Genetic aspects of central hypothyroidism

Central hypothyroidism, characterized by insufficient TSH secretion in the presence of low levels of thyroid hormones, is a rare disorder. It has recently been found that, although mainly due to tumors or infiltrative diseases of the hypothalamo-pituitary area or to pituitary atrophy, central hypothyroidism may be caused by inactivating mutations in several of the genes that code for the various proteins involved in the regulation of the hypothalamo-pituitary-thyroid axis (HPTA). These experiments of nature allow us to better understand the pathophysiology but also the normal physiology of the HPTA. This review will analyze reports of mutations that affect the HPTA and result in either isolated central hypothyroidism or in the syndrome of combined pituitary hormone deficiency (CPHD). Mutations have been identified in the genes for the TRH receptor, the transcription factors Pit-1 and PROP1, and the TSH beta-subunit.