Department of Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh 11211, Saudi Arabia.
Department of Molecular Oncology, King Faisal Specialist Hospital & Research Centre, Riyadh 11211, Saudi Arabia.
J Clin Endocrinol Metab. 2022 Aug 18;107(9):2539-2544. doi: 10.1210/clinem/dgac386.
The majority of cases of epithelial cell-derived thyroid cancer are sporadic. Familial non-medullary thyroid cancer (FNMTC) occurs in about 5% to 9% of cases, either as a part of known syndromes such as Cowden syndrome or in the form of familial clustering of 2 or more affected family members. Hereditary leiomyoma and renal cell cancer (HLRCC) syndrome is a rare familial cancer syndrome. The underlying etiology is heterozygous germline mutations of the fumarate hydratase (FH) gene. In addition to extensive uterine and skin leiomyomas and RCC, other tumors may arise in this syndrome. However, thyroid cancer has never been described as part of HLRCC. Here, we describe a woman who presented with an aggressive poorly differentiated thyroid cancer (PDTC) and was found to have HLRCC syndrome because of a novel heterozygous germline FH mutation.
A 43-year-old woman presented with a large lower neck mass that was found to be PDTC. During her evaluation, she was found to have extensive uterine leiomyomatosis and bilateral adrenal nodules. Whole exome and subsequent Sanger sequencing of leucocyte DNA revealed a novel monoallelic nonsense FH mutation (c.760C>T, p.Q254*). Sequencing of the thyroid tumor tissue showed a biallelic loss at the same mutation site (loss of heterozygosity) and immunohistochemistry of the PDTC showed loss of FH staining in the tumor tissue, indicating the pathogenic role of this mutation in the development of PDTC in this patient.
Thyroid cancer is a novel feature of the FH-related HLRCC syndrome. This syndrome can be added to the rare genetic causes of syndromic FNMTC.
大多数上皮细胞来源的甲状腺癌是散发性的。家族性非髓样甲状腺癌（FNMTC）在约 5%至 9%的病例中发生，要么作为已知综合征的一部分，如 Cowden 综合征，要么以 2 个或更多受影响家庭成员的家族聚集形式出现。遗传性平滑肌瘤和肾细胞癌（HLRCC）综合征是一种罕见的家族性癌症综合征。其潜在病因是延胡索酸水合酶（FH）基因的杂合胚系突变。除了广泛的子宫和皮肤平滑肌瘤和 RCC 外，该综合征还可能出现其他肿瘤。然而，甲状腺癌从未被描述为 HLRCC 的一部分。在这里，我们描述了一位患有侵袭性低分化甲状腺癌（PDTC）的女性，由于新的杂合胚系 FH 突变，被发现患有 HLRCC 综合征。
一名 43 岁女性因大的下颈部肿块就诊，被诊断为 PDTC。在她的评估过程中，发现她患有广泛的子宫平滑肌瘤和双侧肾上腺结节。白细胞 DNA 的全外显子组和随后的 Sanger 测序显示了一种新的单等位基因无义 FH 突变（c.760C>T，p.Q254*）。甲状腺肿瘤组织的测序显示在同一突变位点存在双等位基因缺失（杂合性丢失），PDTC 的免疫组织化学显示肿瘤组织中 FH 染色缺失，表明该突变在该患者 PDTC 的发生中起致病作用。
甲状腺癌是 FH 相关 HLRCC 综合征的一个新特征。该综合征可作为综合征性 FNMTC 的罕见遗传原因之一被添加。
