A large family with hereditary MTC: Role of RET genetic analysis in differential diagnosis between MEN 2A and FMTC

Germline mutations of the RET proto-oncogene cause three different cancer syndromes: multiple endocrine neoplasia type ZA (MEN ZA), multiple endocrine neoplasia type 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC), In the absence of biochemical and/or clinical evidence of pheochromocytoma and hyperparathyroidism, patients with MEN ZA disease display the same phenotype of FMTC disease, although prognosis and clinical management in both affected and unaffected familial members are quite different. We studied a family with hereditary MTC, whose proband was referred to us because of enlarged cervical nodes and increased calcitonin serum levels 28 years after the total thyroidectomy for MTC. Cervical node dissection was carried out and subsequently the presence of MTC metastasis was histologically confirmed. A RET genomic mutation at codon 634 (TGC --> TTC) was identified in the proband and in seven out of 19 familial members studied. Accordingly, a hereditary disease was suggested. However, the strong association of RET mutation at codon 634 with the presence of pheochromocytoma in MEN 2 disease suggested a more rigorous management in all gene carriers. Indeed, during the follow-up pheochromocytoma was subsequently identified in the proband. This finding suggests that all families with a pedigree suggestive of FMTC should be regarded at risk from MEN ZA disease, at least when a critical mutation in the RET cysteine domain is detected.