Two novel mutations in the thyroid hormone receptor in patients with Resistance to Thyroid Hormone (RTH ): clinical, biochemical, and molecular data

Abstract

The syndrome of resistance to thyroid hormone (RTH ) is an inherited disorder characterized by variable tissue hyposensitivity to 3,5,30-l-triiodothyronine (T-3), with persistent elevation of free-circulating T-3 (FT3) and free thyroxine (FT4) levels in association with nonsuppressed serum thyrotropin (TSH). Clinical presentation is variable and the molecular analysis of THRB gene provides a short cut diagnosis. Here, we describe 2 cases in which RTH was suspected on the basis of laboratory findings. The diagnosis was confirmed by direct THRB sequencing that revealed 2 novel mutations: the heterozygous p.Ala317Ser in subject 1 and the heterozygous p.Arg438Pro in subject 2. Both mutations were shown to be deleterious by SIFT, PolyPhen, and Align GV-GD predictive methods