Genetic testing for RET germline mutations affords rapid identification of germline carriers, offering the prospect of cure before C-cell hyperplasia (CCH) has progressed to medullary thyroid carcinoma (MTC). Although nonindex RET mutation carriers have a better prognosis than do the index patients, it remains to be ascertained whether age represents a risk factor for MTC when screening patients. The current institutional study (October 1994 through June 1999) was set up to compare asymptomatic nonindex patients who were grouped by age: < 20 years and > or = 20 years. Inclusion criteria were confirmed RET mutations in the germline, with no MTC being more advanced than pT1pN1M0. Adult patients (> or = 20 years) had MTC significantly more often (84% vs. 43%), significantly larger tumors (5 mm vs. 3 mm), and significantly higher basal calcitonin levels preoperatively (78.0 vs. 9.7 pg/ml) than their pediatric/adolescent counterparts (< 20 years). There was a close correlation between pT1 MTC and an elevated basal serum calcitonin level (r = 0.67; Spearman's rho). All three patients with lymph node metastases from MTC had elevated basal calcitonin levels. The two groups did not differ in terms of multifocality of MTC (pT1b), lymph node involvement (pN1) or bilateral lymph node metastasis (pN1b), or preoperative stimulated and postoperative basal and stimulated serum calcitonin. Prophylactic thyroidectomy should not be postponed beyond the age of 20, and it should be performed before basal serum calcitonin has turned positive. Pathologic conversion of stimulated serum calcitonin obviously marks the time in carriers of RET germline mutations when surgery should be scheduled at the latest to be prophylactic.