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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.

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.

ObjectiveTo elucidate the molecular cause in a well-characterized cohort of patients with Congenital Hypothyroidism (CH) and Dyshormonogenesis (DH) by using targeted next-generation sequencing (TNGS).Study designWe studied 19 well-characterized patients diagnosed with CH and DH by targeted NGS including genes involved in thyroid hormone production. The pathogenicity of novel mutations was assessed based on in silico prediction tool results, functional studies when possible, variant location in important protein domains, and a review of the recent literature.ResultsTNGS with variant prioritization and detailed assessment identified likely disease-causing mutations in 10 patients (53%). Monogenic defects most often involved TG, followed by DUOXA2, DUOX2, and NIS and were usually homozygous or compound heterozygous. Our review shows the importance of the detailed phenotypic description of patients and accurate analysis of variants to provide a molecular diagnosis.ConclusionsIn a clinically well-characterized cohort, TNGS had a diagnostic yield of 53%, in accordance with previous studies using a similar strategy. TG mutations were the most common genetic defect. TNGS identified gene mutations causing DH, thereby providing a rapid and cost-effective genetic diagnosis in patients with CH due to DH.

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.

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.

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.