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ObjectiveThe adipogenic PPARG-encoded PPARγ nuclear receptor also displays essential placental functions. We evaluated the metabolic, reproductive, and perinatal features of patients with PPARG-related lipodystrophy.MethodsCurrent and retrospective data were collected in patients referred to a National Rare Diseases Reference Centre.Results26 patients from 15 unrelated families were studied (18 women, median age 43 years). They carried monoallelic PPARG variants except a homozygous patient with congenital generalized lipodystrophy. Among heterozygous patients aged 16 or more (n = 24), 92% had diabetes, 96% partial lipodystrophy (median age at diagnosis 24 and 37 years), 78% hypertriglyceridaemia, 71% liver steatosis, and 58% hypertension. The mean BMI was 26 ± 5.0 kg/m2. Women (n = 16) were frequently affected by acute pancreatitis (n = 6) and/or polycystic ovary syndrome (n = 12). Eleven women obtained one or several pregnancies, all complicated by diabetes (n = 8), hypertension (n = 4), and/or hypertriglyceridaemia (n = 10). We analysed perinatal data of patients according to the presence (n = 8) or absence (n = 9) of a maternal dysmetabolic environment. The median gestational age at birth was low in both groups (37 and 36 weeks of amenorrhea, respectively). As expected, the birth weight was higher in patients exposed to a foetal dysmetabolic environment of maternal origin. In contrast, 85.7% of non-exposed patients, in whom the variant is, or is very likely to be, paternally-inherited, were small for gestational age.ConclusionsLipodystrophy-related PPARG variants induce early metabolic complications. Our results suggest that placental expression of PPARG pathogenic variants carried by affected foetuses could impair prenatal growth and parturition. This justifies careful pregnancy monitoring in affected families.

Context Pituitary stalk interruption syndrome (PSIS) is rare in the pediatric population. It combines ectopic posterior pituitary stalk interruption and anterior pituitary hypoplasia with hormonal deficiencies. The phenotype is highly heterogeneous and obesity/overweight seems to be underreported in the literature. Objective To identify patients with PSIS and obesity or overweight, describe their phenotype, and compare them with patients with PSIS without overweight/obesity. Methods Sixty-nine children and young adults with PSIS in a Toulouse cohort from 1984 to 2019 were studied. We identified 25 obese or overweight patients (OB-OW group), and 44 were nonobese/overweight (NO group). Then the groups were compared. Results All cases were sporadic. The sex ratio was 1.6. The main reason for consultation in both groups was growth retardation (61% in OB-OW group, 77% in NO group). History of neonatal hypoglycemia was more common in the OB-OW than in the NO group (57% vs 14%, P = .0008), along with extrapituitary malformations (64% vs 20%, P < 0001). The incidence of caesarean section was higher in the OB-OW group (52%) than in the NO group (23%), although not significant (P = .07). Conclusion Patients with PSIS who are obese/overweight display interesting phenotypic differences that suggest hypothalamic defects. Studies are needed that include additional information on hormonal levels, particularly regarding oxytocin and ghrelin.

STUDY QUESTION Can mutations of genes other than AMH or AMHR2, namely PPP1R12A coding myosin phosphatase, lead to persistent Müllerian duct syndrome (PMDS)? SUMMARY ANSWER The detection of PPP1R12A truncation mutations in five cases of PMDS suggests that myosin phosphatase is involved in Müllerian regression, independently of the anti-Müllerian hormone (AMH) signaling cascade. WHAT IS KNOWN ALREADY Mutations of AMH and AMHR2 are detectable in an overwhelming majority of PMDS patients but in 10% of cases, both genes are apparently normal, suggesting that other genes may be involved. STUDY DESIGN, SIZE, DURATION DNA samples from 39 PMDS patients collected from 1990 to present, in which Sanger sequencing had failed to detect biallelic AMH or AMHR2 mutations, were screened by massive parallel sequencing. PARTICIPANTS/MATERIALS, SETTING, METHODS To rule out the possibility that AMH or AMHR2 mutations could have been missed, all DNA samples of good quality were analyzed by targeted next-generation sequencing. Twenty-four samples in which the absence of AMH or AMHR2 biallelic mutations was confirmed were subjected to whole-exome sequencing with the aim of detecting variants of other genes potentially involved in PMDS. MAIN RESULTS AND THE ROLE OF CHANCE Five patients out of 24 (21%) harbored deleterious truncation mutations of PP1R12A, the gene coding for the regulatory subunit of myosin phosphatase, were detected. In addition to PMDS, three of these patients presented with ileal and one with esophageal atresia. The congenital abnormalities associated with PMDS in our patients are consistent with those described in the literature for PPP1R12A variants and have never been described in cases of AMH or AMHR2 mutations. The role of chance is therefore extremely unlikely. LIMITATIONS, REASONS FOR CAUTION The main limitation of the study is the lack of experimental validation of the role of PPP1R12A in Müllerian regression. Only circumstantial evidence is available, myosin phosphatase is required for cell mobility, which plays a major role in Müllerian regression. Alternatively, PPP1R12A mutations could affect the AMH transduction pathway. WIDER IMPLICATIONS OF THE FINDINGS The study supports the conclusion that failure of Müllerian regression in males is not necessarily associated with a defect in AMH signaling. Extending the scope of molecular analysis should shed light upon the mechanism of the initial steps of male sex differentiation. STUDY FUNDING/COMPETING INTEREST(S) The study was funded by la Fondation Maladies Rares, GenOmics 2021_0404 and la Fondation pour la Recherche Médicale, grant EQU201903007868. The authors report no conflict of interest. TRIAL REGISTRATION NUMBER N/A.

International audience; Objective: To study the diagnostic yield, including variants in genes yet to be incriminated, of whole exome sequencing (WES) in familial cases of premature ovarian insufficiency (POI). Design: Cross-sectional study. Setting: Endocrinology and reproductive medicine teaching hospital departments. Patients: Familial POI cases were recruited as part of a nationwide multicentric cohort. A total of 36 index cases in 36 different families were studied. Fifty-two relatives were available, including 25 with POI and 27 affected who were nonaffected. Karyotype analysis, FMR1 screening, single nucleotide polymorphism array analysis, and WES were performed in all subjects. Interventions: None. Main Outcome Measures: The primary outcome was a molecular etiology, as diagnosed by karyotype, FMR1 screening, single nucleotide polymorphism array, and WES. Results: A likely molecular etiology (pathogenic or likely pathogenic variant) was identified in 18 of 36 index cases (50% diagnostic yield). In 12 families, we found a pathogenic or likely pathogenic variant in a gene previously incriminated in POI, and in 6 families, we found a pathogenic or likely pathogenic variant in new candidate genes. Most of the variants identified were located in genes involved in cell division and meiosis (n = 11) or DNA repair (n = 4). Conclusions: The genetic etiologic diagnosis in POI allows for genetic familial counseling, anticipated pregnancy planning, and ovarian tissue preservation or oocyte preservation. Identifying new genes may lead to future development of therapeutics in reproduction based on disrupted molecular pathways. Clinical Trial Registration Number: NCT 01177891. ((C) 2021 by American Society for Reproductive Medicine.) El resumen esta disponible en Espanol al final del articulo.

Resume Objectifs En appui sur les donnees issues d’une vaste recherche medico-psychopathologique proposee a des jeunes filles atteintes d’une agenesie utero-vaginale — syndrome de Rokitansky ou Mayer-Rokitansky-Kuster-Hauser (MRKH) — notre travail propose l’analyse psychodynamique de la valeur et de la fonction pour l’economie psychosomatique d’une reaction frequente a l’annonce diagnostique : le developpement d’un desordre alimentaire de type prise de poids chez 4 patientes sur 40. La mise en perspective de l’analyse de deux cas de patientes permet d’affiner la comprehension du sens de cette emergence alimentaire dont nous faisons l’hypothese qu’elle constitue a la fois une modalite defensive signalant les impasses du processus de construction du feminin mais aussi possiblement un levier de transformation psychique de ses incidences traumatiques. Methode Quarante jeunes femmes MRKH âgees de 19 a 34 ans (avec un âge moyen de 25 ans ½) ont ete rencontrees. La recherche leur a ete proposee de 2 a 17 ans apres leur annonce diagnostique et le travail clinique a consiste en une analyse retrospective de leur experience traumatique adolescente. Le recit des patientes a ete recueilli a l’aide d’un entretien clinique a visee de recherche non directif. Deux epreuves projectives (Rorschach et Thematic Apperception Test – TAT) leur ont egalement ete proposees pour apprehender plus finement les modalites de leur fonctionnement psychique. Les donnees des entretiens font l’objet d’une analyse clinique thematique ; les protocoles du Rorschach et du TAT sont analyses selon la methode d’interpretation de l’Ecole Francaise referee a la theorie psychanalytique du fonctionnement psychique. Le materiel issu des rencontres avec deux patientes diagnostiquees a l’âge de 17 ans et ayant presente dans la suite de cette annonce une prise de poids de 10 kg est ici compare de maniere approfondie. Resultats Le reperage de contrastes en termes de problematiques et de niveaux d’elaboration entre l’entretien et les protocoles projectifs est saisissant pour chaque patiente. A travers l’analyse de l’entretien, le symptome alimentaire de la patiente 1 parait survenir dans un contexte psychique ou l’interiorite feminine semble irrepresentable. Les protocoles projectifs revelent a l’inverse l’acces a un travail du feminin conflictuel et symbolise. De meme, le discours de la patiente 2 sur son symptome est a premiere vue bien plus elabore que celui de la patiente 1 puisque celle-ci etablit un lien subjectif entre le renoncement au projet de maternite implique par l’annonce du MRKH et la dimension compensatoire procuree par la prise de poids. Pourtant, le contraste offert par les tests projectifs dont les productions traduisent au contraire les fragilites identitaires et une insuffisante symbolisation du sexuel temoigne de la valeur defensive de l’exces de symbolisation de son discours manifeste dans l’entretien. Discussion Ces contrastes amenent a envisager le remplissage alimentaire comme une tentative de traitement d’une sexualite feminine deja conflictuelle voire en impasse avant la decouverte du MRKH. Ses accents traumatiques sont reactualises et potentialises a la faveur de l’annonce diagnostique. Les differents niveaux de problematiques reperes peuvent cohabiter chez une meme femme, qu’il s’agisse d’un feminin ni construit ni integre, d’un impossible investissement du corps interne ou d’un contre-investissement de l’impossible maternite. Dans ce contexte, l’etiopathogenie de la prise de poids qui succede a l’annonce du diagnostic est pour chaque jeune fille singuliere mais toujours en lien avec un feminin et/ou un maternel atteint. Conclusion En conclusion, si la prise de poids qui suit le diagnostic traduit une entrave voire une impasse (eventuellement ponctuelle) du traitement psychique de ses effets, cette annonce medicale a l’adolescence peut constituer une nouvelle chance pour ces jeunes filles, celle d’un apres-coup a la valeur potentiellement mutative.

Context Little is known about the physical health of individuals with 46,XY disorders of sex development (DSD). Objective To assess physical and reported subjective health of individuals with XY DSD. Methods As part of the dsd-LIFE study, patients with an XY DSD condition were analyzed in different diagnosis groups for metabolic parameters, comorbidities, metabolic syndrome, bone outcomes, and reported subjective health. Findings were evaluated by descriptive statistics. Results A total of 222 patients with XY DSD were included with a mean age of 28.8 ± 12.2 years, mean height of 175.3 ± 7.7 cm, mean weight of 74.3 ± 20.0 kg, and mean body mass index of 24.1 ± 6.0 kg/m2. Obesity rate was not increased when descriptively compared with Eurostat data. Fourteen patients had metabolic syndrome (14/175; 8.0%). In descriptive comparison with data from the DECODE study and World Health Organization, subjects fared better in the categories waist circumference, glucose, triglyceride, cholesterol, and high-density lipoprotein. Of participants with available bone health data, 19/122 (15.6%) patients had a Z-score ≤ –2.0 at lumbar spine indicating lowered bone mineral density (BMD). Mostly gonadectomized individuals with complete androgen insensitivity syndrome (CAIS) and no estrogen therapy had lowered BMD at lumbar spine. Individuals with XY DSD performed poorly in the category subjective health in descriptive comparison with Eurostat data. Conclusion Participants reported a lower subjective health status than Eurostat data but their overall metabolic health status was good. Decreased BMD at lumbar spine was especially present in gonadectomized individuals with CAIS and no estrogen therapy.

Summary Background Surgery is performed in many individuals with disorders/differences of sex development (DSD). Irreversibility of some surgical procedures, lack of information about the procedures, and lack of follow-up care for physical and psychological outcomes, lead to wish for more knowledge from both surgeons and patients. After the consensus conference in 2006, multidisciplinary care is provided to a higher degree with psychological support and more restricted surgical procedures. Outcome studies after genital surgery often lack of patient's perspective. Objective To describe surgical procedures in relation to diagnosis, to evaluate the outcomes of surgery through genital examination, and through patient's and observer's satisfaction with the anatomical and functional result after genital surgery. Study design In a cross-sectional clinical study performed in six European countries in 2014/15, we have included 500 participants where surgery was performed, from a total of 1040 adolescents (≥16years) and adults with a DSD. Diagnoses included Turner syndrome (n = 301), mixed gonadal dysgenesis (45,XO/46,XY; n = 45), Klinefelter syndrome (n = 218), XYY (n = 1), 46, XY DSD (n = 222) and 46, XX DSD (n = 253). Study protocol included clinical report files, an optional gynecological or urological examination, patient reported outcomes including received surgical interventions, satisfaction with appearance and function after surgery, and impact of the surgical procedure on life. Results Five hundred participants had received genital or breast surgery, with the highest rate in 46, XY DSD and the lowest in Turner syndrome. Altogether; 240 participants had feminizing surgery, 112 had masculinizing surgery, and 217 underwent gonadectomy. Physicians evaluated anatomical appearance at genital examination as poor in less than 10%. Dissatisfaction with anatomical appearance was reported by 22% of the participants, dissatisfaction with function by 20%. Being (very) dissatisfied with anatomical appearance and function was reported by 13% of the study participants. Most participants reported no impact, or positive impact, of the surgical procedures on their lives, but 29% experienced a negative effect of gonadectomy on their life. Discussion There might be a selection bias and/or a recall bias for participating in our studies. Due to poor data quality about surgical procedures performed in the past, we also relied on participants memory about surgical procedures in their past. Ideally, patient reported outcomes should be evaluated both before and after surgical procedures. Conclusion A vast majority are satisfied with appearance and function, but still genital or breast surgery have a long-lasting effect on patient's life. Self-reported satisfaction is usually lower than the observer's evaluation regarding both appearance and function. Download : Download high-res image (217KB) Download : Download full-size image Summary Figure . Satisfaction with anatomy and function after genital surgery in individuals with DSD (appearance: n = 244; function: n = 257) (n = total number of participants).

Resume Ces Recommandations pour la pratique clinique en contraception sont les premieres promues par le College national des gynecologues et obstetriciens francais (CNGOF), afin d'aider le praticien a prendre une decision medicale en lui fournissant une synthese des donnees scientifiques existantes sur le sujet. La methodologie de la Haute Autorite de sante (HAS) a ete adoptee. Douze questions pratiques ont ete selectionnees par le comite d'organisation et le groupe de travail. La litterature a ete analysee jusqu'en decembre 2017, des recommandations basees sur le niveau de preuve ont ete proposees affectees d'un grade. Les textes longs, dont cette synthese est issue, ont ete relus par des experts en contraception et des praticiens du secteur prive ou public, ayant une activite en contraception. Des recommandations pratiques sont ainsi proposees pour la conduite de la consultation de contraception, l'information sur les methodes contraceptives, leurs risques et benefices non contraceptifs, la gestion de la contraception hormonale en pratique, la contraception intra-uterine, la contraception d'urgence, les methodes locales et naturelles, la contraception chez les adolescentes, apres 40 ans, en situation a risque vasculaire ou carcinologique. La contraception definitive et l'emploi pour la contraception de molecules ne disposant pas d'une autorisation de mise sur le marche ont ete exclus du champ de ces recommandations. L'avenir de la contraception a court et moyen terme tel qu'il peut etre anticipe aujourd'hui, passe avant tout par le bon usage des moyens dont nous disposons aujourd'hui, l'information des femmes et l'amelioration de l'acces aux contraceptions pour toutes les femmes. C'est l'objectif poursuivi par ces recommandations de pratique clinique du CNGOF.

Context Abnormalities in the hypothalamo–pituitary–gonadal axis have long been reported in Noonan syndrome (NS) males with only few data available in prepubertal children. Objective The aim of this study was to describe the gonadal function of NS males from childhood to adulthood. Design It is a retrospective chart review. Patients and methods A total of 37 males with a genetically confirmed diagnosis of NS were included. Clinical and genetic features, as well as serum hormone levels (LH, FSH, testosterone, anti-Müllerian hormone (AMH), and inhibin B) were analysed. Results Of the 37 patients, 16 (43%) children had entered puberty at a median age of 13.5 years (range: 11.4–15.0 years); age at pubertal onset was negatively correlated with BMI SDS (r = −0.541; P = 0.022). In pubertal boys, testosterone levels were normal suggesting a normal Leydig cell function. In contrast, NS patients had significant lower levels of AMH (mean SDS: −0.6 ± 1.1; P = 0.003) and inhibin B (mean SDS: −1.1 ± 1.2; P NS-PTPN11 patients, whereas these markers did not differ from healthy children in SOS1 patients. No difference was found between cryptorchid and non-cryptorchid patients for AMH and inhibin B levels (P = 0.43 and 0.62 respectively). Four NS-PTPN11 patients had a severe primary hypogonadism with azoospermia/cryptozoospermia. Conclusions NS males display Sertoli cell-specific primary testicular insufficiency, whereas Leydig cell function seems to be unaffected.

International audience; Premature ovarian insufficiency (POI) is a rare pathology affecting 1-2% of under-40 year-old women, 1 in 1000 under-30 year-olds and 1 in 10,000 under-20 year-olds. There are multiple etiologies, which can be classified as primary (chromosomal, genetic, auto-immune) and secondary or iatrogenic (surgical, or secondary to chemotherapy and/or radiotherapy). Despite important progress in genetics, more than 60% of cases of primary POI still have no identifiable etiology; these cases are known as idiopathic POI. POI is defined by the association of 1 clinical and 1 biological criterion: primary or secondary amenorrhea or spaniomenorrhea of>4 months with onset before 40 year of age, and elevated follicle-stimulating hormone (FSH)>25IU/L on 2 assays at>4 weeks' interval. Estradiol level is low, and anti-Müllerian hormone (AMH) levels have usually collapsed. Initial etiological work-up comprises auto-immune assessment, karyotype, FMR1 premutation screening and gene-panel study. If all of these are normal, the patient and parents may be offered genome-wide analysis under the "France Génomique" project. The term ovarian insufficiency suggests that the dysfunction is not necessarily definitive. In some cases, ovarian function may fluctuate, and spontaneous pregnancy is possible in around 6% of cases. In confirmed POI, hormone replacement therapy is to be recommended at least up to the physiological menopause age of 51 years. Management in a rare diseases center may be proposed.

This study aimed to assess the application of the French guidelines for pregnancies in Turner syndrome (TS) and their impact on perinatal prognosis.We performed a French multi-center retrospective study (14 centers), including TS pregnant patients (spontaneously or by Assisted Reproductive Technology (ART)) between January 2006 and July 2017. Only clinical pregnancies were analyzed. The adjustment of medical follow-up modalities to French guidelines was evaluated for all pregnancies after 2009. Pregnancies from oocyte donation (OD) after 2009 were compared to those of a cohort of TS pregnancies obtained by OD before 2009, which were reported by the French Study Group for Oocyte Donation.One hundred seventy pregnancies in 103 patients were included: 35 spontaneous, 5 by means of intra-conjugal ART, and 130 with OD. No serious maternal complications were observed. We reported two stillbirths and one intra uterine fetal death. The French guidelines were partially respected. The preconceptional assessment was carried out in 74% of cases. Cardiology follow-up during pregnancy was performed in accordance with guidelines in 74% of patients. Postpartum cardiac ultrasonography was performed in 45% of pregnancies but only in 11% within 8 days post-partum. When compared to the 2009 historical cohort, the rates of high blood pressure (19% vs. 38%; p 0.005) pre-eclampsia (8% vs. 21%; p 0.005) and prematurity35 weeks (15% vs 38%; p 0.0001) were lower.The implementation of guidelines has allowed the standardization of TS pregnancy care and improved perinatal indicators for both mothers and children. However, an effort must be done, in a postpartum survey.

Although musculoskeletal abnormalities have long been described in patients with Noonan syndrome (NS), only a few studies have investigated the bone status of these patients. The aim of this retrospective observational study was to describe the bone health of children with NS. Thirty-five patients with a genetically confirmed diagnosis of NS were enrolled. We analyzed the axial skeleton (lumbar spine) using dual energy X-ray absorptiometry and the appendicular skeleton (hand) with the BoneXpert system. Bone metabolism markers, including mineral homeostasis parameters, serum 25-hydroxy vitamin D (25-OHD) levels and markers of bone formation and resorption were also reported. Compared to the general population, axial and appendicular bone mass was significantly decreased in children with NS (p 0.0001). Serum 25-OHD levels were low in about half of the patients and were negatively correlated with age (r = -0.52; p 0.0001). Patients with NS exhibited reduced bone formation marker levels and increased bone resorption marker levels (p 0.0001). No gender difference or genotype-phenotype correlations were found for the different bone parameters. Muscle mass and, to a lesser extent, serum insulin-like growth factor 1 (IGF-1) levels were independent predictors of whole-body bone mineral content (p 0.0001 for both parameters; adjusted R

La ginecologia infantil se dirige sobre todo a las ninas antes de la pubertad o al comienzo de esta. Es una consulta frecuente en medicina privada y tiene algunas especificidades. El tratamiento se basa en el conocimiento del desarrollo ginecologico de la recien nacida y de la nina, asi como del desarrollo puberal clinico y ecografico. En este articulo se describen desde un punto de vista anatomico las afecciones que implican a la vulva y al clitoris, las anomalias congenitas de la vagina y del utero y las masas ovaricas. La observacion clinica del desarrollo somatico y la exploracion ginecologica externa suelen ser los unicos actos esenciales y suficientes en el tratamiento de las ninas. Los metodos de inspeccion de la vulva deben efectuarse sin exigencias, con el consentimiento de la paciente y en presencia del adulto que la acompana. Las vulvitis y vulvovaginitis de la nina son, con mucho, los motivos de consulta mas frecuentes. Su diagnostico es clinico y no necesita toma de muestras. Se detallaran las afecciones infecciosas de la vulva para ayudar al medico a adaptar el tratamiento, detectar la presencia de un cuerpo extrano o tratar de manera correcta una infeccion bacteriana. Algunas afecciones vulvares no infecciosas y las que afectan al clitoris tienen particularidades pediatricas que no deben ignorarse. El estudio por imagen pelvico, representado en primer lugar por la ecografia, es la exploracion decisiva en la deteccion de las anomalias congenitas de la vagina y del utero, asi como para el diagnostico de las masas ovaricas. Estas son infrecuentes, casi siempre benignas, y el sintoma principal es el dolor. El estudio por imagen hace posible la orientacion etiologica. En relacion con las diferentes etiologias, se describen el tratamiento de urgencia de una torsion de anexos, las caracteristicas de un quiste ovarico, el tipo tisular de los tumores organicos y su orden de frecuencia.

International audience; The French College of Obstetrics and Gynecology (CNGOF) has released its first comprehensive recommendations for clinical practices in contraception, to provide physicians with an updated synthesis of the available data as a basis for their practice. The organizing committee and the working group adopted the objective methodological principles defined by the French Authority for Health (HAS) and selected 12 themes relevant to medical professionals' clinical practices concerning contraception. The available literature was screened through December 2017 and served as the basis of 12 texts, reviewed by experts and physicians from public and private practices, with experience in this field. These texts enabled us to develop evidence based, graded recommendations. Male and female sterilization, as well as the use of hormonal treatments not authorized for contraception ("off-label") were excluded from the scope of our review. Specific practical recommendations are provided for the management of contraception prescription, patient information concerning effectiveness, risks, and benefits of the different methods, patient follow-up, intrauterine contraception, emergency contraception, local and natural methods, contraception in teenagers, in women after 40, for women at high thromboembolism or cardiovascular risk, and for those at of primary cancer or relapse. The short- and mid-term future of contraception depends mainly on improving the use of currently available methods. This includes reinforced information for users and increased access to contraception for women, regardless of their social and clinical contexts. The objective of these guidelines is to aid in enabling this improvement.

Turner syndrome (TS) affects approximately one out of 2500 females. Previous research indicates that women with TS experience impairment in several psychosocial domains as well as in quality of life (QoL). Data, however, mainly focus on girls, whereas data on adult women is extremely scarce, inconsistent and mainly low in sample size. Separate analysis of adult women, however, is important since women face other challenges of TS than girls.We compared 301 women with TS aged 16-73 years (from 14 centres in six European countries) to healthy controls with regard to depression, anxiety, self-esteem, attention deficit/hyperactivity disorder (ADHD), autism, romantic relationships, social participation, amount of working hours and satisfaction with income as well as with regard to psychological, physical, environmental, social and global QoL. The influence of psychosocial well-being on the different QoL-domains was examined via multiple regression models.Women with TS showed impairments in all psychosocial variables (anxiety, depression, ADHD, autism, self-esteem, social participation all p 0.001) except for the amount of working hours (p = 0.062) and satisfaction with income (p = 0.369). They also showed lower social (p 0.001), psychological (p 0.001) and physical QoL (p 0.001) compared to controls. Depression, satisfaction with income and self-esteem could be shown to be the best predictors for QoL.In conclusion, quality of life in TS is impaired, in particular it seems to be negatively affected by depression and low self-esteem whereas satisfaction with income has a positive influence. These results implicate that medical staff needs to pay attention on possible psychosocial impairments when treating women with TS. Strengthening self-esteem and counteracting depression potentially raises their QoL.

Variation in karyotype may be associated with the phenotype of patients with Turner syndrome (TS). Our objective was to identify these associations between karyotype and phenotype in TS patients. This study was part of the European multicentre dsd-LIFE study. We evaluated the associations between different karyotypes of TS patients and age at diagnosis, Turner stigmata, cardiac/renal involvement and gonadal function. Information was available for 328 TS patients. Participants had a monosomy 45,X (46%), mosaicism 45,X/46,XX (10%), karyotype with isochromosome (18%), or other karyotype (26%). The clinical signs of TS were the most severe in patients with monosomy 45,X and the least severe in patients with mosaicism 45,X/46,XX. Patients with isochromosome and y-material showed an intermediate phenotype. Despite the more severe features in patients with monosomy 45,X, the median age at diagnosis was only slightly lower compared to patients with other karyotypes, which suggests opportunities for improvement of knowledge and diagnostics.

How to perform a gynecological examination in the girl ? Precautionary gynecological examination is very important in the pre-pubescent girl, since it allows the diagnosis of most pathologies. Parents should be present in order to establish a climate of trust. The most suitable position is that of "the frog". The use of MEOPA (nitrogen monoxide-oxygen mixture) is valuable. The main reasons for consultation are vulvitis, leucorrhea and genital haemorrhage. Complementary examinations are rarely indicated, particularly bacteriological samples which are painful and usually unnecessary.Comment réaliser un examen gynécologique chez la petite fille ? Chez la petite fille prépubère, un examen gynécologique soigneux et bien conduit est primordial puisqu’il permet de diagnostiquer la plupart des pathologies. Il est souhaitable que les parents soient présents, afin d’établir un climat de confiance. La position la plus adaptée est celle de la grenouille. L’utilisation du mélange équimoléculaire oxygène-protoxyde d’azote (MEOPA) est une aide précieuse. Les principaux motifs de consultation sont la vulvite, les leucorrhées, les hémorragies génitales. Les examens complémentaires sont rarement indiqués, notamment les prélèvements bactériologiques, qui sont douloureux et le plus souvent inutiles.

The French College of Obstetrics and Gynecology (CNGOF) releases its first global recommendations for clinical practice in contraception, to provide physicians with an updated synthesis of available data as a basis for their practice. The French Health Authority (HAS) methodology was used. Twelve practical issues were selected by the organizing committee and the task force members. The available literature was screened until December 2017, and allowed the release of evidence-based, graded recommendations. This synthesis is issued from 12 developed texts, previously reviewed by experts and physicians from public and private practices, with an experience in the contraceptive field. Male and female sterilization, as well as the use of hormonal treatments without contraceptive label were excluded from the field of this analysis. Specific practical recommendations on the management of contraception prescription, patient information including efficacy, risks, and benefits of the different contraception methods, follow up, intrauterine contraception, emergency contraception, local and natural methods, contraception in teenagers and after 40, contraception in vascular high-risk situations, and in case of cancer risk are provided. The short/mid-term future of contraception mostly relies on improving the use of currently available methods. This includes reinforced information for users and increased access to contraception for women, whatever the social and clinical context. That is the goal of these recommendations.

International audience; Context - Silver-Russell syndrome (SRS) (mainly secondary to 11p15 molecular disruption) and Temple syndrome (TS) (secondary to 14q32.2 molecular disruption) are imprinting disorders with phenotypic (prenatal and postnatal growth retardation, early feeding difficulties) and molecular overlap. Objective - To describe the clinical overlap between SRS and TS and extensively study the molecular aspects of TS. Patients - We retrospectively collected data on 28 patients with disruption of the 14q32.2 imprinted region, identified in our center, and performed extensive molecular analysis. Results - Seventeen (60.7%) patients showed loss of methylation of the MEG3/DLK1 intergenic differentially methylated region by epimutation. Eight (28.6%) patients had maternal uniparental disomy of chromosome 14 and three (10.7%) had a paternal deletion in 14q32.2. Most patients (72.7%) had a Netchine-Harbison SRS clinical scoring system ≥4/6, and consistent with a clinical diagnosis of SRS. The mean age at puberty onset was 7.2 years in girls and 9.6 years in boys; 37.5% had premature pubarche. The body mass index of all patients increased before pubarche and/or the onset of puberty. Multilocus analysis identified multiple methylation defects in 58.8% of patients. We identified four potentially damaging genetic variants in genes encoding proteins involved in the establishment or maintenance of DNA methylation. Conclusions - Most patients with 14q32.2 disruption fulfill the criteria for a clinical diagnosis of SRS. These clinical data suggest similar management of patients with TS and SRS, with special attention to their young age at the onset of puberty and early increase of body mass index.

Toll-like receptor 7 (TLR7) is critical to the induction of antiviral immunity, but TLR7 dosage is also a key pathogenic factor in systemic lupus erythematosus (SLE), an autoimmune disease with strong female bias. SLE prevalence is also elevated in individuals with Klinefelter syndrome, who carry one or more supernumerary X chromosomes, suggesting that the X chromosome complement contributes to SLE susceptibility. TLR7 is encoded by an X chromosome locus, and we examined here whether the TLR7 gene evades silencing by X chromosome inactivation in immune cells from women and Klinefelter syndrome males. Single-cell analyses of TLR7 allelic expression demonstrated that substantial fractions of primary B lymphocytes, monocytes, and plasmacytoid dendritic cells not only in women but also in Klinefelter syndrome males express TLR7 on both X chromosomes. Biallelic B lymphocytes from women displayed greater TLR7 transcriptional expression than the monoallelic cells, correlated with higher TLR7 protein expression in female than in male leukocyte populations. Biallelic B cells were preferentially enriched during the TLR7-driven proliferation of CD27+ plasma cells. In addition, biallelic cells showed a greater than twofold increase over monoallelic cells in the propensity to immunoglobulin G class switch during the TLR7-driven, T cell-dependent differentiation of naive B lymphocytes into immunoglobulin-secreting cells. TLR7 escape from X inactivation endows the B cell compartment with added responsiveness to TLR7 ligands. This finding supports the hypothesis that enhanced TLR7 expression owing to biallelism contributes to the higher risk of developing SLE and other autoimmune disorders in women and in men with Klinefelter syndrome.

Context Current knowledge on gonadal function in congenital adrenal hyperplasia (CAH) is mostly limited to single-center/country studies enrolling small patient numbers. Overall data indicate that gonadal function can be compromised in men with CAH. Objective To determine gonadal function in men with CAH within the European ‘dsd-LIFE’ cohort. Design Cross-sectional clinical outcome study, including retrospective data from medical records. Methods Fourteen academic hospitals included 121 men with CAH aged 16–68 years. Main outcome measures were serum hormone concentrations, semen parameters and imaging data of the testes. Results At the time of assessment, 14/69 patients had a serum testosterone concentration below the reference range; 7 of those were hypogonadotropic, 6 normogonadotropic and 1 hypergonadotropic. In contrast, among the patients with normal serum testosterone (55/69), 4 were hypogonadotropic, 44 normogonadotropic and 7 hypergonadotropic. The association of decreased testosterone with reduced gonadotropin concentrations (odds ratio (OR) = 12.8 (2.9–57.3)) was weaker than the association between serum androstenedione/testosterone ratio ≥1 and reduced gonadotropin concentrations (OR = 39.3 (2.1–732.4)). Evaluation of sperm quality revealed decreased sperm concentrations (15/39), motility (13/37) and abnormal morphology (4/28). Testicular adrenal rest tumor (TART)s were present in 39/80 patients, with a higher prevalence in patients with the most severe genotype (14/18) and in patients with increased current 17-hydroxyprogesterone 20/35) or androstenedione (12/18) serum concentrations. Forty-three children were fathered by 26/113 patients. Conclusions Men with CAH have a high risk of developing hypothalamic-pituitary-gonadal disturbances and spermatogenic abnormalities. Regular assessment of endocrine gonadal function and imaging for TART development are recommended, in addition to measures for fertility protection.

Background: dsd-LIFE is a comprehensive cross-sectional clinical outcome study of individuals with disorders/differences of sex development (DSD). This study focuses on various rare genetic conditions characterized by impaired gonadal or adrenal functionality.Methods/Design: The study aims to assess quality of life (QoL) as a measure of psychosocial adaptation, psychosexual and mental health aspects as major outcomes. Health status and functioning, medical and surgical therapies, participants' views on health care, psychological and social support, sociodemographic factors and their interrelations will be investigated as factors associated with the outcomes. In addition, ethical considerations in the field of DSD are addressed and previous experiences with health care were gathered. One thousand and forty participants with different DSD conditions were recruited by 14 study centres in 6 European countries (France, Germany, the Netherlands, Poland, Sweden and the United Kingdom) from February 2014 until September 2015. The conditions included were: Turner syndrome (n = 301); 45,X0/46,XY conditions (n = 45); Klinefelter syndrome (n = 218); 47,XYY (n = 1); 46,XY gonadal dysgenesis/ovotestes (n = 63); complete androgen insensitivity (CAIS) (n = 71); partial androgen insensitivity (PAIS) (n = 35) and androgen synthesis disorders (n = 20); severe hypospadias (n = 25); other or non-classified 46,XY DSD (n = 8); 46,XX congenital adrenal hyperplasia (CAH) (n = 226); 46,XX gonadal dysgenesis/ovotestis (n = 21); and 46,XX in males (n = 6). For an add-on study, 121 46,XY male-assigned individuals with CAH due to 21-hydroxylase deficiency were recruited. Mean age of participants' was 32.4 (+/− 13.6 years).Discussion: Participation was high in conditions not commonly described as DSD, such as Turner and Klinefelter syndromes or CAH. Recruitment of individuals with XY DSD conditions proved to be more difficult. The data collection of PROs resulted in high data quality. Within medical and physical examination data, more missings and/or inaccurate data were found than expected. The European dsd-LIFE study recruited and evaluated the largest cross-sectional sample of individuals with different conditions classified under the term DSD. The data from this large sample will provide a sufficient basis for evidence-based recommendations for improvement of clinical care of individuals affected by a DSD condition.Trial registration: German Clinical Trials Register DRKS00006072.

International audience; OBJECTIVE:To investigate fertility outcome in individuals with different forms of disorders of sex development (DSD), if assisted reproductive technology (ART) was used, and the patients' satisfaction with the information they had received.DESIGN:A cross-sectional multicenter study, dsd-LIFE.SETTING:Not applicable.PATIENT(S):A total of 1,040 patients aged ≥16 years with different DSD diagnoses participated.INTERVENTION(S):A web-based questionnaire was filled out by all participants. The participants could chose to take part in somatic investigations including ultrasonography.MAIN OUTCOME MEASURE(S):Information on partner, number of children, ART, adoption and step-children, general health, presence of gonads and uterus, current education and economic situation, received information on fertility issues, and satisfaction with the information, was collected.RESULT(S):In the total cohort, mean age 32 years, 33% lived with a partner, but only 14% reported having at least one child including 7% with ART, 4% adopted. Only 3.5% of the total cohort had been able to reproduce without ART, most frequently women with congenital adrenal hyperplasia, and only 0.7% of participants with other diagnoses. Of the participants, 72% had received information on fertility, but 17% were not satisfied with the information.CONCLUSION(S):Fertility outcome is significantly reduced in all types of DSD; however, fertility potential should be assessed individually. The satisfaction with how fertility problems have been discussed can be improved. The care of patients with DSD is complex, should be individualized, and new treatment possibilities incorporated. A close collaboration in multidisciplinary teams is therefore essential to improve the situation for individuals with DSD.

Objective Urethral prolapse (UP) is a complete eversion of the distal urethral mucosa through the external meatus. UP must be distinguished by examination from trauma, prolapsed ureterocele, tumors or sexual abuse. Its management remains controversial. The aim of the study was to promote the benefits of primary surgical management for UP. Methods A retrospective multicenter review of children who received surgery for UP between 1991 and 2011 was carried out. Non-complicated UP was primarily treated conservatively. A total of 19 patients were referred for complicated UP and underwent resection of the prolapsed urethral mucosa. Results The mean delay in diagnosis was 2.2 days (range 1–6) and the most common symptoms were vaginal spotting and bleeding. No predisposing factor was found, but most patients had a mean weight, height and BMI greater than the 50th percentile. All patients underwent surgery successfully. One patient experienced a complication, i.e., dysuria. There was no case of recurrence after a mean 28 months of follow-up. Conclusion Early detection is based on bedside examination. The first-line treatment strategy for uncomplicated UP should be conservative management. Surgical resection is safe and effective for patients with significant symptoms.

Autism is a neurodevelopmental disorder that usually arises on the basis of a complex genetic predisposition. The most significant susceptibility region in the first whole genome screen of multiplex families was on chromosome 7q, although this linkage was evident only in UK IMGSAC families. Subsequently all other genome screens of non-UK families have found some evidence of increased allele sharing in an overlapping 40 cM region of 7q. To further characterize this susceptibility locus, linkage analysis has now been completed on 170 multiplex IMGSAC families. Using a 5 cM marker grid, analysis of 125 sib pairs meeting stringent inclusion criteria resulted in a multipoint maximum LOD score (MLS) of 2.15 at D7S477, whereas analysis of all 153 sib pairs generated an MLS of 3.37. The 71 non-UK sib pairs now contribute to this linkage. Linkage disequilibrium mapping identified two regions of association-one lying under the peak of linkage, the other some 27 cM distal. These results are supported in part by findings in independent German and American singleton families.

Puberty is a series of biological events that lead to sexual maturity. The first event is the initiation of pulsatile GnRH secretion from the hypothalamus. Physiological variability and multiple factors influence onset of puberty: ethnic, genetic, nutritional and environmental factors. We observe a secular trends of puberty in industrialized countries, but menarche is stabilized at 12 ½ years in these countries since 30 to 40 years

Objective Beyond the classic triad of peripheral precocious puberty, cafe-au-lait skin pigmentation and polyostotic fibrous dysplasia, partial presentation McCune–Albright syndrome (MAS) has been reported, including the association of isolated recurrent ovarian cysts in early infancy. The aims of this study were to determine whether isolated voluminous fetal unilateral ovarian cysts (diameter > 4 cm) may be associated with a Gsα activating mutation, suggestive of MAS. Design We followed five female fetuses presenting with voluminous unilateral ovarian cysts by ultrasonography until delivery. At birth, all patients underwent percutaneous cyst aspiration and two patients later underwent ovariectomy. A sensitive PCR-based method was used to analyze the Gsα activating mutation in DNA obtained from ovarian cystic fluids or tissue. Results Among the five cases, one Gsα mutation (R201C) was identified in the ovarian tissue. Conclusions We demonstrate for the first time that voluminous fetal unilateral ovarian cysts may be suggestive of MAS. Systematic search for the Gsα mutation should be performed in all newborns with voluminous fetal unilateral ovarian cysts requiring percutaneous cyst aspiration, because early diagnosis of MAS prevents unnecessary oophorectomy to eliminate questions of malignancy and imposes long-term clinical, biological, and imaging follow-up to detect other early manifestations of MAS. © 2012 John Wiley & Sons, Ltd.

Depot gonadotropin-releasing hormone (GnRH) analogs represent the first-line therapy in sexual precocity due to central precocious puberty. GnRH analogs desensitize the pituitary and account for the suppression of luteinizing hormone and follicle-stimulating hormone leading to a decrease of sex steroid levels. The conventional indications are central puberty starting before the age of 8 years in girls and 9 years in boys. These indications can be extended to difficult conditions with poor adult height prognosis or marked psychosocial impact. This includes children after irradiation, international adoption, and children with a physical handicap or mental disabilities. There are different formulations of depot preparations of GnRH analogs; long-acting 1- or 3-month forms are widely used in Europe and all are well tolerated with minor side effects. Overweight is often present at the onset of precocious puberty and some etiologies such as hamartomas predispose to obesity, requiring appropriate care for weight control during and after the cessation of GnRH analog treatment. Many studies have reported on the effects on adult height, which seems to be especially beneficial when treatment is started before the age of 6; however, few studies have focused on the establishment of the 1st menstruation, 1st sexual intercourse, socioprofessional outcome and subsequent fertility.

Depot gonadotropin-releasing hormone (GnRH) analogs represent the first-line therapy in sexual precocity due to central precocious puberty. GnRH analogs desensitize the pituitary and account for the suppression of luteinizing hormone and follicle-stimulating hormone leading to a decrease of sex steroid levels. The conventional indications are central puberty starting before the age of 8 years in girls and 9 years in boys. These indications can be extended to difficult conditions with poor adult height prognosis or marked psychosocial impact. This includes children after irradiation, international adoption, and children with a physical handicap or mental disabilities. There are different formulations of depot preparations of GnRH analogs; long-acting 1- or 3-month forms are widely used in Europe and all are well tolerated with minor side effects. Overweight is often present at the onset of precocious puberty and some etiologies such as hamartomas predispose to obesity, requiring appropriate care for weight control during and after the cessation of GnRH analog treatment. Many studies have reported on the effects on adult height, which seems to be especially beneficial when treatment is started before the age of 6; however, few studies have focused on the establishment of the 1st menstruation, 1st sexual intercourse, socioprofessional outcome and subsequent fertility.

Objectifs Decrire l’âge de menarche et le deroulement pubertaire des filles atteintes de mucoviscidose. Patients, methodes Il s’agit d’une etude transversale, multicentrique, chez 164 jeunes filles de plus de 8 ans suivies pour mucoviscidose dans 7 CRCM. L’âge median aux premieres regles a ete estime par la methode de Kaplan-Meier chez 164 filles dont 97 reglees. Nous avons compare certains parametres lies a la maladie entre le groupe des filles avec une puberte retardee (PR) et le groupe avec une puberte normale (PN). Resultats L’âge median aux premieres regles est estime a 13 ans [11–21 ans]. Ces resultats correspondent a ceux observes dans la population generale, mais la distribution des âges montre une proportion plus importante de pubertes retardees (17,3 % versus 5 %, p Conclusion Il s’agit de la plus grande cohorte de suivi pubertaire de patientes atteintes de mucoviscidose montrant un âge de menarche comparable a la population generale. Les precedentes etudes sont anciennes et decrivaient un retard de menarche de 2 ans. Cependant, il faut rester vigilant sur le depistage des retards pubertaires qui demeurent plus frequents que dans la population generale.

The observation of ambiguous genitalia in the newborn signals a medical, surgical and psychological emergency. The most crucial decision will be the choice of sex assignment. Rapid and precise diagnosis is thus essential. In XY newborns with normal/high plasma testosterone (T), partial androgen insensitivity syndrome (PAIS) is usually the first diagnosis evoked, which implies an androgen receptor (AR) defect. The diagnosis of steroid-5-alpha-reductase deficiency is rarely considered by the paediatrician. We report three new SRD5A2 gene mutations in four newborns from France, Morocco and Turkey. The newborns presented with ambiguous genitalia and normal plasma T values and the initial diagnosis\PAIS. In all four cases, normal sequences of the complete AR gene excluded this diagnosis and raised the hypothesis of 5α-reductase deficiency. The entire coding region (5 exons) of the SRD5A2 gene was assessed by PCR and direct sequencing analysis. For patient 1, we identified a new homozygous 2bp deletion in exon 1 (c.122_123delAG). Patient 2 had a known homozygous mutation, p.G115D, in exon 2. New compound heterozygous mutations in exon 4 (p.A215V) and exon 5 (p.X255Q) were found in patient 3. Patient 4 presented a new substitution in exon 1 (p.S14R) associated with a known polymorphism (p.V89L). Our data confirm our previous experience and clearly demonstrate that a 5-α reductase defect should be considered in all XY newborns with ambiguous genitalia and normal plasma T secretion, whatever their geographic area or ethnic group; moreover, this defect was not linked to specific phenotype. Early molecular diagnosis is indispensable for the crucial decision of the newborn's sex of rearing.

Vaginal agenesis in Mayer-Rokitansky-Küster-Hauser syndrome can be managed either by various surgeries or dilation. The choice still depends on surgeon's preferences rather than on quality comparative studies and validated protocols.We sought to compare dilation and surgical management of vaginal agenesis in Mayer-Rokitansky-Küster-Hauser syndrome, in terms of quality of life, anatomical results, and complications in a large multicenter population.Our multicenter study included 131 patients18 years, at least 1 year after completing vaginal agenesis management. All had an independent gynecological evaluation including a standardized pelvic exam, and completed the World Health Organization Quality of Life instrument (general quality of life) as well as the Female Sexual Function Index and Female Sexual Distress Scale-Revised (sexual quality of life) scales. Groups were: surgery (N = 84), dilation therapy (N = 26), and intercourse (N = 20). One patient was secondarily excluded because of incomplete surgical data. For statistics, data were compared using analysis of variance, Student, Kruskal-Wallis, Wilcoxon, and Student exact test.Mean age was 26.5 ± 5.5 years at inclusion. In all groups, World Health Organization Quality of Life scores were not different between patients and the general population except for lower psychosocial health and social relationship scores (which were not different between groups). Global Female Sexual Function Index scores were significantly lower in the surgery and dilation therapy groups (median 26 range [2.8-34.8] and 24.7 [2.6-34.4], respectively) than the intercourse group (30.2 [7.8-34.8], P = .044), which had a higher score only in the satisfaction dimension (P = .004). However, the scores in the other dimensions of Female Sexual Function Index were not different between groups. The Female Sexual Distress Scale-Revised median scores were, respectively, 17 [0-52], 20 [0-47], and 10 [10-40] in the surgery, dilation therapy, and intercourse groups (P = .38), with sexual distress in 71% of patients. Median vaginal depth was shorter in dilatation therapy group (9.6 cm [5.5-12]) compared to surgery group (11 cm [6-15]) and intercourse group (11 cm [6-12.5]) (P = .039), but remained within normal ranges. One bias in the surgery group was the high number of sigmoid vaginoplasties (57/84, 68%), but no differences were observed between surgeries. Only 4 patients achieved vaginas6.5 cm. Delay between management and first intercourse was 6 months (not significant). Seventy patients (53%) had dyspareunia (not significant), and 17 patients all from the surgery group had an abnormal pelvic exam. In the surgery group, 34 patients (40.5%) had complications, requiring 20 secondary surgeries in 17 patients, and 35 (42%) needed postoperative dilation. In the dilation therapy group, 13 (50%) needed maintenance dilation.Surgery is not superior to therapeutic or intercourse dilation, bears complications, and should therefore be only a second-line treatment. Psychological counseling is mandatory at diagnosis and during therapeutic management.

The aims of this study were to evaluate survival and ovarian prognosis in patients treated for ovarian germ cell tumor (OGCT) and to propose a decision-making protocol.Charts of girls operated on for OGCT from 1976 up to 2009 were reviewed retrospectively. Tumor characteristics were assessed by tumor markers, imaging, and pathology.Charts were available in 71 children presenting 75 OGCT. Tumors were benign in 58 cases and malignant in 17 cases. The average of the largest diameter of benign OGCT was significantly lower than that of malignant OGCT (76.5 +/- 49 mm versus 169 +/- 54 mm, P.0001). Ovarian-sparing tumorectomy was carried out in 27 benign OGCT; 23 (85%) preserved ovaries were follicular. Malignant OGCTs were managed according to the protocols of the French Society for Pediatric Oncology. Bilateral oophorectomy had to be performed in 2 children. One patient presented a recurrence and 1 died.In our series, both benign and malignant OGCTs have a good prognosis. A 75-mm cutoff size is proposed as an important criterion to preoperatively differentiate between benign and malignant tumors. In benign OGCT, ovarian-sparing tumorectomy leads to preserve ovaries in approximately 85% of cases, and in malignant OGCT, high survival rate has been obtained.

Background/Purpose Ovarian torsion in childhood and adolescence is a rare entity. Traditionally, treatment is oophorectomy. The aim of this study was to evaluate ovarian outcome and to propose a decision-making protocol for suspected ovarian torsion. Methods Between January 1986 and December 2007, 45 ovarian torsion cases in 40 girls were operated on. In all the cases, when the ovary was preserved, patients were clinically and ultrasonographically followed up for several months. Results Median age was 11 years. Median delay between the first symptoms and surgical procedure was 3 days. There was a statistical difference ( P = .0003) between the mean of the largest diameter of twisted normal ovary and the mean of the largest diameter of twisted diseased ovary. Underlying pathology was benign in 22 cases and low-grade malignancy in 2 (one grade II immature teratoma and one steroid cell tumor). Conservative management was performed in 26 cases. At follow-up, 17 ovaries were follicular, 7 being black-bluish during surgery. Conclusions Conservative approach after detorsion of black-bluish ovaries is safe and effective in children. Although very unlikely, the fear of missing malignancy must incite to proceed with caution and can lead, when the size of the twisted ovary is greater than 75 mm, to prefer laparotomy to laparoscopy.

Context: Müllerian duct development depends on gene and hormone interactions. Female Wnt4-knockout mice lack müllerian ducts and are virilized due to the inappropriate expression of the enzymes required for androgen production (normally repressed in female ovary). The WNT4 mutation was recently reported to be associated with failure of müllerian duct formation and virilization in two 46, XX women. Objectives: This collaborative work was designed to determine whether the WNT4 mutation could be identified in a group of adolescent girls with Mayer-Rokitansky-Küster-Hauser syndrome. Results: We analyzed 28 DNA samples from adolescent girls with primary amenorrhea and failure of müllerian duct formation by direct sequencing and identified a new L12P mutation within exon 1 of the WNT4 gene. The substitution of leucine by proline is crucial for the conformation of the expressed protein. This amino acid substitution is unlikely to be a polymorphism because it was not found in 100 DNAs from control subjects. Functional analysis revealed that the mutation induces significantly increased expression of the enzymes involved in androgen biosynthesis (3β-hydroxysteroid dehydrogenase and 17α-hydroxylase). It is interesting to note that the adolescent carrying the mutation was referred to our clinic for primary amenorrhea and hyperandrogenism (severe acne and plasma testosterone: 1.8 vs. 1.2 nmol/liter in controls). She also presented with uterine hypoplasia and follicle depletion. Conclusions: We suggest that in adolescent girls with primary amenorrhea, müllerian duct abnormalities, and hyperandrogenism, a WNT4 mutation should be sought. Moreover, our data confirm that WNT4 is involved in the regulation of müllerian duct development and ovarian androgen biosynthesis. WNT4 may also contribute to human follicle development and/or maintenance.

Background Patients with pituitary stalk interruption syndrome (PSIS) are initially referred for hypoglycemia during the neonatal period or growth retardation during childhood. PSIS is either isolated (nonsyndromic) or associated with extra-pituitary malformations (syndromic). Objective To compare baseline characteristics and long-term evolution in patients with PSIS according to the initial presentation. Study Design Sixty-seven patients with PSIS were included. Data from subgroups were compared: neonates (n = 10) versus growth retardation patients (n = 47), and syndromic (n = 32) versus nonsyndromic patients (n = 35). Results Neonates displayed a more severe hormonal and radiological phenotype than children referred for growth retardation, with a higher incidence of multiple hormonal deficiencies (100% versus 34%; P = 0.0005) and a nonvisible anterior pituitary lobe (33% versus 2%; P = 0.0017). Regular follow-up of growth might have allowed earlier diagnosis in the children with growth retardation, as decreased growth velocity and growth retardation were present respectively 3 and 2 years before referral. We documented a progressive worsening of endocrine impairment throughout childhood in these patients. Presence of extra-pituitary malformations (found in 48%) was not associated with more severe hormonal and radiological characteristics. Growth under GH treatment was similar in the patient groups and did not vary according to the pituitary MRI findings. Conclusions PSIS diagnosed in the neonatal period has a particularly severe hormonal and radiological phenotype. The progressive worsening of endocrine impairment throughout childhood justifies periodic follow-up to check for additional hormonal deficiencies.

We report long-term evolution of endocrine functions and the results of GH treatment in 35 patients (26 male and 9 female) with pituitary stalk interruption. At diagnosis, mean chronological age was 4.8 ± 2.7 years, mean SDS for height –3.1 ± 0.8 with a bone age retardation of 2.3 ± 1.3 years and a mean SDS for growth velocity of –0.5 ± 1.1; 80% presented complete GH deficiency (GHD) and 20% partial GHD; thyroid deficiency was present in 47.1% of children with complete GHD but absent in all partial GHD. Diagnosis was made during the first months of life in only 2 patients while 23% presented with severe neonatal distress; neonatal signs were only observed in the group with pituitary height below 2 mm (45.7% of patients). GHD was isolated in 40.6% of patients below 10 years while multiple hormone deficiencies was consistent at completion of growth in all patients. Height gain was significantly higher in patients who started GH treatment before 4 years (p = 0.002). GH treatment is very effective: in 13 patients, final height was –0.4 ± 1.0, total height gain 3.2 ± 1.2 and distance to target height –0.3 ± 1.6 SDS.

It is now a consensus to resume GH treatment in adolescents with severe GH deficiency (GHD) at retesting to prevent the occurrence of adult GHD syndrome. However, we do not have any data on the follow-up of adolescents with nonsevere GHD at completion of treatment. This report presents preliminary data from a 1-yr prospective study that includes the first 91 patients retested. Anthropometric data, IGF-I and IGF binding protein-3 levels, glycemia and insulinemia, lipid profile, and body composition using dual x-ray absorptiometry and abdominal computed tomography scan were recorded at completion of GH treatment and 1 yr later. Body composition was significantly different at both evaluations, with increased total body fat and decreased lean body mass in the partial GHD group vs. the normal group. Moreover, these alterations worsened after 1 yr without GH in the partial GHD group, whereas there were no modifications in the normal group. We did not find any metabolic alterations such as elevated triglyceride, total cholesterol, or insulin levels. Adolescents with reconfirmed partial GHD exhibit alterations in body composition after 1 yr without GH, whereas those retested normal do not. These changes are similar to those described in severe GHD, although less marked, and justify a precise follow-up.

Recombinant GH (rGH) treatment does not invariably correct height deficits in GH-deficient children once puberty has begun. The addition of GnRH analogs (GnRHa) to delay puberty has been advocated, but published results are few and sometimes conflicting. We retrospectively compared GH-deficient children treated with rGH and GnRHa for at least 1 yr after entering puberty and having attained their final height (n = 23) with a matched control group treated only with rGH. Overall, combined therapy did not significantly increase final height relative to rGH alone. However, the shortest girls at the onset of puberty (75th percentile) in both final height relative to predicted height and pubertal catch-up growth. In the control group, patients having experienced intrauterine growth retardation (IUGR) attained a lower mean final height than patients without IUGR (difference significant in boys, but not in girls). In the combined therapy group, IUGR did not affect the final height of either sex. Our results suggest that two populations might benefit most from combined GnRHa and rGH therapy: girls particularly short at the onset of puberty and patients who had experienced IUGR. Further prospective studies are required to confirm these preliminary hypothesis.

Objectif Determiner la frequence du syndrome metabolique (SM) des patientes ayant un syndrome de Turner (ST) dans la cohorte DSD Life composee de 14 centres europeens ( http://www.dsd-life.eu/ ). Methodes Cette etude fait partie de l’etude DSD Life ( http://www.dsd-life.eu/ ). Apres information et signature du consentement, les differents elements du syndrome metabolique ont ete releves dans un iCRF. Glycemie, triglycerides, HDL cholesterol ont ete preleves a jeun. Selon l’American Heart Association (AHA) et le National Heart, Lung and Blood Institute (NHLBI), le SM se definit par au moins 3 facteurs de risque dont : ratio TT sur taille > 0,5 ; TG > 150 mg/dL ; HDLc 130 mmHg et TAd > 85 mmHg ou prise d’antihypertenseurs ; glycemie a jeun > 100 mg/dL ou prise d’anti-diabetiques. Resultats Trois cent une patientes ST inclues avaient un caryotype : 45X (47 %), 45X/46XX (10 %), isochromosomeX (19 %) ou autre caryotype (25 %). Âgees de 28 ans (15–73), elles mesuraient 153 cm (132–172), l’IMC etait de 24,2 kg/m2 (16–45) ; 24,9 % des patientes avaient un surpoids et 15,66 % presentaient une obesite. Des donnees sont manquantes chez 63 patientes (20,9 %). Les divers caryotypes n’influencent pas l’existence d’un SM. Parmi les dossiers complets 51 (17 %) patientes presentaient 3 criteres ou plus, 44 (14 %) ont 2 criteres ; 79 patientes (26 %) ont 0 ou 1 critere. Conclusion Un tiers des patientes ST presentent 2 ou 3 facteurs du SM. Nous recommandons un depistage regulier des facteurs du SM et leur prevention par conseils dietetiques et l’activite physique reguliere.