Multiple Endocrine Neoplasia Syndromes of MEN are inherited as autosomal dominant traits and cause a predisposition to the development

of tumors in different tissues, particularly involving endocrine glands (see Table 26-11). Men 1 (Wermer's Syndrome) MEN 1 is a familial autosomal dominant multiglandular syndrome, with a prevalence of 210 per 100,000 people. The presentation of MEN 1 is quite variable, even in the same kindred. Parathyroid, enteropancreatic, and pituitary tumors can be present in one individual, though not necessarily at the same time. Nonendocrine tumors also occur, such as subcutaneous lipomas, facial angiofibromas, and collagenomas. In some affected individuals, tumors may start developing in childhood, whereas in others, tumors develop late in adult life. About 90% of patients with MEN 1 gave germline mutations that are inherited as an autosomal dominant trait. Patients with MEN 1 usually have detectable mutations in the 10 exons of the menin gene, located P.1216 on the long arm of chromosome 11 (11q13). MEN 1 gene testing is available at a few centers and is able to detect the specific mutation in 6095% of cases. If no mutation is detected, genetic linkage analysis can be done if there are several affected members in the kindred. Gene testing permits the rest of the kindred to be tested for the specific gene defect and allows informed genetic counseling. With close endocrine surveillance of affected individuals, the initial biochemical manifestations (usually hypercalcemia) can often be detected as early as age 1418 years in patients with a MEN 1 gene mutation, although clinical manifestations do not usually present until the third or fourth decade. Hyperparathyroidism is the first clinical manifestation of MEN 1 in two-thirds of affected patients, but it may present at any time of life. Patients with the MEN 1 mutation have a > 90% lifetime risk of developing hyperparathyroidism. Hyperparathyroidism presents with hypercalcemia, caused by hyperplasia or adenomas of several parathyroid glands. The hyperparathyroidism of MEN 1 is notoriously difficult to treat surgically, due to multiple gland involvement and the frequency of supernumerary glands and ectopic parathyroid tissue. Typically, three and one-half glands are resected, leaving one-half of the most normal-appearing gland intact. Also, during neck surgery, a thymectomy is performed to resect any intrathymic parathyroid glands or occult thymic carcinoid tumors. Nevertheless, the surgical failure rate is about 38%, and there is a recurrence rate of about 16%, with hypercalcemia often recurring many years after neck surgery. Aggressive parathyroid resection can cause permanent hypoparathyroidism. Patients with persistent or recurrent hyperparathyroidism should avoid oral calcium supplements and thiazide diuretics; oral therapy with calcimimetic drug, such as cinacalcet, is effective but expensive. The diagnosis and treatment of hyperparathyroidism is described earlier in this chapter. Enteropancreatic tumors occur in about 75% of patients with MEN 1. Nonsecretory neuroendocrine tumors occur and do not secrete hormones; they tend to be large and very aggressive. Gastrinomas occur in about 35% of patients with MEN 1; they secrete gastrin, thereby causing severe gastric hyperacidity (Zollinger-Ellison syndrome) with peptic ulcer disease or diarrhea. Concurrent hypercalcemia, due to hyperparathyroidism (see above), stimulates gastrin and gastric acid secretion; control of the hypercalcemia often reduces gastric

acid secretion and serum gastrin levels. These gastrinomas tend to be small, multiple, and ectopic; they are frequently found outside the pancreas, usually in the duodenum. Gastrinomas of MEN 1 can metastasize to the liver; but in patients with MEN 1, depending upon the kindred, hepatic metastases tend to be less aggressive than those from sporadic gastrinomas. Treatment of patients with gastrinomas in MEN 1 is usually conservative, utilizing long-term high-dose proton pump inhibitor therapy and control of hypercalcemia; surgery is palliative and usually reserved for aggressive gastrinomas and those tumors arising in the duodenum. Zollinger-Ellison syndrome is also discussed in Chapter 14. Insulinomas cause hyperinsulinism and fasting hypoglycemia. They occur in about 15% of patients with MEN 1. Surgery is usually attempted, but the tumors can be small, multiple, and difficult to detect. The diagnosis and treatment of insulinomas are described in Chapter 27. Glucagonomas (1.6%) secrete glucagon and cause diabetes and migratory necrolytic erythema. VIPomas (1%) secrete VIP and cause profuse watery diarrhea, hypokalemia, and achlorhydria (WDHA, Verner-Morrison syndrome). Somatostatinomas (0.7%) can cause diabetes mellitus, steatorrhea, and cholelithiasis. Pituitary adenomas occur in about 42% of patients with MEN 1. They are more common in women (50%) than men (31%) and are the presenting tumor in 17% of patients with MEN 1. These tumors tend to be more aggressive macroadenomas (> 1 cm diameter, 85%) compared to sporadic pituitary tumors (42%). Of MEN 1-associated pituitary tumors, about 62% secrete PRL, 8% secrete GH, 13% secrete both PRL and GH, and 13% are nonsecretory; only 4% secrete ACTH and cause Cushing's disease. The diagnosis and treatment of pituitary tumors and Cushing's disease were described earlier in this chapter. These pituitary tumors can produce local pressure effects and hypopituitarism. Adrenal adenomas or hyperplasia occurs in about 37% of patients with MEN 1 and 50% are bilateral. They are generally benign and nonfunctional. In one series, one out of 12 of these patients developed a feminizing adrenal carcinoma. These adrenal lesions are pituitary independent. Nonendocrine tumors occur commonly in MEN 1. Small facial angiofibromas and subcutaneous lipomas are common. Collagenomas can present as firm dermal nodules. Malignant melanomas have been reported. The differential diagnosis of MEN 1 includes sporadic or familial tumors of the pituitary, parathyroids, or pancreatic islets. Hypercalcemia (from any cause) may cause gastrointestinal symptoms and increased gastrin levels, simulating a gastrinoma. Routine suppression of gastric acid secretion with H2-blockers or proton pump inhibitors causes a physiologic increase in serum gastrin that can be mistaken for a gastrinoma. H2-blockers and metoclopramide cause hyperprolactinemia, simulating a pituitary prolactinoma. Variants of MEN 1 also occur. Kindreds with MEN 1 Burin variant have a high prevalence of prolactinomas, late-onset hyperparathyroidism, and carcinoid tumors, but rarely enteropancreatic tumors.

Men 2A (Sipple's Syndrome)

MEN 2A is a rare familial multiglandular syndrome that is inherited as an autosomal dominant trait. Patients with MEN 2A should have genetic testing for a ret protooncogene (RET) mutation. Their first-degree relatives may then be tested for the specific RET mutation. Patients with MEN 2A may have medullary thyroid carcinoma (> 90%); hyperparathyroidism P.1217

(2050%), due to hyperplasia or multiple adenomas in over 70% of cases; pheochromocytomas (2035%), which are often bilateral; or Hirschsprung's disease. The medullary thyroid carcinoma is of mild to moderate aggressiveness. Children harboring an MEN 2A RET gene mutation are advised to have a prophylactic total thyroidectomy by age 6 years. Siblings or children of patients with MEN 2A should have genetic testing to determine if they have a mutation of the ret protooncogene (RET) on chromosome 10cen-10q11.2; this identifies about 95% of affected individuals. Each kindred has a certain ret codon mutation that correlates with the particular variation in the MEN 2 syndrome, such as the age of onset and aggressiveness of medullary thyroid cancer. The specific mutation as well as case histories of family members should guide the timing for prophylactic thyroidectomy. Before any surgical procedure, MEN 2 carriers should be screened for pheochromocytoma. There is incomplete penetrance, and about 30% of those with such mutations never manifest endocrine tumors. Patients may be screened for medullary thyroid carcinoma with a serum calcitonin drawn after 3 days of omeprazole, 20 mg orally twice daily; calcitonin levels rise in the presence of medullary thyroid carcinoma to above 80 pg/mL in women or above 190 pg/mL in men.

Men 2B
MEN 2B is a familial, autosomal dominant multiglandular syndrome that is caused by a mutation of the ret protooncogene (RET) on chromosome 10. MEN 2B is characterized by mucosal neuromas (> 90%) with bumpy and enlarged lips and tongue, Marfan-like habitus (75%), adrenal pheochromocytomas (60%) that are rarely malignant and often bilateral, and medullary thyroid carcinoma (80%). Patients also have intestinal abnormalities (75%) such as intestinal ganglioneuromas, skeletal abnormalities (87%), and delayed puberty (43%). Medullary thyroid carcinoma is aggressive and presents early in life. Therefore, infants having a parent with MEN 2B receive genetic screening; those carrying the RET mutation undergo a prophylactic total thyroidectomy by age 6 months.