ESPE Abstracts

Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and one of the most common preventable cause of intellectual disability in the world. CH may be due to developmental or functional thyroid defects (primary or peripheral CH) or be hypothalamo-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 aetiology of CH is mostly unknown and may include contributions from individual and environmental factors. In recent years, the detail phenotypic description of patients, high-throughput sequencing technologies, thyroid organoids and the use of animal models have made it possible to discover new genes and signaling pathways involved in the development or function of the thyroid gland, including Borealin and Tubb1 by our team. The genetic transmission modes in CH will also be discussed, including oligogenic model and our new digenic model for CH-TD. NGS studies in different cohorts around the world have shown a low rate of genetic elucidation and GWAS have helped to start decipher the molecular mechanisms of CH-TD. CH is no longer simply a dominant disease for cases of CH-TD and recessive for cases of CH-DH, but a far more complex disorder, where genetics and environment may interact. Funding: our studies were funded by the French Ministry of Health (Programme Hospitalier de Recherche Clinique AOM11184). AS was supported in part by a Belgian Kids’ Fund for Pediatric Research Grant, an Onassis Foundation Grant, and a European Society for Pediatric Endocrinology Research Fellowship Grant. AC and MP received financial support from three corporations (EDF, Sandoz SAS, and Merck Serono France), the non-profit Princess Grace Foundation of Monaco, and public funds from the Agence Nationale de la Recherche (ANR): ANR-MITHYPLA (ANR-21-CE14-0055-01) and ANR 2024 THYMIGEN.