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ObjectiveTo look at the association of socioeconomic status (SES) with the suitability of the maternity where children are born and its association with mortality.DesignRetrospective analysis of a prospective cohort constituted using hospital discharge databases.SettingFrancePopulationLive births in 2012–2014 in maternity hospitals in mainland France followed until discharge from the hospital.Main outcome measureUnsuitability of the maternity to newborns’ needs based on birth weight and gestational age, early transfers (within 24 hours of birth) and in-hospital mortality.Results2 149 454 births were included, among which 155 646 (7.2%) were preterm. Preterm newborns with low SES were less frequently born in level III maternities than those with high SES. They had higher odds of being born in an unsuitable maternity (OR=1.174, 95% CI 1.114 to 1.238 in the lowest SES quintile compared with the highest), and no increase in the odds of an early transfer (OR=0.966, 95% CI 0.849 to 1.099 in the lowest SES quintile compared with the highest). Overall, newborns from the lowest SES quintile had a 40% increase in their odds of dying compared with the highest (OR=1.399, 95% CI 1.235 to 1.584).ConclusionsNewborns with the lowest SES were less likely to be born in level III maternity hospitals compared with those with the highest SES, despite having higher prematurity rates. This was associated with a significantly higher mortality in newborns with the lowest SES. Strategies must be developed to increase health equity among mothers and newborns.

Fetal and neonatal dysfunctions include rare serious disorders involving abnormal thyroid function during the second half of gestation, which may persist throughout life, as for most congenital thyroid disorders, or be transient, resolving in the first few weeks of life, as in autoimmune hyperthyroidism or hypothyroidism and some cases of congenital hypothyroidism (CH) with the thyroid gland in situ. Primary CH is diagnosed by neonatal screening, which has been implemented for 40 years in developed countries and should be introduced worldwide, as early treatment prevents irreversible neurodevelopmental delay. Central CH is a rarer entity occurring mostly in association with multiple pituitary hormone deficiencies. Other rare disorders impair the action of thyroid hormones. Neonatal Graves’ disease (GD) results from the passage of thyrotropin receptor antibodies (TRAbs) across the placenta, from mother to fetus. It may affect the fetuses and neonates of mothers with a history of current or past GD, but hyperthyroidism develops only in those with high levels of stimulatory TRAb activity. The presence of antibodies predominantly blocking thyroid-stimulating hormone receptors may result in transient hypothyroidism, possibly followed by neonatal hyperthyroidism, depending on the balance between the antibodies present. Antithyroid drugs taken by the mother cross the placenta, treating potential fetal hyperthyroidism, but they may also cause transient fetal and neonatal hypothyroidism. Early diagnosis and treatment are key to optimizing the child’s prognosis. This review focuses on the diagnosis and management of these patients during the fetal and neonatal periods. It includes the description of a case of fetal and neonatal autoimmune hyperthyroidism.

Objective Neonatal hyperthyroidism may be caused by a permanent non-autoimmune genetic disorder or, more frequently, by maternally transmitted high serum TRAb levels. Variable thyroid dysfunction may be observed in this second context. We aimed to evaluate the prevalence of neonatal non-autoimmune hyperthyroidism and of the different types of thyroid function in neonates with a high risk of hyperthyroidism due to maternal Graves’ disease (GD). Design and methods This observational cohort study included all neonates identified in the database of a single academic pediatric care center, over a period of 13 years, as having non-autoimmune hyperthyroidism or an autoimmune disorder with high TRAb levels (above 6 IU/L) transmitted by their mothers. Patients were classified as having neonatal hyperthyroidism, hypothyroidism, or euthyroidism with a permanent or transient disorder. Results Two of the 34 consecutive neonates selected (6%) had permanent non-autoimmune hyperthyroidism due to germline (n = 1) or somatic (n = 1) mutations of the TSH receptor gene. The patients with high serum TRAb levels at birth had transient hyperthyroidism (n = 23), hypothyroidism (primary n = 2, central n = 3) or persistent euthyroidism (n = 4). Conclusion These original findings highlight the need for careful and appropriate monitoring of thyroid function in the long term, not only for the rare patients with non-autoimmune neonatal hyperthyroidism, but also for repeat monitoring during the first month of life in neonates with maternally transmitted high TRAb levels, to ensure the early identification of thyrotoxicosis in more than two thirds of cases and to detect primary or central hypothyroidism, thereby potentially decreasing associated morbidity.

Aims/HypothesisCaused by biallelic mutations of the gene encoding the transcription factor RFX6, the rare Mitchell–Riley syndrome (MRS) comprises neonatal diabetes, pancreatic hypoplasia, gallbladder agenesis or hypoplasia, duodenal atresia, and severe chronic diarrhea. So far, sixteen cases have been reported, all with a poor prognosis. This study discusses the multidisciplinary intensive clinical management of 4 new cases of MRS that survived over the first 2 years of life. Moreover, it demonstrates how the mutations impair the RFX6 function.MethodsClinical records were analyzed and described in detail. The functional impact of two RFX6R181W and RFX6V506G variants was assessed by measuring their ability to transactivate insulin transcription and genes that encode the L-type calcium channels required for normal pancreatic beta-cell function.ResultsAll four patients were small for gestational age (SGA) and prenatally diagnosed with duodenal atresia. They presented with neonatal diabetes early in life and were treated with intravenous insulin therapy before switching to subcutaneous insulin pump therapy. All patients faced recurrent hypoglycemic episodes, exacerbated when parenteral nutrition (PN) was disconnected. A sensor-augmented insulin pump therapy with a predictive low-glucose suspension system was installed with good results. One patient had a homozygous c.1517T>G (p.Val506Gly) mutation, two patients had a homozygous p.Arg181Trp mutation, and one patient presented with new compound heterozygosity. The RFX6V506G and RFX6R181W mutations failed to transactivate the expression of insulin and genes that encode L-type calcium channel subunits required for normal pancreatic beta-cell function.Conclusions/InterpretationMultidisciplinary and intensive disease management improved the clinical outcomes in four patients with MRS, including adjustment of parenteral/oral nutrition progression and advanced diabetes technologies. A better understanding of RFX6 function, in both intestine and pancreas cells, may break ground in new therapies, particularly regarding the use of drugs that modulate the enteroendocrine system.

Objective Isolated central precocious puberty (CPP) includes sporadic, familial and adoption-related forms, and the characterization of its etiology is challenging. This study investigated the prevalence and clinical characteristics of isolated CPP. Design and methods This observational cohort study included all patients (n = 395) with CPP included in the database of a single academic pediatric care center over a period of 11.5 years. Results In total, 332 of the 395 patients (84%) had isolated forms of CPP; the proportion of male patients was lower in this group than for non-isolated CPP (4 vs 33%, P < 0.0001). These patients had sporadic (n = 228, 68.5%), familial (n = 82, 25%) or adoption-related (n = 22, 6.5%) forms. Clinical characteristics at diagnosis were similar between groups, but girls with sporadic CPP were older at referral than those with familial or adoption-related CPP (P < 0.02), and birth weight SDS was lower in adopted patients than in those from the sporadic and familial groups (P < 0.01). In the 72 families containing patients with familial forms, both recessive and dominant transmissions were observed between first-degree relatives. Potential maternal or paternal transmission was identified in two-thirds of the studied families, in similar proportions. An autosomal dominant mode of transmission with low penetrance was suggested by the high proportion of affected parents (33 of the 72 families, 46%). Clinical presentation was similar whatever the mode of inheritance. Conclusion These findings highlight the need for careful monitoring of the various forms of CPP. Future studies should explore pathophysiological mechanisms, particularly for familial forms.

Low-dose IL-2 (ld-IL2) selectively activates and expands regulatory T cells (Tregs) and thus has the potential to skew the regulatory/effector T (Treg/Teff) cell balance towards improved regulation. We investigated which low doses of IL-2 would more effectively and safely activate Tregs during a 1 year treatment in children with recently diagnosed type 1 diabetes. Dose Finding Study of IL-2 at Ultra-low Dose in Children With Recently Diagnosed Type 1 Diabetes (DF-IL2-Child) was a multicentre, double-blinded, placebo-controlled, dose-finding Phase I/II clinical trial conducted in four centres at university hospitals in France: 24 children (7–14 years old) with type 1 diabetes diagnosed within the previous 3 months were randomly assigned 1:1:1:1 to treatment by a centralised randomisation system, leading to a 7/5/6/6 patient distribution of placebo or IL-2 at doses of 0.125, 0.250 or 0.500 million international units (MIU)/m2, given daily for a 5 day course and then fortnightly for 1 year. A study number was attributed to patients by an investigator unaware of the randomisation list and all participants as well as investigators and staff involved in the study conduct and analyses were blinded to treatments. The primary outcome was change in Tregs, expressed as a percentage of CD4+ T cells at day 5. It pre-specified that a ≥60% increase in Tregs from baseline would identify Treg high responders. There were no serious adverse events. Non-serious adverse events (NSAEs) were transient and mild to moderate. In treated patients vs placebo, the commonest NSAE was injection site reaction (37.9% vs 3.4%), whereas other NSAEs were at the same level (23.3% vs 19.2%). ld-IL2 induced a dose-dependent increase in the mean proportion of Tregs, from 23.9% (95% CI −11.8, 59.6) at the lowest to 77.2% (44.7, 109.8) at the highest dose, which was significantly different from placebo for all dose groups. However, the individual Treg responses to IL-2 were variable and fluctuated over time. Seven patients, all among those treated with the 0.250 and 0.500 MIU m−2 day−1 doses, were Treg high responders. At baseline, they had lower Treg proportions in CD4+ cells than Treg low responders, and serum soluble IL-2 receptor α (sIL-2RA) and vascular endothelial growth factor receptor 2 (VEGFR2) levels predicted the Treg response after the 5 day course. There was no significant change in glycaemic control in any of the dose groups compared with placebo. However, there was an improved maintenance of induced C-peptide production at 1 year in the seven Treg high responders as compared with low responders. The safety profile at all doses, the dose-dependent effects on Tregs and the observed variability of the Treg response to ld-IL2 in children with newly diagnosed type 1 diabetes call for use of the highest dose in future developments. The better preservation of insulin production in Treg high responders supports the potential of Tregs in regulating autoimmunity in type 1 diabetes, and warrants pursuing the investigation of ld-IL2 for its treatment and prevention. ClinicalTrials.gov NCT01862120. Assistance Publique-Hopitaux de Paris, Investissements d’Avenir programme (ANR-11-IDEX-0004-02, LabEx Transimmunom and ANR-16-RHUS-0001, RHU iMAP) and European Research Council Advanced Grant (FP7-IDEAS-ERC-322856, TRiPoD).

Background: Gonadotropin-releasing hormone analogues (GnRHa) administered as depot formulations are the standard of care for children with central precocious puberty (CPP). Puberty resumes after treatment discontinuation, but little is known concerning fertility in women who have been treated with GnRHa for CPP during childhood. Methods: The PREFER (PREcocious puberty, FERtility) study prospectively analysed fertility, via a series of questionnaires, in women treated during childhood with triptorelin (depot formulation) for CPP. Co-primary endpoints were the proportion of women wanting a pregnancy any time before study inclusion and during the follow-up period but not pregnant 6 and 12 months after stopping contraception and the waiting time to pregnancy (WTP). Results: A total of 574 women were identified, and 194 women were included in the analysis. Although there were not enough data for primary endpoint assessment, few women (1.7%) reported issues with fertility or were unable to become pregnant despite trying to conceive. Most pregnancies (84.4%, 95% CI [67.2–94.7%]) occurred within 1 year of trying to conceive, in line with the WTP for women without previous CPP. Conclusion: The results, based on a limited sample of patients, suggest that CPP treated with triptorelin does not negatively impact women’s fertility in adulthood. These results need to be consolidated with a subsequent study performed when these women will have reached their mid-thirties.

Hyponatremia is one of the most common electrolyte disorders in hospitalized children. The underlying mechanisms are poorly understood and potentially multifactorial, making management difficult, particularly in neonates. This retrospective study aimed to determine the incidence and etiologies of hyponatremia in hospitalized children under the age of 100 days, in our pediatric tertiary care hospital over a 1-year period. The etiology of hyponatremia was determined by reviewing the data noted in each patient's medical reports. Neonatal hyponatremia had a prevalence of 4.3% (86/2012 patients) and was mostly hospital-acquired (74/86 patients). Fifty-nine patients (68.9%) were preterm neonates. The etiology was iatrogenic in 26 cases (30.2%). In other cases, hyponatremia was due to transient (23 patients, 26.7%) or genetic abnormalities of the renal mineralocorticoid pathway (3 patients, 3.4%), SIADH (12 patients, 14%), digestive disease (3 patients, 3.5%), acute renal failure (3 patients, 3.5%), or heart failure (1 patient, 1.2%).Conclusion: Our findings confirm that hyponatremia is a frequent electrolyte disorder in neonates. Various mechanisms underlie this condition, most of which could be prevented by optimized management. The prevalence of genetic hypoaldosteronism and pseudohypoaldosteronism was higher than expected. We provide a simple diagram to help physicians identify the mechanisms underlying neonatal hyponatremia. What is Known: • In neonates, hyponatremia may be multifactorial, making it difficult to treat. • Newborns display partial resistance to aldosterone, and preterms have a defect in aldosterone secretion. What is New: • Four percent of hospitalized neonates had hyponatremia, 86% hospital-acquired. Hyponatremia was due to a transient or constitutional defect of the mineralocorticoid pathway in 26/86 patients (30%) which is higher than expected. • We propose a tree diagram for improving the management of hyponatremia in neonates.

Precocious puberty (PP) is defined as the onset of clinical signs of puberty before the age of 8 years in girls and 9.5 years in boys. It may be caused by central or peripheral mechanisms. Central PP (CPP) results from premature reactivation of the hypothalamo–pituitary–gonadal axis, with a hormonal pattern similar to that of normal puberty. CPP may be due to hypothalamic lesions or idiopathic in most cases, particularly in girls. It may have consequences for growth and psychosocial development. Thorough evaluation is required to identify its cause and potential for progression. Gonadotropin-releasing hormone agonists are the standard treatment for progressive CPP. The available data indicate that this treatment does not seem to cause or aggravate obesity or have repercussions for body composition, bone mineral density and fertility. Recent studies have implicated a genetic cause for paternally transmitted familial CPP, but such defects do not underlie maternally transmitted CPP and are rarely involved in sporadic forms.

International audience; Objective: SRY-negative 46,XX testicular and ovotesticular disorders/differences of sex development (T/OTDSD) represent a very rare and unique DSD condition where testicular tissue develops in the absence of a Y chromosome. To date, very few studies have described the phenotype, clinical and surgical management and long-term outcomes of these patients. Particularly, early blockade of the gonadotropic axis in patients raised in the female gender to minimize postnatal androgenization has never been reported.Design: Retrospective description of sixteen 46,XX T/OTDSD patients.Results: Sixteen 46,XX SRY-negative T/OTDSD were included. Most (12/16) were diagnosed in the neonatal period. Sex of rearing was male for six patients and female for ten, while the clinical presentation varied, with an external masculinization score from 1 to 10. Five patients raised as girl were successfully treated with GnRH analog to avoid virilization during minipuberty. Ovotestes/testes were found bilaterally for 54% of the patients and unilaterally for the others (with a contralateral ovary). Gonadal surgery preserved appropriate tissue in the majority of cases. Spontaneous puberty occurred in two girls and one boy, while two boys required hormonal induction of puberty. One of the girls conceived spontaneously and had an uneventful pregnancy. DNA analyses (SNP-array, next-generation sequencing and whole-exome sequencing) were performed. A heterozygous frameshit mutation in the NR2F2 gene was identified in one patient.Conclusions: This study presents a population of patients with 46,XX SRY-negative T/OTDSD. Early blockade of gonadotropic axis appears efficient to reduce and avoid further androgenization in patients raised as girls.

Context Unlike homozygous variants, the implication of heterozygous variants on the leptin–melanocortin pathway in severe obesity has not been established. Objective To describe the frequency, the phenotype, and the genotype–phenotype relationship for heterozygous variants in LEP, LEPR, POMC, and PCSK1 in severe obesity. Methods In this retrospective study, genotyping was performed on at least 1 of the LEP, LEPR, POMC, and PCSK1 genes in 1486 probands with severe obesity (600 children, 886 adults). The phenotype was collected in 60 subjects with heterozygous variants and 16 with homozygous variants. We analyzed variant frequency, body mass index (BMI), age of obesity onset, food impulsivity, and endocrine abnormalities. Results The frequency of subjects with homozygous variants was 1.7% (n = 26), and 6.7% (n = 100) with heterozygous variants. Adults with homozygous variants had a higher BMI (66 vs 53 kg/m2, P = .015), an earlier onset of obesity (0.4 vs 5.4 years, P < .001), more often food impulsivity (83% vs 42%, P = .04), and endocrine abnormalities (75% vs 26%, P < .01). The BMI was higher for subjects with high-impact heterozygous variants (61 vs 50 kg/m², P = .045) and those with a second heterozygous variant on the pathway (65 vs 49 kg/m², P < .01). In children, no significant differences were found for the age of obesity onset and BMI. Conclusion Heterozygous variants in LEP, LEPR, POMC, and PCSK1 are frequent in severe obesity and sometimes associated with a phenotype close to that of homozygotes. These data suggest a systematic search for variants in severe early-onset obesity, to discuss therapy that targets this key pathway.

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.

Context There has been concern that GH treatment of children might increase meningioma risk. Results of published studies have been inconsistent and limited. Objective To examine meningioma risks in relation to GH treatment. Design Cohort study with follow-up via cancer registries and other registers. Setting Population-based. Patients A cohort of 10,403 patients treated in childhood with recombinant GH in five European countries since this treatment was first used in 1984. Expected rates from national cancer registration statistics. Main Outcome Measures Risk of meningioma incidence. Results During follow-up, 38 meningiomas occurred. Meningioma risk was greatly raised in the cohort overall [standardized incidence ratio (SIR) = 75.4; 95% CI: 54.9 to 103.6], as a consequence of high risk in subjects who had received radiotherapy for underlying malignancy (SIR = 658.4; 95% CI: 460.4 to 941.7). Risk was not significantly raised in patients who did not receive radiotherapy. Risk in radiotherapy-treated patients was not significantly related to mean daily dose of GH, duration of GH treatment, or cumulative dose of GH. Conclusions Our data add to evidence of very high risk of meningioma in patients treated in childhood with GH after cranial radiotherapy, but suggest that GH may not affect radiotherapy-related risk, and that there is no material raised risk of meningioma in GH-treated patients who did not receive radiotherapy., In a five-country cohort of 10,403 patients treated with recombinant growth hormone, meningioma risk was greatly raised in relation to radiotherapy, but not apparently related to growth hormone.

Hyperthyroidism in children is a rare heterogeneous syndrome characterized by excessive thyroid hormone production. Its manifestations differ according to disease severity. For all forms of hyperthyroidism, treatment aims to restore a euthyroid state, enabling the child to demonstrate appropriate metabolism, growth, and neurocognitive development. Graves' disease is the most frequent cause of hyperthyroidism in children. Treatment modalities include antithyroid drugs, with the advantage that prolonged treatment for several years can be followed by freedom from medical intervention in about 40-50% of cases. It may also be treated with radioactive iodine or, less frequently, thyroidectomy, these more radical treatments both necessitating subsequent lifelong levothyroxine treatment. Particular care is required in the management of pregnant women with Graves' disease. Fetal and neonatal forms of hyperthyroidism are transient and rare, but nevertheless serious. Here, we provide an overview of the best approach to hyperthyroidism diagnosis and management, from fetal development to adolescence.

An increase in the incidence of congenital hypothyroidism (CH) with a normally located gland has been reported worldwide. Affected individuals display transient or permanent CH during follow-up in childhood. This study aimed to determine the prevalence of transient CH and to investigate the possibility of distinguishing between transient and permanent CH in early infancy.This observational cohort study included all patients identified by systematic neonatal screening for CH in the northern Parisian region between 2002 and 2012 and treated for CH with a normally sited gland. A standardized data collection form was completed prospectively at diagnosis. Patients were classified during follow-up as having transient or permanent CH.Of the 92 patients initially treated for CH with a normally located gland during the neonatal period, 49 (54%) had a transient form of CH after the cessation of levothyroxine (LT4) treatment at 1.5 (0.6-3.2) years of age. Multivariate analysis revealed that transient CH was associated with a lower likelihood of having a first-degree family history of CH (p = 0.03) and a lower LT4 dose at six months of age (p = 0.03) than permanent CH. Sex, ethnicity, neonatal problems (e.g., prematurity, being small for gestational age, and/or neonatal distress), iodine status, coexisting malformations, initial CH severity, and thyroid morphology at diagnosis had no effect. Receiver operating characteristics curve analysis showed that a cutoff of 3.2 μg/kg/day for LT4 dose requirement at six months of age had a sensitivity of 71% and a specificity of 79% for predicting transient CH, with values below this threshold considered predictive of transient CH.In patients with CH and a normally located gland, these findings highlight the need to evaluate LT4 dose requirements early, at six months of age, particularly in patients with no family history of CH, for early identification of the approximately 50% of patients for whom treatment should be stopped.

Objectives Precocious puberty seems to be increasing but epidemiological data are scarce. Our objective was to improve the epidemiologic knowledge on this disease. We analyzed the national incidence and spatial trends of idiopathic central precocious puberty in France in 2011–2013 in a cross-sectional descriptive study. Design We used an indicator based on treatment reimbursements recorded in the national insurance database, in girls under the age of nine years and in boys under the age of 10 years. We considered a time lag of up to one year from the onset of puberty to first drug delivery. We tested four different predictive spatial models at the département scale, selecting the model best fitting the data. We carried out semi-structured interviews with qualified hospital teams in five selected regions to investigate spatial differences in medical practices. Results The national annual incidence was 2.68 (95% CI: 2.55, 2.81) per 10 000 girls under the age of 9 years and 0.24 (95% CI: 0.21, 0.27) per 10 000 boys under the age of 10 years. Incidence rates conformed to a purely spatial heterogeneity model in girls, consistent between age groups, with a large incidence range. A similar pattern was observed for boys, with peaks in the South West and Center East. Differences in medical practices may have slightly affected incidence locally, but could not entirely explain the marked geographic pattern. Conclusions The results suggest that the risk factors are similar for boys and girls and justify further investigations of the role of the environment.

Graves’ disease is an autoimmune disorder. It is the leading cause of hyperthyroidism, but is rare in children. Patients are initially managed with antithyroid drugs (ATDs), such as methimazole/carbimazole. A major disadvantage of treatment with ATD is the high risk of relapse, exceeding 70% of children treated for duration of 2 years, and the potential major side effects of the drug reported in exceptional cases. The major advantage of ATD treatment is that normal homeostasis of the hypothalamus–pituitary–thyroid axis may be restored, with periods of drug treatment followed by freedom from medical intervention achieved in approximately 40–50% of cases after prolonged treatment with ATD, for several years, in recent studies. Alternative ablative treatments such as radioactive iodine and, less frequently and mostly in cases of very high volume goiters or in children under the age of 5 years, thyroidectomy, performed by pediatric surgeons with extensive experience should be proposed in cases of non-compliance, intolerance to medical treatment or relapse after prolonged medical treatment. Ablative treatments are effective against hyperthyroidism, but they require the subsequent administration of levothyroxine throughout the patient’s life. This review considers data relating to the prognosis for Graves’ disease remission in children and explores the limitations of study designs and results; and the emerging proposal for management through the prolonged use of ATD drugs.

Introduction Les pseudohypoparathyroidies et l’acrodysostose sont des maladies metaboliques caracterisees par une resistance a l’hormone parathyroidienne, causee par des defauts moleculaires sur la voie de signalisation d’AMP cyclique. D’autres recepteurs hormonaux couples aux proteines G empruntent cette voie, notamment les recepteurs des gonadotrophines. Cependant, l’existence d’une resistance aux gonadotrophines chez ces patients reste incertaine. Notre objectif est de caracteriser la fonction testiculaire des hommes atteints de pseudohypoparathyroidie et d’acrodysostose. Patients Les hommes âges d’au moins 16 ans, suivis au CRMR du Calcium, avec un diagnostic genetique confirme de PHP1A (mutations inactivatrices ou deletions de GNAS), PHP1B (anomalies de methylation du locus GNAS) ou d’acrodysostose (mutations de PRKAR1A ou de PDE4D) ont ete inclus. Resultats Nous avons evalue 32 patients : 10 PHP1A, 18 PHP1B et 4 acrodysostoses. L’echographie testiculaire retrouve une diminution du volume testiculaire chez les patients PHP1A par rapport aux patients PHP1B (6,9 mL [4,8 ;13,1] versus 13,4 mL [9 ;20], p = 0,005). Les concentrations plasmatiques de testosterone, d’inhibine B et des gonadotrophines sont comparables et majoritairement dans les valeurs normales. Chez 2 patients avec acrodysostose, l’echographie a retrouve une agenesie deferentielle en absence de mutation de CFTR2. En conclusion, les patients avec PHP1A presentent une hypotrophie testiculaire, probablement liee a l’atteinte de la spermatogenese (en cours d’evaluation). L’empreinte parentale du locus GNAS semble s’appliquer sur l’epithelium spermatogenique, mais pas a la cellule de Sertoli ni a la cellule de Leydig. L’acrodysostose est associee a des anomalies du developpement des canaux deferents, absentes dans la pseudohypoparathyroidie.

International audience; PURPOSE:XY individuals with disorders/differences of sex development (DSD) are characterized by reduced androgenization caused, in some children, by gonadal dysgenesis or testis regression during fetal development. The genetic etiology for most patients with 46,XY gonadal dysgenesis and for all patients with testicular regression syndrome (TRS) is unknown.METHODS:We performed exome and/or Sanger sequencing in 145 individuals with 46,XY DSD of unknown etiology including gonadal dysgenesis and TRS.RESULTS:Thirteen children carried heterozygous missense pathogenic variants involving the RNA helicase DHX37, which is essential for ribosome biogenesis. Enrichment of rare/novel DHX37 missense variants in 46,XY DSD is highly significant compared with controls (P value = 5.8 × 10-10). Five variants are de novo (P value = 1.5 × 10-5). Twelve variants are clustered in two highly conserved functional domains and were specifically associated with gonadal dysgenesis and TRS. Consistent with a role in early testis development, DHX37 is expressed specifically in somatic cells of the developing human and mouse testis.CONCLUSION:DHX37 pathogenic variants are a new cause of an autosomal dominant form of 46,XY DSD, including gonadal dysgenesis and TRS, showing that these conditions are part of a clinical spectrum. This raises the possibility that some forms of DSD may be a ribosomopathy.

Objective: Most children with endocrine diseases require long-term continuity of care. We investigated the prevalence of loss to follow-up (LTFU) in pediatric patients with chronic endocrine diseases and the risk factors associated with LTFU. Methods: This observational cohort study included all children with chronic endocrine diseases included in the database of a single academic pediatric care center over a period of 8 years. LTFU was defined as a lack of attendance at clinical visits for over 2 years, for unknown reasons. Results: LTFU was recorded for 154 of the 1,067 patients included (14%). Median age at diagnosis was 5.8 (0.3–11.8) vs. 1.2 (0.0–6.9) years, and age at last visit was 14.1 (9.7–16.1) vs. 11.7 (6.1–15.8) years, for the LTFU and no-LTFU groups, respectively. In multivariate analysis, the risk of LTFU increased with age at diagnosis (OR 1.18; 95% CI 1.12–1.24) and was higher for patients diagnosed before 2006 (vs. after 2006; OR 4.80; 95% CI 3.00–7.66), with fewer visits in the last 3 years (OR 0.72; 95% CI 0.65–0.80; p < 0.0001) and a lower health insurance classification (OR 1.79; 95% CI 1.10–2.89; p = 0.02). The risk of LTFU was higher for patients with isolated growth hormone deficiency than for those with other endocrine conditions, such as multiple pituitary deficiencies, hypogonadotropic hypogonadism, Turner syndrome, or thyroid, adrenal, or gonadal disorders (OR 5.24; 95% CI 1.13–24.37; p = 0.03). Conclusion: This study provides the first epidemiological data for LTFU in children and adolescents with chronic endocrine diseases. It should facilitate the targeting of interventions to improve adherence to medical care and healthcare organization during the pediatric period.

International audience; Isolated growth hormone deficiency (IGHD) is a rare condition mainly caused by mutations in GH1. The aim of this study was to assess the contribution of GHRHR mutations to IGHD in an unusually large group of patients. All GHRHR coding exons and flanking intronic regions were sequenced in 312 unrelated patients with nonsyndromic IGHD. Functional consequences of all newly identified missense variants were assessed in vitro (i.e., study of the expression of recombinant GHRHRs and their ability to activate the cyclic adenosine monophosphate (cAMP) signaling pathway). Genotype-phenotype correlation analyses were performed according to the nature of the identified mutation. We identified 20 different disease-causing GHRHR mutations (truncating and missense loss-of-function mutations), among which 15 are novel, in 24 unrelated patients. Of note, about half (13/24) of those patients represent sporadic cases. The clinical phenotype of patients with at least one missense GHRHR mutation was found to be indistinguishable from that of patients with bi-allelic truncating mutations. This study, which unveils disease-causing GHRHR mutations in 8% (24/312) of IGHD cases, identifies GHRHR as the second IGHD gene most frequently involved after GH1. The finding that 8% of IGHD cases without GH1 mutations are explained by GHRHR molecular defects (including missense mutations), together with the high proportion of sporadic cases among those patients, has important implications for genetic counseling.

Background: APECED syndrome is a rare monogenic disease caused by homozygous mutation of AIRE gene. It classically presents with chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency with an early onset in childhood. Non-endocrine manifestations as ectodermic dystrophy, asplenism and pneumonitis are also observed but their incidence remains unknown and their mechanisms not well understood. APECED has been poorly reported in France although it is widely described in several European countries. The aim of this study was to report on rare manifestations of APECED syndrome in a French cohort. Patients and methods: We performed a multicentric prospective observational study in France in order to collect clinical, biological, immunological and genetic data, after written informed consent in the frame of a PHRC (Hospital Project of Clinical Research #1927). Bronchiolitis, splenic atrophy and ocular manifestations were systematically investigated. Results We enrolled 25 patients between 2009 and 2016. Clinically, the median age at diagnosis was 12 while the median age of the first manifestation was 6, so there was diagnostic delay. The median number of manifestations was seven. 76 % of patients presented with the classical triad. Reduction of lung function was observed in 62% of patients, asplenism in 26%, and ocular manifestation in 33%. Genetically, eleven mutations of the AIRE gene were identified, two of which never previously reported: an intronic variation c.653-70G>A (intron 5) in a patient with hypoparathyroidism as unique manifestation , and c.1066del (p.Arg356GlyfsX22) (exon 9) in a patient from Guadeloupe with composite heterozygous mutations (c.967_979del13; exon 8). The most common AIRE mutation was the mutation R257X. Median age was 26 and sex ratio was 1.1. Biologically, 100% of tested sera were positive for anti-IFNα-antibodies, 15/18 for anti-IL-22, and 13/18 for anti-IL-17F antibodies. Conclusion: This series shows a high genotypic and phenotypic variability of APECED in France, that could be explained by different ethnic origins. The systematic screening for non-classic manifestations shows a more frequent occurrence than in other series. Systematic screening of asplenism and bronchiolitis could be a useful strategy to make an earlier diagnosis, to prevent infections by vaccination and to treat earlier pulmonary involvement. Lastly, antibodies against Th17 cytokines appear as good soluble markers for diagnosis of non-classical presentation of the syndrome.

Context Parathormone (PTH) resistance is characterized by hypocalcaemia, hyperphosphatemia, and elevated PTH in the absence of vitamin D deficiency. Pseudohypoparathyroidism type 1A [PHP1A, or inactivating parathormone (PTH)/PTHrp signaling disorder 2, according to the new classification (iPPSD2)], is caused by mutations in the maternal GNAS allele. Objective To assess PTH resistance over time in 20 patients affected by iPPSD2 (PHP1A), diagnosed because of family history, ectopic ossification, or short stature, and carrying a GNAS mutation. Methods We gathered retrospective data for calcium, phosphate, thyrotropin (TSH), and PTH levels at regular intervals. PTH infusion testing (teriparatide) was performed in 1 patient. Results Patients were diagnosed at a mean age of 3.9 years and had a mean follow-up of 2 years. TSH resistance was already present at diagnosis in all patients (TSH, 13.3 ± 9.0 mIU/L). Over time, PTH levels increased (179 to 306 pg/mL; P < 0.05), and calcium levels decreased (2.31 to 2.21 mmol/L; P < 0.05), but phosphate levels did not decrease with age as expected for healthy individuals. One patient born with ectopic ossifications showed an increase in cyclic adenosine monophosphate upon PTH infusion, similar to that of controls, at 7 months of age, but an impaired response at 4 years of age. Conclusions In patients with iPPSD2 (PHP1A), PTH resistance and hypocalcemia develop over time. These findings highlight the importance of screening for maternal GNAS mutations in the presence of ectopic ossifications or family history, even in the absence of PTH resistance and hypocalcemia. The follow-up of these patients should include regular assessments of calcium, phosphate, and PTH levels.

International audience; Context: Growth hormone (GH) is known to be diabetogenic, but the risk of diabetes in individuals treated with GH in childhood has been little evaluated, and conflicting results have been obtained.Objective: To investigate the prevalence of diabetes and gestational diabetes in a population-based cohort of patients treated with GH for short stature in childhood in France.Design, setting, and participants: Participants were a population-based cohort of 5100 children with idiopathic isolated GH deficiency, idiopathic short stature, or short stature in children born short for gestational age who started GH treatment between 1985 and 1996. Data on the delivery of diabetes drugs in 2009 and 2010 were obtained from the French national health insurance database. Cases in patients and controls were identified from diabetes drugs deliveries.Main outcome measure: The prevalence of diabetes was calculated and compared with that in the general population, determined on the basis of data from the same source, with the same definition.Results: At a mean age of 30 years, no difference in the prevalence of treated diabetes (oral drugs or insulin) was found between subjects treated with GH and the general population in France, regardless of sex. Similarly, the risk of insulin-treated gestational diabetes was similar in patients and in the reference population.Conclusions: No difference in the risk of diabetes was found between GH-treated patients and the reference population. These results are reassuring, but further studies with a longer follow-up are required to evaluate the risk of diabetes with age in these patients.

Gender dysphoria, originally called gender identity disorder, is characterized by the dissociation between one's expressed gender and the gender of rearing as assigned at birth, which generates significant clinical distress and social, academic, and other important forms of isolation. This state is also known as transgender or transsexualism and is recognized as a medical disease. Adults with gender dysphoria can benefit from psychological, medical, and surgical care. However, gender dysphoria rarely occurs in adulthood but rather emerges in childhood or adolescence, generating deep social and academic difficulties, especially at puberty. For the last 10years, the management of gender dysphoria in children and adolescents has developed in several countries, specifically in Europe, but remains under-recognized in France. Since 2013, several pediatric psychiatry and endocrinology departments have initiated a multidisciplinary evaluation and management approach for these patients. This article reviews the clinical criteria helping diagnose gender dysphoria and presents the different steps in the assessment and management of these patients in accordance with international guidelines.

Autosomal dominant hypercholesterolemia (ADH) is a human disorder characterized phenotypically by isolated high-cholesterol levels. Mutations in the low density lipoprotein receptor ( LDLR ), APOB, and proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) genes are well known to be associated with the disease. To characterize the genetic background associated with ADH in France, the three ADHassociated genes were sequenced in a cohort of 120 children and 109 adult patients. Fifty-one percent of the cohort had a possible deleterious variant in LDLR, 3.1% in APOB, and 1.7% in PCSK9. We identifi ed 18 new variants in LDLR and 2 in PCSK9. Three LDLR variants, including two newly identifi ed, were studied by minigene reporter assay confi rming the predicted effects on splicing. Additionally, as recently an in-frame deletion in the APOE gene was found to be linked to ADH, the sequencing of this latter gene was performed in patients without a deleterious variant in the three former genes. An APOE variant was identifi ed in three patients with isolated severe hypercholesterolemia giving a frequency of 1.3% in the cohort. Therefore, even though LDLR mutations are the major cause of ADH with a large mutation spectrum, APOE variants were found to be signifi-cantly associated with the disease. Furthermore, using structural analysis and modeling, the identifi ed APOE sequence changes were predicted to impact protein function., SCOPUS: ar.j, info:eu-repo/semantics/published

Summary Central precocious puberty results from the premature activation of the hypothalamic-pituitary-gonadal axis. It mimics physiological pubertal development, although at an inappropriate chronological age (before 8 years in girls and 9 years in boys). It can be attributable to cerebral congenital malformations or acquired insults, but the cause in most cases in girls remains unknown. MKRN3 gene defects have been identified in familial disease, with important basic and clinical results. Indeed, genetic analysis of this gene should be included in the routine clinical investigation of familial and idiopathic cases of central precocious puberty. Gonadotropin-releasing hormone agonists are the gold-standard treatment. The assessment and management of this disease remain challenging for paediatric endocrinologists. In this Series paper, we describe current challenges involving the precise diagnosis and adequate treatment of this disorder.

International audience; BACKGROUND: Lipodystrophic syndromes are rare diseases of genetic or acquired origin characterized by partial or generalized lack of body fat. Early detection and diagnosis are crucial to prevent and manage associated metabolic dysfunctions, i.e. insulin resistance, dyslipidemia, fatty liver, and diabetes, and to provide appropriate genetic counseling. By means of several representative case studies, this article illustrates the diagnostic and management challenges of lipodystrophic syndromes.REVIEW: Berardinelli-Seip congenital lipodystrophy (BSCL) is typically diagnosed at birth, or soon thereafter, with generalized lipoatrophy and hepatomegaly secondary to hepatic steatosis. Physicians must also consider this diagnosis in adults with atypical non-autoimmune diabetes, hypertriglyceridemia, and a lean and muscular phenotype. The BSCL1 subtype due to mutations in the AGPAT2 gene can have an unusual presentation, especially in neonates and infants. Particular attention should be paid to infants presenting failure to thrive who also have hepatomegaly and metabolic derangements. The BSCL2 sub-type due to mutations in the BSCL gene tends to be more severe than BSCL1, and is characterized by greater fat loss, mild intellectual disability, earlier onset of diabetes, and higher incidence of premature death. Effective management from an earlier age may moderate the natural disease course. Partial lipodystrophies may easily be confused with common central obesity and/or metabolic syndrome. In patients with unexplained pancreatitis and hypertriglyceridemia, lipodystrophies such as familial partial lipodystrophy type 2 (FPLD2; Dunnigan type, due to LMNA mutations) should be considered. Oral combined contraceptives, which can reveal the disease by inducing severe hypertriglyceridemia, are contraindicated. Endogenous estrogens may also lead to "unmasking" of the FPLD2 phenotype, which often appears at puberty, and is more severe in females than males.CONCLUSIONS: Diet and exercise, adapted to age and potential comorbidities, are essential prerequisites for therapeutic management of lipodystrophic syndromes. Metreleptin therapy can be useful to manage lipodystrophy-related metabolic complications

Background: Low-dose interleukin 2 (ld-IL2) selectively activates and expands regulatory T cells (Tregs) and thus has the potential to skew the regulatory/effector T (Treg/Teff) cell balance towards improved regulation. Regimens of ld-IL2 are actively investigated as a treatment for various autoimmune diseases, including type 1 diabetes (T1D). We previously reported a dose-dependent specific activation and expansion of Tregs in adults with established T1D receiving a short 5-day treatment with ld-IL2. We report results from the DF-Child trial, in which we investigated which low doses of IL2 would more effectively activate Treg cells during a 1-year treatment in children with recently diagnosed T1D. Methods: DF-Child was a multicentre, double-blinded, phase 1/2 clinical trial: 24 children (7-14 years-old) with T1D diagnosed within the previous 3 months were randomized in a 1:1:1:1 ratio to s.c. injection of placebo or IL2, at doses of 0.125, 0.250, or 0.500 MIU/m2, given daily for a 5-day course and then fortnightly for 1 year. The primary outcome was change in Treg cells expressed as a percentage of CD4+ T cells at day-5, and pre-specified that an increased on Tregs ≥60% from baseline would identify Treg high responders. This trial is registered with ClinicalTrials.gov, NCT01862120. Findings: Twenty-four patients were randomized between June 27, 2013, and Jan 1, 2016. IL2 was well tolerated at all doses, with no serious adverse events. Non-serious adverse events were transient and mild to moderate. Ld-IL2 induced a dose dependent increase in the proportion of Tregs. Although the mean Treg responses of all dose-groups were significantly different from placebo, the individual Treg responses to IL-2 were variable and fluctuated over time. All treated subjects showed an increase in Tregs, and we identified 7 Treg high responders among those treated with the 0.250 and 0.500 MIU/m2/day doses (3 and 4, respectively). There was no significant change in glycaemic control in any of the dose-groups compared to placebo, and no differences reported in insulin doses. However, there was a trend for an improved maintenance of induced C-peptide production at one year in the 7 Treg high responders. Interpretation: The good safety profile at all doses, the dose-dependent effects on Tregs and the observed variability of the Treg response to ld-IL2 in newly diagnosed T1D children call for using the highest dose in future developments. The better preservation of insulin production in Treg high responders supports the potential of Tregs in regulating autoimmunity in T1D and warrants pursuing the investigation of ld-IL2 for its treatment and prevention. Trial Registration Number: This trial is registered with ClinicalTrials.gov, NCT01862120. Funding: Assistance Publique-Hopitaux de Paris, Investissements d’Avenir programme (ANR-11-IDEX-0004-02, LabEx Transimmunom and ANR-16-RHUS-0001, RHU iMAP) and European Research Council Advanced Grant (FP7-IDEAS-ERC-322856, TRiPoD). Declaration of Interest: DK, MR and CB are co-inventor of a patent entitled “IL 2 based therapy” (OEB 11 305269.0) and DK and MR are shareholders in ILTOO pharma, the exclusive licensee of this patent. Ethical Approval: The study was approved by the institutional review board of Pitie-Salpetriere Hospital, and conducted in accordance with the Declaration of Helsinki and good clinical practice guidelines. Written informed consent was obtained from all participants before enrolment in the study.

Introduction et but de l’etude La voie leptine-melanocortines joue un role-cle dans l’homeostasie energetique. Les variants homozygotes sur les genes de cette voie sont associes a une obesite severe et precoce avec anomalies endocriniennes. Le role des variants heterozygotes sur ces memes genes n’est pas etabli dans l’obesite. Le but de l’etude etait de decrire leur frequence et la relation genotype/phenotype dans une cohorte d’enfants et d’adultes avec obesite severe. Materiel et methodes Le sequencage direct sur au moins un gene de la voie (LEP, LEPR, POMC, PCSK1 et MC4R) a ete realise chez 6347 patients avec obesite severe et/ou precoce. La fonctionnalite des variants a ete determinee a partir des consequences proteiques predites, de 7 outils de prediction, et des etudes fonctionnelles decrites. Le phenotype incluait l’âge de debut d’obesite et sa severite, le comportement alimentaire et les anomalies endocriniennes associees. Le phenotype des sujets porteurs heterozygotes (n = 60 dont 29 enfants) a ete compare a celui des homozygotes (n = 16 dont 4 enfants) mais aussi selon la fonctionnalite des variants et le nombre de variants heterozygotes presents chez un meme patient (variants combines) a la recherche d’un effet cumulatif. Resultats et analyse statistique La frequence des variants homozygotes etait de 0,8 % (n = 26) et des variants heterozygotes de 3,3 % (n = 110) dont 1,7 % de variants heterozygotes avec impact fonctionnel (LEP n = 0/22, LEPR n = 23/40, POMC n = 10/21, PCSK1 n = 23/27). Douze sujets (12 %) etaient porteurs de plusieurs variants heterozygotes (MC4R inclus). Chez les enfants, aucune difference significative n’a ete mise en evidence pour l’âge de debut d’obesite et sa severite entre les porteurs heterozygotes et homozygotes. L’IMC moyen des adultes etait significativement superieur pour les porteurs homozygotes compare a celui des porteurs heterozygotes (IMC 66 vs 53 kg/m2, p = 0,015). De meme, l’âge de debut d’obesite etait plus precoce (0,4 vs 5,4 ans, p Conclusion La presence d’un ou plusieurs variants heterozygotes avec impact fonctionnel sur la voie leptine-melanocortines est associee a une obesite severe et precoce avec parfois des anomalies endocriniennes et donc un phenotype proche de celui des sujets porteurs homozygotes. Ces donnees sont donc en faveur de la recherche systematique de variants sur cette voie cle du controle de la prise alimentaire en cas d’obesite precoce et severe avec ou sans anomalie endocrinienne associee afin de discuter l’indication d’un traitement par agoniste MC4R.

Context Growth hormone (GH) therapy may improve statural growth outcomes in patients with severe juvenile idiopathic arthritis (JIA). Objectives To evaluate the effect of GH treatment on adult height and to identify determinants of growth outcomes in JIA. Design and Patients Data from 58 patients with JIA, including 53 receiving GH, enrolled in three prospective clinical trials between 1997 and 2002 were analyzed. Intervention GH (0.056 mg/kg/d [interquartile range (IQR), 0.050 to 0.062]) for a median duration of 6.5 years (IQR, 4.7 to 7.9 years). Main Outcome Measures Factors associated with a favorable growth outcome (adult height - target height ≤ -1.5 standard deviations) were identified by multivariate logistic regression. Results Adult height was available for 48 patients 8.6 years after GH initiation (IQR, 6.0 to 10.2 years). Height standard deviation score (SDS) increased from -2.9 (IQR, -4.4 to -1.6) at baseline to -1.7 (IQR, -3.9 to -0.1) in adulthood (P < 0.001). Median adult height was below target height [SDS, -0.2 (IQR, -1.4 to 0.4); P < 0.001]. Corrected adult height SDS was -1.3 (IQR, -3.0 to -0.2). Growth outcome was favorable in 24 (52.2%) patients. Significant independent determinants of growth outcome were age at GH initiation [adjusted odds ratio (aOR), 0.68 per additional year; 95% confidence interval (CI), 0.47 to 0.99], height at GH initiation (aOR, 2.6 per additional SDS; 95% CI, 1.15 to 5.9), and mean C-reactive protein levels during follow up (aOR, 0.51 per additional 10 mg/L; 95% CI, 0.28 to 0.92). Conclusion Long-term GH treatment significantly increased growth in patients with JIA but did not fully restore the genetic growth potential. The response showed marked interindividual variability and was weaker in patients with severe inflammation.

Objective Non-idiopathic CPP is caused by acquired or congenital hypothalamic lesions visible on MRI or is associated with various complex genetic and/or syndromic disorders. This study investigated the different types and prevalence of non-isolated CPP phenotypes. Design and Methods This observational cohort study included all patients identified as having non-idiopathic CPP in the database of a single academic pediatric care center over a period of 11.5 years. Patients were classified on the basis of MRI findings for the CNS as having either hypothalamic lesions or complex syndromic phenotypes without structural lesions of the hypothalamus. Results In total, 63 consecutive children (42 girls and 21 boys) with non-isolated CPP were identified. Diverse diseases were detected, and the hypothalamic lesions visible on MRI (n = 28, 45% of cases) included hamartomas (n = 17; either isolated or with an associated syndromic phenotype), optic gliomas (n = 8; with or without neurofibromatosis type 1), malformations (n = 3) with interhypothalamic adhesions (n = 2; isolated or associated with syndromic CNS midline abnormalities, such as optic nerve hypoplasia, ectopic posterior pituitary) or arachnoid cysts (n = 1). The patients with non-structural hypothalamic lesions (n = 35, 55% of cases) had narcolepsy (n = 9), RASopathies (n = 4), encephalopathy or autism spectrum disorders with or without chromosomal abnormalities (n = 15) and other complex syndromic disorders (n = 7). Conclusion Our findings suggest that a large proportion (55%) of patients with non-isolated probable non-idiopathic CPP may have complex disorders without structural hypothalamic lesions on MRI. Future studies should explore the pathophysiological relevance of the mechanisms underlying CPP in these disorders.

Aim To compare the efficacy of three strategies for real-time continuous glucose monitoring (RT-CGM) over 12 months in children and adolescents with type 1 diabetes. Methods A French multicenter trial (NCT00949221) with a randomized, controlled, prospective, open, and parallel-group design was conducted. After 3 months of RT-CGM, patients were allocated to one of three groups: return to self-monitoring of blood glucose, continuous CGM (80% of the time), or discontinuous CGM (40% of the time). The primary outcome was hemoglobin A1c (HbA1c) levels from 3 to 12 months. The secondary outcomes were acute metabolic events, hypoglycemia, satisfaction with CGM and cost. Results We included 151 subjects, aged 2 to 17 years, with a mean HbA1c level of 8.5% (SD0.7; 69 mmol/mol). The longitudinal change in HbA1c levels was similar in all three groups, at 3, 6, 9 and 12 months. The medical secondary endpoints did not differ between groups. The rate of severe hypoglycemia was significantly lower than that for the pretreatment year for the entire study population. Subjects reported consistent use and good tolerance of the device, regardless of age or insulin treatment. The use of full-time RT-CGM for 3 months costs the national medical insurance system €2629 per patient. Conclusion None of the three long-term RT-CGM strategies evaluated in pediatric type 1 diabetes was superior to the others in terms of HbA1c levels. CGM-use for 3 months decreased rates of severe hypoglycemia. Our results confirm the feasibility of long-term RT-CGM-use and the need to improve educational support for patients and caregivers.

Context: Neonatal central diabetes insipidus (CDI) with or without adipsia is a very rare complication of various complex hypothalamic disorders. It is associated with greater morbidity and a high risk of developing both hypernatremia and hyponatremia, due to the condition itself or secondary to treatment with vasopressin analogs or fluid administration. Its outcomes have yet to be evaluated. Objective: To investigate the clinical outcomes of patients with neonatal-onset CDI or adipsic CDI with hypernatremia. Design, Setting, and Participants: All patients diagnosed with neonatal CDI in a university hospital-based observational study and followed between 2005 and 2015 were included and analyzed retrospectively. Main Outcome Measures: The various causes of CDI were grouped. Clinical outcome and comorbidities were analyzed. Results: Ten of the 12 patients had an underlying condition with brain malformations: optic nerve hypoplasia (n = 3), septo-optic dysplasia (n = 2), semilobar holoprosencephaly (n = 1), ectopic neurohypophysis (n = 3), and unilateral absence of the internal carotid artery (n = 1). The other two were idiopathic cases. During the median follow-up period of 7.8 (4.9–16.8) years, all but one patient displayed anterior pituitary deficiency. Transient CDI was found in three (25%) patients for whom a posterior pituitary hyperintense signal was observed with (n = 2) and without (n = 1) structural hypothalamic pituitary abnormalities, and with no other underlying cerebral malformations. Patients with permanent CDI with persistent adipsia (n = 4) and without adipsia (n = 5) required adequate fluid intake and various doses of desamino-D-arginine-8-vasopressin. Those with adipsia were more likely to develop hypernatremia (45 vs 33%), hyponatremia (16 vs 4%) (P < .0001), and severe neurodevelopmental delay (P < .05) than those without adipsia. Comorbidities were common. The underlying cause remains unknown at the age of 23 years for one patient with CDI and normal thirst. Conclusion: Neonatal CDI may be transient or permanent. These vulnerable patients have high rates of comorbidity and require careful monitoring.

Context and objectiveIdiopathic central precocious puberty (iCPP) is defined as early activation of the hypothalamic–pituitary–gonadal axis in the absence of identifiable central lesions. Mutations of the makorin RING finger 3 (MKRN3) gene are associated with iCPP. We aimed to assess the frequency of MKRN3 mutations in iCPP and to compare the phenotypes of patients with and without MKRN3 mutations.DesignAn observational study was carried out on patients recruited at pediatric hospitals in France and Italy. Forty-six index CPP cases were screened for mutations in the MKRN3 coding sequence: 28 index cases of familial cases and 18 cases did not report any familial history of CPP. The endocrine phenotype was compared between MKRN3 mutated and non-mutated patients.ResultsMKRN3 mutations were identified in one sporadic and 13 familial cases. We identified five new heterozygous missense mutations predicted to be deleterious for protein function and two frameshift mutations, one new and the other recurrent, predicted to result in truncated proteins. Age at puberty onset varied very little among patients with MKRN3 mutations and puberty occurred earlier in these patients than in those without MKRN3 mutations (6.0 years (5.4–6.0) vs 7.0 years (6.0–7.0), P=0.01).ConclusionsMKRN3 mutations are common in familial iCPP. MKRN3 is one of the gatekeepers of the postnatal activation of the gonadotropic axis.

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.