Resistance to thyroid hormone is a manifestation of thyroid hormone receptor defects

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Updated version of a contribution by the same author to Clinics in Laboratory Medicine Philadelphia: W. B. Saunders Co.; 1993; with permission.

Generalized resistance to thyroid hormone (GRTH) is an inherited syndrome characterized by hyposensitivity of target tissues to thyroid hormone. The clinical presentation is variable. The syndrome is usually suspected when elevated serum thyroid hormone levels are associated with a nonsuppressed serum thyrotropin (TSH). Whereas goiter and thyroid test abnormalities more often have led to the suspicion of thyroid gland dysfunction, short stature, hyperactivity, learning disability, and goiter in children or adolescents and recalcitrant goiter in adults should raise the suspicion of GRTH. Hypothyroidism has been considered when growth or mental retardation was the presenting symptom, and thyrotoxicosis, when confronted with attention deficit, hyperactivity. or tachycardia. Failure to recognize the inappropriate persistence of TSH secretion in spite of elevated thyroid hormone levels has commonly resulted in erroneous diagnosis leading to antithyroid treatment. More than 300 subjects with this syndrome have been identified. The mode of inheritance in the majority of families is autosomal dominant. Recessive transmission has been found in only one family. It has long been speculated that this defect is likely caused by an abnormal thyroid hormone receptor (TR), but this hypothesis could not be directly tested until the isolation of two TR genes, TRα and TRβ. Mutations in the TRβ gene have been identified in 42 families with GRTH. All are located in the triiodothyronine-binding domain straddling the putative dimerization region and exhibit various degrees of hormone-binding impairment. This finding and the fact that heterozygous subjects with complete TR deletion are not affected, whereas those with point mutations are, indicates that interactions of a mutant TR with normal TRs and with other factors are responsible for the dominant inheritance of GRTH and its heterogeneity. Elucidation of the etiology of GRTH not only has added a new means for the early diagnosis of the syndrome but also has provided new insights in the understanding of the mechanism of hormone action.

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