Syndromes of Resistance to Thyroid Hormone Action

Thyroid hormone (TH) action is crucial for the development of several tissues.A number of syndromes are associated with reduced responsiveness to thyroid hormones, expanding the original definition of thyroid hormone resistance, firstly described by Refetoff and collaborators in 1967, which is characterized by elevated circulating levels of T4 and T3 with measurable serum TSH concentrations, as a consequence of mutations of thyroid hormone receptor beta (TR\u3b2), recently named as RTH\u3b2. More recently, another form of insensitivity to TH has been identified due to mutations in the thyroid hormone receptor alpha (TR\u3b1), named RTH\u3b1. In this chapter we will focus the discussion on the phenotype of RTH\u3b2 and RTH\u3b1. These diseases share the same pathogenic mechanism caused by dominant negative mutations in TH receptor genes that reduce T3 binding or affect the recruitment of cofactors. As a consequence, thyroid hormone actions are impaired at the tissue level. The phenotypic manifestations of RTH\u3b2 and RTH\u3b1 are to some extent correlated with the degree of disruption and the tissue distribution of the TRs being characterized by variable coexistence of hypothyroid or thyrotoxic manifestations in RTH\u3b2 or by a congenital hypothyroid features in RTH\u3b1 despite normal TSH and borderline low free T4