Multiple endocrine neoplasia syndromes (MEN1, MEN2, MEN4)
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.
Overview
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.
Management 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.
Open 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.
State of the art
- 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.
Anatomy and lymph node drainage
- Oral cavity and tongue
- Oropharynx: tonsil, base of tongue (HPV)
- Nasopharynx (EBV)
- Larynx and hypopharynx
- Parotid and other salivary glands
- Thyroid
- Nodes: level I (submandibular)
- Nodes: level II (upper jugular)
- Nodes: level III-IV (jugular)
- Nodes: level V (posterior)
- Nodes: level VI (central, thyroid)
- Nodes: retropharyngeal (nasopharynx)
Site decides cause and behaviour: HPV drives oropharyngeal cancer, EBV drives nasopharyngeal cancer, tobacco drives oral and laryngeal cancer; all drain into the neck node levels that surgeons and radiotherapists map.
- Oral cavity and tongue
- Oropharynx: tonsil, base of tongue (HPV)
- Nasopharynx (EBV)
- Larynx and hypopharynx
- Parotid and other salivary glands
- ThyroidMEN1 (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)
- level I (submandibular)
- level II (upper jugular)
- level III-IV (jugular)
- level V (posterior)
- level VI (central, thyroid)
- retropharyngeal (nasopharynx)
Same organ: Thyroid cancer
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.
- Somatostatin receptor PET (68Ga/64Cu-DOTATATE)Standard of care
Nothing recorded yet.
Nothing recorded yet.
Also on Nuclide: Roadmaps.
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.
Selpercatinib (LIBRETTO-531: superior to cabozantinib or vandetanib); pralsetinib, cabozantinib or vandetanib as alternatives.
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.
Subtypes & biomarkers
top- 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)
- 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)
How often this target appears
- 1954Wermer describes familial adenomatosis of endocrine glands (MEN1)
- 1961Sipple describes the association of pheochromocytoma and thyroid carcinoma (MEN2)
- 1993RET mutations cause MEN2A
Mulligan and colleagues, Nature; Donis-Keller and colleagues.
- 1997MEN1 gene cloned
Chandrasekharappa and colleagues, Science; menin identified.
- 2015ATA guideline: codon-based timing of prophylactic thyroidectomy
- 2020Selpercatinib and pralsetinib approved for RET-mutant MTC
- 2023LIBRETTO-531: selpercatinib beats multikinase inhibitors in RET-mutant MTC
Hadoux and colleagues, NEJM.
Dated changes read from the records linked to this indication: approvals, regulatory steps, reported trials, guideline versions and milestones. Newest first; no date is inferred.
All 10 changes by month →- 2026-09-10This recordMultiple endocrine neoplasia syndromes (MEN1, MEN2, MEN4)Facts on this page last checked
When this page itself was last checked or edited.
- 2023MilestoneMultiple endocrine neoplasia syndromes (MEN1, MEN2, MEN4)LIBRETTO-531: selpercatinib beats multikinase inhibitors in RET-mutant MTC
Hadoux and colleagues, NEJM.
- 2020MilestoneMultiple endocrine neoplasia syndromes (MEN1, MEN2, MEN4)Selpercatinib and pralsetinib approved for RET-mutant MTC
A milestone in how this cancer is treated.
- 2015GuidelineMultiple endocrine neoplasia syndromes (MEN1, MEN2, MEN4)Guideline American Thyroid Association medullary thyroid carcinoma guideline 2015: MEN2 carriers (RET-positive)
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.
- 2015MilestoneThyroid cancerATA guideline: codon-based timing of prophylactic thyroidectomy
A milestone in how this cancer is treated.
- 2012GuidelineMultiple endocrine neoplasia syndromes (MEN1, MEN2, MEN4)Guideline MEN1 clinical practice guidelines (Thakker, JCEM 2012): MEN1 carriers
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.
What is in development for Multiple endocrine neoplasia syndromes (MEN1, MEN2, MEN4), drawn from the whole corpus: 0 items. Drugs are grouped by the most advanced trial phase they have reached anywhere; approved treatments sit under standard of care. Technologies are the methods being tested for this cancer, trials are the studies recorded here, and ideas are proposals not yet in a trial.
Nothing recorded in development for this cancer yet.
Open problems and what is being done
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.
What is being done about thisResistance to treatmentAvailable now- CabozantinibApproved
In trialsNothing recorded yet.
Ideas and roadmapsNothing recorded yet.
Also on Nuclide: Open problems.
Lifelong surveillance costs and psychological burden in carriers identified as children.
Trials
topTrials recruiting now
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Direct links plus the targets, companies, and technologies of this cancer's products.
isotopes
1technologies
3targets
1drugs
4companies
3Latest papers
topQuery for this indication: (TITLE:"Multiple endocrine neoplasia syndromes" OR ABSTRACT:"Multiple endocrine neoplasia syndromes" OR TITLE:"MEN1, MEN2, MEN4" OR ABSTRACT:"MEN1, MEN2, MEN4" OR TITLE:"MEN1" OR ABSTRACT:"MEN1" OR TITLE:"MEN2A" OR ABSTRACT:"MEN2A" OR TITLE:"MEN2B" OR ABSTRACT:"MEN2B" OR TITLE:"MEN4" OR ABSTRACT:"MEN4") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Multiple endocrine neoplasia syndromes (MEN1, MEN2, MEN4), not a curated reading list.
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