Genetics of congenital hypothyroidism

Primary congenital hypothyroidism (CH) is the most frequent endocrine metabolic disease in the infancy, with an incidence of about 1/3000 live births. With the exception of the rare cases of central hypothyroidism, CH is characterized by the presence of elevated TSH levels in response to reduced thyroid hormone production.In 15% of cases, the disease is caused by inborn errors in the mechanisms required for thyroid hormone synthesis and are indicated with the term of dyshormonogenesis. In the remaining 85%, CH is due to alterations occurring during the gland's organogenesis, which result in a thyroid gland that is absent (thyroid agenesis or athyreosis), severely reduced in size (thyroid hypoplasia) or located in an unusual position (thyroid ectopy). All these entities are grouped under the term “thyroid dysgenesis” (TD).Thyroid dyshormonogenesis shows classical Mendelian recessive inheritance and very frequently leads to enlargement of the gland (goiter), presumably as a consequence of the elevated TSH levels. Among the genes causing dyshormonogenesis, initially it was described a role of the thyroid peroxidase and thyroglobulin genes. More recently, also other genes have beed demonstrated to be involved, including Pendrin (PDS, in Pendred syndrome), the sodium iodide symporter (NIS), and THOX2 (thyroid oxidase 2) gene.TD occurs mostly as a sporadic disease. However a genetic cause of the disease it has been demonstrated in about 5% of the studied cases. Genes associated with TD includes several thyroid transcription factors expressed in the early phases of thyroid organogenesis (NKX2.1/TITF1, FOXE1/TITF2, PAX8, NKX2.5) as well as genes, like the thyrotropin receptor gene (TSHR) expressed in the late phases of the gland morphogenesis. The more recent aspects of the genetics of congenital hypothyroidism will be reviewed, providing inputs for the discussion.