First reported in 1963 by Paul Wermer, multiple endocrine neoplasia (MEN) syndromes consist of rare, autosomal dominant mutations in genes that regulate cell growth. Current classification recognizes type 1 MEN and type 2 MEN, with subcategories type 2A MEN (Sipple syndrome) and type 2B MEN. The menin protein produced from the MENIN gene is a tumor suppressor. Loss of this protein allows tumors to arise. Alternatively, Ret protein produced from the RET gene, a proto-oncogene, can be constitutively activated, causing abnormal cell proliferation.

Type 1 MEN is defined by hyperfunctioning tumors in all 4 parathyroid glands, pancreatic islets (eg, gastrinoma, insulinoma, glucagonoma, vasoactive intestinal peptide tumor [VIPoma], pancreatic polypeptide–producing tumor [PPoma]), and the anterior pituitary (eg, prolactinoma, somatotropinoma, corticotropinoma, nonfunctioning tumors). Other associated tumors include lipomas, angiofibromas, or those located in the adrenal gland cortex (rarely, in the adrenal medulla).

Type 2A MEN is defined by medullary thyroid carcinoma (MTC), pheochromocytoma (about 50% of cases), and hyperparathyroidism caused by parathyroid gland hyperplasia (about 20% of cases).
Familial MTC is also recognized. Familial MTC is hereditary MTC without other associated endocrinopathies, although adrenomedullary hyperplasia secondary to a germline RET mutation may still be present but undiagnosed.

Type 2B MEN is defined by medullary thyroid cancer and pheochromocytoma. Associated abnormalities include mucosal neuromas, medullated corneal nerve fibers, and marfanoid habitus.
Pathophysiology.

The MENIN gene responsible for type 1 MEN is located on chromosome 11 and produces a tumor suppressor protein called menin. The MENIN gene is ubiquitously expressed and is localized to the nucleus of cells. The former term “amine precursor uptake and decarboxylation (APUD) system” is obsolete. Neuroendocrine tumors can derive from various tissues, including the so-called APUD cells, but also arise from pluripotent stem cells of the respective tissue (eg, pituitary tissue). Patients with type 1 MEN possess a germline mutation in the MENIN gene and develop tumors when inactivation of the wild-type allele occurs.

Most tumors arise in the pituitary gland and pancreatic islet cells and most cases of hyperparathyroidism are sporadic. Only a few cases are related to type 1 MEN.

The gene responsible for type 2 MEN is a proto-oncogene called RET. In contrast to MENIN of type 1 MEN, RET is specifically expressed in neural crest–derived cells, such as the C cells in the thyroid gland and the chromaffin cells in the adrenal gland. Whether RET is also expressed in the parathyroid glands remains unknown, especially considering the low rate of hyperparathyroidism in patients with type 2A MEN and the lack of hyperparathyroidism in type