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Familial Multiple Endocrine Neoplasia Type 1


What is FMEN1?

Familial multiple endocrine neoplasia type 1 (FMEN1) is an inherited disorder that affects the endocrine glands. It is sometimes called familial multiple endocrine adenomatosis type 1 or Wermer's syndrome, after one of the first doctors to recognize it. FMEN1 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 FMEN1, usually 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 FMEN1.


How Does FMEN1 Affect the Endocrine Glands?

The Parathyroid Glands

The parathyroids are the endocrine glands most often affected by FMEN1. 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 a chemical called parathyroid hormone, which helps maintain a normal supply of calcium in the blood, bones, and urine.

In FMEN1, 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 FMEN1 will develop overactive parathyroid glands (hyperparathyroidism) by age 60, but the disorder can often be detected before age 20. Hyperparathyroidism may cause problems such as tiredness, weakness, muscle or bone pain, constipation, indigestion, kidney stones, or thinning of bones.

Treatment of Hyperparathyroidism. It is sometimes difficult to decide whether hyperparathyroidism in FMEN1 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 should continue, since the small piece of parathyroid tissue can grow back 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

The pancreas gland, located behind the stomach, releases digestive juices into the intestines and 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.
In FMEN1, one or more tumors producing high amounts of gastrin tend to develop in the pancreas and small intestine. Gastrin is a hormone that 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 FMEN1 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 FMEN1 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. Recently, however, researchers have identified very powerful blockers of stomach acid release, called acid pump inhibitors. Taken by mouth, these have proven effective in controlling most cases of ZollingerEllison 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 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 six persons with FMEN1. This overactivity can usually be traced to very small, benign tumors in the gland that release too much prolactin, called prolactinomas. 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.

Treatment of Prolactinomas. 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 be needed.


Rare Complications of FMEN1

Occasionally, a person who has FMEN1 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. 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 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 FMEN1 Cancerous?

The overactive endocrine glands associated with FMEN1 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 people with FMEN1. 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 FMEN1.

Another type of benign tumor often seen in people with FMEN1 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 FMEN1 tend to be numerous and small, but most are benign and do not release active hormones into the blood. A proportion of pancreatic islet cell tumors in FMEN1 are cancerous.

Treatment of Pancreatic Endocrine Cancer in FMEN1. Since the type of pancreatic endocrine cancer associated with FMEN1 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 cancers in FMEN1 before they spread and become 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 FMEN1.

Doctors agree that excessive release of certain hormones (such as gastrin) from pancreatic endocrine cancer in FMEN1 needs to be treated, and medications are often effective in blocking the effects of these hormones. Some tumors, such as insulinproducing 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 FMEN1 the Same in Everyone?

Although FMEN1 tends to follow certain patterns, it can affect a person's health in many different ways. Not only do the features of FMEN1 vary among members of the same family, but some families with FMEN1 tend to have a higher rate of prolactin-secreting pituitary tumors and a much lower frequency of gastrin-secreting pancreatic tumors.

In addition, the age at which FMEN1 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.


Can FMEN1 Be Cured?

There is no cure for FMEN1 itself, but most of the health problems caused by FMEN1 can be recognized at an early stage and controlled or treated before they become serious problems.

If you have been diagnosed with FMENl, it is important to get periodic checkups because FMEN1 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 FMEN1.


How Is FMEN1 Detected?

Each of us has millions of genes in each of our cells, which determine how our cells and bodies function. In people with FMEN1, there is a mutation, or mistake, in one gene. A carrier is a person who has the FMEN1 gene mutation. The FMEN1 gene mutation is transmitted directly to a child from a parent carrying the gene.

In the next few years, scientists hope to develop a simple test that will identify the abnormal FMEN1 gene. Such a test would be given once in a person's lifetime to find out whether he or she has inherited the FMEN1 gene.

In the meantime, though, screening of close relatives of persons with FMEN1, who are at high risk, generally involves testing for hyperparathyroidism, the most common and usually the earliest sign of FMEN1. Any doctor can screen for hyperparathyroidism by testing the blood for calcium and sometimes one or two other substances such as ionized calcium and parathyroid hormone. An abnormal result indicates that the person probably has FMEN1, but a normal finding 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.


Why Screen for FMEN1?

FMEN1 is not an infectious or contagious disease, nor is it caused by environmental factors. Because FMEN1 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 blood chemical problems caused by FMEN1 many years before these complications develop. Finding these hormonal imbalances early enables your doctor to begin preventive treatment, reducing the chances that FMEN1 will cause problems later.


Who Should Be Screened for FMEN1?

Close relatives of persons with FMEN1, such as parents, brothers, sisters, and children have a 50 percent risk of having inherited the FMEN1 gene, and they should be screened. Though the abnormal gene is present before birth, it tends to become evident at varying ages and in different organs. A "silent" carrier has the gene but has not yet shown any hormonal disturbance caused by the gene. Periodic testing may also be considered in people whose nearest affected relative is a grandparent, uncle, or aunt (that is, a second-degree relative), if there is reason to believe that the parent may be a silent FMEN1 gene-carrier.


When and How Often Should Screening Be Done?

Hyperparathyroidism, most often the first sign of FMEN1, 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 FMEN1 gene. However, a person with normal testing beyond age 50 is very unlikely to have inherited the FMEN1 gene.


Should a Person Who Has FMEN1 Avoid Having Children?

A person who has FMEN1 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 FMEN1 has a 50-50 risk with each pregnancy of having a child with FMEN1. At present, it is difficult to detect FMEN1 before birth or even before age 15.

  • FMEN1 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 FMEN1 cannot be used to predict the severity of FMEN1 in a child.

  • FMEN1 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, productive adulthood.

  • Prolactin-releasing tumors in a man or woman 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.


Research in FMEN1

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 FMEN1. Researchers have begun to locate the FMEN1 gene by showing that it is on chromosome 11. Researchers have also suggested that the FMEN1 gene contributes to common endocrine tumors outside of the familial setting.


Additional Information

After reading this fact sheet, you may think of questions that you would like answered. Some sources of additional information are medical textbooks, physicians, nurses, and genetic counselors. Genetic counseling can help couples through the decision-making process about family planning. Genetic counselors provide information but do not tell anyone what to do.

The following articles about FMEN1 can be found in medical libraries, some college and university libraries, and through interlibrary loan in most public libraries.

Metz, D. C., Jensen, R. T., Bale, A., Skarulis, M.C., Eastman, R.C., Nieman, L., Norton, J.A. Friedman, E., Larson, C., Amorosi, A., Brandi, M.L., Marx, S.J., "Multiple endocrine neoplasia type 1: Clinical features and management," in The Parathyroids, ed by Bilezekian, J.P., Levine, M.A., and Marcus R. Raven Press, 1994, 591-646.

Friedman, E., Larsson, C., Amorosi, A., Brandi, M.L., Bale, A., Metz, D., Jensen, R.T., Skarulis, M., Eastman, R.C., Nieman, L., Norton, J.A., Marx, S.J., "Multiple endocrine neoplasia type 1: Pathology, pathophysiology, and differential diagnosis," in Bilezekian et al, 647-680.


Other Resources

The following organizations might also be able to assist with certain types of information:

Office of Health Research Reports
National Institute of Diabetes and Digestive and Kidney Diseases
Building 31, Room 9A04
Bethesda, MD 20892

March of Dimes/Birth Defects Foundation
1275 Mamaroneck Avenue
White Plains, NY 10605
(914) 428-7100

Alliance for Genetic Support Groups
35 Wisconsin Circle, Suite 440
Chevy Chase, MD 20815
1-800-336-GENE or (301) 652-5553

This publication 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 Office.

This epub is not copyrighted. Readers are encouraged to duplicate and distribute as many copies as needed. Printed single copies may be obtained from NlDDK's Office of Health Research Reports at the address given under "Other Resources" in this etext.


NIH Publication No. 96-3048
October 1996

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