Narumi Satoshi, Hasegawa Tomonobu
Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
Endocr J. 2015;62(5):393-8. doi: 10.1507/endocrj.EJ15-0131. Epub 2015 Mar 21.
Genetic defects of hormone receptors are the most common form of end-organ hormone resistance. One example of such defects is TSH resistance, which is caused by biallelic inactivating mutations in the TSH receptor gene (TSHR). TSH, a master regulator of thyroid functions, affects virtually all cellular processes involving thyroid hormone production, including thyroidal iodine uptake, thyroglobulin iodination, reuptake of iodinated thyroglobulin and thyroid cell growth. Resistance to TSH results in defective thyroid hormone production from the neonatal period, namely congenital hypothyroidism. Classically, clinical phenotypes of TSH resistance due to inactivating TSHR mutations were thought to vary depending on the residual mutant receptor activity. Nonfunctional mutations in the two alleles produce severe thyroid hypoplasia with overt hypothyroidism (uncompensated TSH resistance), while hypomorphic mutations in at least one allele produce normal-sized thyroid gland with preserved hormone-producing capacity (compensated TSH resistance). More recently, a new subgroup of TSH resistance (nonclassic TSH resistance) that is characterized by paradoxically high thyroidal iodine uptake has been reported. In this article, the pathophysiology and clinical features of TSH resistance due to inactivating TSHR mutations are reviewed, with particular attention to the nonclassic form.
激素受体的基因缺陷是终末器官激素抵抗最常见的形式。此类缺陷的一个例子是促甲状腺激素（TSH）抵抗，它由TSH受体基因（TSHR）的双等位基因失活突变引起。TSH是甲状腺功能的主要调节因子，几乎影响涉及甲状腺激素产生的所有细胞过程，包括甲状腺碘摄取、甲状腺球蛋白碘化、碘化甲状腺球蛋白的再摄取以及甲状腺细胞生长。对TSH的抵抗导致新生儿期甲状腺激素产生缺陷，即先天性甲状腺功能减退。传统上，由于TSHR失活突变导致的TSH抵抗的临床表型被认为取决于残余突变受体的活性。两个等位基因中的无功能突变会导致严重的甲状腺发育不全并伴有明显的甲状腺功能减退（未代偿性TSH抵抗），而至少一个等位基因中的亚效突变会导致甲状腺大小正常且具有保留的激素产生能力（代偿性TSH抵抗）。最近，已报道了一种新的TSH抵抗亚组（非经典TSH抵抗），其特征是甲状腺碘摄取异常高。在本文中，将对由于TSHR失活突变导致的TSH抵抗的病理生理学和临床特征进行综述，尤其关注非经典形式。
