Multiple endocrine neoplasia syndromes are rare, inherited disorders in which several endocrine glands develop noncancerous (benign) or cancerous (malignant) tumors or grow excessively without forming tumors.
Multiple endocrine neoplasia syndromes are caused by gene mutations, so they tend to run in families.
There are several types of multiple endocrine neoplasia (MEN) syndromes, including MEN type 1 (MEN 1), MEN type 2A (MEN 2A), MEN type 2B (MEN 2B), and MEN type 4 (MEN 4).
Symptoms vary depending on which glands are affected.
Genetic screening tests can be done to confirm a diagnosis and identify which family members have multiple endocrine neoplasia syndromes.
No cure is available, but doctors treat the changes in each gland as they occur with surgery or with medications to control excess hormone production.
Multiple endocrine neoplasia syndromes can appear in infants or in people throughout life. These syndromes are usually inherited.
The tumors and the abnormally large glands often produce excess hormones. Although tumors or abnormal growth may occur in more than one gland at the same time, changes often take place over time.
Multiple endocrine neoplasia syndromes are caused by genetic mutations, which are usually inherited from a parent. A single gene responsible for MEN 1 has been identified. Abnormalities in a different gene have been identified in people with MEN 2A and MEN 2B , and a third gene is responsible for MEN 4.
Types of MEN Syndromes
Multiple endocrine neoplasia syndromes occur in four patterns, called MEN 1, MEN 2A, MEN 2B, and MEN 4, although the types occasionally overlap.
MEN type 1
People with multiple endocrine neoplasia type 1 develop tumors, or excessive growth and activity, of two or more of the following glands:
The parathyroid glands (the small glands located next to the thyroid gland in the base of the neck)
The pancreas
The pituitary gland
The adrenal glands (less often affected)
primary hyperparathyroidismkidney stones.
Many (30 to 90%) of people with MEN type 1 also develop tumors of the hormone-producing cells (islet cells) of the pancreas (also called pancreatic neuroendocrine tumors).
More than half of islet cell tumors produce excessive gastrin, which stimulates the stomach to overproduce acid. People with tumors that produce gastrin generally develop peptic ulcers that often bleed, develop holes (perforate), and leak stomach contents into the abdomen, or block the stomach. The high acid levels commonly interfere with the activity of enzymes from the pancreas, resulting in diarrhea and fatty, smelly stools (steatorrhea). Some of these tumors produce high levels of insulin and, consequently, very low levels of sugar in the blood (hypoglycemia), especially if the person has not eaten for several hours. The remaining islet cell tumors may produce other hormones, such as vasoactive intestinal polypeptide, which can cause severe diarrhea and lead to dehydration. Some islet cell tumors produce no hormones at all.
Some of the islet cell tumors are cancerous and able to spread (metastasize) to other areas of the body. In people who have MEN type 1, cancerous islet cell tumors tend to grow more slowly than cancerous islet cell tumors that develop in people who do not have this condition.
Some people with MEN type 1 develop pituitary gland tumors. Some of these tumors produce the hormone prolactin, causing menstrual abnormalities and often breast secretions (galactorrhea) in women who are not nursing and decreased sexual desire and erectile dysfunction (impotence) in men. Other tumors produce growth hormone, leading to acromegaly). A small percentage of pituitary tumors produce corticotropin, which overstimulates the adrenal glands, leading them to produce high levels of corticosteroid hormones and causing Cushing syndrome. A few pituitary tumors produce no hormones at all. Some pituitary tumors cause headaches, impaired vision, and decreased pituitary gland function by pressing against nearby parts of the brain.
In some people with MEN type 1, tumors or excessive growth and activity of the adrenal glands develop. A small percentage of people develop a different type of tumor, known as carcinoid tumors. Some people also develop noncancerous growths just below the skin.
Women with MEN type 1 may be at higher risk of breast cancer.
MEN type 2A
People with multiple endocrine neoplasia type 2A develop tumors or excessive growth and activity in two or three of the following glands:
The thyroid gland
The adrenal glands
The parathyroid glands
Occasionally, an itchy skin condition called cutaneous lichen amyloidosis occurs in people with MEN type 2A. Hirschsprung disease is present in 2 to 5% of people with MEN type 2A.
© Springer Science+Business Media
Image courtesy of Karen McKoy, MD.
Almost everyone with MEN type 2A develops medullary thyroid cancer. About 40 to 50% develop certain tumors of the adrenal glands (pheochromocytomas), which usually raise blood pressure because of the epinephrine and other substances they produce. The high blood pressure may be intermittent or constant and is often very severe.
kidney stones in about 25% of people.
MEN type 2B
Multiple endocrine neoplasia type 2B can consist of
Growths around nerves (neuromas)
Many people with MEN type 2B have no family history of it. In these people, the condition is the result of a new gene defect (genetic mutation).
The medullary thyroid cancer that occurs in MEN type 2B tends to develop at an early age and has been found in infants as young as 3 months of age. The medullary thyroid tumors in MEN type 2B grow faster and spread more rapidly than those in MEN type 2A.
Most people with MEN type 2B develop neuromas in their mucous membranes. The neuromas appear as glistening bumps around the lips, tongue, and lining of the mouth. Neuromas may also occur on the eyelids and glistening surfaces of the eyes, including the conjunctiva and cornea. The eyelids and lips may thicken, and the lips may turn inside out (become everted).
© Springer Science+Business Media
Digestive tract abnormalities cause constipation and diarrhea. Occasionally, the colon develops large, dilated loops (megacolon). These abnormalities probably result from neuromas growing on the intestinal nerves.
People with MEN type 2B often develop spinal abnormalities, especially curvature of the spine. They may also have abnormalities of the bones of the skull, feet, and thighs. Most people with MEN 2B have long limbs and loose joints and appear quite thin. Some of these abnormalities are similar to those that occur in Marfan syndrome.
MEN type 4
MEN type 4 is similar to MEN type 1 but is due to an abnormality in a different gene and is much less common. People with MEN type 4 develop tumors in their
Parathyroid glands
Pancreas
Pituitary gland
In people with MEN type 4, usually only one parathyroid gland is affected. In MEN type 1 , several parathyroid glands are affected. Also, people with MEN type 4 do not have the same skin symptoms as people with MEN type 1 do.
Diagnosis of MEN Syndromes
Genetic tests
Hormone levels in blood and urine
Sometimes imaging tests
Tests are available to identify the genetic abnormality present in each of the multiple endocrine neoplasia syndromes. Doctors usually do these genetic tests in people who have one of the tumors typical of multiple endocrine neoplasia and in family members of people already diagnosed with one of the syndromes. Screening of family members, sometimes even before birth, is particularly important because about half of the children of people with a multiple endocrine neoplasia syndrome inherit the disease. In rare cases, a person with multiple endocrine neoplasia may have normal genetic test results.
Blood and urine tests are done to detect elevated hormone levels.
Imaging tests, such as ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET), are also needed to help doctors determine locations of the tumors.
Treatment of MEN Syndromes
Tumor removal
Often removal of the thyroid gland
Medications
No overall cure is known for any of the multiple endocrine neoplasia syndromes. Doctors treat the changes in each gland individually.
A tumor is treated by removing it surgically when possible. Some small pancreatic islet cell tumors are not removed immediately but are monitored to see whether they are increasing and treated if they become large enough to cause problems. Before removal or if removal is not possible, doctors give medications to correct the hormone imbalance caused by gland overactivity. An excessively large and overactive gland without a tumor is treated with medications to counteract the effects of the overactivity.
Because medullary thyroid cancer is ultimately fatal if untreated, doctors will most likely recommend preventive surgical removal of the thyroid gland if genetic testing has revealed evidence of multiple endocrine neoplasia type 2A or type 2B. This preventive surgery is done even if the diagnosis of medullary thyroid cancer has not been made before the surgery. Unlike other types of thyroid cancer, this aggressive type of thyroid cancer cannot be treated with radioactive iodine. Once the thyroid is removed, people must take thyroid hormone for the rest of their lives. If thyroid cancer has spread, other treatments (such as chemotherapy or other drugs) can sometimes help the person live longer. Pheochromocytomas must be removed surgically after the person’s blood pressure has been controlled with appropriate drugs.
Because tumors may not all develop at the same time, people with multiple endocrine neoplasia may become anxious and worried about when or whether another tumor will develop. Periodic monitoring with blood and imaging studies is important but may add to the anxiety. Counseling may be needed to help people better understand their disease and cope with this anxiety.
