Multiple Endocrine Neoplasia (MEN)

What multiple endocrine neoplasia is

Endocrine glands release hormones into the blood. In MEN, an inherited gene change removes a brake on cell growth (in MEN1) or switches on a growth signal (in MEN2), so tumors form in several glands, often more than one tumor in the same gland. Most are benign but cause problems by producing too much hormone. Some, especially medullary thyroid cancer and some pancreatic tumors, are malignant.

MEN1 vs MEN2A vs MEN2B

A rarer MEN4, caused by the CDKN1B gene, resembles MEN1.

Symptoms

Symptoms come from the hormones each tumor makes.

MEN1

• Hyperparathyroidism: high calcium causing kidney stones, thirst, frequent urination, constipation, bone thinning, tiredness and low mood. It is usually the first feature, often appearing in the 20s.
• Gastrinoma (Zollinger-Ellison syndrome): excess stomach acid, causing multiple or recurrent ulcers, heartburn and diarrhea.
• Insulinoma: episodes of low blood sugar with sweating, shakiness, confusion or fainting, especially when fasting.
• Pituitary tumors: prolactinoma causes irregular periods, breast milk discharge and low sex drive. Others cause acromegaly, headaches or vision problems.

MEN2

• Medullary thyroid cancer: a neck lump, swollen neck glands, and sometimes diarrhea or flushing from the hormone calcitonin. In gene carriers it is usually found by screening before symptoms.
• Pheochromocytoma: episodes of headache, pounding heartbeat, sweating and high blood pressure.
• Hyperparathyroidism in MEN2A, usually milder than in MEN1.

Diagnosis

MEN is suspected when someone has two or more typical tumors, one typical tumor with a family history, or an endocrine tumor at an unusually young age.

1. Genetic testing: a blood test for MEN1 or RET variants. Once a family variant is known, relatives can be tested precisely. Genetic counseling before and after is recommended.
2. Hormone blood tests: calcium and parathyroid hormone, gastrin, fasting glucose and insulin, prolactin and IGF-1, calcitonin and CEA, and plasma or urine metanephrines.
3. Imaging: MRI of the pituitary and pancreas, CT, endoscopic ultrasound, neck ultrasound and specialized nuclear scans such as gallium-68 DOTATATE PET.

Treatment

MEN1

• Parathyroid surgery: usually removal of three and a half glands, or all four with a small piece reimplanted, because all the glands are affected. Recurrence is common.
• Pancreatic and duodenal tumors: surgery for tumors that make hormones or are growing or larger than about 2 cm. Proton pump inhibitors control acid from gastrinomas.
• Pituitary tumors: medicines such as cabergoline for prolactinomas. Surgery or radiation for others.
• Advanced neuroendocrine tumors: somatostatin analogs, targeted drugs, PRRT (peptide receptor radionuclide therapy) and chemotherapy.

MEN2

• Preventive thyroidectomy: removing the thyroid before cancer develops or spreads, timed by the specific RET variant. For the highest-risk variant (MEN2B), surgery is advised in the first year of life. For high-risk variants it is advised at or before age 5. For moderate-risk variants, timing is guided by calcitonin levels.
• Pheochromocytoma: always ruled out and treated first, before any other surgery, because operating with an untreated pheochromocytoma can cause a dangerous blood pressure crisis. Surgery follows a period of alpha-blocker medication.
• Advanced medullary thyroid cancer: targeted RET inhibitors (selpercatinib, pralsetinib) and other kinase inhibitors.

People who have had their thyroid removed take lifelong thyroid hormone replacement.

Lifelong screening

Gene carriers have regular screening, often starting in early childhood:

• MEN1: yearly blood tests for calcium, PTH, prolactin, IGF-1, fasting glucose and gastrin, with periodic MRI or CT of the pancreas and pituitary, from about age 5.
• MEN2: calcitonin and neck ultrasound, plus yearly metanephrines from about age 11 (high-risk variants) or 16 (moderate-risk), and calcium in MEN2A.

Outlook

Screening and early surgery have changed the outlook. In MEN2, preventive thyroidectomy can prevent medullary thyroid cancer entirely. In MEN1, the main threat to life is malignant pancreatic and thymic neuroendocrine tumors, so regular imaging matters. Most people with MEN live full lives with ongoing monitoring by an endocrine team.

Frequently asked questions

What is the difference between MEN1 and MEN2?

MEN1, caused by the MEN1 gene, mainly affects the parathyroid glands, pancreas and pituitary gland. MEN2, caused by the RET gene, mainly causes medullary thyroid cancer and pheochromocytoma, plus parathyroid tumors in MEN2A. They need different screening and treatment plans.

Is multiple endocrine neoplasia hereditary?

Yes. Both main types are inherited in an autosomal dominant pattern, so each child of an affected parent has a 50% chance of inheriting the gene change. Some people have a new variant with no family history, and their children can then inherit it.

What are the first symptoms of MEN1?

The most common first sign is high calcium from overactive parathyroid glands, which can cause kidney stones, tiredness, thirst and bone thinning, often in a person's 20s or 30s. Others first notice stomach ulcers, low blood sugar episodes, or symptoms of a pituitary tumor.

Why do children with MEN2 have their thyroid removed?

Almost everyone with a MEN2 RET variant develops medullary thyroid cancer, which can spread early. Removing the thyroid before cancer develops is preventive and very effective. The best age depends on the specific variant, ranging from the first year of life to later childhood.

Should my family members be tested for MEN?

If you have MEN1 or MEN2 with a known gene variant, your parents, siblings and children should be offered genetic testing, ideally with genetic counseling. Relatives who test negative do not need screening. Those who carry the variant begin a monitoring program.