{"entity":{"id":"multiple-endocrine-neoplasia","kind":"cancer","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","pituitary-tumours","parathyroid-carcinoma"],"cancers":[],"sections":[],"technologies":["germline-testing","kinase-inhibitors","prrt","sstr-pet"],"targets":["ret","menin","sstr2"],"drugs":["selpercatinib","pralsetinib","cabozantinib","vandetanib","octreotide-lanreotide","everolimus","sunitinib","lutathera"],"companies":["eli-lilly"],"institutions":[],"pathways":["rtk-activation","ras-mapk","oncogene-activation-two-hit"],"terms":["men1-hereditary-net","hereditary-cancer-syndromes","germline-vs-somatic"],"trials":["libretto-531"],"people":[],"bottlenecks":["b-hereditary-risk","b-rare-cancers"],"keyPapers":["paper-thakker-j-clin-endocrinol-metab"],"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","germline-testing","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":["selpercatinib","libretto-531","pralsetinib","cabozantinib","vandetanib"],"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":["men1-hereditary-net","octreotide-lanreotide","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":["ret"]},{"year":1997,"title":"MEN1 gene cloned","note":"Chandrasekharappa and colleagues, Science; menin identified.","refs":["menin"]},{"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":["selpercatinib","pralsetinib"]},{"year":2023,"title":"LIBRETTO-531: selpercatinib beats multikinase inhibitors in RET-mutant MTC","note":"Hadoux and colleagues, NEJM.","refs":["selpercatinib","libretto-531"]}],"pipeline":["selpercatinib","libretto-531","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":"/cancers/multiple-endocrine-neoplasia/","neighbours":{"cancer":[{"id":"hyperparathyroidism-jaw-tumour-syndrome","kind":"cancer","name":"Hyperparathyroidism-jaw tumour syndrome (CDC73-related parathyroid carcinoma)","route":"/cancers/hyperparathyroidism-jaw-tumour-syndrome/"},{"id":"medullary-thyroid-cancer","kind":"cancer","name":"Medullary thyroid cancer","route":"/cancers/medullary-thyroid-cancer/"},{"id":"men1-syndrome","kind":"cancer","name":"Multiple endocrine neoplasia type 1 (MEN1)","route":"/cancers/men1-syndrome/"},{"id":"men2-syndrome","kind":"cancer","name":"Multiple endocrine neoplasia type 2 (MEN2A and MEN2B)","route":"/cancers/men2-syndrome/"},{"id":"neuroendocrine","kind":"cancer","name":"Neuroendocrine tumours","route":"/cancers/neuroendocrine/"},{"id":"parathyroid-carcinoma","kind":"cancer","name":"Parathyroid carcinoma","route":"/cancers/parathyroid-carcinoma/"},{"id":"pheochromocytoma-paraganglioma","kind":"cancer","name":"Pheochromocytoma and paraganglioma (PPGL)","route":"/cancers/pheochromocytoma-paraganglioma/"},{"id":"pituitary-tumours","kind":"cancer","name":"Pituitary tumours (pituitary neuroendocrine tumours) and pituitary carcinoma","route":"/cancers/pituitary-tumours/"},{"id":"rare-childhood-cancers","kind":"cancer","name":"Rare cancers of childhood (NCI PDQ umbrella)","route":"/cancers/rare-childhood-cancers/"},{"id":"thyroid","kind":"cancer","name":"Thyroid cancer","route":"/cancers/thyroid/"}],"technology":[{"id":"germline-testing","kind":"technology","name":"Germline (hereditary) testing","route":"/technologies/germline-testing/"},{"id":"prrt","kind":"technology","name":"Peptide receptor radionuclide therapy (PRRT)","route":"/technologies/prrt/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"},{"id":"sstr-pet","kind":"technology","name":"Somatostatin receptor PET (68Ga/64Cu-DOTATATE)","route":"/technologies/sstr-pet/"},{"id":"thyroid-cancer-markers","kind":"technology","name":"Thyroglobulin, calcitonin and CEA in thyroid cancer follow-up","route":"/technologies/thyroid-cancer-markers/"}],"target":[{"id":"menin","kind":"target","name":"Menin","route":"/targets/menin/"},{"id":"ret","kind":"target","name":"RET","route":"/targets/ret/"},{"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":"pralsetinib","kind":"drug","name":"Pralsetinib","route":"/drugs/pralsetinib/"},{"id":"selpercatinib","kind":"drug","name":"Selpercatinib","route":"/drugs/selpercatinib/"},{"id":"octreotide-lanreotide","kind":"drug","name":"Somatostatin analogues (octreotide, lanreotide)","route":"/drugs/octreotide-lanreotide/"},{"id":"sunitinib","kind":"drug","name":"Sunitinib","route":"/drugs/sunitinib/"},{"id":"vandetanib","kind":"drug","name":"Vandetanib","route":"/drugs/vandetanib/"}],"company":[{"id":"eli-lilly","kind":"company","name":"Eli Lilly (incl. Loxo)","route":"/companies/eli-lilly/"}],"pathway":[{"id":"oncogene-activation-two-hit","kind":"pathway","name":"Drivers, passengers & the two-hit model","route":"/pathways/oncogene-activation-two-hit/"},{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"},{"id":"rtk-activation","kind":"pathway","name":"Receptor tyrosine kinase activation","route":"/pathways/rtk-activation/"}],"term":[{"id":"germline-vs-somatic","kind":"term","name":"Germline vs somatic mutations","route":"/terms/germline-vs-somatic/"},{"id":"hereditary-cancer-syndromes","kind":"term","name":"Hereditary cancer syndromes","route":"/terms/hereditary-cancer-syndromes/"},{"id":"men1-hereditary-net","kind":"term","name":"MEN1 and hereditary neuroendocrine syndromes","route":"/terms/men1-hereditary-net/"}],"trial":[{"id":"libretto-531","kind":"trial","name":"LIBRETTO-531","route":"/trials/libretto-531/"}],"bottleneck":[{"id":"b-hereditary-risk","kind":"bottleneck","name":"Inherited risk is mostly unidentified","route":"/bottlenecks/b-hereditary-risk/"},{"id":"b-rare-cancers","kind":"bottleneck","name":"Rare and paediatric cancers without markets","route":"/bottlenecks/b-rare-cancers/"}],"paper":[{"id":"paper-thakker-j-clin-endocrinol-metab","kind":"paper","name":"Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1)","route":"/key-papers/paper-thakker-j-clin-endocrinol-metab/"}]}}