RESISTANCE TO THYROID-HORMONE

Resistance to thyroid hormone (RTH) is usually dominantly inherited an d is characterized by elevated free thyroid hormones in the serum and failure to suppress pituitary thyroid stimulating hormone (TSH) secret ion with variable refractoriness to hormone action in peripheral tissu es. Two major forms of the disorder are recognized: asymptomatic indiv iduals with generalized resistance (GRTH) and patients with thyrotoxic features, suggesting predominant pituitary resistance (PRTH). Molecul ar genetic analyses indicate that both GRTH and PRTH are associated wi th diverse mutations in the thyroid hormone receptor beta gene, which localize to three regions in the hormone binding domain of the recepto r. In addition to being functionally impaired, the mutant receptors ar e also able to inhibit their wild-type counterparts in a dominant nega tive manner. Recognized features of RTH include failure to thrive, gro wth retardation and attention-deficit hyperactivity disorder in childh ood, and goitre and thyrotoxic cardiac symptoms in adults. The pathoge nesis of variable tissue resistance is not fully understood but may be related to the differing tissue distributions of a and b thyroid horm one receptors and variable dominant negative activity of mutant recept ors on different target genes.