Objectives To report the clinical spectrum of genital defects diagnosed before birth, identify predictive factors for severe phenotypes at birth, and determine the rate of associated malformations. Patients and methods A retrospective study (2008–2017) of 4580 fetuses, identified prenatally with abnormalities evaluated by our Reference Center for Fetal Medicine, included cases with fetal sonographic findings of abnormal genitalia or uncertainty of fetal sex determination. Familial, prenatal and postnatal data were collected via a standardised questionnaire. Results In all, 61 fetuses were included. The positive predictive value (PPV) of the prenatal diagnosis of genital defects was 90.1%. Most cases were 46,XY‐undervirilized boys, 42 cases (68.8%), which included 29 with mid‐penile or posterior hypospadias, nine with anterior hypospadias, and epispadias, micropenis, scrotal transposition, and buried penis (one each). In all, 46,XX‐virilized girls were identified in seven cases (11.5%), which included four with congenital adrenal hyperplasia, two with isolated clitoromegaly, and one with ovotestis. Other defects included prune belly syndrome and persistent cloaca (six cases). Early detection during the second trimester (58.1% vs 18.8%, P = 0.03), intra‐uterine growth restriction (IUGR) (45.2% vs 9.1%, P = 0.06), and curvature of the penis (38.7% vs 0%, P = 0.02), were more frequently related to severe defects in male newborns. Associated malformations (14 cases, 22.9%) and genetic defects (six) were frequent in undervirilized boys. Conclusion Prenatal imaging of genital defects leads to a wide range of phenotypes at birth. Its PPV is high and extra‐urinary malformations are frequent. Early diagnosis during the second trimester, associated IUGR, and curvature of the genital tubercle, should raise suspicion of a severe phenotype and may justify delivery near a multidisciplinary disorders/differences of sex development team.
Androgens are critical in male external genital development. Alterations in the androgen sensitivity pathway have been identified in severely undermasculinized boys, and mutations of the androgen receptor gene (AR) are usually found in partial or complete androgen insensitivity syndrome (AIS).The aim of this study was to determine whether even the most minor forms of isolated hypospadias are associated with AR mutations and thus whether all types of hypospadias warrant molecular analysis of the AR.Two hundred and ninety-two Caucasian children presenting with isolated hypospadias without micropenis or cryptorchidism and 345 controls were included prospectively. Mutational analysis of the AR through direct sequencing (exons 1-8) was performed. In silico and luciferase functional assays were performed for unreported variants.Five missense mutations of the AR were identified in 9 patients with glandular or penile anterior (n = 5), penile midshaft (n = 2) and penile posterior (n = 2) hypospadias, i.e., 3%: p.Q58L (c.173A>T), 4 cases of p.P392S (c.1174C>T), 2 cases of p.A475V (c.1424C>T), p.D551H (c.1651G>C) and p.Q799E (c.2395C>G). None of these mutations was present in the control group. One mutation has never been reported to date (p.D551H). It was predicted to be damaging based on 6 in silico models, and in vitro functional studies confirmed the lowered transactivation function of the mutated protein. Three mutations have never been reported in patients with genital malformation but only in isolated infertility: p.Q58L, p.P392S, and p.A475V. It is notable that micropenis, a cardinal sign of AIS, was not present in any patient.AR mutations may play a role in the cause of isolated hypospadias, even in the most minor forms. Identification of this underlying genetic alteration may be important for proper diagnosis and longer follow-up is necessary to find out if the mutations cause differences in sexual function and fertility later in life.
Summary Objective Disorders of sex development ( DSD ) are a heterogeneous group of conditions affecting the differentiation and development of the internal and external genitalia. Here, we aimed at identifying the genetic cause of DSD in two 46, XY sisters from a consanguineous family. Design We performed a whole‐exome sequencing of two 46, XY female individuals. Sanger sequencing was used to validate the most likely candidate variant, affecting the desert hedgehog ( DHH ) gene. Molecular dynamics simulations were performed to get insights into the impact of the variant on protein structure and on its interaction with the protein partner BOC (brother of CDO /cell adhesion molecule, downregulated by oncogenes). Patients The index patient presented with a female phenotype, primary amenorrhoea (low oestradiol and testosterone and high FSH and LH ). She also had an apparent absence of intra‐abdominal gonads and uterus, facial dysmorphy, psychomotor retardation and neuropathy. Her sister displayed a similar gonadal and endocrinological picture, without dysmorphy or psychomotor retardation. Results Whole‐exome sequencing revealed a homozygous variant in DHH leading to the p.Trp173Cys substitution. The relevant Trp residue is conserved, and its alteration was predicted to be deleterious. Molecular dynamics simulations showed that the mutation increases the conformational flexibility of the protein and potentially alters its interaction with BOC , a positive regulator of Hedgehog signalling. We do not exclude an interference of the mutation with DHH ‐intein‐mediated auto‐processing. Conclusions This report increases the number of described homozygous DHH variants and highlights the importance of advanced bioinformatic tools to better understand the pathogenicity of human variants.
Although a rare occurrence, previously undiagnosed disorders of sex development (DSD) with hyperandrogenism are sometimes detected by hormonal screening during the international sports competitions. Identifying the cause of XY,DSD raises medical and ethical concerns, especially with regard to issues of the eligibility to compete.The aim of this study was to determine whether the detection of high plasma T in young elite female athletes during hormonal screening would reveal an unsuspected XY DSD.The study was performed in the Nice and Montpellier University Hospitals (France), which collaborate as reference centers for DSD in elite athletes on behalf of sports governing bodies.Four cases of elite young athletes with female phenotypes but high plasma T detected during hormonal screening were investigated for undiagnosed XY DSD.Evaluation of clinical, biological, radiological (magnetic resonance imaging and dual-energy x-ray absorptiometry) and genetic characteristics was conducted.The 4 athletes presented as tall, slim, muscular women with a male bone morphotype, no breast development, clitoromegaly, partial or complete labial fusion, and inguinal/intralabial testes. All reported primary amenorrhea. The hormonal analysis evidenced plasma T within the male range, the karyotype was 46, XY, and molecular analysis of the 5α-reductase type 2 (srd5A2) gene identified a homozygotic mutation in 2 cases, a heterozygotic compound in 1 case, and a deletion in 1 case.5α-Reductase deficiency should be investigated in elite young female athletes with primary amenorrhea and high male T levels detected during antidoping programs to identify undiagnosed XY DSD.
Background: Primary ovarian insufficiency (POI), a public health problem, affects 1-3.7% of women under 40 yielding infertility and decreased longevity. Most causes are unknown. Recently, genetic causes were identified, mostly in single families. We studied an unprecedented cohort of POI to unravel its molecular pathophysiology.Methods: 318 patients with 66 families were studied using targeted (88 genes) or exome sequencing with pathogenic/likely-pathogenic variant selection. Mitomycin-induced chromosome breakages were studied in patients’ lymphocytes.Findings: A high-yield of 36.5 % supports a clinical genetic diagnosis of POI. We found 77 new variants, involved 13 novel genes: AKT1, LAST2, ELAVL2, NLRP11, CENPE, SYCP3, XPNPEP2, SPATA33, CCDC150, CCDC185, including DNA repair genes MCM81P, HELQ, SWI5 yielding high chromosomal fragility, and confirmed the causal role of BNC1, ERCC6, BMPR1A, BMPR1B, BMPR2, CAV1, SPIDR, RCBTB1, ATG7. In 10.4% of cases, POI is the unique phenotype of a multi-organ genetic disease. New pathways were identified: Hippo-AKT, a novel therapeutic target of POI during in vitro follicular activation (IVA), inflammation, post-transcriptional/translational regulations, mitochondrial autophagy providing future therapeutic targets. Three new genes had been involved in the age of natural menopause supporting a genetic link.Interpretation: We have developed high-performance genetic diagnostic of POI, dissecting the molecular pathogenesis of POI and leading to personalized medicine to i) prevent/cure comorbidities for tumor/cancer susceptibility genes that could affect longevity, or for genetically-revealed syndromic POI, ii) predict residual ovarian reserve. Genetics could select responder patients to IVA, greatly improving its success in treating infertility.Funding Information: This study was supported by Université Paris Sud-Paris Saclay, Hôpitaux Universitaires Paris Saclay (AH, MM), the Institut National de la Santé et de la Recherche Médicale-INSERM (AH, MM), and by the Agence Nationale de Biomédecine (AH, MM) Declaration of Interests: The authors declare no conflict of interest.Ethics Approval Statement: The study was approved by all the institutions involved and by the Agence de Biomedecine (reference number PFS12-002). Written informed consent was received from participants prior to inclusion in the study.
Cross-sectional studies have demonstrated that physical activity can improve bone mass acquisition. However, this design is not adequate to describe the specific kinetics of bone mass gain during pubertal development.To compare the kinetics of bone mass acquisition in female adolescent athletes of sports that impose different mechanical loads and untrained controls throughout puberty.A total of 72 girls with ages ranging from 10.8 to 18.0 years were recruited: 24 rhythmic gymnasts (RG, impact activity group), 24 swimmers (SW, no-impact activity), and 24 age-matched controls (CON).Areal bone mineral density (aBMD) was determined using dual-energy x-ray absorptiometry and bone turnover markers were analyzed. All the investigations were performed at baseline and after 1 year.At baseline and after 1 year of follow-up, RG presented significantly greater aBMD adjusted for age, fat-free soft tissue, and fat mass compared with CON and SW, only at the femoral region. When aBMD variation throughout the pubertal period was modeled for each group from individual values, the aBMD at the femoral region was significantly higher in RG compared with the other 2 groups from 12.5 to 14 years, and this difference lasted up to 18 years. Moreover, the mean annual aBMD gain tended to be higher in RG compared with SW and CON only at the femoral region and this gain lasted longer in RG. Bone remodeling markers decreased similarly with age in the 3 groups.This study, which was based on linear mixed models for longitudinal data, demonstrated that the osteogenic effect of gymnastics is characterized by greater bone mass gain localized at mechanically loaded bone (ie, the proximal femur) principally around the menarcheal period. Moreover, the bone mass gain lasts longer in gymnasts, which may be explained by the delay in sexual maturation.
