Refetoff S
Department of Medicine, University of Chicago, Illinois 60637-1470.
Acta Paediatr Jpn. 1994 Feb;36(1):1-15. doi: 10.1111/j.1442-200x.1994.tb03121.x.
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 non-suppressed thyroid-stimulating hormone (TSH). While goiter and thyroid test abnormalities have more often 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 to be 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 and TR beta. Mutations in the TR beta gene have been identified in 42 families with GRTH. All are located in the T3-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 while those with point mutations are, indicates that interactions of a mutant TR with normal TR and with other factors are responsible for the dominant inheritance of GRTH and its heterogeneity. Elucidation of the etiology of GRTH has not only added a new means for the early diagnosis of the syndrome but provided new insights in the understanding of the mechanism of hormone action.
全身性甲状腺激素抵抗（GRTH）是一种遗传性综合征，其特征为靶组织对甲状腺激素反应低下。临床表现多样。当血清甲状腺激素水平升高而促甲状腺激素（TSH）未被抑制时，通常会怀疑患有该综合征。虽然甲状腺肿大和甲状腺检查异常常常导致怀疑甲状腺功能障碍，但儿童或青少年身材矮小、多动、学习障碍以及甲状腺肿大，还有成人难治性甲状腺肿大，都应引起对GRTH的怀疑。当以生长或智力发育迟缓为主要症状时，曾被认为是甲状腺功能减退；当出现注意力缺陷、多动或心动过速时，则被认为是甲状腺毒症。尽管甲状腺激素水平升高，但未能认识到TSH分泌持续异常，通常会导致错误诊断并进行抗甲状腺治疗。现已确定300多名患有该综合征的患者。大多数家族的遗传方式为常染色体显性遗传。仅在一个家族中发现了隐性遗传。长期以来一直推测，这种缺陷可能是由异常的甲状腺激素受体（TR）引起的，但在分离出两个TR基因（TRα和TRβ）之前，这一假设无法得到直接验证。在42个GRTH家族中已鉴定出TRβ基因突变。所有突变均位于跨越假定二聚化区域的T3结合域，并且表现出不同程度的激素结合受损。这一发现，以及完全缺失TR的杂合子个体未受影响而存在点突变的个体受影响这一事实，表明突变的TR与正常TR以及其他因子之间的相互作用是GRTH显性遗传及其异质性的原因。GRTH病因的阐明不仅为该综合征的早期诊断增添了新方法，还为理解激素作用机制提供了新的见解。
