Multiple endocrine neoplasia type 1 is caused by a mutation in the MEN1 gene (chromosome 11q13; prevalence 1:30,000), which encodes the tumor suppresssor protein menin. A mutation in this gene prevents the tumor suppressor protein from being produced correctly. The most common manifestations of this disease are pancreatic neuroendocrine tumors, primary hyperparathyroidism (tumors of the parathyroid glands) and pituitary adenomas (3 “P”: pancreas, parathyroid, pituitary). Neuroendocrine tumors of the lungs, thymus (carcinoid), tumors of the thyroid, adrenal gland or lipomas occur less frequently but are also associated with MEN1.

Multiple endocrine neoplasia type 2 is caused by a mutation in the RET proto-oncogene (chromosome 10q11.2; prevalence 1:35,000). The most common manifestation is medullary thyroid carcinoma (MTC), which arises from the calcitonin-producing C-cell in the thyroid gland. Calcitonin is an excellent tumor marker that can be determined in the blood and its level correlates excellently with the extent of disease. Mutations in the RET proto-oncogene also lead to the development of tumors that produce stress hormones (catecholamines). These can occur in the adrenal glands (pheochromocytoma) or extraadrenally (paraganglioma). The coincidence of MTC with stress hormone-producing tumors makes it necessary to clarify the stress hormone profile of every patient with elevated calcitonin before thyroid surgery is performed, because (unrecognized) elevated stress hormones represent an anesthesiological risk that may be difficult to control.

MEN2 is divided into a subgroup of mutations in which MTC is the only manifestation, this is referred to as familial MTC (fMTC), into the group MEN2A (also referred to as actual MEN2), which manifests as a triad of MTC, catecholamine producing tumors and primary hyperparathyroidism, as well as MEN2B (also MEN3), in which patients show a Marfanoid habitus and it is also frequently correlated with aganglionosis of the intestine (Hirschsprung’s disease).

MEN4 is caused by a mutation in a cell cycle protein, CDKN1b, is extremely rare and has a similar clinical presentation to MEN1.

Von Hippel-Lindau syndrome is caused by a mutation in the VHL tumor suppressor gene. The most common clinical manifestations are catecholamine-producing tumors of the adrenal gland, renal cell carcinomas and neuroendocrine tumors of the pancreas.

NF1 or Recklinghausen’s disease is caused by a mutation in the protein neurofibromin. Typical (sub)cutaneous changes (cafe-au-lait spots, neurofibromas) usually lead to the diagnosis. The variety of clinical manifestations ranges from tumors of the central nervous system to neuroendocrine tumors of the pancreas and catecholamine-producing tumors.

The succinate dehydrogenase complex consists of 4 enzymes that are responsible for mitochondrial energy production. Mutations have been described in each of the 4 subunits A-D and lead to the formation of catecholamine-producing tumors.