Association Between an R338L Mutation in the Thyroid Hormone Receptor-β Gene and Thyrotoxic Features in Two Unrelated Kindreds with Resistance to Thyroid Hormone

Resistance to thyroid hormone (RTH) is a rare syndrome characterized by reduced sensitivity to thyroid hormone due to thyroid hormone receptor-β (TRβ) gene mutations or deletion. RTH has been classified on the basis of clinical features into generalized (GRTH) and pituitary (PRTH) resistance. There is, however, overlap of clinical and biochemical findings in patients with the two forms of resistance, and similar TRβ gene mutations have been identified in both. The 2 subtypes of RTH, therefore, are considered to be different manifestations of a single genetic entity. We report a mutation of the TRβ gene, an arginine to leucine substitution at codon 338 (R338L), in 2 unrelated RTH kindreds of northern Italian ancestry. The same mutation was already reported in a single unrelated kindred affected by PRTH. Five individuals, 3 in the first and 2 in the second family, were clinically evaluated and followed for 3-11 years. During the long-term follow-up, the patients manifested symptoms and signs of hyperthyroidism including palpitations, fine tremors, heat intolerance, increased sweating, increased deep tendon reflexes, moist and warm skin, cardiac rhythm abnormalities, reduced body weight, and reduced bone mineral density. The clinical features of these kindreds are consistent with a predominant PRTH phenotype.