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

BACKGROUND: 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. PATIENT: 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. CONCLUSION: 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.