Han Rulai, Ye Lei, Jiang Xiaohua, Zhou Xiaoyi, Billon Cyrielle, Guan Wenyue, Gauthier Karine, Fang Weiyuan, Wang Weiqing, Samarut Jacques, Ning Guang
Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, 200025, People's Republic of China.
Shanghai Key Laboratory for Endocrine Tumors and Shanghai Clinical Center for Endocrine and Metabolic Diseases, Ruijin Hospital, 197 Ruijin 2nd Road, Shanghai, 200025, People's Republic of China.
Endocrine. 2015 Dec;50(3):689-97. doi: 10.1007/s12020-015-0622-x. Epub 2015 Jun 4.
Resistance to thyroid hormone (RTH) is a rare genetic disease caused by reduced tissue sensitivity to thyroid hormone. The hallmark of RTH is elevated serum levels of thyroid hormone with unsuppressed thyrotropin (TSH). However, the most common form of RTH results from minor defects in the ligand-binding domain or hinge domain of the TRβ gene, resulting in impaired T3-induced transcriptional activity, often showing mild presentation. Early diagnosis can be challenging. The objective of the current study was to characterize this specific group of RTH patients. This was a retrospective study. Patients diagnosed as RTH with TRβ mutations were enrolled in a single institute between 2004 and 2014. A total of 14 patients were diagnosed as RTH with mutation in THβ gene. The median age at diagnosis was 22.5 (IQR: 13.25-32.75). Goiter was the most common clinical finding. TSH was significantly elevated after TRH injection (median peak was 21.83 μIU/l, IQR: 13.59-31.48), 9.2-fold compared to the basal level. We found 10 mutations in TRβ gene, all located in the last four exons, and including one novel mutation, H271D. In vitro study found that H271D mutation reduced TR affinity to T3. Four patients with intact thyroid were diagnosed after 16 years old, defined as late manifestation. Compared to those diagnosed before 10 years old, patients with late manifestation presented with normal growth and mental development. Interestingly, three of them carried R438H mutation. We identified a novel p.H271D mutation in TRβ associated with RTH. Endocrinologists should be alert that RTH is frequently found in euthyroid patients with mild symptoms and often leads to misleading diagnosis as well as inappropriate treatment.
甲状腺激素抵抗（RTH）是一种罕见的遗传性疾病，由组织对甲状腺激素的敏感性降低引起。RTH的标志是血清甲状腺激素水平升高而促甲状腺激素（TSH）未被抑制。然而，最常见的RTH形式是由TRβ基因的配体结合域或铰链域的微小缺陷导致的，从而导致T3诱导的转录活性受损，通常表现为症状较轻。早期诊断可能具有挑战性。本研究的目的是对这一特定组的RTH患者进行特征描述。这是一项回顾性研究。2004年至2014年期间，在一家单一机构中纳入了被诊断为具有TRβ突变的RTH患者。共有14例患者被诊断为具有THβ基因突变的RTH。诊断时的中位年龄为22.5岁（四分位间距：13.25 - 32.75）。甲状腺肿大是最常见的临床表现。注射促甲状腺激素释放激素（TRH）后TSH显著升高（中位峰值为21.83 μIU/l，四分位间距：13.59 - 31.48），是基础水平的9.2倍。我们在TRβ基因中发现了10个突变，均位于最后四个外显子中，包括一个新突变H271D。体外研究发现H271D突变降低了TR对T3的亲和力。4例甲状腺功能正常的患者在16岁后被诊断出来，定义为迟发性表现。与10岁前诊断的患者相比，迟发性表现的患者生长和智力发育正常。有趣的是，其中3例携带R438H突变。我们在TRβ中鉴定出一个与RTH相关的新的p.H271D突变。内分泌学家应警惕，RTH在甲状腺功能正常但症状轻微的患者中经常被发现，并且常常导致误诊以及不恰当的治疗。
