Fumarate hydratase is a novel gene for familial non-medullary thyroid cancer

J Clin Endocrinol Metab. 2022 Jun 25;dgac386. doi: 10.1210/clinem/dgac386. Online ahead of print.


Context: the majority of cases of epithelial cell-derived thyroid cancer are sporadic. Familial non-medullary thyroid cancer (FNMTC) occurs in about 5-9% 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 gene (FH). In addition to extensive uterine and skin leiomyomas and renal cell cancer (RCC), other tumors may arise in this syndrome. However, thyroid cancer has never been described as part of HLRCC. Here, we describe a young woman who presented with an aggressive poorly differentiated thyroid cancer (PDTC) and was found to have HLRCC syndrome due to a novel heterozygous germline FH mutation.

Results: A 44-year-old lady 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.

Conclusion: 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.

Keywords: Fumarate hydratase; Leiomyoma; familial thyroid cancer; mutation; thyroid cancer.