RESISTANCE TO THYROID-HORMONE - AN HISTORICAL OVERVIEW

Resistance to thyroid hormone (RTH) is an inherited syndrome character ized by reduced tissue responsiveness to thyroid hormone. Subjects hav e elevated serum thyroid hormone levels in association with a nonsuppr essed TSH. Goiter and thyroid test abnormalities have most often led t o further investigation, underscoring the paucity of specific clinical manifestations of RTH. Hypothyroidism has been considered when growth or mental retardation was the presenting symptom and thyrotoxicosis w hen dealing with attention deficit or hyperactivity. Failure to recogn ize the inappropriate persistence of TSH secretion, in spite of elevat ed thyroid hormone levels, has commonly resulted in erroneous; diagnos is leading to treatment aimed to normalize the thyroid hormone level. More than 400 subjects with this syndrome have been identified. The mo de of inheritance appears to be autosomal dominant in the majority of families. It has long been suspected that RTH is most likely caused by an abnormal thyroid hormone receptor (TR), but this hypothesis could not be directly tested until the isolation of two TR genes, TR alpha a nd TR beta, located in chromosomes 17 and 3, respectively. TR beta gen e mutations have been recently identified in 68 families with RTH. All mutations are located in the T-3-binding domain, straddling the putat ive TR-dimerization region. Mutant TRs exhibit hormone-binding impairm ent, the degree of which does not correlate with the severity of clini cal manifestations. This finding, and the fact that heterozygous subje cts with complete TR deletion are not affected, while those with point mutations are, indicated that interactions of the mutant TRs with nor mal TRs and with other factors, are responsible for the dominant inher itance of RTH and its clinical heterogeneity. Elucidation of the etiol ogy of RTH has not only provided the means for early diagnosis of the syndrome but added a new dimension to the understanding of the mechani sms of hormone action.