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

Source: https://nuclide.cc/indications/multiple-endocrine-neoplasia/  
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## 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: Indication
- 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)

## 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://nuclide.cc/indications/thyroid/), [Pheochromocytoma and paraganglioma (PPGL)](https://nuclide.cc/indications/pheochromocytoma-paraganglioma/))
- Advanced RET-mutant medullary thyroid carcinoma: Selpercatinib (LIBRETTO-531: superior to cabozantinib or vandetanib); pralsetinib, cabozantinib or vandetanib as alternatives. ([Cabozantinib](https://nuclide.cc/drugs/cabozantinib/))
- 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. ([Everolimus](https://nuclide.cc/drugs/everolimus/), [Sunitinib](https://nuclide.cc/drugs/sunitinib/), [Lutetium-177 dotatate](https://nuclide.cc/drugs/lutathera/), [Peptide receptor radionuclide therapy (PRRT)](https://nuclide.cc/technologies/prrt/), [Neuroendocrine tumours](https://nuclide.cc/indications/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

- indications: [Neuroendocrine tumours](https://nuclide.cc/indications/neuroendocrine/), [Pheochromocytoma and paraganglioma (PPGL)](https://nuclide.cc/indications/pheochromocytoma-paraganglioma/), [Thyroid cancer](https://nuclide.cc/indications/thyroid/)
- isotopes: [Lutetium-177](https://nuclide.cc/isotopes/lu-177/)
- technologies: [Peptide receptor radionuclide therapy (PRRT)](https://nuclide.cc/technologies/prrt/), [Somatostatin receptor PET (68Ga/64Cu-DOTATATE)](https://nuclide.cc/technologies/sstr-pet/)
- targets: [Somatostatin receptor 2](https://nuclide.cc/targets/sstr2/)
- drugs: [Cabozantinib](https://nuclide.cc/drugs/cabozantinib/), [Everolimus](https://nuclide.cc/drugs/everolimus/), [Lutetium-177 dotatate](https://nuclide.cc/drugs/lutathera/), [Sunitinib](https://nuclide.cc/drugs/sunitinib/)
- companies: [Eli Lilly (incl. Loxo)](https://nuclide.cc/companies/eli-lilly/)

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