Resistance to Thyroid Hormone Alpha: Clinical Spectrum, Diagnostic Clues, and Therapeutic Strategies - A Narrative Review.

Resistance to thyroid hormone alpha (RTHα) is a rare, inherited disorder of thyroid hormone action caused by pathogenic variants in the thyroid hormone receptor alpha gene. Unlike resistance to thyroid hormone beta, RTHα typically presents with near-normal thyroid function tests and a non-elevated thyroid-stimulating hormone (TSH), contributing to substantial underdiagnosis. The biochemical hallmark is a low or low-normal free thyroxine (FT4) level with a disproportionately high free triiodothyronine (FT3) level, yielding a reduced FT4:FT3 ratio and often a low or low-normal reverse T3. Clinical features reflect the tissue distribution of TRα1 and include growth retardation, delayed skeletal maturation, constipation, normocytic anemia, neurodevelopmental delay, dyspraxia, and macrocephaly. These closely mimic primary hypothyroidism but occur without TSH elevation. Most pathogenic THRA variants are heterozygous and act through a dominant-negative mechanism, whereby mutant receptors interfere with co-expressed wild-type TRα activity. Frameshift and nonsense variants generally produce more severe phenotypes than missense variants, though considerable variability exists even among individuals carrying identical mutations. Levothyroxine remains the only therapeutic intervention reported, with evidence suggesting that earlier treatment initiation is associated with better neurodevelopmental and growth outcomes, while established skeletal abnormalities show limited reversibility. Standard newborn screening programs typically fail to detect RTHα, contributing to diagnostic delay. This narrative review consolidates current knowledge on the genetic basis, molecular pathophysiology, clinical spectrum, differential diagnosis, and treatment outcomes of RTHα. Its aim is to enhance clinician recognition and guide future research, including expanded screening strategies and genotype-informed treatments.