Resistance to Thyroid Hormone Alpha in an 18-Month-Old Girl: Clinical, Therapeutic, and Molecular Characteristics

Background: Recently, the first patients with resistance to thyroid hormone alpha (RTH) due to inactivating mutations in the thyroid hormone receptor alpha (TR) were identified. These patients are characterized by growth retardation, variable motor and cognitive defects, macrocephaly, and abnormal thyroid function tests. The objective was to characterize a young girl (18 months old) with a mutation in both TR1 and TR2, and to study the effects of early levothyroxine (LT4) treatment. Methods: The patient was assessed clinically and biochemically before and during 12 months of LT4 treatment. In addition, the consequences of the mutation for TR1/2 receptor function were studied in vitro. Results: At 18 months of age, the patient presented with axial hypotonia, delayed motor development, severe growth retardation, and abnormally elevated triiodothyronine (T3)/thyroxine (T4) ratios. RTH was suspected, and concomitantly a c.632A>G/p.D211G missense mutation was identified, affecting both the TR1 and TR2 proteins. This mutation was also found in the girl's father. LT4 treatment was started, resulting in a marked improvement of her hypotonia, motor skills, and growth. Functionally, the missense mutation led to decreased transcriptional activity of TR1, which could be overcome by higher T3 levels in vitro. The mutant TR1 showed a moderate dominant negative activity on wild type (WT) TR1. In contrast, WT TR2 and mutant TR2 had negligible transcriptional activity and showed no dominant-negative effect over TR1. Conclusions: This report describes the phenotype of a young RTH patient with a mild TR mutation before and during early LT4 treatment. Treatment had beneficial effects on her muscle tone, motor development, and growth.