Multiple endocrine neoplasia syndromes



Definition

The multiple endocrine neoplasia (MEN) syndromes are three related inherited disorders affecting the thyroid and other hormone producing (endocrine) glands of the body. Before the early 2000s, MEN was called familial endocrine adenomatosis.

Description

There are three types of MEN: MEN 1 (Wermer's syndrome), MEN 2A (Sipple syndrome), and MEN 2B (previously known as MEN 3). All MEN types are the result of inherited genetic mutations that predispose the individual to excessive growth of cells (hyperplasia) and tumor formation in multiple endocrine glands. For all types of MEN, the children of an affected individual have a 50 percent chance of inheriting the defective gene that causes the disorder.

Demographics

MEN 1 is uncommon and occurs in only about one of every 30,000 individuals. The disorder runs in families, and males are twice as likely to develop the disorder as females. Individuals with MEN 1 can show symptoms of excessive parathyroid secretion by age five, and almost all individuals with MEN 1 show parathyroid symptoms by age 40.

MEN 2 affects about one in every 40,000 individuals. MEN 2A is ten to 20 times more common than MEN 2B.

Causes and symptoms

MEN 1 is caused by a mutation at the PYGM gene on chromosome 11. PYGM is one of a group of genes known as tumor suppressor genes that help to control cell division. An individual who inherits one defective copy of a tumor suppressor gene from either parent has a strong likelihood of developing MEN 1, because there is a high probability of another mutation developing in the other copy of the PYGM gene at some point during the thousands of cell divisions that occur with growth and development. When a second mutation occurs, the cell that contains the mutation no longer has any normal copy of the tumor suppressor gene. When both copies are defective, tumor suppression fails and tumors develop.

As a result, individuals with MEN 1 have uncontrolled cell growth and develop tumors in several endocrine glands, including the parathyroid glands (80–95% of patients), the pancreas (about 50% of patients) and the pituitary (around 25% of patients). The most frequent symptom of MEN 1 is hyperparathyroidism, which is excessive growth of the parathyroid gland and excessive secretion of parathyroid hormone. This condition leads to increased amounts of calcium in the blood, kidney stones, weakened bones, and nervous system depression. Children with MEN 1 can show signs of hyperparathyroidism as young as age five.

Tumors of the pancreas, known as gastrinomas, are also common in MEN 1. Excessive secretion of gastrin (a hormone secreted into the stomach to aid in digestion) by these tumors can cause upper gastrointestinal ulcers. The anterior pituitary gland and the adrenal glands can also be affected. Unlike MEN 2, the thyroid gland is rarely involved in MEN 1 symptoms. Children with MEN1 rarely develop tumors of the pancreas until they reach adulthood.

There are two types of MEN 2. Both MEN 2A and MEN 2B are caused by mutations in another gene, known as RET. A mutation in only one copy of the RET gene is sufficient to cause disease. A number of different mutations can lead to MEN 2A, but only one specific genetic alteration causes MEN 2B.

Patients with both MEN 2A and MEN 2B experience two main symptoms, medullary thyroid cancer (MTC) and a tumor of the adrenal gland medulla known as pheochromocytoma. MTC is a slow-growing cancer, but one that can be cured in less than 50 percent of cases. Pheochromocytoma is usually a benign (noncancerous) tumor that causes excessive secretion of adrenal hormones. This, in turn, can cause life-threatening high blood pressure ( hypertension ) and irregular heart beat (cardiac arrhythmia).

The two forms of MEN 2 are distinguished by other symptoms. Individuals with MEN 2A have a predisposition to develop tumors of the parathyroid gland. Although similar to MEN 1, less than 20 percent of MEN 2A patients show parathyroid involvement.

Individuals with MEN 2B show a variety of additional conditions: a characteristic facial appearance with swollen lips; tumors of the mucous membranes of the eye, mouth, tongue, and nasal cavity; enlarged colon; and skeletal abnormalities. Symptoms develop early in life (often before five years of age) in cases of MEN 2B and the medullary thyroid cancer is much more aggressive and may develop in patients who are one year old.

When to call the doctor

Since MEN is inherited and runs in families, the doctor should be informed of this history when the child is born, so that genetic testing can be done immediately.

Diagnosis

In the past, classical diagnosis of MEN was based on clinical features and on testing for elevated hormone levels. For MEN 1, the relevant hormone was parathyroid hormone. For both types of MEN 2, the greatest concern is development of medullary thyroid cancer. MTC can be detected by measuring levels of the thyroid hormone, calcitonin. Numerous other hormone levels can be measured to assess the involvement of the various other endocrine glands.

Diagnosis of MEN 2B can be made by physical examination alone. However, MEN 2A shows no distinct physical features and must be identified by measuring hormone levels or by finding endocrine tumors.

Since 1994, genetic screening using DNA technology has been available for both MEN 1 and MEN 2. This methodology allows diagnosis before the onset of symptoms. Before the development of genetic testing, there was no way to definitively identify which children had inherited the defective gene. As a result, all offspring of individuals with MEN had to be considered at risk. In the case of MEN 2A and MEN 2B, children would undergo frequent calcitonin testing. Molecular techniques as of the early 2000s allow a positive distinction to be made between children who are and are not carrying the defective genes that cause MEN.

Treatment

As of 2004 no comprehensive treatment is available for genetic conditions such as MEN. However, some of the consequences of MEN can be symptomatically treated. Pheochromocytoma in both types of MEN 2 can be cured by surgical removal of this slow growing tumor.

Treatment of MTC is by surgical removal of the thyroid. After thyroidectomy, the patient receives normal levels of thyroid hormone by mouth or by injection. Even when thyroid surgery is performed early, metastatic spread of the cancer may have already occurred. Since MTC is slow growing, metastasis may not be obvious. Metastasis is very serious in MTC because chemotherapy and radiation therapy are not effective in controlling its spread.

Prognosis

Diagnosed early through genetic testing, the prognosis for the MEN diseases is reasonably good, even for MEN 2B, the most dangerous of the three forms. Even in the absence of treatment, a few individuals with MEN 2A mutations never show any symptoms at all. Analysis of at-risk family members using molecular genetic techniques leads to earlier treatment and improved outcomes.

KEY TERMS

Adrenal glands —A pair of endocrine glands (glands that secrete hormones directly into the bloodstream) that are located on top of the kidneys. The outer tissue of the glands (cortex) produces several steroid hormones, while the inner tissue (medulla) produces the hormones epinephrine (adrenaline) and norepinephrine.

Endocrine —Refers to glands that secrete hormones circulated in the bloodstream or lymphatic system.

Medullary thyroid cancer —A slow-growing tumor associated with multiple endocrine neoplasia syndromes.

Neoplasm —An abnormal formation of new tissue. A neoplasm may be malignant or benign.

Pancreas —A five-inch-long gland that lies behind the stomach and next to the duodenum. The pancreas releases glucagon, insulin, and some of the enzymes which aid digestion.

Parathyroid gland —A pair of glands adjacent to the thyroid gland that primarily regulate blood calcium levels.

Parathyroid hormone —A chemical substance produced by the parathyroid glands. This hormone plays a major role in regulating calcium concentration in the body.

Pheochromocytoma —A tumor that originates from the adrenal gland's chromaffin cells, causing overproduction of catecholamines, powerful hormones that induce high blood pressure and other symptoms.

Pituitary gland —The most important of the endocrine glands (glands that release hormones directly into the bloodstream), the pituitary is located at the base of the brain. Sometimes referred to as the "master gland," it regulates and controls the activities of other endocrine glands and many body processes including growth and reproductive function. Also called the hypophysis.

Thyroid gland —An endocrine gland in the neck overlying the windpipe (trachea) that regulates the speed of metabolic processes by producing a hormone, thyroxin.

Prevention

As of 2004 there is no way to block the occurrence of genetic mutations that cause MEN. One of the most serious consequences of MEN is MTC. Children who are identified as carriers of the RET gene can be offered total thyroidectomy as a preventative (prophylactic) measure to prevent the development of MTC.

Parental concerns

MEN is an inherited disorder. Individuals who have MEN in their families may wish to get genetic counseling before attempting a pregnancy.

Resources

BOOKS

Gagel, Robert F., and Stephen J. Marx. "Multiple Endocrine Neoplasia." In Williams Textbook of Endocrinology , 10th ed. Edited by P. Reed Larsen. Philadelphia: Saunders, 2003.

ORGANIZATIONS

Alliance of Genetic Support Groups. 4301 Connecticut Avenue NW, Suite 404, Washington, DC 20008–2304. Web site: http://www.geneticalliance.org.

Pituitary Network Association. 223 East Thousand Oaks Blvd. #320, Thousand Oaks, CA 91360. Web site: http://www.pituitary.org.

WEB SITES

Radebold, Klaus, and Christian A. Kock. "Multiple Endocrine Neoplasia." eMedicine.com , July 26, 2004. Available online at http://www.emedicine.com/ped/topic1496.htm (accessed January 13, 2005).

Tish Davidson, A.M. Victor Leipzig, PhD



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