CLINICAL SCREENING AS COMPARED WITH DNA ANALYSIS IN FAMILIES WITH MULTIPLE ENDOCRINE NEOPLASIA TYPE 2A

Background. Multiple endocrine neoplasia type 2A (MEN-2A) is character ized by medullary thyroid carcinoma in combination with pheochromocyto ma and sometimes parathyroid adenoma. Missense mutations in the RET pr oto-oncogene are associated with MEN-2A. Their detection by DNA analys is allows the identification of carriers of the gene, in whom the risk of medullary thyroid carcinoma is 100 percent. We compared the reliab ility of biochemical tests with that of DNA analysis in identifying ca rriers of the MEN2A gene. Methods. Starting in 1975, we screened 300 s ubjects in four large families with MEN-2A for expression of the disea se, using measurements of plasma calcitonin after stimulation with pen tagastrin or calcium and urinary excretion of catecholamines and catec holamine metabolites. We tested for carrier status by DNA analysis, in cluding linkage analysis, and more recently by analysis of mutations i n the RET gene. Results. Of 80 MEN2A gene carriers (in 61 of whom carr ier status was proved by DNA analysis), 66 had abnormal plasma calcito nin values and medullary thyroid carcinoma. Fourteen young carriers ha d normal results of plasma calcitonin tests. In 8 of these 14, thyroid ectomy revealed small foci of medullary thyroid carcinoma; the remaini ng 6 have not yet been operated on. Of the other 220 family members, 6 8 were found by DNA analysis not to carry the MEN2A gene. None of thes e 68 subjects had medullary thyroid carcinoma or pheochromocytoma; 6 h ad elevated plasma calcitonin concentrations and underwent thyroidecto my but had only C-cell hyperplasia. Conclusions. Unlike biochemical te sts, DNA analysis permits the unambiguous identification of MEN2A gene carriers.