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Depuis la création de consultations dédiées en 2014, les enfants et adolescent(e)s transgenres peuvent être accompagnés en France par des équipes pluridisciplinaires. L’accompagnement personnalisé qui s’y est développé s’appuie sur des recommandations internationales, reposant elles-mêmes sur des études scientifiques qui ont démontré l’impact bénéfique d’un tel accompagnement à court et moyen termes. De nombreuses questions persistent néanmoins, à la fois médicales, en particulier sur les effets à long terme des traitements ou l’impact sur la fertilité, mais aussi éthiques. L’accumulation de données au long cours permettra d’apporter à ces jeunes et à leur famille les informations les plus éclairées possibles.

International audience; Cushing's syndrome is defined by prolonged exposure to glucocorticoids, leading to excess morbidity and mortality. Diagnosis of this rare pathology is difficult due to the low specificity of the clinical signs, the variable severity of the clinical presentation, and the difficulties of interpretation associated with the diagnostic methods. The present consensus paper by 38 experts of the French Society of Endocrinology and the French Society of Pediatric Endocrinology and Diabetology aimed firstly to detail the circumstances suggesting diagnosis and the biologic diagnosis tools and their interpretation for positive diagnosis and for etiologic diagnosis according to ACTH-independent and -dependent mechanisms. Secondly, situations making diagnosis complex (pregnancy, intense hypercortisolism, fluctuating Cushing's syndrome, pediatric forms and genetically determined forms) were detailed. Lastly, methods of surveillance and diagnosis of recurrence were dealt with in the final section.

Transgender children and adolescents can be supported in France by multidisciplinary teams since the creation of dedicated consults in 2014. The personalized support provided relies on international recommendations based on scientific studies that have demonstrated the beneficial impact of such support in the short and medium term. However, many ethical and medical questions remain, particularly on the long-term effects of treatments or the impact on fertility. The continuing accumulation of data will provide these young people and their families with the most enlightened information possible.Accompagnement des transidentiteés chez l’enfant et l’adolescent(e).Depuis la création de consultations dédiées en 2014, les enfants et adolescent(e)s transgenres peuvent être accompagnés en France par des équipes pluridisciplinaires. L’accompagnement personnalisé qui s’y est développé s’appuie sur des recommandations internationales, reposant elles-mêmes sur des études scientifiques qui ont démontré l’impact bénéfique d’un tel accompagnement à court et moyen termes. De nombreuses questions persistent néanmoins, à la fois médicales, en particulier sur les effets à long terme des traitements ou l’impact sur la fertilité, mais aussi éthiques. L’accumulation de données au long cours permettra d’apporter à ces jeunes et à leur famille les informations les plus éclairées possibles.

Preterm birth is associated with immaturity of several crucial physiological functions notably those prevailing in the lung and kidney. Recently, a steroid secretion deficiency was identified in very preterm neonates, associated with a partial yet transient deficiency in 11β-hydroxylase activity, sustaining cortisol synthesis. However, the P450c11β enzyme is expressed in preterm adrenal glands, we hypothesized an inhibition of cortisol production by adrenomedullin (ADM), a peptide highly produced in neonates and whose effect on steroidogenesis remains poorly known. We studied the effects of ADM on three models: 104 cord-blood samples of the PREMALDO neonate cohort, genetically targeted mice overexpressing ADM, and two human adrenocortical cell lines (H295R and HAC15 cells). Mid-regional-proADM (MR-proADM) quantification in cord-blood samples showed strong negative correlation with gestational age (P = 0.0004), cortisol production (P < 0.0001), and 11β-hydroxylase activity index (P < 0.0001). Mean MR-proADM was higher in very preterm than in term neonates (1.12 vs 0.60 nmol/L, P < 0.0001). ADM-overexpression mice revealed a lower 11β-hydroxylase activity index (P < 0.05). Otherwise, aldosterone levels measured by LC-MS/MS were higher in ADM-overexpression mice (0.83 vs 0.46 ng/mL, P < 0.05). More importantly, the negative relationship between adrenal ADM expression and aldosterone production found in control was lacking in the ADM-overexpression mice. Finally, LC-MS/MS and gene expression studies on H295R and HAC15 cells revealed an ADM-induced inhibition of both cortisol secretion in cell supernatants and CYP11B1 expression. Collectively, our results converge toward an inhibitory effect of ADM on glucocorticoid synthesis in humans and should be considered to explain the steroid secretion deficiency observed at birth in premature newborns.

Since the end of the 1990s, the management of transgender adolescents has developed in many countries following the Dutch Approach initiated in the Netherlands. Dedicated consultations have been developed in France since 2013, welcoming a growing number of children and adolescents. What kind of support is offered to children and their families?

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.

A major complication of feminizing genitoplasty in children is the loss of clitoral sensation with serious impact at adult life. We suggest a new method to evaluate the surgical results during childhood based on the bulbocavernosus or clitoro-perineal reflex (CPR). The afferent pathway of CPR implies the intact sensory receptors on the clitoral glans. Girls with congenital adrenal hyperplasia who were followed-up medically without surgery or who underwent feminizing genitoplasty with or without clitoroplasty were included (2002–2018). All clitoroplasties were standardized reduction clitoroplasty with preservation of neurovascular bundles associated with vaginoplasty and vestibuloplasty. Standardized examinations were prospectively performed including the CPR starting at one year postoperatively. The reflex was triggered by gentle touch of the glans by a cotton swab. Contraction of the perineal muscles was considered positive. Thirty-two children were operated at a median age of 8.6 months (5.8–12.1). Median follow-up (FU) was 3.9 years (1.3–6.4). Twenty-four patients had clitoroplasties: 17 were tested for CPR at one-year FU, and all had a positive test. Eight girls had genitoplasty without clitoral surgery, two of them were tested and were positive. Ten patients were managed without surgery, two of them were tested for the CPR and were positive. The reflex was always triggered easily and repeated at least twice during the FU. The clitoro-perineal reflex is a simple, non-invasive and reproducible test in early childhood and may serve as an early evaluation tool of clitoral innervation after feminizing genitoplasty. These results need to be confirmed at long term and completed at adult life.

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.

Missense variants in the RNA-helicase DHX37 are associated with either 46,XY gonadal dysgenesis or 46,XY testicular regression syndrome (TRS). DHX37 is required for ribosome biogenesis, and this subgroup of XY DSD is a new human ribosomopathy. In a cohort of 140 individuals with 46,XY DSD, we identified 7 children with either 46,XY complete gonadal dysgenesis or 46,XY TRS carrying rare or novel DHX37 variants. A novel p.R390H variant within the RecA1 domain was identified in a girl with complete gonadal dysgenesis. A paternally inherited p.R487H variant, previously associated with a recessive congenital developmental syndrome, was carried by a boy with a syndromic form of 46,XY DSD. His phenotype may be explained in part by a novel homozygous loss-of-function variant in the NGLY1 gene, which causes a congenital disorder of deglycosylation. Remarkably, a homozygous p.T477H variant was identified in a boy with TRS. His fertile father had unilateral testicular regression with typical male genital development. This expands the DSD phenotypes associated with DHX37. Structural analysis of all variants predicted deleterious effects on helicase function. Similar to all other known ribosomopathies, the mechanism of pathogenesis is unknown.

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.

Renal and cardiovascular complications of prematurity are well established, notably the development of hypertension in adulthood. However, the underlying molecular mechanisms remain poorly understood. Our objective was to investigate the impact of prematurity on the ontogenesis of renal corticosteroid pathways, to evaluate its implication in perinatal renal complications and in the emergence of hypertension in adulthood. Swiss CD1 pregnant mice were injected with lipopolysaccharides at 18 days of gestation (E18) to induce prematurity at E18.5. Pups were sacrificed at birth, 7 days and 6 months of life. Second (F2) and third (F3) generations, established by mating prematurely born adult females with wild-type males, were also analyzed. Former preterm males developed hypertension at M6 (P, High blood pressure: Exploring inheritance A propensity towards high blood pressure may be passed down through several generations from adults who were born preterm. People who are born prematurely often suffer from kidney (renal) problems, high blood pressure and cardiovascular disease as they age. Recent research suggests adults born prematurely can pass dysregulated blood pressure to their children. Laetitia Martinerie at INSERM Unit 1185, Le Kremlin Bicêtre and Robert Debré Hospital in Paris, France, and co-workers studied generations of mice to explore how epigenetic alterations, DNA modifications that do not change the DNA code, affect blood pressure from birth through to adulthood. The team identified tissue-specific alterations in renal signaling pathways in premature mice. They also traced the associated overexpression of a gene called Gilz, known to play a role in blood pressure maintenance, through second and third generation mice born to the first generation preterms.

OBJECTIVES To understand how children perceive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in relation to public representations and to evaluate their interpretations. METHODS Children’s perceptions of SARS-CoV-2 were evaluated by asking 103 French children, aged 5 to 17 years old, first to draw a coronavirus and then to identify SARS-CoV-2 in a series of 16 images during summer 2020. RESULTS One hundred three children were included in the study, either during outpatient visits at the hospital (in Marseille and Paris) or through the authors’ social network, and were grouped in terms of age, parents’ occupation, mode of recruitment, and recollection of having previously seen a representation of a coronavirus. Half of the children drew the coronavirus as circular in shape, and almost all included a crownlike feature. One-third of the drawings had anthropomorphic features. Although the pictorial representations of the virus were fairly accurate overall, the children’s interpretations of the crownlike structure were imaginative. The explanations the children gave for their drawings were in some cases surprising. Among the 16 pictures they were shown, the children correctly identified those of SARS-CoV-2, other than the electron micrograph, in more than two-thirds of cases. CONCLUSIONS Children of all ages, even the youngest, and both sexes had a relatively accurate perception of SARS-CoV-2, as evaluated through their drawings and their ability to recognize it among other pictures. The children’s drawings of the coronavirus were colorful and had a less frightening tone than expected in the light of media coverage, suggesting that they had developed coping mechanisms.

Since the end of the 1990s, the management of transgender adolescents has developed in many countries following the Dutch Approach initiated in the Netherlands. Dedicated consultations have been developed in France since 2013, welcoming a growing number of children and adolescents. What kind of support is offered to children and their families?

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.

Sexual dimorphism involves differences between biological sexes that go beyond sexual characteristics. In mammals, differences between sexes have been demonstrated regarding various biological processes, including blood pressure and predisposition to develop hypertension early in adulthood, which may rely on early events during development and in the neonatal period. Recent studies suggest that corticosteroid signaling pathways (comprising glucocorticoid and mineralocorticoid signaling pathways) have distinct tissue-specific expression and regulation during this specific temporal window in a sex-dependent manner, most notably in the kidney. This review outlines the evidence for a gender differential expression and activation of renal corticosteroid signaling pathways in the mammalian fetus and neonate, from mouse to human, that may favor mineralocorticoid signaling in females and glucocorticoid signaling in males. Determining the effects of such differences may shed light on short term and long term pathophysiological consequences, markedly for males.

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.

International audience; Sodium and water homeostasis are drastically modified at birth, in mammals, by the transition from aquatic life to terrestrial life. Accumulating evidence during the past ten years underscores the central role for the mineralocorticoid signaling pathway, in the fine regulation of this equilibrium, at this critical period of development. Interestingly, regarding evolution, while the mineralocorticoid receptor is expressed in fish, the appearance of its related ligand, aldosterone, coincides with terrestrial life, as it is first detected in lungfish and amphibian. Thus, aldosterone is likely one of the main hormones regulating the transition from an aquatic environment to an air environment. This review will focus on the different actors of the mineralocorticoid signaling pathway from aldosterone secretion in the adrenal gland, to mineralocorticoid receptor expression in the kidney, summarizing their regulation and roles throughout fetal and neonatal development, in the light of evolution.

In the ancient Indian parable of the blind men and an elephant, the shape of the animal is appreciated differently by six blind men who conceptualise it only by touching part of its body.1 In a similar way, children may conceptualise severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in their own unique ways. Although SARS-CoV-2 infection is less severe in children2 (rare instances of multisystem inflammatory syndrome in children notwithstanding34), young people have nonetheless been at the forefront of policy makers’ concerns. This year …

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.

21-Hydroxylase deficiency (21OHD) is a rare genetic disorder in which salt-wasting syndrome occurs in 75% of cases, due to inability to synthesize cortisol and aldosterone. Recent mass spectrometry progress allowed identification of 21-deoxysteroids, i.e., 17-hydroxyprogesterone (17OHP), 21-deoxycortisol (21DF), and 21-deoxycorticosterone (21DB). We hypothesized that they may interfere with mineralocorticoid signaling and fludrocortisone therapy in patients with congenital adrenal hyperplasia (CAH) without effective glucocorticoid replacement and ACTH suppression. Our goal was to quantify circulating 21-deoxysteroids in a pediatric cohort with CAH related to 21OHD and to examine their impact on mineralocorticoid receptor (MR) activation. Twenty-nine patients with salt-wasting phenotype were classified in two groups according to their therapeutic control. During routine follow-up, 17OHP, 21DF, 21DB, and cortisol levels were quantified by liquid chromatography with tandem mass spectrometry before hydrocortisone intake and 1 and 2.5 h following treatment administration. Luciferase reporter gene assays were performed on transfected HEK293T cells while in silico modeling examined structural interactions between these steroids within ligand-binding domain of MR. Plasma 17OHP, 21DF, and 21DB accumulate in uncontrolled patients reaching micromolar concentrations even after hydrocortisone intake. 21DF and 21DB act as partial MR agonists with antagonist features similar to 17OHP, consistent with altered anchoring to Asn770 and unfavorable contact with Ala773 in ligand-binding pocket of MR. Our results demonstrate a complex interaction between all accumulating 21-deoxysteroids in uncontrolled 21OHD patients and mineralocorticoid signaling and suggest that appropriate steroid profiling should optimize management and follow-up of such patients, as keeping those steroids to low plasma levels should attest therapeutic efficacy and prevent interference with MR signaling.

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.

Fetal steroidome in late pregnancy receives multiple contributions from both maternal and fetal adrenals as well as from placenta. Depressed glucocorticoid levels have been reported in fetal blood at birth, yet studies on mineralocorticoid pathways are sparse. To investigate biosynthesis pathways at birth, adrenal steroids profiles were established in paired mothers and neonates. Forty-six paired healthy term newborns and their mothers from the Aldo cohort were assessed. Steroidomic profiles of mineralocorticoids, glucocorticoids and adrenal androgens were established from umbilical cord and maternal blood at birth using a highly sensitive and specific LC-MS/MS methodology. As compared to maternal blood, umbilical cord blood exhibited high levels of steroids precursors (progesterone and 11-deoxycorticosterone) contrasting with a collapse in corticosterone levels. Consecutively, 18-hydroxycorticosterone and aldosterone levels were also depressed in neonates. Similarly, umbilical cord blood levels of both 17-hydroxyprogesterone and 11-deoxycortisol were higher while cortisol levels sharply decreased. The product-to-substrate ratios evaluating the 11-hydroxylation step (corticosterone/11-deoxycorticosterone and cortisol/11-deoxycortisol) fell for both pathways. As expected, cortisone and 11-dehydrocorticosterone levels exceed those of cortisol and corticosterone in umbilical cord blood reflecting the strong placental 11-β-hydroxysteroid-dehydrogenase type 2 (11βHSD2) activity. Dehydroepiandrosterone-sulphate levels are higher in neonates, while both androstenedione and testosterone levels sharply fell. No significant difference in steroid levels could be observed according the gender except higher testosterone concentrations in umbilical cord of boys. Moreover, a strong and negative relationship between testosterone and progesterone levels was recorded in umbilical cord of boys. These adrenal steroidomic profiling demonstrate a deficit in mineralocorticoids (aldosterone, 18-hydroxycorticosterone and corticosterone) and glucocorticoids (cortisol) in term neonates, reflecting either a relative defect in 11-hydroxylase activity or more likely the strong placental 11-β-HSD2 activity. Collectively, these findings should be taken into account for a better understanding of regulatory interactions between placenta and fetal adrenal.

INTRODUCTION Health care simulation, as a complement to traditional learning, has spread widely and seems to benefit both students and patients. The teaching methods involved in health care simulation require substantial human, logistical, and financial investments that might preclude their spread in developing countries. The aim of this study was to analyze the health care simulation experiences in developing countries. METHODS A comprehensive literature search was performed from January 2000 to December 2016. Articles reporting studies on educational health care simulation in developing countries were included. RESULTS In total, 1161 publications were retrieved, of which 156 were considered eligible based on title and abstract screening. Thirty articles satisfied our predefined selection criteria. Most of the studies were case series; 76.7% (23/30) were prospective and comparative, and five were randomized trials. The development of dedicated task trainers and telesimulation were the primary techniques assessed. The retrieved studies showed encouraging trends in terms of trainee satisfaction with improvement after training, but the improvements were mainly tested on the training tool itself. Two of the tools have been proven to be construct valid with clinical impact. CONCLUSION Health care simulation in developing countries seems feasible with encouraging results. Higher-quality studies are required to assess the educational value and promote the development of health care simulation programs.

Objectifs La variabilite inter-individuelle dans la reponse aux glucocorticoides a conduit a la decouverte du polymorphisme N363S du Recepteur glucocorticoide (GR). Le GR agit comme un facteur de transcription relayant les effets des glucocorticoides, notamment le retrocontrole negatif sur l’axe corticotrope par trans-repression du gene de la ProOpioMelanoCortine (POMC) pouvant etre responsable d’une insuffisance corticotrope. Le variant N363S semble etre associe a une hypersensibilite aux glucocorticoides et a une augmentation de leurs effets indesirables mais son impact sur le retrocontrole negatif au niveau de l’hypophyse reste a explorer. Materiels et methodes L’etude fonctionnelle du variant N363S sur le gene de la POMC a ete realisee dans des cellules indifferenciees humaines (HEK 293 T) mais aussi dans des cellules corticotropes murines (AtT-20). Resultats Nous avons observe, dans les cellules HEK 293 T, une augmentation de la capacite maximale de transactivation du GR N363S par rapport au GR WT (+30 %) sans modification de l’EC50 (0,36 vs 0,40 nM). En revanche, la trans-repression sur le promoteur du gene de la POMC semble etre conditionnee par la presence d’autres facteurs de transcription (NeuroD1, NuR77), et est en cours d’etude dans les cellules AtT-20, qui expriment la machinerie transcriptionnelle necessaire. Nous etudierons aussi la diminution de la secretion d’ACTH en reponse a la dexamethasone. Discussion La comprehension des mecanismes moleculaires de l’insuffisance corticotrope induite par les glucocorticoides et la mise en evidence du variant N363S du GR comme facteur predictif d’une hypersensibilite aux glucocorticoides, pourraient permettre une adaptation personnalisee de leur prescription.

Objectif L’aldosterone et le Recepteur mineralocorticoide (MR) jouent un role essentiel dans le controle de la balance hydrosodee. Notre equipe a montre que l’expression renale du MR est faible a la naissance expliquant la perte d’eau et de sel physiologique des nouveau-nes. Or, les mecanismes moleculaires sous-jacents demeurent inconnus. Nous avons demontre que l’expression renale du MR dans le rein adulte est controlee par des proteines de liaison a l’ARN (Tis11b, HuR) et/ou des microARNs (miR-30c-2-3p, miR-324-5p) en reponse aux variations de tonicite observees dans le nephron. Ce travail vise a etudier l’implication de ces regulateurs post-transcriptionnels dans la regulation de l’expression renale du MR en periode perinatale. Methodes L’expression de ces regulateurs et celle du MR ont ete analysees par RT-qPCR dans des reins de souris a J0 et J8. Puis, nous avons module l’expression de ces regulateurs dans des cultures organotypiques de reins de souris a J0 et J8. Resultats Une correlation negative entre l’expression de Tis11b, miR-324-5p, miR-30c-2-3p et celle du MR est observee a J8. La surexpression de HuR augmente de 150 % les transcrits MR a J0 alors que la surexpression du miR-30c-2-3p et de Tis11b diminuent ceux du MR a J8 respectivement de 30 % et 50 %. L’impact de ces modulations sur la signalisation mineralocorticoide va etre analyse. Discussion L’identification de nouveaux regulateurs post-transcriptionnels de l’expression renale du MR en periode perinatale devrait ouvrir sur de nouvelles avancees pour les prematures presentant un desequilibre hydrosode majeur.

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.

Glucocorticoid hormone metabolism and action are regulated by the 11-beta hydroxysteroid dehydrogenase (11βHSD) isozymes: the 11βHSD2, mostly expressed in the distal nephron, converts cortisol [F] into cortisone [E] in humans or corticosterone [B] into 11-dehydrocorticosterone [A] in rodents (11-dehydro derivatives being inactive compounds), and the 11βHSD1, ubiquitously expressed but abundant in the liver, catalyzes the opposite reaction. Under pathophysiological conditions of severe hypothyroidism, altered glucocorticoid metabolism has been observed, with decreased [F] to [E] conversion1,2. However, direct functional relationship between these two hormonal pathways has never been demonstrated to date. Using bioinformatics analyses, we identified five thyroid hormone response elements in the promoter region of the murine hsd11b2 gene. Therefore, we aimed at investigating whether thyroid hormones (T3) directly regulate expression and/or activity of the 11βHSD2 enzyme. We used three complementary models: human and mouse translational studies and molecular analyses in HEK293T cells and in fully differentiated KC3AC1 cortical collecting duct cells. Children and adults in hypo- or hyperthyroidism status were first compared either to age- and sex-matched euthyroid controls, or to themselves after reaching a euthyroid status. The urinary [E]/[F] ratio measured by LC-MS/MS method, was used as an index of renal 11βHSD2 activity. Interestingly, a 60% decrease in the [E]/[F] ratio was observed in hypothyroid patients, corroborating our hypothesis (p

Congenital adrenal hyperplasia (CAH), associated with 21-hydroxylase deficiency (21OHD), is a severe autosomic recessive disease. It may lead to life-threatening adrenal insufficiency with cortisol and aldosterone secretion defect, requiring hormone replacement therapy with hydrocortisone and fludrocortisone, often difficult to handle especially in pediatric patients, with risks of stunting, obesity and hypertension. Plasma steroidomic profiling, obtained by LC-MS/MS technology, of 20 pediatric patients presenting with CAH, established a precise quantification of the entire steroidogenesis pathway, and confirmed previous results with substantial increase not only in 17-hydroxyprogesterone (17OHP) but also in 11-hydroxylated steroids, i.e 21-deoxycortisol (21DF) and for the first time 21-deoxycorticosterone (21DB) levels, up to 1 µM concentration in uncontrolled patients. To determine functional consequences upon mineralocorticoid signaling pathway of the accumulation of such steroids, previously shown for 17OHP, their biological activities were evaluated by transient transfection assays with Luc-reporter plasmid and in human renal cells stably expressing the human mineralocorticoid receptor (hMR) by analyzing expression of MR target genes such as aENaC, Gilz, Sgk1 or PER1. Here, we demonstrate that 21DF and 21DB both activate hMR in a partial agonist manner (ED50 (21DF) = 180 nM and ED50 (21DB) = 13 nM, vs ED50 (Aldosterone) = 0.1 nM), displaying de facto an intrinsic antagonist activity to a lesser extent than 17OHP, progesterone or spironolactone. Thereby, both 21DF and 21DB could repress the aldosterone-induced expression of target genes involved in sodium reabsorption. These findings have been further validated by tridimensional structural modeling. Docking within the hMR ligand-binding domain (LBD) showed that, in contrast to aldosterone, the lack of 21-hydroxyl group in 21DF and 21DB alter their anchoring to Asn770. Moreover, the 11β-hydroxyl group of both ligands forms an unfavorable contact with Ala773, likely explaining their weak agonistic and partial antagonistic characters. These original findings are of major importance and could explain why salt wasting remains so difficult to manage in some unbalanced CAH treated-patients, sometimes justifying the use of enhanced doses of fludrocortisone in those patients. These results also underscore the need to establish steroidomic profiles at the initial diagnostic phase of any adrenal enzymatic deficiency, but also during the patient follow-up for optimized therapy.

Introduction: Prematurity, a worldwide health issue, is often associated with renal tubular immaturity leading to major salt loss, whose mechanisms remain poorly understood. Moreover, these premature infants are prone to develop early hypertension in adulthood. Objective: To study ontogenesis of renal mineralocorticoid and glucocorticoid signaling pathways in preterm mice, and to evaluate their contribution to neonatal adaptation and to the emergence of hypertension in adulthood. Materials and Methods: We have developed a murine model of prematurity induced by intra-peritoneal injection of O111/B4 lipopolysaccharides (LPS) at 18 days of gestation in Swiss CD1 mice. Offspring of injected mice, when LPS did not trigger preterm birth, were used as a control to exclude intrinsic LPS effects. Pups were sacrificed at various developmental stages (D0, D7 and M6). Blood pressure and heart rate were measured in males at M6 and their plasma steroid profiles were measured using LC-MSMS. Renal mRNA and protein expression of major players of corticosteroid signaling pathways were examined using RT-qPCR and western-blot analyses. Second (F2) and third (F3) generations, established by mating prematurely born adult females with wild type males, were also analyzed. We performed Methylation DNA Immunoprecipitation-qPCR to study the methylation status of candidate corticosteroid target genes that were differentially expressed between the 2 populations. Results: As anticipated, preterm newborn mice presented with maladaptation, high neonatal mortality (35%), and a lower birth weight compared to controls (1.29±0.21 vs 1.46±0.15g, P=0.0027). Former preterm males developed hypertension at M6 (123.1±1.43 vs 114.5±0.79mmHg, P

Over the past 20 years, the care for transgender adolescents has developed throughout many countries following the ‘Dutch Approach’ initiated in the 90s in pioneer countries as the Netherlands, United States and Canada, with increasing numbers of children and adolescents seeking care in transgender clinics. This medical approach has considerable positive impacts on the psychological outcomes of these adolescents, and several studies have been recently published underlining the relative safety of such treatments. This paper reviews the current standards of care for transgender children and adolescents with particular emphasis on disparities among countries and short-to-medium-term outcomes. Finally, it highlights ethical considerations regarding categorization of gender dysphoria, timing of treatment initiation, infertility and how to deal with the long-term consequences.

La dysphorie de genre est caracterisee par une inadequation entre le genre exprime d’un individu et le genre assigne a la naissance, generant une detresse clinique significative. Cet etat est reconnu sur le plan medical. Depuis une dizaine d’annees, la dysphorie de genre est prise en charge chez les enfants et adolescents dans un certain nombre de pays, et fait intervenir une evaluation conjointe par les pedopsychiatres et les endocrinologues pediatres. Cet article reprend les differents elements de l’evaluation et de la prise en charge medicale de ces enfants/adolescents telle qu’elle est proposee en France, basee sur les recommandations internationales.