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IntroductionCongenital hypothyroidism with gland-in-situ (CH-GIS) is usually attributed to mutations in the genes involved in thyroid hormone production. The diagnostic yield of targeted next-generation sequencing (NGS) varied widely between studies. We hypothesized that the molecular yield of targeted NGS would depend on the severity of CH.MethodsTargeted NGS was performed in 103 CH-GIS patients from the French national screening program referred to the Reference Center for Rare Thyroid Diseases of Angers University Hospital. The custom targeted NGS panel contained 48 genes. Cases were classified as solved or probably solved depending on the known inheritance of the gene, the classification of the variants according to the American College of Medical Genetics and Genomics, the familial segregation, and published functional studies. Thyroid-stimulating hormone at CH screening and at diagnosis (TSHsc and TSHdg) and free T4 at diagnosis (FT4dg) were recorded.ResultsNGS identified 95 variants in 10 genes in 73 of the 103 patients, resulting in 25 solved cases and 18 probably solved cases. They were mainly due to mutations in the TG (n = 20) and TPO (n = 15) genes. The molecular yield was, respectively, 73% and 25% if TSHsc was ≥ and < 80 mUI/L, 60% and 30% if TSHdg was ≥ and < 100 mUI/L, and 69% and 29% if FT4dg was ≤ and > 5 pmol/L.ConclusionNGS in patients with CH-GIS in France found a molecular explanation in 42% of the cases, increasing to 70% when TSHsc was ≥ 80 mUI/L or FT4dg was ≤ 5 pmol/L.

Aim To describe the presenting features and molecular genetics of primary hyperparathyroidism (PHPT) in the paediatric population. Methods Retrospective study of 63 children diagnosed with primary PHPT from 1998 to 2018. Results Compared to older children, infants were often asymptomatic (54% vs 15%, P = 0.002) with a milder form of PHPT. When symptomatic, children and adolescents mostly presented with non-specific complaints such as asthenia, depression, weight loss, vomiting or abdominal pain. A genetic cause of PHPT was identified in about half of this cohort (52%). The infancy period was almost exclusively associated with mutation in genes involved in the calcium-sensing receptor (CaSR) signalling pathway (i.e. CaSR and AP2S1 genes, ‘CaSR group’; 94% of infants with mutations) whereas childhood and adolescence were associated with mutation in genes involved in parathyroid cell proliferation (i.e. MEN1, CDC73, CDKN1B and RET genes, ‘cell proliferation group’; 69% of children and adolescents with mutations). Although serum calcium levels did not differ between the two groups (P = 0.785), serum PTH levels and the urinary calcium/creatinine ratio were significantly higher in ‘cell proliferation group’ patients compared to those in the ‘CaSR group’ (P = 0.001 and 0.028, respectively). Conclusion Although far less common than in adults, PHPT can develop in children and is associated with significant morbidity. Consequently, this diagnosis should be considered in children with non-specific complaints and lead to monitoring of mineral homeostasis parameters. A genetic cause of PHPT can be identified in about half of these patients.

Objectives To examine the changes in diagnostic practices and clinical management of patients with 5α-reductase type 2 (SRD5A2) or 17β-hydroxysteroid dehydrogenase type 3 (HSD17B3) deficiency since molecular diagnoses became available. Methods Clinical, laboratory, and therapeutic data were retrieved from the medical records of 52 patients with a molecular diagnosis of SRD5A2 (n = 31) or HSD17B3 (n = 21) deficiency. Temporal trends regarding age at assessment and initial sex assignment over 1994–2020 were qualitatively analyzed. Age at molecular diagnosis was compared between two subgroups of patients according to their year of birth. Results Fifty-eight percent (n = 30) patients were diagnosed during the perinatal period, 33% (n = 17) during infancy, and 9% (n = 5) during adolescence or adulthood. Over the studied period, the patients’ age at initial assessment and diagnosis frankly decreased. The median (range) age at diagnostic confirmation was 10.5 (0–53.2) years for patients born before 2007 and 0.4 (0–9.3) years for those born in 2007 or later (P = 0.029). Genetic testing identified 27 different variants for the SRD5A2 gene (30% novel, n = 8) and 18 for the HSD17B3 gene (44% novel, n = 8). Before 2002, most patients were initially assigned as females (95%, n = 19), but this proportion dropped for those born later (44%, n = 14; P < 0.001). The influence of initial genital appearance on these decisions seemingly decreased in the most recent years. Therapeutic interventions differed according to the sex of rearing. Ten percent (n = 2) patients requested female-to-male reassignment during adulthood. Conclusion This study showed, over the past two decades, a clear trend toward earlier diagnosis and assignment of affected newborns as males.

OBJECTIVE The effect of advanced carbohydrate counting (ACC) on metabolic and quality of life (QOL) outcomes is uncertain in children with type 1 diabetes. Our aim was to determine whether ACC would improve HbA1c and QOL scores as compared with standard nutrition in this population. METHODS We randomized 87 patients using pump and rapid-acting analogs in a 1 year randomized multicenter study (age 9.6 ± 3.5 years, diabetes duration 4.6 ± 2.7 years, HbA1c 7.8 ± 0.5% [62 ± 5 mmol/mol]). The ACC group received CC education and the control group received traditional dietary education. HbA1c was measured every 3 months. At 0 and 1 year, general, diabetes-specific, and diet-related QOL were respectively assessed by the KIDSCREEN and WHO-5 questionnaires, the diabetes-specific module of the DISABKIDS, and the diet restriction items of the DSQOLS. RESULTS Mean HbA1c was lower in the ACC than the control group at 3 months (P

International audience

International audience; Pycnodysostosis is a lysosomal autosomal recessive skeletal dysplasia characterized by osteosclerosis, short stature, acro-osteolysis, facial features and an increased risk of fractures. The clinical heterogeneity of the disease and its rarity make it difficult to provide patients an accurate prognosis, as well as appropriate care and follow-up. French physicians from the OSCAR network have been asked to fill out questionnaires collecting molecular and clinical data for 27 patients issued from 17 unrelated families. All patients showed short stature (mean = -3.5 SD) which was more severe in females (P = .006). The mean fracture rate was moderate (0.21 per year), with four fractures in total average. About 75% underwent at least one surgery, with an average number of 2.1 interventions per patient. About 50% required non-invasive assisted ventilation due to sleep apnea (67%). About 29% showed psychomotor difficulties and 33% needed a school assistant or adapted schooling. No patient had any psychological evaluation or follow-up. Molecular data were available for 14 families. Growth hormone administration was efficient on linear growth in 40% of cases. We propose several axis of management, such as systematic cerebral MRI for Chiari malformation screening at diagnosis and regular psychological follow-up.

BackgroundThe incidence of childhood type 1 diabetes (T1D) incidence is rising in many countries, supposedly because of changing environmental factors, which are yet largely unknown.PurposeTo unravel environmental markers associated with T1D. Methods: Cases were children with T1D from the French Isis-Diab cohort. Controls were schoolmates or friends of the patients. Parents were asked to fill a 845-item questionnaire investigating the child’s environment before diagnosis. The analysis took into account the matching between cases and controls. A second analysis used propensity score methods.ResultsWe found a negative association of several lifestyle variables, gastroenteritis episodes, dental hygiene, hazelnut cocoa spread consumption, wasp and bee stings with T1D, consumption of vegetables from a farm and death of a pet by old age.ConclusionsThe found statistical association of new environmental markers with T1D calls for replication in other cohorts and investigation of new environmental areas.

Objective Few studies of patients with a 45,X/46,XY mosaicism have considered those with normal male phenotype. The purpose of this study was to evaluate the clinical outcome of 45,X/46,XY boys born with normal or minor abnormalities of external genitalia, notably in terms of growth and pubertal development. Methods Retrospective longitudinal study of 40 patients followed between 1982 and 2017 in France. Results Twenty patients had a prenatal diagnosis, whereas 20 patients had a postnatal diagnosis, mainly for short stature. Most patients had stunted growth, with abnormal growth spurt during puberty and a mean adult height of 158 ± 7.6 cm, i.e. −2.3 DS with correction for target height. Seventy percent of patients presented Turner-like syndrome features including cardiac (6/23 patients investigated) and renal malformations (3/19 patients investigated). Twenty-two patients had minor abnormalities of external genitalia. One patient developed a testicular embryonic carcinoma, suggesting evidence of partial gonadal dysgenesis. Moreover, puberty occurred spontaneously in 93% of patients but 71% (n = 5) of those evaluated at the end of puberty presented signs of declined Sertoli cell function (low inhibin B levels and increased FSH levels). Conclusion This study emphasizes the need to identify and follow-up 45,X/46,XY patients born with normal male phenotype until adulthood, as they present similar prognosis than those born with severe genital anomalies. Currently, most patients are diagnosed in adulthood with azoospermia, consistent with our observations of decreased testicular function at the end of puberty. Early management of these patients may lead to fertility preservation strategies.

Introduction au Tchad, la transmission de la poliomyélite a été interrompue en 2000, mais les importations à partir du Nigéria et la faiblesse des couvertures vaccinales constituent un risque majeur de relance de la maladie. L'objectif de ce travail était d'analyser les connaissances, attitudes et pratiques des parents vis-à-vis de la vaccination contre la poliomyélite des enfants âgés de 0 à 5 ans au Tchad. Méthodes cette étude transversale a été réalisée dans les six arrondissements d'Abéché. Seuls les ménages qui avaient des enfants de moins de 5 ans ont été inclus. Les données ont été recueillies par des entretiens avec les parents et tuteurs d'enfants éligibles à l'aide d'un questionnaire testé et validé. Résultats nous avons interrogé 210 ménages. Aucune famille ne possédait de carnet de vaccination de leurs enfants. Cependant, 97% ont déclaré avoir des enfants ayant participé aux campagnes de vaccination de masse. Près de 97% connaissaient la poliomyélite et 98% avaient entendu parler des campagnes de vaccination. Les canaux d'information les plus cités étaient la radio (98%) et les agents vaccinateurs (72%). Seul 3% des parents interrogés ont déclaré avoir refusé la vaccination. Il existait une association entre l'influence négative de l'entourage et la non vaccination des enfants (p = 0,005). Conclusion les connaissances sur la maladie et le vaccin sont bonnes au Tchad malgré l'existence de rumeurs concernant notamment les effets des vaccins. L'absence de carnet de vaccination a limité l'analyse des résultats de l'enquête, uniquement déclarative avec un taux de vaccination très élevé déclaré. Dans le cadre de l'éradication, le carnet est indispensable pour accompagner la politique de prévention.

Objectif Evaluation de la prise en charge des patients atteints du syndrome de Prader-Willi au CHU de Nantes, sur les themes de la transition et de la sexualite. Materiels et methodes Recueil retrospectif de donnees de 16 patients adultes Prader-Willi suivis en endocrinologie au CHU de Nantes depuis 2000. Resultats Les dossiers de 10 femmes et 6 hommes de 19 a 46 ans ont ete etudies. Seuls 7 des 16 patients ont eu un suivi pediatrique en CHU, dont tous ceux nes apres 1992 (n = 5). Quatre de ces 7 patients ont beneficie d’une consultation de transition dediee, a un âge median de 19 ans. Seuls deux tiers des patients ont un suivi endocrinologique annuel, dont tous ceux ayant eu une consultation transition. Huit femmes sur 10 femmes et 6/6 hommes ont eu une puberte spontanee partielle mais tous les patients avaient un hypogonadisme a l’âge adulte avec seulement 4/10 femmes et 3/6 hommes sous traitement hormonal substitutif. Quatre patients sur 16 patients se declaraient en couple, 7 rapportaient avoir deja eu une relation sentimentale. Seuls 2 patients etaient autonomes, les autres vivaient chez leurs parents ou en structure specialisee. Discussion Il nous parait necessaire de generaliser les consultations de transition, qui sont un temps fort de la construction de la relation medecin–patient et du projet de vie global. Des etudes recentes evoquent un benefice du traitement hormonal substitutif et de « l’education sexuelle » sur le plan de la sante et de la qualite de vie chez ces patients, pourtant ces sujets restent encore insuffisamment abordes.

Telomeric associations (TAs) are fusions between two telomeres of two different chromosomes without visible loss of chromosomal material. Constitutional telomeric associations are rare chromosomal anomalies. We report on the cytogenetic and molecular analyses of a TA involving chromosomes Y and 7 in a child with a female phenotype. Prenatal cytogenetic analysis showed a 45,X chromosome complement in all cells. No fetal abnormality was identified at ultrasound examinations and the pregnancy went to term. During childhood, the proband had gonadal dysgenesis but no other phenotypic manifestations of Turner syndrome. Molecular genetic analyses showed the presence of genomic DNA of the SRY gene without any mutation. Karyotyping and fluorescent in situ hybridization (FISH) analyses on blood showed two cell lines: one cell line with a TA involving chromosomes Y and 7 [46,X,tas(Y;7)(p11.32;q36.3)] and a second cell line with a 45,X pattern. A human pantelomeric repeat TTAGGG probe hybridized to the junction of the TA within the derivative chromosome. FISH and array comparative genomic hybridization (aCGH) analyses demonstrated that tas(Y;7) occurred without detectable loss of any sequence at the derivative chromosome. SNP array analysis excluded an uniparental isodisomy of chromosome 7. Knowing more about TAs will help geneticists to deliver accurate genetic counseling.

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

Sex chromosome aneuploidies (SCA) is a group of conditions in which individuals have an abnormal number of sex chromosomes. SCA, such as Klinefelter’s syndrome, XYY syndrome, and Triple X syndrome are associated with a large range of neurological outcome. Another genetic event such as another cytogenetic abnormality may explain a part of this variable expressivity. In this study, we have recruited fourteen patients with intellectual disability or developmental delay carrying SCA associated with a copy-number variant (CNV). In our cohort (four patients 47,XXY, four patients 47,XXX, and six patients 47,XYY), seven patients were carrying a pathogenic CNV, two a likely pathogenic CNV and five a variant of uncertain significance. Our analysis suggests that CNV might be considered as an additional independent genetic factor for intellectual disability and developmental delay for patients with SCA and neurodevelopmental disorder.

BackgroundGrowth patterns of patients with Noonan syndrome (NS) were established before the involved genes were identified.ObjectiveThe goal of this study was to compare growth parameters according to genotype in patients with NS.Subjects and methodsThe study population included 420 patients (176 females and 244 males) harboring mutations in thePTPN11,SOS1,RAF1, orKRASgenes. NS-associatedPTPN11mutations (NS-PTPN11) and NS with multiple lentigines-associatedPTPN11mutations (NSML-PTPN11) were distinguished. Birth measures and height and body mass index (BMI) measures at 2, 5, 10 years, and adulthood were compared with the general population and between genotypes.ResultsPatients with NS were shorter at birth (mean birth length standard deviation score (SDS): –1.0 ± 1.4;P< 0.001) and throughout childhood than the healthy population, with height SDS being –2.1 ± 1.3 at 2 years, and –2.1 ± 1.2 at 5 and 10 years and adulthood (P< 0.001). At birth, patients withNS-PTPN11were significantly shorter and thinner than patients withNSML-PTPN11,SOS1, orKRAS. Growth retardation was significantly less severe and less frequent at 2 years in patients withNSML-PTPN11andSOS1than in patients withNS-PTPN11(P< 0.001 andP= 0.002 respectively). Patients with NS had lower BMI at 10 years (P< 0.001). No difference between genotypes was demonstrated.ConclusionDetermining the growth patterns of patients with NS according to genotype should better inform clinicians about the natural course of growth in NS so that they can optimize the follow-up and management of these patients.

Objectif Les patients porteurs d’une mosaique 45,X/46,XY peuvent presenter une large variete de phenotypes. Peu d’etudes se sont interessees aux patients avec phenotype masculin normal a la naissance, bien qu’ils representent 90 % de ces patients. L’objectif de cette etude est de decrire la croissance, l’evolution pubertaire et l’existence de pathologies associees dans une cohorte de garcons presentant une mosaique 45,X/46,XY, sans anomalie de la differenciation des organes genitaux externes. Methodes Etude retrospective longitudinale multicentrique sur une cohorte de 35 patients, suivis entre 1982 et 2016. Resultats Vingt patients ont eu un diagnostic en prenatal et 14 patients en postnatal principalement pour petite taille. Ces patients presentent majoritairement un retard de croissance qui s’aggrave a la puberte avec une taille adulte moyenne de 156 cm (± 6 cm) soit a 2,3 DS de leur taille cible (± 0,9 DS). Soixante-dix pour cent des patients avaient des signes turneriens dont 8 patients avec malformations cardiaques ou renales. Quinze patients presentaient une anomalie mineure des organes genitaux dont 9 cryptorchidies unilaterales et un patient a developpe un carcinome embryonnaire testiculaire, temoignant d’un certain degre de dysgenesie gonadique. De plus, le malgre un developpement pubertaire spontane dans 92 % des cas, la fonction testiculaire s’epuise, puisque 56 % des patients avaient des signes biologiques d’insuffisance sertolienne en fin de la puberte. Conclusion Cette etude souligne la necessite de suivre au long cours l’ensemble des patients 45,X/46,XY quel que soit leur mode de diagnostic, avec une attention particuliere sur la croissance, la fonction gonadique, et le depistage de malformations associees.

Patients Eleven patients with 46,XY PGD were divided into two groups. Six symptomatic girls (group 1) were referred for amenorrhea (n = 3), gonadal tumor (n = 2) or campomelic dysplasia (n = 1). Five asymptomatic screened patients (group 2) were diagnosed as 46,XY PGD after familial investigation of the two probands with gonadal tumor. Bilateral gonadectomy was performed in all patients. Results In group 1, pathologic examination revealed an association of dysgerminoma with gonadoblastoma (n = 2), bilateral gonadoblastoma (n = 2) and streak gonads (n = 2). Prophylactic gonadectomy in asymptomatic patients (group 2) also showed asymptomatic dysgerminoma with gonadoblastoma (n = 1), bilateral gonadoblastoma (n = 2) and streak gonads (n = 2). Conclusions A gonadal tumor arising in a girl with pubertal delay may be related to dysgenesis of the gonad. Primary amenorrhea or diagnosis of dysgerminoma should warrant karyotype, and familial study if 46,XY PGD is found. Considering the high incidence of gonadoblastoma and the early occurrence of dysgerminoma, early bilateral gonadectomy is recommended.

Context: The SRY gene encodes a transcription factor responsible for initiating testis differentiation. Mutations in SRY almost always result in XY sex reversal with pure gonadal dysgenesis and an increased risk of gonadal tumor. Most of these mutations are de novo, affecting only one individual in a family. Only a small subset of mutations is shared between a phenotypically normal father and one or more of his affected children. Incomplete penetrance and somatic mosaicism are two hypotheses that may explain a normal phenotype in a father carrying a SRY mutation. Patients and Results: We describe a family with two sisters with XY sex reversal and pure gonadal dysgenesis and a phenotypically normal brother. A novel constitutional frameshift SRY mutation was identified in both sisters and was absent in the brother. The single base pair deletion (c.71delA) led to a premature stop codon in position 60 of the protein, removing entirely the high-mobility group domain and the DNA-binding domain of SRY. The father of the three children presented with hypospadias; cryptorchidism; testicular seminoma and oligoasthenozoospermia, an association termed testicular dysgenesis syndrome (TDS); and the SRY mutation in a mosaic state in the peripheral blood and the tumor. Conclusions: This observation of somatic and germinal mosaicism for a SRY mutation may explain the variable penetrance in some familial gonadal dysgenesis. Importantly, the present report is the first one describing the association of SRY mutation in a male with TDS. This suggests that mutations in a sex-determining gene may contribute to the pathogenesis of TDS. A fertile man is described with hypospadias, cryptorchidism, testicular seminoma, and oligoasthenozoospermia, and a mosaic SRY mutation.

Introduction Le deficit en cytochrome P450 oxydoreductase (mutation POR) est une forme particuliere d’hyperplasie congenitale des surrenales entrainant des deficits multiples dans la steroidogenese. Observation Mlle G. (23 ans), presentait a la naissance un trouble de la differenciation sexuelle avec virilisation des organes genitaux externes et des malformations du squelette caracteristiques du syndrome d’Antley–Bixler. Elle a presente une insuffisance ovarienne partielle prematuree necessitant l’induction de la puberte par estrogenes puis de volumineux kystes ovariens. A l’âge adulte elle ne presentait pas de deficit mineralo ni glucocorticoide. Discussion Le deficit en proteine POR est caracterise par un trouble de la differenciation sexuelle survenant dans les deux sexes. Chez la fille, la virilisation fœtale est causee par l’existence d’une voie accessoire a la synthese de dihydrotestosterone (DHT) : la 17-OHP accumulee au niveau surrenalien et ovarien est convertie directement en DHT par une 5α-reductase de type 1 dont l’expression s’arrete apres la naissance. Il est rapporte un risque de retard pubertaire (defaut de synthese des estrogenes), de kystes ovariens et d’insuffisance ovarienne prematuree, dont les mecanismes restent discutes. Il existe egalement un risque d’interaction medicamenteuse si co-prescription de medicaments metabolises par le cytochrome P450. Conclusion Le deficit en proteine POR est une pathologie rare entrainant des troubles dans la steroidogenese et des malformations. Le diagnostic est suspecte devant le phenotype clinicobiologique mais doit etre confirme par une etude genetique. Le conseil genetique et la preservation de la fertilite sont les enjeux de la transition de l’endocrinologie pediatrique a l’endocrinologie adulte.

This study aimed to analyse data from two different studies (phase II and phase III) regarding the safety and efficacy of treatment with alum formulated glutamic acid decarboxylase GAD65 (GAD-alum) at 30 months after administration to children and adolescents with type 1 diabetes.The phase II trial was a double-blind, randomised placebo-controlled study, including 70 children and adolescents who were followed for 30 months. Participants received a subcutaneous injection of either 20 µg of GAD-alum or placebo at baseline and 1 month later. During a subsequent larger European phase III trial including three treatment arms, participants received two or four subcutaneous injections of either 20 µg of GAD-alum and/or placebo at baseline, 1, 3 and 9 months. The phase III trial was prematurely interrupted at 15 months, but of the 148 Swedish patients, a majority completed the 21 months follow-up, and 45 patients completed the trial at 30 months. Both studies included GAD65 auto-antibodies-positive patients with fasting C-peptide ≥ 0.10 nmol/l. We have now combined the results of these two trials.There were no treatment related adverse events. In patients treated with 2 GAD-alum doses, stimulated C-peptide area under the curve had decreased significantly less (9 m: p 0.037; 15 m: p 0.032; 21 m: p 0.003 and 30 m: p 0.004), and a larger proportion of these patients were also able to achieve a peak stimulated C-peptide0.2 nmol/L (p 0.05), as compared with placebo.Treatment with two doses of GAD-alum in children and adolescents with recent-onset type 1 diabetes shows no adverse events and preserves residual insulin secretion.

The aim of this study was to relate human fetal growth retardation to specific hormone alterations. Serum levels of GH, IGF-I, IGF-II, and IGF binding protein (BP) 3 were measured during the second half of gestation after cordocentesis in 230 fetuses who were classified into normally grown (n = 166) and growth-retarded (n = 64) groups according to ante- and neonatal measurements. The normally grown group showed a progressive decline in serum GH levels toward term (r = -0.42, p = 0.0001), whereas serum IGF-I was increased (r = 0.55, p = 0.0001), as were serum IGF-II (r = 0.21, p = 0.008) and IGFBP3 levels (r = 0.19, p = 0.02), although less markedly. For all hormone levels, wide individual differences were found at any given age of gestation. The incidental presence of fetal malformations in either the normally grown group (n = 107 cases) or the growth-retarded group (n = 50 cases) had no apparent effect on these hormone levels as compared with members of the groups showing no fetal malformations (n = 73 cases). Comparison of the normally grown group with the growth-retarded group showed that serum IGF-I levels were significantly lower in the growth-retarded group (p = 0.001). No differences were found between the groups in serum GH, IGF-II, and IGFBP3 levels, although if data for the third trimester were taken alone, serum IGF-II levels were found to be lower in the growth-retarded group (p = 0.05). In conclusion, during the second half of gestation, fetal serum IGF-I levels may be influenced by nutritional factors controlling fetal growth. However, the wide individual differences in measurements make it a very poor biologic marker of intrauterine growth retardation.

The 65-kD isoform of glutamic acid decarboxylase (GAD65) is a major autoantigen in type 1 diabetes. We hypothesized that alum-formulated GAD65 (GAD-alum) can preserve beta-cell function in patients with recent-onset type 1 diabetes.We studied 334 patients, 10 to 20 years of age, with type 1 diabetes, fasting C-peptide levels of more than 0.3 ng per milliliter (0.1 nmol per liter), and detectable serum GAD65 autoantibodies. Within 3 months after diagnosis, patients were randomly assigned to receive one of three study treatments: four doses of GAD-alum, two doses of GAD-alum followed by two doses of placebo, or four doses of placebo. The primary outcome was the change in the stimulated serum C-peptide level (after a mixed-meal tolerance test) between the baseline visit and the 15-month visit. Secondary outcomes included the glycated hemoglobin level, mean daily insulin dose, rate of hypoglycemia, and fasting and maximum stimulated C-peptide levels.The stimulated C-peptide level declined to a similar degree in all study groups, and the primary outcome at 15 months did not differ significantly between the combined active-drug groups and the placebo group (P=0.10). The use of GAD-alum as compared with placebo did not affect the insulin dose, glycated hemoglobin level, or hypoglycemia rate. Adverse events were infrequent and mild in the three groups, with no significant differences.Treatment with GAD-alum did not significantly reduce the loss of stimulated C peptide or improve clinical outcomes over a 15-month period. (Funded by Diamyd Medical and the Swedish Child Diabetes Foundation; ClinicalTrials.gov number, NCT00723411.).

ContextGender assignment followed by surgery and hormonal therapy is a difficult decision in the management of 45,X/46,XY patients with abnormal external genitalia at birth considering the paucity of studies evaluating pubertal development and fertility outcome, most notably for patients raised as boys.ObjectiveThe purpose of this study was to describe the pubertal course of 20 45,X/46,XY patients born with ambiguous genitalia and raised as boys.MethodsThis is a multicenter retrospective study.ResultsMean age at study was 25.6±2.4 years. Eighty-five percent of the patients presented a ‘classical’ mixed gonadal dysgenetic phenotype at birth. Puberty was initially spontaneous in all but three boys, although in six other patients, testosterone therapy was subsequently necessary for completion of puberty. Sixty-seven percent of the remaining patients presented signs of declined testicular function at the end of puberty (increased levels of FSH and low levels of testosterone and/or inhibin B). Moreover, an abnormal structure of the Y chromosome, known to alter fertility, was found in 10 out of 16 (63%) patients. Two patients developed testicular cancer. Half of the patients have adult penile length of ConclusionsIn summary, 45,X/46,XY children born with ambiguous genitalia and raised as boys have an altered pubertal course and impaired fertility associated with adult short stature, which should, therefore, be taken into consideration for the management of these patients.

This report describes two unrelated boys presenting with short stature, femoral metaphyseal abnormalities, platyspondyly, and retinitis pigmentosa. Patients share similar findings with cases described by Ehara et al. [Ehara et al. (1997); Eur J Pediatr 156:627–630] described as axial spondylometaphyseal dysplasia. The presence of consanguinity in one of our patients further supports an autosomal recessive mode of inheritance of what, we believe, constitutes a separate and distinct entity. © 2010 Wiley-Liss, Inc.

The CUL4B gene encodes a member of Cullin-RING ubiquitin ligase complex. Point mutations in CUL4B were identified recently in patients with syndromic X-linked mental retardation (XLMR). Here, using oligoarray-based comparative genomic hybridization (array CGH), we identified a de novo deletion of the CUL4B gene in a boy with syndromic mental retardation, minor facial anomalies, short stature, delayed puberty, hypogonadism, relative macrocephaly, gait ataxia, and pes cavus, all manifestations described previously in patients with CUL4B point mutations. Interestingly, our patient also presented with aortic valvular "dysplasia" and vertebral anomalies similar to those seen in Scheuermann disease, both of which may also be part of this syndrome. This report further suggests that point mutations and deletions of the CUL4B gene lead to a recognizable phenotype. The association of facial anomalies, short stature, hypogonadism, and gait ataxia in a mentally retarded boy should prompt molecular analyses of the CUL4B gene.

Clinical utility gene card for: Leri-Weill dyschondrosteosis (LWD) and Langer mesomelic dysplasia (LMD)

46,XY gonadal dysgenesis is characterized by abnormal testicular determination. We describe a large kindred in which various disorders of sexual development were observed, ranging from completely female phenotype without ambiguities of the external genitalia (five cases) to men with isolated penile or perineal hypospadias (four cases), including two cases with moderate virilization and one case with ambiguity of the external genitalia. Histologic examination of gonadal tissue was performed on seven subjects. These findings were suggestive of complete gonadal dysgenesis in one patient, partial gonadal dysgenesis in three patients, and mixed gonadal dysgenesis in three patients. Four patients developed gonadal tumors (two gonadoblastoma, two dysgerminoma, and one immature teratoma, i.e., one patient had a dysgerminoma with some areas of gonadoblastoma). All affected subjects had no other congenital anomalies or dysmorphic features. Analysis of families with several affected individuals with 46,XY gonadal dysgenesis implied an X-linked mode of inheritance because of the apparent absence of male-to-male transmission. However, a sex-limited autosomal dominant mode of inheritance affecting only XY individuals could not be ruled out. Analysis of the pedigree we report indicated an autosomal dominant mode of inheritance because of male-to-male transmission. This kindred supports the involvement of at least one autosomal gene in non-syndromic 46,XY gonadal dysgenesis.

Objectif La mise en place de sejour educatif necessite des competences d'organisation et de pratique d'education therapeutique (ETP). L'experience d'une equipe soignante facilite l'organisation d'un sejour commun reunissant 2 centres de diabetologie pediatrique : adolescents et leurs soignants. L'objectif principal du sejour est la rencontre et l'echange de savoir faire entre equipes, avec l'objectif commun d'aider le jeune a vivre avec son diabete et apprendre a gerer une activite sportive sur plusieurs jours. Patients et methodes Le 1 er temps a ete la participation d'une equipe de diabetologie pediatrique (E1) (pediatre, puericultrice et dieteticienne) a un sejour sportif de 5 jours organise par une autre equipe experimentee d'une autre region (E2). L'ensemble des adolescents de 15 a 17 ans des 2 centres ont ete invites, 24 adolescents ont participe (12 et 12) accompagnes par chaque equipe locale. Entre soignants les echanges quotidiens de savoir faire ont facilite la deuxieme etape, un an plus tard, avec l'organisation par l'equipe E1 d'un sejour educatif et sportif de 3 jours avec 2 centres de diabetologie pediatrique voisins de la meme region, ces 3 equipes travaillent ensemble dans le cadre d'un reseau regional coordonnant la prise en charge et l'ETP des enfants diabetiques. 24 adolescents des 3 centres ont participe, entoures de 2 a 3 soignants de chaque equipe. Resultats Les benefices de ces sejours co-organises sont pour les soignants : les echanges et l'apprentissage en pratique concernant le traitement et la pratique de l'education therapeutique au quotidien avec des adolescents, l'experience de la co-animation et le renforcement de l'esprit d'equipe. Les benefices pour les adolescents sont : les rencontres avec d'autres jeunes, la confrontation a d'autres pratiques, la pratique du sport dans un environnement securise, les liens rapproches avec les soignants qui favorisent la confiance. Conclusion Cette experience de transmissions peut etre proposee a d'autres equipes pour promouvoir des idees nouvelles de prise en charge educative.

Purpose Gonadal dysgenesis corresponds to an impaired development of the gonad. One of its major characteristic is its high propensity to malignancy. This study presented the cases of 46, XY pure gonadal dysgenesis (GD) managed in our center over an 18 years period. Material and Methods The charts of 10 patients treated for 46, XY pure GD (non ambiguous female phenotype) were reviewed. Results The diagnosis circumstances were: Gonadal tumour (2 girls): dysgerminomas. In the first case (7 years old), the diagnosis of GD was made post operatively. For the other case (17 years old), this diagnosis was suspected on the association of tumour with slight pubertal development and low HCG blood level. A preoperative karyotype confirmed the diagnosis. Genetic familial investigations in these 2 families led to diagnose 4 additional cases of affected children. Amenorrhea (2 patients, aged 15 and 23 years) Clitoromegaly (1 patient, neonate) Campomelic dysplasia (1 patient, 4 years) Thus, bilateral gonadectomy was performed for therapeutic reasons in the 2 cases of dysgerminomas. In the remaining 8 patients, gonadectomy was performed for prophylactic reasons (median age 7.25 years, range 0-23) but revealed 5 gonadoblastomas with an associated dysgerminoma in one case (11 years old). Of note, the 23 year-old patient seen for amenorrhea had breast and pubic hair development related to hormonal tumoral secretion. Conclusions A gonadal tumour arising in girl with pubertal delay may be related to the dysgenesis of this gonad. The diagnosis of germ cell tumour in girls with low HCG level is likely to be a dysgerminoma.The diagnosis of dysgerminomas should warrant karyotype study and familial screening if 46, XY pure GD is confirmed and should drive to early removal of the gonads.