Genetic basis of hypothyroidism: recent advances, gaps and strategies for future research

Hypothyroidism is the most common congenital endocrine disorder. Its etiology mainly resides in the disturbed development and function of the thyroid gland or its hypothalamic-pituitary regulatory system. During the past two decades, the genetic basis of congenital hypothyroidism (CH) has been partly elucidated with the identification of molecular defects in pituitary- and thyroid-specific proteins in patients with various types of hypothyroidism. Recently, hydrogen peroxide generation defects in the thyroid have been causally related to permanent and transient CH. Overall, the molecular defects so far identified only explain a few cases of hypothyroidism. Hence, novel research strategies are required to fill in the numerous gaps in the molecular events necessary for the formation of a mature, fully functional hypothalamus-pituitary-thyroid axis and to identify novel disease-related genes. Here, we discuss recent advances in the molecular pathogenesis of hypothyroidism and analyze the potential of novel genomics technologies in the mechanistic characterization of the disease