# Multiple endocrine neoplasia syndromes (MEN1, MEN2, MEN4)

Source: https://onco.cc/cancers/multiple-endocrine-neoplasia/  
OnCo record `multiple-endocrine-neoplasia` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

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.

## Fields

- Kind: Cancer
- Last checked: 2026-09-10
- Also known as: MEN1; MEN2A; MEN2B; MEN4; Wermer syndrome; Sipple syndrome
- Tags: nci-coverage; rare; endocrine; hereditary
- 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)

## Sections of this record

The page is a hub with ten sections in reading order; large sections have their own page. The same plan as JSON: https://onco.cc/api/v1/cancers/multiple-endocrine-neoplasia/sections.json

- Overview (on the hub): The TL;DR, the family this cancer belongs to, the organ, who gets it and what the state of the art is. https://onco.cc/cancers/multiple-endocrine-neoplasia/#overview [2 subtypes, 4 state-of-the-art points]
- What it is (on the hub): Anatomy, the subtypes and how they differ, how it is staged, and where advanced disease spreads. https://onco.cc/cancers/multiple-endocrine-neoplasia/#what-it-is [7 subtypes]
- Finding it (on the hub): How it shows itself, how it is confirmed, what screening exists, and the biomarkers clinicians test for. https://onco.cc/cancers/multiple-endocrine-neoplasia/#finding-it [5 biomarkers]
- Treating it (on the hub): The standard of care by setting, the medicines, surgery and radiotherapy named in it, and the regimens behind them. https://onco.cc/cancers/multiple-endocrine-neoplasia/#treating-it [3 settings, 2 decisions with options]
- Evidence (on the hub): Trials recruiting now, the landmark trials, the key papers and what they mean, the latest literature, and the milestones year by year. https://onco.cc/cancers/multiple-endocrine-neoplasia/#evidence [1 trial, 1 key paper, 7 milestones]
- The science (on the hub): The molecular landscape: the targets and how often each appears, the pathways, the mechanics stages and the preclinical models. https://onco.cc/cancers/multiple-endocrine-neoplasia/#science [9 targets, 3 pathways]
- Where you are (own page): Cases by country, the UK and NHS pathway and other country lenses, and the expert centres with trials on record. https://onco.cc/cancers/multiple-endocrine-neoplasia/where-you-are/
- Living with it (on the hub): The decisions you may face, the aids that walk through them, the warnings on record, the first sixty days and the questions to ask. https://onco.cc/cancers/multiple-endocrine-neoplasia/#living-with-it [15 questions, 6 red cards]
- What is coming (own page): Everything in development, the open problems and what is being done about them, the roadmaps, and what changed on this record. https://onco.cc/cancers/multiple-endocrine-neoplasia/coming/ [8 medicines, 4 open problems]
- Data (own page): Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked. https://onco.cc/cancers/multiple-endocrine-neoplasia/data/ [43 connected records]

## Standard of care

- 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. ([Thyroid cancer](https://onco.cc/cancers/thyroid/), [Germline (hereditary) testing](https://onco.cc/technologies/germline-testing/), [Pheochromocytoma and paraganglioma (PPGL)](https://onco.cc/cancers/pheochromocytoma-paraganglioma/))
- Advanced RET-mutant medullary thyroid carcinoma: Selpercatinib (LIBRETTO-531: superior to cabozantinib or vandetanib); pralsetinib, cabozantinib or vandetanib as alternatives. ([Selpercatinib](https://onco.cc/drugs/selpercatinib/), [LIBRETTO-531](https://onco.cc/trials/libretto-531/), [Pralsetinib](https://onco.cc/drugs/pralsetinib/), [Cabozantinib](https://onco.cc/drugs/cabozantinib/), [Vandetanib](https://onco.cc/drugs/vandetanib/))
- 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. ([MEN1 and hereditary neuroendocrine syndromes](https://onco.cc/terms/men1-hereditary-net/), [Somatostatin analogues (octreotide, lanreotide)](https://onco.cc/drugs/octreotide-lanreotide/), [Everolimus](https://onco.cc/drugs/everolimus/), [Sunitinib](https://onco.cc/drugs/sunitinib/), [Lutetium-177 dotatate](https://onco.cc/drugs/lutathera/), [Peptide receptor radionuclide therapy (PRRT)](https://onco.cc/technologies/prrt/), [Neuroendocrine tumours](https://onco.cc/cancers/neuroendocrine/))

## 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.

## Open problems

- 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.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Multiple_endocrine_neoplasia
- NCI PDQ: multiple endocrine neoplasia syndromes: https://www.cancer.gov/types/multiple-endocrine-neoplasia
- ATA medullary thyroid carcinoma guideline (2015): https://doi.org/10.1089/thy.2014.0335
- MEN1 clinical practice guidelines (JCEM 2012): https://doi.org/10.1210/jc.2012-1230
- LIBRETTO-531 (NEJM 2023): https://doi.org/10.1056/NEJMoa2309719

## Connected records

- cancers: [Hyperparathyroidism-jaw tumour syndrome (CDC73-related parathyroid carcinoma)](https://onco.cc/cancers/hyperparathyroidism-jaw-tumour-syndrome/), [Medullary thyroid cancer](https://onco.cc/cancers/medullary-thyroid-cancer/), [Multiple endocrine neoplasia type 1 (MEN1)](https://onco.cc/cancers/men1-syndrome/), [Multiple endocrine neoplasia type 2 (MEN2A and MEN2B)](https://onco.cc/cancers/men2-syndrome/), [Neuroendocrine tumours](https://onco.cc/cancers/neuroendocrine/), [Parathyroid carcinoma](https://onco.cc/cancers/parathyroid-carcinoma/), [Pheochromocytoma and paraganglioma (PPGL)](https://onco.cc/cancers/pheochromocytoma-paraganglioma/), [Pituitary tumours (pituitary neuroendocrine tumours) and pituitary carcinoma](https://onco.cc/cancers/pituitary-tumours/), [Rare cancers of childhood (NCI PDQ umbrella)](https://onco.cc/cancers/rare-childhood-cancers/), [Thyroid cancer](https://onco.cc/cancers/thyroid/)
- technologies: [Germline (hereditary) testing](https://onco.cc/technologies/germline-testing/), [Peptide receptor radionuclide therapy (PRRT)](https://onco.cc/technologies/prrt/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/), [Somatostatin receptor PET (68Ga/64Cu-DOTATATE)](https://onco.cc/technologies/sstr-pet/), [Thyroglobulin, calcitonin and CEA in thyroid cancer follow-up](https://onco.cc/technologies/thyroid-cancer-markers/)
- targets: [Menin](https://onco.cc/targets/menin/), [RET](https://onco.cc/targets/ret/), [Somatostatin receptor 2](https://onco.cc/targets/sstr2/)
- drugs: [Cabozantinib](https://onco.cc/drugs/cabozantinib/), [Everolimus](https://onco.cc/drugs/everolimus/), [Lutetium-177 dotatate](https://onco.cc/drugs/lutathera/), [Pralsetinib](https://onco.cc/drugs/pralsetinib/), [Selpercatinib](https://onco.cc/drugs/selpercatinib/), [Somatostatin analogues (octreotide, lanreotide)](https://onco.cc/drugs/octreotide-lanreotide/), [Sunitinib](https://onco.cc/drugs/sunitinib/), [Vandetanib](https://onco.cc/drugs/vandetanib/)
- companies: [Eli Lilly (incl. Loxo)](https://onco.cc/companies/eli-lilly/)
- pathways: [Drivers, passengers & the two-hit model](https://onco.cc/pathways/oncogene-activation-two-hit/), [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/), [Receptor tyrosine kinase activation](https://onco.cc/pathways/rtk-activation/)
- terms: [Germline vs somatic mutations](https://onco.cc/terms/germline-vs-somatic/), [Hereditary cancer syndromes](https://onco.cc/terms/hereditary-cancer-syndromes/), [MEN1 and hereditary neuroendocrine syndromes](https://onco.cc/terms/men1-hereditary-net/)
- trials: [LIBRETTO-531](https://onco.cc/trials/libretto-531/)
- bottlenecks: [Inherited risk is mostly unidentified](https://onco.cc/bottlenecks/b-hereditary-risk/), [Rare and paediatric cancers without markets](https://onco.cc/bottlenecks/b-rare-cancers/)
- key papers: [Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1)](https://onco.cc/key-papers/paper-thakker-j-clin-endocrinol-metab/)

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JSON: https://onco.cc/api/v1/entities/multiple-endocrine-neoplasia.json