Types of MEN (Multiple Endocrine Neoplasia) Syndromes

Multiple endocrine neoplasia syndromes, commonly known as MEN syndromes, are rare, genetic disorders that cause multiple tumors to form within the endocrine system. MEN syndrome tumors may be benign (non-cancerous) or malignant (cancerous).

The endocrine system is comprised of glands, organs, and other structures. It's responsible for producing, regulating, and releasing hormones throughout the body. MEN syndrome tumors can form anywhere within this system.

The major forms of MEN syndromes are:

• MEN1 (also known as Wermer's syndrome)
• MEN2a (also known as Sipple syndrome)
• MEN2b (formerly known as MEN3)
• MEN4

This article will explain the causes and symptoms of MEN syndromes. It will also discuss the testing and treatment options commonly used for these disorders.

MEN Syndromes: What Is MEN1?

MEN1 syndrome is a genetic condition that is usually inherited from a parent. The most common sites for MEN1 tumors are the islet cells of the pancreas, the pituitary gland, and the parathyroid glands. MEN1 tumors are usually benign. But tumors within the pancreas may sometimes become malignant.

MEN1 is the most common type of MEN syndrome. This condition occurs in approx. 1 in 30,000 people. MEN1 affects people of all sexes equally.

Symptoms

MEN1 tumors produce and secrete excess hormones. This can result in a variety of health issues and symptoms. The type of hormone produced and the symptoms it causes are determined by the location of the tumors:

• Tumors in the parathyroid gland can cause hyperparathyroidism (overproduction of parathyroid hormone). Symptoms include fatigue, bone pain, and kidney stones. Parathyroid gland tumors may also raise blood calcium levels.
• Tumors in the pituitary gland (pituitary adenoma) can disrupt the menstrual cycle, causing infertility. They may also cause lactation (breast milk production). Severe headaches and changes in vision are other possible symptoms.
  
• Tumors in the pancreas (pancreatic neuroendocrine tumors) can cause overproduction of stomach acid, leading to ulcers.

Causes

A mutation (change) in the MEN1 gene causes MEN1. This gene sends instructions to the body's cells to produce menin, a protein that suppresses tumor formation.

The vast majority of people with MEN1 syndrome inherit it from one affected parent through an autosomal dominant pattern of inheritance. Autosomal dominant means only one copy of the gene is needed to produce the condition, and the gene is carried on a chromosome other than X or Y, so it affects people of any sex equally.

People born with this condition have one mutated copy of the MEN1 gene in each cell. Most people with MEN1 acquire a second MEN1 gene mutation in certain cells at some point during their lifetime. The occurrence of this second mutation may trigger tumor formation.

Occasionally, MEN1 gene mutations occur in people with no family history of MEN1 syndrome.

MEN Syndromes: What Is MEN2?

MEN2 is categorized into two distinct subtypes: MEN2a and MEN2b. Approx. 95% of people with MEN2 have the MEN2a subtype. MEN2b, the rarer form, produces more effects and obvious physical symptoms. Both subtypes typically affect the thyroid, adrenal, and parathyroid glands.

Familial medullary thyroid carcinoma (FMTC), a type of thyroid cancer, occurs in around 90% of people with MEN2a, and 98% of people with MEN2b. FMTC starts in cells that release calcitonin, a type of hormone.

MEN2b may also cause pheochromocytoma (adrenal gland tumors) or parathyroid gland disease.

Symptoms

People with MEN2a sometimes get cutaneous lichen amyloidosis, an intensely itchy skin condition that causes scaly patches of raised bumps on the shins, forearms, and other parts of the body.

People with MEN2b may get benign nerve tumors, called mucosal neuromas, on their tongues, lips, or eyes. Mucosal neuromas may also grow within the gastrointestinal tract, causing problems with digestion.

Other physical symptoms of MEN2b include thickened, bumpy eyelids and lips. Skeletal problems such as a curved spine, loose joints, or longer-than-average arms and legs may also occur.

MEN2 symptoms are often determined by the secondary conditions it can cause.

If medullary thyroid cancer occurs, symptoms that signal this condition include:

• Hoarseness
• Neck pain
• A lump in the throat or neck
• Persistent coughing
• Shortness of breath
• Difficulty swallowing

If pheochromocytoma occurs, symptoms may include:

• Feeling dizzy or shaky
• Irregular heartbeat
• Excessive sweating
• Irritability
• Dangerously high blood pressure
• Headache
• Pain in the chest or abdomen

If parathyroid gland disease occurs, symptoms may include:

• Broken or painful bones
• Flank, back, or stomach pain
• Hypercalcemia (excess amounts of calcium in the blood)
• Neck lump
• Difficulty swallowing or speaking
  

Causes

The vast majority of people with MEN2 inherit a RET gene mutation from an affected parent through an autosomal dominant pattern of inheritance.

RET genes instruct cells to produce a protein that initiates signaling within cells. Mutated RET genes interfere with this process by altering the ability of cells to respond to their environment correctly. This can stimulate or trigger rampant cell division and tumor formation.

Only one copy of the mutated RET gene is necessary for MEN2 to occur. Like MEN1, MEN2 may occasionally occur in a person with no family history of the disorder.

What Is MEN4?

MEN4 is extremely rare, more so than MEN1 and MEN2. Its symptoms are often the same as those caused by MEN1. But it is caused by a mutation in a different gene.

Like MEN1, MEN4 often causes hyperparathyroidism. Tumors may also form in the pituitary glands, other endocrine glands, and nonendocrine tissue, including lipomas (benign tumors of the fat cells) and meningiomas (benign tumors of the lining of the brain or spinal cord).

Symptoms

MEN4 symptoms are often caused by hyperparathyroidism, which raises calcium levels in the blood. Symptoms usually include bone pain, bone thinning, and kidney stones. Muscle weakness, fatigue, and depression are other common symptoms.

If tumors form in the pituitary gland, it may cause cessation of menstruation in people who menstruate.

Causes

MEN4 is caused by a mutation in the CDKN1B gene. This gene instructs cells to make the p27 protein. P27 suppresses the formation of tumors by controlling cell division and growth. 

People with MEN4 usually inherit it from one affected parent through an autosomal dominant pattern of inheritance. Very occasionally, a person with no family history of MEN4 will have the disorder.

How Do You Know If You Have MEN Syndrome?

The overwhelming majority of people with MEN syndromes have a close relative, such as a parent or sibling, with the condition. If you're concerned that you or your child may have inherited MEN syndrome, genetic testing can be done, even if there are no symptoms. Genetic testing identifies the genetic mutations that cause MEN syndromes.

Genetic testing is also called DNA testing. It is done with either a blood or saliva sample. Once you know that you or your child has MEN syndrome, screening for complications, like the formation of tumors, can help you manage the condition more effectively. It can also mitigate the risk of certain cancers, like thyroid cancer.

Your healthcare provider may recommend diagnostic testing for MEN syndromes if you meet any of these criteria:

• Family history of MEN syndromes, plus one tumor associated with MENs
• Two tumors associated with MENs
• Physical characteristics that might indicate MEN2
• You have hyperparathyroidism

Diagnostic tests for MEN syndromes include:

• Blood and urine tests that measure hormones, blood sugar, and calcium levels
• Imaging tests of the endocrine system to look for tumors and gland enlargement. These tests may include sonograms, magnetic resonance imaging tests (MRIs), and computed tomography (CT) scans

Treatment to Remove MEN Syndrome Tumors 

MEN syndrome tumors can form at any time during childhood or adulthood. Typically, MEN tumors start to form during the teens or twenties. Treatment for MEN tumors varies based on their location and whether or not they are benign or cancerous.

Small, benign tumors may be left intact, provided they don't grow or cause symptoms. Tumor growth will be monitored through ongoing imaging tests.

Sometimes, tumors may be treated with medicines that shrink them in size. This helps eliminate the symptoms they cause, such as severe gastric acid production.

It is very common for people with MEN syndromes to have many tumors at once. Even benign tumors can cause health problems due to the hormonal disruption they cause. These tumors are often removed surgically. Tumors in the parathyroid glands may warrant the removal of the entire gland.

Children diagnosed early with MEN2 may have their thyroid removed, even if they have no symptoms. This helps eliminate the risk of thyroid cancer.

Malignant tumors are usually removed surgically. Sometimes, they may be burned or frozen rather than surgically excised (removed by cutting). Additional treatments may also be used, particularly if metastasis (spread) has occurred. These treatments include targeted therapy, chemotherapy, and radiation.

Specialists and Organizations

If you have, or suspect that you have an MEN syndrome, your healthcare provider will recommend that you see an endocrinologist. Endocrinologists are specialists who treat diseases and disorders of hormonal glands and the endocrine system. If surgery is required, you will be treated by an endocrine surgeon.

To learn more and get support from professionals and peers with MEN syndromes, reach out to these organizations:

• American Multiple Neoplasia Support (AMEN Support)
• Association for Multiple Endocrine Neoplasia Disorders (AMEND USA)

Follow-Up Testing With MEN Syndromes

 It is possible to have tumors grow back after surgical removal. Monitoring for gland growth and new tumor formation will most likely become part of your normal routine.

Your endocrinologist will advise you on the frequency needed for follow-up testing. Follow-ups usually include imaging tests and blood tests.

Summary

MEN syndromes are a group of rare genetic disorders that cause tumor growth in the endocrine system. The vast majority of people with MEN syndromes have a family history of the condition.

MEN syndromes are caused by gene mutations. The type you have is determined by the affected gene.

MEN1 is the most common form of this disease. MEN2 is the second most common type. People with MEN2a or MEN2b are very likely to have complications that include familial medullary thyroid cancer. MEN4 is the rarest form of this disease. It presents with symptoms that are very similar or the same as MEN1.

Treatment depends on whether the tumors are benign or cancerous. They may be removed surgically. Ongoing monitoring with blood tests and imaging will screen for the development of new tumors or recurrence.