Update on the MEN 2A c804 RET mutation: is prophylactic thyroidectomy indicated?

BACKGROUND: Mutations of the RET proto-oncogene co-segregate with multiple endocrine neoplasia type 2A. A rare sequence abnormality at codon 804 (c804) has been reported in 6 kindreds and linked to mild C-cell disease, which raises the question of the appropriateness of thyroidectomy in childhood. The purpose of this study was to (1) report the clinical correlates of 5 additional c804 kindreds, and (2) clarify therapeutic options in children.
METHODS: Thirty-eight members from five c804 kindreds underwent genetic analysis. Biochemical, operative, and pathology reports were reviewed.
RESULTS: Twenty-three gene carriers were identified, of whom 14 had thyroidectomy. Medullary thyroid carcinoma was found in 7 patients (aged 5-56 years), C-cell hyperplasia in 6 patients (aged 13-40 years), and normal histology in a single patient (aged 27 years). One patient with medullary thyroid carcinoma died of metastases (aged 12 years). Nine of the 23 gene carriers delayed operation, 4 of whom had calcitonin testing. Three of the 4 patients had abnormal calcitonin levels and a single patient was negative (aged 40 years). Of the remaining 9 patients, 2 await thyroidectomy, and 3 have refused evaluation.
CONCLUSIONS: Penetrance of the c804 mutation is highly variable. Medullary thyroid carcinoma associated with this genotype has aggressive potential. Prophylactic thyroidectomy in childhood is a viable approach.