Search

Introduction A gonadectomy is currently recommended in patients with Turner syndrome (TS) and a 45,X/46,XY karyotype, due to a potential risk of gonadoblastoma (GB). However, the quality of evidence behind this recommendation is low. Objective This study aimed to evaluate the prevalence of GB, its characteristics, as well as its risk factors, according to the type of Y chromosomal material in the karyotype. Methods Our study within French rare disease centers included patients with TS and a 45,X/46,XY karyotype, without ambiguity of external genitalia. Clinical characteristics of the patients, their age at gonadectomy, and gonadal histology were recorded. The regions of the Y chromosome, the presence of TSPY regions, and the percentage of 45,X/46,XY mosaicism were evaluated. Results A total of 70 patients were recruited, with a median age of 29.5 years (21.0–36.0) at the end of follow-up. Fifty-eight patients had a gonadectomy, at a mean age of 15 ± 8 years. GB was present in nine cases. Two were malignant, which were discovered at the age of 14 and 32 years, without metastases. Neither the percentage of XY cells within the 45,X/46,XY mosaicism nor the number of TSPY copies was statistically different in patients with or without GB (P = 0.37). However, the entire Y chromosome was frequent in patients with GB (6/9). Conclusions In our study, including a large number of patients with 45,X/46,XY TS, the prevalence of gonadoblastoma is 12.8%. An entire Y chromosome appears as the main risk factor of GB and should favor early gonadectomy. Significant statement About 10% of patients with TS have a karyotype containing Y chromosomal material: 45,X/46,XY. Its presence is related to the risk of GB. Therefore, a prophylactic gonadectomy is currently recommended in such patients. However, the quality of evidence is low. Our objective was to evaluate the prevalence of GB according to the type of Y-chromosomal material. We found a prevalence of GB of 12.8% in a cohort of 70 TS patients. No sign of hyperandrogenism was observed. The entire Y chromosome was the most frequent type of Y-material in patients with GB. As the prognosis of these tumors was good, a delay of surgery might be discussed.

Inborn and acquired deficits of type I interferon (IFN) immunity predispose to life-threatening COVID-19 pneumonia. We longitudinally profiled the B cell response to mRNA vaccination in SARS-CoV-2 naive patients with inherited TLR7, IRF7, or IFNAR1 deficiency, as well as young patients with autoantibodies neutralizing type I IFNs due to autoimmune polyendocrine syndrome type-1 (APS-1) and older individuals with age-associated autoantibodies to type I IFNs. The receptor-binding domain spike protein (RBD)-specific memory B cell response in all patients was quantitatively and qualitatively similar to healthy donors. Sustained germinal center responses led to accumulation of somatic hypermutations in immunoglobulin heavy chain genes. The amplitude and duration of, and viral neutralization by, RBD-specific IgG serological response were also largely unaffected by TLR7, IRF7, or IFNAR1 deficiencies up to 7 mo after vaccination in all patients. These results suggest that induction of type I IFN is not required for efficient generation of a humoral response against SARS-CoV-2 by mRNA vaccines. ispartof: JOURNAL OF EXPERIMENTAL MEDICINE vol:220 issue:1 ispartof: location:United States status: published

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

Context Children with anorexia nervosa (AN) are at risk of adult height deficit due to prolonged low height velocity (HV). Objective To investigate the effects of human growth hormone (GH) injections on HV in children with AN and severe growth impairment. Design and participants In this prospective, randomized, double-blind, single-center, proof-of-concept trial, children with AN and low HV (≤2 cm/year) for at least 18 months, and a bone age ≤12 years for girls and ≤14 years for boys, were randomized to receive daily subcutaneous injections of human GH (0.050 mg/kg/day) or placebo for 12 months. Main outcome measures Change in HV after 12 months. Results In total, 8 patients were assigned to the GH group and 6 to the placebo group. Patients had a median (25th-75th percentile) HV of 1.0 (0.5;1.5) cm/year. The effect of GH treatment increased strongly after 6 months, with a height gain after 12 months of 9.65 (8.0;11.6) cm for the GH group vs 3.85 (1.7;7.3) cm for the placebo group, with an absolute median (2.5th-97.5th percentile) difference between the groups of 5.8 (−1.85;9.68) cm after bootstrapping. The percentage of patients with a HV > 5 cm/year during the study period was higher in the GH group than in the placebo group (100% vs 50%, P = 0.05). Adverse events occurred in similar numbers in the 2 groups, were mild or nonfatal, and did not lead to treatment being stopped. Conclusion GH administration to improve HV is a potentially valid option for increasing HV in children with AN and prolonged severe growth failure.

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.

IntroductionVitamin D–dependent rickets type 1A (VDDR1A) is a rare genetic disease associated with loss-of-function variations in the gene encoding the vitamin D–activating enzyme 1α-hydroxylase (CYP27B1). Phenotype-genotype correlation is unclear. Long-term outcome data are lacking. The objective of this study was to describe characteristics and outcomes to search for a phenotype-genotype correlation.MethodsWe retrospectively collected clinical data, genetic features, and outcomes from 24 genetically confirmed cases from 10 French centers; results are presented as median (min–max).ResultsClinical symptoms at diagnosis (age, 1.5 [0.5-8.7] years) were mainly bone and neurological abnormalities, and laboratory data showed hypocalcemia (1.97 [1.40-2.40] mmol/L), hypophosphatemia (−3.4 [−13.4 to (−)0.2] SD score for age), low 25OHD and low 1,25(OH)2D3, secondary hyperparathyroidism with PTH at 6.6 (1.3-13.7) times the upper limit for normal (ULN; PTH expressed as ULN to homogenize data presentation), and increased alkaline phosphatase (1968 [521-7000] IU/L). Bone radiographs were abnormal in 83% of patients. We identified 17 variations (11 missense, 3 frameshift, 2 truncating, and 1 acceptor splice site variations) in 19 families (homozygous state in 58% [11/19]). The partial loss-of-function variation p.(Ala129Thr) was associated with a milder phenotype: older age at diagnosis, higher serum calcium (2.26 vs 1.85 mmol/L), lower PTH (4.7 vs 7.5 ULN), and lower alkaline phosphatase (759 vs 2082 IU/L). Patients were treated with alfacalcidol. Clinical (skeletal, neurological), biochemical, and radiological outcomes were satisfactory, and complications occurred if there was bad adherence.ConclusionOverall, our findings highlight good outcomes under substitutive treatment and the need of a closer follow-up of eyes, teeth, kidneys, and blood pressure in VDDR1A.

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: An ENDO-European Reference Network (ERN) initiative was launched that was endorsed by the European Society for Pediatric Endocrinology and the European Society for Endocrinology with 22 participants from the ENDO-ERN and the two societies. The aim was to update the practice guidelines for the diagnosis and management of congenital hypothyroidism (CH). A systematic literature search was conducted to identify key articles on neonatal screening, diagnosis, and management of primary and central CH. The evidence-based guidelines were graded with the Grading of Recommendations, Assessment, Development and Evaluation system, describing both the strength of recommendations and the quality of evidence. In the absence of sufficient evidence, conclusions were based on expert opinion. Summary: The recommendations include the various neonatal screening approaches for CH as well as the etiology (also genetics), diagnostics, treatment, and prognosis of both primary and central CH. When CH is diagnosed, the expert panel recommends the immediate start of correctly dosed levothyroxine treatment and frequent follow-up including laboratory testing to keep thyroid hormone levels in their target ranges, timely assessment of the need to continue treatment, attention for neurodevelopment and neurosensory functions, and, if necessary, consulting other health professionals, and education of the child and family about CH. Harmonization of diagnostics, treatment, and follow-up will optimize patient outcomes. Lastly, all individuals with CH are entitled to a well-planned transition of care from pediatrics to adult medicine. Conclusions: This consensus guidelines update should be used to further optimize detection, diagnosis, treatment, and follow-up of children with all forms of CH in the light of the most recent evidence. It should be helpful in convincing health authorities of the benefits of neonatal screening for CH. Further epidemiological and experimental studies are needed to understand the increased incidence of this condition.

ObjectiveTurner Syndrome is associated with several phenotypic conditions associated with a higher risk of subsequent comorbidity. We aimed to evaluate the prevalence of congenital malformations and the occurrence of age-related comorbid conditions and to determine whether the frequencies of congenital and acquired conditions depend on X chromosome gene dosage, as a function of karyotype subgroup.Design and methodsThis national retrospective observational cohort study includes 1501 patients. We evaluated the prevalence of congenital malformations and the cumulative incidence of subsequent specific comorbidities at five-year intervals, from the ages of 10 to 30 years, with stratification by karyotype subgroup: 45,X (n = 549), 45,X/46,isoXq (n = 280), 46,X,r(X)/46,XX (n = 106), 45,X/46,XX (n = 221), presence of Y (n = 87).ResultsMedian age was 9.4 (3.7–13.7) years at first evaluation and 16.8 (11.2–21.4) years at last evaluation. Congenital heart (18.9%) malformations were more frequent in 45,X patients, and congenital renal (17.2%) malformations were more frequent in 45,X, 45,X/46,isoXq and 46,X,r(X)/46,XX patients than in those with 45,X/46,XX mosaicism or a Y chromosome (P ConclusionThese data suggest that X gene chromosome dosage, particularly for Xp genes, contributes to the risk of developing comorbidities.

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

International audience; L’hypothyroïdie congénitale est une maladie due à une sécrétion insuffisante d’hormones thyroïdiennes. Les causes sont multiples, mais les plus fréquentes sont dues à une anomalie de développement de la glande thyroïde ou à un trouble de l’hormonosynthèse thyroïdienne. Cette insuffisance thyroïdienne avait jadis des conséquences très graves sur le développement de l’enfant, dues essentiellement à un traitement bien trop tardif du déficit hormonal. Le dépistage néonatal systématique, mis en place depuis plus de 40 ans en France, permet actuellement une prise en charge dès le début de la deuxième semaine après la naissance. Il a transformé le pronostic de l’affection tant sur le plan de la croissance que sur celui du développement intellectuel et de l’insertion socio-professionnelle, qui sont normaux. Une augmentation de l’incidence de la maladie a été rapportée ces dernières années. Elle concerne essentiellement les formes avec glande thyroïde en place. Il est nécessaire de réévaluer la fonction thyroïdienne de ces patients car ces hypothyroïdies peuvent être transitoires.

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.

Background Early-onset anorexia nervosa (EO-AN) represents a significant clinical burden to paediatric and mental health services. The impact of EO-AN on bone mineral abnormalities has not been thoroughly investigated due to inadequate control for pubertal status. In this study, we investigated bone mineral abnormalities in girls with EO-AN regardless of pubertal development stage. Method We conducted a cross-sectional study of 67 girls with EO-AN (median age = 12.4 [10.9–13.7 years]) after a median duration of disease of 1.3 [0.6–2.0] years, and 67 healthy age-, sex-, pubertal status- matched control subjects. We compared relevant bone mineral parameters between groups: the total body bone mineral density [TB-BMD], the lumbar spine BMD [LS-BMD], the total body bone mineral content [TB-BMC] and the ratio of the TB-BMC to lean body mass [TB-BMC/LBM]. Results TB-BMD, TB-BMC, LS-BMD and TB-BMC/LBM were all significantly lower in patients with AN compared to controls. In the EO-AN group, older age, later pubertal stages and higher lean body mass were associated with higher TB-BMC, TB-BMD, and LS-BMD values. Discussion Girls with EO-AN displayed deficits in bone mineral content and density after adjustment for pubertal maturation. Age, higher pubertal stage and lean body mass were identified as determinants of bone maturation in the clinical population of patients with EO-AN. Bone health should be promoted in patients, specifically in those with an onset of disorder before 14 years old and with a delayed puberty.

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 increase in the incidence of congenital hypothyroidism (CH) reported worldwide may partly be explained by an increase in the transient form of CH. Objective We aimed to estimate the proportion of transient CH (TCH) in France, and to identify associated neonatal and young child characteristics. Methods We used probabilistic record linkage to link children with eutopic gland born between 2006 and 2012 recorded in the national French CH registry and the French national health data system (SNDS). Of the 703 children recorded, 484 (68.8%) were linked. We retrospectively examined reimbursement for oral levothyroxine (LT4) between January 1, 2006, and December 31, 2017. Children who had discontinued treatment for 6 months or more before December 31, 2017, were classified as having TCH. We used a Cox model to examine the factors associated with TCH. Results Among the main study sample (n = 471), 53.5% were female, 14.2% were preterm, and 13.8% had low birth weight. One-quarter (n = 111, 24.3%) had mild CH (thyroid-stimulating hormone [TSH] Conclusion One-third of the children had TCH, and it was associated with several characteristics at birth and postpartum. These data are useful for CH medical management and epidemiological surveillance.

Objective The transition from paediatric to adult medicine involves risks of poor patient outcomes and of significant losses of patients to follow up. The research aimed to analyse the implementation in an initial cohort of patients of a new programme of transition to adult care based on a case management approach. Design A longitudinal study of the case management approach to transition, initiated in a university hospital in France in September 2016. Methods Patients with the endocrine or metabolic disease diagnosed during childhood and transferred to adult care were included. The transition programme includes three steps based on case management: liaising with paediatric services, personalising care pathways, and liaising with structures outside the hospital (general practitioners, agencies in the educational and social sector). Results The cohort included 500 patients, with malignant brain tumour (n = 56 (11%)), obesity (n = 55 (11%)), type 1 diabetes (n = 54 (11%)), or other disease (n = 335 (67%)). Their median age at transfer was 19, and the sex ratio was 0.5. At median 21 months of follow-up, 439 (88%) had a regular follow-up in or outside the hospital, 47 (9%) had irregular follow-up (absence at the last appointment or no appointment scheduled within the time recommended), 4 had stopped care on doctor’s advice, 4 had died, 3 had moved, and 3 had refused care. The programme involved 9615 case management actions; 7% of patients required more than 50 actions. Patients requiring most support were usually those affected by a rare genetic form of obesity. Conclusions Case managers successfully addressed the complex needs of patients. Over time, the cohort will provide unprecedented long-term outcome results for patients with various conditions who experienced this form of transition.

Women with thyroid diseases at the beginning of pregnancy may have suboptimal thyroid hormone levels because of potential difficulties in compensating for the physiological thyroid hormone changes occurring in pregnancy. Our objective was to study the association between preexisting thyroid diseases, pregnancy complications, and neonatal anthropometry. In total, 16,395 women from the ELFE French longitudinal birth cohort were included, and 273 declared pre-pregnancy thyroid diseases. Associations were investigated with multivariable regression models, with adjustment for relevant potential confounders. Body mass index (BMI) was additionally adjusted for in a second stage. As compared with other women, women with pre-pregnancy thyroid diseases were more frequently obese (19.6% vs. 9.8%) and had greater odds of gestational diabetes development (odds ratio [OR] = 1.58 [95% confidence interval [CI] 1.08, 2.30]) or had undergone treatment for infertility (OR = 1.57 [95% CI 1.07, 2.31]). After adjustment for BMI, the association with gestational diabetes was no longer significant (OR = 1.27 [95% CI 0.86, 1.88]). After excluding women with another medical history, those with pre-pregnancy thyroid diseases had increased odds of premature rupture of membranes (OR = 1.51 [95% CI 1.01, 2.25]). Children born from mothers with hypothyroidism before conception due to a disease or as a potential side effect of treatment had a smaller head circumference at birth than other children (β = −0.23 [95% CI −0.44, −0.01] cm). In conclusion, pre-pregnancy thyroid diseases were associated with risk of infertility treatment, gestational diabetes, and premature rupture of membranes. The association between history of hypothyroidism and moderate adverse effects on fetal head circumference growth needs replication.

Refeeding in anorexia nervosa is a collaborative enterprise involving multidisciplinary care plans, but clinicians currently lack guidance, as treatment guidelines are based largely on clinical confidence rather than more robust evidence. It seems crucial to identify reproducible approaches to refeeding that simultaneously maximize weight recovery and minimize the associated risks, in addition to improving long-term weight and cognitive and behavioral recovery and reducing relapse rates. We discuss here various approaches to refeeding, including, among others, where, by which route, how rapidly patients are best refed, and ways of choosing between them, taking into account the precautions or the potential effects of medication or of psychological care, to define better care plans for use in clinical practice.Conclusion: The importance of early weight gain for long-term recovery has been demonstrated by several studies in both outpatient and inpatient setting. Recent studies have also provided evidence to support a switch in current care practices for refeeding from a conservative approach to higher calorie refeeding. Finally, the risks of undernutrition/"underfeeding syndrome" and a maintenance of weight suppression are now better identified. Greater caution should still be applied for more severely malnourished 70% average body weight and/or chronically ill, adult patients. What is Known: • Refeeding is a central part of the treatment in AN and should be a multidisciplinary and collaborative enterprise, together with nutritional rehabilitation and psychological support, but there are no clear guidelines on the management of refeeding in clinical practice. • The risk of a refeeding syndrome is well known and well managed in severely malnourished patients ("conservative approaches"). What is New: • There is evidence that early weight restoration has an impact on outcome, justifying an aggressive approach to refeeding in the early stages of the illness. • The risks of "underfeeding syndrome" and of a maintenance of weight suppression are now better identified and there is sufficient evidence to support a switch in current care practices for refeeding from a conservative approach to higher calorie refeeding. Graphical abstract.

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

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

Context Hyperthyroidism affects all age groups, but epidemiological data for children are scarce. Objective To perform a nationwide epidemiological survey of hyperthyroidism in children and adolescents. Design A cross-sectional descriptive study. Setting Identification of entries corresponding to reimbursements for antithyroid drugs in the French national insurance database. Participants All cases of childhood hyperthyroidism (6 months to 17 years of age) in 2015. Main Outcome Measures National incidence rate estimated with a nonlinear Poisson model and spatial distribution of cases. Results A total of 670 cases of childhood hyperthyroidism were identified. Twenty patients (3%) had associated autoimmune or genetic disease, with type 1 diabetes and Down syndrome the most frequent. The annual incidence for 2015 was 4.58/100,000 person-years (95% CI 3.00 to 6.99/100,000). Incidence increased with age, in both sexes. This increase accelerated after the age of 8 in girls and 10 in boys and was stronger in girls. About 10% of patients were affected before the age of 5 years (sex ratio 1.43). There was an interaction between age and sex, the effect of being female increasing with age: girls were 3.2 times more likely to be affected than boys in the 10 to 14 years age group and 5.7 times more likely to be affected in the 15 to 17 years age group. No conclusions about spatial pattern emerged. Conclusion These findings shed light on the incidence of hyperthyroidism and the impact of sex on this incidence during childhood and adolescence. The observed incidence was higher than expected from the results published for earlier studies in Northern European countries.

Objective Maternal thyroid dysfunction during pregnancy is associated with neurodevelopmental impairment in the offspring. No data are currently available for the offspring of patients treated early for congenital hypothyroidism (CH). The aim of this study was to investigate motor and language milestones at one year of age in a population-based registry of children born to young women with CH. Design and methods We assessed 110 children born to mothers with CH, and 1367 children from the EDEN French population-based birth cohort study prospectively, at the age of one year, with identical questionnaires. Outcomes were assessed in terms of scores for childhood developmental milestones relating to mobility, motor coordination, communication, motricity and language skills. Results After adjustment for confounding factors, children born to mothers with CH were found to have a higher risk of poor motor coordination than those of the EDEN cohort (OR: 4.18, 95% CI: 2.52–6.93). No differences were identified for the other four domains investigated. Children born to mothers with gestational diabetes have a higher risk of low motor coordination score than their peers (OR: 2.10, 95% CI: 1.21–3.66). Children born to mothers with TSH ≥ 10 IU/L during the first six months of pregnancy were more likely to have low motricity or communication skills scores than those born to mothers with lower TSH concentrations (56% vs 21% for each score, P Conclusions Maternal CH may have slight adverse effects on some developmental milestones in the child at one year of age, particularly for children born to mothers with uncontrolled hypothyroidism. However, it remains unclear whether these adverse effects modify subsequent neurodevelopment.

Resume Introduction Les filles porteuses d’un syndrome de Turner (ST) presentent des malformations craniofaciales (hypoplasie et dysfonctionnement des trompes d’Eustache, dysfonctionnement velo-palatin) qui favorisent la survenue d’otites moyennes aigues (OMA). L’objectif de cette etude a ete d’etudier les affections otologiques a l’âge pediatrique du syndrome de Turner lors de la premiere consultation ORL dans notre centre. Patients et methodes Nous avons repris les donnees des consultations ORL de patientes en âge pediatrique suivies pour syndrome de Turner dans notre institution entre 2005 et 2015 et releve : l’otoscopie, le seuil auditif, les antecedents d’OMA et chirurgicaux ORL. Nous avons compare ces donnees selon le caryotype des patientes [monosomie (45,X), mosaique (45,X/46,XX), isochromosome (46,Xi(Xq)), chromosome X en anneau (XrX), contenant du materiel Y et « autres » caryotypes]. Resultats Quatre-vingt-dix patientes, avec un âge moyen de 11,9 ans (± 4,8 ans) lors de la premiere consultation ORL dans notre institution, ont ete incluses : 29 % presentaient une anomalie tympanique a l’otoscopie, 21 % une hypoacousie, et 24 % des antecedents d’OMA a repetition. D’un point de vue chirurgical, 18 % ont ete operees d’une adenoidectomie, 24 % ont eu une pose d’ATT, 5,6 % ont eu une tympanoplastie. Aucun caryotype ne presentait plus qu’un autre un risque de surdite ou d’OMA. Conclusion Ces resultats montrent que les patientes porteuses d’un ST presentent une forte prevalence d’affections otologiques a l’âge pediatrique et necessitent un suivi ORL regulier et rapproche.

Introduction Dans une gonade dysgenesique, la presence du gene TSPY, situe sur le bras court du chromosome Y (locus GBY) jouerait un role dans la formation du gonadoblastome. Il existe peu de donnees chez les patientes avec un syndrome de Turner (ST) ayant du chromosome Y. L’objectif de notre etude etait d’evaluer la prevalence du gonadoblastome, ses caracteristiques, en particulier selon le type de materiel chromosomique Y. Methodes Etude retrospective incluant 10 centres en France. Analyse du caryotype afin de determiner le pourcentage et la region du chromosome Y presente, âge de la gonadectomie et histologie des gonades. Resultats Treize enfants et 57 adultes avec materiel chromosomique Y ont ete incluses. 36/70 (51 %) avaient un chromosome Y entier, 20/70 (29 %) un isodicentrique du bras court et 7/70 (10 %) un isodicentrique du bras long. 57/70 ont eu une gonadectomie a un âge moyen de 14 ± 8 ans. Un gonadoblastome a ete identifie chez 8/57 patientes, aucun apres l’âge de 20 ans. Une seule avait un seminome, decouvert a l’âge de 14 ans. Le chromosome Y entier etait la formule la plus frequente (6/8) et le pourcentage de mosaique XY n’etait pas statistiquement plus eleve (p = 0,28), en cas de gonadoblastome. Conclusion Notre etude incluant un nombre important de patientes ayant un ST avec materiel chromosomique Y a montre une prevalence du gonadoblastome de 11,4 %. La presence d’un chromosome Y entier doit fortement inciter a la gonadectomie. Une etude chromosomique sur d’autres tissus pourrait aider a la prise de decision.

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

International audience; Thyroid scintigraphy holds a key place in the etiologic workup of neonatal hypothyroidism. Routine screening for this disorder in maternity hospitals in industrialized countries, for nearly 40 years, has permitted early treatment and thereby helped to prevent its physical and mental complications. Neonatal hypothyroidism affects approximately 1 in 3000 births. The most common causes are abnormal thyroid gland development and defective hormone synthesis by an eutopic thyroid gland. The incidence of the latter has risen in recent years, for reasons that remain unclear. A thorough etiologic workup helps to determine the disease type. Current guidelines recommend thyroid imaging by means of ultrasound and scintigraphy. Ultrasound should be done by a practitioner trained to examine the cervical region of newborns, as the thyroid is very small and must be distinguished from the particular aspect of the “thyroid empty lodge.” Ultrasound lacks sensitivity for detecting small ectopic glands but is the gold standard for measuring thyroid dimensions. Scintigraphy provides an etiologic diagnosis in most cases. The two isotopes used in this setting are technetium-99m and iodine-123. The latter isotope gives more contrast and allows the perchlorate discharge test to be performed to detect abnormal iodide organification in the neonate with an eutopic thyroid. If scintigraphy cannot be performed during the neonatal period, a postponed procedure can be achieved after 3 years of age. Close cooperation between the nuclear medicine physician and the pediatric endocrinologist is crucial for timely and optimized scintigraphy.

In what seems like the blink of an eye, many of the routines and certainties of our personal and professional worlds have been systematically dismantled. The global march of the novel coronavirus SARS-CoV-2 and the disease it causes, Covid-19, has played out at exponential pace, and almost no facet of our lives has been left untouched. Many are wrestling with worries for their own health and that of their families, often also riven with concern for their livelihoods. We are denied many of life’s pleasures and leisure activities, prevented from travelling, and starved of gatherings with friends. Endocrinologists share this personal reality, but have a critical professional role to play as well. Many combine endocrine practice with contribution to acute internal medicine and so can frequently be found on the ‘front line’, directly caring for the most unwell. They must also look to the patients with endocrine or metabolic disease under their speciality care, while dealing with access restrictions to the diagnostic and therapeutic tools we are used to. Endocrinologists must continue to deliver urgent care for their patients while minimising risks of viral transmission, and they must prepare the vulnerable for the worst-case scenario of severe Covid-19. This must be achieved while mitigating collateral harm arising from enforced pausing of less urgent clinical services. Fortunately, children appear to be more mildly affected than adults; however, clinical care delivery for children with endocrine disorders is adjusted in similar ways as in adults due to the overall healthcare crisis. The clinical practice of endocrinology as we know it depends on quantitative biochemical assessments of hormonal status, often coupled to imaging, generally reliant on sophisticated laboratory and radiological support. Treatments are often delivered by multidisciplinary teams, encompassing nurse specialists, radiologists, surgeons, oncologists, nuclear medicine physicians, ophthalmologists, clinical biochemists, and pathologists among others. We aim for evidence-based practice, with service innovation informed by randomised trials, replicated, corroborated, and meta-analysed. The process is cautious and deliberative, informed by the injunction first to do no harm. Now the rulebook has been ripped up. The exponentially accelerating speed of the pandemic spread in many countries, and the upheaval of clinical care it has engendered, demands an immediate and rational response. There is no time to ensure that care in times of Covid-19 crisis is strictly evidence-based, and service remodelling must be implemented while facing evolving staff shortages as the pandemic illness also strikes healthcare workers. We must, in short, be adept and nimble at delivering clinical care outside our comfort zone, without resources that we normally take for granted. Consequently, sharing of expert opinion and leadership has rarely been of more importance. The European Journal of Endocrinology is responding to this challenge by providing a platform to share and disseminate such expert advice. We have already started to commission international key opinion leaders involved in front-line endocrine care to deliver clinical management guidance documents in an accessible, bullet point format to facilitate rapid information and adjustment of endocrine service delivery in this time of crisis. In a departure from normal practice, peer review will be highly expedited and open, with reviewers named in the final articles, recognising their critical role in refining recommendations and making them rapidly available. Articles will appear over the next few weeks, with all publication fees waived, and online Open Access publication on the EJE website as soon as the final revised version has been accepted. We start the first wave of these publication with clinical management guidance on the endocrine and metabolic conditions identified by the EJE Lead Editors as requiring most urgent advice: Adrenal Insufficiency; Cushing’s Syndrome; Pituitary Tumours; Hyponatraemia and Diabetes Insipidus; Hyper- and Hypo-thyroidism; Diabetes in Pregnancy; Restructuring of Diabetes Services in the Time of Crisis; Primary Hyperparathyroidism and Hypercalcaemia; Thyroid Cancer; Adrenal Tumours; and Neuroendocrine Tumours. These guidance statements are not based on systematic review or meta-analysis (there is no evidence on how to adopt endocrine care in times of a pandemic), but rather on rapid expert consensus; neither are these guidance statements intended to determine absolute standards of medical care. This should, as ever, be carefully tailored to individual circumstances of specific patients, specific hospitals, and specific countries. Nevertheless, in commissioning this series, we have been mindful of the perils of excessive deliberation or over-thinking. As war-based imagery splashes across media coverage of the pandemic, it is perhaps apt to remember the words of the British physicist Robert Watson-Watt, charged with rapidly assembling radar defences at the onset of a world war. In his ‘cult of the imperfect’, channelling an idea articulated by thinkers from Aristotle to Voltaire, he said ‘give them the third best; the second best is too slow and the best never arrives’. This spirit of pragmatic expediency must now animate the endocrine community’s immediate response to help adapt endocrine care to the unforeseen demands of the pandemic crisis. Focus on short term crisis management does not mean abandoning an evidence-based ideal, however. Hand in hand with forced service re-organisation, many are creatively incorporating research into clinical practice, optimising data and sample acquisition, or even undertaking intervention studies. In due course, these efforts may allow practice to be more solidified around an evidence base, and we shall revisit each of the areas covered now in the time of crisis with more reflective, data-informed analysis once the first peak has passed. Finally, we have also asked authors to consider where opportunity may arise in disruption. Multidisciplinary, patient-focused care of long-term endocrine conditions lends itself to creative use of remote review and conferencing; both rapid triage of new referrals and regular follow-up of patients with established diagnosis could be undertaken effectively via teleconferencing, preferably by video link, linked to diagnostic assessment in to-be-established peripheral blood letting satellite centres. For many endocrine conditions, self-management by patients is of paramount importance, and a staggered approach, choosing or alternating between face-to-face contact and teleconferencing, would also permit systematic enhancement of patients’ involvement in their own care, following the principles of the 3E framework (Educate, Equip, Empower) and reinforcing their motivation and resilience. In the response to Covid-19 lies a major opportunity to breach barriers to implementation of more streamlined care pathways exploiting transformative online technologies. Importantly, this challenge forces us to concentrate on the essentials, the ‘clinical bioassay’, that is, the patient himself/herself. This may also facilitate the development of care pathways highly suited to endocrine care delivery in countries with chronically restricted access to the latest and most sophisticated diagnostic and therapeutic modalities. The Chinese word for crisis can be translated either as ‘danger’ or ‘opportunity’. If the endocrine community can grasp this opportunity with determination and ingenuity, then a lasting legacy of good may yet emerge from the dark times in which we currently live. The gauntlet has been thrown down, and the European Journal of Endocrinology looks forward to playing its part in the response. Declaration of interest Wiebke Arlt is Editor-in-Chief of European Journal of Endocrinology. Olaf Dekkers, Juliane Leger, and Rob Semple are Lead Editors of European Journal of Endocrinology. They were not involved in the editorial or review process of this paper, on which they are listed as authors. Funding This editorial did not receive any funding from any funding agency in the public, commercial, or not-for-profit sector.

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.

This manuscript provides guidance on the management of thyroid dysfunction during the COVID-19 pandemic. Autoimmune thyroid diseases are not linked to increased risks of COVID-19. Uncontrolled thyrotoxicosis may result in more severe complications from SARS-CoV-2 infection, including thyroid storm. The management of patients with a new diagnosis of hyperthyroidism is best undertaken with a block-and-replace regimen due to limited biochemical testing availability. Antithyroid drug (ATD)-induced neutropenia may favour the progression of COVID-19 and symptoms of infection may be confused with SARS-CoV-2 infection. The withdrawal of ATDs and urgent measurement of neutrophils should be considered in case of flu-like manifestations occurring in the initial months of treatment. Urgent surgery or 131-I may be undertaken in selected cases of uncontrolled thyrotoxicosis. Patients with COVID-19 infection may present with conjunctivitis, which could cause diagnostic difficulties in patients with new or existing Graves' ophthalmopathy. Patients who are on replacement treatment with thyroid hormones should ensure they have sufficient supply of medication. The usual advice to increase dosage of levothyroxine during pregnancy should be adhered to. Many newly presenting and previously diagnosed patients with thyroid dysfunction can be managed through virtual telephone or video clinics supported by a dedicated nurse-led service, depending on available facilities.

Introduction Congenital hypothyroidism (CH) is a condition of thyroid hormone deficiency present at birth. Untreated CH results in severe mental impairment. An increased incidence of CH has been reported in France and worldwide that could be explained by an increase in transient forms of CH (TCH). We aimed to estimate the proportion of transient eutopic gland based on the characteristics of children at birth. Methods A probabilistic matching data from French CH neonatal screening program and French national health data system (SNDS) of children born between 2006 and 2012 (1, 763 with CH) allowed to linking 484 (68.8%) among 703 children with eutopic gland. Infants with six months or greater discontinuation of levothyroxine (LT4) treatment before the 31th December 2017 were classified transient CH. We used the Cox model to examine the predictors of TCH. Results Among infants with eutopic gland, 52.9% were female, 14.9% were preterm and 14, 1 % had low birth weight, 11.8 % had a first degree family history of thyroid diseases, 48.1% of mild CH (TSH Conclusions Prematurity and TSH level were predictors of transient CH. Additional analyses are ongoing to determine whether the occurrence of transient forms of TCH is increasing over the study period. Key messages Transient congenital hypothyroidism represent a significant part of HC at 10 years of follow-up. This finding has important implication on medical practices and should trigger research on the etiology of these transient forms.

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.

The genetic causes of congenital hypothyroidism due to thyroid dysgenesis (TD) remain largely unknown. We identified three novel TUBB1 gene mutations that co‐segregated with TD in three distinct families leading to 1.1% of TUBB1 mutations in TD study cohort. TUBB1 (Tubulin, Beta 1 Class VI) encodes for a member of the β‐tubulin protein family. TUBB1 gene is expressed in the developing and adult thyroid in humans and mice. All three TUBB1 mutations lead to non‐functional α/β‐tubulin dimers that cannot be incorporated into microtubules. In mice, Tubb1 knock‐out disrupted microtubule integrity by preventing β1‐tubulin incorporation and impaired thyroid migration and thyroid hormone secretion. In addition, TUBB1 mutations caused the formation of macroplatelets and hyperaggregation of human platelets after stimulation by low doses of agonists. Our data highlight unexpected roles for β1‐tubulin in thyroid development and in platelet physiology. Finally, these findings expand the spectrum of the rare paediatric diseases related to mutations in tubulin‐coding genes and provide new insights into the genetic background and mechanisms involved in congenital hypothyroidism and thyroid dysgenesis.

Perinatal characteristics of children with non-acquired GHD are highly variable. Children with structural hypothalamic-pituitary abnormalities such as ectopic posterior pituitary (EPP) with/without pituitary stalk interruption syndrome, septo-optic dysplasia (SOD), or isolated anterior pituitary aplasia/hypoplasia (AP/HP) usually display more severe GHD than those with normal hypothalamic-pituitary magnetic resonance imaging (MRI) findings, and a higher prevalence of multiple pituitary hormone deficiencies (MPHD). Birth and perinatal characteristics in patients with structural hypothalamic-pituitary findings were assessed using data from the Genetics and Neuroendocrinology of Short Stature International study (GeNeSIS). Patients were grouped according to investigator-provided diagnoses: 1) EPP (N=396; including interrupted pituitary stalk; reported MPHD 57%); 2) SOD (N=202; MPHD 78%); 3) AP/HP (N=509; MPHD 36%); and 4) Other GHD (N=10470; non-acquired, non-pituitary abnormality associated; MPHD 9%). Birth/perinatal characteristics for EPP were compared to other diagnoses by ANOVA (all other diagnoses) and pairwise using Dunnett adjustment for continuous variables, and Chi-Square (all other diagnoses) and Fisher’s exact test (pairwise) for categorical variables. Gestation duration was ≈39 weeks for all diagnoses. Mean birth weight standard deviation scores (SDS) were 0.02 for EPP, -0.11 for SOD (p value for difference from EPP=0.651), -0.26 for AP/HP (p=0.020), and -0.38 for Other (p