Incidental identification of a thyroid hormone receptor beta (THRB) gene variant in a family with autoimmune thyroid...

Resistance to thyroid hormone (RTH) is a rare condition usually diagnosed in patients with classic thyroid function tests (TFTs) of elevated thyroid hormone levels with nonsuppressed TSH. The presence of autoimmune thyroid disease (AITD) can confound the clinical diagnosis of RTH. A family was evaluated because several members had elevated TSH and normal or low serum T4 concentrations with AITD. While these individuals were initially reported to have RTH, they were found to have a normal thyroid hormone receptor beta (THRB) gene sequence, and three other asymptomatic family members were found to harbor the variant TRβ G339S.

The THRB gene was sequenced in 19 members of a large Mexican/Aztec family. In vitro expression of the mutant TRβ protein was performed, as well as computer modeling of the variant compared to known mutations in the flanking codons.

Investigation of an individual with AITD who was incorrectly diagnosed with RTH led to the fortuitous discovery of a THRB gene variant (G339S) in the proposita's father, paternal aunt, and cousin. This variant was not detected in analysis of 124 unrelated alleles. All individuals harboring G339S had normal TFTs. Normal in vitro expression and function of G339S and molecular modeling predicted that this variant would not have an effect on the hypothalamic-pituitary-thyroid axis as determined by thyroid hormone binding in vitro and thyroid function tests in vivo, despite profound effects seen in mutations in the adjacent codons 338 and 340.

We report an individual with normal TFTs and AITD harboring a novel THRB gene variant. In addition to illustrating the importance of accurate diagnosis of thyroid disease so that proper treatment and counseling can be given, TRβ codon 339 is not essential for normal TRβ function.