Molecular Genetics of Primary Congenital Hypothyroidism: Established and Emerging Contributors to Thyroid Dysgenesis

Congenital hypothyroidism (CH) is one of the most common endocrine disorders of childhood. The primary form of CH is attributable to thyroid dysgenesis (agenesis, hypoplasia, or ectopy) in 65–85% of cases, with the remaining cases being attributed to dyshormogenesis. Thyroid dysgenesis was considered a sporadic disease. However, the recent advantages of molecular techniques have significantly contributed to the understanding of the pathogenesis of the disease. The higher prevalence of congenital malformations and syndromes in patients with CH compared to the general population supports the genetic basis. This narrative review aims to provide an overview of the identified and potential genetic causes of thyroid dysgenesis. Mutations in ten genes involved in thyroid gland development during embryogenesis, TSHR, PAX8, NKX2-1, NKX2-5, FOXE1, JAG1, NTN1, GLIS3, CDC8A, and TUBB1, have been identified in cohorts of patients with thyroid dysgenesis. However, most cases remain unexplained. Novel candidate genes have been proposed. The extant evidence suggests that the pathogenesis of thyroid dysgenesis involves a spectrum of genetic etiologies, ranging from monogenic to multigenic, and that epigenetic or environmental factors may also contribute. As molecular techniques are continuously refined, future studies are expected to elucidate the complex genetic background of thyroid dysgenesis.