'They have ears but do not hear' (Psalms 135:17): non-thyroid hormone receptor beta (non-TRbeta) resistance to thyroid hormone.

摘要

Although the fiest report of resistance to thyroid hormone (RTH) appeared in 1967 (1), and the etiology-was shown to be abnormal nuclear binding of thyroid hormone (TH) (2), it was not until after the discovery of the TH receptor beta (TRbeta) (3,4) that cases of RTH were reported to have a mutation in the TRbeta gene (5,6). Prior to the availability of molecular diagnosis, RTH was diagnosed on clinical criteria as a "syndrome" of reduced end-organ responsiveness to TH characterized by goiter, elevated TH level, and nonsuppressed thyroid-stimulating hormone (TSH) level in the blood. The identification of a mutant receptor made things simple: an abnormal receptor with abnormal binding of TH led to an abnormal response to TH and ergo, the clinical syndrome of RTH. Variations in the clinical characteristics of the syndrome were thought to be related to the relative degree of tissue-specific expression of the mutant receptor and/or the impairment of TH binding to the TR and/or the degree of dominant negative interaction of the mutant receptor with the wild-type receptor in these individuals, most of whom were heterozygous for the mutant TRbeta gene. Today, TRbeta gene defects have been identified in 344 families comprising 124 distinct mutations, usually with an autosomal dominant mode of inheritance. However, as more RTH subjects were reported, it became apparent that kindreds with the same TRbeta mutation had different pheno-types with respect to their psychological profiles, or growth velocities, or to the degree of abnormality in their thyroid function tests. The impression among most investigators was that factors other than mutations of TRbeta were responsible for some of the variation in the clinical of presentation RTH (7).