene, Serpinf1, are the cause of OI VI. Whether PEDF restoration in a murine model of OI Type VI could improve bone mass and function was previously unknown. In Belinsky et al, we provided evidence that PEDF delivery enhanced bone mass and improved parameters of bone function in vivo. Further, we demonstrated that PEDF temporally inhibits Wnt signaling to enhance osteoblast differentiation. Here, we demonstrate that generation of induced pluripotent stem cells (iPSCs) from a PEDF null patient provides additional evidence for PEDF's role in regulating extracellular matrix proteins secreted from osteoblasts. PEDF null iPSCs have marked abnormalities in secreted matrix proteins, capturing a key feature of human OI Type VI, which were normalized by exogenous PEDF. Lastly, we place our recent findings within the broader context of PEDF biology and the developmental signaling pathways that are implicated in its actions. PMID:27579219

  17. Osteochondritis dissecans of the lateral femoral condyle in a patient affected by osteogenesis imperfecta: a case report.

    PubMed

    Persiani, Pietro; Di Domenica, Marica; Martini, Lorena; Ranaldi, Filippo M; Zambrano, Anna; Celli, Mauro; Villani, Ciro

    2015-11-01

    Osteochondritis dissecans is a very uncommon phenomenon in osteogenesis imperfecta (OI). A 14-year-old boy, affected by OI and followed in our Center for Congenital Osteodystrophies, had a knee trauma and MRI indicated a hollowed area of 2.5×1.5 cm in the lateral femoral condyle, which was classified as grade III. The patient underwent surgery, performed as a one-step surgical treatment: the osteochondral fragment was removed, curettage of lesion's bottom was performed, and a biphasic scaffold was used to fill the defect, implanted with a press-fit technique. MRI at 12 and 24 months after surgery showed scaffold integration. At the final follow-up, the patient did not feel any pain or articular limitations. It is difficult to provide a guideline on osteochondritis dissecans in patients affected by OI because of the lack of literature reports on this rare disorder in a rare disease. According to our experience, in these patients, osteosynthesis of the bone fragment and the use of autograft are not recommended because of the patient's bone weakness and osteoporosis. Moreover, compared with two-step surgery, one-step surgery is preferred to reduce the risk related to anesthesia, often observed to be higher in these patients. PMID:25919806

  18. Rapidly Growing Brtl/+ Mouse Model of Osteogenesis Imperfecta Improves Bone Mass and Strength with Sclerostin Antibody Treatment

    PubMed Central

    Sinder, Benjamin P.; Salemi, Joseph D.; Ominsky, Michael S.; Caird, Michelle S.; Marini, Joan C.; Kozloff, Kenneth M.

    2014-01-01

    Osteogenesis imperfecta (OI) is a heritable collagen-related bone dysplasia, characterized by brittle bones with increased fracture risk that presents most severely in children. Anti-resorptive bisphosphonates are frequently used to treat pediatric OI and controlled clinical trials have shown bisphosphonate therapy improves vertebral outcomes but has little benefit on long bone fracture rate. New treatments which increase bone mass throughout the pediatric OI skeleton would be beneficial. Sclerostin antibody (Scl-Ab) is a potential candidate anabolic therapy for pediatric OI and functions by stimulating osteoblastic bone formation via the canonical wnt signaling pathway. To explore the effect of Scl-Ab on the rapidly growing OI skeleton, we treated rapidly growing 3 week old Brtl/+ mice, harboring a typical heterozygous OI-causing Gly->Cys substitution on col1a1, for 5 weeks with Scl-Ab. Scl-Ab had anabolic effects in Brtl/+ and led to new cortical bone formation and increased cortical bone mass. This anabolic action resulted in improved mechanical strength to WT Veh levels without altering the underlying brittle nature of the material. While Scl-Ab was anabolic in trabecular bone of the distal femur in both genotypes, the effect was less strong in these rapidly growing Brtl/+ mice compared to WT. In conclusion, Scl-Ab was able to stimulate bone formation in a rapidly growing Brtl/+ murine model of OI, and represents a potential new therapy to improve bone mass and reduce fracture risk in pediatric OI. PMID:25445450

  19. Cardiopulmonary dysfunction in the Osteogenesis imperfecta mouse model Aga2 and human patients are caused by bone-independent mechanisms

    PubMed Central

    Thiele, Frank; Cohrs, Christian M.; Flor, Armando; Lisse, Thomas S.; Przemeck, Gerhard K. H.; Horsch, Marion; Schrewe, Anja; Gailus-Durner, Valerie; Ivandic, Boris; Katus, Hugo A.; Wurst, Wolfgang; Reisenberg, Catherine; Chaney, Hollis; Fuchs, Helmut; Hans, Wolfgang; Beckers, Johannes; Marini, Joan C.; Hrabé de Angelis, Martin

    2012-01-01

    Osteogenesis imperfecta (OI) is an inherited connective tissue disorder with skeletal dysplasia of varying severity, predominantly caused by mutations in the collagen I genes (COL1A1/COL1A2). Extraskeletal findings such as cardiac and pulmonary complications are generally considered to be significant secondary features. Aga2, a murine model for human OI, was systemically analyzed in the German Mouse Clinic by means of in vivo and in vitro examinations of the cardiopulmonary system, to identify novel mechanisms accounting for perinatal lethality. Pulmonary and, especially, cardiac fibroblast of perinatal lethal Aga2/+ animals display a strong down-regulation of Col1a1 transcripts in vivo and in vitro, resulting in a loss of extracellular matrix integrity. In addition, dysregulated gene expression of Nppa, different types of collagen and Agt in heart and lung tissue support a bone-independent vicious cycle of heart dysfunction, including hypertrophy, loss of myocardial matrix integrity, pulmonary hypertension, pneumonia and hypoxia leading to death in Aga2. These murine findings are corroborated by a pediatric OI cohort study, displaying significant progressive decline in pulmonary function and restrictive pulmonary disease independent of scoliosis. Most participants show mild cardiac valvular regurgitation, independent of pulmonary and skeletal findings. Data obtained from human OI patients and the mouse model Aga2 provide novel evidence for primary effects of type I collagen mutations on the heart and lung. The findings will have potential benefits of anticipatory clinical exams and early intervention in OI patients. PMID:22589248

  20. The recurrent causal mutation for osteogenesis imperfecta type V occurs at a highly methylated CpG dinucleotide within the IFITM5 gene

    PubMed Central

    Corradi, Massimiliano; Monti, Elena; Venturi, Giacomo; Gandini, Alberto; Mottes, Monica; Antoniazzi, Franco

    2014-01-01

    Recent studies have identified the molecular defect underlying autosomal dominant osteogenesis imperfecta (OI) type V. Unlike all other OI types, which are characterized by high genetic heterogeneity, OI type V appears consistently associated to a unique de novo C>T transition within the 5′ UTR of the IFITM5 gene. Although the precise frequency of OI type V is not known, this recurrent base substitution may well represent a mutational hotspot in the human genome. We show that it occurs at a CpG dinucleotide that is highly methylated in several tissues and particularly in the sperm DNA, suggesting a mutational mechanism common to other de novo recurrent dominant mutations.

  1. Evolution of the radiographic appearance of the metaphyses over the first year of life in type V osteogenesis imperfecta: clues to pathogenesis.

    PubMed

    Arundel, Paul; Offiah, Amaka; Bishop, Nicholas J

    2011-04-01

    We present the first report of the development of characteristic radiologic appearances of long bones during the first year of life in an infant with type V osteogenesis imperfecta (OI). We show the evolution of metaphyseal abnormalities from a rickets-like appearance to the classically described dense metaphyseal bands. These abnormalities suggest that the underlying defect in type V OI may involve a molecule common to both bone and cartilage that is involved in the regulation of growth plate development and metadiaphyseal ossification. Our findings provide new insights into skeletal development in type V OI and potentially yield useful clues to the identity of the defect underpinning the condition. PMID:20872883

  2. [Contradictions of public health policies geared to rare disorders: the example of the Osteogenesis Imperfecta Treatment Program in the Brazilian Unified Health System (SUS)].

    PubMed

    Lima, Maria Angelica de Faria Domingues de; Horovitz, Dafne Dain Gandelman

    2014-02-01

    The scope of this paper is to examine the process of consolidation of a public health policy in Brazil geared to a rare disorder, namely osteogenesis imperfecta, the treatment for which has fallen under the responsibility of the Brazilian Unified Health System (SUS) after the publication of Ministerial Ruling GM/MS2305/2001. The implementation of this law has been accompanied by many contradictions, especially with respect to therapeutic decisions and the strengthening of the specialized network for addressing this condition. These attitudes are clearly shown both by the drafting process and the final text of the new law (Ministerial Ruling 714/2010). PMID:24863824

  3. Mutations in SEC24D, Encoding a Component of the COPII Machinery, Cause a Syndromic Form of Osteogenesis Imperfecta

    PubMed Central

    Garbes, Lutz; Kim, Kyungho; Rieß, Angelika; Hoyer-Kuhn, Heike; Beleggia, Filippo; Bevot, Andrea; Kim, Mi Jeong; Huh, Yang Hoon; Kweon, Hee-Seok; Savarirayan, Ravi; Amor, David; Kakadia, Purvi M.; Lindig, Tobias; Kagan, Karl Oliver; Becker, Jutta; Boyadjiev, Simeon A.; Wollnik, Bernd; Semler, Oliver; Bohlander, Stefan K.; Kim, Jinoh; Netzer, Christian

    2015-01-01

    As a result of a whole-exome sequencing study, we report three mutant alleles in SEC24D, a gene encoding a component of the COPII complex involved in protein export from the ER: the truncating mutation c.613C>T (p.Gln205∗) and the missense mutations c.3044C>T (p.Ser1015Phe, located in a cargo-binding pocket) and c.2933A>C (p.Gln978Pro, located in the gelsolin-like domain). Three individuals from two families affected by a similar skeletal phenotype were each compound heterozygous for two of these mutant alleles, with c.3044C>T being embedded in a 14 Mb founder haplotype shared by all three. The affected individuals were a 7-year-old boy with a phenotype most closely resembling Cole-Carpenter syndrome and two fetuses initially suspected to have a severe type of osteogenesis imperfecta. All three displayed a severely disturbed ossification of the skull and multiple fractures with prenatal onset. The 7-year-old boy had short stature and craniofacial malformations including macrocephaly, midface hypoplasia, micrognathia, frontal bossing, and down-slanting palpebral fissures. Electron and immunofluorescence microscopy of skin fibroblasts of this individual revealed that ER export of procollagen was inefficient and that ER tubules were dilated, faithfully reproducing the cellular phenotype of individuals with cranio-lentico-sutural dysplasia (CLSD). CLSD is caused by SEC23A mutations and displays a largely overlapping craniofacial phenotype, but it is not characterized by generalized bone fragility and presented with cataracts in the original family described. The cellular and morphological phenotypes we report are in concordance with the phenotypes described for the Sec24d-deficient fish mutants vbi (medaka) and bulldog (zebrafish). PMID:25683121

  4. Tissue level material composition and mechanical properties in Brtl/+ mouse model of Osteogenesis Imperfecta after sclerostin antibody treatment

    NASA Astrophysics Data System (ADS)

    Lloyd, William R.; Sinder, Benjamin P.; Salemi, Joseph; Ominsky, Michael S.; Marini, Joan C.; Caird, Michelle S.; Morris, Michael D.; Kozloff, Kenneth M.

    2015-02-01

    Osteogenesis imperfecta (OI) is a genetic disorder resulting in defective collagen or collagen-associated proteins and fragile, brittle bones. To date, therapies to improve OI bone mass, such as bisphosphonates, have increased bone mass in the axial skeleton of OI patients, but have shown limited effects at reducing long bone fragility. Sclerostin antibody (Scl- Ab), currently in clinical trials for osteoporosis, stimulates bone formation and may have the potential to reduce long bone fracture rates in OI patients. Scl-Ab has been investigated as an anabolic therapy for OI in the Brtl/+ mouse model of moderately severe Type IV OI. While Scl-Ab increases long bone mass in the Brtl/+ mouse, it is not known whether material properties and composition changes also occur. Here, we report on the effects of Scl-Ab on wild type and Brtl/+ young (3 week) and adult (6 month) male mice. Scl-Ab was administered over 5 weeks (25mg/kg, 2x/week). Raman microspectroscopy and nanoindentation are used for bone composition and biomechanical bone property measurements in excised bone. Fluorescent labels (calcein and alizarin) at 4 time points over the entire treatment period are used to enable measurements at specific tissue age. Differences between wild type and Brtl/+ groups included variations in the mineral and matrix lattices, particularly the phosphate v1, carbonate v1, and the v(CC) proline and hydroxyproline stretch vibrations. Results of Raman spectroscopy corresponded to nanoindentation findings which indicated that old bone (near midcortex) is stiffer (higher elastic modulus) than new bone. We compare and contrast mineral to matrix and carbonate to phosphate ratios in young and adult mice with and without treatment.

  5. Recurrent Proximal Femur Fractures in a Teenager With Osteogenesis Imperfecta on Continuous Bisphosphonate Therapy: Are We Overtreating?

    PubMed

    Vasanwala, Rashida F; Sanghrajka, Anish; Bishop, Nicholas J; Högler, Wolfgang

    2016-07-01

    Long-term bisphosphonate (BP) therapy in adults with osteoporosis is associated with atypical femoral fractures, caused by increased material bone density and prolonged suppression of bone remodeling which may reduce fracture toughness. In children with osteogenesis imperfecta (OI), long-term intravenous BP therapy improves bone structure and mass without further increasing the already hypermineralized bone matrix, and is generally regarded as safe. Here we report a teenage girl with OI type IV, who was started on cyclical intravenous pamidronate therapy at age 6 years because of recurrent fractures. Transiliac bone biopsy revealed classical structural features of OI but unusually low bone resorption surfaces. She made substantial improvements in functional ability, bone mass, and fracture rate. However, after 5 years of pamidronate therapy she started to develop recurrent, bilateral, nontraumatic, and proximal femur fractures, which satisfied the case definition for atypical femur fractures. Some fractures were preceded by periosteal reactions and prodromal pain. Pamidronate was discontinued after 7 years of therapy, following which she sustained two further nontraumatic femur fractures, and continued to show delayed tibial osteotomy healing. Despite rodding surgery, and very much in contrast to her affected, untreated, and normally mobile mother, she remains wheelchair-dependent. The case of this girl raises questions about the long-term safety of BP therapy in some children, in particular about the risk of oversuppressed bone remodeling with the potential for microcrack accumulation, delayed healing, and increased stiffness. The principal concern is whether there is point at which benefit from BP therapy could turn into harm, where fracture risk increases again. This case should stimulate debate whether current adult atypical femoral fracture guidance should apply to children, and whether low-frequency, low-dose cyclical, intermittent, or oral treatment

  6. Osteogenesis imperfecta: Ultrastructural and histological findings on examination of skin revealing novel insights into genotype-phenotype correlation.

    PubMed

    Balasubramanian, M; Sobey, G J; Wagner, B E; Peres, L C; Bowen, J; Bexon, J; Javaid, M K; Arundel, P; Bishop, N J

    2016-01-01

    Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders of bone formation, resulting in low bone mass and an increased propensity to fracture. Over 90% of patients with OI have a mutation in COL1A1/COL1A2, which shows an autosomal dominant pattern of inheritance. In-depth phenotyping and in particular, studies involving manifestations in the skin connective tissue have not previously been undertaken in OI. The aims of the study were to perform histological and ultrastructural examination of skin biopsies in a cohort of patients with OI; to identify common and distinguishing features in order to inform genotype-phenotype correlation; and to identify common and distinguishing features between the different subtypes of OI. As part of the RUDY (Rare Diseases in Bone, Joints and/or Blood Vessels) study, in collaboration with the NIHR Rare Diseases Translational Research Collaboration, we undertook a national study of skin biopsies in patients with OI. We studied the manifestations in the skin connective tissue and undertook in-depth clinical and molecular phenotyping of 16 patients with OI. We recruited 16 patients: analyses have shown that in type 1 collagen mutation positive patients (COL1A1/ COL1A2) (n-4/16) consistent findings included: variable collagen fibril diameter (CFD) and presence of collagen flowers. Histological examination in these patients showed an increase in elastic fibers that are frequently fragmented and clumped. These observations provide evidence that collagen flowers and CFD variability are consistent features in OI due to type 1 collagen defects and reinforce the need for accurate phenotyping in conjunction with genomic analyses. PMID:26863094

  7. Pre- and Postnatal Transplantation of Fetal Mesenchymal Stem Cells in Osteogenesis Imperfecta: A Two-Center Experience

    PubMed Central

    Westgren, Magnus; Shaw, S.W. Steven; Åström, Eva; Biswas, Arijit; Byers, Peter H.; Mattar, Citra N.Z.; Graham, Gail E.; Taslimi, Jahan; Ewald, Uwe; Fisk, Nicholas M.; Yeoh, Allen E.J.; Lin, Ju-Li; Cheng, Po-Jen; Choolani, Mahesh; Le Blanc, Katarina; Chan, Jerry K.Y.

    2014-01-01

    Osteogenesis imperfecta (OI) can be recognized prenatally with ultrasound. Transplantation of mesenchymal stem cells (MSCs) has the potential to ameliorate skeletal damage. We report the clinical course of two patients with OI who received prenatal human fetal MSC (hfMSC) transplantation and postnatal boosting with same-donor MSCs. We have previously reported on prenatal transplantation for OI type III. This patient was retransplanted with 2.8 × 106 same-donor MSCs per kilogram at 8 years of age, resulting in low-level engraftment in bone and improved linear growth, mobility, and fracture incidence. An infant with an identical mutation who did not receive MSC therapy succumbed at 5 months despite postnatal bisphosphonate therapy. A second fetus with OI type IV was also transplanted with 30 × 106 hfMSCs per kilogram at 31 weeks of gestation and did not suffer any new fractures for the remainder of the pregnancy or during infancy. The patient followed her normal growth velocity until 13 months of age, at which time longitudinal length plateaued. A postnatal infusion of 10 × 106 MSCs per kilogram from the same donor was performed at 19 months of age, resulting in resumption of her growth trajectory. Neither patient demonstrated alloreactivity toward the donor hfMSCs or manifested any evidence of toxicities after transplantation. Our findings suggest that prenatal transplantation of allogeneic hfMSCs in OI appears safe and is of likely clinical benefit and that retransplantation with same-donor cells is feasible. However, the limited experience to date means that it is not possible to be conclusive and that further studies are required. PMID:24342908

  8. The Effects of RANKL Inhibition on Fracture Healing and Bone Strength in a Mouse Model of Osteogenesis Imperfecta

    PubMed Central

    Delos, D.; Yang, X.; Ricciardi, B.F.; Myers, E.R.; Bostrom, M.P.G.; Pleshko Camacho, N.

    2009-01-01

    Summary Currently, the standard treatment for osteogenesis imperfecta (OI) is bisphosphonate therapy. Recent studies, however, have shown delayed healing of osteotomies in a subset of OI patients treated with such agents. The current study sought to determine the effects of another therapy, RANKL inhibition, on bone healing and bone strength in the growing oim/oim mouse, a model of moderate-to-severe OI. Mice (73 oim/oim and 69 wildtype (WT)) were injected twice weekly with either soluble murine RANK (RANK-Fc) (1.5mg/kg) or saline beginning at 6 weeks of age. At 8 weeks of age, the animals underwent transverse mid-diaphyseal osteotomies of the right femur. Therapy was continued until sacrifice at 2, 3, 4 or 6 weeks post-fracture. At 6 weeks post-fracture, greater callus area (6.59±3.78mm2 vs 2.67±2.05mm2, p=0.003) and increased radiographic intensity (mineral density) (0.48 ± 0.14 vs. 0.30 ± 0.80, p=0.005) were found in the RANK-Fc vs saline oim/oim group, indicating a delay in callus remodeling. Despite this delay, mechanical tests at 6 weeks post-fracture revealed no significant differences in whole bone properties of stiffness and failure moment. Further, RANKL inhibition resulted in a greater failure moment and greater work to failure for the non-fractured contralateral WT bones compared to the non-fractured saline WT bones. Together, these results demonstrate that RANKL-inhibition does not adversely affect the mechanical properties of healing bone in the oim/oim mice, and is associated with increased strength in intact bone in the WT mice. PMID:17729310

  9. Effect of high-dose vitamin D supplementation on bone density in youth with osteogenesis imperfecta: A randomized controlled trial.

    PubMed

    Plante, Laura; Veilleux, Louis-Nicolas; Glorieux, Francis H; Weiler, Hope; Rauch, Frank

    2016-05-01

    Osteogenesis imperfecta (OI) is a heritable condition characterized by fragile bones. Our previous studies indicated that serum 25-hydroxyvitamin D (25OHD) concentrations were positively associated with lumbar spine areal bone mineral density (LS-aBMD) in children and adolescents with OI. Here we assessed whether one year of high-dose vitamin D supplementation results in higher LS-aBMD z-scores in youth with OI. A one-year double-blind randomized controlled trial conducted at a pediatric orthopedic hospital in Montreal, Canada. Sixty patients (age: 6.0 to 18.9years; 35 female) were randomized in equal numbers to receive either 400 or 2000international units (IU) of vitamin D, stratified according to baseline bisphosphonate treatment status and pubertal stage. At baseline, the average serum 25OHD concentration was 65.6nmol/L (SD 20.4) with no difference between treatment groups (p=0.77); 21% of patients had results <50nmol/L. Vitamin D supplementation was associated with higher serum 25OHD concentrations in 90% of participants. The increase in mean 25OHD was significantly higher (p=0.02) in the group receiving 2000IU of vitamin D (mean [95% CI]=30.5nmol/L [21.3; 39.6]) than in the group receiving 400IU (15.2nmol/L [6.4; 24.1]). No significant differences in LS-aBMD z-score changes were detected between treatment groups. Thus, supplementation with vitamin D at 2000IU increased serum 25OHD concentrations in children with OI more than supplementation with 400IU. However, in this study where about 80% of participants had baseline serum 25OHD concentrations ≥50nmol/L, this difference had no detectable effect on LS-aBMD z-scores. PMID:26924265

  10. Whole exome sequencing is an efficient, sensitive and specific method of mutation detection in osteogenesis imperfecta and Marfan syndrome

    PubMed Central

    McInerney-Leo, Aideen M; Marshall, Mhairi S; Gardiner, Brooke; Coucke, Paul J; Van Laer, Lut; Loeys, Bart L; Summers, Kim M; Symoens, Sofie; West, Jennifer A; West, Malcolm J; Paul Wordsworth, B; Zankl, Andreas; Leo, Paul J; Brown, Matthew A; Duncan, Emma L

    2013-01-01

    Osteogenesis imperfecta (OI) and Marfan syndrome (MFS) are common Mendelian disorders. Both conditions are usually diagnosed clinically, as genetic testing is expensive due to the size and number of potentially causative genes and mutations. However, genetic testing may benefit patients, at-risk family members and individuals with borderline phenotypes, as well as improving genetic counseling and allowing critical differential diagnoses. We assessed whether whole exome sequencing (WES) is a sensitive method for mutation detection in OI and MFS. WES was performed on genomic DNA from 13 participants with OI and 10 participants with MFS who had known mutations, with exome capture followed by massive parallel sequencing of multiplexed samples. Single nucleotide polymorphisms (SNPs) and small indels were called using Genome Analysis Toolkit (GATK) and annotated with ANNOVAR. CREST, exomeCopy and exomeDepth were used for large deletion detection. Results were compared with the previous data. Specificity was calculated by screening WES data from a control population of 487 individuals for mutations in COL1A1, COL1A2 and FBN1. The target capture of five exome capture platforms was compared. All 13 mutations in the OI cohort and 9/10 in the MFS cohort were detected (sensitivity=95.6%) including non-synonymous SNPs, small indels (<10 bp), and a large UTR5/exon 1 deletion. One mutation was not detected by GATK due to strand bias. Specificity was 99.5%. Capture platforms and analysis programs differed considerably in their ability to detect mutations. Consumable costs for WES were low. WES is an efficient, sensitive, specific and cost-effective method for mutation detection in patients with OI and MFS. Careful selection of platform and analysis programs is necessary to maximize success. PMID:24501682

  11. Mutation in a gene for type I procollagen (COL1A2) in a woman with postmenopausal osteoporosis: Evidence for phenotypic and genotypic overlap with mild osteogenesis imperfecta

    SciTech Connect

    Spotila, L.D.; Constantinou, C.D.; Sereda, L.; Ganguly, A.; Prockop, D.J. ); Riggs, B.L. )

    1991-06-15

    Mutations in the two genes for type I collagen (COL1A1 or COL1A2) cause osteogenesis imperfecta (OI), a heritable disease characterized by moderate to extreme brittleness of bone early in life. Here, the authors show that a 52-year-old post menopausal woman with severe osteopenia and a compression fracture of a thoracic vertebra had a mutation in the gene for the {alpha}2(I) chain of type I collagen (COL1A2) similar to mutations that cause OI. cDNA was prepared from the woman's skin fibroblast RNA and assayed for the presence of a mutation by treating DNA heteroduplexes with carbodiimide. The results indicated a sequence variation in the region encoding amino acid residues 660-667 of the {alpha}2(I) chain. Further analysis demonstrated a single-base mutation that caused a serine-for-glycine substitution at position 661 of the {alpha}2(I) triple-helical domain. The substitution produced posttranslational overmodification of the collagen triple helix, as is seen with most glycine substitutions that cause OI. The patient had a history of five previous fractures, slightly blue sclerae, and slight hearing loss. Therefore, the results suggest that there may be phenotypic and genotypic overlap between mild osteogenesis imperfecta and postmenopausal osteoporosis, and that a subset of women with postmenopausal osteoporosis may have mutations in the genes for type I procollagen.

  12. Enhanced Wnt signaling improves bone mass and strength, but not brittleness, in the Col1a1(+/mov13) mouse model of type I Osteogenesis Imperfecta.

    PubMed

    Jacobsen, Christina M; Schwartz, Marissa A; Roberts, Heather J; Lim, Kyung-Eun; Spevak, Lyudmila; Boskey, Adele L; Zurakowski, David; Robling, Alexander G; Warman, Matthew L

    2016-09-01

    Osteogenesis Imperfecta (OI) comprises a group of genetic skeletal fragility disorders. The mildest form of OI, Osteogenesis Imperfecta type I, is frequently caused by haploinsufficiency mutations in COL1A1, the gene encoding the α1(I) chain of type 1 collagen. Children with OI type I have a 95-fold higher fracture rate compared to unaffected children. Therapies for OI type I in the pediatric population are limited to anti-catabolic agents. In adults with osteoporosis, anabolic therapies that enhance Wnt signaling in bone improve bone mass, and ongoing clinical trials are determining if these therapies also reduce fracture risk. We performed a proof-of-principle experiment in mice to determine whether enhancing Wnt signaling in bone could benefit children with OI type I. We crossed a mouse model of OI type I (Col1a1(+/Mov13)) with a high bone mass (HBM) mouse (Lrp5(+/p.A214V)) that has increased bone strength from enhanced Wnt signaling. Offspring that inherited the OI and HBM alleles had higher bone mass and strength than mice that inherited the OI allele alone. However, OI+HBM and OI mice still had bones with lower ductility compared to wild-type mice. We conclude that enhancing Wnt signaling does not make OI bone normal, but does improve bone properties that could reduce fracture risk. Therefore, agents that enhance Wnt signaling are likely to benefit children and adults with OI type 1. PMID:27297606

  13. Heterozygous mutation of c.3521C>T in COL1A1 may cause mild osteogenesis imperfecta/Ehlers-Danlos syndrome in a Chinese family

    PubMed Central

    Shi, Xianlong; Lu, Yanqin; Wang, Yanzhou; Zhang, Yu-ang; Teng, Yuanwei; Han, Wanshui; Han, Zhenzhong; Li, Tianyou; Chen, Mei; Liu, Junlong; Fang, Fengling; Dou, Conghui; Ren, Xiuzhi; Han, Jinxiang

    2015-01-01

    Summary Osteogenesis imperfecta (OI) is an inheritable connective tissue disorder with a broad clinical heterozygosis, which can be complicated by other connective tissue disorders like Ehlers-Danlos syndrome (EDS). OI/EDS are rarely documented. Most OI/EDS mutations are located in the N-anchor region of type I procollagen and predominated by glycine substitution. We identified a c.3521C>T (p.A1174V) heterozygous mutation in COL1A1 gene in a four-generation pedigree with proposed mild OI/EDS phenotype. The affected individuals had blue sclera and dentinogenesis imperfecta (DI) was uniformly absent. The OI phenotype varied from mild to moderate, with the absence of scoliosis and increased skin extensibility. Easy bruising, joint dislocations and high Beighton score were present in some affected individuals. EDS phenotype is either mild or unremarkable in some individuals. The mutation is poorly conserved and in silico prediction support the relatively mild phenotype. The molecular mechanisms of the mutation that leads to the possible OI/EDS phenotype should be further identified by biochemical analysis of N-propeptide processing and steady state collagen analysis. PMID:25674388

  14. Allele Dependent Silencing of Collagen Type I Using Small Interfering RNAs Targeting 3'UTR Indels - a Novel Therapeutic Approach in Osteogenesis Imperfecta

    PubMed Central

    Lindahl, Katarina; Kindmark, Andreas; Laxman, Navya; Åström, Eva; Rubin, Carl-Johan; Ljunggren, Östen

    2013-01-01

    Osteogenesis imperfecta, also known as “brittle bone disease”, is a heterogeneous disorder of connective tissue generally caused by dominant mutations in the genes COL1A1 and COL1A2, encoding the α1 and α2 chains of type I (pro)collagen. Symptomatic patients are usually prescribed bisphosphonates, but this treatment is neither curative nor sufficient. A promising field is gene silencing through RNA interference. In this study small interfering RNAs (siRNAs) were designed to target each allele of 3'UTR insertion/deletion polymorphisms (indels) in COL1A1 (rs3840870) and COL1A2 (rs3917). For both indels, the frequency of heterozygous individuals was determined to be approximately 50% in Swedish cohorts of healthy controls as well as in patients with osteogenesis imperfecta. Cultures of primary human bone derived cells were transfected with siRNAs through magnet-assisted transfection. cDNA from transfected cells was sequenced in order to measure targeted allele/non-targeted allele ratios and the overall degree of silencing was assessed by quantitative PCR. Successful allele dependent silencing was observed, with promising results for siRNAs complementary to both the insertion and non-insertion harboring alleles. In COL1A1 cDNA the indel allele ratios were shifted from 1 to 0.09 and 0.19 for the insertion and non-insertion allele respectively while the equivalent resulting ratios for COL1A2 were 0.05 and 0.01. Reductions in mRNA abundance were also demonstrated; in cells treated with siRNAs targeting the COL1A1 alleles the average COL1A1 mRNA levels were reduced 65% and 78% compared to negative control levels and in cells treated with COL1A2 siRNAs the average COL1A2 mRNA levels were decreased 26% and 49% of those observed in the corresponding negative controls. In conclusion, allele dependent silencing of collagen type I utilizing 3'UTR indels common in the general population constitutes a promising mutation independent therapeutic approach for osteogenesis

  15. Involving Families with Osteogenesis Imperfecta in Health Service Research: Joint Development of the OI/ECE Questionnaire

    PubMed Central

    Dogba, Maman Joyce; Dahan-Oliel, Noémi; Snider, Laurie; Glorieux, Francis H.; Durigova, Michaela; Palomo, Telma; Cordey, Michel; Bédard, Marie-Hélène; Bedos, Christophe; Rauch, Frank

    2016-01-01

    Background Despite the growing interest in understanding the psycho-social impact of rare genetic diseases, few studies examine this concept and even fewer seek to obtain feedback from families who have lived the experience. The aim of this project was to involve families of children living with osteogenesis imperfecta (OI) in the development of a tool to assess the impact of OI on the lives of patients and their families. Methods This project used an integrated knowledge translation approach in which knowledge users (clinicians and people living with OI and their families) were consulted throughout the four steps of development, that is: content mapping, item generation, tool appraisal and pre-testing of the questionnaires. The International Classification of Functioning and Health was used as a framework for content mapping. Based on a scoping review we selected two validated tools to use as a basis for developing the questionnaire. The final parent self-report version measured six domains: experience of diagnosis; use of health services; use of social and psychological support services; expectations about tertiary specialized centers; and socio-demographic information. Results A total of 27 out of 40 families receiving care at the Shriners Hospital for Children-Canada and invited to participate in the pre-test returned the completed questionnaires. In more than two-thirds of families (69%; n = 18) OI was suspected either at or within the first 3 months after birth. Up to 46% of families consulted between 3 and 5 doctors (46%; n = 12) prior to final diagnosis. The use of services by families varied from 0 to 16 consultations, 0 to 9 exploratory examinations and 1 to 10 types of allied health services. In the 12 months prior to the study, fewer than a quarter of children had been admitted, for treatment, for hospital stays of longer than 8 hours or to an emergency department (24% and 9% respectively). Only 29% of parents received psychological support. Conclusion

  16. WDR72 models of structure and function: A stage-specific regulator of enamel mineralization

    PubMed Central

    Katsura, K.A.; Horst, J.A.; Chandra, D.; Le, T.Q.; Nakano, Y.; Zhang, Y.; Horst, O.V.; Zhu, L.; Le, M.H.

    2014-01-01

    Amelogenesis Imperfecta (AI) is a clinical diagnosis that encompasses a group of genetic mutations, each affecting processes involved in tooth enamel formation and thus, result in various enamel defects. The hypomaturation enamel phenotype has been described for mutations involved in the later stage of enamel formation, including Klk4, Mmp20, C4orf26, and Wdr72. Using a candidate gene approach we discovered a novel Wdr72 human mutation in association with AI to be a 5-base pair deletion (c.806_810delGGCAG; p.G255VfsX294). To gain insight into the function of WDR72, we used computer modeling of the full-length human WDR72 protein structure and found that the predicted N-terminal sequence forms two beta-propeller folds with an alpha-solenoid tail at the C-terminus. This domain iteration is characteristic of vesicle coat proteins, such as beta′-COP, suggesting a role for WDR72 in the formation of membrane deformation complexes to regulate intracellular trafficking. Our Wdr72 knockout mouse model (Wdr72−/−), containing a LacZ reporter knock-in, exhibited hypomineralized enamel similar to the AI phenotype observed in humans with Wdr72 mutations. MicroCT scans of Wdr72−/− mandibles affirmed the hypomineralized enamel phenotype occurring at the onset of the maturation stage. H&E staining revealed a shortened height phenotype in the Wdr72−/− ameloblasts with retained proteins in the enamel matrix during maturation stage. H+/Cl− exchange transporter 5 (CLC5), an early endosome acidifier, was co-localized with WDR72 in maturation-stage ameloblasts and decreased in Wdr72−/− maturation-stage ameloblasts. There were no obvious differences in RAB4A and LAMP1 immunostaining of Wdr72−/− mice as compared to wildtype controls. Moreover, Wdr72−/− ameloblasts had reduced amelogenin immunoreactivity, suggesting defects in amelogenin fragment resorption from the matrix. These data demonstrate that WDR72 has a major role in enamel mineralization, most notably

  17. Genomic organization of the human osteopontin gene: Exclusion of the locus from a causative role in the pathogenesis of dentinogenesis imperfecta type II.

    SciTech Connect

    Crosby, A.H.; Edwards, S.J.; Murray, J.C.

    1995-05-01

    Osteopontin (SPP1) is the principal phosphorylated glycoprotein of bone that is also expressed in a limited number of other tissues including dentine. In the current investigation the authors report the genomic organization of the SPP1 gene, which comprises seven exons, six of which contain coding sequence. The splice sites for exon donor and acceptor positions are in close agreement with previously published consensus sequences. Comparison of the human gene with its murine and bovine counterparts revealed a highly homologous organization. A highly informative short tandem repeat polymorphism isolated at the SPP1 locus showed no recombination with the autosomal dominant disorder dentinogenesis imperfecta type II. Nevertheless, sequencing of each exon in individuals affected by this disorder failed to reveal any disease-specific mutations. 25 refs., 2 figs., 2 tabs.

  18. Marrow stromal cells as a source of progenitor cells for nonhematopoietic tissues in transgenic mice with a phenotype of osteogenesis imperfecta

    PubMed Central

    Pereira, Ruth F.; O’Hara, Michael D.; Laptev, Alexey V.; Halford, Kenneth W.; Pollard, Marea D.; Class, Reiner; Simon, Daniela; Livezey, Kristin; Prockop, Darwin J.

    1998-01-01

    Marrow stromal cells from wild-type mice were infused into transgenic mice that had a phenotype of fragile bones resembling osteogenesis imperfecta because they expressed a human minigene for type I collagen. In mice that were irradiated with potentially lethal levels (700 cGy) or sublethal levels (350 cGy), DNA from the donor marrow stromal cells was detected consistently in marrow, bone, cartilage, and lung either 1 or 2.5 mo after the infusions. The DNA also was detected but less frequently in the spleen, brain, and skin. There was a small but statistically significant increase in both collagen content and mineral content of bone 1 mo after the infusion. Similar results were obtained with infusion of relatively large amounts of wild-type whole marrow cells into the transgenic mice. In experiments in which male marrow stromal cells were infused into a female osteogenesis imperfecta-transgenic mouse, fluorescense in situ hybridization assays for the Y chromosome indicated that, after 2.5 mo, donor male cells accounted for 4–19% of the fibroblasts or fibroblast-like cells obtained in primary cultures of the lung, calvaria, cartilage, long bone, tail, and skin. In a parallel experiment in which whole marrow cells from a male mouse were infused into a female immunodeficient rag-2 mouse, donor male cells accounted for 4–6% of the fibroblasts or fibroblast-like cells in primary cultures. The results support previous suggestions that marrow stromal cells or related cells in marrow serve as a source for continual renewal of cells in a number of nonhematopoietic tissues. PMID:9448299

  19. Bone mineral properties in growing Col1a2(+/G610C) mice, an animal model of osteogenesis imperfecta.

    PubMed

    Masci, Marco; Wang, Min; Imbert, Laurianne; Barnes, Aileen M; Spevak, Lyudmila; Lukashova, Lyudmila; Huang, Yihe; Ma, Yan; Marini, Joan C; Jacobsen, Christina M; Warman, Matthew L; Boskey, Adele L

    2016-06-01

    The Col1a2(+/G610C) knock-in mouse, models osteogenesis imperfecta in a large old order Amish family (OOA) with type IV OI, caused by a G-to-T transversion at nucleotide 2098, which alters the gly-610 codon in the triple-helical domain of the α2(I) chain of type I collagen. Mineral and matrix properties of the long bones and vertebrae of male Col1a2(+/G610C) and their wild-type controls (Col1a2(+/+)), were characterized to gain insight into the role of α2-chain collagen mutations in mineralization. Additionally, we examined the rescuability of the composition by sclerostin inhibition initiated by crossing Col1a2(+/G610C) with an LRP(+/A214V) high bone mass allele. At age 10-days, vertebrae and tibia showed few alterations by micro-CT or Fourier transform infrared imaging (FTIRI). At 2-months-of-age, Col1a2(+/G610C) tibias had 13% fewer secondary trabeculae than Col1a2(+/+), these were thinner (11%) and more widely spaced (20%) than those of Col1a2(+/+) mice. Vertebrae of Col1a2(+/G610C) mice at 2-months also had lower bone volume fraction (38%), trabecular number (13%), thickness (13%) and connectivity density (32%) compared to Col1(a2+/+). The cortical bone of Col1a2(+/G610C) tibias at 2-months had 3% higher tissue mineral density compared to Col1a2(+/+); Col1a2(+/G610C) vertebrae had lower cortical thickness (29%), bone area (37%) and polar moment of inertia (38%) relative to Col1a2(+/+). FTIRI analysis, which provides information on bone chemical composition at ~7μm-spatial resolution, showed tibias at 10-days did not differ between genotypes. Comparing identical bone types in Col1a2(+/G610C) to Col1a2(+/+) at 2-months-of-age, tibias showed higher mineral-to-matrix ratio in trabeculae (17%) and cortices (31%). and in vertebral cortices (28%). Collagen maturity was 42% higher at 10-days-of-age in Col1a2(+/G610C) vertebral trabeculae and in 2-month tibial cortices (12%), vertebral trabeculae (42%) and vertebral cortices (12%). Higher acid-phosphate substitution

  20. What Is Osteogenesis Imperfecta?

    MedlinePlus

    ... and Other Related Conditions: NIH Osteoporosis and Related Bone Diseases ~ National Resource Center 2 AMS Circle Bethesda, MD ... FDA-approved drug products. NIH Osteoporosis and Related Bone Diseases ~ National Resource Center 2 AMS Circle Bethesda, MD ...

  1. Osteogenesis Imperfecta Foundation

    MedlinePlus

    ... taking place on November 12, 2016! Learn More Current Research Opportunities Click below to learn more about the OIF's current research opportunities including the Michael Geisman Fellowship and ...

  2. Learning about Osteogenesis Imperfecta

    MedlinePlus

    ... Links for Patient Care Education All About the Human Genome Project Fact Sheets Genetic Education Resources for Teachers Genomic Careers National DNA Day Online Education Kit Online Genetics Education ... Subjects Research Informed Consent for Genomics Research Intellectual ...

  3. Osteogenesis Imperfecta Overview

    MedlinePlus

    ... is extremely rare slightly elevated activity level of alkaline phosphatase (an enzyme linked to bone formation), which ... for people with OI. This treatment involves inserting metal rods through the length of the long bones ...

  4. Osteogenesis Imperfecta Issues: Constipation

    MedlinePlus

    ... cultures that contain the bacteria lactobacillus acidophilus. • Limit soft drinks and drinks containing caffeine such as colas or tea. • Drink water throughout the day. Strive for a diet that keeps the stool soft. Too much fiber has the secondary effect of ...

  5. Pigment epithelium-derived factor restoration increases bone mass and improves bone plasticity in a model of osteogenesis imperfecta type VI via Wnt3a blockade.

    PubMed

    Belinsky, Glenn S; Sreekumar, Bharath; Andrejecsk, Jillian W; Saltzman, W Mark; Gong, Jingjing; Herzog, Raimund I; Lin, Samantha; Horsley, Valerie; Carpenter, Thomas O; Chung, Chuhan

    2016-08-01

    Null mutations in for pigment epithelium-derived factor (PEDF), the protein product of the SERPINF1 gene, are the cause of osteogenesis imperfecta (OI) type VI. The PEDF-knockout (KO) mouse captures crucial elements of the human disease, including diminished bone mineralization and propensity to fracture. Our group and others have demonstrated that PEDF directs human mesenchymal stem cell (hMSC) commitment to the osteoblast lineage and modulates Wnt/β-catenin signaling, a major regulator of bone development; however, the ability of PEDF to restore bone mass in a mouse model of OI type VI has not been determined. In this study, PEDF delivery increased trabecular bone volume/total volume by 52% in 6-mo-old PEDF-KO mice but not in wild-type mice. In young (19-d-old) PEDF-KO mice, PEDF restoration increased bone volume fraction by 35% and enhanced biomechanical parameters of bone plasticity. A Wnt-green fluorescent protein reporter demonstrated dynamic changes in Wnt/β-catenin signaling characterized by early activation and marked suppression during terminal differentiation of hMSCs. Continuous Wnt3a exposure impeded mineralization of hMSCs, whereas the combination of Wnt3a and PEDF potentiated mineralization. Interrogation of the PEDF sequence identified a conserved motif found in other Wnt modulators, such as the dickkopf proteins. Mutation of a single amino acid on a 34-mer PEDF peptide increased mineralization of hMSC cultures compared with the native peptide sequence. These results indicate that PEDF counters Wnt signaling to allow for osteoblast differentiation and provides a mechanistic insight into how the PEDF null state results in OI type VI.-Belinsky, G. S., Sreekumar, B., Andrejecsk, J. W., Saltzman, W. M., Gong, J., Herzog, R. I., Lin, S., Horsley, V., Carpenter, T. O., Chung, C. Pigment epithelium-derived factor restoration increases bone mass and improves bone plasticity in a model of osteogenesis imperfecta type VI via Wnt3a blockade. PMID:27127101

  6. In utero transplantation of adult bone marrow decreases perinatal lethality and rescues the bone phenotype in the knockin murine model for classical, dominant osteogenesis imperfecta.

    PubMed

    Panaroni, Cristina; Gioia, Roberta; Lupi, Anna; Besio, Roberta; Goldstein, Steven A; Kreider, Jaclynn; Leikin, Sergey; Vera, Juan Carlos; Mertz, Edward L; Perilli, Egon; Baruffaldi, Fabio; Villa, Isabella; Farina, Aurora; Casasco, Marco; Cetta, Giuseppe; Rossi, Antonio; Frattini, Annalisa; Marini, Joan C; Vezzoni, Paolo; Forlino, Antonella

    2009-07-01

    Autosomal dominant osteogenesis imperfecta (OI) caused by glycine substitutions in type I collagen is a paradigmatic disorder for stem cell therapy. Bone marrow transplantation in OI children has produced a low engraftment rate, but surprisingly encouraging symptomatic improvements. In utero transplantation (IUT) may hold even more promise. However, systematic studies of both methods have so far been limited to a recessive mouse model. In this study, we evaluated intrauterine transplantation of adult bone marrow into heterozygous BrtlIV mice. Brtl is a knockin mouse with a classical glycine substitution in type I collagen [alpha1(I)-Gly349Cys], dominant trait transmission, and a phenotype resembling moderately severe and lethal OI. Adult bone marrow donor cells from enhanced green fluorescent protein (eGFP) transgenic mice engrafted in hematopoietic and nonhematopoietic tissues differentiated to trabecular and cortical bone cells and synthesized up to 20% of all type I collagen in the host bone. The transplantation eliminated the perinatal lethality of heterozygous BrtlIV mice. At 2 months of age, femora of treated Brtl mice had significant improvement in geometric parameters (P < .05) versus untreated Brtl mice, and their mechanical properties attained wild-type values. Our results suggest that the engrafted cells form bone with higher efficiency than the endogenous cells, supporting IUT as a promising approach for the treatment of genetic bone diseases. PMID:19414862

  7. A case of fetal osteogenesis imperfecta type 2A: longitudinal observation of natural course in utero and pitfalls for prenatal ultrasound diagnosis.

    PubMed

    Kimura, Ibuki; Araki, Ryota; Yoshizato, Toshiyuki; Miyamoto, Shingo

    2015-10-01

    We present a case of osteogenesis imperfecta (OI) type 2A in which a natural course in utero was observed from 23 weeks' gestation to term. At 23 weeks' gestation, a sonographic examination showed a cloverleaf skull-like head, a narrow thorax, and marked shortening of the long bones with bowing of the femurs and humeri. Follow-up examinations showed that the cloverleaf skull-like head was not evident at 28 weeks' gestation. Discontinuity of the ribs and femurs was observed at 26 and 30 weeks' gestation, respectively. This finding suggested bone fractures, which were confirmed by three-dimensional computed tomography at 32 weeks' gestation. Ultrasonographic findings of bones, including the long bones and calvarium, changed with advancing gestation during the second trimester. Characteristic features of OI type 2A were evident during the late second to early third trimesters. Repeated ultrasonographic examinations together with three-dimensional computed tomography are necessary for the definitive diagnosis of OI type 2A in the second trimester. PMID:26576983

  8. Embryonic ablation of osteoblast Smad4 interrupts matrix synthesis in response to canonical Wnt signaling and causes an osteogenesis-imperfecta-like phenotype

    PubMed Central

    Salazar, Valerie S.; Zarkadis, Nicholas; Huang, Lisa; Norris, Jin; Grimston, Susan K.; Mbalaviele, Gabriel; Civitelli, Roberto

    2013-01-01

    Summary To examine interactions between bone morphogenic protein (BMP) and canonical Wnt signaling during skeletal growth, we ablated Smad4, a key component of the TGF-β–BMP pathway, in Osx1+ cells in mice. We show that loss of Smad4 causes stunted growth, spontaneous fractures and a combination of features seen in osteogenesis imperfecta, cleidocranial dysplasia and Wnt-deficiency syndromes. Bones of Smad4 mutant mice exhibited markers of fully differentiated osteoblasts but lacked multiple collagen-processing enzymes, including lysyl oxidase (Lox), a BMP2-responsive gene regulated by Smad4 and Runx2. Accordingly, the collagen matrix in Smad4 mutants was disorganized, but also hypomineralized. Primary osteoblasts from these mutants did not mineralize in vitro in the presence of BMP2 or Wnt3a, and Smad4 mutant mice failed to accrue new bone following systemic inhibition of the Dickkopf homolog Dkk1. Consistent with impaired biological responses to canonical Wnt, ablation of Smad4 causes cleavage of β-catenin and depletion of the low density lipoprotein receptor Lrp5, subsequent to increased caspase-3 activity and apoptosis. In summary, Smad4 regulates maturation of skeletal collagen and osteoblast survival, and is required for matrix-forming responses to both BMP2 and canonical Wnt. PMID:24006258

  9. Burnei’s procedure in the treatment of long bone pseudarthrosis in patients having osteogenesis imperfecta or congenital pseudarthrosis of tibia – preliminary report

    PubMed Central

    Vlad, C; Georgescu, I; Gavriliu, TS; Hodorogea, DI; El Nayef, T; Dan, D

    2012-01-01

    Rationale: given the recalcitrant behaviour of pseudarthrosis in osteogenesis imperfecta (OI) and congenital pseudarthrosis of the tibia (CPT), there is no ideal solution to treat such challenging deformities. The reconsideration of the already known principles, by using the modern technology, may generate new treatment methods. Aim: the present paper presents the preliminary results of an original reconstruction procedure used to treat large bone defects in paediatric orthopaedics. A case series study, the surgical technique, complications and illustrative cases are presented. Methods and results: 3 cases of pseudarthrosis in OI and 2 cases of CPT were operated by using this technique. The principles of the method are to create an optimal osteoconductive and osteoinductive environment by using a bone autograft, bone allograft and bone graft substitutes and to provide a good stabilisation of the bones. We operated 3 patients with OI and 2 patients with CPT. Four patients had multiple previous surgeries. The follow-up period ranged from 3 to 28 months. Four of the five patients are able to ambulate independently at the moment this paper was written. Discussion: we believe that the present technique could be a reliable alternative to other procedures, especially in cases of repeated failures. PMID:22802896

  10. Osteoblast Malfunction Caused by Cell Stress Response to Procollagen Misfolding in α2(I)-G610C Mouse Model of Osteogenesis Imperfecta.

    PubMed

    Mirigian, Lynn S; Makareeva, Elena; Mertz, Edward L; Omari, Shakib; Roberts-Pilgrim, Anna M; Oestreich, Arin K; Phillips, Charlotte L; Leikin, Sergey

    2016-08-01

    Glycine (Gly) substitutions in collagen Gly-X-Y repeats disrupt folding of type I procollagen triple helix and cause severe bone fragility and malformations (osteogenesis imperfecta [OI]). However, these mutations do not elicit the expected endoplasmic reticulum (ER) stress response, in contrast to other protein-folding diseases. Thus, it has remained unclear whether cell stress and osteoblast malfunction contribute to the bone pathology caused by Gly substitutions. Here we used a mouse with a Gly610 to cysteine (Cys) substitution in the procollagen α2(I) chain to show that misfolded procollagen accumulation in the ER leads to an unusual form of cell stress, which is neither a conventional unfolded protein response (UPR) nor ER overload. Despite pronounced ER dilation, there is no upregulation of binding immunoglobulin protein (BIP) expected in the UPR and no activation of NF-κB signaling expected in the ER overload. Altered expression of ER chaperones αB crystalline and HSP47, phosphorylation of EIF2α, activation of autophagy, upregulation of general stress response protein CHOP, and osteoblast malfunction reveal some other adaptive response to the ER disruption. We show how this response alters differentiation and function of osteoblasts in culture and in vivo. We demonstrate that bone matrix deposition by cultured osteoblasts is rescued by activation of misfolded procollagen autophagy, suggesting a new therapeutic strategy for OI. © 2016 American Society for Bone and Mineral Research. PMID:26925839

  11. Defective splicing of mRNA from one COL1A1 allele of type I collagen in nondeforming (type I) osteogenesis imperfecta.

    PubMed Central

    Stover, M L; Primorac, D; Liu, S C; McKinstry, M B; Rowe, D W

    1993-01-01

    Osteogenesis imperfecta (OI) type I is the mildest form of heritable bone fragility resulting from mutations within the COL1A1 gene. We studied fibroblasts established from a child with OI type I and demonstrated underproduction of alpha 1 (I) collagen chains and alpha 1 (I) mRNA. Indirect RNase protection suggested two species of alpha 1 (I) mRNA, one of which was not collinear with fully spliced alpha 1 (I) mRNA. The noncollinear population was confined to the nuclear compartment of the cell, and contained the entire sequence of intron 26 and a G-->A transition in the first position of the intron donor site. The G-->A transition was also identified in the genomic DNA. The retained intron contained an in-frame stop codon and introduced an out-of-frame insertion within the collagen mRNA producing stop codons downstream of the insertion. These changes probably account for the failure of the mutant RNA to appear in the cytoplasm. Unlike other splice site mutations within collagen mRNA that resulted in exon skipping and a truncated but inframe RNA transcript, this mutation did not result in production of a defective collagen pro alpha 1 (I) chain. Instead, the mild nature of the disease in this case reflects failure to process the defective mRNA and thus the absence of a protein product from the mutant allele. Images PMID:8408653

  12. Mapping of the human dentin matrix acidic phosphoprotein gene (DMP1) to the dentinogenesis imperfecta type II critical region at chromosome 4q21

    SciTech Connect

    Aplin, H.M.; Hirst, K.L.; Crosby, A.H.; Dixon, M.J.

    1995-11-20

    Dentinogenesis imperfecta type II (DGI1) is an autosomal dominant disorder of dentin formation, which has been mapped to human chromosome 4q12-q21. The region most likely to contain the DGI1 locus is a 3.2-cM region surrounding the osteopontin (SPP1) locus. Recently, a novel dentin-specific acidic phosphoprotein (dmp1) has been cloned in the rat and mapped to mouse chromosome 5q21. In the current investigation, we have isolated a cosmid containing the human DMP1 gene. The isolation of a short tandem repeat polymorphism at this locus has allowed us to map the DMP1 locus to human chromosome 4q21 and demonstrate that it is tightly linked to DGI1 in two families (Z{sub max} = 11.01, {theta} = 0.001). The creation of a yeast artificial chromosome contig around SPP1 has further allowed us to demonstrate that DMP1 is located within 150 kb of the bone sialoprotein and 490 kb of the SPP1 loci, respectively. DMP1 is therefore a strong candidate for the DGI1 locus. 12 refs., 2 figs., 1 tab.

  13. Ameloblasts express type I collagen during amelogenesis.

    PubMed

    Assaraf-Weill, N; Gasse, B; Silvent, J; Bardet, C; Sire, J Y; Davit-Béal, T

    2014-05-01

    Enamel and enameloid, the highly mineralized tooth-covering tissues in living vertebrates, are different in their matrix composition. Enamel, a unique product of ameloblasts, principally contains enamel matrix proteins (EMPs), while enameloid possesses collagen fibrils and probably receives contributions from both odontoblasts and ameloblasts. Here we focused on type I collagen (COL1A1) and amelogenin (AMEL) gene expression during enameloid and enamel formation throughout ontogeny in the caudate amphibian, Pleurodeles waltl. In this model, pre-metamorphic teeth possess enameloid and enamel, while post-metamorphic teeth possess enamel only. In first-generation teeth, qPCR and in situ hybridization (ISH) on sections revealed that ameloblasts weakly expressed AMEL during late-stage enameloid formation, while expression strongly increased during enamel deposition. Using ISH, we identified COL1A1 transcripts in ameloblasts and odontoblasts during enameloid formation. COL1A1 expression in ameloblasts gradually decreased and was no longer detected after metamorphosis. The transition from enameloid-rich to enamel-rich teeth could be related to a switch in ameloblast activity from COL1A1 to AMEL synthesis. P. waltl therefore appears to be an appropriate animal model for the study of the processes involved during enameloid-to-enamel transition, especially because similar events probably occurred in various lineages during vertebrate evolution. PMID:24570147

  14. Mutations in PPIB (cyclophilin B) delay type I procollagen chain association and result in perinatal lethal to moderate osteogenesis imperfecta phenotypes

    PubMed Central

    Pyott, Shawna M.; Schwarze, Ulrike; Christiansen, Helena E.; Pepin, Melanie G.; Leistritz, Dru F.; Dineen, Richard; Harris, Catharine; Burton, Barbara K.; Angle, Brad; Kim, Katherine; Sussman, Michael D.; Weis, MaryAnn; Eyre, David R.; Russell, David W.; McCarthy, Kevin J.; Steiner, Robert D.; Byers, Peter H.

    2011-01-01

    Recessive mutations in the cartilage-associated protein (CRTAP), leucine proline-enriched proteoglycan 1 (LEPRE1) and peptidyl prolyl cis–trans isomerase B (PPIB) genes result in phenotypes that range from lethal in the perinatal period to severe deforming osteogenesis imperfecta (OI). These genes encode CRTAP (encoded by CRTAP), prolyl 3-hydroxylase 1 (P3H1; encoded by LEPRE1) and cyclophilin B (CYPB; encoded by PPIB), which reside in the rough endoplasmic reticulum (RER) and can form a complex involved in prolyl 3-hydroxylation in type I procollagen. CYPB, a prolyl cis–trans isomerase, has been thought to drive the prolyl-containing peptide bonds to the trans configuration needed for triple helix formation. Here, we describe mutations in PPIB identified in cells from three individuals with OI. Cultured dermal fibroblasts from the most severely affected infant make some overmodified type I procollagen molecules. Proα1(I) chains are slow to assemble into trimers, and abnormal procollagen molecules concentrate in the RER, and bind to protein disulfide isomerase (PDI) and prolyl 4-hydroxylase 1 (P4H1). These findings suggest that although CYPB plays a role in helix formation another effect is on folding of the C-terminal propeptide and trimer formation. The extent of procollagen accumulation and PDI/P4H1 binding differs among cells with mutations in PPIB, CRTAP and LEPRE1 with the greatest amount in PPIB-deficient cells and the least in LEPRE1-deficient cells. These findings suggest that prolyl cis–trans isomerase may be required to effectively fold the proline-rich regions of the C-terminal propeptide to allow proα chain association and suggest an order of action for CRTAP, P3H1 and CYPB in procollagen biosynthesis and pathogenesis of OI. PMID:21282188

  15. Characterization of skin abnormalities in a mouse model of osteogenesis imperfecta using high resolution magnetic resonance imaging and Fourier transform infrared imaging spectroscopy.

    PubMed

    Canuto, H C; Fishbein, K W; Huang, A; Doty, S B; Herbert, R A; Peckham, J; Pleshko, N; Spencer, R G

    2012-01-01

    Evaluation of the skin phenotype in osteogenesis imperfecta (OI) typically involves biochemical measurements, such as histologic or biochemical assessment of the collagen produced from biopsy-derived dermal fibroblasts. As an alternative, the current study utilized non-invasive magnetic resonance imaging (MRI) microscopy and optical spectroscopy to define biophysical characteristics of skin in an animal model of OI. MRI of skin harvested from control, homozygous oim/oim and heterozygous oim/+ mice demonstrated several differences in anatomic and biophysical properties. Fourier transform infrared imaging spectroscopy (FT-IRIS) was used to interpret observed MRI signal characteristics in terms of chemical composition. Differences between wild-type and OI mouse skin included the appearance of a collagen-depleted lower dermal layer containing prominent hair follicles in the oim/oim mice, accounting for 55% of skin thickness in these. The MRI magnetization transfer rate was lower by 50% in this layer as compared to the upper dermis, consistent with lower collagen content. The MRI transverse relaxation time, T2, was greater by 30% in the dermis of the oim/oim mice compared to controls, consistent with a more highly hydrated collagen network. Similarly, an FT-IRIS-defined measure of collagen integrity was 30% lower in the oim/oim mice. We conclude that characterization of phenotypic differences between the skin of OI and wild-type mice by MRI and FT-IRIS is feasible, and that these techniques provide powerful complementary approaches for the analysis of the skin phenotype in animal models of disease. PMID:21845737

  16. Strategy for prenatal diagnosis of osteogenesis imperfecta by linkage analysis to the type I collagen loci COL1A1 and COL1A2.

    PubMed

    Benušienė, E; Kučinskas, V

    2000-01-01

    To improve prenatal diagnosis of osteogenesis imperfecta (OI) in Lithuania, possibilities of indirect molecular genetic diagnosis were investigated in 11 families with dominant OI. Segregation of polymorphic DNA markers closely linked to COL1A1 and COL1A2 genes with OI phenotype was investigated. Polymorphic DNA markers applied were individual haplotypes constructed using a set of restriction enzyme sites within or close to the genes. Comparison of phenotypic features with the concordant collagen locus showed that in four pedigrees with OI Sillence type I segregated with COL1A1, while two pedigrees with OI Sillence type I and OI type IV segregated with COL1A2. Out of six remaining pedigrees with OI Sillence type I, three were concordant at both loci, two pedigrees were discordant at the locus COL1A2 and non-informative at the locus COL1A1 and one pedigree was concordant at the locus COL1A1 and non-informative at the locus COL1A2. Informativity of DNA markers applied was also investigated in the Lithuanian OI families. The frequencies of six restriction enzyme site dimorphisms in type I collagen loci were estimated and polymorphism information content (PIC) values were calculated for each restriction site and for a combination of three sites. COL1A1 locus dimorphisms A/MspI, B/RsaI and F/MnlI, showed PIC values of 0.327, 0.191 and 0.366, respectively, giving a combined PIC of 0.656 at the locus, while COL1A2 locus dimorphisms C/EcoRI, D/MspI and E/RsaI RFLPs had PIC values of 0.357, 0.168 and 0.331, respectively, giving a combined PIC of 0.655 at the locus. PMID:11208313

  17. Absence of the ER Cation Channel TMEM38B/TRIC-B Disrupts Intracellular Calcium Homeostasis and Dysregulates Collagen Synthesis in Recessive Osteogenesis Imperfecta.

    PubMed

    Cabral, Wayne A; Ishikawa, Masaki; Garten, Matthias; Makareeva, Elena N; Sargent, Brandi M; Weis, MaryAnn; Barnes, Aileen M; Webb, Emma A; Shaw, Nicholas J; Ala-Kokko, Leena; Lacbawan, Felicitas L; Högler, Wolfgang; Leikin, Sergey; Blank, Paul S; Zimmerberg, Joshua; Eyre, David R; Yamada, Yoshihiko; Marini, Joan C

    2016-07-01

    Recessive osteogenesis imperfecta (OI) is caused by defects in proteins involved in post-translational interactions with type I collagen. Recently, a novel form of moderately severe OI caused by null mutations in TMEM38B was identified. TMEM38B encodes the ER membrane monovalent cation channel, TRIC-B, proposed to counterbalance IP3R-mediated Ca2+ release from intracellular stores. The molecular mechanisms by which TMEM38B mutations cause OI are unknown. We identified 3 probands with recessive defects in TMEM38B. TRIC-B protein is undetectable in proband fibroblasts and osteoblasts, although reduced TMEM38B transcripts are present. TRIC-B deficiency causes impaired release of ER luminal Ca2+, associated with deficient store-operated calcium entry, although SERCA and IP3R have normal stability. Notably, steady state ER Ca2+ is unchanged in TRIC-B deficiency, supporting a role for TRIC-B in the kinetics of ER calcium depletion and recovery. The disturbed Ca2+ flux causes ER stress and increased BiP, and dysregulates synthesis of proband type I collagen at multiple steps. Collagen helical lysine hydroxylation is reduced, while telopeptide hydroxylation is increased, despite increased LH1 and decreased Ca2+-dependent FKBP65, respectively. Although PDI levels are maintained, procollagen chain assembly is delayed in proband cells. The resulting misfolded collagen is substantially retained in TRIC-B null cells, consistent with a 50-70% reduction in secreted collagen. Lower-stability forms of collagen that elude proteasomal degradation are not incorporated into extracellular matrix, which contains only normal stability collagen, resulting in matrix insufficiency. These data support a role for TRIC-B in intracellular Ca2+ homeostasis, and demonstrate that absence of TMEM38B causes OI by dysregulation of calcium flux kinetics in the ER, impacting multiple collagen-specific chaperones and modifying enzymes. PMID:27441836

  18. A Novel IFITM5 Mutation in Severe Atypical Osteogenesis Imperfecta Type VI Impairs Osteoblast Production of Pigment Epithelium-Derived Factor

    PubMed Central

    Farber, Charles R; Reich, Adi; Barnes, Aileen M; Becerra, Patricia; Rauch, Frank; Cabral, Wayne A; Bae, Alison; Quinlan, Aaron; Glorieux, Francis H; Clemens, Thomas L; Marini, Joan C

    2015-01-01

    Osteogenesis imperfecta (OI) types V and VI are caused, respectively, by a unique dominant mutation in IFITM5, encoding BRIL, a transmembrane ifitm-like protein most strongly expressed in the skeletal system, and recessive null mutations in SERPINF1, encoding pigment epithelium-derived factor (PEDF). We identified a 25-year-old woman with severe OI whose dermal fibroblasts and cultured osteoblasts displayed minimal secretion of PEDF, but whose serum PEDF level was in the normal range. SERPINF1 sequences were normal despite bone histomorphometry consistent with type VI OI and elevated childhood serum alkaline phosphatase. We performed exome sequencing on the proband, both parents, and an unaffected sibling. IFITM5 emerged as the candidate gene from bioinformatics analysis, and was corroborated by membership in a murine bone co-expression network module containing all currently known OI genes. The de novo IFITM5 mutation was confirmed in one allele of the proband, resulting in a p.S40L substitution in the intracellular domain of BRIL but was absent in unaffected family members. IFITM5 expression was normal in proband fibroblasts and osteoblasts, and BRIL protein level was similar to control in differentiated proband osteoblasts on Western blot and in permeabilized mutant osteoblasts by microscopy. In contrast, SERPINF1 expression was decreased in proband osteoblasts; PEDF was barely detectable in conditioned media of proband cells. Expression and secretion of type I collagen was similarly decreased in proband osteoblasts; the expression pattern of several osteoblast markers largely overlapped reported values from cells with a primary PEDF defect. In contrast, osteoblasts from a typical case of type V OI, with an activating mutation at the 5′-terminus of BRIL, have increased SERPINF1 expression and PEDF secretion during osteoblast differentiation. Together, these data suggest that BRIL and PEDF have a relationship that connects the genes for types V and VI OI and

  19. Defective Proteolytic Processing of Fibrillar Procollagens and Prodecorin Due to Biallelic BMP1 Mutations Results in a Severe, Progressive Form of Osteogenesis Imperfecta.

    PubMed

    Syx, Delfien; Guillemyn, Brecht; Symoens, Sofie; Sousa, Ana Berta; Medeira, Ana; Whiteford, Margo; Hermanns-Lê, Trinh; Coucke, Paul J; De Paepe, Anne; Malfait, Fransiska

    2015-08-01

    Whereas the vast majority of osteogenesis imperfecta (OI) is caused by autosomal dominant defects in the genes encoding type I procollagen, mutations in a myriad of genes affecting type I procollagen biosynthesis or bone formation and homeostasis have now been associated with rare autosomal recessive OI forms. Recently, homozygous or compound heterozygous mutations in BMP1, encoding the metalloproteases bone morphogenetic protein-1 (BMP1) and its longer isoform mammalian Tolloid (mTLD), were identified in 5 children with a severe autosomal recessive form of OI and in 4 individuals with mild to moderate bone fragility. BMP1/mTLD functions as the procollagen carboxy-(C)-proteinase for types I to III procollagen but was also suggested to participate in amino-(N)-propeptide cleavage of types V and XI procollagens and in proteolytic trimming of other extracellular matrix (ECM) substrates. We report the phenotypic characteristics and natural history of 4 adults with severe, progressive OI characterized by numerous fractures, short stature with rhizomelic shortening, and deformity of the limbs and variable kyphoscoliosis, in whom we identified novel biallelic missense and frameshift mutations in BMP1. We show that BMP1/mTLD-deficiency in humans not only results in delayed cleavage of the type I procollagen C-propeptide but also hampers the processing of the small leucine-rich proteoglycan prodecorin, a regulator of collagen fibrillogenesis. Immunofluorescent staining of types I and V collagen and transmission electron microscopy of the dermis show impaired assembly of heterotypic type I/V collagen fibrils in the ECM. Our study thus highlights the severe and progressive nature of BMP1-associated OI in adults and broadens insights into the functional consequences of BMP1/mTLD-deficiency on ECM organization. PMID:25656619

  20. Local amino acid sequence patterns dominate the heterogeneous phenotype for the collagen connective tissue disease Osteogenesis Imperfecta resulting from Gly mutations.

    PubMed

    Xiao, Jianxi; Yang, Zhangfu; Sun, Xiuxia; Addabbo, Rayna; Baum, Jean

    2015-10-01

    Osteogenesis Imperfecta (OI), a hereditary connective tissue disease in collagen that arises from a single Gly → X mutation in the collagen chain, varies widely in phenotype from perinatal lethal to mild. It is unclear why there is such a large variation in the severity of the disease considering the repeating (Gly-X-Y)n sequence and the uniform rod-like structure of collagen. We systematically evaluate the effect of local (Gly-X-Y)n sequence around the mutation site on OI phenotype using integrated bio-statistical approaches, including odds ratio analysis and decision tree modeling. We show that different Gly → X mutations have different local sequence patterns that are correlated with lethal and nonlethal phenotypes providing a mechanism for understanding the sensitivity of local context in defining lethal and non-lethal OI. A number of important trends about which factors are related to OI phenotypes are revealed by the bio-statistical analyses; most striking is the complementary relationship between the placement of Pro residues and small residues and their correlation to OI phenotype. When Pro is present or small flexible residues are absent nearby a mutation site, the OI case tends to be lethal; when Pro is present or small flexible residues are absent further away from the mutation site, the OI case tends to be nonlethal. The analysis also reveals the dominant role of local sequence around mutation sites in the Major Ligand Binding Regions that are primarily responsible for collagen binding to its receptors and shows that non-lethal mutations are highly predicted by local sequence considerations alone whereas lethal mutations are not as easily predicted and may be a result of more complex interactions. Understanding the sequence determinants of OI mutations will enhance genetic counseling and help establish which steps in the collagen hierarchy to target for drug therapy. PMID:25980613

  1. Absence of the ER Cation Channel TMEM38B/TRIC-B Disrupts Intracellular Calcium Homeostasis and Dysregulates Collagen Synthesis in Recessive Osteogenesis Imperfecta

    PubMed Central

    Cabral, Wayne A.; Ishikawa, Masaki; Garten, Matthias; Makareeva, Elena N.; Sargent, Brandi M.; Weis, MaryAnn; Barnes, Aileen M.; Webb, Emma A.; Shaw, Nicholas J.; Ala-Kokko, Leena; Lacbawan, Felicitas L.; Högler, Wolfgang; Leikin, Sergey; Blank, Paul S.; Zimmerberg, Joshua; Eyre, David R.; Yamada, Yoshihiko; Marini, Joan C.

    2016-01-01

    Recessive osteogenesis imperfecta (OI) is caused by defects in proteins involved in post-translational interactions with type I collagen. Recently, a novel form of moderately severe OI caused by null mutations in TMEM38B was identified. TMEM38B encodes the ER membrane monovalent cation channel, TRIC-B, proposed to counterbalance IP3R-mediated Ca2+ release from intracellular stores. The molecular mechanisms by which TMEM38B mutations cause OI are unknown. We identified 3 probands with recessive defects in TMEM38B. TRIC-B protein is undetectable in proband fibroblasts and osteoblasts, although reduced TMEM38B transcripts are present. TRIC-B deficiency causes impaired release of ER luminal Ca2+, associated with deficient store-operated calcium entry, although SERCA and IP3R have normal stability. Notably, steady state ER Ca2+ is unchanged in TRIC-B deficiency, supporting a role for TRIC-B in the kinetics of ER calcium depletion and recovery. The disturbed Ca2+ flux causes ER stress and increased BiP, and dysregulates synthesis of proband type I collagen at multiple steps. Collagen helical lysine hydroxylation is reduced, while telopeptide hydroxylation is increased, despite increased LH1 and decreased Ca2+-dependent FKBP65, respectively. Although PDI levels are maintained, procollagen chain assembly is delayed in proband cells. The resulting misfolded collagen is substantially retained in TRIC-B null cells, consistent with a 50–70% reduction in secreted collagen. Lower-stability forms of collagen that elude proteasomal degradation are not incorporated into extracellular matrix, which contains only normal stability collagen, resulting in matrix insufficiency. These data support a role for TRIC-B in intracellular Ca2+ homeostasis, and demonstrate that absence of TMEM38B causes OI by dysregulation of calcium flux kinetics in the ER, impacting multiple collagen-specific chaperones and modifying enzymes. PMID:27441836

  2. Consistent linkage of dominantly inherited osteogenesis imperfecta to the type I collagen loci: COL1A1 and COL1A2.

    PubMed

    Sykes, B; Ogilvie, D; Wordsworth, P; Wallis, G; Mathew, C; Beighton, P; Nicholls, A; Pope, F M; Thompson, E; Tsipouras, P

    1990-02-01

    The segregation of COL1A1 and COL1A2, the two genes which encode the chains of type I collagen, was analyzed in 38 dominant osteogenesis imperfecta (OI) pedigrees by using polymorphic markers within or close to the genes. This was done in order to estimate the consistency of linkage of OI genes to these two loci. None of the 38 pedigrees showed evidence of recombination between the OI gene and both collagen loci, suggesting that the frequency of unlinked loci in the population must be low. From these results, approximate 95% confidence limits for the proportion of families linked to the type I collagen genes can be set between .91 and 1.00. This is high enough to base prenatal diagnosis of dominantly inherited OI on linkage to these genes even in families which are too small for the linkage to be independently confirmed to high levels of significance. When phenotypic features were compared with the concordant collagen locus, all eight pedigrees with Sillence OI type IV segregated with COL1A2. On the other hand, Sillence OI type I segregated with both COL1A1 (17 pedigrees) and COL1A2 (7 pedigrees). The concordant locus was uncertain in the remaining six OI type I pedigrees. Of several other features, the presence or absence of presenile hearing loss was the best predictor of the mutant locus in OI type I families, with 13 of the 17 COL1A1 segregants and none of the 7 COL1A2 segregants showing this feature. PMID:1967900

  3. A Novel DHPLC-Based Procedure for the Analysis of COL1A1 and COL1A2 Mutations in Osteogenesis Imperfecta

    PubMed Central

    Fuccio, Antonella; Iorio, Mariangela; Amato, Felice; Elce, Ausilia; Ingino, Rosaria; Filocamo, Mirella; Castaldo, Giuseppe; Salvatore, Francesco; Tomaiuolo, Rossella

    2011-01-01

    Approximately 90% of patients with osteogenesis imperfecta (OI) exhibit dominant COL1A1 or COL1A2 mutations; however, molecular analysis is difficult because these genes span 51 and 52 exons, respectively. We devised a PCR-denaturing high-performance liquid chromatography (DHPLC) procedure to analyze the COL1A1 or COL1A2 coding regions and validated it using 130 DNA samples from individuals without OI, 25 DNA samples from two cells to investigate the procedure's potential for preimplantation diagnosis, and DNA samples from 10 patients with OI. Three novel intronic variants in vitro were expressed using a minigene assay to assess their effects on splicing. The procedure is rapid, inexpensive, and reproducible. Analysis of samples from individuals without OI revealed six novel and some known polymorphisms useful for linkage diagnosis because of high heterozygosity. Analysis of two-cell samples confirmed the known genotype in 24 of 25 experiments; DNA failed to amplify in only one case. No incidence of allele dropout was recorded. DHPLC revealed six novel mutations, three of which were intronic, in all patients with OI, and these results were confirmed by means of COL1A1 and COL1A2 direct sequencing. Expression of intronic mutations demonstrated that variant 804 + 2_804 + 3delTG in intron 11 disrupts normal splicing, thereby leading to formation of two alternative products. Variants c.3046-4_3046-5dupCT (COL1A1) and c.891 + 77A>T (COL1A2) did not affect splicing. The described DHPLC protocol combined with the minigene assay may contribute to molecular diagnosis in OI. Moreover, this protocol will aid in counseling about prenatal and preimplantation diagnosis. PMID:21884818

  4. COL1A1 and miR-29b show lower expression levels during osteoblast differentiation of bone marrow stromal cells from Osteogenesis Imperfecta patients

    PubMed Central

    2014-01-01

    Background The majority of Osteogenesis Imperfecta (OI) cases are caused by mutations in one of the two genes, COL1A1 and COL1A2 encoding for the two chains that trimerize to form the procollagen 1 molecule. However, alterations in gene expression and microRNAs (miRNAs) are responsible for the regulation of cell fate determination and may be evolved in OI phenotype. Methods In this work, we analyzed the coding region and intron/exon boundaries of COL1A1 and COL1A2 genes by sequence analysis using an ABI PRISM 3130 automated sequencer and Big Dye Terminator Sequencing protocol. COL1A1 and miR-29b expression were also evaluated during the osteoblastic differentiation of mesenchymal stem cell (MSC) by qRT-PCR using an ABI7500 Sequence Detection System. Results We have identified eight novel mutations, where of four may be responsible for OI phenotype. COL1A1 and miR-29b showed lower expression values in OI type I and type III samples. Interestingly, one type III OI sample from a patient with Bruck Syndrome showed COL1A1 and miR-29b expressions alike those from normal samples. Conclusions Results suggest that the miR-29b mechanism directed to regulate collagen protein accumulation during mineralization is dependent upon the amount of COL1A1 mRNA. Taken together, results indicate that the lower levels observed in OI samples were not sufficient for the induction of miR-29b. PMID:24767406

  5. Efficacy of Bisphosphonates on Bone Mineral Density and Fracture Rate in Patients With Osteogenesis Imperfecta: A Systematic Review and Meta-analysis.

    PubMed

    Shi, Chang Gui; Zhang, Ying; Yuan, Wen

    2016-01-01

    Epidemiological evidence suggests that bisphosphonates are the most promising drugs for patients with osteogenesis imperfecta (OI). However, data on this issue are controversial. We conducted a meta-analysis to assess the efficacy of bisphosphonates on bone mineral density (BMD) and fracture rate in patients with OI. Electronic databases were searched to find relevant studies. Two reviewers independently identified relevant randomized controlled trials, which evaluated the efficacy of bisphosphonates in patients with OI. Outcome measures were fracture incidence and BMD changes in different skeletal sites. A total of 9 randomized controlled trials including 557 patients were identified. Meta-analysis demonstrated a beneficial effect of bisphosphonates on spine BMD Z-score and area BMD (in grams per square centimeter) %. Patients treated with bisphosphonates had a lower risk of fracture [risk ratio (RR) = 0.80; 95% confidence interval (CI): 0.66-0.97] compared with those in control groups. In children, bisphosphonates were efficacious in reducing fractures (RR = 0.80; 95% CI: 0.66-0.97), where in adults, bisphosphonates seemed equivalent to placebo in that respect (RR = 0.82; 95% CI: 0.42-1.59), although no significant difference was noted between these 2 RRs (test of interaction, z = -0.07; P = 0.94). There was also no significant difference in reducing fractures between oral and intravenous bisphosphonates (P = 0.23). This study showed that bisphosphonates could increase the BMD and reduce the risk of facture in patients with OI. There was no enough evidence to identify any differences in efficacy between oral and intravenous bisphosphonates on fracture reduction, as well as between children and adults. PMID:25844482

  6. Scoliosis in osteogenesis imperfecta caused by COL1A1/COL1A2 mutations - genotype-phenotype correlations and effect of bisphosphonate treatment.

    PubMed

    Sato, Atsuko; Ouellet, Jean; Muneta, Takeshi; Glorieux, Francis H; Rauch, Frank

    2016-05-01

    Bisphosphonates are widely used to treat children with osteogenesis imperfecta (OI), a bone fragility disorder that is most often caused by mutations in COL1A1 or COL1A2. However, it is unclear whether this treatment decreases the risk of developing scoliosis. We retrospectively evaluated spine radiographs and charts of 437 patients (227 female) with OI caused by mutations in COL1A1 or COL1A2 and compared the relationship between scoliosis, genotype and bisphosphonate treatment history. At the last follow-up (mean age 11.9 [SD: 5.9] years), 242 (55%) patients had scoliosis. The prevalence of scoliosis was highest in OI type III (89%), followed by OI type IV (61%) and OI type I (36%). Moderate to severe scoliosis (Cobb angle ≥25°) was rare in individuals with COL1A1 haploinsufficiency mutations but was present in about two fifth of patients with triple helical glycine substitutions or C-propeptide mutations. During the first 2 to 4years of bisphosphonate therapy, patients with OI type III had lower Cobb angle progression rates than before bisphosphonate treatment, whereas in OI types I and IV bisphosphonate treatment was not associated with a change in Cobb angle progression rates. At skeletal maturity, the prevalence of scoliosis (Cobb angle >10°) was similar in patients who had started bisphosphonate treatment early in life (before 5.0years of age) and in patients who had started therapy later (after the age of 10.0years) or had never received bisphosphonate therapy. Bisphosphonate treatment decreased progression rate of scoliosis in OI type III but there was no evidence of a positive effect on scoliosis in OI types I and IV. The prevalence of scoliosis at maturity was not influenced by the bisphosphonate treatment history in any OI type. PMID:26927310

  7. Effect of anti-sclerostin therapy and osteogenesis imperfecta on tissue-level properties in growing and adult mice while controlling for tissue age.

    PubMed

    Sinder, Benjamin P; Lloyd, William R; Salemi, Joseph D; Marini, Joan C; Caird, Michelle S; Morris, Michael D; Kozloff, Kenneth M

    2016-03-01

    Bone composition and biomechanics at the tissue-level are important contributors to whole bone strength. Sclerostin antibody (Scl-Ab) is a candidate anabolic therapy for the treatment of osteoporosis that increases bone formation, bone mass, and bone strength in animal studies, but its effect on bone quality at the tissue-level has received little attention. Pre-clinical studies of Scl-Ab have recently expanded to include diseases with altered collagen and material properties such as osteogenesis imperfecta (OI). The purpose of this study was to investigate the role of Scl-Ab on bone quality by determining bone material composition and tissue-level mechanical properties in normal wild type (WT) tissue, as well as mice with a typical OI Gly➔Cys mutation (Brtl/+) in type I collagen. Rapidly growing (3-week-old) and adult (6-month-old) WT and Brtl/+ mice were treated for 5weeks with Scl-Ab. Fluorescent guided tissue-level bone composition analysis (Raman spectroscopy) and biomechanical testing (nanoindentation) were performed at multiple tissue ages. Scl-Ab increased mineral to matrix in adult WT and Brtl/+ at tissue ages of 2-4wks. However, no treatment related changes were observed in mineral to matrix levels at mid-cortex, and elastic modulus was not altered by Scl-Ab at any tissue age. Increased mineral-to-matrix was phenotypically observed in adult Brtl/+ OI mice (at tissue ages>3wks) and rapidly growing Brtl/+ (at tissue ages>4wks) mice compared to WT. At identical tissue ages defined by fluorescent labels, adult mice had generally lower mineral to matrix ratios and a greater elastic modulus than rapidly growing mice, demonstrating that bone matrix quality can be influenced by animal age and tissue age alike. In summary, these data suggest that Scl-Ab alters the matrix chemistry of newly formed bone while not affecting the elastic modulus, induces similar changes between Brtl/+ and WT mice, and provides new insight into the interaction between tissue age and

  8. Abnormal Type I Collagen Post-translational Modification and Crosslinking in a Cyclophilin B KO Mouse Model of Recessive Osteogenesis Imperfecta

    PubMed Central

    Cabral, Wayne A.; Perdivara, Irina; Weis, MaryAnn; Terajima, Masahiko; Blissett, Angela R.; Chang, Weizhong; Perosky, Joseph E.; Makareeva, Elena N.; Mertz, Edward L.; Leikin, Sergey; Tomer, Kenneth B.; Kozloff, Kenneth M.; Eyre, David R.; Yamauchi, Mitsuo; Marini, Joan C.

    2014-01-01

    Cyclophilin B (CyPB), encoded by PPIB, is an ER-resident peptidyl-prolyl cis-trans isomerase (PPIase) that functions independently and as a component of the collagen prolyl 3-hydroxylation complex. CyPB is proposed to be the major PPIase catalyzing the rate-limiting step in collagen folding. Mutations in PPIB cause recessively inherited osteogenesis imperfecta type IX, a moderately severe to lethal bone dysplasia. To investigate the role of CyPB in collagen folding and post-translational modifications, we generated Ppib−/− mice that recapitulate the OI phenotype. Knock-out (KO) mice are small, with reduced femoral areal bone mineral density (aBMD), bone volume per total volume (BV/TV) and mechanical properties, as well as increased femoral brittleness. Ppib transcripts are absent in skin, fibroblasts, femora and calvarial osteoblasts, and CyPB is absent from KO osteoblasts and fibroblasts on western blots. Only residual (2–11%) collagen prolyl 3-hydroxylation is detectable in KO cells and tissues. Collagen folds more slowly in the absence of CyPB, supporting its rate-limiting role in folding. However, treatment of KO cells with cyclosporine A causes further delay in folding, indicating the potential existence of another collagen PPIase. We confirmed and extended the reported role of CyPB in supporting collagen lysyl hydroxylase (LH1) activity. Ppib−/− fibroblast and osteoblast collagen has normal total lysyl hydroxylation, while increased collagen diglycosylation is observed. Liquid chromatography/mass spectrometry (LC/MS) analysis of bone and osteoblast type I collagen revealed site-specific alterations of helical lysine hydroxylation, in particular, significantly reduced hydroxylation of helical crosslinking residue K87. Consequently, underhydroxylated forms of di- and trivalent crosslinks are strikingly increased in KO bone, leading to increased total crosslinks and decreased helical hydroxylysine- to lysine-derived crosslink ratios. The altered

  9. An osteopenic nonfracture syndrome with features of mild osteogenesis imperfecta associated with the substitution of a cysteine for glycine at triple helix position 43 in the pro alpha 1(I) chain of type I collagen.

    PubMed Central

    Shapiro, J R; Stover, M L; Burn, V E; McKinstry, M B; Burshell, A L; Chipman, S D; Rowe, D W

    1992-01-01

    Mutations affecting the pro alpha 1(I) or pro alpha 2(I) collagen genes have been identified in each of the major clinical types of osteogenesis imperfecta. This study reports the presence of a heritable connective tissue disorder in a family with an osteopenic syndrome which has features of mild osteogenesis imperfecta but was considered idiopathic osteoporosis in the proband. At age 38, while still premenopausal, she was found to have osteopenia, short stature, hypermobile joints, mild hyperelastic skin, mild scoliosis, and blue sclerae. There was no history of vertebral or appendicular fracture. Hip and vertebral bone mineral density measurements were consistent with marked fracture risk. Delayed reduction SDS-PAGE of pepsin-digested collagens from dermal fibroblast cultures demonstrated an anomalous band migrating between alpha 1(I) and alpha 1(III). This band merged with the normal alpha-chains upon prereduction, indicating an unexpected cysteine residue. Cyanogen bromide peptide mapping suggested that the mutation was in the smaller NH2-terminal peptides. cDNA was reverse transcribed from mRNA and amplified by the polymerase chain reaction. A basepair mismatch between proband and control alpha 1(I) cDNA hybrids was detected by chemical cleavage with hydroxylamine:piperidine. The cysteine substitution was thus localized to alpha 1(I) exon 9 within the cyanogen bromide 4 peptide. Nucleotide sequence analysis localized a G----T point mutation in the first position of helical codon 43, replacing the expected glycine (GGT) residue with a cysteine (TGT). The prevalence of similar NH2-terminal mutations in subjects with this phenotype which clinically overlaps idiopathic osteoporosis remains to be determined. Images PMID:1737847

  10. Nephrocalcinosis (Enamel Renal Syndrome) Caused by Autosomal Recessive FAM20A Mutations

    PubMed Central

    Jaureguiberry, Graciana; De la Dure-Molla, Muriel; Parry, David; Quentric, Mickael; Himmerkus, Nina; Koike, Toshiyasu; Poulter, James; Klootwijk, Enriko; Robinette, Steven L.; Howie, Alexander J.; Patel, Vaksha; Figueres, Marie-Lucile; Stanescu, Horia C.; Issler, Naomi; Nicholson, Jeremy K.; Bockenhauer, Detlef; Laing, Christopher; Walsh, Stephen B.; McCredie, David A.; Povey, Sue; Asselin, Audrey; Picard, Arnaud; Coulomb, Aurore; Medlar, Alan J.; Bailleul-Forestier, Isabelle; Verloes, Alain; Le Caignec, Cedric; Roussey, Gwenaelle; Guiol, Julien; Isidor, Bertrand; Logan, Clare; Shore, Roger; Johnson, Colin; Inglehearn, Christopher; Al-Bahlani, Suhaila; Schmittbuhl, Matthieu; Clauss, François; Huckert, Mathilde; Laugel, Virginie; Ginglinger, Emmanuelle; Pajarola, Sandra; Spartà, Giuseppina; Bartholdi, Deborah; Rauch, Anita; Addor, Marie-Claude; Yamaguti, Paulo M.; Safatle, Heloisa P.; Acevedo, Ana Carolina; Martelli-Júnior, Hercílio; dos Santos Netos, Pedro E.; Coletta, Ricardo D.; Gruessel, Sandra; Sandmann, Carolin; Ruehmann, Denise; Langman, Craig B.; Scheinman, Steven J.; Ozdemir-Ozenen, Didem; Hart, Thomas C.; Hart, P. Suzanne; Neugebauer, Ute; Schlatter, Eberhard; Houillier, Pascal; Gahl, William A.; Vikkula, Miikka; Bloch-Zupan, Agnès; Bleich, Markus; Kitagawa, Hiroshi; Unwin, Robert J.; Mighell, Alan; Berdal, Ariane; Kleta, Robert

    2013-01-01

    Background/Aims Calcium homeostasis requires regulated cellular and interstitial systems interacting to modulate the activity and movement of this ion. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood. Methods We investigated 25 patients from 16 families with unexplained nephrocalcinosis and characteristic dental defects (amelogenesis imperfecta, gingival hyperplasia, impaired tooth eruption). To identify the causative gene, we performed genome-wide linkage analysis, exome capture, next-generation sequencing, and Sanger sequencing. Results All patients had bi-allelic FAM20A mutations segregating with the disease; 20 different mutations were identified. Conclusions This au-tosomal recessive disorder, also known as enamel renal syndrome, of FAM20A causes nephrocalcinosis and amelogenesis imperfecta. We speculate that all individuals with biallelic FAM20A mutations will eventually show nephrocalcinosis. PMID:23434854