Long-term Clinicopathological Features of a Family with Multiple Endocrine Neoplasia Type 2A Caused by C634R RET Gene Mutation

Type 2 multiple endocrine neoplasia (MEN2A) is a variant of hereditary medullary thyroid carcinoma (MTC). MEN2A is characterized by the presence of the following: MTC, hyperparathyroidism, and pheochromocytoma (PHEO). The pathogenesis includes RET proto-oncogene mutation; the most frequently observed mutation is in exon 11 codon 634. We report pedigree of a large Indian family involving three generations including 21 members with MEN2A, in whom RET mutation status was determined. We then analyzed their clinical follow-up details, with a median duration of follow-up of 60 months (range: 9–276 months). Calcitonin (Ctn) levels were routinely checked during the follow-up. The index case was found to carry p.C634R mutation involving exon 11 of the RET gene. RET mutation was positive in 12 members in the family (12/21, i.e., 57%), was negative in 7 patients, and was not tested in 2 patients, as they were not available for the genetic test. Thirteen were clinically affected with MTC and 10 members had PHEO. At the last follow-up, the median Ctn level was 14.3 pg/mL (range: 2–12655 pg/mL). Four patients developed lymph nodal recurrence during follow-up, for which they underwent re-operations with median duration to recurrence being 48 months (range: 9–156 months). We highlight in this article that early diagnosis, adequate surgery, and appropriate genetic counseling with genetic screening are essential to improve the outcome of persons with MTC. Every case of MTC should be seen as familial or index case of hereditary MTC unless otherwise RET mutation excludes it.