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Objective: To explore the clinical characteristics and pathogenic variant in a child with Cantú syndrome (CS)., Methods: A male who was admitted to the Children's Hospital Affiliated to Zhengzhou University on February 23, 2022 was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples of the child and his parents were collected and subjected to whole-exome sequencing (WES). Candidate variant was verified by Sanger sequencing. This study was approved by the Children's Hospital Affiliated to Zhengzhou University (Ethics No. 2023-K-087)., Results: The child, a 3-year-and-2-month-old male, was born with hirsutism, with heavy hair all over the body and peculiar facial features. Routine echocardiography 1 month before had discovered atrial septal defect. Sequencing revealed that the child has harbored a heterozygous c.2438G>C (p.S813T) variant of the ABCC9 gene, which was de novo in origin. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.2438G>C variant was classified as likely pathogenic (PS2+PM2_Supporting+PP3)., Conclusion: The heterozygous c.2438G>C variant of the ABCC9 gene probably underlay the pathogenesis of CS in this child.

Background and Objectives : Polycystic ovary syndrome (PCOS) is a frequent and complex multidisciplinary disorder. Data regarding the role of genes involved in vitamin D metabolism in PCOS are as-yet elusive but suggest an association of VDR (vitamin D receptor) and vitamin D levels with metabolic, endocrine and cutaneous manifestations. The aim of this study was to evaluate the association between VDR gene polymorphisms and cutaneous manifestations, to find a correlation between hormonal parameters, oxidative stress and skin manifestations in women with PCOS, and to determine the impact of VDR gene polymorphisms on these parameters. Materials and Methods : This case-control study included 39 controls and 46 women with PCOS, matched by age and BMI distribution. Acne, hirsutism, seborrhea, androgenetic alopecia, oxidative stress and androgen hormones were recorded. VDR gene polymorphisms ApaI, FokI and TaqI were examined by polymerase chain reaction restriction fragment length polymorphism, and the androgen hormone (total testosterone, DHEAS), SHBG and malondialdehyde levels were assessed. Results : The most frequent skin manifestations in PCOS cases were acne followed by seborrhea, hirsutism and androgenic alopecia. The VDR-FokI polymorphism CC genotype had a significant protective role in the odds of acne (OR = 0.11, 95% CI: [0.02, 0.70], p = 0.015, p-corrected = 0.040) and seborrhea (OR = 0.15, 95% CI: [0.03, 0.75], p = 0.019, p-corrected = 0.039). The results demonstrated a significant protective effect of the C allele on the odds of acne and seborrhea in PCOS cases. Moreover, the dominant genotype of VDR-TaqI could have a protective role against oxidative stress (lower MDA levels) compared to patients carrying the TT genotype. Conclusions : In summary, this is the first study to demonstrate that the FokI CC genotype may have a protective role against both acne and seborrhea in women with PCOS, while the VDR-TaqI dominant genotype is associated with diminished oxidative stress in PCOS patients.

Research suggests that polycystic ovary syndrome (PCOS) traits (e.g., hyperandrogenism) may create a suboptimal intrauterine environment and induce epigenetic modifications. Therefore, we assessed the associations of PCOS traits with neonatal DNA methylation (DNAm) using two independent cohorts. DNAm was measured in both cohorts using the Infinium MethylationEPIC array. Multivariable robust linear regression was used to determine associations of maternal PCOS exposure or preconception testosterone with methylation β-values at each CpG probe and corrected for multiple testing by false-discovery rate (FDR). In the birth cohort, 12% (102/849) had a PCOS diagnosis (8.1% PCOS without hirsutism; 3.9% PCOS with hirsutism). Infants exposed to maternal PCOS with hirsutism compared to no PCOS had differential DNAm at cg02372539 [β(SE): -0.080 (0.010); FDR p  = 0.009], cg08471713 [β(SE):0.077 (0.014); FDR p  = 0.016] and cg17897916 [β(SE):0.050 (0.009); FDR p  = 0.009] with adjustment for maternal characteristics including pre-pregnancy BMI. PCOS with hirsutism was also associated with 8 differentially methylated regions (DMRs). PCOS without hirsutism was not associated with individual CpGs. In an independent preconception cohort, total testosterone concentrations were associated with 3 DMRs but not with individual CpGs, though the top quartile of testosterone compared to the lowest was marginally associated with increased DNAm at cg21472377 near an uncharacterized locus (FDR p  = 0.09). Examination of these probes and DMRs indicate they may be under foetal genetic control. Overall, we found several associations among newborns exposed to PCOS, specifically when hirsutism was reported, and among newborns of women with relatively higher testosterone around conception.

Purpose: The study aimed to investigate whether repeat number in the androgen receptor (AR) gene has any contribution to phenotypes of the disease of androgen excess (polycystic ovary syndrome (PCOS), idiopathic hyperandrogenemia (IHA) and idiopathic hirsutism (IH) in a cohort of Turkish women., Methods: Three hundred and fifty-four voluntary premenopausal women (172 healthy controls and 182 patients with androgen excess disorders and idiopathic hirsutism) 18-45 years of age seen at an outpatient endocrine clinic at Erciyes University Hospital between January 2013 and December 2014 were included. All volunteers have undergone physical examination and biochemical evaluation. The polymorphic (CAG)n repeat of the human AR was determined by fragment analyses., Results: Detailed clinical analyses of the patients ended up with 137 PCOS, 24 IHA, and 21 IH. Pairwise comparisons revealed the CAG repeat number differences between the PCOS and controls (p = 0.005) and IH and controls (p = 0.020). Women with CAG repeat length ≤ 17 had a significantly increased twofold risk for PCOS than those women with > 17 CAG repeats OR: 2.0 (95% CI 1.2-3.3, p = 0.005). Women with CAG repeat length ≤ 17 had a significantly increased threefold risk for IH than those women with > 17 CAG repeats OR: 2.9 (95% CI 1.2-7.3, p = 0.020). When correlation analysis was performed, a weak negative correlation was detected between the short allele and FGS score (r = - 0.131, p = 0.013) and a positive relationship between total testosterone and longer allele in the IHA group (r = 0.425, p = 0.039). Median repeat length of the shorter allele between oligomenorrhea and woman with normal menstrual cycle was found to be statistically significant (p = 0.017)., Conclusion: This study indicated that the risk of PCOS and IH is associated with the inheritance of ARs with shorter CAG repeats.

Non-classical congenital adrenal hyperplasia (NC-CAH) includes a group of genetic disorders due to a broad class of CYP21A2 variants identifying a disease-causing 'C' genotype. The heterozygous carriers of CYP21 mutations are at increased risk of developing clinically evident hyperandrogenism, even though clinical and laboratory characteristics are still underestimated. With the aim of obtaining a more accurate delineation of the phenotype of heterozygous carrier of CAH, we analyzed clinical, biochemical and molecular characteristics in a cohort of Sicilian subjects. Fifty-seven females with biallelic and monoallelic CYP21A2 variants classifying NC-CAH (24) and heterozygous carriers of CAH (33), respectively were selected. Forty-four females age-matched healthy controls were also enrolled and genotyped for CYP21A2. Clinical, hormonal and genetic data were collected. CYP21A2 monoallelic mutations, defining the heterozygous carriers state, were identified in subjects with clinical features including hirsutism, oligomenorrhoea, overweight and a PCO-like phenotype, particularly occurring in the age of adolescence. Consistently, levels of 17OHP and cortisol were found to be significantly different from NC-CAH. Overall, some clinical and laboratory findings including oligomenorrhea and 17OHP/cortisol ratio were observed as independent markers associated with carriers of CAH. Here we report a high prevalence of late-onset signs of polycystic ovary syndrome (PCOS) and hyperandrogenism in heterozygous carriers. The 17OHP/cortisol ratio may be a predictive tool to identify the carriers of CAH, even though specific cut-off values have not yet been identified., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: The purpose of this study is to assess the prevalence of heterozygous CYP21A2 mutation and analyze its correlation with clinical manifestation in patients with acne, hirsutism, or both., Methods: Clinical evaluation, hormone testing, and genetic analysis of the CYP21A2 gene were performed in 60 female patients who visited department of endocrinology of Peking Union Medical College Hospital (PUMCH) for acne, hirsutism, or both from May to November of 2018. The average age of the patients was 26.72 ± 5.73 years. ACTH, Plasma cortisol, LH, FSH, PRL, estradiol, progesterone, testosterone, 17-hydroxyprogesterone (17-OHP), and dehydroepiandrosterone sulfate (DHEA-S) were measured in all participants. Polymerase chain reaction (PCR) combined with sequencing and multiplex ligation dependent probe amplification (MLPA) technique were used to detect the mutation of the CYP21A2 gene. The prevalence of CYP21A2 mutation was compared between the patients and 60 controls, as well as the data in different genetic variant database., Results: A total of 8.3% (5/60) of individuals with acne, hirsutism, or both in this study were found to harbor heterozygotic CYP21A2 mutation, and the frequency was significantly higher than that in public databases. Identified mutations included V282L (n = 2), I173N (n = 1), E6 cluster [I237N, V238E, and M240K (n = 1)] and large deletion (n = 1). There was no significant difference in hormone levels between heterozygous carriers and subjects with normal CYP21A2 genes., Conclusions: The prevalence of heterozygous CYP21A2 mutation detected in patients with acne, hirsutism, or both was significantly higher than in the general population. Whether the heterozygous mutation of CYP21A2 is the cause of clinical symptoms needs further assessment.

Background: Bainbridge-Ropers syndrome is a rare autosomal dominant genetic disorder., Case Characteristics: A 26-day-old neonate presented with feeding difficulties, excessive sleeping, and hirsutism over forehead and lumbosacral skin., Outcome: Whole-exome sequencing identified a novel nonsense mutation., Message: We report a novel mutation in a Chinese neonate with Bainbridge-Ropers syndrome.

Introduction: Hirsutism is a medical sign rather than a disease affects 5-8% of women of reproductive age. Hirsutism is associated with hyperandrogenemia in most patients excluding those with idiopathic hirsutism (IH). The most common cause of hirsutism is polycystic ovary syndrome (PCOS) followed by IH and idiopathic hyperandrogenemia (IHA); however, the clinical presentation of non-classical congenital adrenal hyperplasia (NCAH) in females is often indistinguishable from other hyperandrogenic disorders with common clinical signs such as hirsutism., Objective: The primary aim of the study is to examine the physical properties of the three genes and to make a detailed comparison of the mutations with the clinical data to contribute the etiology of hirsutism., Subjects and Methods: 122 women admitted to the Endocrinology Clinic at Erciyes University Hospital with hirsutism were enrolled in the study between 2013-2014. All the participants were clinically evaluated. Protein-encoding exons, exon-intron boundaries of CYP21A2 (including proximal promoter), CYP11B1 and HSD3B2 genes were analyzed via state-of-the-art genetic studies., Results: DNA sequencing analyses revealed two homozygous and three compound heterozygous 21-hydroxylase deficient (21OHD) NCAH patients. Additionally, three novel CYP21A2 mutations (A89V, M187I and G491S) and two novel CYP11B1 mutations (V188I and G87A) were determined. The frequencies of heterozygous mutations in CYP21A2 (including promoter), CYP11B1 and HSD3B2 genes were determined as 26.5% (15% coding region, 11.5% promoter), 11.5% and 0%, respectively., Conclusion: 21OHD-NCAH prevalence was determined to be ~4%. Unexpectedly, high heterozygous mutation rates were observed in CYP11B1 gene and CYP21A2 promoter region. CYP11B1 and HSD3B2 deficiencies were not prevalent in Turkish women with hirsutism despite the existence of higher heterozygous mutation rate in CYP11B1.

Rubinstein-Taybi syndrome (RSTS) is a rare congenital disorder, mainly characterized by postnatal growth retardation, intellectual disability, and facial and limb abnormalities. Although not considered as characteristic manifestations, numerous cutaneous anomalies have also been reported in patients with RSTS while there has been no report of desquamation so far in any patients with RSTS. We report an unusual case of RSTS in an 8-year-old boy who presented with the typical facial and limb abnormalities of RSTS accompanied with apparent hirsutism and desquamation, but without apparent intellectual disability. Whole exome sequencing identified a novel mutation in the bromodomain of CREBBP (c.3503A>G, p.N1168S), which was further confirmed by targeted Sanger sequencing in comparison with healthy controls. Our findings expand the spectra of genetic mutations and clinical presentations associated with RSTS, and underline the importance of maintaining high awareness of rare presentations and diagnostic difficulties in management of rare genetic diseases such as RSTS., (© 2019 British Association of Dermatologists.)

11β-Hydroxylase deficiency is the second most common enzyme disorder after 21-hydroxylase deficiency causing congenital adrenal hyperplasia (CAH 11β ). In females, the clinical phenotype of CAH 11β classic forms is associated with ambiguous genitalia, virilization and hypertension, while most common complaints in milder non-classic forms include hirsutism, acne, menstrual disturbances, and infertility. Herein, we present clinical and genetic characteristics of an adult woman with 11β-hydroxylase deficiency, hypertension and infertility; she has been followed up from her first pregnancy to her early menopause. Genetic analyses of the patient revealed a compound-heterozygosity due to two variants in the CYP11B1 gene p.Val316Met and p.Asp480ThrfsTer2. Both mutations have not been previously reported as pathogenic in the literature. Emerging questions concerning the clinical management, fertility potential, mineral corticoid abnormalities and perimenopausal transition in patients with non-classic CAH 11β have also been briefly discussed. The presented case of an adult woman with CAH 11β shows that the proper diagnosis and close monitoring of patients with different CAH forms might ensure good therapy adherence and successful fertility.

Chromosome 1p36 deletion is the most common subtelomeric deletion syndrome characterized by variable features including unique facial appearance, intellectual disability, developmental delay, cardiac defects, seizures and hypotonia. Here, we report a patient with developmental delay, dilated cardiomyopathy, seizures, hirsutism and cutis laxa who was diagnosed with 1p36 deletion syndrome by chromosome microarray analysis. This patient is the first reported case of 1p36 deletion syndrome associated with cutis laxa and our results suggest that the 1p36 region contains one or more genes relevant to cutis laxa. This case also indicates the importance of considering chromosome abnormalities (microdeletion/microduplication syndromes) in patients presenting skin disorders combined with unexplained developmental delay, intellectual disability or multiple congenital abnormalities., (© 2018 Japanese Dermatological Association.)

Purpose: Variations in the degree of hirsutism among women of different ethnic backgrounds may stem from multiple etiologies. Shorter length of the polymorphic CAG repeats of the androgen receptor (AR) gene may be associated with increased activity of the receptor leading to hirsutism. We hypothesized that there are ethnic differences in the degree of hirsutism that is unrelated to androgen levels among Israeli women, and that the CAG repeats length may contribute to these differences. Anti-androgenic therapies, such as spironolactone, could be suggested if a shorter CAG repeats length is found to affect the difference in the degree of hirsutism between the ethnic groups., Methods: Healthy Israeli Jewish women aged 18-45 years of Ashkenazi and non-Ashkenazi origin were invited to participate. Hirsutism was assessed using the simplified Ferriman-Gallwey (sFG) score, and serum total testosterone levels were measured as well. The CAG repeats length was determined by PCR. Methylation-sensitive methods were used to detect the fractional activity of each allele, and the weighted mean was calculated for the CAG repeats length., Results: One-hundred and eight women were recruited (49 Ashkenazi and 59 non-Ashkenazi). The Ashkenazi women had a significantly lower degree of hirsutism (P<0.01), lower mean BMI (P = 0.003), total testosterone levels (P = 0.017), and longer weighted bi-allelic CAG repeats mean (P = 0.015) compared to non-Ashkenazi women. For the group as a whole, there was a significant negative correlation between the number of CAG repeats in the AR gene and the sFG score, while the number of repeats was not related to testosterone levels. Stepwise logistic regression revealed that ethnic origin and the CAG repeats length were the strongest factors affecting hirsutism (P<0.001, P = 0.03, respectively)., Conclusions: There is a significant difference in the degree of hirsutism between Ashkenazi and non-Ashkenazi women in Israel that is partially explained by CAG repeats length.

Barber-Say syndrome is a rare autosomal dominant disease characterized by dysmorphic features, mainly of the eyelids and skin. It is caused by heterozygous mutations in gene TWIST2, localized in chromosome 2q37.3. The authors present the case of a pediatric patient with a clinical diagnosis of Barber-Say syndrome with ocular symptoms related to exposure keratitis. Molecular analysis of her DNA revealed a mutation on TWIST2 gene confirming the diagnosis of Barber-Say syndrome. Surgical treatment of the patient's eyelids resolved her signs and symptoms.

Introduction: Inactivating mutations in the enzyme hexose-6-phosphate dehydrogenase (H6PDH), the enzyme responsible for NADPH generation playing critical role in 11-hydroxysteroid dehydrogenase type 1 (11b-HSD1) activity, cause apparent cortisone reductase deficiency (ACRD). It leads to increased metabolic clearance rate of cortisol due to a defect in cortisone to cortisol conversion by 11b-HSD1. We want to analyse the process of the disease, efficacy of long-lasting treatment with glucocorticoids throughout childhood and adolescence in only male patient with ACRD., Case Presentation: A 23 year-old male patient was diagnosed with ACRD at the age of 7 years. The clinical manifestation of ACRD was presented by precocious pubarche. His bone age was assessed as 11.5 years old. Blood tests indicated increased the plasma androgen, with elevated 17-hydroxyprogesterone concentration. A steroid profile analysis of a 24-h urine collection showed extremely reduced THF + allo-THF/THE ratio - 0.021 (normal range: 0.7-1.2). Two months of hydrocortisone therapy was ineffective and dexamethasone was administered in initial dose of 0.375 mg/24 h. Next dosage beetwen 0.125 mg/24h and 0.375 mg/24h has been changed depending on the patient's results of laboratory tests and condition. Control laboratory studies indicated suppression of excess adrenal androgen synthesis, but we never got the THF + allo-THF/THE ratio in normal values. He did not develop any serious side effects, although dexamethasone is the most potent adrenal suppression drug., Conclusions: Hydrocortisone treatment is ineffective in ACRD patients because it was rapidly metabolized to cortisone. We have found the balance between the dexamethasone treatment effects of adrenal suppression and the achievement of full height potential considering the condition of our patient., (© Polish Society for Pediatric Endocrinology and Diabetology.)

Insulin receptor mutations cause extreme insulin resistance resulting in acanthosis nigricans and hyperandrogenism. We report a pre-menarchal adolescent female with normal weight, with severe acanthosis nigricans, acne, and hirsutism. Initial investigation revealed elevated fasting and post-prandial insulin and high testosterone and androstenedione levels. Her father had frequent complaints of hypoglycemia. Coding sequence and splice junction analysis of the INSR gene, in our patient and her father, revealed a heterozygous missense mutation in the β subunit of the insulin receptor (Arg1131Trp), resulting in receptor loss of function. Metformin therapy and carbohydrate control improved acanthosis and menarche ensued within 3 months. Our case highlights the importance of distinguishing insulin resistance commonly associated with obesity from monogenic defects. Although, there is no consensus on treatment of children with monogenic forms of insulin resistance due to its rarity, dietary and lifestyle modifications and insulin-sensitizing agents play a key role in management.

Barber-Say syndrome (BSS) and Ablepharon-Macrostomia syndrome (AMS) are congenital malformation syndromes caused by heterozygous mutations in TWIST2. Here we provide a critical review of all patients published with these syndromes. We excluded several earlier reports due to misdiagnosis or insufficient data for reliable confirmation of the diagnosis. There remain 16 reliably diagnosed individuals with BSS and 16 with AMS. Major facial characteristics present in both entities, albeit often in differing frequencies, are excessive facial creases, hypertelorism, underdevelopment of the anterior part of the eyelids (anterior lamella), ectropion, broad nasal ridge and tip, thick and flaring alae nasi, protruding maxilla, wide mouth, thin upper vermillion, and attached ear lobes. In BSS a remarkable extension of the columella on the philtrum can be seen, and in both the medial parts of the cheeks bulge towards the corners of the mouth (cheek pads). Scalp hair is sparse in AMS only, but sparse eyebrows and eyelashes occur in both entities, and general hypertrichosis occurs in BSS. We compare these characteristics with those in Setleis syndrome which can also be caused by TWIST2 mutations. The resemblance between the three syndromes is considerable, and likely differences seem larger than they actually are due to insufficiently complete evaluation for all characteristics of the three entities in the past. It is likely that with time it can be concluded that BSS. AMS and Setleis syndrome form a continuum. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder affecting 5-10 % of women of reproductive age. It generally manifests with oligo/anovulatory cycles, hirsutism and polycystic ovaries, together with a considerable prevalence of insulin resistance. Although the aetiology of the syndrome is not completely understood yet, PCOS is considered a multifactorial disorder with various genetic, endocrine and environmental abnormalities. Moreover, PCOS patients have a higher risk of metabolic and cardiovascular diseases and their related morbidity, if compared to the general population.

Objective: Hirsutism results from hyperandrogenemia and/or exaggerated androgen responsiveness. Among various causes of hirsutism, some patients do not exhibit androgen excess which is called idiopathic hirsutism (IH). The pathogenesis of IH could not so far be clearly established., Design: To investigate the mRNA expression of aromatase enzyme and the other enzymes having functional roles in the steroidogenic pathway, in freshly obtained skin tissue from subumbilical skin and the arm of the patients with IH and healthy women., Methods: Twenty-one women with IH and 15 healthy women were included in the study. We aimed to determine mRNA expressions of genes associated with local androgen synthesis and metabolism (CYP11A1, STS, CYP19A1, SRD5A1, SRD5A2, HSD3B1, AR, COMT, ESR1, ESR2, HSD3B2, CYP17A1, SULT2A1, SULT1E1, HSD17B2, IL6, TGFB1, TNFA) from skin biopsy and blood samples of patients with IH and the data compared with healthy subjects., Results: Patients with IH exhibit significantly lower interleukin 6 (IL6) mRNA expression and higher steroid sulphatase (STS) and hydroxysteroid (17beta) dehydrogenase 2 (HSD17B2), gene mRNA expression, respectively, in the subumbilical region skin biopsies. Similarly, patients with IH exhibit significantly lower IL6 mRNA expression and higher STS and HSD17B2 gene mRNA expression, respectively, in the arm skin compared to healthy women's subumbilical region., Conclusions: In both arm and subumbilical skin biopsy of patients with IH, we observed an up-regulation of HSD17B2 and STS, decreased IL6 mRNA expression, probably determining an increase in the local amount of active androgens, which could then be used as substrate for other androgen metabolic routes., (© 2015 European Society of Endocrinology.)

Background: Severe, early-onset insulin resistance in the absence of obesity, hepatic steatosis and dyslipidaemia is frequently attributable to a genetic defect affecting the insulin receptor. We describe a patient with severe insulin resistance in whom insulin receptor mutation analysis was mistakenly recorded as normal. Western blot analysis of skeletal muscle showed reduced insulin receptor protein and led to re-evaluation of the insulin receptor and the discovery of a novel mutation., Case Report: A Niuean women, first evaluated at age 6 years for severe acanthosis nigricans, hirsutism, poor growth and cognitive impairment, had extremely elevated fasting insulin levels of 10740 IU/l (fasting reference range 4-24 IU/l) and a normal glucose concentration (4.9 mmol/l). Diabetes was diagnosed at age 9 years and metformin treatment introduced. By age 14 years, she developed refractory hyperglycaemia despite metformin, rosiglitazone and 240 IU insulin daily. Insulin receptor genetic analysis was documented as normal. At age 23 years, with a blood glucose concentration of 37 mmol/l and an HbA1c concentration of 116 mmol/mol, U500 insulin 2000 IU/day was required for glycaemic control. She developed severe proliferative diabetic retinopathy with neovascular glaucoma leading to blindness. There was no renal dysfunction, dyslipidaemia or hepatic steatosis. A muscle biopsy was performed to evaluate the insulin signalling pathway and showed reduced insulin receptor protein. Sequencing of the insulin receptor showed a homozygous p.Val1010Leu missense mutation., Conclusion: This patient illustrates the use of muscle biopsy in the evaluation of a patient with unexplained severe insulin resistance. This approach may usefully be applied to other cases of severe insulin resistance, where genetic testing for known mutations in the insulin signalling pathway has been negative., (© 2015 The Authors. Diabetic Medicine © 2015 Diabetes UK.)

Background: Natural mutations in the human glucocorticoid receptor (hGR, NR3C1) gene cause Chrousos syndrome, a rare condition characterized by generalized, partial, target-tissue insensitivity to glucocorticoids., Objective: To present a new case of Chrousos syndrome caused by a novel mutation in the hGR gene, and to elucidate the molecular mechanisms through which the natural mutant receptor affects glucocorticoid signal transduction., Design and Results: The index case presented with hirsutism, acne, alopecia, anxiety, fatigue and irregular menstrual cycles, but no clinical manifestations suggestive of Cushing's syndrome. Endocrinologic evaluation revealed elevated 08:00 h plasma adrenocorticotropic hormone, serum cortisol and androstenedione concentrations and increased urinary free cortisol excretion. The patient harbored a novel A > G transition at nucleotide position 2177, which resulted in histidine (H) to arginine (R) substitution at amino acid position 726 of the receptor (c.2177A > G, p.H726R). Compared with the wild-type receptor, the mutant receptor hGRαH726R demonstrated decreased ability to transactivate glucocorticoid-responsive genes and to transrepress the nuclear factor-κB signalling pathway, displayed 55% lower affinity for the ligand and a four-fold delay in nuclear translocation, and interacted with the glucocorticoid receptor-interacting protein 1 coactivator mostly through its activation function-1 domain. Finally, a 3-dimensional molecular modelling study of the H726R mutation revealed a significant structural shift in the rigidity of helix 10 of the receptor, which resulted in reduced flexibility and decreased affinity of the mutant receptor for binding to the ligand., Conclusions: The natural mutant receptor hGRαH726R impairs multiple steps of glucocorticoid signal transduction, thereby decreasing tissue sensitivity to glucocorticoids., (© 2015 Stichting European Society for Clinical Investigation Journal Foundation.)

Ablepharon macrostomia syndrome (AMS) and Barber-Say syndrome (BSS) are rare congenital ectodermal dysplasias characterized by similar clinical features. To establish the genetic basis of AMS and BSS, we performed extensive clinical phenotyping, whole exome and candidate gene sequencing, and functional validations. We identified a recurrent de novo mutation in TWIST2 in seven independent AMS-affected families, as well as another recurrent de novo mutation affecting the same amino acid in ten independent BSS-affected families. Moreover, a genotype-phenotype correlation was observed, because the two syndromes differed based solely upon the nature of the substituting amino acid: a lysine at TWIST2 residue 75 resulted in AMS, whereas a glutamine or alanine yielded BSS. TWIST2 encodes a basic helix-loop-helix transcription factor that regulates the development of mesenchymal tissues. All identified mutations fell in the basic domain of TWIST2 and altered the DNA-binding pattern of Flag-TWIST2 in HeLa cells. Comparison of wild-type and mutant TWIST2 expressed in zebrafish identified abnormal developmental phenotypes and widespread transcriptome changes. Our results suggest that autosomal-dominant TWIST2 mutations cause AMS or BSS by inducing protean effects on the transcription factor's DNA binding., (Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome characterized by fetal macrosomia, macroglossia, and abdominal wall defects. BWS patients are at risk to develop Wilms tumor, neuroblastoma, hepatoblastoma, and adrenal tumors. A young woman with BWS features, but with inconclusive genetic evidence for the disease, came to clinical observation for signs of virilization at the age of 16 years. An adrenocortical tumor was diagnosed and surgically resected. The tumor underwent 2 local relapses that were also surgically treated. The patient was also operated to remove a breast fibroadenoma. SNP arrays were used to analyze chromosome abnormalities in normal and tumor samples from the patient and her parents. The patient presented genome-wide mosaic paternal uniparental disomy (patUPD) both in the adrenocortical and the breast tumors, with different degrees of loss of heterozygosity (LOH). The more recent relapses of the adrenocortical tumor showed a loss of part of chromosome 17p that was absent in the first tumor. Analysis of a skin biopsy sample also showed mosaic patUPD with partial LOH, while no LOH was detected in leukocyte DNA. This case shows that virilizing adrenocortical tumors may be a clinical feature of patients with BWS. The SNP array technology is useful to diagnose genome-wide patUPD mosaicism in BWS patients with an inconclusive molecular diagnosis and underlines the tumorigenic potential of the absence of the maternal genome combined with an excess of the paternal genome., (© Georg Thieme Verlag KG Stuttgart · New York.)

Risk factors related to secondary oligomenorrhea (SOM) are the presence of chronic extragenital pathology, abrupt changes in body mass during a short period of time, a burdened perinatal history at the onset of SOM after a year of regular menstruations. Adolescent girls with SOM differ from their healthy peers by a frequent occurrence of hirsutism, obesity and body mass deficit, uterine hypoplasia.

The differential diagnosis of 46,XY disorders of sex development (DSD) is based on the distinction between forms of gonadal dysgenesis and disorders of androgen biosynthesis and action. However, clinical and endocrine evaluations are often not conclusive. Here, we describe an adolescent female with hirsutism and hyperandrogenization at puberty. Her karyotype was 46,XY, and clinical investigation demonstrated clitoromegaly, but no uterine remnants were detected. Histology of the gonads revealed a testicular structure with a Sertoli-cell-only pattern. Endocrine evaluation showed hypergonadotropic hypogonadism, and the Sertoli cell markers inhibin B and anti-Müllerian hormone were also low. Several molecular genetic studies were initiated. While analyses of the androgen receptor gene, the SRD5A2 gene and HSD17B3 gene were uninformative, a novel p.L230R mutation was found in the NR5A1 gene. A mutant construct proved a severe dysfunction of this variant in functional analysis after recreation and transfection into HeLa cells. We conclude that the NR5A1 p.L230R mutation most likely leads to a spatial and time-dependent Leydig cell and Sertoli cell dysfunction during development not causing the classical gonadal dysgenesis phenotype. This case demonstrates that the current classification should be updated to encompass the overlapping phenotypes of some genetic conditions within 46,XY DSD., (© 2015 S. Karger AG, Basel.)

Cornelia de Lange syndrome (CdLS) is a developmental disorder characterized by limb reduction defects, characteristic facial features and impaired cognitive development. Mutations in the NIPBL gene predominate; however, mutations in other cohesin complex genes have also been implicated, particularly in atypical and mild CdLS cases. Missense mutations and whole gene deletions in RAD21 have been identified in children with growth retardation, minor skeletal anomalies and facial features that overlap findings in individuals with CdLS. We report the first intragenic deletion and frameshift mutations identified in RAD21 in two patients presenting with atypical CdLS. One patient had an in-frame deletion of exon 13, while the second patient had a c.592&#95;593dup frameshift mutation. The first patient presented with developmental delay, hypospadias, inguinal hernia and dysmorphic features while, the second patient presented with developmental delay, characteristic facial features, hirsutism, and hand and feet anomalies, with the first patient being milder than the second. The in-frame deletion mutation was found to be inherited from the mother who had a history of melanoma and other unspecified medical problems. This study expands the spectrum of RAD21 mutations and emphasizes the clinical utility of performing RAD21 mutation analysis in patients presenting with atypical forms of CdLS. Moreover, the variability of clinical presentation within families and low penetrance of mutations as well as the significance of performing molecular genetic testing in mildly affected patients are discussed., (Published by Elsevier B.V.)

Context: Steroid 11β-hydroxylase (CYP11B1) deficiency (11OHD) is the second most common form of congenital adrenal hyperplasia. Milder nonclassic forms are rare and at risk to be missed., Objective: The objective of the study was to demonstrate the challenges in diagnosing nonclassic 11OHD., Patients and Methods: Patient 1, a 10-year-old boy, presented with high-normal blood pressure and previously unexplained exaggerated adrenarche from age 4 years. Previous tests at the age of 8 years showed normal 17-hydroxyprogesterone concentrations with increased androgens. Patient 2, a 14-year-old female, presented with facial hirsutism, primary amenorrhea, and high-normal blood pressure. Novel CYP11B1 mutations were functionally analyzed in transiently transfected COS7 cells measuring the conversion of 11-deoxycortisol to cortisol by liquid chromatography-tandem mass spectrometry., Results: Biochemical findings including urinary steroid metabolite analysis by gas chromatography-mass spectrometry were suggestive of 11OHD in all patients. CYP11B1 mutation analysis revealed compound heterozygosity in patient 1 (g.235T>A, p.F79I/g.2608C>T, p.R138C) and a homozygous mutation in patient 2 and two siblings (g.2623C>T, p.R143W). Functional in vitro analysis demonstrated partially impaired CYP11B1 activity compared with wild-type (p.F79I: 8.8% ± 0.8% (SEM); p.R138C: 9.8% ± 0.8%; p.R143W: 10.6% ± 1.2%)., Conclusion: In addition to nonclassic 21-hydroxylase deficiency and steroid-secreting tumors, nonclassic 11OHD should be considered as an important differential diagnosis in patients with unexplained hyperandrogenism without 46,XX disorder of sex development. Nonclassic 11OHD is likely to be missed when relying on measuring standard steroid hormone panels. This diagnosis needs to be established early in life to avoid long-term health problems such as short stature, hyperandrogenism-related metabolic complications, potentially severe arterial hypertension, and cardiovascular consequences.

Objective: To determine whether manifestations of polycystic ovary syndrome (PCOS), particularly androgen excess, differ between Caucasian and Asian women in the San Francisco Bay Area., Design: Cross-sectional study., Setting: Multidisciplinary PCOS clinic at a tertiary academic center., Patient(s): 121 Caucasian and 28 Asian women, aged 18-44, examined between 2006 and 2011 with PCOS verified by a reproductive endocrinologist and dermatologist according to the Rotterdam criteria., Intervention(s): Transvaginal ultrasounds, comprehensive dermatologic exams, and serum testing., Main Outcome Measure(s): Hirsutism defined as a modified Ferriman-Gallwey (mFG) score ≥ 8, acne, androgenic alopecia, and biochemical hyperandrogenism., Result(s): Caucasian and Asian women had a similar prevalence of all measures of androgen excess. Both groups had similar total mFG scores and site-specific mFG scores, except Asian women had a lower site-specific mFG score for the chest. Although Asian women were more likely to use laser hair removal, the results were unchanged when the women with a history of laser hair removal were excluded., Conclusion(s): Caucasian and Asian women with PCOS living in the same geographic region had a similar prevalence of hirsutism as well as other markers for androgen excess. Further studies are necessary to evaluate the need for ethnic-specific mFG scores in women with PCOS., (Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

There is a strong correlation between the severity of genotypes and 17OH-progesterone levels in patients with the nonclassical form of 21-hydroxylase deficiency (NC-CAH); however, there are few studies regarding the correlation with clinical signs. The aim of the study was to evaluate whether genotypes correlate with the severity of the hyperandrogenic phenotype. A cohort of 114 NC-CAH patients were diagnosed by stimulated-17OHP ≥10 ng/ml. CYP21A2 genotypes were divided into 2 groups according to the severity of enzymatic impairment; mild and severe. Clinical data and hormonal profiles were compared between the 2 groups. Age at onset of manifestations did not differ between children or adults carrying both mild and severe genotypes. Frequencies of precocious pubarche and hirsutism, with or without menstrual abnormalities, were similar between the 2 groups. There were no differences in basal testosterone levels of adult symptomatic females carrying both genotypes, but there were differences between adult females with (92.9±49.5 ng/dl) and without hirsutism (43.8±38 ng/dl) (p=0.0002). Similar frequencies of both genotypes were observed in asymptomatic females and in those with clitoromegaly. Nonclassical genotypes do not predict the severity of phenotype. Asymptomatic and virilized females carrying the same genotype suggest that there is a modulatory effect of genes involved in the androgen pathway on the phenotype., (© Georg Thieme Verlag KG Stuttgart · New York.)

Unlabelled: Deficiency of 17β-hydroxysteroid dehydrogenase type 3 (17βHSD3), an enzyme converting androstenedione (A) to testosterone (T), is a rare cause of autosomal recessive 46,XY disorder of sexual development (DSD). A 18-years phenotypically female patient from southern Italy presented with primary amenorrhea. She had deep voice, macrocephaly, enlarged and bulbous nasal tip, macrostomia, facial acne, breast asymmetry, hypoplasia of the first finger of right hand, proximal implant of the fifth metatarsus bilaterally as well as an increased muscle mass and hirsutism, with hair distribution on face, neck, chest, abdomen, pubic region and on upper and lower limbs. Genital exam showed thickened labra majora with absence of labra minora and a blind-ending pseudo-vagina with clitoris enlargement. Karyotype analysis showed a male genotype (46,XY). Hormonal evaluation showed decreased T (188 ng/dL-6.5 nmol/L) and increased A (10 ng/mL-34,96 nmol/L), considering male reference ranges, resulting in a decreased T/A ratio (0,186). MRI identified testicles in inguinal regions. Human Chorionic Gonadotropin test showed T/A ratio permanently under 0,8. These evidences were suggestive of a 46,XY DSD due to 17βHSD3 deficiency. An homozygous mutation (IVS3 -1 G>C or c.326-1G>C) of the 17βHSD3 gene was discovered. Psychologist identified a well determined female gender identity. It was decided to proceed with gonadectomy and vaginal enlargement by use of dilatators., Conclusion: The case described represents a new case of DSD due to 17βHSD3 deficiency. This patient, raised as a girl, is diagnosed in a very late stage. The identified mutation, previously reported only in Dutch and Brazilian population, is one of 27 presently known mutations of 17βHSD3 gene and is never reported in Italian population.

Context: Inactivating mutations in the enzyme hexose-6-phosphate dehydrogenase (H6PDH, encoded by H6PD) cause apparent cortisone reductase deficiency (ACRD). H6PDH generates cofactor NADPH for 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1, encoded by HSD11B1) oxo-reductase activity, converting cortisone to cortisol. Inactivating mutations in HSD11B1 cause true cortisone reductase deficiency (CRD). Both ACRD and CRD present with hypothalamic-pituitary-adrenal (HPA) axis activation and adrenal hyperandrogenism., Objective: To describe the clinical, biochemical and molecular characteristics of two additional female children with ACRD and to illustrate the diagnostic value of urinary steroid profiling in identifying and differentiating a total of six ACRD and four CRD cases., Design: Clinical, biochemical and genetic assessment of two female patients presenting during childhood. In addition, results of urinary steroid profiling in a total of ten ACRD/CRD patients were compared to identify distinguishing characteristics., Results: Case 1 was compound heterozygous for R109AfsX3 and a novel P146L missense mutation in H6PD. Case 2 was compound heterozygous for novel nonsense mutations Q325X and Y446X in H6PD. Mutant expression studies confirmed loss of H6PDH activity in both cases. Urinary steroid metabolite profiling by gas chromatography/mass spectrometry suggested ACRD in both cases. In addition, we were able to establish a steroid metabolite signature differentiating ACRD and CRD, providing a basis for genetic diagnosis and future individualised management., Conclusions: Steroid profile analysis of a 24-h urine collection provides a diagnostic method for discriminating between ACRD and CRD. This will provide a useful tool in stratifying unresolved adrenal hyperandrogenism in children with premature adrenarche and adult females with polycystic ovary syndrome (PCOS).

Tel Hashomer camptodactyly syndrome (THCS) is a rare autosomal recessive camptodactyly with muscular involvement. The manifestations of THCS other than camptodactyly are clubbed feet, thenar and hypothenar hypoplasia, abnormal palmar creases and dermatoglyphic ridges, spina bifida and mitral valve prolapse. The syndrome was first described by Goodman et al in 1972 and thereafter two further cases with similar phenotype were seen. Herein, we present another case report and review of the literature of other syndromes associated with camptodactyly and mitral valve prolapse. Further cases with this syndrome need to be reported for mapping of the candidate loci. This will help in planning management and genetic counselling.

Context: Polycystic ovary syndrome (PCOS) is the most common endocrine disease among premenopausal women. A recent study found association between three single nucleotide polymorphisms (SNPs) and PCOS in a cohort of Han Chinese women., Objective: To investigate the association between rs13405728 (LHCGR gene), rs13429458 (THADA gene) and rs2479106 (DENND1A gene), PCOS, hirsutism and metabolic and hormonal parameters in a well characterized cohort of Caucasian patients of Danish descendant with PCOS or hirsutism., Study Design: Patients underwent clinical examination, hormone analyses, oral glucose tolerance test and transvaginal ultrasound. Genetic variation was tested using allelic discrimination by real-time PCR., Patients: 268 patients referred to The Department of Endocrinology, Odense University Hospital, Denmark with PCOS or hirsutism between 1997 and 2011. Two hundred and forty-eight healthy females were included as controls., Results: Genotype distributions and allele frequencies of rs13405728, rs13429458, and rs2479106 were comparable in patients and controls. The rs2479106 G allele was associated with a decreased PCOS susceptibility. None of the SNPs were associated with hirsutism or increased metabolic parameters., Conclusions: The rs2479106 G allele was associated with decreased PCOS susceptibility, thus confirming previously reported findings of association between rs2479106 and PCOS. Metabolic and hormonal parameters were comparable between genotypes of rs13405728 and rs2479106., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Purpose of Review: Disease states characterized by abnormal cellular function or proliferation frequently reflect aberrant genetic information. By revealing disease-specific DNA mutations, we gain insight into normal physiology, pathophysiology, potential therapeutic targets and are better equipped to evaluate an individual's disease risks. This review examines recent advances in our understanding of the genetic basis of adrenal cortical disease., Recent Findings: Important advances made in the past year have included identification of KCNJ5 potassium channel mutations in the pathogenesis of both aldosterone-producing adenomas and familial hyperaldosteronism type III; characterization of phosphodiesterase 11A as a modifier of phenotype in Carney complex caused by protein kinase, cAMP-dependent, regulatory subunit, type-I mutations; the finding of 11β-hydroxysteroid dehydrogenase type I mutations as a novel mechanism for cortisone reductase deficiency; and demonstration of potential mortality benefit in pursuing comprehensive presymptomatic screening for patients with Li-Fraumeni syndrome, including possible reduction in risks associated with adrenocortical carcinoma., Summary: This research review provides a framework for the endocrinologist to maintain an up-to-date understanding of adrenal cortical disease genetics.

Purpose of Review: Late-onset or nonclassic congenital adrenal hyperplasia (NCAH) due to 21-hydroxylase deficiency is one of the most common autosomal recessive disorders. Reported prevalence ranges from 1 in 30 to 1 in 1000. Affected individuals typically present due to signs and symptoms of androgen excess. The purpose of this review is to provide current information regarding the pathophysiology, molecular genetics, and management of this common disorder., Recent Findings: Subfertility and the consequences of elevated progesterone concentrations have been increasingly documented for women with NCAH. Although testicular adrenal rest tumors (TARTs) are more common in men with classical congenital adrenal hyperplasia, oligospermia and TARTs have been described in men with NCAH. The phenotypic spectrum of defects in other components of the steroidogenic pathway such as P450 oxidoreductase and steroidogenic acute regulatory protein has been expanded to include milder forms., Summary: Treatment needs to be directed toward the symptoms. Goals of treatment include normal linear growth velocity, normal rate of skeletal maturation, 'on-time' puberty, regular menstrual cycles, prevention of or limited progression of hirsutism and acne, and fertility. Treatment needs to be individualized and should not be initiated merely to decrease abnormally elevated hormone concentrations.

A 16-year-old female with mild hirsutism was noted to have a small, smooth, non-tender goitre. A resting peripheral tremor, but no other symptoms or signs of thyroid dysfunction were present. Her only medication was the contraceptive pill. There was no family history of thyroid disease. Investigation showed elevated free thyroxine (28 pmol/l) and total triiodothyronine (3.4 nmol/l) with non-suppressed thyroid stimulating hormone (1.4 mU/l). Radioiodine uptake scan of the thyroid showed bilateral increased tracer uptake, suggestive of Graves' disease, however thyroid peroxidase and antithyroid stimulating hormone (TSH) receptor antibody testing was negative and sex hormone binding globulin concentration was normal. Laboratory analyses excluded assay artefact or abnormal circulating thyroid hormone binding proteins. Genetic analysis identified a thyroid hormone receptor gene mutation (T277I), making a diagnosis of resistance to thyroid hormone (RTH). RTH is a disorder characterised by elevated thyroid hormones, failure to suppress pituitary TSH secretion and variable refractoriness to hormone action in peripheral tissues.

Aims: To assess whether a single nucleotide polymorphism (SNP50) of the aromatase gene (CYP19) is associated with polycystic ovary syndrome (PCOS) phenotypes and to investigate the influence of this polymorphism on the response of PCOS to treatment with oral contraceptive pills (OCP)., Methods: 162 hirsute women were stratified into a classic PCOS group (hyperandrogenism, ovulatory dysfunction, c-PCOS) and an ovulatory PCOS group (hyperandrogenism, ovulatory cycles, polycystic ovaries, ov-PCOS). 51 women completed a 6-month OCP trial (20 µg ethinyl estradiol + 75 µg gestodene, 21/28 days per cycle, plus 100 mg spironolactone in 32 women with moderate to severe hirsutism). We considered the presence of the polymorphic allele A (AG+AA) in comparison to the absence of the polymorphism (GG) to express results and to perform the comparisons regarding clinical variables., Results: Mean age was 23.3 ± 6.9 years. Hirsutism score was similar in c-PCOS and ov-PCOS (15 (11-20) vs. 13 (11-20)). The differences in hormone and metabolic variables between phenotypes were independent of the presence of allele A. In the OCP trial subsample, no differences were observed between genotypes after 6 months' treatment., Conclusion: The differences between c-PCOS and ov-PCOS cannot be explained by the genetic variation at SNP50 in the CYP19 gene., (Copyright © 2012 S. Karger AG, Basel.)

Objective: To investigate the occurrence of oligo-amenorrhoea and hirsutism, infertility and metabolic morbidity among first-degree relatives of women with and without self-reported oligo-amenorrhoea and hirsutism., Design: Nested case-control study. SETTING, POPULATION AND METHODS: A postal questionnaire about symptoms of oligo-amenorrhoea and hirsutism was sent to all women of the Northern Finland Birth Cohort 1966 (n = 5889). From this population were randomly selected 98 women with both symptoms and 163 without symptoms. A further questionnaire on the occurrence of oligo-amenorrhoea, hirsutism, infertility, early balding and metabolic morbidity in their relatives was sent to this subpopulation., Main Findings: We obtained data on 183 relatives of 43 women with symptoms and 412 relatives of 86 symptomless women. Compared with relatives of symptomless women, mothers of women with symptoms suffered significantly more often from hirsutism and menstrual disorders, and sisters more often from hirsutism and infertility, and had fewer children and were more often childless. There was an increased prevalence of diabetes in the sisters and of hypertension in the fathers of women with symptoms., Conclusions: These results strengthen earlier findings of significantly increased metabolic and reproductive morbidity in the relatives of women with symptoms of PCOS.

Objective: To evaluate idiopathic hirsutism etiology via molecular studies testing peripheral and local aromatase and 5α-reductase expression., Design: Assessment of the expression of messenger RNA (mRNA) for type 1 and 2,5α-reductase isoenzyme gene (SDR5A1, SDR5A2) and aromatase (CYP19A) in dermal papillae cells and peripheral blood mononuclear cells., Setting: University hospital., Patient(s): 28 untreated idiopathic hirsute patients and 20 healthy women (controls)., Intervention(s): Human skin biopsies and peripheral venous blood., Main Outcome Measure(s): SDR5A1, SDR5A2, CYP19A gene expression in skin biopsies and peripheral blood., Result(s): A statistically significant reduction of SRD5A1, SRD5A2, and CYP19A gene expression was found in the dermal papillae cells and peripheral blood mononuclear cell between the study and control group., Conclusion(s): Further study, including protein expression and enzyme activity assays, are warranted to characterize the paradoxically low gene expression levels of local 5α-reductase and aromatase in women with idiopathic hirsutism., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

In peripheral target tissues, levels of active glucocorticoid hormones are controlled by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a dimeric enzyme that catalyzes the reduction of cortisone to cortisol within the endoplasmic reticulum. Loss of this activity results in a disorder termed cortisone reductase deficiency (CRD), typified by increased cortisol clearance and androgen excess. To date, only mutations in H6PD, which encodes an enzyme supplying cofactor for the reaction, have been identified as the cause of disease. Here we examined the HSD11B1 gene in two cases presenting with biochemical features indicative of a milder form of CRD in whom the H6PD gene was normal. Novel heterozygous mutations (R137C or K187N) were found in the coding sequence of HSD11B1. The R137C mutation disrupts salt bridges at the subunit interface of the 11β-HSD1 dimer, whereas K187N affects a key active site residue. On expression of the mutants in bacterial and mammalian cells, activity was either abolished (K187N) or greatly reduced (R137C). Expression of either mutant in a bacterial system greatly reduced the yield of soluble protein, suggesting that both mutations interfere with subunit folding or dimer assembly. Simultaneous expression of mutant and WT 11β-HSD1 in bacterial or mammalian cells, to simulate the heterozygous condition, indicated a marked suppressive effect of the mutants on both the yield and activity of 11β-HSD1 dimers. Thus, these heterozygous mutations in the HSD11B1 gene have a dominant negative effect on the formation of functional dimers and explain the genetic cause of CRD in these patients.

Combined genomics and metabolomics approaches were used to unravel molecular mechanisms behind interactions between winter cress (Barbarea vulgaris) and flea beetle (Phyllotreta nemorum). B. vulgaris comprises two morphologically, biochemically and cytologically deviating types, which differ in flea beetle resistance, saponin and glucosinolate profiles, as well as leaf pubescence. An F2 population generated from a cross between the two B. vulgaris types was used to construct a B. vulgaris genetic map based on 100 AFLP and 31 microsatellite markers. The map was divided into eight linkage groups. QTL (quantitative trait loci) analysis revealed a total of 15 QTL affecting eight traits, including nine QTL for four saponins, two QTL for two glucosinolates, two QTL for hairiness, and two QTL for flea beetle resistance. The two QTL for resistance towards flea beetles in B. vulgaris co-localized with QTL for the four saponins associated with resistance. Furthermore, global QTL analysis of B. vulgaris metabolites identified QTL for a number of flavonoid glycosides and additional saponins from both resistant and susceptible types. The transcriptome of the resistant B. vulgaris type was sequenced by pyrosequencing, and sequences containing microsatellites were identified. Microsatellite types in B. vulgaris were similar to Arabidopsis thaliana but different from Oryza sativa. Comparative analysis between B. vulgaris and A. thaliana revealed a remarkable degree of synteny between a large part of linkage groups 1 and 4 of B. vulgaris harboring the two QTL for flea beetle resistance and Arabidopsis chromosomes 3 and 1. Gene candidates that may underlie QTL for resistance and saponin biosynthesis are discussed., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

We report hyperandrogenism with severe acne, hirsutism and alopecia in a set of non-obese triplet sisters presenting at an early age. Interestingly, one of the triplets had hyperthyroidism and had significantly lower androgen level as well as hirsutism compared to her sisters. Treatment of hyperthyroidism with radioiodine ablation led to significant elevation of androgen levels and worsening of hirsutism suggesting that hyperthyroidism masks the biochemical and clinical expression of hyperandrogenism in susceptible females.

A previously unreported case of Barber-Say syndrome is described with special attention to dental manifestations. A 7-year-old female with multiple congenital anomalies such mammary gland hypoplasia, hypertrichosis, ectropion, and redundant skin was seen at the School of Dentistry of the University of São Paulo. Oral examination revealed macrostomia, broad alveolar ridges, gingival fibromatosis, taurodontism, delayed tooth eruption, and malocclusion. Dental treatment included gingivoplasty and orthodontic treatment., (Copyright © 2010 Wiley-Liss, Inc.)

Objective: To test the hypothesis that women with polycystic ovary syndrome (PCOS) are distinguishable from those with 21-hydroxylase-deficient nonclassic adrenal hyperplasia on the basis of having polycystic ovaries and metabolic dysfunction., Design: Prospective observational., Setting: Tertiary care center., Patient(s): Fifty-two lean and 54 obese women with PCOS according to the 1990 National Institutes of Health criteria, 23 women with nonclassic adrenal hyperplasia, and 27 controls., Intervention(s): History and physical examination, blood sampling, ovarian sonography, oral glucose tolerance, and acute adrenocorticotropin stimulation testing., Main Outcome Measure(s): The frequency of clinical, biochemical, and metabolic features., Result(s): Women with PCOS had a higher frequency of oligomenorrhea or amenorrhea than those with nonclassic adrenal hyperplasia. Mean androstenedione and DHEAS levels were highest in nonclassic adrenal hyperplasia. The degree of metabolic dysfunction was greatest in obese women with PCOS; women with nonclassic adrenal hyperplasia and lean women with PCOS did not differ in degree of metabolic dysfunction. Women with nonclassic adrenal hyperplasia had a lower prevalence of polycystic ovaries than those with PCOS. The proportion of patients with an LH/FSH ratio >2 was greater in women with PCOS, compared with those with nonclassic adrenal hyperplasia. Basal 17-hydroxyprogesterone levels >2 ng/mL were found in 87%, 25%, 20%, and 7% of women with nonclassic adrenal hyperplasia, lean women with PCOS, obese women with PCOS, and controls, respectively., Conclusion(s): Nonclassic adrenal hyperplasia should be excluded in all women presenting with hirsutism, with use of a basal follicular phase 17-hydroxyprogesterone level, regardless of the presence of polycystic ovaries or metabolic dysfunction; however, women with nonclassic adrenal hyperplasia have a higher prevalence of normal ovulation and lower likelihood of having an LH/FSH ratio >2 or polycystic ovaries., (Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Whatever the origin of severe insulin resistance (primary insulin receptors defects or lipodystrophies), in vivo hyperinsulinemia has been clearly shown to promote ovarian growth and androgen synthesis independently of gonadotropins. In lipodystrophic syndromes, the endocrine deficiency of adipose tissue has been shown to play important pathophysiological roles in metabolic alterations. In particular leptin is decreased, contributing to the ectopic lipid storage in non-adipose cells, which inhibits insulin signalling (lipotoxicity). Finally, polycystic ovary syndrome (PCOS) features are not always present in insulin resistance syndromes with lipodystrophy. This is in favour of an aggravating, but not a primary role of post-receptor insulin resistance on ovary dysfunctions., (Copyright 2010 Elsevier Masson SAS. All rights reserved.)