Resistance to Thyroid Hormone due to Heterozygous Mutations in Thyroid Hormone Receptor Alpha

Thyroid hormone (TH) acts via nuclear thyroid hormone receptors (TRs). TR isoforms (TRα1, TRα2, TRβ1, TRβ2) are encoded by distinct genes (THRA and THRB) and show differing tissue distributions. Patients with mutations in THRB, exhibiting resistance within the hypothalamic-pituitary-thyroid axis with elevated TH and nonsuppressed thyroid-stimulating hormone (TSH) levels, were first described decades ago. In 2012, the first patients with mutations in THRA were identified. Scope of this review: This review describes the clinical and biochemical characteristics of patients with resistance to thyroid hormone alpha (RTHα) due to heterozygous mutations in THRA. The genetic basis and molecular pathogenesis of the disorder together with effects of levothyroxine treatment are discussed.

The severity of the clinical phenotype of RTHα patients seems to be associated with the location and type of mutation in THRA. The most frequent abnormalities observed include anemia, constipation, and growth and developmental delay. In addition, serum (F)T3 levels can be high-normal to high, (F)T4 and rT3 levels normal to low, while TSH is normal or mildly raised. Despite heterogeneous consequences of mutations in THRA, RTHα should be suspected in subjects with even mild clinical features of hypothyroidism together with high/high-normal (F)T3, low/low-normal (F)T4, and normal TSH.