Multiple Endocrine Neoplasia

Multiple endocrine neoplasia is a group of rare but potentially lethal disorders. MEN comprises a set of inherited disorders with tumors or excessive growth in two or more endocrine organs.

• They are inherited as complex autosomal dominant disorders that are linked to a variety of mutations in developmental or tumor suppressor genes.

Manifestations of the disorders depend on the size and location of the tumors, their malignancy, and whether they produce hormones. MEN 1 aka, Wermer syndrome Associated with a mutation in MEN1 genes, which code for menin, a tumor suppressor protein.

• Up to 25% of MEN 1 patients do not have this mutation; a subset of these cases represent "phenocopies" in which the disorder is attributed to another etiology.

MEN 2A and MEN 2B aka, Sipple syndrome aka, MEN 2 & MEN 3 Associated with RET mutations (RET = rearranged during transfection).

• RET codes for a receptor tyrosine kinase that is involved in the development of various cell lineages and is therefore expressed in several areas of the body, including the adrenal medulla chromaffin cells, thyroid c-cells, and ganglia of the peripheral nervous system.
• As we'll see, RET mutations effect these cells in MEN 2 syndromes.
• Interestingly, it appears that specific RET mutations are associated with severity of the disorder, which may prove beneficial for diagnosis; furthermore, cancer interventions that focus on the RET protein are a promising area of research.

MEN 4 Associated with mutations in CDKN1B genes – we will not cover MEN 4 in this tutorial. Diagnosis Diagnosis of MEN syndrome requires: a) two or more MEN tumors or b) one MEN tumor and a first degree relative with MEN, or, c) a MEN mutation. Treatment Treatment of multiple endocrine neoplasia is difficult because of the multiplicity and potential aggressiveness of the tumors.

• In the cases of thyroid gland or parathyroid gland tumors, it is often possible to surgically remove the tumors or the glands themselves; however, this is less feasible with pancreatic tumors. In other cases, medications that counter hormone overproduction or their effects are beneficial.

Related disorders Also characterized by multiple tumors:

• Carney Complex: Tumors in the heart, endocrine system, and skin, with spotty skin pigmentation.
• McCune-Albright Syndrome: Endocrine abnormalities leading to precocious puberty, fibrous dysplasia of bone, and "cafe-au-lait" skin spotting.
• Neurofibromatosis Type 1: Tumors grow along the nerve fibers with skin pigmentation changes.
• Von Hippel-Lindau disease: Tumors in CNS, kidneys, reproductive tract, pancreas, adrenal glands.

Let's begin our diagram with a Venn diagram to show how the three most common MEN disorders are related. We'll use the "P's & M's" to help us organize. MEN 1 is characterized by three "Ps" – tumors in the Pituitary (specifically, the anterior lobe), the Pancreas (and duodenum), and the Parathyroid glands. MEN 2 is characterized by "2 Ps + 1 M" – Parathyroid gland tumors, Pheochromocytomas (tumors in the adrenal glands), and, Medullary thyroid carcinoma. MEN 3 is characterized by "1 P + 3 M's " – Pheochromocytomas, plus medullary thyroid carcinoma, mucosal neuromas, and Marfanoid habitus. Importantly, pituitary tumor growth can cause headaches, hypopituitarism, and visual disturbances. Prolactinomas are the most common pituitary tumors in MEN 1 patients.

• Prolactinomas can secrete high levels of prolactin, which may cause galactorrhea, the secretion of a milk-like discharge, in women.

Somatotrophinomas are the second most common MEN 1 pituitary tumors – recall that too much exposure to growth hormone can cause acromegaly. Other hormone-producing tumors are possible, but rare. Hormonal effects can be treated with medications (i.e., dopamine agonists in prolactinomas), but surgical intervention may be required. Gastrinomas are the most common pancreatic and duodenal tumors in MEN 1. These tumors can cause Zollinger-Ellison Syndrome. Gastrinomas can produce high levels of gastrin, which can lead to overproduction of gastric acid in the stomach; in turn, this can cause peptic ulcers in the stomach and duodenum. These mucosal lesions cause abdominal pain and diarrhea. We can treat Zollinger-Ellison Syndrome with proton-pump inhibitors, which reduce stomach acid production. Insulinomas are the second most common pancreatic tumors in MEN 1; these can cause fasting hypoglycemia. Other functional tumor types include glucagonomas and somatostatinomas, but these are rare. Importantly, both non-functioning and functioning pancreatic tumors have high malignancy potential, and thus are the most common cause of death in patients with MEN1. Surgical intervention is difficult due to the number of and small size of pancreatic tumors, especially gastrinomas, which are known to metastasize to the liver. Involved in almost all MEN 1 cases (up to 95%); this is often the first manifestation of MEN 1, at approximately 20 years of age. The parathyroid glands secrete parathyroid hormone, which regulates calcium levels in the blood; thus, hyperfunctioning parathyroid tumors can lead to hypercalcemia. Hypercalcemia can cause bone loss and kidney stones, as well as constipation, polydipsia and polyuria, depression, lethargy, confusion, and a shortened QT interval. Partial or complete parathyroidectomy may be necessary to protect against hypercalcemia and/or malignancy. Other, rarer tumors in MEN 1 include adrenal cortical tumors, lipomas, meningiomas, bronchopulmonary and thymic tumors, etc. Medullary thyroid carcinoma is the most common feature of MEN 2A – nearly all patients will develop carcinoma. Metastasis is common, and medullary thyroid carcinoma is the most common cause of death in MEN 2A patients Tumors often develop during childhood. Medullary thyroid carcinoma is preceded by c-cell hyperplasia. Thyroid removal is often the best course of treatment. Familial medullary thyroid carcinoma is now considered a variant of MEN 2A, rather than its own subtype. Though they have RET mutations and a high risk of medullary thyroid cancer, these patients are less likely to develop the other endocrine tumors of MEN 2A, and the age of onset is usually later. C-cells produce calcitonin, which is an important marker of hyperplasia and can cause diarrhea. Pheochromocytomas Tumors of the chromaffin cells of the adrenal medulla, and are present in 30-50% of MEN 2A patients. Pheochromocytomas produce elevated levels of catecholamines. An important and potentially lethal effect is hypertension. Many MEN 2A patients experience paroxysmal hypertension, but some are chronically hypertensive. 10-30% of MEN 2A patients have hyperparathyroidism or parathyroid adenomas with hypercalcemia. Both are related to RET gene mutations: Cutaneous lichen amyloidosis, which presents as a scaly, itchy rash with dark papules and plaques. Hirschsprung disease, which is a congenital disease of the large intestine characterized by lack of parasympathetic neuronal ganglia leading to megacolon. Rare Medullary thyroid cancer A primary feature of MEN 2B, but tumors develop earlier, often in young children, and are more aggressive. Pheochromocytomas Approximately 50% of patients have pheochromocytomas. Mucosal neuromas or intestinal ganglioneuromatosis Most have oral and/or ocular mucosal neuromas or intestinal ganglioneuromatosis – these are often another early sign of MEN 2B. Mucosal neuromas tend to appear on the lips, tongue, and buccal surface; these raised nodules comprise bundles of hypertrophied, elongated nerve cells and, rarely, ganglion cells. Similarly, ganglioneuromatosis in the intestinal tract are masses of ganglion cells in the enteric plexuses that can cause distention of the GI tract, constipation, and discomfort. Many patients with MEN 2B will develop skeletal abnormalities, particularly Marfanoid habitus – long limbs with elongated hands, fingers, feet, and toes. For full references, please see the tutorial on MEN.