Men
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"multiple endocrine neoplasia"[MeSH Terms]
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Multiple Endocrine Neoplasia (MEN) Syndromes
MEN syndromes are a group of inherited disorders in which genetic alterations lead to tumor development in multiple endocrine organs. There are four well-characterized types.
MEN 1 ("Wermer Syndrome")
Genetics
- Gene: MEN1 (chromosome 11q13), encodes the tumor suppressor protein menin (610 amino acids)
- Inheritance: Autosomal dominant; follows the Knudson "two-hit" model
- Prevalence: 1-3 per 100,000
-
10% of mutations arise de novo
Classic Triad (the "3 P's")
| Component | Frequency | Features |
|---|---|---|
| Parathyroid adenomas | 90-97% | Most common/earliest; multigland hyperplasia; hypercalcemia |
| Pancreatic/GI NETs | 30-70% | Gastrinomas (most common - 50%), insulinomas (up to 30% of functional NETs), glucagonomas, VIPomas |
| Pituitary adenomas | 15-50% | Prolactinomas (most common), GH-secreting, non-functioning |
Other Tumors
- Thymic carcinoid tumors
- Adrenal adenomas
- Lipomas, angiofibromas, collagenomas (skin findings may allow presymptomatic diagnosis)
- Ependymomas
Key Points
- Gastrinoma in MEN1 causes Zollinger-Ellison Syndrome (ZES): recurrent multiple peptic ulcers, abdominal pain, diarrhea, GERD
- Diagnosis of ZES: fasting gastrin >1000 pg/mL with gastric acid present, or secretin stimulation test (rise >=200 pg/mL)
- Parathyroidectomy in patients with co-occurring PHPT + gastrinoma is recommended - lowering calcium reduces gastrin levels
- ~5-25% of patients lack germline MEN1 mutations (phenocopies or other gene mutations)
Screening Indications for MEN1 Testing
- Index case with two or more MEN1-associated tumors
- Asymptomatic first-degree relatives of a known MEN1 carrier
- Symptomatic/biochemical-positive first-degree relatives of a carrier
- Parathyroid adenoma before age 30, or multigland parathyroid disease
- Gastrinoma or multiple pancreatic NETs at any age
MEN 2
Gene: RET proto-oncogene (gain-of-function mutations) - a receptor tyrosine kinase
MEN 2A ("Sipple Syndrome") - Most common variant (~95%)
| Component | Frequency |
|---|---|
| Medullary thyroid cancer (MTC) | Nearly 100% - often first manifestation |
| Pheochromocytoma | ~50% (may be bilateral) |
| Primary hyperparathyroidism | ~20% |
- May rarely occur with Hirschsprung's disease (absent ganglionic cells in terminal hindgut)
- May be associated with cutaneous lichen amyloidosis (pruritic lesion on upper back)
MEN 2B ("MEN 3") - ~5% of all MEN 2
| Component | Features |
|---|---|
| Medullary thyroid cancer | Earliest onset, most aggressive |
| Pheochromocytoma | Present |
| Mucosal neuromas | Lips, tongue, eyelids |
| Marfanoid habitus | Tall, long limbs |
| Ganglioneuromatosis | Throughout GI tract |
- No parathyroid involvement (unlike MEN 2A)
- Most commonly caused by codon 918 (exon 16) RET mutation - highest risk category
- MTC in MEN 2B is the most aggressive - prophylactic thyroidectomy should be done as soon as possible, by age <1 year
RET Mutation Risk Categories & Management (ATA Guidelines)
| Risk | Example Mutations | Prophylactic Thyroidectomy |
|---|---|---|
| + (moderate) | Ex8, 10, 13, 14, 15, 16 (except 918) | By age 5 (or based on calcitonin) |
| ++ (high) | Ex11 (634), Ex15 (883) | By age 5 |
| +++ (highest) | Ex15 (883), Ex16 (918) | ASAP, by age <1 |
Important: Pheochromocytoma must be excluded before any surgical intervention in MEN 2 patients.
MEN 4
- Gene: CDKN1B (chromosome 12p13) - encodes p27kip1, a cyclin-dependent kinase inhibitor (tumor suppressor)
- Clinical features: Similar to MEN 1 (parathyroid, pituitary, pancreatic NETs), but also gonadal, adrenal, renal, and thyroid tumors
- Represents ~3% of patients with MEN 1-like phenotype but no MEN1 mutation
- Management: Similar to MEN 1
MEN 5 (Rare)
- Gene: MAX (chromosome 14q23.3) - encodes MYC-associated factor X transcription factor
- Features: Pheochromocytoma/paraganglioma + pituitary adenomas + parathyroid adenomas; also chondrosarcoma, lung adenocarcinoma, pancreatic NETs, renal carcinoma
- Most patients develop early-onset pheochromocytoma
Quick Comparison Summary
| Feature | MEN 1 | MEN 2A | MEN 2B | MEN 4 |
|---|---|---|---|---|
| Gene | MEN1 (menin) | RET | RET | CDKN1B (p27) |
| Parathyroid | Yes (90%+) | Yes (20%) | No | Yes |
| Thyroid | No | MTC (100%) | MTC (100%) | Possible |
| Pancreas/GI | Yes (NETs) | No | Ganglioneuromatosis | Yes |
| Pituitary | Yes | No | No | Yes |
| Pheo | No | Yes (50%) | Yes | Possible |
| Other | Lipomas, skin tumors | Hirschsprung's, lichen amyloidosis | Mucosal neuromas, marfanoid | Adrenal, renal, gonadal |
Sources:
- Sabiston Textbook of Surgery, 21st ed. - Chapter 78 on MEN syndromes
- Harrison's Principles of Internal Medicine, 22nd ed. (2025) - Chapter 400 (MEN)
- A 2025 Lancet Diabetes & Endocrinology review on MEN1 guidelines (PMID 40523372) and a 2024 Primary Care review on MEN types 1, 2A, 2B (PMID 39067973) are available as recent updates.
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