Endocrine Abstracts

Resistance to thyroid hormone (RTH) is usually due to heterozygous mutations in THRB gene with rare cases being homozygous for receptor defects. We describe an RTH case due to a homozygous TRβ mutation (R243Q).

The Proband (male, 8.4 years), was born at term with low birth weight (1.9 kg) to consanguineous parents. He has a prominent nasal bridge, goitre, low body weight (10th centile), recurrent tonsillitis, hyperactivity and has mild hearing impairment. He has a sinus tachycardia of 125 bpm, mitral and tricuspid regurgitation, and reduced ejection fraction for age (EF 55%). NT-proBNP, a marker of cardiac dysfunction, is elevated (298 pg/ml; rr 10–157).

His circulating thyroid hormones (FT₄ >fourfold; FT₃ >eightfold raised) are very elevated, with normal TSH levels. THRB gene sequencing showed homozygosity for a nucleotide substitution, corresponding to an arginine to glutamine change at codon 243 (R243Q) in TRβ. Less abnormal thyroid function (FT₄ 1.2–1.8-fold, FT₃ 1.2–1.9-fold raised) in each parent and three siblings was associated with heterozygosity for the R243Q TRβ mutation.

Goitre, hyperactivity and recurrent infections had also been noted in another sibling. He developed mitral regurgitation and cardiomegaly and died of heart failure at 13 years, despite diuretic therapy. Although his THRB mutation status is unknown, elevation of his thyroid hormones (FT₄ >threefold, FT₃ >13-fold raised, comparable to the Proband suggest homozygous RTH, with cardiac hyperthyroidism contributing to his mortality.

Previous functional studies indicated unique properties of R243Q TRβ, with significantly impaired ligand-dependent dissociation of mutant receptor homodimers bound to DNA and delayed corepressor release. This might account for unexpectedly significant dominant negative inhibition by R243Q mutant TRβ in vitro, correlating with our observed severe homozygous RTH phenotype. Controlling cardiac hyperthyroidism with either medical therapy or thyroid ablation to prevent life threatening decompensation will be a therapeutic challenge.