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Congenital hypothyroidism (CH) is the most frequent neonatal endocrine disorder and the most common preventable cause of development delay and growth failure if diagnosed and treated early. The thyroid is the first endocrine gland to develop during embryonic life and to be recognizable in humans. Thyroid development and maturation can be divided into 2 phases: a first phase of embryogenesis and a second phase of folliculogenesis and differentiation with thyroid hormone production at the final steps. Regulation of the thyroid function requires normal development of the hypothalamic–pituitary–thyroid axis, which occurs during the embryonic and neonatal period. Defects in any of steps of thyroid development, differentiation, and regulation lead to permanent CH. Newborn screening programs, established in only one-third of countries worldwide, detect CH and are cost-effective and highly sensitive and specific. During the last decade, epidemiology of CH has changed with increased frequency of thyroid in situ in primary CH. Advances in molecular testing have expanded knowledge and understanding of thyroid development and function. However, a molecular cause is identified in only 5% of CH due to thyroid dysgenesis. The purpose of this article is to describe the clinical approach to the child with CH, focusing on diagnostic work-up and future challenges on optimizing thyroid replacement therapy and regenerative medicine. The review is written from the perspective of the case of 2 girls referred for CH after newborn screening and diagnosed with thyroid ectopy. The genetic work-up revealed novel mutations in TUBB1 gene, associated with large platelets and abnormal platelet physiology.

In monogenic diabetes due to KCNJ11 and ABCC8 mutations that impair KATP- channel function, sulfonylureas improve long-term glycemic control. Although KATP channels are extensively expressed in the brain, the effect of sulfonylureas on neurological function has varied widely. We evaluated published evidence about potential effects of sulfonylureas on neurological features, especially epilepsy, cognition, motor function and muscular tone, visuo-motor integration, and attention deficits in children and adults with KCNJ11 and ABCC8-related neonatal-onset diabetes mellitus.We conducted a systematic review and meta-analyses of the literature (PROSPERO, CRD42021254782), including individual-patient data, according to PRISMA, using RevMan software. We also graded the level of evidence.We selected 34 of 776 publications. The evaluation of global neurological function before and after sulfonylurea (glibenclamide) treatment in 114 patients yielded a risk difference (RD) of 58% (95%CI, 43%-74%; IGlibenclamide significantly improved neurological abnormalities in patients with neonatal-onset diabetes due to KCNJ11 or ABCC8 mutations. Hypotonia was the symptom that responded best. Earlier treatment initiation was associated with greater benefits.

ContextEndocrine complications are common in pediatric brain tumor patients.ObjectiveTo describe hypothalamic–pituitary–gonadal axis (HPGA) function in patients treated in childhood for a primary brain tumor more than 5 years earlier, in order to identify risk factors for HPGA impairment.MethodsWe retrospectively included 204 patients diagnosed with a primary brain tumor before 18 years of age and monitored at the pediatric endocrinology unit of the Necker Enfants-Malades University Hospital (Paris, France) between January 2010 and December 2015. Patients with pituitary adenoma or untreated glioma were excluded.ResultsAmong patients with suprasellar glioma not treated by radiotherapy, the prevalence of advanced puberty was 65% overall and 70% when the diagnosis occurred before 5 years of age. Medulloblastoma chemotherapy caused gonadal toxicity in 70% of all patients and in 87.5% of those younger than 5 years at diagnosis. In the group with craniopharyngioma, 70% of patients had hypogonadotropic hypogonadism, which was consistently accompanied by growth hormone deficiency.ConclusionTumor type, location, and treatment were the risk main factors for HPGA impairment. Awareness that onset can be delayed is essential to guide information of parents and patients, patient monitoring, and timely hormone replacement therapy.

ContextCraniopharyngioma is a benign brain tumor with frequent local recurrence or progression after treatment. GH replacement therapy (GHRT) is prescribed in children with GH deficiency resulting from childhood-onset craniopharyngioma.ObjectiveTo evaluate whether a shorter delay of GHRT initiation after childhood-onset craniopharyngioma completion therapy increased the risk of a new event (progression or recurrence).MethodsRetrospective, observational, monocenter study. We compared a cohort of 71 childhood-onset patients with craniopharyngiomas treated with recombinant human GH (rhGH). Twenty-seven patients were treated with rhGH at least 12 months after craniopharyngioma treatment (>12-month group) and 44 patients before 12 months (12-month group and in the ResultsIn the >12-month group, the 2- and 5-year event-free survivals were respectively 81.5% (95% CI, 61.1-91.9) and 69.4% (95% CI, 47.9-83.4) compared with 72.2% (95% CI, 56.3-83.1) and 69.8% (95% CI, 53.8-81.2) in the The median time for event was not statistically different.In univariate and multivariate analysis, the risk of craniopharyngioma new event was not associated with the GHRT time delay after craniopharyngioma treatment.ConclusionsNo association was found between GHRT time delay after childhood-onset craniopharyngioma treatment and an increased risk of recurrence or tumor progression, suggesting GH replacement therapy can be initiated 6 months after last treatment for craniopharyngiomas.

Context Endocrine complications are common in pediatric brain tumor patients. Objective We aimed to describe the endocrine follow-up of patients with primary brain tumors. Methods This is a noninterventional observational study based on data collection from medical records of 221 patients followed at a Pediatric Endocrinology Department. Results Median age at diagnosis was 6.7 years (range, 0-15.9), median follow-up 6.7 years (0.3-26.6), 48.9% female. Main tumor types were medulloblastoma (37.6%), craniopharyngioma (29.0%), and glioma (20.4%). By anatomic location, 48% were suprasellar (SS) and 52% non-suprasellar (NSS). Growth hormone deficiency (GHD) prevalence was similar in both groups (SS: 83.0%, NSS: 76.5%; P = 0.338), appearing at median 1.8 years (−0.8 to 12.4) after diagnosis; postradiotherapy GHD appeared median 1.6 years after radiotherapy (0.2-10.7). Hypothyroidism was more prevalent in SS (76.4%), than NSS (33.9%) (P < 0.001), as well as ACTH deficiency (SS: 69.8%, NSS: 6.1%; P < 0.001). Early puberty was similar in SS (16%) and NSS (12.2%). Hypogonadotropic hypogonadism was predominant in SS (63.1%) vs NSS (1.3%), P < 0.001, and postchemotherapy gonadal toxicity in NSS (29.6%) vs SS (2.8%), P < 0.001. Adult height was lower for NSS compared to target height (−1.0 SD, P < 0.0001) and to SS patients (P < 0.0001). Thyroid nodules were found in 13/45 patients (28.8%), including 4 cancers (4.8-11.5 years after radiotherapy). Last follow-up visit BMI was higher in both groups (P = 0.0001), and obesity incidence was higher for SS (46.2%) than NSS (17.4%). Conclusion We found a high incidence of early-onset endocrine disorders. An endocrine consultation and nutritional evaluation should be mandatory for all patients with a brain tumor, especially when the tumor is suprasellar or after hypothalamus/pituitary irradiation.

Context Early treatment is essential to avoid the cardiac complication of neonatal hyperthyroidism (NH). Our results have direct implications for clinical care. Objective NH can cause potentially fatal neonatal thyrotoxicosis. Here, we have evaluated the feasibility of neonatal hyperthyroidism screening using the thyroid-stimulating hormone value in dried blood collected routinely on filter paper on the third postnatal day of life for congenital hypothyroidism screening. Methods Retrospective case–control study. Cases were identified using data from our previously published study of 280 000 infants born in 10 maternity units in France in 2007-2014. Controls were identified among the 1 362 564 infants born in the Ile-de-France region during the same period. Results A screening thyroid-stimulating hormone level below 0.18 mIU/L on the third postnatal day had 71% (95% CI 44-90%) sensitivity, 99% (95% CI 99-100%) specificity, 81% (95% CI 74-86%) positive predictive value, and 98% (95% CI 97-99%) negative predictive value for detecting severe NH. By univariate regression analysis, the screening thyroid-stimulating hormone value was the strongest predictor of NH (P < .00001), with an area under the receiver-operating characteristics curve of 0.98 (95% CI 0.95-1.0). Expected frequencies were not significantly different from observed frequencies (Hosmer–Lemeshow test, P = .99). Conclusion The screening thyroid-stimulating hormone test can be used to detect severe NH, the optimal cut-off being 0.18 mIU/L. The additional cost compared with screening for congenital hypothyroidism would be small. Infants with neonatal hyperthyroidism would benefit from an earlier diagnosis with treatment initiation at the presymptomatic stage in many cases, ensuring optimal outcomes.

Congenital hypothyroidism (CH) is the most frequent neonatal endocrine disorder. CH is due to thyroid development or thyroid function defects (primary) or may be of hypothalamic-pituitary origin (central). Primary CH is caused essentially by abnormal thyroid gland morphogenesis (thyroid dysgenesis, TD) or defective thyroid hormone synthesis (dyshormonogenesis, DH). DH accounts for about 35% of CH and a genetic cause is identified in 50% of patients. However, TD accounts for about 65% of CH, and a genetic cause is identified in less than 5% of patients. The pathogenesis of CH is largely unknown and may include the contribution of individual and environmental factors. During the last years, detailed phenotypic description of patients, next-generation sequence technologies and use of animal models allowed the discovery of novel candidate genes in thyroid development and function. We provide an overview of recent genetic causes of primary and central CH. In addition, mode of inheritance and the oligogenic model of CH are discussed.Génétique de l’hypothyroïdie congénitale.L’hypothyroïdie congénitale (HC) est la maladie endocrinienne néonatale la plus fréquente. Elle peut être due à des défauts de développement ou de la fonction de la thyroïde (HC primaire ou périphérique) ou d’origine hypothalamo-hypophysaire (HC centrale). L’HC primaire est causée dans la majorité des cas par une anomalie du développement de la glande (dysgénésie thyroïdienne, DT) ou par un défaut de synthèse des hormones thyroïdiennes (dyshormonogenèse, DH). Une origine génétique est identifiée chez 50 % des patients présentant une HCDH mais dans moins de 5 % des patients présentant une HCDT. Cette revue fait le point sur l’ensemble des causes génétiques des HC et sur les différents modes de transmission. L’HC n’est plus simplement une maladie dominante pour les dysgénésies thyroïdiennes et récessive pour les dyshormonogenèses, mais est devenue une maladie plus complexe.

Background: Automated insulin delivery is an efficient treatment for patients with type 1 diabetes. Little is known on its impact on patients with excessive time in hypoglycaemia. Methods: We performed a post hoc analysis of three randomized control trials that used the DBLG1 (Diabeloop Generation 1) hybrid closed-loop solution. Patients whose time below 70 mg/dL during baseline, open-loop phase exceeded 5% were selected. The outcomes were the differences between the closed-loop and the open-loop phases in time in various ranges and Glycemia Risk Index (GRI). Results: We identified 45 patients exhibiting ≥5% of time below 70 mg/dL during the open-loop phase. Under closed-loop, the time in hypoglycaemia (54 to −4). The time below 54 mg/dL decreased from 1.9% (SD 1.3) to 0.8% (SD 0.7) (difference −0.9% [−1.4; –0.8], P < 10−4). The time in range (TIR 70-180 mg/dL) improved from 63.3 (SD 9.5) to 68.2% (SD 8.2) (difference 5.1% [2.9; 7.0], P < 10−4). The GRI improved from 51.2 (SD 12.4) to 38.0 (SD 10.9) (difference 13.2 [10.4; 16.0], P < 10−4). Conclusion: DBLG1 decreased time in hypoglycaemia by more than 50% even in patients with excessive time in hypoglycaemia at baseline, while also improving both TIR and GRI, under real-life conditions. The improvement in GRI (13.2%) exceeded that of the improvement in TIR (5.1%) indicating that in this data set, GRI was more sensitive than TIR to the improvement in glycaemia achieved with closed-loop. These results support the safety and efficacy of this treatment.

Introduction: The DBLG1 Hybrid Closed-Loop system improves time in range and glycemic control in adults. However, the efficacy and safety of the system had not yet been evaluated in children. Objective: of this study is to evaluate the non-inferiority of the DBL4K (Diabeloop for Kids) hybrid closed-loop system (Kaleido pump + Dexcom G6 = CL) compared to a Dexcom G6 sensor augmented pump (open loop = OL) in prepubescent children. Materials and Methods: Multicenter open-label randomized controlled trial in 3 pediatric diabetology centers, 2 of which are French. The CL and OL are allocated for 4 days in hospital, followed by 6 weeks at home for the French centers. Results: Seventeen patients (mean age: 8.3+/- 1.6 years) were included for evaluation at 6 weeks at home between March and December 2019. The percentage of time spent in range (0.7-1.8 g/L) was significantly higher in the CL group during the 6 weeks at home (66.19% in CL vs. 58.68% in OL, p Conclusions: The DBL4K Closed-Loop System is suitable for prepubescent children. It is not inferior to sensor augmented pump therapy in children. Just as in adults it improves the time in range while decreasing the time spent in hypoglycemia. It could allow for better long-term glucose control in children with diabetes. Disclosure D. Kariyawasam: None. C. Morin: None. K. Casteels: None. C. Le Tallec: None. C. Godot: None. A. Sfez: None. N. Garrec: None. M. Polak: Other Relationship; Self; AMMTeK. G. Charpentier: Other Relationship; Self; Diabeloop. S. Franc: Advisory Panel; Self; Diabeloop SA. Board Member; Self; Novo Nordisk. Research Support; Self; Merck Sharp & Dohme Corp. Stock/Shareholder; Self; Diabeloop SA. Other Relationship; Self; Abbott Diabetes. J. Beltrand: None.

Congenital Adrenal Hyperplasia (CAH) is a genetic disorder, mostly (95%) due to CYP21A2 mutations. Its incidence in France is 1/15,000 to 1/16,000 births. The screening of newborns in France is effective since 1996, by using a 17-hydroxyprogesterone dosage on a dried blood spot. This screening allowed, as in other countries, a decrease in mortality and in morbidity by earlier management of adrenal crisis usually symptomatic from the 2Le dépistage néonatal de l’hyperplasie congénitale des glandes surrénales.L’hyperplasie congénitale des glandes surrénales (HCS) est une maladie génétique autosomique récessive liée à une anomalie du gène CYP21A2 dans 95 % des cas, avec une incidence entre 1/15 000 et 1/16 000 naissances. Elle est dépistée sur une goutte de sang séché (sur papier buvard), en France depuis 1996, par dosage de la 17-hydroxyprogestérone, ce qui a permis une diminution de la mortalité et de la morbidité liées à l’insuffisance surrénalienne pouvant survenir dès la deuxième semaine après la naissance. La stratégie française de dépistage consiste en un dosage immunologique en deux étapes sur le même papier buvard. Cette stratégie assure une bonne sensibilité, mais la valeur prédictive positive reste médiocre, laissant place à d’autres stratégies telles que l’utilisation de la chromatographie en phase liquide couplée à la spectrométrie de masse.

L’hyperplasie congénitale des glandes surrénales (HCS) est une maladie génétique autosomique récessive liée à une anomalie du gène CYP21A2 dans 95 % des cas, avec une incidence entre 1/15 000 et 1/16 000 naissances. Elle est dépistée sur une goutte de sang séché (sur papier buvard), en France depuis 1996, par dosage de la 17-hydroxyprogestérone, ce qui a permis une diminution de la mortalité et de la morbidité liées à l’insuffisance surrénalienne pouvant survenir dès la deuxième semaine après la naissance. La stratégie française de dépistage consiste en un dosage immunologique en deux étapes sur le même papier buvard. Cette stratégie assure une bonne sensibilité, mais la valeur prédictive positive reste médiocre, laissant place à d’autres stratégies telles que l’utilisation de la chromatographie en phase liquide couplée à la spectrométrie de masse.

Background Children have a low rate of COVID-19 and secondary severe multisystem inflammatory syndrome (MIS) but present a high prevalence of symptomatic seasonal coronavirus infections. Aim We tested if prior infections by seasonal coronaviruses (HCoV) NL63, HKU1, 229E or OC43 as assessed by serology, provide cross-protective immunity against SARS-CoV-2 infection. Methods We set a cross-sectional observational multicentric study in pauci- or asymptomatic children hospitalised in Paris during the first wave for reasons other than COVID (hospitalised children (HOS), n = 739) plus children presenting with MIS (n = 36). SARS-CoV-2 antibodies directed against the nucleoprotein (N) and S1 and S2 domains of the spike (S) proteins were monitored by an in-house luciferase immunoprecipitation system assay. We randomly selected 69 SARS-CoV-2-seropositive patients (including 15 with MIS) and 115 matched SARS-CoV-2-seronegative patients (controls (CTL)). We measured antibodies against SARS-CoV-2 and HCoV as evidence for prior corresponding infections and assessed if SARS-CoV-2 prevalence of infection and levels of antibody responses were shaped by prior seasonal coronavirus infections. Results Prevalence of HCoV infections were similar in HOS, MIS and CTL groups. Antibody levels against HCoV were not significantly different in the three groups and were not related to the level of SARS-CoV-2 antibodies in the HOS and MIS groups. SARS-CoV-2 antibody profiles were different between HOS and MIS children. Conclusion Prior infection by seasonal coronaviruses, as assessed by serology, does not interfere with SARS-CoV-2 infection and related MIS in children.

Classic galactosemia is a rare inborn error of galactose metabolism with a birth prevalence of about 1/30,000–60,000. Long-term complications occurring despite dietary treatment consist of premature ovarian insufficiency (POI) and neurodevelopmental impairments. We performed with the French Reference Centers for Rare Diseases a multisite collaborative questionnaire survey for classic galactosemic patients. Its primary objective was to assess their puberty, pregnancy, gonadotropic axis, and pelvic morphology by ultrasound. The secondary objective was to determine predictive factors for pregnancy without oocyte donation. Completed questionnaires from 103 patients, 56 females (median age, 19 years (3–52 years)) and 47 males (median age, 19 years (3–45 years)), were analyzed. Among the 43 females older than 13 years old, mean age for breast development first stage was 13.8 years; spontaneous menarche occurred in 21/31 females at a mean age of 14.6 years. In these 21 women, 62% had spaniomenorrhea and 7/17 older than 30 years had amenorrhea. All age-groups confounded, FSH was above reference range for 65.7% of the patients, anti-Müllerian hormone and inhibin B were undetectable, and the ovaries were small with few or no follicles detected. Among the 5 females who sought to conceive, 4 had pregnancies. Among the 47 males, 1 had cryptorchidism, all have normal testicular function and none had a desire to conceive children. Thus, spontaneous puberty and POI are both common in this population. Spontaneous menarche seems to be the best predictive factor for successful spontaneous pregnancy.

Background Smoothened inhibitors (SMOi) have shown activity in Sonic Hedgehog (SHH) medulloblastoma, however this therapeutic class was not developed in children due to severe effects reported on growth. We hereby report long-term follow-up of young patients treated with SMOi for recurrent medulloblastoma. Methods Clinical data on response and toxicity from patients treated with vismodegib or sonidegib from 2011 to 2019 for a SHH medulloblastoma were retrospectively reviewed. Methylation analysis and whole exome sequencing were performed whenever possible. Results All patients with a somatic PTCH1 mutation responded to SMOi (6/8), including 2 prolonged complete responses. One patient was free of disease 8.2 years after treatment. SMOi was challenged again for 3 patients. Two of them had a response, one with SMOi alone, the other one in combination with temozolomide despite previous progression under monotherapy. SMO resistance mutations were found in patients from biopsy at relapse. Combination with temozolomide or surgery plus radiotherapy was associated with very long disease control in 2 patients. The most severe adverse events were myalgia and growth plate fusion with metaphyseal sclerosis. Normal growth velocity was recovered for 1 patient although her final height was below estimated target height. Conclusions Targeting SMO in mutated PTCH1 is an interesting strategy for long-term responses. Combination of SMOi with chemotherapy or surgery and local radiotherapy is an appealing strategy to prevent early resistance and diminish SMOi exposure, especially in young patients. Inhibition of SHH pathway causes growth and development impairment but partial recovery of the growth velocity is possible.

Congenital hypothyroidism (CH) is the most frequent neonatal endocrine disorder and one of the most common preventable forms of mental retardation worldwide. CH is due to thyroid development or thyroid function defects (primary) or may be of hypothalamic-pituitary origin (central). Primary CH is caused essentially by abnormal thyroid gland morphogenesis (thyroid dysgenesis, TD) or defective thyroid hormone synthesis (dyshormonogenesis, DH). TD accounts for about 65% of CH, however a genetic cause is identified in less than 5% of patients. The pathogenesis of CH is largely unknown and may include the contribution of individual and environmental factors. During the last years, detailed phenotypic description of patients, next-generation sequence technologies and use of animal models allowed the discovery of novel candidate genes in thyroid development, function and pathways. We provide an overview of recent genetic causes of primary and central CH. In addition, mode of inheritance and the oligogenic model of CH are discussed.

BackgroundPerinatal treatment with lopinavir boosted by ritonavir (LPV/r) is associated with steroidogenic abnormalities. Long-term effects in infants have not been studied.MethodsAdrenal-hormone profiles were compared at weeks 6 and 26 between human immunodeficiency virus (HIV)-1–exposed but uninfected infants randomly assigned at 7 days of life to prophylaxis with LPV/r or lamivudine (3TC) to prevent transmission during breastfeeding. LPV/r in vitro effect on steroidogenesis was assessed in H295R cells.ResultsAt week 6, 159 frozen plasma samples from Burkina Faso and South Africa were assessed (LPV/r group: n = 92; 3TC group: n = 67) and at week 26, 95 samples from Burkina Faso (LPV/r group: n = 47; 3TC group: n = 48). At week 6, LPV/r-treated infants had a higher median dehydroepiandrosterone (DHEA) level than infants from the 3TC arm: 3.91 versus 1.48 ng/mL (P < .001). Higher DHEA levels (>5 ng/mL) at week 6 were associated with higher 17-OH-pregnenolone (7.78 vs 3.71 ng/mL, P = .0004) and lower testosterone (0.05 vs 1.34 ng/mL, P = .009) levels in LPV/r-exposed children. There was a significant correlation between the DHEA and LPV/r AUC levels (ρ = 0.40, P = .019) and Ctrough (ρ = 0.40, P = .017). At week 26, DHEA levels remained higher in the LPV/r arm: 0.45 versus 0.13 ng/mL (P = .002). Lopinavir, but not ritonavir, inhibited CYP17A1 and CYP21A2 activity in H295R cells.ConclusionsLopinavir was associated with dose-dependent adrenal dysfunction in infants. The impact of long-term exposure and potential clinical consequences require evaluation.Clinical Trials RegistrationNCT00640263

BackgroundChildren have a lower rate of COVID-19, potentially related to cross-protective immunity conferred by seasonal coronaviruses (HCoVs). We tested if prior infections with seasonal coronaviruses impacted SARS-CoV-2 infections and related Multisystem Inflammatory Syndrome (MIS).MethodsThis cross-sectional observational study in Paris hospitals enrolled 739 pauci or asymptomatic children (HOS group) plus 36 children with suspected MIS (MIS group). Prevalence, antigen specificity and neutralizing capability of SARS-CoV-2 antibodies were tested. Antibody frequency and titres against Nucleocapsid (N) and Spike (S) of the four seasonal coronaviruses (NL63, HKU1, 229E, OC43) were measured in a subset of seropositive patients (54 SARS-CoV-2 (HOS-P subgroup) and 15 MIS (MIS-P subgroup)), and in 118 matched SARS-CoV-2 seronegative patients (CTL subgroup).FindingsSARS-CoV-2 mean prevalence rate in HOSP children was 11.7% from April 1 to June 1. Neutralizing antibodies were found in 55·6% of seropositive children, and their relative frequency increased with time (up to 100 % by mid-May). A majority of MIS children (25/36) were SARS-CoV-2 seropositive, of which all tested (n=15) had neutralizing antibodies. On average, seropositive MIS children had higher N and S1 SARS-CoV-2 titres as compared to HOS children. Patients from HOS-P, MIS-P, and CTL subgroups had a similar prevalence of antibodies against the four seasonal HCoVs (66·9 −100%). The level of anti-SARS-CoV-2 antibodies was not significantly different in children who had prior seasonal coronavirus infection.InterpretationPrior infection with HCoVs does not prevent SARS-CoV-2 infection and related MIS in children. Children develop neutralizing antibodies after SARS-CoV-2 infection.Evidence before this studyChildren seem to be less likely affected by SARS-CoV-2 infection and clinical course of COVID-19 is less severe than in adults. As those asymptomatic or mildly symptomatic children are underdiagnosed and their viral loads are comparable to those of adults, they may act as an asymptomatic reservoir for the spread of the virus. One explanation of the difference between the adult and the pediatric infectious profile might be that infection with seasonal human coronaviruses, which is very frequent from a very young age, could lead to cross protective immunity. We searched in PubMed, MedRxiv and BioRxiv for publications from inception to June 15, 2020, using the terms “COVID-19, SARS-CoV-2, children, serology, Kawasaki, Corona Virus”.Added value of this studySARS-CoV-2 mean prevalence rate was 11.7% from April 1 to June 1 and neutralizing antibodies were found in 55% of the tested seropositive children. Among patients with a Multisystem Inflammatory Syndrome, Kawasaki-like disease, 70% were SARS-CoV-2 seropositive and had neutralizing antibodies. COVID-19 and MIS attack rates, and anti-SARS-CoV-2 antibodies titres were not significantly impacted by prior seasonal coronavirus infection.Implications of all the available evidencePrior infection by seasonal coronaviruses does not prevent SARS-CoV-2 infection and associated Multisystem Inflammatory Syndrome in children As antibodies against seasonal coronaviruses are very frequent and as these viruses circulate efficiently in human populations every winter, our results question to what extent the concept of herd immunity based on circulating antibodies can be applied to seasonal coronaviruses and possibly SARS-CoV-2.

Chromosome 6 abnormalities such as paternal uniparental isodisomy, paternal 6q24 duplication, and maternal DMR (differentially methylated region) hypomethylation are a common cause of transient neonatal diabetes mellitus (TNDM). Oral sulfonylurea (SU) is used off-label to treat permanent neonatal diabetes mellitus owing to potassium channel mutation but has not been evaluated in TNDM. Our objective was to evaluate the efficacy and safety of SU therapy in chromosome 6-related TNDM. Description of 3 case reports and literature review was the subject of the study. SU therapy was successful in 2 patients (initiated during neonatal life in 1 patient and during relapse in the other) but failed in the other despite the use of high dosage. The literature review identified 11 cases of patients with chromosome 6-related TNDM treated with SU, including 4 treated before remission and 7 after the relapse. SU therapy was consistently effective, although 4 patients treated after the relapse required multiple oral medications. None of the patients needed associated insulin therapy. No side effects of SU or complications of diabetes were reported. SU seems effective and safe in chromosome 6-related TNDM treatment when used to treat the initial episode of diabetes or the relapse. It improves patients' and families' quality of life. SU is available only as oral tablets. A pediatric dosage form would facilitate the treatment of neonates and infants.

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.

SUMMARY Activating mutations in the canonical Wnt/β-catenin pathway are key drivers of hyperplasia, the gateway for tumor development. In a wide range of tissues, this occurs primarily through enhanced effects on cellular proliferation. Whether additional mechanisms contribute to β-catenin-driven hyperplasia remains unknown. The adrenal cortex is an ideal system in which to explore this question, as it undergoes hyperplasia following somatic β-catenin gain-of-function (βcat-GOF) mutations. Targeting βcat-GOF to zona Glomerulosa (zG) cells leads to a progressive hyperplastic expansion in the absence of increased proliferation. Instead, we find that hyperplasia results from a functional block in the ability of zG cells to transdifferentiate into zona Fasciculata (zF) cells. Mechanistically, zG cells demonstrate an upregulation of Pde2a, an inhibitor of zF-specific cAMP/PKA signaling. Hyperplasia is further exacerbated by trophic factor stimulation leading to organomegaly. Together, these data indicate that β-catenin drives adrenal hyperplasia through both proliferation-dependent and -independent mechanisms., Graphical Abstract, In Brief Using the adrenal cortex as a model for slow-cycling tissues, Pignatti et al. show that activation of the canonical Wnt/β-catenin pathway leads to tissue hyperplasia by blocking cellular differentiation/cell-fate commitment, independent of its effects on cellular proliferation.

The most common thyroid abnormality among Down syndrome (DS) children corresponds to a mildly elevated TSH, with T4 decreased or in the normal range and thyroid hypoplasia, from the neonatal period onward, which aggravate their mental impairment. Transgenic Dyrk1A mice, obtained by bacterial artificial chromosome engineering (mBACTgDyrk1A), have 3 copies of the Dyrk1A gene. The objective is to determine whether this transgenic Dyrk1A (Dyrk1A+/++) mouse is an adequate murine model for the study of thyroid dysgenesis in DS. Embryonic thyroid development from embryonic day 13.5 (E13.5) to E17.5 was analyzed in wild-type (WT) and Dyrk1A+/++ mice by immunofluorescence with anti-Nkx2–1, anti-thyroglobulin, and anti-T4 antibodies, markers of early thyroid development, hormonogenesis, and final differentiation, respectively. The expression of transcription factors Nkx2–1, Pax8, and Foxe1 involved in thyroidogenesis were studied by quantitative RT-PCR at the same embryonic stages. We then compared the adult phenotype at 8 to 12 weeks in Dyrk1A+/++ and WT mice for T4 and TSH levels, thyroidal weight, and histological analysis. Regarding thyroidal development, at E15.5, Dyrk1A+/++ thyroid lobes are double the size of WT thyroids (P = .01), but the thyroglobulin stained surface in Dyrk1A+/++ thyroids is less than a third as large at E17.5 (P = .04) and their differentiated follicular surface half the size (P = .004). We also observed a significant increase in Nkx2–1, Foxe1, and Pax8 RNA levels in E13.5 and E17.5 Dyrk1A+/++ embryonic thyroids. Dyrk1A+/++ young adult mice have significantly lower plasma T4 (2.4 ng/mL versus WT, 3.7 ng/mL; P = 0.019) and nonsignificantly higher plasma TSH (114 mUI/L versus WT, 73mUI/L; P = .09). In addition, their thyroids are significantly heavier (P = .04) and exhibit large disorganized regions. Dyrk1A overexpression directly leads to thyroidal embryogenetic, functional and morphological impairment. The young adult thyroid phenotype is probably a result of embryogenetic impairment. The Dyrk1A+/++ mouse can be considered a suitable study model for thyroid dysgenesis in DS.

Down syndrome is characterized by a high prevalence of thyroid dysfunction during childhood. In this paper, we review the different kinds of thyroid dysfunction that occur excluding those of autoimmune origin: congenital hypothyroidism (elevated plasma TSH with low plasma T4 occurring at birth usually detected by neonatal screening), subclinical hypothyroidism (elevated plasma TSH with plasma T4 in the normal range, which can be congenital or acquired) and acquired primary hypothyroidism (elevated plasma TSH and low plasma T4 occurring after birth). These dysfunctions, while not due to autoimmunity, are of thyroidal origin. However, the mechanisms leading to these different thyroidal abnormalities have not been clearly defined; in particular, it is difficult to determine whether the different types of dysfunction have a common cause, or if the causes are distinct. Treatment is prescribed according to the type of thyroidal abnormality.

Congenital hypothyroidism is the most common neonatal endocrine disorder and is primarily caused by developmental abnormalities otherwise known as thyroid dysgenesis (TD). We performed whole exome sequencing (WES) in a consanguineous family with TD and subsequently sequenced a cohort of 134 probands with TD to identify genetic factors predisposing to the disease. We identified the novel missense mutations p.S148F, p.R114Q and p.L177W in the BOREALIN gene in TD-affected families. Borealin is a major component of the Chromosomal Passenger Complex (CPC) with well-known functions in mitosis. Further analysis of the missense mutations showed no apparent effects on mitosis. In contrast, expression of the mutants in human thyrocytes resulted in defects in adhesion and migration with corresponding changes in gene expression suggesting others functions for this mitotic protein. These results were well correlated with the same gene expression pattern analysed in the thyroid tissue of the patient with BOREALIN-p.R114W. These studies open new avenues in the genetics of TD in humans.

Thyroid dysgenesis (TD) is the most common cause of congenital hypothyroidism in iodine-sufficient regions and includes a spectrum of developmental anomalies. The genetic components of TD are complex. Although a sporadic disease, advances in developmental biology have revealed monogenetic forms of TD. Inheritance is not based on a simple Mendelian pattern and additional genetic elements might contribute to the phenotypic spectrum. This article summarizes the key steps of normal thyroid development and provides an update on responsible genes and underlying mechanisms of TD. Up-to-date technologies in genetics and biology will allow us to advance in our knowledge of TD.

Type 2 diabetes is caused by a limited capacity of insulin-producing pancreatic β cells to increase their mass and function in response to insulin resistance. The signaling pathways that positively regulate functional β cell mass have not been fully elucidated. DYRK1A (also called minibrain/MNB) is a member of the dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family. A significant amount of data implicates DYRK1A in brain growth and Down syndrome, and recent data indicate that Dyrk1A haploinsufficient mice have a low functional β cell mass. Here we ask whether Dyrk1A upregulation could be a way to increase functional β cell mass. We used mice overexpressing Dyrk1A under the control of its own regulatory sequences (mBACTgDyrk1A). These mice exhibit decreased glucose levels and hyperinsulinemia in the fasting state. Improved glucose tolerance is observed in these mice as early as 4 weeks of age. Upregulation of Dyrk1A in β cells induces expansion of β cell mass through increased proliferation and cell size. Importantly, mBACTgDyrk1A mice are protected against high-fat-diet-induced β cell failure through increase in β cell mass and insulin sensitivity. These studies show the crucial role of the DYRK1A pathway in the regulation of β cell mass and carbohydrate metabolism in vivo. Activating the DYRK1A pathway could thus represent an innovative way to increase functional β cell mass.

Homozygous loss-of-function mutations in the FOXE1 gene have been reported in several patients with partial or complete Bamforth-Lazarus syndrome: congenital hypothyroidism (CH) with thyroid dysgenesis (usually athyreosis), cleft palate, spiky hair, with or without choanal atresia, and bifid epiglottis. Here, our objective was to evaluate potential functional consequences of a FOXE1 mutation in a patient with a similar clinical phenotype.FOXE1 was sequenced in eight patients with thyroid dysgenesis and cleft palate. Transient transfection was performed in HEK293 cells using the thyroglobulin (TG) and thyroid peroxidase (TPO) promoters in luciferase reporter plasmids to assess the functional impact of the FOXE1 mutations. Primary human thyrocytes transfected with wild type and mutant FOXE1 served to assess the impact of the mutation on endogenous TG and TPO expression.We identified and characterized the function of a new homozygous FOXE1 missense mutation (p.R73S) in a boy with a typical phenotype (athyreosis, cleft palate, and partial choanal atresia). This new mutation located within the forkhead domain was inherited from the heterozygous healthy consanguineous parents. In vitro functional studies in HEK293 cells showed that this mutant gene enhanced the activity of the TG and TPO gene promoters (1.5-fold and 1.7-fold respectively vs. wild type FOXE1; p0.05), unlike the five mutations previously reported in Bamforth-Lazarus syndrome. The gain-of-function effect of the FOXE1-p.R73S mutant gene was confirmed by an increase in endogenous TG production in primary human thyrocytes.We identified a new homozygous FOXE1 mutation responsible for enhanced expression of the TG and TPO genes in a boy whose phenotype is similar to that reported previously in patients with loss-of-function FOXE1 mutations. This finding further delineates the role for FOXE1 in both thyroid and palate development, and shows that enhanced gene activity should be considered among the mechanisms underlying Bamforth-Lazarus syndrome.

Aims/hypothesis: Growth factors and nutrients are important regulators of pancreatic beta cell mass and function. However, the signalling pathways by which these factors modulate these processes have not yet been fully elucidated. DYRK1A (also named minibrain/MNB) is a member of the dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family that has been conserved across evolution. A significant amount of data implicates DYRK1A in brain growth and function, as well as in neurodegenerative processes in Alzheimer's disease and Down's syndrome. We investigated here whether DYRK1A would be an attractive candidate for beta cell growth modulation. Methods: To study the role of DYRK1A in beta cell growth, we used Dyrk1a-deficient mice. Results: We show that DYRK1A is expressed in pancreatic islets and provide evidence that changes in Dyrk1a gene dosage in mice strongly modulate glycaemia and circulating insulin levels. Specifically, Dyrk1a-haploinsufficient mice show severe glucose intolerance, reduced beta cell mass and decreased beta cell proliferation. Conclusions/interpretation: Taken together, our data indicate that DYRK1A is a critical kinase for beta cell growth as Dyrk1a-haploinsufficient mice show a diabetic profile. © 2014 Springer-Verlag Berlin Heidelberg., The research leading to these results received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement No. 115439, comprising financial contributions from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies. The RS laboratory belongs to the Laboratoire d’Excellence consortium Revive. This work was supported by grants from Inserm ‘Junior 5-year Contract’ (LR)

Background: Human deficiency virus (HIV) protease inhibitors (PIs) are widely used drugs whose effects are pharmacologically enhanced by ritonavir, a potent cytochrome P450 inhibitor. We reported previously that prophylactic postnatal ritonavir-PI therapy in HIV-exposed neonates was associated with increases in plasma 17-hydroxyprogesterone (17-OHP) and dehydroepiandrosterone sulfate (DHEA-S). Aims: To further investigate adrenal function in neonates and adolescents given ritonavir-PI. Methods: Adrenal function was assessed prospectively in 3 HIV-exposed neonates given short-term prophylactic treatment and 3 HIV-infected adolescents given long-term treatment. Plasma cortisol, 17-OHP, 17-OH-pregnenolone, DHEA-S, and androstenedione were measured before and after ACTH administration. Results: None of the patients had clinical signs of adrenal dysfunction. The only neonate exposed to ritonavir-PI in utero had up to 3-fold increases in plasma 17-OHP. Increases in 17-OH-pregnenolone of up to 3.1-fold were noted in 4 of the 6 patients, and all 6 patients had elevations in DHEA-S (up to 20.4-fold increase) and/or DHEA (up to 4.7-fold) and/or androstenedione (up to 5.2-fold). All these parameters improved after treatment completion. Conclusion: Neonates and adolescents given ritonavir-PI exhibit a similar adrenal dysfunction profile consistent with an impact on multiple adrenal enzymes. These abnormalities require evaluation, given the potentially long exposure times.

Lopinavir-ritonavir is a human immunodeficiency virus 1 (HIV-1) protease inhibitor boosted by ritonavir, a cytochrome p450 inhibitor. A warning about its tolerance in premature newborns was recently released, and transient elevation of 17-hydroxyprogesterone (17OHP) was noted in 2 newborns treated with lopinavir-ritonavir in France.To evaluate adrenal function in newborns postnatally treated with lopinavir-ritonavir.Retrospective cross-sectional analysis of the database from the national screening for congenital adrenal hyperplasia (CAH) and the French Perinatal Cohort. Comparison of HIV-1-uninfected newborns postnatally treated with lopinavir-ritonavir and controls treated with standard zidovudine.Plasma 17OHP and dehydroepiandrosterone-sulfate (DHEA-S) concentrations during the first week of treatment. Clinical and biological symptoms compatible with adrenal deficiency.Of 50 HIV-1-uninfected newborns who received lopinavir-ritonavir at birth for a median of 30 days (interquartile range [IQR], 25-33), 7 (14%) had elevated 17OHP levels greater than 16.5 ng/mL for term infants (23.1 ng/mL for preterm) on days 1 to 6 vs 0 of 108 controls having elevated levels. The median 17OHP concentration for 42 term newborns treated with lopinavir-ritonavir was 9.9 ng/mL (IQR, 3.9-14.1 ng/mL) vs 3.7 ng/mL (IQR, 2.6-5.3 ng/mL) for 93 term controls (P.001). The difference observed in median 17OHP values between treated newborns and controls was higher in children also exposed in utero (11.5 ng/mL vs 3.7 ng/mL; P.001) than not exposed in utero (6.9 ng/mL vs 3.3 ng/mL; P = .03). The median DHEA-S concentration among 18 term newborns treated with lopinavir-ritonavir was 9242 ng/mL (IQR, 1347-25,986 ng/mL) compared with 484 ng/mL (IQR, 218-1308 ng/mL) among 17 term controls (P.001). The 17OHP and DHEA-S concentrations were positively correlated (r = 0.53; P = .001). All term newborns treated with lopinavir-ritonavir were asymptomatic, although 3 premature newborns experienced life-threatening symptoms compatible with adrenal insufficiency, including hyponatremia and hyperkalemia with, in 1 case, cardiogenic shock. All symptoms resolved following completion of the lopinavir-ritonavir treatment.Among newborn children of HIV-1-infected mothers exposed in utero to lopinavir-ritonavir, postnatal treatment with a lopinavir-ritonavir-based regimen, compared with a zidovudine-based regimen, was associated with transient adrenal dysfunction.

Introduction Les facteurs de croissance et les nutriments sont des regulateurs majeurs de la masse et de la fonction des cellules beta pancreatiques. Les voies de signalisation par lesquelles ces facteurs de croissance et nutriments agissent ne sont pas completement elucidees. DYRK1A (egalement nommee MNB/ minibrain) est un membre d’un groupe de kinases fortement conservees a travers l’evolution. Des donnees recentes associent DYRK1A a la croissance et au fonctionnement du cerveau, ainsi qu’a la neurodegenerescence et au syndrome de Down. Nos travaux decrits ci-dessous demontrent que DYRK1A est un candidat d’interet pour controler la croissance de la masse des cellules beta. Materiels et methodes Pour etudier le role de Dyrk1A sur la croissance des cellules beta, nous avons utilise des souris deficientes ou surexprimant Dyrk1A. Resultats Nous apportons la preuve que des changements dans l’expression genique de Dyrk1A chez la souris modulent les taux sanguins d’insuline. Des experiences sur des souris haplo-insuffisantes pour DYRK1A montrent une severe intolerance au glucose associee a une reduction de la masse des cellules beta, due a une diminution de leur proliferation. En miroir, les souris surexprimant Dyrk1A presentent une hypoglycemie associee a une hyperinsulinemie due a une expansion de la masse des cellules beta. Cette surexpression de Dyrk1A a pour resultat une augmentation de la proliferation et de la taille de la cellule beta. Enfin, la surexpression de Dyrk1A protege les souris d’une induction du diabete suite a un regime gras. Conclusion En conclusion, nos donnees suggerent que Dyrk1A est une kinase majeure pour le controle de la proliferation des cellules beta de souris. Des modulateurs chimiques de cette kinase pourraient permettre d’augmenter la masse de cellules beta.