The multiple endocrine neoplasia (MEN) syndromes are three related
inherited disorders affecting the thyroid and other hormone producing
(endocrine) glands of the body. Before the early 2000s, MEN was called
familial endocrine adenomatosis.
There are three types of MEN: MEN 1 (Wermer's syndrome), MEN 2A
(Sipple syndrome), and MEN 2B (previously known as MEN 3). All MEN types
are the result of inherited genetic mutations that predispose the
individual to excessive growth of cells (hyperplasia) and tumor formation
in multiple endocrine glands. For all types of MEN, the children of an
affected individual have a 50 percent chance of inheriting the defective
gene that causes the disorder.
MEN 1 is uncommon and occurs in only about one of every 30,000
individuals. The disorder runs in families, and males are twice as likely
to develop the disorder as females. Individuals with MEN 1 can show
symptoms of excessive parathyroid secretion by age five, and almost all
individuals with MEN 1 show parathyroid symptoms by age 40.
MEN 2 affects about one in every 40,000 individuals. MEN 2A is ten to 20
times more common than MEN 2B.
Causes and symptoms
MEN 1 is caused by a mutation at the PYGM gene on chromosome 11. PYGM is
one of a group of genes known as tumor suppressor genes that help to
control cell division. An individual who inherits one defective copy of a
tumor suppressor gene from either parent has a strong likelihood of
developing MEN 1, because there is a high probability of another mutation
developing in the other copy of the PYGM gene at some point during the
thousands of cell divisions that occur with growth and development. When a
second mutation occurs, the cell that contains the mutation no longer has
any normal copy of the tumor suppressor gene. When both copies are
defective, tumor suppression fails and tumors develop.
As a result, individuals with MEN 1 have uncontrolled cell growth and
develop tumors in several endocrine glands, including the parathyroid
glands (80–95% of patients), the pancreas (about 50% of patients)
and the pituitary (around 25% of patients). The most frequent symptom of
MEN 1 is hyperparathyroidism, which is excessive growth of the parathyroid
gland and excessive secretion of parathyroid hormone. This condition leads
to increased amounts of calcium in the blood, kidney stones, weakened
bones, and nervous system depression. Children with MEN 1 can show signs
of hyperparathyroidism as young as age five.
Tumors of the pancreas, known as gastrinomas, are also common in MEN 1.
Excessive secretion of gastrin (a hormone secreted into the stomach to aid
in digestion) by these tumors can cause upper gastrointestinal ulcers. The
anterior pituitary gland and the adrenal glands can also be affected.
Unlike MEN 2, the thyroid gland is rarely involved in MEN 1 symptoms.
Children with MEN1 rarely develop tumors of the pancreas until they reach
There are two types of MEN 2. Both MEN 2A and MEN 2B are caused by
mutations in another gene, known as RET. A mutation in only one copy of
the RET gene is sufficient to cause disease. A number of different
mutations can lead to MEN 2A, but only one specific genetic alteration
causes MEN 2B.
Patients with both MEN 2A and MEN 2B experience two main symptoms,
(MTC) and a tumor of the adrenal gland medulla known as pheochromocytoma.
MTC is a slow-growing cancer, but one that can be cured in less than 50
percent of cases. Pheochromocytoma is usually a benign (noncancerous)
tumor that causes excessive secretion of adrenal hormones. This, in turn,
can cause life-threatening high blood pressure (
) and irregular heart beat (cardiac arrhythmia).
The two forms of MEN 2 are distinguished by other symptoms. Individuals
with MEN 2A have a predisposition to develop tumors of the parathyroid
gland. Although similar to MEN 1, less than 20 percent of MEN 2A patients
show parathyroid involvement.
Individuals with MEN 2B show a variety of additional conditions: a
characteristic facial appearance with swollen lips; tumors of the mucous
membranes of the eye, mouth, tongue, and nasal cavity; enlarged colon; and
skeletal abnormalities. Symptoms develop early in life (often before five
years of age) in cases of MEN 2B and the medullary thyroid cancer is much
more aggressive and may develop in patients who are one year old.
Since MEN is inherited and runs in families, the doctor should be informed
of this history when the child is born, so that genetic testing can be
In the past, classical diagnosis of MEN was based on clinical features and
on testing for elevated hormone levels. For MEN 1, the relevant hormone
was parathyroid hormone. For both types of MEN 2, the greatest concern is
development of medullary thyroid cancer. MTC
can be detected by measuring levels of the thyroid hormone, calcitonin.
Numerous other hormone levels can be measured to assess the involvement of
the various other endocrine glands.
Diagnosis of MEN 2B can be made by physical examination alone. However,
MEN 2A shows no distinct physical features and must be identified by
measuring hormone levels or by finding endocrine tumors.
Since 1994, genetic screening using DNA technology has been available for
both MEN 1 and MEN 2. This methodology allows diagnosis before the onset
of symptoms. Before the development of genetic testing, there was no way
to definitively identify which children had inherited the defective gene.
As a result, all offspring of individuals with MEN had to be considered at
risk. In the case of MEN 2A and MEN 2B, children would undergo frequent
calcitonin testing. Molecular techniques as of the early 2000s allow a
positive distinction to be made between children who are and are not
carrying the defective genes that cause MEN.
As of 2004 no comprehensive treatment is available for genetic conditions
such as MEN. However, some of the consequences of MEN can be
symptomatically treated. Pheochromocytoma in both types of MEN 2 can be
cured by surgical removal of this slow growing tumor.
Treatment of MTC is by surgical removal of the thyroid. After
thyroidectomy, the patient receives normal levels of thyroid hormone by
mouth or by injection. Even when thyroid surgery is performed early,
metastatic spread of the cancer may have already occurred. Since MTC is
slow growing, metastasis may not be obvious. Metastasis is very serious in
and radiation therapy are not effective in controlling its spread.
—A pair of endocrine glands (glands that secrete hormones
directly into the bloodstream) that are located on top of the kidneys.
The outer tissue of the glands (cortex) produces several steroid
hormones, while the inner tissue (medulla) produces the hormones
epinephrine (adrenaline) and norepinephrine.
—Refers to glands that secrete hormones circulated in the
bloodstream or lymphatic system.
Medullary thyroid cancer
—A slow-growing tumor associated with multiple endocrine
—An abnormal formation of new tissue. A neoplasm may be malignant
—A five-inch-long gland that lies behind the stomach and next to
the duodenum. The pancreas releases glucagon, insulin, and some of the
enzymes which aid digestion.
—A pair of glands adjacent to the thyroid gland that primarily
regulate blood calcium levels.
—A chemical substance produced by the parathyroid glands. This
hormone plays a major role in regulating calcium concentration in the
—A tumor that originates from the adrenal gland's
chromaffin cells, causing overproduction of catecholamines, powerful
hormones that induce high blood pressure and other symptoms.
—The most important of the endocrine glands (glands that release
hormones directly into the bloodstream), the pituitary is located at the
base of the brain. Sometimes referred to as the "master
gland," it regulates and controls the activities of other
endocrine glands and many body processes including growth and
reproductive function. Also called the hypophysis.
—An endocrine gland in the neck overlying the windpipe (trachea)
that regulates the speed of metabolic processes by producing a hormone,
As of 2004 there is no way to block the occurrence of genetic mutations
that cause MEN. One of the most serious consequences of MEN is MTC.
Children who are identified as carriers of the RET gene can be offered
total thyroidectomy as a preventative (prophylactic) measure to prevent
the development of MTC.
MEN is an inherited disorder. Individuals who have MEN in their families
may wish to get genetic counseling before attempting a pregnancy.
Gagel, Robert F., and Stephen J. Marx. "Multiple Endocrine
Williams Textbook of Endocrinology
, 10th ed. Edited by P. Reed Larsen. Philadelphia: Saunders, 2003.
Alliance of Genetic Support Groups.
4301 Connecticut Avenue NW, Suite 404, Washington, DC 20008–2304.
Web site: http://www.geneticalliance.org.
Pituitary Network Association.
223 East Thousand Oaks Blvd. #320, Thousand Oaks, CA 91360. Web site:
Radebold, Klaus, and Christian A. Kock. "Multiple Endocrine
, July 26, 2004. Available online at
http://www.emedicine.com/ped/topic1496.htm (accessed January 13,