Introduction

Multiple endocrine neoplasia Type 2 (MEN-2) is a distinct autosomal dominant inherited tumor syndrome with three recognized clinical subtypes and a common genetic origin from mutation of the RET proto-oncogene. The syndrome was originally identified by Sipple (1961), who reported an association of pheochromocytoma with medullary thyroid carcinoma (MTC). MEN-2A was originally known as Sipple's syndrome – the triad of MTC, pheochromocytoma, and hyperparathyroidism. Wagenmann (1922) and Froboese (1923) initially described the clinical syndrome of mucosal neuromas, and Williams and Pollack (1966) further delineated the MEN-2B phenotype with the description of a syndrome of mucosal neuromas, intestinal ganglioneuromatosis, pheochromocytoma, and MTC.

A great deal has been learned regarding the origins, pathogenesis, and clinical manifestations of the disease since its original descriptions. The isolation of the RET proto-oncogene has revolutionized screening for the disease in affected kindreds as well as the approach to management of the clinical manifestations. The clinical spectrum of MEN-2 is currently defined in the Operational Classification of MEN-2 Disease Phenotype by the International RET Mutation Consortium, summarized in Table 11.1 (Eng et al., 1996). MEN-2A is by far the most common variant, accounting for over 90% of cases of MEN-2. MEN-2B comprises about 5% of cases, and Familial MTC (FMTC) accounts for the remainder (Eng, 1999). Virtually all patients with MEN-2 develop C-cell hyperplasia and/or MTC, and MTC is responsible for a majority of the mortality associated with MEN-2. MEN-2A is also associated with pheochromocytoma in 50% and hyperparathyroidism in 20–30% of patients.