Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + Download Section PDF Listen ++ For further information, see CMDT Part 26-27: MEN Types 1–4 + Key Features Download Section PDF Listen +++ +++ Essentials of Diagnosis ++ MEN 1: tumors of the parathyroid glands, endocrine pancreas and duodenum, anterior pituitary, adrenal, thyroid; carcinoid tumors; lipomas and facial angiofibromas MEN 2 (formerly MEN 2A): medullary thyroid cancers, hyperparathyroidism, pheochromocytomas, Hirschsprung disease MEN 3 (formerly MEN 2B): medullary thyroid cancers, pheochromocytomas, Marfan-like habitus, mucosal neuromas, intestinal ganglioneuroma, delayed puberty MEN 4: tumors of the parathyroid glands, anterior pituitary gland, adrenal gland, ovary, testicle, kidney +++ General Considerations +++ MULTIPLE ENDOCRINE NEOPLASIA (MEN) 1 (WERMER SYNDROME) ++ Parathyroid, enteropancreatic, and pituitary tumors Nonendocrine tumors Small head-neck angiofibromas (85%) Lipomas (30%) Collagenomas (70%) Incidental adrenal nodules are found in about 50% of affected patients but are rarely secretory Mutations in the menin gene (11q13) detectable in 60–95% of cases Variants of MEN 1 occur, eg, kindreds with MEN 1 Burin have a high prevalence of prolactinomas, late-onset hyperparathyroidism, and carcinoid tumors, but rarely enteropancreatic tumors In patients with MEN 1 gastrinomas, depending on the kindred, hepatic metastases tend to be less aggressive than in those with sporadic gastrinomas +++ MEN 2 (FORMERLY MEN 2A; SIPPLE SYNDROME) ++ Medullary thyroid carcinoma, hyperparathyroidism, pheochromocytomas Nonendocrine: Hirschsprung disease Caused by a mutation of the ret proto-oncogene (RET) on chromosome 10 (95%) 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 +++ MEN 3 (FORMERLY MEN 2B) ++ Adrenal pheochromocytomas, medullary thyroid carcinoma, mucosal neuromas Nonendocrine manifestations Intestinal ganglioneuromas Marfan-like habitus Skeletal abnormalities Delayed puberty +++ MEN 4 ++ Rare autosomal-dominant familial tumor syndrome caused by germline mutations in the gene CDKN1B Affected patients are particularly prone to parathyroid adenomas (80%), pituitary adenomas (less aggressive than those seen with MEN 1), pancreatic neuroendocrine tumors, and adrenal tumors They also appear to be prone to adrenal tumors, renal tumors, testicular cancer, neuroendocrine cervical carcinoma, and primary ovarian failure +++ OTHER SYNDROMES RELATED To MEN ++ Carney complex Adrenocortical nodular hyperplasia that can produce skin abnormalities Cushing syndrome GH-secreting pituitary adenomas or hyperplasia with acromegaly Thyroid tumors Gonadal Sertoli cell tumors Myxomas of heart and breast Other malignancies McCune-Albright syndrome: Precocious puberty (particularly girls) due to gonadal hypersecretion Cushing syndrome caused by multiple adrenal nodules Hyperthyroidism from functioning thyroid nodules Acromegaly caused by GH-secreting pituitary tumors may develop Fibrous dysplasia of bones and hypophosphatemia, and bone fractures are common Sudden death has been reported Type 2 von Hippel Lindau (VHL) syndrome Associated with pheochromocytomas, pancreatic/duodenal neuroendocrine tumors, hyperparathyroidism, and pituitary tumors Hemangiomas and renal cell carcinomas Hypoxia Inducible Factor 2A (HIF2A) germline mutations predispose to Pheochromocytomas, pancreatic/duodenal somatostatinomas Erythrocytosis Retinal abnormalities Neurofibromatosis type 1 (NF1) Associated with pheochromocytomas and pancreatic/duodenal somatostatinomas as well as neurofibromas and hypothalamic hamartomas Beckwith Wiedemann syndrome is associated with an increased risk for malignancies, particularly Wilms tumor and hepatoblastoma, but also neuroblastoma, adrenocortical carcinoma, neuroblastoma, pheochromocytoma, and paraganglioma + Clinical Findings Download Section PDF Listen +++ +++ Symptoms and Signs +++ MEN 1 ++ Tumors may develop in childhood or adulthood; presentation variable, even in same kindred Hyperparathyroidism in > 90%; initial presentation in two-thirds of patients Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in up to 70% Gastrinomas in 40% (Zollinger-Ellison syndrome) Gastrinomas tend to be small, multiple and ectopic Occur frequently in the duodenum Can metastasize to the liver Concurrent hyperparathyroidism stimulates gastrin and gastric acid secretion Insulinomas in ~10% of patients cause fasting hypoglycemia Glucagonomas (1.6%) cause diabetes mellitus and migratory necrolytic erythema VIPomas (1%) cause profuse watery diarrhea, hypokalemia, and achlorhydria (WDHA, Verner-Morrison syndrome) Somatostatinomas (0.7%) can cause diabetes mellitus, steatorrhea, and cholelithiasis Extrapancreatic neuroendocrine tumors include carcinoid tumors that tend to occur in foregut locations (69%), such as the lung, thymus, duodenum, or stomach; such carcinoid tumors are frequently malignant Pituitary adenomas in 42%; presenting tumor in 29% Adrenal adenomas or hyperplasia in ~40%; bilateral in 50%; generally benign and nonfunctional Nonendocrine tumors are common Small facial angiofibromas and subcutaneous lipomas Collagenomas (firm skin nodules) Malignant melanomas can occur +++ MEN 2 (FORMERLY MEN 2A) ++ Pheochromocytomas (often bilateral) Serum calcitonin levels in medullary thyroid carcinoma are usually > 80 pg/mL in women or > 190 pg/mL in men +++ MEN 3 (FORMERLY MEN 2B) ++ Medullary thyroid carcinoma is aggressive and presents early in life Mucosal neuromas (> 90%) with bumpy and enlarged lips and tongue Marfan-like habitus (75%) Adrenal pheochromocytomas (60%), often bilateral and rarely malignant Medullary thyroid carcinoma (80%) Intestinal abnormalities (eg, ganglioneuromas) (75%) Skeletal abnormalities (87%) Delayed puberty (43%) +++ MEN 4 ++ Adenomas of the pituitary, parathyroid glands, and neuroendocrine tumors of the pancreas Adrenal tumors Renal tumors Testicular cancer Neuroendocrine cervical carcinoma +++ Differential Diagnosis ++ Tumors of pituitary, parathyroids, or pancreatic islets Other causes of hypercalcemia may increase gastrin levels, simulating gastrinoma + Diagnosis Download Section PDF Listen +++ +++ Laboratory Tests +++ MEN 1 ++ Genetic linkage analysis can be done if there are several affected members in the kindred Menin mutation genetic testing permits the rest of the kindred to be tested for the specific gene defect and allows informed genetic counseling +++ MEN 2 (FORMERLY MEN 2A) ++ RET mutation genetic testing permits first-degree relatives to be tested for the specific gene defect and allows informed genetic counseling Serum calcitonin level drawn after 3 days of omeprazole, 20 mg twice daily orally, enables screening for medullary thyroid carcinoma +++ MEN 3 (FORMERLY MEN 2B) ++ Genetic testing of infants who have a parent with MEN 2B is possible +++ MEN 4 ++ No mutation in the menin gene, which differentiates MEN 4 from MEN 1 + Treatment Download Section PDF Listen +++ +++ Medications +++ MEN 1 ++ Cinacalcet orally may be effective for hyperparathyroidism Conservative treatment for patients with gastrinomas in MEN 1 High-dose proton pump inhibitor therapy Control of hypercalcemia +++ Surgery +++ MEN 1 ++ Parathyroidectomy (3½ glands resected, along with thymectomy) for patients with hyperparathyroidism is effective in 62% Surgery for gastrinomas is palliative and usually reserved for aggressive gastrinomas and those tumors arising in the duodenum Surgical resection is usually attempted for insulinomas, but the tumors can be small, multiple, and difficult to detect +++ MEN 2 (FORMERLY MEN 2A) ++ Prophylactic total thyroidectomy for children with a MEN 2 RET gene mutation, usually by age 6, though ~30% never manifest endocrine tumors Screen MEN 2 mutation carriers for pheochromocytoma before any surgical procedure + Outcome Download Section PDF Listen +++ +++ Complications +++ MEN 1 ++ Aggressive parathyroid resection can cause permanent hypoparathyroidism Control of the hypercalcemia can reduce serum gastrin levels, gastric acidity, and frequency of peptic ulcer disease +++ Prognosis +++ MEN 1 ++ Hyperparathyroidism recurrence rate is 16%, with hypercalcemia often recurring many years after neck surgery Overall, patients with MEN 1 face an increased mortality risk with a mean life expectancy of only 55 years + References Download Section PDF Listen +++ + +Hyde SM et al. Genetics of multiple endocrine neoplasia type 1/multiple endocrine neoplasia type 2 syndromes. Endocrinol Metab Clin North Am. 2017 Jun;46(2):491–502. [PubMed: 28476233] + +Kamilaris CDC et al. Carney complex. Exp Clin Endocrinol Diabetes. 2019 Feb;127(2-03):156–64. [PubMed: 30428497] + +Kiernan CM et al. Surgical management of multiple endocrine neoplasia 1 and multiple endocrine neoplasia 2. Surg Clin North Am. 2019 Aug;99(4):693–709. [PubMed: 31255200] + +Marx SJ. Recent topics around multiple endocrine neoplasia Type 1. J Clin Endocrinol Metab. 2018 Apr;103(4):1296–301. [PubMed: 29897580] + +McDonnell JE et al. Multiple endocrine neoplasia: an update. Intern Med J. 2019 Aug;49(8):954–61. [PubMed: 31387156]