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

Abstract Background: 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. Conclusions: 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.