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Design Thyroid-stimulating hormone deficiency (TSHD) is a rare disease. It may be isolated, secondary to abnormalities of genes involved in TSH biosynthesis, or associated with other pituitary deficits or abnormalities of genes involved in pituitary ontogenesis. Several genes are involved in thyrotroph development and function. Objective Our aim was to determine the genetic causes of TSHD, either isolated (ITSHD) or associated with somatotroph deficiency (TSHD-GHD), in the cohort of patients from the GENHYPOPIT network. Methods Next-generation sequencing (NGS) analyses were performed as a panel of genes on a cohort of patients with non-syndromic ITSHD or TSHGHD. The variants were classified according to the American College of Medical Genetics classification reviewed by the NGS-Diag network and correlated with the phenotype. Class 3, 4, and 5 single-nucleotide variants were checked by Sanger sequencing and copy number variants by multiplex ligation-dependent probe amplification (MLPA). Results A total of 64 index cases (22 ITSHD and 42 TSHD-GHD) were included in this cohort. A genetic cause was identified in 26.5% of patients, with 36.3% in the ITSHD group (variants in TSHβ and IGSF1) and 21.4% in TSHD-GHD (variants in IGSF1, TSHβ, TRHR, GH1, POU1F1, and PROP1). Among the pathogenic and likely pathogenic variants identified, 42% were in IGSF1, including six not previously reported. Conclusion Our results show that IGSF1 variants represent the most frequent aetiology of TSH deficiency. Despite a systematic NGS approach and the identification of new variants, most patients remain without a molecular diagnosis. Larger scale studies, such as exome or genome studies, should be considered in the future.

International audience; ContextHypoparathyroidism (hypoPTH) in adults is mainly due to total thyroidectomy. Conventional therapies (calcium, active vitamin D) can fail to normalize calcemia, expose the patient to hypercalciuria and impact quality-of-life. Human parathormone (PTH) replacement therapy is a suitable option in these cases, although few clinical reports have been published so far.MethodsWe describe two cases of patients with refractory postsurgical hypoPTH, in whom subcutaneous infusion of recombinant PTH (teriparatide) through the Omnipod® pump was initiated after failure of all other therapeutic options. Besides, we performed a review of literature of hypoPTH cases treated by continuous infusion of teriparatide.ResultsTwo women aged 46 and 61 years old failed to normalize calcemia either with conventional treatments (calcium 8 g/day + calcitriol 9 mcg/day and calcium 5 g/day + calcitriol 12 mcg/day) or with thrice daily subcutaneous injections of teriparatide. As a last resort, teriparatide infusion via Omnipod® device normalized their calcemia and allowed calcium/vitamin D withdrawal, with average teriparatide dose of 23 and 32 mcg/day, respectively. The flow of teriparatide was adapted according to a protocol based on measured calcemia, under medical supervision. In the literature, 15 adult cases (13 women, mean age 44.5 ± 5.2 years old) are reported. HypoPTH was consecutive to surgery in all of them. Mean dose of teriparatide administered was 25 ± 6 mcg/day with improvement of calcemia level and quality-of-life in all patients.ConclusionsContinuous administration of teriparatide through Omnipod® appears as an efficient therapeutic option in refractory hypoPTH, whose administration to the patient can be assisted by medically-supervised protocol.

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

Introduction: Congenital central hypothyroidism (CCH) is a rare disorder that can be caused by X-linked mutations in the immunoglobulin superfamily member 1 (IGSF1) gene. Here, we describe four familial cases with a variable presentation due to a novel IGSF1 pathogenic variant. Case Presentation: In the index case, an investigation at birth of a suspected brain-lung-thyroid syndrome surprisingly revealed a central hypothyroidism. Next-generation sequencing uncovered a novel IGSF1 pathogenic variant: a hemizygous single base duplication (G) resulting in a premature stop codon (NM_001555.4: c.2485dup, p.Ala829Glyfs*15). Further family investigations revealed missed neonatal CCH for the older brother who presented with prolonged jaundice (thyroid stimulating hormone 3.06 mUI/L, FT4 9.4 pmol/L, FT3 4.2 pmol/L). It also led to the diagnosis of CCH at 11 months of age for the younger brother, whose thyroid function was considered normal at birth. Neuropsychological evaluations showed no cognitive impairment for the eldest two brothers, but a slightly reduced processing-speed index compared with the other parameters for the oldest. Furthermore, a maternal uncle was diagnosed with biochemical CCH at 34 years of age, despite having few symptoms, and a complete workup revealed prolactin deficiency and macroorchidism. Discussion: This report of a rare case of neonatal CCH caused by IGSF1 deficiency highlights the importance of recognizing the neonatal signs of hypothyroidism to diagnose CCH as early as possible. Our results also show the importance of performing family genetic screening if a pathogenic variant is identified, to properly monitor carriers as CCH may develop over time. We suggest that these families should be followed up in the long term to better understand the natural history of this syndrome and evaluate the need for hormone substitution.

Background: FOXL2 is the gene involved in blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES). There have been few single case reports of growth hormone deficiency (GHD) with this syndrome, and Foxl2 is known to be involved in pituitary development in mice. Our aim was to analyze the prevalence of FOXL2 gene alteration in a series of patients with congenital hypopituitarism and eyelid anomalies. Methods: FOXL2 was analyzed in 10 patients with hypopituitarism (ranging from isolated GHD to complete pituitary hormone deficiency) and eyelid anomalies (typical BPES in 4 patients and milder anomalies in 6 patients). In patients with an FOXL2 mutation, we ruled out other possible molecular explanations by analyzing a panel of 20 genes known to be associated with hypopituitarism, and a candidate gene approach was used for patients without an FOXL2mutation. Results: Three patients had an FOXL2mutation. All 3 had typical BPES. Their pituitary phenotype varied from GHD to complete pituitary hormone deficiency and their pituitary morphology ranged from normal to an interrupted pituitary stalk. No mutations were found in genes previously associated with hypopituitarism. Conclusion: Our study shows that some patients with BPES have hypopituitarism with no molecular explanation other than FOXL2 mutation. This points toward an involvement of FOXL2 in human pituitary development.

Context : Hypoparathyroidism (hypoPTH) in adults is mainly due to total thyroidectomy. Conventional therapies (calcium, active vitamin D) can fail to normalize calcemia, expose the patient to hypercalciuria and impact quality-of-life. Human parathormone (hPTH) replacement therapy is a suitable option in these cases, although few clinical reports have been published so far. Methods we describe two cases of refractory postsurgical hypoPTH for which subcutaneous infusion of recombinant parathormone (teriparatide) through the Omnipod® pump was started after failure of all other therapeutic options. Besides, we performed a review of literature of hypoPTH cases treated by continuous infusion of teriparatide. Results two women aged 46 and 61yo failed to normalize calcemia either with conventional treatments (calcium 8g/d + calcitriol 9µg/d and calcium 5g/d + calcitriol 12µg/d) or with thrice-daily subcutaneous injections of teriparatide. As a last resort, teriparatide infusion via Omnipod® device normalized their calcemia and allowed calcium/vitamin D withdrawal, with average teriparatide dose of 23 and 32 µg/day, respectively. Notably, a dedicated protocol currently allow each patient to be autonomous with its pump without adverse dyscalcemia until now. In the literature, 15 adult cases (13 women, mean age 44.5 ± 5.2 yo) are reported. HypoPTH was consecutive to surgery in all of them. Mean dose of teriparatide administered was 25 ± 6 µg/d with improvement of calcemia level and quality-of-life in all patients. Conclusion Continuous administration of teriparatide through Omnipod® is a safe and efficient therapeutic option in refractory hypoPTH, which can, furthermore, be safely self-managed by the patient.

OBJECTIVES Polyuria-polydipsia syndrome (PPS) is a common presentation in children but the differential diagnosis rests on burdensome water deprivation tests. The aims of this study were to determine a copeptin threshold to distinguish patients with central diabetes insipidus from those with primary polydipsia and to estimate the normal range of copeptin concentrations in children. DESIGN Single-centre retrospective descriptive study. PATIENTS Two hundred and seventy-eight children aged 2 months to 18 years who consulted for PPS (N = 40) or other reasons (control group, N = 238) at La Timone University Hospital in Marseille, France, between April 2015 and September 2019 and had a copeptin assay. MEASUREMENTS Ultrasensitive copeptin assays on blood samples. RESULTS Among the children with PPS, the mean copeptin concentrations were 1.72, 55.2 and 15.7 pmol/l in those with central diabetes insipidus (N = 21), nephrogenic diabetes insipidus (N = 3), and primary polydipsia (N = 16), respectively. Copeptin levels lower than 3.53 pmol/l were diagnostic of central diabetes insipidus with 100% sensitivity and 87.4% specificity (p

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 The international GENHYPOPIT network collects phenotypical data and screens genetic causes of non‐acquired hypopituitarism. Aims To describe main phenotype patterns and their evolution through life. Design Patients were screened according to their phenotype for coding sequence variations in 8 genes: HESX1, LHX3, LHX4, PROP1, POU1F1, TBX19, OTX2 and PROKR2. Results Among 1213 patients (1143 index cases), the age of diagnosis of hypopituitarism was congenital (24%), in childhood (28%), at puberty (32%), in adulthood (7.2%) or not available (8.8%). Noteworthy, pituitary hormonal deficiencies kept on evolving during adulthood in 49 of patients. Growth Hormone deficiency (GHD) affected 85.8% of patients and was often the first diagnosed deficiency. AdrenoCorticoTropic Hormone deficiency rarely preceded GHD, but usually followed it by over 10 years. Pituitary Magnetic Resonance Imaging (MRI) abnormalities were common (79.7%), with 39.4% pituitary stalk interruption syndrome (PSIS). The most frequently associated extrapituitary malformations were ophthalmological abnormalities (16.1%). Prevalence of identified mutations was 7.3% of index cases (84/1143) and 29.5% in familial cases (n = 146). Genetic analysis in 449 patients without extrapituitary phenotype revealed 36 PROP1, 2 POU1F1 and 17 TBX19 mutations. Conclusion This large international cohort highlights atypical phenotypic presentation of constitutional hypopituitarism, such as post pubertal presentation or adult progression of hormonal deficiencies. These results justify long‐term follow‐up, and the need for systematic evaluation of associated abnormalities. Genetic defects were rarely identified, mainly PROP1 mutations in pure endocrine phenotypes.

Tall stature is not a common motive for medical consultation, even though by definition 2.5 % of children in the general population are concerned. It is usually defined as height greater than + 2 standard deviations (SD) using the appropriate growth chart for age and gender, or a difference greater than +2 SD between actual height and target height. With a patient presenting tall stature, the physician has to determine whether it is a benign feature or a disease. Indeed, making the diagnosis is essential for hormonal disease or genetic overgrowth syndromes. The past medical history including parents’ height, prenatal and birth data, physical examination along with anthropometry (height, weight, head circumference, body mass index), and growth chart evaluation with the detailed growth pattern are generally sufficient to make the diagnosis such as familial tall stature, obesity, or early puberty. Bone age estimation may be helpful for some specific etiologies and is also necessary to help predict final adult height. After exclusion of common causes, further investigation is required. Sudden growth acceleration often reveals endocrine pathology such as early puberty, hyperthyroidism, or acrogigantism. Tall stature accompanied by dysmorphic features, congenital malformations, developmental delay, or a family medical history may be related to genetic disorders such as Marfan, Sotos, or Wiedemann-Beckwith syndromes. We relate here the most frequent etiologies of overgrowth syndromes.

Le syndrome polyuro-polydipsique (SPUPD) est frequent en pediatrie. Apres elimination d’un diabete sucre, la demarche etiologique s’oriente entre diabete insipide central (DIC), nephrogenique, ou polydipsie primaire (PP). La copeptine, secretee de facon equimolaire a l’hormone anti-diuretique, plus stable in vitro est un nouvel outil utilise chez l’adulte permettant de surseoir a la restriction hydrique. Chez l’enfant, peu de donnees sont rapportees. L’objectif principal etait de determiner le seuil basal de copeptine discriminant DIC et PP devant un SPUPD de l’enfant. L’objectif secondaire etait de decrire les valeurs d’une population pediatrique temoin. Ont ete inclus retrospectivement les patients âges de 2 mois a 18 ans ayant beneficie d’un dosage de copeptine entre 2015 et 2020 a l’hopital Timone enfants. Apres exclusion des facteurs confondants, 278 dosages de copeptine ont ete etudies, 238 temoins et 40 patients avec SPUPD dont 21 DIC, 3 diabetes insipides nephrogeniques et 16 PP. La copeptine moyenne etait significativement differente (respectivement 1,72 pmol/l, 55,2 pmol/l et 15,7 pmol/l). Chez les temoins, les valeurs de copeptine 5e–95e p etaient comprises entre 2,53 et 21,03 pmol/l, elles etaient significativement plus hautes chez les garcons, mais sans correlation avec l’âge, le stade pubertaire ou l’IMC. Un seuil de copeptine basale superieur a 3,53 pmol/l permettait d’eliminer un DIC (sensibilite 100 %, specificite 87,4 %, p

Les enjeux lies a la transition sont au cœur du suivi des patients en endocrinologie pediatrique puis adulte Objectifs L’objectif principal etait de connaitre le vecu des adolescents ayant eu une consultation de transition en endocrinologie a Marseille entre 2010 et 2020. Les objectifs secondaires etaient de decrire les difficultes rencontrees par ces jeunes patients et leurs attentes. Methode Il s’agit d’une etude retrospective observationnelle unicentrique. Un questionnaire de transition a ete distribue a distance de la consultation. Resultats 115 patients presentant des pathologies endocriniennes variees ont ete inclus. La moyenne d’âge lors de la consultation de transition etait de 18,8 ans. Un total de 96 % avaient poursuivi la prise en charge en endocrinologie adulte dont 76 % a long terme (moyenne 4,5 ans). 81 questionnaires de transition ont ete recueillis. Pour 89 %, la consultation de transition etait ressentie comme benefique. Pour 23 %, la transition avait eu lieu « trop tot ». 36 % rapportaient des difficultes liees a la transition, d’ordre : psychologique, logistique ou medicale. Leurs attentes de cette consultation etaient principalement : la transmission des informations medicales et la rencontre du nouveau medecin. Pour 53 % la transition s’est « bien passee, sans point a ameliorer », pour les autres, plusieurs pistes d’amelioration ont ete abordees comme la realisation de plusieurs consultations de transition ou une preparation plus progressive. Conclusion Les consultations communes de transition ont ete ressenties comme benefiques. Cependant, certaines difficultes ont ete soulevees, justifiant d’approfondir les recherches et de developper d’autres outils therapeutiques.

Introduction L’hypoparathyroidie definitive est une complication rare, mais severe de la chirurgie thyroidienne, exposant les patients a une hypocalcemie chronique et a une degradation significative de leur qualite de vie. L’utilisation d’analogue de la parathormone humaine (Teriparatide) en injection sous-cutanee fut proposee pour palier au deficit hormonal, mais se heurte a une demi-vie plasmatique courte. Methode Nous rapportons le cas d’une patiente de 46 ans souffrant d’hypoparathyroidie chronique post-thyroidectomie, chez laquelle nous avons initie un traitement par Teriparatide en administration sous-cutanee par pompe Omnipod (dans laquelle 2 mL equivaut a 200 UI). Un total de 0,6 mL de teriparatide (Forsteo, 250 μg/mL) fut melange a 1,4 mL d’eau sterile soit 200 UI = 150 μg de teriparatide. Le debit initial etait de 0,5 UI/h. La patiente fut hospitalisee a l’initiation du traitement et les parametres phosphocalciques (calcemie, phosphoremie, 24 h-calciurie) furent surveillee regulierement. Resultats Apres 48 h de traitement, la calcemie fut normalisee et une amelioration des symptomes fut observee. Une modification du debit etait possible selon les calcemies obtenues, sans jamais depasser 0,1 UI/h, pour finalement atteindre 0,8 UI/h (14,4 μg/j de teriparatide) au terme de 2 mois de traitement. Une diminution de la calciurie journaliere s’est perennisee. Une education au protocole de remplissage, a la manipulation de l’Omnipod permet a la patiente de poursuivre le traitement en autonomie et de reprendre son activite professionnelle. Conclusion L’administration de teriparatide par la pompe Omnipod est une option therapeutique efficace en cas d’hypoparathyroidie refractaire au traitement conventionnel.

Introduction : many structured educational programs, using the concept of self-efficacy, have been studied in English-speaking countries. Background : tools were developed in English to assess this concept along with treatment adherence. However, there seems to be no French version of these tools in scientific literature. Aim : to adapt the tools to the French language and to test the psychometric properties of the Self-Efficacy for Diabetes Self-Management (SEDM) and the Diabetes Self-Management Profile (DSMP). Methods : a cross-cultural adaptation of the SEDM and DSMP in French was performed. The psychometric properties were tested in a pilot study that took place between January 1st and December 31st, 2015. Results : Cronbach’s alpha coefficient of SEDM in French was 0.84, test-retest reliability 0.80 and sensitivity to change was moderate. The Cronbach’s alpha and sensitivity to change of the French DSMP were low, and the test-retest was 0.71. Discussion and conclusions : the first results of the psychometric properties of French SEDM were rather encouraging. The use of the French version of DSMP seems compromised in terms of psychometric properties and the opinion of the participants.

Background/Aim: Congenital hypothyroidism (CH) is a heterogeneous entity. Neonatal screening programs based on thyrotropin (TSH) determination allow primary CH diagnosis but miss central CH (CCH). CCH causes morbidity, alerts to other pituitary deficiencies, and is more prevalent than previously thought. We aimed at developing a pilot neonatal screening program for CCH detection. Patients and Methods: A prospective 2-year pilot neonatal screening study based on simultaneous dried blood specimen TSH and thyroxine (T4) measurements was implemented in term newborns aged 2-7 days. Those with T4 ≤4.5 μg/dL (-2.3 SDS) and TSH

Diabetes insipidus is characterized by hypoosmotic polyuria related to deficiency of arginine-vasopressin (AVP) secretion (central diabetes insipidus, CDI) or renal insensitivity to AVP (nephrogenic diabetes insipidus, NDI). The water deprivation test with assessment of AVP activity is currently the gold standard for differential diagnosis in patients presenting polyuria-polydipsia syndrome. Nevertheless, it can be dangerous without proper surveillance and its interpretation may be challenging. Other markers have been suggested. Direct quantification of circulating AVP is not sufficient for diagnosis: vasopressin is unstable, analysis is complex. AVP comes from prohormone preprovasopressin with concomitant release of copeptin (C-terminal moiety) in the equimolar ratio. Copeptin is stable in vitro, with easy and rapid measurement (4h). Past studies have shown greater sensitivity and specificity of copeptin versus AVP to discriminate etiologies of polyuria in adults, but its value has not been demonstrated in infants yet.A 7-month-old infant presented polyuria-polydipsia syndrome with poor weight gain. Laboratory tests pointed out hypernatremia (170mmol/L) and blood hyperosmolarity (330mOsm/L) with inappropriate urinary hypoosmolarity (168mOsm/L). Plasmatic copeptin measurement was found at a very high level, 303pmol/L (1-14pmol/L). DdAVP administration did not improve the polyuria, confirming the final diagnosis of NDI. Hyperhydration with a hypoosmolar diet normalized the hydration status and circulating levels of copeptin within 1 week.Copeptin, a stable peptide reflecting AVP secretion, could be a safer and faster biomarker for etiological diagnosis of polyuria-polydipsia syndrome in children. Before regularization of hydration status, a single baseline measurement may be enough to discriminate NDI from other etiologies without the water deprivation test.

FOXL2 is the gene involved in blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES). There have been few single case reports of growth hormone deficiency (GHD) with this syndrome, and Foxl2 is known to be involved in pituitary development in mice. Our aim was to analyze the prevalence of FOXL2 gene alteration in a series of patients with congenital hypopituitarism and eyelid anomalies.FOXL2 was analyzed in 10 patients with hypopituitarism (ranging from isolated GHD to complete pituitary hormone deficiency) and eyelid anomalies (typical BPES in 4 patients and milder anomalies in 6 patients). In patients with an FOXL2 mutation, we ruled out other possible molecular explanations by analyzing a panel of 20 genes known to be associated with hypopituitarism, and a candidate gene approach was used for patients without an FOXL2mutation.Three patients had an FOXL2mutation. All 3 had typical BPES. Their pituitary phenotype varied from GHD to complete pituitary hormone deficiency and their pituitary morphology ranged from normal to an interrupted pituitary stalk. No mutations were found in genes previously associated with hypopituitarism.Our study shows that some patients with BPES have hypopituitarism with no molecular explanation other than FOXL2 mutation. This points toward an involvement of FOXL2 in human pituitary development.

Summary Background Both national and WHO growth charts have been found to be poorly calibrated with the physical growth of children in many countries. We aimed to generate new national growth charts for French children in the context of huge datasets of physical growth measurements routinely collected by office-based health practitioners. Methods We recruited 32 randomly sampled primary care paediatricians and ten volunteer general practitioners from across the French metropolitan territory who used the same electronic medical records software, from which we extracted all physical growth data for the paediatric patients, with anonymisation. We included measurements from all children born from Jan 1, 1990, and aged 1 month to 18 years by Feb 8, 2018, with birthweight greater than 2500 g, to which an automated process of data cleaning developed to detect and delete measurement or transcription errors was applied. Growth charts for weight and height were derived by using generalised additive models for location, scale, and shape with the Box-Cox power exponential distribution. We compared the new charts to WHO growth charts and existing French national growth charts, and validated our charts using growth data from recent national cross-sectional surveys. Findings After data cleaning, we included 1 458 468 height and 1 690 340 weight measurements from 238 102 children. When compared with the existing French national and WHO growth charts, all height SD and weight percentile curves for the new growth charts were distinctly above those for the existing French national growth charts, as early as age 1 month, with an average difference of −0·75 SD for height and −0·50 SD for weight for both sexes. Comparison with national cross-sectional surveys showed satisfactory calibration, with generally good fit for children aged 5–6 years and 10–11 years in height and weight and small differences at age 14–15 years. Interpretation We successfully produced calibrated paediatric growth charts by using a novel big-data approach applied to data routinely collected in clinical practice that could be used in many fields other than anthropometry. Funding The French Ministry of Health; Laboratoires Guigoz—General Pediatrics section of the French Society of Pediatrics—Pediatric Epidemiological Research Group; and the French Association for Ambulatory Pediatrics.

Acute liver failure (ALF) in childhood is a life-threatening emergency. ALF is often caused by drug toxicity, autoimmune hepatitis, inherited metabolic diseases, and infections. However, despite thorough investigations, a cause cannot be determined in approximately 50% of cases. Here, we report three cases with recurrent ALF caused by NBAS and SCYL1 pathogenic variants. These patients did not present with any other phenotypic sign usually associated with NBAS and SCYL1 pathogenic variants. Two of them underwent liver transplantation and are healthy without recurrence of ALF. We propose NBAS and SCYL1 genetic analysis in children with unexplained fever-triggered recurrent ALF even without a typical phenotype.

LHX3 and LHX4 are LIM domain transcription factors involved in the early steps of pituitary organogenesis. They are necessary for the proper differentiation of Rathke's pouch that gives rise to the anterior pituitary lobe. Mutations of these transcription factors are involved in congenital hypopituitarism: to date, nine mutations of LHX3 have been reported, responsible for variable pituitary hormone deficiencies and extrapituitary manifestations, including limited neck rotation. By contrast, only five LHX4 mutations have been reported, responsible for variable hormone deficiencies, and pituitary/intracranial abnormalities. Future investigations will aim to better understand human pituitary organogenesis and to shed light on the interspecies differences in the roles of these transcription factors.

International audience; LHX3 is an LIM domain transcription factor involved in the early steps of pituitary ontogenesis. We report here functional studies of three allelic variants, including the first heterozygous variant of LHX3 NM_178138.5(LHX3)c.587T>C (p.(Leu196Pro)) that may be responsible for a milder phenotype of hypopituitarism. Our functional studies showed that NM_178138.5(LHX3)c.587T>C (p.(Leu196Pro)) was not able to activate target promoters in vitro, as it did not bind DNA, and likely affected LHX3 function via a mechanism of haplo-insufficiency. Our study demonstrates the possibility that patients with a heterozygous variant of LHX3 may have pituitary deficiencies, with a milder phenotype than patients with homozygous variants. It is thus of vital to propose an optimal follow-up of such patients, who, until now, were considered as not being at risk of presenting pituitary deficiency. The second variant NM_178138.5(LHX3)c.622C>G (p.(Arg208Gly)), present in a homozygous state, displayed decreased transactivating ability without loss of binding capacity in vitro, concordant with in silico analysis; it should thus be considered to affect LHX3 function. In contrast, the NM_178138.5(LHX3)c.929G>C (p.(Arg310Pro)) variant, in a heterozygous state, also predicted as deleterious in silico, proved functionally active in vitro, and should thus still be classified as a variant of unknown significance. Our study emphasizes the need for functional studies due to the limits of software-based predictions of new variants, and the possible association of a pituitary phenotype to heterozygous LHX3 variants.

Aims: To understand the opinions of children with type 1 diabetes about their everyday use of flash glucose monitoring. (FGM). Methods: Children with type 1 diabetes using the FreeStyle Libre (R) FGM system and/or their parents were surveyed in several French medical centers between December 2016 and June 2017, regardless of their treatment regimen and metabolic control. Results: Of the 347 patients recruited, 79.5% had been using the sensor for more than three months (average usage time: 285 days). The main reported motivations for initiating this type of monitoring were to avoid finger prick pain (for 85.9% of patients) and to allow parents to check nocturnal glucose levels (60.8%). Two-thirds of respondents experienced difficulties, mainly the sensor falling off (47.6%), measurement discrepancies (25.1%) and cutaneous reactions (22.2%); 89.5% changed their habits: 70.6% took more scans, 37.2% corrected their hyperglycemia more promptly, and 37.5% used trends to adjust their insulin dosage. About one-third of the study group (35.1%) experienced lower HbA1c levels, and two thirds (67.1%) were satisfied with the device. Conclusions: Our results show that FGM is a widely accepted option for self-monitoring diabetes, but that specific training is required to improve its use for insulin dosage adjustment and metabolic results. (C) 2018 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.

The genetic basis for congenital hypopituitarism and related disorders is beginning to emerge, and over 30 causal genes have been identified. Mutations in some of these genes can also cause holoprosencephaly (HPE) or septo-optic dysplasia. SIX3 is a homeodomain protein expressed in the developing brain, pituitary gland, and eye. Heterozygous mutations in SIX3 cause variable HPE in humans and mice. We identified two children with neonatal GH and TSH deficiency and stalk interruption who were doubly heterozygous for rare, likely deleterious variants in SIX3 and POU1F1. Functional studies demonstrated that both variants are disruptive. We used Six3 and Pou1f1 loss of function mice to assess the genetic interaction between Six3 and Pou1f1. Six3 heterozygotes have variable pituitary gland dysmorphology, while Pou1f1 heterozygotes are normal. A significant portion of the Six3+/-; Pou1f1+/dw doubly heterozygous mice have a more pronounced pituitary phenotype than Six3+/-, supporting the possibility of digenic pituitary disease. To understand the role of SIX3 in pituitary and hypothalamic development, we used Prop1-cre and Nkx2.1-cre to delete Six3. Disruption of Six3 expression in Rathke’s pouch caused poor activation of Lhx3 expression and arrested anterior pituitary development. The Nkx2.1-cre, Six3flox/flox embryos had no evidence of infundibulum evagination and failed to induce FGF and BMP signaling, which normally drive expansion of Rathke’s pouch. By E11.5 cells in Rathke’s pouch underwent apoptosis. The Nkx2.1-cre, Six3flox/flox embryos failed to activate expression of Lhx2 and Tbx3 in the neural ectoderm. These embryos had elevated CCND1, MYCN, and Axin2 expression in the area of the presumptive infundibulum. This indicates that SIX3 is necessary to repress cell proliferation and Wnt/beta-catenin signals to promote formation of the pituitary stalk. Thus, Six3 has essential roles in both the neural and oral ectoderm for hypothalamic and pituitary development, respectively. Heterozygous loss of function variants in SIX3 could be a contributor to multiple pituitary hormone deficiencies in children, especially if there are associated craniofacial abnormalities or PSIS.

International audience; Steroidogenic acute regulatory protein (StAR) mutations are the most frequent aetiologies of congenital lipoid adrenal hyperplasia (CLAH). Phenotypes may vary, and puberty may be absent in affected individuals. To date, only two pregnancies have been described in 46,XX CLAH patients with StAR mutations; these patients exhibited ovarian steroidogenesis along with spontaneous puberty and menarche and normal menses. The patient described here presented with CLAH caused by the homozygous (unreported, 1 bp) deletion c.719del in the StAR gene, which was diagnosed after acute adrenal insufficiency when the patient was 10 days old. The patient did not undergo spontaneous puberty, so puberty was induced by HRT when the patient was 13 years old. At the age of 25 years, the patient was referred to our reproductive unit because she desired to conceive. An initial cycle of clomiphene, stimulation produced follicular growth with two mature follicles measuring 18 and 15 mm, respectively, but the plasma oestradiol levels remained low (18 pg/ml) and the endometrium was thin (3 mm). Pregnancy was finally achieved after ovarian stimulation, IVF and transfer of frozen-thawed embryos after endometrial preparation with HRT. A normal female child was delivered following a 40 weeks' uneventful pregnancy. We therefore report the first IVF pregnancy achieved in a 46,XX CLAH patient homozygous for a StAR mutation, with inadequate ovarian steroidogenesis and no spontaneous puberty.

Resume La diversification alimentaire du nourrisson a connu une succession rapide de recommandations dont le respect par les pediatres n’a pas ete evalue. Objectif Evaluer les pratiques des pediatres au regard des recommandations recentes de la Societe francaise de pediatrie (SFP). Methodes Il s’est agi d’une etude observationnelle se deroulant du 1er novembre 2014 au 31 mars 2015 ayant inclus 97 pediatres varois et 84 internes en pediatrie affectes a la faculte Aix-Marseille. Le questionnaire comportait des questions sur les caracteristiques des medecins interroges, les modalites de diversification alimentaire chez l’enfant sain ou a risque atopique et le deroulement de la consultation pediatrique. Les reponses attendues reposaient sur les recommandations 2008 de la SFP actualisant celles de 2003. Resultats Quatre-vingt-quatre reponses ont ete obtenues (51 %) de la part de 50 pediatres (51 %) et 34 internes (40 %). Seize items ont ete classes en fonction de l’existence d’une actualisation posterieure a 2003 ou non. Plus de 80 % des medecins introduisaient conformement aux recommandations les aliments solides et le gluten chez l’enfant sain et les hydrolysats de proteines de lait de vache et le lait de vache chez l’enfant atopique. Au mieux, 65 % des medecins ont repondu conformement aux recommandations pour les items sans actualisation recente : âge d’introduction du lait de vache, des desserts lactes, des proteines carnees, du miel, des corps gras, et des legumineuses, utilisation d’un lait hypoallergenique (HA), et prolongation de l’allaitement maternel chez l’enfant atopique. Soixante-douze pour cent des medecins ne tenaient pas compte du statut allergenique de l’enfant pour introduire les aliments les plus allergeniques. Les internes, pediatres en formation, ont eu des reponses similaires a celles des pediatres installes. Conclusion Les pediatres, y compris les internes en formation, ne suivent que partiellement les recommandations.

Purpose The purpose of this study was twofold: (1) to describe the content of recent diabetes education programs and their outcomes in terms of glycemic control, disease management, and psychosocial criteria for children and adolescents with type 1 diabetes and (2) to gauge the match between these programs and the recommendations of the International Society for Pediatric and Adolescent Diabetes (ISPAD). Methods The integrative review was carried out according to the Cochrane recommendations. Thirteen databases were searched for evaluations of education programs published from 2009 to 2014. Program characteristics and outcomes were described. Quality of studies was assessed, and program match with ISPAD recommendations was gauged. Results Of 2528 studies found, 43 covering 36 education programs intended for youth with type 1 diabetes were retained for review. Nine of these centered on self-care competencies, 18 on psychosocial competencies, and 9 on both types of competency (mixed program). Programs varied widely in terms of organization, procedure, and content. Glycemic control was an indicator assessed in the majority of programs, but only half of these (for the most part, self-care programs) reported positive findings in this regard. Few programs seemed to affect psychosocial indicators. An online mixed program, which was the program that best met the ISPAD recommendations, proved to have an influence on glycemic control and several psychosocial criteria. Conclusions Various avenues can be considered to improve participant engagement in education programs and to align these programs more closely with international recommendations. Further research is required to enhance knowledge in this field.

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.

Objectif Comprendre les bases moleculaires des insensibilites completes aux androgenes (ICA) avec une sequence codante du RA normale. Patients et methodes Deux patientes de 37 et 36 ans avec un phenotype typique d’ICA. Le diagnostic d’ICA a ete evoque pour la premiere dans l’enfance du fait de la palpation de gonades inguinales, et de l’absence d’uterus a l’echographie pelvienne. Pour la seconde il l’a ete a l’âge adulte face a une amenorrhee primaire associee a des caracteristiques cliniques (S5P2), echographiques (absence d’uterus) et hormonales (testosterone 17 ng/ml, LH 36 UI/L) typiques d’ICA. Le caryotype etait 46, XY dans les deux cas et le sequencage en Sanger du RA etait normale. L’etude en NGS de 132 genes impliques dans les DSD et de leurs regions regulatrices a ete realisee. Resultats Un nouveau variant c.-829C > T de la region 5′UTR du RA a ete mis en evidence chez ces deux patientes. Il n’a jamais ete rapporte dans la population generale et est a l’origine d’un nouvel AUG 296 pb en aval du site initiateur de transcription. Discussion et conclusions Ce nouveau uORF est traduit en un court peptide qui gene la traduction de la forme native du RA, comme cela a ete demontre (Hornig, 2016) pour un autre cas d’ICA due a un variant similaire de la region 5′UTR. Ce second cas de variant de la region 5′UTR du RA chez deux patientes ICA souligne l’importance d’analyser non seulement les exons, mais aussi les regions non codantes du RA dans les cas d’ICA typiques.

Introduction :Les programmes d’éducation thérapeutique du patient offrent un soutien aux enfants qui ont un diabète de type 1 et à leurs familles. Les infirmières participent en équipe pluridisciplinaire à ces programmes, mais leurs activités sont actuellement insuffisamment documentées dans la littérature.Objectif :Décrire l’activité infirmière dans les programmes d’éducation thérapeutique du patient en diabétologie pédiatrique.Méthode :Étude qualitative descriptive par entretiens semi-dirigés individuels auprès d’infirmières travaillant en secteur hospitalier ou en séjours éducatifs, avec analyse lexicométrique des discours.Résultats :Vingt infirmières, dont dix infirmières puéricultrices ont participé à l’étude. Les participantes décrivent les compétences de communication et d’adaptation mobilisées pour gérer l’activité éducative et sa traçabilité. Les besoins spécifiques des patients sont pris en compte par l’adaptabilité et la variété des méthodes et outils pédagogiques mobilisés en fonction de l’âge, du niveau de compréhension, et de la culture.Discussion :Les infirmières semblent développer des compétences relationnelles pour dispenser et coordonner l’éducation thérapeutique, sans forcément être coordinatrice. Elles confirment la nécessité de tenir compte des besoins spécifiques de l’enfant et de l’adolescent. Les contraintes organisationnelles apparaissent comme génératrices de compétences collectives entre soignants-soignés et entre pairs.Conclusion :Cette étude permet de prendre en considération la perception des infirmières dans l’élaboration d’un programme éducatif interrégional.

The GNAS postzygotic mosaic activating mutations involved in fibrous dysplasia and McCune-Albright syndrome (MAS) are not detectable in leukocytes by Sanger sequencing. Digital droplet polymerase chain reaction detects GNAS mutations in 7 of 12 patients (58.3%) suspected to have fibrous dysplasia/MAS from whole blood DNA, and in 4 of 5 patients (80%) from circulating cell-free DNA.

International audience; PURPOSE:While familial forms of complex disorders/differences of sex development have been widely reported, data regarding isolated hypospadias are sparse and a family history is thought to be less frequent. We aimed to determine the frequency of hypospadias in families of boys with hypospadias, to establish whether these familial forms exhibit a particular phenotype and to evaluate the prevalence of genetic defects of the main candidate genes.MATERIALS AND METHODS:A total of 395 boys with hypospadias were prospectively screened for a family history with a standardized questionnaire, extensive clinical description, family tree and sequencing of AR, SF1, SRD5A2 and MAMLD1.RESULTS:Family history of hypospadias was more frequent than expected (88 patients, 22.3%). In 17 instances (19.3%) familial hypospadias cases were multiple. Familial hypospadias was related to the paternal side in 59.1% of cases, consisting of the father himself (30.7%) as well as paternal uncles and cousins. Premature birth, assisted reproductive techniques, other congenital abnormalities and growth retardation were not more frequent in familial hypospadias than in sporadic cases. The severity of phenotype was similar in both groups. The results of genetic analysis combined with previous data on androgen receptor sequencing revealed that familial cases more frequently tend to demonstrate genetic defects than sporadic cases (5.68% vs 1.63%, p = 0.048).CONCLUSIONS:Familial forms of hypospadias are far more frequent than previously reported. Even minor and isolated forms justify a full clinical investigation of the family history. Detecting these hereditary forms may help to determine the underlying genetic defects, and may improve followup and counseling of these patients.

International audience; The French endocrinology society (SFE) and the French pediatric endocrinology society (DFSDP) have drawn up recommendations for the management of primary and secondary adrenal insufficiency in the adult and child, based on an analysis of the literature by 19 experts in 6 work-groups. A diagnosis of adrenal insufficiency should be suspected in the presence of a number of non-specific symptoms except hyperpigmentation which is observed in primary adrenal insufficiency. Diagnosis rely on plasma cortisol and ACTH measurement at 8am and/or the cortisol increase after synacthen administration. When there is a persistant doubt of secondary adrenal insufficiency, insulin hypoglycemia test should be carried out in adults, adolescents and children older than 2 years. For determining the cause of primary adrenal insufficiency, measurement of anti-21-hydroxylase antibodies is the initial testing. An adrenal CT scan should be performed if auto-antibody tests are negative, then assay for very long (Y. Reznik). chain fatty acids is recommended in young males. In children, a genetic anomaly is generally found, most often congenital adrenal hyperplasia. In the case of isolated corticotropin (ACTH) insufficiency, it is recommended to first eliminate corticosteroid-induced adrenal insufficiency, then perform an hypothalamic-pituitary MRI. Acute adrenal insufficiency is a serious condition, a gastrointestinal infection being the most frequently reported initiating factor. After blood sampling for cortisol and ACTH assay, treatment should be commenced by parenteral hydrocortisone hemisuccinate together with the correction of hypoglycemia and hypovolemia. Prevention of acute adrenal crisis requires an education of the patient and/or parent in the case of pediatric patients and the development of educational programs. Treatment of adrenal insufficiency is based on the use of hydrocortisone given at the lowest possible dose, administered several times per day. Mineralocorticoid replacement is often necessary for primary adrenal insufficiency but not for corticotroph deficiency. Androgen replacement by DHEA may be offered in certain conditions. Monitoring is based on the detection of signs of under-and over-dosage and on the diagnosis of associated auto-immune disorders.; La Société française d'endocrinologie (SFE) et la Société française d'endocrinologie pédiatrique (SFEDP) ont élaboré des recommandations sur la prise en charge de l'insuffisance surrénale primaire et secondaire de l'adulte et de l'enfant, à partir d'une analyse de la littérature réalisée par 19 experts répartis en 6 groupes de travail. Le diagnostic d'insuffisance surrénale doit être évoqué devant l'association de signes cliniques et biologiques non spé-cifiques, en dehors de la mélanodermie observée dans l'insuffisance surrénale primaire. Le diagnostic repose sur les dosages du cortisol et de l'ACTH le matin et/ou le dosage du cortisol après stimulation par l'ACTH synthétique (synacthène). En cas de doute, le test d'hypoglycémie insulinique est le test de référence chez l'adulte l'adolescent et l'enfant de plus de 2 ans. La recherche étiologique est basée sur le dosage en 1 re intention des anticorps anti 21-hydroxylase. En cas de négativité, un scanner surrénalien sera réalisé, puis le dosage des acides gras à chaînes longues sera effectué chez le garçon. Chez l'enfant, une cause génétique sera recherchée, principalement l'hyperplasie congénitale des surrénales. Devant un déficit corticotrope, après la recherche d'une prise prolongée de glucocorticoïdes sera effectuée une imagerie hypothalamo-hypophysaire. L'insuffisance surrénale aiguë est une complication grave souvent déclenchée par une infection gastro-intestinale. Elle nécessite après prélèvement pour dosage du cortisol et ACTH l'administration parentérale d'hémisuccinate d'hydrocortisone et la correction de l'hypovolémie et/ou de l'hypoglycémie. Sa prévention repose sur l'éducation thérapeutique du patient pour laquelle des programmes seront développés. Le traitement de l'insuffisance surrénale s'appuie sur la prise pluriquotidienne d'hydrocortisone à la dose la plus faible possible. La substitution minéralocorticoïde est réalisée en cas d'insuffisance surrénale primaire mais n'est pas nécessaire en cas d'insuffisance surrénale secondaire. La substitution androgénique par la DHEA peut être proposée dans cer-taines indications précises. La monitoring comportera la recherche de signes cliniques et biologiques de sous/surdosage et de maladies auto-immunes associées.

International audience

Resume Introduction L’obesite de l’enfant expose a des complications multiples, notamment cardiovasculaires et metaboliques a l’âge adulte. Elle peut aussi occasionner des troubles respiratoires, encore insuffisamment recherches. L’objectif de cette etude etait de faire une evaluation des pratiques pour le depistage et le diagnostic des troubles respiratoires des enfants obeses adresses dans un centre specialise pediatrique de l’obesite. Patients et methodes Etude retrospective des enfants atteints d’obesite severe non syndromique ou explores en hospitalisation (duree de recueil : 21 mois). Les caracteristiques cliniques (antecedents, parametres anthropometriques, habitudes alimentaires, acanthosis nigricans, symptomes de syndrome d’apnees obstructives du sommeil [SAOS]), paracliniques (bilan endocrinien, gazometrie, enregistrement du sommeil) et la prise en charge ont ete relevees. Resultats Parmi 102 enfants inclus (âge moyen de 10,5 ± 3,3 ans, Z-score d’indice de masse corporelle [IMC] moyen de 4,52 DS ± 1,5), 30 presentaient une symptomatologie de SAOS et 9 avaient une polysomnographie pathologique confirmant le SAOS. Huit d’entre eux ont ete ventiles : ces enfants avaient une obesite plus severe avec un rebond d’adiposite plus precoce (2,17 ± 1,2 ans vs 4,0 ± 2,2 ans, p = 0,01) et un Z-score plus eleve (7,2 DS ± 2,3 vs 4,3 DS ± 1,1, p = 0,027). Un syndrome obesite-hypoventilation (SOH) a ete diagnostique pour 4 d’entre eux. Conclusion Les diagnostics du SAOS et du SOH, souvent meconnus chez l’enfant obese, necessitent une demarche systematique et precoce de depistage clinique des troubles respiratoires. Une meilleure accessibilite aux explorations respiratoires permettrait d’ameliorer la qualite de prise en charge de ces enfants particulierement preoccupants.

We report on the case of a 3-year-old child presenting bilateral bronchiectasis due to recurrent pneumonia with esophageal achalasia. The final diagnosis was triple A syndrome. This presentation is particularly atypical and rare at this age.