Thyroid hormone resistance syndromes: Emerging insights and clinical implications

Thyroid hormone resistance syndromes (RTH) represent rare disorders characterized by reduced tissue responsiveness to circulating thyroid hormones, leading to variable biochemical and clinical manifestations. Despite elevated serum thyroid hormone levels, affected patients often display nonsuppressed thyroid-stimulating hormone (TSH) concentrations, posing diagnostic and therapeutic challenges. This review summarizes the current understanding of the molecular mechanisms, clinical phenotypes, diagnostic strategies, and management approaches in thyroid hormone resistance syndromes, with emphasis on recent genetic and translational advances. RTH is primarily caused by mutations in the thyroid hormone receptor β ( THRB ) gene, though emerging evidence implicates α-isoform defects and postreceptor signaling pathways. Clinical manifestations vary from asymptomatic to overlapping hypo- and hyperthyroid features. Diagnosis requires careful integration of biochemical, genetic, and imaging findings to distinguish RTH from conditions such as TSH-secreting pituitary adenoma or assay interference. Treatment remains individualized, ranging from observation to selective thyromimetic or antithyroid therapy depending on tissue sensitivity patterns.