Multiple endocrine neoplasia type 1
Multiple endocrine neoplasia
type 1 (MEN1) is an inherited disorder that affects the endocrine
glands. It is sometimes called multiple endocrine adenomatosis or
Wermer's syndrome, after one of the first doctors to recognize it.
MEN1 is quite rare, occurring in about 3 to 20 persons out of
100,000. It affects both sexes equally and shows no geographical,
racial, or ethnic preferences.
Endocrine glands are different from other organs in the body because
they release hormones into the bloodstream. Hormones are powerful
chemicals that travel through the blood, controlling and instructing
the functions of various organs. Normally, the hormones released by
endocrine glands are carefully balanced to meet the body's needs.
In patients with MEN1, sometimes more than one group of endocrine
glands, such as the parathyroid, the pancreas, and the pituitary
become overactive at the same time. Most people who develop
overactivity of only one endocrine gland do not have MEN1.
How Does MEN1 Affect the
The Parathyroid Glands
The parathyroids are the
endocrine glands earliest and most often affected by MEN1.
The human body normally has four parathyroid glands, which
are located close to the thyroid gland in the front of the
neck. The parathyroids release into the bloodstream a
chemical called parathyroid hormone, which helps maintain a
normal supply of calcium in the blood, bones, and urine.
In MEN1, all four parathyroid glands tend to be overactive.
They release too much parathyroid hormone, leading to excess
calcium in the blood. High blood calcium, known as
hypercalcemia, can exist for many years before it is found
by accident or by family screening. Unrecognized
hypercalcemia can cause excess calcium to spill into the
urine, leading to kidney stones or kidney damage.
Nearly everyone who inherits
a susceptibility to MEN1 (a "carrier") will develop
overactive parathyroid glands (hyperparathyroidism) by age
50, but the disorder can often be detected before age 20.
Hyperparathyroidism may cause no problems for many years or
it may cause problems such as tiredness, weakness, muscle or
bone pain, constipation, indigestion, kidney stones, or
thinning of bones.
It is sometimes difficult to decide whether
hyperparathyroidism in MEN1 is severe enough to need
treatment, especially in a person who has no symptoms. The
usual treatment is an operation to remove the three largest
parathyroid glands and all but a small part of the fourth.
After parathyroid surgery, regular testing of blood calcium
should continue, since the small piece of remaining
parathyroid tissue can grow larger and cause recurrent
hyperparathyroidism. People whose parathyroid glands have
been completely removed by surgery must take daily
supplements of calcium and vitamin D to prevent hypocalcemia
(low blood calcium).
The pancreas gland, located
behind the stomach, releases digestive juices into the
intestines and releases key hormones into the bloodstream.
Some hormones produced in the islet cells of the pancreas
and their effects are:
Gastrin is another hormone that
can be oversecreted in people with MEN1. The gastrin comes
from one or more tumors in the pancreas and small intestine.
Gastrin normally circulates in the blood, causing the
stomach to secrete enough acid needed for digestion. If
exposed to too much gastrin, the stomach releases excess
acid, leading to the formation of severe ulcers in the
stomach and small intestine. Too much gastrin can also cause
- insulin--lowers blood
- glucagon--raises blood
About one in three patients
with MEN1 has gastrin-releasing tumors, called gastrinomas.
(The illness associated with these tumors is sometimes
called Zollinger-Ellison syndrome.) The ulcers caused by
gastrinomas are much more dangerous than typical stomach or
intestinal ulcers; left untreated, they can cause rupture of
the stomach or intestine and even death.
Treatment of Gastrinomas.
The gastrinomas associated with MEN1 are difficult to cure
by surgery, because it is difficult to find the multiple
small gastrinomas in the pancreas and small intestine. In
the past, the standard treatment for gastrinomas was the
surgical removal of the entire stomach to prevent acid
production. The mainstay of treatment is now very powerful
medicines that block stomach acid release, called acid pump
inhibitors. Taken by mouth, these have proven effective in
controlling most cases of Zollinger-Ellison syndrome.
The Pituitary Gland
The pituitary is a small
gland inside the head, behind the bridge of the nose. Though
small, it produces many important hormones that regulate
basic body functions. The major pituitary hormones and their
The pituitary gland becomes
overactive in about one of four persons with MEN1. This
overactivity can usually be traced to a very small, benign
tumor in the gland that releases too much prolactin, called
a prolactinoma. High prolactin can cause excessive
production of breast milk or it can interfere with fertility
in women or with sex drive and fertility in men.
formation of breast milk, influences fertility, and
influences bone strength;
hormone--regulates body growth, especially during
(ACTH)--stimulates the adrenal glands to produce
- thyrotropin (TSH)--stimulates
the thyroid gland to produce thyroid hormones;
- luteinizing hormone (LH)--stimulates
the ovaries or testes to produce sex hormones that
determine many features of "maleness" or "femaleness";
- follicle stimulating
hormone (FSH)--regulates fertility in men through sperm
production and in women through ovulation.
Most prolactinomas are small, and treatment may not be
needed. If treatment is needed, a very effective type of
medicine known as a dopamine agonist can lower the
production of prolactin and shrink the prolactinoma.
Occasionally, prolactinomas do not respond well to this
medication. In such cases, surgery, radiation, or both may
Rare Complications of MEN1
Occasionally, a person who has MEN1 develops islet tumors of
the pancreas that secrete high levels of pancreatic hormones
other than gastrin. Insulinomas, for example, produce too
much insulin, causing serious low blood sugar, or
hypoglycemia. Pancreatic tumors that secrete too much
glucagon or somatostatin can cause diabetes, and too much
vasoactive intestinal peptide can cause diarrhea.
Other rare complications
arise from pituitary tumors that release high amounts of
ACTH, which in turn stimulates the adrenal glands to produce
excess cortisol. Pituitary tumors that produce growth
hormone cause excessive bone growth or disfigurement.
Another rare complication is
an endocrine tumor inside the chest or in the stomach, known
as a carcinoid. In general, surgery is the mainstay of
treatment for all of these rare types of tumors, except for
gastric carcinoids which usually require no treatment.
Are the Tumors Associated
With MEN1 Cancerous?
The overactive endocrine glands associated with MEN1 may
contain benign tumors, but usually they do not have any
signs of cancer. Benign tumors can disrupt normal function
by releasing hormones or by crowding nearby tissue. For
example, a prolactinoma may become quite large in someone
with MEN1. As it grows, the tumor can press against and
damage the normal part of the pituitary gland or the nerves
that carry vision from the eyes. Sometimes impaired vision
is the first sign of a pituitary tumor in MEN1.
Another type of benign tumor
often seen in people with MEN1 is a plum-sized, fatty tumor
called a lipoma, which grows under the skin. Lipomas cause
no health problems and can be removed by simple cosmetic
surgery if desired. These tumors are also fairly common in
the general population.
Benign tumors do not spread
to or invade other parts of the body. Cancer cells, by
contrast, break away from the primary tumor and spread, or
metastasize, to other parts of the body through the
bloodstream or lymphatic system.
The pancreatic islet cell
tumors associated with MEN1 tend to be numerous and small,
but most are benign and do not release active hormones into
the blood. Eventually, about half of MEN1 cases will develop
a cancerous pancreatic tumor.
Treatment of Pancreatic
Endocrine Cancer in MEN1.
Since the type of pancreatic endocrine cancer associated
with MEN1 can be difficult to recognize, difficult to treat,
and very slow to progress, doctors have different views
about the value of surgery in managing these tumors.
One approach is to "watch and
wait," using medical, or nonsurgical treatments. According
to this school of thought, pancreatic surgery has serious
complications, so it should not be attempted unless it will
cure a tumor that is secreting too much hormone.
Another school advocates
early surgery, perhaps when a tumor grows to a certain size,
to remove pancreatic endocrine cancer in MEN1 (even if it
does not over secrete a hormone) before it spreads and
becomes dangerous. There is no clear evidence, however, that
aggressive surgery to prevent pancreatic endocrine cancer
from spreading actually leads to longer survival for
patients with MEN1.
Doctors agree that excessive
release of certain hormones (such as gastrin) from
pancreatic endocrine cancer in MEN1 needs to be treated, and
medications are often effective in blocking the effects of
these hormones. Some tumors, such as insulin-producing
tumors of the pancreas, are usually benign and single and
are curable by pancreatic surgery. Such surgery needs to be
considered carefully in each patient's case.
Is MEN1 the Same in
Although MEN1 tends to follow certain patterns, it can
affect a person's health in many different ways. Not only do
the features of MEN1 vary among members of the same family,
but some families with MEN1 tend to have a higher rate of
prolactin-secreting pituitary tumors and a much lower
frequency of gastrin-secreting tumors.
In addition, the age at which
MEN1 can begin to cause endocrine gland overfunction can
differ strikingly from one family member to another. One
person may have only mild hyperparathyroidism beginning at
age 50, while a relative may develop complications from
tumors of the parathyroid, pancreas, and pituitary by age
Sometimes a patient with MEN1
knows of no other case of MEN1 among relatives. The
commonest explanations are that knowledge about the family
is incomplete or that the patient carries a new MEN1
Can MEN1 Be Cured?
There is no cure for MEN1 itself, but most of the health
problems caused by MEN1 can be recognized at an early stage
and controlled or treated before they become serious
If you have been diagnosed
with MENl, it is important to get periodic checkups because
MEN1 can affect different glands, and even after treatment,
residual tissue can grow back. Careful monitoring enables
your doctor to adjust your treatment as needed and to check
for any new disturbances caused by MEN1. Most people with
MEN1 will have long and productive lives.
How Is MEN1 Detected?
Each of us has millions of genes in each of our cells, which
determine how our cells and bodies function. In people with
MEN1, there is a mutation, or mistake, in one gene of every
cell. A carrier is a person who has the MEN1 gene
mutation. The MEN1 gene mutation is transmitted
directly to a child from a parent carrying the gene
The MEN1 gene was very
recently identified. As of 2001, a small number of centers
around the world have begun to offer MEN1 gene
testing on a research or commercial basis. The likelihood of
finding a mutation in an MEN1 family has varied from 60
percent to 94 percent depending on methods. When a mutation
is found, further testing in other relatives can become much
easier. Many relatives can be tested once and be found
without the known MEN1 mutation in their family, and
then they can be freed from uncertainty and from any further
testing ever for MEN1. When a mutation is not found in a
family or isolated case, it does not prove that no MEN1
mutation is present. Depending on the clinical and
laboratory information, it may still be very likely that a
mutation is present but undetected.
In the meantime, though,
screening of close relatives of persons with MEN1, who are
at high risk, generally involves testing for
hyperparathyroidism, the most common and usually the
earliest sign of MEN1. Any doctor can screen for
hyperparathyroidism by testing the blood for total calcium
and sometimes one or two other substances such as ionized
calcium and parathyroid hormone. An abnormal result
indicates that the person probably has MEN1, but a normal
finding in all cannot rule out the chance that he or she
will develop hyperparathyroidism at a later time. Blood
testing can usually show signs of early hyperparathyroidism
many years before symptoms of hyperparathyroidism occur.
What is the Role for Genetic
Counseling with MEN1 Gene Testing?
Genetic counseling, which should accompany the gene testing,
can assist family member(s) to address how the test results
affect them individually and as a family. In genetic
counseling, there can be a review and discussion of issues
about the psychosocial benefits and risks of the genetic
testing results. Genetic testing results can affect
self-image, self-esteem, and individual and family identity.
In genetic counseling, issues related to how and with whom
genetic test results will be shared and their possible
effect on important matters such as health and life
insurance coverage can be reviewed and discussed. The times
for these discussions can be when a family member is
deciding whether or not to go ahead with the gene testing
and again later when the gene testing results are available.
The person, who provides the genetic counseling to the
family member(s), may be a professional from the disciplines
of genetics, nursing, or medicine.
Who Should Consider MEN1
Who Should Consider MEN1
Screening by Gene Testing?
Screening may be offered to
persons with MEN1 or with features resembling it. Affected
relatives of persons with MEN1 can be tested. Asymptomatic
offspring, brothers, or sisters of a person with MEN1 were
born with a 50 percent chance of having inherited the gene;
they too can be offered gene testing. While gene testing for
certain genes can be definitive at any age, it is usually
not offered to children below age 18 unless the test outcome
would have an important effect on their medical treatment.
Since treatable tumors occasionally begin by age 5 in MEN1,
gene testing and tumor surveillance can begin at age 5.
Who Should Consider MEN1
Screening by Laboratory Tests?
MEN1 screening by gene testing
will be the most definitive test, when it is available.
However, it is not yet widely available, and, when no gene
mutation is found in a MEN1 family, then it may be necessary
to rely upon laboratory tests for diagnosis.
Hyperparathyroidism, most often the first sign of MEN1, can
usually be detected by blood tests between the ages of 15
and 50. Periodic testing should begin around age 10 and be
repeated every year. There is no age at which periodic
testing should stop, since doctors cannot rule out the
chance that a person has inherited the MEN1 gene
mutation. However, a person with normal testing beyond age
50 is very unlikely to have inherited the MEN1 gene
Why Screen for MEN1 Tumors?
MEN1 is not an infectious or contagious disease, nor is it
caused by environmental factors. Because MEN1 is a genetic
disorder inherited from one parent, and its transmission
pattern is well understood, family members at high risk for
the disorder can be easily identified.
Testing can detect the
problems caused by MEN1 tumors many years before their later
complications develop. Finding these tumors early enables
your doctor to begin preventive treatment, reducing the
chances that MEN1 will cause problems later.
Should a Person Who Has MEN1
Avoid Having Children?
person who has MEN1 or who has a positive MEN1 gene
mutation may have a hard time deciding whether to have a
child. No one can make this decision for anyone else, but
some of the important facts can be summarized as follows:
- A man or a woman with
MEN1 has a 50-50 risk with each pregnancy of having a
child with MEN1.
- MEN1 tends to fit a
broad pattern within a given family, but the severity of
the disorder varies widely from one family member to
another. In particular, a parent's experience with MEN1
cannot be used to predict the severity of MEN1 in a
- MEN1 is a problem that
does not usually develop until adulthood. Treatment may
require regular monitoring and considerable expense, but
the disease usually does not prevent an active,
tumors in a man or woman with MEN1 may inhibit fertility
and make it difficult to conceive. Also,
hyperparathyroidism in a woman during pregnancy may
raise the risks of complications for mother and child.
Genetic counseling can help individuals and couples through
the decision-making process with family planning. Genetic
counselors will provide information to help with the
decision-making process, but they will not tell individuals
or couples what decision to make or how to make it.
Research in MEN1
The National Institute of Diabetes and Digestive and Kidney
Diseases (NIDDK) was established by Congress in 1950 as part
of the National Institutes of Health (NIH), whose mission is
to improve human health through biomedical research. The NIH
is the research arm of the Public Health Service under the
U.S. Department of Health and Human Services.
The NIDDK conducts and
supports a variety of research in endocrine disorders,
including MEN1. NIDDK and other NIH researchers isolated the
MEN1 gene in 1997. Researchers have also shown that the
MEN1 gene contributes to common endocrine tumors outside
of the setting.
After reading this e-text, you may think of questions that
you would like answered. Some sources of additional
information are medical textbooks, physicians, nurses, and
The following articles about
MEN1 can be found in medical libraries, some college and
university libraries, and through interlibrary loan in most
Guru, S.C., Manickam, P., Olufemi, S., Collins, F.S. Emmert-Buck,
M.R., Debelenko, L.V., Zhuang, Z., Lubensky, I.A., Liotta,
L.A., Crabtree, J.S., Wang, Y., Roe, B.A., Weisemann, J.,
Boguski, M.S., Agarwal, S.K., Kester, M.B., Kim, Y.S.,
Heppner, C., Dong, Q., Spiegel, A.M., Burns, A.L., Marx, S.J.,
"Positional cloning of the gene for multiple endocrine
neoplasia-type 1," Science 276:404-407, 1997.
Marx SJ. Multiple endocrine
neoplasia type 1. In: Metabolic Basis of Inherited Diseases,
8th Ed. ed. Scriver CS, et al. McGraw Hill, NY, 2001. pp
Schussheim DH, Skarulis MC,
Agarwal SK, Simonds WF, Burns AL, Spiegel AM, Marx SJ. MEN1:
New clinical and basic findings. Trends Endocrinol Metab 12:
The following organizations might also be able to assist
with certain types of information:
Pituitary Network Association
223 East Thousand Oaks Blvd., #320
Thousand Oaks, CA 91360
Fax: (805) 557-1161
Office of Scientific and
National Institute of Diabetes and Digestive and Kidney
Building 31, Room 9A04
Bethesda, MD 20892
March of Dimes/Birth Defects
1275 Mamaroneck Avenue
White Plains, NY 10605
Alliance of Genetic Support
4301 Connecticut Avenue, NW., Suite 404
Washington, DC 20008-2304
Telephone: (202) 966-5557
Helpline: (800) 336-GENE (4363)
Fax: (202) 966-8553
This e-pub was written by
Stephen J. Marx, M.D. and reviewed by Robert T. Jensen,
M.D., both of the National Institute of Diabetes and
Digestive and Kidney Diseases. It is based in part on the
booklet, "Understanding Multiple Endocrine Neoplasia Type
1," published by the NIH Clinical Center's Communications