Multiple Endocrine Neoplasia
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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 multiple 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.
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 "cancer") 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:
- insulin--lowers blood sugar;
- glucagon--raises blood sugar;
- somatostatin--inhibits many cells.
- Gastrin is another hormone that can be over secreted in 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 serious diarrhea.
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.
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 the complications from high gastrin in most cases of Zollinger-Ellison
syndrome.
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 effects are:
- prolactin--controls formation of breast milk, influences fertility, and
influences bone strength;
- growth hormone--regulates body growth, especially during adolescence;
- adrenocorticotropin (ACTH)--stimulates the adrenal glands to produce cortisol;
- 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"; and
- follicle stimulating hormone (FSH)--regulates fertility in men through
sperm production and in women through ovulation.
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.
Some 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 be needed.
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Occasionally, a person who has MEN1 develops an islet tumor of the pancreas which
secretes 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 watery 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 a person with MEN1 a carcinoid tumor rarely
secretes a hormone. 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.
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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
or a cancerous carcinoid 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 prevent or 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. This is partly because these complex operations can have their own
side effects.
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.
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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
20.
Sometimes a patient with MEN1 knows of no other case of MEN1 among relatives.
The commonest explanation is that knowledge about the family is incomplete;
less often, the patient carries a new MEN1 gene mutation.
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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 problems.
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
MEN1 cases will have a long and productive life.
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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 mutation.
The MEN1 gene was recently identified. As of 2001, a small number of
centers around the world began 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 95 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.
When the MEN1 mutation test is normal in an effected relative or when the
test is not available, 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.
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Genetic counseling, which should accompany the gene testing, can assist family
member(s) 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.
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Screening may be offered to persons with MEN1 or with features resembling
them. 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 any genetic disease 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.
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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 5 and 50. Periodic
tumor testing should begin between ages 5 to 10 and be repeated every year.
There is no age at which periodic testing should stop, since (lacking a specific
DNA test) doctors cannot rule out the chance that a person has inherited the MEN1 gene
mutation. However, a person with normal tumor testing beyond age 50 is very
unlikely to have inherited the MEN1 gene mutation.
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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 50-50 risk for
the disorder can be easily identified.
Streamlined tumor testing can be used to identify an MEN1 carrier. After a
carrier is identified, more detailed tumor surveys are generally recommended.
Tumor 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.
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A person who has MEN1 or who has a 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 eventual severity
of MEN1 in a child.
- The tumor that result from MEN1 do not usually develop until adulthood.
Treatment may require regular monitoring and considerable expense, but the
disease usually does not prevent an active, productive adulthood.
- Prolactin-releasing 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 and other professionals
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.
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Alliance of Genetic
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