Sulfonylurea for improving neurological features in neonatal diabetes: A systematic review and meta-analyses.

OBJECTIVE: 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. RESEARCH DESIGN AND METHODS: 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. RESULTS: 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%; I2  = 54%) overall and 73% (95%CI, 32%-113%; I2  = 0%) in the subgroup younger than 4 years; the level of evidence was moderate and high, respectively. EEG studies of epilepsy showed a RD of 56% (95%CI, 23%-89%; I2  = 34%) in patients with KCNJ11 mutations, with a high quality of evidence. For hypotonia and motor function, the RDs were 90% (95%CI, 69%-111%; I2  = 0%) and 73% (95%CI, 35%-111%; I2  = 0%), respectively, with a high level of evidence. CONCLUSIONS: Glibenclamide 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.

Prior infection by seasonal coronaviruses, as assessed by serology, does not prevent SARS-CoV-2 infection and disease in children, France, April to June 2020.

BackgroundChildren have a low rate of COVID-19 and secondary severe multisystem inflammatory syndrome (MIS) but present a high prevalence of symptomatic seasonal coronavirus infections.AimWe 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.MethodsWe 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.ResultsPrevalence 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.ConclusionPrior infection by seasonal coronaviruses, as assessed by serology, does not interfere with SARS-CoV-2 infection and related MIS in children.

Lopinavir-Ritonavir Impairs Adrenal Function in Infants.

BACKGROUND: Perinatal treatment with lopinavir boosted by ritonavir (LPV/r) is associated with steroidogenic abnormalities. Long-term effects in infants have not been studied. METHODS: Adrenal-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. RESULTS: At 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. CONCLUSIONS: Lopinavir was associated with dose-dependent adrenal dysfunction in infants. The impact of long-term exposure and potential clinical consequences require evaluation. CLINICAL TRIALS REGISTRATION: NCT00640263.

Mutations in BOREALIN cause thyroid dysgenesis.

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.

Successful off-label sulfonylurea treatment of neonatal diabetes mellitus due to chromosome 6 abnormalities.

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.

Dyrk1a haploinsufficiency induces diabetes in mice through decreased pancreatic beta cell mass.

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.

Very long-term outcomes of pediatric patients treated for optic pathway gliomas: A longitudinal cohort study.

BACKGROUND: Optic pathway gliomas (OPGs) represent 5% of childhood brain tumors. Successive relapses lead to multiple treatments exposing to late complications. METHODS: We included patients treated at Gustave Roussy (GR) between January 1980 and December 2015 for OPG, before 18 years old and alive at 5 years from diagnosis. Mortality and physical health conditions data were extracted from medical data files and updated, thanks to the GR long-term follow-up program and French national mortality registry for patients included in the French Childhood Cancer Survivor Study. RESULTS: We included 182 5-year OPG-childhood survivors in the analysis (sex ratio M/F 0.8, 35% with neurofibromatosis type 1 [NF1]). With a median follow-up of 17.2 years (range = 5-41), we registered 82 relapses, 9 second malignancies, and 15 deaths as first events after 5 years, resulting in 20-year conditional overall survival (C-OS) and late events-free survival of 79.9% (95% confidence interval [CI] = 71-86) and 43.5% (95% CI = 36-51), respectively. Radiotherapy exposure in NF1 patients (hazard ratio [HR] = 6, 95% CI = 1.7-21.2) and hypothalamic involvement (HR = 3.2, 95% CI = 1.4-7.3) were significantly associated with C-OS in multivariable analyses. Ninety-five percent of 5-year OPG survivors suffered from any health condition, especially visual acuity "<1/10" (n = 109), pituitary deficiency (n = 106), and neurocognitive impairment (n = 89). NF1 (HR 2.1) was associated with precocious puberty. With a median time post-diagnosis of 4.2 years, 33 cerebrovascular events were observed in 21 patients. CONCLUSIONS: Late relapses, second malignancies, and cerebrovascular diseases are severe late events resulting in premature mortality. Morbidity is high and needs after-cancer care to improve quality of life. Risk factors could be considered to better stratify long-term follow-up.

Long-term weight gain in children with craniopharyngioma.

OBJECTIVE: Adamantinomatous craniopharyngioma mainly affects children. Excessive weight gain is a major long-term complication. The primary objective of this study was to assess long-term weight changes in children treated for craniopharyngioma. The secondary objectives were to identify risk factors for excessive weight gain and to look for associations with hypothalamic damage by the tumour or treatment. DESIGN: Single-centre retrospective cohort study. METHOD: Children managed for craniopharyngioma at our centre between 1990 and 2019 were included. The body mass index (BMI) standard deviation scores (SDS) at baseline and at last follow-up were compared. Univariate and multivariate analyses were performed in order to identify variables associated with the long-term BMI-SDS variation. RESULTS: The 108 patients had a mean follow-up of 10.4 years. The mean BMI-SDS increase over time was 2.11 (P < .001) overall, 1.21 (P < .001) in the group without hypothalamic involvement by the tumour, and 1.95 (P < .001) in the group managed using intended hypothalamus-sparing surgery. The absence of hypothalamic involvement by the tumour or treatment was significantly associated with less weight gain (P = .046 and P < .01, respectively). After adjustment, factors associated with a BMI-SDS change greater than 2 were female sex (P = .023), tumour involving the hypothalamus (P = .04), and higher baseline BMI (P < .001). CONCLUSION: Clinically significant weight gain occurred in nearly all children treated for craniopharyngioma, including those whose hypothalamus was spared by the tumour and intentionally by treatment. However, hypothalamus integrity was associated with less weight gain. Despite hypothalamus-sparing strategies, hypothalamic obesity remains a major concern, indicating a need for novel treatment approaches.

Diagnosis and management of children and adult craniopharyngiomas: a French Endocrine Society/French Society for Paediatric Endocrinology & Diabetes Consensus Statement.

Craniopharyngiomas are rare hypothalamic-pituitary tumors found in young children, adolescents and adults, and their multidisciplinary management required, calls for consistent practices for practicioners, patients and families. The French Endocrine Society and French Society for Pediatric Endocrinology & Diabetes enlisted and coordinated adult and paediatric endocrinologists, neurosurgeons, pathologists, radiotherapists as well as psychologists, dieticians and a patient association, to draft a reference document on this severe disease. The management of craniopharyngiomas remains complex due to their aggressive nature, invasive behavior, and propensity for recurrence, requiring a sequential and measured therapeutic approach and follow-up in expert centers. Although patient survival rates are high, the consequences of both the tumor and its treatment can lead to serious comorbidities and impaired quality of life, particularly in those patients with lesional hypothalamic syndrome. Recent advances have allowed the two described tumor types - papillary and adamantinomatous - to be associated with distinct molecular signatures, specific pathophysiological mechanisms and ipso facto, distinct therapeutic approaches, including innovative medications for hyperphagia, that will continue to evolve. This consensus statement covers all stages in the management of patients with craniopharyngioma, from diagnosis to therapeutic strategies including the long-term follow-up.

First Generation of a Modular Interoperable Closed-Loop System for Automated Insulin Delivery in Patients With Type 1 Diabetes: Lessons From Trials and Real-Life Data.

BACKGROUND: DBLG1 (Diabeloop Generation 1) stands as one of the five commercially available closed-loop solution worldwide for patients with type 1 diabetes as of 2023. Our aim was to provide an overview of all data obtained with this system regarding outcomes and populations, with an emphasis on interoperability. METHODS: This report includes all available sources of data (three randomized control trials and five surveys on real-life data). Collection ran from March 3, 2017 to April 30, 2022. RESULTS: We gathered data from 6859 adult patients treated with closed-loop from three to 12 months. Overall, all sources of data showed that time in range (TIR) 70 to 180 mg/dL, starting from 47.4% to 56.6%, improved from 12.2 to 17.3 percentage points. Time in hypoglycemia was reduced by 48% in average (range: 26%-70%) and reached a level of 1.3% in the largest and most recent cohort. In patients with excessive time in hypoglycemia at baseline (≥5%), closed-loop allowed a reduction in time below range (TBR) by 59%. The comparison of days with declared physical activity versus days without physical activity did not show differences in TBR. The improvement in TIR observed with three different pump systems (Vicentra Kaleido, n = 117; Sooil Dana-I, n = 84; and Roche Insight, n = 6684) ranged from 15.4 to 17.3 percentage points. DISCUSSION: These data obtained in different European countries were consistent throughout all reports, showing that this closed-loop system is efficient (high improvement in TIR), safe (remarkably low level of TBR), and interoperable (three pump settings so far).

Glucose pattern in children with classical congenital adrenal hyperplasia: evidence from continuous glucose monitoring.

BACKGROUND: While the risk for hypoglycemia during acute illness is well described in children with classical congenital adrenal hyperplasia (CAH), there is little evidence for the prevalence of asymptomatic hypoglycemia and the daily glucose patterns in CAH. Herein, we explored the daytime glucose profile of children with classical CAH. METHODS: We conducted an observational study in 11 children (6 female; age 3.1 years [1.4, 5.1]; body mass index 17.3 kg/m2 [15.6, 17.9]) with a genetic diagnosis of classical CAH receiving hydrocortisone and fludrocortisone replacement therapy. Participants underwent 2 14-day continuous glucose monitoring (CGM) sessions and an inpatient 24 h series cortisol and adrenocorticotropic hormone (ACTH) measures. Data were analyzed for 3 daytime lags (7 Am-4 Pm, 4 Pm-10pm, 10 Pm-7 Am) corresponding to the hydrocortisone dosing period with cortisol and ACTH measured before the hydrocortisone dose. RESULTS: Eleven participants completed at least 1 CGM session, and 7 out of 11 underwent both the CGM session and the cortisol/ACTH serial measures. In the whole cohort, the percentage of time of sensor glucose values <70 mg/dL was higher during the 10 Pm-7 Am and the 7 Am-4 Pm time slots than in the late afternoon period (17% [7, 54] and 15% [6.8, 24] vs 2% [1.1, 16.7] during the periods 7 Am-4 Pm and 4 Pm-10 Pm, respectively [P = .006 and P = .003]). Nighttime hypoglycemia was mostly spent below the 65 mg/dL (10.9% [4.1, 34]). The glycemic pattern paralleled the nadir of daily cortisol at 7 Am (10.3±4.4 µg/dL). A greater percentage of time in hypoglycemia was associated with lower cortisol concentration at 7 Am and 10 Pm (P < .001 and P = .005). CONCLUSIONS: Continuous glucose monitoring demonstrated a disrupted daily glucose pattern in children with CAH, paralleled by a lower cortisol concentration. CLINICALTRIALS.GOV REGISTRATION: NCT04322435.

Borealin/CDCA8 deficiency alters thyroid development and results in papillary tumor-like structures.

Background: BOREALIN/CDCA8 mutations are associated with congenital hypothyroidism and thyroid dysgenesis. Borealin is involved in mitosis as part of the Chromosomal Passenger Complex. Although BOREALIN mutations decrease thyrocyte adhesion and migration, little is known about the specific role of Borealin in the thyroid. Methods: We characterized thyroid development and function in Borealin-deficient (Borealin +/-) mice using histology, transcriptomic analysis, and quantitative PCR. Results: Thyroid development was impaired with a hyperplastic anlage on embryonic day E9.5 followed by thyroid hypoplasia from E11.5 onward. Adult Borealin +/- mice exhibited euthyroid goiter and defect in thyroid hormone synthesis. Borealin +/- aged mice had disorganized follicles and papillary-like structures in thyroids due to ERK pathway activation and a strong increase of Braf-like genes described by The Cancer Genome Atlas (TCGA) network of papillary thyroid carcinoma. Moreover, Borealin +/- thyroids exhibited structural and transcriptomic similarities with papillary thyroid carcinoma tissue from a human patient harboring a BOREALIN mutation, suggesting a role in thyroid tumor susceptibility. Conclusion: These findings demonstrate Borealin involvement in critical steps of thyroid structural development and function throughout life. They support a role for Borealin in thyroid dysgenesis with congenital hypothyroidism. Close monitoring for thyroid cancer seems warranted in patients carrying BOREALIN mutations.

Identifying patient-related predictors of permanent growth hormone deficiency.

Objective: Isolated childhood growth hormone deficiency (GHD) can persist into adulthood, and re-testing at the transition period is needed to determine whether continued growth hormone therapy is indicated. Here, our objective was to identify predictors of permanent GHD. Design: Retrospective single-centre study of patients with childhood-onset GHD who were re-tested after adult height attainment. Methods: Auxological, clinical, laboratory, and MRI data throughout follow-up were collected. Results: We included 101 patients. At GH treatment initiation, age was 8.1 ± 0.4 years, height -2.25 ± 0.8, and BMI -0.27 ± 0.1 SDS. The 29 (28.7%) patients with persistent GHD had lower height SDS (-2.57 ± 0.1 vs. -2.11 ± 0.1, p<0.001) and mean GH peaks (8.4 ± 1.0 vs.13.2 ± 0.5 mIU/L, p<0.001) at GHD diagnosis; at adult height, they had lower IGF1 (232 ± 19.9 vs. 331 ± 9.1 ng/mL, p<0.001) and higher BMI SDS (-0.15 ± 0.27 vs. -0.73 ± 0.13, p<0.005). By multivariate analysis, the best predictive model included height and BMI SDS, both GH peaks, and MRI findings at diagnosis. Patients with height at diagnosis <-3 SDS had a 7.7 (95% IC 1.4-43.1, p=0.02) fold higher risk of persistent GHD after adjustment on BMI SDS. An abnormal pituitary region by MRI was the strongest single predictor (7.2 times, 95% CI 2.7-19.8) and after multivariate analysis adjustment for GH peaks and height SDS at diagnosis, the risk increased to 10.6 (1.8 - 61.3) times. Conclusions: Height <-3 SDS at GHD diagnosis and pituitary MRI abnormalities should lead to a high index of suspicion for persistent GHD.

GH and Childhood-onset Craniopharyngioma: When to Initiate GH Replacement Therapy?

CONTEXT: Craniopharyngioma 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. OBJECTIVE: To evaluate whether a shorter delay of GHRT initiation after childhood-onset craniopharyngioma completion therapy increased the risk of a new event (progression or recurrence). METHODS: Retrospective, 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), among which 29 patients were treated between 6 and 12 months (6-12 month group). The main outcome was the risk of tumor new event (progression of residual tumor or tumor recurrence after complete resection) after primary treatment in the >12-month group and in the <12 month or in the 6- to 12-month group patients. RESULTS: In 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 <12-month group. The 2- and 5-year event-free survivals were the same in the 6- to 12-month group (72.4%; 95% CI, 52.4-85.1). By log-rank test, the event-free survival was not different between groups (P = .98 and P = .91).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. CONCLUSIONS: No 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.

Assessment of Puberty and Hypothalamic-Pituitary-Gonadal Axis Function After Childhood Brain Tumor Treatment.

CONTEXT: Endocrine complications are common in pediatric brain tumor patients. OBJECTIVE: To 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. METHODS: We 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. RESULTS: Among 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. CONCLUSION: Tumor 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.

Genetics of congenital hypothyroidism: Modern concepts.

Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and one of the most common preventable causes of intellectual disability in the world. CH may be due to developmental or functional thyroid defects (primary or peripheral CH) or be hypothalamic-pituitary in origin (central CH). In most cases, primary CH is caused by a developmental malformation of the gland (thyroid dysgenesis, TD) or by a defect in thyroid hormones synthesis (dyshormonogenesis, DH). TD represents about 65% of CH and a genetic cause is currently identified in fewer than 5% of patients. The remaining 35% are cases of DH and are explained with certainty at the molecular level in more than 50% of cases. The etiology of CH is mostly unknown and may include contributions from individual and environmental factors. In recent years, the detailed phenotypic description of patients, high-throughput sequencing technologies, and the use of animal models have made it possible to discover new genes involved in the development or function of the thyroid gland. This paper reviews all the genetic causes of CH. The modes by which CH is transmitted will also be discussed, including a new oligogenic model. CH is no longer simply a dominant disease for cases of CH due to TD and recessive for cases of CH due to DH, but a far more complex disorder.

[Genetic of congenital hypothyroidism]. / Génétique de l'hypothyroïdie congénitale.

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.

Title: Génétique de l'hypothyroïdie congénitale. Abstract: 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.

Neonatal Screening for Hyperthyroidism Proof of Concept.

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.

Approach to the Patient With Congenital Hypothyroidism.

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.

Efficacy of a Hybrid Closed-Loop Solution in Patients With Excessive Time in Hypoglycaemia: A Post Hoc Analysis of Trials With DBLG1 System.

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 <70 mg/dL) dropped from 7.9% (SD 2.4) to 3.2% (SD 1.6) (difference -4.7% [-5.3; -4.1], P < 10-4). 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.