Multiple endocrine neoplasia type 2 (MEN 2) and familial medullary thyroid carcinoma (FMTC) are autosomal dominantly inherited cancer syndromes that predispose to the development of C-cell hyperplasia and MTC. MEN 2A and FMTC are caused by multiple mutations in exons 10, 11, 13, 14 and 15 of the RET proto-oncogene. Associations between phenotype and specific germline RET mutations in exons 10, 11 and 13 have been established. We have studied 2 large FMTC families with a mutation in codon 804 in exon 14 (GTG→ATG; Val804Met) in which some individuals over age 70 had no overt clinical evidence of medullary thyroid carcinoma despite carrying or transmitting this mutation, In addition, some affected individuals with metastatic disease have had a relatively benign course, suggesting that this mutation causes a less aggressive form of MTC. Because of the presence of active MTC, including metastasis, in younger individuals within these families, we have continued to advocate thyroid surgery on the basis of mutation analysis. However, the apparent absence of disease in older individuals caused some of the younger individuals also known to be gene carriers to be reluctant to accept the recommended prophylactic thyroidectomy. Thus, counseling issues remain difficult in families with FMTC for specific mutations, even in a genetic disease usually considered to have a high penetrance, often with expression at much younger ages. These families emphasize the importance of molecular genetic testing in individuals or families with a history of FMTC, since identifying the specific RET mutation significantly influences the decision-making process for the affected individuals.
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Feldman, G., Schuffeneeker, I., Lenoir, G. et al. Variable expressivity of Familial Medullary Thyroid Carcinoma (FMTC) due to a RET V804M (GTGG→ATG) mutation in two families: Reluctance of gene carriers to accept prophylactic thyroidectomy. Genet Med 1, 45 (1999). https://doi.org/10.1097/00125817-199901000-00023