{"entity":{"id":"multiple-endocrine-neoplasia","kind":"indication","name":"Multiple endocrine neoplasia syndromes (MEN1, MEN2, MEN4)","aka":["MEN1","MEN2A","MEN2B","MEN4","Wermer syndrome","Sipple syndrome"],"tldr":"The MEN syndromes are inherited faults in a single gene that cause tumours in several hormone glands over a lifetime. Because the gene can be found in childhood, at-risk relatives can be tested, watched and in MEN2 have the thyroid removed before cancer develops; and for MEN2 thyroid cancer that does spread there is now a precise pill, selpercatinib, that blocks the faulty RET protein.","summary":"MEN1 is caused by germline loss-of-function mutations in MEN1, encoding the tumour suppressor menin, and produces parathyroid hyperplasia (nearly universal), duodenopancreatic neuroendocrine tumours (gastrinoma, insulinoma, non-functioning PanNETs, the main cause of death), anterior pituitary tumours, and adrenal, thymic and bronchial neuroendocrine tumours. MEN2 is caused by germline activating mutations in the RET receptor tyrosine kinase: MEN2A (codon 634 most often) causes medullary thyroid carcinoma (MTC), pheochromocytoma and parathyroid disease; MEN2B (M918T) causes early aggressive MTC, pheochromocytoma, mucosal neuromas and a marfanoid habitus. MEN4 (CDKN1B) is a rare MEN1 phenocopy. These syndromes are on the NCI list because their management is oncological: surveillance, prophylactic surgery and, when tumours spread, targeted therapy.\n\nManagement is genotype-driven. In MEN2, the American Thyroid Association (2015) assigns RET codons to risk levels that set the age of prophylactic thyroidectomy (within the first year for M918T, before age 5 for codon 634, later with calcitonin monitoring for moderate-risk codons), an intervention that prevents MTC in carriers identified early. Pheochromocytoma must be excluded before any surgery. Advanced RET-mutant MTC is treated with selpercatinib, which outperformed cabozantinib or vandetanib in the randomised LIBRETTO-531 trial (NEJM 2023), with pralsetinib as an alternative. In MEN1, surveillance (calcium and PTH, gastrin and fasting gut hormones, pituitary hormones, pancreatic MRI or endoscopic ultrasound) begins in childhood; parathyroidectomy, proton pump inhibitors for gastrinoma, and surgery for PanNETs above about 2 cm or functioning; advanced PanNETs are treated as sporadic NETs with somatostatin analogues, everolimus, sunitinib and 177Lu-DOTATATE.\n\nOpen problems are the timing of pancreatic surgery in MEN1, the lack of menin-directed therapy for MEN1 tumours (menin inhibitors developed for leukaemia work by a different mechanism), and equitable access to genetic testing and lifelong surveillance.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Multiple_endocrine_neoplasia","links":[{"label":"NCI PDQ: multiple endocrine neoplasia syndromes","url":"https://www.cancer.gov/types/multiple-endocrine-neoplasia"},{"label":"ATA medullary thyroid carcinoma guideline (2015)","url":"https://doi.org/10.1089/thy.2014.0335"},{"label":"MEN1 clinical practice guidelines (JCEM 2012)","url":"https://doi.org/10.1210/jc.2012-1230"},{"label":"LIBRETTO-531 (NEJM 2023)","url":"https://doi.org/10.1056/NEJMoa2309719"}],"tags":["nci-coverage","rare","endocrine","hereditary"],"related":["neuroendocrine","thyroid","pheochromocytoma-paraganglioma","lu-177"],"indications":[],"sections":[],"technologies":["prrt","sstr-pet"],"targets":["sstr2"],"drugs":["cabozantinib","everolimus","sunitinib","lutathera"],"companies":["eli-lilly"],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"endocrine","burden":"MEN1 affects about 2 to 3 per 100,000 people and MEN2 about 1 in 30,000; both are inherited in an autosomal dominant pattern with near-complete penetrance.","subtypes":["MEN1 (menin; parathyroid, pancreatic NET, pituitary)","MEN2A (RET; medullary thyroid carcinoma, pheochromocytoma, parathyroid)","MEN2B (RET M918T; early MTC, pheochromocytoma, mucosal neuromas)","Familial medullary thyroid carcinoma (MEN2A variant)","MEN4 (CDKN1B)"],"biomarkers":["Germline MEN1, RET or CDKN1B mutation (diagnostic; codon defines MEN2 risk level)","Calcitonin and CEA (MTC surveillance)","Calcium and PTH, gastrin, fasting glucose and insulin, prolactin and IGF-1 (MEN1 surveillance)","Plasma metanephrines before any surgery (pheochromocytoma exclusion)","Pancreatic imaging (MRI, endoscopic ultrasound, 68Ga-DOTATATE PET)"],"standardOfCare":[{"setting":"MEN2 carriers (RET-positive)","approach":"Prophylactic total thyroidectomy timed by ATA risk level (highest risk within the first year, high risk before age 5, moderate risk guided by calcitonin); annual screening for pheochromocytoma and hyperparathyroidism.","refs":["thyroid","pheochromocytoma-paraganglioma"],"guideline":{"version":"American Thyroid Association medullary thyroid carcinoma guideline 2015","url":"https://doi.org/10.1089/thy.2014.0335"}},{"setting":"Advanced RET-mutant medullary thyroid carcinoma","approach":"Selpercatinib (LIBRETTO-531: superior to cabozantinib or vandetanib); pralsetinib, cabozantinib or vandetanib as alternatives.","refs":["cabozantinib"],"guideline":{"nccn":"Category 1 (selpercatinib)","version":"NCCN Thyroid Carcinoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1470"}},{"setting":"MEN1 carriers","approach":"Surveillance from childhood; subtotal or total parathyroidectomy with autotransplantation for hyperparathyroidism; proton pump inhibitors for gastrinoma; resection of functioning or larger PanNETs; sporadic NET pathways (somatostatin analogues, everolimus, sunitinib, PRRT) for advanced disease.","refs":["everolimus","sunitinib","lutathera","prrt","neuroendocrine"],"guideline":{"version":"MEN1 clinical practice guidelines (Thakker, JCEM 2012)","url":"https://doi.org/10.1210/jc.2012-1230"}}],"stateOfArt":["MEN2 is the clearest example of genotype-directed prevention in oncology: a RET codon result sets the age of an operation that prevents a lethal cancer.","Selpercatinib converted RET-mutant MTC from multikinase-inhibitor territory into precision oncology, with better responses and fewer toxicities in a randomised comparison.","MEN1 surveillance protocols detect pancreatic NETs early, and 68Ga-DOTATATE PET and endoscopic ultrasound have replaced CT for pancreatic screening in many centres.","Cascade genetic testing of relatives, often in childhood, is standard and effective."],"history":[{"year":1954,"title":"Wermer describes familial adenomatosis of endocrine glands (MEN1)","refs":[]},{"year":1961,"title":"Sipple describes the association of pheochromocytoma and thyroid carcinoma (MEN2)","refs":[]},{"year":1993,"title":"RET mutations cause MEN2A","note":"Mulligan and colleagues, Nature; Donis-Keller and colleagues.","refs":[]},{"year":1997,"title":"MEN1 gene cloned","note":"Chandrasekharappa and colleagues, Science; menin identified.","refs":[]},{"year":2015,"title":"ATA guideline: codon-based timing of prophylactic thyroidectomy","refs":["thyroid"]},{"year":2020,"title":"Selpercatinib and pralsetinib approved for RET-mutant MTC","refs":[]},{"year":2023,"title":"LIBRETTO-531: selpercatinib beats multikinase inhibitors in RET-mutant MTC","note":"Hadoux and colleagues, NEJM.","refs":[]}],"pipeline":["lutathera","everolimus"],"openProblems":["MEN1 has no menin-restoring or pathway-directed therapy; PanNET progression remains the main cause of death, addressed by earlier detection and NET therapies.","Timing and extent of pancreatic surgery in MEN1: prospective registries are comparing strategies.","Resistance to selpercatinib (RET solvent-front mutations): next-generation RET inhibitors are in trials.","Lifelong surveillance costs and psychological burden in carriers identified as children."]},"route":"/indications/multiple-endocrine-neoplasia/","neighbours":{"indication":[{"id":"neuroendocrine","kind":"indication","name":"Neuroendocrine tumours","route":"/indications/neuroendocrine/"},{"id":"pheochromocytoma-paraganglioma","kind":"indication","name":"Pheochromocytoma and paraganglioma (PPGL)","route":"/indications/pheochromocytoma-paraganglioma/"},{"id":"thyroid","kind":"indication","name":"Thyroid cancer","route":"/indications/thyroid/"}],"isotope":[{"id":"lu-177","kind":"isotope","name":"Lutetium-177","route":"/isotopes/lu-177/"}],"technology":[{"id":"prrt","kind":"technology","name":"Peptide receptor radionuclide therapy (PRRT)","route":"/technologies/prrt/"},{"id":"sstr-pet","kind":"technology","name":"Somatostatin receptor PET (68Ga/64Cu-DOTATATE)","route":"/technologies/sstr-pet/"}],"target":[{"id":"sstr2","kind":"target","name":"Somatostatin receptor 2","route":"/targets/sstr2/"}],"drug":[{"id":"cabozantinib","kind":"drug","name":"Cabozantinib","route":"/drugs/cabozantinib/"},{"id":"everolimus","kind":"drug","name":"Everolimus","route":"/drugs/everolimus/"},{"id":"lutathera","kind":"drug","name":"Lutetium-177 dotatate","route":"/drugs/lutathera/"},{"id":"sunitinib","kind":"drug","name":"Sunitinib","route":"/drugs/sunitinib/"}],"company":[{"id":"eli-lilly","kind":"company","name":"Eli Lilly (incl. Loxo)","route":"/companies/eli-lilly/"}]}}