NORD gratefully acknowledges Maria Luisa Brandi, MD, PhD, Director, Regional Center for Hereditary Endocrine Tumors, University of Florence, Florence, Italy and President F.I.R.M.O. Foundation, for assistance in the preparation of this report.
Multiple endocrine neoplasia (MEN) type 1 is a rare genetic disorder characterized by multiple tumors arising from cells of specific neuroendocrine tissues. The endocrine system is the network of glands that secrete hormones into the bloodstream to reach their target organs along the entire body. These hormones regulate the chemical processes (metabolism) that influence the function of various organs and activities within the body. Hormones are involved in numerous vital and metabolic processes, including regulating heart rate, body temperature and blood pressure, as well as cell differentiation and growth.
In individuals with MEN type 1, tumors develop in multiple endocrine glands, principally the parathyroids, gastro-entero-pancreatic tract and pituitary gland. These affected glands secrete excessive amounts of hormones into the bloodstream, which can result in a variety of symptoms and related syndromes. Some tumors associated with MEN type 1 are cancerous (malignant) (i.e gastrinomas and carcinoids) and can spread to other organs (metastasize). Other, less frequent, clinical manifestations of the MEN1 syndrome are: neuroendocrine tumors of thymus and bronchi, adrenocortical tumors, lipomas, visceral leiomyomas, truncal and facial collagenomas, facial angiofibromas, breast carcinoma, meningioma and ependymomas. MEN type 1 can run in families or can occur as the result of a new gene mutation in the affected person.
MEN type 1-associated symptoms depend on which glands are affected by the overgrowth of tissue (hyperplasia) or tumor formation. Although most tumors are benign (noncancerous), tissue overgrowth or tumor formation causes the affected glands to become hyperactive and produce excess hormones. Elevated hormone levels are the main cause of MEN type 1-associated signs and symptoms. Certain tumors, such as gastrinomas and carcinoid tumors can potentially become malignant. The clinical expression of MEN type 1 is highly variable even within members of the same family and identical twins.
More than 20 different endocrine and non-endocrine tumors have been identified in individuals with MEN type 1. Affected individuals will not necessarily develop tumors at the same age or in the same locations and, therefore, they can manifest variable spectra of clinical signs and symptoms during their lifetime. Some individuals may only develop mild symptoms; others may develop serious, life-threatening complications. Some individuals may develop symptoms as young adults or adolescents; other may not develop symptoms until middle-age or older. It is important to note that individual cases are highly variable and that affected individuals will not develop all of the symptoms discussed below.
The most common affected endocrine glands in MEN type 1 are parathyroids, both as tissue hyperplasia and/or adenomas. More than 90 percent of individuals with MEN type 1 develop, by age 50, primary hyperparathyroidism (PHPT). Mean age of onset is the third decade of life. In some cases, hyperparathyroidism may be detected during adolescence and infancy (by the age of 5). PHPT is the first sign of MEN type 1 in about 90% of cases. Parathyroid glands are generally represented by four very small glands (approximately the size of a pea) located in the neck that secrete parathyroid hormone (PTH), which controls the homeostasis of serum calcium level. Hyperparathyroidism is the medical term indicating a constantly high level of circulating PTH.
PHPT can be very mild and may not cause any obvious symptoms (asymptomatic). Untreated hyperparathyroidism generally results in elevated serum level of calcium (hypercalcemia), which can cause kidney stones or damage the kidneys. Hyperparathyroidism can cause additional symptoms in some cases including fatigue, weakness, constipation, nausea, ulcers, indigestion, high blood pressure (hypertension), and muscle or bone pain. Central nervous system abnormalities can eventually develop including mental status changes, lethargy, depression, and confusion, as consequence of severe hypercalcemia. Some individuals may develop abnormal thinning of bones (osteoporosis), which can result in an increased risk of fragility fractures. Most individuals with hyperparathyroidism do not develop all of these symptoms, especially when the condition is diagnosed early.
PANCREAS AND DUODENUM
Approximately 40 percent of adults with MEN type 1 develope multiple gastrinomas, usually located in the first portion of duodenum, and more rarely in the pancreas. Approximately, 50% of MEN1-gastrinomas have already metastasized at the time of clinical diagnosis. The pancreas is a small gland located behind the stomach. It contains specialized endocrine cells called islet cells, which secrete several hormones including insulin (which lowers blood sugar levels), glucagon (which raises blood sugar levels), and hormones that travel to the intestines and aid in digestion such as gastrin. The duodenum is the first portion of the small intestine, which connects the intestines to the stomach.
Gastrinomas are benign tumors that secrete gastrin. Elevated levels of gastrin induce the stomach to release too much acid, which, in turn, can result in abdominal pain, diarrhea, backflow of the contents of the stomach into the esophagus (esophageal reflux) and peptic ulcers. This condition is clinically referred to as Zollinger-Ellison syndrome (ZES). Peptic ulcers are open sores lining the stomach, esophagus, and intestines. Peptic ulcers can cause a burning pain in the stomach, diarrhea, nausea, vomiting and fatty, smelly stools. In severe cases, peptic ulcers can cause serious complications including internal bleeding, vomiting up of blood, obstruction of the passage of food through the digestive tract (gastric outlet obstruction) or the development of a hole in the wall of the stomach or small intestines (perforation), allowing the contents of the stomach or intestines to leak into the abdomen.
Less common symptoms associated with gastrinomas include unintended weight loss and heartburn. Gastrinomas and other tumors that arise from islet cells can potentially become malignant and spread (metastasize) to other areas of the body, especially nearby lymph nodes and the liver.
Multiple gastrinomas are also found in a non-syndromic disorder called Zollinger-Ellison syndrome, which usually occurs randomly for unknown reasons.
Additional tumors can affect the pancreas. Insulinoma, a benign tumor that secretes insulin, is the second most common tumor affecting the pancreas, occurring in approximately 10 percent of individuals with MEN type 1. Insulinoma can cause low blood sugar (hypoglycemia), especially when not eating over a period of time (fasting). Hypoglycemia can cause a variety of symptoms including confusion, abnormal behavior, blurred vision, double vision, anxiety, heart palpitations, sweating and hunger.
Tumors that secrete too much glucagon or somatostatin (glucagonomas and somatostatinomas) can also occur in the pancreas. These tumors result in elevated levels of blood sugar (hyperglycemia). Hyperglycemia can cause diabetes.
In rare cases, individuals with MEN type 1 can develop a VIPoma, a tumor that secretes a hormone called vasoactive intestinal peptide (VIP). VIPomas can cause chronic, watery diarrhea and eventually cause dehydration.
In approximately 40 percent of cases, non-functioning pancreatic tumors, often multiple, small and scattered to the entire organ, may occur in MEN1 patients.
Approximately 25 percent of individuals with MEN type 1 develop benign overgrowth of the pituitary gland. In some cases, symptoms of pituitary gland involvement may be the first sign of the disorder. The pituitary is small pea-sized gland that sits in the base of brain and is sometimes called “the master gland” because it oversees the function of most of the endocrine glands in the body. The pituitary gland secretes a variety of different hormones including prolactin, which influences fertility and stimulates breast milk production; growth hormone, which regulates body growth especially during adolescence; and several hormones that stimulate the activity of other glands including the adrenal and thyroid glands and ovaries and testes.
Benign tumors that secrete prolactin (prolactinomas) are the most common pituitary gland tumors associated with MEN type 1. They are the third most common tumors associated with MEN type 1 after parathyroid tumors and gastrinomas. In women, prolactinomas can cause irregular menstrual periods (oligomenorrhea to amenorrhea), infertility, diminished sexual drive, painful intercourse and the production of breast milk in women who are not pregnant (galactorrhea). The most common clinical manifestations in males are impotence and gynecomastia.
Pituitary tumors, especially when more than 1 centimeter in diameter (macrodenoma), can result in additional symptoms because they can apply pressure upon other tissues of the brain. Resulting symptoms may include headaches and visual problems, such as blurred vision.
In addition to a prolactinoma, other tumors affecting the pituitary gland may occur. One of these tumors can secrete excess growth hormone resulting in a condition characterized by excessive bone growth and enlargement of certain structures of the body such as the jaw, hands and feet (acromegaly) in post-puberal patients. Another of these tumors may secrete adrenocorticotrophin (ACTH), a hormone that stimulates the adrenal glands, which results in excessive corticosteroid production. Excessive corticosteroid levels can eventually cause a condition called Cushing’s syndrome which is characterized by a wide variety of signs and symptoms including a rounded face (moon face), increased fat around the neck, weight gain around the midsection and upper back, muscle weakness, fatigue and high blood pressure.
Affected individuals may also have benign tumors that do not produce any hormones (non-functioning tumors). In approximately 20-40% of cases non-functioning tumors of the adrenal glands may occur. The adrenal glands are located on top of the kidneys. In rare cases, these tumors result in the overproduction of corticosteroid hormones and the development of Cushing’s syndrome.
Approximately 10-15% of individuals with MEN type 1 develop slow-growing carcinoid tumors. These tumors usually develop in the stomach (gastric carcinoids), the large tubes that carry air to and from the lungs (bronchial tubes) (bronchial carcinoids) and the thymus (thymic carcinoids), a small gland located in the upper chest just behind the breastbone. Carcinoid tumors of the bronchial tubes primarily affect women; carcinoid tumors of the thymus primarily affect men.
In most cases, these tumors do not produce hormones (non-functioning tumors) and usually do not cause any symptoms (asymptomatic), but they can present a rapid growth and malignant progression being responsible of some MEN1-asscociated deaths. In rare cases, carcinoid tumors may overproduce different hormones including ACTH, calcitonin, growth hormone releasing hormone (GHRH), serotonin, and histamine. When carcinoid tumors secrete serotonin, they can cause carcinoid syndrome, a condition characterized by migraines, diarrhea and episodes of feeling flushed.
Carcinoid tumors associated with MEN type 1 are usually identified later during life, with a mean diagnosis of age 50. These tumors may be benign, but malignant (cancerous) carcinoids can develop. Thymic carcinoids associated with MEN type 1 may be particularly aggressive, especially in male smokers.
ADDITIONAL ENDOCRINE TUMORS
In extremely rare cases, about 1%, a pheochromocytoma (PHEO) may occur in an individual with MEN type 1. Most PHEOs originate in the inner layer (medulla) of one of the two adrenal glands. Symptoms may include high blood pressure, headaches, excessive sweating, and heart palpitations. PHEOs occur much more often in individuals with multiple endocrine neoplasia type 2.
NON-ENDOCRINE BENIGN TUMORS
Several tumors that do not arise from endocrine cells may also occur in individuals with MEN type 1. The most common is lipoma, a benign tumor consisting of fat cells. Lipomas usually develop just under the surface of the skin and are common in the general population. Multiple lipomas often form. Lipomas are not usually associated with any symptoms. Some individuals with MEN type 1 may also develop benign raised, reddish spots on the face (angiofibromas), and benign, raised, whitish spots on the skin (collagenomas).
Less common, non-endocrine, benign tumors associated with MEN type 1 include tumors arising from the membranes (meninges) lining the brain and spinal cord (meningioma), tumors arising from smooth muscle cells (leiomyoma) and tumors arising from central nervous system tissue (ependymomas). These tumors generally do not cause any symptoms.
MEN type 1 is a rare genetic disorder caused by mutations of the MEN1 gene. The MEN1 gene encodes a nuclear protein known as menin. The exact role of menin is not fully understood. The MEN1 gene is a tumor suppressor gene, a gene that when it operates normally may have several functions including inhibiting cell division, repairing and replicating DNA, and instructing cells when to die (a normal process called apoptosis). When tumor suppressor genes malfunction, certain cells may continue to grow and reproduce causing tumor formation.
This genetic mutation may be inherited in an autosomal dominant pattern or occur as a new gene mutation in the affected person.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual at the embryo level. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females.
MEN type 1 affects males and females in equal numbers. It affects approximately 1 in 30,000 individuals. Some researchers believe that many cases of MEN type 1 go undiagnosed, making it difficult to determine its true frequency in the general population. The onset of the disorder can vary widely and it has been identified in children as young as 8 and adults as old as 80. MEN type 1 was first recognized as a genetic disorder in 1954.
Affected individuals may receive a diagnosis of MEN type 1 following a thorough clinical evaluation, a detailed patient and family history and the identification of at least two of the three characteristic endocrine tumors associated with the disorder (i.e., parathyroid and pituitary tumors and islet cell tumors in the pancreas or duodenum). Individuals with only one of the associated tumors and a positive family history of the disorder may also receive a diagnosis of MEN type 1. The identification of an inactivating MEN1 gene mutation is a genetic diagnosis of the syndrome, with a complete penetrance by the age of 55. A variety of tests to detect elevated levels of certain hormones in the blood may be necessary to aid in the identification of tumors. For example, identification of elevated levels of PTH together with hypercalcemia can indicate the presence of a parathyroid tumor. A variety of imaging scans may be performed to aid in identifying the size and location of specific tumors.
A diagnosis of MEN type 1 can be confirmed through genetic testing of the MEN1 gene, which can reveal the characteristic mutations of the MEN1 gene that causes the disorder. Individual clinical manifestations cannot be foreseen by the result of the genetic analysis (No direct genotype-phenotype correlation exists.).
The treatment of MEN type 1 may require the coordinated efforts of a team of specialists. Endocrinologists, surgeons, cancer specialists (oncologists), and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Treatment is directed toward the specific symptoms that are apparent in each individual and may include drugs to counteract the effects of excess hormones, surgical removal of tumors or ,medical therapies, such as SSAs, peptide receptor radionuclide therapy (PRRT), cytotoxic chemotherapy (i.e. streptozocin and 5-fluorouracil, doxorubicin, temozolomide with capecitabine), inhibitors of thyrosin kinase receptors (i.e. sunitinib), inhibitors of mammalian target of rapamycin (mTOR; i.e. everolimus), and rarely radiation therapy or stereotaxic radiosurgery to help shrink or destroy tumors.
Specific therapeutic procedures and interventions may vary depending upon numerous factors, such as primary tumor location; the size and type of tumor; the severity of symptoms due to excess hormone production; whether malignant tumors are present and whether they have spread to lymph nodes or distant sites; individual’s age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference; and other appropriate factors.
The main treatment for parathyroid tumors is surgery, although the best type of surgery and the best time for surgery is still controversial. Surgical removal of the parathyroid glands is called a parathyroidectomy. One approach is to remove three parathyroid glands entirely and a portion of the fourth (subtotal parathyroidectomy). There is a 50 percent risk that of recurrence of a parathyroid tumor with this method. Another approach is to remove all four glands (total parathyroidectomy). This procedure is usually followed by the transplantation of some of the apparently healthy parathyroid tissue into another area of the body (usually the nondominant forearm). Because of the high risk of disease recurrence, this would spare affected individuals from being operated on in the same area (i.e., the neck). In some cases, healthy parathyroid tissue is saved through cryopreservation (the process of cooling and storing tissue) and re-implanted at a later date Nonsurgical options in the treatment of MEN1-associated primary hyperparathyroidism, is cinacalcet in patients who do not meet the criteria for parathyroidectomy, for those who failed a previous intervention, or for those presenting recurrence who refuse to undergo any further surgical interventions.
Surgical removal of part or all of the parathyroid glands may result in hypoparathyroidism (low levels of parathyroid hormones and calcium in the blood). Affected individuals may require daily supplementation of calcium and vitamin D to prevent the effects of hypoparathyroidism.
Pituitary tumors that secrete prolactin (prolactinomas) may be treated with dopamine agonists, drugs that lower the levels of prolactin in the blood and shrink pituitary tumors. Some prolactinomas are small enough that no therapy is required. In cases where drug therapy is ineffective or cannot be tolerated, trans-sphenoidal surgery (procedure in which surgeons go through the cavity (sphenoid sinus) directly behind the nose) may be required.
Pituitary tumors that produce ACTH are usually treated by transsphenoidal surgery. In cases of persistent hypercortisolism after surgery the medical therapies used provides adrenal steroidogenesis inhibitors such as ketoconazole, metyrapone.
Pituitary tumors that produce GH are treated by transsphenoidal surgery. In patients with postoperative active disease pharmacological treatment includes SSAs (octreotide, lanreotide and pasireotide), dopamine agonist (cabergoline) and GH receptor antagonist (pegvisomant).
In all pituitary tumors stereotaxic radiosurgery can be used when medical therapy is unavailable, unsuccessful or not tolerated.
The objective of treatment for tumors that secrete gastrin (gastrinomas) is to reduce and control gastric acid hypersecretion with histamine-2 receptor antagonists (cimetidine, ranitidine, famotidine), proton pump inhibitors (PPIs; omeprazole, lansoprazole, pantoprazole) or somatostatin analogues (SSAs; octreotide and lanreotide).
Timing and type of surgery (i.e. Thompson procedure (i.e., wide longitudinal duodenotomy with excision of duodenal gastrinomas and of peri-pancreatic lymph nodes, pancreatoduodenectomy (PD), or duodenectomy with reimplants of the papilla) are still controversial.
Insulinomas are usually surgically removed through enucleation of the greatest pancreatic lesions or distal pancreatic resection preserving splenic vessels and spleen. If the tumor cannot be completely removed by surgery, the drug inhibits insulin release and it is able to control hypoglicemia in at least 50% of patients.
Non-functioning neuroendocrine tumors of the gastro-entero-pancreatic tract are usually treated by surgery. Surgery is indicated when the dimension of tumors is approximately 2 cm in diameter or when imaging exams during the follow-up shows a significant growth of lesions. In case of unresectable tumors or advanced metastatic cancer some medical therapies can be considered: SSAs, peptide receptor radionuclide therapy (PRRT), cytotoxic chemotherapy, inhibitors of thyrosin kinase receptors, inhibitors of mammalian target of rapamycin.
Carcinoid tumors are generally removed surgically. Medications including octreotide and lanreotide can be used to treat excess hormone production from these tumors, but the risk for malignant transformation remains. For this purpose, removal of thymus, through a transcervical approach, is recommended at the time of neck surgery for parathyroidectomy.
Lipomas may be removed surgically.
Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Contact for additional information about multiple endocrine neoplasia type 1:
Maria Luisa Brandi, MD, PhD
Center for Hereditary Endocrine Tumors
University of Florence
Largo Palagi 1
50139 Florence, Italy
Phone: 39 337685511
Fax: 39 0557946303
Email: [email protected]
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
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