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 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 special 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 FMEN1, specific endocrine glands such as the parathyroid glands tend to become overactive. Also, it is common for people with FMEN1 to have more than one group of endocrine glands become overactive at the same time (for example, the parathyroids, pancreas, and pituitary), leading to complications that can vary greatly from one person to another. FMEN1 is quite rare, however, and most people who develop overactivity of 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. Overactive parathyroid glands secrete 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 parathyroid overactivity (hyperparathyroidism) by age 60. Hyperparathyroidism can 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 secretes key hormones into the bloodstream. Some hormones produced in the islet cells of the pancreas and their effects are listed below:

* gastrin-increases stomach acid;

* insulin-lowers blood sugar;

* glucagon-raises blood sugar;

* vasoactive intestinal peptide (VIP)-stimulates

many cells;

* somatostatin-inhibits many cells.

A common problem in FMEN1 is the tendency of the pancreas to develop one or more islet cell tumors that produce high amounts of gastrin. 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, which leads to the formation of severe stomach ulcers. Too much gastrin can also cause serious diarrhea.

Among persons with FMEN1 who have overactive glands, about one in three has gastrin-releasing pancreatic 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 cannot be cured by pancreatic surgery because it is nearly impossible to remove the gastrin-producing tumors without a dangerous operation. In the past, the standard treatment for gastrinomas was the surgical removal of the entire stomach. Recently, however, researchers have identified very powerful blockers of stomach acid release that 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 effects are:

* prolactin-controls formation of breast milk and influences fertility;

* 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 (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 medicine called bromocryptine lowers the production of prolactin and shrinks the prolactinoma. Occasionally, prolactinomas do not respond well to bromocryptine. In such cases, surgery, radiation, or both may be needed.

Rare Complications of FMEN1

Occasionally, a person who has FMEN1 develops 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, known as a carcinoid. In general, surgery is the mainstay of treatment for all of these rare types of tumors.

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 crowding nearby structures, but they 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.

An example of a benign tumor that may become quite large in people with FMEN1 is the pituitary tumor called prolactinoma. As it grows, the tumor can press against nearby tissues, damaging 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. These tumors are also fairly common in the general population.

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. Occasionally, however, pancreatic islet cell tumors in FMEN1 are cancerous. Treatment of Pancreatic Cancer in FMEN1. Since the type of pancreatic 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, methods of treatment. According to this school of thought, pancreatic surgery has serious complications, so surgery should not be attempted unless surgery will result in the cure of a tumor that is secreting too much of a hormone.

Another school advocates early surgery to try to remove pancreatic cancers in FMEN1 before they spread outside the pancreas. According to this view, surgery should be considered at an early stage in an attempt to cure cancers that might later become dangerous. There is no clear evidence, however, that aggressive surgery to prevent pancreatic cancer from spreading actually leads to longer survival in FMEN1. (Also, surgery of the pancreas rarely succeeds in removing all of the multiple, gastrin-producing tumors that are commonly found in FMEN1.)

Doctors agree that excessive release of certain hormones (such as gastrin) from pancreatic cancer in FMEN1 needs to be treated, and medications are often effective in blocking the effects of these hormones. The role of pancreatic surgery needs to be considered carefully in each patient's case, since some tumors (for example, insulin-producing tumors of the pancreas) are usually benign and single, thus curable by pancreatic surgery.

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 FMEN1, 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.

Is FMEN1 the Same in Everyone?

Although FMEN1 tends to follow certain patterns as described earlier, there is considerable variation in the ways FMEN1 can affect a person's health. 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 member may have only mild hyperparathyroidism beginning at age 50, while another may develop complications from tumors of the parathyroid, pancreas, and pituitary by age 20.

How Is FMEN1 Detected?

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 persons at high (50-50) risk generally involves testing for hyperparathyroidism. Hyperparathyroidism is 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 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 disturbances that are typical of early hyperparathyroidism many years before complications of hyprpairathyroidism occur.

Why Screen for FMEN1?

FMEN1 is not an infectious or contagious disease, nor is it caused by environmental factors. FMEN1 is a genetic disorder that can only be inherited from one parent. Because FMEN1's transmission pattern is so well understood, family members at high risk for the disorder can be easily identified. For this reason, screening can yield important information for people at high risk of inheriting FMEN1.

Testing is also useful because it can detect the blood chemical problems caused by FMEN1 many years before major complications develop. Finding these hormonal imbalances early enables your doctor to begin preventive treatment, reducing the chances that FMEN1 win cause problems later.

Who Should Be Screened for FMEN1?

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. The FMEN1 gene is transmitted directly to a child from a parent carrying the gene. The chances that any child of an FMEN1 "carrier" win inherit this disorder are 50-50.

The persons who should be screened are the first-degree relatives (parents, brothers, sisters, and children) of persons with FMEN1, since these family members are at 50-50 risk of already having inherited the FMEN1 gene. 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?

Most often, the first sign of FMEN1 is hyperparathyroidism, which can usually be detected by blood tests between ages 20 to 50. Periodic testing should begin around age 15 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, there is no way of detecting FMEN1 before birth or even before age 15, although such tests will probably become possible in the next 5 years.

* 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. NIDDK scientists recently showed that plasma from FMEN1 patients contains a growth factor that stimulates parathyroid cells. This factor may be the cause of hyperparathyroidism in FMEN1. Researchers have also begun to locate the FMEN1 gene by showing that it is on chromosome 11.

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 decisionmaking 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.

Brandi, M.L., Marx, S.J., Aurbach, G.D., and Fitzpatrick, L.A., "Familial Multiple Endocrine Neoplasia Type 1: A new look at pathophysiology." Endocrine Reviews, vol. 8, 1987, pp 391-404.

Larsson, C., Skogseid, B., Oberg, K., Nakamura, Y., and Nordenskgold, M., "Multiple Endocrine Neoplasia Type I Gene Maps to Chromosome 11 and Is Lost in Insulinoma." Nature, vol. 332, 1988, pp 85-87.

Marx, S.J., Vinik, A.I., Santen, R.J., Floyd, J.C. Jr., Mills, J., and Green J. III, "Multiple Endocrine Neoplasia Type 1: Assessment of laboratory tests to screen for the gene in a large kindred. Medicine, vol. 65, 1986, pp 226-241.

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

Budding 31, Room 9AO4

Bethesda, MD 20892

(301) 496-3583

March of Dimes/Birth Defects Foundation

1275 Mamaroneck Avenue

White Plains, NY 10605

(914) 428-7100

National Center for Education in Maternal

and Child Health

38th and R Streets, NW.

Washington, DC 20057

(202) 625-8400

This fact sheet was written by Stephen J. Marx, M.D., 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 fact sheet is not copyrighted. Readers are encouraged to duplicate and distribute as many copies as needed. Single copies may be obtained from NIDDK's Office of Health Research Reports at the address given under "Other Resources" in this fact sheet.

COPYRIGHT 1989 National Institute of Diabetes & Digestive & Kidney Diseases
COPYRIGHT 2004 Gale Group