Multiple Endocrine Neoplasia (MEN)

Multiple endocrine neoplasia (MEN) is a group of inherited conditions. Each one causes tumors in the endocrine glands. Those are the glands that make hormones.

Some of these tumors are benign, which means not cancer. Some are cancer. Many cause harm in a third way. They make far too much of one hormone, and that hormone changes how the body works.

There are three named types: MEN1, MEN2 and MEN4. MEN2 splits again into MEN2A and MEN2B. Each type comes from a change in a different gene. Each puts a different set of glands at risk.

MEN1 affects about 1 in 30,000 people. MEN2 affects about 1 in 35,000. MEN4 is rare, and its true frequency is not known.

Your type is the first thing to pin down. It sets your whole monitoring plan.

MEN1 comes from a change in the MEN1 gene. That gene makes a protein called menin. Menin normally holds tumor growth in check.

MEN1 targets three main sites.

• The parathyroid glands. These are four small glands in the neck. They control the calcium level in your blood. Overactive parathyroid glands, called hyperparathyroidism, is the most common feature of MEN1. It reaches 100% of people by age 50. It usually starts between ages 20 and 25.
• The pituitary gland. This sits at the base of the brain and directs other glands. Pituitary adenomas occur in 15% to 55% of people, depending on the group studied.
• The pancreas. Neuroendocrine tumors here often make hormones. Gastrinomas flood the stomach with acid and occur in about 40%. Insulinomas drop blood sugar and occur in about 10%. Tumors that make no hormone occur in about 55%.

More than half of people with MEN1 show some feature by age 20. By age 40 the figure is 95%.

MEN2 comes from a change in the RET gene. The change switches the gene on too strongly.

The central risk in MEN2 is medullary thyroid carcinoma, or MTC. This is a cancer of the C cells of the thyroid. C cells make a hormone called calcitonin. MTC is not the common kind of thyroid cancer, and it behaves differently.

MEN2A is the more common form. About 95% of people with MEN2A develop MTC. About 50% develop a pheochromocytoma. That is an adrenal gland tumor that pours out adrenaline-type hormones. Parathyroid disease affects 20% to 30%.

MEN2B is rarer and more aggressive. Nearly everyone with MEN2B develops MTC, and it starts younger. About 50% develop a pheochromocytoma. Parathyroid disease is uncommon, under 1%. MEN2B also shows outward signs. Benign growths can form on the lips, the tongue, or inside the mouth. MEN2B makes up about 5% of all MEN2.

Familial medullary thyroid carcinoma (FMTC) sits inside the MEN2A group. Nearly everyone with FMTC develops MTC. But pheochromocytoma and parathyroid disease each stay under 1%.

MEN4 comes from a change in the CDKN1B gene. It looks much like MEN1. Overactive parathyroid glands are again the most common feature, then pituitary tumors. MEN4 is rare.

In MEN2, the precise spot inside the RET gene drives the plan. Clinicians sort RET changes into three risk levels.

• Highest risk. The p.Met918Thr change. About 95% of people with MEN2B have a change at codon 918.
• High risk. Changes at codon 634, plus p.Ala883Phe.
• Moderate risk. All other RET changes that switch the gene on.

Ask for your genetic report in writing. You want three things on it: the gene name, the exact variant, and the risk level. Do not rely on a relative's report alone.

MTC risk in MEN2 is close to certain. So the thyroid is often removed before any cancer appears. This is called prophylactic, or risk-reducing, thyroidectomy. Timing follows the risk level.

• Highest risk: as soon as possible in the first year of life.
• High risk: before age 5.
• Moderate risk: may be delayed past age 5 if agreed criteria are met.

NCI puts it in plainer terms for families. Children with MEN2A and certain RET changes usually have the thyroid removed before age 5. Children with MEN2B and certain RET changes usually have the thyroid removed too, to lessen the chance cancer will form.

After the thyroid is out, thyroid hormone replacement is needed for life. It is not a temporary bridge.

In MEN2. Checks for pheochromocytoma start at age 11 for highest-risk and high-risk variants. They start at age 16 for moderate-risk variants. Checks for overactive parathyroid glands follow the same ages: 11 for high risk, 16 for moderate risk. NCI's family-facing page says pheochromocytoma checks begin at age 10 and continue for life. The two ages differ by one year. Ask your team which schedule they follow.

In MEN1. Blood tests begin at age 5 and repeat every year. They include fasting calcium, prolactin, IGF-1, fasting glucose and insulin. A head MRI is repeated every 3 to 5 years. From age 8, chromogranin-A, pancreatic polypeptide, glucagon and VIP are added each year. From age 20, yearly fasting gastrin is added. Abdominal imaging or endoscopic ultrasound is considered every 3 to 5 years. NCI tells families that checks start at age 5 and continue for life.

That MEN1 panel is a lot of tubes. Ask for one standing annual order, so you are not chasing separate lab slips each year.

MEN is inherited in an autosomal dominant pattern. Each child of a person with MEN2 has a 50% chance of inheriting the RET change.

Testing relatives runs on the same clock as surgery. For MEN2A and FMTC, RET testing should be offered to at-risk children by age 5. For MEN2B, testing should happen as soon as possible after birth for any child known to be at risk.

About half of MEN2B cases come from a new gene change rather than an inherited one. So a clean family history does not rule MEN2B out.

Signs of high blood calcium. Overactive parathyroid glands push blood calcium up. Contact your provider if you notice nausea or vomiting, poor appetite, constipation, more thirst or more urination, muscle weakness or twitches, tiredness or confusion, or bone pain. Most people with high calcium have no symptoms at all, and it is usually found on a routine blood test. Symptoms alone cannot tell you your calcium is safe.

Signs of a pheochromocytoma. These are high blood pressure, headache, heavy sweating for no clear reason, a strong, fast or irregular heartbeat, shakiness, and looking very pale. The most common sign is high blood pressure that is hard to control. NCI warns that very high blood pressure can cause an irregular heartbeat, a heart attack, a stroke, or death. If these signs come on suddenly and severely, call 911. Do not wait it out.

This page describes patterns across MEN as a group. It cannot set your personal screening dates or surgical timing. Those come from your gene result, your own test history, and an endocrine team that treats MEN regularly.

• Multiple Endocrine Neoplasia — MedlinePlus Genetics
• Multiple Endocrine Neoplasia (MEN) Syndromes — National Cancer Institute
• Childhood MEN1 Syndrome — National Cancer Institute
• Childhood MEN2 Syndrome — National Cancer Institute
• Childhood Multiple Endocrine Neoplasia Syndromes Treatment (PDQ), Health Professional Version — National Cancer Institute
• Multiple Endocrine Neoplasia Type 2 — GeneReviews, NCBI Bookshelf
• Multiple Endocrine Neoplasia Type 1 — GeneReviews, NCBI Bookshelf
• Hypercalcemia — MedlinePlus Medical Encyclopedia
• Pheochromocytoma and Paraganglioma Treatment (PDQ), Patient Version — National Cancer Institute