Familial multiple endocrine neoplasia: the first 100 years

In 1903, Erdheim described the case of an acromegalic patient with a pituitary adenoma and three enlarged parathyroid glands. Fifty years later, Underdahl et al reported 8 patients with a syndrome of pituitary, parathyroid, and pancreatic islet adenomas. In 1954, Wermer found that the syndrome was transmitted as a dominant trait. In 1959, Hazard et al described medullary (solid) thyroid carcinoma (MTC), a tumor that later was found to be a component of two endocrine syndromes. The first of these described by Sipple in 1961 comprised pheochromocytoma, MTC, and parathyroid adenoma. The second, described by Williams et al in 1966, was the combination of mucosal neuromas, pheochromocytoma, and MTC. In 1968, Steiner et al introduced the term "multiple endocrine neoplasia" (MEN) to describe disorders featuring combinations of endocrine tumors; they designated the Wermer syndrome as MEN 1 and the Sipple syndrome as MEN 2. In 1974, Sizemore et al concluded that the MEN 2 category included two groups of patients with MTC and pheochromocytoma: one with parathyroid disease and a normal appearance (MEN 2A) and the other without parathyroid disease but with mucosal neuromas and mesodermal abnormalities (MEN 2B). Later, additional nonendocrine conditions (von Recklinghausen neurofibromatosis and von Hippel-Lindau disease) were found accompanying other more recently described familial MEN syndromes, indicating that these diseases are very complicated disorders.