Multiple endocrine neoplasias

Definition

The multiple endocrine neoplasia (MEN) syndromes are four related disorders affecting the thyroid and other hormonal (endocrine) glands of the body. MEN has previously been known as familial endocrine adenomatosis.

The four related disorders are all neuroendocrine tumors. These tumorous cells have something in common, they produce hormones, or regulatory substances for the body's homeostasis. They come from the APUD (amine precursor and uptake decarboxylase) system, and have to do with the cell apparatus and function to make these substances common to the cell line. Neuroendocrine tumors cause syndromes associated with each other by genetic predisposition.

Description

The four forms of MEN are MEN1 (Wermer syndrome), MEN2A (Sipple syndrome), MEN2B (previously known as MEN3), and familial medullary thyroid carcinoma (FMTC). Each is an autosomal dominant genetic condition, and all except FMTC predisposes to hyperplasia (excessive growth of cells) and tumor formation in a number of endocrine glands. FMTC predisposes only to this type of thyroid cancer .

Individuals with MEN1 experience hyperplasia of the parathyroid glands and may develop tumors of several endocrine glands including the pancreas and pituitary. The most frequent symptom of MEN1 is hyperparathyroidism. Hyperparathyroidism results from overgrowth of the parathyroid glands leading to excessive secretion of parathyroid hormone, which in turn leads to elevated blood calcium levels (hypercalcemia), kidney stones, weakened bones, fatigue, and weakness. Almost all individuals with MEN1 show parathyroid symptoms by the age of 50 years with some individuals developing symptoms in childhood.

Tumors of the pancreas, called pancreatic islet cell carcinomas, may develop in individuals with MEN1. These tumors tend to be benign, meaning that they do not spread to other body parts. However, on occasion these tumors may become malignant or cancerous and thereby a risk of metastasis, or spreading, of the cancer to other body parts becomes a concern. The pancreatic tumors associated with MEN1 may be called non-functional tumors as they do not result in an increase in hormone production and consequently, no symptoms are produced. However, in some cases, extra hormone is produced by the tumor and this results in symptoms; the symptoms depend upon the hormone produced. These symptomatic tumors are referred to as functional tumors. The most common functional tumor is gastrinoma followed by insulinoma. Other less frequent functional tumors are VIPoma and glucagonoma. Gastrinoma results in excessive secretion of gastrin (a hormone secreted into the stomach to aid in digestion), which in turn may cause upper gastrointestinal ulcers; this condition is sometimes referred to as Zollinger-Ellison syndrome. About one in three people with MEN1 develop a gastrinoma. Insulinoma causes an increase in insulin levels, which in turn causes glucose levels to decrease. This tumor causes symptoms consistent with low glucose levels (hypoglycemia, low blood sugar) which include anxiety, confusion, tremor, and seizure during periods of fasting. About 40–70% of individuals with MEN1 develop a pancreatic tumor.

The pituitary may also be affected—the consequence being extra production of hormone. The most frequently occurring pituitary tumor is prolactinoma, which results in extra prolactin (affects bone strength and fertility) being produced. Less commonly, the thymus and adrenal glands may also be affected and in rare cases, a tumor called a carcinoid may develop. Unlike MEN2, the thyroid gland is rarely involved in MEN1 symptoms.

Patients with MEN2A experience two main symptoms, medullary thyroid carcinoma (MTC) and a tumor of the adrenal gland known as pheochromocytoma. Medullary thyroid carcinoma is a slow-growing cancer that is preceded by a condition called C-cell hyperplasia. C-cells are a type of cell within the thyroid gland that produce a hormone called calcitonin. About 40–50% of individuals with MEN2A develop C-cell hyperplasia followed by MTC by the time they are 50 years old and 70% will have done so by the time they are 70 years old. In some cases, individuals develop C-cell hyperplasia and MTC in childhood. Medullary thyroid carcinoma tumors are often multifocal and bilateral.

Pheochromocytoma is usually a benign tumor that causes excessive secretion of adrenal hormones, which in turn can cause life-threatening hypertension (high blood pressure) and cardiac arrhythmia (abnormal heart beats). About 40% of people with MEN2A will develop a pheochromocytoma. Individuals with MEN2A also have a tendency for the parathyroid gland to increase in size (hypertrophy) as well as for tumors to develop in the parathyroid gland. It has been found that about 25–35% of individuals with MEN2A will develop parathyroid involvement.

Individuals with MEN2B also develop MTC and pheochromocytoma. However, the medullary thyroid carcinomas often develop at much younger ages, often before the age of one year, and they tend to be more aggressive tumors. About half of the individuals with MEN2B develop a pheochromocytoma with some cases being diagnosed in childhood. All individuals with MEN2B develop additional conditions, which make it distinct from MEN2A. These extra features include 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, such as long bones and problems with spinal curving. Hyperparathyroidism is not seen in MEN2B as it is in MEN2A. Unlike the other three MEN syndromes, individuals with MEN2B may not have a family history of MEN2B. In at least half of the cases and perhaps more, the condition is new in the individual affected.

Medullary thyroid carcinoma may also occur in families but family members do not develop the other endocrine conditions seen in MEN2A and MEN2B. This is referred to as familial medullary thyroid carcinoma (FMTC) and it is a subtype of MEN2. Familial medullary thyroid cancer is suggested when other family members have also developed MTC, if the tumor is bilateral, and/or if the tumor is multifocal. In comparison to MEN2A and MEN2B, individuals with FMTC tend to develop MTC at older ages and the disease appears to be more indolent or slow progressing.

About one fourth (25%) of MTC occurs in individuals who have MEN2A, MEN2B, and FMTC.

Genetic profile

All four MEN syndromes follow autosomal dominant inheritance , meaning that every individual diagnosed with a MEN syndrome has a 50% (1 in 2) chance of passing on the condition to each of his or her children. Additionally, both men and women may inherit and pass on the genetic mutation.

MEN1 results from alterations or mutations in the MEN1 gene . Nearly every individual inheriting the MEN1 gene alteration will develop hyperparathyroidism, although the age at which it is diagnosed may differ among family members. Individuals inheriting the familial mutation may also develop one of the other characteristic features of MEN1, however, this often differs among family members as well.

The three subtypes of MEN2 are caused by mutations in another gene known as RET. Every individual who inherits a RET mutation will develop MTC during his or her lifetime, although the age at the time of diagnosis is often different in each family member. Multiple different mutations have been identified in individuals and families that have MEN2A. Likewise, several different mutations have been identified in individuals and families with FMTC. An interesting finding has been that a few families that clearly have MEN2A and a few families that clearly have FMTC have the same mutation. The reason the families have developed different clinical features is not known. In contrast to MEN2A and FMTC, individuals with MEN2B have been found, in more than 90% of cases, to have the same RET mutation. This mutation is located in a part of the gene that has never been affected in individuals and families with MEN2A and FMTC.

Demographics

MEN syndromes are not common. It has been estimated that MEN1 occurs in 3–20 out of 100,000 people. The incidence of MEN2 has not been published, but it has been reported that MEN2B is about ten-fold less common than MEN2A. MEN syndromes affect both men and women and it occurs worldwide.

Signs and symptoms

General symptoms of the characteristic features of the MEN syndromes and their causes include:

• Hyperparathyroidism, which may or may not cause symptoms. Symptoms that occur are related to the high levels of calcium in the bloodstream such as kidney stones, fatigue, muscle or bone pain, indigestion, and constipation.
• Medullary thyroid carcinoma may cause diarrhea, flushing, and depression.
• Pheochromocytoma may cause a suddenly high blood pressure and headache, palpitations or pounding of the heart, a fast heart beat, excessive sweating without exertion, and/or development of these symptoms after rising suddenly from bending over.

Diagnosis

Diagnosis of the MEN syndromes has in the past depended upon clinical features and laboratory test results. Now that the genes responsible for these conditions have been identified, genetic testing provides another means of diagnosing individuals and families with these conditions. However, all of these tumors have a higher incidence of sporadic cases. It is important to ask the patient about family members when one of these types of tumor is diagnosed.

MEN1 is typically diagnosed from clinical features and from testing for parathyroid hormone (PTH). An elevated PTH indicates that hyperparathyroidism is present. When an individual develops a MEN1 related symptom or tumor, a complete family history should also be taken. If no family history of MEN1 or related problems such as kidney stones and peptic ulcers exists and close family members, i.e. parents, siblings and children, have normal serum calcium levels, then the person unlikely has MEN1. However, if the individual is found to have a second symptom or tumor characteristic of MEN1, the family history is suggestive of MEN1, and/or close family members have increased serum calcium levels, then MEN1 may be the correct diagnosis.

As of 1998, genetic testing for the MEN1 gene has helped with evaluating individuals and families for MEN1. If an individual apparently affected by MEN1 is found to have a mutation in the MEN1 gene, then this positive test result confirms the diagnosis. However, as of 2001, genetic testing of the MEN1 gene does not identify all mutations causing MEN1; consequently, a negative test result does not remove or exclude the diagnosis.

MEN2A is typically diagnosed from clinical features and from laboratory testing of calcitonin levels. Elevated calcitonin levels indicate that C-cell hyperplasia and/or MTC is present. When an individual develops a MEN2A related symptom or tumor, a complete family history should be taken. If no family history of related problems exists and close family members, i.e. parents, siblings, and children, have normal calcitonin levels, then the person unlikely has MEN2A. However, if the individual is found to have a second symptom or tumor characteristic of MEN2A, the family history is suggestive of MEN2A, and/or close family members have increased calcitonin levels, then MEN2A may be the correct diagnosis.

As of 1993, genetic testing for the RET gene has helped with evaluating an individual and/or family for MEN2A. If an individual apparently affected by MEN2A is found to have a mutation in the RET gene, then this positive test result confirms the diagnosis. However, as of 2001, genetic testing of the RET gene does not identify all mutations causing MEN2A and FMTC; consequently, a negative test result does not remove or exclude the diagnosis.

Diagnosis of MEN2B can be made by physical examination and a complete medical history.

Diagnosis of FMTC may be made when the family history includes four other family members having developed MTC with no family member having developed a pheochromocytoma or pituitary tumor. Genetic testing of the RET gene may also assist with diagnosis.

Genetic testing of the MEN1 gene and of the RET gene allows individuals to be diagnosed prior to the onset of symptoms; this is often called predictive genetic testing. It is important to note that individuals should not undergo predictive genetic testing prior to the identification of the familial genetic mutation. Genetic testing of a family member clinically affected by the condition needs to be done first in order to identify the familial mutation. If this is not done, a negative result in an asymptomatic individual may not be a true negative test result.

Association of multiple endocrine neoplasias with other conditions

Prenatal diagnosis of unborn babies is now technically possible via amniocentesis or chorionic villus sampling (CVS). However, prior to undergoing these procedures, the familial mutation needs to have been identified. An additional issue in prenatal diagnosis is how the test result will be used with regard to continuation of the pregnancy. Individuals considering prenatal diagnosis of MEN1 or MEN2 should confirm its availability prior to conception.

Genetic testing is best done in consultation with a geneticist (a doctor specializing in genetics) and/or genetic counselor.

Treatment and management

No cure or comprehensive treatment is available for the MEN syndromes. However, some of the consequences of the MEN syndromes can be symptomatically treated and complications may be lessened or avoided by early identification.

For individuals affected by MEN1, hyperparathyroidism is often treated by surgery. The parathyroids may be partially or entirely removed. If they are entirely removed, the individual will need to take calcium and vitamin D supplements. The pancreatic tumors that develop may also be removed surgically or pharmacological treatment (medication) may be given to provide relief from symptoms. As of 2001, the treatment of pancreatic tumors remains controversial as the most effective treatment has not been identified. Pituitary tumors that develop may not require treatment, but if so, medication has often been effective. Surgery and radiation are used in rare cases.

Children of a parent affected by MEN1 should begin regular medical screening in childhood. It has been suggested that children beginning at five to 10 years of age begin having annual measurements of serum calcium, serum prolactin and of the pancreatic, pituitary, and parathyroid hormones. The child should also undergo radiographic imaging (ultrasound, MRI examination) of the pancreas and pituitary. If the family history includes family members developing symptoms of MEN1 at younger than usual ages, then the children will need to begin medical screening at a younger age as well.

For the three types of MEN2, the greatest concern is the development of medullary thyroid carcinoma. Medullary thyroid carcinoma can be detected by measuring levels of the thyroid hormone, calcitonin.

Treatment of MTC is by surgical removal of the thyroid and the neighboring lymph nodes, although doctors may disagree at what stage to remove the thyroid. After thyroidectomy, the patient will receive normal levels of thyroid hormone orally or by injection. Even when surgery is performed early, metastatic spread of the cancer may have already occurred. Since this cancer 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.

KEY TERMS

Medullary thyroid cancer (MTC)

—A slow-growing tumor associated with MEN.

In the past, children who had a parent affected by one of the MEN2 syndromes were screened for MTC by annual measurement of calcitonin levels. More recently, it has been determined that MTC can be prevented by prophylactic thyroidectomy, meaning that the thyroid gland is removed without it being obviously affected by cancer. As of 2001, it is not uncommon for a child as young as one year of age, when the family history is of MEN2B, or six years of age, when the family history is of MEN2A or FMTC, to undergo prophylactic thyroidectomy in order to prevent the occurrence of MTC.

Pheochromocytomas that occur in MEN2A and MEN2B can be cured by surgical removal of this slow growing tumor. Pheochromocytomas may be screened for using annual abdominal ultrasound or CT examination and laboratory testing.

For individuals diagnosed with MEN2, it is also recommended that the pituitary be screened by laboratory tests.

In general, each tumor may be approached surgically. However, problems occur when the tumors are multiple, when the whole gland is involved (hyperplasia as opposed to tumor), when replacement therapy is difficult (pituitary or adrenal), or when the gland makes multiple hormones (if the gland is removed, hormone replacement therapy becomes necessary).

Prognosis

Diagnosed early, the prognosis for the MEN conditions is reasonably good, even for MEN2B, the most dangerous of the four forms. Medullary thyroid cancer can be cured when identified early. The availability of genetic testing to identify family members at risk for developing the conditions will hopefully lead to earlier treatment and improved outcomes.

Resources

BOOKS

Offit, Kenneth. "Multiple Endocrine Neoplasias." Clinical Cancer Genetics: Risk Counseling and Management. New York: John Wiley & Sons, 1998.

PERIODICALS

Hoff, A. O., G. J. Cote, and R. F. Gagel. "Multiple endocrine neoplasias." (Review). Annual Review of Physiology 62 (2000): 377–422.

ORGANIZATIONS

Canadian Multiple Endocrine Neoplasia Type 1 Society, Inc. (CMEN). PO Box 100, Meota, SK S0M 1X0. Canada (306) 892-2080.

Genetic Alliance. 4301 Connecticut Ave. NW, #404, Washington, DC 20008-2304. (800) 336-GENE (Helpline) or (202) 966-5557. Fax: (888) 394-3937 info@geneticalliance. <http://www.geneticalliance.org>.

National Institute of Diabetes and Digestive and Kidney Diseases. Building 31, room 9A04, Bethesda, MD 20892. <http://www.niddk.nih.gov>.

WEBSITES

Gagel, Robert F. Familial Medullary Thyroid Carcinoma: A guide for families. <http://endocrine.mdacc.tmc.edu/educational/mtc.htm>.

Gagel, Robert F., MD. "Medullary Thyroid Carcinoma." M.D. Anderson Cancer Center, University of Texas. <http://endocrine.mdacc.tmc.edu/educational/thyroid.htm>.

Marx, Stephen J. "Familial Multiple Endocrine Neoplasia Type 1." National Institutes of Health. <http://www.niddk.nih.gov/health/endo/pubs/fmen1/fmen1.htm>.

National Institute of Diabetes and Digestive and Kidney Diseases. "Hyperparathyroidism." National Institutes of Health. <http://www.niddk.nih.gov/health/endo/pubs/hyper/hyper.htm>.

Wiesner, Georgia L., and Karen Snow. " Multiple Endocrine Neoplasia Type 2." GeneClinics. University of Washington, Seattle. <http://www.geneclinics.org/>.

Cindy L. Hunter, MS, CGC