Physiological Basis for the Etiology, Diagnosis, and Treatment of Adrenal Disorders: Cushing’s Syndrome, Adrenal Insufficiency, and Congenital Adrenal Hyperplasia

PubMed Central

Raff, Hershel; Sharma, Susmeeta T.; Nieman, Lynnette K.

2014-01-01

The hypothalamic-pituitary-adrenal (HPA) axis is a classic neuroendocrine system. One of the best ways to understand the HPA axis is to appreciate its dynamics in the variety of diseases and syndromes that affect it. Excess glucocorticoid activity can be due to endogenous cortisol overproduction (spontaneous Cushing’s syndrome) or exogenous glucocorticoid therapy (iatrogenic Cushing’s syndrome). Endogenous Cushing’s syndrome can be subdivided into ACTH-dependent and ACTH-independent, the latter of which is usually due to autonomous adrenal overproduction. The former can be due to a pituitary corticotroph tumor (usually benign) or ectopic ACTH production from tumors outside the pituitary; both of these tumor types overexpress the proopiomelanocortin gene. The converse of Cushing’s syndrome is the lack of normal cortisol secretion and is usually due to adrenal destruction (primary adrenal insufficiency) or hypopituitarism (secondary adrenal insufficiency). Secondary adrenal insufficiency can also result from a rapid discontinuation of long-term, pharmacological glucocorticoid therapy because of HPA axis suppression and adrenal atrophy. Finally, mutations in the steroidogenic enzymes of the adrenal cortex can lead to congenital adrenal hyperplasia and an increase in precursor steroids, particularly androgens. When present in utero, this can lead to masculinization of a female fetus. An understanding of the dynamics of the HPA axis is necessary to master the diagnosis and differential diagnosis of pituitary-adrenal diseases. Furthermore, understanding the pathophysiology of the HPA axis gives great insight into its normal control. PMID:24715566

Sonographic Appearance of Testicular Adrenal Rest Tumour in a Patient with Congenital Adrenal Hyperplasia.

PubMed

Deshpande, Saurabh S; Shetty, Devdas; Saifi, Shenaz

2017-01-01

Testicular adrenal rest tumours (TARTs) are benign testicular masses that are found in inadequately treated patients with congenital adrenal hyperplasia (CAH). Recognizing this association and identifying characteristic ultrasound features of TARTs is important so as to avoid misdiagnosing them as malignancies, which can lead to unnecessary interventions. We describe a case of a 9-year-old boy, with a diagnosis of CAH and precocious puberty, who was referred to our department for an ultrasound evaluation of the abdomen and scrotum. On ultrasound, there were well-defined, heterogeneous, predominantly hypoechoic, round-to-oval masses in both testes. Taking into account the presence of CAH and a typical sonographic appearance of bilateral testicular masses, a diagnosis of testicular adrenal rest tumour was made; biopsy was deferred and hormonal treatment was modified. Prompt diagnosis of testicular adrenal rest tumours is essential, as it only indicates inadequate hormonal control. Moreover, it can prevent unnecessary biopsies and orchidectomies, and can maintain fertility. TARTs have a typical imaging appearance that every radiologist must be aware of.

Sonographic Appearance of Testicular Adrenal Rest Tumour in a Patient with Congenital Adrenal Hyperplasia

PubMed Central

Shetty, Devdas; Saifi, Shenaz

2017-01-01

Summary Background Testicular adrenal rest tumours (TARTs) are benign testicular masses that are found in inadequately treated patients with congenital adrenal hyperplasia (CAH). Recognizing this association and identifying characteristic ultrasound features of TARTs is important so as to avoid misdiagnosing them as malignancies, which can lead to unnecessary interventions. Case Report We describe a case of a 9-year-old boy, with a diagnosis of CAH and precocious puberty, who was referred to our department for an ultrasound evaluation of the abdomen and scrotum. On ultrasound, there were well-defined, heterogeneous, predominantly hypoechoic, round-to-oval masses in both testes. Taking into account the presence of CAH and a typical sonographic appearance of bilateral testicular masses, a diagnosis of testicular adrenal rest tumour was made; biopsy was deferred and hormonal treatment was modified. Conclusions Prompt diagnosis of testicular adrenal rest tumours is essential, as it only indicates inadequate hormonal control. Moreover, it can prevent unnecessary biopsies and orchidectomies, and can maintain fertility. TARTs have a typical imaging appearance that every radiologist must be aware of. PMID:29662583

Mistaken gender identity in non-classical congenital adrenal hyperplasia.

PubMed

Kukreti, Prerna; Kandpal, Manish; Jiloha, R C

2014-04-01

Gender identity is the sense of belonging that one feels for a particular sex psychologically and socially, independent of one's biological sex. There is much less systematic data on gender identity in females with congenital adrenal hyperplasia (CAH). We report a case of non-classical CAH presenting as a case of gender identity disorder.

Diagnosis and management of classical congenital adrenal hyperplasia.

PubMed

Marumudi, Eunice; Khadgawat, Rajesh; Surana, Vineet; Shabir, Iram; Joseph, Angela; Ammini, Ariachery C

2013-08-01

Congenital adrenal hyperplasia (CAH) is among the most common genetic disorders. Deficiency of adrenal steroid 21-hydroxylase deficiency due to mutations in the CYP21A2 gene accounts for about 95% cases of CAH. This disorder manifests with androgen excess with or without salt wasting. It also is a potentially life threatening disorder; neonatal screening with 17-hydroxyprogesterone measurement can diagnose the condition in asymptomatic children. Carefully monitored therapy with glucocorticoid and mineralocorticoid supplementation will ensure optimal growth and development for children with CAH. Genital surgery may be required for girls with CAH. Continued care is required for individuals with CAH as adults to prevent long-term adverse consequences of the disease, including infertility, metabolic syndrome and osteoporosis. Copyright © 2013 Elsevier Inc. All rights reserved.

Parental management of adrenal crisis in children with congenital adrenal hyperplasia

PubMed Central

Fleming, Louise; Knafl, Kathleen; Knafl, George; Van Riper, Marcia

2018-01-01

Purpose Congenital adrenal hyperplasia (CAH) requires parents to inject their child with hydro-cortisone intramuscularly during times of illness and adrenal crisis. The purpose of this study was to describe circumstances surrounding adrenal crisis events in children with CAH; to explore parents’ perceptions of the consequences of having a child with a life-threatening condition; and to examine a relationship between parents’ perceived management ability and the impact CAH has on the family. Methods In Phase 1 of this mixed-methods, cross-sectional study, 77 parents were asked to complete questionnaires comprising measures of family life in the context of childhood illness. Descriptive statistics were computed with four separate analyses using linear mixed models allowing for correlation between responses from parents of the same family and for the variance to be different for fathers and mothers. The following relationships were examined: (1) parental management ability and type of provider instruction on how to manage adrenal crises; (2) parental management ability and child age; (3) the perceived impact of the condition on the family and management ability; and (4) the age of the child and number of adrenal crisis events. In Phase 2, 16 semi-structured interviews were conducted to elicit detailed descriptions of parents’ experiences in managing crises. Results There was a significant, positive relationship between detailed provider instruction to parents on adrenal crisis management and perceived management ability (p = .02), additionally the stronger the perceived management ability, the less impact CAH had on the family (p < .001). From birth to age 5, parents reported more frequent crisis events and less perceived ability to manage the condition when compared with parents of older children (p = .009). The threat of an adrenal crisis event is a pervasive concern for parents, especially when they are not being properly prepared by providers. Practice

Parental management of adrenal crisis in children with congenital adrenal hyperplasia.

PubMed

Fleming, Louise; Knafl, Kathleen; Knafl, George; Van Riper, Marcia

2017-10-01

Congenital adrenal hyperplasia (CAH) requires parents to inject their child with hydrocortisone intramuscularly during times of illness and adrenal crisis. The purpose of this study was to describe circumstances surrounding adrenal crisis events in children with CAH; to explore parents' perceptions of the consequences of having a child with a life-threatening condition; and to examine a relationship between parents' perceived management ability and the impact CAH has on the family. In Phase 1 of this mixed-methods, cross-sectional study, 77 parents were asked to complete questionnaires comprising measures of family life in the context of childhood illness. Descriptive statistics were computed with four separate analyses using linear mixed models allowing for correlation between responses from parents of the same family and for the variance to be different for fathers and mothers. The following relationships were examined: (1) parental management ability and type of provider instruction on how to manage adrenal crises; (2) parental management ability and child age; (3) the perceived impact of the condition on the family and management ability; and (4) the age of the child and number of adrenal crisis events. In Phase 2, 16 semi-structured interviews were conducted to elicit detailed descriptions of parents' experiences in managing crises. There was a significant, positive relationship between detailed provider instruction to parents on adrenal crisis management and perceived management ability (p = .02), additionally the stronger the perceived management ability, the less impact CAH had on the family (p < .001). From birth to age 5, parents reported more frequent crisis events and less perceived ability to manage the condition when compared with parents of older children (p = .009). The threat of an adrenal crisis event is a pervasive concern for parents, especially when they are not being properly prepared by providers. Provider support is needed for these parents

Mistaken gender identity in non-classical congenital adrenal hyperplasia

PubMed Central

Kukreti, Prerna; Kandpal, Manish; Jiloha, R. C.

2014-01-01

Gender identity is the sense of belonging that one feels for a particular sex psychologically and socially, independent of one's biological sex. There is much less systematic data on gender identity in females with congenital adrenal hyperplasia (CAH). We report a case of non-classical CAH presenting as a case of gender identity disorder. PMID:24891708

A novel mutation in FRMD7 causing X-linked idiopathic congenital nystagmus in a large family

PubMed Central

He, Xiang; Gu, Feng; Wang, Yujing; Yan, Jinting; Zhang, Meng; Huang, Shangzhi

2008-01-01

Purpose To identify the gene responsible for causing an X-linked idiopathic congenital nystagmus (XLICN) in a six-generation Chinese family. Methods Forty-nine members of an XLICN family were recruited and examined after obtaining informed consent. Affected male individuals were genotyped with microsatellite markers around the FRMD7 locus. Mutations were comprehensively screened by direct sequencing using gene specific primers. An X-inactivation pattern was investigated by X chromosome methylation analysis. Results The patients showed phenotypes consistent with XLICN. Genotype analysis showed that male affected individuals in the family shared a common haplotype with the selected markers. Sequencing FRMD7 revealed a G>T transversion (c.812G>T) in exon 9, which caused a conservative substitution of Cys to Phe at codon 271 (p.C271F). This mutation co-segregated with all affected individuals and was present in the obligate, non-penetrant female carriers. However, the mutation was not observed in unaffected familial males or 400 control males. Females with the mutant gene could be affected or carrier and they shared the same inactivated X chromosome harboring the mutation in blood cells, which showed there is no clear causal link between X-inactivation pattern and phenotype. Conclusions We identified a novel mutation in FRMD7 and confirmed the role of this mutation in the pathogenesis of X-linked congenital nystagmus. PMID:18246032

Congenital Adrenal Hyperplasia: Unresolved Issues.

PubMed

Yau, Mabel; Khattab, Ahmed; Poppas, Dix; Ghizzoni, Lucia; New, Maria

2016-01-01

Congenital adrenal hyperplasia (CAH) describes a family of disorders that comes from enzymatic deficiencies in cortisol production, with 21-hydroxylase deficiency causing ∼90% of cases. Distinction is made between the severe classical form and milder nonclassical form of CAH. Molecular genetic analysis is used to confirm the hormonal diagnosis. A high rate of genotype-phenotype disconcordance has been found in 21-hydroxylase deficiency. The goal of treatment is to replace with synthetic glucocorticoids and mineralocorticoids and suppress adrenal androgen production. The treatment of patients affected with nonclassical CAH, particularly males, remains controversial. Variable synthetic glucocorticoids are used and new modes of glucocorticoid delivery are under investigation. To improve height, growth hormone and other adjuvant therapies are employed. Long-term outcomes of genital surgery using modern techniques in females affected with classical CAH continue to be investigated. Prenatal treatment with dexamethasone is available to avoid ambiguous genitalia in these females. Although studies have shown its safety to mother and fetus, prenatal treatment is still regarded as experimental. Currently, prenatal diagnosis of CAH can only be obtained through invasive methods. Recently, the detection of cell-free fetal DNA in maternal plasma has made it possible to make this diagnosis earlier and noninvasively. © 2016 S. Karger AG, Basel.

Review Recent progress in identification and characterization of loci associated with sex-linked congenital cataract.

PubMed

Zhang, D D; Du, J Z; Topolewski, J; Wang, X M

2016-07-29

Congenital cataract is a common cause of blindness in children; however, its pathogenesis remains unclear. Genetic factors have been shown to play an important role in the pathogenesis of congenital cataract. The current genetic models of congenital cataract include autosomal dominant, autosomal recessive, and sex-linked inheritance. Sex-linked congenital cataract could be inherited through the X or Y chromosome. Congenital cataract is a symptom associated with several X-linked disorders, including Nance-Horan syndrome, Lowe syndrome, Conradi-Hünermann-Happle syndrome, oculo-facio-cardio-dental syndrome, and Alport syndrome. On the other hand, the mechanism and characteristics of Y-linked congenital cataract remains to be identified. Despite its rarity, sex-linked congenital cataract has been known to seriously affect the quality of life of patients. In this review, we present our current understanding of the genes and loci associated with sex-linked congenital cataract. This could help identify novel approaches for the prevention, early diagnosis, and comprehensive disease treatment.

X-linked congenital panhypopituitarism.

PubMed

Schimke, R N; Spaulding, J J; Hollowell, J G

1971-05-01

Two half brothers with panhypopituitary dwarfism are reported who have the same mother and different, unrelated fathers. The subject of hereditary panhypopituitarism is reviewed briefly. It is concluded that there are at least two forms of hereditary panhypopituitary dwarfism, one of which may be X-linked.

Early diagnosis of salt-losing congenital adrenal hyperplasia in a newborn boy.

PubMed Central

Hughes, I. A.; Winter, J. S.

1977-01-01

Assays of serum 17-hydroxyprogesterone concentration may be relied upon to establish a diagnosis of congenital adrenal hyperplasia within a few hours of birth. In a male infant the concentration of 17-hydroxyprogesterone was increased in cord serum and remained elevated until glucocorticoid therapy was started on the 5th day of life. Plasma renin activity was increased only slightly in the first few days, but a striking increase on day 5, along with a gradual increase in the serum potassium concentration, confirmed that the infant had the salt-losing form of congenital adrenal hyperplasia. It was not possible to demonstrate an increased concentration of 17-hydroxyprogesterone, in amniotic fluid obtained at 30 weeks' gestation, presumably because of interference in this assay by cross-reacting steroids. Studies of the mother's serum concentration of 17-hydroxyprogesterone and cortisol during delivery did not disclose any deviation from normal. PMID:890632

Clinical and molecular profile of newborns with confirmed or suspicious congenital adrenal hyperplasia detected after a public screening program implementation.

PubMed

Kopacek, Cristiane; Prado, Mayara J; da Silva, Claudia M D; de Castro, Simone M; Beltrão, Luciana A; Vargas, Paula R; Grandi, Tarciana; Rossetti, Maria L R; Spritzer, Poli Mara

2018-04-30

To describe the results obtained in a neonatal screening program after its implementation and to assess the clinical and molecular profiles of confirmed and suspicious congenital adrenal hyperplasia cases. A cross-sectional study was conducted. Newborns with suspected disease due to high 17-hydroxyprogesterone levels and adjusted for birth weight were selected. Classical congenital adrenal hyperplasia (salt-wasting and simple virilizing forms) was diagnosed by an increase in 17-hydroxyprogesterone levels as confirmed in the retest, clinical evaluation, and genotype determined by SNaPshot and multiplex ligation-dependent probe amplification. After 24 months, 15 classic congenital adrenal hyperplasia cases were diagnosed in a total of 217,965 newborns, with an estimated incidence of 1:14,531. From 132 patients, seven non-classical and 14 heterozygous patients were screened for CYP21A2 mutations, and 96 patients presented false positives with wild type CYP21A2. On retest, increased 17-hydroxyprogesterone levels were found in classical congenital adrenal hyperplasia patients and showed significant correlation with genotype-related classical genital adrenal hyperplasia. The most frequent mutations were IVS2-13A/C>G followed by gene deletion or rearrangement events in the classical form. In non-classical and heterozygous diseases, p.Val282Leu was the most common mutation. The results underscore the effectiveness of congenital adrenal hyperplasia neonatal screening in the public health system and indicate that the adopted strategy was appropriate. The second sample collection along with genotyping of suspected cases helped to properly diagnose both severe and milder cases and delineate them from false positive patients. Copyright © 2018. Published by Elsevier Editora Ltda.

Magnetic Resonance Imaging of the Vocal Folds in Women with Congenital Adrenal Hyperplasia and Virilized Voices

ERIC Educational Resources Information Center

Nygren, Ulrika; Isberg, Bengt; Arver, Stefan; Hertegård, Stellan; Södersten, Maria; Nordenskjöld, Agneta

2016-01-01

Purpose: Women with congenital adrenal hyperplasia (CAH) may develop a virilized voice due to late diagnosis or suboptimal suppression of adrenal androgens. Changes in the vocal folds due to virilization have not been studied in vivo. The purpose was to investigate if the thyroarytenoid (TA) muscle is affected by virilization and correlate…

Feminising genitoplasty: one-stage genital reconstruction in congenital adrenal hyperplasia: 30 years' experience.

PubMed

Roll, M F; Kneppo, C; Roth, H; Bettendorf, M; Waag, K-L; Holland-Cunz, S

2006-10-01

The study objective is to evaluate the results of our surgical technique for children with congenital adrenal hyperplasia and ambiguous genitalia at the University Hospital of Heidelberg, Department of Paediatric Surgery. The records of 19 patients with congenital adrenal hyperplasia treated between 1972 and 2004 were reviewed with respect to age at surgery, operative procedures and outcome. We describe the recession clitoroplasty technique currently used in our hospital and highlight the importance of short and long-term follow-up results with respect to appearance, position and size of the clitoris and quality of the vagina. One-stage recession clitoroplasty and vaginoplasty gives very satisfactory cosmetic and functional results, with few complications and a reduced need for secondary surgical interventions. The results of this study support the assumption that total correction can be achieved through a single-stage operation, performed in infancy.

Congenital adrenal hyperplasia with localized aggressive periodontitis and amelogenesis imperfecta.

PubMed

Ajlan, Sumaiah Abdulbaqi

2015-11-01

Congenital adrenal hyperplasia (CAH) is an inherited medical condition that implies defects in steroid biosynthesis. The dental findings of a female patient with CAH are reported. The patient suffered from severe periodontal tissue destruction, obvious enamel defects, as well as some occlusal problems. The management approach is presented and the possibility of interrelation of her dental findings with her medical condition is discussed. © 2015 Japanese Teratology Society.

p.R182C mutation in Korean twin with congenital lipoid adrenal hyperplasia

PubMed Central

Park, Hye Won; Kwak, Byung Ok; Kim, Gu-Hwan; Yoo, Han-Wook

2013-01-01

Congenital lipoid adrenal hyperplasia (CLAH) is the most severe form of congenital adrenal hyperplasia which is caused by mutations in the steroidogenic acute regulatory protein (StAR). The mutations in StAR gene resulted in failure of the transport cholesterol into mitochondria for steroidogenesis in the adrenal gland. Twin sisters (A, B) with normal 46, XX were born at 36+2 gestational week, premature to nonrelated parents. They had symptoms as hyperpigmentation, slightly elevated potassium level and low level of sodium. Laboratory finding revealed normal 17-hydroxyprogesterone level, elevated adrenocorticotropin hormone (A, 4,379.2 pg/mL; B, 11,616.1 pg/mL), and high plasma renin activity (A, 49.02 ng/mL/hr; B, 52.7 ng mL/hr). However, the level of plasma cortisol before treatment was low (1.5 µg/dL) in patient B but normal (8.71 µg/dL) in patient A. Among them, only patient A was presented with adrenal insufficiency symptoms which was suggestive of CLAH and prompted us to order a gene analysis in both twin. The results of gene analysis of StAR in twin revealed same heterozygous conditions for c.544C>T (Arg182Cys) in exon 5 and c.722C>T (Gln258*) in exon 7. We report the first case on the mutation of p.R182C in exon 5 of the StAR gene in Korea. PMID:24904850

Should male gender assignment be considered in the markedly virilized patient With 46,XX and congenital adrenal hyperplasia?

PubMed

Lee, Peter A; Houk, Christopher P; Husmann, Douglas A

2010-10-01

We assess the outcome in 46,XX men with congenital adrenal hyperplasia who were born with Prader 4 or 5 genitalia and assigned male gender at birth. After receiving institutional review board approval and subject consent we reviewed the medical records of 12 men 35 to 69 years old with 46,XX congenital adrenal hyperplasia, of whom 6 completed social and gender issue questionnaires. All subjects were assigned male gender at birth, were diagnosed with virilizing congenital adrenal hyperplasia at age greater than 3 years and indicated a male gender identity with sexual orientation to females. Ten of the 12 subjects had always lived as male and 2 who were reassigned to female gender in childhood subsequently self-reassigned as male. Nine of the 12 men had long-term female partners, including 7 married 12 years or more. The 3 subjects without a long-term female partner included 1 priest, 1 who was reassigned female gender, married, divorced and self-reassigned as male, and 1 with a girlfriend and sexual activity. All except the priest and the subject who was previously married when female indicated a strong libido and frequent orgasmic sexual activity. Responses to self-esteem, masculinity, body image, social adjustment and symptom questionnaires suggested adjustments related to the extent of familial and social support. Outcome data on severely masculinized 46,XX patients with congenital adrenal hyperplasia who were assigned male gender at birth indicate male gender identity in adulthood with satisfactory male sexual function in those retaining male genitalia. In men who completed questionnaires results were poorer in those lacking familial/social support. Male gender of rearing may be a viable option for parents whose children are born with congenital adrenal hyperplasia, a 46,XX karyotype and male genitalia, although positive parental and other support, and counseling are needed for adjustment. Copyright © 2010 American Urological Association Education and Research

X-Linked Congenital Hypertrichosis Syndrome Is Associated with Interchromosomal Insertions Mediated by a Human-Specific Palindrome near SOX3

PubMed Central

Zhu, Hongwen; Shang, Dandan; Sun, Miao; Choi, Sunju; Liu, Qing; Hao, Jiajie; Figuera, Luis E.; Zhang, Feng; Choy, Kwong Wai; Ao, Yang; Liu, Yang; Zhang, Xiao-Lin; Yue, Fengzhen; Wang, Ming-Rong; Jin, Li; Patel, Pragna I.; Jing, Tao; Zhang, Xue

2011-01-01

X-linked congenital generalized hypertrichosis (CGH), an extremely rare condition characterized by universal overgrowth of terminal hair, was first mapped to chromosome Xq24-q27.1 in a Mexican family. However, the underlying genetic defect remains unknown. We ascertained a large Chinese family with an X-linked congenital hypertrichosis syndrome combining CGH, scoliosis, and spina bifida and mapped the disease locus to a 5.6 Mb critical region within the interval defined by the previously reported Mexican family. Through the combination of a high-resolution copy-number variation (CNV) scan and targeted genomic sequencing, we identified an interchromosomal insertion at Xq27.1 of a 125,577 bp intragenic fragment of COL23A1 on 5q35.3, with one X breakpoint within and the other very close to a human-specific short palindromic sequence located 82 kb downstream of SOX3. In the Mexican family, we found an interchromosomal insertion at the same Xq27.1 site of a 300,036 bp genomic fragment on 4q31.2, encompassing PRMT10 and TMEM184C and involving parts of ARHGAP10 and EDNRA. Notably, both of the two X breakpoints were within the short palindrome. The two palindrome-mediated insertions fully segregate with the CGH phenotype in each of the families, and the CNV gains of the respective autosomal genomic segments are not present in the public database and were not found in 1274 control individuals. Analysis of control individuals revealed deletions ranging from 173 bp to 9104 bp at the site of the insertions with no phenotypic consequence. Taken together, our results strongly support the pathogenicity of the identified insertions and establish X-linked congenital hypertrichosis syndrome as a genomic disorder. PMID:21636067

Adrenal rest tissue in gonads of patients with classical congenital adrenal hyperplasia: multicenter study of 45 French male patients.

PubMed

Pierre, Peggy; Despert, François; Tranquart, François; Coutant, Régis; Tardy, Véronique; Kerlan, Véronique; Sonnet, Emmanuel; Baron, Sabine; Lorcy, Yannick; Emy, Philippe; Delavierre, Dominique; Monceaux, Françoise; Morel, Yves; Lecomte, Pierre

2012-12-01

Several cases of testicular adrenal rest tumours have been reported in men with congenital adrenal hyperplasia (CAH) due to the classical form of 21-hydroxylase deficiency but the prevalence has not been established. The aims of this report were to evaluate the frequency of testicular adrenal rest tissue in this population in a retrospective multicentre study involving eight endocrinology centres, and to determine whether treatment or genetic background had an impact on the occurrence of adrenal rest tissue. Testicular adrenal rest tissue (TART) was sought clinically and with ultrasound examination in forty-five males with CAH due to the classical form of 21-hydroxylase deficiency. When the diagnosis of testicular adrenal rest tumours was sought, good observance of treatment was judged on biological concentrations of 17-hydroxyprogesterone (17OHP), delta4-androstenedione, active renin and testosterone. The results of affected and non-affected subjects were compared. TART was detected in none of the 18 subjects aged 1 to 15years but was detected in 14 of the 27 subjects aged more than 15years. Five patients with an abnormal echography result had no clinical signs. Therapeutic control evaluated at diagnosis of TART seemed less effective when diagnosis was made in patients with adrenal rest tissue compared to TART-free subjects. Various genotypes were observed in patients with or without TART. Due to the high prevalence of TART in classical CAH and the delayed clinical diagnosis, testicular ultrasonography must be performed before puberty and thereafter regularly during adulthood even if the clinical examination is normal. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Fetal endocrine therapy for congenital adrenal hyperplasia should not be done.

PubMed

Miller, Walter L

2015-06-01

Prenatal treatment of congenital adrenal hyperplasia by administering dexamethasone to a woman presumed to be carrying an at-risk fetus remains a controversial experimental treatment. Review of data from animal experimentation and human trials indicates that dexamethasone cannot be considered safe for the fetus. In animals, prenatal dexamethasone decreases birth weight, affects renal, pancreatic beta cell and brain development, increases anxiety and predisposes to adult hypertension and hyperglycemia. In human studies, prenatal dexamethasone is associated with orofacial clefts, decreased birth weight, poorer verbal working memory, and poorer self-perception of scholastic and social competence. Numerous medical societies have cautioned that prenatal treatment of adrenal hyperplasia with dexamethasone is not appropriate for routine clinical practice and should only be done in Institutional Review Board approved, prospective clinical research settings with written informed consent. The data indicate that this treatment is inconsistent with the classic medical ethical maxim to 'first do no harm'. Copyright © 2015 Elsevier Ltd. All rights reserved.

HYDROCORTISONE THERAPY AND GROWTH TRAJECTORY IN CHILDREN WITH CLASSICAL CONGENITAL ADRENAL HYPERPLASIA.

PubMed

Bizzarri, Carla; Improda, Nicola; Maggioli, Chiara; Capalbo, Donatella; Roma, Silvia; Porzio, Ottavia; Salerno, Mariacarolina; Cappa, Marco

2017-05-01

Poor linear growth is one of the main concerns in children with congenital adrenal hyperplasia (CAH). We aimed to analyze factors affecting growth trajectory in children with classical CAH. Clinical records of children followed from infancy up to the end of growth at two Italian tertiary referral hospitals were reviewed. Fifty-seven patients (31 males), treated with hydrocortisone and fludrocortisone only, were included. Clinical observations were divided into three groups: 0 to 2 years, 172 observations; from 2 years to puberty onset, 813 observations; after puberty onset, 527 observations. Height velocity, pubertal growth spurt, and final height were evaluated as outcomes. Final height standard deviation score (SDS) was lower than target height SDS (-0.74 ± 1.1 versus -0.31 ± 1.01; P<.001). Target-adjusted final height SDS was -0.44 ± 1.8 in males and -0.13 ± 1.1 in females (P = .001). Total pubertal growth was 21.9 ± 7.3 cm in males and 19.2 ± 8.2 cm in females (P = .19). Hydrocortisone dose increased and height-velocity SDS decreased during puberty. At multivariable analysis, height-velocity SDS was adversely affected by hydrocortisone dose (P = .038) and directly related to adrenocorticotropic hormone (ACTH) levels (P = .023). Target-adjusted final-height SDS was adversely affected by hydrocortisone dose (P<.001) and positively related to mineralocorticoid therapy (P = .001) and ACTH levels (P = .02). Total pubertal growth (cm) was positively related to ACTH levels (P = .01). Height outcome of CAH patients is now better than previously reported. During puberty, the lowest effective dose of hydrocortisone should be used to optimize pubertal growth spurt and final height. 17-OHP = 17-alpha-hydroxyprogesterone ACTH = adrenocorticotropic hormone BMI = body mass index CAH = congenital adrenal hyperplasia GH = growth hormone HPA = hypothalamus-pituitary-adrenal PRA = plasma renin activity SDS = standard deviation score SV = simple virilizing SW = salt-wasting.

Congenital Adrenal Hyperplasia in an Elite Female Soccer Player; What Sports Medicine Clinicians Should Know about This?

PubMed

Angoorani, Hooman; Haratian, Zohreh; Halabchi, Farzin

2012-09-01

Congenital Adrenal Hyperplasia (CAH) refers to a group of congenital conditions characterized by disordered cortisol synthesis. The correlation between CAH and sports performance has been less studied before and there is very limited information regarding the impacts of this congenital disease on sports performance. Probably, there are some limitations for patients who suffer from CAH in sports, but at the same time, they may enjoy some advantage due to the probable effect of endogenous hyperandrogenism on their exercise performance. The case is a 14 - year old girl with male phenotype who is a known case of congenital adrenal hyperplasia. She plays in the women's national soccer team of under 16. She has been in the first division league of indoor soccer for 4 years and was also selected in the preparation training camp of women's football team for Singapore's youth Olympic Games. Her illness and dependence on corticosteroid have caused some concerns for her participation in the international competitions of women. However, following consultations with the Therapeutic Use Exemption (TUE) Committee of games organization, she received TUE to use corticosteroid only within the games period. Despite all her problems, she is now playing in the Second Division League of indoor soccer. A female adolescent with CAH may compete at the high level of outdoor and indoor soccer. However, there are many questions regarding the advantages and disadvantages of this congenital disorder and its treatment on sports related issues.

Lipoid congenital adrenal hyperplasia due to STAR mutations in a Caucasian patient.

PubMed

Kaur, Jasmeet; Casas, Luis; Bose, Himangshu S

2016-01-01

Lipoid congenital adrenal hyperplasia (lipoid CAH), the most severe form of CAH, is most commonly caused by mutations in steroidogenic acute regulatory protein (STAR), which is required for the movement of cholesterol from the outer to the inner mitochondrial membranes to synthesize pregnenolone. This study was performed to evaluate whether the salt-losing crisis and the adrenal inactivity experienced by a Scandinavian infant is due to a de novo STAR mutation. The study was conducted at the University of North Dakota, the Mercer University School of Medicine and the Memorial University Medical Center to identify the cause of this disease. The patient was admitted to a pediatric endocrinologist at the Sanford Health Center for salt-losing crisis and possible adrenal failure. Lipoid CAH is an autosomal recessive disease, we identified two de novo heterozygous mutations (STAR c.444C>A (STAR p.N148K) and STAR c.557C>T (STAR p.R193X)) in the STAR gene, causing lipoid CAH. New onset lipoid CAH can occur through de novo mutations and is not restricted to any specific region of the world. This Scandinavian family was of Norwegian descent and had lipoid CAH due to a mutation in S TAR exons 4 and 5. Overexpression of the STAR p.N148K mutant in nonsteroidogenic COS-1 cells supplemented with an electron transport system showed activity similar to the background level, which was ∼10% of that observed with wild-type (WT) STAR. Protein-folding analysis showed that the finger printing of the STAR p.N148K mutant is also different from the WT protein. Inherited STAR mutations may be more prevalent in some geographical areas but not necessarily restricted to those regions. STAR mutations cause lipoid CAH.This is a pure population from a caucasian family.Mutation ablated STAR activity.The mutation resulted in loosely folded conformation of STAR.

[Diffuse hypertrichosis revealing non-classical congenital adrenal hyperplasia].

PubMed

Berthin, C; Sibilia, P; Martins-Hericher, J; Donzeau, A; Martin, L

2018-04-01

Non-classical congenital adrenal hyperplasia (NC-CAH) is a recessive autosomal disease caused by a deficiency of adrenal steroidogenesis enzymes. It must be distinguished from classical CAH, either simple virilising or salt-wasting, diagnosed during the neonatal period and responsible for potentially lethal disorders of sexual differentiation. NC-CAH presents a simpler and less specific clinical picture. Herein, we present two cases comprising twin girls consulting for diffuse hypertrichosis. Two 5-year-old twin girls were seen at our consultation for increased pilosity on all four limbs, but with no facial pilosity or synophrys, as well as comedones on the chin. Their height and weight and psychomotor development was normal, with no signs of precocious puberty and no clitoral hypertrophy. Levels of 17OH-P and SDHA were high, while FSH and LH were low and IGF1 and TSH were normal. Analysis of gene CYP21 associated with NC-CAH showed mutations p.V281L and IVS2-13A/C>G. Mutation p.V281L was present in the heterozygous state in the older sister and the father, together with moderate hyperpilosity but without hirsutism or acne. No mutations were found in the mother, indicating either de novo appearance of mutation IVS2-13A/C>G in the twins or germline mosaicism in the mother. We diagnosed NC-CAH as the cause of diffuse hypertrichosis in these twins. This disease is not rare, with a prevalence of 1/1000 to 1500 among peoples of European descent. It is often diagnosed late since routine neonatal screening is not performed. In some cases, NC-CAH remains asymptomatic. The appearance of pubic hair at around 5 to 7 years is the initial reason for consultation, particularly with a dermatologist. Hyperandrogenism varies, involving hirsutism, acne, fertility disorders and premature ageing of bone. Cortisol and aldosterone levels are generally normal. The risk of acute adrenal insufficiency is extremely low. Differential diagnosis concerns ovarian or adrenal tumors and

Growth in disorders of adrenal hyperfunction.

PubMed

Magiakou, Maria Alexandra

2004-08-01

This article reviews how growth is affected in disorders of adrenal hyperfunction. Growth is disturbed by adrenal hypersecretion of androgens or cortisol. Adrenal androgens, when in excess, lead to advanced linear growth and skeletal maturation, and prolonged hypercortisolemia leads to the suppression of growth hormone (GH) secretion and inhibition of somatomedin C and other growth factor effects on their target tissues. In virilizing adrenal tumors height is increased at diagnosis, but after surgical cure the final height is usually in the normal range. In congenital adrenal hyperplasia height is usually compromised by advanced skeletal maturation or by suppressed growth, particularly in the first years of life, due to excess glucocorticoid treatment. The final height is reduced in both clinical forms (salt wasting and simple virilizing) and sexes in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Growth impairment is also the hallmark of Cushing syndrome of whatever etiology when it occurs in children and growing adolescents, and the final height of these patients, even after surgical cure, remains compromised. This is apparently due to direct or indirect growth impairment by the hypercortisolism during the disease, followed by inadequate catch-up growth. Although it seems that GH treatment might be beneficial for improving final height both in patients with congenital adrenal hyperplasia who have poor height predictions and in patients with Cushing disease and GH deficiency, a larger number of studies is needed to confirm this suggestion.

[Class I HLA antigens in children from families with congenital adrenal hyperplasia].

PubMed

Turowska-Heydel, D; Pietrzyk, J J; Turowski, G

1995-02-01

Congenital adrenal hyperplasia (CAH) is a syndrome of adrenal steroid metabolism errors with an autosomal inheritance model. The most common metabolic defect is 21-hydroxylase deficiency. It has been demonstrated that 21-hydroxylase genes are in close association with HLA antigens. I HLA antigens were typed in a group of 32 families of children with CAH-type 21-hydroxylase deficiency with salt loss. The antigen frequencies were determined and compared to those of the control population. The studies revealed that two HLA antigens determined by the B Locus, i.e. HLA-B47 and HLA-B61, showed a highly significant frequency (chi 2 corresponding to 404,5259 and 23,7808, respectively). The calculated relative risk and etiologic fraction values were extremely high, distinguishing the population of patients and their parents. The RR value among patients was 427.1 for HLA-B47 and 7.8 for HLA-B61 antigen. Studies on the correlation between HLA and CAH indicate an association with HLA-B47 and HLA-B61 antigens.

Management issues of congenital adrenal hyperplasia during the transition from pediatric to adult care.

PubMed

Choi, Jin-Ho; Yoo, Han-Wook

2017-02-01

Steroid 21-hydroxylase deficiency is the most prevalent form of congenital adrenal hyperplasia (CAH), accounting for approximately 95% of cases. With the advent of newborn screening and hormone replacement therapy, most children with CAH survive into adulthood. Adolescents and adults with CAH experience a number of complications, including short stature, obesity, infertility, tumor, osteoporosis, and reduced quality of life. Transition from pediatric to adult care and management of long-term complications are challenging for both patients and health-care providers. Psychosocial issues frequently affect adherence to glucocorticoid treatment. Therefore, the safe transition of adolescents to adult care requires regular follow-up of patients by a multidisciplinary team including pediatric and adult endocrinologists. The major goals for management of adults with 21-hydroxylase deficiency are to minimize the long-term complications of glucocorticoid therapy, reduce hyperandrogenism, prevent adrenal or testicular adrenal rest tumors, maintain fertility, and improve quality of life. Optimized medical or surgical treatment strategies should be developed through coordinated care, both during transition periods and throughout patients' lifetimes. This review will summarize current knowledge on the management of adults with CAH, and suggested appropriate approaches to the transition from pediatric to adult care.

Noninvasive Prenatal Diagnosis of Congenital Adrenal Hyperplasia.

PubMed

Khattab, Ahmed; Yuen, Tony; Sun, Li; Yau, Mabel; Barhan, Ariella; Zaidi, Mone; Lo, Y M Dennis; New, Maria I

2016-01-01

A major hallmark of classical congenital adrenal hyperplasia (CAH) is genital ambiguity noted at birth in affected females, which leads to psychological and psychosexual issues in adult life. Attempts to correct genital ambiguity through surgical intervention have been partially successful. Fetal hyperandrogenemia and genital ambiguity have been shown to be preventable by prenatal administration of low-dose dexamethasone initiated before the 9th week of gestation. In 7 of 8 at-risk pregnancies, the unaffected fetus is unnecessarily exposed to dexamethasone for weeks until the diagnosis of classical CAH is ruled out by invasive procedures. This therapeutic dilemma calls for early prenatal diagnosis so that dexamethasone treatment can be directed to affected female fetuses only. We describe the utilization of cell-free fetal DNA in mothers carrying at-risk fetuses as early as 6 gestational weeks by targeted massively parallel sequencing of the genomic region including and flanking the CYP21A2 gene. Our highly personalized and innovative approach should permit the diagnosis of CAH before genital development begins, therefore restricting the purposeful administration of dexamethasone to mothers carrying affected females. © 2016 S. Karger AG, Basel.

Confirmation of congenital adrenal hyperplasia by adrenal steroid profiling of filter paper dried blood samples using ultra-performance liquid chromatography-tandem mass spectrometry.

PubMed

Rossi, Claudia; Calton, Lisa; Brown, Heather A; Gillingwater, Scott; Wallace, A Michael; Petrucci, Francesca; Ciavardelli, Domenico; Urbani, Andrea; Sacchetta, Paolo; Morris, Michael

2011-04-01

The specificity of screening for congenital adrenal hyperplasia by direct measurement of 17-hydroxyprogesterone in filter paper dried blood spot samples by immunoassay is low and has a high false-positive rate. In order to reduce the false-positive rate of this test, we developed a rapid, robust, specific confirmatory procedure in which cortisol, 4-androstene-3,17-dione and 17-hydroxyprogesterone were measured simultaneously by ultra-performance liquid chromatography-tandem mass spectrometry. After extraction, samples were analysed by ultra-performance liquid chromatography-tandem mass spectrometry and 17-hydroxyprogesterone was quantified accurately. Other steroids were determined using stable deuterated internal standards. In total, 25 patient blood spot samples and 92 control samples were analysed. The assay was linear for 17-hydroxyprogesterone, with a coefficient of determination >0.997 and imprecision ≤ 6.5%. An upper limit of normal for 17-hydroxyprogester-one of 4.45 nmol/L was established by analysing a cohort of samples from unaffected newborns. In addition, a cut-off of 3.5 for the peak areas ratio (17-hydroxyprogesterone+4-androstene-3,17-dione)/cortisol, allows confirmation of the affected steroidogenic enzyme. A high throughput method for the detection of steroids related to congenital adrenal hyperplasia has been developed, allowing the false-positive rate associated with screening for 17-hydroxyprogesterone by immunoassay to be determined.

[X-linked adrenoleukodystrophy: a report of three cases. The importance of early diagnosis].

PubMed

López Úbeda, Marta; de Arriba Muñoz, Antonio; Ferrer Lozano, Marta; Labarta Aizpún, José I; García Jiménez, María C

2017-10-01

X-linked adrenoleukodystrophy is the most common peroxisomal disorder. This disease is caused by a defect in the ABCD1 gen. Saturated very long chain fatty acids are accumulated in serum, adrenal cortex and central nervous system white matter. The clinical spectrum is characterized by progressive neurological dysfunction and adrenal insufficiency with a devastating prognosis. We report a first case of X-linked adrenoleukodystrophy with fatal evolution which identified two asymptomatic family members and established a preventive treatment. Although there is no definitive cure, we stress the importance of family study and evaluation of the individual in situation of risk to establish an early preventive treatment and to give in each particular situation suitable professional advice. Sociedad Argentina de Pediatría.

[Recommendations for the diagnosis and treatment of classic forms of 21-hydroxylase-deficient congenital adrenal hyperplasia].

PubMed

Rodríguez, Amparo; Ezquieta, Begoña; Labarta, José Igancio; Clemente, María; Espino, Rafael; Rodriguez, Amaia; Escribano, Aranzazu

2017-08-01

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is an autosomal recessive disorder caused by mutations in the CYP21A2 gene. Cortisol and aldosterone synthesis are impaired in the classic forms (adrenal insufficiency and salt-wasting crisis). Females affected are virilised at birth, and are at risk for genital ambiguity. In this article we give recommendations for an early as possible diagnosis and an appropriate and individualised treatment. A patient and family genetic study is essential for the diagnosis of the patient, and allows genetic counselling, as well as a prenatal diagnosis and treatment for future pregnancy. Copyright © 2016 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

Psychological evaluation of treated females with virilizing congenital adrenal hyperplasia.

PubMed

Hurtig, A L; Radhakrishnan, J; Reyes, H M; Rosenthal, I M

1983-12-01

The psychological development of females with congenital adrenal hyperplasia (CAH) has been previously studied by Money, et al, who found that psychological development of sex identity was consistent with sex assignment despite virilizing adrenal hormones and abnormal external genitalia requiring surgical correction. In this study, using a variety of psychological tests, we assessed the sex-dimorphic behavior, body image, cognitive functioning, and sex-role identity of nine patients ranging in age from 13 to 21, all treated with glucocorticoids and surgical correction. Four of the nine showed moderate virilization despite treatment. Psychological measures included the Wechsler Intelligence Scale for Children-Revised (WISC-R), the Bem Sex-Role Inventory, the Draw-A-Person (DAP) and an interview with patient and family. Results indicate that patients fall within the normal expectable range for this developmental period in visual-spatial and verbal cognitive functioning, in sex-role identity, and in social interpersonal early behaviors. In two areas of functioning these patients demonstrated some variance from the norms, specifically in sexual identity and early activity levels. This suggests that sexual identity and physical activity are most prone to hormonal and psychological impact but that cognition and sex-role identity are not affected. Future studies of this sample will look at personality dimensions such as ego functioning, defense and affect to consider the impact of body image concerns and conflicts.

Mapping X-linked ophthalmic diseases. IV. Provisional assignment of the locus for X-linked congenital cataracts and microcornea (the Nance-Horan syndrome) to Xp22.2-p22.3.

PubMed

Lewis, R A; Nussbaum, R L; Stambolian, D

1990-01-01

The Nance-Horan syndrome (NHS) is an infrequent X-linked disorder typified by dense congenital central cataracts, microcornea, anteverted and simplex pinnae, brachymetacarpalia, and numerous dental anomalies. The regional location of the genetic mutation causing NHS is unknown. The authors applied the modern molecular techniques of analysis of restriction fragment length polymorphisms to five multigenerational kindreds in which NHS segregated. Provisional linkage is established to two DNA markers--DXS143 at Xp22.3-p22.2 and DXS43 at Xp22.2. Regional localization of NHS will provide potential antenatal diagnosis in families at risk for the disease and will enhance understanding of the multifaceted genetic defects.

Linkage analysis in a Dutch family with X-linked recessive congenital stationary night blindness (XL-CSNB).

PubMed

Berger, W; van Duijnhoven, G; Pinckers, A; Smits, A; Ropers, H H; Cremers, F

1995-01-01

Linkage analysis has been performed in a large Dutch pedigree with X-linked recessive congenital stationary night blindness (CSNB) by utilizing 16 DNA markers from the proximal short arm of the human X chromosome (Xp21.1-11.2). Thirteen polymorphic markers are at least partially informative and have enabled pairwise and multipoint linkage analysis. For three loci, i.e. DXS228, the monoamine oxidase B gene and the Norrie disease gene (NDG), multipoint linkage studies have yielded maximum lod scores of > 3.0 at a recombination fraction of zero. Analysis of recombination events has enabled us to rule out the possibility that the underlying defect in this family is allelic to RP3; the gene defect could also be excluded from the proximal part of the region known to carry RP2. Linkage data are consistent with a possible involvement of the NDG but mutations in the open reading frame of this gene have not been found.

Congenital Adrenal Hyperplasia: Review from a Surgeon’s Perspective in the Beginning of the Twenty-First Century

PubMed Central

Piaggio, Lisandro Ariel

2013-01-01

Congenital adrenal hyperplasia (CAH) most commonly due to 21-hydroxylase deficiency is the most common type of disorder of sex development. This review will focus on CAH addressing historical and current surgical techniques with their anatomical foundations, with special attention to long-term results and outcomes on sexual function, patient satisfaction, patient attitude toward surgery, and ongoing controversies in management of these patients. PMID:24400298

JS-X syndrome: A multiple congenital malformation with vocal cord paralysis, ear deformity, hearing loss, shoulder musculature underdevelopment, and X-linked recessive inheritance.

PubMed

Hoeve, Hans L J; Brooks, Alice S; Smit, Liesbeth S

2015-07-01

We report on a family with a not earlier described multiple congenital malformation. Several male family members suffer from laryngeal obstruction caused by bilateral vocal cord paralysis, outer and middle ear deformity with conductive and sensorineural hearing loss, facial dysmorphisms, and underdeveloped shoulder musculature. The affected female members only have middle ear deformity and hearing loss. The pedigree is suggestive of an X-linked recessive inheritance pattern. SNP-array revealed a deletion and duplication on Xq28 in the affected family members. A possible aetiology is a neurocristopathy with most symptoms expressed in structures derived from branchial arches. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

A Phase 2 Study of Continuous Subcutaneous Hydrocortisone Infusion in Adults With Congenital Adrenal Hyperplasia.

PubMed

Nella, Aikaterini A; Mallappa, Ashwini; Perritt, Ashley F; Gounden, Verena; Kumar, Parag; Sinaii, Ninet; Daley, Lori-Ann; Ling, Alexander; Liu, Chia-Ying; Soldin, Steven J; Merke, Deborah P

2016-12-01

Classic congenital adrenal hyperplasia (CAH) management remains challenging, given that supraphysiologic glucocorticoid doses are often needed to optimally suppress the ACTH-driven adrenal androgen overproduction. This study sought to approximate physiologic cortisol secretion via continuous subcutaneous hydrocortisone infusion (CSHI) and evaluate the safety and efficacy of CSHI in patients with difficult-to-treat CAH. Eight adult patients with classic CAH participated in a single-center open-label phase I-II study comparing CSHI to conventional oral glucocorticoid treatment. All patients had elevated adrenal steroids and one or more comorbidities at study entry. Assessment while receiving conventional therapy at baseline and 6 months following CSHI included: 24-hour hormonal sampling, metabolic and radiologic evaluation, health-related quality-of-life (HRQoL), and fatigue questionnaires. The ability of CSHI to approximate physiologic cortisol secretion and the percent of patients with 0700-hour 17-hydroxyprogesterone (17-OHP) ≤1200 ng/dL was measured. CSHI approximated physiologic cortisol secretion. Compared with baseline, 6 months of CSHI resulted in decreased 0700-hour and 24-hour area under the curve 17-OHP, androstenedione, ACTH, and progesterone, increased osteocalcin, c-telopeptide and lean mass, and improved HRQoL (and SF-36 Vitality Score), and fatigue. One of three amenorrheic women resumed menses. One man had reduction of testicular adrenal rest tissue. CSHI is a safe and well-tolerated modality of cortisol replacement that effectively approximates physiologic cortisol secretion in patients with classic CAH poorly controlled on conventional therapy. Improved adrenal steroid control and positive effects on HRQoL suggest that CSHI should be considered a treatment option for classic CAH. The long-term effect on established comorbidities requires further study.

Congenital primary adrenal insufficiency and selective aldosterone defects presenting as salt-wasting in infancy: a single center 10-year experience.

PubMed

Bizzarri, Carla; Olivini, Nicole; Pedicelli, Stefania; Marini, Romana; Giannone, Germana; Cambiaso, Paola; Cappa, Marco

2016-08-02

Salt-wasting represents a relatively common cause of emergency admission in infants and may result in life-threatening complications. Neonatal kidneys show low glomerular filtration rate and immaturity of the distal nephron leading to reduced ability to concentrate urine. A retrospective chart review was conducted for infants hospitalized in a single Institution from 1(st) January 2006 to 31(st) December 2015. The selection criterion was represented by the referral to the Endocrinology Unit for hyponatremia (serum sodium <130 mEq/L) of suspected endocrine origin at admission. Fifty-one infants were identified. In nine infants (17.6 %) hyponatremia was related to unrecognized chronic gastrointestinal or renal salt losses or reduced sodium intake. In 10 infants (19.6 %) hyponatremia was related to central nervous system diseases. In 19 patients (37.3 %) the final diagnosis was congenital adrenal hyperplasia (CAH). CAH was related to 21-hydroxylase deficiency in 18 patients, and to 3β-Hydroxysteroid dehydrogenase (3βHSD) deficiency in one patient. Thirteen patients (25.5 %) were affected by different non-CAH salt-wasting forms of adrenal origin. Four familial cases of X-linked adrenal hypoplasia congenita due to NROB1 gene mutation were identified. Two unrelated girls showed aldosterone synthase deficiency due to mutation of the CYP11B2 gene. Two unrelated infants were affected by familial glucocorticoid deficiency due to MC2R gene mutations. One girl showed pseudohypoaldosteronism related to mutations of the SCNN1G gene encoding for the epithelial sodium channel. Transient pseudohypoaldosteronism was identified in two patients with renal malformations. In two infants the genetic aetiology was not identified. Emergency management of infants presenting with salt wasting requires correction of water losses and treatment of electrolyte imbalances. Nevertheless, the differential diagnosis may be difficult in emergency settings, and sometimes hospitalized infants

Woman with virilizing congenital adrenal hyperplasia and Leydig cell tumor of the ovary.

PubMed

Fernández-García Salazar, Rosario; Muñoz-Darias, Carmen; Haro-Mora, Juan Jesús; Almaraz, M Cruz; Audí, Laura; Martínez-Tudela, Juana; Yahyaoui, Raquel; Esteva, Isabel

2014-08-01

We report the case of a 36-year-old woman with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, and corticosteroid replacement therapy since birth. She manifested persistent virilization and high testosterone levels that were attributed to nonadherence to medical treatment. The patient was referred to our gender unit for genitoplastic surgery. We recommended the patient for left oophorectomy after detecting an ovarian mass. Pathologic findings confirmed an ovarian hilus cell tumor. Testosterone levels fell back to normal and masculinization disappeared but ACTH remained elevated. This case represents a very rare type of primary ovarian tumor that must be considered in persistent virilizing symptoms in women with CAH.

Prenatal Androgens and Gender-Typed Behavior: A Study of Girls with Mild and Severe Forms of Congenital Adrenal Hyperplasia.

ERIC Educational Resources Information Center

Servin, Anna; Nordenstrom, Anna; Larsson, Agne; Bohlin, Gunilla

2003-01-01

Examined gender-typed behavior and interests in 2- to 10-year-old girls with congenital adrenal hyperplasia (CAH) and in unaffected girls matched for age. Found that, compared with unaffected girls, girls with CAH were more interested in masculine toys and less interested in feminine toys and were more likely to report having male playmates and…

Allelic variation of the FRMD7 gene in congenital idiopathic nystagmus.

PubMed

Self, James E; Shawkat, Fatima; Malpas, Crispin T; Thomas, N Simon; Harris, Christopher M; Hodgkins, Peter R; Chen, Xiaoli; Trump, Dorothy; Lotery, Andrew J

2007-09-01

To perform a genotype-phenotype correlation study in an X-linked congenital idiopathic nystagmus pedigree (pedigree 1) and to assess the allelic variance of the FRMD7 gene in congenital idiopathic nystagmus. Subjects from pedigree 1 underwent detailed clinical examination including nystagmology. Screening of FRMD7 was undertaken in pedigree 1 and in 37 other congenital idiopathic nystagmus probands and controls. Direct sequencing confirmed sequence changes. X-inactivation studies were performed in pedigree 1. The nystagmus phenotype was extremely variable in pedigree 1. We identified 2 FRMD7 mutations. However, 80% of X-linked families and 96% of simplex cases showed no mutations. X-inactivation studies demonstrated no clear causal link between skewing and variable penetrance. We confirm profound phenotypic variation in X-linked congenital idiopathic nystagmus pedigrees. We demonstrate that other congenital nystagmus genes exist besides FRMD7. We show that the role of X inactivation in variable penetrance is unclear in congenital idiopathic nystagmus. Clinical Relevance We demonstrate that phenotypic variation of nystagmus occurs in families with FRMD7 mutations. While FRMD7 mutations may be found in some cases of X-linked congenital idiopathic nystagmus, the diagnostic yield is low. X-inactivation assays are unhelpful as a test for carrier status for this disease.

A Phase 2 Study of Continuous Subcutaneous Hydrocortisone Infusion in Adults With Congenital Adrenal Hyperplasia

PubMed Central

Mallappa, Ashwini; Perritt, Ashley F.; Gounden, Verena; Kumar, Parag; Sinaii, Ninet; Daley, Lori-Ann; Ling, Alexander; Liu, Chia-Ying; Soldin, Steven J.; Merke, Deborah P.

2016-01-01

Context: Classic congenital adrenal hyperplasia (CAH) management remains challenging, given that supraphysiologic glucocorticoid doses are often needed to optimally suppress the ACTH-driven adrenal androgen overproduction. Objective: This study sought to approximate physiologic cortisol secretion via continuous subcutaneous hydrocortisone infusion (CSHI) and evaluate the safety and efficacy of CSHI in patients with difficult-to-treat CAH. Design: Eight adult patients with classic CAH participated in a single-center open-label phase I–II study comparing CSHI to conventional oral glucocorticoid treatment. All patients had elevated adrenal steroids and one or more comorbidities at study entry. Assessment while receiving conventional therapy at baseline and 6 months following CSHI included: 24-hour hormonal sampling, metabolic and radiologic evaluation, health-related quality-of-life (HRQoL), and fatigue questionnaires. Main Outcome Measures: The ability of CSHI to approximate physiologic cortisol secretion and the percent of patients with 0700-hour 17-hydroxyprogesterone (17-OHP) ≤1200 ng/dL was measured. Results: CSHI approximated physiologic cortisol secretion. Compared with baseline, 6 months of CSHI resulted in decreased 0700-hour and 24-hour area under the curve 17-OHP, androstenedione, ACTH, and progesterone, increased osteocalcin, c-telopeptide and lean mass, and improved HRQoL (and SF-36 Vitality Score), and fatigue. One of three amenorrheic women resumed menses. One man had reduction of testicular adrenal rest tissue. Conclusions: CSHI is a safe and well-tolerated modality of cortisol replacement that effectively approximates physiologic cortisol secretion in patients with classic CAH poorly controlled on conventional therapy. Improved adrenal steroid control and positive effects on HRQoL suggest that CSHI should be considered a treatment option for classic CAH. The long-term effect on established comorbidities requires further study. PMID:27680873

Prenatal Hormones and Postnatal Socialization by Parents as Determinants of Male-Typical Toy Play in Girls With Congenital Adrenal Hyperplasia

ERIC Educational Resources Information Center

Pasterski, Vickie L.; Geffner, Mitchell E.; Brain, Caroline; Hindmarsh, Peter; Brook, Charles; Hines, Melissa

2005-01-01

Toy choices of 3- to 10-year-old children with congenital adrenal hyperplasia (CAH) and of their unaffected siblings were assessed. Also assessed was parental encouragement of sex-typed toy play. Girls with CAH displayed more male-typical toy choices than did their unaffected sisters, whereas boys with and without CAH did not differ. Mothers and…

A family study of congenital X linked sideroblastic anaemia.

PubMed Central

Holmes, J; May, A; Geddes, D; Jacobs, A

1990-01-01

We report on the cytogenetic findings in a family study of pyridoxine responsive, X linked sideroblastic anaemia. An increase in the number of X chromosomes was observed in a small proportion of metaphases prepared from five female members, but these findings did not strictly correlate with the carrier status of the condition. No consistent cytogenetic abnormality could be identified or associated with this rare familial condition. The diagnosis and counselling of carriers of this condition is discussed. Images PMID:2308152

Ovarian carcinoma in a 14-year-old with classical salt-wasting congenital adrenal hyperplasia and bilateral adrenalectomy.

PubMed

Pina, Christian; Khattab, Ahmed; Katzman, Philip; Bruckner, Lauren; Andolina, Jeffrey; New, Maria; Yau, Mabel

2015-05-01

A 14-year-old female with classical congenital adrenal hyperplasia because of 21-hydroxylase deficiency underwent bilateral adrenalectomy at 6 years of age as a result of poor hormonal control. Because the patient was adrenalectomized, extra adrenal androgen production was suspected. Imaging studies including pelvic ultrasound and pelvic magnetic resonance imaging (MRI) were obtained to evaluate for adrenal rest tumors of the ovaries. Abdominal MRI was obtained to evaluate for residual adrenal tissue. A cystic lesion arising from her right ovary suspicious for ovarian neoplasm was noted on pelvic MRI. Right salpingo-oophorectomy was performed and histopathological examination revealed ovarian serous adenocarcinoma, low-grade, and well-differentiated. Tumor marker CA-125 was elevated and additional ovarian cancer staging workup confirmed stage IIIC due to one lymph node positive for carcinoma. The patient then developed a large left ovarian cyst, which led to a complete total abdominal hysterectomy and removal of the left ovary and fallopian tube. Pathology confirmed ovarian serous adenocarcinoma with microscopic focus of carcinoma in the left ovary. After numerous complications, the patient responded well to chemotherapy, CA-125 levels fell and no evidence of carcinoma was observed on subsequent imaging. To our knowledge, this is the first reported case of an ovarian serous adenocarcinoma in a patient with CAH. Although rare, we propose that the ovaries were the origin of androgen production and not residual adrenal tissue. The relationship between CAH and ovarian carcinomas has yet to be established, but further evaluation is needed given the poor survival rate of high-grade serous ovarian carcinoma.

Reconstructive surgery for females with congenital adrenal hyperplasia due to 21-hydroxylase deficiency: a review from the Prince of Wales Hospital.

PubMed

Houben, C H; Tsui, S Y; Mou, J W; Chan, K W; Tam, Y H; Lee, K H

2014-12-01

To present the results of feminising genitoplasty done in female patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Case series. A tertiary referral centre in Hong Kong. Female patients with congenital adrenal hyperplasia undergoing corrective surgery for virilisation between 1993 and 2012. The operative result was judged with a scoring system (1-3) for four areas: appearance of clitoris, labia and vagina, plus requirement for revision surgery. A total of 23 female patients with congenital adrenal hyperplasia with a median age of 17.5 (range, 1.5-33.8) years were identified. Of these individuals, 17 presented in the neonatal period and early infancy, of which four had an additional salt-losing crisis. Six patients-including four migrants from mainland China-were late presenters at a median age of 2 (range, 0.5-14) years. Twenty-two patients had corrective surgery at a median age of 2 (range, 1-14) years. Clitoral reduction was performed in all, and further surgery in 21 patients. The additional surgery was flap vaginoplasty in 10 patients, a modified Passerini procedure in six, and a labial reconstruction in five; one patient with prominent clitoris was for observation only. Minor revision surgery (eg mucosal trimming) was required in three patients; a revision vaginoplasty was done in one individual. Of the 23 patients, 18 (78%) with a median age of 20 (range, 9.3-33.8) years participated in the outcome evaluation: a 'good' outcome (4 points) was seen in 12 patients and a 'satisfactory' (5-9 points) result in five patients. Nearly three quarters of our cohort (n=17) presented with classic virilising form of 21-hydroxylase deficiency. Only four (25%) patients experienced a salt-losing crisis. Female gender assignment at birth was maintained for all individuals in this group. 'Good' and 'satisfactory' outcomes of surgery were reported in nearly all participants.

STAR splicing mutations cause the severe phenotype of lipoid congenital adrenal hyperplasia: insights from a novel splice mutation and review of reported cases.

PubMed

Camats, Núria; Pandey, Amit V; Fernández-Cancio, Mónica; Fernández, Juan M; Ortega, Ana M; Udhane, Sameer; Andaluz, Pilar; Audí, Laura; Flück, Christa E

2014-02-01

The steroidogenic acute regulatory protein (StAR) transports cholesterol to the mitochondria for steroidogenesis. Loss of StAR function causes lipoid congenital adrenal hyperplasia (LCAH) which is characterized by impaired synthesis of adrenal and gonadal steroids causing adrenal insufficiency, 46,XY disorder of sex development (DSD) and failure of pubertal development. Partial loss of StAR activity may cause adrenal insufficiency only. A newborn girl was admitted for mild dehydration, hyponatremia, hyperkalemia and hypoglycaemia and had normal external female genitalia without hyperpigmentation. Plasma cortisol, 17OH-progesterone, DHEA-S, androstendione and aldosterone were low, while ACTH and plasma renin activity were elevated, consistent with the diagnosis of primary adrenal insufficiency. Imaging showed normal adrenals, and cytogenetics revealed a 46,XX karyotype. She was treated with fluids, hydrocortisone and fludrocortisone. Genetic studies revealed a novel homozygous STAR mutation in the 3' acceptor splice site of intron 4, c.466-1G>A (IVS4-1G>A). To test whether this mutation would affect splicing, we performed a minigene experiment with a plasmid construct containing wild-type or mutant StAR gDNA of exons-introns 4-6 in COS-1 cells. The splicing was assessed on total RNA using RT-PCR for STAR cDNAs. The mutant STAR minigene skipped exon 5 completely and changed the reading frame. Thus, it is predicted to produce an aberrant and shorter protein (p.V156GfsX19). Computational analysis revealed that this mutant protein lacks wild-type exons 5-7 which are essential for StAR-cholesterol interaction. STAR c.466-1A skips exon 5 and causes a dramatic change in the C-terminal sequence of the protein, which is essential for StAR-cholesterol interaction. This splicing mutation is a loss-of-function mutation explaining the severe phenotype of our patient. Thus far, all reported splicing mutations of STAR cause a severe impairment of protein function and phenotype. �

Genotype-Phenotype Correlation in 153 Adult Patients With Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency: Analysis of the United Kingdom Congenital Adrenal Hyperplasia Adult Study Executive (CaHASE) Cohort

PubMed Central

Krone, Nils; Rose, Ian T.; Willis, Debbie S.; Hodson, James; Wild, Sarah H.; Doherty, Emma J.; Hahner, Stefanie; Parajes, Silvia; Stimson, Roland H.; Han, Thang S.; Carroll, Paul V.; Conway, Gerry S.; Walker, Brian R.; MacDonald, Fiona; Arlt, Wiebke

2013-01-01

Context: In congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, a strong genotype-phenotype correlation exists in childhood. However, similar data in adults are lacking. Objective: The objective of the study was to test whether the severity of disease-causing CYP21A2 mutations influences the treatment and health status in adults with CAH. Research Design and Methods: We analyzed the genotype in correlation with treatment and health status in 153 adults with CAH from the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive cohort. Results: CYP21A2 mutations were distributed similarly to previously reported case series. In 7 patients a mutation was identified on only 1 allele. Novel mutations were detected on 1.7% of alleles (5 of 306). Rare mutations were found on 2.3% of alleles (7 of 306). For further analysis, patients were categorized into CYP21A2 mutation groups according to predicted residual enzyme function: null (n = 34), A (n = 42), B (n = 36), C (n = 34), and D (n = 7). Daily glucocorticoid dose was highest in group null and lowest in group C. Fludrocortisone was used more frequently in patients with more severe genotypes. Except for lower female height in group B, no statistically significant associations between genotype and clinical parameters were found. Androgens, blood pressure, lipids, blood glucose, and homeostasis model assessment of insulin resistance were not different between groups. Subjective health status was similarly impaired across groups. Conclusions: In adults with classic CAH and women with nonclassic CAH, there was a weak association between genotype and treatment, but health outcomes were not associated with genotype. The underrepresentation of males with nonclassic CAH may reflect that milder genotypes result in a milder condition that is neither diagnosed nor followed up in adulthood. Overall, our results suggest that the impaired health status of adults with CAH coming to medical attention is

A three-year follow-up of congenital adrenal hyperplasia newborn screening.

PubMed

Pezzuti, Isabela L; Barra, Cristina B; Mantovani, Rafael M; Januário, José N; Silva, Ivani N

2014-01-01

congenital adrenal hyperplasia (CAH) newborn screening can prevent neonatal mortality in children with the salt-wasting form of the disease and prevent incorrect gender assignments, which can occur in females. However, the occurrence of false-positive results in preterm or low-birth-weight newborns creates some diagnostic difficulties, with consequent therapeutic implications. This study aimed to report the results of a pilot project for neonatal CAH screening conducted in the state of Minas Gerais, Brazil from 09/2007 to 05/2008 with a three-year follow-up. dried blood specimens were collected on filter paper cards three to seven days after birth of all newborns in the period. Samples were analyzed for 17-hydroxyprogesterone using an enzyme-linked immunosorbent assay (ELISA). a total of 159,415 children were screened. The apparent incidence of the classic variant of the disease was 1:9,963, based on initial diagnoses following newborn screening. During the follow-up period, eight of 16 children initially diagnosed with CAH were reclassified as unaffected, resulting in a revised incidence of 1:19,927. The false-positive rate was 0.31%, and the positive predictive value was 2.1%. Sensitivity and specificity were 100% and 99.7%, respectively. newborn screening is an important public health policy in developing countries such as Brazil, where CAH remains underdiagnosed. It has great potential to identify children with the disease who otherwise cannot be diagnosed earlier. Long-term follow-up and monitoring of all children with positive screening results are crucial to ensure a correct diagnosis and to calculate a reliable incidence ratio of the disease. Copyright © 2014 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

Growth and development in children with classic congenital adrenal hyperplasia.

PubMed

Bonfig, Walter

2017-02-01

Final height outcome in classic congenital adrenal hyperplasia (CAH) has been of interest for many years. With analysis of growth patterns and used glucocorticoid regimens, enhanced treatment strategies have been developed and are still under development. Most of the current reports on final height outcome are confirmative of previous results. Final height data is still reported in cohorts that were diagnosed clinically and not by newborn screening. Clinical diagnosis of CAH leads to delayed diagnosis especially of simple virilizing CAH with significantly advanced bone age resulting in early pubertal development and reduced final height. In contrast salt-wasting CAH is diagnosed at an earlier stage in most cases resulting in better final height outcome in some cohorts. Nevertheless, final height outcome in patients with CAH treated with glucocorticoids is lower than the population norm and also at the lower end of genetic potential. Achievement of regular adult height is still a challenge with conventional glucocorticoid treatment in patients with CAH, which is why new hydrocortisone formulations and new treatment options for CAH are underway.

Manifestations of X-linked congenital stationary night blindness in three daughters of an affected male: Demonstration of homozygosity

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

Bech-Hansen, N.T.; Pearce, W.G.

1993-01-01

X-linked congenital stationary night blindness (CSNB1) is a hereditary retinal disorder in which clinical features in affected males usually include myopia, nystagmus, and impaired visual acuity. Electroretinography demonstrates a marked reduction in b-wave amplitude. In the study of a large Mennonite family with CSNB1, three of five sisters in one sibship were found to have manifestations of CSNB1. All the sons of these three sisters were affected. Each of the two nonmanifesting sisters had at least one unaffected son. Analysis of Xp markers in the region Xp21.1-Xp11.22 showed that the two sisters who were unaffected had inherited the same maternalmore » X chromosome (i.e., M2). Two of the daughters who manifested with CSNB had inherited the other maternal X chromosome (M1). The third manifesting sister inherited a recombinant X chromosome with a crossover between TIMP and DXS255, which suggests that the CSNB1 locus lies proximal to TIMP. One of the affected daughters' sons had inherited the maternal M1 X chromosome, a finding consistent with that chromosome carrying a mutant CSNB gene; the other affected sons inherited the grandfather's X chromosome (i.e., P). Molecular analysis of DNA from three sisters with manifestations of CSNB is consistent with their being homozygous at the CSNB1 locus and with their mother being a carrier of CSNB1. 23 refs., 4 figs., 3 tabs.« less

News about the genetics of congenital primary adrenal insufficiency.

PubMed

Roucher-Boulez, Florence; Mallet-Motak, Delphine; Tardy-Guidollet, Véronique; Menassa, Rita; Goursaud, Claire; Plotton, Ingrid; Morel, Yves

2018-04-13

Primary adrenal insufficiency (PAI) is characterized by impaired production of steroid hormones due to an adrenal cortex defect. This condition incurs a risk of acute insufficiency which may be life-threatening. Today, 80% of pediatric forms of PAI have a genetic origin but 5% have no clear genetic support. Recently discovered mutations in genes relating to oxidative stress have opened the way to research on genes unrelated to the adrenal gland. Identification of causal mutations in a gene responsible for PAI allows genetic counseling, guidance of follow-up and prevention of complications. This is particularly true for stress oxidative anomalies, as extra-adrenal manifestations may occur due to the sensitivity to oxidative stress of other organs such as the heart, thyroid, liver, kidney and pancreas. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Gender reversal in 46XX congenital virilizing adrenal hyperplasia.

PubMed

Sripathi, V; Ahmed, S; Sakati, N; al-Ashwal, A

1997-05-01

To review the results of gender reversal in six patients with 46XX congenital virilizing adrenal hyperplasia (CVAH). Fifty-one patients with 46XX CVAH were seen in an 8 year period; 45 were managed by conventional feminizing genitoplasty, but six underwent gender reversal and were managed as males. The clinical decision for gender reversal was made after appropriate counselling and was based primarily on parental choice, this being influenced significantly by a delayed diagnosis in four patients. Surgical management consisted of gonadectomy, excision of Müllerian structures and staged hypospadias repair/ chordee correction in four patients, and circumcision in two completely masculinized children. All six boys are well adjusted to their gender of rearing, with ages ranging from 3 years to 16.5 years (mean 8.5) at the time of review. Two children have normal penises and four have a satisfactory result after two-stage repair of hypospadias/chordee. Most patients with 46XX CVAH are preferably raised as females and require a feminizing genitoplasty. However, the clinical decision may be influenced by many factors, including delay in diagnosis, social bias and the premium on male rearing in certain communities. When male rearing is chosen, early gonadectomy and excision of Müllerian structures, together with staged hypospadias repair, gives satisfactory results.

X-linked cataract and Nance-Horan syndrome are allelic disorders.

PubMed

Coccia, Margherita; Brooks, Simon P; Webb, Tom R; Christodoulou, Katja; Wozniak, Izabella O; Murday, Victoria; Balicki, Martha; Yee, Harris A; Wangensteen, Teresia; Riise, Ruth; Saggar, Anand K; Park, Soo-Mi; Kanuga, Naheed; Francis, Peter J; Maher, Eamonn R; Moore, Anthony T; Russell-Eggitt, Isabelle M; Hardcastle, Alison J

2009-07-15

Nance-Horan syndrome (NHS) is an X-linked developmental disorder characterized by congenital cataract, dental anomalies, facial dysmorphism and, in some cases, mental retardation. Protein truncation mutations in a novel gene (NHS) have been identified in patients with this syndrome. We previously mapped X-linked congenital cataract (CXN) in one family to an interval on chromosome Xp22.13 which encompasses the NHS locus; however, no mutations were identified in the NHS gene. In this study, we show that NHS and X-linked cataract are allelic diseases. Two CXN families, which were negative for mutations in the NHS gene, were further analysed using array comparative genomic hybridization. CXN was found to be caused by novel copy number variations: a complex duplication-triplication re-arrangement and an intragenic deletion, predicted to result in altered transcriptional regulation of the NHS gene. Furthermore, we also describe the clinical and molecular analysis of seven families diagnosed with NHS, identifying four novel protein truncation mutations and a novel large deletion encompassing the majority of the NHS gene, all leading to no functional protein. We therefore show that different mechanisms, aberrant transcription of the NHS gene or no functional NHS protein, lead to different diseases. Our data highlight the importance of copy number variation and non-recurrent re-arrangements leading to different severity of disease and describe the potential mechanisms involved.

X-linked cataract and Nance-Horan syndrome are allelic disorders

PubMed Central

Coccia, Margherita; Brooks, Simon P.; Webb, Tom R.; Christodoulou, Katja; Wozniak, Izabella O.; Murday, Victoria; Balicki, Martha; Yee, Harris A.; Wangensteen, Teresia; Riise, Ruth; Saggar, Anand K.; Park, Soo-Mi; Kanuga, Naheed; Francis, Peter J.; Maher, Eamonn R.; Moore, Anthony T.; Russell-Eggitt, Isabelle M.; Hardcastle, Alison J.

2009-01-01

Nance-Horan syndrome (NHS) is an X-linked developmental disorder characterized by congenital cataract, dental anomalies, facial dysmorphism and, in some cases, mental retardation. Protein truncation mutations in a novel gene (NHS) have been identified in patients with this syndrome. We previously mapped X-linked congenital cataract (CXN) in one family to an interval on chromosome Xp22.13 which encompasses the NHS locus; however, no mutations were identified in the NHS gene. In this study, we show that NHS and X-linked cataract are allelic diseases. Two CXN families, which were negative for mutations in the NHS gene, were further analysed using array comparative genomic hybridization. CXN was found to be caused by novel copy number variations: a complex duplication–triplication re-arrangement and an intragenic deletion, predicted to result in altered transcriptional regulation of the NHS gene. Furthermore, we also describe the clinical and molecular analysis of seven families diagnosed with NHS, identifying four novel protein truncation mutations and a novel large deletion encompassing the majority of the NHS gene, all leading to no functional protein. We therefore show that different mechanisms, aberrant transcription of the NHS gene or no functional NHS protein, lead to different diseases. Our data highlight the importance of copy number variation and non-recurrent re-arrangements leading to different severity of disease and describe the potential mechanisms involved. PMID:19414485

Molecular and clinical studies of X-linked deafness among Pakistani families.

PubMed

Waryah, Ali M; Ahmed, Zubair M; Bhinder, Munir A; Binder, Munir A; Choo, Daniel I; Sisk, Robert A; Shahzad, Mohsin; Khan, Shaheen N; Friedman, Thomas B; Riazuddin, Sheikh; Riazuddin, Saima

2011-07-01

There are 68 sex-linked syndromes that include hearing loss as one feature and five sex-linked nonsyndromic deafness loci listed in the OMIM database. The possibility of additional such sex-linked loci was explored by ascertaining three unrelated Pakistani families (PKDF536, PKDF1132 and PKDF740) segregating X-linked recessive deafness. Sequence analysis of POU3F4 (DFN3) in affected members of families PKDF536 and PKDF1132 revealed two novel nonsense mutations, p.Q136X and p.W114X, respectively. Family PKDF740 is segregating congenital blindness, mild-to-profound progressive hearing loss that is characteristic of Norrie disease (MIM#310600). Sequence analysis of NDP among affected members of this family revealed a novel single nucleotide deletion c.49delG causing a frameshift and premature truncation (p.V17fsX1) of the encoded protein. These mutations were not found in 150 normal DNA samples. Identification of pathogenic alleles causing X-linked recessive deafness will improve molecular diagnosis, genetic counseling and molecular epidemiology of hearing loss among Pakistanis.

Molecular and Clinical Studies of X-linked Deafness Among Pakistani Families

PubMed Central

Waryah, Ali M.; Ahmed, Zubair M.; Choo, Daniel I.; Sisk, Robert A.; Binder, Munir A.; Shahzad, Mohsin; Khan, Shaheen N.; Friedman, Thomas B.; Riazuddin, Sheikh; Riazuddin, Saima

2011-01-01

There are 68 sex-linked syndromes that include hearing loss as one feature and five sex-linked nonsyndromic deafness loci listed in the OMIM database. The possibility of additional such sex-linked loci was explored by ascertaining three unrelated Pakistani families (PKDF536, PKDF1132, PKDF740) segregating X-linked recessive deafness. Sequence analysis of POU3F4 (DFN3) in affected members of families PKDF536 and PKDF1132 revealed two novel nonsense mutations, p.Q136X and p.W114X, respectively. Family PKDF740 is segregating congenital blindness, mild to profound progressive hearing loss that is characteristic of Norrie disease (MIM#310600). Sequence analysis of NDP among affected members of this family revealed a novel single nucleotide deletion c.49delG causing a frameshift and premature truncation (p.V17fsX1) of the encoded protein. These mutations were not found in 150 normal DNA samples. Identification of pathogenic alleles causing X-linked recessive deafness will improve molecular diagnosis, genetic counseling, and molecular epidemiology of hearing loss among Pakistanis. PMID:21633365

A unique haplotype of RCCX copy number variation: from the clinics of congenital adrenal hyperplasia to evolutionary genetics

PubMed Central

Doleschall, Márton; Luczay, Andrea; Koncz, Klára; Hadzsiev, Kinga; Erhardt, Éva; Szilágyi, Ágnes; Doleschall, Zoltán; Németh, Krisztina; Török, Dóra; Prohászka, Zoltán; Gereben, Balázs; Fekete, György; Gláz, Edit; Igaz, Péter; Korbonits, Márta; Tóth, Miklós; Rácz, Károly; Patócs, Attila

2017-01-01

There is a difficulty in the molecular diagnosis of congenital adrenal hyperplasia (CAH) due to the c.955C>T (p.(Q319*), formerly Q318X, rs7755898) variant of the CYP21A2 gene. Therefore, a systematic assessment of the genetic and evolutionary relationships between c.955C>T, CYP21A2 haplotypes and the RCCX copy number variation (CNV) structures, which harbor CYP21A2, was performed. In total, 389 unrelated Hungarian individuals with European ancestry (164 healthy subjects, 125 patients with non-functioning adrenal incidentaloma and 100 patients with classical CAH) as well as 34 adrenocortical tumor specimens were studied using a set of experimental and bioinformatic methods. A unique, moderately frequent (2%) haplotypic RCCX CNV structure with three repeated segments, abbreviated to LBSASB, harboring a CYP21A2 with a c.955C>T variant in the 3′-segment, and a second CYP21A2 with a specific c.*12C>T (rs150697472) variant in the middle segment occurred in all c.955C>T carriers with normal steroid levels. The second CYP21A2 was free of CAH-causing mutations and produced mRNA in the adrenal gland, confirming its functionality and ability to rescue the carriers from CAH. Neither LBSASB nor c.*12C>T occurred in classical CAH patients. However, CAH-causing CYP21A2 haplotypes with c.955C>T could be derived from the 3′-segment of LBSASB after the loss of functional CYP21A2 from the middle segment. The c.*12C>T indicated a functional CYP21A2 and could distinguish between non-pathogenic and pathogenic genomic contexts of the c.955C>T variant in the studied European population. Therefore, c.*12C>T may be suitable as a marker to avoid this genetic confound and improve the diagnosis of CAH. PMID:28401898

A unique haplotype of RCCX copy number variation: from the clinics of congenital adrenal hyperplasia to evolutionary genetics.

PubMed

Doleschall, Márton; Luczay, Andrea; Koncz, Klára; Hadzsiev, Kinga; Erhardt, Éva; Szilágyi, Ágnes; Doleschall, Zoltán; Németh, Krisztina; Török, Dóra; Prohászka, Zoltán; Gereben, Balázs; Fekete, György; Gláz, Edit; Igaz, Péter; Korbonits, Márta; Tóth, Miklós; Rácz, Károly; Patócs, Attila

2017-06-01

There is a difficulty in the molecular diagnosis of congenital adrenal hyperplasia (CAH) due to the c.955C>T (p.(Q319*), formerly Q318X, rs7755898) variant of the CYP21A2 gene. Therefore, a systematic assessment of the genetic and evolutionary relationships between c.955C>T, CYP21A2 haplotypes and the RCCX copy number variation (CNV) structures, which harbor CYP21A2, was performed. In total, 389 unrelated Hungarian individuals with European ancestry (164 healthy subjects, 125 patients with non-functioning adrenal incidentaloma and 100 patients with classical CAH) as well as 34 adrenocortical tumor specimens were studied using a set of experimental and bioinformatic methods. A unique, moderately frequent (2%) haplotypic RCCX CNV structure with three repeated segments, abbreviated to LBSASB, harboring a CYP21A2 with a c.955C>T variant in the 3'-segment, and a second CYP21A2 with a specific c.*12C>T (rs150697472) variant in the middle segment occurred in all c.955C>T carriers with normal steroid levels. The second CYP21A2 was free of CAH-causing mutations and produced mRNA in the adrenal gland, confirming its functionality and ability to rescue the carriers from CAH. Neither LBSASB nor c.*12C>T occurred in classical CAH patients. However, CAH-causing CYP21A2 haplotypes with c.955C>T could be derived from the 3'-segment of LBSASB after the loss of functional CYP21A2 from the middle segment. The c.*12C>T indicated a functional CYP21A2 and could distinguish between non-pathogenic and pathogenic genomic contexts of the c.955C>T variant in the studied European population. Therefore, c.*12C>T may be suitable as a marker to avoid this genetic confound and improve the diagnosis of CAH.

Identification of five novel STAR variants in ten Chinese patients with congenital lipoid adrenal hyperplasia.

PubMed

Huang, Zhuo; Ye, Jun; Han, Lianshu; Qiu, Wenjuan; Zhang, Huiwen; Yu, Yongguo; Liang, Lili; Gong, Zhuwen; Gu, Xuefan

2016-04-01

Congenital lipoid adrenal hyperplasia (CLAH) is a rare autosomal recessive disorder caused by defective synthesis of all steroids. This disorder is characterized by 46,XY sex reversal, skin hyperpigmentation, early-onset adrenal crisis and enlarged adrenal with fatty accumulation. CLAH is caused by mutations in the STAR gene. The clinical features and STAR gene mutation spectrum of a large cohort of Chinese patients with CLAH were not reported previously. We performed clinical retrospective review and genetic analysis of the STAR gene in ten unrelated Chinese phenotypic female patients who were clinically diagnosed with CLAH and followed up in our hospital from 2006 to 2015. All ten patients, including two 46,XY females and eight 46,XX females, presented skin hyperpigmentation and early salt-wasting episode, and showed normal growth and development after steroid replacement treatment. Totally 20 mutant alleles containing 11 different STAR gene mutations were identified in these ten patients, including five novel variants (two missense and three null variants), all predicted to be pathogenic in bioinformatics analysis, and six mutations described in previous literature. Among these 11 mutations, a reported mutation c.772C>T and a novel variant c.707_708delinsCTT were most frequent, accounting for 35% and 15% of the total mutant alleles, respectively. This is the first report of a large Chinese cohort with CLAH, presenting the mutation spectrum of the STAR gene and two possible founder mutations in the Chinese population, which may contribute to better genetic counseling and prenatal diagnosis. Copyright © 2016 Elsevier Inc. All rights reserved.

Long-term follow-up of a female with congenital adrenal hyperplasia due to P450-oxidoreductase deficiency.

PubMed

Bonamichi, Beatriz D S F; Santiago, Stella L M; Bertola, Débora R; Kim, Chong A; Alonso, Nivaldo; Mendonca, Berenice B; Bachega, Tania A S S; Gomes, Larissa G

2016-10-01

P450 oxidoreductase deficiency (PORD) is a variant of congenital adrenal hyperplasia that is caused by POR gene mutations. The POR gene encodes a flavor protein that transfers electrons from nicotinamide adenine dinucleotide phosphate (NADPH) to all microsomal cytochrome P450 type II (including 21-hydroxylase, 17α-hydroxylase 17,20 lyase and aromatase), which is fundamental for their enzymatic activity. POR mutations cause variable impairments in steroidogenic enzyme activities that result in wide phenotypic variability ranging from 46,XX or 46,XY disorders of sexual differentiation, glucocorticoid deficiency, with or without skeletal malformations similar to Antley-Bixler syndrome to asymptomatic newborns diagnosed during neonatal screening test. Little is known about the PORD long-term evolution. We described a 46,XX patient with mild atypical genitalia associated with severe bone malformation, who was diagnosed after 13 years due to sexual infantilism. She developed large ovarian cysts and late onset adrenal insufficiency during follow-up, both of each regressed after hormone replacement therapies. We also described a late surgical approach for the correction of facial hypoplasia in a POR patient.

A novel UBE2A mutation causes X-linked intellectual disability type Nascimento.

PubMed

Tsurusaki, Yoshinori; Ohashi, Ikuko; Enomoto, Yumi; Naruto, Takuya; Mitsui, Jun; Aida, Noriko; Kurosawa, Kenji

2017-01-01

X-linked intellectual disability (ID) type Nascimento (MIM #300860), also known as ubiquitin-conjugating enzyme E2 A (UBE2A) deficiency syndrome, is a congenital malformation syndrome characterized by moderate to severe ID, speech impairment, dysmorphic facial features, genital anomalies and skin abnormalities. Here, we report a Japanese patient with severe ID and congenital cataract. We identified a novel hemizygous mutation (c.76G>A, p.Gly26Arg) in UBE2A by whole-exome sequencing.

A novel UBE2A mutation causes X-linked intellectual disability type Nascimento

PubMed Central

Tsurusaki, Yoshinori; Ohashi, Ikuko; Enomoto, Yumi; Naruto, Takuya; Mitsui, Jun; Aida, Noriko; Kurosawa, Kenji

2017-01-01

X-linked intellectual disability (ID) type Nascimento (MIM #300860), also known as ubiquitin-conjugating enzyme E2 A (UBE2A) deficiency syndrome, is a congenital malformation syndrome characterized by moderate to severe ID, speech impairment, dysmorphic facial features, genital anomalies and skin abnormalities. Here, we report a Japanese patient with severe ID and congenital cataract. We identified a novel hemizygous mutation (c.76G>A, p.Gly26Arg) in UBE2A by whole-exome sequencing. PMID:28611923

A novel AVPR2 gene mutation of X-linked congenital nephrogenic diabetes insipidus in an Asian pedigree

PubMed Central

Guo, Wei-Hong; Li, Qiang; Wei, Hong-Yan; Lu, Hong-Yan; Qu, Hui-Qi

2016-01-01

Polyuria and polydipsia are the characteristics of congenital nephrogenic diabetes insipidus (CNDI). Approximately 90% of all patients with CNDI have X-linked hereditary disease, which is due to a mutation of the arginine vasopressin receptor 2 (AVPR2) gene. This case report describes a 54-year-old male with polyuria and polydipsia and several male members of his pedigree who had the same symptoms. The proband was diagnosed with diabetes insipidus using a water-deprivation and arginine vasopressin stimulation test. Genomic DNA from the patient and his family members was extracted and the AVPR2 gene was sequenced. A novel missense mutation of a cytosine to guanine transition at position 972 (c.972C > G) was found, which resulted in the substitution of isoleucine for methionine at amino acid position 324 (p.I324M) in the seventh transmembrane domain of the protein. The proband’s mother and daughter were heterozygous for this mutation. The novel mutation of the AVPR2 gene further broadens the phenotypic spectrum of the AVPR2 gene. PMID:27565746

A novel AVPR2 gene mutation of X-linked congenital nephrogenic diabetes insipidus in an Asian pedigree.

PubMed

Guo, Wei-Hong; Li, Qiang; Wei, Hong-Yan; Lu, Hong-Yan; Qu, Hui-Qi; Zhu, Mei

2016-10-01

Polyuria and polydipsia are the characteristics of congenital nephrogenic diabetes insipidus (CNDI). Approximately 90% of all patients with CNDI have X-linked hereditary disease, which is due to a mutation of the arginine vasopressin receptor 2 ( AVPR2) gene. This case report describes a 54-year-old male with polyuria and polydipsia and several male members of his pedigree who had the same symptoms. The proband was diagnosed with diabetes insipidus using a water-deprivation and arginine vasopressin stimulation test. Genomic DNA from the patient and his family members was extracted and the AVPR2 gene was sequenced. A novel missense mutation of a cytosine to guanine transition at position 972 (c.972C > G) was found, which resulted in the substitution of isoleucine for methionine at amino acid position 324 (p.I324M) in the seventh transmembrane domain of the protein. The proband's mother and daughter were heterozygous for this mutation. The novel mutation of the AVPR2 gene further broadens the phenotypic spectrum of the AVPR2 gene.

MANAGEMENT OF ENDOCRINE DISEASE: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: update on the management of adult patients and prenatal treatment.

PubMed

Bachelot, Anne; Grouthier, Virginie; Courtillot, Carine; Dulon, Jérôme; Touraine, Philippe

2017-04-01

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is characterized by cortisol and in some cases aldosterone deficiency associated with androgen excess. Goals of treatment are to replace deficient hormones and control androgen excess, while avoiding the adverse effects of exogenous glucocorticoid. Over the last 5 years, cohorts of adults with CAH due to 21-hydroxylase deficiency from Europe and the United States have been described, allowing us to have a better knowledge of long-term complications of the disease and its treatment. Patients with CAH have increased mortality, morbidity and risk for infertility and metabolic disorders. These comorbidities are due in part to the drawbacks of the currently available glucocorticoid therapy. Consequently, novel therapies are being developed and studied in an attempt to improve patient outcomes. New management strategies in the care of pregnancies at risk for congenital adrenal hyperplasia using fetal sex determination and dexamethasone have also been described, but remain a subject of debate. We focused the present overview on the data published in the last 5 years, concentrating on studies dealing with cardiovascular risk, fertility, treatment and prenatal management in adults with classic CAH to provide the reader with an updated review on this rapidly evolving field of knowledge. © 2017 European Society of Endocrinology.

Long-term 12 year follow-up of X-linked congenital retinoschisis

PubMed Central

Kjellström, Sten; Vijayasarathy, Camasamudram; Ponjavic, Vesna; Sieving, Paul A.; Andréasson, Sten

2010-01-01

Purpose To investigate the retinal structure and function during the progression of X-linked retinoschisis (XLRS) from childhood to adulthood. Methods Ten patients clinically diagnosed with XLRS were investigated at 6–15 years of age (mean age 9 years) with a follow-up 8 to 14 years later (mean 12 years). The patients underwent regular ophthalmic examination as well as testing of best corrected visual acuity (BCVA), visual field (VF) and assessment of full-field electroretinography (ERG) during their first visit. During the follow-up, the same clinical protocols were repeated. In addition, macular structure and function was examined with multifocal electroretinography (mfERG) and optical coherence tomography (OCT). The patients were 18–25 years of age (mean age 21 years) at the follow-up examination. All exons and exon-intron boundaries of RS1-gene were sequenced for gene mutations in 9 out of the 10 patients. Results Best corrected VA and VF were stable during this follow-up period. No significant progression in cone or rod function could be measured by full-field ERG. Multifocal electroretinography and OCT demonstrated a wide heterogeneity of macular changes in retinal structure and function at the time of follow-up visit. Three different mutations were detected in these nine patients, including a known nonsense mutation in exon 3, a novel insertion in exon 5 and an intronic mutation at 5' splice site of intron 3. Conclusions Clinical follow-up (mean 12 years) of ten young XLRS patients (mean age of 9 years) with a typical congenital retinoschisis phenotype revealed no significant decline in retinal function during this time period. MfERG and OCT demonstrated a wide variety of macular changes including structure and dysfunction. The XLRS disease was relatively stable during this period of observation and would afford opportunity for therapy studies to judge benefit against baseline and against the fellow eye. PMID:20569020

Pubertal presentation in seven patients with congenital adrenal hyperplasia due to P450 oxidoreductase deficiency.

PubMed

Idkowiak, Jan; O'Riordan, Stephen; Reisch, Nicole; Malunowicz, Ewa M; Collins, Felicity; Kerstens, Michiel N; Köhler, Birgit; Graul-Neumann, Luitgard Margarete; Szarras-Czapnik, Maria; Dattani, Mehul; Silink, Martin; Shackleton, Cedric H L; Maiter, Dominique; Krone, Nils; Arlt, Wiebke

2011-03-01

P450 oxidoreductase (POR) is a crucial electron donor to all microsomal P450 cytochrome (CYP) enzymes including 17α-hydroxylase (CYP17A1), 21-hydroxylase (CYP21A2) and P450 aromatase. Mutant POR causes congenital adrenal hyperplasia with combined glucocorticoid and sex steroid deficiency. P450 oxidoreductase deficiency (ORD) commonly presents neonatally, with disordered sex development in both sexes, skeletal malformations, and glucocorticoid deficiency. The aim of the study was to describe the clinical and biochemical characteristics of ORD during puberty. Clinical, biochemical, and genetic assessment of seven ORD patients (five females, two males) presenting during puberty was conducted. Predominant findings in females were incomplete pubertal development (four of five) and large ovarian cysts (five of five) prone to spontaneous rupture, in some only resolving after combined treatment with estrogen/progestin, GnRH superagonists, and glucocorticoids. Pubertal development in the two boys was more mildly affected, with some spontaneous progression. Urinary steroid profiling revealed combined CYP17A1 and CYP21A2 deficiencies indicative of ORD in all patients; all but one failed to mount an appropriate cortisol response to ACTH stimulation indicative of adrenal insufficiency. Diagnosis of ORD was confirmed by direct sequencing, demonstrating disease-causing POR mutations. Delayed and disordered puberty can be the first sign leading to a diagnosis of ORD. Appropriate testosterone production during puberty in affected boys but manifest primary hypogonadism in girls with ORD may indicate that testicular steroidogenesis is less dependent on POR than adrenal and ovarian steroidogenesis. Ovarian cysts in pubertal girls may be driven not only by high gonadotropins but possibly also by impaired CYP51A1-mediated production of meiosis-activating sterols due to mutant POR.

Manifestations and characteristics of congenital adrenal hyperplasia-associated encephalopathy.

PubMed

Abe, Yuichi; Sakai, Tetsuro; Okumura, Akihisa; Akaboshi, Shinjiro; Fukuda, Mitsumasa; Haginoya, Kazuhiro; Hamano, Shin-Ichiro; Hirano, Kouichi; Kikuchi, Kenjiro; Kubota, Masaya; Lee, Sooyoung; Maegaki, Yoshihiro; Sanefuji, Masafumi; Shimozato, Sachiko; Suzuki, Motomasa; Suzuki, Yasuhiro; Takahashi, Mitsugi; Watanabe, Kenji; Mizuguchi, Masashi; Yamanouchi, Hideo

2016-08-01

This study aimed to clarify the characteristics of acute encephalopathic episodes in patients with congenital adrenal hyperplasia (CAH), which we termed "CAH-associated encephalopathy (CAHE)." This retrospective study was conducted using a questionnaire as a nationwide survey of patients with CAH with acute encephalopathy and related episodes. Fifteen patients were recruited on the bases of clinical data that supported a diagnosis of CAHE. Fourteen patients displayed seizures at onset, and 12 patients exhibited refractory seizures. Deep coma lasting >24h was noted in 12 patients. Neuroimaging studies revealed some heterogeneous features. Diffuse or focal edematous lesions in the cerebrum, which produce high signal intensity on diffusion-weighted magnetic resonance imaging or low density on computer tomography, were found in the acute period in all 15 patients. In the chronic period, 14 patients survived, 11 of whom had some degree of neurological sequelae. Moreover, various degrees of cerebral shrinkage were observed in 11 of 14 surviving patients. Surprisingly, there were no abnormal neuroimaging findings in the basal ganglia, brainstem, and cerebellum in any patient. Our results indicated that patients with CAH have a risk of developing CAHE, and thus, they should be followed closely because not only status epilepticus or deep coma but also minor symptoms, such as fever and nausea, may lead to CAHE. Because CAHE may feature some heterogeneous encephalopathic episodes, further validation is needed to clarify its etiology. Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Gender Identity in Patients with Congenital Adrenal Hyperplasia.

PubMed

Razzaghy-Azar, Maryam; Karimi, Sakineh; Shirazi, Elham

2017-07-01

Sex assignment in infancy for patients with disorder of sex development (DSD) is a challenging problem. Some of the patients with congenital adrenal hyperplasia (CAH) have DSD that may affect their gender identity. The study aimed to assess gender identity in patients with CAH. In this study, 52 patients with CAH, including 22 prepubertal children and 30 adolescents and adults, were assessed using two separate gender identity questionnaires for children and adults based on the criteria of diagnostic and statistical manual of mental disorders, 5th edition. In the children group, compatibility was seen between gender identity and rearing gender. In the adult group, there were three cases of mismatching between gender identity and sex assignment composed of two females with poor control and one male with good control with 21-hydroxylase deficiency (21-OHD). Three girls with 11-hydroxylase deficiency (11-OHD) were reared as boy. Two of them with late diagnosis at 5 and 6 years of age had pseudoprecocious puberty. Parents and children did not accept to change the gender. One of them is 36 years old now, is depressed and unsatisfied with her gender, another girl is still child and has male sexual identity. One girl with 11-OHD and early diagnosis at birth with Prader 5 virilization but with good hormonal control was changed to female gender at 12 years of age when female sexual characteristics appeared; she is 34-years-old now, married, and with two children, and she is satisfied with her gender. In patients with CAH, gender identity disorder is a rare finding. Hormonal control, social, familial, and religious beliefs have impacts on gender identity of these patients.

The genetic landscape of familial congenital hydrocephalus.

PubMed

Shaheen, Ranad; Sebai, Mohammed Adeeb; Patel, Nisha; Ewida, Nour; Kurdi, Wesam; Altweijri, Ikhlass; Sogaty, Sameera; Almardawi, Elham; Seidahmed, Mohammed Zain; Alnemri, Abdulrahman; Madirevula, Sateesh; Ibrahim, Niema; Abdulwahab, Firdous; Hashem, Mais; Al-Sheddi, Tarfa; Alomar, Rana; Alobeid, Eman; Sallout, Bahauddin; AlBaqawi, Badi; AlAali, Wajeih; Ajaji, Nouf; Lesmana, Harry; Hopkin, Robert J; Dupuis, Lucie; Mendoza-Londono, Roberto; Al Rukban, Hadeel; Yoon, Grace; Faqeih, Eissa; Alkuraya, Fowzan S

2017-06-01

Congenital hydrocephalus is an important birth defect, the genetics of which remains incompletely understood. To date, only 4 genes are known to cause Mendelian diseases in which congenital hydrocephalus is the main or sole clinical feature, 2 X-linked (L1CAM and AP1S2) and 2 autosomal recessive (CCDC88C and MPDZ). In this study, we aimed to determine the genetic etiology of familial congenital hydrocephalus with the assumption that these cases represent Mendelian forms of the disease. Exome sequencing combined, where applicable, with positional mapping. We identified a likely causal mutation in the majority of these families (21 of 27, 78%), spanning 16 genes, none of which is X-linked. Ciliopathies and dystroglycanopathies were the most common etiologies of congenital hydrocephalus in our cohort (19% and 26%, respectively). In 1 family with 4 affected members, we identified a homozygous truncating variant in EML1, which we propose as a novel cause of congenital hydrocephalus in addition to its suggested role in cortical malformation. Similarly, we show that recessive mutations in WDR81, previously linked to cerebellar ataxia, mental retardation, and disequilibrium syndrome 2, cause severe congenital hydrocephalus. Furthermore, we confirm the previously reported candidacy of MPDZ by presenting a phenotypic spectrum of congenital hydrocephalus associated with 5 recessive alleles. Our study highlights the importance of recessive mutations in familial congenital hydrocephalus and expands the locus heterogeneity of this condition. Ann Neurol 2017;81:890-897. © 2017 American Neurological Association.

[Congenital adrenal hyperplasia due to lack of 17α-hydroxylase: a report of a new mutation in the gene CYP17A1].

PubMed

Perales Martínez, J I; Pina Marqués, B; de Arriba Muñoz, A; Mayayo Dehesa, E; Labarta Aizpún, J I; Loidi Fernández, L

2015-01-01

P450c17 enzyme catalyses two different reactions: the 17α-hydroxylation of progesterone and pregnenolone, and segmenting the carbon 17-20 binding from the 17,20lyase producing adrenal androgens. This enzyme is coded by the CYP17A1 gene. The case is presented of a 14 year old patient with delayed pubertal development and a high blood pressure for height and age. 46,XX karyotype. Hormonal studies highlighted hypergonadotropic hypogonadism, adrenal insufficiency and mineralocorticoid excess. Subsequent genetic studies showed a homozygous mutation in the CYP17A1 gene (c.753+G>A), not previously described, which is responsible for the pathophysiology of 17α-hydroxylase deficiency. This entity is a rare form of congenital adrenal hyperplasia. The disease often goes unnoticed until adolescence or early adult life, and should be suspected in 46,XY individuals with ambiguous genitalia or 46,XX with delayed puberty associated with hypertension and/or hypokalaemia. Copyright © 2013 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

X-linked recessive nephrogenic diabetes insipidus: a clinico-genetic study.

PubMed

Hong, Che Ry; Kang, Hee Gyung; Choi, Hyun Jin; Cho, Min Hyun; Lee, Jung Won; Kang, Ju Hyung; Park, Hye Won; Koo, Ja Wook; Ha, Tae-Sun; Kim, Su-Yung; Il Cheong, Hae

2014-01-01

A retrospective genotype and phenotype analysis of X-linked congenital nephrogenic diabetes insipidus (NDI) was conducted on a nationwide cohort of 25 (24 male, 1 female) Korean children with AVPR2 gene mutations, comparing non-truncating and truncating mutations. In an analysis of male patients, the median age at diagnosis was 0.9 years old. At a median follow-up of 5.4 years, urinary tract dilatations were evident in 62% of patients and their median glomerular filtration rate was 72 mL/min/1.73 m2. Weights and heights were under the 3rd percentile in 22% and 33% of patients, respectively. One patient had low intelligence quotient and another developed end-stage renal disease. No statistically significant genotype-phenotype correlation was found between non-truncating and truncating mutations. One patient was female; she was analyzed separately because inactivation and mosaicism of the X chromosome may influence clinical manifestations in female patients. Current unsatisfactory long-term outcome of congenital NDI necessitates a novel therapeutic strategy.

HDR syndrome with a novel mutation in GATA3 mimicking a congenital X-linked stapes gusher: a case report.

PubMed

Yang, Aram; Kim, Jinsup; Ki, Chang-Seok; Hong, Sung Hwa; Cho, Sung Yoon; Jin, Dong-Kyu

2017-10-26

Hypoparathyroidism, sensorineural hearing loss, and renal disease (HDR) syndrome, also known as Barakat syndrome, is a rare genetic disorder with high phenotypic heterogeneity caused by haploinsufficiency of the GATA3 gene on chromosome 10p14-p15. For these reasons, the diagnosis of HDR syndrome is challenging and requires a high index of suspicion as well as genetic analysis. A 14-month-old boy, with sensorineural hearing loss in both ears, showed typical radiological features of X-linked stapes gusher on preoperative temporal bone computed tomography (CT) for cochlear implantations. Then after his discharge from hospital, he suffered a hypocalcemic seizure and we discovered a renal cyst during investigation of hypocalcemia. He was finally diagnosed with HDR syndrome by clinical findings, which were confirmed by molecular genetic testing. Direct sequencing of the GATA3 gene showed a heterozygous 2-bp deletion (c.1201_1202delAT), which is predicted to cause a frameshift of the reading frame (p.Met401Valfs*106). To our knowledge, this is the first case of HDR syndrome with a novel de novo variant mimicking a congenital X-linked stapes gusher syndrome. Novel mutations and the diversity of clinical manifestations expand the genotypic and phenotypic spectrum of HDR syndrome. Diagnosis of HDR syndrome is still challenging, but clinicians should consider it in their differential diagnosis for children with a wide range of clinical manifestations including hypocalcemia induced seizures and deafness. We hope that this case will contribute to further understanding and studies of HDR-associated GATA3 mutations.

Recommendations for Treatment of Nonclassic Congenital Adrenal Hyperplasia (NCCAH): an Update

PubMed Central

Trapp, Christine M.; Oberfield, Sharon E.

2013-01-01

Congenital adrenal hyperplasia (CAH) is a family of autosomal recessive disorders. 21-hydroxylase deficiency, in which there are mutations in CYP21A2 (the gene encoding the adrenal 21-hydroxylase enzyme), is the most common form (90%) of CAH. In classic CAH there is impaired cortisol production with diagnostic increased levels of 17-OH progesterone. Excess androgen production results in virilization and in the newborn female may cause development of ambiguous external genitalia. Three-fourths of patients with classic CAH also have aldosterone insufficiency, which can result in salt-wasting; in infancy this manifests as shock, hyponatremia and hyperkalemia. CAH has a reported incidence of 1:10,000–1:20,000 births although there is an increased prevalence in certain ethnic groups. Nonclassic CAH (NCCAH) is a less severe form of the disorder, in which there is 20–50% of 21-hydroxylase enzyme activity (vs. 0–5% in classic CAH) and no salt wasting. The degree of symptoms related to androgen excess is variable and may be progressive with age, although some individuals are asymptomatic. NCCAH has an incidence of 1:1000–1:2000 births (0.1–0.2% prevalence) in the White population; an even higher prevalence is noted in certain ethnic groups such as Ashkenazi Jews (1–2%). As many as two-thirds of persons with NCCAH are compound heterozygotes and carry a severe and mild mutation on different alleles. This paper discusses the genetics of NCCAH, along with its variable phenotypic expression, and reviews the clinical course in untreated patients, which includes rapid early childhood growth, advanced skeletal age, premature adrenarche, acne, impaired reproductive function in both sexes and hirsutism as well as menstrual disorders in females. Finally, it addresses treatment with glucocorticoids vs. and other alternatives, particularly with respect to long term issues such as adult metabolic disease including insulin resistance, cardiovascular disease, metabolic syndrome

Transition of Care from Childhood to Adulthood: Congenital Adrenal Hyperplasia.

PubMed

Bachelot, Anne

2018-01-01

Deficiency of the 21-hydroxylase enzyme is the most common form of congenital adrenal hyperplasia (CAH), accounting for more than 95% of the cases. With the advent of newborn screening and hormone replacement therapy, most children with CAH survive into adulthood. Adolescents and adults with CAH experience a number of complications, including short stature, obesity, infertility, impaired bone mineral density, and reduced quality of life. Transition from pediatric to adult care and management of long-term complications are challenging for both patients and practitioners. In adulthood, the aims of the medical treatment are to substitute cortisol and, when necessary, aldosterone deficiency, to ensure normal fertility, and to avoid the long-term consequences of glucocorticoid use on bone, metabolism, and cardiovascular risk. Recent data suggest that poor health status is likely to begin in adolescence and persist into adulthood, highlighting the importance of this time period in a patient's endocrine care. During transition from pediatric to adult specific care, a shift in treatment goals is thus needed. Successful transition from pediatric to adult health care requires a regular follow-up of patients by a multidisciplinary team including pediatric endocrinologists, urologists, gynecologists, psychiatrists, and adult endocrinologists. All of this could be included in a specific therapeutic education program regarding transition and/or CAH. © 2018 S. Karger AG, Basel.

X-linked ocular albinism in Blacks. Ocular albinism cum pigmento.

PubMed

O'Donnell, F E; Green, W R; Fleischman, J A; Hambrick, G W

1978-07-01

X-linked ocular albinism can be an unsuspected cause of congenital nystagmus in blacks. In this study, eight of ten black ocular albinos from two kindreds had nonalbinotic, moderately pigmented fundi and no transillumination of the iris. We refer to this paradoxical condition as "ocular albinism cum pigmento." The only constant ophthalmoscopic feature was a foveal hypoplasia. Biopsy of clinically normal skin to demonstrate giant pigment granules is the most accurate means of diagnosis.

Stigma Associated with Classical Congenital Adrenal Hyperplasia in Women's Sexual Lives.

PubMed

Meyer-Bahlburg, Heino F L; Khuri, Jananne; Reyes-Portillo, Jazmin; Ehrhardt, Anke A; New, Maria I

2018-05-01

The risk of intersex-related stigma often serves as social indication for "corrective" genital surgery, but has not been comprehensively documented. In preparation for the development of an intersex-specific stigma assessment tool, this qualitative project aimed to explore stigma in girls and women with classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. As part of a comprehensive follow-up project, 62 adult women with classical CAH (age range 18-51 years) took part in an open-ended retrospective interview focusing on the impact of CAH and its treatment on various aspects of girls' and women's lives. Deductive qualitative content analysis (Patton, 2014) of de-identified transcripts involved categorization of three types of stigma: experienced, anticipated, and internalized. Two-fifths of the participants reported CAH-related stigma in romantic/sexual situations. Stigma enactment by romantic partners occurred in reaction to both genital and non-genital sex-atypical features of CAH and sometimes included explicit questioning of the women's true gender. Stigma anticipation by the women and their related avoidance of nudity, genital exposure, and romantic involvement altogether were frequent. Internalization of stigma occurred as well. In conclusion, the data suggest that many women with CAH experience, anticipate, and/or internalize intersex-related stigma in the context of their romantic/sexual lives.

Motor development in individuals with congenital adrenal hyperplasia: strength, targeting, and fine motor skill.

PubMed

Collaer, Marcia L; Brook, Charles G D; Conway, Gerard S; Hindmarsh, Peter C; Hines, Melissa

2009-02-01

This study investigated early androgen influence on the development of human motor and visuomotor characteristics. Participants, ages 12-45 years, were individuals with congenital adrenal hyperplasia (CAH), a disorder causing increased adrenal androgen production before birth (40 females, 29 males) and their unaffected relatives (29 females, 30 males). We investigated grip strength and visuomotor targeting tasks on which males generally outperform females, and fine motor pegboard tasks on which females generally outperform males. Physical characteristics (height and weight) were measured to explore whether body parameters could explain differences in motor skills. Females with CAH were stronger and showed better targeting than unaffected females and showed reduced fine visuomotor skill on one pegboard measure, with no difference on the other. Males with CAH were weaker than unaffected males in grip strength but did not differ on the targeting or pegboard measures. Correction for body size could not explain the findings for females, but suggests that the reduced strength of males with CAH may relate to their smaller stature. Further, the targeting advantage in females with CAH persisted following adjustment for their greater strength. Results in females support the hypothesis that androgen may masculinize, or promote, certain motor characteristics at which males excel, and contribute to defeminization of certain fine motor characteristics at which females excel. Thus, these data suggest that organizational effects of androgens on behavior during prenatal life may extend to motor characteristics and may contribute to general sex differences in motor-related behaviors; however, alternative explanations based on activational influences of androgen or altered experiential factors cannot be excluded without further study.

Gender Identity in Patients with Congenital Adrenal Hyperplasia

PubMed Central

Razzaghy-Azar, Maryam; Karimi, Sakineh; Shirazi, Elham

2017-01-01

Background Sex assignment in infancy for patients with disorder of sex development (DSD) is a challenging problem. Some of the patients with congenital adrenal hyperplasia (CAH) have DSD that may affect their gender identity. Objectives The study aimed to assess gender identity in patients with CAH. Methods In this study, 52 patients with CAH, including 22 prepubertal children and 30 adolescents and adults, were assessed using two separate gender identity questionnaires for children and adults based on the criteria of diagnostic and statistical manual of mental disorders, 5th edition. Results In the children group, compatibility was seen between gender identity and rearing gender. In the adult group, there were three cases of mismatching between gender identity and sex assignment composed of two females with poor control and one male with good control with 21-hydroxylase deficiency (21-OHD). Three girls with 11-hydroxylase deficiency (11-OHD) were reared as boy. Two of them with late diagnosis at 5 and 6 years of age had pseudoprecocious puberty. Parents and children did not accept to change the gender. One of them is 36 years old now, is depressed and unsatisfied with her gender, another girl is still child and has male sexual identity. One girl with 11-OHD and early diagnosis at birth with Prader 5 virilization but with good hormonal control was changed to female gender at 12 years of age when female sexual characteristics appeared; she is 34-years-old now, married, and with two children, and she is satisfied with her gender. Conclusions In patients with CAH, gender identity disorder is a rare finding. Hormonal control, social, familial, and religious beliefs have impacts on gender identity of these patients. PMID:29201068

Congenital adrenal hyperplasia: as viewed by parents of affected children in India--a pilot study.

PubMed

Bhakhri, Bhanu Kiran; Jain, Vandana

2011-01-01

A spectrum of myths and misconceptions about congenital adrenal hyperplasia (CAH) is prevalent among the parents of affected children in India. The perceptions of parents may affect several aspects of these children's management, and to explore these perceptions we carried out a cross-sectional questionnaire-based descriptive study during May 2010. Twenty-eight individuals (17 males and 11 females), parents of 22 affected children aged < 5 years, completed the questionnaire. Their responses showed the prevalence among the parents of misconceptions about CAH. These misconceptions were resulting in potentially harmful practices, and in addition there was immense societal pressure on the families as a result of ignorance and myths about the disorder. There is a need for regular CAH education and interaction programs to provide an acceptable platform for the parents and patients, where their concerns can be expressed and shared and their requirements addressed appropriately by a multidisciplinary team.

Paternal inheritance of classic X-linked bilateral periventricular nodular heterotopia.

PubMed

Kasper, Burkhard S; Kurzbuch, Katrin; Chang, Bernard S; Pauli, Elisabeth; Hamer, Hajo M; Winkler, Jürgen; Hehr, Ute

2013-06-01

Periventricular nodular heterotopia (PNH) is a developmental disorder of the central nervous system, characterized by heterotopic nodules of gray matter resulting from disturbed neuronal migration. The most common form of bilateral PNH is X-linked dominant inherited, caused by mutations in the Filamin A gene (FLNA) and associated with a wide variety of other clinical findings including congenital heart disease. The typical patient with FLNA-associated PNH is female and presents with difficult to treat seizures. In contrast, hemizygous FLNA loss of function mutations in males are reported to be perinatally lethal. In X-linked dominant traits like FLNA-associated PNH the causal mutation is commonly inherited from the mother. Here, we present an exceptional family with paternal transmission of classic bilateral FLNA-associated PNH from a mildly affected father with somatic and germline mosaicism for a c.5686G>A FLNA splice mutation to both daughters with strikingly variable clinical manifestation and PNH extent in cerebral MR imaging. Our observations emphasize the importance to consider in genetic counseling and risk assessment the rare genetic constellation of paternal transmission for families with X-linked dominant inherited FLNA-associated PNH. Copyright © 2013 Wiley Periodicals, Inc.

Comparison of Adrenal Suppression between Etomidate and Dexmedetomidine in Children with Congenital Heart Disease.

PubMed

Gu, Hongbin; Zhang, Mazhong; Cai, Meihua; Liu, Jinfen

2015-05-29

The aim of this study was to compare plasma cortisol concentration during anesthesia of children with congenital heart disease who received dexmedetomidine (DEX) with those who received etomidate (ETO). We recruited 99 ASA physical status II-III pediatric patients scheduled for congenital heart disease (CHD) corrective surgery and divided into them into 3 groups. Group DEX received an infusion of DEX intravenously with a bolus dose of 0.5 µg·kg-1 within 10 min during anesthesia induction, followed by a maintenance dose of DEX 0.5 µg·kg-1·h-1. Group ETO received ETO intravenously with a bolus dose of 0.3 mg·kg-1 without a maintenance dose. Group CON received routine anesthetics as controls. The preset timepoints were: before anesthesia induction (T0), at the end of induction (T1), 30 min after anesthesia induction (T2), at the time of aortic and inferior vena catheterization (T3), and at 180 min (T4) and 24 h (T5) after anesthesia induction. The cortisol concentration decreased gradually after anesthesia induction in all groups, and returned to baseline values after 24 h. The cortisol concentration was significantly lower in Group ETO children than in Group DEX or group CON at T4. The plasma concentrations of cortisol decreased in CHD children after the operation, but returned to baseline after 24 h of anesthesia induction. The adrenal cortex function inhibition induced by ETO in CHD children is longer and more serious than that induced by DEX (if any) during the preoperative period.

Are there parental socialization effects on the sex-typed behavior of individuals with congenital adrenal hyperplasia?

PubMed

Wong, Wang I; Pasterski, Vickie; Hindmarsh, Peter C; Geffner, Mitchell E; Hines, Melissa

2013-04-01

Influences of prenatal androgen exposure on human sex-typical behavior have been established largely through studies of individuals with congenital adrenal hyperplasia (CAH). However, evidence that addresses the potential confounding influence of parental socialization is limited. Parental socialization and its relationship to sex-typical toy play and spatial ability were investigated in two samples involving 137 individuals with CAH and 107 healthy controls. Females with CAH showed more boy-typical toy play and better targeting performance than control females, but did not differ in mental rotations performance. Males with CAH showed worse mental rotations performance than control males, but did not differ in sex-typical toy play or targeting. Reported parental encouragement of girl-typical toy play correlated with girl-typical toy play in all four groups. Moreover, parents reported encouraging less girl-typical, and more boy-typical, toy play in females with CAH than in control females and this reported encouragement partially mediated the relationship between CAH status and sex-typical toy play. Other evidence suggests that the reported parental encouragement of sex-atypical toy play in girls with CAH may be a response to the girls' preferences for boys' toys. Nevertheless, this encouragement could further increase boy-typical behavior in girls with CAH. In contrast to the results for toy play, we found no differential parental socialization for spatial activities and little evidence linking parental socialization to spatial ability. Overall, evidence suggests that prenatal androgen exposure and parental socialization both contribute to sex-typical toy play.

Neuropsychological assessment in prepubertal patients with congenital adrenal hyperplasia: preliminary study.

PubMed

Somajni, F; Sovera, V; Albizzati, A; Russo, G; Peroni, P; Seragni, G; Lenti, C

2011-02-01

Individuals with congenital adrenal hyperplasia (CAH) provide a test population for the theory that elevated testosterone levels alter pre-/perinatal brain development. Seven prepuberal girls with CAH and seven matched controls has been submitted to a neuropsychological evaluation. We measured abilities where gender differences repeatedly has been observed or that had earlier shown differences between CAH subjects and controls. The following cognitive functions were tested: general intelligence, attention, verbal and non-verbal abilities, cerebral dominance for verbal and non-verbal material, frontal functions, peripheral dominance and motor fluency. Since several animal studies shown hippocampal morphological changes induced by prolonged hydrocortisone exposure, we also investigated memory functions. No differences were recorded between two groups on those abilities that are not sexually dimorphic. The mean general intelligence level of the patients was significantly lower than the controls', in agreement with previous studies. The verbal and non-verbal tasks revealed an age-related male-like pattern (i.e., verbal disadvantage) and an inversion of the hemispheric dominances. The latter observation was supported by a right-to-left shift of the peripheral dominances. The patients memory performances were all inferior to the controls'. The results are discussed in the light of possible hormonal influences. Our main findings support the hypothesis that elevated pre-/perinatal androgen exposure can influence some cognitive pattern of specific sexual dimorphic abilities in prepubertal subjects.

Neonatal Bartter Syndrome in association with congenital adrenal hyperplasia in a neonate - a rare combination.

PubMed

Hussain, Shabbir

2016-05-01

Neonatal Bartter syndrome (NBS) is an autosomal recessive renal tubulopathy characterized by hypokalaemic, hypochloraemic metabolic alkalosis associated with increased urinary loss of sodium, potassium, calcium and chloride. There is hyperreninaemia and hyperaldosteronaemia but normotension. Congenital adrenal hyperplasia (CAH), another autosomal recessive condition, may present in the neonatal period with vomiting, hypovolaemia, failure to gain weight or ambiguous genitalia. We report a case of NBS and CAH combination in a neonate. A male neonate born at term was admitted with history of recurrent vomiting and dehydration episodes. Investigations revealed electrolytes imbalance, metabolic alkalosis, raised aldosterone and renin levels suggestive of NBS. He was treated successfully and discharged. He was re-admitted with the same symptoms. Further evaluation confirmed the presence of CAH as well. We report this case because of the rarity of this combination (NBS plus CAH) and to the best of our knowledge this is the first such case report from Pakistan.

Renal and adrenal tumors: Pathology, radiology, ultrasonography, therapy, immunology

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

Lohr, E.; Leder, L.D.

1987-01-01

Aspects as diverse as radiology, pathology, urology, pediatrics and immunology have been brought together in one book. The most up-do-date methods of tumor diagnosis by CT, NMR, and ultrasound are covered, as are methods of catheter embolization and radiation techniques in case of primarily inoperable tumors. Contents: Pathology of Renal and Adrenal Neoplasms; Ultrasound Diagnosis of Renal and Pararenal Tumors; Computed-Body-Tomography of Renal Carcinoma and Perirenal Masses; Magnetic Resonance Imaging of Renal Mass Lesions; I-125 Embolotherapy of Renal Tumors; Adrenal Mass Lesions in Infants and Children; Computed Tomography of the Adrenal Glands; Scintigraphic Studies of Renal and Adrenal Function; Surgicalmore » Management of Renal Cell Carcinoma; Operative Therapy of Nephroblastoma; Nonoperative Treatment of Renal Cell Carcinoma; Prenatal Wilms' Tumor; Congenital Neuroblastoma; Nonsurgical Management of Wilms' Tumor; Immunologic Aspects of Malignant Renal Disease.« less

Children with classic congenital adrenal hyperplasia have elevated serum leptin concentrations and insulin resistance: potential clinical implications.

PubMed

Charmandari, Evangelia; Weise, Martina; Bornstein, Stefan R; Eisenhofer, Graeme; Keil, Margaret F; Chrousos, George P; Merke, Deborah P

2002-05-01

Leptin is secreted by the white adipose tissue and modulates energy homeostasis. Nutritional, neural, neuroendocrine, paracrine, and autocrine factors, including the sympathetic nervous system and the adrenal medulla, have been implicated in the regulation of leptin secretion. Classic congenital adrenal hyperplasia (CAH) is characterized by a defect in cortisol and aldosterone secretion, impaired development and function of the adrenal medulla, and adrenal hyperandrogenism. To examine leptin secretion in patients with classic CAH in relation to their adrenomedullary function and insulin and androgen secretion, we studied 18 children with classic CAH (12 boys and 6 girls; age range 2-12 yr) and 28 normal children (16 boys and 12 girls; age range 5-12 yr) matched for body mass index (BMI). Serum leptin concentrations were significantly higher in patients with CAH than in control subjects (8.1 +/- 2.0 vs. 2.5 +/- 0.6 ng/ml, P = 0.01), and this difference persisted when leptin values were corrected for BMI. When compared with their normal counterparts, children with CAH had significantly lower plasma epinephrine (7.1 +/- 1.3 vs. 50.0 +/- 4.2, P < 0.001) and free metanephrine concentrations (18.4 +/- 2.4 vs. 46.5 +/- 4.0, P < 0.001) and higher fasting serum insulin (10.6 +/- 1.4 vs. 3.2 +/- 0.2 microU/ml, P < 0.001) and testosterone (23.7 +/- 5.3 vs. 4.6 +/- 0.5 ng/dl, P = 0.003) concentrations. Insulin resistance determined by the homeostasis model assessment method was significantly greater in children with classic CAH than in normal children (2.2 +/- 0.3 vs. 0.7 +/- 0.04, P < 0.001). Leptin concentrations were significantly and negatively correlated with epinephrine (r = -0.50, P = 0.001) and free metanephrine (r = -0.48, P = 0.002) concentrations. Stepwise multiple linear regression analysis indicated that serum leptin concentrations were best predicted by BMI in both patients and controls. Gender predicted serum leptin concentrations in controls but not in patients

Relationship between final height and health outcomes in adults with congenital adrenal hyperplasia: United Kingdom congenital adrenal hyperplasia adult study executive (CaHASE).

PubMed

Han, T S; Conway, G S; Willis, D S; Krone, N; Rees, D A; Stimson, R H; Arlt, W; Walker, B R; Ross, R J

2014-08-01

Treatment of congenital adrenal hyperplasia (CAH) in childhood focuses on growth and development and adult final height (FH) is a measure of effective treatment. We hypothesized that shorter adults will have more severe underlying disease and worse health outcomes. This was a cross-sectional analysis of 199 adults with CAH. FH and quality of life were expressed as z-scores adjusted for midparental target height or UK population height. FH correlated inversely with age (men, r = -0.38; women, r = -0.26, P < .01). Men and women had z-scores adjusted for midparental target height of -2 and -1, respectively, and both groups had UK population height z-scores of -1 below the UK population (P < .01). In women, FH was shorter in non-salt-wasting than salt-wasting classic CAH (P < .05) and in moderately affected genotype group B women than either more severely affected groups null and A (P < .01) or the mildest group C (P < .001). Short stature and a higher prevalence of hypertension were observed in classic CAH patients diagnosed late (after 1 y) compared with those diagnosed early and in women treated with glucocorticoid only compared with those treated with both glucocorticoids and mineralocorticoids (P < .05). FH did not associate with insulin sensitivity, lipid profile, adiposity, or quality of life. Adult CAH patients remain short, although height prognosis has improved over time. The shortest adults are those diagnosed late with moderate severity CAH and are at increased risk of adult hypertension; we hypothesize that these patients are exposed in childhood to high androgens and/or excessive glucocorticoids with potential programming of hypertension. Another possibility is inadequate mineralocorticoid treatment early in life in the late-diagnosed patient group. Prospective studies are now required to examine these hypotheses.

The Recalled Childhood Gender Questionnaire-Revised: a psychometric analysis in a sample of women with congenital adrenal hyperplasia.

PubMed

Meyer-Bahlburg, Heino F L; Dolezal, Curtis; Zucker, Kenneth J; Kessler, Suzanna J; Schober, Justine M; New, Maria I

2006-11-01

We administered the 18-item Recalled Childhood Gender Questionnaire-Revised (RCGQ-R), female version, to 147 adult women with congenital adrenal hyperplasia (CAH) representing three different degrees of prenatal androgenization due to 21-hydroxylase deficiency and to non-CAH controls. A principal components analysis generated three components accounting for 46%, 9%, and 6% of the variance, respectively. Corresponding unit-weighted scales (high scores = feminine) were labeled Gender Role (13 items; Cronbach alpha = .91), Physical Activity (3 items; alpha = .64), and Cross-Gender Desire (2 items; alpha = .47). Discriminant validity was demonstrated in terms of highly significant comparisons across the four groups. We conclude that the first 2 RCGQ-R scales show good psychometric qualities, but that the third scale needs to be further evaluated in a sample that includes women with gender identity disorder.

Molecular characterization of a novel X-linked syndrome involving developmental delay and deafness.

PubMed

Hildebrand, Michael S; de Silva, Michelle G; Tan, Tiong Yang; Rose, Elizabeth; Nishimura, Carla; Tolmachova, Tanya; Hulett, Joanne M; White, Susan M; Silver, Jeremy; Bahlo, Melanie; Smith, Richard J H; Dahl, Hans-Henrik M

2007-11-01

X-linked syndromes associated with developmental delay and sensorineural hearing loss (SNHL) have been characterized at the molecular level, including Mohr-Tranebjaerg syndrome and Norrie disease. In this study we report on a novel X-linked recessive, congenital syndrome in a family with developmental delay and SNHL that maps to a locus associated with mental retardation (MR) for which no causative gene has been identified. The X-linked recessive inheritance and congenital nature of the syndrome was confirmed by detailed clinical investigation and the family history. Linkage mapping of the X-chromosome was conducted to ascertain the disease locus and candidate genes were screened by direct sequencing and STRP analysis. The recessive syndrome was mapped to Xp11.3-q21.32 and a deletion was identified in a regulatory region upstream of the POU3F4 gene in affected family members. Since mutations in POU3F4 cause deafness at the DFN3 locus, the deletion is the likely cause of the SNHL in this family. The choroideremia (CHM) gene was also screened and a novel missense change was identified. The alteration changes the serine residue at position 89 in the Rab escort 1 protein (REP-1) to a cysteine (S89C). Prenylation of Rab proteins was investigated in patients and the location of REP-1 expression in the brain determined. However, subsequent analysis revealed that this change in CHM was polymorphic having no effect on REP-1 function. Although the causative gene at the MR locus in this family has not been identified, there are a number of genes involved in syndromic and nonsyndromic forms of MR that are potential candidates. Copyright 2007 Wiley-Liss, Inc.

Newborn screening for congenital adrenal hyperplasia in Cuba: six years of experience.

PubMed

González, Ernesto Carlos; Carvajal, Frank; Frómeta, Amarilys; Arteaga, Ana Luisa; Castells, Elisa María; Espinosa, Tania; Coto, Remigio; Pérez, Pedro Lucio; Tejeda, Yileidis; Del Río, Lesley; Segura, Mary Triny; Almenares, Pedro; Robaina, René; Fernández, José Luis

2013-06-05

Since 2005, a newborn screening program for congenital adrenal hyperplasia (CAH) by measuring 17-alpha-hydroxyprogesterone (17OHP) in dried blood spots was introduced in Cuba. The hormone was measured by the 17OHP Neonatal UMELISA method, in samples collected on the 5th day as average. Confirmatory test was performed to those neonates with 17OHP values above 55 nmol/l. Some perinatal factors that can influence on 17OHP levels were studied. From January 2005 to December 2010, 621,303 newborns were screened and 39 CAH cases were detected. Coverage of the program reached 98%. The incidence of CAH in Cuba was 1:15,931, similar to that reported by other programs. A recall for suspected CAH was performed in 10,799 cases (1.74%). Therapy in classical CAH patients was started at the mean age of 22 days. 17OHP levels were significantly higher in newborns with lower birth-weight (BW) and/or gestational age (GA). In addition, 17OHP values were affected by the gender, twin status or mode of delivery. In Cuba, the nationwide newborn screening program has allowed the early detection of CAH. The use of an optimized cut-off level for BW or GA could lead to a reduction in the percentage of recalled babies. Copyright © 2013 Elsevier B.V. All rights reserved.

Pilot proficiency testing study for second tier congenital adrenal hyperplasia newborn screening.

PubMed

De Jesús, Víctor R; Simms, David A; Schiffer, Jarad; Kennedy, Meredith; Mei, Joanne V; Hannon, W Harry

2010-11-11

Congenital adrenal hyperplasia (CAH) is caused by inherited defects in steroid biosynthesis. The Newborn Screening Quality Assurance Program (NSQAP) initiated a pilot, dried-blood spot (DBS)-based proficiency testing program designed to investigate materials and laboratory performance for second tier CAH screening by tandem mass spectrometry (MS/MS). The ratio of 17-α-hydroxyprogesterone (17-OHP), androstenedione (4-AD) and cortisol is used as an indicator of CAH in laboratory protocols for second tier analysis of DBS specimens. DBS prepared by NSQAP contained a range of steroid concentrations resulting in different clinical ratios. Laboratories received blind-coded DBS specimens and reported results to NSQAP for evaluation. Quantitative values reported by participants for 17-OHP, 4-AD, and cortisol, reflected small differences in their analytical methods. Average quantitative values for 17-OHP increased from 81% to 107% recovery over the 3.5-year period; cortisol recoveries increased from 61.9% to 89.5%; and 4-AD recoveries decreased from 184% to 68%. Laboratory participation in the CAH second tier proficiency testing program has resulted in improved analyte recoveries and enhanced sample preparation methodologies. NSQAP services for the second tier CAH analysis in DBS demonstrate the need for surveillance to ensure harmonization and continuous improvements, and to achieve sustained high-performance of newborn screening laboratories worldwide. Published by Elsevier B.V.

Fetal adrenal gland enlargement - prenatal and postnatal management.

PubMed

Lackova, Eliska; Cunderlik, Anton; Ticha, Lubica; Gabor, Maria

2017-11-01

The enlargement of suprarenal gland is related to preterm birth and the birth weight. The ultrasound measurement of fetal adrenal gland volume may identify women at risk for impending preterm birth. The aim of our study was to investigate the newborns in the region of western Slovakia followed up due to suprarenal gland enlargement. To set the ratio of prenatally diagnosed suprarenal gland enlargment, postnatal managment and treatment and interventions. The newborns with congenital adrenal hyperplasia were excluded. We have analyzed 6 years of medical records of all cases from the western Slovakia region of suprarenal gland enlargement encountered to 1st Pediatric Department, Children's University Hospital Bratislava Republic in the time period of January 2010 to Janurary 2016. The diagnosis of suprarenal gland enlargement was set by ultrasound examination performed on the 4th postnatal day as an overall screening test. Newborns with positive laboratory screening on congenital adrenal hyperplasia (CAH) were excluded from our study. We analyzed the origin of surarenal gland enlargement, gestation week on the due date, the birth weight and other comorbidities and genetic pathologies in newborns with the enlarged suprarenal glands. There were 6 newborns followed up due to suprarenal gland enlargement. All of the patients had diagnosed the adrenal haemorrhage. Adrenal lesions like adrenal cysts or neuroblastomas were not confirmed. All of the adrenal enlargements were benign with no need of other medical or surgical intervention. None of the newborn patients had other genetic abnormalities, mineral or hormonal imbalances, problems with arterial pressure or haemodynamic instability. All of the patients underwent at least 5 prenatal ultrasound tests and at least 2 postnatal ultrasound measurements. The avarage birth weight was 3030 grams (2700 grams - to 3750 grams). The avarage birth lenght was 50 cm (47 centimeter to 53 cm).The average gestation week (gw) on due date

Association of leptin with cardiometabolic factors in schoolchildren and adolescents with congenital adrenal hyperplasia.

PubMed

Zurita-Cruz, Jessie Nallely; Villasís-Keever, Miguel Ángel; Damasio-Santana, Leticia; Manuel-Apolinar, Leticia; Ferrusca-Ceja, Rosalba; Nishimura-Meguro, Elisa; Rivera-Hernández, Aleida de J; Garrido-Magaña, Eulalia

2018-01-01

In congenital adrenal hyperplasia (CAH), obesity, hyperinsulinemia and leptin levels are increased. To identify the frequency of cardiometabolic risk factors (CRF) in children and adolescents with CAH and to explore the relationship with leptin levels. Cross-sectional study of 40 patients who underwent anthropometric measurements and had fasting glucose, insulin, triglycerides, 17-hidroxyprogesterone, leptin, HDL and LDL-cholesterol assessed. The patients were classified according to the number of CRFs, and leptin levels were analyzed with the Kruskal-Wallis test. Pearson's correlation was applied between leptin, body mass index (BMI) z-score and body fat percentage. Fifty percent of the patients had obesity and overweight, 59% had hypertriglyceridemia, 40%, hypoalphalipoproteinemia, 27.5%, high LDL-cholesterol and 22.5% insulin resistance. There was positive correlation between leptin and body fat percentage (r = 0.64), BMI z-score (r = 0.55) and the number of CRFs (r = 0.65). In the obesity-adjusted multivariate analysis, leptin levels were associated with the number of CRFs. CAH had a high frequency of CRFs and leptin appeared to be associated with a more adverse cardiometabolic profile in subjects with obesity and overweight. Copyright: © 2018 SecretarÍa de Salud.

Vitreoretinal surgery without schisis cavity excision for the management of juvenile X linked retinoschisis.

PubMed

García-Arumí, J; Corcóstegui, I A; Navarro, R; Zapata, M A; Berrocal, M H

2008-11-01

Juvenile X linked retinoschisis (XLRS) is a congenital X linked recessive retinal disorder characterised by cystic maculopathy and peripheral schisis. This study presents the case of an 8-month-old boy with a documented positive family history of XLRS, with a large retinoschisis cavity affecting the macula, first in the left eye and 1 year later in the right eye. The patient underwent pars plana vitrectomy in both eyes using 23-G instruments, posterior hyaloid dissection, a small retinotomy, fluid drainage with a 42-G cannula, infrared diode laser and silicone oil as internal tamponade. The anatomical and functional outcomes at 3 years following the first surgery are described. To the authors' knowledge, there is no previously reported experience with this technique in patients with XLRS.

Gender role across development in adult women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

PubMed

Long, Dominique N; Wisniewski, Amy B; Migeon, Claude J

2004-10-01

This study evaluated the degree of femininity and masculinity at different developmental stages in a group of adult women, some of whom were exposed to elevated prenatal adrenal androgens as a result of congenital adrenal hyperplasia (CAH) due to 21 hydroxylase (21-OH) deficiency. Women who had presented to the Johns Hopkins Hospital Pediatric Endocrine Clinic for treatment of CAH due to 21-OH deficiency were included. The control group consisted of sisters of CAH participants and women referred for evaluation of polycystic ovary syndrome. Study participants were given a questionnaire asking them to indicate their degree of masculinity and femininity during childhood, adolescence, and adulthood. In addition, participants were asked questions related to their play behavior during childhood, including playmate preferences, toy preferences, and admiration of male or female characters during fantasy play. Across participant groups, self-reported femininity decreased in a dose response manner, according to prenatal androgen exposure. For all groups, femininity increased through developmental stages. Women with salt-losing CAH remained less feminine than controls into adulthood. Conversely, self-reported masculinity increased in a dose-response manner, according to prenatal androgen exposure, across participant groups. Women with CAH showed a decrease in masculinity across developmental stages, such that by adulthood, there were no significant differences in masculinity between controls and the women with CAH. Women with salt-losing CAH were more likely to recall preferences for boy playmates, male-typical toys, and admiration for male characters during childhood than other study participants. Our data support the effect of both prenatal androgen exposure and socialization on gender role behavior in adult women with CAH due to 21-OH deficiency.

Irradiation with X-rays phase-advances the molecular clockwork in liver, adrenal gland and pancreas.

PubMed

Müller, Mareike Hildegard; Rödel, Franz; Rüb, Udo; Korf, Horst-Werner

2015-02-01

The circadian clock of man and mammals shows a hierarchic organization. The master clock, located in the suprachiasmatic nuclei (SCN), controls peripheral oscillators distributed throughout the body. Rhythm generation depends on molecular clockworks based on transcriptional/translational interaction of clock genes. Numerous studies have shown that the clockwork in peripheral oscillators is capable to maintain circadian rhythms for several cycles in vitro, i.e. in the absence of signals from the SCN. The aim of the present study is to analyze the effects of irradiation with X-rays on the clockwork of liver, adrenal and pancreas. To this end organotypic slice cultures of liver (OLSC) and organotypic explant cultures of adrenal glands (OAEC) and pancreas (OPEC) were prepared from transgenic mPer2(luc) mice which express luciferase under the control of the promoter of an important clock gene, Per2, and allow to study the dynamics of the molecular clockwork by bioluminometry. The preparations were cultured in a membrane-based liquid-air interface culturing system and irradiated with X-rays at doses of 10 Gy and 50 Gy or left untreated. Bioluminometric real-time recordings show a stable oscillation of all OLSC, OAEC and OPEC for up to 12 days in vitro. Oscillations persist after irradiation with X-rays. However, a dose of 50 Gy caused a phase advance in the rhythm of the OLSC by 5 h, in the OPEC by 7 h and in the OAEC by 6 h. Our study shows that X-rays affect the molecular clockwork in liver, pancreas and adrenal leading to phase advances. Our results confirm and extend previous studies showing a phase-advancing effect of X-rays at the level of the whole animal and single cells.

Mapping of the X-linked cataract (Xcat) mutation, the gene implicated in the Nance Horan syndrome, on the mouse X chromosome.

PubMed

Stambolian, D; Favor, J; Silvers, W; Avner, P; Chapman, V; Zhou, E

1994-07-15

The Xcat mutation in the mouse, an X-linked inherited disorder, is characterized by the congenital onset of cataracts. The cataracts have morphologies similar to those of cataracts found in the human Nance Horan (X-linked cataract dental) syndrome, suggesting that Xcat is an animal model for Nance Horan. The Xcat mutation provides an opportunity to investigate, at the molecular level, the pathogenesis of cataract. As a first step to cloning the Xcat gene, we report the localization of the Xcat mutation with respect to known molecular markers on the mouse X chromosome. Back-cross progeny carrying the Xcat mutation were obtained from an interspecific cross. Genomic DNA from each mouse was subjected to Southern and PCR analysis to identify restriction fragment length polymorphisms and simple sequence length polymorphisms, respectively. Our results refine the location of Xcat to a 2-cM region, eliminate several genes from consideration as the Xcat mutation, identify molecular probes tightly linked with Xcat, and suggest candidate genes responsible for the Xcat phenotype.

Congenital adrenal hyperplasia: problems with developmental anomalies of the external genitalia and sex assignment.

PubMed

Al-Maghribi, Hussein

2007-09-01

A retrospective study was performed on all patients with congenital adrenal hyperplasia (CAH) who were followed up at the King Hussein Medical Center (KHMC), Amman, Jordan, during the period from January 1996 to June 2006. The aim was to evaluate the clinical features, special problems, and corrective interventions for these patients. The records of 73 children (39 were genetic females and 34 were genetic males) with CAH were reviewed in the study. The age of the patients at last follow-up was between five months and 18 years. Diagnostic criteria for CAH were typical clinical features of the illness (salt loss, dehydration, virilization, macrogenitosomia, ambiguous genitalia, and accelerated growth) and typical hormonal abnormalities (decreased serum cortisol and elevated serum 17-hydroxyprogesterone). There were 62 patients with classical presentation; among them, salt-wasting (SW) form was seen in 41 patients (66%). There were 5 patients with the nonclassic form, while 6 others had cryptic presentation. Seven patients (9%) had hypertension, mostly due to salt-retaining CAH. Among the 39 females with CAH, 27 had developed mental anomalies of the external genitalia; 20 of them underwent surgical interventions of their external genitalia. Fourteen genetically female patients were wrongly diagnosed as 'male sex' at birth due to severe virilization. Seven of them were reassigned 'female sex' socially, legally, and surgically; the parents of one of them (a four-year-old girl) wanted the surgical intervention postponed for two to three years. Hysterectomy and gonadectomy were carried out for 6 of the other 7 patients who chose to keep the male gender. Our study indicates that newborns with developmental anomalies of the external genitalia should be diagnosed as early as possible so that medical, psychological, and social complications are minimized. A neonatal screening program for such a disorder can identify infants at risk for the development of life

Trails on 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Leading to Diagnosis of Testicular Adrenal Rest Tumor.

PubMed

Kashyap, Raghava

2018-01-01

Testicular adrenal rest tumors (TARTs) are secondary to hypertrophy of adrenal rest cells in the rete testis in settings of hypersecretion of androgens. We present a case of congenital adrenal hyperplasia with TART with clues to the diagnosis on 18 F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG PET/CT). To the best of our knowledge, this is the first reported case on the role of 18 F-FDG PET/CT in TART.

A new compound heterozygous frameshift mutation in the type II 3{beta}-hydroxysteroid dehydrogenase 3{beta}-HSD gene causes salt-wasting 3{beta}-HSD deficiency congenital adrenal hyperplasia

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

Zhang, L.; Sakkal-Alkaddour, S.; Chang, Ying T.

1996-01-01

We report a new compound heterozygous frameshift mutation in the type II 3{Beta}-hydroxysteroid dehydrogenase (3{beta}-HSD) gene in a Pakistanian female child with the salt-wasting form of 3{Beta}-HSD deficiency congenital adrenal hyperplasia. The etiology for her congenital adrenal hyperplasia was not defined. Although the family history suggested possible 3{beta}-HSd deficiency disorder, suppressed adrenal function caused by excess glucocorticoid therapy in this child at 7 yr of age did not allow hormonal diagnosis. To confirm 3{beta}-HSD deficiency, we sequenced the type II 3{beta}-HSD gene in the patient, her family, and the parents of her deceased paternal cousins. The type II 3{beta}-HSD genemore » region of a putative promotor, exons I, II, III, and IV, and exon-intron boundaries were amplified by PCR and sequenced in all subjects. The DNA sequence of the child revealed a single nucleotide deletion at codon 318 [ACA(Thr){r_arrow}AA] in exon IV in one allele, and two nucleotide deletions at codon 273 [AAA(Lys){r_arrow}A] in exon IV in the other allele. The remaining gene sequences were normal. The codon 318 mutation was found in one allele from the father, brother, and parents of the deceased paternal cousins. The codon 273 mutation was found in one allele of the mother and a sister. These findings confirmed inherited 3{beta}-HSD deficiency in the child caused by the compound heterozygous type II 3{beta}-HSD gene mutation. Both codons at codons 279 and 367, respectively, are predicted to result in an altered and truncated type II 3{beta}-HSD protein, thereby causing salt-wasting 3{beta}-HSD deficiency in the patient. 21 refs., 2 figs., 1 tab.« less

Prenatal hormones and postnatal socialization by parents as determinants of male-typical toy play in girls with congenital adrenal hyperplasia.

PubMed

Pasterski, Vickie L; Geffner, Mitchell E; Brain, Caroline; Hindmarsh, Peter; Brook, Charles; Hines, Melissa

2005-01-01

Toy choices of 3- to 10-year-old children with congenital adrenal hyperplasia (CAH) and of their unaffected siblings were assessed. Also assessed was parental encouragement of sex-typed toy play. Girls with CAH displayed more male-typical toy choices than did their unaffected sisters, whereas boys with and without CAH did not differ. Mothers and fathers encouraged sex-typical toy play in children with and without CAH. However, girls with CAH received more positive feedback for play with girls' toys than did unaffected girls. Data show that increased male-typical toy play by girls with CAH cannot be explained by parental encouragement of male-typical toy play. Although parents encourage sex-appropriate behavior, their encouragement appears to be insufficient to override the interest of girls with CAH in cross-sexed toys.

Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency.

PubMed

Khattab, Ahmed; Haider, Shozeb; Kumar, Ameet; Dhawan, Samarth; Alam, Dauood; Romero, Raquel; Burns, James; Li, Di; Estatico, Jessica; Rahi, Simran; Fatima, Saleel; Alzahrani, Ali; Hafez, Mona; Musa, Noha; Razzghy Azar, Maryam; Khaloul, Najoua; Gribaa, Moez; Saad, Ali; Charfeddine, Ilhem Ben; Bilharinho de Mendonça, Berenice; Belgorosky, Alicia; Dumic, Katja; Dumic, Miroslav; Aisenberg, Javier; Kandemir, Nurgun; Alikasifoglu, Ayfer; Ozon, Alev; Gonc, Nazli; Cheng, Tina; Kuhnle-Krahl, Ursula; Cappa, Marco; Holterhus, Paul-Martin; Nour, Munier A; Pacaud, Daniele; Holtzman, Assaf; Li, Sun; Zaidi, Mone; Yuen, Tony; New, Maria I

2017-03-07

Congenital adrenal hyperplasia (CAH), resulting from mutations in CYP11B1 , a gene encoding 11β-hydroxylase, represents a rare autosomal recessive Mendelian disorder of aberrant sex steroid production. Unlike CAH caused by 21-hydroxylase deficiency, the disease is far more common in the Middle East and North Africa, where consanguinity is common often resulting in identical mutations. Clinically, affected female newborns are profoundly virilized (Prader score of 4/5), and both genders display significantly advanced bone ages and are oftentimes hypertensive. We find that 11-deoxycortisol, not frequently measured, is the most robust biochemical marker for diagnosing 11β-hydroxylase deficiency. Finally, computational modeling of 25 missense mutations of CYP11B1 revealed that specific modifications in the heme-binding (R374W and R448C) or substrate-binding (W116C) site of 11β-hydroxylase, or alterations in its stability (L299P and G267S), may predict severe disease. Thus, we report clinical, genetic, hormonal, and structural effects of CYP11B1 gene mutations in the largest international cohort of 108 patients with steroid 11β-hydroxylase deficiency CAH.

Quantitative trait locus mapping of genes associated with vacuolation in the adrenal X-zone of the DDD/Sgn inbred mouse.

PubMed

Suto, Jun-Ichi

2012-11-06

Adrenal gland of mice contains a transient zone between the adrenal cortex and the adrenal medulla: the X-zone. There are clear strain differences in terms of X-zone morphology. Nulliparous females of the inbred mouse DDD strain develop adrenal X-zones containing exclusively vacuolated cells, whereas females of the inbred mouse B6 strain develop X-zones containing only non-vacuolated cells. The X-zone vacuolation is a physiologic process associated with the X-zone degeneration and is tightly regulated by genetic factors. Identification of the genetic factors controlling such strain differences should help analyze the X-zone function. In this study, a quantitative trait locus (QTL) analysis for the extent of X-zone vacuolation was performed for two types of F2 female mice: F2Ay mice (F2 mice with the Ay allele) and F2 non-Ay mice (F2 mice without the Ay allele). These were produced by crossing B6 females and DDD.Cg-Ay males. DDD.Cg-Ay is a congenic mouse strain for the Ay allele at the agouti locus and is used for this study because a close association between the X-zone morphology and the agouti locus genotype has been suggested. The Ay allele is dominant and homozygous lethal; therefore, living Ay mice are invariably heterozygotes. Single QTL scans identified significant QTLs on chromosomes 1, 2, 6, and X for F2 non-Ay mice, and on chromosomes 2, 6, and 12 for F2Ay mice. The QTL on chromosome 2 was considered to be because of the agouti locus, which has been suggested to be associated with X-zone vacuolation. A significant QTL that interacted with the agouti locus was identified on chromosome 8. The extent of X-zone vacuolation in DDD females was controlled by multiple genes with complex interactions. The murine X-zone is considered analogous structure to the human fetal zone. Therefore, the results of this study will aid in understanding function of not only of the X-zone but also of the human fetal zone. Identifying the genes responsible for the QTLs will be

Quantitative trait locus mapping of genes associated with vacuolation in the adrenal X-zone of the DDD/Sgn inbred mouse

PubMed Central

2012-01-01

Background Adrenal gland of mice contains a transient zone between the adrenal cortex and the adrenal medulla: the X-zone. There are clear strain differences in terms of X-zone morphology. Nulliparous females of the inbred mouse DDD strain develop adrenal X-zones containing exclusively vacuolated cells, whereas females of the inbred mouse B6 strain develop X-zones containing only non-vacuolated cells. The X-zone vacuolation is a physiologic process associated with the X-zone degeneration and is tightly regulated by genetic factors. Identification of the genetic factors controlling such strain differences should help analyze the X-zone function. In this study, a quantitative trait locus (QTL) analysis for the extent of X-zone vacuolation was performed for two types of F2 female mice: F2Ay mice (F2 mice with the Ay allele) and F2 non-Ay mice (F2 mice without the Ay allele). These were produced by crossing B6 females and DDD.Cg-Ay males. DDD.Cg-Ay is a congenic mouse strain for the Ay allele at the agouti locus and is used for this study because a close association between the X-zone morphology and the agouti locus genotype has been suggested. The Ay allele is dominant and homozygous lethal; therefore, living Ay mice are invariably heterozygotes. Results Single QTL scans identified significant QTLs on chromosomes 1, 2, 6, and X for F2 non-Ay mice, and on chromosomes 2, 6, and 12 for F2Ay mice. The QTL on chromosome 2 was considered to be because of the agouti locus, which has been suggested to be associated with X-zone vacuolation. A significant QTL that interacted with the agouti locus was identified on chromosome 8. Conclusions The extent of X-zone vacuolation in DDD females was controlled by multiple genes with complex interactions. The murine X-zone is considered analogous structure to the human fetal zone. Therefore, the results of this study will aid in understanding function of not only of the X-zone but also of the human fetal zone. Identifying the genes

Genetics Home Reference: 3-beta-hydroxysteroid dehydrogenase deficiency

MedlinePlus

... Topic: Adrenal Gland Disorders Health Topic: Assisted Reproductive Technology Health Topic: Infertility Genetic and Rare Diseases Information Center (1 link) 3-beta-hydroxysteroid dehydrogenase deficiency Educational Resources (6 links) Boston Children's Hospital: Congenital Adrenal ...

Unusual phenotype of congenital adrenal hyperplasia (CAH) with a novel mutation of the CYP21A2 gene.

PubMed

Raisingani, Manish; Contreras, Maria F; Prasad, Kris; Pappas, John G; Kluge, Michelle L; Shah, Bina; David, Raphael

2016-07-01

Gonadotropin independent sexual precocity (SP) may be due to congenital adrenal hyperplasia (CAH), and its timing usually depends on the type of mutation in the CYP21A2 gene. Compound heterozygotes are common and express phenotypes of varying severity. The objective of this case report was to investigate the hormonal pattern and unusual genetic profile in a 7-year-old boy who presented with pubic hair, acne, an enlarged phallus, slightly increased testicular volume and advanced bone age. Clinical, hormonal and genetic studies were undertaken in the patient as well as his parents. We found elevated serum 17-hydroxyprogesterone (17-OHP) and androstenedione that were suppressed with dexamethasone, and elevated testosterone that actually rose after giving dexamethasone, indicating activity of the hypothalamic-pituitary-gonadal (HPG) axis. An initial search for common mutations was negative, but a more detailed genetic analysis of the CYP21A2 gene revealed two mutations including R341W, a non-classical mutation inherited from his mother, and g.823G>A, a novel not previously reported consensus donor splice site mutation inherited from his father, which is predicted to be salt wasting. However, the child had a normal plasma renin activity. He was effectively treated with low-dose dexamethasone and a GnRH agonist. His father was an unaffected carrier, but his mother had evidence of mild non-classical CAH. In a male child presenting with gonadotropin independent SP it is important to investigate adrenal function with respect to the androgen profile, and to carry out appropriate genetic studies.

Possible influences on the expression of X chromosome-linked dystrophin abnormalities by heterozygosity for autosomal recessive Fukuyama congenital muscular dystrophy

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

Beggs, A.H.; Neumann, P.E.; Anderson, M.S.

1992-01-15

Abnormalities of dystrophin, a cytoskeletal protein of muscle and nerve, are generally considered specific for Duchenne and Becker muscular dystrophy. However, several patients have recently been identified with dystrophin deficiency who, before dystrophin testing, were considered to have Fukuyama congenital muscular dystrophy (FCMD) on the basis of clinical findings. Epidemiologic data suggest that only 1/3,500 males with autosomal recessive FCMD should have abnormal dystrophin. To explain the observation of 3/23 FCMD males with abnormal dystrophin, the authors propose that dystrophin and the FCMD gene product interact and that the earlier onset and greater severity of these patients' phenotype (relative tomore » Duchenne muscular dystrophy) are due to their being heterozygous for the FCMD mutation in addition to being hemizygous for Duchenne muscular dystrophy, a genotype that is predicted to occur in 1/175,000 Japanese males. This model may help explain the genetic basis for some of the clinical and pathological variability seen among patients with FCMD, and it has potential implications for understanding the inheritance of other autosomal recessive disorders in general. For example, sex ratios for rare autosomal recessive disorders caused by mutations in proteins that interact with X chromosome-linked gene products may display predictable deviation from 1:1.« less

Genotype-phenotype variations in five Spanish families with Norrie disease or X-linked FEVR.

PubMed

Riveiro-Alvarez, Rosa; Trujillo-Tiebas, Maria José; Gimenez-Pardo, Ascension; Garcia-Hoyos, Maria; Cantalapiedra, Diego; Lorda-Sanchez, Isabel; Rodriguez de Alba, Marta; Ramos, Carmen; Ayuso, Carmen

2005-09-02

Norrie disease (OMIM 310600) is a rare X-linked disorder characterized by congenital blindness in males. Approximately 40 to 50% of the cases develop deafness and mental retardation. X-linked familial exudative vitreoretinopathy (XL-FEVR) is a hereditary ocular disorder characterized by a failure of peripheral retinal vascularization. Both X-linked disorders are due to mutations in the NDP gene, which encodes a 133 amino acid protein called Norrin, but autosomal recessive (AR) and autosomal dominant (AD) forms of FEVR have also been described. In this study, we report the molecular findings and the related phenotype in five Spanish families affected with Norrie disease or XL-FEVR due to mutations of the NDP gene. The study was conducted in 45 subjects from five Spanish families. These families were clinically diagnosed with Norrie disease or similar conditions. The three exons of the NDP gene were analyzed by automatic DNA sequencing. Haplotype analyses were also performed. Two new nonsense mutations, apart from other mutations previously described in the NDP gene, were found in those patients affected with ND or X-linked FEVR. An important genotype-phenotype variation was found in relation to the different mutations of the NDP gene. In fact, the same mutation may be responsible for different phenotypes. We speculate that there might be other molecular factors that interact in the retina with Norrin, which contribute to the resultant phenotypes.

Nonsalt-losing congenital adrenal hyperplasia due to 3 beta-hydroxysteroid dehydrogenase deficiency with normal glomerulosa function.

PubMed

Pang, S; Levine, L S; Stoner, E; Opitz, J M; Pollack, M S; Dupont, B; New, M I

1983-04-01

glucuronide, suggesting the presence of normal peripheral 3 beta-HSD activity. We propose that in these siblings, there is a deficiency of 3 beta-HSD in the adrenal zona fasciculata and zona reticularis, whereas 3 beta-HSD activity is intact in the zona glomerulosa. In addition, in these siblings, 3 beta-HSD deficiency was present in the gonads, while peripheral 3 beta-HSD activity appeared to be intact. These cases demonstrate further the heterogeneity of congenital adrenal hyperplasia due to 3 beta-HSD deficiency.

Effects on gender identity of prenatal androgens and genital appearance: evidence from girls with congenital adrenal hyperplasia.

PubMed

Berenbaum, Sheri A; Bailey, J Michael

2003-03-01

To address questions about sex assignment in children with ambiguous genitalia, we studied gender identity in girls with congenital adrenal hyperplasia (CAH) in relation to characteristics of the disease and treatment, particularly genital appearance and surgery. A 9-item gender identity interview was administered to 43 girls with classical CAH ranging in age from 3-18 yr, 7 tomboys, and 29 sister control girls. Groups were compared on total score and on individual items. Results showed that, on the total gender identity score, 88% of girls with CAH had scores overlapping those of control girls, but the average score was intermediate between control girls and tomboys. On individual items of gender identity (discomfort as a girl, wish to be a boy), girls with CAH were similar to control girls. Gender identity in girls with CAH was not related to degree of genital virilization or age at which genital reconstructive surgery was done. Thus, moderate androgen excess early in development appears to produce a small increase in the risk of atypical gender identity, but this risk cannot be predicted from genital virilization.

Combination of a Haploidentical Stem Cell Transplant With Umbilical Cord Blood for Cerebral X-Linked Adrenoleukodystrophy.

PubMed

Jiang, Hua; Jiang, Min-Yan; Liu, Sha; Cai, Yan-Na; Liang, Cui-Li; Liu, Li

2015-08-01

Childhood cerebral X-linked adrenoleukodystrophy is a rapidly progressive neurodegenerative disorder that affects central nervous system myelin and the adrenal cortex. Hematopoietic stem cell transplantation is the best available curative therapy if performed during the early stages of disease. Only 30% of patients who might benefit from a hematopoietic stem cell transplant will have a full human leukocyte antigen-matched donor, which is considered to be the best choice. We present a 5-year-old boy with cerebral X-linked adrenoleukodystrophy whose brain magnetic resonance imaging severity score was 7 and who needed an immediate transplantation without an available full human leukocyte antigen-matched donor. We combined haploidentical and umbilical cord blood sources for transplantation and saw encouraging results. After transplantation, the patient showed neurological stability for 6 months and the level of very long chain fatty acids had decreased. By 1 year, the patient appeared to gradually develop cognition, motor, and visual disturbances resulting from possible mix chimerism. Transplantation of haploidentical stem cells combined with the infusion of umbilical cord blood is a novel approach for treating cerebral X-linked adrenoleukodystrophy. It is critical to monitor posttransplant chimerism and carry out antirejection therapy timely for a beneficial clinical outcome. Copyright © 2015 Elsevier Inc. All rights reserved.

AB067. X-linked adrenoleukodystrophy: Phenotype and genotype in Vietnamese patients

PubMed Central

Nguyen, Khanh Ngoc; Nguyen, Ha Thu; Can, Ngoc Thi Bich; Bui, Thao Phuong; Nobuyuki, Shimozawa; Vu, Huynh Anh; Do, Mai Thi Thanh; Vu, Dung Chi

2017-01-01

Background X-linked adrenoleukodystrophy (X-ALD) is caused by a defect in the gene ABCD1, which maps to Xq28 and codes for a peroxisomal membrane protein that is a member of the ATP-binding cassette transporter superfamily. This disease characterized by progressive neurologic dysfunction, occasionally associated with adrenal insufficiency. Objective is to identify phenotype and genotype in Vietnamese patients with X-ALD. Methods Genomic DNA from 20 Vietnamese patients from 18 unrelated families was extracted using standard procedures from the peripheral blood leukocytes. Mutation analysis of ABCD1 was performed using polymerase chain reaction (PCR) and DNA direct sequencing. Results We identified 17 different mutations of ABCD1 in 20 patients including missense mutations (2/17), deletion (4/17), frameshift mutation (1/17) and splice site mutation (1/17). Of which, six novel mutations including c.1202G>T (p.Arg401Trp); c.1208T>A (p.Met403Lys); IVS8+28-551bp del; c.1668G>C (p.Q556H); c.292_296delTCGGC (p.S98RfsX95); and the extent of deletion included between IVS1+505 and IVS2+1501, containing whole the exon 2 (4243bp), plus insertion of 79bp from BAP31 and 8bp from unknown origin in this deleted region were identified in six unrelated patients. Eleven reported mutations including c.796G>A (p.Gly266Arg); c.1628C>T (p.Pro543Leu); c.1553G>A (p.Arg518Gln); c.1552 C>T (p.Arg518Trp); c.854G>C (p.R285P); c.1825G>A (p.E609K); c.1415_1416delAG (p.Q472RfsX83) and c.46-53del insG, c.1553G>A (p.Arg518Gln), c.1946-1947insA (p.Asp649fsX733), c.1978C>T (p.Arg660Trp) were identified in 14 patients from 12 families. Most of patients (17/20) presented cerebral ALD type with/without adrenal insufficiency and only 3 patients presented Addison type. Conclusions Mutation analysis of ABCD1 gene helped confirmation of diagnosis of X-ALD, genetic counselling and prenatal diagnosis but could not be used to predict the specific phenotype of X-ALD.

Prenatal androgens and gender-typed behavior: a study of girls with mild and severe forms of congenital adrenal hyperplasia.

PubMed

Servin, Anna; Nordenström, Anna; Larsson, Agne; Bohlin, Gunilla

2003-05-01

Gender-typed behaviors and interests were investigated in 26 girls, aged 2-10 years, affected with congenital adrenal hyperplasia (CAH) and in 26 unaffected girls matched for age. Girls with CAH were more interested in masculine toys and less interested in feminine toys and were more likely to report having male playmates and to wish for masculine careers. Parents of girls with CAH rated their daughters' behaviors as more boylike than did parents of unaffected girls. A relation was found between disease severity and behavior indicating that more severely affected CAH girls were more interested in masculine toys and careers. No parental influence could be demonstrated on play behavior, nor did the comparison of parents' ratings of wished for behavior versus perceived behavior in their daughters indicate an effect of parental expectations. The results are interpreted as supporting a biological contribution to differences in play behavior between girls with and without CAH.

Congenital diaphragmatic hernia as a part of Nance-Horan syndrome?

PubMed

Kammoun, Molka; Brady, Paul; De Catte, Luc; Deprest, Jan; Devriendt, Koenraad; Vermeesch, Joris Robert

2018-03-01

Nance-Horan syndrome is a rare X-linked developmental disorder characterized by bilateral congenital cataract, dental anomalies, facial dysmorphism, and intellectual disability. Here, we identify a patient with Nance-Horan syndrome caused by a new nonsense NHS variant. In addition, the patient presented congenital diaphragmatic hernia. NHS gene expression in murine fetal diaphragm was demonstrated, suggesting a possible involvement of NHS in diaphragm development. Congenital diaphragmatic hernia could result from NHS loss of function in pleuroperitoneal fold or in somites-derived muscle progenitor cells leading to an impairment of their cells migration.

Syndromes that Link the Endocrine System and Genitourinary Tract.

PubMed

Özlük, Yasemin; Kılıçaslan, Işın

2015-01-01

The endocrine system and genitourinary tract unite in various syndromes. Genitourinary malignancies may cause paraneoplastic endocrine syndromes by secreting hormonal substances. These entities include Cushing`s syndrome, hypercalcemia, hyperglycemia, polycythemia, hypertension, and inappropriate ADH or HCG production. The most important syndromic scenarios that links these two systems are hereditary renal cancer syndromes with specific genotype/phenotype correlation. There are also some very rare entities in which endocrine and genitourinary systems are involved such as Carney complex, congenital adrenal hyperplasia and Beckwith-Wiedemann syndrome. We will review all the syndromes regarding manifestations present in endocrine and genitourinary organs.

Genetics Home Reference: X-linked thrombocytopenia

MedlinePlus

... Facebook Twitter Home Health Conditions X-linked thrombocytopenia X-linked thrombocytopenia Printable PDF Open All Close All ... Javascript to view the expand/collapse boxes. Description X-linked thrombocytopenia is a bleeding disorder that primarily ...

Fundamental studies of adrenal retinoid-X-receptor: Protein isoform, tissue expression, subcellular distribution, and ligand availability.

PubMed

Cheng, Behling; Al-Shammari, Fatema H; Ghader, Isra'a A; Sequeira, Fatima; Thakkar, Jitendra; Mathew, Thazhumpal C

2017-07-01

Adrenal gland reportedly expresses many nuclear receptors that are known to heterodimerize with retinoid-X-receptor (RXR) for functions, but the information regarding the glandular RXR is not adequate. Studies of rat adrenal homogenate by Western blotting revealed three RXR proteins: RXRα (55kDa), RXRβ (47kDa) and RXR (56kDa). RXRγ was not detectable. After fractionation, RXRα was almost exclusively localized in the nuclear fraction. In comparison, substantial portions of RXRβ and RXR were found in both nuclear and post-nuclear particle fractions, suggesting genomic and non-genomic functions. Cells immunostained for RXRα were primarily localized in zona fasciculata (ZF) and medulla, although some stained cells were found in zona glomerulosa (ZG) and zona reticularis (ZR). In contrast, cells immunostained for RXRβ were concentrated principally in ZG, although some stained cells were seen in ZR, ZF, and medulla (in descending order, qualitatively). Analysis of adrenal lipid extracts by LC/MS did not detect 9-cis-retinoic acid (a potent RXR-ligand) but identified all-trans retinoic acid. Since C20 and C22 polyunsaturated fatty acids (PUFAs) can also activate RXR, subcellular availabilities of unesterified fatty acids were investigated by GC/MS. As results, arachidonic acid (C20:4), adrenic acid (C22:4), docosapentaenoic acid (C22:5), and cervonic acid (C22:6) were detected in the lipids extracted from each subcellular fraction. Thus, the RXR-agonizing PUFAs are available in all the main subcellular compartments considerably. The present findings not only shed light on the adrenal network of RXRs but also provide baseline information for further investigations of RXR heterodimers in the regulation of adrenal steroidogenesis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Guidelines for the Development of Comprehensive Care Centers for Congenital Adrenal Hyperplasia: Guidance from the CARES Foundation Initiative

PubMed Central

Auchus, Richard J.; Witchel, Selma Feldman; Leight, Kelly R.; Aisenberg, Javier; Azziz, Ricardo; Bachega, Tânia A.; Baker, Linda A.; Baratz, Arlene B.; Baskin, Laurence S.; Berenbaum, Sheri A.; Breault, David T.; Cerame, Barbara I.; Conway, Gerard S.; Eugster, Erica A.; Fracassa, Stephanie; Gearhart, John P.; Geffner, Mitchell E.; Harris, Katharine B.; Hurwitz, Richard S.; Katz, Aviva L.; Kalro, Brinda N.; Lee, Peter A.; Alger Lin, Gretchen; Loechner, Karen J.; Marshall, Ian; Merke, Deborah P.; Migeon, Claude J.; Miller, Walter L.; Nenadovich, Tamara L.; Oberfield, Sharon E.; Pass, Kenneth A.; Poppas, Dix P.; Lloyd-Puryear, Michele A.; Quigley, Charmian A.; Riepe, Felix G.; Rink, Richard C.; Rivkees, Scott A.; Sandberg, David E.; Schaeffer, Traci L.; Schlussel, Richard N.; Schneck, Francis X.; Seely, Ellen W.; Snyder, Diane; Speiser, Phyllis W.; Therrell, Bradford L.; VanRyzin, Carol; Vogiatzi, Maria G.; Wajnrajch, Michael P.; White, Perrin C.; Zuckerman, Alan E.

2010-01-01

Patients with rare and complex diseases such as congenital adrenal hyperplasia (CAH) often receive fragmented and inadequate care unless efforts are coordinated among providers. Translating the concepts of the medical home and comprehensive health care for individuals with CAH offers many benefits for the affected individuals and their families. This manuscript represents the recommendations of a 1.5 day meeting held in September 2009 to discuss the ideal goals for comprehensive care centers for newborns, infants, children, adolescents, and adults with CAH. Participants included pediatric endocrinologists, internal medicine and reproductive endocrinologists, pediatric urologists, pediatric surgeons, psychologists, and pediatric endocrine nurse educators. One unique aspect of this meeting was the active participation of individuals personally affected by CAH as patients or parents of patients. Representatives of Health Research and Services Administration (HRSA), New York-Mid-Atlantic Consortium for Genetics and Newborn Screening Services (NYMAC), and National Newborn Screening and Genetics Resource Center (NNSGRC) also participated. Thus, this document should serve as a “roadmap” for the development phases of comprehensive care centers (CCC) for individuals and families affected by CAH. PMID:21274448

Role of ALDP (ABCD1) and Mitochondria in X-Linked Adrenoleukodystrophy

PubMed Central

McGuinness, M. C.; Lu, J.-F.; Zhang, H.-P.; Dong, G.-X.; Heinzer, A. K.; Watkins, P. A.; Powers, J.; Smith, K. D.

2003-01-01

Peroxisomal disorders have been associated with malfunction of peroxisomal metabolic pathways, but the pathogenesis of these disorders is largely unknown. X-linked adrenoleukodystrophy (X-ALD) is associated with elevated levels of very-long-chain fatty acids (VLCFA; C>22:0) that have been attributed to reduced peroxisomal VLCFA β-oxidation activity. Previously, our laboratory and others have reported elevated VLCFA levels and reduced peroxisomal VLCFA β-oxidation in human and mouse X-ALD fibroblasts. In this study, we found normal levels of peroxisomal VLCFA β-oxidation in tissues from ALD mice with elevated VLCFA levels. Treatment of ALD mice with pharmacological agents resulted in decreased VLCFA levels without a change in VLCFA β-oxidation activity. These data indicate that ALDP does not determine the rate of VLCFA β-oxidation and that VLCFA levels are not determined by the rate of VLCFA β-oxidation. The rate of peroxisomal VLCFA β-oxidation in human and mouse fibroblasts in vitro is affected by the rate of mitochondrial long-chain fatty acid β-oxidation. We hypothesize that ALDP facilitates the interaction between peroxisomes and mitochondria, resulting, when ALDP is deficient in X-ALD, in increased VLCFA accumulation despite normal peroxisomal VLCFA β-oxidation in ALD mouse tissues. In support of this hypothesis, mitochondrial structural abnormalities were observed in adrenal cortical cells of ALD mice. PMID:12509471

Gender of rearing and psychosocial aspect in 46 XX congenital adrenal hyperplasia

PubMed Central

Gangaher, Arushi; Jyotsna, Viveka P.; Chauhan, Vasundhera; John, Jomimol; Mehta, Manju

2016-01-01

Background: In congenital adrenal hyperplasia (CAH) with ambiguous genitalia, assigning gender of rearing can be complex, especially If genitalia is highly virilized. Apart from karyotype, prenatal androgen exposure, patient's gender orientation, sociocultural, and parental influences play a role. The aim of this study was to assess gender dysphoria and psychosocial issues in patients of CAH raised as males and females. Materials and Methods: This is a cross-sectional study that includes patients (old and new) with CAH who were treated by us in the last 6 months. A semi-structured interview proforma was used to elicit history and psychosocial background of the patients. The clinical and biochemical details were noted. For psychological analysis, patients were screened for gender dysphoria using Parent Report Gender Identity Questionnaire for children <12 years and Gender Identity/Gender Dysphoria Questionnaire for Adolescents and Adults. Results: We analyzed 22 46 XX CAH patients among which, 3 were reared as males and 19 as females. Among the 19 patients reared as females, 17 patients showed no gender dysphoria. Two patients revealed gender dysphoria as indicated by their marginally low scores on the gender dysphoria assessment. However, in view of current literature and the age groups of the patients, behavior of the 6-year-old patient can be best understood as being tomboyish. Gender dysphoria in the 22-year-old can be explained by the dominance of psychosocial factors and not hormones alone. Among the three patients reared as males, two prepubertal were satisfied with their male gender identity. The third patient, aged 32 years, had gender dysphoria when reared as a male that resolved when gender was reassigned as female and feminizing surgery was done. Conclusion: Gender assignment in 46 XX CAH is guided by factors such as degree of virilization of genitalia, gender orientation, patient involvement, sociocultural, and parental influences. PMID:27867895

Gender of rearing and psychosocial aspect in 46 XX congenital adrenal hyperplasia.

PubMed

Gangaher, Arushi; Jyotsna, Viveka P; Chauhan, Vasundhera; John, Jomimol; Mehta, Manju

2016-01-01

In congenital adrenal hyperplasia (CAH) with ambiguous genitalia, assigning gender of rearing can be complex, especially If genitalia is highly virilized. Apart from karyotype, prenatal androgen exposure, patient's gender orientation, sociocultural, and parental influences play a role. The aim of this study was to assess gender dysphoria and psychosocial issues in patients of CAH raised as males and females. This is a cross-sectional study that includes patients (old and new) with CAH who were treated by us in the last 6 months. A semi-structured interview proforma was used to elicit history and psychosocial background of the patients. The clinical and biochemical details were noted. For psychological analysis, patients were screened for gender dysphoria using Parent Report Gender Identity Questionnaire for children <12 years and Gender Identity/Gender Dysphoria Questionnaire for Adolescents and Adults. We analyzed 22 46 XX CAH patients among which, 3 were reared as males and 19 as females. Among the 19 patients reared as females, 17 patients showed no gender dysphoria. Two patients revealed gender dysphoria as indicated by their marginally low scores on the gender dysphoria assessment. However, in view of current literature and the age groups of the patients, behavior of the 6-year-old patient can be best understood as being tomboyish. Gender dysphoria in the 22-year-old can be explained by the dominance of psychosocial factors and not hormones alone. Among the three patients reared as males, two prepubertal were satisfied with their male gender identity. The third patient, aged 32 years, had gender dysphoria when reared as a male that resolved when gender was reassigned as female and feminizing surgery was done. Gender assignment in 46 XX CAH is guided by factors such as degree of virilization of genitalia, gender orientation, patient involvement, sociocultural, and parental influences.

Congenital adrenal hyperplasia clinical characteristics and genotype in newborn, childhood and adolescence.

PubMed

Pasqualini, Titania; Alonso, Guillermo; Tomasini, Rosangela; Galich, Ana Maria; Buzzalino, Noemi; Fernandez, Cecilia; Minutolo, Carolina; Alba, Liliana; Dain, Liliana

2007-01-01

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is a disorder which can adopt three clinical expressions: two classical forms -salt-wasting (SW), with residual enzymatic activity (EA) < or = 1% and simple virilizing (SV), with EA 1-2%- and a mild late onset or nonclassical (NC) form, with EA 10-60%. Our objective is to describe clinical characteristics, growth, and bone mass in a group of patients affected by 21-hydroxylase deficiency. Besides, molecular genetics studies were performed in patients, and also when available in their parents and siblings. Nine patients with neonatal diagnosis and 8 with pre or postpubertal diagnosis were studied. Analyses of 10-point mutations in the CYP21A2 gene were performed. We found that all the patients with the classical expression, except one with a de novo mutation R356W in one allele, were fully genotyped with predictive < 2% EA mutations. Signs of hyperandrogenism were present in 5/6 NC patients; one was diagnosed by searching for mutations in asymptomatic siblings. All the NC patients were compound heterozygotes carrying V281L mutation in one allele and a predictive low EA in the other, except for one not yet determined. In patients with neonatal diagnosis, mean height was low at one year of age, though it showed a significant increase before the onset of puberty. We conclude that neonatal diagnosis of classical CAH allows an adequate follow up enhancing growth. Molecular analyses of all members of an affected family may disclose asymptomatic patients. The presence of de novo mutations, as well as, the presence of mutations with low predicted EA in NC patients reinforces the importance of genotyping for appropriate genetic counseling. In fully genotyped NC patients, the lowest value of ACTH-stimulated 17OHP was 14 ng/ml. Lower cut-off values might overestimate the diagnosis of the NC form.

Improving Information on Maternal Medication Use by Linking Prescription Data to Congenital Anomaly Registers: A EUROmediCAT Study.

PubMed

de Jonge, Linda; Garne, Ester; Gini, Rosa; Jordan, Susan E; Klungsoyr, Kari; Loane, Maria; Neville, Amanda J; Pierini, Anna; Puccini, Aurora; Thayer, Daniel S; Tucker, David; Vinkel Hansen, Anne; Bakker, Marian K

2015-11-01

Research on associations between medication use during pregnancy and congenital anomalies is significative for assessing the safe use of a medicine in pregnancy. Congenital anomaly (CA) registries do not have optimal information on medicine exposure, in contrast to prescription databases. Linkage of prescription databases to the CA registries is a potentially effective method of obtaining accurate information on medicine use in pregnancies and the risk of congenital anomalies. We linked data from primary care and prescription databases to five European Surveillance of Congenital Anomalies (EUROCAT) CA registries. The linkage was evaluated by looking at linkage rate, characteristics of linked and non-linked cases, first trimester exposure rates for six groups of medicines according to the prescription data and information on medication use registered in the CA databases, and agreement of exposure. Of the 52,619 cases registered in the CA databases, 26,552 could be linked. The linkage rate varied between registries over time and by type of birth. The first trimester exposure rates and the agreements between the databases varied for the different medicine groups. Information on anti-epileptic drugs and insulins and analogue medicine use recorded by CA registries was of good quality. For selective serotonin reuptake inhibitors, anti-asthmatics, antibacterials for systemic use, and gonadotropins and other ovulation stimulants, the recorded information was less complete. Linkage of primary care or prescription databases to CA registries improved the quality of information on maternal use of medicines in pregnancy, especially for medicine groups that are less fully registered in CA registries.

Quality of life in adults with congenital adrenal hyperplasia relates to glucocorticoid treatment, adiposity and insulin resistance: United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE)

PubMed Central

Han, Thang S; Krone, Nils; Willis, Debbie S; Conway, Gerard S; Hahner, Stefanie; Rees, D Aled; Stimson, Roland H; Walker, Brian R; Arlt, Wiebke; Ross, Richard J

2013-01-01

Context Quality of life (QoL) has been variously reported as normal or impaired in adults with congenital adrenal hyperplasia (CAH). To explore the reasons for this discrepancy we investigated the relationship between QoL, glucocorticoid treatment and other health outcomes in CAH adults. Methods Cross-sectional analysis of 151 adults with 21-hydroxylase deficiency aged 18–69 years in whom QoL (assessed using the Short Form Health Survey), glucocorticoid regimen, anthropometric and metabolic measures were recorded. Relationships were examined between QoL, type of glucocorticoid (hydrocortisone, prednisolone and dexamethasone) and dose of glucocorticoid expressed as prednisolone dose equivalent (PreDEq). QoL was expressed as z-scores calculated from matched controls (14 430 subjects from UK population). Principal components analysis (PCA) was undertaken to identify clusters of associated clinical and biochemical features and the principal component (PC) scores used in regression analysis as predictor of QoL. Results QoL scores were associated with type of glucocorticoid treatment for vitality (P=0.002) and mental health (P=0.011), with higher z-scores indicating better QoL in patients on hydrocortisone monotherapy (P<0.05). QoL did not relate to PreDEq or mutation severity. PCA identified three PCs (PC1, disease control; PC2, adiposity and insulin resistance and PC3, blood pressure and mutations) that explained 61% of the variance in observed variables. Stepwise multiple regression analysis demonstrated that PC2, reflecting adiposity and insulin resistance (waist circumference, serum triglycerides, homeostasis model assessment of insulin resistance and HDL-cholesterol), related to QoL scores, specifically impaired physical functioning, bodily pain, general health, Physical Component Summary Score (P<0.001) and vitality (P=0.002). Conclusions Increased adiposity, insulin resistance and use of prednisolone or dexamethasone are associated with impaired QoL in adults

Genetics Home Reference: X-linked dilated cardiomyopathy

MedlinePlus

... Twitter Home Health Conditions X-linked dilated cardiomyopathy X-linked dilated cardiomyopathy Printable PDF Open All Close ... Javascript to view the expand/collapse boxes. Description X-linked dilated cardiomyopathy is a form of heart ...

Genetics Home Reference: X-linked myotubular myopathy

MedlinePlus

... Twitter Home Health Conditions X-linked myotubular myopathy X-linked myotubular myopathy Printable PDF Open All Close ... Javascript to view the expand/collapse boxes. Description X-linked myotubular myopathy is a condition that primarily ...

Genetics Home Reference: X-linked sideroblastic anemia

MedlinePlus

... Twitter Home Health Conditions X-linked sideroblastic anemia X-linked sideroblastic anemia Printable PDF Open All Close ... Javascript to view the expand/collapse boxes. Description X-linked sideroblastic anemia is an inherited disorder that ...

A FRMD7 variant in a Japanese family causes congenital nystagmus.

PubMed

Kohmoto, Tomohiro; Okamoto, Nana; Satomura, Shigeko; Naruto, Takuya; Komori, Takahide; Hashimoto, Toshiaki; Imoto, Issei

2015-01-01

Idiopathic congenital nystagmus (ICN) is a genetically heterogeneous eye movement disorder that causes a large proportion of childhood visual impairment. Here we describe a missense variant (p.L292P) within a mutation-rich region of FRMD7 detected in three affected male siblings in a Japanese family with X-linked ICN. Combining sequence analysis and results from structural and functional predictions, we report p.L292P as a variant potentially disrupting FRMD7 function associated with X-linked ICN.

A FRMD7 variant in a Japanese family causes congenital nystagmus

PubMed Central

Kohmoto, Tomohiro; Okamoto, Nana; Satomura, Shigeko; Naruto, Takuya; Komori, Takahide; Hashimoto, Toshiaki; Imoto, Issei

2015-01-01

Idiopathic congenital nystagmus (ICN) is a genetically heterogeneous eye movement disorder that causes a large proportion of childhood visual impairment. Here we describe a missense variant (p.L292P) within a mutation-rich region of FRMD7 detected in three affected male siblings in a Japanese family with X-linked ICN. Combining sequence analysis and results from structural and functional predictions, we report p.L292P as a variant potentially disrupting FRMD7 function associated with X-linked ICN. PMID:27081518

[Congenital adrenal hyperplasia: a qualitative study on sex definition and redesignation dilation surgery and psychological support (part II)].

PubMed

Telles-Silveira, Mariana; Tonetto-Fernandes, Vânia F; Schiller, Paulo; Kater, Claudio E

2009-12-01

To identify relevant questions related to sex definition and re-designation and reconstructive surgery in patients with congenital adrenal hyperplasia (CAH), and to understand the role of the psychologist in providing care for these patients. We selected 21 subjects: 7 pediatric endocrinologists from 5 Brazilian Public Health System institutions, 9 parents and 6 patients with CAH, according to a qualitative research model. In this paper, 3 of the studied categories are analyzed: 'sex definition and re-designation', 'reconstructive surgery/vaginal dilation', and 'psychology'. Parents' main anguish relates to the situation of an unnamed sex at birth, whereas sex re-designation was distressful to physicians. A sense of loneliness when dealing with the disease and treatment was a common anguish among patients; dilation procedures were the major complaint. In general, physicians recommend that genital reconstructive surgery be performed early on to avoid future trauma. In such a complex scenario, it is remarkable that not all the reference service staff have a psychologist on duty. Difficulties to deal with questions involving sexuality were evident and dilation procedures are an additional source of trauma for these patients.

Assembling a Functional Clitoris and Vulva from a Pseudo-Penis: A Surgical Technique for an Adult Woman with Congenital Adrenal Hyperplasia.

PubMed

Tjalma, Wiebren A A

2017-06-01

Congenital adrenal hyperplasia (CAH) is associated with a genital deformation that might cause a negative body image. The genital ambiguity is generally "corrected" surgically during early infancy. The advantage is a psychological benefit. The disadvantages are multiple surgical procedures and the loss of orgasm. A 22-year-old woman with CAH consulted for genital reconstructive surgery. She had a pseudopenis of 4 cm and could achieve an orgasm by masturbating. During surgery, the penis was dismantled and with the preserved glans penis and the corpora cavernosa, a clitoris and vestibules were constructed, respectively. On the basis of the anamneses during the follow-up, she had a functional vagina and could still achieve orgasms. Genital correction surgery for CAH at an older age was easier, could be done in 1 step, and enabled the preservation of orgasm. Copyright © 2016 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.

Comparison of one-tier and two-tier newborn screening metrics for congenital adrenal hyperplasia.

PubMed

Sarafoglou, Kyriakie; Banks, Kathryn; Gaviglio, Amy; Hietala, Amy; McCann, Mark; Thomas, William

2012-11-01

Newborn screening (NBS) for the classic forms of congenital adrenal hyperplasia (CAH) is mandated in all states in the United States. Compared with other NBS disorders, the false-positive rate (FPR) of CAH screening remains high and has not been significantly improved by adjusting 17α-hydroxyprogesterone cutoff values for birth weight and/or gestational age. Minnesota was the first state to initiate, and only 1 of 4 states currently performing, second-tier steroid profiling for CAH. False-negative rates (FNRs) for CAH are not well known. This is a population-based study of all Minnesota infants (769,834) born 1999-2009, grouped by screening protocol (one-tier with repeat screen, January 1999 to May 2004; two-tier with second-tier steroid profiling, June 2004 to December 2009). FPR, FNR, and positive predictive value (PPV) were calculated per infant, rather than per sample, and compared between protocols. Overall, 15 false-negatives (4 salt-wasting, 11 simple-virilizing) and 45 true-positives were identified from 1999 to 2009. With two-tier screening, FNR was 32%, FPR increased to 0.065%, and PPV decreased to 8%, but these changes were not statistically significant. Second-tier steroid profiling obviated repeat screens of borderline results (355 per year average). In comparing the 2 screening protocols, the FPR of CAH NBS remains high, the PPV remains low, and false-negatives occur more frequently than has been reported. Physicians should be cautioned that a negative NBS does not necessarily rule out classic CAH; therefore, any patient for whom there is clinical concern for CAH should receive immediate diagnostic testing.

Prenatal hormones and childhood sex-segregation: Playmate and play style preferences in girls with congenital adrenal hyperplasia

PubMed Central

Pasterski, Vickie; Geffner, Mitchell E.; Brain, Caroline; Hindmarsh, Peter; Brook, Charles; Hines, Melissa

2011-01-01

We investigated playmate and play style preference in children with congenital adrenal hyperplasia (CAH) (26 females, 31 males) and their unaffected siblings (26 females, 17 males) using the Playmate and Play Style Preferences Structured Interview (PPPSI). Both unaffected boys and girls preferred same-sex playmates and sex-typical play styles. In the conflict condition where children chose between a same-sex playmate engaged in an other-sex activity or an other-sex playmate engaged in a same-sex activity, boys (both CAH and unaffected brothers) almost exclusively chose playmates based on the preferred play style of the playmate as opposed to the preferred gender label of the playmate. By contrast, unaffected girls used play style and gender label about equally when choosing playmates. Girls with CAH showed a pattern similar to that of boys: their playmate selections were more masculine than unaffected girls, they preferred a boy-typical play style and, in the conflict condition, chose playmates engaged in a masculine activity. These findings suggest that prenatal androgen exposure contributes to sex differences in playmate selection observed in typically-developing children, and that, among boys and girls exposed to high levels of androgens prenatally, play style preferences drive sex segregation in play. PMID:21338606

Prenatal hormones and childhood sex segregation: playmate and play style preferences in girls with congenital adrenal hyperplasia.

PubMed

Pasterski, Vickie; Geffner, Mitchell E; Brain, Caroline; Hindmarsh, Peter; Brook, Charles; Hines, Melissa

2011-04-01

We investigated playmate and play style preference in children with congenital adrenal hyperplasia (CAH) (26 females, 31 males) and their unaffected siblings (26 females, 17 males) using the Playmate and Play Style Preferences Structured Interview (PPPSI). Both unaffected boys and girls preferred same-sex playmates and sex-typical play styles. In the conflict condition where children chose between a same-sex playmate engaged in an other-sex activity or an other-sex playmate engaged in a same-sex activity, boys (both CAH and unaffected brothers) almost exclusively chose playmates based on the preferred play style of the playmate as opposed to the preferred gender label of the playmate. By contrast, unaffected girls used play style and gender label about equally when choosing playmates. Girls with CAH showed a pattern similar to that of boys: their playmate selections were more masculine than unaffected girls, they preferred a boy-typical play style and, in the conflict condition, chose playmates engaged in a masculine activity. These findings suggest that prenatal androgen exposure contributes to sex differences in playmate selection observed in typically developing children and that, among boys and girls exposed to high levels of androgens prenatally, play style preferences drive sex segregation in play. Copyright © 2011 Elsevier Inc. All rights reserved.

Molecular defects of the CYP21A2 gene in Greek-Cypriot patients with congenital adrenal hyperplasia.

PubMed

Skordis, Nicos; Kyriakou, Andreas; Tardy, Véronique; Ioannou, Yiannis S; Varvaresou, Athanasia; Dracopoulou-Vabouli, Maria; Patsalis, Philippos C; Shammas, Christos; Neocleous, Vassos; Phylactou, Leonidas A

2011-01-01

To determine the mutations in the CYP21A2 gene in Greek-Cypriots with congenital adrenal hyperplasia (CAH) and attempt a genotype-phenotype correlation. Molecular analysis was performed by multiplex ligation-dependent probe amplification and direct sequencing of PCR products of the CYP21A2 gene in 32 CAH patients. The most frequent genetic defect in the classic salt-wasting and simple virilizing forms was the IVS2-13A/C>G (55%) mutation, followed by Large lesion (20%) and in the non-classical form, the p.V281L (79.5%). Genotypes were categorized in 4 mutation groups (null, A, B and C). All 3 patients in the null group manifested the salt-wasting form and all 6 patients in mutation group A presented with the classical form. One patient in group B had the simple virilizing form and 22 patients in group C exhibited the non-classical form. The spectrum of mutations of the CYP21A2 gene in our population is comparable to the most common reported in similar ethnic groups. The knowledge of the ethnic specificity of the CYP21A2 mutations represents a valuable diagnostic tool for all forms of CAH. Copyright © 2010 S. Karger AG, Basel.

Mapping the x-linked lymphoproliferative syndrome

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

Skare, J.C.; Milunsky, A.; Byron, K.S.

1987-04-01

The X-linked lymphoproliferative syndrome is triggered by Epstein-Barr virus infection and results in fatal mononucleosis, immunodeficiency, and lymphoproliferative disorders. This study shows that the mutation responsible for X-linked lymphoproliferative syndrome is genetically linked to a restriction fragment length polymorphism detected with the DXS42 probe (from Xq24-q27). The most likely recombination frequency between the loci is 4%, and the associated logarithm of the odds is 5.26. Haplotype analysis using flanking restriction fragment length polymorphism markers indicates that the locus for X-linked lymphoproliferative syndrome is distal to probe DXS42 but proximal to probe DXS99 (from Xq26-q27). It is now possible to predictmore » which members of a family with X-linked lymphoproliferative syndrome are carrier females and to diagnose the syndrome prenatally.« less

Inflammatory profile in X-linked adrenoleukodystrophy patients: Understanding disease progression.

PubMed

Marchetti, Desirèe Padilha; Donida, Bruna; Jacques, Carlos Eduardo; Deon, Marion; Hauschild, Tatiane Cristina; Koehler-Santos, Patricia; de Moura Coelho, Daniella; Coitinho, Adriana Simon; Jardim, Laura Bannach; Vargas, Carmen Regla

2018-01-01

X-linked adrenoleukodystrophy (X-ALD) is an inherited disease characterized by progressive inflammatory demyelization in the brain, adrenal insufficiency, and an abnormal accumulation of very long chain fatty acids (VLCFA) in tissue and body fluids. Considering that inflammation might be involved in pathophysiology of X-ALD, we aimed to investigate pro- and anti-inflammatory cytokines in plasma from three different male phenotypes (CCER, AMN, and asymptomatic individuals). Our results showed that asymptomatic patients presented increased levels of pro-inflammatory cytokines IL-1β, IL-2, IL-8, and TNF-α and the last one was also higher in AMN phenotype. Besides, asymptomatic patients presented higher levels of anti-inflammatory cytokines IL-4 and IL-10. AMN patients presented higher levels of IL-2, IL-5, and IL-4. We might hypothesize that inflammation in X-ALD is related to plasmatic VLCFA concentration, since there were positive correlations between C26:0 plasmatic levels and pro-inflammatory cytokines in asymptomatic and AMN patients and negative correlation between anti-inflammatory cytokine and C24:0/C22:0 ratio in AMN patients. The present work yields experimental evidence that there is an inflammatory imbalance associated Th1, (IL-2, IL-6, and IFN-γ), Th2 (IL-4 and IL-10), and macrophages response (TNF-α and IL-1β) in the periphery of asymptomatic and AMN patients, and there is correlation between VLCFA plasmatic levels and inflammatory mediators in X-ALD. Furthermore, we might also speculate that the increase of plasmatic cytokines in asymptomatic patients could be considered an early biomarker of brain damage and maybe also a predictor of disease progression. © 2017 Wiley Periodicals, Inc.

Maxillary distraction osteogenesis for treatment of cleft lip and palate in a patient with X-linked agammaglobulinemia.

PubMed

Sato, Yutaka; Mishimagi, Takashi; Katsuki, Yuko; Harada, Kiyoshi

2014-07-01

X-linked agammaglobulinemia (XLA) is a congenital immune deficiency disorder caused by abnormal antibody production. It is a rare disease with an estimated frequency of 1 in 379,000 that has X-linked recessive heredity and develops only in males. The clinical problems include bacterial infection such as otitis media, sinusitis, and bronchitis. In recent years it has become possible to diagnose XLA in the early stage and intravenous immunoglobulin replacement therapy has permitted survival to adulthood. However, there have been no reports of oral surgery in patients with XLA. Here, we describe a case in which immunoglobulin replacement therapy given pre- and postoperatively was used to control infection in oral surgery and maxillary distraction osteogenesis performed for improving occlusion and appearance of a cleft lip and palate in a patient with XLA. Copyright © 2014 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

[Importance of family examination in juvenile X-linked retinoschisis].

PubMed

Kłosowska-Zawadka, A; Bernardczyk-Meller, J; Gotz-Wieckowska, A; Krawczyński, M

2005-12-01

Congenital (juvenile) retinoschisis belongs to the group of hereditary vitreoretinopathies. This disorder is inherited in an X-linked recessive pattern and its onset usually occurs in 5- to 10-year-old boys. Presenting clinical signs include decreased visual acuity due to maculopathy. The authors present a case of a 17-year-old boy with decreased visual acuity, hypermetropia, and bilateral retinoschisis with maculopathy upon fundus examination. In view of a 50% risk of the disorder occurring in the brothers of the affected male, they underwent full ophthalmological and electrophysiological examinations (until then asymptomatic). In one of them decreased visual acuity, mixed astigmatism, and maculopathy were present, without any changes of the peripheral retina. In the youngest brother decreased visual acuity, hypermetropia, and maculopathy were diagnosed. Genetic counseling and ophthalmological examination of family members at risk facilitated early recognition of the pathological changes in the siblings. Genetic counseling with pedigree analysis and genetic analysis, if possible, should be offered to all affected patients and family members.

From Knowing Nothing to Knowing What, How and Now: Parents' Experiences of Caring for their Children With Congenital Adrenal Hyperplasia.

PubMed

Lundberg, Tove; Lindström, Anders; Roen, Katrina; Hegarty, Peter

2017-06-01

This study investigates various kinds of knowing that European parents use when caring for their children with congenital adrenal hyperplasia (CAH). Semi-structured qualitative interviews with 20 parents of 22 children with CAH. Parents emphasized the importance of knowing what CAH is and what support their child needs, but also knowing how to cope and make sense of the new situation, how to attend to their child's medical needs as well as how to talk to their child. Parents also reported challenges related to connecting with their social network, experiences of emergency care, and how to help their children become independent. These challenges require knowing now : being able to respond appropriately to unique circumstances. Parents experience diverse challenges that may moderate the effects of the diagnosis on children's well-being. Parenting children with CAH requires the development of knowing that goes beyond medical information. © The Author 2016. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Correlation between NFATC1 gene polymorphisms and congenital heart disease in children.

PubMed

Li, C-L; Niu, L; Fu, M-Y; Tian, J; Wang, Q-W; An, X-J

2017-08-01

To analyze the links between NFATC1 gene polymorphism and congenital heart disease in children. In the present study, we selected 85 children patients with congenital heart disease who were hospitalized from February 2013 to February 2015 as research subjects (observation group), and 92 healthy subjects as control group. Restriction fragment length polymorphism (RFLP) was used for analysis of NFATC1 gene in samples from each group. The distribution of NFATC1 genotype and allele between the observation group (children with congenital heart disease) and the control group showed no significant difference (p >0.05), but AA, GG genotypes, and allele frequency between pathological samples of children with congenital heart disease and the control group displayed significant difference (p <0.05) (X2 = 16.04, p <0.05; X2 = 16.29, p <0.05). Further analyses showed that AA, GG, AG genotype and allele frequency among children with congenital heart disease in observation group also showed a difference, i.e., homozygote (AA, GG) ratio in children with severe congenital heart disease is relatively high. There is a correlation between NFATC1 genes and the incidence of congenital heart disease in children, and a correlation between different genotypes and allele frequency and the incidence of the disease.

Thyroid and adrenal relationships

PubMed Central

Parsons, Victor; Ramsay, Ian

1968-01-01

A brief review of the actions of adrenal medullary and thyroid hormones is presented and the ways in which they interact are examined. It is concluded that thyroid hormone produces the necessary intracellular environment without which the steady state and emergency actions of cathecholamines would be vitiated. In hyperthyroidism the increased concentration of thyroid hormones results in a lowering of the threshold for catecholamine action. For this reason it is possible to alleviate many of the symptoms of thyrotoxicosis by means of drugs which block β-adrenergic receptors. Attention is also drawn to the simultaneous occurrence of thyroid and adrenal disease, in the hope that this will encourage the search for further links in this field of endocrinology. PMID:5655216

[Clinical management of adrenal incidentalomas: results of a survey].

PubMed

Moreno-Fernández, Jesús; García-Manzanares, Alvaro; Sánchez-Covisa, Miguel Aguirre; García, E Inés Rosa Gómez

2009-12-01

Incidentalomas are clinically silent adrenal masses that are discovered incidentally during diagnostic testing for clinical conditions unrelated to suspicion of adrenal disease. Several decision algorithms are used in the management of adrenal masses. We evaluated the routine use of these algorithms through a clinical activity questionnaire. The questionnaire included data on the work center, initial hormonal and radiological study, imaging and hormonal tests performed to complete the study, surgical indications and clinical follow-up. Thirty-three endocrinologists (79%) attending the annual congress of the Castilla-La Mancha Society of Endocrinology, Nutrition and Diabetes completed the questionnaire. Forty-six percent considered tumoral size to be the most important factor suggesting malignancy in the initial evaluation of adrenal incidentalomas, the limit being 4 cm for 78% of the endocrinologists. Imaging study was completed by magnetic resonance imaging by 39%. All the physicians always performed screening for hypercortisolism and pheochromocytoma. Other assessments always conducted in all incidentalomas included hyperaldosteronism (76%), sex hormone-producing tumor (51%) and congenital adrenal hyperplasia (30%). Seventy-nine percent of respondents began to refer incidentalomas larger than 4 cm for surgical treatment, and 46% referred all tumors larger than 6 cm for surgical treatment. With regard to hormonal function, patients with pheochromocytoma, Cushing's syndrome, hyperaldosteronism with poorly controlled blood pressure or sex hormoneproducing tumors were more frequently referred for surgery. Seventy-six percent of endocrinologists performed clinical follow-up in adrenal incidentalomas larger than 4 cm, preferably through computerized tomography (81%), and repeated studies for hormonal hypercortisolism (97%), primary hyperaldosteronism (42%) and pheochromocytoma (76%) over a 4-5 year period (67%). Clinical practice varied among the endocrinologists

[Vasopressin V2 receptor-related pathologies: congenital nephrogenic diabetes insipidus and nephrogenic syndrome of inappropiate antidiuresis].

PubMed

Morin, Denis

2014-12-01

Congenital nephrogenic diabetes insipidus is a rare hereditary disease with mainly an X-linked inheritance (90% of the cases) but there are also autosomal recessive and dominant forms. Congenital nephrogenic diabetes insipidus is characterized by a resistance of the renal collecting duct to the action of the arginine vasopressin hormone responsible for the inability of the kidney to concentrate urine. The X-linked form is due to inactivating mutations of the vasopressin 2 receptor gene leading to a loss of function of the mutated receptors. Affected males are often symptomatic in the neonatal period with a lack of weight gain, dehydration and hypernatremia but mild phenotypes may also occur. Females carrying the mutation may be asymptomatic but, sometimes, severe polyuria is found due to the random X chromosome inactivation. The autosomal recessive and dominant forms, occurring in both genders, are linked to mutations in the aquaporin-2 gene. The treatment remains difficult, especially in infants, and is based on a low osmotic diet with increased water intake and the use of thiazides and indomethacin. The main goal is to avoid hypernatremic episodes and maintain a good hydration state. Potentially, specific treatment, in some cases of X-linked congenital nephrogenic diabetes insipidus, with pharmacological chaperones such as non-peptide vasopressin-2 receptor antagonists will be available in the future. Conversely, the nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is linked to a constitutive activation of the V(2)-receptor due to activating mutations with clinical and biological features of inappropriate antidiuresis but with low or undetectable plasma arginine vasopressin hormone levels. Copyright © 2014 Association Société de néphrologie. Published by Elsevier SAS. All rights reserved.

Health Status of Adults with Congenital Adrenal Hyperplasia: A Cohort Study of 203 Patients

PubMed Central

Arlt, Wiebke; Willis, Debbie S.; Wild, Sarah H.; Krone, Nils; Doherty, Emma J.; Hahner, Stefanie; Han, Thang S.; Carroll, Paul V.; Conway, Gerry S.; Rees, D. Aled; Stimson, Roland H.; Walker, Brian R.; Connell, John M. C.; Ross, Richard J.

2010-01-01

Context: No consensus exists for management of adults with congenital adrenal hyperplasia (CAH) due to a paucity of data from cohorts of meaningful size. Objective: Our objective was to establish the health status of adults with CAH. Design and Setting: We conducted a prospective cross-sectional study of adults with CAH attending specialized endocrine centers across the United Kingdom. Patients: Participants included 203 CAH patients (199 with 21-hydroxylase deficiency): 138 women, 65 men, median age 34 (range 18–69) years. Main Outcome Measures: Anthropometric, metabolic, and subjective health status was evaluated. Anthropometric measurements were compared with Health Survey for England data, and psychometric data were compared with appropriate reference cohorts. Results: Glucocorticoid treatment consisted of hydrocortisone (26%), prednisolone (43%), dexamethasone (19%), or a combination (10%), with reverse circadian administration in 41% of patients. Control of androgens was highly variable with a normal serum androstenedione found in only 36% of patients, whereas 38% had suppressed levels suggesting glucocorticoid overtreatment. In comparison with Health Survey for England participants, CAH patients were significantly shorter and had a higher body mass index, and women with classic CAH had increased diastolic blood pressure. Metabolic abnormalities were common, including obesity (41%), hypercholesterolemia (46%), insulin resistance (29%), osteopenia (40%), and osteoporosis (7%). Subjective health status was significantly impaired and fertility compromised. Conclusions: Currently, a minority of adult United Kingdom CAH patients appear to be under endocrine specialist care. In the patients studied, glucocorticoid replacement was generally nonphysiological, and androgen levels were poorly controlled. This was associated with an adverse metabolic profile and impaired fertility and quality of life. Improvements in the clinical management of adults with CAH are

Characterization of novel StAR (steroidogenic acute regulatory protein) mutations causing non-classic lipoid adrenal hyperplasia.

PubMed

Flück, Christa E; Pandey, Amit V; Dick, Bernhard; Camats, Núria; Fernández-Cancio, Mónica; Clemente, María; Gussinyé, Miquel; Carrascosa, Antonio; Mullis, Primus E; Audi, Laura

2011-01-01

Steroidogenic acute regulatory protein (StAR) is crucial for transport of cholesterol to mitochondria where biosynthesis of steroids is initiated. Loss of StAR function causes lipoid congenital adrenal hyperplasia (LCAH). StAR gene mutations causing partial loss of function manifest atypical and may be mistaken as familial glucocorticoid deficiency. Only a few mutations have been reported. To report clinical, biochemical, genetic, protein structure and functional data on two novel StAR mutations, and to compare them with published literature. Collaboration between the University Children's Hospital Bern, Switzerland, and the CIBERER, Hospital Vall d'Hebron, Autonomous University, Barcelona, Spain. Two subjects of a non-consanguineous Caucasian family were studied. The 46,XX phenotypic normal female was diagnosed with adrenal insufficiency at the age of 10 months, had normal pubertal development and still has no signs of hypergonodatropic hypogonadism at 32 years of age. Her 46,XY brother was born with normal male external genitalia and was diagnosed with adrenal insufficiency at 14 months. Puberty was normal and no signs of hypergonadotropic hypogonadism are present at 29 years of age. StAR gene analysis revealed two novel compound heterozygote mutations T44HfsX3 and G221S. T44HfsX3 is a loss-of-function StAR mutation. G221S retains partial activity (∼30%) and is therefore responsible for a milder, non-classic phenotype. G221S is located in the cholesterol binding pocket and seems to alter binding/release of cholesterol. StAR mutations located in the cholesterol binding pocket (V187M, R188C, R192C, G221D/S) seem to cause non-classic lipoid CAH. Accuracy of genotype-phenotype prediction by in vitro testing may vary with the assays employed.

Characterization of Novel StAR (Steroidogenic Acute Regulatory Protein) Mutations Causing Non-Classic Lipoid Adrenal Hyperplasia

PubMed Central

Flück, Christa E.; Pandey, Amit V.; Dick, Bernhard; Camats, Núria; Fernández-Cancio, Mónica; Clemente, María; Gussinyé, Miquel; Carrascosa, Antonio; Mullis, Primus E.; Audi, Laura

2011-01-01

Context Steroidogenic acute regulatory protein (StAR) is crucial for transport of cholesterol to mitochondria where biosynthesis of steroids is initiated. Loss of StAR function causes lipoid congenital adrenal hyperplasia (LCAH). Objective StAR gene mutations causing partial loss of function manifest atypical and may be mistaken as familial glucocorticoid deficiency. Only a few mutations have been reported. Design To report clinical, biochemical, genetic, protein structure and functional data on two novel StAR mutations, and to compare them with published literature. Setting Collaboration between the University Children's Hospital Bern, Switzerland, and the CIBERER, Hospital Vall d'Hebron, Autonomous University, Barcelona, Spain. Patients Two subjects of a non-consanguineous Caucasian family were studied. The 46,XX phenotypic normal female was diagnosed with adrenal insufficiency at the age of 10 months, had normal pubertal development and still has no signs of hypergonodatropic hypogonadism at 32 years of age. Her 46,XY brother was born with normal male external genitalia and was diagnosed with adrenal insufficiency at 14 months. Puberty was normal and no signs of hypergonadotropic hypogonadism are present at 29 years of age. Results StAR gene analysis revealed two novel compound heterozygote mutations T44HfsX3 and G221S. T44HfsX3 is a loss-of-function StAR mutation. G221S retains partial activity (∼30%) and is therefore responsible for a milder, non-classic phenotype. G221S is located in the cholesterol binding pocket and seems to alter binding/release of cholesterol. Conclusions StAR mutations located in the cholesterol binding pocket (V187M, R188C, R192C, G221D/S) seem to cause non-classic lipoid CAH. Accuracy of genotype-phenotype prediction by in vitro testing may vary with the assays employed. PMID:21647419

How to learn from patients: Fuller Albright's exploration of adrenal function.

PubMed

Schwartz, T B

1995-08-01

Fuller Albright (1900-1969) was acknowledged as the preeminent clinical and investigative endocrinologist of his day by many of his contemporaries, but his many achievements are all but unknown to the present generation of physicians. This article describes how he used his clinical knowledge and a few tools--the measurement of urinary 17-ketosteroid excretion and the administration of methyltestosterone--to elucidate the major hormonal functions of the adrenal cortex and to clarify the pathophysiology of the Cushing syndrome. In addition, in a tour de force of clinical reasoning, he predicted, 5 years before the event, the discovery of a hormone that would reverse the endocrinologic abnormalities of congenital adrenal hyperplasia. Fittingly, he and pioneer pediatric endocrinologist Lawson Wilkins were the first to treat this disease successfully with cortisone.

Genetics Home Reference: X-linked severe combined immunodeficiency

MedlinePlus

... Facebook Twitter Home Health Conditions X-linked SCID X-linked severe combined immunodeficiency Printable PDF Open All ... Javascript to view the expand/collapse boxes. Description X-linked severe combined immunodeficiency (SCID) is an inherited ...

Genetics Home Reference: X-linked chondrodysplasia punctata 1

MedlinePlus

... Home Health Conditions X-linked chondrodysplasia punctata 1 X-linked chondrodysplasia punctata 1 Printable PDF Open All ... Javascript to view the expand/collapse boxes. Description X-linked chondrodysplasia punctata 1 is a disorder of ...

Splicing mutation in CYP21 associated with delayed presentation of salt-wasting congenital adrenal hyperplasia

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

Kohn, B.; Patel, S.V.; Pelczar, J.V.

1995-07-03

Patients with salt-wasting congenital adrenal hyperplasia (SW-CAH) most commonly carry an A-G transition at nucleotide 656 (nt 656 A{r_arrow}G), causing abnormal splicing of exons 2 and 3 in CYP21, the gene encoding active steroid 21-hydroxylase. Affected infants are severely deficient in cortisol and aldosterone, and usually come to medical attention during the neonatal period. We report on 2 affected boys, homozygous for the nt 656 mutation, who thrived in early infancy, but suffered salt-wasting crises unusually late in infancy, at 3.5 and 5.5 months, respectively. Laboratory studies at presentation showed hyponatremia, hyperkalemia, dehydration, and acidosis; serum aldosterone was low inmore » spite of markedly elevated plasma renin activity. Basal 17-hydroxyprogesterone levels were only moderately elevated, yet the stimulated levels were more typical of severe, classic CAH due to 21-hydroxylase deficiency. Genomic DNA from the patients was analyzed. Southern blot showed no major deletions or rearrangements. CYP21-specific amplification by polymerase chain reaction, coupled with allele-specific hybridization using wild-type and mutant probes at each of 9 sites for recognized disease-causing mutations, revealed a single, homozygous mutation in each patient: nt 656 A{r_arrow}G. These results were confirmed by sequence analysis. We conclude that the common nt 656 A{r_arrow}G mutation is sometimes associated with delayed phenotypic expression of SW-CAH. We speculate that variable splicing of the mutant CYP21 may modify the clinical manifestation of this disease. 22 refs., 1 fig., 1 tab.« less

A rare CYP21A2 mutation in a congenital adrenal hyperplasia kindred displaying genotype-phenotype nonconcordance.

PubMed

Khattab, Ahmed; Yuen, Tony; Al-Malki, Sultan; Yau, Mabel; Kazmi, Diya; Sun, Li; Harbison, Madeleine; Haider, Shozeb; Zaidi, Mone; New, Maria I

2016-01-01

Congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency is caused by the autosomal recessive inheritance of mutations in the gene CYP21A2. CYP21A2 mutations lead to variable impairment of the 21-hydroxylase enzyme, which, in turn, is associated with three clinical phenotypes, namely, salt wasting, simple virilizing, and nonclassical CAH. However, it is known that a given mutation can associate with different clinical phenotypes, resulting in a high rate of genotype-phenotype nonconcordance. We aimed to study the genotype-phenotype nonconcordance in a family with three siblings affected with nonclassical CAH. All had hormonal evidence of nonclassical CAH, but this phenotype could not be explained by the genotype obtained from commercial CYP21A2 genetic testing, which revealed heterozygosity for the maternal 30 kb deletion mutation. We performed Sanger sequencing of the entire CYP21A2 gene in this family to search for a rare mutation that was not covered by commercial testing and found in the three siblings a second, rare c.1097G>A (p.R366H) mutation in exon 8. Computational modeling confirmed that this was a mild mutation consistent with nonclassical CAH. We recommend that sequencing of entire genes for rare mutations should be carried out when genotype-phenotype nonconcordance is observed in patients with autosomal recessive monogenic disorders, including CAH. © 2015 New York Academy of Sciences.

Identification of a mutation in the MTM1 gene, associated with X-linked myotubular myopathy, in a Greek family

PubMed Central

Fidani, L; Karagianni, P; Tsakalidis, C; Mitsiako, G; Hatziioannidis, I; Biancalana, V; Nikolaidis, N

2011-01-01

X-linked myotubular myopathy (XLMTM) is a rare congenital myopathy, usually characterized by severe hypotonia and respiratory insufficiency at birth, in affected, male infants. The disease is causally associated with mutations in the MTM1 gene, coding for phosphatase myotubularin. We report a severe case of XLMTM with a novel mutation, at a donor splicing site (c.1467+1G) previously associated with severe phenotype. The mutation was also identified in the patient's mother, providing an opportunity for sound genetic counseling. PMID:22435031

Identification of a mutation in the MTM1 gene, associated with X-linked myotubular myopathy, in a Greek family.

PubMed

Fidani, L; Karagianni, P; Tsakalidis, C; Mitsiako, G; Hatziioannidis, I; Biancalana, V; Nikolaidis, N

2011-07-01

X-linked myotubular myopathy (XLMTM) is a rare congenital myopathy, usually characterized by severe hypotonia and respiratory insufficiency at birth, in affected, male infants. The disease is causally associated with mutations in the MTM1 gene, coding for phosphatase myotubularin. We report a severe case of XLMTM with a novel mutation, at a donor splicing site (c.1467+1G) previously associated with severe phenotype. The mutation was also identified in the patient's mother, providing an opportunity for sound genetic counseling.

Cell signaling pathways in the adrenal cortex: Links to stem/progenitor biology and neoplasia.

PubMed

Penny, Morgan K; Finco, Isabella; Hammer, Gary D

2017-04-15

The adrenal cortex is a dynamic tissue responsible for the synthesis of steroid hormones, including mineralocorticoids, glucocorticoids, and androgens in humans. Advances have been made in understanding the role of adrenocortical stem/progenitor cell populations in cortex homeostasis and self-renewal. Recently, large molecular profiling studies of adrenocortical carcinoma (ACC) have given insights into proteins and signaling pathways involved in normal tissue homeostasis that become dysregulated in cancer. These data provide an impetus to examine the cellular pathways implicated in adrenocortical disease and study connections, or lack thereof, between adrenal homeostasis and tumorigenesis, with a particular focus on stem and progenitor cell pathways. In this review, we discuss evidence for stem/progenitor cells in the adrenal cortex, proteins and signaling pathways that may regulate these cells, and the role these proteins play in pathologic and neoplastic conditions. In turn, we also examine common perturbations in adrenocortical tumors (ACT) and how these proteins and pathways may be involved in adrenal homeostasis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Complete virilization in congenital adrenal hyperplasia: clinical course, medical management and disease-related complications.

PubMed

Woelfle, J; Hoepffner, W; Sippell, W G; Brämswig, J H; Heidemann, P; Deiss, D; Bökenkamp, A; Roth, C; Irle, U; Wollmann, H A; Zachmann, M; Kubini, K; Albers, N

2002-02-01

In girls with congenital adrenal hyperplasia (CAH), genital ambiguity usually leads to a rapid neonatal diagnosis. Rarely, CAH causes complete virilization and male sex assignment with a delayed diagnosis. After being confronted with very specific problems in two of such patients, we collected data of patients with CAH and complete virilization in a nationwide study to delineate specific problems of these rare patients in order to improve their management. Through the German Working Group of Paediatric Endocrinology (Arbeitsgemeinschaft Pädiatrische Endokrinologie, APE), questionnaires were sent to all members caring for patients with CAH and complete virilization in their endocrine clinics. Data from 16 patients from 10 paediatric endocrine centres were assessed by questionnaire. The following problems have been encountered. (1) Sex assignment/gender identity: initially all patients had a male sex assignment. Six patients were diagnosed during the first month of life. Five were reassigned to female sex immediately, one at the age of 19 months. Except in one girl demonstrating some tomboyish behaviour, gender role behaviour in these patients did not differ from unaffected girls. Ten patients were diagnosed late at 3.4--7 years of age. In seven patients with a late diagnosis, male sex assignment was maintained; one of them expressed some concerns about living as a male. In three patients late sex reversal was performed, gender identity is very poor in one and new sex assignment is currently under consideration. (2) SURGERY: irrespective of the sex assigned, all patients had between one and three surgical procedures, including clitoris reduction and (repeated) vaginoplasties in patients with female sex assignment. Hysterectomy and ovarectomy were performed in patients with male sex assignment. (3) Short stature: patients with a late diagnosis of CAH had extremely advanced bone ages of +6.3 to +9.5 years, leading to severely reduced final height of 137 to 150 cm in

Adrenal Fatigue

MedlinePlus

... unlikely to cover the costs. What is the theory behind adrenal fatigue? Supporters of adrenal fatigue believe ... by producing hormones like cortisol. According to the theory of adrenal fatigue, when people are faced with ...

Utility of a precursor-to-product ratio in the evaluation of presumptive positives in newborn screening of congenital adrenal hyperplasia.

PubMed

Tieh, P Y; Yee, J K; Hicks, R A; Mao, C S; Lee, W-Np

2017-03-01

Screening for congenital adrenal hyperplasia (CAH) caused by 21-α-hydroxylase deficiency is challenging because factors such as prematurity and stress increase intermediate steroid metabolite levels in newborn infants. The objective of this study was to explore the use of the 17-α-hydroxyprogesterone (17-OHP)/11-deoxycortisol ratio as an adjunct measure in the follow-up evaluation of infants with presumptive positive newborn screens for CAH to distinguish between infants with no disorder and those with CAH. This was a retrospective cohort study of infants with presumptive positive newborn screens for CAH. The precursor-to-product ratio of 17-OHP/11-deoxycortisol was compared between infants with no disorder (n=47) and infants with CAH (n=5). The CAH infants had higher 17-OHP/11-deoxycortisol ratios than infants with no disorder: 26 (18 to 58) and 1.05 (0.69 to 1.46), respectively (P<0.05). Among infants with no disorder, higher levels of serum 17-OHP did not reflect higher ratios, indicating sufficient enzyme activity. The results suggest that a low 17-OHP/11-deoxycortisol ratio represents 21-α-hydroxylase sufficiency among presumptive positives in newborn screening of CAH.

Percutaneous interstitial brachytherapy for adrenal metastasis: technical report.

PubMed

Kishi, Kazushi; Tamura, Shinji; Mabuchi, Yasushi; Sonomura, Tetsuo; Noda, Yasutaka; Nakai, Motoki; Sato, Morio; Ino, Kazuhiko; Yamanaka, Noboru

2012-09-01

We developed and evaluated the feasibility of a brachytherapy technique as a safe and effective treatment for adrenal metastasis. Adapting a paravertebral insertion technique in radiofrequency ablation of adrenal tumors, we developed an interstitial brachytherapy for adrenal metastasis achievable on an outpatient basis. Under local anesthesia and under X-ray CT guidance, brachytherapy applicator needles were percutaneously inserted into the target. A treatment plan was created to eradicate the tumor while preserving normal organs including the spinal cord and kidney. We applied this interstitial brachytherapy technique to two patients: one who developed adrenal metastasis as the third recurrence of uterine cervical cancer after reirradiation, and one who developed metachronous multiple metastases from malignant melanoma. The whole procedure was completed in 2.5 hours. There were no procedure-related or radiation-related early/late complications. FDG PET-CT images at two and three months after treatment showed absence of FDG uptake, and no recurrence of the adrenal tumor was observed for over seven months until expiration, and for six months until the present, respectively. This interventional interstitial brachytherapy procedure may be useful as a safe and eradicative treatment for adrenal metastasis.

A gene for autosomal dominant congenital nystagmus localizes to 6p12

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

Kerrison, J.B.; Arnould, V.J.; Koenekoop, R.K.

1996-05-01

Congenital nystagmus is an idiopathic disorder characterized by bilateral ocular oscillations usually manifest during infancy. Vision is typically decreased due to slippage of images across the fovea. As such, visual acuity correlates with nystagmus intensity, which is the amplitude and frequency of eye movements at a given position of gaze. X-linked, autosomal dominant, and autosomal recessive pedigrees have been described, but no mapping studies have been published. We recently described a large pedigree with autosomal dominant congenital nystagmus. A genome-wide search resulted in six markers on 6p linked by two-point analysis at {theta} = 0 (D6S459, D6S452, D6S465, FTHP1, D6S257,more » D6S430). Haplotype analysis localizes the gene for autosomal dominant congenital motor mystagmus to an 18-cM region between D6S271 and D6S455. 16 refs., 1 fig., 1 tab.« less

A case of adrenal Cushing's syndrome with bilateral adrenal masses.

PubMed

Guo, Ya-Wun; Hwu, Chii-Min; Won, Justin Ging-Shing; Chu, Chia-Huei; Lin, Liang-Yu

2016-01-01

A functional lesion in corticotrophin (ACTH)-independent Cushing's syndrome is difficult to distinguish from lesions of bilateral adrenal masses. Methods for distinguishing these lesions include adrenal venous sampling and (131)I-6β-iodomethyl-19-norcholesterol ((131)I-NP-59) scintigraphy. We present a case of a 29-year-old Han Chinese female patient with a history of hypercholesterolaemia and polycystic ovary syndrome. She presented with a 6month history of an 8kg body weight gain and gradual rounding of the face. Serial examinations revealed loss of circadian rhythm of cortisol, elevated urinary free-cortisol level and undetectable ACTH level (<5pg/mL). No suppression was observed in both the low- and high-dose dexamethasone suppression tests. Adrenal computed tomography revealed bilateral adrenal masses. Adrenal venous sampling was performed, and the right-to-left lateralisation ratio was 14.29. The finding from adrenal scintigraphy with NP-59 was consistent with right adrenal adenoma. The patient underwent laparoscopic right adrenalectomy, and the pathology report showed adrenocortical adenoma. Her postoperative cortisol level was 3.2μg/dL, and her Cushingoid appearance improved. In sum, both adrenal venous sampling and (131)I-NP-59 scintigraphy are good diagnostic methods for Cushing's syndrome presenting with bilateral adrenal masses. The clinical presentation of Cushing' syndrome includes symptoms and signs of fat redistribution and protein-wasting features.The diagnosis of patients with ACTH-independent Cushing's syndrome with bilateral adrenal masses is challenging for localisation of the lesion.Both adrenal venous sampling and (131)I-NP-59 scintigraphy are good methods to use in these patients with Cushing's syndrome presenting with bilateral adrenal masses.

Genetics Home Reference: X-linked lissencephaly with abnormal genitalia

MedlinePlus

... Health Conditions X-linked lissencephaly with abnormal genitalia X-linked lissencephaly with abnormal genitalia Printable PDF Open ... Javascript to view the expand/collapse boxes. Description X-linked lissencephaly with abnormal genitalia (XLAG) is a ...

Genetics Home Reference: X-linked sideroblastic anemia and ataxia

MedlinePlus

... Health Conditions X-linked sideroblastic anemia and ataxia X-linked sideroblastic anemia and ataxia Printable PDF Open ... Javascript to view the expand/collapse boxes. Description X-linked sideroblastic anemia and ataxia is a rare ...

Genetics Home Reference: X-linked intellectual disability, Siderius type

MedlinePlus

... Health Conditions X-linked intellectual disability, Siderius type X-linked intellectual disability, Siderius type Printable PDF Open ... Javascript to view the expand/collapse boxes. Description X-linked intellectual disability, Siderius type is a condition ...

Influence of hormonal control on LH pulsatility and secretion in women with classical congenital adrenal hyperplasia.

PubMed

Bachelot, Anne; Chakhtoura, Zeina; Plu-Bureau, Geneviève; Coudert, Mathieu; Coussieu, Christiane; Badachi, Yasmina; Dulon, Jérome; Charbit, Beny; Touraine, Philippe

2012-10-01

Women with classical congenital adrenal hyperplasia (CAH) exhibit reduced fertility due to several factors including anovulation. This has been attributed to a disturbed gonadotropic axis as in polycystic ovary syndrome (PCOS), but there is no precise evaluation. Our aim was to evaluate the gonadotropic axis and LH pulsatility patterns and to determine factor(s) that could account for the potential abnormality of LH pulsatility. Case/control study. Sixteen CAH women (11 with the salt-wasting form and five with the simple virilizing form), aged from 18 to 40 years, and 16 age-matched women, with regular menstrual cycles (28 ± 3 days), were included. LH pulse patterns over 6 h were determined in patients and controls. No differences were observed between patients and controls in terms of mean LH levels, LH pulse amplitude, or LH frequency. In CAH patients, LH pulsatility patterns were heterogeneous, leading us to perform a clustering analysis of LH data, resulting in a two-cluster partition. Patients in cluster 1 had similar LH pulsatility patterns to the controls. Patients in cluster 2 had: lower LH pulse amplitude and frequency and presented menstrual cycle disturbances more frequently; higher 17-OH progesterone, testosterone, progesterone, and androstenedione levels; and lower FSH levels. LH pulsatility may be normal in CAH women well controlled by hormonal treatment. Undertreatment is responsible for hypogonadotropic hypogonadism, with low LH pulse levels and frequency, but not PCOS. Suppression of progesterone and androgen concentrations during the follicular phase of the menstrual cycle should be a major objective in these patients.

Genetics Home Reference: X-linked hyper IgM syndrome

MedlinePlus

... Home Health Conditions X-linked hyper IgM syndrome X-linked hyper IgM syndrome Printable PDF Open All ... Javascript to view the expand/collapse boxes. Description X-linked hyper IgM syndrome is a condition that ...

Genetics Home Reference: X-linked dystonia-parkinsonism

MedlinePlus

... X-linked dystonia-parkinsonism syndrome (XDP): clinical and molecular genetic analysis. Brain Pathol. 1992 Oct;2(4):287-95. Review. Citation on PubMed Kaji R, Goto S, Tamiya G, Ando S, Makino S, Lee LV. Molecular dissection and anatomical basis of dystonia: X-linked ...

Congenital heart disease linked to maternal autoimmunity against cardiac myosin.

PubMed

Cole, Charles R; Yutzey, Katherine E; Brar, Anoop K; Goessling, Lisa S; Van Vickle-Chavez, Sarah J; Cunningham, Madeleine W; Eghtesady, Pirooz

2014-05-01

Structural congenital heart disease (CHD) has not previously been linked to autoimmunity. In our study, we developed an autoimmune model of structural CHD that resembles hypoplastic left heart syndrome (HLHS), a life-threatening CHD primarily affecting the left ventricle. Because cardiac myosin (CM) is a dominant autoantigen in autoimmune heart disease, we hypothesized that immunization with CM might lead to transplacental passage of maternal autoantibodies and a prenatal HLHS phenotype in exposed fetuses. Elevated anti-CM autoantibodies in maternal and fetal sera, as well as IgG reactivity in fetal myocardium, were correlated with structural CHD that included diminished left ventricular cavity dimensions in the affected progeny. Further, fetuses that developed a marked HLHS phenotype had elevated serum titers of anti-β-adrenergic receptor Abs, as well as increased protein kinase A activity, suggesting a potential mechanism for the observed pathological changes. Our maternal-fetal model presents a new concept linking autoimmunity against CM and cardiomyocyte proliferation with cardinal features of HLHS. To our knowledge, this report shows the first evidence in support of a novel immune-mediated mechanism for pathogenesis of structural CHD that may have implications in its future diagnosis and treatment.

Long term outcomes in 46, XX adult patients with congenital adrenal hyperplasia reared as males.

PubMed

Khattab, A; Yau, M; Qamar, A; Gangishetti, P; Barhen, A; Al-Malki, S; Mistry, H; Anthony, W; Toralles, M B; New, Maria I

2017-01-01

Patients with Congenital Adrenal Hyperplasia (CAH) owing to 21-hydroxylase deficiency and whose karyotype is 46, XX are usually assigned to the female gender. Reported herein are the long term outcomes in three patients with CAH whose karyotype is 46, XX and who were reared as males. A retrospective review of three CAH patients with a 46, XX karyotype who were reared as males was conducted. Gender assignment, clinical and biochemical data, pre and post-genitoplasty genital examinations were reviewed. Gender identity was tested by an extensive questionnaire. Gender role, sexual preference, marital status and sexual satisfaction were evaluated by interview. The three patients were genotyped for the CYP21A2 gene confirming the diagnosis of CAH. Owing to genital virilization, cultural preferences for male gender and the lack of newborn screening programs the three patients reported herein were assigned to the male gender at birth before the diagnosis of CAH was established. In adulthood the patients remained significantly virilized. Thorough psychosexual assessments in adulthood revealed well established male gender identities compatible with their male gender assignments at birth. In all three patients, gender role and behavior were consistent with male gender identity including sexual intercourse with female partners. The three patients reported herein revealed that male gender assignment to CAH patients with a 46, XX karyotype may have a successful outcome providing there is strong parental support and expert endocrine care. No standard guidelines have been published for the gender assignment of CAH patients with a 46, XX karyotype and genital ambiguity. More studies concerning gender assignment in CAH patients with a 46, XX karyotype reared as males are needed. Copyright © 2016 Elsevier Ltd. All rights reserved.

Noninvasive Prenatal Diagnosis of Congenital Adrenal Hyperplasia Using Cell-Free Fetal DNA in Maternal Plasma

PubMed Central

Tong, Yu K.; Yuen, Tony; Jiang, Peiyong; Pina, Christian; Chan, K. C. Allen; Khattab, Ahmed; Liao, Gary J. W.; Yau, Mabel; Kim, Se-Min; Chiu, Rossa W. K.; Sun, Li; Zaidi, Mone

2014-01-01

Context: Congenital adrenal hyperplasia (CAH) is an autosomal recessive condition that arises from mutations in CYP21A2 gene, which encodes for the steroidogenic enzyme 21-hydroxylase. To prevent genital ambiguity in affected female fetuses, prenatal treatment with dexamethasone must begin on or before gestational week 9. Currently used chorionic villus sampling and amniocentesis provide genetic results at approximately 14 weeks of gestation at the earliest. This means that mothers who want to undergo prenatal dexamethasone treatment will be unnecessarily treating seven of eight fetuses (males and three of four unaffected females), emphasizing the desirability of earlier genetic diagnosis in utero. Objective: The objective of the study was to develop a noninvasive method for early prenatal diagnosis of fetuses at risk for CAH. Patients: Fourteen families, each with a proband affected by phenotypically classical CAH, were recruited. Design: Cell-free fetal DNA was obtained from 3.6 mL of maternal plasma. Using hybridization probes designed to capture a 6-Mb region flanking CYP21A2, targeted massively parallel sequencing (MPS) was performed to analyze genomic DNA samples from parents and proband to determine parental haplotypes. Plasma DNA from pregnant mothers also underwent targeted MPS to deduce fetal inheritance of parental haplotypes. Results: In all 14 families, the fetal CAH status was correctly deduced by targeted MPS of DNA in maternal plasma, as early as 5 weeks 6 days of gestation. Conclusions: MPS on 3.6 mL plasma from pregnant mothers could potentially provide the diagnosis of CAH, noninvasively, before the ninth week of gestation. Only affected female fetuses will thus be treated. Our strategy represents a generic approach for noninvasive prenatal testing for an array of autosomal recessive disorders. PMID:24606108

Adrenal venous sampling in a patient with adrenal Cushing syndrome

PubMed Central

Villa-Franco, Carlos Andrés; Román-Gonzalez, Alejandro; Velez-Hoyos, Alejandro; Echeverri-Isaza, Santiago

2015-01-01

The primary bilateral macronodular adrenal hyperplasia or the independent adrenocorticotropic hormone bilateral nodular adrenal hyperplasia is a rare cause hypercortisolism, its diagnosis is challenging and there is no clear way to decide the best therapeutic approach. Adrenal venous sampling is commonly used to distinguish the source of hormonal production in patients with primary hyperaldosteronism. It could be a useful tool in this context because it might provide information to guide the treatment. We report the case of a patient with ACTH independent Cushing syndrome in whom the use of adrenal venous sampling with some modifications radically modified the treatment and allowed the diagnosis of a macronodular adrenal hyperplasia. PMID:26309345

Congenital adrenal hyperplasia and risk for psychiatric disorders in girls and women born between 1915 and 2010: A total population study.

PubMed

Engberg, Hedvig; Butwicka, Agnieszka; Nordenström, Anna; Hirschberg, Angelica Lindén; Falhammar, Henrik; Lichtenstein, Paul; Nordenskjöld, Agneta; Frisén, Louise; Landén, Mikael

2015-10-01

Congenital adrenal hyperplasia (CAH) is a chronic condition and individuals are exposed to elevated androgen levels in utero as a result of the endogenous cortisol deficiency. Prenatal androgen exposure has been suggested to influence mental health, but population based studies on psychiatric morbidity among girls and women with CAH are lacking. Therefore, we performed a cohort study based on Swedish nationwide registers linked with the national CAH register. Girls and women with CAH due to 21-hydroxylase deficiency (n = 335) born between January 1915 and January 2010 were compared with aged-matched female (n = 33500) and male controls (n = 33500). Analyses were stratified by phenotype [salt wasting (SW), simple virilizing (SV), and non-classical type (NC)] and by CYP21A2 genotype subgroups (null, I2splice, I172N, and P30L). Results are presented as estimated risks (OR, 95%CI) of psychiatric disorders among girls and women with CAH compared with age-matched controls. Any psychiatric diagnoses were more common in CAH females compared with female and male population controls [1.9 (1.4-2.5), and 2.2 (1.7-2.9)]. In particular, the risk of alcohol misuse was increased compared with female and male population controls [2.8 (1.7-4.7) and 2.1 (1.2-3.5)], and appeared most common among the girls and women with the most severe null genotype [6.7 (2.6-17.8)]. The risk of stress and adjustment disorders was doubled compared with female population controls [2.1 (1.3-3.6)]. Girls and women with CAH have an increased risk of psychiatric disorders in general and substance use disorders in particular compared with unexposed females, with the highest risk among those with the most severe genotype. Prenatal androgen exposure and deficient endogenous cortisol and/or adrenaline production may provide explanations for these findings, but other factors related to CAH cannot be excluded. Copyright © 2015 Elsevier Ltd. All rights reserved.

Male gender identity in children with 46,XX DSD with congenital adrenal hyperplasia after delayed presentation in mid-childhood.

PubMed

Chowdhury, Tanvir Kabir; Laila, Kamrun; Hutson, John M; Banu, Tahmina

2015-12-01

Girls with congenital adrenal hyperplasia (CAH) diagnosed at birth have some masculine behaviors but rarely convert to male gender. In developing countries, however, diagnosis and treatment (with secondary androgen suppression) are delayed. We aimed to assess effect of delayed treatment of CAH on gender identity. As part of a cross-sectional, case-control study of children with disorders of sex development (DSD), there were 11 patients with CAH. Patients and caregivers answered a questionnaire about gender identity, and behavior was assessed by observing toy play. Patients were examined for Prader score and gender identity. Of 11 CAH patients initially raised as girls, 3 (27%) had converted to male gender at presentation (5, 9, 9years) (Prader 3, 4, 4). Of the remaining 8 patients, one 4-year-old (Prader 2) had a male gender identity score. The remaining girls (2-13years, mean 8.1) (Prader 1-3) had gender identity scores in the female range. One third (4/11) of CAH patients presenting in mid-childhood had male gender identity scores, and ¾ had assumed male gender role. Although social and cultural factors are important in developing countries, this result suggests that delayed treatment may trigger male gender identity, and delayed female genital surgery may be unwise. Copyright © 2015 Elsevier Inc. All rights reserved.

Prevalence of and markers for the attenuated form of congenital adrenal hyperplasia and hyperprolactinemia masquerading as polycystic ovarian disease.

PubMed

Benjamin, F; Deutsch, S; Saperstein, H; Seltzer, V L

1986-08-01

To determine the prevalence of the attenuated form of congenital adrenal hyperplasia (CAH) and hyperprolactinemia (HPPN) relative to polycystic ovarian disease (PCOD), 100 consecutive women presenting with the classic clinical features of PCOD were evaluated by basal hormonal profiles and subsequent adrenocorticotropic hormone (ACTH) stimulation tests. The study also sought biochemical markers for CAH other than ACTH stimulation. The prevalences were found to be as follows: PCOD, 65%; PCOD with HPPN, 9%; HPPN, 3%, end-organ hypersensitivity (EOH), 4%; homozygotic CAH, 4%; and heterozygotic CAH, 15%. Other than the differential response to ACTH, the only other biochemical markers observed for homozygotic CAH were significantly higher basal levels of testosterone (T) and 17 alpha-hydroxyprogesterone (17-OHP). Luteinizing hormone/follicle-stimulating hormone ratio, androstenedione, and dehydroepiandrosterone sulfate all showed no significant differences between homozygotic CAH, heterozygotic CAH, HPPN, PCOD, and EOH. This study establishes the relative prevalences of the syndromes commonly mimicking PCOD. We also conclude that the observed low incidence of CAH does not justify routine ACTH testing on all patients presenting with features of PCOD--however, our data suggest that patients with basal serum levels of T and 17-OHP greater than 50% above the upper limit of normal should undergo this dynamic test, especially if there are also certain clinical features suggestive of CAH.

A child with hypertension and ambiguous genitalia - an uncommon variant of congenital adrenal hyperplasia: a case report.

PubMed

Pant, Vivek; Baral, Suman; Shrestha, Bishal; Tumbapo, Arjun

2017-06-23

Deficiency in 11β-hydroxylase as a cause of congenital adrenal hyperplasia is uncommon. It should be considered in the differential diagnosis of hypertension with virilization in any prepubescent child. A 12-year-old Asian boy from eastern Nepal presented with pain in his abdomen and hypertension. He was raised as a male but had absent testicles since birth and had precocious puberty. Plasma testosterone, follicle-stimulating hormone, and luteinizing hormone were below baseline level. Basal 17-hydroxyprogesterone was elevated. Magnetic resonance imaging of his pelvis showed presence of Müllerian structures and karyotyping revealed 46,XX genotype. A clinical diagnosis of 11β-hydroxylase deficiency was made in view of hypertension with severe virilization in a 46,XX individual. Our patient's legal guardian was unwilling for our patient to change gender and because our patient is underage, the condition was well explained to his parents. He was managed with steroids and antihypertensive drugs. He was on regular follow-up; after 2 years there was no hypertension but he developed true puberty with functional ovaries. He was prescribed leuprolide (gonadotropin-releasing hormone analogue), letrozole (aromatase inhibitor), and a continuation of antihypertensive drugs. This case highlights the importance of a thorough physical examination of the external genitalia at birth and appropriate referral, and addresses issues in the management of such a disorder. Ethical issues pertaining to consent and who is entitled to give it should be clear so that the affected individual will have optimal psychological development and quality of life.

Sexual orientation and medical history among Iranian people with Complete Androgen Insensitivity Syndrome and Congenital Adrenal Hyperplasia.

PubMed

Khorashad, Behzad S; Roshan, Ghasem M; Reid, Alistair G; Aghili, Zahra; Hiradfar, Mehran; Afkhamizadeh, Mozhgan; Talaei, Ali; Aarabi, Azadeh; Ghaemi, Nosrat; Taghehchian, Negin; Saberi, Hedieh; Farahi, Nazanin; Abbaszadegan, Mohammad Reza

2017-01-01

To report sexual orientation, relationship status and medical history of Iranian people with Differences of Sex Development (DSD) who were raised female. Our participants consisted of nineteen 46,XY individuals with Complete Androgen Insensitivity Syndrome (CAIS) and eighteen 46,XX individuals with Congenital Adrenal Hyperplasia (CAH) who were raised as females and older than 13years. As well as their relationship status and detailed medical history, an expert psychiatrist assessed their sexual orientation by a semi-structured psychiatric interview with them and, where applicable, their parents. Five percent of CAH participants and 42% of CAIS participants were in a relationship, which was significantly different. All CAH individuals had been diagnosed at birth; 89% of CAIS had been diagnosed after puberty and due to primary amenorrhea and 11% were diagnosed in childhood due to inguinal hernia. Genital reconstructive surgery had been performed in 100% of CAH participants and 37% of CAIS. Regarding sexual contact experiences and sexual fantasies (androphilic, gynephilic or both), no significant differences were found. However, CAH females had significantly more gynephilic dreams (P=0.045). This study, notable as one of the rare from a non-western culture, described sexual, medical and socioeconomic status of 46,XX CAH and 46,XY CAIS individuals living in Iran. Although broadly in line with previous findings from Western cultures, Iranian CAH individuals had fewer romantic relationships, but in contrast to previous studies their sexual orientation was only different from CAIS in the contents of sexual dreams. Copyright © 2016 Elsevier Inc. All rights reserved.

Syndrome-Related Stigma in the General Social Environment as Reported by Women with Classical Congenital Adrenal Hyperplasia.

PubMed

Meyer-Bahlburg, Heino F L; Reyes-Portillo, Jazmin A; Khuri, Jananne; Ehrhardt, Anke A; New, Maria I

2017-02-01

Stigma defined as "undesired differentness" (Goffman, 1963) and subtyped as "experienced" or "enacted," "anticipated," and "internalized" has been documented for patients with diverse chronic diseases. However, no systematic data exist on the association of stigma with somatic intersexuality. The current report concerns women with classical congenital adrenal hyperplasia (CAH), the most prevalent intersex syndrome, and provides descriptive data on CAH-related stigma as experienced in the general social environment (excluding medical settings and romantic/sexual partners) during childhood, adolescence, and adulthood. A total of 62 adult women with classical CAH [41 with the salt-wasting (SW) variant and 21 with the simple-virilizing (SV) variant] underwent a qualitative retrospective interview, which focused on the impact of CAH and its medical treatment on many aspects of women's lives. Deductive content analysis was performed on the transcribed texts. The women's accounts of CAH-related stigma were identified and excerpted as vignettes, and the vignettes categorized according to social context, stigma type, and the associated features of the CAH condition. Nearly two-thirds of women with either variant of CAH provided stigma vignettes. The vignettes included all three stigma types, and most involved some somatic or behavioral feature related to sex or gender. Stigma situations were reported for all ages and all social contexts of everyday life: family, peers, colleagues at work, strangers, and the media. We conclude that there is a need for systematic documentation of stigma in intersexuality as a basis for the development of improved approaches to prevention and intervention.

Genetics Home Reference: alpha thalassemia X-linked intellectual disability syndrome

MedlinePlus

... thalassemia X-linked intellectual disability syndrome Alpha thalassemia X-linked intellectual disability syndrome Printable PDF Open All ... view the expand/collapse boxes. Description Alpha thalassemia X-linked intellectual disability syndrome is an inherited disorder ...

Diagnosis of adrenal insufficiency.

PubMed

Dorin, Richard I; Qualls, Clifford R; Crapo, Lawrence M

2003-08-05

The cosyntropin stimulation test is the initial endocrine evaluation of suspected primary or secondary adrenal insufficiency. To critically review the utility of the cosyntropin stimulation test for evaluating adrenal insufficiency. The MEDLINE database was searched from 1966 to 2002 for all English-language papers related to the diagnosis of adrenal insufficiency. Studies with fewer than 5 persons with primary or secondary adrenal insufficiency or with fewer than 10 persons as normal controls were excluded. For secondary adrenal insufficiency, only studies that stratified participants by integrated tests of adrenal function were included. Summary receiver-operating characteristic (ROC) curves were generated from all studies that provided sensitivity and specificity data for 250-microg and 1-microg cosyntropin tests; these curves were then compared by using area under the curve (AUC) methods. All estimated values are given with 95% CIs. At a specificity of 95%, sensitivities were 97%, 57%, and 61% for summary ROC curves in tests for primary adrenal insufficiency (250-microg cosyntropin test), secondary adrenal insufficiency (250-microg cosyntropin test), and secondary adrenal insufficiency (1-microg cosyntropin test), respectively. The area under the curve for primary adrenal insufficiency was significantly greater than the AUC for secondary adrenal insufficiency for the high-dose cosyntropin test (P < 0.001), but AUCs for the 250-microg and 1-microg cosyntropin tests did not differ significantly (P > 0.5) for secondary adrenal insufficiency. At a specificity of 95%, summary ROC analysis for the 250-microg cosyntropin test yielded a positive likelihood ratio of 11.5 (95% CI, 8.7 to 14.2) and a negative likelihood ratio of 0.45 (CI, 0.30 to 0.60) for the diagnosis of secondary adrenal insufficiency. Cortisol response to cosyntropin varies considerably among healthy persons. The cosyntropin test performs well in patients with primary adrenal insufficiency, but the

FARVATX: Family-Based Rare Variant Association Test for X-Linked Genes.

PubMed

Choi, Sungkyoung; Lee, Sungyoung; Qiao, Dandi; Hardin, Megan; Cho, Michael H; Silverman, Edwin K; Park, Taesung; Won, Sungho

2016-09-01

Although the X chromosome has many genes that are functionally related to human diseases, the complicated biological properties of the X chromosome have prevented efficient genetic association analyses, and only a few significantly associated X-linked variants have been reported for complex traits. For instance, dosage compensation of X-linked genes is often achieved via the inactivation of one allele in each X-linked variant in females; however, some X-linked variants can escape this X chromosome inactivation. Efficient genetic analyses cannot be conducted without prior knowledge about the gene expression process of X-linked variants, and misspecified information can lead to power loss. In this report, we propose new statistical methods for rare X-linked variant genetic association analysis of dichotomous phenotypes with family-based samples. The proposed methods are computationally efficient and can complete X-linked analyses within a few hours. Simulation studies demonstrate the statistical efficiency of the proposed methods, which were then applied to rare-variant association analysis of the X chromosome in chronic obstructive pulmonary disease. Some promising significant X-linked genes were identified, illustrating the practical importance of the proposed methods. © 2016 WILEY PERIODICALS, INC.

FARVATX: FAmily-based Rare Variant Association Test for X-linked genes

PubMed Central

Choi, Sungkyoung; Lee, Sungyoung; Qiao, Dandi; Hardin, Megan; Cho, Michael H.; Silverman, Edwin K; Park, Taesung; Won, Sungho

2016-01-01

Although the X chromosome has many genes that are functionally related to human diseases, the complicated biological properties of the X chromosome have prevented efficient genetic association analyses, and only a few significantly associated X-linked variants have been reported for complex traits. For instance, dosage compensation of X-linked genes is often achieved via the inactivation of one allele in each X-linked variant in females; however, some X-linked variants can escape this X chromosome inactivation. Efficient genetic analyses cannot be conducted without prior knowledge about the gene expression process of X-linked variants, and misspecified information can lead to power loss. In this report, we propose new statistical methods for rare X-linked variant genetic association analysis of dichotomous phenotypes with family-based samples. The proposed methods are computationally efficient and can complete X-linked analyses within a few hours. Simulation studies demonstrate the statistical efficiency of the proposed methods, which were then applied to rare-variant association analysis of the X chromosome in chronic obstructive pulmonary disease (COPD). Some promising significant X-linked genes were identified, illustrating the practical importance of the proposed methods. PMID:27325607

Fecal Glucocorticoid Analysis: Non-invasive Adrenal Monitoring in Equids.

PubMed

Yarnell, Kelly; Purcell, Rebecca S; Walker, Susan L

2016-04-25

Adrenal activity can be assessed in the equine species by analysis of feces for corticosterone metabolites. During a potentially aversive situation, corticotrophin releasing hormone (CRH) is released from the hypothalamus in the brain. This stimulates the release of adrenocorticotrophic hormone (ACTH) from the pituitary gland, which in turn stimulates release of glucocorticoids from the adrenal gland. In horses the glucocorticoid corticosterone is responsible for several adaptations needed to support equine flight behaviour and subsequent removal from the aversive situation. Corticosterone metabolites can be detected in the feces of horses and assessment offers a non-invasive option to evaluate long term patterns of adrenal activity. Fecal assessment offers advantages over other techniques that monitor adrenal activity including blood plasma and saliva analysis. The non-invasive nature of the method avoids sampling stress which can confound results. It also allows the opportunity for repeated sampling over time and is ideal for studies in free ranging horses. This protocol describes the enzyme linked immunoassay (EIA) used to assess feces for corticosterone, in addition to the associated biochemical validation.

Left-sided congenital heart lesions in mosaic Turner syndrome.

PubMed

Bouayed Abdelmoula, Nouha; Abdelmoula, Balkiss; Smaoui, Walid; Trabelsi, Imen; Louati, Rim; Aloulou, Samir; Aloulou, Wafa; Abid, Fatma; Kammoun, Senda; Trigui, Khaled; Bedoui, Olfa; Denguir, Hichem; Mallek, Souad; Ben Aziza, Mustapha; Dammak, Jamila; Kaabi, Oldez; Abdellaoui, Nawel; Turki, Fatma; Kaabi, Asma; Kamoun, Wafa; Jabeur, Jihen; Ltaif, Wided; Chaker, Kays; Fourati, Haytham; M'rabet, Samir; Ben Ameur, Hedi; Gouia, Naourez; Mhiri, Mohamed Nabil; Rebai, Tarek

2018-04-01

In the era of the diseasomes and interactome networks, linking genetics with phenotypic traits in Turner syndrome should be studied thoroughly. As a part of this stratagem, mosaicism of both X and Y chromosome which is a common finding in TS and an evaluation of congenital heart diseases in the different situations of mosaic TS types, can be helpful in the identification of disturbed sex chromosomes, genes and signaling pathway actors. Here we report the case of a mosaic TS associated to four left-sided CHD, including BAV, COA, aortic aneurysms and dissections at an early age. The mosaicism included two cell lines, well-defined at the cytogenetic and molecular levels: a cell line which is monosomic for Xp and Xq genes (45,X) and another which is trisomic for pseudoautosomal genes that are present on the X and Y chromosomes and escape X inactivation: 45,X[8]/46,X,idic(Y)(pter→q11.2::q11.2→pter)[42]. This case generates two hypotheses about the contribution of genes linked to the sex chromosomes and the signaling pathways involving these genes, in left-sided heart diseases. The first hypothesis suggests the interaction between X chromosome and autosomal genes or loci of aortic development, possibly dose-dependent, and which could be in the framework of TGF-β-SMAD signaling pathways. The second implies that left-sided congenital heart lesions involve sex chromosomes loci. The reduced dosage of X chromosome gene(s), escaping X inactivation during development, contributes to this type of CHD. Regarding our case, these X chromosome genes may have homologues at the Y chromosome, but the process of inactivation of the centromeres of the isodicentric Y spreads to the concerned Y chromosome genes. Therefore, this case emerges as an invitation to consider the mosaics of Turner syndrome and to study their phenotypes in correlation with their genotypes to discover the underlying developmental and genetic mechanisms, especially the ones related to sex chromosomes.

Angiotensin II receptors in cortical and medullary adrenal tumors.

PubMed

Opocher, G; Rocco, S; Cimolato, M; Vianello, B; Arnaldi, G; Mantero, F

1997-03-01

Several pieces of evidences suggest that angiotensin II (Ang II) has mitogenic effects, and a link between Ang II receptors and adrenal tumors can be suggested. In various adrenal tumors, aldosterone-producing adenoma (APA), Cushing's adrenal adenomas (Cush), pheochromocytomas (Pheo), and adrenal carcinomas, we studied the density, affinity, and subtype of Ang II receptors. Ang II binding was tested in cell membrane homogenates. [125I]Ang II was used as ligand, and Losartan and CGP 42112 were used as selective Ang II type 1 and type 2 antagonists, respectively. In APA, Ang II receptor density was 178.5 +/- 82.7 fmol/mg: however, due to the high degree of variability, the receptor density was not significantly higher than that in nontumorous adrenal cortex (59.3 +/- 8.4 fmol/mg). In Cush, the receptor density (27.6 +/- 8.2 fmol/mg; P < 0.05) was significantly lower than that in controls, whereas in Pheo and cortical carcinoma, Ang II binding was very low and in several cases almost undetectable. There was no remarkable difference in the Ang II receptor affinity among all tissues tested. The ratio between type 1 and type 2 Ang II receptors showed a large prevalence of type 1 in controls, APA, and three cases of Cush; in two cases of Cush, this ratio was reversed. In conclusion, our data indicate that Ang II receptors are normally expressed in APA and can also be detected in Cush, whereas they have a very low density in Pheo and adrenal carcinoma. Therefore, Ang II receptors are not involved in the lack of response to Ang II that is characteristic of APA; additionally, a reduction of Ang II receptors can be associated with dedifferentiation or malignancy of adrenal tumors. Further investigation of the expression and functional characterization of Ang II receptors is required to better clarify their possible role in adrenal tumorigenesis.

Phenotype-genotype correlation in potential female carriers of X-linked developmental cataract (Nance-Horan syndrome).

PubMed

Khan, Arif O; Aldahmesh, Mohammed A; Mohamed, Jawahir Y; Alkuraya, Fowzan S

2012-06-01

To correlate clinical examination with underlying genotype in asymptomatic females who are potential carriers of X-linked developmental cataract (Nance-Horan syndrome). An ophthalmologist blind to the pedigree performed comprehensive ophthalmic examination for 16 available family members (two affected and six asymptomatic females, five affected and three asymptomatic males). Facial features were also noted. Venous blood was collected for sequencing of the gene NHS. All seven affected family members had congenital or infantile cataract and facial dysmorphism (long face, bulbous nose, abnormal dentition). The six asymptomatic females ranged in age from 4-35 years old. Four had posterior Y-suture centered lens opacities; these four also exhibited the facial dysmorphism of the seven affected family members. The fifth asymptomatic girl had scattered fine punctate lens opacities (not centered on the Y-suture) while the sixth had clear lenses, and neither exhibited the facial dysmorphism. A novel NHS mutation (p.Lys744AsnfsX15 [c.2232delG]) was found in the seven patients with congenital or infantile cataract. This mutation was also present in the four asymptomatic girls with Y-centered lens opacities but not in the other two asymptomatic girls or in the three asymptomatic males (who had clear lenses). Lens opacities centered around the posterior Y-suture in the context of certain facial features were sensitive and specific clinical signs of carrier status for NHS mutation in asymptomatic females. Lens opacities that did not have this characteristic morphology in a suspected female carrier were not a carrier sign, even in the context of her affected family members.

Congenital Disorders of Platelet Function and Number.

PubMed

Sharma, Ruchika; Perez Botero, Juliana; Jobe, Shawn M

2018-06-01

Mucocutaneous bleeding symptoms and/or persistent thrombocytopenia occur in individuals with congenital disorders of platelet function and number. Apart from bleeding, these disorders are often associated with additional hematologic and clinical manifestations, including auditory, immunologic, and oncologic disease. Autosomal recessive, dominant, and X-linked inheritance patterns have been demonstrated. Precise delineation of the molecular cause of the platelet disorder can aid the pediatrician in the detection and prevention of specific disorder-associated manifestations and guide appropriate treatment and anticipatory care for the patient and family. Copyright © 2018 Elsevier Inc. All rights reserved.

[Addison's disease : Primary adrenal insufficiency].

PubMed

Pulzer, A; Burger-Stritt, S; Hahner, S

2016-05-01

Adrenal insufficiency, a rare disorder which is characterized by the inadequate production or absence of adrenal hormones, may be classified as primary adrenal insufficiency in case of direct affection of the adrenal glands or secondary adrenal insufficiency, which is mostly due to pituitary or hypothalamic disease. Primary adrenal insufficiency affects 11 of 100,000 individuals. Clinical symptoms are mainly nonspecific and include fatigue, weight loss, and hypotension. The diagnostic test of choice is dynamic testing with synthetic ACTH. Patients suffering from chronic adrenal insufficiency require lifelong hormone supplementation. Education in dose adaption during physical and mental stress or emergency situations is essential to prevent life-threatening adrenal crises. Patients with adrenal insufficiency should carry an emergency card and emergency kit with them.

Gene of a new X-linked syndrome with multiple congenital anomalies and severe mental retardation maps in Xp22-pter

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

Wittwer, B.; Kircheisen, R.; Leutelt, J.

1994-09-01

We report on a family with 3 males presenting with a not yet described new X-chromosomal syndrome of multiple congenital anomalies and severe mental retardation. Two sisters have (with 3 different partners) 3 severely handicapped sons. In each case, oligohydramnios and intrauterine growth retardation were observed. Delivery was in the 34th, 31st, and 38th gestational week, respectively. Two of the patients had microcephaly (head circumference of the third case at birth is unknown). On physical examination, high and broad forehead, frontal bossing, downslanting palpebral fissures, long philtrum, thin upper lip, high arched palate, and deeply set anteverted ears were seen.more » One of the boys has microphthalmos and sclerocornea, while his cousin shows atrophy of the optic nerve. All three patients show a severe statomotor and mental retardation, they are most likely deaf and blind, have pathologic EEG, and seizures. Important additional findings are hydronephrosis, renal duplication, vesicorenal reflux, and agenesis of corpus callosum. The karyotype is normal (46,XY). We performed a segregation analysis in the family using more than 20 DNA polymorphisms distributed over the X chromosome. Linkage without recombination was found to KAL, DXS278, and DXS16 in Xp22. Analysis of multiple informative meioses suggested a location of the disease locus distal to DXS207. Recombinants were identified with all other marker loci from Xp22-Xpter.« less

Phenotype-genotype correlations in X linked retinitis pigmentosa.

PubMed Central

Kaplan, J; Pelet, A; Martin, C; Delrieu, O; Aymé, S; Bonneau, D; Briard, M L; Hanauer, A; Larget-Piet, L; Lefrançois, P

1992-01-01

Retinitis pigmentosa (RP) represents a group of clinically heterogeneous retinal degenerations in which all modes of inheritance have been described. We have previously found two different clinical profiles in X linked RP as a function of age and mode of onset. The first clinical form has very early onset with severe myopia. The second form starts later with night blindness with mild myopia or none. At least two genes have been identified in X linked forms, namely RP2 (linked to DXS7, DXS255, and DXS14) and RP3 (linked to DXS84 and OTC) on the short arm of the X chromosome. In order to contribute to phenotype-genotype correlations in X linked RP, we tested the hypothesis that the two clinical profiles could be accounted for by the two different gene loci. The present study provides evidence for linkage of the clinical form with early myopia as the onset symptom with the RP2 gene (pairwise linkage to DXS255: Z = 3.13 at theta = 0), while the clinical form with later night blindness as the onset symptom is linked to the RP3 gene (pairwise linkage to OTC: Z = 4.16 at theta = 0). Images PMID:1357178

Rapid steroid hormone quantification for congenital adrenal hyperplasia (CAH) in dried blood spots using UPLC liquid chromatography-tandem mass spectrometry.

PubMed

Janzen, Nils; Sander, Stefanie; Terhardt, Michael; Steuerwald, Ulrike; Peter, Michael; Das, Anibh M; Sander, Johannes

2011-12-11

Newborn screening for congenital adrenal hyperplasia (CAH) is usually done by quantifying 17α-hydroxyprogesterone using immunoassay. However, this test produces high rates of false positive results caused by cross reacting steroids. Therefore we have developed a selective and specific method with a short run time (1.25 min) for quantification of 17α-hydroxyprogesterone, 21-deoxycortisol, 11-deoxycortisol, 11-deoxycorticosterone and cortisol from dried blood spots. The extraction procedure is very simple and steroid separation is ensured on a BEH C18 column and an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Analysis was done in positive ionization mode (ESI+) and recorded in multiple reaction monitoring mode (MRM). The method gave linear results for all steroids over a range of 5-200 (cortisol: 12.5-500)nmol/L with coefficients of regression >0.992. Absolute recovery was >64.1%. Across the analytical range the inter-assay coefficient of variation (CV) was <3%. Newborn blood samples of patients with confirmed 21-CAH and 11-CAH could clearly be distinguished from samples of unaffected newborns falsely positive on immunoassay. The method is not influenced by cross reactions as found on immunoassay. Analysis of dried blood spots shows that this method is sensitive and fast enough to allow rapid analysis and can therefore improve the newborn screening program. Copyright © 2011 Elsevier Inc. All rights reserved.

Sex-specific silencing of X-linked genes by Xist RNA

PubMed Central

Gayen, Srimonta; Maclary, Emily; Hinten, Michael; Kalantry, Sundeep

2016-01-01

X-inactive specific transcript (Xist) long noncoding RNA (lncRNA) is thought to catalyze silencing of X-linked genes in cis during X-chromosome inactivation, which equalizes X-linked gene dosage between male and female mammals. To test the impact of Xist RNA on X-linked gene silencing, we ectopically induced endogenous Xist by ablating the antisense repressor Tsix in mice. We find that ectopic Xist RNA induction and subsequent X-linked gene silencing is sex specific in embryos and in differentiating embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs). A higher frequency of XΔTsixY male cells displayed ectopic Xist RNA coating compared with XΔTsixX female cells. This increase reflected the inability of XΔTsixY cells to efficiently silence X-linked genes compared with XΔTsixX cells, despite equivalent Xist RNA induction and coating. Silencing of genes on both Xs resulted in significantly reduced proliferation and increased cell death in XΔTsixX female cells relative to XΔTsixY male cells. Thus, whereas Xist RNA can inactivate the X chromosome in females it may not do so in males. We further found comparable silencing in differentiating XΔTsixY and 39,XΔTsix (XΔTsixO) ESCs, excluding the Y chromosome and instead implicating the X-chromosome dose as the source of the sex-specific differences. Because XΔTsixX female embryonic epiblast cells and EpiSCs harbor an inactivated X chromosome prior to ectopic inactivation of the active XΔTsix X chromosome, we propose that the increased expression of one or more X-inactivation escapees activates Xist and, separately, helps trigger X-linked gene silencing. PMID:26739568

Adrenal Insufficiency

MedlinePlus

... three types of steroid hormones. In adrenal insufficiency (AI), the cortex does not make enough steroid hormones. ... unlike “adrenal fatigue.” There are two kinds of AI: • Primary AI, also called Addison’s disease. In this ...

Intrinsic factors, adrenal gland morphology, and disease burden in captive cheetahs (Acinonyx jubatus) in South Africa.

PubMed

Gillis-Germitsch, Nina; Vybiral, Pamela-Rose; Codron, Daryl; Clauss, Marcus; Kotze, Antoinette; Mitchell, Emily P

2017-01-01

Adrenal gland weight (AW) and corticomedullary ratio (ACMR) are used as indicators of stress in animals. Captive cheetahs (Acinonyx jubatus) have higher ACMRs than free-ranging ones and stress has been linked to gastritis, amyloidosis, glomerulosclerosis, and myocardial fibrosis. We reviewed age, sex, body weight (BW), kidney weight (KW), and left AW and ACMR with necropsy findings in 51 South African captive cheetahs. Eleven common histopathologic lesions were counted for each animal as measure of its disease burden. Adrenal corticomedullary hyperplasia was significantly correlated with left AW and ACMR. Males had significantly higher AWs than females; other parameters showed no difference between the sexes. Disease burden, gastritis, and myocardial fibrosis were moderately correlated with adrenal morphology supporting prior evidence that gastritis and myocardial fibrosis are linked to stress. Glomerulosclerosis was not correlated with adrenal morphology and neither kidney nor liver amyloidosis contributed significantly to variation in AW or ACMR on multivariate analyses. Interstitial nephritis showed much stronger correlations with kidney and liver amyloidosis than gastritis. All three adrenal parameters were correlated with age; age was the only significant variable affecting ACMR on the multivariate analyses; and disease burden as well as systemic amyloidosis and kidney disease (except for fibrosis) showed moderate correlations with age. Age may, therefore, be important in the pathogenesis of disease in captive cheetahs, particularly of amyloidosis and kidney disease. None of the intrinsic measurements or adrenal parameters were sufficiently closely linked to disease to be used as ante-mortem proxies for disease burden or specific diseases. Zoo Biol. 36:40-49, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Inheritance of congenital cataracts and microphthalmia in the Miniature Schnauzer.

PubMed

Gelatt, K N; Samuelson, D A; Bauer, J E; Das, N D; Wolf, E D; Barrie, K P; Andresen, T L

1983-06-01

Congenital cataracts and microphthalmia in the Miniature Schnauzer were inherited as an autosomal recessive trait. Eighteen matings of affected X affected Miniature Schnauzers resulted in 87 offspring with congenital cataracts and microphthalmia (49 males/38 females). Two matings of congenital cataractous and microphthalmic Miniature Schnauzers (2 females) X a normal Miniature Schnauzer (1 male) yielded 11 clinically normal Miniature Schnauzers (7 males/4 females). Eighteen matings of congenital cataractous and microphthalmic Miniature Schnauzers (6 males) X carrier Miniature Schnauzers (9 females) produced 81 offspring; 39 exhibited congenital cataracts and microphthalmia (20 males/19 females) and 42 had clinically normal eyes (17 males/25 females).

A Comparison of Selective Pressures in Plant X-Linked and Autosomal Genes

PubMed Central

Krasovec, Marc; Filatov, Dmitry A.

2018-01-01

Selection is expected to work differently in autosomal and X-linked genes because of their ploidy difference and the exposure of recessive X-linked mutations to haploid selection in males. However, it is not clear whether these expectations apply to recently evolved sex chromosomes, where many genes retain functional X- and Y-linked gametologs. We took advantage of the recently evolved sex chromosomes in the plant Silene latifolia and its closely related species to compare the selective pressures between hemizygous and non-hemizygous X-linked genes as well as between X-linked genes and autosomal genes. Our analysis, based on over 1000 genes, demonstrated that, similar to animals, X-linked genes in Silene evolve significantly faster than autosomal genes—the so-called faster-X effect. Contrary to expectations, faster-X divergence was detectable only for non-hemizygous X-linked genes. Our phylogeny-based analyses of selection revealed no evidence for faster adaptation in X-linked genes compared to autosomal genes. On the other hand, partial relaxation of purifying selection was apparent on the X-chromosome compared to the autosomes, consistent with a smaller genetic diversity in S. latifolia X-linked genes (πx = 0.016; πaut = 0.023). Thus, the faster-X divergence in S. latifolia appears to be a consequence of the smaller effective population size rather than of a faster adaptive evolution on the X-chromosome. We argue that this may be a general feature of “young” sex chromosomes, where the majority of X-linked genes are not hemizygous, preventing haploid selection in heterogametic sex. PMID:29751495

A Comparison of Selective Pressures in Plant X-Linked and Autosomal Genes.

PubMed

Krasovec, Marc; Nevado, Bruno; Filatov, Dmitry A

2018-05-03

Selection is expected to work differently in autosomal and X-linked genes because of their ploidy difference and the exposure of recessive X-linked mutations to haploid selection in males. However, it is not clear whether these expectations apply to recently evolved sex chromosomes, where many genes retain functional X- and Y-linked gametologs. We took advantage of the recently evolved sex chromosomes in the plant Silene latifolia and its closely related species to compare the selective pressures between hemizygous and non-hemizygous X-linked genes as well as between X-linked genes and autosomal genes. Our analysis, based on over 1000 genes, demonstrated that, similar to animals, X-linked genes in Silene evolve significantly faster than autosomal genes—the so-called faster-X effect. Contrary to expectations, faster-X divergence was detectable only for non-hemizygous X-linked genes. Our phylogeny-based analyses of selection revealed no evidence for faster adaptation in X-linked genes compared to autosomal genes. On the other hand, partial relaxation of purifying selection was apparent on the X-chromosome compared to the autosomes, consistent with a smaller genetic diversity in S. latifolia X-linked genes (π x = 0.016; π aut = 0.023). Thus, the faster-X divergence in S. latifolia appears to be a consequence of the smaller effective population size rather than of a faster adaptive evolution on the X-chromosome. We argue that this may be a general feature of “young” sex chromosomes, where the majority of X-linked genes are not hemizygous, preventing haploid selection in heterogametic sex.

X-Linked adrenoleukodystrophy is a frequent cause of idiopathic Addison`s disease in young adult male patients

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

Laureti, S.; Casucci, G.; Santeusanio, F.

1996-02-01

X-Linked adrenoleukodystrophy (ALD) is a genetic disease associated with demyelination of the central nervous system, adrenal insufficiency, and accumulation of very long chain fatty acids in tissue and body fluids. ALD is due to mutation of a gene located in Xq28 that encodes a peroxisomal transporter protein of unknown function. The most common phenotype of ALD is the cerebral form (45%) that develops in boys between 5-12 yr. Adrenomyeloneuropathy (AMN) involves the spinal cord and peripheral nerves in young adults (35%). Adrenal insufficiency (Addison`s disease) is frequently associated with AMN or cerebral ALD and may remain the only clinical expressionmore » of ALD (8% of cases). The prevalence of ALD among adults with Addison`s disease remains unknown. To evaluate this prevalence, we performed biochemical analysis of very long chain fatty acids in 14 male patients (age ranging from 12-45 yr at diagnosis) previously diagnosed as having primary idiopathic adrenocortical insufficiency. In 5 of 14 patients (35%), elevated plasma concentrations of very long chain fatty acids were detected. None of these patients had adrenocortical antibodies. By electrophysiological tests and magnetic resonance imaging it was determined that two patients had cerebral ALD, one had adrenomyeloneuropathy with cerebral involvement, and two had preclinical AMN. Our data support the hypothesis that ALD is a frequent cause of idiopathic Addison`s disease in children and adults. 30 refs., 5 tabs.« less

Genetic forms of nephrogenic diabetes insipidus (NDI): Vasopressin receptor defect (X-linked) and aquaporin defect (autosomal recessive and dominant).

PubMed

Bichet, Daniel G; Bockenhauer, Detlef

2016-03-01

Nephrogenic diabetes insipidus (NDI), which can be inherited or acquired, is characterized by an inability to concentrate urine despite normal or elevated plasma concentrations of the antidiuretic hormone, arginine vasopressin (AVP). Polyuria with hyposthenuria and polydipsia are the cardinal clinical manifestations of the disease. About 90% of patients with congenital NDI are males with X-linked NDI who have mutations in the vasopressin V2 receptor (AVPR2) gene encoding the vasopressin V2 receptor. In less than 10% of the families studied, congenital NDI has an autosomal recessive or autosomal dominant mode of inheritance with mutations in the aquaporin-2 (AQP2) gene. When studied in vitro, most AVPR2 and AQP2 mutations lead to proteins trapped in the endoplasmic reticulum and are unable to reach the plasma membrane. Prior knowledge of AVPR2 or AQP2 mutations in NDI families and perinatal mutation testing is of direct clinical value and can avert the physical and mental retardation associated with repeated episodes of dehydration. Copyright © 2016 Elsevier Ltd. All rights reserved.

Persistent Primary Aldosteronism Despite Iatrogenic Adrenal Hemorrhage After Adrenal Vein Sampling.

PubMed

Okamura, Keisuke; Okuda, Tetsu; Shirai, Kazuyuki; Abe, Ichiro; Kobayashi, Kunihisa; Ishii, Tatsu; Haraoka, Seiji; Urata, Hidenori

2018-01-01

Before surgery for primary aldosteronism (PA), localization is evaluated with adrenal vein sampling (AVS). A 56-year-old Japanese woman had a right adrenal mass, hypokalemia, and a high aldosterone/renin ratio. Stress tests confirmed the diagnosis of PA. Subsequently, preoperative AVS was performed and right adrenal hemorrhage (AH) occurred unexpectedly. Because hypertension persisted, laparoscopic right adrenalectomy was performed. Postoperatively, the blood pressure was normalized. Pathological examination revealed an adrenal cortical adenoma largely unaffected by necrosis and hemorrhage. Previous reports have also indicated that AH may not ameliorate PA. We discussed the clinical progress of AH and the measures to prevent causing AH.

Traumatic and non-traumatic adrenal emergencies.

PubMed

Chernyak, Victoria; Patlas, Michael N; Menias, Christine O; Soto, Jorge A; Kielar, Ania Z; Rozenblit, Alla M; Romano, Luigia; Katz, Douglas S

2015-12-01

Multiple traumatic and non-traumatic adrenal emergencies are occasionally encountered during the cross-sectional imaging of emergency department patients. Traumatic adrenal hematomas are markers of severe polytrauma, and can be easily overlooked due to multiple concomitant injuries. Patients with non-traumatic adrenal emergencies usually present to an emergency department with a non-specific clinical picture. The detection and management of adrenal emergencies is based on cross-sectional imaging. Adrenal hemorrhage, adrenal infection, or rupture of adrenal neoplasm require immediate detection to avoid dire consequences. More often however, adrenal emergencies are detected incidentally in patients being investigated for non-specific acute abdominal pain. A high index of suspicion is required for the establishment of timely diagnosis and to avert potentially life-threatening complications. We describe cross-sectional imaging findings in patients with traumatic and non-traumatic adrenal hemorrhage, adrenal infarctions, adrenal infections, and complications of adrenal masses.

Persistent Primary Aldosteronism Despite Iatrogenic Adrenal Hemorrhage After Adrenal Vein Sampling

PubMed Central

Okamura, Keisuke; Okuda, Tetsu; Shirai, Kazuyuki; Abe, Ichiro; Kobayashi, Kunihisa; Ishii, Tatsu; Haraoka, Seiji; Urata, Hidenori

2018-01-01

Before surgery for primary aldosteronism (PA), localization is evaluated with adrenal vein sampling (AVS). A 56-year-old Japanese woman had a right adrenal mass, hypokalemia, and a high aldosterone/renin ratio. Stress tests confirmed the diagnosis of PA. Subsequently, preoperative AVS was performed and right adrenal hemorrhage (AH) occurred unexpectedly. Because hypertension persisted, laparoscopic right adrenalectomy was performed. Postoperatively, the blood pressure was normalized. Pathological examination revealed an adrenal cortical adenoma largely unaffected by necrosis and hemorrhage. Previous reports have also indicated that AH may not ameliorate PA. We discussed the clinical progress of AH and the measures to prevent causing AH. PMID:29238437

Macular hole in juvenile X-linked retinoschisis.

PubMed

Al-Swaina, Nayef; Nowilaty, Sawsan R

2013-10-01

An 18 year-old male with no antecedent of trauma, systemic syndrome or myopia was referred for surgical treatment of a full thickness macular hole in the left eye. A more careful inspection revealed discrete foveal cystic changes in the fellow eye and subtle peripheral depigmented retinal pigment epithelial changes in both eyes. A spectral-domain optical coherence tomography (SD-OCT) scan confirmed, in addition to the full thickness macular hole in the left eye, microcystic spaces in the nuclear layers of both retinae. The diagnosis of X-linked retinoschisis was confirmed with a full field electroretinogram displaying the typical negative ERG. Macular holes are uncommon in the young and those complicating X-linked retinoschisis are rare. This report highlights the importance of investigating the presence of a macular hole in a young patient and illustrates the clinical and SD-OCT clues beyond the foveal center which led to the correct diagnosis of X-linked juvenile retinoschisis.

X-linked dominant retinitis pigmentosa in an American family

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

McGuire, R.E.; Daiger, S.P.; Blanton, S.H.

1994-09-01

Retinitis pigmentosa is a genetically heterogeneous disease with autosomal dominant (adRP), autosomal recessive and X-linked forms. At least 3 forms of X-linked retinitis pigmentosa have been reported: RP2 which maps to Xp11.4-p 11.23, RP3 which maps to Xp21.1 and RP6, which maps to Xp21.3-p21.1. The X-linked forms of retinitis pigmentosa are generally considered to be recessive as female carriers are not affected or are much less affected than males. Here we report a five generation American family with X-linked retinitis pigmentosa in which both males and females are significantly affected. The disease locus in this family appears to be distinctmore » from RP2 and RP3. The American family (UTAD054) presents with early-onset retinitis pigmentosa. The family appeared to fit an autosomal dominant pattern; however, linkage testing excluded all known adRP loci. Absence of male-to-male transmission in the pedigree suggested the possibility of X-linked dominant inheritance. Thus we tested six microsatellite markers that map to Xp (DXS987, DXS989, DXS993, DXS999, DXS1003 and DXS1110). Of these, DXS989 showed tight linkage with one allele (199) showing a 100% concordance with disease status. The odds favoring an X-linked dominant mode of inheritance in this family, versus autosomal dominant, are 10{sup 5}:1. In addition, recombinations for DXS999, and dXS1110, the two markers flanking DXS989, were observed in affected individuals. These data map the disease locus in this family to a 9 mb region on the X chromosome between Xp22.11 and Xp21.41. In addition, the recombinant individuals exclude close linkage to RP2 and RP3. The observance of high penetrance in females indicates that this family has X-linked dominant retinitis pigmentosa. We suggest that this mode of inheritance should be considered in other families with dominant retinitis pigmentosa but an absence of male-to-male transmission.« less

Adrenocorticotropin-dependent precocious puberty of testicular origin in a boy with X-linked adrenal hypoplasia congenita due to a novel mutation in the DAX1 gene.

PubMed

Domenice, S; Latronico, A C; Brito, V N; Arnhold, I J; Kok, F; Mendonca, B B

2001-09-01

Primary adrenal insufficiency is a rare condition in pediatric age, and its association with precocious sexual development is very uncommon. We report a 2-yr-old Brazilian boy with DAX1 gene mutation whose first clinical manifestation was isosexual gonadotropin-independent precocious puberty. He presented with pubic hair, enlarged penis and testes, and advanced bone age. T levels were elevated, whereas basal and GnRH-stimulated LH levels were compatible with a prepubertal pattern. Chronic GnRH agonist therapy did not reduce T levels, supporting the diagnosis of gonadotropin-independent precocious puberty. Testotoxicosis was ruled out after normal sequencing of exon 11 of the LH receptor gene. At age 3 yr he developed clinical and hormonal features of severe primary adrenal insufficiency. The entire coding region of the DAX1 gene was analyzed through direct sequencing. A nucleotide G insertion between nucleotides 430 and 431 in exon 1, resulting in a novel frameshift mutation and a premature stop codon at position 71 of DAX-1, was identified. Surprisingly, steroid replacement therapy induced a clear decrease in testicular size and T levels to the prepubertal range. These findings suggest that chronic excessive ACTH levels resulting from adrenal insufficiency may stimulate Leydig cells and lead to gonadotropin-independent precocious puberty in some boys with DAX1 gene mutations.

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

PubMed

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

2006-08-01

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

Impact of food, alcohol and pH on modified-release hydrocortisone developed to treat congenital adrenal hyperplasia.

PubMed

Karunasena, Nayananjani; Margetson, Daniel N; Neal, Greg; Whitaker, Martin J; Ross, Richard Jm

2017-04-01

We developed a modified-release hydrocortisone, Chronocort, to replace the cortisol rhythm in patients with congenital adrenal hyperplasia. Food, alcohol and pH affect drug absorption, and it is important to assess their impact when replicating a physiological rhythm. In vitro dissolution to study impact of alcohol and pH on Chronocort. A phase 1, three-period, cross over study in 18 volunteers to assess the impact of food on Chronocort and to compare bioavailability to immediate-release hydrocortisone. In vitro dissolution of Chronocort was not affected by gastrointestinal pH up to 6.0 nor by an alcohol content up to 20% v/v. Food delayed and reduced the rate of absorption of Chronocort as reflected by a longer T max (fed vs fasted: 6.75 h vs 4.5 h, P  = 0005) and lower C max (549.49 nmol/L vs 708.46 nmol/L, ratio 77% with CI 71-85). Cortisol exposure was similar in fed and fasted state: Geo LSmean ratio (CI) AUC 0t for fed/fasted was 108.33% (102.30-114.72%). Cortisol exposure was higher for Chronocort compared to immediate-release hydrocortisone: Geo LSmean ratios (CI) 118.83% (111.58-126.54%); however, derived free cortisol showed cortisol exposure CIs were within 80.0-125.0%: Geo LSmean ratio (CI) for AUC 0t 112.73% (105.33-120.65%). Gastric pH ≤6.0 and alcohol do not affect hydrocortisone release from Chronocort. Food delays Chronocort absorption, but cortisol exposure is similar in the fasted and fed state and exposure as assessed by free cortisol is similar between Chronocort and immediate-release hydrocortisone. © 2017 The authors.

Impact of food, alcohol and pH on modified-release hydrocortisone developed to treat congenital adrenal hyperplasia

PubMed Central

Karunasena, Nayananjani; Margetson, Daniel N; Neal, Greg; Whitaker, Martin J

2017-01-01

Background We developed a modified-release hydrocortisone, Chronocort, to replace the cortisol rhythm in patients with congenital adrenal hyperplasia. Food, alcohol and pH affect drug absorption, and it is important to assess their impact when replicating a physiological rhythm. Subjects and methods In vitro dissolution to study impact of alcohol and pH on Chronocort. A phase 1, three-period, cross over study in 18 volunteers to assess the impact of food on Chronocort and to compare bioavailability to immediate-release hydrocortisone. Results In vitro dissolution of Chronocort was not affected by gastrointestinal pH up to 6.0 nor by an alcohol content up to 20% v/v. Food delayed and reduced the rate of absorption of Chronocort as reflected by a longer Tmax (fed vs fasted: 6.75 h vs 4.5 h, P = 0005) and lower Cmax (549.49 nmol/L vs 708.46 nmol/L, ratio 77% with CI 71–85). Cortisol exposure was similar in fed and fasted state: Geo LSmean ratio (CI) AUC0t for fed/fasted was 108.33% (102.30–114.72%). Cortisol exposure was higher for Chronocort compared to immediate-release hydrocortisone: Geo LSmean ratios (CI) 118.83% (111.58–126.54%); however, derived free cortisol showed cortisol exposure CIs were within 80.0–125.0%: Geo LSmean ratio (CI) for AUC0t 112.73% (105.33–120.65%). Conclusions Gastric pH ≤6.0 and alcohol do not affect hydrocortisone release from Chronocort. Food delays Chronocort absorption, but cortisol exposure is similar in the fasted and fed state and exposure as assessed by free cortisol is similar between Chronocort and immediate-release hydrocortisone. PMID:28100629

Functional studies of novel CYP21A2 mutations detected in Norwegian patients with congenital adrenal hyperplasia

PubMed Central

Brønstad, Ingeborg; Breivik, Lars; Methlie, Paal; Wolff, Anette S B; Bratland, Eirik; Nermoen, Ingrid; Løvås, Kristian; Husebye, Eystein S

2014-01-01

In about 95% of cases, congenital adrenal hyperplasia (CAH) is caused by mutations in CYP21A2 gene encoding steroid 21-hydroxylase (21OH). Recently, we have reported four novel CYP21A2 variants in the Norwegian population of patients with CAH, of which p.L388R and p.E140K were associated with salt wasting (SW), p.P45L with simple virilising (SV) and p.V211M+p.V281L with SV to non-classical (NC) phenotypes. We aimed to characterise the novel variants functionally utilising a newly designed in vitro assay of 21OH enzyme activity and structural simulations and compare the results with clinical phenotypes. CYP21A2 mutations and variants were expressed in vitro. Enzyme activity was assayed by assessing the conversion of 17-hydroxyprogesterone to 11-deoxycortisol by liquid chromatography tandem mass spectroscopy. PyMOL 1.3 was used for structural simulations, and PolyPhen2 and PROVEAN for predicting the severity of the mutants. The CYP21A2 mutants, p.L388R and p.E140K, exhibited 1.1 and 11.3% of wt 21OH enzyme activity, respectively, in vitro. We could not detect any functional deficiency of the p.P45L variant in vitro; although prediction tools suggest p.P45L to be pathogenic. p.V211M displayed enzyme activity equivalent to the wt in vitro, which was supported by in silico analyses. We found good correlations between phenotype and the in vitro enzyme activities of the SW mutants, but not for the SV p.P45L variant. p.V211M might have a synergistic effect together with p.V281L, explaining a phenotype between SV and NC CAH. PMID:24671123

Interrelationships among cortisol, 17-hydroxyprogesterone, and androstenendione exposures in the management of children with congenital adrenal hyperplasia.

PubMed

Sarafoglou, Kyriakie; Zimmerman, Cheryl L; Gonzalez-Bolanos, Maria T; Willis, Brian A; Brundage, Richard

2015-01-01

Hydrocortisone is the standard replacement therapy for children with congenital adrenal hyperplasia (CAH). Relationships between cortisol exposures and pharmacodynamic responses of 17-hydroxyprogesterone and androstenedione exposures have not been systematically evaluated. (1) Assess individual oral hydrocortisone pharmacokinetics; (2) relate the observed cortisol exposure in each subject to the observed exposures of 17-hydroxyprogesterone and androstenedione; (3) determine potential individualized treatment regimens based on each subject's pharmacokinetic and pharmacodynamic parameters. Thirty-four patients (18 boys, 16 girls, aged 1.4 to 18.1 years) with CAH underwent 6-hour pharmacokinetic studies. Results were analyzed by noncompartmental methods to obtain the area under the curve (AUC) for cortisol, 17-hydroxyprogesterone, and androstenedione; maximum concentration and time-to-maximum concentration for cortisol; and minimum and time-to-minimum concentration for 17-hydroxyprogesterone and androstenedione. Mean (SD) cortisol half-life and Cmax were 1.01 (0.20) hours and 24.4 (5.4) μg/dL, respectively. The AUCs for cortisol, 17-hydroxyprogesterone and androstenedione were 40.8 (14.5) μg hour/dL, 29,490 (23,539) ng hour/dL, and 680 (795) ng hour/dL, respectively. No significant relationships existed between cortisol AUCs and the AUCs of either 17-hydroxyprogesterone (P=0.32) or androstenedione (P=0.99); nor were there differences between the change-from-baseline concentrations for cortisol with either 17-hydroxyprogesterone (P=0.80) or androstenedione (P=0.40). Cortisol simulations indicated that although four daily doses decreased 24-hour hypercortisolemia and hypocortisolemia, substantial periods of each remained. Concentration profiles of cortisol, 17-hydroxyprogesterone, and androstenedione are highly variable in children with CAH, and knowledge of them can assist in personalizing the therapy of CAH patients. Hydrocortisone's rapid half-life and the lack of

Intra-adrenal Aldosterone Secretion: Segmental Adrenal Venous Sampling for Localization.

PubMed

Satani, Nozomi; Ota, Hideki; Seiji, Kazumasa; Morimoto, Ryo; Kudo, Masataka; Iwakura, Yoshitsugu; Ono, Yoshikiyo; Nezu, Masahiro; Omata, Kei; Ito, Sadayoshi; Satoh, Fumitoshi; Takase, Kei

2016-01-01

To use segmental adrenal venous sampling (AVS) (S-AVS) of effluent tributaries (a version of AVS that, in addition to helping identify aldosterone hypersecretion, also enables the evaluation of intra-adrenal hormone distribution) to detect and localize intra-adrenal aldosterone secretion. The institutional review board approved this study, and all patients provided informed consent. S-AVS was performed in 65 patients with primary aldosteronism (34 men; mean age, 50.9 years ± 11 [standard deviation]). A microcatheter was inserted in first-degree tributary veins. Unilateral aldosterone hypersecretion at the adrenal central vein was determined according to the lateralization index after cosyntropin stimulation. Excess aldosterone secretion at the adrenal tributary vein was considered to be present when the aldosterone/cortisol ratio from this vein exceeded that from the external iliac vein; suppressed secretion was indicated by the opposite pattern. Categoric variables were expressed as numbers and percentages; continuous variables were expressed as means ± standard errors of the mean. The AVS success rate, indicated by a selectivity index of 5 or greater, was 98% (64 of 65). The mean numbers of sampled tributaries on the left and right sides were 2.11 and 1.02, respectively. The following diagnoses were made on the basis of S-AVS results: unilateral aldosterone hypersecretion in 30 patients, bilateral hypersecretion without suppressed segments in 22 patients, and bilateral hypersecretion with at least one suppressed segment in 12 patients. None of the patients experienced severe complications. S-AVS could be used to identify heterogeneous intra-adrenal aldosterone secretion. Patients who have bilateral aldosterone-producing adenomas can be treated with adrenal-sparing surgery or other minimally invasive local therapies if any suppressed segment is identified at S-AVS. © RSNA, 2015.

Gendered Peer Involvement in Girls with Congenital Adrenal Hyperplasia: Effects of Prenatal Androgens, Gendered Activities, and Gender Cognitions.

PubMed

Berenbaum, Sheri A; Beltz, Adriene M; Bryk, Kristina; McHale, Susan

2018-05-01

A key question in understanding gender development concerns the origins of sex segregation. Children's tendencies to interact with same-sex others have been hypothesized to result from gender identity and cognitions, behavioral compatibility, and personal characteristics. We examined whether prenatal androgen exposure was related to time spent with boys and girls, and how that gendered peer involvement was related to sex-typed activities and gender identity and cognitions. We studied 54 girls with congenital adrenal hyperplasia (CAH) aged 10-13 years varying in degree of prenatal androgen exposure: 40 girls with classical CAH (C-CAH) exposed to high prenatal androgens and 14 girls with non-classical CAH (NC-CAH) exposed to low, female-typical, prenatal androgens. Home interviews and questionnaires provided assessments of gendered activity interests and participation, gender identity, and gender cognitions. Daily phone calls over 7 days assessed time spent in gendered activities and with peers. Girls with both C-CAH and NC-CAH interacted more with girls than with boys, with no significant group differences. The groups did not differ significantly in gender identity or gender cognitions, but girls with C-CAH spent more time in male-typed activities and less time in female-typed activities than did girls with NC-CAH. Time spent with girls reflected direct effects of gender identity/cognitions and gender-typed activities, and an indirect effect of prenatal androgens (CAH type) through gender-typed activities. Our results extend findings that prenatal androgens differentially affect gendered characteristics and that gendered peer interactions reflect combined effects of behavioral compatibility and feelings and cognitions about gender. The study also shows the value of natural experiments for testing hypotheses about gender development.

EFFECTS OF PERTUSSIS SENSITIZATION AND ROENTGEN IRRADIATION ON THE ADRENAL GLANDS OF RATS AND MICE (in Japanese)

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

Nakamura, M.

1962-10-01

Histaminase activity was estimated by the coupled oxidation and deamination method in lung tissue from rats and mice followrng adrenal gland x irradiation, sensitization with B. pertussis, or pertussis sensitization followed by adrenal gland irradiation. Histamine activity was greatly reduced in lung tissue from animals sensitized with pertussis followed by adrenal irradiation, moderately reduced in lung tissue from pertussis sensitized animals, and slightly decreased in lung tissue from the adrenal irradiated group. The activity of succinoxidose and monoamine oxidose in lung tissue was not affected by either adrenal irradiation or pertussis sensitization. The possibility that steroid hormone balance may bemore » affected by disturbance of the adrenal glands in animals sensitized with pertussis is discussed. (C.H.)« less

X-linked infantile spinal muscular atrophy: clinical definition and molecular mapping.

PubMed

Dressman, Devin; Ahearn, Mary Ellen; Yariz, Kemal O; Basterrecha, Hugo; Martínez, Francisco; Palau, Francesc; Barmada, M Michael; Clark, Robin Dawn; Meindl, Alfons; Wirth, Brunhilde; Hoffman, Eric P; Baumbach-Reardon, Lisa

2007-01-01

X-linked infantile spinal-muscular atrophy (XL-SMA) is a rare disorder, which presents with the clinical characteristics of hypotonia, areflexia, and multiple congenital contractures (arthrogryposis) associated with loss of anterior horn cells and death in infancy. We have previously reported a single family with XL-SMA that mapped to Xp11.3-q11.2. Here we report further clinical description of XL-SMA plus an additional seven unrelated (XL-SMA) families from North America and Europe that show linkage data consistent with the same region. We first investigated linkage to the candidate disease gene region using microsatellite repeat markers. We further saturated the candidate disease gene region using polymorphic microsatellite repeat markers and single nucleotide polymorphisms in an effort to narrow the critical region. Two-point and multipoint linkage analysis was performed using the Allegro software package. Linkage analysis of all XL-SMA families displayed linkage consistent with the original XL-SMA region. The addition of new families and new markers has narrowed the disease gene interval for a XL-SMA locus between SNP FLJ22843 near marker DXS 8080 and SNP ARHGEF9 which is near DXS7132 (Xp11.3-Xq11.1).

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

PubMed

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

2015-07-01

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

Adrenal Gland Cancer

MedlinePlus

... either benign or malignant. Benign tumors aren't cancer. Malignant ones are. Most adrenal gland tumors are ... and may not require treatment. Malignant adrenal gland cancers are uncommon. Types of tumors include Adrenocortical carcinoma - ...

Genetics Home Reference: immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome

MedlinePlus

... Health Conditions IPEX syndrome Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome Printable PDF Open All Close All ... expand/collapse boxes. Description Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome primarily affects males and is ...

Functional analysis of human cytochrome P450 21A2 variants involved in congenital adrenal hyperplasia

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

Wang, Chunxue; Pallan, Pradeep S.; Zhang, Wei

Cytochrome P450 (P450, CYP) 21A2 is the major steroid 21-hydroxylase, converting progesterone to 11-deoxycorticosterone and 17α-hydroxyprogesterone (17α-OH-progesterone) to 11-deoxycortisol. More than 100 CYP21A2 variants give rise to congenital adrenal hyperplasia (CAH). We previously reported a structure of WT human P450 21A2 with bound progesterone and now present a structure bound to the other substrate (17α-OH-progesterone). We found that the 17α-OH-progesterone- and progesterone-bound complex structures are highly similar, with only some minor differences in surface loop regions. Twelve P450 21A2 variants associated with either salt-wasting or nonclassical forms of CAH were expressed, purified, and analyzed. The catalytic activities of these 12more » variants ranged from 0.00009% to 30% of WT P450 21A2 and the extent of heme incorporation from 10% to 95% of the WT. Substrate dissociation constants (Ks) for four variants were 37–13,000-fold higher than for WT P450 21A2. Cytochrome b5, which augments several P450 activities, inhibited P450 21A2 activity. Similar to the WT enzyme, high noncompetitive intermolecular kinetic deuterium isotope effects (≥ 5.5) were observed for all six P450 21A2 variants examined for 21-hydroxylation of 21-d3-progesterone, indicating that C–H bond breaking is a rate-limiting step over a 104-fold range of catalytic efficiency. Using UV-visible and CD spectroscopy, we found that P450 21A2 thermal stability assessed in bacterial cells and with purified enzymes differed among salt-wasting- and nonclassical-associated variants, but these differences did not correlate with catalytic activity. Our in-depth investigation of CAH-associated P450 21A2 variants reveals critical insight into the effects of disease-causing mutations on this important enzyme.« less

Adrenal cortical oncocytoma mimicking pheochromocytoma.

PubMed

Kiriakopoulos, Andreas; Papaioannou, Dimitrios; Linos, Dimitrios

2011-01-01

Adrenal tumors present with clinical features and signs unique to their specific hormonal hypersecretion. However, there have been cases in which the clinical expression has been in conflict with the histologic features of the tumor. In this communication we report an unusual clinical presentation of an adrenal cortical tumor with histologic features of an oncocytoma that clinically mimicked a pheochromocytoma. A 49-year old man was referred to our Unit due to type B aortic dissection and a mass of the left adrenal gland. Computed tomography and magnetic resonance imaging confirmed the presence of aortic dissection extending from the left subclavian artery to both iliac arteries and also revealed a 6 cm tumor on the left adrenal gland. Preoperative endocrine evaluation showed a near tenfold increase of urinary vanillylmandelic acid (VMA) and metanephrine values. Transperitoneal laparoscopic adrenalectomy was successfully performed. The adrenal tumor proved to be an adrenal cortical neoplasm with histologic features of oncocytoma. Although the case of an adrenal cortical adenoma clinically mimicking a pheochromocytoma has been described in the literature, to the best of our knowledge, there has been no previous report of an adrenal cortical neoplasm with predominant features of oncocytoma.

Polycystic ovarian disease: the adrenal connection.

PubMed

Marouliss, George B; Triantafillidis, Ioannis K

2006-01-01

Polycystic ovarian disease (PCOD) is characterized by hyperandrogenemia, ovulatory dysfunction and polycystic ovaries (PCO). The increased androgen production in PCOD comes primarily from the ovaries. However, in about 40% of patients there is excessive adrenal androgen production (DHEA, DHEA-Sulfate, Androstenedione, Testosterone and Dihydrotestosterone). The contribution of the adrenal in the PCOD is suggested by the presence of adrenal androgen excess in PCO, the presence of PCO in women with enzymatic adrenal hyperplasia as well as in women with adrenal tumors. However, the cause of adrenal androgen hypersecretion is not yet fully understood but it may include endogenous hypersecretion of the zona reticularis of unclear cause, hypersecretion of cortical-androgen-stimulating hormone (CASH), stress, hyperprolactinemia, adrenal enzymatic defects etc. This short review covers the aspects of adrenal androgen hypersecretion in PCOD.

Congenital portosystemic venous shunt.

PubMed

Papamichail, M; Pizanias, M; Heaton, N

2018-03-01

Congenital portosystemic venous shunts are rare developmental anomalies resulting in diversion of portal flow to the systemic circulation and have been divided into extra- and intrahepatic shunts. They occur during liver and systemic venous vascular embryogenesis and are associated with other congenital abnormalities. They carry a higher risk of benign and malignant liver tumors and, if left untreated, can result in significant medical complications including systemic encephalopathy and pulmonary hypertension. This article reviews the various types of congenital portosystemic shunts and their anatomy, pathogenesis, symptomatology, and timing and options of treatment. What is Known: • The natural history and basic management of this rare congenital anomaly are presented. What is New: • This paper is a comprehensive review; highlights important topics in pathogenesis, clinical symptomatology, and treatment options; and proposes an algorithm in the management of congenital portosystemic shunt disease in order to provide a clear idea to a pediatrician. An effort has been made to emphasize the indications for treatment in the children population and link to the adult group by discussing the consequences of lack of treatment or delayed diagnosis.

X-linked hypophosphatemia attributable to pseudoexons of the PHEX gene.

PubMed

Christie, P T; Harding, B; Nesbit, M A; Whyte, M P; Thakker, R V

2001-08-01

X-linked hypophosphatemia is commonly caused by mutations of the coding region of PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome). However, such PHEX mutations are not detected in approximately one third of X-linked hypophosphatemia patients who may harbor defects in the noncoding or intronic regions. We have therefore investigated 11 unrelated X-linked hypophosphatemia patients in whom coding region mutations had been excluded, for intronic mutations that may lead to mRNA splicing abnormalities, by the use of lymphoblastoid RNA and RT-PCRs. One X-linked hypophosphatemia patient was found to have 3 abnormally large transcripts, resulting from 51-bp, 100-bp, and 170-bp insertions, all of which would lead to missense peptides and premature termination codons. The origin of these transcripts was a mutation (g to t) at position +1268 of intron 7, which resulted in the occurrence of a high quality novel donor splice site (ggaagg to gtaagg). Splicing between this novel donor splice site and 3 preexisting, but normally silent, acceptor splice sites within intron 7 resulted in the occurrences of the 3 pseudoexons. This represents the first report of PHEX pseudoexons and reveals further the diversity of genetic abnormalities causing X-linked hypophosphatemia.

Craniofacial and dental manifestations of triple X syndrome associated with congenital hypothyroidism: a case report.

PubMed

Ferrazzo, Kívia Linhares; Payeras, Marcia Rodrigues; Ferrazzo, Vilmar Antonio; Mezomo, Maurício Barbieri

2014-01-01

Triple X syndrome (47,XXX) is a numerical chromosomal alteration that affects 1/1,000 women, in which the woman is born with an extra X chromosome. Some oral changes have been reported in the literature, as hypodontia, influence on deposition of crown enamel and discrepancies in cephalometric measurements. Other systemic complications may lead to oral abnormalities similar to those seen in triple X patients, such as congenital hypothyroidism (CH). This paper reports a triple X syndrome case associated with CH later treated. Besides delay in cognitive and intellectual development, the patient had changes in teeth development and in cephalometric measurements with deficiencies in the maxilla and mandible. This is the first report of a triple X syndrome associated with CH. Both conditions may result in changes in dentofacial development. © 2013 Special Care Dentistry Association and Wiley Periodicals, Inc.

Impaired plasticity of macrophages in X-linked adrenoleukodystrophy.

PubMed

Weinhofer, Isabelle; Zierfuss, Bettina; Hametner, Simon; Wagner, Magdalena; Popitsch, Niko; Machacek, Christian; Bartolini, Barbara; Zlabinger, Gerhard; Ohradanova-Repic, Anna; Stockinger, Hannes; Köhler, Wolfgang; Höftberger, Romana; Regelsberger, Günther; Forss-Petter, Sonja; Lassmann, Hans; Berger, Johannes

2018-05-30

X-linked adrenoleukodystrophy is caused by ATP-binding cassette transporter D1 (ABCD1) mutations and manifests by default as slowly progressive spinal cord axonopathy with associated demyelination (adrenomyloneuropathy). In 60% of male cases, however, X-linked adrenoleukodystrophy converts to devastating cerebral inflammation and demyelination (cerebral adrenoleukodystrophy) with infiltrating blood-derived monocytes and macrophages and cytotoxic T cells that can only be stopped by allogeneic haematopoietic stem cell transplantation or gene therapy at an early stage of the disease. Recently, we identified monocytes/macrophages but not T cells to be severely affected metabolically by ABCD1 deficiency. Here we found by whole transcriptome analysis that, although monocytes of patients with X-linked adrenoleukodystrophy have normal capacity for macrophage differentiation and phagocytosis, they are pro-inflammatory skewed also in patients with adrenomyloneuropathy in the absence of cerebral inflammation. Following lipopolysaccharide activation, the ingestion of myelin debris, normally triggering anti-inflammatory polarization, did not fully reverse the pro-inflammatory status of X-linked adrenoleukodystrophy macrophages. Immunohistochemistry on post-mortem cerebral adrenoleukodystrophy lesions reflected the activation pattern by prominent presence of enlarged lipid-laden macrophages strongly positive for the pro-inflammatory marker co-stimulatory molecule CD86. Comparative analyses of lesions with matching macrophage density in cases of cerebral adrenoleukodystrophy and acute multiple sclerosis showed a similar extent of pro-inflammatory activation but a striking reduction of anti-inflammatory mannose receptor (CD206) and haemoglobin-haptoglobin receptor (CD163) expression on cerebral adrenoleukodystrophy macrophages. Accordingly, ABCD1-deficiency leads to an impaired plasticity of macrophages that is reflected in incomplete establishment of anti-inflammatory responses

Expression of adrenomedullin 2/intermedin in human adrenal tumors and attached non-neoplastic adrenal tissues.

PubMed

Morimoto, Ryo; Satoh, Fumitoshi; Murakami, Osamu; Hirose, Takuo; Totsune, Kazuhito; Imai, Yutaka; Arai, Yoichi; Suzuki, Takashi; Sasano, Hironobu; Ito, Sadayoshi; Takahashi, Kazuhiro

2008-07-01

Adrenomedullin 2/intermedin (AM2/IMD) is a new member of calcitonin/calcitonin gene-related peptide family. AM is expressed in various tumors including adrenocortical tumors and modulates tumor growth. The AM2/IMD expression has not been studied, however, in adrenal tumors. The expression of AM2/IMD and AM was therefore studied in human adrenal tumors and attached non-neoplastic adrenal tissues by immunocytochemistry (ICC). Immunoreactive (IR)-AM2/IMD was measured by RIA. Furthermore, the expression of AM2/IMD and its receptor components, calcitonin receptor-like receptor (CRLR), and receptor activity-modifying proteins (RAMPs) 1, 2, and 3 mRNA in these tissues was studied by reverse transcription PCR (RT-PCR). ICC showed that AM2/IMD and AM immunoreactivities were localized in adrenocortical tumors and pheochromocytomas. AM2/IMD and AM immunoreactivities were detected in medulla of attached non-neoplastic tissues, while the degree of immunoreactivity for AM2/IMD and AM in cortices of attached adrenals was relatively weak or undetectable. RIA detected IR-AM2/IMD in adrenal tumors (0.414+/-0.12 to 0.786+/-0.27 pmol/g wet weight, mean+/-S.E.M.) and attached adrenal tissues (0.397+/-0.052 pmol/g wet weight). Reverse-phase high-performance liquid chromatography showed one broad peak eluted in the similar position to synthetic AM2/IMD with several minor peaks. RT-PCR showed expression of AM2/IMD, CRLR, and RAMP1, RAMP2, and RAMP3 mRNA in tissues of adrenal tumors and attached adrenal glands. In conclusion, AM2/IMD is expressed in human adrenal tumors and attached non-neoplastic adrenal tissues and may play (patho-)physiological roles in normal and neoplastic adrenals as an autocrine/paracrine regulator.

Should we question early feminizing genitoplasty for patients with congenital adrenal hyperplasia and XX karyotype?

PubMed

Binet, A; Lardy, H; Geslin, D; Francois-Fiquet, C; Poli-Merol, M L

2016-03-01

There is a wide difference of opinion between the medical-surgical community and advocacy group regarding Disorders of Sexual Development (DSD) secondary to congenital adrenal hyperplasia (CAH) being ranked in the intersex category. This rupture is even more evident when the issue of genitoplasty is brought up. For physicians it is obvious and unequivocal that a person with CAH and an XX karyotype has a female gender identity, whereas associations tend to rank persons with CAH in the intersex category and advocate holding-off on surgical management. A retrospective case study vs. control group, spanning over 40years, included 21 patients who were treated in 3 different centers. Each patient and their parents were contacted independently and interviewed regarding interpersonal relationships, psychological impact of genitoplasty, gender identity and opinion on optimal care management for this disorder. Three couples controls (parent-child) per CAH patients were used and matched according to age, sex assigned at birth and ethnic origin. Sex assigned at birth seemed to concord with the gender identity perceived by the patients in 85.7% of cases. In fact, 89.7% of patients and 100% of parents felt that feminizing genitoplasty should be performed within the first year of life. There is however a significant difference compared to controls who felt that surgical management should occur later on in life. No difference was highlighted during childhood regarding parents-child relationships or social integration. However, during adolescence, the parents-child relationship tended to be significantly more painful for the CAH group. Integrating their parenting role was significantly harder for patients in the CAH-DSD group. In the population of CAH-DSD patients who had genitoplasty the level of sexual fulfillment was not lower to the one reported by the control group. Female sex assignment seems legitimate according to this study and the development of gender identity in these

A Rare Case of Congenital Diabetes Insipidus.

PubMed

Rege, Tanvi; Polsani, Srujana; Jim, Belinda

2015-01-01

Congenital nephrogenic diabetes insipidus (NDI) is a conformation disease resulting from protein misfolding. Ninety percent of mutations result from the inactivating mutations of the arginine vasopressin receptor 2 (AVPR2) gene transmitted in an X-linked fashion, blocking the response to vasopressin, resulting in the inability to concentrate urine. Clinical features include polyuria, polydispsia, dehydration, and hypernatremia. They are generally more severely in affected males but present variably in females due to skewed inactivation of the X chromosome. We describe a case of a 40-year-old woman with a history of Type 2 diabetes mellitus, hyperlipidemia, and obesity, who presents with debilitating polyuria since the age of 5 with no clear diagnosis. Interestingly, her son was diagnosed with NDI. Genetic testing revealed that she was heterozygous for the Val88Met mutation in the AVPR2 gene while her son was hemizygous for the same. The patient has since been successfully treated with diuretics and a low solute diet. We highlight that although X-linked NDI patients are mostly males, it should be considered in symptomatic females to prevent delays in the diagnosis. Conformational diseases such as NDI are presently the subject of research using pharmacological chaperones to restore proper receptor membrane localization and function.

A Rare Case of Congenital Diabetes Insipidus

PubMed Central

Rege, Tanvi; Polsani, Srujana; Jim, Belinda

2015-01-01

Congenital nephrogenic diabetes insipidus (NDI) is a conformation disease resulting from protein misfolding. Ninety percent of mutations result from the inactivating mutations of the arginine vasopressin receptor 2 (AVPR2) gene transmitted in an X-linked fashion, blocking the response to vasopressin, resulting in the inability to concentrate urine. Clinical features include polyuria, polydispsia, dehydration, and hypernatremia. They are generally more severely in affected males but present variably in females due to skewed inactivation of the X chromosome. We describe a case of a 40-year-old woman with a history of Type 2 diabetes mellitus, hyperlipidemia, and obesity, who presents with debilitating polyuria since the age of 5 with no clear diagnosis. Interestingly, her son was diagnosed with NDI. Genetic testing revealed that she was heterozygous for the Val88Met mutation in the AVPR2 gene while her son was hemizygous for the same. The patient has since been successfully treated with diuretics and a low solute diet. We highlight that although X-linked NDI patients are mostly males, it should be considered in symptomatic females to prevent delays in the diagnosis. Conformational diseases such as NDI are presently the subject of research using pharmacological chaperones to restore proper receptor membrane localization and function. PMID:26217664

Coexistence of Cushing syndrome from functional adrenal adenoma and Addison disease from immune-mediated adrenalitis.

PubMed

Colucci, Randall; Jimenez, Rafael E; Farrar, William; Malgor, Ramiro; Kohn, Leonard; Schwartz, Frank L

2012-06-01

A 56-year-old woman presented with an incidental adrenal adenoma and physical examination findings that included moderate obesity, a slight cervicothoracic fat pad ("buffalo hump"), increased supraclavicular fat pads, and white abdominal striae. Biochemical workup revealed elevated levels of 24-hour urinary free cortisol but normal serum morning cortisol and suppressed levels of corticotropin, suggestive of adrenal-dependent Cushing syndrome. The resected adrenal gland revealed macronodular cortical hyperplasia with a dominant nodule. Other findings included an absent cortisol response to corticotropin stimulation, presence of serum anti-21-hydroxylase antibodies, and mononuclear cell infiltration--consistent with adrenalitis. The findings represent, to the authors' knowledge, the first known case of a patient with coexistent functional cortisol-secreting macronodular adrenal tumor resulting in Cushing syndrome and immune-mediated adrenalitis resulting in Addison disease.

Genetics Home Reference: X-linked spondyloepiphyseal dysplasia tarda

MedlinePlus

... Educational Resources (6 links) Cincinnati Children's Hospital: Coxa Vera Disease InfoSearch: Spondyloepiphyseal dysplasia tarda X-linked Johns ... Free article on PubMed Central Savarirayan R, Thompson E, Gécz J. Spondyloepiphyseal dysplasia tarda (SEDL, MIM #313400). ...

Case Report: Congenital Erythroleukemia in a Premature Infant with Dysmorphic Features.

PubMed

Helin, Heidi; van der Walt, Jon; Holder, Muriel; George, Simi

2016-01-01

We present a case of pure erythroleukemia, diagnosed at autopsy, in a dysmorphic premature infant who died of multiorgan failure within 24 hours of birth. Dysmorphic features included facial and limb abnormalities with long philtrum, microagnathia, downturned mouth, short neck as well as abnormal and missing nails, missing distal phalanx from the second toe, and overlapping toes. Internal findings included gross hepatomegaly and patchy hemorrhages in the liver, splenomegaly, and cardiomegaly; and subdural, intracerebral, and intraventricular hemorrhages. Histology revealed infiltration of bone marrow, kidney, heart, liver, adrenal, lung, spleen, pancreas, thyroid, testis, thymus, and placenta by pure erythroleukemia. Only 6 cases of congenital erythroleukemia have been previously reported with autopsy findings similar to those of this case. The dysmorphic features, although not fitting any specific syndrome, make this case unique. Congenital erythroleukemia and possible syndromes suggested by the dysmorphic features are discussed.

Comparison of different glucocorticoid regimens in the management of classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

PubMed

Ajish, T P; Praveen, V P; Nisha, B; Kumar, Harish

2014-11-01

There are recommendations regarding the total dose of hydrocortisone to be administered in the treatment of classical congenital adrenal hyperplasia (CAH) to achieve the twin objectives of glucocorticoid replacement and control of hyperandrogenism. However, there is evidence gap regarding the breakup, timing and type of the steroid regimen. Efficacy of three different glucocorticoid regimens having the same total dose of steroid, differing in either the timing or type of evening steroid administered, in achieving biochemical control of the disease was assessed. The study was done in 13 prepubertal children with classical CAH over a 6-month period with 2 months devoted to each regimen. We used a prospective cross-over design using 10-15 mg/m(2) total dose of hydrocortisone. Two-fifths of the total dose of hydrocortisone was administered in the morning and one-fifth of the total dose was administered at noon in all the regimens. The regimens differed in the timing of the evening dose of hydrocortisone, 06.00-07.00 pm in regimen 1 and 09.00-10.00 pm in regimen 2. The third regimen had the evening dose of hydrocortisone replaced by an equivalent dose of prednisolone suspension which was administered at 10.00 pm. Serum 17-hydroxyprogesterone and testosterone levels were compared to assess the efficacy of treatment regimens. The three different regimens were found to be similar in their ability to control 17-hydroxyprogesterone and testosterone levels. The percentage of patients with predefined criteria for biochemically controlled disease was similar in all the three regimens. However, there was a trend toward better control of 17-hydroxyprogesterone levels in patients receiving evening dose of prednisolone. There is no significant advantage in administering the hydrocortisone dose late at night in patients with classical CAH.

Cushing's syndrome and the nodular adrenal gland.

PubMed

Samuels, M H; Loriaux, D L

1994-09-01

This article examines Cushing's syndrome in four main categories as associated with nodular adrenal glands: adrenal adenoma, adrenal carcinoma, primary pigmented nodular adrenal dysplasia, and macronodular adrenal hyperplasia. A summary of clinical features of these four categories is presented.

Prenatal androgenization affects gender-related behavior but not gender identity in 5-12-year-old girls with congenital adrenal hyperplasia.

PubMed

Meyer-Bahlburg, Heino F L; Dolezal, Curtis; Baker, Susan W; Carlson, Ann D; Obeid, Jihad S; New, Maria I

2004-04-01

Gender assignment of children with intersexuality and related conditions has recently become highly controversial. On the basis of extensive animal research and a few human case reports, some authors have proposed the putative masculinization of the brain by prenatal hormones-indicated by the degree of genital masculinization-as the decisive criterion of gender assignment and have derived the recommendation that 46,XX newborns with congenital adrenal hyperplasia (CAH) and full genital masculinization should be assigned to the male gender. The purpose of this study was to test in CAH girls of middle childhood the assumption that prenatal androgens determine the development of gender identity. Fifteen girls with CAH (range of genital Prader stage, 2-4/5), 30 control girls, and 16 control boys (age range, 5-12 years) underwent 2 gender-play observation sessions, and a gender identity interview yielding scales of gender confusion/dysphoria. About half a year earlier, mothers had completed 2 questionnaires concerning their children's gender-related behavior. The results showed that, as expected, CAH girls scored more masculine than control girls on all scales measuring gender-related behavior, with robust effect sizes. By contrast, neither conventionally significant differences nor trends were found on the 3 scales of the gender identity interview. We conclude that prenatal androgenization of 46,XX fetuses leads to marked masculinization of later gender-related behavior, but the absence of any increased gender-identity confusion/dysphoria does not indicate a direct determination of gender identity by prenatal androgens and does not, therefore, support a male gender assignment at birth of the most markedly masculinized girls.

Sodium Chloride Supplementation Is Not Routinely Performed in the Majority of German and Austrian Infants with Classic Salt-Wasting Congenital Adrenal Hyperplasia and Has No Effect on Linear Growth and Hydrocortisone or Fludrocortisone Dose.

PubMed

Bonfig, Walter; Roehl, Friedhelm; Riedl, Stefan; Brämswig, Jürgen; Richter-Unruh, Annette; Fricke-Otto, Susanne; Hübner, Angela; Bettendorf, Markus; Schönau, Eckhard; Dörr, Helmut; Holl, Reinhard W; Mohnike, Klaus

2018-01-01

Sodium chloride supplementation in salt-wasting congenital adrenal hyperplasia (CAH) is generally recommended in infants, but its implementation in routine care is very heterogeneous. To evaluate oral sodium chloride supplementation, growth, and hydrocortisone and fludrocortisone dose in infants with salt-wasting CAH due to 21-hydroxylase in 311 infants from the AQUAPE CAH database. Of 358 patients with classic CAH born between 1999 and 2015, 311 patients had salt-wasting CAH (133 females, 178 males). Of these, 86 patients (27.7%) received oral sodium chloride supplementation in a mean dose of 0.9 ± 1.4 mmol/kg/day (excluding nutritional sodium content) during the first year of life. 225 patients (72.3%) were not treated with sodium chloride. The percentage of sodium chloride-supplemented patients rose from 15.2% in children born 1999-2004 to 37.5% in children born 2011-2015. Sodium chloride-supplemented and -unsupplemented infants did not significantly differ in hydrocortisone and fludrocortisone dose, target height-corrected height-SDS, and BMI-SDS during the first 2 years of life. In the AQUAPE CAH database, approximately one-third of infants with salt-wasting CAH receive sodium chloride supplementation. Sodium chloride supplementation is performed more frequently in recent years. However, salt supplementation had no influence on growth, daily fludrocortisone and hydrocortisone dose, and frequency of adrenal crisis. © 2017 S. Karger AG, Basel.

siRNAs from an X-linked satellite repeat promote X-chromosome recognition in Drosophila melanogaster.

PubMed

Menon, Debashish U; Coarfa, Cristian; Xiao, Weimin; Gunaratne, Preethi H; Meller, Victoria H

2014-11-18

Highly differentiated sex chromosomes create a lethal imbalance in gene expression in one sex. To accommodate hemizygosity of the X chromosome in male fruit flies, expression of X-linked genes increases twofold. This is achieved by the male- specific lethal (MSL) complex, which modifies chromatin to increase expression. Mutations that disrupt the X localization of this complex decrease the expression of X-linked genes and reduce male survival. The mechanism that restricts the MSL complex to X chromatin is not understood. We recently reported that the siRNA pathway contributes to localization of the MSL complex, raising questions about the source of the siRNAs involved. The X-linked 1.688 g/cm(3) satellite related repeats (1.688(X) repeats) are restricted to the X chromosome and produce small RNA, making them an attractive candidate. We tested RNA from these repeats for a role in dosage compensation and found that ectopic expression of single-stranded RNAs from 1.688(X) repeats enhanced the male lethality of mutants with defective X recognition. In contrast, expression of double-stranded hairpin RNA from a 1.688(X) repeat generated abundant siRNA and dramatically increased male survival. Consistent with improved survival, X localization of the MSL complex was largely restored in these males. The striking distribution of 1.688(X) repeats, which are nearly exclusive to the X chromosome, suggests that these are cis-acting elements contributing to identification of X chromatin.

Hypotension following patent ductus arteriosus ligation: the role of adrenal hormones

PubMed Central

Clyman, Ronald I.; Wickremasinghe, Andrea; Merritt, T. Allen; Solomon, Tabitha; McNamara, Patrick; Jain, Amish; Singh, Jaideep; Chu, Alison; Noori, Shahab; Sekar, Krishnamurthy; Lavoie, Pascal M.; Attridge, Joshua T.; Swanson, Jonathan R.; Gillam-Krakauer, Maria; Reese, Jeff; DeMauro, Sara; Poindexter, Brenda; Aucott, Sue; Satpute, Monique; Fernandez, Erika; Auchus, Richard J.

2014-01-01

Objective To test the hypothesis that an impaired adrenal response to stress might play a role in the hypotension that follows patent ductus arteriosus (PDA) ligation. Study design We performed a multicenter study of infants born at <32 weeks gestation who were about to undergo PDA ligation. Serum adrenal steroids were measured three times: before and after a cosyntropin (1.0 microgram/kg) stimulation test (performed prior to the ligation), and at 10–12 hours after the ligation. A standardized approach for diagnosis and treatment of postoperative hypotension was followed at each site. A modified Inotrope Score (1 x dopamine (μg/kg/min) + 1 x dobutamine) was used to monitor the catecholamine support an infant received. Infants were considered to have catecholamine-resistant hypotension if their highest Inotrope Score was >15. Results Of 95 infants enrolled, 43 (45%) developed hypotension and 14 (15%) developed catecholamine-resistant hypotension. Low post-operative cortisol levels were not associated with the overall incidence of hypotension following ligation. However, low cortisol levels were associated with the refractoriness of the hypotension to catecholamine treatment. In a multivariate analysis: the odds ratio for developing catecholamine-resistant hypotension was OR=36.6, CI=2.8–476, p=0.006. Low cortisol levels (in infants with catecholamine-resistant hypotension) were not due to adrenal immaturity or impairment; their cortisol precursor concentrations were either low or unchanged and their response to cosyntropin was similar to infants without catecholamine-resistant hypotension. Conclusion Infants with low cortisol concentrations following PDA ligation are likely to develop postoperative catecholamine-resistant hypotension. We speculate that decreased adrenal stimulation, rather than an impaired adrenal response to stimulation, may account for the decreased production. PMID:24636853

Congenital neutropenia: diagnosis, molecular bases and patient management.

PubMed

Donadieu, Jean; Fenneteau, Odile; Beaupain, Blandine; Mahlaoui, Nizar; Chantelot, Christine Bellanné

2011-05-19

The term congenital neutropenia encompasses a family of neutropenic disorders, both permanent and intermittent, severe (<0.5 G/l) or mild (between 0.5-1.5 G/l), which may also affect other organ systems such as the pancreas, central nervous system, heart, muscle and skin. Neutropenia can lead to life-threatening pyogenic infections, acute gingivostomatitis and chronic parodontal disease, and each successive infection may leave permanent sequelae. The risk of infection is roughly inversely proportional to the circulating polymorphonuclear neutrophil count and is particularly high at counts below 0.2 G/l.When neutropenia is detected, an attempt should be made to establish the etiology, distinguishing between acquired forms (the most frequent, including post viral neutropenia and auto immune neutropenia) and congenital forms that may either be isolated or part of a complex genetic disease.Except for ethnic neutropenia, which is a frequent but mild congenital form, probably with polygenic inheritance, all other forms of congenital neutropenia are extremely rare and have monogenic inheritance, which may be X-linked or autosomal, recessive or dominant.About half the forms of congenital neutropenia with no extra-hematopoietic manifestations and normal adaptive immunity are due to neutrophil elastase (ELANE) mutations. Some patients have severe permanent neutropenia and frequent infections early in life, while others have mild intermittent neutropenia.Congenital neutropenia may also be associated with a wide range of organ dysfunctions, as for example in Shwachman-Diamond syndrome (associated with pancreatic insufficiency) and glycogen storage disease type Ib (associated with a glycogen storage syndrome). So far, the molecular bases of 12 neutropenic disorders have been identified.Treatment of severe chronic neutropenia should focus on prevention of infections. It includes antimicrobial prophylaxis, generally with trimethoprim-sulfamethoxazole, and also granulocyte

Congenital neutropenia: diagnosis, molecular bases and patient management

PubMed Central

2011-01-01

The term congenital neutropenia encompasses a family of neutropenic disorders, both permanent and intermittent, severe (<0.5 G/l) or mild (between 0.5-1.5 G/l), which may also affect other organ systems such as the pancreas, central nervous system, heart, muscle and skin. Neutropenia can lead to life-threatening pyogenic infections, acute gingivostomatitis and chronic parodontal disease, and each successive infection may leave permanent sequelae. The risk of infection is roughly inversely proportional to the circulating polymorphonuclear neutrophil count and is particularly high at counts below 0.2 G/l. When neutropenia is detected, an attempt should be made to establish the etiology, distinguishing between acquired forms (the most frequent, including post viral neutropenia and auto immune neutropenia) and congenital forms that may either be isolated or part of a complex genetic disease. Except for ethnic neutropenia, which is a frequent but mild congenital form, probably with polygenic inheritance, all other forms of congenital neutropenia are extremely rare and have monogenic inheritance, which may be X-linked or autosomal, recessive or dominant. About half the forms of congenital neutropenia with no extra-hematopoetic manifestations and normal adaptive immunity are due to neutrophil elastase (ELANE) mutations. Some patients have severe permanent neutropenia and frequent infections early in life, while others have mild intermittent neutropenia. Congenital neutropenia may also be associated with a wide range of organ dysfunctions, as for example in Shwachman-Diamond syndrome (associated with pancreatic insufficiency) and glycogen storage disease type Ib (associated with a glycogen storage syndrome). So far, the molecular bases of 12 neutropenic disorders have been identified. Treatment of severe chronic neutropenia should focus on prevention of infections. It includes antimicrobial prophylaxis, generally with trimethoprim-sulfamethoxazole, and also granulocyte

Genetics Home Reference: X-linked agammaglobulinemia

MedlinePlus

... Sep;104(3):221-30. Citation on PubMed Smith CIE, Berglöf A. X-Linked Agammaglobulinemia. 2001 Apr ... Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): ...

Intraadrenal corticotropin in bilateral macronodular adrenal hyperplasia.

PubMed

Louiset, Estelle; Duparc, Céline; Young, Jacques; Renouf, Sylvie; Tetsi Nomigni, Milène; Boutelet, Isabelle; Libé, Rossella; Bram, Zakariae; Groussin, Lionel; Caron, Philippe; Tabarin, Antoine; Grunenberger, Fabienne; Christin-Maitre, Sophie; Bertagna, Xavier; Kuhn, Jean-Marc; Anouar, Youssef; Bertherat, Jérôme; Lefebvre, Hervé

2013-11-28

Bilateral macronodular adrenal hyperplasia is a rare cause of primary adrenal Cushing's syndrome. In this form of hyperplasia, hypersecretion of cortisol suppresses the release of corticotropin by pituitary corticotrophs, which results in low plasma corticotropin levels. Thus, the disease has been termed corticotropin-independent macronodular adrenal hyperplasia. We examined the abnormal production of corticotropin in these hyperplastic adrenal glands. We obtained specimens of hyperplastic macronodular adrenal tissue from 30 patients with primary adrenal disease. The corticotropin precursor proopiomelanocortin and corticotropin expression were assessed by means of a polymerase-chain-reaction assay and immunohistochemical analysis. The production of corticotropin and cortisol was assessed in 11 specimens with the use of incubated explants and cell cultures coupled with hormone assays. Corticotropin levels were measured in adrenal and peripheral venous blood samples from 2 patients. The expression of proopiomelanocortin messenger RNA (mRNA) was detected in all samples of hyperplastic adrenal tissue. Corticotropin was detected in steroidogenic cells arranged in clusters that were disseminated throughout the adrenal specimens. Adrenal corticotropin levels were higher in adrenal venous blood samples than in peripheral venous samples, a finding that was consistent with local production of the peptide within the hyperplastic adrenals. The release of adrenal corticotropin was stimulated by ligands of aberrant membrane receptors but not by corticotropin-releasing hormone or dexamethasone. A semiquantitative score for corticotropin immunostaining in the samples correlated with basal plasma cortisol levels. Corticotropin-receptor antagonists significantly inhibited in vitro cortisol secretion. Cortisol secretion by the adrenals in patients with macronodular hyperplasia and Cushing's syndrome appears to be regulated by corticotropin, which is produced by a subpopulation of

Sildenafil for the Treatment of Congenital Nephrogenic Diabetes Insipidus.

PubMed

Assadi, Farahnak; Sharbaf, Fatemeh Ghane

2015-01-01

Congenital nephrogenic diabetes insipidus (NDI) is characterized by massive polyuria and polydipsia due to defects in the vasopressin-sensitive signaling system expression of the acuaporin-2 (AQP2) water channel of the kidney collecting duct principal cells. Current conventional treatment regimen including hydration, diuretics and nonsteroidal anti-inflammatory drugs can only partially reduce polyuria. Recent experimental studies have suggested that treatment with sildenafil, a selective phosphodiesterase inhibitor, may enhance cyclic guanosine monophosphate (cGMP)-mediated apical trafficking of AQP2 and may be effective in increasing water reabsorption in patients with congenital NDI. A 4-year old boy with X-linked NDI resistant to conventional therapy was treated with sildenafil for 10 days after a 2-day washout period between the 2 treatment regimens. Aliquots of the 24-hour urine collections before and after treatment were analyzed for urine volume, osmolality, cGMP and AQP2 determinations. Blood samples were also obtained for sodium and osmolality measurements. The primary endpoint was 24-hour urine volume after 10 days of sildenafil and conventional treatments. Compared to conventional therapy, treatment with sildenafil resulted in substantial reduction in 24-hour urine volume (1,764 vs. 950 ml) and serum sodium (148 vs. 139) mEq/l, and increased urine osmolality (104 vs. 215 mOsm/l), and AQP2 excretion (5 vs. 26 fmol/mg creatinine). The patient tolerated sildenafil well and experienced no adverse effects. Sildenafil citrate should be considered an alternative agent in the treatment of X-linked NDI resistant to conventional therapy. © 2015 S. Karger AG, Basel

Severe manifestations in carrier females in X linked retinitis pigmentosa.

PubMed Central

Souied, E; Segues, B; Ghazi, I; Rozet, J M; Chatelin, S; Gerber, S; Perrault, I; Michel-Awad, A; Briard, M L; Plessis, G; Dufier, J L; Munnich, A; Kaplan, J

1997-01-01

Retinitis pigmentosa (RP) is a group of progressive hereditary disorders of the retina in which various modes of inheritance have been described. Here, we report on X linked RP in nine families with constant and severe expression in carrier females. In our series, however, the phenotype was milder and delayed in carrier females compared to hemizygous males. This form of X linked RP could be regarded therefore as partially dominant. The disease gene maps to chromosome Xp2.1 in the genetic interval encompassing the RP3 locus (Zmax=13.71 at the DXS1100 locus). Single strand conformation polymorphism and direct sequence analysis of the retinitis pigmentosa GTPase regulator (RPGR) gene, which accounts for RP3, failed to detect any mutation in our families. Future advances in the identification of X linked RP genes will hopefully help to elucidate the molecular basis of this X linked dominant RP. Images PMID:9350809

Abnormal gel flotation caused by contrast media during adrenal vein sampling.

PubMed

Lima-Oliveira, Gabriel; Lippi, Giuseppe; Salvagno, Gian Luca; Gelati, Matteo; Bassi, Antonella; Contro, Alberto; Pizzolo, Francesca; Guidi, Gian Cesare

2016-10-15

During adrenal venous sampling (AVS) procedure, radiologists administer a contrast agent via the catheter to visualize the proper catheter position. A patient with primary aldosteronism diagnostic-hypothesis was admitted for AVS. A venogram was performed to
confirm the catheter's position with 2mL of Iopamidol 300 mg/mL. Samples were collected with syringe connected to a hydrophilic coated catheter by low-pressure aspiration from each of the four collection sites: inferior vena cava in the suprarenal portion, inferior vena cava in the infrarenal portion, left adrenal vein, and right adrenal vein; then immediately transferred from syringe to tubes with gel separator. All tubes were centrifuged at 1200 x g for 10 minutes. At the end of centrifugation process, primary blood tubes containing blood from inferior vena cava and left adrenal vein exhibited the standard gel separator barrier, while tubes from right adrenal vein showed abnormal flotation of gel separator. The radiologist confirmed the usage of 2.6 mL instead of 2.0 mL of Iopamidol 300 mg/mL. This iodinated contrast media, with 1.33 g/cm 3 of density, was used close to the right adrenal vein due to some difficulty to access it. The abnormal flotation of gel separator in samples taken from right adrenal vein can be explained by the usage of the iodinated
contrast media. We suggest using plain-tubes (without gel separator) for AVS in order to avoid preanalytical nonconformities. Moreover, a blood volume equivalent to twice the catheter extension should be discarded to eliminate residual contrast media before collection of samples for laboratory assays.

Abnormal gel flotation caused by contrast media during adrenal vein sampling

PubMed Central

Lima-Oliveira, Gabriel; Lippi, Giuseppe; Salvagno, Gian Luca; Gelati, Matteo; Bassi, Antonella; Contro, Alberto; Pizzolo, Francesca; Guidi, Gian Cesare

2016-01-01

Introduction During adrenal venous sampling (AVS) procedure, radiologists administer a contrast agent via the catheter to visualize the proper catheter position. Materials and methods A patient with primary aldosteronism diagnostic-hypothesis was admitted for AVS. A venogram was performed to
confirm the catheter’s position with 2mL of Iopamidol 300 mg/mL. Samples were collected with syringe connected to a hydrophilic coated catheter by low-pressure aspiration from each of the four collection sites: inferior vena cava in the suprarenal portion, inferior vena cava in the infrarenal portion, left adrenal vein, and right adrenal vein; then immediately transferred from syringe to tubes with gel separator. All tubes were centrifuged at 1200 x g for 10 minutes. Results At the end of centrifugation process, primary blood tubes containing blood from inferior vena cava and left adrenal vein exhibited the standard gel separator barrier, while tubes from right adrenal vein showed abnormal flotation of gel separator. The radiologist confirmed the usage of 2.6 mL instead of 2.0 mL of Iopamidol 300 mg/mL. This iodinated contrast media, with 1.33 g/cm3 of density, was used close to the right adrenal vein due to some difficulty to access it. Conclusion The abnormal flotation of gel separator in samples taken from right adrenal vein can be explained by the usage of the iodinated
contrast media. We suggest using plain-tubes (without gel separator) for AVS in order to avoid preanalytical nonconformities. Moreover, a blood volume equivalent to twice the catheter extension should be discarded to eliminate residual contrast media before collection of samples for laboratory assays. PMID:27812311

Facts about Congenital Heart Defects

MedlinePlus

... Living With Heart Defects Data & Statistics Tracking & Research Articles & Key Findings Free Materials Multimedia and Tools Links to Other Websites Information For… Media Policy Makers Basics about Congenital Heart Defects Language: ...

Factors predicting the duration of adrenal insufficiency in patients successfully treated for Cushing disease and nonmalignant primary adrenal Cushing syndrome.

PubMed

Prete, Alessandro; Paragliola, Rosa Maria; Bottiglieri, Filomena; Rota, Carlo Antonio; Pontecorvi, Alfredo; Salvatori, Roberto; Corsello, Salvatore Maria

2017-03-01

Successful treatment of Cushing syndrome causes transient or permanent adrenal insufficiency deriving from endogenous hypercortisolism-induced hypothalamus-pituitary-adrenal-axis suppression. We analyzed pre-treatment factors potentially affecting the duration of adrenal insufficiency. We conducted a retrospective analysis on patients successfully treated for Cushing disease (15 patients) who underwent transsphenoidal surgery, and nonmalignant primary adrenal Cushing syndrome (31 patients) who underwent unilateral adrenalectomy, divided into patients with overt primary adrenal Cushing syndrome (14 patients) and subclinical primary adrenal Cushing syndrome (17 patients). Epidemiological data, medical history, and hormonal parameters depending on the etiology of hypercortisolism were collected and compared to the duration of adrenal insufficiency. The median duration of follow-up after surgery for Cushing disease and primary adrenal Cushing syndrome was 70 and 48 months, respectively. In the Cushing disease group, the median duration of adrenal insufficiency after transsphenoidal surgery was 15 months: younger age at diagnosis and longer duration of signs and symptoms of hypercortisolism before diagnosis and surgery were associated with longer duration of adrenal insufficiency. The median duration of adrenal insufficiency was 6 months for subclinical primary adrenal Cushing syndrome and 18.5 months for overt primary adrenal Cushing syndrome. The biochemical severity of hypercortisolism, the grade of hypothalamus-pituitary-adrenal-axis suppression, and treatment with ketoconazole before surgery accounted for longer duration of adrenal insufficiency. In patients with Cushing disease, younger age and delayed diagnosis and treatment predict longer need for glucocorticoid replacement therapy after successful transsphenoidal surgery. In patients with primary adrenal Cushing syndrome, the severity of hypercortisolism plays a primary role in influencing the duration of

X linked mental retardation: a clinical guide.

PubMed

Raymond, F L

2006-03-01

Mental retardation is more common in males than females in the population, assumed to be due to mutations on the X chromosome. The prevalence of the 24 genes identified to date is low and less common than expansions in FMR1, which cause Fragile X syndrome. Systematic screening of all other X linked genes in X linked families with mental retardation is currently not feasible in a clinical setting. The phenotypes of genes causing syndromic and non-syndromic mental retardation (NLGN3, NLGN4, RPS6KA3(RSK2), OPHN1, ATRX, SLC6A8, ARX, SYN1, AGTR2, MECP2, PQBP1, SMCX, and SLC16A2) are first discussed, as these may be the focus of more targeted mutation analysis. Secondly, the relative prevalence of genes causing only non-syndromic mental retardation (IL1RAPL1, TM4SF2, ZNF41, FTSJ1, DLG3, FACL4, PAK3, ARHGEF6, FMR2, and GDI) is summarised. Thirdly, the problem of recurrence risk where a molecular genetics diagnosis has not been made and what proportion of the male excess of mental retardation is due to monogenic disorders of the X chromosome are discussed.

Reduced short term memory in congenital adrenal hyperplasia (CAH) and its relationship to spatial and quantitative performance.

PubMed

Collaer, Marcia L; Hindmarsh, Peter C; Pasterski, Vickie; Fane, Briony A; Hines, Melissa

2016-02-01

Girls and women with classical congenital adrenal hyperplasia (CAH) experience elevated androgens prenatally and show increased male-typical development for certain behaviors. Further, individuals with CAH receive glucocorticoid (GC) treatment postnatally, and this GC treatment could have negative cognitive consequences. We investigated two alternative hypotheses, that: (a) early androgen exposure in females with CAH masculinizes (improves) spatial perception and quantitative abilities at which males typically outperform females, or (b) CAH is associated with performance decrements in these domains, perhaps due to reduced short-term-memory (STM). Adolescent and adult individuals with CAH (40 female and 29 male) were compared with relative controls (29 female and 30 male) on spatial perception and quantitative abilities as well as on Digit Span (DS) to assess STM and on Vocabulary to assess general intelligence. Females with CAH did not perform better (more male-typical) on spatial perception or quantitative abilities than control females, failing to support the hypothesis of cognitive masculinization. Rather, in the sample as a whole individuals with CAH scored lower on spatial perception (p ≤ .009), a quantitative composite (p ≤ .036), and DS (p ≤ .001), despite no differences in general intelligence. Separate analyses of adolescent and adult participants suggested the spatial and quantitative effects might be present only in adult patients with CAH; however, reduced DS performance was found in patients with CAH regardless of age group. Separate regression analyses showed that DS predicted both spatial perception and quantitative performance (both p ≤ .001), when age, sex, and diagnosis status were controlled. Thus, reduced STM in CAH patients versus controls may have more general cognitive consequences, potentially reducing spatial perception and quantitative skills. Although hyponatremia or other aspects of salt-wasting crises or additional hormone

Aldosterone hypersecretion in “non-salt-losing” congenital adrenal hyperplasia

PubMed Central

Bartter, Frederic C.; Henkin, Robert I.; Bryan, George T.

1968-01-01

Patients with the “non-salt-losing” form of the adrenogenital syndrome were studied before and after suppression of adrenal cortical activity with carbohydrate-active steroids. The response of aldosterone secretion to sodium deprivation was measured; in some patients response to adrenocorticotropic hormone (ACTH) was measured as well. The aldosterone secretion was normal and responded normally to sodium deprivation in all patients studied during suppression with carbohydrate-active steroids. This finding suggests that 21-hydroxylation of progesterone is normal in this syndrome. The sole abnormality in the production of aldosterone in these patients was found to be excessive secretion of aldosterone while they were not receiving suppressive doses of carbohydrate-active steroids. This finding strongly supports the view that the biogenetic pathways through which aldosterone is produced from progesterone are intact in this syndrome. No patient showed hypertension or hypokalemic alkalosis despite very high aldosterone secretion rates. This observation suggests that the hyper-aldosteronism is secondary to a tendency to sodium loss in the patient whose ACTH production is not suppressed. These studies provide additional evidence in support of the hypothesis that the salt-losing and “non-salt-losing” forms of adrenogenital syndrome are genetically and biochemically distinct. PMID:4299011

A Simulation of X-Linked Inheritance.

ERIC Educational Resources Information Center

Harrell, Pamela Esprivalo

1997-01-01

Describes how to lead students through a classroom-based simulation to teach a variety of concepts such as X-linked traits, sex determination, and sex anomalies. The simulation utilizes inexpensive materials such as plastic eggs that twist apart to represent human eggs and sperm. (AIM)

Linking the Congenital Heart Surgery Databases of the Society of Thoracic Surgeons and the Congenital Heart Surgeons’ Society: Part 1—Rationale and Methodology

PubMed Central

Jacobs, Jeffrey P.; Pasquali, Sara K.; Austin, Erle; Gaynor, J. William; Backer, Carl; Hirsch-Romano, Jennifer C.; Williams, William G.; Caldarone, Christopher A.; McCrindle, Brian W.; Graham, Karen E.; Dokholyan, Rachel S.; Shook, Gregory J.; Poteat, Jennifer; Baxi, Maulik V.; Karamlou, Tara; Blackstone, Eugene H.; Mavroudis, Constantine; Mayer, John E.; Jonas, Richard A.; Jacobs, Marshall L.

2014-01-01

Purpose The Society of Thoracic Surgeons Congenital Heart Surgery Database (STS-CHSD) is the largest Registry in the world of patients who have undergone congenital and pediatric cardiac surgical operations. The Congenital Heart Surgeons’ Society Database (CHSS-D) is an Academic Database designed for specialized detailed analyses of specific congenital cardiac malformations and related treatment strategies. The goal of this project was to create a link between the STS-CHSD and the CHSS-D in order to facilitate studies not possible using either individual database alone and to help identify patients who are potentially eligible for enrollment in CHSS studies. Methods Centers were classified on the basis of participation in the STS-CHSD, the CHSS-D, or both. Five matrices, based on CHSS inclusionary criteria and STS-CHSD codes, were created to facilitate the automated identification of patients in the STS-CHSD who meet eligibility criteria for the five active CHSS studies. The matrices were evaluated with a manual adjudication process and were iteratively refined. The sensitivity and specificity of the original matrices and the refined matrices were assessed. Results In January 2012, a total of 100 centers participated in the STS-CHSD and 74 centers participated in the CHSS. A total of 70 centers participate in both and 40 of these 70 agreed to participate in this linkage project. The manual adjudication process and the refinement of the matrices resulted in an increase in the sensitivity of the matrices from 93% to 100% and an increase in the specificity of the matrices from 94% to 98%. Conclusion Matrices were created to facilitate the automated identification of patients potentially eligible for the five active CHSS studies using the STS-CHSD. These matrices have a sensitivity of 100% and a specificity of 98%. In addition to facilitating identification of patients potentially eligible for enrollment in CHSS studies, these matrices will allow (1) estimation of

Adrenic acid as an inflammation enhancer in non-alcoholic fatty liver disease.

PubMed

Horas H Nababan, Saut; Nishiumi, Shin; Kawano, Yuki; Kobayashi, Takashi; Yoshida, Masaru; Azuma, Takeshi

2017-06-01

This study was designed to identify novel links between lipid species and disease progression in non-alcoholic fatty liver disease (NAFLD). We analyzed lipid species in the liver and plasma of db/db mice fed a choline-deficient l-amino acid-defined, high-fat diet (CDAHFD) using liquid chromatography/mass spectrometry (LC/MS). An in vitro experiment was performed using HepG2 cells stimulated with recombinant human TNFα or IL1β. The expression of steatosis-, inflammation-, and fibrosis-related genes were analyzed. Plasma samples from NAFLD patients were also analyzed by LC/MS. The CDAHFD-fed db/db mice with hepatic steatosis, inflammation, mild fibrosis, obesity, and hypercholesterolemia displayed significantly higher hepatic and plasma levels of free adrenic acid (p < 0.05). The accumulated adrenic acid in the CDAHFD-fed db/db mice was associated with increased expression of ELOVL2 and 5, and the suppression of the acyl-CoA oxidase 1 gene during peroxisomal β-oxidation. The pretreatment of HepG2 cells with adrenic acid enhanced their cytokine-induced cytokines and chemokines mRNA expression. In NAFLD patients, the group with the highest ALT levels exhibited higher plasma adrenic acid concentrations than the other ALT groups (p-value for trend <0.001). Data obtained demonstrated that adrenic acid accumulation contributes to disease progression in NAFLD. Copyright © 2017 Elsevier Inc. All rights reserved.

Escape of X-linked miRNA genes from meiotic sex chromosome inactivation

PubMed Central

Sosa, Enrique; Flores, Luis; Yan, Wei; McCarrey, John R.

2015-01-01

Past studies have indicated that transcription of all X-linked genes is repressed by meiotic sex chromosome inactivation (MSCI) during the meiotic phase of spermatogenesis in mammals. However, more recent studies have shown an increase in steady-state levels of certain X-linked miRNAs in pachytene spermatocytes, suggesting that either synthesis of these miRNAs increases or that degradation of these miRNAs decreases dramatically in these cells. To distinguish between these possibilities, we performed RNA-FISH to detect nascent transcripts from multiple miRNA genes in various spermatogenic cell types. Our results show definitively that Type I X-linked miRNA genes are subject to MSCI, as are all or most X-linked mRNA genes, whereas Type II and III X-linked miRNA genes escape MSCI by continuing ongoing, active transcription in primary spermatocytes. We corroborated these results by co-localization of RNA-FISH signals with both a corresponding DNA-FISH signal and an immunofluorescence signal for RNA polymerase II. We also found that X-linked miRNA genes that escape MSCI locate non-randomly to the periphery of the XY body, whereas genes that are subject to MSCI remain located within the XY body in pachytene spermatocytes, suggesting that the mechanism of escape of X-linked miRNA genes from MSCI involves their relocation to a position outside of the repressive chromatin domain associated with the XY body. The fact that Type II and III X-linked miRNA genes escape MSCI suggests an immediacy of function of the encoded miRNAs specifically required during the meiotic stages of spermatogenesis. PMID:26395485

PROTECTION OF THE EMBRYO AGAINST THE CONGENITAL AND LETHAL EFFECTS OF X- IRRADIATION. PART I

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

Rugh, R.; Grupp, E.

1960-04-01

The effects of 15 agents, some given before and some after x irradiation to 200 r, have been studied for their effectiveness in protecting the 8.5-day mouse embryo against embryonic or fetal death and the development of the severe cephalic congenital anomaly known as exencephalia (or brain hernia). Some 4979 fetuses were examined. Of the agents studied, only cysteinamine, cystamine, and anoxia proved to be statistically "protective" at all. Cysteinamine and cystamine (both -SH compounds) given I.P. before x irradiation to 200 r allowed 73 to 80% of the 8.5-day embryos to survive to term while the untreated but irradiatedmore » control litters had a survival of only 41%. Funther, there was considerable reduction in bcth uterine death and the congenital anomaly of exencephalia. Anoxia (6% O/sub 2/ + 94% N/sub 2/) aIlowed 71% to come through as ""apparently normal," an increase of 30% over the unprotected irradiated controls. Whether there is long-term damage to the 8.5day embryo from the temporary anoxia alone has not been determined, although the anoxic controls showed 96% " apparently nornnal." Distilled water given I.P. before irradiation, making the milieu of the embryos hypotonic, appeared to be deleterious, causing 2% exencephalia even without x irradiation. When combined with x rays, distilled water reduced the "apparentiy normals" to 31%, or 10% lower than with irradiation alone. Saline in various concentrations was not protective. None of the tissue homogenates (spleen, marrow, liver, or brain of a homologous newborn source) proved to be of any protective value. It is suggested that the protective element in such tissue homogenates may be cellular since the placenta acts as the most efficient filter to allow only the dialyzable substances through to the embryo. However, the fact that the 8.5-day mouse embryo has not yet developed its hematopoietic syatem may explain the failure of homogenates which seem to protect through hematopoietic regeneration

Adrenal Gland Tumors: Statistics

MedlinePlus

... Gland Tumor: Statistics Request Permissions Adrenal Gland Tumor: Statistics Approved by the Cancer.Net Editorial Board , 03/ ... primary adrenal gland tumor is very uncommon. Exact statistics are not available for this type of tumor ...

Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement

PubMed Central

Sun, Yu; Bak, Beata; Schoenmakers, Nadia; van Trotsenburg, A.S. Paul; Oostdijk, Wilma; Voshol, Peter; Cambridge, Emma; White, Jacqueline K.; le Tissier, Paul; Gharavy, S. Neda Mousavy; Martinez-Barbera, Juan P.; Stokvis-Brantsma, Wilhelmina H.; Vulsma, Thomas; Kempers, Marlies J.; Persani, Luca; Campi, Irene; Bonomi, Marco; Beck-Peccoz, Paolo; Zhu, Hongdong; Davis, Timothy M.E.; Hokken-Koelega, Anita C.S.; Del Blanco, Daria Gorbenko; Rangasami, Jayanti J.; Ruivenkamp, Claudia A.L.; Laros, Jeroen F.J.; Kriek, Marjolein; Kant, Sarina G.; Bosch, Cathy A.J.; Biermasz, Nienke R.; Appelman-Dijkstra, Natasha M.; Corssmit, Eleonora P.; Hovens, Guido C.J.; Pereira, Alberto M.; den Dunnen, Johan T.; Wade, Michael G.; Breuning, Martijn H.; Hennekam, Raoul C.; Chatterjee, Krishna; Dattani, Mehul T.; Wit, Jan M.; Bernard, Daniel J.

2012-01-01

Congenital central hypothyroidism occurs either in isolation or in conjunction with other pituitary hormone deficits. Using exome and candidate gene sequencing, we identified eight distinct mutations and two deletions in IGSF1 in males from eleven unrelated families with central hypothyroidism, testicular enlargement, and variably low prolactin concentrations. IGSF1 is a membrane glycoprotein highly expressed in the anterior pituitary gland and the identified mutations impair its trafficking to the cell surface in heterologous cells. Igsf1-deficient male mice show diminished pituitary and serum thyroid-stimulating hormone (TSH) concentrations, reduced pituitary thyrotropin-releasing hormone (TRH) receptor expression, decreased triiodothyronine concentrations, and increased body mass. Collectively, our observations delineate a novel X-linked disorder in which loss-of-function mutations in IGSF1 cause central hypothyroidism, likely secondary to an associated impairment in pituitary TRH signaling. PMID:23143598

[Adrenal tumours in childhood].

PubMed

Martos-Moreno, G A; Pozo-Román, J; Argente, J

2013-09-01

This special article aims to summarise the current knowledge regarding the two groups of tumours with their origin in the adrenal gland: 1) adrenocortical tumours, derived from the cortex of the adrenal gland and 2) phaeochromocytomas and paragangliomas, neuroendocrine tumours derived from nodes of neural crest derived cells symmetrically distributed at both sides of the entire spine (paragangliomas [PG]). These PGs can be functioning tumors that secrete catecholamines, which confers their typical dark colour after staining with chromium salts (chromaffin tumors). Among these, the term phaeochromocytoma (PC) is restricted to those PGs derived from the chromaffin cells in the adrenal medulla (intra-adrenal PGs), whereas the term PG is used for those sympathetic or parasympathetic ones in an extra-adrenal location. We analyse the state of the art of their pathogenic and genetic bases, as well as their clinical signs and symptoms, the tests currently available for performing their diagnosis (biochemical, hormonal, imaging and molecular studies) and management (surgery, pre- and post-surgical medical treatment), considering the current and developing strategies in chemo- and radiotherapy. Copyright © 2013 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

Adrenal hormones before and after venography during adrenal venous sampling: a self-controlled study.

PubMed

Koike, Yuya; Matsui, Seishi; Omura, Masao; Makita, Kohzoh; Obara, Alfonso W D; Moriya, Nobukazu; Nishikawa, Tetsuo

2017-03-01

A stress reaction involving increased adrenal hormone release occurs when starting adrenal venous sampling (AVS). The purpose of the present study was to investigate the effect of single shot venography on adrenal hormone production during AVS. This was a prospective self-controlled study. We enrolled 54 consecutive patients (21 men, 33 women; mean age 52 ± 11 years) with primary aldosteronism who underwent AVS from May 2014 to February 2015. Under non-stimulated conditions, blood samples were obtained from a common trunk of the left adrenal vein before and after single shot venography. The initial plasma aldosterone and cortisol concentration (PAC and PCC) were compared with those measured after venography for each patient. PAC and PCC were slightly but significantly decreased between before and after venography (after log transformation 2.12 ± 0.73 vs 2.07 ± 0.72, P = 0.00066, 1.89 ± 0.52 vs 1.83 ± 0.53, P = 0.00031, respectively). During non-stimulated left AVS, adrenal hormone secretion was slightly but significantly decreased after venography, similar to the normal time-related stress reaction. Venography did not increase the adrenal hormone secretion.

Screening for X-linked adrenoleukodystrophy among adult men with Addison's disease.

PubMed

Horn, Morten A; Erichsen, Martina M; Wolff, Anette S B; Månsson, Jan-Eric; Husebye, Eystein S; Tallaksen, Chantal M E; Skjeldal, Ola H

2013-09-01

X-linked adrenoleukodystrophy is an important cause of Addison's disease in boys, but less is known about its contribution to Addison's disease in adult men. After surveying all known cases of X-linked adrenoleukodystrophy in Norway in a separate study, we aimed to look for any missed cases among the population of adult men with nonautoimmune Addison's disease. Among 153 adult men identified in a National Registry for Addison's Disease (75% of identified male cases of Addison's disease in Norway), those with negative indices for 21-hydroxylase autoantibodies were selected. Additionally, cases with low autoantibody indices (48-200) were selected. Sera from subjects included were analysed for levels of very long-chain fatty acids, which are diagnostic for X-linked adrenoleukodystrophy in men. Eighteen subjects had negative indices and 17 had low indices for 21-hydroxylase autoantibodies. None of those with low indices and only one of those with negative indices were found to have X-linked adrenoleukodystrophy; this subject had already been diagnosed because of the neurological symptoms. Cases of Addison's disease proved to be caused by X-linked adrenoleukodystrophy constitute 1·5% of all adult male cases in Norway; the proportion among nonautoimmune cases was 15%. We found X-linked adrenoleukodystrophy to be an uncommon cause of Addison's disease in adult men. However, this aetiological diagnosis has far-reaching consequences both for the patient and for his extended family. We therefore recommend that all adult men with nonautoimmune Addison's disease be analysed for levels of very long-chain fatty acids. © 2013 John Wiley & Sons Ltd.

Growth hormone therapy alone or in combination with gonadotropin-releasing hormone analog therapy to improve the height deficit in children with congenital adrenal hyperplasia.

PubMed

Quintos, J B; Vogiatzi, M G; Harbison, M D; New, M I

2001-04-01

Short stature in the adult patient with congenital adrenal hyperplasia (CAH) is commonly seen, even among patients in excellent adrenal control during childhood and puberty. In this study we examine the effect of GH therapy on height prediction in children with both CAH and compromised height prediction. Leuprolide acetate, a GnRH analog (GnRHa), was given to patients with evidence of early puberty. GH (n = 12) or the combination of GH and GnRHa (n = 8) was administered to 20 patients with CAH while they continued therapy with glucocorticoids. Each patient in the treatment group was matched according to age, sex, bone age, puberty, and type of CAH with another CAH patient treated only with glucocorticoid replacement. The match was made at the start of GH treatment. Of the 20 patients, 12 have completed 2 yr of therapy. After 1 yr of GH or combination GH and GnRHa therapy, the mean growth rate increased from 5 +/- 1.9 to 7.8 +/- 1.6 cm/yr vs. 5.4 +/- 1.7 to 5 +/- 2 cm/yr in the group not receiving GH (P < 0.0001). During the second year of treatment, the mean growth rate was 6 +/- 1.6 vs. 4.2 +/- 2.1 cm/yr in the group not receiving GH (P < 0.001). The height SD score for chronological age in the treatment group at the end of 1 and 2 yr of treatment improved significantly more than the nontreatment group (P < 0.01). A similar improvement in the height SD score for bone age was found in the treatment group after 1 (-1.4 +/- 0.9 vs. -1.7 +/- 0.9; P < 0.0001) and 2 yr of therapy (-0.67 +/- 0.68 vs. -1.7 +/- 1.2; P < 0.0004). The mean predicted adult height improved from 159 +/- 11 (baseline) to 170 +/- 7.5 cm (after 2 yr of therapy) closely approximating target height (173 +/- 8 cm). All patients continued the hydrocortisone treatment. In patients with CAH and compromised height prediction, treatment with GH or the combination of GH and GnRHa results in an improvement of growth rate and height prediction and a reduction in height deficit for bone age.

Two episodes of hemoperitoneum from luteal cysts rupture in a patient with congenital factor X deficiency.

PubMed

Dafopoulos, Konstantinos; Galazios, Georgios; Georgadakis, Georgios; Boulbou, Maria; Koutsoyiannis, Dimitrios; Plakopoulos, Apostolos; Anastasiadis, Panagiotis

2003-01-01

The clinical manifestation of two episodes of hemoperitoneum from ruptured corpus luteum cysts, during the luteal phase of the cycle in a young patient with the rare congenital factor X deficiency, is reported for the first time in literature. The correct diagnosis of the underlying disorder, the gynecological management and the regular follow-up can minimize the risks of this potentially life-threatening hematological disorder. Copyright 2003 S. Karger AG, Basel

Congenital microcephaly: A diagnostic challenge during Zika epidemics.

PubMed

Alvarado-Socarras, Jorge L; Idrovo, Álvaro J; Contreras-García, Gustavo A; Rodriguez-Morales, Alfonso J; Audcent, Tobey A; Mogollon-Mendoza, Adriana C; Paniz-Mondolfi, Alberto

2018-02-19

The multiple, wide and diverse etiologies of congenital microcephaly are complex and multifactorial. Recent advances in genetic testing have improved understanding of novel genetic causes of congenital microcephaly. The recent Zika virus (ZIKV) epidemic in Latin America has highlighted the need for a better understanding of the underlying pathological mechanisms of microcephaly including both infectious and non-infectious causes. The diagnostic approach to microcephaly needs to include potential infectious and genetic etiologies, as well as environmental in-utero exposures such as alcohol, toxins, and medications. Emerging genetic alterations linked to microcephaly include abnormal mitotic microtubule spindle structure and abnormal function of centrosomes. We discuss the diagnostic challenge of congenital microcephaly in the context of understanding the links with ZIKV emergence as a new etiological factor involved in this birth defect. Copyright © 2018 Elsevier Ltd. All rights reserved.

MULTIMODAL IMAGING OF MOSAIC RETINOPATHY IN CARRIERS OF HEREDITARY X-LINKED RECESSIVE DISEASES.

PubMed

Wu, An-Lun; Wang, Jung-Pan; Tseng, Yun-Ju; Liu, Laura; Kang, Yu-Chuan; Chen, Kuan-Jen; Chao, An-Ning; Yeh, Lung-Kun; Chen, Tun-Lu; Hwang, Yih-Shiou; Wu, Wei-Chi; Lai, Chi-Chun; Wang, Nan-Kai

2018-05-01

To investigate the clinical features in carriers of X-linked retinitis pigmentosa, X-linked ocular albinism, and choroideremia (CHM) using multimodal imaging and to assess their diagnostic value in these three mosaic retinopathies. We prospectively examined 14 carriers of 3 X-linked recessive disorders (X-linked retinitis pigmentosa, X-linked ocular albinism, and CHM). Details of abnormalities of retinal morphology were evaluated using fundus photography, fundus autofluorescence (FAF) imaging, and spectral domain optical coherence tomography. In six X-linked retinitis pigmentosa carriers, fundus appearance varied from unremarkable to the presence of tapetal-like reflex and pigmentary changes. On FAF imaging, all carriers exhibited a bright radial reflex against a dark background. By spectral domain optical coherence tomography, loss of the ellipsoid zone in the macula was observed in 3 carriers (50%). Regarding the retinal laminar architecture, 4 carriers (66.7%) showed thinning of the outer nuclear layer and a dentate appearance of the outer plexiform layer. All five X-linked ocular albinism carriers showed a characteristic mud-splatter patterned fundus, dark radial streaks against a bright background on FAF imaging, and a normal-appearing retinal structure by spectral domain optical coherence tomography imaging. Two of the 3 CHM carriers (66.7%) showed a diffuse moth-eaten appearance of the fundus, and all 3 showed irregular hyper-FAF and hypo-FAF spots throughout the affected area. In the CHM carriers, the structural changes observed by spectral domain optical coherence tomography imaging were variable. Our findings in an Asian cohort suggest that FAF imaging is a practical diagnostic test for differentiating X-linked retinitis pigmentosa, X-linked ocular albinism, and CHM carriers. Wide-field FAF is an easy and helpful adjunct to testing for the correct diagnosis and identification of lyonization in carriers of these three mosaic retinopathies.

Increased Cross-Gender Identification Independent of Gender Role Behavior in Girls with Congenital Adrenal Hyperplasia: Results from a Standardized Assessment of 4- to 11-Year-Old Children.

PubMed

Pasterski, Vickie; Zucker, Kenneth J; Hindmarsh, Peter C; Hughes, Ieuan A; Acerini, Carlo; Spencer, Debra; Neufeld, Sharon; Hines, Melissa

2015-07-01

While reports showing a link between prenatal androgen exposure and human gender role behavior are consistent and the effects are robust, associations to gender identity or cross-gender identification are less clear. The aim of the current study was to investigate potential cross-gender identification in girls exposed prenatally to high concentrations of androgens due to classical congenital adrenal hyperplasia (CAH). Assessment included two standardized measures and a short parent interview assessing frequency of behavioral features of cross-gender identification as conceptualized in Part A of the diagnostic criteria for gender identity disorder (GID) in the DSM-IV-TR. Next, because existing measures may have conflated gender role behavior with gender identity and because the distinction is potentially informative, we factor analyzed items from the measures which included both gender identity and gender role items to establish the independence of the two constructs. Participants were 43 girls and 38 boys with CAH and 41 unaffected female and 31 unaffected male relatives, aged 4- to 11-years. Girls with CAH had more cross-gender responses than female controls on all three measures of cross-gender identification as well as on a composite measure of gender identity independent of gender role behavior. Furthermore, parent report indicated that 5/39 (12.8 %) of the girls with CAH exhibited cross-gender behavior in all five behavioral domains which comprise the cross-gender identification component of GID compared to 0/105 (0.0 %) of the children in the other three groups combined. These data suggest that girls exposed to high concentrations of androgens prenatally are more likely to show cross-gender identification than girls without CAH or boys with and without CAH. Our findings suggest that prenatal androgen exposure could play a role in gender identity development in healthy children, and may be relevant to gender assignment in cases of prenatal hormone disruption

A Novel Mutation of the Arginine Vasopressin Receptor 2 Gene in a Patient with Congenital Nephrogenic Diabetes Insipidus

PubMed Central

Tajima, Asako; Miyata, Ichiro; Katayama, Akira; Toyoda, Shigeru; Eto, Yoshikatsu

2005-01-01

We have identified a novel mutation of the arginine vasopressin receptor 2 (AVPR2) gene in a case of congenital X-linked nephrogenic diabetes insipidus (NDI). The patient was a 2-mo-old Japanese boy with persistent fever and failure to thrive. He was diagnosed as having congenital NDI by clinical and laboratory findings. Molecular analysis demonstrated that he was hemizygous for a G to C transversion in exon 2 of the AVPR2 gene which resulted in a glycine to arginine substitution (G107R) at the 107th codon of the first extracellular loop. His mother was heterozygous for the same mutation. We speculated that the G107R mutation would interfere with the binding capacity of the AVPR2, since G107R is located near F105 and R106, both of which are crucial for ligand binding. In cases of X-linked NDI, mutations in the AVPR2 gene are distributed widely. Thus, DNA analysis throughout the gene is of clinical value for the identification of female carriers, and it also gives precise information for genetic counseling. PMID:24790307

Congenital Hyperinsulinism in Infants with Turner Syndrome: Possible Association with Monosomy X and KDM6A Haploinsufficiency.

PubMed

Gibson, Christopher E; Boodhansingh, Kara E; Li, Changhong; Conlin, Laura; Chen, Pan; Becker, Susan A; Bhatti, Tricia; Bamba, Vaneeta; Adzick, N Scott; De Leon, Diva D; Ganguly, Arupa; Stanley, Charles A

2018-06-14

Previous case reports have suggested a possible association of congenital hyperinsulinism with Turner syndrome. We examined the clinical and molecular features in girls with both congenital hyperinsulinism and Turner syndrome seen at The Children's Hospital of Philadelphia (CHOP) between 1974 and 2017. Records of girls with hyperinsulinism and Turner syndrome were reviewed. Insulin secretion was studied in pancreatic islets and in mouse islets treated with an inhibitor of KDM6A, an X chromosome gene associated with hyperinsulinism in Kabuki syndrome. Hyperinsulinism was diagnosed in 12 girls with Turner syndrome. Six were diazoxide-unresponsive; 3 had pancreatectomies. The incidence of Turner syndrome among CHOP patients with hyperinsulinism (10 of 1,050 from 1997 to 2017) was 48 times more frequent than expected. The only consistent chromosomal anomaly in these girls was the presence of a 45,X cell line. Studies of isolated islets from 1 case showed abnormal elevated cytosolic calcium and heightened sensitivity to amino acid-stimulated insulin release; similar alterations were demonstrated in mouse islets treated with a KDM6A inhibitor. These results demonstrate a higher than expected frequency of Turner syndrome among children with hyperinsulinism. Our data suggest that haploinsufficiency for KDM6A due to mosaic X chromosome monosomy may be responsible for hyperinsulinism in Turner syndrome. © 2018 S. Karger AG, Basel.

Genetics Home Reference: X-linked lymphoproliferative disease

MedlinePlus

... infects most humans. In some people it causes infectious mononucleosis (commonly known as "mono"). Normally, after initial infection, ... severe susceptibility to EBV infection severe susceptibility to infectious mononucleosis X-linked lymphoproliferative syndrome XLP Related Information How ...

Clinical Value of Specific Immunoglobulin E Detection by Enzyme-Linked Immunosorbent Assay in Cases of Acquired and Congenital Toxoplasmosis

PubMed Central

Foudrinier, F.; Villena, I.; Jaussaud, R.; Aubert, D.; Chemla, C.; Martinot, F.; Pinon, J. M.

2003-01-01

The clinical value of immunoenzymatic (enzyme-linked immunosorbent assay) detection of anti-Toxoplasma immunoglobulin E (IgE) was assessed by studying 2,036 sera from 792 subjects, comprising seronegative controls and subjects with acute, active, reactivated, or congenital toxoplasmosis. Included were nonimmunized adults; pregnant women with recently acquired infection (acute toxoplasmosis); immunocompetent subjects with recently acquired severe infection (active toxoplasmosis) expressed as fever, adenopathies, splenomegaly, pneumonia, meningitis, or disseminated infection; subjects—some of them immunocompromised—whose previously moderate IgG antibody levels rose, suggesting a reactivation of quiescent toxoplasmosis; and infants born to seroconverted mothers and evaluated for diagnosis of congenital infection and therapeutic management. Specific IgE antibodies were never detected in seronegative subjects. They were present in 85.7% of asymptomatic seroconverters and in 100% of seroconverters with overt toxoplasmosis, following two different kinetics: in the former, the specific IgE titer generally presented a brief peak 2 to 3 months postinfection and then fell rapidly, whereas specific IgE persisted at a very high titer for several months in the latter. IgE emerged concomitantly with the increase in IgG during toxoplasmic reactivation. For neonatal diagnosis of congenital toxoplasmosis, IgE was less informative than IgM and IgA (sensitivities, 59.5, 64.3, and 76.2%, respectively) and had a specificity of 91.9%. Nevertheless, simultaneous measurement of the three isotypes at birth improved the diagnostic yield to 81% relative to the combination of IgA and IgM. Emergence of specific IgE during postnatal treatment for congenital toxoplasmosis is a sign of poor adherence or inadequate dosing. PMID:12682160

Inheritance of Adrenal Phenylethanolamine N-Methyltransferase Activity in the Rat

PubMed Central

Stolk, Jon M.; Vantini, Guido; Guchhait, Ras B.; Hurst, Jeffrey H.; Perry, Bruce D.; U'Prichard, David C.; Elston, Robert C.

1984-01-01

Phenylethanolamine N-methyltransferase (PNMT) is the enzyme that catalyzes the S-adenosyl-l-methionine-dependent methylation of (-)norepinephrine to (-)epinephrine in the adrenal medulla. Adrenal PNMT activity is markedly different in two highly inbred rat strains; enzyme activity in the F344 strain is more than fivefold greater than that in the Buf strain. Initial characterization of the enzyme in the two inbred strains reveals evidence for catalytic and structural differences, as reflected in dissimilar Km values for the cosubstrate (S-adenosyl-l-methionine) and prominent differences in thermal inactivation curves. To assess adrenal PNMT activity in an F344 x Buf pedigree, we employed a statistical procedure to test for one- and two-locus hypotheses in the presence of within-class correlations due to cage or litter effects. The PNMT data in the pedigree are best accounted for by segregation at a simple major locus superimposed upon a polygenic background; data obtained from the biochemical studies suggest that the major locus is a structural gene locus. PMID:6149973

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder.

PubMed

Frints, Suzanna G M; Ozanturk, Aysegul; Rodríguez Criado, Germán; Grasshoff, Ute; de Hoon, Bas; Field, Michael; Manouvrier-Hanu, Sylvie; E Hickey, Scott; Kammoun, Molka; Gripp, Karen W; Bauer, Claudia; Schroeder, Christopher; Toutain, Annick; Mihalic Mosher, Theresa; Kelly, Benjamin J; White, Peter; Dufke, Andreas; Rentmeester, Eveline; Moon, Sungjin; Koboldt, Daniel C; van Roozendaal, Kees E P; Hu, Hao; Haas, Stefan A; Ropers, Hans-Hilger; Murray, Lucinda; Haan, Eric; Shaw, Marie; Carroll, Renee; Friend, Kathryn; Liebelt, Jan; Hobson, Lynne; De Rademaeker, Marjan; Geraedts, Joep; Fryns, Jean-Pierre; Vermeesch, Joris; Raynaud, Martine; Riess, Olaf; Gribnau, Joost; Katsanis, Nicholas; Devriendt, Koen; Bauer, Peter; Gecz, Jozef; Golzio, Christelle; Gontan, Cristina; Kalscheuer, Vera M

2018-05-04

RLIM, also known as RNF12, is an X-linked E3 ubiquitin ligase acting as a negative regulator of LIM-domain containing transcription factors and participates in X-chromosome inactivation (XCI) in mice. We report the genetic and clinical findings of 84 individuals from nine unrelated families, eight of whom who have pathogenic variants in RLIM (RING finger LIM domain-interacting protein). A total of 40 affected males have X-linked intellectual disability (XLID) and variable behavioral anomalies with or without congenital malformations. In contrast, 44 heterozygous female carriers have normal cognition and behavior, but eight showed mild physical features. All RLIM variants identified are missense changes co-segregating with the phenotype and predicted to affect protein function. Eight of the nine altered amino acids are conserved and lie either within a domain essential for binding interacting proteins or in the C-terminal RING finger catalytic domain. In vitro experiments revealed that these amino acid changes in the RLIM RING finger impaired RLIM ubiquitin ligase activity. In vivo experiments in rlim mutant zebrafish showed that wild type RLIM rescued the zebrafish rlim phenotype, whereas the patient-specific missense RLIM variants failed to rescue the phenotype and thus represent likely severe loss-of-function mutations. In summary, we identified a spectrum of RLIM missense variants causing syndromic XLID and affecting the ubiquitin ligase activity of RLIM, suggesting that enzymatic activity of RLIM is required for normal development, cognition and behavior.

Exome Sequencing of 18 Chinese Families with Congenital Cataracts: A New Sight of the NHS Gene

PubMed Central

Sun, Wenmin; Xiao, Xueshan; Li, Shiqiang; Guo, Xiangming; Zhang, Qingjiong

2014-01-01

Purpose The aim of this study was to investigate the mutation spectrum and frequency of 34 known genes in 18 Chinese families with congenital cataracts. Methods Genomic DNA and clinical data was collected from 18 families with congenital cataracts. Variations in 34 cataract-associated genes were screened by whole exome sequencing and then validated by Sanger sequencing. Results Eleven candidate variants in seven of the 34 genes were detected by exome sequencing and then confirmed by Sanger sequencing, including two variants predicted to be benign and the other pathogenic mutations. The nine mutations were present in 9 of the 18 (50%) families with congenital cataracts. Of the four families with mutations in the X-linked NHS gene, no other abnormalities were recorded except for cataract, in which a pseudo-dominant inheritance form was suggested, as female carriers also had different forms of cataracts. Conclusion This study expands the mutation spectrum and frequency of genes responsible for congenital cataract. Mutation in NHS is a common cause of nonsyndromic congenital cataract with pseudo-autosomal dominant inheritance. Combined with our previous studies, a genetic basis could be identified in 67.6% of families with congenital cataracts in our case series, in which mutations in genes encoding crystallins, genes encoding connexins, and NHS are responsible for 29.4%, 14.7%, and 11.8% of families, respectively. Our results suggest that mutations in NHS are the common cause of congenital cataract, both syndromic and nonsyndromic. PMID:24968223

Effectiveness of Prenatal Screening and Treatment to Prevent Congenital Syphilis, Louisiana and Florida, 2013-2014.

PubMed

Matthias, James M; Rahman, Mohammad M; Newman, Daniel R; Peterman, Thomas A

2017-08-01

From 2012 to 2014, rates of congenital syphilis increased in Louisiana and Florida. We evaluated the effectiveness of early (first or second) and third trimester syphilis screening for the prevention of congenital syphilis in these high-morbidity states. Reported syphilis cases among pregnant women in Louisiana and Florida during January 1, 2013, to December 31, 2014, were reviewed for documented screening for syphilis in the first 2 trimesters and third trimester. Pregnant women with syphilis were linked to congenital syphilis records and stratified by whether the pregnancy led to a reported congenital syphilis case. Seven hundred ten pregnant women with syphilis in Louisiana and Florida were linked to 155 congenital syphilis cases. Three hundred seventy (52%) pregnant women with syphilis were staged as early syphilis (n = 270) or high-titer late or unknown duration-latent syphilis (n = 100), and 109 (70% of the total) were linked to congenital syphilis cases. Screening in the first 2 trimesters identified 513 pregnant women who tested positive for syphilis, and 470 (92%) potential congenital syphilis were averted. One hundred nine pregnant women tested positive for syphilis in the third trimester, and 85 (78%) had babies without congenital syphilis. During their pregnancy, 85 (12%) women tested negative at least once, and 55 (65%) had babies with congenital syphilis. Thirty-nine women had no reported syphilis screening 30 days or longer before delivery. Screening for syphilis both early and in the third trimester prevented many pregnant women with syphilis from having a baby with congenital syphilis. Preventing all congenital syphilis would likely require preventing all syphilis among women.

Functional reconstitution of prostaglandin E receptor from bovine adrenal medulla with guanine nucleotide binding proteins

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

Negishi, M.; Ito, S.; Yokohama, H.

1988-05-15

Prostaglandin E/sub 2/ (PEG/sub 2/) was found to bind specifically to a 100,000 x g pellet prepared from bovine adrenal medulla. The PGE receptor was associated with a GTP-binding protein (G-protein) and could be covalently cross-linked with this G-protein by dithiobis(succinimidyl propionate) in the 100,000 x g pellet. In order to characterize the G-protein associated with the PGE receptor and reconstitute these proteins in phospholipid vesicles, the authors purified the G-protein to apparent homogeneity from the 100,000 x g pellet. The G-protein served as a substrate of pertussis toxin but differed in its ..cap alpha.. subunit from two known pertussismore » toxin substrate G-proteins (G/sub i/ and G/sub 0/) purified from bovine brain. The molecular weight of the ..cap alpha.. subunit was 40,000, which is between those of G/sub i/ and G/sub 0/. The purified protein was also distinguished immunologically from G/sub i/ and G/sub 0/ and was referred to as G/sub am/. Reconstitution of the PGE receptor with pure C/sub am/, G/sub i/, or G/sub 0/ in phospholipid vesicles resulted in a remarkable restoration of (/sup 3/H)PGE/sub 2/ binding activity in a GTP-dependent manner. The efficiency of these three G-proteins in this capacity was roughly equal. When pertussis toxin- or N-ethylmaleimide-treated G-proteins, instead of the native ones, were reconstituted into vesicles, the restoration of binding activity was no longer observed. These results indicate that the PGE receptor can couple functionally with G/sub am/, G/sub i/, or G/sub 0/ in phospholipid vesicles and suggest that G/sub am/ may be involved in signal transduction of the PGE receptor in bovine adrenal medulla.« less

Congenital nephrogenic diabetes insipidus: the current state of affairs.

PubMed

Wesche, Daniel; Deen, Peter M T; Knoers, Nine V A M

2012-12-01

The anti-diuretic hormone arginine vasopressin (AVP) is released from the pituitary upon hypovolemia or hypernatremia, and regulates water reabsorption in the renal collecting duct principal cells. Binding of AVP to the arginine vasopressin receptor type 2 (AVPR2) in the basolateral membrane leads to translocation of aquaporin 2 (AQP2) water channels to the apical membrane of the collecting duct principal cells, inducing water permeability of the membrane. This results in water reabsorption from the pro-urine into the medullary interstitium following an osmotic gradient. Congenital nephrogenic diabetes insipidus (NDI) is a disorder associated with mutations in either the AVPR2 or AQP2 gene, causing the inability of patients to concentrate their pro-urine, which leads to a high risk of dehydration. This review focuses on the current knowledge regarding the cell biological aspects of congenital X-linked, autosomal-recessive and autosomal-dominant NDI while specifically addressing the latest developments in the field. Based on deepened mechanistic understanding, new therapeutic strategies are currently being explored, which we also discuss here.

Autonomic control of adrenal function.

PubMed Central

Edwards, A V; Jones, C T

1993-01-01

Recent studies of adrenal function in conscious calves are reviewed. These have involved collecting the whole of the adrenal effluent blood from the right adrenal gland at intervals and, where necessary, prior functional hypophysectomy by destruction of the pituitary stalk under general halothane anaesthesia 3 d previously. The adrenal medulla was found to release numerous neuropeptides, in addition to catecholamines, in response to stimulation of the peripheral end of the right splanchnic nerve, which was carried out below behavioural threshold. Many of these responses were enhanced by stimulating intermittently at a relatively high frequency. Intra-aortic infusions of a relatively low dose of acetylcholine (4.5 nmol min-1 kg-1) elicited similar responses. In the adrenal cortex, agonists which either potentiated the steroidogenic response to ACTH or exerted a direct steroidogenic action included VIP, CGRP, CRF and ACh acting via muscarinic receptors. Stimulation of the peripheral end of the right splanchnic nerve strongly potentiated the steroidogenic response to ACTH and there is compelling evidence that the innervation normally plays an important part in cortisol secretion. PMID:8300417

Clinical, hormonal, ovarian, and genetic aspects of 46,XX patients with congenital adrenal hyperplasia due to CYP17A1 defects.

PubMed

Carvalho, Luciane Carneiro de; Brito, Vinicius Nahime; Martin, Regina Matsunaga; Zamboni, Aline Machado; Gomes, Larissa Garcia; Inácio, Marlene; Mermejo, Livia Mara; Coeli-Lacchini, Fernanda; Teixeira, Virginia Ribeiro; Gonçalves, Fabrícia Torres; Carrilho, Alexandre José Faria; Del Toro Camargo, Kenny Yelena; Finkielstain, Gabriela Paula; Taboada, Giselle Fernandes; Frade Costa, Elaine Maria; Domenice, Sorahia; Mendonca, Berenice Bilharinho

2016-06-01

To perform a clinical, biochemical, and molecular evaluation of patients with CYP17A1 defects, including ovarian imaging. Retrospective study. Tertiary care center. Sixteen patients with congenital adrenal hyperplasia due to CYP17A1 defects with a median chronological age of 20 years and belonging to 10 unrelated families. None. Clinical and biochemical parameters, molecular diagnosis, ovarian imaging, and therapeutic management. Seventy-one percent of patients presented with primary amenorrhea, 50% had no breast development, and pubic hair was absent or sparse in all patients; 88% had high blood pressure at diagnosis. Basal LH and P levels were high, and androgen levels were low in all patients. Ultrasound revealed ovarian enlargement in 68.7% and ovarian macrocysts in 62.5% of patients before treatment; three patients had a previous surgical correction of ovarian torsion or rupture. Molecular analysis revealed inactivating CYP17A1 mutations in all patients. The most prevalent mutation was p.W406R, and one patient bore a novel p.G478S/p.I223Nfs*10 compound heterozygous mutation. Treatment with dexamethasone, estrogen, and P resulted in reduction of ovarian volume. Amenorrhea, absent/sparse pubic hair, hypertension, and ovarian macrocysts, whichincrease the risk of ovarian torsion, are important elements in the diagnosis of 46,XX patients with CYP17A1 defects. High basal P levels in patients with hypergonadotropic hypogonadism point to the diagnosis of CYP17A1 defects. Fertility can be achieved in these patients with novel reproductive techniques. Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Gender role behavior, sexuality, and psychosocial adaptation in women with congenital adrenal hyperplasia due to CYP21A2 deficiency.

PubMed

Frisén, Louise; Nordenström, Anna; Falhammar, Henrik; Filipsson, Helena; Holmdahl, Gundela; Janson, Per Olof; Thorén, Marja; Hagenfeldt, Kerstin; Möller, Anders; Nordenskjöld, Agneta

2009-09-01

Gender-atypical behavior has been described in young girls as well as in women with congenital adrenal hyperplasia (CAH) due to a CYP21A2 deficiency. The aim of the study was to assess health-related, psychosexual, and psychosocial parameters and correlate the results to CYP21A2 genotype. Sixty-two Swedish women with CAH and age-matched controls completed a 120-item questionnaire and a validated quality of life instrument [psychological general well-being (PGWB) formula] to identify psychosexual and psychosocial parameters. The patients were divided into four CYP21A2 genotype groups. The women with CAH held more male-dominant occupations (30%) compared to controls (13%) (P = 0.04), especially those in the null genotype group (55%) (P = 0.006). They also reported a greater interest in rough sports (74%) compared to controls (50%) (P = 0.007). Eight women with CAH (14%) reported a prime interest in motor vehicles, compared to none of the controls (P = 0.002). Non-heterosexual orientation was reported by 19% of women with CAH (P = 0.005), 50% in the null genotype group (P = 0.0001), 30% in I2 splice (NS), and 5% in I172N (NS). PGWB total score did not differ between patients and controls. We identified increased gender-atypical behavior in women with CAH that could be correlated to the CYP21A2 genotype. This speaks in favor of dose-dependent effects of prenatal androgens on the development of higher brain functions. The impact of the disease on upbringing and interpersonal relationships did not correlate with disease severity, indicating that other factors, such as coping strategies, are important for psychosocial adaptation. This illustrates the need for psychological support to parents and patients.

Obesity in children with congenital adrenal hyperplasia in the Minnesota cohort: importance of adjusting body mass index for height-age.

PubMed

Sarafoglou, Kyriakie; Forlenza, Gregory P; Yaw Addo, O; Kyllo, Jennifer; Lteif, Aida; Hindmarsh, P C; Petryk, Anna; Gonzalez-Bolanos, Maria Teresa; Miller, Bradley S; Thomas, William

2017-05-01

To evaluate obesity and overweight in children with congenital adrenal hyperplasia (CAH) and associations with glucocorticoids, fludrocortisone and disease control. Adjusting body mass index-for-height-age (BMI HA ) percentile is proposed to correct misclassification of obese/overweight status in CAH children with advanced bone age and tall-for-age stature. Longitudinal. One hundred and ninety-four children with CAH seen from 1970 to 2013: 124 salt wasting (SW); 70 simple virilizing (SV); 102 females. Body mass index (BMI) end-points were overweight (85-94 percentile) and obese (≥95 percentile). Approximately 50% of the children had at least one BMI measurement ≥95 percentile and about 70% had at least one ≥85 percentile. Using BMI HA percentiles, obesity incidence decreased slightly in SW children (47-43%) and markedly in SV children (50-33%); however, overweight status was not reduced. Only 6% of SW and 1% of SV children were persistently obese (≥3 clinic visits) when BMI HA was applied, whereas overweight status persisted in 35% of SW and 33% of SV children. Most obesity or overweight when using BMI HA occurred before age 10 and there was no association with hydrocortisone (HC) or fludrocortisone dosing. Adiposity rebound for SW children occurred by 3·3 years and in SV females by age 3·8 years, over a year earlier than the adiposity rebound for healthy children. Children with CAH are at higher risk for early onset obesity and overweight with or without using BMI HA but rates of persistent obesity were lower than previously reported. Careful HC dosing during early childhood is needed to prevent increased weight gain and an early adiposity rebound. © 2017 John Wiley & Sons Ltd.

A novel pipeline for adrenal tumour segmentation.

PubMed

Koyuncu, Hasan; Ceylan, Rahime; Erdogan, Hasan; Sivri, Mesut

2018-06-01

Adrenal tumours occur on adrenal glands surrounded by organs and osteoid. These tumours can be categorized as either functional, non-functional, malign, or benign. Depending on their appearance in the abdomen, adrenal tumours can arise from one adrenal gland (unilateral) or from both adrenal glands (bilateral) and can connect with other organs, including the liver, spleen, pancreas, etc. This connection phenomenon constitutes the most important handicap against adrenal tumour segmentation. Size change, variety of shape, diverse location, and low contrast (similar grey values between the various tissues) are other disadvantages compounding segmentation difficulty. Few studies have considered adrenal tumour segmentation, and no significant improvement has been achieved for unilateral, bilateral, adherent, or noncohesive tumour segmentation. There is also no recognised segmentation pipeline or method for adrenal tumours including different shape, size, or location information. This study proposes an adrenal tumour segmentation (ATUS) pipeline designed to eliminate the above disadvantages for adrenal tumour segmentation. ATUS incorporates a number of image methods, including contrast limited adaptive histogram equalization, split and merge based on quadtree decomposition, mean shift segmentation, large grey level eliminator, and region growing. Performance assessment of ATUS was realised on 32 arterial and portal phase computed tomography images using six metrics: dice, jaccard, sensitivity, specificity, accuracy, and structural similarity index. ATUS achieved remarkable segmentation performance, and was not affected by the discussed handicaps, on particularly adherence to other organs, with success rates of 83.06%, 71.44%, 86.44%, 99.66%, 99.43%, and 98.51% for the metrics, respectively, for images including sufficient contrast uptake. The proposed ATUS system realises detailed adrenal tumour segmentation, and avoids known disadvantages preventing accurate

FOXG1 Is Responsible for the Congenital Variant of Rett Syndrome

PubMed Central

Ariani, Francesca; Hayek, Giuseppe; Rondinella, Dalila; Artuso, Rosangela; Mencarelli, Maria Antonietta; Spanhol-Rosseto, Ariele; Pollazzon, Marzia; Buoni, Sabrina; Spiga, Ottavia; Ricciardi, Sara; Meloni, Ilaria; Longo, Ilaria; Mari, Francesca; Broccoli, Vania; Zappella, Michele; Renieri, Alessandra

2008-01-01

Rett syndrome is a severe neurodevelopmental disease caused by mutations in the X-linked gene encoding for the methyl-CpG-binding protein MeCP2. Here, we report the identification of FOXG1-truncating mutations in two patients affected by the congenital variant of Rett syndrome. FOXG1 encodes a brain-specific transcriptional repressor that is essential for early development of the telencephalon. Molecular analysis revealed that Foxg1 might also share common molecular mechanisms with MeCP2 during neuronal development, exhibiting partially overlapping expression domain in postnatal cortex and neuronal subnuclear localization. PMID:18571142

X-chromosomal inactivation directly influences the phenotypic manifestation of X-linked protoporphyria

PubMed Central

Brancaleoni, V.; Balwani, M.; Granata, F.; Graziadei, G.; Missineo, P.; Fiorentino, V.; Fustinoni, S.; Cappellini, M.D.; Naik, H.; Desnick, R.J.; Di Pierro, E.

2015-01-01

X-linked protoporphyria (XLP), a rare erythropoietic porphyria, results from terminal exon gain-of-function mutations in the ALAS2 gene causing increased ALAS2 activity and markedly increased erythrocyte protoporphyrin levels. Patients present with severe cutaneous photosensitivity and may develop liver dysfunction. XLP was originally reported as X-linked dominant with 100% penetrance in males and females. We characterized 11 heterozygous females from six unrelated XLP families and show markedly varying phenotypic and biochemical heterogeneity, reflecting the degree of X-chromsomal inactivation of the mutant gene. ALAS2 sequencing identified the specific mutation and confirmed heterozygosity among the females. Clinical history, plasma and erythrocyte protoporphyrin levels were determined. Methylation assays of the androgen receptor and zinc-finger MYM type 3 short tandem repeat polymorphisms estimated each heterozygotes X-chromosomal inactivation pattern. Heterozygotes with equal or increased skewing, favoring expression of the wild-type allele had no clinical symptoms and only slightly increased erythrocyte protoporphyrin concentrations and/or frequency of protoporphyrin-containing peripheral blood fluorocytes. When the wild-type allele was preferentially inactivated, heterozygous females manifested the disease phenotype and had both higher erythrocyte protoporphyrin levels and circulating fluorocytes. These findings confirm that the previous dominant classification of XLP is inappropriate and genetically misleading, as the disorder is more appropriately designated XLP. PMID:25615817

Monogenic Disorders of Adrenal Steroidogenesis.

PubMed

Baranowski, Elizabeth S; Arlt, Wiebke; Idkowiak, Jan

2018-06-06

Disorders of adrenal steroidogenesis comprise autosomal recessive conditions affecting steroidogenic enzymes of the adrenal cortex. Those are located within the 3 major branches of the steroidogenic machinery involved in the production of mineralocorticoids, glucocorticoids, and androgens. This mini review describes the principles of adrenal steroidogenesis, including the newly appreciated 11-oxygenated androgen pathway. This is followed by a description of pathophysiology, biochemistry, and clinical implications of steroidogenic disorders, including mutations affecting cholesterol import and steroid synthesis, the latter comprising both mutations affecting steroidogenic enzymes and co-factors required for efficient catalysis. A good understanding of adrenal steroidogenic pathways and their regulation is crucial as the basis for sound management of these disorders, which in the majority present in early childhood. © 2018 The Author(s) Published by S. Karger AG, Basel.

Linkage localization of X-linked Charcot-Marie-Tooth disease

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

Bergoffen, J.; Trofatter, J.; Haines, J.L.

1993-02-01

Charcot-Marie-Tooth disease (CMT), also known as hereditary motor and sensory neuropathy, is a heterogeneous group of slowly progressive, degenerative disorders of peripheral nerve. X-linked CMT (CMTX) (McKusick 302800), a subdivision of type I, or demyelinating, CMT is an X-linked dominant condition with variable penetrance. Previous linkage analysis using RFLPs demonstrated linkage to markers on the proximal long and short arms of the X chromosome, with the more likely localization on the proximal long arm of the X chromosome. Available variable simple-sequence repeats (VSSRs) broaden the possibilities for linkage analysis. This paper presents new linkage data and recombination analysis derived frommore » work with four VSSR markers - AR, PGKP1, DXS453, and DXYS1X - in addition to analysis using RFLP markers described elsewhere. These studies localize the CMTX gene to the proximal Xq segment between PGKP1 (Xq11.2-12) and DXS72 (Xq21.1), with a combined maximum multipoint lod score of 15.3 at DXS453 ([theta] = 0). 32 refs., 3 figs., 2 tabs.« less

X-inactivation patterns in female Leber`s hereditary optic neuropathy patients do not support a strong X-linked determinant

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

Pegoraro, E.; Hoffman, E.P.; Carelli, V.

1996-02-02

Leber`s hereditary optic neuropathy (LHON) accounts for about 3% of the cases of blindness in young adult males. The underlying mitochondrial pathogenesis of LHON has been well studied, with specific mitochondrial DNA (mtDNA) mutations of structural genes described and well characterized. However, enigmatic aspects of the disease are not explained by mutation data, such as the higher proportion of affected males, the later onset of the disease in females, and the presence of unaffected individuals with a high proportion of mutant mtDNA. A hypothesis which has been put forward to explain the unusual disease expression is a dual model ofmore » mtDNA and X-linked nuclear gene inheritance. If a nuclear X-linked modifier gene influences the expression of the mitochondrial-linked mutant gene then the affected females should be either homozygous for the nuclear determinant, or if heterozygous, lyonization should favor the mutant X. In order to determine if an X-linked gene predisposes to LHON phenotype we studied X-inactivation patterns in 35 females with known mtDNA mutations from 10 LHON pedigrees. Our results do not support a strong X-linked determinant in LHON cause: 2 of the 10 (20%) manifesting carriers showed skewing of X-inactivation, as did 3 of the 25 (12%) nonmanifesting carriers. 39 refs., 2 figs., 1 tab.« less

Mortality throughout early childhood for Michigan children born with congenital anomalies, 1992-1998.

PubMed

Berger, Katherine H; Zhu, Bao-Ping; Copeland, Glenn

2003-09-01

Congenital anomalies are a leading cause of infant deaths, accounting for almost a fifth of all infant deaths. Few studies have researched the survival experience of infants born with congenital anomalies past the infant stage. Using birth and death files routinely linked to the Michigan Birth Defects Registry, we identified all singleton infants during calendar years 1992 through 1998 with reportable congenital anomalies for our study. A comparative file of children born without congenital anomalies during the same time period was developed using linked birth and death files. The mortality data were assessed by age at death (through age six) and race to determine mortality rates, relative risks, hazard ratios, and survival trends. Throughout early childhood, children born with congenital anomalies had a high risk of mortality compared with all other children. The overall 7-year hazard ratio comparing children with congenital anomalies with all other children was 7.2. Overall mortality rates for black children were significantly higher than white children through the age of seven, irrespective of whether they had congenital anomalies. Among children with congenital anomalies, this disparity disappeared after adjusting for birth weight, sex, mother's age, mother's education, and number of organ systems affected. Compared with children without congenital anomalies, children born with congenital anomalies had a higher risk of mortality well beyond the infant period. Racial disparities in mortality rates among children with congenital anomalies were due to confounding factors.

[Congenital nephrogenic diabetes insipidus: about a case report].

PubMed

Esselmani, Hicham; Yassine, Asmaa; Bouabdellah, Mounya; Benchekroun, Laila; Handor, Najat; Elalami, Sanae; Chabraoui, Layachi

2013-01-01

Congenital nephrogenic diabetes insipidus is a rare, hereditary in nature, characterized by an inability of the kidney to concentrate urine, secondary to the manifold resistance to the action of vasopressin. X-linked forms of transmission (90%) are expressed in boys, from the neonatal period in general, by polyuria and polydipsia. Symptomatology in transmissive girls is variable but can sometimes be quite marked. These forms are secondary to mutations in the gene encoding the vasopressin V2 receptor, located at position Xq28, responsible for a loss of function of this receptor. Some of these mutations may cause a partial phenotype, less severe. Forms of autosomal, recessive or dominant are more rare (10%). Treatment is symptomatic, sometimes difficult in infants. It aims to avoid episodes of dehydration. It is based on a conventional diet hypo-osmotic and administration of hydrochlorothiazide and indomethacin. We report here the case of a child with congenital nephrogenic diabetes insipidus hospitalized at Children's Hospital of Rabat and throughout this case we review the pathophysiology and clinical and biological characteristics of the disease and including importance of contribution of clinical biochemistry laboratory in the diagnosis and monitoring of this disease.

Acute encephalopathy with unilateral cortical-subcortical lesions in two unrelated kindreds treated with glucocorticoids prenatally for congenital adrenal hyperplasia due to 21-hydroxylase deficiency: established facts and novel insight.

PubMed

Grunt, Sebastian; Steinlin, Maja; Weisstanner, Christian; Schöning, Martin; Mullis, Primus E; Flück, Christa E

2013-01-01

Prenatal glucocorticoid (GC) treatment of the female fetus with 21-hydroxylase deficiency (21-OHD) may prevent genital virilization and androgen effects on the brain, but prenatal GC therapy is controversial because of possible adverse effects on fetal programming, the cardiovascular system and the brain. We report 2 patients with congenital adrenal hyperplasia (CAH) due to 21-OHD who were treated prenatally with dexamethasone, suffered from an acute encephalopathy and showed focal and multifocal cortical and subcortical diffusion restrictions in early MRI and signs of permanent alterations in the follow-up neuroimaging studies. Both patients recovered from the acute episode. Whereas the first patient recovered without neurological sequelae the second patient showed hemianopsia and spastic hemiplegia in the neurological follow-up examination. These are 2 children with CAH, both treated prenatally with high doses of dexamethasone to prevent virilization. The question arises whether prenatal high-dose GC treatment in patients with CAH might represent a risk factor for brain lesions in later life. Adverse effects/events should be reported systematically in patients undergoing prenatal GC treatment and long-term follow-up studies involving risk factors for cerebrovascular disease should be performed. Copyright © 2013 S. Karger AG, Basel.

Genome-wide misexpression of X-linked versus autosomal genes associated with hybrid male sterility.

PubMed

Lu, Xuemei; Shapiro, Joshua A; Ting, Chau-Ti; Li, Yan; Li, Chunyan; Xu, Jin; Huang, Huanwei; Cheng, Ya-Jen; Greenberg, Anthony J; Li, Shou-Hsien; Wu, Mao-Lien; Shen, Yang; Wu, Chung-I

2010-08-01

Postmating reproductive isolation is often manifested as hybrid male sterility, for which X-linked genes are overrepresented (the so-called large X effect). In contrast, X-linked genes are significantly under-represented among testis-expressing genes. This seeming contradiction may be germane to the X:autosome imbalance hypothesis on hybrid sterility, in which the X-linked effect is mediated mainly through the misexpression of autosomal genes. In this study, we compared gene expression in fertile and sterile males in the hybrids between two Drosophila species. These hybrid males differ only in a small region of the X chromosome containing the Ods-site homeobox (OdsH) (also known as Odysseus) locus of hybrid sterility. Of genes expressed in the testis, autosomal genes were, indeed, more likely to be misexpressed than X-linked genes under the sterilizing action of OdsH. Since this mechanism of X:autosome interaction is only associated with spermatogenesis, a connection between X:autosome imbalance and the high rate of hybrid male sterility seems plausible.

Genetics Home Reference: 21-hydroxylase deficiency

MedlinePlus

... Urinary Tract Defects Orphanet: Congenital adrenal hyperplasia Screening, Technology, and Research in Genetics (PDF) Vanderbilt Childrens Hospital: Congenital Adrenal Hyperplasia (PDF) Virginia Department of ...

[No X-chromosome linked juvenile foveal retinoschisis].

PubMed

Pérez Alvarez, M J; Clement Fernández, F

2002-08-01

To describe the clinical characteristics of two cases of juvenile foveal retinoschisis in women with an atypical hereditary pattern, no X-chromosome linked. An autosomal recessive inheritance is proposed. Two generations of a family (5 members) in which only two sisters were evaluated. The complete examination of these two cases includes retinography, fluorescein angiography, automated perimetry, color vision testing, electroretinogram, electrooculogram and visually evoked potentials. Comparing our cases with the classic form of X-linked juvenile retinoschisis, they are less severely affected. The best visual acuity and the less disturbed or even normal electroretinogram confirm this fact. We emphasise the existence of isolated plaques of retinal pigment epithelium atrophy with perivascular pigment clumps without foveal schisis in one patient, which could represent an evolved form of this entity. The hereditary foveal juvenile retinoschisis in women suggests an autosomal inheritance (autosomal recessive in our cases) and presents less severe involvement (Arch Soc Esp Oftalmol 2002; 77: 443-448).

Congenital toxoplasmosis presenting with fetal atrial flutter after maternal ingestion of infected moose meat.

PubMed

Colosimo, Sarah M; Montoya, Jose G; Westley, Benjamin P; Jacob, Jack; Isada, Nelson B

2013-09-01

Consumption of undercooked game meat during pregnancy is considered a risk factor for congenital toxoplasmosis, but cases definitively linking ingestion of infected meat to clinical disease are lacking. We report a confirmed case of congenital toxoplasmosis identified because of atrial flutter in the fetus and linked to maternal consumption of Toxoplasma gondii PCR-positive moose meat.

[Correlations between the hypothalamo-pituitary-adrenal axis and the metabolic syndrome].

PubMed

Góth, Miklós; Hubina, Erika; Korbonits, Márta

2005-01-09

The metabolic syndrome has several similarities with Cushing's syndrome (impaired glucose tolerance, hypertension, dyslipidemia, central obesity) suggesting that abnormalities in the regulation of the hypothalamic-pituitary-adrenal axis may have a link with the metabolic syndrome. Several studies suggested an association between the clinical signs of the metabolic syndrome and the increased hypothalamic-pituitary-adrenal axis activity based on increased cortisol concentration at 09.00 a.m. and increased cortisol response to corticotropin. According to the Barker hypothesis the fetal malnutrition could determine adult cardiovascular diseases (coronary heart disease, hypertension), some endocrine and metabolic disorders (obesity, type 2 diabetes and hyperlipidemia). The suggested mechanism of the phenomenon is that the suboptimal fetal nutrition results in glucocorticoid overproduction. The 11beta-hydroxysteroid dehydrogenase (converts biological inactive cortisone to cortisol and vice versa) is an important enzyme in cortisol metabolism. The increased expression of 11beta-hydroxysteroid dehydrogenase type 1 in fat tissue could lead to central obesity and impaired glucose tolerance. The hypothesis that increased corticotropin-releasing hormone production drives the overactive hypothalamo-pituitary-adrenal axis was not proven. Further investigations are needed to identify additional pathogenetic factors and to find new therapeutic possibilities.

Steroid Profiling by Gas Chromatography–Mass Spectrometry and High Performance Liquid Chromatography–Mass Spectrometry for Adrenal Diseases

PubMed Central

McDonald, Jeffrey G.; Matthew, Susan

2012-01-01

The ability to measure steroid hormone concentrations in blood and urine specimens is central to the diagnosis and proper treatment of adrenal diseases. The traditional approach has been to assay each steroid hormone, precursor, or metabolite using individual aliquots of serum, each with a separate immunoassay. For complex diseases, such as congenital adrenal hyperplasia and adrenocortical cancer, in which the assay of several steroids is essential for management, this approach is time consuming and costly, in addition to using large amounts of serum. Gas chromatography/mass spectrometry profiling of steroid metabolites in urine has been employed for many years but only in a small number of specialized laboratories and suffers from slow throughput. The advent of commercial high-performance liquid chromatography instruments coupled to tandem mass spectrometers offers the potential for medium- to high-throughput profiling of serum steroids using small quantities of sample. Here, we review the physical principles of mass spectrometry, the instrumentation used for these techniques, the terminology used in this field and applications to steroid analysis. PMID:22170384

Renin knockout rat: control of adrenal aldosterone and corticosterone synthesis in vitro and adrenal gene expression

PubMed Central

Gehrand, Ashley; Bruder, Eric D.; Hoffman, Matthew J.; Engeland, William C.; Moreno, Carol

2014-01-01

The classic renin-angiotensin system is partly responsible for controlling aldosterone secretion from the adrenal cortex via the peptide angiotensin II (ANG II). In addition, there is a local adrenocortical renin-angiotensin system that may be involved in the control of aldosterone synthesis in the zona glomerulosa (ZG). To characterize the long-term control of adrenal steroidogenesis, we utilized adrenal glands from renin knockout (KO) rats and compared steroidogenesis in vitro and steroidogenic enzyme expression to wild-type (WT) controls (Dahl S rat). Adrenal capsules (ZG; aldosterone production) and subcapsules [zona reticularis/fasciculata (ZFR); corticosterone production] were separately dispersed and studied in vitro. Plasma renin activity and ANG II concentrations were extremely low in the KO rats. Basal and cAMP-stimulated aldosterone production was significantly reduced in renin KO ZG cells, whereas corticosterone production was not different between WT and KO ZFR cells. As expected, adrenal renin mRNA expression was lower in the renin KO compared with the WT rat. Real-time PCR and immunohistochemical analysis showed a significant decrease in P450aldo (Cyp11b2) mRNA and protein expression in the ZG from the renin KO rat. The reduction in aldosterone synthesis in the ZG of the renin KO adrenal seems to be accounted for by a specific decrease in P450aldo and may be due to the absence of chronic stimulation of the ZG by circulating ANG II or to a reduction in locally released ANG II within the adrenal gland. PMID:25394830

Equine fetal adrenal, gonadal and placental steroidogenesis.

PubMed

Legacki, Erin L; Ball, Barry A; Corbin, C Jo; Loux, Shavahn C; Scoggin, Kirsten E; Stanley, Scott D; Conley, Alan J

2017-10-01

Equine fetuses have substantial circulating pregnenolone concentrations and thus have been postulated to provide significant substrate for placental 5α-reduced pregnane production, but the fetal site of pregnenolone synthesis remains unclear. The current studies investigated steroid concentrations in blood, adrenal glands, gonads and placenta from fetuses (4, 6, 9 and 10 months of gestational age (GA)), as well as tissue steroidogenic enzyme transcript levels. Pregnenolone and dehydroepiandrosterone (DHEA) were the most abundant steroids in fetal blood, pregnenolone was consistently higher but decreased progressively with GA. Tissue steroid concentrations generally paralleled those in serum with time. Adrenal and gonadal tissue pregnenolone concentrations were similar and 100-fold higher than those in allantochorion. DHEA was far higher in gonads than adrenals and progesterone was higher in adrenals than gonads. Androstenedione decreased with GA in adrenals but not in gonads. Transcript analysis generally supported these data. CYP17A1 was higher in fetal gonads than adrenals or allantochorion, and HSD3B1 was higher in fetal adrenals and allantochorion than gonads. CYP11A1 transcript was also significantly higher in adrenals and gonads than allantochorion and CYP19 and SRD5A1 transcripts were higher in allantochorion than either fetal adrenals or gonads. Given these data, and their much greater size, the fetal gonads are the source of DHEA and likely contribute more than fetal adrenal glands to circulating fetal pregnenolone concentrations. Low CYP11A1 but high HSD3B1 and SRD5A1 transcript abundance in allantochorion, and low tissue pregnenolone, suggests that endogenous placental pregnenolone synthesis is low and likely contributes little to equine placental 5α-reduced pregnane secretion. © 2017 Society for Reproduction and Fertility.

Toxic effects of X-linked adrenoleukodystrophy-associated, very long chain fatty acids on glial cells and neurons from rat hippocampus in culture.

PubMed

Hein, Sabine; Schönfeld, Peter; Kahlert, Stefan; Reiser, Georg

2008-06-15

Saturated very long chain fatty acids (VLCFAs; > or =C22:0) accumulate in X-linked adrenoleukodystrophy (X-ALD, OMIM 300100), a severe hereditary neurodegenerative disease, due to peroxisomal impairment. Previous studies analysed the development of X-ALD in humans and gene knockout animal models. However, the toxic effect of VLCFA leading to severe symptoms with progressive and multifocal demyelination, adrenal insufficiency and inflammation still remains unclear. To understand the toxic effects of VLCFA in the brain, here we exposed neural cells to VLCFA and analysed the cellular consequences. We found that oligodendrocytes and astrocytes challenged with docosanoic- (C22:0), tetracosanoic- (C24:0) and hexacosanoic acids (C24:0) die within 24 h. VLCFA-induced depolarization of mitochondria in situ and increased intracellular Ca2+ level in all three brain cell types provides indications about the mechanism of toxicity of VLCFA. Interestingly, VLCFAs affect to the largest degree the myelin-producing oligodendrocytes. In isolated mitochondria, VLCFAs exert a detrimental effect by affecting the inner mitochondrial membrane and promoting the permeability transition. In conclusion, we suggest that there is a potent toxic activity of VLCFA due to dramatic cell physiological effects with mitochondrial dysfunction and Ca2+ deregulation. This provides the first evidence for mitochondrial-based cell death mechanisms in neurodegenerative disease with peroxisomal defects and subsequent VLCFA accumulation.

Congenital myasthenic syndromes due to mutations in ALG2 and ALG14.

PubMed

Cossins, Judith; Belaya, Katsiaryna; Hicks, Debbie; Salih, Mustafa A; Finlayson, Sarah; Carboni, Nicola; Liu, Wei Wei; Maxwell, Susan; Zoltowska, Katarzyna; Farsani, Golara Torabi; Laval, Steven; Seidhamed, Mohammed Zain; Donnelly, Peter; Bentley, David; McGowan, Simon J; Müller, Juliane; Palace, Jacqueline; Lochmüller, Hanns; Beeson, David

2013-03-01

Congenital myasthenic syndromes are a heterogeneous group of inherited disorders that arise from impaired signal transmission at the neuromuscular synapse. They are characterized by fatigable muscle weakness. We performed linkage analysis, whole-exome and whole-genome sequencing to determine the underlying defect in patients with an inherited limb-girdle pattern of myasthenic weakness. We identify ALG14 and ALG2 as novel genes in which mutations cause a congenital myasthenic syndrome. Through analogy with yeast, ALG14 is thought to form a multiglycosyltransferase complex with ALG13 and DPAGT1 that catalyses the first two committed steps of asparagine-linked protein glycosylation. We show that ALG14 is concentrated at the muscle motor endplates and small interfering RNA silencing of ALG14 results in reduced cell-surface expression of muscle acetylcholine receptor expressed in human embryonic kidney 293 cells. ALG2 is an alpha-1,3-mannosyltransferase that also catalyses early steps in the asparagine-linked glycosylation pathway. Mutations were identified in two kinships, with mutation ALG2p.Val68Gly found to severely reduce ALG2 expression both in patient muscle, and in cell cultures. Identification of DPAGT1, ALG14 and ALG2 mutations as a cause of congenital myasthenic syndrome underscores the importance of asparagine-linked protein glycosylation for proper functioning of the neuromuscular junction. These syndromes form part of the wider spectrum of congenital disorders of glycosylation caused by impaired asparagine-linked glycosylation. It is likely that further genes encoding components of this pathway will be associated with congenital myasthenic syndromes or impaired neuromuscular transmission as part of a more severe multisystem disorder. Our findings suggest that treatment with cholinesterase inhibitors may improve muscle function in many of the congenital disorders of glycosylation.

Variant adrenal venous anatomy in 546 laparoscopic adrenalectomies.

PubMed

Scholten, Anouk; Cisco, Robin M; Vriens, Menno R; Shen, Wen T; Duh, Quan-Yang

2013-04-01

Knowing the types and frequency of adrenal vein variants would help surgeons identify and control the adrenal vein during laparoscopic adrenalectomy. To establish the surgical anatomy of the main vein and its variants for laparoscopic adrenalectomy and to analyze the relationship between variant adrenal venous anatomy and tumor size, pathologic diagnosis, and operative outcomes. In a retrospective review of patients at a tertiary referral hospital, 506 patients underwent 546 consecutive laparoscopic adrenalectomies between April 22, 1993, and October 21, 2011. Patients with variant adrenal venous anatomy were compared with patients with normal adrenal venous anatomy regarding preoperative variables (patient and tumor characteristics [size and location] and clinical diagnosis), intraoperative variables (details on the main adrenal venous drainage, any variant venous anatomy, duration of operation, rate of conversion to hand-assisted or open procedure, and estimated blood loss), and postoperative variables (transfusion requirement, reoperation for bleeding, duration of hospital stay, and histologic diagnosis). Laparoscopic adrenalectomy. Prevalence of variant adrenal venous anatomy and its relationship to tumor characteristics, pathologic diagnosis, and operative outcomes. Variant venous anatomy was encountered in 70 of 546 adrenalectomies (13%). Variants included no main adrenal vein identifiable (n = 18), 1 main adrenal vein with additional small veins (n = 11), 2 adrenal veins (n = 20), more than 2 adrenal veins (n = 14), and variants of the adrenal vein drainage to the inferior vena cava and hepatic vein or of the inferior phrenic vein (n = 7). Variants occurred more often on the right side than on the left side (42 of 250 glands [17%] vs. 28 of 296 glands [9%], respectively; P = .02). Patients with variant anatomy compared with those with normal anatomy had larger tumors (mean, 5.1 vs 3.3 cm, respectively; P < .001), more pheochromocytomas (24 of 70 [35%] vs

Genome-wide misexpression of X-linked versus autosomal genes associated with hybrid male sterility

PubMed Central

Lu, Xuemei; Shapiro, Joshua A.; Ting, Chau-Ti; Li, Yan; Li, Chunyan; Xu, Jin; Huang, Huanwei; Cheng, Ya-Jen; Greenberg, Anthony J.; Li, Shou-Hsien; Wu, Mao-Lien; Shen, Yang; Wu, Chung-I

2010-01-01

Postmating reproductive isolation is often manifested as hybrid male sterility, for which X-linked genes are overrepresented (the so-called large X effect). In contrast, X-linked genes are significantly under-represented among testis-expressing genes. This seeming contradiction may be germane to the X:autosome imbalance hypothesis on hybrid sterility, in which the X-linked effect is mediated mainly through the misexpression of autosomal genes. In this study, we compared gene expression in fertile and sterile males in the hybrids between two Drosophila species. These hybrid males differ only in a small region of the X chromosome containing the Ods-site homeobox (OdsH) (also known as Odysseus) locus of hybrid sterility. Of genes expressed in the testis, autosomal genes were, indeed, more likely to be misexpressed than X-linked genes under the sterilizing action of OdsH. Since this mechanism of X:autosome interaction is only associated with spermatogenesis, a connection between X:autosome imbalance and the high rate of hybrid male sterility seems plausible. PMID:20511493

An acute adrenal insufficiency revealing pituitary metastases of lung cancer in an elderly patient.

PubMed

Marmouch, Hela; Arfa, Sondes; Mohamed, Saoussen Cheikh; Slim, Tensim; Khochtali, Ines

2016-01-01

Metastases of solid tumors to the pituitary gland are often asymptomatic or appereas as with diabetes insipid us. Pituitary metastases more commonly affect the posterior lobe and the infundibulum than the anterior lobe. The presentation with an acute adrenal insufficiency is a rare event. A 69-year-old men presented with vomiting, low blood pressure and hypoglycemia. Hormonal exploration confirmed a hypopituitarism. Appropriate therapy was initiated urgently. The hypothalamic-pituitary MRI showed a pituitary hypertrophy, a nodular thickening of the pituitary stalk. The chest X Rays revealed pulmonary opacity. Computed tomography scan of the chest showed a multiples tumors with mediastinal lymphadenopathy. Bronchoscopy and biopsy demonstrated a pulmonary adenocarcinoma. Hence we concluded to a lung cancer with multiple pituitary and adrenal gland metastases. This case emphasizes the need for an etiological investigation of acute adrenal insufficiency after treatment of acute phase.

An acute adrenal insufficiency revealing pituitary metastases of lung cancer in an elderly patient

PubMed Central

Marmouch, Hela; Arfa, Sondes; Mohamed, Saoussen Cheikh; Slim, Tensim; Khochtali, Ines

2016-01-01

Metastases of solid tumors to the pituitary gland are often asymptomatic or appereas as with diabetes insipid us. Pituitary metastases more commonly affect the posterior lobe and the infundibulum than the anterior lobe. The presentation with an acute adrenal insufficiency is a rare event. A 69-year-old men presented with vomiting, low blood pressure and hypoglycemia. Hormonal exploration confirmed a hypopituitarism. Appropriate therapy was initiated urgently. The hypothalamic-pituitary MRI showed a pituitary hypertrophy, a nodular thickening of the pituitary stalk. The chest X Rays revealed pulmonary opacity. Computed tomography scan of the chest showed a multiples tumors with mediastinal lymphadenopathy. Bronchoscopy and biopsy demonstrated a pulmonary adenocarcinoma. Hence we concluded to a lung cancer with multiple pituitary and adrenal gland metastases. This case emphasizes the need for an etiological investigation of acute adrenal insufficiency after treatment of acute phase. PMID:27200139

Genetics Home Reference: X-linked cardiac valvular dysplasia

MedlinePlus

... inflammation of the inner lining of the heart (endocarditis), abnormal blood clots, or sudden death. X-linked ... Johns Hopkins Medicine: Mitral Valve Prolapse MedlinePlus Encyclopedia: Endocarditis MedlinePlus Encyclopedia: Mitral Valve Prolapse General Information from ...

A phase 2 study of Chronocort, a modified-release formulation of hydrocortisone, in the treatment of adults with classic congenital adrenal hyperplasia.

PubMed

Mallappa, Ashwini; Sinaii, Ninet; Kumar, Parag; Whitaker, Martin J; Daley, Lori-Ann; Digweed, Dena; Eckland, David J A; Van Ryzin, Carol; Nieman, Lynnette K; Arlt, Wiebke; Ross, Richard J; Merke, Deborah P

2015-03-01

Treatment of congenital adrenal hyperplasia (CAH) is suboptimal. Inadequate suppression of androgens and glucocorticoid excess are common and current glucocorticoid formulations cannot replace the cortisol circadian rhythm. The primary objective was to characterize the pharmacokinetic profile of Chronocort, a modified-release hydrocortisone formulation, in adults with CAH. Secondary objectives included examining disease control following 6 months of Chronocort with dose titration. Sixteen adults (eight females) with classic CAH participated in an open-label, nonrandomized, Phase 2 study at the National Institutes of Health Clinical Center. Twenty-four-hour blood sampling was performed on conventional glucocorticoids and following 6 months of Chronocort. Chronocort was initiated at 10 mg (0700 h) and 20 mg (2300 h). Dose titration was performed based on androstenedione and 17-hydroxyprogresterone (17-OHP) levels and clinical symptomatology. The primary outcome was cortisol pharmacokinetics of Chronocort and secondary outcomes included biomarkers of CAH control (androstenedione and 17-OHP). In patients with CAH, Chronocort cortisol profiles were similar to physiologic cortisol secretion. Compared with conventional therapy, 6 months of Chronocort resulted in a decrease in hydrocortisone dose equivalent (28 ± 11.8 vs 25.9 ± 7.1 mg/d), with lower 24-hour (P = .004), morning (0700-1500 h; P = .002), and afternoon (1500-2300 h; P = .011) androstenedione area under the curve (AUC) and lower 24-hour (P = .023) and morning (0700-1500 h; P = .02) 17-OHP AUC. Twice-daily Chronocort approximates physiologic cortisol secretion, and was well tolerated and effective in controlling androgen excess in adults with CAH. This novel hydrocortisone formulation represents a new treatment approach for patients with CAH.

Two-year pilot study of newborn screening for congenital adrenal hyperplasia in New South Wales compared with nationwide case surveillance in Australia.

PubMed

Gleeson, Helena K; Wiley, Veronica; Wilcken, Bridget; Elliott, Elizabeth; Cowell, Christopher; Thonsett, Michael; Byrne, Geoffrey; Ambler, Geoffrey

2008-10-01

To assess the benefits and practicalities of setting up a newborn screening (NBS) program in Australia for congenital adrenal hyperplasia (CAH) through a 2 year pilot screening in ACT/NSW and comparing with case surveillance in other states. The pilot newborn screening occurred between 1/10/95 and 30/9/97 in NSW/ACT. Concurrently, case reporting for all new CAH cases occurred through the Australian Paediatric Surveillance Unit (APSU) across Australia. Details of clinical presentation, re-sampling and laboratory performance were assessed. 185,854 newborn infants were screened for CAH in NSW/ACT. Concurrently, 30 cases of CAH were reported to APSU, twelve of which were from NSW/ACT. CAH incidence was 1 in 15 488 (screened population) vs 1 in 18,034 births (unscreened) (difference not significant). Median age of initial notification was day 8 with confirmed diagnosis at 13(5-23) days in the screened population vs 16(7-37) days in the unscreened population (not significant). Of the 5 clinically unsuspected males in the screened population, one had mild salt-wasting by the time of notification, compared with salt-wasting crisis in all 6 males from the unscreened population. 96% of results were reported by day 10. Resampling was requested in 637 (0.4%) and median re-sampling delay was 11(0-28) days with higher resample rates in males (p < 0.0001). The within-laboratory cost per case of clinically unsuspected cases was A$42 717. There seems good justification for NBS for CAH based on clear prevention of salt-wasting crises and their potential long-term consequences. Also, prospects exist for enhancing screening performance.

Bilateral adrenal masses: a single-centre experience

PubMed Central

Bandgar, Tushar; Khare, Shruti; Jadhav, Swati; Lila, Anurag; Goroshi, Manjunath; Kasaliwal, Rajeev; Khadilkar, Kranti; Shah, Nalini S

2016-01-01

Background Bilateral adrenal masses may have aetiologies like hyperplasia and infiltrative lesions, besides tumours. Hyperplastic and infiltrative lesions may have coexisting hypocortisolism. Bilateral tumours are likely to have hereditary/syndromic associations. The data on clinical profile of bilateral adrenal masses are limited. Aims To analyse clinical, biochemical and radiological features, and management outcomes in patients with bilateral adrenal masses. Methods Retrospective analysis of 70 patients with bilateral adrenal masses presenting to a single tertiary care endocrine centre from western India (2002–2015). Results The most common aetiology was pheochromocytoma (40%), followed by tuberculosis (27.1%), primary adrenal lymphoma (PAL) (10%), metastases (5.7%), non-functioning adenomas (4.3%), primary bilateral macronodular adrenal hyperplasia (4.3%), and others (8.6%). Age at presentation was less in patients with pheochromocytoma (33 years) and tuberculosis (41 years) compared with PAL (48 years) and metastases (61 years) (P<0.001). The presenting symptoms for pheochromocytoma were hyperadrenergic spells (54%) and abdominal pain (29%), whereas tuberculosis presented with adrenal insufficiency (AI) (95%). The presenting symptoms for PAL were AI (57%) and abdominal pain (43%), whereas all cases of metastasis had abdominal pain. Mean size of adrenal masses was the largest in lymphoma (5.5cm) followed by pheochromocytoma (4.8cm), metastasis (4cm) and tuberculosis (2.1cm) (P<0.001). Biochemically, most patients with pheochromocytoma (92.8%) had catecholamine excess. Hypocortisolism was common in tuberculosis (100%) and PAL (71.4%) and absent with metastases (P<0.001). Conclusion In evaluation of bilateral adrenal masses, age at presentation, presenting symptoms, lesion size, and biochemical features are helpful in delineating varied underlying aetiologies. PMID:27037294

Clinical and genetic features in autosomal recessive and X-linked Alport syndrome.

PubMed

Wang, Yanyan; Sivakumar, Vanessa; Mohammad, Mardhiah; Colville, Deb; Storey, Helen; Flinter, Frances; Dagher, Hayat; Savige, Judy

2014-03-01

This study determined the family history and clinical features that suggested autosomal recessive rather than X-linked Alport syndrome. All patients had the diagnosis of Alport syndrome and the mode of inheritance confirmed by genetic testing, and underwent examination at a single centre. Patients comprised 9 males and 6 females with autosomal recessive Alport syndrome, and 18 males and 22 females with X-linked disease. Fourteen (93 %) individuals with autosomal recessive Alport syndrome developed early end-stage renal failure, all 15 had hearing loss, and most had lenticonus (12, 80 %), and a central (13, 87 %) or peripheral (13, 87 %) retinopathy. These features occurred as often as in males with X-linked disease. Females with autosomal recessive inheritance were less likely to have an affected family member in another generation (p = 0.01) than females with X-linked disease. They were more likely to have renal failure (p = 0.003), hearing loss (p = 0.02) and lenticonus (p < 0.001). Fifty percent had a central retinopathy compared with 18 % with X-linked disease (p = 0.14), but peripheral retinopathy prevalence was not different (p = 0.64). Nonsense mutations accounted for 67 % (8/12) of these disease-causing mutations. Autosomal recessive inheritance is increased in females with Alport syndrome and early onset renal failure, hearing loss, lenticonus, and, possibly, central retinopathy.

[Hemorrhagic adrenal pseudocyst: case report].

PubMed

Basile, G; Buffone, A; Cicciarella, G; di Mari, P; Cirino, E

2004-01-01

Adrenal cysts are usually asymptomatic; they are usually identified occasionally during ultrasound or C.T. scans (incidentaloma). Among adrenal cysts the most common types are epithelial cysts and pseudocysts. Intracystic haemorrhage is one of the possible complications of adrenal pseudocysts. We report a case of a young woman with right superior abdominal pain, fever and acute anemia. A C.T. scan showed a 10 cm. mass between the liver and the right kidney. To be sure of the nature of this mass also M.R., urography and C.T.-guided biopsy were carried out. This latter only let us make the final diagnosis of hemorrhagic adrenal pseudocyst. Thereafter, a laparotomic right adrenalectomy was performed, with full recovery of the patient. Adrenal cysts may cause differential diagnostic problems with masses of contiguous organs like kidney, liver and gallbladder. For this reason, ultrasound and C.T. scans may not be sufficient and must be completed by M.R., urography and/or C.T.-guided biopsy. Intracystic hamorrhage, spontaneous or post-traumatic, may cause to the patient acute anemia which, as soon as the diagnosis is confirmed, indicates surgery. The operation usually is a laparotomic adrenalectomy, since the laparoscopic approach is not sufficient to control large masses with active bleeding inside.

Genetics Home Reference: congenital bilateral absence of the vas deferens

MedlinePlus

... Pathway of sperm (image) Health Topic: Assisted Reproductive Technology Health Topic: Male Infertility Genetic and Rare Diseases Information Center (1 link) Congenital bilateral absence of the vas deferens Educational Resources (3 links) American Society for Reproductive Medicine: ...

Clinicopathological correlates of adrenal Cushing's syndrome.

PubMed

Duan, Kai; Hernandez, Karen Gomez; Mete, Ozgur

2015-06-01

Endogenous Cushing's syndrome is a rare endocrine disorder that incurs significant cardiovascular morbidity and mortality, due to glucocorticoid excess. It comprises adrenal (20%) and non-adrenal (80%) aetiologies. While the majority of cases are attributed to pituitary or ectopic corticotropin (ACTH) overproduction, primary cortisol-producing adrenal cortical lesions are increasingly recognised in the pathophysiology of Cushing's syndrome. Our understanding of this disease has progressed substantially over the past decade. Recently, important mechanisms underlying the pathogenesis of adrenal hypercortisolism have been elucidated with the discovery of mutations in cyclic AMP signalling (PRKACA, PRKAR1A, GNAS, PDE11A, PDE8B), armadillo repeat containing 5 gene (ARMC5) a putative tumour suppressor gene, aberrant G-protein-coupled receptors, and intra-adrenal secretion of ACTH. Accurate subtyping of Cushing's syndrome is crucial for treatment decision-making and requires a complete integration of clinical, biochemical, imaging and pathology findings. Pathological correlates in the adrenal glands include hyperplasia, adenoma and carcinoma. While the most common presentation is diffuse adrenocortical hyperplasia secondary to excess ACTH production, this entity is usually treated with pituitary or ectopic tumour resection. Therefore, when confronted with adrenalectomy specimens in the setting of Cushing's syndrome, surgical pathologists are most commonly exposed to adrenocortical adenomas, carcinomas and primary macronodular or micronodular hyperplasia. This review provides an update on the rapidly evolving knowledge of adrenal Cushing's syndrome and discusses the clinicopathological correlations of this important disease. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Clinicopathological correlates of adrenal Cushing's syndrome.

PubMed

Duan, Kai; Gomez Hernandez, Karen; Mete, Ozgur

2015-03-01

Endogenous Cushing's syndrome is a rare endocrine disorder that incurs significant cardiovascular morbidity and mortality, due to glucocorticoid excess. It comprises adrenal (20%) and non-adrenal (80%) aetiologies. While the majority of cases are attributed to pituitary or ectopic corticotropin (ACTH) overproduction, primary cortisol-producing adrenal cortical lesions are increasingly recognised in the pathophysiology of Cushing's syndrome. Our understanding of this disease has progressed substantially over the past decade. Recently, important mechanisms underlying the pathogenesis of adrenal hypercortisolism have been elucidated with the discovery of mutations in cyclic AMP signalling (PRKACA, PRKAR1A, GNAS, PDE11A, PDE8B), armadillo repeat containing 5 gene (ARMC5) a putative tumour suppressor gene, aberrant G-protein-coupled receptors, and intra-adrenal secretion of ACTH. Accurate subtyping of Cushing's syndrome is crucial for treatment decision-making and requires a complete integration of clinical, biochemical, imaging and pathology findings. Pathological correlates in the adrenal glands include hyperplasia, adenoma and carcinoma. While the most common presentation is diffuse adrenocortical hyperplasia secondary to excess ACTH production, this entity is usually treated with pituitary or ectopic tumour resection. Therefore, when confronted with adrenalectomy specimens in the setting of Cushing's syndrome, surgical pathologists are most commonly exposed to adrenocortical adenomas, carcinomas and primary macronodular or micronodular hyperplasia. This review provides an update on the rapidly evolving knowledge of adrenal Cushing's syndrome and discusses the clinicopathological correlations of this important disease. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

[Progress in diagnosis and treatment of adrenal metastases tumor].

PubMed

Wu, Chu-jun; Qiu, Min; Ma, Lu-lin

2015-08-18

The adrenal gland is a common site of metastases, only second to pulmonary, liver and bone. The prevalence of adrenal metastases in patients with a history of cancer is between 10%-25%.The most common sites of origin are cancers of the lung, kidney, breast, gastrointestinal tract, and skin (melanoma).The mainstays of adrenal metastases diagnosis are computerized tomogramphy (CT), magnetic resonance imaging (MRI), and positron emission tomogramphy (PET). All patients should undergo complete hormonal evaluation to rule out functional adrenal tumors. Adrenal biopsy should be reserved for cases in which the results of non-invasive techniques are equivocal. In patients with isolated adrenal metastases, adrenalectomy is recommended, because of improved overall survival. For the patient with unresectable adrenal metastases tumor, radiotherapy and ablative therapy are feasible and useful methods for controlling adrenal metastases and offer patients opportunities for improved survival.

Genetics Home Reference: Fukuyama congenital muscular dystrophy

MedlinePlus

... Fujii T, Aiba H, Toda T. Seizure-genotype relationship in Fukuyama-type congenital muscular dystrophy. Brain Dev. ... for Links Data Files & API Site Map Subscribe Customer Support USA.gov Copyright Privacy Accessibility FOIA Viewers & ...

X-linked mental retardation associated with macro-orchidism.

PubMed Central

Turner, G; Eastman, C; Casey, J; McLeay, A; Procopis, P; Turner, B

1975-01-01

Two families are described with an X-linked form of mental retardation in whom the affected males were found to have bilateral enlargement of the testes. No conclusive evidence of any endocrinological disturbance was found. Images PMID:1240971

Editorial: X-chromosome-linked Kallmann's syndrome: Pathology at the molecular level

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

Prager, D.; Braunstein, G.D.

Kallmann's syndrome or olfactogenital dysplasia refers to a disorder characterized by hypogonadotropic hypogonadism and anosmia or hyposmia which can occur sporadically or in a familial setting. Originally described in 1856, the first familial cases were reported by Kallmann et al., in 1944. Based on segregation analysis of multiple families, three modes of transmission have been documented: X-linked, autosomal dominant with variable penetrance, and autosomal recessive. Kallmann's syndrome occurs in less than 1 in 10,000 male births, with a 5-fold excess of affected males to females, suggesting that the X-linked form is the most frequent. By genetic linkage analysis the X-linkedmore » form of Kallmann's syndrome was localized to Xp22.3. This was confirmed by the description of patients with contiguous gene syndromes due to deletions of various portions of the distal short arm of the X-chromosome. Such patients present with complex phenotypes characterized by a combination of Kallmann's syndrome with X-linked icthyosis due to steroid sulfatase deficiency, chondrodysplasia punctata, short stature, and mental retardation. DNA analysis has identified and mapped the genes responsible for these disorders. 10 refs., 1 fig., 1 tab.« less

European Adrenal Insufficiency Registry (EU-AIR): a comparative observational study of glucocorticoid replacement therapy.

PubMed

Ekman, Bertil; Fitts, David; Marelli, Claudio; Murray, Robert D; Quinkler, Marcus; Zelissen, Pierre M J

2014-05-09

Increased morbidity and mortality associated with conventional glucocorticoid replacement therapy for primary adrenal insufficiency (primary AI; estimated prevalence 93-140/million), secondary AI (estimated prevalence, 150-280/million, respectively) or congenital adrenal hyperplasia (estimated prevalence, approximately 65/million) may be due to the inability of typical glucocorticoid treatment regimens to reproduce the normal circadian profile of plasma cortisol. A once-daily modified-release formulation of hydrocortisone has been developed to provide a plasma cortisol profile that better mimics the daytime endogenous profile of cortisol. Here, we describe the protocol for the European Adrenal Insufficiency Registry (EU-AIR), an observational study to assess the long-term safety of modified-release hydrocortisone compared with conventional glucocorticoid replacement therapies in routine clinical practice (ClinicalTrials.gov identifier: NCT01661387). Patients enrolled in EU-AIR have primary or secondary AI and are receiving either modified-release or conventional glucocorticoid replacement therapy. The primary endpoints of EU-AIR are the incidence of intercurrent illness, adrenal crisis and serious adverse events (SAEs), as well as the duration of SAEs and dose changes related to SAEs. Data relating to morbidity, mortality, adverse drug reactions, dosing and concomitant therapies will be collected. Patient diaries will record illness-related dose changes between visits. All decisions concerning medical care are made by the registry physician and patient. Enrolment is targeted at achieving 3600 patient-years of treatment (1800 patient-years per group) for the primary analysis, which is focused on determining the non-inferiority of once-daily modified-release replacement therapy compared with conventional glucocorticoid therapy. Recruitment began in August 2012 and, as of March 2014, 801 patients have been enrolled. Fifteen centres are participating in Germany, the UK

Adrenal clocks and the role of adrenal hormones in the regulation of circadian physiology.

PubMed

Leliavski, Alexei; Dumbell, Rebecca; Ott, Volker; Oster, Henrik

2015-02-01

The mammalian circadian timing system consists of a master pacemaker in the suprachiasmatic nucleus (SCN) and subordinate clocks that disseminate time information to various central and peripheral tissues. While the function of the SCN in circadian rhythm regulation has been extensively studied, we still have limited understanding of how peripheral tissue clock function contributes to the regulation of physiological processes. The adrenal gland plays a special role in this context as adrenal hormones show strong circadian secretion rhythms affecting downstream physiological processes. At the same time, they have been shown to affect clock gene expression in various other tissues, thus mediating systemic entrainment to external zeitgebers and promoting internal circadian alignment. In this review, we discuss the function of circadian clocks in the adrenal gland, how they are reset by the SCN and may further relay time-of-day information to other tissues. Focusing on glucocorticoids, we conclude by outlining the impact of adrenal rhythm disruption on neuropsychiatric, metabolic, immune, and malignant disorders. © 2014 The Author(s).

Image-Guided Ablation of Adrenal Lesions

PubMed Central

Yamakado, Koichiro

2014-01-01

Although laparoscopic adrenalectomy has remained the standard of care for the treatment for adrenal tumors, percutaneous image-guided ablation therapy, such as chemical ablation, radiofrequency ablation, cryoablation, and microwave ablation, has been shown to be clinically useful in many nonsurgical candidates. Ablation therapy has been used to treat both functioning adenomas and malignant tumors, including primary adrenal carcinoma and metastasis. For patients with functioning adenomas, biochemical and symptomatic improvement is achieved in 96 to 100% after ablation; for patients with malignant adrenal neoplasms, however, the survival benefit from ablation therapy remains unclear, though good initial results have been reported. This article outlines the current role of ablation therapy for adrenal lesions, as well as identifying some of the technical considerations for this procedure. PMID:25049444

Xenopus: An Emerging Model for Studying Congenital Heart Disease

PubMed Central

Kaltenbrun, Erin; Tandon, Panna; Amin, Nirav M.; Waldron, Lauren; Showell, Chris; Conlon, Frank L.

2011-01-01

Congenital heart defects affect nearly 1% of all newborns and are a significant cause of infant death. Clinical studies have identified a number of congenital heart syndromes associated with mutations in genes that are involved in the complex process of cardiogenesis. The African clawed frog, Xenopus, has been instrumental in studies of vertebrate heart development and provides a valuable tool to investigate the molecular mechanisms underlying human congenital heart diseases. In this review, we discuss the methodologies that make Xenopus an ideal model system to investigate heart development and disease. We also outline congenital heart conditions linked to cardiac genes that have been well-studied in Xenopus and describe some emerging technologies that will further aid in the study of these complex syndromes. PMID:21538812

Diagnosis and classification of Addison's disease (autoimmune adrenalitis).

PubMed

Brandão Neto, Rodrigo Antonio; de Carvalho, Jozélio Freire

2014-01-01

Autoimmune adrenalitis, or autoimmune Addison disease (AAD), is the most prevalent cause of primary adrenal insufficiency in the developed world. AAD is rare and can easily be misdiagnosed as other conditions. The diagnosis depends on demonstrating inappropriately low cortisol production and the presence of high titers of adrenal cortex autoantibodies (ACAs), along with excluding other causes of adrenal failure using other tests as necessary. The treatment corticosteroid replacement, and the prognosis following the treatment is the same as the normal population. Spontaneous recovery of adrenal function has been described but is rare. Copyright © 2014 Elsevier B.V. All rights reserved.

Radioguided Adrenal Surgery

PubMed Central

Deus, Javier; Millera, Alfonso; Andrés, Alejandro; Prats, Enrique; Gil, Ismael; Suarez, Manuel; Salcini, José L.; Lahoz, Manuel

2015-01-01

Abstract The laparoscopic adrenalectomy is considered as the procedure of choice for the treatment of adrenal hyperplasia and tumor lesions. However, some special situations may limit the use of this method due to the difficulty to locate the gland and perform the lesion excision. We analyze 2 patients of a left adrenal tumor, explaining how they have overcome the difficulties in both situations. The first case was a patient with a history of intra-abdominal surgery and the other patient suffered from severe obesity. We performed with the use of the gamma probe, and the 2 cases, was of great help to access and glandular localization. The help of gamma probe test was achieved in the surgical bed, that removal was complete. The use of the portable gamma probe facilitated the access to the left adrenal gland as well as conducting the glandular excision without delay, despite the difficulties due to the intra abdominal surgery caused by the previous surgery, and in the case of severe obesity. PMID:26426608

Effects of cytokines on the pituitary-adrenal axis in cancer patients.

PubMed

Nolten, W E; Goldstein, D; Lindstrom, M; McKenna, M V; Carlson, I H; Trump, D L; Schiller, J; Borden, E C; Ehrlich, E N

1993-10-01

Cytokines, which include interferons (IFNs), interleukins (ILs), and tumor necrosis factor (TNF), are immunoregulatory proteins produced by lymphocytes and inflammatory cells. Several cytokines, most noteworthy IFNs and ILs, stimulate glucocorticoid secretion. In this study, the effects of variable doses and repetitive administration of IFNs and TNF on secretion of pituitary hormones and cortisol were measured. Patients were given for a period of 15 days on alternating days injections of IFN-beta (IFN-beta ser), 90 or 450 x 10(6) IU, IFN-gamma, 0.1-100 x 10(6) IU, or TNF 125-275 micrograms/m2. Sixty to 120 min after IFN-beta ser injection median levels of cortisol, adrenocorticotropin (ACTH), prolactin (PRL), and growth hormone (GH) rose two-fold. Urinary free cortisol excretion increased significantly during the day following IFN-beta ser administration. IFN-gamma > or = 30 x 10(6) IU caused a comparable rise in plasma cortisol. TNF induced two- to four-fold increases in ACTH and cortisol. The fact that increased cortisol secretion was associated with a rise in the level of ACTH as well as PRL and GH suggests that the cytokines increased cortisol by stimulating the anterior pituitary. The hormonal response induced by cytokines was unrelated to their pyrogenic effect, undiminished with repetitive treatment, and not dose-dependent above a threshold level. These observations reinforce the concept of a physiologic link between the immune system and the hypothalamic-pituitary-adrenal (HPA) axis.

In vivo effects of chronic contamination with 137 cesium on testicular and adrenal steroidogenesis.

PubMed

Grignard, Elise; Guéguen, Yann; Grison, Stéphane; Lobaccaro, Jean-Marc A; Gourmelon, Patrick; Souidi, Maâmar

2008-09-01

More than 20 years after Chernobyl nuclear power plant explosion, radionuclides are still mainly bound to the organic soil layers. The radiation exposure is dominated by the external exposure to gamma-radiation following the decay of (137)Cs and by soil-to-plant-to-human transfer of (137)Cs into the food chain. Because of this persistence of contamination with (137)Cs, questions regarding public health for people living in contaminated areas were raised. We investigated the biological effects of chronic exposure to (137)Cs on testicular and adrenal steroidogenesis metabolisms in rat. Animals were exposed to radionuclide in their drinking water for 9 months at a dose of 6,500 Bq/l (610 Bq/kg/day). Cesium contamination decreases the level of circulating 17beta-estradiol, and increases corticosterone level. In testis, several nuclear receptors messenger expression is disrupted; levels of mRNA encoding Liver X receptor alpha (LXRalpha) and LXRbeta are increased, whereas farnesoid X receptor mRNA presents a lower level. Adrenal metabolism presents a paradoxical decrease in cyp11a1 gene expression. In conclusion, our results show for the first time molecular and hormonal modifications in testicular and adrenal steroidogenic metabolism, induced by chronic contamination with low doses of (137)Cs.

A cAMP-specific phosphodiesterase (PDE8B) that is mutated in adrenal hyperplasia is expressed widely in human and mouse tissues: a novel PDE8B isoform in human adrenal cortex

PubMed Central

Horvath, Anelia; Giatzakis, Christoforos; Tsang, Kitman; Greene, Elizabeth; Osorio, Paulo; Boikos, Sosipatros; Libè, Rossella; Patronas, Yianna; Robinson-White, Audrey; Remmers, Elaine; Bertherat, Jerôme; Nesterova, Maria; Stratakis, Constantine A.

2009-01-01

Bilateral adrenocortical hyperplasia (BAH) is the second most common cause of corticotropin-independent Cushing syndrome (CS). Genetic forms of BAH have been associated with complex syndromes such as Carney Complex and McCune Albright syndrome or may present as isolated micronodular adrenocortical disease (iMAD) usually in children and young adults with CS. A genome-wide association study identified inactivating phosphodiesterase (PDE) 11A (PDE11A) sequencing defects as low-penetrance predisposing factors for iMAD and related abnormalities; we also described a mutation (c.914A>C/H305P) in cAMP-specific PDE8B, in a patient with iMAD. In this study we further characterize this mutation; we also found a novel PDE8B isoform, highly expressed in the adrenal gland. This mutation is shown to significantly affect the ability of the protein to degrade cAMP in vitro. Tumor tissues from patients with iMAD and no mutations in the coding PDE8B sequence or any other related genes (PRKAR1A, PDE11A) showed down-regulated PDE8B expression (compared to normal adrenal cortex). Pde8b is detectable in the adrenal gland of newborn mice and is widely expressed in other mouse tissues. We conclude that PDE8B is another PDE gene linked to iMAD; it is a candidate causative gene for other adrenocortical lesions linked to the cAMP-signaling pathway, and possibly for tumors in other tissues. PMID:18431404

Relation of adrenal-derived steroids with bone maturation, mineral density and geometry in healthy prepubertal and early pubertal boys.

PubMed

Vandewalle, S; Taes, Y; Fiers, T; Toye, K; Van Caenegem, E; Kaufman, J-M; De Schepper, J

2014-12-01

Little is known about the effects of adrenal steroids on skeletal maturation and bone mass acquisition in healthy prepubertal boys. To study whether adrenal-derived steroids within the physiological range are associated with skeletal maturation, areal and volumetric bone mineral density (aBMD and vBMD) and bone geometry in healthy prepubertal and early pubertal boys. 98 healthy prepubertal and early pubertal boys (aged 6-14 y) were studied cross-sectionally. Androstenedione (A) and estrone (E1) were determined by liquid chromatography tandem mass spectrometry and DHEAS was determined by immunoassay. Whole body and lumbar spine aBMD and bone area were determined by dual-energy X-ray absorptiometry. Trabecular (distal site) and cortical (proximal site) vBMD and bone geometry were assessed at the non-dominant forearm and leg using peripheral QCT. Skeletal age was determined by X-ray of the left hand. Adrenal-derived steroids (DHEAS, A and E1) are positively associated with bone age in prepubertal and early pubertal children, independently of age. There are no associations between the adrenal-derived steroids and the studied parameters of bone size (lumbar spine and whole body bone area, trabecular or cortical area at the radius or tibia, periosteal circumference and cortical thickness at the radius or tibia) or BMD (aBMD or vBMD). In healthy prepubertal and early pubertal boys, serum adrenal-derived steroid levels, are associated with skeletal maturation, independently of age, but not with bone size or (v)BMD. Our data suggest that adrenal derived steroids are not implicated in the accretion of bone mass before puberty in boys. Copyright © 2014 Elsevier Inc. All rights reserved.

The multifocal electroretinogram in X-linked juvenile retinoschisis.

PubMed

Huang, Shizhou; Wu, Dezheng; Jiang, Futian; Luo, Guangwei; Liang, Jiongji; Wen, Feng; Yu, Minzhong; Long, Shixian; Wu, Lezheng

2003-05-01

To measure and compare the multifocal electroretinography in normal control and X-linked juvenile retinoschisis, 13 cases (13 right eyes) of normal control and nine cases (17 eyes) of X-linked juvenile retinoschisis were measured with VERIS Science 4.0. Four cases (eight eyes) out of the nine retinoschisis cases were tested with Ganzfeld ERG at the same day. The results showed statistically significant difference of average response densities and latencies in six ring retinal regions between the normal control and retinoschisis. The trace array and 3-D topography of multifocal ERG showed multi-area amplitude decrease with absence or reduction of central peak amplitude in patients with retinoschisis. The P1/N1 ratio of multifocal ERG average response densities in six ring retinal regions was different from the b/a ratio of Ganzfeld ERG. The multifocal ERG and Ganzfeld ERG each had its advantage in the diagnosis of retinoschisis.

ADC histogram analysis for adrenal tumor histogram analysis of apparent diffusion coefficient in differentiating adrenal adenoma from pheochromocytoma.

PubMed

Umanodan, Tomokazu; Fukukura, Yoshihiko; Kumagae, Yuichi; Shindo, Toshikazu; Nakajo, Masatoyo; Takumi, Koji; Nakajo, Masanori; Hakamada, Hiroto; Umanodan, Aya; Yoshiura, Takashi

2017-04-01

To determine the diagnostic performance of apparent diffusion coefficient (ADC) histogram analysis in diffusion-weighted (DW) magnetic resonance imaging (MRI) for differentiating adrenal adenoma from pheochromocytoma. We retrospectively evaluated 52 adrenal tumors (39 adenomas and 13 pheochromocytomas) in 47 patients (21 men, 26 women; mean age, 59.3 years; range, 16-86 years) who underwent DW 3.0T MRI. Histogram parameters of ADC (b-values of 0 and 200 [ADC 200 ], 0 and 400 [ADC 400 ], and 0 and 800 s/mm 2 [ADC 800 ])-mean, variance, coefficient of variation (CV), kurtosis, skewness, and entropy-were compared between adrenal adenomas and pheochromocytomas, using the Mann-Whitney U-test. Receiver operating characteristic (ROC) curves for the histogram parameters were generated to differentiate adrenal adenomas from pheochromocytomas. Sensitivity and specificity were calculated by using a threshold criterion that would maximize the average of sensitivity and specificity. Variance and CV of ADC 800 were significantly higher in pheochromocytomas than in adrenal adenomas (P < 0.001 and P = 0.001, respectively). With all b-value combinations, the entropy of ADC was significantly higher in pheochromocytomas than in adrenal adenomas (all P ≤ 0.001), and showed the highest area under the ROC curve among the ADC histogram parameters for diagnosing adrenal adenomas (ADC 200 , 0.82; ADC 400 , 0.87; and ADC 800 , 0.92), with sensitivity of 84.6% and specificity of 84.6% (cutoff, ≤2.82) with ADC 200 ; sensitivity of 89.7% and specificity of 84.6% (cutoff, ≤2.77) with ADC 400 ; and sensitivity of 94.9% and specificity of 92.3% (cutoff, ≤2.67) with ADC 800 . ADC histogram analysis of DW MRI can help differentiate adrenal adenoma from pheochromocytoma. 3 J. Magn. Reson. Imaging 2017;45:1195-1203. © 2016 International Society for Magnetic Resonance in Medicine.

Posterior retroperitoneoscopic adrenal surgery for clinical and subclinical Cushing's syndrome in patients with bilateral adrenal disease.

PubMed

Lowery, Aoife J; Seeliger, Barbara; Alesina, Pier F; Walz, Martin K

2017-08-01

The treatment of hypercortisolism for patients with bilateral adrenal disease (BAD) is controversial. Bilateral total adrenalectomy results in permanent hypocortisolaemia requiring lifelong steroid replacement. A more conservative surgical approach, with less than bilateral total adrenalectomy (leaving functional adrenal tissue either unilaterally or bilaterally), represents an alternative option; however, long-term outcome or recurrence data are limited. We report our experience with the surgical management of hypercortisolism caused by BAD. Between 2004 and 2016, 42 patients (12 male, 30 female; mean age 58 ± 10 years) with clinical or subclinical Cushing's syndrome (CS/sCS) caused by BAD underwent adrenal surgery via the posterior retroperitoneoscopic approach. Adrenal surgery was defined as "adrenalectomy" when total gland excision was performed or "resection" when a partial or subtotal adrenal resection was performed. Clinical, radiological and biochemical parameters were evaluated preoperatively and postoperatively. Seventy adrenal operations performed in total included unilateral resection (n = 3), unilateral adrenalectomy (n = 15), bilateral resection (n = 9), adrenalectomy and contralateral resection (n = 14) and bilateral total adrenalectomy (n = 3). Median operating time was 47.5 min (30-150) with no difference between unilateral and bilateral (synchronous included) procedures (p = 0.15). Mortality was zero. Clavien-Dindo grade of postoperative complications was I (n = 5) and IV (n = 3). All but one patient with CS and 17/31 patients with sCS received postoperative steroid supplementation for a median duration of 20 (1.5-129) months. After median follow-up of 40 months (3-129), the remission rate was 92%; 11 patients required ongoing steroid supplementation. There were three biochemical recurrences (two underwent contralateral resection); two patients with new/progressive radiological nodularity are biochemically eucortisolaemic. A

X-Linked Retinoschisis: Phenotypic Variability in a Chinese Family

PubMed Central

Xiao, Yangyan; Liu, Xiao; Tang, Luosheng; Wang, Xia; Coursy, Terry; Guo, Xiaojian; Li, Zhuo

2016-01-01

X-linked juvenile retinoschisis (XLRS), a leading cause of juvenile macular degeneration, is characterized by a spoke-wheel pattern in the macular region of the retina and splitting of the neurosensory retina. Our study is to describe the clinical characteristics of a four generations of this family (a total of 18 members)with X-linked retinoschisis (XLRS) and detected a novel mutations of c.3G > A (p.M1?) in the initiation codon of the RS1 gene. by direct sequencing.Identification of this mutation in this family provides evidence about potential genetic or environmental factors on its phenotypic variance, as patients presented with different phenotypes regardless of having the same mutation. Importantly, OCT has proven vital for XLRS diagnosis in children. PMID:26823236

X-Linked Retinoschisis: Phenotypic Variability in a Chinese Family.

PubMed

Xiao, Yangyan; Liu, Xiao; Tang, Luosheng; Wang, Xia; Coursey, Terry G; Coursy, Terry; Guo, Xiaojian; Li, Zhuo

2016-01-29

X-linked juvenile retinoschisis (XLRS), a leading cause of juvenile macular degeneration, is characterized by a spoke-wheel pattern in the macular region of the retina and splitting of the neurosensory retina. Our study is to describe the clinical characteristics of a four generations of this family (a total of 18 members)with X-linked retinoschisis (XLRS) and detected a novel mutations of c.3G > A (p.M1?) in the initiation codon of the RS1 gene. by direct sequencing.Identification of this mutation in this family provides evidence about potential genetic or environmental factors on its phenotypic variance, as patients presented with different phenotypes regardless of having the same mutation. Importantly, OCT has proven vital for XLRS diagnosis in children.

Adrenal Incidentaloma

MedlinePlus

... or subclinical hypercortisolism: conditions caused by too much cortisol Hyperaldosteronism : too much aldosterone A pheochromocytoma: a rare ... in which the adrenal glands make too little cortisol and aldosterone, and too much androgen Cancer of ...

Experience with long-term glucocorticoid treatment in congenital adrenal hyperplasia: growth pattern compared with genetic height potential.

PubMed

Aycan, Zehra; Ocal, Gonul; Berberoglu, Merih; Cetinkaya, Ergun; Adiyaman, Pelin; Evliyaoglu, Olcay

2006-03-01

Long-term replacement treatment with high doses of steroids in congenital adrenal hyperplasia (CAH) is known to have a negative influence on growth. We evaluated the effects of long-term steroid treatment in patients with classical CAH on height development in relation to genetic height potential. Twenty-three patients with CAH (16 females, 7 males, mean age: 9.8 +/- 3.5 years) were included in this longitudinal study. The effect of steroid treatment on growth was determined by monitoring patients for 8.61 +/- 3.46 years (2-17 years) while they were treated with hydrocortisone at a mean dosage of 17.64 +/- 3.60 mg/m2/day. The height standard deviation scores (Ht-SDS), target Ht-SDS, and corrected Ht-SDS for target height was calculated for all patients. Predicted adult height according to bone age was calculated and it was determined whether height was developing according to the genetic height potential. In addition, patients were grouped as 'tight control' or 'poor control' according to their mean serum 17OH-progesterone or ACTH levels while on treatment. We evaluated whether height development was different for the tight and poor control groups. The mean chronological age of our patients at the time of the study was 9.89 +/- 3.53 years, Ht-SDS -0.77 +/- 1.57, target height (TH) 161.03 +/- 6.54 cm, TH-SDS -0.60 +/- 0.90, predicted height (PH) 157.2 +/- 11.16 cm, PH-SDS -1.1 +/- 1.69, and corrected Ht-SDS -0.75 +/- 1.14. There was no significant difference between the actual Ht-SDS and TH-SDS of our patients (p >0.05) but the corrected Ht-SDS was less than zero. Only 28.5% of our patients had normal height according to their genetic potential while 71.5% were shorter than their genetic height potential. While the Ht-SDS and corrected Ht-SDS were similar in the tight and poor metabolic control groups, the predicted height was significantly greater in the tight control group. We demonstrated that a hydrocortisone dose of 17.64 +/- 3.60 mg/m2/day in classical CAH had

X-linked adrenoleukodystrophy in heterozygous female patients: women are not just carriers.

PubMed

Lourenço, Charles Marques; Simão, Gustavo Novelino; Santos, Antonio Carlos; Marques, Wilson

2012-07-01

X-linked adrenoleukodystrophy (X-ALD) is a recessive X-linked disorder associated with marked phenotypic variability. Female carriers are commonly thought to be normal or only mildly affected, but their disease still needs to be better described and systematized. To review and systematize the clinical features of heterozygous women followed in a Neurogenetics Clinic. We reviewed the clinical, biochemical, and neuroradiological data of all women known to have X-ADL. The nine women identified were classified into three groups: with severe and aggressive diseases; with slowly progressive, spastic paraplegia; and with mildly decreased vibratory sensation, brisk reflexes, and no complaints. Many of these women did not have a known family history of X-ALD. Heterozygous women with X-ADL have a wide spectrum of clinical manifestations, ranging from mild to severe phenotypes.

Congenital abnormalities in Japanese patients with Menkes disease.

PubMed

Gu, Yan-Hong; Kodama, Hiroko; Kato, Tadaaki

2012-10-01

Menkes disease (MNK) is an X-linked recessive disorder. Incidence of live-born infants with MNK is 2.8 per million live births in Japan. The aim of this study was to observe congenital malformations (CMs) in MNK patients. Subjects comprised 35 Japanese male patients with classical MNK who received copper histidine treatment. Patient clinical data were obtained anonymously from medical records or medical record summaries by pediatrician's retrospective review through a survey. We observed 21 different CMs in 14 patients. Eight of these had a single CM, while six had multiple CMs. The most frequent CM was higher arched palate with other CMs found in five patients. There was no relationship between CMs and mutations in the ATP7A gene. Using Mann-Whitney U tests, age at death was also significantly lower in MNK patients with CMs (P<0.05), compared to those without CMs, even though there was no significant difference of age onset, age at diagnosis and age at start of treatment with copper histidine between both groups of patients. Sudden death occurred in three MNK patients with CMs only: two with congenital heart disease, and one with microphallus. Copyright © 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Laparoscopic Adrenalectomy for Adrenal Tumors

PubMed Central

Chuan-yu, Sun; Yat-faat, Ho; Wei-hong, Ding; Yuan-cheng, Gou; Qing-feng, Hu; Ke, Xu; Bin, Gu; Guo-wei, Xia

2014-01-01

Objective. To evaluate the indication and the clinical value of laparoscopic adrenalectomy of different types of adrenal tumor. Methods. From 2009 to 2014, a total of 110 patients were diagnosed with adrenal benign tumor by CT scan and we performed laparoscopic adrenalectomy. The laparoscopic approach has been the procedure of choice for surgery of benign adrenal tumors, and the upper limit of tumor size was thought to be 6 cm. Results. 109 of 110 cases were successful; only one was converted to open surgery due to bleeding. The average operating time and intraoperative blood loss of pheochromocytoma were significantly more than the benign tumors (P < 0.05). After 3 months of follow-up, the preoperative symptoms were relieved and there was no recurrence. Conclusions. Laparoscopic adrenalectomy has the advantages of minimal invasion, less blood loss, fewer complications, quicker recovery, and shorter hospital stay. The full preparation before operation can decrease the average operating time and intraoperative blood loss of pheochromocytomas. Laparoscopic adrenalectomy should be considered as the first choice treatment for the resection of adrenal benign tumor. PMID:25132851

Diagnosis and management of pediatric adrenal insufficiency.

PubMed

Uçar, Ahmet; Baş, Firdevs; Saka, Nurçin

2016-08-01

Adrenal insufficiency (AI) is a wellknown cause of potentially life-threatening disorders. Defects at each level of the hypothalamic-pituitary-adrenal axis can impair adrenal function, leading to varying degrees of glucocorticoid (GC) deficiency. Iatrogenic AI induced by exogenous GCs is the most common cause of AI. The criteria for the diagnosis and management of iatrogenic AI, neonatal AI, and critical illness-related corticosteroid insufficiency (CIRCI) are not clear. We reviewed the recent original publications and classical data from the literature, as well as the clinical, diagnostic and management strategies of pediatric AI. Practical points in the diagnosis and management of AI with an emphasis on iatrogenic AI, neonatal AI, and CIRCI are provided. Given the lack of sensitive and practical biochemical tests for diagnosis of subtle AI, GC treatment has to be tailored to highly suggestive clinical symptoms and signs. Treatment of adrenal crisis is well standardized and patients almost invariably respond well to therapy. It is mainly the delay in treatment that is responsible for mortality in adrenal crisis. Education of patients and health care professionals is mandatory for timely interventions for patients with adrenal crisis.

GLUCOCORTICOID TREATMENT—EFFECT ON ADRENAL MEDULLARY CATECHOLAMINE PRODUCTION

PubMed Central

Sharara-Chami, Rana I.; Joachim, Maria; Pacak, Karel; Majzoub, Joseph A.

2016-01-01

Glucocorticoid and epinephrine are important stress hormones secreted from the adrenal gland during critical illness. Adrenal glucocorticoid stimulates phenylethanolamine N-methyltransferase (PNMT) to convert norepinephrine to epinephrine in the adrenal medulla. Glucocorticoid is sometimes used in catecholamine-resistant septic shock in critically ill patients. By suppressing adrenal glucocorticoid production, glucocorticoid therapy might also reduce the secretion of epinephrine during stress. To investigate this, we used a mouse model subjected to glucocorticoid therapy under basal conditions (experiment 1) and during stress (experiment 2). In experiment 1, pellets containing 0% to 8% dexamethasone were implanted subcutaneously in mice for 4 weeks. In experiment 2, animals received 14 days of intraperitoneal injections of normal saline, low- or high-dose dexamethasone, followed by 2 h of restraint. We found that in experiment 1, adrenal corticosterone did not differ with dexamethasone treatment. Phenylethanolamine N-methyltransferase messenger RNA levels and adrenal catecholamines were highest in the 8% dexamethasone group. Compared with experiment 1, restrained control mice in experiment 2 had high adrenal corticosterone, which decreased with dexamethasone. Phenylethanolamine N-methyltransferase messenger RNA content doubled with restraint but decreased with dexamethasone treatment. As in experiment 1, adrenal catecholamine content increased significantly with dexamethasone treatment. We conclude that without stress, when adrenocorticotropic hormone is low, high doses of exogenous dexamethasone stimulate PNMT and catecholamine synthesis, likely independently of adrenal corticosterone concentration. After stress, adrenocorticotropic hormone levels are elevated, and exogenous dexamethasone suppresses endogenous corticosterone and PNMT production. Nonetheless, catecholamines increase, possibly due to direct neural stimulation, which may override the hormonal

A sup 125 I-radioimmunoassay for measuring androstenedione in serum and in blood-spot samples from neonates

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

Thomson, S.; Wallace, A.M.; Cook, B.

1989-08-01

We developed a radioimmunoassay with a gamma-emitting radioligand to measure androstenedione in human serum and in dried blood-spot samples from newborns. Antisera were raised in rabbits against androstenedione linked to bovine serum albumin at positions 3, 6, or 11 on the steroid nucleus. Radioligands were prepared by linking ({sup 125}I)iodohistamine at positions 3, 6, or 11. Linkages were through either carboxymethyloxime or hemisuccinate bridges. All label and antibody combinations were examined, and the most sensitive and specific combination (antiserum raised against androstenedione-3-carboxymethyloxime-bovine serum albumin with an androstenedione-carboxymethyloxime-({sup 125}I)iodohistamine label) was selected for full evaluation. We report the performance of thesemore » selected reagents in an immunoassay for androstenedione in both serum and dried blood-spot samples from neonates. We measured concentrations of androstenedione in serum under normal and pathological conditions such as congenital adrenal hyperplasia and polycystic ovarian disease. Diurnal variation in normal men was observed. Androstenedione was measured in blood spots from neonates born at term or prematurely, with respiratory distress syndrome, or with congenital adrenal hyperplasia.« less

Postnatal Cardiac Autonomic Nervous Control in Pediatric Congenital Heart Disease

PubMed Central

Nederend, Ineke; Jongbloed, Monique R. M.; de Geus, Eco J. C.; Blom, Nico A.; ten Harkel, Arend D. J.

2016-01-01

Congenital heart disease is the most common congenital defect. During childhood, survival is generally good but, in adulthood, late complications are not uncommon. Abnormal autonomic control in children with congenital heart disease may contribute considerably to the pathophysiology of these long term sequelae. This narrative review of 34 studies aims to summarize current knowledge on function of the autonomic nervous system in children with a congenital heart defect. Large scale studies that measure both branches of the nervous system for prolonged periods of time in well-defined patient cohorts in various phases of childhood and adolescence are currently lacking. Pending such studies, there is not yet a good grasp on the extent and direction of sympathetic and parasympathetic autonomic function in pediatric congenital heart disease. Longitudinal studies in homogenous patient groups linking autonomic nervous system function and clinical outcome are warranted. PMID:29367565

[Adrenal tumors. Principles of diagnostics and operative treatment].

PubMed

Gonsior, A; Pfeiffer, H; Führer, D; Liatsikos, E; Schwalenberg, T; Stolzenburg, J-U

2010-05-01

Adrenal masses are very heterogeneous and comprise benign or malignant tumors, unilateral or bilateral masses and variable endocrine activity. Because of these attributes adrenal gland masses are a clinical challenge. This article gives a summary of diagnostic steps and indications for adrenal surgery including perioperative management.

A Phase 2 Study of Chronocort, a Modified-Release Formulation of Hydrocortisone, in the Treatment of Adults With Classic Congenital Adrenal Hyperplasia

PubMed Central

Sinaii, Ninet; Kumar, Parag; Whitaker, Martin J.; Daley, Lori-Ann; Digweed, Dena; Eckland, David J. A.; Van Ryzin, Carol; Nieman, Lynnette K.; Arlt, Wiebke; Merke, Deborah P.

2015-01-01

Context: Treatment of congenital adrenal hyperplasia (CAH) is suboptimal. Inadequate suppression of androgens and glucocorticoid excess are common and current glucocorticoid formulations cannot replace the cortisol circadian rhythm. Objectives: The primary objective was to characterize the pharmacokinetic profile of Chronocort, a modified-release hydrocortisone formulation, in adults with CAH. Secondary objectives included examining disease control following 6 months of Chronocort with dose titration. Design, Setting, and Patients: Sixteen adults (eight females) with classic CAH participated in an open-label, nonrandomized, Phase 2 study at the National Institutes of Health Clinical Center. Twenty-four-hour blood sampling was performed on conventional glucocorticoids and following 6 months of Chronocort. Chronocort was initiated at 10 mg (0700 h) and 20 mg (2300 h). Dose titration was performed based on androstenedione and 17-hydroxyprogresterone (17-OHP) levels and clinical symptomatology. Main Outcome Measures: The primary outcome was cortisol pharmacokinetics of Chronocort and secondary outcomes included biomarkers of CAH control (androstenedione and 17-OHP). Results: In patients with CAH, Chronocort cortisol profiles were similar to physiologic cortisol secretion. Compared with conventional therapy, 6 months of Chronocort resulted in a decrease in hydrocortisone dose equivalent (28 ± 11.8 vs 25.9 ± 7.1 mg/d), with lower 24-hour (P = .004), morning (0700–1500 h; P = .002), and afternoon (1500–2300 h; P = .011) androstenedione area under the curve (AUC) and lower 24-hour (P = .023) and morning (0700–1500 h; P = .02) 17-OHP AUC. Conclusions: Twice-daily Chronocort approximates physiologic cortisol secretion, and was well tolerated and effective in controlling androgen excess in adults with CAH. This novel hydrocortisone formulation represents a new treatment approach for patients with CAH. PMID:25494662

Study of adrenal function in patients with tuberculosis.

PubMed

Sarin, Bipan Chander; Sibia, Keerat; Kukreja, Sahiba

2018-07-01

Although subclinical adrenal insufficiency has been documented in tuberculosis but it has been neglected in mainstream management of TB due to inconclusive data on its prevalence in TB. The fact that adrenal insufficiency may result not only in poor general condition of the patient but also sudden death due to adrenal crisis, makes it all the more important to address this issue seriously. In this non-randomized interventional study comprising of 100 cases of TB, our aim was to assess the adreno-cortical functions in patients with pulmonary TB (50 cases) and extra-pulmonary TB (50 cases) in an attempt to determine if there is any compromise of adrenal function. In this study, 100 cases of active TB were investigated for adrenal insufficiency by measuring morning fasting basal serum cortisol levels, followed by low dose ACTH stimulation test using 1μg synacthen (synthetic ACTH analog). The post-stimulation serum cortisol levels were estimated. Basal serum cortisol levels<220nmol/L or post-stimulation test serum cortisol level increment<200nmol/L or post-stimulation serum cortisol levels<500nmol/L were suggestive of adrenal insufficiency. Basal serum cortisol level was low in 16% cases and after low dose ACTH stimulation test, cortisol response was subnormal in 76% cases. Incidence of adrenal insufficiency in pulmonary TB (74%) and extra-pulmonary TB (78%) were comparable. The number of females having adrenal insufficiency in both the groups was higher than the males (67.3% males and 83.3% females) but the difference was statistically significant only in extra-pulmonary TB group (p=0.011). On analysing the data, the sensitivity of basal serum cortisol level estimation in diagnosing adrenal insufficiency was observed to be 21.05% and its specificity was 100%. Positive predictive value was 100% and negative predictive value was 28.57%. Diagnostic accuracy of basal serum cortisol level estimation was observed to be 40%. The incidence of subclinical adrenal

Neovascular glaucoma in a patient with X-linked juvenile retinoschisis.

PubMed

Zuo, Chengguo; Chen, Changzheng; Xing, Yiqiao; Du, Lei

2005-09-01

To report the rubeosis iridis and neovascular glaucoma findings in one patient of X-linked juvenile retinoschisis(XLRS). Color fundus photography, fluorescein angiography (FFA), OCT and B-scan were performed in a patient with X-linked juvenile retinoschisis complicated with neovascular glaucoma. Color fundus photography, fluorescein angiography (FFA), OCT and B-scan unveiled a rare condition of XLRS complicated with neovascular glaucoma. XLRS may complicate with neovascular glaucoma. It is necessary to test OCT, FFA, ERG and carefully examine the fundus of the follow eye when it comes to uncertain neovascular glaucoma of youth and child. And only in this way, can we exclude XLRS.

Genotypic analysis of X-linked retinoschisis in Western Australia.

PubMed

Lamey, Tina; Laurin, Sarina; Chelva, Enid; De Roach, John

2010-01-01

X-linked Retinoschisis is a leading cause of juvenile macular degeneration. Four Western Australian families affected by X-Linked Retinoschisis were analysed using DNA and clinical information from the Australian Inherited Retinal Disease (IRD) Register and DNA Bank. By direct sequencing of the RS1 gene, three genetic variants were identified; 52+1G > T, 289T > G and 416delA. 289T > G has not been previously reported and is likely to cause a substitution of a membrane binding residue (W92G) in the functional discoidin domain. All clinically diagnosed individuals showed typical electronegative ERGs. The 52+1G > T obligate carrier also recorded a bilaterally abnormal rod ERG and mildly abnormal photopic responses. mfERG trace arrays showed reduced response densities in the paramacular region extending futher temporally for each eye.

Adult-onset cerebello-brainstem dominant form of X-linked adrenoleukodystrophy presenting as multiple system atrophy: Case report and literature review

PubMed Central

Ogaki, Kotaro; Koga, Shunsuke; Aoki, Naoya; Lin, Wenlang; Suzuki, Kinuko; Ross, Owen A.; Dickson, Dennis W.

2015-01-01

X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder and is caused by ABCD1 mutations. A cerebello-brainstem dominant form that mainly involves the cerebellum and brainstem is summarized in a review of the literature, with autopsy confirmed cases exceedingly rare. We report a 69-year-old white man who was diagnosed with this rare disorder and describe neuropathologic, ultrastructural and genetic analyses. He did not have adrenal insufficiency or a family history of X-ALD or Addison’s disease. His initial symptom was temporary loss of eyesight at age 34 years. His major symptoms were chronic and progressive gait disorder, weakness in his lower extremities, and spasticity, as well as autonomic failure and cerebellar ataxia suggesting possible multiple system atrophy (MSA). He also had seizures, hearing loss, and sensory disturbances. His brain MRI showed no obvious atrophy or significant white matter pathology in cerebrum, brainstem or cerebellum. He died at age 69 years with a diagnosis of multiple system atrophy. Microscopic analysis showed mild, patchy myelin rarefaction with perivascular clusters of PAS-positive, CD68-positive macrophages in the white matter most prominent in the cerebellum and occipital lobe, but also affecting optic tract and internal capsule. Electron microscopy of cerebellar white matter showed cleft-like trilamellar cytoplasmic inclusions in macrophages typical of X-ALD, which prompted genetic analysis that revealed a novel ABCD1 mutation, p.R163G. Given the relatively mild pathological findings and long disease duration, it is likely that the observed pathology was the result of a slow and indolent disease process. We described a patient who had sporadic cerebello-brainstem dominant form of X-ALD with long clinical course, mild pathological findings, and an ABCD1 p.R163G substitution. We also review a total of 34 cases of adult-onset cerebello-brainstem dominant form of X-ALD. Although rare, X-ALD should be

Pyoderma Gangrenosum–Like Ulcer in a Patient With X-Linked Agammaglobulinemia

PubMed Central

Murray, Patrick R.; Jain, Ashish; Uzel, Gulbu; Ranken, Raymond; Ivy, Cristina; Blyn, Lawrence B.; Ecker, David J.; Sampath, Rangarajan; Lee, Chyi-Chia Richard; Turner, Maria L.

2011-01-01

Background Pyoderma gangrenosum–like ulcers and cellulitis of the lower extremities associated with recurrent fevers in patients with X-linked (Bruton) agammaglobulinemia have been reported to be caused by Helicobacter bilis (formerly classified as Flexispira rappini and then Helicobacter strain flexispira taxon 8). Consistent themes in these reports are the difficulty in recovering this organism in blood and wound cultures and in maintaining isolates in vitro. We confirmed the presence of this organism in a patient’s culture by using a novel application of gene amplification polymerase chain reaction and electrospray ionization time-of-flight mass spectrometry. Observation An adolescent boy with X-linked agammaglobulinemia presented with indurated plaques and a chronic leg ulcer whose origin was strongly suspected to be an H bilis organism. Histologic analysis demonstrated positive Warthin-Starry staining of curvilinear rods, which grew in culture but failed to grow when sub-cultured. They could not be identified by conventional techniques. A combination of gene amplification by polymerase chain reaction and electrospray ionization time-of-flight mass spectrometry confirmed the identity of this organism. Conclusions This novel technology was useful in the identification of a difficult-to-grow Helicobacter organism, the cause of pyoderma gangrenosum–like leg ulcers in patients with X-linked agammaglobulinemia. Correct identification of this organism as the cause of pyoderma gangrenosum–like ulcers in patients with X-linked agammaglobulinemia is of great importance for the early initiation of appropriate and curative antibiotic therapy. PMID:20479300

Transcription map of Xq27: candidates for several X-linked diseases.

PubMed

Zucchi, I; Jones, J; Affer, M; Montagna, C; Redolfi, E; Susani, L; Vezzoni, P; Parvari, R; Schlessinger, D; Whyte, M P; Mumm, S

1999-04-15

Human Xq27 contains candidate regions for several disorders, yet is predicted to be a gene-poor cytogenetic band. We have developed a transcription map for the entire cytogenetic band to facilitate the identification of the relatively small number of expected candidate genes. Two approaches were taken to identify genes: (1) a group of 64 unique STSs that were generated during the physical mapping of the region were used in RT-PCR with RNA from human adult and fetal brain and (2) ESTs that have been broadly mapped to this region of the chromosome were finely mapped using a high-resolution yeast artificial chromosome contig. This combined approach identified four distinct regions of transcriptional activity within the Xq27 band. Among them is a region at the centromeric boundary that contains candidate regions for several rare developmental disorders (X-linked recessive hypoparathyroidism, thoracoabdominal syndrome, albinism-deafness syndrome, and Borjeson-Forssman-Lehman syndrome). Two transcriptionally active regions were identified in the center of Xq27 and include candidate regions for X-linked mental retardation syndrome 6, X-linked progressive cone dystrophy, X-linked retinitis pigmentosa 24, and a prostate cancer susceptibility locus. The fourth region of transcriptional activity encompasses the FMR1 (FRAXA) and FMR2 (FRAXE) genes. The analysis thus suggests clustered transcription in Xq27 and provides candidates for several heritable disorders for which the causative genes have not yet been found. Copyright 1999 Academic Press.

Juvenile muscular atrophy of the distal upper extremities associated with x-linked periventricular heterotopia with features of Ehlers-Danlos syndrome.

PubMed

Hommel, Alyson L; Jewett, Tamison; Mortenson, Megan; Caress, James B

2016-10-01

Juvenile muscular atrophy of the distal upper extremities (JMADUE) is a rare, sporadic disorder that affects adolescent males and is characterized by progressive but self-limited weakness of the distal upper extremities. The etiology is unknown, but cervical hyperflexion has been hypothesized. We report a case of an adolescent male who presented with typical JMADUE but also had joint hypermobility and multiple congenital anomalies, including periventricular heterotopias, suggesting a multisystem syndrome. Subsequent diagnostic testing confirmed a diagnosis of JMADUE, and sequencing of the filamin-A gene showed a novel, pathogenic mutation that confirmed an additional diagnosis of X-linked periventricular heterotopias with features of Ehlers-Danlos syndrome (XLPH-EDS). The concurrent diagnosis of these 2 rare conditions suggests a pathogenic connection. It is likely that the joint hypermobility from XLPH-EDS predisposed this patient to developing JMADUE. This supports the cervical hyperflexion theory of pathogenesis. This case also expands the phenotype associated with FLNA mutations. Muscle Nerve 54: 794-797, 2016. © 2016 Wiley Periodicals, Inc.

Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia.

PubMed

Jonsson, Kenneth B; Zahradnik, Richard; Larsson, Tobias; White, Kenneth E; Sugimoto, Toshitsugu; Imanishi, Yasuo; Yamamoto, Takehisa; Hampson, Geeta; Koshiyama, Hiroyuki; Ljunggren, Osten; Oba, Koichi; Yang, In Myung; Miyauchi, Akimitsu; Econs, Michael J; Lavigne, Jeffrey; Jüppner, Harald

2003-04-24

Mutations in fibroblast growth factor 23 (FGF-23) cause autosomal dominant hypophosphatemic rickets. Clinical and laboratory findings in this disorder are similar to those in oncogenic osteomalacia, in which tumors abundantly express FGF-23 messenger RNA, and to those in X-linked hypophosphatemia, which is caused by inactivating mutations in a phosphate-regulating endopeptidase called PHEX. Recombinant FGF-23 induces phosphaturia and hypophosphatemia in vivo, suggesting that it has a role in phosphate regulation. To determine whether FGF-23 circulates in healthy persons and whether it is elevated in those with oncogenic osteomalacia or X-linked hypophosphatemia, an immunometric assay was developed to measure it. Using affinity-purified, polyclonal antibodies against [Tyr223]FGF-23(206-222)amide and [Tyr224]FGF-23(225-244)amide, we developed a two-site enzyme-linked immunosorbent assay that detects equivalently recombinant human FGF-23, the mutant form in which glutamine is substituted for arginine at position 179 (R179Q), and synthetic human FGF-23(207-244)amide. Plasma or serum samples from 147 healthy adults (mean [+/-SD] age, 48.4+/-19.6 years) and 26 healthy children (mean age, 10.9+/-5.5 years) and from 17 patients with oncogenic osteomalacia (mean age, 43.0+/-13.3 years) and 21 patients with X-linked hypophosphatemia (mean age, 34.9+/-17.2 years) were studied. Mean FGF-23 concentrations in the healthy adults and children were 55+/-50 and 69+/-36 reference units (RU) per milliliter, respectively. Four patients with oncogenic osteomalacia had concentrations ranging from 426 to 7970 RU per milliliter, which normalized after tumor resection. FGF-23 concentrations were 481+/-528 RU per milliliter in those with suspected oncogenic osteomalacia and 353+/-510 RU per milliliter (range, 31 to 2335) in those with X-linked hypophosphatemia. FGF-23 is readily detectable in the plasma or serum of healthy persons and can be markedly elevated in those with oncogenic

Adrenal medullary hyperplasia. Hyperplasia-pheochromocytoma sequence.

PubMed

Kurihara, K; Mizuseki, K; Kondo, T; Ohoka, H; Mannami, M; Kawai, K

1990-09-01

We present a case of unilateral adrenal medullary hyperplasia in a 63-year-old woman with clinical signs and symptoms of pheochromocytoma unassociated with multiple endocrine neoplasia. The surgically removed adrenal gland revealed diffuse medullary hyperplasia with multiple micronodules measuring up to 2 mm. The micronodules were composed of enlarged chromaffin cells with atypia, histologically similar to those of pheochromocytoma, forming small solid alveolar patterns separated by a fibrovascular stroma. Removal of the hyperplastic adrenal gland resulted in disappearance of paroxysmal nocturnal hypertension and palpitation. These results suggest that diffuse and nodular medullary hyperplasia is the precursor of pheochromocytoma.

Unusual phenotypic expression of an XLRS1 mutation in X-linked juvenile retinoschisis.

PubMed

Dodds, Jodi A; Srivastava, Anand K; Holden, Kenton R

2006-04-01

X-linked juvenile retinoschisis is a rare progressive vitreoretinal degenerative process that appears in early childhood, results in decreased visual acuity and blindness (if severe), and is caused by various mutations within the XLRS1 gene at Xp22.2. We report an affected family of Western European ancestry with X-linked juvenile retinoschisis. The family was found to carry a 304C-->T substitution in exon 4 of the XLRS1 gene, resulting in an Arg102Trp amino acid substitution. Two of the four available clinical cases in this family were found to carry the mutation. All available mothers of affected males were found to be unaffected carriers of the mutation, a typical feature of X-linked diseases. Two new female carriers, sisters of affected males, were identified and counseled accordingly. Questionnaires on visual functioning were given to the affected family members to examine the psychologic and sociologic impact of X-linked juvenile retinoschisis, which documented an associated stigma even when affected with a "mild" phenotype.

Submicroscopic interstitial deletion of the X chromosome explains a complex genetic syndrome dominated by Norrie disease.

PubMed

Gal, A; Wieringa, B; Smeets, D F; Bleeker-Wagemakers, L; Ropers, H H

1986-01-01

Norrie disease (ND), an X-linked recessive disorder, is characterized by congenital blindness followed by bulbar atrophy. We have examined a three-generation family in which ND is part of a complex X-linked syndrome with severe mental retardation, hypogonadism, growth disturbances, and increased susceptibility to infections as additional features. This syndrome is apparently due to an interstitial deletion, as evidenced by the failure of the L1.28 DNA probe (DXS7 locus, Xp11.3) to detect complementary DNA sequences on the defective X chromosome of an affected male and of several obligatory heterozygotes. Attempts to further define this deletion with other DNA probes from the proximal short arm of the X chromosome or by prometaphase chromosome analysis were unsuccessful.

Therapeutic patient education in adrenal insufficiency.

PubMed

Guignat, Laurence

2018-06-01

It is essential to encourage patient autonomy in the management of their illness, and notably their participation in treatment education programs; specific programs target avoidance or early preventive treatment of acute adrenal insufficiency, which is a life-threatening complication. Therapeutic patient education is recommended by the two international consensus statements on the management of primary adrenal insufficiency and the French consensus on adrenal insufficiency. Although there is no common international reference framework to date, the objective of the French consensus was to provide a frame of reference to facilitate the development of therapeutic education for patients with adrenal insufficiency. The principal educational objectives were: for the patient to always carry the necessary emergency equipment; be able to identify situations of increased risk and the early signs of adrenal crisis; know how to adjust oral glucocorticoid treatment; be capable of administering hydrocortisone by subcutaneous injection; be able to adjust treatment to different situations (heat, physical exercise, travel); and be able to appropriately use the resources of the healthcare services. Other programs could also be developed to respond to patients' needs and expectations, notably concerning hydrocortisone dose adjustment to avoid overdose in the context of chronic fatigue syndrome. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Expression pattern of X-linked genes in sex chromosome aneuploid bovine cells.

PubMed

Basrur, Parvathi K; Farazmand, Ali; Stranzinger, Gerald; Graphodatskaya, Daria; Reyes, Ed R; King, W Allan

2004-01-01

Expression of the X-inactive specific transcript (XIST) gene is a prerequisite step for dosage compensation in mammals, accomplished by silencing one of the two X chromosomes in normal female diploid cells or all X chromosomes in excess of one in sex chromosome aneuploids. Our previous studies showing that XIST expression does not eventuate the inactivation of X-linked genes in fetal bovine testis had suggested that XIST expression may not be an indicator of X inactivation in this species. In this study, we used a semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) approach on cultures of bovine cells with varying sex chromosome constitution (XY, XX, XXY and XXX) to test whether the levels of XIST expressed conform to the number of late replicating (inactive) X chromosomes displayed by proliferating cells in these cultures. Expression patterns of four X-linked genes, including hypoxanthine phosphorybosyl transferase (HPRT), glucose-6-phosphate dehydrogenase (G6PD), zinc finger protein locus on the X (ZFX). and 'selected mouse cDNA on the X' (SMCX), in all these cells were also tested. Results showed that XIST expression was significantly higher (p < 0.05) in XXX cells compared to XX and XXY cells and that G6PD. HPRT, and SMCX loci are subject to X inactivation. The significantly higher levels of ZFX expressed in XXX cells compared to XX and XXY cells (p < 0.05) confirmed that this bovine locus, as human ZFX, escapes X inactivation. However, the levels of XIST and ZFX expressed were not proportional to the X chromosome load in these cells suggesting that X-linked loci escaping inactivation may be regulated at transcription (or post-transcription) level by mechanisms that prevent gene-specific product accumulation beyond certain levels in sex chromosome aneuploids.

Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors.

PubMed

Fassnacht, Martin; Arlt, Wiebke; Bancos, Irina; Dralle, Henning; Newell-Price, John; Sahdev, Anju; Tabarin, Antoine; Terzolo, Massimo; Tsagarakis, Stylianos; Dekkers, Olaf M

2016-08-01

: By definition, an adrenal incidentaloma is an asymptomatic adrenal mass detected on imaging not performed for suspected adrenal disease. In most cases, adrenal incidentalomas are nonfunctioning adrenocortical adenomas, but may also represent conditions requiring therapeutic intervention (e.g. adrenocortical carcinoma, pheochromocytoma, hormone-producing adenoma or metastasis). The purpose of this guideline is to provide clinicians with best possible evidence-based recommendations for clinical management of patients with adrenal incidentalomas based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. We predefined four main clinical questions crucial for the management of adrenal incidentaloma patients, addressing these four with systematic literature searches: (A) How to assess risk of malignancy?; (B) How to define and manage low-level autonomous cortisol secretion, formerly called 'subclinical' Cushing's syndrome?; (C) Who should have surgical treatment and how should it be performed?; (D) What follow-up is indicated if the adrenal incidentaloma is not surgically removed? SELECTED RECOMMENDATIONS: (i) At the time of initial detection of an adrenal mass establishing whether the mass is benign or malignant is an important aim to avoid cumbersome and expensive follow-up imaging in those with benign disease. (ii) To exclude cortisol excess, a 1mg overnight dexamethasone suppression test should be performed (applying a cut-off value of serum cortisol ≤50nmol/L (1.8µg/dL)). (iii) For patients without clinical signs of overt Cushing's syndrome but serum cortisol levels post 1mg dexamethasone >138nmol/L (>5µg/dL), we propose the term 'autonomous cortisol secretion'. (iv) All patients with '(possible) autonomous cortisol' secretion should be screened for hypertension and type 2 diabetes mellitus, to ensure these are appropriately treated. (v) Surgical treatment should be considered in an individualized approach in patients with

X-linked cardiomyopathy is heterogeneous

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

Wilson, M.J.; Sillence, D.O.; Mulley, J.C.

Two major loci of X-linked cardiomyopathy have been mapped by linkage analysis. The gene for X-linked dilated cardiomyopathy (XLCM) is mapped to the dystrophin locus at Xp21, while Barth syndrome has been localised to distal Xq28. XLCM usually presents in juvenile males with no skeletal disease but decreased dystrophin in cardiac muscle. Barth syndrome most often presents in infants and is characterized by skeletal myopathy, short stature and neutropenia in association with cardiomyopathy of variable severity. Prior to carrier or prenatal diagnosis in a family, delineation of the cardiomyopathy locus involved is essential. We report the linkage mapping of amore » large kindred in which several male infants have died with hypertrophic cardiomyopathy. There is a family history of unexplained death of infant males less than 6 months old over 4 generations. Features of Barth syndrome such as short stature, skeletal myopathy and neutropenia have not been observed. Genotyping at 10 marker loci in Xq28 has revealed significant pairwise lod scores with the cardiomyopathy phenotype at DXS52 (Z=2.21 at {theta}=0.0), at markers p26 and p39 near DXS15 (Z=2.30 at {theta}=0.0) and at F8C (Z=2.24 at {theta}=0.0). A recombinant detected with DXS296 defines the proximal limit to the localization. No recombinants were detected at any of the loci distal to DXS296. The most distal marker in Xq28, DXS1108, is within 500 kb of the telomere. As the gene in this family is localized to Xq28, it is possible that this disorder is an allelic variant at the Barth syndrome locus.« less

X-Linked Intellectual Disability: Unique Vulnerability of the Male Genome

ERIC Educational Resources Information Center

Stevenson, Roger E.; Schwartz, Charles E.

2009-01-01

X-linked intellectual disability (XLID) accounts for approximately 16% of males with intellectual disability (ID). This is, in part, related to the fact that males have a single X chromosome. Progress in the clinical and molecular characterization of XLID has outpaced progress in the delineation of ID due to genes on the other 22 chromosomes.…

Silencing of X-Linked MicroRNAs by Meiotic Sex Chromosome Inactivation

PubMed Central

Royo, Hélène; Seitz, Hervé; ElInati, Elias; Peters, Antoine H. F. M.; Stadler, Michael B.; Turner, James M. A.

2015-01-01

During the pachytene stage of meiosis in male mammals, the X and Y chromosomes are transcriptionally silenced by Meiotic Sex Chromosome Inactivation (MSCI). MSCI is conserved in therian mammals and is essential for normal male fertility. Transcriptomics approaches have demonstrated that in mice, most or all protein-coding genes on the X chromosome are subject to MSCI. However, it is unclear whether X-linked non-coding RNAs behave in a similar manner. The X chromosome is enriched in microRNA (miRNA) genes, with many exhibiting testis-biased expression. Importantly, high expression levels of X-linked miRNAs (X-miRNAs) have been reported in pachytene spermatocytes, indicating that these genes may escape MSCI, and perhaps play a role in the XY-silencing process. Here we use RNA FISH to examine X-miRNA expression in the male germ line. We find that, like protein-coding X-genes, X-miRNAs are expressed prior to prophase I and are thereafter silenced during pachynema. X-miRNA silencing does not occur in mouse models with defective MSCI. Furthermore, X-miRNAs are expressed at pachynema when present as autosomally integrated transgenes. Thus, we conclude that silencing of X-miRNAs during pachynema in wild type males is MSCI-dependent. Importantly, misexpression of X-miRNAs during pachynema causes spermatogenic defects. We propose that MSCI represents a chromosomal mechanism by which X-miRNAs, and other potential X-encoded repressors, can be silenced, thereby regulating genes with critical late spermatogenic functions. PMID:26509798

New X-linked mental retardation syndrome with the gene mapped tentatively in Xp22.3

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

Wittwer, B.; Kircheisen, R.; Leutelt, J.

1996-07-12

X-linked mental retardation (XLMR) is genetically heterogeneous and clinically variable. We describe a new XLMR syndrome of severe mental retardation and multiple congenital anomalies. Two sisters have (with 3 different partners) 3 severely handicapped sons. In 2 cases, oligohydramnios and intrauterine growth retardation were noted. Common anomalies included a square-shaped face, high and broad forehead, frontal bossing, downward slant of palpebral fissures, hypertelorism, epicanthic folds, long philtrum, thin upper lip, and apparently low-set ears. One boy has bilateral microphthalmos and sclerocornea, and his cousin has atrophy of the optic nerve. All 3 patients are blind and have profound statomotor andmore » mental retardation, seizures, and a grossly abnormal electroencephalographic pattern. Additional findings are short stature, delayed bone matuation, hydronephrosis, vesicorenal reflux, cryptorchidism, clinodactyly of the 5th fingers, and transverse palmar creases. The karyotype is normal (46,XY). Segregation analysis showed perfect coinheritance between the clinical phenotype and alleles at several loci in Xp22.3, whereas recombinants were identified with marker loci from Xp22.2-qter. Analysis of multiple informative meioses suggests that the disease locus maps in Xp22.3 distal to DXS16. 9 refs., 5 figs., 2 tabs.« less

Whole exome sequencing confirms the clinical diagnosis of Marfan syndrome combined with X-linked hypophosphatemia.

PubMed

Sheng, Xunlun; Chen, Xue; Lei, Bo; Chen, Rui; Wang, Hui; Zhang, Fangxia; Rong, Weining; Ha, Ruoshui; Liu, Yani; Zhao, Feng; Yang, Peizeng; Zhao, Chen

2015-06-04

To determine the genetic lesions and to modify the clinical diagnosis for a Chinese family with significant intrafamilial phenotypic diversities and unusual presentations. Three affected patients and the asymptomatic father were included and received comprehensive systemic examinations. Whole exome sequencing (WES) was performed for mutation detection. Structural modeling test was applied to analyze the potential structural changes caused by the missense substitution. The proband showed a wide spectrum of systemic anomalies, including bilateral ectopia lentis, atrial septal defect, ventricular septal defect, widening of tibial metaphysis with medial bowing, and dolichostenomelia in digits, while her mother and elder brother only demonstrated similar skeletal changes. A recurrent mutation, PHEX p.R291*, was found in all patients, while a de novo mutation, FBN1 p.C792F, was only detected in the proband. The FBN1 substitution was also predicted to cause significant conformational change in fibrillin-1 protein, thus changing its physical and biological properties. Taken together, we finalized the diagnosis for this family as X-linked hypophosphatemia (XLH), and diagnosed this girl as Marfan syndrome combined with XLH, and congenital heart disease. Our study also emphasizes the importance of WES in assisting the clinical diagnosis for complicated cases when the original diagnoses are challenged.

Mutational studies in X-linked Charcot-Marie-Tooth disease (CMTX)

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

Cherryson, A.K.; Yeung, L.; Kennerson, M.L.

1994-09-01

Charcot-Marie-Tooth disease, also known as hereditary motor and sensory neuropathy (HMSN), is a heterogeneous group of slowly progressive disorders of the peripheral nerve. X-linked CMT (CMTX) is characterized by slow motor nerve conduction velocities in affected males and the presence of mildly affected or normal carrier females with intermediate or normal nerve conduction velocities. CMTX, which has an incidence of 3.1 per 100,000 and accounts for approximately 10% of CMT cases, has been mapped to Xq13. One of the genes lying in this region, connexin 32, has been found to contain alterations in individuals affected with X-linked CMT. We havemore » identified our X-linked families from dominant type 1 CMT families using the clinical criteria given above. These families were screened for point mutations in connexin 32. We have identified three missense mutations, a G{r_arrow}A transition at amino acid 35 (valine to methionine), a C{r_arrow}G transition at amino acid 158 (proline to alanine) and a T{r_arrow}A transition at amino acid 182 (serine to threonine). Another family showed a 18 bp deletion, which removed the amino acid 111 to 116 inclusive (histidine, glycine, aspartic acid, proline, leucine, histidine).« less

Genetics Home Reference: Wiskott-Aldrich syndrome

MedlinePlus

... other disorders: X-linked thrombocytopenia and severe congenital neutropenia . These conditions have overlapping signs and symptoms and ... Aldrich syndrome , X-linked thrombocytopenia , and severe congenital neutropenia are sometimes collectively referred to as WAS-related ...

Severe X-linked chondrodysplasia punctata in nine new female fetuses.

PubMed

Lefebvre, Mathilde; Dufernez, Fabienne; Bruel, Ange-Line; Gonzales, Marie; Aral, Bernard; Saint-Onge, Judith; Gigot, Nadège; Desir, Julie; Daelemans, Caroline; Jossic, Frédérique; Schmitt, Sébastien; Mangione, Raphaele; Pelluard, Fanny; Vincent-Delorme, Catherine; Labaune, Jean-Marc; Bigi, Nicole; D'Olne, Dominique; Delezoide, Anne-Lise; Toutain, Annick; Blesson, Sophie; Cormier-Daire, Valérie; Thevenon, Julien; El Chehadeh, Salima; Masurel-Paulet, Alice; Joyé, Nicole; Vibert-Guigue, Claude; Rigonnot, Luc; Rousseau, Thierry; Vabres, Pierre; Hervé, Philippe; Lamazière, Antonin; Rivière, Jean-Baptiste; Faivre, Laurence; Laurent, Nicole; Thauvin-Robinet, Christel

2015-07-01

Conradi-Hünermann-Happle [X-linked dominant chondrodysplasia punctata 2 (CDPX2)] syndrome is a rare X-linked dominant skeletal dysplasia usually lethal in men while affected women show wide clinical heterogeneity. Different EBP mutations have been reported. Severe female cases have rarely been reported, with only six antenatal presentations. To better characterize the phenotype in female fetuses, we included nine antenatally diagnosed cases of women with EBP mutations. All cases were de novo except for two fetuses with an affected mother and one case of germinal mosaicism. The mean age at diagnosis was 22 weeks of gestation. The ultrasound features mainly included bone abnormalities: shortening (8/9 cases) and bowing of the long bones (5/9), punctuate epiphysis (7/9) and an irregular aspect of the spine (5/9). Postnatal X-rays and examination showed ichthyosis (8/9) and epiphyseal stippling (9/9), with frequent asymmetric short and bowed long bones. The X-inactivation pattern of the familial case revealed skewed X-inactivation in the mildly symptomatic mother and random X-inactivation in the severe fetal case. Differently affected skin samples of the same fetus revealed different patterns of X-inactivation. Prenatal detection of asymmetric shortening and bowing of the long bones and cartilage stippling should raise the possibility of CPDX2 in female fetuses, especially because the majority of such cases involve de novo mutations. © 2015 John Wiley & Sons, Ltd.

Androgen and psychosexual development: core gender identity, sexual orientation and recalled childhood gender role behavior in women and men with congenital adrenal hyperplasia (CAH).

PubMed

Hines, Melissa; Brook, Charles; Conway, Gerard S

2004-02-01

We assessed core gender identity, sexual orientation, and recalled childhood gender role behavior in 16 women and 9 men with CAH and in 15 unaffected female and 10 unaffected male relatives, all between the ages of 18 and 44 years. Women with congenital adrenal hyperplasia (CAH) recalled significantly more male-typical play behavior as children than did unaffected women, whereas men with and without CAH did not differ. Women with CAH also reported significantly less satisfaction with the female sex of assignment and less heterosexual interest than did unaffected women. Again, men with CAH did not differ significantly from unaffected men in these respects. Our results for women with CAH are consistent with numerous prior reports indicating that girls with CAH show increased male-typical play behavior. They also support the hypotheses that these women show reduced heterosexual interest and reduced satisfaction with the female sex of assignment. Our results for males are consistent with most prior reports that boys with CAH do not show a general alteration in childhood play behavior. In addition, they provide initial evidence that core gender identity and sexual orientation are unaffected in men with CAH. Finally, among women with CAH, we found that recalled male-typical play in childhood correlated with reduced satisfaction with the female gender and reduced heterosexual interest in adulthood. Although prospective studies are needed, these results suggest that those girls with CAH who show the greatest alterations in childhood play behavior may be the most likely to develop a bisexual or homosexual orientation as adults and to be dissatisfied with the female sex of assignment.

Complement component 4 copy number variation and CYP21A2 genotype associations in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

PubMed

Chen, Wuyan; Xu, Zhi; Nishitani, Miki; Van Ryzin, Carol; McDonnell, Nazli B; Merke, Deborah P

2012-12-01

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is an autosomal recessive disorder of cortisol biosynthesis caused by CYP21A2 mutations. An increase in gene copy number variation (CNV) exists at the CYP21A2 locus. CNV of C4, a neighboring gene that encodes complement component 4, is associated with autoimmune disease susceptibility. In this study, we performed comprehensive genetic analysis of the RP-C4-CYP21-TNX (RCCX) region in 127 unrelated 21-OHD patients (100 classic, 27 nonclassic). C4 copy number was determined by Southern blot. C4 CNV and serum C4 levels were evaluated in relation to CYP21A2 mutations and relevant phenotypes. We found that the most common CYP21A2 mutation associated with the nonclassic form of CAH, V281L, was associated with high C4 copy number (p = 7.13 × 10(-16)). Large CYP21A2 deletion, a common mutation associated with the classic form of CAH, was associated with low C4 copy number (p = 1.61 × 10(-14)). Monomodular RCCX with a short C4 gene, a risk factor for autoimmune disease, was significantly less frequent in CAH patients compared to population estimates (2.8 vs. 10.6 %; p = 1.08 × 10(-4)). In conclusion, CAH patients have increased C4 CNV, with mutation-specific associations that may be protective for autoimmune disease. The study of CYP21A2 in relation to neighboring genes provides insight into the genetics of CNV hotspots, an important determinant of human health.

Adrenal tuberculosis in Cushing's disease with bilateral macronodular adrenocortical hyperplasia.

PubMed

Kwon, Hyuk-Sang; Kim, Sang-Il; Yoo, Soon-Jib; Yoon, Kun-Ho; Lee, Kwang-Woo; Kang, Moon-Won; Son, Ho-Young; Kang, Sung-Koo; Cha, Bong-Yun

2006-04-01

Cushing's disease is a disorder of hypercortisolism caused by a pituitary micro- or macro-adenoma. Most patients with Cushing's disease have a bilateral adrenal enlargement, which depends on the duration of the disease, as a result of the long standing ACTH stimulation of both adrenal glands. However, in macronodular adrenocortical hyperplasia (MNH) that is caused by Cushing's disease, if the MNH gains autonomy, a bilateral adrenalectomy, as well as the removal of pituitary adenoma, is often essential. We encountered a patient diagnosed with Cushing's disease with bilateral adrenal tuberculosis simulating MNH. She had taken anti-tuberculosis medications one year prior to admission due to spinal tuberculosis. Sellar MRI revealed a pituitary macroadenoma, but adrenal CT showed enlargement in both adrenal glands that appeared to be MNH. A hormonal study and bilateral inferior petrosal sinus sampling revealed Cushing's disease. Therefore, she underwent trans-sphenoidal surgery of the pituitary mass. The pituitary surgery was successful and the serum cortisol returned to normal range. However, the adrenal mass rapidly enlarged after removing the pituitary tumor without showing evidence of a recurrence or adrenal autonomy of hypercortisolism. Accordingly, a laparoscopic left adrenalectomy was performed to examine the nature of the mass. The resected left adrenal gland was pathologically determined to have a lesion of tuberculosis with some part of the intact cortex. So we assumed that the cause of rapid adrenal enlargement might be due to adrenal tuberculosis. In summary, to the best of our knowledge, this is the first case of Cushing's disease coexisting with both adrenal tuberculosis simulating a bilateral MNH.

Genetics Home Reference: X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia

MedlinePlus

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Primary adrenal insufficiency is associated with impaired natural killer cell function: a potential link to increased mortality.

PubMed

Bancos, Irina; Hazeldine, Jon; Chortis, Vasileios; Hampson, Peter; Taylor, Angela E; Lord, Janet M; Arlt, Wiebke

2017-04-01

Mortality in patients with primary adrenal insufficiency (PAI) is significantly increased, with respiratory infections as a major cause of death. Moreover, patients with PAI report an increased rate of non-fatal infections. Neutrophils and natural killer (NK) cells are innate immune cells that provide frontline protection against invading pathogens. Thus, we compared the function and phenotype of NK cells and neutrophils isolated from PAI patients and healthy controls to ascertain whether altered innate immune responses could be a contributory factor for the increased susceptibility of PAI patients to infection. We undertook a cross-sectional study of 42 patients with PAI due to autoimmune adrenalitis ( n =  37) or bilateral adrenalectomy ( n =  5) and 58 sex- and age-matched controls. A comprehensive screen of innate immune function, consisting of measurements of neutrophil phagocytosis, reactive oxygen species production, NK cell cytotoxicity (NKCC) and NK cell surface receptor expression, was performed on all subjects. Neutrophil function did not differ between PAI and controls. However, NKCC was significantly reduced in PAI (12.0 ± 1.5% vs 21.1 ± 2.6%, P  < 0.0001). Phenotypically, the percentage of NK cells expressing the activating receptors NKG2D and NKp46 was significantly lower in PAI, as was the surface density of NKG2D (all P  < 0.0001). Intracellular granzyme B expression was significantly increased in NK cells from PAI patients ( P  < 0.01). Adrenal insufficiency is associated with significantly decreased NKCC, thereby potentially compromising early recognition and elimination of virally infected cells. This potential impairment in anti-viral immune defense may contribute to the increased rate of respiratory infections and ultimately mortality in PAI. © 2017 The authors.

Sex differences in oestrogen receptor levels in adrenal glands of sheep during the breeding season.

PubMed

van Lier, E; Meikle, A; Bielli, A; Akerberg, S; Forsberg, M; Sahlin, L

2003-11-01

The concentrations of the oestrogen receptor (ER), and the mRNA levels of ERalpha, progesterone receptor (PR) and insulin-like growth factor I (IGF-I) were characterised in adrenal glands and uterine tissue of adult Corriedale sheep during the breeding season. The sheep were of different sex and gonadal status. Ewes had higher levels of cytosolic ER in the adrenals than the rams (mean+/-S.E.M.: 7.3+/-2.0 fmol/mg protein and 2.5+/-1.0 fmol/mg protein, respectively; P=0.0091) and gonadectomy increased ER (mean+/-S.E.M.: 2.9+/-1.2 fmol/mg protein and 8.6+/-2.3 fmol/mg protein, intact and gonadectomised sheep, respectively; P=0.0071). No differences could be observed in mRNA levels for ERalpha and IGF-I in the adrenal glands of all of the sheep. PR mRNA levels were reduced in ovariectomised ewes and enhanced in castrated rams (sex x gonadal status: P=0.009). PR mRNA levels tended to be higher in ewes in the follicular phase than in ovariectomised ewes and intact rams (P<0.1). All of the animals had positive nuclear staining for ERalpha in the adrenal cortex, but no differences were observed between the groups. In this study, we demonstrated the existence of ER in the adrenal gland of sheep and found varying sensitivity to oestrogens as the ER levels differed among sex and gonadal status. These findings indicate that oestrogens most likely affect steroidogenesis directly at the adrenal cortex and suggest that oestrogens are partly responsible for the sex differences in cortisol secretion in sheep.

[Factor V congenital deficiency: about a case].

PubMed

Boujrad, Saloua; El Hasbaoui, Brahim; Echahdi, Hanae; Malih, Mohamed; Agadr, Aomar

2017-01-01

Factor V congenital deficiency is a rare coagulation disorder initially described by Owren in 1947 and known as para hemophilia. It is transmitted through autosomal-recessive inheritance and homozygous cases are usually symptomatic. Factor V is an essential cofactor in the conversion of prothrombin to thrombin by activated factor X. In the absence of factor V, thrombin generation is slowed down and fibrin formation is delayed. This results in a bleeding tendency. We report a case of factor V congenital deficiency in an infant with recurrent epistaxis.

C-Arm Computed Tomography-Assisted Adrenal Venous Sampling Improved Right Adrenal Vein Cannulation and Sampling Quality in Primary Aldosteronism.

PubMed

Park, Chung Hyun; Hong, Namki; Han, Kichang; Kang, Sang Wook; Lee, Cho Rok; Park, Sungha; Rhee, Yumie

2018-05-04

Adrenal venous sampling (AVS) is a gold standard for subtype classification of primary aldosteronism (PA). However, this procedure has a high failure rate because of the anatomical difficulties in accessing the right adrenal vein. We investigated whether C-arm computed tomography-assisted AVS (C-AVS) could improve the success rate of adrenal sampling. A total of 156 patients, diagnosed with PA who underwent AVS from May 2004 through April 2017, were included. Based on the medical records, we retrospectively compared the overall, left, and right catheterization success rates of adrenal veins during the periods without C-AVS (2004 to 2010, n=32) and with C-AVS (2011 to 2016, n=134). The primary outcome was adequate bilateral sampling defined as a selectivity index (SI) >5. With C-AVS, the rates of adequate bilateral AVS increased from 40.6% to 88.7% (P<0.001), with substantial decreases in failure rates (43.7% to 0.8%, P<0.001). There were significant increases in adequate sampling rates from right (43.7% to 91.9%, P<0.001) and left adrenal veins (53.1% to 95.9%, P<0.001) as well as decreases in catheterization failure from right adrenal vein (9.3% to 0.0%, P<0.001). Net improvement of SI on right side remained significant after adjustment for left side (adjusted SI, 1.1 to 9.0; P=0.038). C-AVS was an independent predictor of adequate bilateral sampling in the multivariate model (odds ratio, 9.01; P<0.001). C-AVS improved the overall success rate of AVS, possibly as a result of better catheterization of right adrenal vein. Copyright © 2018 Korean Endocrine Society.

A novel MYH7 mutation links congenital fiber type disproportion and myosin storage myopathy.

PubMed

Ortolano, Saida; Tarrío, Rosa; Blanco-Arias, Patricia; Teijeira, Susana; Rodríguez-Trelles, Francisco; García-Murias, María; Delague, Valerie; Lévy, Nicolas; Fernández, José M; Quintáns, Beatriz; Millán, Beatriz San; Carracedo, Angel; Navarro, Carmen; Sobrido, María-Jesús

2011-04-01

This study aimed to identify the genetic defect in a multigenerational family presenting an autosomal dominant myopathy with histological features of congenital fiber type disproportion. Linkage analysis and genetic sequencing identified, in all affected members of the family, the c.5807A>G heterozygous mutation in MYH7, which encodes the slow/β-cardiac myosin heavy chain. This mutation causes skeletal but not cardiac involvement. Myosin heavy chain expression pattern was also characterized by immunohistochemistry, western blot and q-PCR in muscle biopsies from two patients aged 25 and 62, respectively. While only congenital fiber type disproportion was observed in the younger patient, older patient's biopsy presented aggregates of slow myosin heavy chains, in fiber sub-sarcolemmal region. These clinico-pathologic findings suggest a novel phenotype within the emerging group of hereditary myosin myopathies, which in this family presents typical characteristics of congenital fiber type disproportion in early stages and later evolves to myosin storage myopathy. Copyright © 2011 Elsevier B.V. All rights reserved.

60 YEARS OF POMC: Adrenal and extra-adrenal functions of ACTH.

PubMed

Gallo-Payet, Nicole

2016-05-01

The pituitary adrenocorticotropic hormone (ACTH) plays a pivotal role in homeostasis and stress response and is thus the major component of the hypothalamo-pituitary-adrenal axis. After a brief summary of ACTH production from proopiomelanocortin (POMC) and on ACTH receptor properties, the first part of the review covers the role of ACTH in steroidogenesis and steroid secretion. We highlight the mechanisms explaining the differential acute vs chronic effects of ACTH on aldosterone and glucocorticoid secretion. The second part summarizes the effects of ACTH on adrenal growth, addressing its role as either a mitogenic or a differentiating factor. We then review the mechanisms involved in steroid secretion, from the classical Cyclic adenosine monophosphate second messenger system to various signaling cascades. We also consider how the interaction between the extracellular matrix and the cytoskeleton may trigger activation of signaling platforms potentially stimulating or repressing the steroidogenic potency of ACTH. Finally, we consider the extra-adrenal actions of ACTH, in particular its role in differentiation in a variety of cell types, in addition to its known lipolytic effects on adipocytes. In each section, we endeavor to correlate basic mechanisms of ACTH function with the pathological consequences of ACTH signaling deficiency and of overproduction of ACTH. © 2016 Society for Endocrinology.

Molecular genetic analysis of patients with sporadic and X-linked infantile nystagmus

PubMed Central

Zhao, Hui; Huang, Xiu-Feng; Zheng, Zhi-Li; Deng, Wen-Li; Lei, Xin-Lan; Xing, Dong-Jun; Ye, Liang; Xu, Su-Zhong; Chen, Jie; Zhang, Fang; Yu, Xin-Ping; Jin, Zi-Bing

2016-01-01

Objectives Infantile nystagmus (IN) is a genetically heterogeneous condition characterised by involuntary rhythmic oscillations of the eyes accompanied by different degrees of vision impairment. Two genes have been identified as mainly causing IN: FRMD7 and GPR143. The aim of our study was to identify the genetic basis of both sporadic IN and X-linked IN. Design Prospective analysis. Patients Twenty Chinese patients, including 15 sporadic IN cases and 5 from X-linked IN families, were recruited and underwent molecular genetic analysis. We first performed PCR-based DNA sequencing of the entire coding region and the splice junctions of the FRMD7 and GPR143 genes in participants. Mutational analysis and co-segregation confirmation were then performed. Setting All clinical examinations and genetic experiments were performed in the Eye Hospital of Wenzhou Medical University. Results Two mutations in the FRMD7 gene, including one novel nonsense mutation (c.1090C>T, p.Q364X) and one reported missense mutation (c.781C>G, p.R261G), were identified in two of the five (40%) X-linked IN families. However, none of putative mutations were identified in FRMD7 or GPR143 in any of the sporadic cases. Conclusions The results suggest that mutations in FRMD7 appeared to be the major genetic cause of X-linked IN, but not of sporadic IN. Our findings provide further insights into FRMD7 mutations, which could be helpful for future genetic diagnosis and genetic counselling of Chinese patients with nystagmus. PMID:27036142

Congenital Adrenal Hyperplasia

MedlinePlus

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X-linked intellectual disability update 2017.

PubMed

Neri, Giovanni; Schwartz, Charles E; Lubs, Herbert A; Stevenson, Roger E

2018-04-25

The X-chromosome comprises only about 5% of the human genome but accounts for about 15% of the genes currently known to be associated with intellectual disability. The early progress in identifying the X-linked intellectual disability (XLID)-associated genes through linkage analysis and candidate gene sequencing has been accelerated with the use of high-throughput technologies. In the 10 years since the last update, the number of genes associated with XLID has increased by 96% from 72 to 141 and duplications of all 141 XLID genes have been described, primarily through the application of high-resolution microarrays and next generation sequencing. The progress in identifying genetic and genomic alterations associated with XLID has not been matched with insights that improve the clinician's ability to form differential diagnoses, that bring into view the possibility of curative therapies for patients, or that inform scientists of the impact of the genetic alterations on cell organization and function. © 2018 Wiley Periodicals, Inc.

Direct effects of recurrent hypoglycaemia on adrenal catecholamine release.

PubMed

Orban, Branly O; Routh, Vanessa H; Levin, Barry E; Berlin, Joshua R

2015-01-01

In Type 1 and advanced Type 2 diabetes mellitus, elevation of plasma epinephrine plays a key role in normalizing plasma glucose during hypoglycaemia. However, recurrent hypoglycaemia blunts this elevation of plasma epinephrine. To determine whether recurrent hypoglycaemia affects peripheral components of the sympatho-adrenal system responsible for epinephrine release, male rats were administered subcutaneous insulin daily for 3 days. These recurrent hypoglycaemic animals showed a smaller elevation of plasma epinephrine than saline-injected controls when subjected to insulin-induced hypoglycaemia. Electrical stimulation of an adrenal branch of the splanchnic nerve in recurrent hypoglycaemic animals elicited less release of epinephrine and norepinephrine than in controls, without a change in adrenal catecholamine content. Responsiveness of isolated, perfused adrenal glands to acetylcholine and other acetylcholine receptor agonists was also unchanged. These results indicate that recurrent hypoglycaemia compromised the efficacy with which peripheral neuronal activity stimulates adrenal catecholamine release and demonstrate that peripheral components of the sympatho-adrenal system were directly affected by recurrent hypoglycaemia. © The Author(s) 2014.

Congenital glaucoma and CYP1B1: an old story revisited.

PubMed

Alsaif, Hessa S; Khan, Arif O; Patel, Nisha; Alkuraya, Hisham; Hashem, Mais; Abdulwahab, Firdous; Ibrahim, Niema; Aldahmesh, Mohammed A; Alkuraya, Fowzan S

2018-03-19

Primary congenital glaucoma is a trabecular meshwork dysgenesis with resultant increased intraocular pressure and ocular damage. CYP1B1 mutations remain the most common identifiable genetic cause. However, important questions about the penetrance of CYP1B1-related congenital glaucoma remain unanswered. Furthermore, mutations in other genes have been described although their exact contribution and potential genetic interaction, if any, with CYP1B1 mutations are not fully explored. In this study, we employed modern genomic approaches to re-examine CYP1B1-related congenital glaucoma. A cohort of 193 patients (136 families) diagnosed with congenital glaucoma. We identified biallelic CYP1B1 mutations in 80.8% (87.5 and 66.1% in familial and sporadic cases, respectively, p < 0.0086). The large family size of the study population allowed us to systematically examine penetrance of all identified alleles. With the exception of c.1103G>A (p.R368H), previously reported pathogenic mutations were highly penetrant (91.2%). We conclude from the very low penetrance and genetic epidemiological analyses that c.1103G>A (p.R368H) is unlikely to be a disease-causing recessive mutation in congenital glaucoma as previously reported. All cases that lacked biallelic CYP1B1 mutations underwent whole exome sequencing. No mutations in LTBP2, MYOC or TEK were encountered. On the other hand, mutations were identified in genes linked to other ophthalmic phenotypes, some inclusive of glaucoma, highlighting conditions that might phenotypically overlap with primary congenital glaucoma (SLC4A4, SLC4A11, CPAMD8, and KERA). We also encountered candidate causal variants in genes not previously linked to human diseases: BCO2, TULP2, and DGKQ. Our results both expand and refine the genetic spectrum of congenital glaucoma with important clinical implications.

Ultrasonographic adrenal gland findings in healthy semi-captive cheetahs (Acinonyx jubatus).

PubMed

Kirberger, Robert M; Tordiffe, Adrian S W

2016-05-01

Cheetahs in captivity are believed to suffer from stress predisposing them to poor health. To date fecal glucocorticoids have been used as a non-invasive indicator of chronic stress. This study examines, the feasibility of transabdominal adrenal gland ultrasonography in cheetahs and determined normal adrenal measurements that can potentially be used as a more reliable indicator of chronic stress and/or adrenal function. Thirty-three adult cheetahs, aged between 2 and 13 years, accommodated in large off-display camps were examined over 9 days under general anesthesia. The adrenals were readily identified, with the right adrenal being more difficult to find and measure than the left, and were smaller than those expected in similar sized dogs. The left adrenal was shorter and slightly more oval shaped than the right with a length and cranial pole width at a 95% prediction interval of 16.3-22.4 and 4.1-8.7 mm. The same measurements for the right adrenal were 16.8-26.2 and 3.4-10.8 mm, respectively. Corticomedullary ratios were larger for the left adrenal. When corrected for body size, females had significantly longer and greater left adrenal corticomedullary ratios than males. Adrenal measurements did not correlate with left renal length, body size measurements, or enclosure size. Measurements that increased with age included the cortical and total adrenal widths. Adrenal ultrasonography offers potential benefits in assessment of individual cheetah adrenal pathology or the evaluation of stress induced adrenomegally especially in combination with other evaluations such as non-invasive fecal glucocorticoid analyses. Zoo Biol. 35:260-268, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Use of topical dorzolamide for patients with X-linked juvenile retinoschisis: case report.

PubMed

Bastos, André Luís Carvalho de Moura; Freitas, Bruno de Paula; Villas Boas, Oscar; Ramiro, Alexandre Campelo

2008-01-01

X-linked juvenile retinoschisis (XLRS) is a recessively inherited vitreoretinal degeneration characterized by macular pathology and splitting of the neuroretinal layers that is associated with alterations in the XLRS1 gene. There have been no therapeutic interventions known to be effective for patients with X-linked juvenile retinoschisis, but some studies are trying to determine the importance of dorzolamide for the treatment of foveal lesions in this disease. The authors, using optical coherence tomography, describe findings in a patient with X-linked juvenile retinoschisis, before and after a topical use of dorzolamide. Besides the improvement in his visual acuity, further studies are required to elucidate the real prevalence of nonresponse to dorzolamide and the frequency with which there may be a recurrence of foveal cystic changes during continued treatment.

Adrenal Ewing's Sarcoma in an Elderly Man.

PubMed

Toda, Kazuyoshi; Ishii, Sumiyasu; Yasuoka, Hidetoshi; Nishioka, Masaki; Kobayashi, Takayuki; Horiguchi, Kazuhiko; Tomaru, Takuya; Ozawa, Atsushi; Shibusawa, Nobuyuki; Satoh, Tetsurou; Koshi, Hiromi; Segawa, Atsuki; Shimizu, Shin-Ichi; Oyama, Tetsunari; Yamada, Masanobu

2018-02-15

Ewing's sarcoma usually arises in the bones of children and adolescents. We herein report a 74-year-old man with Ewing's sarcoma in the adrenal gland. The diagnosis was confirmed by a genetic test, pathological studies, and several imaging studies. He already had multiple liver metastases when he was transferred to our hospital and died on the 37th day. The diagnosis was further confirmed by autopsy studies. Adrenal Ewing's sarcoma is very rare, and our patient was older than other reported cases. Ewing's sarcoma should be considered even in elderly patients with adrenal tumors.

Adrenal tuberculosis after a pheochromocytoma: a misleading tumoral presentation.

PubMed

Hiéronimus, S; Bernard, J-L; Chevallier, P; Chevallier, A; Chyderiotis, G; Fenichel, P; Landraud, L

2007-06-01

Adrenal gland involvement could account for 6% of active tuberculosis. The diagnosis of this extrapulmonary form of tuberculosis is difficult, especially when presenting as unilateral adrenal tumor. This report describes an unusual case of adrenal tuberculosis presenting as a tumor occurring shortly after surgical removal of an adrenal pheochromocytoma located in the opposite gland, in a 63-year-old woman with a previous history of breast cancer. At initial presentation, the patient suffered from symptomatic paroxysmal hypertension. A pheochromocytoma in the left adrenal was diagnosed and resected. One year later, while physical examination and biological parameters were unremarkable, an enhanced adrenal computed tomography (CT) scan showed a right adrenal mass mimicking the CT features of the resected pheochromocytoma. A peripheral tissular rim delineating a central hypodensity characterized this tumor. Magnetic resonance imaging (MRI) showed the same findings on gadolinium-enhanced T1-weighted slices, while the mass was not seen on T2-weighted images. No tumoral signal loss was observed on out of phase images when using the in phase-out of phase T1-weighted sequence. Because of the tumoral evolution and the uncertainty of the nature of that lesion, the patient underwent a second adrenalectomy. Definitive diagnosis was provided by culture of tissue sample, which resulted in the identification of Mycobacterium tuberculosis. In an era of tuberculosis resurgence, this unusual case underscores the necessity of keeping in mind adrenal tuberculosis as a possible differential diagnosis in adrenal tumors of uncertainty nature. It stresses the importance of culture of biopsy tumor, whenever feasible, to avoid unnecessary operations. In the near future, interferon-gamma assay could be a valuable means to recognize extrapulmonary forms of tuberculosis.

Lamellar macular hole in X linked retinoschisis

PubMed Central

Kumar, Vinod; Goel, Neha

2016-01-01

X linked retinoschisis (XLRS) is the most common juvenile onset retinal degeneration. The disorder leads to poor vision in old age. Complications, however, can lead to earlier loss of vision in this condition. This report describes two patients of XLRS, who had presented with poor vision because of having had a lamellar macular hole at a young age. Lamellar macular holes are rare and have never been reported to cause early onset poor vision in XLRS. PMID:27170611

Optical coherence tomography in the diagnosis of juvenile X-linked retinoschisis.

PubMed

Eriksson, Urban; Larsson, Eva; Holmström, Gerd

2004-04-01

To describe the value of optical coherence tomography (OCT) as a diagnostic tool in the diagnosis of X-linked retinoschisis. We report three boys aged between 8 and 17 years, diagnosed with X-linked retinoschisis. During investigations they were examined with OCT (Zeiss Humphrey OCT 1, upgraded version). Single scans of the central posterior pole and the region around the vascular arcades were obtained. Two of the boys underwent full-field ERG according to ISCEV standards. Genetic analysis was performed in all three boys, with sequencing of the XLRS gene. The OCT results revealed a pattern with a cleavage of the retina in two distinct planes, one deep (outer retina) and one superficial. This was very obvious in one patient and a similar but not as pronounced pattern was seen in the other two cases. The two layers were superficially connected with thin-walled, vertical palisades, separated by low reflective, cystoid spaces, confluent and most prominent in the foveal region. Full-field ERG and/or DNA analysis are well known methods used for diagnosis of X-linked juvenile retinoschisis. In this paper, we suggest that OCT can also be a helpful diagnostic tool.

Incidence and Cause of Hypertension During Adrenal Radiofrequency Ablation

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

Yamakado, Koichiro, E-mail: yama@clin.medic.mie-u.ac.jp; Takaki, Haruyuki; Yamada, Tomomi

Purpose: To evaluate the incidence and cause of hypertension prospectively during adrenal radiofrequency ablation (RFA). Methods: For this study, approved by our institutional review board, written informed consent was obtained from all patients. Patients who received RFA for adrenal tumors (adrenal ablation) and other abdominal tumors (nonadrenal ablation) were included in this prospective study. Blood pressure was monitored during RFA. Serum adrenal hormone levels including epinephrine, norepinephrine, dopamine, and cortisol levels were measured before and during RFA. The respective incidences of procedural hypertension (systolic blood pressure >200 mmHg) of the two patient groups were compared. Factors correlating with procedural systolicmore » blood pressure were evaluated by regression analysis.ResultsNine patients underwent adrenal RFA and another 9 patients liver (n = 5) and renal (n = 4) RFA. Asymptomatic procedural hypertension that returned to the baseline by injecting calcium blocker was found in 7 (38.9%) of 18 patients. The incidence of procedural hypertension was significantly higher in the adrenal ablation group (66.7%, 6/9) than in the nonadrenal ablation group (11.1%, 1/9, P < 0.0498). Procedural systolic blood pressure was significantly correlated with serum epinephrine (R{sup 2} = 0.68, P < 0.0001) and norepinephrine (R{sup 2} = 0.72, P < 0.0001) levels during RFA. The other adrenal hormones did not show correlation with procedural systolic blood pressure. Conclusion: Hypertension occurs frequently during adrenal RFA because of the release of catecholamine.« less

Naloxone inhibits and morphine potentiates. The adrenal steroidogenic response to ACTH

NASA Technical Reports Server (NTRS)

Heybach, J. P.; Vernikos, J.

1980-01-01

The adrenal actions were stereospecific since neither the positve stereoisomer of morphine, nor that of naloxone, had any effect on the adrenal response to exogenous adrenocorticotrophic hormone (ACTH). The administration of human beta endorphin to phyophysectomized rats had no effect on the adrenal corticosterone concentration nor did it alter the response of the adrenal gland to ACTH. These results indicate that morphine can potentiate the action of ACTH on the adrenal by a direct, stereospecific, dose dependent mechanism that is prevented by naloxone pretreatment and which may involve competition for ACTH receptors on the corticosterone secreting cells of the adrenal cortex.

Genetic localization and phenotypic expression of X-linked cataract (Xcat) in Mus musculus.

PubMed

Favor, J; Pretsch, W

1990-01-01

Linkage data relative to the markers tabby and glucose-6-phosphate dehydrogenase are presented to locate X-linked cataract (Xcat) in the distal portion of the mouse X-chromosome between jimpy and hypophosphatemia. The human X-linked cataract-dental syndrome, Nance-Horan Syndrome, also maps closely to human hypophosphatemia and would suggest homology between mouse Xcat and human Nance-Horan Syndrome genes. In hemizygous males and homozygous females penetrance is complete with only slight variation in the degree of expression. Phenotypic expression in Xcat heterozygous females ranges from totally clear to totally opaque lenses. The phenotypic expression between the two lenses of a heterozygous individual could also vary between totally clear and totally opaque lenses. However, a correlation in the degree of expression between the eyes of an individual was observed. A variegated pattern of lens opacity was evident in female heterozygotes. Based on these observations, the site of gene action for the Xcat locus is suggested to be endogenous to the lens cells and the precursor cell population of the lens is concluded to be small. The identification of an X-linked cataract locus is an important contribution to the estimate of the number of mutable loci resulting in cataract, an estimate required so that dominant cataract mutagenesis results may be expressed on a per locus basis. The Xcat mutation may be a useful marker for a distal region of the mouse X-chromosome which is relatively sparsely marked and the X-linked cataract mutation may be employed in gene expression and lens development studies.

Standards of ultrasound imaging of the adrenal glands

PubMed Central

Jakubowski, Wiesław S.; Dobruch-Sobczak, Katarzyna; Kasperlik-Załuska, Anna A.

2015-01-01

Adrenal glands are paired endocrine glands located over the upper renal poles. Adrenal pathologies have various clinical presentations. They can coexist with the hyperfunction of individual cortical zones or the medulla, insufficiency of the adrenal cortex or retained normal hormonal function. The most common adrenal masses are tumors incidentally detected in imaging examinations (ultrasound, tomography, magnetic resonance imaging), referred to as incidentalomas. They include a range of histopathological entities but cortical adenomas without hormonal hyperfunction are the most common. Each abdominal ultrasound scan of a child or adult should include the assessment of the suprarenal areas. If a previously non-reported, incidental solid focal lesion exceeding 1 cm (incidentaloma) is detected in the suprarenal area, computed tomography or magnetic resonance imaging should be conducted to confirm its presence and for differentiation and the tumor functional status should be determined. Ultrasound imaging is also used to monitor adrenal incidentaloma that is not eligible for a surgery. The paper presents recommendations concerning the performance and assessment of ultrasound examinations of the adrenal glands and their pathological lesions. The article includes new ultrasound techniques, such as tissue harmonic imaging, spatial compound imaging, three-dimensional ultrasound, elastography, contrast-enhanced ultrasound and parametric imaging. The guidelines presented above are consistent with the recommendations of the Polish Ultrasound Society. PMID:26807295

The principles of management of congenital anomalies of the upper limb.

PubMed

Watson, S

2000-07-01

Management of congenital anomalies of the upper limb is reviewed with reference to classification and aetiology, incidence, diagnosis before birth, broad principles of treatment, timing of x rays and scans, functional aims, cosmetic appearance, counselling of parents, therapists, scars, skin grafts, growth, and timing of surgery. Notes on 11 congenital hand conditions are given.

Human X-Linked genes regionally mapped utilizing X-autosome translocations and somatic cell hybrids.

PubMed Central

Shows, T B; Brown, J A

1975-01-01

Human genes coding for hypoxanthine phosphoribosyltransferase (HPRT, EC 2.4.2.8; IMP:pyrophosphate phosphoribosyltransferase), glucose-6-phosphate dehydrogenase (G6PD, EC 1.1.1.49; D-glucose-6-phosphate:NADP+ 1-oxidoreductase), and phosphoglycerate kinase (PGK, EC 2.7.2.3; ATP:3-phospho-D-glycerate 1-phosphotransferase) have been assigned to specific regions on the long arm of the X chromosome by somatic cell gentic techniques. Gene assignment and linear order were determined by employing human somatic cells possessing an X/9 translocation or an X/22 translocation in man-mouse cell hybridization studies. The X/9 translocation involved the majority of the X long arm translocated to chromosome 9 and the X/22 translocation involved the distal half of the X long arm translocated to 22. In each case these rearrangements appeared to be reciprocal. Concordant segregation of X-linked enzymes and segments of the X chromosome generated by the translocations indicated assignment of the PGK gene to a proximal long arm region (q12-q22) and the HPRT and G6PD genes to the distal half (q22-qter) of the X long arm. Further evidence suggests a gene order on the X long arm of centromere-PGK-HPRT-G6PD. Images PMID:1056018

Acute adrenal crisis

MedlinePlus

... condition that occurs when there is not enough cortisol. This is a hormone produced by the adrenal ... parts. The outer portion, called the cortex, produces cortisol. This is an important hormone for controlling blood ...

A case of bilateral aldosterone-producing adenomas differentiated by segmental adrenal venous sampling for bilateral adrenal sparing surgery

PubMed Central

Morimoto, R; Satani, N; Iwakura, Y; Ono, Y; Kudo, M; Nezu, M; Omata, K; Tezuka, Y; Seiji, K; Ota, H; Kawasaki, Y; Ishidoya, S; Nakamura, Y; Arai, Y; Takase, K; Sasano, H; Ito, S; Satoh, F

2016-01-01

Primary aldosteronism due to unilateral aldosterone-producing adenoma (APA) is a surgically curable form of hypertension. Bilateral APA can also be surgically curable in theory but few successful cases can be found in the literature. It has been reported that even using successful adrenal venous sampling (AVS) via bilateral adrenal central veins, it is extremely difficult to differentiate bilateral APA from bilateral idiopathic hyperaldosteronism (IHA) harbouring computed tomography (CT)-detectable bilateral adrenocortical nodules. We report a case of bilateral APA diagnosed by segmental AVS (S-AVS) and blood sampling via intra-adrenal first-degree tributary veins to localize the sites of intra-adrenal hormone production. A 36-year-old man with marked long-standing hypertension was referred to us with a clinical diagnosis of bilateral APA. He had typical clinical and laboratory profiles of marked hypertension, hypokalaemia, elevated plasma aldosterone concentration (PAC) of 45.1 ng dl−1 and aldosterone renin activity ratio of 90.2 (ng dl−1 per ng ml−1 h−1), which was still high after 50 mg-captopril loading. CT revealed bilateral adrenocortical tumours of 10 and 12 mm in diameter on the right and left sides, respectively. S-AVS confirmed excess aldosterone secretion from a tumour segment vein and suppressed secretion from a non-tumour segment vein bilaterally, leading to the diagnosis of bilateral APA. The patient underwent simultaneous bilateral sparing adrenalectomy. Histopathological analysis of the resected adrenals together with decreased blood pressure and PAC of 5.2 ng dl−1 confirmed the removal of bilateral APA. S-AVS was reliable to differentiate bilateral APA from IHA by direct evaluation of intra-adrenal hormone production. PMID:26538381

Principles and management of adrenal cancer

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

Javadpour, N.

1987-01-01

This book provides information on adrenal diseases of latest developments and guides the clinicians in the care of their patients. The book is divided into two parts. The first section gives an overview of the embryology, anatomy, physiology, markers, pathology, imaging and the current progress in the field. The second edition covers specific diseases of the adrenal cortex and medulla. The increasingly significant roles played by steroids, catecholamines, blockers, computed tomography and magnetic resonance are elucidated and discussed. The contents include: Overview of progress; current problems, and perspectives - embryology anatomy, physiology, and biologic markers; pathology; advances in diagnosis; imagingmore » techniques; adrenal disorders in childhood; primary aldosteronism; Cushing's syndrome; carcinoma; pheochromocytoma; neuroblastoma; metastatic disease; surgical management; and subject index.« less

Lamellar macular hole in X linked retinoschisis.

PubMed

Kumar, Vinod; Goel, Neha

2016-05-11

X linked retinoschisis (XLRS) is the most common juvenile onset retinal degeneration. The disorder leads to poor vision in old age. Complications, however, can lead to earlier loss of vision in this condition. This report describes two patients of XLRS, who had presented with poor vision because of having had a lamellar macular hole at a young age. Lamellar macular holes are rare and have never been reported to cause early onset poor vision in XLRS. 2016 BMJ Publishing Group Ltd.

The principles of management of congenital anomalies of the upper limb

PubMed Central

Watson, S.

2000-01-01

Management of congenital anomalies of the upper limb is reviewed with reference to classification and aetiology, incidence, diagnosis before birth, broad principles of treatment, timing of x rays and scans, functional aims, cosmetic appearance, counselling of parents, therapists, scars, skin grafts, growth, and timing of surgery. Notes on 11 congenital hand conditions are given.

 PMID:10868991

Congenital Heart Disease: Causes, Diagnosis, Symptoms, and Treatments.

PubMed

Sun, RongRong; Liu, Min; Lu, Lei; Zheng, Yi; Zhang, Peiying

2015-07-01

The congenital heart disease includes abnormalities in heart structure that occur before birth. Such defects occur in the fetus while it is developing in the uterus during pregnancy. About 500,000 adults have congenital heart disease in USA (WebMD, Congenital heart defects medications, www.WebMD.com/heart-disease/tc/congenital-heart-defects-medications , 2014). 1 in every 100 children has defects in their heart due to genetic or chromosomal abnormalities, such as Down syndrome. The excessive alcohol consumption during pregnancy and use of medications, maternal viral infection, such as Rubella virus, measles (German), in the first trimester of pregnancy, all these are risk factors for congenital heart disease in children, and the risk increases if parent or sibling has a congenital heart defect. These are heart valves defects, atrial and ventricular septa defects, stenosis, the heart muscle abnormalities, and a hole inside wall of the heart which causes defect in blood circulation, heart failure, and eventual death. There are no particular symptoms of congenital heart disease, but shortness of breath and limited ability to do exercise, fatigue, abnormal sound of heart as heart murmur, which is diagnosed by a physician while listening to the heart beats. The echocardiogram or transesophageal echocardiogram, electrocardiogram, chest X-ray, cardiac catheterization, and MRI methods are used to detect congenital heart disease. Several medications are given depending on the severity of this disease, and catheter method and surgery are required for serious cases to repair heart valves or heart transplantation as in endocarditis. For genetic study, first DNA is extracted from blood followed by DNA sequence analysis and any defect in nucleotide sequence of DNA is determined. For congenital heart disease, genes in chromosome 1 show some defects in nucleotide sequence. In this review the causes, diagnosis, symptoms, and treatments of congenital heart disease are described.

Effect of calcium(ion) uptake by rat adrenal mitochondria on pregnenolone formation and spectral properties of cytochrome P-450.

PubMed

Simpson, E R; Williams-Smith, D L

1975-10-09

The effect of calcium on pregnenolone formation from endogenous precursors has been studied in mitochondria from rat decapsulated and capsular adrenal glands. In the presence of succinate, addition of calcium chloride in the concentration range 20-150 muM caused an inhibition of pregnenolone formation in both decapsulated and capsular adrenal mitochondria. 11beta-hydroxylation of added deoxycosticosterone in decapsulated adrenal mitochondria was also inhibited. Under these conditions, calcium inhibited the reduction of adrenodoxin, a component of the cytochrome P-450 reductase system, presumably because uptake of calcium by the mitochondria competes with energy-linked transhydrogenase for high-energy intermediates. For this reason, incubations were carried out in the presence of succinate plus isocitrate plus NADP+. Under these conditions, calcium chloride in the concentration range 120-875 muM caused a 2-4-fold stimulation of pregnenolone formation, but had no effect on corticosterone formation from added deoxycorticosterone. The effect of calcium on the optical spectra of cytochrome P-450 has also been examined in mitochondria from decapsulated and capsular rat adrenals. In the presence of succinate, calcium induced a spectral change resembling a type I difference spectrum of cytochrome P-450. Thus it appears that uptake of calcium by adrenal mitochondria can stimulate pregnenolone formation by increasing the interaction of mitochondrial cytochrome P-450 with endogenous substrate.

Congenital Amusia: A Short-Term Memory Deficit for Non-Verbal, but Not Verbal Sounds

ERIC Educational Resources Information Center

Tillmann, Barbara; Schulze, Katrin; Foxton, Jessica M.

2009-01-01

Congenital amusia refers to a lifelong disorder of music processing and is linked to pitch-processing deficits. The present study investigated congenital amusics' short-term memory for tones, musical timbres and words. Sequences of five events (tones, timbres or words) were presented in pairs and participants had to indicate whether the sequences…

A major X-linked locus affects kidney function in mice

PubMed Central

Leduc, Magalie S.; Savage, Holly S.; Stearns, Timothy M.; Cario, Clinton L.; Walsh, Kenneth A.; Paigen, Beverly; Berndt, Annerose

2012-01-01

Chronic kidney disease is a common disease with increasing prevalence in the western population. One common reason for chronic kidney failure is diabetic nephropathy. Diabetic nephropathy and hyperglycemia are characteristics of the mouse inbred strain KK/HlJ, which is predominantly used as a model for metabolic syndrome due to its inherited glucose intolerance and insulin resistance. We used KK/HlJ, an albuminuria-sensitive strain, and C57BL/6J, an albuminuria-resistant strain, to perform a quantitative trait locus (QTL) cross to identify the genetic basis for chronic kidney failure. Albumin-creatinine-ratio (ACR) was measured in 130 F2 male offspring. One significant QTL was identified on chromosome (Chr) X and four suggestive QTLs were found on Chrs 6, 7, 12, and 13. Narrowing of the QTL region was focused on the X-linked QTL and performed by incorporating genotype and expression analyses for genes located in the region. From the 485 genes identified in the X-linked QTL region, a few candidate genes were identified using a combination of bioinformatic evidence based on genomic comparison of the parental strains and known function in urine homeostasis. Finally, this study demonstrates the significance of the X chromosome in the genetic determination of albuminuria. PMID:23011808

The clinical manifestations, diagnosis, and treatment of adrenal emergencies.

PubMed

Tucci, Veronica; Sokari, Telematé

2014-05-01

Emergency medicine physicians should be able to identify and treat patients whose clinical presentations, including key historical, physical examination, and laboratory findings are consistent with diagnoses of primary, secondary, and tertiary adrenal insufficiency, adrenal crisis, and pheochromocytoma. Failure to make a timely diagnosis leads to increased morbidity and mortality. As great mimickers, adrenal emergencies often present with a constellation of nonspecific signs and symptoms that can lead even the most diligent emergency physician astray. The emergency physician must include adrenal emergencies in the differential diagnosis when encountering such clinical pictures. Copyright © 2014 Elsevier Inc. All rights reserved.

Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants in Pregnancy and Congenital Anomalies: Analysis of Linked Databases in Wales, Norway and Funen, Denmark

PubMed Central

Morris, Joan K.; Davies, Gareth I.; Tucker, David; Thayer, Daniel S.; Luteijn, Johannes M.; Morgan, Margery; Garne, Ester; Hansen, Anne V.; Klungsøyr, Kari; Engeland, Anders; Boyle, Breidge; Dolk, Helen

2016-01-01

Background Hypothesised associations between in utero exposure to selective serotonin reuptake inhibitors (SSRIs) and congenital anomalies, particularly congenital heart defects (CHD), remain controversial. We investigated the putative teratogenicity of SSRI prescription in the 91 days either side of first day of last menstrual period (LMP). Methods and Findings Three population-based EUROCAT congenital anomaly registries- Norway (2004–2010), Wales (2000–2010) and Funen, Denmark (2000–2010)—were linked to the electronic healthcare databases holding prospectively collected prescription information for all pregnancies in the timeframes available. We included 519,117 deliveries, including foetuses terminated for congenital anomalies, with data covering pregnancy and the preceding quarter, including 462,641 with data covering pregnancy and one year either side. For SSRI exposures 91 days either side of LMP, separately and together, odds ratios with 95% confidence intervals (ORs, 95%CI) for all major anomalies were estimated. We also explored: pausing or discontinuing SSRIs preconception, confounding, high dose regimens, and, in Wales, diagnosis of depression. Results were combined in meta-analyses. SSRI prescription 91 days either side of LMP was associated with increased prevalence of severe congenital heart defects (CHD) (as defined by EUROCAT guide 1.3, 2005) (34/12,962 [0.26%] vs. 865/506,155 [0.17%] OR 1.50, 1.06–2.11), and the composite adverse outcome of 'anomaly or stillbirth' (473/12962, 3.65% vs. 15829/506,155, 3.13%, OR 1.13, 1.03–1.24). The increased prevalence of all major anomalies combined did not reach statistical significance (3.09% [400/12,962] vs. 2.67% [13,536/506,155] OR 1.09, 0.99–1.21). Adjusting for socio-economic status left ORs largely unchanged. The prevalence of anomalies and severe CHD was reduced when SSRI prescriptions were stopped or paused preconception, and increased when >1 prescription was recorded, but differences were

Genetics Home Reference: congenital cataracts, facial dysmorphism, and neuropathy

MedlinePlus

... sensory cells. This nerve damage is known as peripheral neuropathy. Weakness in the legs, followed by the arms, ... and Neuropathy MedlinePlus Encyclopedia: Congenital Cataract MedlinePlus Encyclopedia: Peripheral Neuropathy General Information from MedlinePlus (5 links) Diagnostic Tests ...

Refined genetic mapping of X-linked Charcot-Marie-Tooth neuropathy

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

Fain, P.R.; Barker, D.F.; Chance, P.F.

1994-02-01

Genetic linkage studies were conducted in four multigenerational families with X-linked Charcot-Marie-Tooth disease (CMTX), using 12 highly polymorphic short-tandem-repeat markers for the pericentromeric region of the X Chromosome. Pairwise linkage analysis with individual markers confirmed tight linkage of CMTX to the pericentromeric region in each family. Multipoint analyses strongly support the order DXS337-CMTX-DXS441-(DXS56, PGK1). 38 refs., 2 figs., 1 tab.

[Primary hyperaldosteronism due to unilateral adrenal hyperplasia with surgical resolution].

PubMed

Rubio-Puchol, O; Garzón-Pastor, S; Salom-Vendrell, C; Hernández-Mijares, A

Unilateral adrenal hyperplasia is a rare cause of primary hyperaldosteronism (around a 3%) that has surgical treatment. A case of a patient with hypertension resistant to conventional therapy in treatment with 7 drugs who presented with primary hyperaldosteronism due to unilateral adrenal hyperplasia is presented. A left adrenalectomy was performed, and the patient had a good clinical response, with no need of any drug after 2 years of surgery. Unilateral adrenal hyperplasia is a different entity and it is not an asymmetric variant of the bilateral adrenal hyperplasia. In the study of patients with primary hyperaldosteronism and imaging tests with absence of adenoma is a diagnosis that must be considered before cataloguing patients with bilateral adrenal hyperplasia and start a medical treatment, because unilateral adrenal hyperplasia would have a surgical resolution. Copyright © 2016 SEH-LELHA. Publicado por Elsevier España, S.L.U. All rights reserved.

Mortality of Septic Mice Strongly Correlates With Adrenal Gland Inflammation.

PubMed

Jennewein, Carla; Tran, Nguyen; Kanczkowski, Waldemar; Heerdegen, Lars; Kantharajah, Ajith; Dröse, Stefan; Bornstein, Stefan; Scheller, Bertram; Zacharowski, Kai

2016-04-01

Sepsis and septic shock are commonly present in the ICU and accompanied by significant morbidity, mortality, and cost. The frequency of secondary adrenal insufficiency in sepsis remains open to debate and a challenge to identify and treat appropriately. Animal models of sepsis using genetic or surgical initiation of adrenal insufficiency resulted in increased mortality, but the mechanisms are still unclear. The present study investigates the impact of adrenal inflammation in septic mice challenged with cecal ligation and puncture. Prospective experimental study. University laboratory. C57BL/6N wild-type mice. Sepsis, induced by cecal ligation and puncture for 24 and 48 hours. Both septic and control mice were carefully monitored (every 30 min) for up to 48 hours and divided into survivors and nonsurvivors. We observed a significant and massive increase of interleukin-6, interleukin-1β, and tumor necrosis factor-α in adrenal protein extracts of nonsurvivors compared with sham animals and survivors. This pattern was partly reflected in liver and lung but not in plasma samples. Notably, a significant increase in nonsurvivors compared with survivors was only found for lung interleukin-6. In line with these findings, we detected a higher degree of leukocyte infiltration and hemorrhage in the adrenal glands of deceased mice. Evaluation of the hypothalamic-pituitary-adrenal axis response in these animals revealed an increase of adrenocorticotropic hormone, which was only partly reflected in the corticosterone level. Notably, using the adrenocorticotropic hormone stimulation test, we found an impaired adrenocorticotropic hormone response, particularly in nonsurvivors, which significantly correlated with the number of infiltrated leukocytes. Cecal ligation and puncture-induced murine sepsis induces a strong inflammatory response in the adrenal glands, which is accompanied by cell death and hemorrhage. Our data suggest that mortality and adrenal incapacitation are

X-linked Alport syndrome caused by splicing mutations in COL4A5.

PubMed

Nozu, Kandai; Vorechovsky, Igor; Kaito, Hiroshi; Fu, Xue Jun; Nakanishi, Koichi; Hashimura, Yuya; Hashimoto, Fusako; Kamei, Koichi; Ito, Shuichi; Kaku, Yoshitsugu; Imasawa, Toshiyuki; Ushijima, Katsumi; Shimizu, Junya; Makita, Yoshio; Konomoto, Takao; Yoshikawa, Norishige; Iijima, Kazumoto

2014-11-07

X-linked Alport syndrome is caused by mutations in the COL4A5 gene. Although many COL4A5 mutations have been detected, the mutation detection rate has been unsatisfactory. Some men with X-linked Alport syndrome show a relatively mild phenotype, but molecular basis investigations have rarely been conducted to clarify the underlying mechanism. In total, 152 patients with X-linked Alport syndrome who were suspected of having Alport syndrome through clinical and pathologic investigations and referred to the hospital for mutational analysis between January of 2006 and January of 2013 were genetically diagnosed. Among those patients, 22 patients had suspected splice site mutations. Transcripts are routinely examined when suspected splice site mutations for abnormal transcripts are detected; 11 of them showed expected exon skipping, but others showed aberrant splicing patterns. The mutation detection strategy had two steps: (1) genomic DNA analysis using PCR and direct sequencing and (2) mRNA analysis using RT-PCR to detect RNA processing abnormalities. Six splicing consensus site mutations resulting in aberrant splicing patterns, one exonic mutation leading to exon skipping, and four deep intronic mutations producing cryptic splice site activation were identified. Interestingly, one case produced a cryptic splice site with a single nucleotide substitution in the deep intron that led to intronic exonization containing a stop codon; however, the patient showed a clearly milder phenotype for X-linked Alport syndrome in men with a truncating mutation. mRNA extracted from the kidney showed both normal and abnormal transcripts, with the normal transcript resulting in the milder phenotype. This novel mechanism leads to mild clinical characteristics. This report highlights the importance of analyzing transcripts to enhance the mutation detection rate and provides insight into genotype-phenotype correlations. This approach can clarify the cause of atypically mild phenotypes in X-linked

A review of the anatomy and clinical significance of adrenal veins.

PubMed

Cesmebasi, Alper; Du Plessis, Maira; Iannatuono, Mark; Shah, Sameer; Tubbs, R Shane; Loukas, Marios

2014-11-01

The adrenal veins may present with a multitude of anatomical variants, which surgeons must be aware of when performing adrenalectomies. The adrenal veins originate during the formation of the prerenal inferior vena cava (IVC) and are remnants of the caudal portion of the subcardinal veins, cranial to the subcardinal sinus in the embryo. The many communications between the posterior cardinal, supracardinal, and subcardinal veins of the primordial venous system provide an explanation for the variable anatomy. Most commonly, one central vein drains each adrenal gland. The long left adrenal vein joins the inferior phrenic vein and drains into the left renal vein, while the short right adrenal vein drains immediately into the IVC. Multiple variations exist bilaterally and may pose the risk of surgical complications. Due to the potential for collaterals and accessory adrenal vessels, great caution must be taken during an adrenalectomy. Adrenal venous sampling, the gold standard in diagnosing primary hyperaldosteronism, also requires the clinician to have a thorough knowledge of the adrenal vein anatomy to avoid iatrogenic injury. The adrenal vein acts as an important conduit in portosystemic shunts, thus the nature of the anatomy and hypercoagulable states pose the risk of thrombosis. © 2014 Wiley Periodicals, Inc.

Laser autofluorescent spectroscopy in adrenal tumor surgery

NASA Astrophysics Data System (ADS)

Vetshev, Petr S.; Ippolitov, Leonid I.; Loschenov, Victor B.; Kazaryan, Airazat M.; Minnibaev, Marat T.; Vetshev, Sergei P.

1999-12-01

Determination of a histological type of adrenal lesion at the preoperative or intraoperative stage allows to choose the optimal volume of surgery and in the short time effectively correct the postoperative hormonal therapy. 12 patients with different adrenal tumours (3 - lightcellular adenoma, 3 - mixedcellular adenoma, 1 - darkcellular adenoma, 1 - trabecular adenoma, 1 - malignant lymphoma, 3 - aldosteroma, 1 - pheochromocytoma, including the chance of combination of mixedcellular adenoma and aldosteroma of left adrenal) were operated on. The patients' aged varied from 33 to 62 years. For the first time we made intraoperative laser autofluorescent spectroscopy (IOLAS). The laser ve1ength was 632.8 nm. We defined a autofluorescent intensity. Portable equipment was used. The duration of the procedure did not exceed 2mm. The autofluorescent peak of adrenal tissue was 1.33+/-0.05 relativistic unit (RU) at 685 nm. The autofiurescent peaks of adrenal adenomas were 1 .07 RU, 0.9-1 .15 RU, 1.7-1 .9 RU, 3.4 RU accordingly for trabecular adenoma, lightcellular adenoma, mixedcellular adenoma, darkcellular adenoma Besides greater contribution of longwave component to auflurescence is characteristic for mixecellular adenoma and especially for darkcellular adenoma. The autofiurescent peaks of aldosteroma and pheochromocytoma were accordingly 1.2-1.4 RU and 2.2 RU. Spectral distribution of intensity was like mixedcellular adenoma's one. In the case of malignant lymphoma the autofiurescence peak was 2,3 RU and we also noted displacement of maximum of autoflurescence (-15 nm, from 685 nm to 670 nm).The results of IOLAS application as a adjuvant diagnosticmethod point to promise for intraoperative rapid diagnostics of adrenal tumours.

X linked exudative vitreoretinopathy: clinical features and genetic linkage analysis.

PubMed

Fullwood, P; Jones, J; Bundey, S; Dudgeon, J; Fielder, A R; Kilpatrick, M W

1993-03-01

A four generation family in which familial exudative vitreoretinopathy is inherited as an X linked condition is described. Essentially the condition is one of abnormal vascularisation and signs at birth are those of a retinopathy superficially resembling retinopathy of prematurity, retinal folds, or, in advanced cases, enophthalmos or even phthisis. Prognosis depends on the progression of the retinal changes. The family members, including seven affected males and five obligate carrier females, have been types for 20 DNA markers, and linkage analysis suggests a gene locus either at Xq21.3 or at Xp11. As the latter region includes the locus for the gene for Norrie disease, it is possible that this and X linked vitreoretinopathy are allelic. We can further speculate that the differences in severity of the clinical manifestations are dependent only upon the timing of the insult.

Adrenal venous sampling for stratifying patients for surgery of adrenal nodules detected using dynamic contrast enhanced CT

PubMed Central

Kim, Jin Young; Kim, See Hyung; Lee, Hee Jung; Kim, Young Hwan; Kim, Mi Jeong; Cho, Seung Hyun

2014-01-01

PURPOSE We aimed to assess the value of adrenal venous sampling (AVS) for diagnosing primary aldosteronism (PA) subtypes in patients with a unilateral nodule detected on adrenal computed tomography (CT) and scheduled for adrenalectomy. MATERIALS AND METHODS This retrospective study included 80 consecutive patients with PA undergoing CT and AVS. Different lateralization indices were assessed, and a cutoff established using receiver operating characteristic curve analysis. The value of CT alone versus CT with AVS for differentiating PA subtypes was compared. The adrenalectomy outcome was assessed, and predictors of cure were determined using univariate analysis. RESULTS AVS was successful in 68 patients. A cortisol-corrected aldosterone affected-to-unaffected ratio cutoff of 2.0 and affected-to-inferior vena cava ratio cutoff of 1.4 were the best lateralization indices, with accuracies of 82.5% and 80.4%, respectively. CT and AVS diagnosed 38 patients with aldosterone-producing adenomas, five patients with unilateral adrenal hyperplasia, and 25 patients with bilateral adrenal hyperplasia. Of the 52 patients with a nodule detected on CT, subsequent AVS diagnosed bilateral adrenal hyperplasia in 14 patients (27%). Compared to the results of combining CT with AVS, the accuracy of CT alone for diagnosing aldosterone-producing adenomas was 71.1% (P < 0.001). The cure rate for hypertension after adrenalectomy was 39.2%, with improvement in 53.5% of patients. On univariate analysis, predictors of persistent hypertension were male gender and preoperative systolic blood pressure. CONCLUSION To avoid inappropriate surgery, AVS is necessary for diagnosing unilateral nodules with aldosterone hypersecretion detected by CT. PMID:24047720

Adrenal Function Status in Patients with Paracoccidioidomycosis after Prolonged Post-Therapy Follow-Up

PubMed Central

Tobón, Angela M.; Agudelo, Carlos A.; Restrepo, Carlos A.; Villa, Carlos A.; Quiceno, William; Estrada, Santiago; Restrepo, Angela

2010-01-01

This study assessed adrenal function in patients with paracoccididioidomycosis who had been treated to determine a possible connection between high antibody titers and adrenal dysfunction attributable to persistence of the fungus in adrenal gland. Adrenal gland function was studied in 28 previously treated patients, 2 (7.1%) of whom were shown to have adrenal insufficiency and 7 (259%) who showed a below normal response to stimuli by adrenocorticotropic hormone. Paracoccidioides brasiliensis was detected in the adrenal gland from one of the patients with adrenal insufficiency. Although the study failed to demonstrate a significant difference between high antibody titers and low cortisol levels, the proportion of adrenal insufficiency detected and the subnormal response to adrenocorticotropic hormone confirmed that adrenal damage is an important sequela of paracoccidioidomycosis. Studies with a larger number of patients should be conducted to confirm the hypothesis of persistence of P. brasiliensis in adrenal gland after therapy. PMID:20595488

A family with X-linked anophthalmia: exclusion of SOX3 as a candidate gene.

PubMed

Slavotinek, Anne; Lee, Stephen S; Hamilton, Steven P

2005-10-01

We report on a four-generation family with X-linked anophthalmia in four affected males and show that this family has LOD scores consistent with linkage to Xq27, the third family reported to be linked to the ANOP1 locus. We sequenced the SOX3 gene at Xq27 as a candidate gene for the X-linked anophthalmia based on the high homology of this gene to SOX2, a gene previously mutated in bilateral anophthlamia. However, no amino acid sequence alterations were identified in SOX3. We have improved the definition of the phenotype in males with anophthalmia linked to the ANOP1 locus, as microcephaly, ocular colobomas, and severe renal malformations have not been described in families linked to ANOP1. (c) 2005 Wiley-Liss, Inc.

Characterization of Adrenal Adenoma by Gaussian Model-Based Algorithm.

PubMed

Hsu, Larson D; Wang, Carolyn L; Clark, Toshimasa J

2016-01-01

We confirmed that computed tomography (CT) attenuation values of pixels in an adrenal nodule approximate a Gaussian distribution. Building on this and the previously described histogram analysis method, we created an algorithm that uses mean and standard deviation to estimate the percentage of negative attenuation pixels in an adrenal nodule, thereby allowing differentiation of adenomas and nonadenomas. The institutional review board approved both components of this study in which we developed and then validated our criteria. In the first, we retrospectively assessed CT attenuation values of adrenal nodules for normality using a 2-sample Kolmogorov-Smirnov test. In the second, we evaluated a separate cohort of patients with adrenal nodules using both the conventional 10HU unit mean attenuation method and our Gaussian model-based algorithm. We compared the sensitivities of the 2 methods using McNemar's test. A total of 183 of 185 observations (98.9%) demonstrated a Gaussian distribution in adrenal nodule pixel attenuation values. The sensitivity and specificity of our Gaussian model-based algorithm for identifying adrenal adenoma were 86.1% and 83.3%, respectively. The sensitivity and specificity of the mean attenuation method were 53.2% and 94.4%, respectively. The sensitivities of the 2 methods were significantly different (P value < 0.001). In conclusion, the CT attenuation values within an adrenal nodule follow a Gaussian distribution. Our Gaussian model-based algorithm can characterize adrenal adenomas with higher sensitivity than the conventional mean attenuation method. The use of our algorithm, which does not require additional postprocessing, may increase workflow efficiency and reduce unnecessary workup of benign nodules. Copyright © 2016 Elsevier Inc. All rights reserved.

CAPILLARY NETWORK ALTERATIONS IN X-LINKED RETINOSCHISIS IMAGED ON OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

PubMed

Romano, Francesco; Arrigo, Alessandro; Chʼng, Soon Wai; Battaglia Parodi, Maurizio; Manitto, Maria Pia; Martina, Elisabetta; Bandello, Francesco; Stanga, Paulo E

2018-06-05

To assess foveal and parafoveal vasculature at the superficial capillary plexus, deep capillary plexus, and choriocapillaris of patients with X-linked retinoschisis by means of optical coherence tomography angiography. Six patients with X-linked retinoschisis (12 eyes) and seven healthy controls (14 eyes) were recruited and underwent complete ophthalmologic examination, including best-corrected visual acuity, dilated fundoscopy, and 3 × 3-mm optical coherence tomography angiography macular scans (DRI OCT Triton; Topcon Corp). After segmentation and quality review, optical coherence tomography angiography slabs were imported into ImageJ 1.50 (NIH; Bethesda) and digitally binarized. Quantification of vessel density was performed after foveal avascular zone area measurement and exclusion. Patients were additionally divided into "responders" and "nonresponders" to dorzolamide therapy. Foveal avascular zone area resulted markedly enlarged at the deep capillary plexus (P < 0.001), particularly in nonresponders. Moreover, patients disclosed a significant deep capillary plexus rarefaction, when compared with controls (P: 0.04); however, a subanalysis revealed that this damage was limited to the fovea (P: 0.006). Finally, the enlargement of foveal avascular zone area positively correlated with a decline in best-corrected visual acuity (P: 0.01). Prominent foveal vascular impairment is detectable in the deep capillary plexus of patients with X-linked retinoschisis. Our results correlate with functional outcomes, suggesting a possible vascular role in X-linked retinoschisis clinical manifestations.

Enabling secure, distributed collaborations for adrenal tumor research.

PubMed

Stell, Anthony; Sinnott, Richard; Jiang, Jipu

2010-01-01

Many e-Health strategies rely on the secure integration of datasets that have previously resided in isolated locations, but can now in principle be accessed over the Internet. Of paramount importance in the health domain is the need for the security and privacy of data that is transmitted across these networks. One such collaboration, which spans several specialist centres across France, Germany, Italy and the UK, is ENSAT - the European Network for the Study of Adrenal Tumors. The rarity of the tumors under study means the value of accessing, aggregating and comparing data from many centres is great indeed. However this is especially challenging given that ENSAT require clinical and genomic data to be seamlessly linked, but in such a way that the information governance, ethics and privacy concerns of the patients and associated stakeholders involved are visibly satisfied. Key to this is the clear separation of clinical and genomic data sets and support for rigorous patient-identity protecting access control. This is especially challenging when such data sets exist across different organisational boundaries. In this paper we describe a prototype solution offering a security-oriented tailored portal supported by a layered encryption-driven linkage technology (VANGUARD) that offers precisely such patient-privacy protecting capabilities. We describe the architecture, implementation and use to date of this facility to support the ENSAT adrenal cancer research network.

Case report of a bilateral adrenal myelolipoma associated with Cushing disease.

PubMed

Park, Se Yoon; Kwak, Mi Kyung; Kim, Hye Jeong; Park, Hyeong Kyu; Suh, Kyo-Il; Yoo, Myung Hi; Jin, So Young; Yun, Sumi; Byun, Dong Won

2017-12-01

Adrenal myelolipomas are rare benign tumors, composed of a variable mixture of mature adipose tissue and hematopoietic tissue. These tumors are frequently detected incidentally and are usually asymptomatic, and hormonally inactive. During a routine health checkup, a 52-year-old man was found to have a tumor on the bilateral adrenal glands. Abdominal computed tomography revealed a well-defined, heterogeneously enhanced bilateral adrenal mass, suggesting a myelolipoma. The hormonal evaluation revealed adrenocorticotropic hormone (ACTH) dependent Cushing syndrome. The patient underwent left adrenalectomy, and transsphenoidal resection of a pituitary mass. The final diagnosis was adrenal myelolipoma associated with Cushing disease. Growth of right adrenal myelolipoma was detected during the 7-year follow-up. There were enhancing pituitary lesions in repeat magnetic resonance imaging of the sellar region, which implies persistent or recurrent pituitary adenoma. This case reinforces relationship between Cushing disease and adrenal myelolipoma. To the best of our knowledge, this is the first reported pathologically confirmed bilateral adrenal myelolipoma associated with Cushing disease. This report supports the idea that ACTH is associated with the development of adrenal myelolipoma. Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.

Nomenclature for congenital and paediatric cardiac disease: historical perspectives and The International Pediatric and Congenital Cardiac Code.

PubMed

Franklin, Rodney C G; Jacobs, Jeffrey Phillip; Krogmann, Otto N; Béland, Marie J; Aiello, Vera D; Colan, Steven D; Elliott, Martin J; William Gaynor, J; Kurosawa, Hiromi; Maruszewski, Bohdan; Stellin, Giovanni; Tchervenkov, Christo I; Walters Iii, Henry L; Weinberg, Paul; Anderson, Robert H

2008-12-01

Research Team, will link images and videos to the International Paediatric and Congenital Cardiac Code. The images and videos will be acquired from cardiac morphologic specimens and imaging modalities such as echocardiography, angiography, computerized axial tomography and magnetic resonance imaging, as well as intraoperative images and videos. Efforts are ongoing to expand the usage of The International Paediatric and Congenital Cardiac Code to other areas of global healthcare. Collaborative efforts are underway involving the leadership of The International Nomenclature Committee for Pediatric and Congenital Heart Disease and the representatives of the steering group responsible for the creation of the 11th revision of the International Classification of Diseases, administered by the World Health Organisation. Similar collaborative efforts are underway involving the leadership of The International Nomenclature Committee for Pediatric and Congenital Heart Disease and the International Health Terminology Standards Development Organisation, who are the owners of the Systematized Nomenclature of Medicine or "SNOMED". The International Paediatric and Congenital Cardiac Code was created by specialists in the field to name and classify paediatric and congenital cardiac disease and its treatment. It is a comprehensive code that can be freely downloaded from the internet (http://www.IPCCC.net) and is already in use worldwide, particularly for international comparisons of outcomes. The goal of this effort is to create strategies for stratification of risk and to improve healthcare for the individual patient. The collaboration with the World Heath Organization, the International Health Terminology Standards Development Organisation, and the healthcare industry, will lead to further enhancement of the International Code, and to its more universal use.

X-linked Acrogigantism (X-LAG) Syndrome: Clinical Profile and Therapeutic Responses

PubMed Central

Beckers, Albert; Lodish, Maya Beth; Trivellin, Giampaolo; Rostomyan, Liliya; Lee, Misu; Faucz, Fabio R; Yuan, Bo; Choong, Catherine S; Caberg, Jean-Hubert; Verrua, Elisa; Naves, Luciana Ansaneli; Cheetham, Tim D; Young, Jacques; Lysy, Philippe A; Petrossians, Patrick; Cotterill, Andrew; Shah, Nalini Samir; Metzger, Daniel; Castermans, Emilie; Ambrosio, Maria Rosaria; Villa, Chiara; Strebkova, Natalia; Mazerkina, Nadia; Gaillard, Stéphan; Barra, Gustavo Barcelos; Casulari, Luis Augusto; Neggers, Sebastian J.; Salvatori, Roberto; Jaffrain-Rea, Marie-Lise; Zacharin, Margaret; Santamaria, Beatriz Lecumberri; Zacharieva, Sabina; Lim, Ee Mun; Mantovani, Giovanna; Zatelli, Maria Chaira; Collins, Michael T; Bonneville, Jean-François; Quezado, Martha; Chittiboina, Prashant; Oldfield, Edward H.; Bours, Vincent; Liu, Pengfei; De Herder, Wouter; Pellegata, Natalia; Lupski, James R.; Daly, Adrian F.; Stratakis, Constantine A.

2015-01-01

X-linked acro-gigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, which is highly upregulated in pituitary tumors. We conducted this study to explore the clinical, radiological and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X-LAG and a microduplication in chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in 2 families was dominant with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2–3 months of age (median 12 months). At diagnosis (median delay 27 months), patients had a median height and weight SDS score of >+3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF-1 and prolactin, usually due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despite moderate to high somatostatin receptor subtype-2 expression in tumor tissue. Postoperative adjuvant pegvisomant achieved control of IGF-1 all 5 cases in which it was employed. X-LAG is a new infant-onset gigantism syndrome that has a severe clinical phenotype leading to challenging disease management. PMID:25712922

Adrenal incidentaloma caused by extramedullary haematopoiesis: conservative management is optimal.

PubMed

Sekar, Suganya; Burad, Deepak; Abraham, Aby; Paul, Mazhuvanchary Jacob

2015-09-21

We present a thalassaemic patient with extramedullary haematopoiesis in the adrenal gland, which is one of the rare sites of involvement. A 29-year-old man presented with a history of anaemia since childhood which required blood transfusion recently. On examination, he had pallor, icterus and splenomegaly with no other palpable abdominal mass. He was diagnosed to have β-thalassaemia. Ultrasonography of the abdomen showed an incidental right adrenal mass with splenomegaly; CT revealed a large right adrenal mass with heterogeneous density. Adrenal adenoma, carcinoma and extramedullary haematopoiesis were considered in the differential diagnosis. After excluding a functioning tumour, the diagnosis was confirmed by ultrasound-guided biopsy. Since the patient was asymptomatic, the adrenal lesion was managed conservatively. 2015 BMJ Publishing Group Ltd.

Over-the-Counter "Adrenal Support" Supplements Contain Thyroid and Steroid-Based Adrenal Hormones.

PubMed

Akturk, Halis Kaan; Chindris, Ana Maria; Hines, Jolaine M; Singh, Ravinder J; Bernet, Victor J

2018-03-01

To assess whether dietary supplements that are herbal and/or animal-derived products, marketed for enhancing metabolism or promoting energy, "adrenal fatigue," or "adrenal support," contain thyroid or steroid hormones. Twelve dietary adrenal support supplements were purchased. Pregnenolone, androstenedione, 17-hydroxyprogesterone, cortisol, cortisone, dehydroepiandrosterone sulfate, synthetic glucocorticoids (betamethasone, dexamethasone, fludrocortisone, megestrol acetate, methylprednisolone, prednisolone, prednisone, budesonide, and triamcinolone acetonide) levels were measured twice in samples in a blinded fashion. This study was conducted between February 1, 2016, and November 1, 2016. Among steroids, pregnenolone was the most common hormone in the samples. Budesonide, 17-hydroxyprogesterone, androstenedione, cortisol, and cortisone were the others in order of prevalence. All the supplements revealed a detectable amount of triiodothyronine (T3) (63-394.9 ng/tablet), 42% contained pregnenolone (66.12-205.2 ng/tablet), 25% contained budesonide (119.5-610 ng/tablet), 17% contained androstenedione (1.27-7.25 ng/tablet), 8% contained 17-OH progesterone (30.09 ng/tablet), 8% contained cortisone (79.66 ng/tablet), and 8% contained cortisol (138.5 ng/tablet). Per label recommended doses daily exposure was up to 1322 ng for T3, 1231.2 ng for pregnenolone, 1276.4 ng for budesonide, 29 ng for androstenedione, 60.18 ng for 17-OH progesterone, 277 ng for cortisol, and 159.32 ng for cortisone. All the supplements studied contained a small amount of thyroid hormone and most contained at least 1 steroid hormone. This is the first study that measured thyroid and steroid hormones in over-the-counter dietary "adrenal support" supplements in the United States. These results may highlight potential risks of hidden ingredients in unregulated supplements. Copyright © 2017 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

Congenital panfollicular nevus associated with polydactyly.

PubMed

Kim, Jinah; Zambrano, Eduardo V; McNiff, Jennifer M

2007-12-01

A 2-year-old girl presented with ulnar-sided duplication of the left thumb distal to the interphalangeal joint and syndactyly of the first web space. She also had several asymptomatic pink-tan cutaneous papules, involving the first and second ray of the left hand and wrist, clinically resembling a linear epidermal nevus. Microscopically, the papules were composed of well-circumscribed aggregates of basaloid epithelium within the dermis. No normal hair follicles were identified. Follicular germ and papillae were identified, representing abortive attempts at hair follicle formation. The features were remarkably similar to a novel entity described by Finn and Argenyi as congenital panfollicular nevus. In our case, the congenital panfollicular nevus was associated with distal thumb polysyndactyly, which may suggest an important link between limb patterning and hair follicle development.

Nomenclature for congenital and paediatric cardiac disease: the International Paediatric and Congenital Cardiac Code (IPCCC) and the Eleventh Iteration of the International Classification of Diseases (ICD-11).

PubMed

Franklin, Rodney C G; Béland, Marie J; Colan, Steven D; Walters, Henry L; Aiello, Vera D; Anderson, Robert H; Bailliard, Frédérique; Boris, Jeffrey R; Cohen, Meryl S; Gaynor, J William; Guleserian, Kristine J; Houyel, Lucile; Jacobs, Marshall L; Juraszek, Amy L; Krogmann, Otto N; Kurosawa, Hiromi; Lopez, Leo; Maruszewski, Bohdan J; St Louis, James D; Seslar, Stephen P; Srivastava, Shubhika; Stellin, Giovanni; Tchervenkov, Christo I; Weinberg, Paul M; Jacobs, Jeffrey P

2017-12-01

An internationally approved and globally used classification scheme for the diagnosis of CHD has long been sought. The International Paediatric and Congenital Cardiac Code (IPCCC), which was produced and has been maintained by the International Society for Nomenclature of Paediatric and Congenital Heart Disease (the International Nomenclature Society), is used widely, but has spawned many "short list" versions that differ in content depending on the user. Thus, efforts to have a uniform identification of patients with CHD using a single up-to-date and coordinated nomenclature system continue to be thwarted, even if a common nomenclature has been used as a basis for composing various "short lists". In an attempt to solve this problem, the International Nomenclature Society has linked its efforts with those of the World Health Organization to obtain a globally accepted nomenclature tree for CHD within the 11th iteration of the International Classification of Diseases (ICD-11). The International Nomenclature Society has submitted a hierarchical nomenclature tree for CHD to the World Health Organization that is expected to serve increasingly as the "short list" for all communities interested in coding for congenital cardiology. This article reviews the history of the International Classification of Diseases and of the IPCCC, and outlines the process used in developing the ICD-11 congenital cardiac disease diagnostic list and the definitions for each term on the list. An overview of the content of the congenital heart anomaly section of the Foundation Component of ICD-11, published herein in its entirety, is also included. Future plans for the International Nomenclature Society include linking again with the World Health Organization to tackle procedural nomenclature as it relates to cardiac malformations. By doing so, the Society will continue its role in standardising nomenclature for CHD across the globe, thereby promoting research and better outcomes for fetuses

Effect of Space Flight on Adrenal Medullary Function

NASA Technical Reports Server (NTRS)

Lelkes, Peter I.

1999-01-01

We hypothesize that microgravity conditions during space flight alter the expression and specific activities of the adrenal medullary CA synthesizing enzymes (CASE). Previously, we examined adrenals from six rats flown for six days aboard STS 54 and reported that microgravity induced a decrease in the expression and specific activity of rat adrenal medullary tyrosine hydroxylase, the rate limiting enzyme of CA synthesis, without affecting the expression of other CASE. In the past, we analyzed some of the > 300 adrenals from two previous Space Shuttle missions (PARE 03 and SLS 2). The preliminary results (a) attest to the good state of tissue preservation, thus proving the feasibility of subsequent large-scale evaluation, and (b) confirm and extend our previous findings. With this grant we will be able to expeditiously analyze all our specimens and to complete our studies in a timely fashion.

Near fatal spontaneous intraperitoneal bleeding: A rare manifestation in a congenital factor X deficiency carrier.

PubMed

Vinod, K V; Hitha, B; Kaaviya, R; Dutta, T K

2015-03-01

Congenital factor X (FX) deficiency is a rare coagulation disorder of autosomal recessive inheritance, characterized by bleeding of variable severity. Bleeding severity generally correlates with the level of FX functional activity and severe bleeding usually occurs in moderate and severe deficiency, when FX coagulant activity is <5%. FX activity above 10% is infrequently associated with severe bleeding. Here we report the rare occurrence of life-threatening massive spontaneous intraperitoneal bleeding with hypovolemic shock, resulting from spontaneous rupture of an ovarian luteal cyst in a 25-year-old FX deficiency carrier woman, with a FX activity of 26%. She was managed successfully conservatively, with fresh frozen plasma and packed red blood cell transfusions and she showed gradual improvement. The case is being reported to discuss the diagnosis and management of this rare inherited coagulation disorder.

Genetic Analysis of a Kindred With X-linked Mental Handicap and Retinitis Pigmentosa

PubMed Central

Aldred, M. A.; Dry, K. L.; Knight-Jones, E. B.; Hardwick, L. J.; Teague, P. W.; Lester, D. H.; Brown, J.; Spowart, G.; Carothers, A. D.; Raeburn, J. A.; Bird, A. C.; Fielder, A. R.; Wright, A. F.

1994-01-01

A kindred is described in which X-linked nonspecific mental handicap segregates together with retinitis pigmentosa. Carrier females are mentally normal but may show signs of the X-linked retinitis pigmentosa carrier state and become symptomatic in their later years. Analysis of polymorphic DNA markers at nine loci on the short arm of the X chromosome shows that no crossing-over occurs between the disease and Xp11 markers DXS255, TIMP, DXS426, MAOA, and DXS228. The 90% confidence limits show that the locus is in the Xp21-q21 region. Haplotype analysis is consistent with the causal gene being located proximal to the Xp21 loci DXS538 and 5'-dystrophin on the short arm of the X chromosome. The posterior probability of linkage to the RP2 region of the X chromosome short arm (Xp11.4-p11.23) is .727, suggesting the possibility of a contiguous-gene-deletion syndrome. No cytogenetic abnormality has been identified. PMID:7977353

Adrenal suppression in bronchiectasis and the impact of inhaled corticosteroids.

PubMed

Holme, J; Tomlinson, J W; Stockley, R A; Stewart, P M; Barlow, N; Sullivan, A L

2008-10-01

The present study identified three patients with bronchiectasis receiving inhaled corticosteroids (ICSs) who had symptomatic adrenal suppression secondary to ICS. The prevalence of adrenal suppression is unknown in bronchiectasis. The frequency of adrenal suppression and the impact of ICS use in bronchiectasis patients were examined. In total, 50 outpatients (33 receiving ICSs) underwent a short Synacthen test and completed a St George's Respiratory Questionnaire (SGRQ). Symptoms of adrenal suppression, steroid use and lung function were compared between subjects who were suppressed and those who were not. Adrenal suppression was evident in 23.5% of subjects who did not receive ICSs and 48.5% of those who did. Basal cortisol and the increments by which cortisol increased 30 min after Synacthen were lower in suppressed than in nonsuppressed subjects. The incremental cortisol rise was negatively correlated with SGRQ impacts and total score, suggesting a worse quality of life in those who had an impaired adrenal response. The greatest frequency of generalised symptoms was seen in the suppressed group. A significant proportion of subjects with bronchiectasis have evidence of adrenal suppression, and this is increased when inhaled corticosteroids are also used. Impairment of the cortisol response to stimulation is associated with poorer health status.

A heterozygous mutation in RPGR associated with X-linked retinitis pigmentosa in a patient with Turner syndrome mosaicism (45,X/46,XX).

PubMed

Zhou, Qi; Yao, Fengxia; Wang, Feng; Li, Hui; Chen, Rui; Sui, Ruifang

2018-01-01

Turner syndrome with retinitis pigmentosa (RP) is rare, with only three cases reported based on clinical examination alone. We summarized the 4-year follow-up and molecular findings in a 28-year-old patient with Turner syndrome and the typical features of short stature and neck webbing, who also had X-linked RP. Her main complaints were night blindness and progressive loss of vision since the age of 9 years. Ophthalmologic examination, optical coherent tomographic imaging, and visual electrophysiology tests showed classic manifestations of RP. The karyotype of peripheral blood showed mosaicism (45,X [72%]/46,XX[28%]). A novel heterozygous frameshift mutation (c.2403_2406delAGAG, p.T801fsX812) in the RP GTPase regulator (RPGR) gene was detected using next generation sequencing and validated by Sanger sequencing. We believe that this is the first report of X-linked RP in a patient with Turner syndrome associated with mosaicism, and an RPGR heterozygous mutation. We hypothesize that X-linked RP in this woman is not related to Turner syndrome, but may be a manifestation of the lack of a normal paternal X chromosome with intact but mutated RPGR. © 2017 Wiley Periodicals, Inc.

Foveomacular schisis in juvenile X-linked retinoschisis: an optical coherence tomography study.

PubMed

Yu, Jia; Ni, Yingqin; Keane, Pearse A; Jiang, Chunhui; Wang, Wenji; Xu, Gezhi

2010-06-01

To explore the structural features of juvenile X-linked retinoschisis using spectral-domain optical coherence tomography (OCT). Retrospective, observational cross-sectional study. Eighteen male patients (34 eyes) who were diagnosed with juvenile X-linked retinoschisis at the Eye & ENT Hospital of Fudan University over an 18-month period were included. Their OCT images, which were obtained using spectral-domain OCT (Cirrus HD-OCT; Carl Zeiss Meditec), were analyzed. The anatomic location of the schisis cavity in juvenile X-linked retinoschisis was characterized by direct inspection of OCT images. On OCT, the schisis cavity was visible at the fovea in all 34 eyes, and it was associated with increased retinal thickness. Schisis was present at the retinal nerve fiber layer in 4 eyes, at the inner nuclear layer in 29 eyes, and at the outer nuclear layer/outer plexiform layer in 22 eyes. In most cases, widespread foveomacular schisis was detected using OCT; however, in 9 eyes (6 patients), the schisis was confined to the fovea. Schisis of the inner nuclear layer and outer nuclear layer/outer plexiform layer almost always involved the foveal center, but retinal nerve fiber layer schisis was seen only in the parafoveal area. Despite conventional wisdom, in patients with X-linked retinoschisis, the schisis cavity can occur in a number of different layers of the neurosensory retina (retinal nerve fiber layer, inner nuclear layer, and outer nuclear layer/outer plexiform layer). In addition, different forms of schisis may affect different locations in the macula (foveal vs parafoveal), and, in most eyes, the schisis involves the entire foveomacular region. Copyright 2010 Elsevier Inc. All rights reserved.

Mental retardation, congenital heart defect, cleft palate, short stature, and facial anomalies: A new X-linked multiple congenital anomalies/mental retardation syndrome: Clinical description and molecular studies

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

Hamel, B.C.J.; Mariman, E.C.M.; Beersum, S.E.C. van

1994-07-15

We report on two brothers and their two maternal uncles with severe mental retardation, congenital heart defect, cleft or highly arched palate, short stature and craniofacial anomalies consisting of microcephaly, abnormal ears, bulbous nose, broad nasal bridge, malar hypoplasia, and micro-gnathia. Three of the four patients died at an early age. The mother of the two brothers had an atrial septal defect. She is assumed to be manifesting carrier of a mutant gene, which is expressed in her two sons and two brothers. By multipoint linkage analysis it is found that the most likely location of the responsible gene ismore » the pericentromeric region Xp21.3-q21.3 with DMD and DXS3 as flanking markers. Maximum information is obtained with marker DXS453 (Z = 1.20 at {theta} = 0.0). 24 refs., 12 figs., 1 tab.« less

A Novel Mutation in the XLRS1 Gene in a Korean Family with X-linked Retinoschisis

PubMed Central

Jwa, Nam Soo; Kim, Sung Soo; Lee, Sung Chul; Kwon, Oh Woong

2006-01-01

Purpose To report a novel missense mutation in the XLRS1 gene in a Korean family with X-linked retinoschisis. Methods Observation case report of a family with a proband with X-linked retinoschisis underwent complete ophthalmologic examination. Genomic DNA was excluded from the family's blood and all exons of the XLRS1 gene were amplified by polymerase chain reaction and analyzed using a direct sequencing method. Results A novel Leu103Phe missense mutation was identified. Conclusions A novel Leu103Phe mutation is an additional missense mutation which is responsible for the pathogenesis of X-linked retinoschisis. PMID:16768192

X-linked nephrogenic diabetes insipidus mutations in North America and the Hopewell hypothesis.

PubMed Central

Bichet, D G; Arthus, M F; Lonergan, M; Hendy, G N; Paradis, A J; Fujiwara, T M; Morgan, K; Gregory, M C; Rosenthal, W; Didwania, A

1993-01-01

In X-linked nephrogenic diabetes insipidus (NDI) the urine of male patients is not concentrated after the administration of the antidiuretic hormone arginine-vasopressin. This disease is due to mutations in the V2 receptor gene that maps to chromosome region Xq28. In 1969, Bode and Crawford suggested that most NDI patients in North America shared common ancestors of Ulster Scot immigrants who arrived in Halifax in 1761 on the ship Hopewell. A link between this family and a large Utah kindred was also suggested. DNA was obtained from 17 affected male patients from the "Hopewell" kindred and from four additional families from Nova Scotia and New Brunswick who shared the same Xq28 NDI haplotype. The Utah kindred and two families (Q2, Q3) from Quebec were also studied. The "Hopewell" mutation, W71X, is a single base substitution (G-->A) that changes codon 71 from TGG (tryptophan) to TGA (stop). The W71X mutation was found in affected members of the Hopewell and of the four satellite families. The W71X mutation is the cause of X-linked NDI for the largest number of related male patients living in North America. Other families (Utah, Q2 and Q3) that are historically and ethnically unrelated bear other mutations in the V2 receptor gene. Images PMID:8104196

Burosumab Therapy in Children with X-Linked Hypophosphatemia.

PubMed

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

2018-05-24

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

The forensic value of X-linked markers in mixed-male DNA analysis.

PubMed

He, HaiJun; Zha, Lagabaiyila; Cai, JinHong; Huang, Jian

2018-05-04

Autosomal genetic markers and Y chromosome markers have been widely applied in analysis of mixed stains at crime scenes by forensic scientists. However, true genotype combinations are often difficult to distinguish using autosomal markers when similar amounts of DNA are contributed by multiple donors. In addition, specific individuals cannot be determined by Y chromosomal markers because male relatives share the same Y chromosome. X-linked markers, possessing characteristics somewhere intermediate between autosomes and the Y chromosome, are less universally applied in criminal casework. In this paper, X markers are proposed to apply to male mixtures because their true genes can be more easily and accurately recognized than the decision of the genotypes of AS markers. In this study, an actual two-man mixed stain from a forensic case file and simulated male-mixed DNA were examined simultaneously with the X markers and autosomal markers. Finally, the actual mixture was separated successfully by the X markers, although it was unresolved by AS-STRs, and the separation ratio of the simulated mixture was much higher using Chr X tools than with AS methods. We believe X-linked markers provide significant advantages in individual discrimination of male mixtures that should be further applied to forensic work.

Comparison of cortisol exposures and pharmacodynamic adrenal steroid responses to hydrocortisone suspension vs. commercial tablets.

PubMed

Sarafoglou, Kyriakie; Gonzalez-Bolanos, Maria T; Zimmerman, Cheryl L; Boonstra, Timothy; Yaw Addo, O; Brundage, Richard

2015-04-01

The Endocrine Society Clinical Practice Guidelines on congenital adrenal hyperplasia (CAH) recommend against using hydrocortisone suspension based on a study that examined a commercial suspension. Our objective was to examine the absorption of an extemporaneously prepared hydrocortisone suspension and compare it to tablets. Secondary objectives were to evaluate the 17-hydroxyprogesterone and androstenedione adrenal steroid responses. Using a parallel design, 34 children diagnosed with CAH received either suspension (n = 9; median age 1.8 years) or tablets (n = 25; median age 7.5 years). Patients were given their usual morning hydrocortisone formulation and dose; 12 serial blood samples were obtained and the area under the curve (AUC) was calculated. The mg/m(2) dose-normalized cortisol AUCs were no different in the suspension and tablet groups (P = ·06), nor was there a significant difference in the C(max) or T(max) (P = .08 and P = .41, respectively). Although there were no differences in the 17-hydroxyprogesterone change-from-baseline AUCs, baseline concentrations, or the nadir concentrations when comparing suspension and tablet formulations, the androstenedione values were significantly lower as expected in the younger aged suspension group. Our results offer compelling evidence that an extemporaneously prepared hydrocortisone suspension provides comparable cortisol exposures to commercially available tablet formulations in children and can be used to safely and effectively treat CAH. © 2014, The American College of Clinical Pharmacology.

Variation in the X-Linked EFHC2 Gene Is Associated with Social Cognitive Abilities in Males

PubMed Central

Startin, Carla M.; Fiorentini, Chiara; de Haan, Michelle; Skuse, David H.

2015-01-01

Females outperform males on many social cognitive tasks. X-linked genes may contribute to this sex difference. Males possess one X chromosome, while females possess two X chromosomes. Functional variations in X-linked genes are therefore likely to impact more on males than females. Previous studies of X-monosomic women with Turner syndrome suggest a genetic association with facial fear recognition abilities at Xp11.3, specifically at a single nucleotide polymorphism (SNP rs7055196) within the EFHC2 gene. Based on a strong hypothesis, we investigated an association between variation at SNP rs7055196 and facial fear recognition and theory of mind abilities in males. As predicted, males possessing the G allele had significantly poorer facial fear detection accuracy and theory of mind abilities than males possessing the A allele (with SNP variant accounting for up to 4.6% of variance). Variation in the X-linked EFHC2 gene at SNP rs7055196 is therefore associated with social cognitive abilities in males. PMID:26107779

Serotonin and Serotonin Transporters in the Adrenal Medulla: A Potential Hub for Modulation of the Sympathetic Stress Response.

PubMed

Brindley, Rebecca L; Bauer, Mary Beth; Blakely, Randy D; Currie, Kevin P M

2017-05-17

Serotonin (5-HT) is an important neurotransmitter in the central nervous system where it modulates circuits involved in mood, cognition, movement, arousal, and autonomic function. The 5-HT transporter (SERT; SLC6A4) is a key regulator of 5-HT signaling, and genetic variations in SERT are associated with various disorders including depression, anxiety, and autism. This review focuses on the role of SERT in the sympathetic nervous system. Autonomic/sympathetic dysfunction is evident in patients with depression, anxiety, and other diseases linked to serotonergic signaling. Experimentally, loss of SERT function (SERT knockout mice or chronic pharmacological block) has been reported to augment the sympathetic stress response. Alterations to serotonergic signaling in the CNS and thus central drive to the peripheral sympathetic nervous system are presumed to underlie this augmentation. Although less widely recognized, SERT is robustly expressed in chromaffin cells of the adrenal medulla, the neuroendocrine arm of the sympathetic nervous system. Adrenal chromaffin cells do not synthesize 5-HT but accumulate small amounts by SERT-mediated uptake. Recent evidence demonstrated that 5-HT 1A receptors inhibit catecholamine secretion from adrenal chromaffin cells via an atypical mechanism that does not involve modulation of cellular excitability or voltage-gated Ca 2+ channels. This raises the possibility that the adrenal medulla is a previously unrecognized peripheral hub for serotonergic control of the sympathetic stress response. As a framework for future investigation, a model is proposed in which stress-evoked adrenal catecholamine secretion is fine-tuned by SERT-modulated autocrine 5-HT signaling.

Adrenal trauma: Elvis Presley Memorial Trauma Center experience.

PubMed

Mehrazin, Reza; Derweesh, Ithaar H; Kincade, Matthew C; Thomas, Adam C; Gold, Robert; Wake, Robert W

2007-11-01

Adrenal gland injury is a potentially devastating event if unrecognized in the treatment course of a trauma patient. We reviewed our single-center experience and outcomes in patients with adrenal gland trauma. We performed a retrospective review of all patients presenting with trauma to the Regional Medical Center at Memphis who had adrenal gland injuries from January 1991 through March 2006. Each chart was reviewed with attention to the demographics, associated injuries, complications, and outcomes. Patients were stratified into two subgroups according to age (35 years or younger and older than 35 years) to allow for an age-based comparison between the two groups. Of 58,000 patients presenting with trauma, 130 (0.22%) were identified with adrenal injuries, of which 8 (6.2%) were isolated and 122 (93.8%) were not. Of these 130 patients, 125 (96.2%) had their injury diagnosed by computed tomography and 5 (3.8%) had their injury diagnosed during exploratory laparotomy. Right-sided injuries predominated (78.5%), with six (4.6%) bilateral. Four patients (3.1%) underwent adrenalectomy. Seven patients (5.4%) with adrenal injuries died. One patient (0.77%) required chronic steroid therapy. Patients older than 35 years were more likely to have complications such as deep venous thrombosis, pneumonia, and urinary tract infections. Patient age of 35 years or younger was associated with a significantly increased incidence of liver lacerations. Adrenal gland injury is uncommon, although mostly associated with greater injury severity. Although adding to morbidity, most are self-limited and do not require intervention.