Resistance to thyroid hormone.
Resistance to thyroid hormone.
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DOI：
10.1023/a:1010072605757
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发表时间：
2000-01-01
影响因子：
8.2
通讯作者：
Refetoff, S
中科院分区：
文献类型：
--
作者：
Weiss, R E;Refetoff, S
甲状腺激素抵抗（RTH）是一种组织对甲状腺激素反应性降低的遗传综合征。第一例患者由Refetoff、DeWind和DeGroot于1967年报告[1]。1964年，Loren T. DeWind被咨询来评估一个6岁的聋哑女孩，她有斑点状骨骺。后一个发现是偶然的放射学检查进行，以排除骨折后，被击中的卡车，她没有听到未来。耳聋、所有主要骨化中心的点画和体格检查发现的小甲状腺肿相结合，提示先天性甲状腺功能减退症是由于先天性缺陷所致，因为一个哥哥也有类似的发现。然而，血清蛋白结合碘（PBI）测定的结果，然后估计甲状腺激素含量的常规测试，是最令人惊讶的。尽管存在明显的临床正常代谢状态，但发现了一个高值而不是低值。为了进行进一步的研究，德温特得到了塞缪尔·雷费托夫（Samuel Refetoff）的帮助。雷费托夫是洛杉矶好撒玛利亚医院的住院医生，刚从蒙特利尔来到这里，在那里他与著名的甲状腺组织学家CP Leblond一起工作。DeWind和Refetoff发现，这些儿童代谢正常，没有任何先前已知的甲状腺激素合成或运输缺陷。一个新生的兄弟姐妹和其他六个孩子中的两个孩子表现出相同的发现，这些孩子的父母是堂兄弟姐妹。Refetoff离开去波士顿继续他的训练，在那里他寻求莱斯利·德格鲁特的帮助。后者促使对碘的周转进行研究，这些研究与以前在洛杉矶进行的研究一起表明"抑制甲状腺激素转运到组织或器官对碘的抵抗“。1966年在马萨诸塞州理工学院的临床研究中心和1969年在芝加哥大学继续进行研究。数据排除了组织转运缺陷，确定了循环甲状腺激素的真实性，并通过组织对大剂量甲状腺激素及其类似物给药的反应性降低证实了激素抵抗[2]。在首次报告之后，六年过去了，直到另一个RTH病例发表[3]。到1980年，又有来自5个家庭的18人被报告患有RTH。这与迄今为止报告的300多个家庭RTH形成对比[4]。激素抵抗的概念在30年前由Fuller Albright等人提出。[5]假性甲状旁腺功能减退症的描述在RTH的情况下，很难确定激素抵抗的确切原因，直到1986年Weinberger等人克隆了甲状腺激素受体（TR）β基因。这使得在贝塞斯达国立卫生研究院布鲁斯温特劳布实验室工作的斯蒂芬·乌萨拉能够证明RTH表型与3号染色体上的TRH基因之间的联系[6]。1989年，在芝加哥大学，Refetoff和DeGroot离开波士顿后搬到了那里，在另一个RTH家族中发现了第一个RTH突变[7]。1992年，Refetoff的研究小组报告称，来自洛杉矶的索引家族中RTH的病因是由于TRâ基因的纯合缺失[8]。这些观察结果对我们理解RTH的发病机制和甲状腺激素作用的分子基础至关重要。
Resistance to thyroid hormone (RTH) is an inherited syndrome of reduced tissue responsiveness to thyroid hormone. The first patient was reported by Refetoff, DeWind and DeGroot in 1967 [1]. In 1964, Dr. Loren T. DeWind was consulted to evaluate a 6 year deaf-mute girl with stippled epiphyses. The latter finding was incidental to a radiological survey performed to rule out bone fractures after being hit by a truck which she did not hear coming. The combination of deafness, stippling of all major ossification centers, and the finding of a small goiter on physical examination suggested congenital hypothyroidism due to an inborn error in view of a similar finding in an older brother. However, results of serum protein bound iodine (PBI) determination, then the routine test for estimating thyroid hormone content, was most surprising. A high rather than a low value was found, despite the apparent clinical eumetabolic state. To carry out further studies, DeWind obtained assistance from Samuel Refetoff, a resident at the Good Samaritan Hospital in Los Angeles, who had just arrived from Montreal where he worked with the renowned thyroid histologist, CP Leblond. DeWind and Refetoff found that the children were eumetabolic and did not have any of the previously known defects of thyroid hormone synthesis or transport. A newborn sib exhibited the same finding as the other two out of six children born to parents that were cousins once removed. Refetoff left to continue his training in Boston where he solicited the help of Leslie DeGroot. The latter instigated studies of iodine turnover which together with those carried out previously in Los Angeles suggested an``inhibition of thyroid hormone transport into tissues or an organ resistance to the hormone''. Studies continued at the clinical research centers of Massachusetts Institute of Technology in 1966 and at the University of Chicago in 1969. Data excluded a tissue transport defect, established the authenticity of the circulating thyroid hormone and confirmed the hormonal resistance by the reduced tissue responsiveness to the administration of large doses of thyroid hormone and its analogues [2]. After the initial report, six years had elapsed until the publication of another RTH case [3]. By 1980 an additional 18 individuals belonging to five families had been reported to have RTH. This contrasts to over 300 families RTH that have reported to date [4]. The concept of hormone resistance was introduced 30 years earlier by Fuller Albright et al.[5] with the description of pseudohypoparathyroidism. In the case of RTH, it was difficult to establish the precise cause of the hormonal resistance, until the cloning of the thyroid hormone receptor (TR) û gene by Weinberger et al. in 1986. This allowed Stephen Usala, working in the laboratory of Bruce Weintraub at the National Institutes of Health in Bethesda, to demonstrate a link between the phenotype of RTH and the TRû gene on chromosome 3 [6]. It was in 1989 at the University of Chicago, where Refetoff and DeGroot had moved after leaving Boston, that the first mutation in the TRû was indentified in another family with RTH [7]. In 1992, Refetoff's group reported that the etiology of RTH in the index family from Los Angeles, was due to a homozygous deletion of the TRû gene [8]. These observations have been pivotal in our understanding of the pathogenesis of RTH and the molecular basis of thyroid hormone action.