Multiple Endocrine Neoplasia Type 2
NORD is very grateful to Maria Luisa Brandi, MD, PhD, Director, Regional Center for Hereditary Endocrine Tumors, University of Florence, Florence, Italy, for assistance in the preparation of this report.
Synonyms of Multiple Endocrine Neoplasia Type 2
- MEN-2 syndrome
- familial medullary thyroid carcinoma (FMTC)
- MEN 2A (Sipple syndrome)
- MEN 2B (multiple neuroma syndrome)
- multiple endocrine neoplasia type 2A
- multiple endocrine neoplasia type 2B
- Wagenmann-Froboese syndrome
Multiple endocrine neoplasia (MEN) type 2 is a rare genetic disorder characterized by an increased risk of developing a specific form of thyroid cancer (medullary thyroid carcinoma) and benign tumors affecting additional glands of the endocrine system. The endocrine system is the network of glands that secrete hormones into the bloodstream where they travel to various areas of the 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 processes including regulating heart rate, body temperature and blood pressure. Glands affected in MEN type 2 may secrete excessive amounts of hormones into the bloodstream, which can result in a variety of symptoms.
MEN type 2 is divided into three subtypes: MEN type 2A, MEN type 2B, and familial medullary thyroid carcinoma (FMTC). Medullary thyroid carcinoma (MTC) affects nearly all individuals with MEN type 2 regardless of the subtype. Additional symptoms may occur depending upon the specific subtype present. In FMTC, no other symptoms besides the carcinoma are present. MEN type 2 can run in families or can occur as the result of a spontaneous genetic change (i.e., new mutation) that occurs randomly for no apparent reason.
The onset, progression, and specific symptoms of each case of MEN type 2 can vary, even among members of the same family. Some individuals may only develop mild symptoms; others may develop serious, life-threatening complications. Some individuals may develop symptoms during infancy or early childhood; others may not develop symptoms until adolescence or young adulthood. Some cases of MEN type 2 may not become apparent until later during adulthood.
Nearly all individuals with MEN type 2 develop medullary thyroid carcinoma (MTC), usually very early in life. Additional symptoms vary depending upon the specific subtype present. 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 three glands most often affected by MEN type 2 are the thyroid and the parathyroid and the adrenal glands. The thyroid is a small, butterfly-shaped gland located in the front of the neck. The thyroid absorbs iodine (a substance found in many foods) from the blood. The thyroid converts iodine into thyroid hormones, which are essential to regulate the chemical processes (metabolism) of virtually every cell in the body. The parathyroid glands are four very small glands (approximately the size of a pea) located in the neck that secrete parathyroid hormone, which helps regulate the amount of calcium in the body. The adrenal glands are located on top of the kidneys and produce two hormones called epinephrine and norepinephrine. Other hormones produced by the adrenal glands help to regulate the fluid and electrolyte balance in the body.
Multiple Endocrine Neoplasia Type 2A
The first symptom associated with MEN type 2A in the majority of cases is medullary thyroid carcinoma. Some individuals may have overgrowth (hyperplasia) of thyroid cells (C-cell hyperplasia), a condition that is a benign process, but is considered a precursor to the development of medullary thyroid carcinoma. Nearly all individuals with MEN type 2A develop C-cell hyperplasia or medullary thyroid carcinoma at some point during their lives. Signs of medullary thyroid carcinoma can be seen early during childhood. If medullary thyroid carcinoma is not detected and treated during childhood, most individuals will develop a mass in the neck or pain in the neck between 15 to 20 years of age.
Approximately 50 percent of individuals with MEN type 2A will develop a pheochromocytoma, a usually benign tumor found most often in the adrenal glands. In many cases, one pheochromocytoma will develop in each adrenal gland (bilateral). The first symptom of a pheochromocytoma in MEN type 2A is usually high blood pressure that does not respond to therapy (intractable hypertension). In some cases, a pheochromocytoma can be the first noticeable symptom in individuals with MEN type 2A. A pheochromocytoma is almost always benign (noncancerous), but in approximately 4 percent of cases of MEN type 2A, malignant transformation of a pheochromocytoma has occurred.
Approximately 20-30 percent of individuals with MEN type 2A have hyperparathyroidism due to overgrowth (hyperplasia) of parathyroid tissue or the development of a benign tumor in the parathyroid glands (adenoma).
There are also a few extremely rare variants of MEN type 2A. These variants have additional symptoms that do not affect most individuals with MEN type 2A. One variant of MEN type 2A is associated with cutaneous lichen amyloidosis, a condition in which a scaly, itchy skin rash develops due to the accumulation of certain proteins (amyloids) in the skin.
Another variant of MEN type 2A is associated with Hirschsprung disease, a gastrointestinal condition characterized by absence of certain nerve cell bodies (ganglia) in the smooth muscle wall within a region of the large intestine (i.e., colon). As a result, there is absence or impairment of the involuntary, rhythmic contractions that propel food through the GI tract (peristalsis). Symptoms of Hirschsprung disease include constipation, vomiting, loss of appetite, bloating or swelling (distention) of the abdomen, abnormal accumulation of feces within the colon, and widening of the colon above the affected segment (megacolon). Hirschsprung disease can eventually cause diarrhea, dehydration, and failure to grow and gain weight at the expected rate (failure to thrive).
Multiple Endocrine Neoplasia Type 2B
The MEN type 2B subtype accounts for only 10 percent of all cases of MEN type 2. MEN type 2B was formerly called MEN type 3, and is the most aggressive form of the disease. Associated symptoms can vary greatly from one person to another. Some symptoms can be very subtle in certain cases.
Medullary thyroid carcinoma usually occurs earlier in MEN type 2B than in MEN type 2A and is usually more aggressive. A neck mass may be detectable during childhood. Most affected children receive a thyroidectomy (surgical removal of the thyroid) at an early age because medullary thyroid carcinoma can potentially spread (metastasize) at a very early age.
A pheochromocytoma occurs in approximately 50 percent of cases of MEN type 2B. The development of one or more pheochromocytomas in MEN type 2B does not differ much from their occurrence in individuals with MEN type 2A. Approximately 50 percent of individuals with MEN type 2B develop pheochromocytomas in both adrenal glands (bilateral pheochromoctyoma). Parathyroid disease is extremely uncommon in MEN type 2B.
Individuals with MEN2B also have additional symptoms not present in the other MEN 2 subtypes including the development of multiple, benign growths called neuromas. Neuromas are tumors arising from certain nerve cells and may be detected during infancy or early childhood. Neuromas associated in the MEN type 2B usually affect the mucous membranes (mucosa) lining the surface of the tongue, lips, the roof of the mouth (palate), eyelids, voice box (larynx), pharynx and nasal passages. The conjunctiva, the thin, clear membrane that covers the whites of the eyes, may also be affected. The presence of multiple neuromas can cause affected areas to appear swollen such as the lips, which often appear full and prominent. Infants and children with MEN type 2B may have additional distinctive facial features including eyelids that are flared forwarded (anteverted), broad-based nose, a wide-expression, and a coarse, elongated facial appearance. These distinctive facial features are not always present.
In MEN type 2B, benign growths arising from nerve cells called ganglion cells may also occur (ganglioneuromatosis). These growths occur in the gastrointestinal tract and may cause swelling (distention) of the abdomen, diarrhea, constipation, and an abnormally enlarged colon (megacolon). Affected infants often fail to gain weight and grow at the expected rate for age and sex (failure to thrive).
Some individuals with MEN type 2B may develop additional symptoms including a sunken breastbone (pectus excavatum), lax or loose joints, abnormal curvature of the spine, muscle weakness, and a "marfanoid habitus", a condition in which affected individuals tend to be thin with unusually tall stature; long, slender fingers and toes (arachnodactyly); and elongated arms and legs. The term "marfanoid" refers to Marfan syndrome, a distinct genetic disorder in which these findings are characteristic. MEN type 2B is unrelated to Marfan syndrome other than sharing some similarities in build.
Familial Medullary Thyroid Carcinoma
By definition, familial medullary thyroid carcinoma (FMTC) must occur in at least four members of a family in the absence of additional signs and symptoms MEN type 2A or MEN type 2B such as pheochromocytoma or benign tumors of the parathyroid glands. Medullary thyroid carcinoma is less aggressive in the familial form then when it is associated with MEN types 2A or 2B. Onset is usually during adulthood.
Medullary Thyroid Carcinoma
Medullary thyroid carcinoma (MTC) is a form of cancer that arises from certain cells within the thyroid called C cells (parafollicular cells). This type of cell produces the hormone calcitonin, which helps to regulate calcium metabolism. MTC is an aggressive form of cancer and may spread via the lymph nodes or bloodstream to affect other organs. The first sign of MTC is often a firm mass in the thyroid or abnormal enlargement of nearby lymph nodes (lymphadenopathy). An MTC mass in the neck may be painful. MTC can spread (metastasize) to other areas of the body. Because MTC can be cured by surgical removal of the thyroid, prompt diagnosis of this condition is essential to prevent the cancer from spreading. Individuals with MTC that progresses to cause a large tumor or that spreads to other areas of the body may develop chronic diarrhea as a result of the overproduction of calcitonin. If medullary thyroid carcinoma spreads, it may cause abdominal pain, jaundice and in rare cases bone pain or tenderness.
Pheochromocytoma is a rare type of tumor that arises from certain cells known as chromaffin cells, which produce hormones necessary for the body to function properly. Pheochromocytomas produce norepinephrine and epinephrine, hormones that are involved with the sympathetic nervous system, which controls various involuntary activities in the body such as raising blood pressure or regulating the heartbeat. Most pheochromocytomas originate in one of the two adrenal glands located above the kidneys. Most chromaffin cells are found in the adrenal gland's inner layer, which is known as the adrenal medulla.
Symptoms associated with pheochromocytomas include high blood pressure (hypertension), chronic headaches, excessive sweating, and/or heart palpitations. Nervousness, anxiety, and loss of color (blanching) of the skin may also occur. High blood pressure associated with pheochromocytomas often does not respond to therapy (intractable hypertension).
In some cases, an undetected pheochromocytoma can potentially cause life-threatening complications such as hypertensive crisis when undergoing procedures requiring anesthesia. Hypertensive crisis is a severe increase in blood pressure that can damage blood vessels and lead to a stroke. However, because of better diagnosis, recognition, and therapies regarding pheochromocytomas, such life-threatening complications are rare in individuals with MEN type 2 who develop pheochromocytomas.
The parathyroid glands are four very small glands (approximately the size of a pea) located in the neck that secrete parathyroid hormone, which helps regulate the amount of calcium in the body. Hyperparathyroidism is the medical term for when there is too much parathyroid hormone in the body.
Hyperparathyroidism can be very mild and may not cause any obvious symptoms (asymptomatic). Hyperparathyroidism can result in too much calcium building up in the blood (hypercalcemia), which can eventually 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. Some individuals may develop abnormal thinning of bones (osteoporosis), which can result in an increased risk of fractures. Most individuals with hyperparathyroidism do not develop all of these symptoms, especially when the condition is diagnosed early.
MEN type 2 is a rare genetic disorder caused by disruption or changes (mutation) of the RET gene. This genetic mutation may be inherited as an autosomal dominant trait or occur as a spontaneous genetic change (i.e., new mutation) that occurs randomly for no apparent reason.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. 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. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.
Investigators have determined that the RET gene is located on the long arm (q) of chromosome 10 (10q11.2). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 10q11.2" refers to band 11.2 on the long arm of chromosome 10. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The RET gene is an oncogene, a mutated gene that has been identified to play a role in the development of cancer. When operating normally, the RET gene may have several functions including playing a role in cell division or instructing cells when to die (a normal process called apoptosis). When an oncogene malfunctions, certain cells may continue to grow and reproduce causing tumor formation. Researchers have determined that the RET gene contains instructions for creating (encoding) a protein (enzyme) known as tyrosine kinase, which plays a key role in normal cell function.
MEN type 2 affects males and females in equal numbers. It has been estimated to affect 1 in 30,000 people in the general population. Some researchers believe that many cases of MEN type 2 go undiagnosed or misdiagnosed, making it difficult to determine the disorder's true frequency in the general population. MEN type 2A is the most common subtype accounting for more than 80 percent of cases. MEN type 2B is the least common accounting for approximately 10 percent of cases. All cases of medullary thyroid carcinoma (i.e., both those are associated with MEN type 2 and those are not) account for approximately 5-10 percent of thyroid cancers.
Symptoms of the following disorders can be similar to those of MEN type 2. Comparisons may be useful for a differential diagnosis.
Thyroid cancer (carcinoma) is cancer affecting the thyroid gland, a butterfly-shaped structure located at the base of the neck. The thyroid is part of the endocrine system, the network of glands that secrete hormones that regulate the chemical processes (metabolism) that influence the body's activities as well as regulating the heart rate, body temperature, and blood pressure. Hormones are secreted directly into the bloodstream where they travel to various areas of the body. In many cases, there are no symptoms (asymptomatic) associated with thyroid cancer. Pain in the neck, hoarseness and swollen lymph nodes especially in the neck may be present in some cases. Different forms of cancer, including thyroid cancer, may be classified based upon the cell type involved, the specific nature of the malignancy, and the disease's clinical course. The four main types of thyroid cancer are papillary, follicular, medullary and anaplastic. Rare forms of thyroid cancer include thyroid teratoma, lymphoma, and squamous cell carcinoma. Although thyroid cancer is rare, it is the most common form of cancer affecting the endocrine system. Most forms rarely cause pain or disability and are easily treated with surgery and follow-up therapy. (For more information on this disorder, choose "thyroid cancer" as your search term in the Rare Disease Database.)
Multiple endocrine neoplasia (MEN) type 1 is a rare genetic disorder in which benign (noncancerous) tumors arise from the cells of various glands of the endocrine system. The endocrine system is the network of glands that secrete hormones into the bloodstream where they travel to various areas of the 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 processes including regulating heart rate, body temperature and blood pressure. In individuals with MEN type 1, benign tumors develop in multiple endocrine glands, most often the parathyroid, pancreas and pituitary glands. These affected glands secrete excessive amounts of hormones into the bloodstream, which can result in a variety of symptoms. Some benign tumors associated with MEN type 1 can become malignant (cancerous). MEN type 1 can run in families or can occur as the result of a spontaneous genetic change (i.e., new mutation) that occurs randomly for no apparent reason. (For more information on this disorder, choose "multiple endocrine neoplasia" as your search term in the Rare Disease Database.)
The various tumors associated with MEN type 1 can occur as isolated conditions or as part of other disorders including familial isolated hyperparathyroidism, hereditary hyperparathyroidism and jaw tumor, von Hippel-Lindau syndrome, Carney complex, and Zollinger-Ellison syndrome. When these tumors secrete excessive hormones into the bloodstream a variety of different conditions can result including hyperparathyroidism, acromegaly, Cushing's syndrome, hypoglycemia, hyperglycemia, and carcinoid syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
Affected individuals may receive a diagnosis of MEN type 2 following a thorough clinical evaluation, a detailed patient history and the identification of characteristic features. The characteristic features of MEN type 2A are the presence of two or more specific endocrine tumors (i.e., medullary thyroid carcinoma, pheochromocytoma, and parathyroid hyperplasia or adenoma). Diagnostic features of MEN type 2B include the identification of medullary thyroid carcinoma, multiple neuromas, distinctive facial features, and a "marfanoid" habitus. Familial medullary thyroid carcinoma is diagnosed in individuals with medullary thyroid carcinoma in at least four family members without the presence of other symptoms associated with MEN type 2A or 2B.
A variety of tests can aid in the diagnosis of MEN type 2. Such tests include those designed to detect elevated levels of certain hormones in the blood. Identification of elevated hormones in the blood can be an indication of specific endocrine tumors. For example, identification of elevated levels of calcitonin can indicate the presence of medullary thyroid carcinoma, elevated levels of parathyroid hormone can indicate the presence of a parathyroid tumor, and elevated levels of substances called catecholamines and catecholamine may indicate the presence a pheochromocytoma. A variety of imaging (x-ray) scans may also be performed to aid in identifying the size and specific location of tumors.
A diagnosis of MEN type 2 can be confirmed through molecular genetic testing, which can reveal the characteristic mutation of the RET gene that causes the disorder. Molecular genetic testing is available on a clinical basis.
The treatment of MEN type 2 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 surgical removal of tumors and drugs to counteract the effects of excess hormones or replacement of hormones no longer produced by the body (i.e., following surgical removal of a gland).
Specific therapeutic procedures and interventions may vary depending upon numerous factors, such as the specific subtype present, whether C-cell hyperplasia or cancer has developed; the size and type of tumors; the severity of symptoms due to excess hormone production; whether malignant cancer is already present and whether it has spread to lymph nodes or distant sites; an 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 healthcare 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.
Because of advancements made in the recognition, genetics (i.e., identifying the mutated gene), and treatment of MEN type 2, certain serious, life-threatening complications associated with the disorder such as the spread (metastasis) of medullary thyroid carcinoma or rare complications of a pheochromocytoma have been greatly reduced.
The standard therapy for individuals with MEN type 2 is surgical removal of the thyroid, a procedure called a thyroidectomy. Surgical removal of the thyroid is often performed as a preventive measure, even if cancer or C-cell hyperplasia has developed yet. Individuals will require life-long hormone replacement therapy of the hormones normally produced by the thyroid. The age that this surgery is performed may vary depending upon the specific subtype and gene mutation present. For example, some infants with MEN type 2B may undergo surgical removal of the thyroid before reaching six months of age. The recommendations on the timing of prophylactic thyroidectomy and extent of surgery are based on a classification into four risk levels utilizing the genotype–phenotype correlations.
A thyroidectomy can potentially affect the parathyroid glands causing low levels of parathyroid hormone in the body (hypoparathyroidism). As such, many physicians surgically remove the parathyroid glands at the same time the thyroid is removed. Some parathyroid tissue is then re-implanted (autotransplant) into an arm.
Primary hyperparathyroidism, which is associated with some cases of MEN type 2A, is also treated by the surgical removal of the parathyroid gland followed by the re-implantation of some healthy parathyroid tissue into the arm. Because there is a risk of a benign tumor recurring in the healthy parathyroid tissue, transplanting that tissue into the arm would spare affected individuals from being operated on in the same area (i.e., the neck)
Surgery is the main form of therapy for individuals with a pheochromocytoma. Surgical removal of one or both of the adrenal glands is often performed. Both adrenal glands are often removed even in individuals with a pheochromocytoma affecting only one gland (unilateral) because of the high risk of the other adrenal gland becoming affected later on. The most common surgical procedure for treating a pheochromocytoma is laparoscopic laparotomy. During this procedure, a small incision is made in the abdomen, a small tube is inserted (laparoscope) through the incision, and the tumor is removed. Before surgery, some affected individuals may need to be treated with alpha-adrenergic blockers and beta-adrenergic blockers to minimize the effects of adrenal hormones. Alpha-adrenergic blockers such as phenoxybenzamine are used to control hypertension. In some cases, beta-adrenergic blockers such as propranolol can also be used to treat hypertension.
In cases, where medullary thyroid carcinoma has spread or where malignant transformation of a pheochromocytoma has occurred chemotherapy or radiation therapy may be used.
Before any surgery for individuals with MEN type 2, screening for the presence of a pheochromocytoma should be performed because of the risk of anesthesia-induced hypertensive crisis.
Genetic counseling may be of benefit for affected individuals and their families.
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Multiple Endocrine Neoplasia Type 2 Resources
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