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 (TRβ). Recently, other forms of insensitivity to TH have been identified: defects in cell surface transporters such as the monocarboxylate transporter 8 (MCT8), genetic disorders of thyroid hormone metabolism due to alterations of selenoprotein synthesis, which comprise the deiodinase enzymes, and finally, mutations in the thyroid hormone receptor alpha (TRα). Since the syndromes of TH insensitivity are characterized by extremely variable clinical manifestations and different molecular mechanisms, this group of thyroid disorders has been very recently reclassified and a novel nomenclature proposed. In this chapter, we will summarize the various phenotypes associated with these syndromes, with the exception of the inherited defects in thyroid hormone transporters such as the monocarboxylate transporter 8 (MCT-8), described elsewhere in this book.