Congenital hypothyroidism (CH) occurs in 1/3000-4000 neonates worldwide and may be classified as permanent or transient. Primary CH accounts for the majority of affected children, while secondary and tertiary CH are rare. In iodine-sufficient countries, thyroid dysgenesis (TD) is the most frequent cause of CH. Hereditary inborn errors of thyroid hormonogenesis account for about 10-20% CH children. Environmental, genetic and autoimmune factors have been implicated in the etiology of CH, but in the majority of cases the cause of TD remains to be clarified. Candidates for playing a pathogenetic role in TD are genes involved in thyroid gland ontogeny, such as those of thyroid transcription factors TITF1, TITF2, PAX-8 and the TSH-receptor (TSHR). No abnormality in the TITF1 gene has yet been found in CH, while mutations in the PAX-8 gene were identified in at least 5 neonates with TD. Loss of function mutations of the TSHR gene, although not involved in TD, may produce a spectrum of congenital defects ranging from euthyroid hyperthyrotropinemia to overt hypothyroidism with a hypoplastic gland. The cloning of genes implicated in the biosynthesis of thyroid hormones, such as those of thyroperoxidase (TPO) and thyroglobulin (Tg), has led to the identification of mutations responsible for some cases of goitrous hypothyroidism due to iodide organification defect or abnormalities in Tg synthesis. Recently, the molecular basis of the iodide transport defect and Pendred’s syndrome were reported, due to mutations, respectively, on the NIS and PDS genes. In conclusion, we still do not have elucidated the molecular basis of TD, the most common of the defects affecting neonates with CH.
Thyroid; Congenital hypothyroidism; Thyroid dysgenesis; TSH receptor; Molecular biology
