Extreme resistance to thyroid hormone caused by a novel mosaic thyroid hormone receptor beta mutation

Patients with resistance to thyroid hormone β (RTHβ) show elevated thyroid hormone concentrations with non-suppressed thyroid-stimulating hormone (TSH) concentrations and large phenotypic variability. Triac therapy has been successfully applied in some patients. Mosaic mutations causing mild RTHβ have been reported three times so far.

We present a case of severe RTHβ caused by a mosaic frameshift mutation in the thyroid hormone receptor β (p.R438Lfs445X). Methimazole and Triac combination therapy was commenced at the age of 8 years, resulting in a substantial decrease in free T4 concentrations and an increase in TSH concentrations (follow-up duration of >18 months). His extreme agitation, motor restlessness, weight, and some motor and communication skills improved. The mutation was fully unresponsive to stimulation with T3 in in vitro and ex vivo analyses.

The p.R438Lfs445X mutation leads to a severe phenotype of RTHβ. Mosaicism might underlie a subset of patients with the clinical phenotype of RTHβ. Combined methimazole/Triac therapy had beneficial effects on several thyrotoxic features.