Resistance to Thyroid Hormone Alpha in an 18 Months Old Girl; Clinical, Therapeutic and Molecular Characteristics.

Resistance to Thyroid Hormone Alpha in an 18 Months Old Girl; Clinical, Therapeutic and Molecular Characteristics.

Thyroid. 2016 Jan 18;

Authors: van Gucht A, Meima M, Zwaveling-Soonawala N, Visser WE, Fliers E, Wennink J, Henny C, Visser TJ, Peeters R, van Trotsenburg AS

Abstract
BACKGROUND: Recently, the first patients with resistance to thyroid hormone (RTHα) due to inactivating mutations in the thyroid hormone receptor alpha (TRα) were identified. These patients are characterized by growth retardation, variable motor and cognitive defects, macrocephaly and abnormal thyroid function tests. Our objective was to characterize a young girl (18 months) with a mutation in both TRα1 and TRα2, and 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, we studied the consequences of the mutation for TRα1/2 receptor function in vitro.
RESULTS: At 18 months of age, the patient presented with axial hypotonia, delayed motor development, severe growth retardation and abnormally elevated T3/T4 ratios. RTHα was suspected and concomitantly a c.632A>G/p.D211G missense mutation was identified, affecting both the TRα1 and TRα2 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 a decreased transcriptional activity of TRα1, which could be overcome by higher T3 levels in vitro. The mutant TRα1 showed a moderate dominant negative activity on WT TRα1. In contrast, WT TRα2 and mutant TRα2 had negligible transcriptional activity and showed no dominant-negative effect over TRα1.
CONCLUSIONS: This report describes the phenotype of a young RTHα patient with a mild TRα mutation before and during early LT4 treatment. Treatment had beneficial effects on her muscle tone, motor development and growth.

PMID: 26782358 [PubMed - as supplied by publisher]

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