MULTIPLE ENDOCRINE NEOPLASIA (MEN)MEN is where there is neoplasia of two or more endocrine glands. It is best characterised in humans. They are autosomal dominant disorders, but sporadic forms occur. Distinct syndromes occur. These are: MEN I, (Werner's syndrome)MEN 1 is a syndrome of parathyroid hyperplasia (and hyperparathyroidism), and pancreatic islet cell tumour with or without an anterior pituitary adenoma/carcinoma. Carcinoid tumours of the lung, thymus, and gastrointestinal system may also be present. MEN IIAThis syndrome exists when there is C-cell carcinoma (medullary thyroid carcinoma, MTC) and a phaeochromocytoma with or without parathyroid hyperplasia. MEN IIBThis is a syndrome of C-cell carcinoma, phaeochromocytoma, with or without multiple mucosal neuromas. MIXED MULTIPLE NEOPLASIA SYNDROMESThese are overlap syndromes where there are mixtures of the above conditions. MEN in animalsMultiple endocrine neoplasia is rare in animals. It is recorded in bulls where the syndrome is similar to MEN II. REFERENCESDeLellis RA (1995) Multiple endocrine neoplasia syndromes revisited. Laboratory Investigation 72: 494-503
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 recognise 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.
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Treatment of Hyperparathyroidism. 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 over-secreted in people with MEN1. The gastrin comes from one or more tumours 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 diarrhoea.
About one in three patients with MEN1 has gastrin-releasing tumours, called gastrinomas. (The illness associated with these tumours 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 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:
The pituitary gland becomes overactive in about one of four persons with MEN1. This over-activity can usually be traced to a very small, benign tumour 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.
Treatment of Prolactinomas.
Occasionally, a person who has MEN1 develops islet tumours 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 tumours that secrete too much glucagon or somatostatin can cause diabetes, and too much vasoactive intestinal peptide can cause diarrhoea.
Other rare complications arise from pituitary tumours that release high amounts of ACTH, which in turn stimulates the adrenal glands to produce excess cortisol. Pituitary tumours that produce growth hormone cause excessive bone growth or disfigurement.
Another rare complication is an endocrine tumour 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 tumours, except for gastric carcinoids which usually require no treatment.
The overactive endocrine glands associated with MEN1 may contain benign tumours, but usually they do not have any signs of cancer. Benign tumours 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 tumour 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 tumour in MEN1.
Another type of benign tumour often seen in people with MEN1 is a plum-sized, fatty tumour called a lipoma, which grows under the skin. Lipomas cause no health problems and can be removed by simple cosmetic surgery if desired. These tumours are also fairly common in the general population.
Benign tumours do not spread to or invade other parts of the body. Cancer cells, by contrast, break away from the primary tumour and spread, or metastasise, to other parts of the body through the bloodstream or lymphatic system.
The pancreatic islet cell tumours 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 tumour.
Treatment of Pancreatic Endocrine Cancer in MEN1. One approach is to "watch and wait," using medical, or non-surgical treatments. According to this school of thought, pancreatic surgery has serious complications, so it should not be attempted unless it will cure a tumour that is secreting too much hormone.
Another school advocates early surgery, perhaps when a tumour 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 tumours, such as insulin-producing tumours 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.
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 tumours and a much lower frequency of gastrin-secreting tumours.
In addition, the age at which MEN1 can begin to cause endocrine gland over-function 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 tumours 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 explanations are that knowledge about the family is incomplete or that the patient carries a new MEN1 gene mutation.
There is no cure for MEN1 itself, but most of the health problems caused by MEN1 can be recognised at an early stage and controlled or treated before they become serious problems.
If you have been diagnosed with MEN1, it is important to get periodic check-ups 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.
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 very recently identified. As of 2001, a small number of centres 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 ionised 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.
Genetic counselling, 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 counselling, 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 counselling, 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 counselling to the family member(s), may be a professional from the disciplines of genetics, nursing, or medicine.
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 tumours occasionally begin by age 5 in MEN1, gene testing and tumour surveillance can begin at age 5.
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 mutation.
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 tumours many years before their later complications develop. Finding these tumours early enables your doctor to begin preventive treatment, reducing the chances that MEN1 will cause problems later.
A 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 summarised as follows:
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 tumours 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 genetic counsellors.
The following articles about MEN1 can be found in medical libraries, some college and university libraries, and through interlibrary loan in most public libraries.
Chandrasekharappa, S.C., 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 943-966.
Schussheim DH, Skarulis MC, Agarwal SK, Simonds WF, Burns AL, Spiegel AM, Marx SJ. MEN1: New clinical and basic findings. Trends Endocrinol Metab 12: 173-178, 2001.
The following organisations might also be able to assist with certain types of information:
Office of Scientific and Health Information March of Dimes/Birth Defects Foundation Alliance of Genetic Support Groups 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 Centre's Communications Office.
E-text last reviewed: August 2001 |
