Syndromes of Resistance to Thyroid Hormone

Disorders of cellular uptake, metabolism, or action of thyroid hormones comprise syndromes of resistance to thyroid hormone. Reduced entry of thyroid hormones into the central nervous system via a membrane transporter mediates severe mental and psychomotor retardation associated with peripheral hyperthyroidism. Failure of selenocysteine incorporation into 25 different proteins results in a multisystem, selenoprotein deficiency, disorder associated with abnormal thyroid function due to impaired activity of deiodinase selenoenzymes. Resistance to Thyroid Hormone β‎, due to thyroid hormone β‎ receptor mutations, is characterized by elevated circulating thyroid hormones, impaired feedback inhibition of thyroid-stimulating hormone (TSH) secretion and variable hormone resistance in peripheral tissues. Thyroid hormone receptor α‎ defects cause resistance to thyroid hormone α‎, characterized by features of hypothyroidism in specific tissues but paradoxically associated with near-normal thyroid hormone levels. We describe the genetic basis, clinical features, pathogenesis, and management of these disorders.