Abstract
The syndromes of resistance to thyroid hormone (RTH) are generally characterized by reduced tissue responsiveness to thyroid hormone (TH) despite elevated circulating levels of free T3 and/or T4 (Refetoff et al., 1993). It is associated with an inappropriately normal or raised serum TSH characteristic of impaired thyrotroph sensitivity. The original clinical description of RTH was reported by Refetoff et al. (1967) in two subjects with deaf-mutism, delayed bone age, and stippled epiphyses. Despite these symptoms of hypothyroidism, serum levels of TH were high. Furthermore, administration of exogenous TH failed to produce the expected metabolic effects and failed to suppress thyrotropin-releasing hormone-stimulated TSH. These observations lead to the diagnosis of RTH. Twenty years later, the molecular basis of the syndrome was found to be due to a mutation in the TH receptor β (THRB and TRβ) gene (Sakurai et al., 1989; Usala et al., 1990). To date, 186 different mutations in the TRβ gene, found in > 3000 individuals in 500 families, have been described. As our knowledge of the different thyroid function phenotypes has evolved, it has become clear that RTH is part of a larger group of conditions known as impaired sensitivity to thyroid hormone (Refetoff et al., 2014). Those with classic RTH due to TRβ mutations are known as RTH-beta. This is to distinguish them from a group of patients with mutations in the TH receptor alpha (THRA and TRa) gene RTH-alpha who have low serum T4, borderline high T3, and very low rT3 with normal to elevated TSH concentrations (Espiard et al., 2015; Moran et al., 2013, 2014; Tinnikov et al., 2002). A high ratio of free T3 to free T4 seems to be a common finding in the 14 cases of RTH-alpha described to date. Two other syndromes belonging to the group of impaired sensitivity to thyroid hormone include patients with gene mutations affecting TH metabolism, such as SBP2 (Di Cosmo et al., 2009; Dumitrescu et al., 2005) or transport via MCT8 (Dumitrescu et al., 2004; Friesema et al., 2004, 2010). The latter is associated with severe psychomotor defects. Knowledge of the molecular mechanisms involved in mediation of TH action allows the recognition of the phenotypes caused by genetic defects in the involved pathways.