Multiple endocrine neoplasia is a group of disorders that affect the body's network of hormone-producing glands called the endocrine system. Hormones are chemical messengers that travel through the bloodstream and regulate the function of cells and tissues throughout the body. Multiple endocrine neoplasia typically involves tumors (neoplasia) in at least two endocrine glands; tumors can also develop in other organs and tissues. These growths can be noncancerous (benign) or cancerous (malignant). If the tumors become cancerous, the condition can be life-threatening.

The major forms of multiple endocrine neoplasia are called type 1, type 2, and type 4. These types are distinguished by the genes involved, the types of hormones made, and the characteristic signs and symptoms.

Many different types of tumors are associated with multiple endocrine neoplasia. Type 1 frequently involves tumors of the parathyroid glands, the pituitary gland, and the pancreas. Tumors in these glands can lead to the overproduction of hormones. The most common sign of multiple endocrine neoplasia type 1 is overactivity of the parathyroid glands (hyperparathyroidism). Hyperparathyroidism disrupts the normal balance of calcium in the blood, which can lead to kidney stones, thinning of bones, nausea and vomiting, high blood pressure (hypertension), weakness, and fatigue.

The most common sign of multiple endocrine neoplasia type 2 is a form of thyroid cancer called medullary thyroid carcinoma. Some people with this disorder also develop a pheochromocytoma, which is an adrenal gland tumor that can cause dangerously high blood pressure. Multiple endocrine neoplasia type 2 is divided into three subtypes: type 2A, type 2B (formerly called type 3), and familial medullary thyroid carcinoma (FMTC). These subtypes differ in their characteristic signs and symptoms and risk of specific tumors; for example, hyperparathyroidism occurs only in type 2A, and medullary thyroid carcinoma is the only feature of FMTC. The signs and symptoms of multiple endocrine neoplasia type 2 are relatively consistent within any one family.

Multiple endocrine neoplasia type 4 appears to have signs and symptoms similar to those of type 1, although it is caused by mutations in a different gene. Hyperparathyroidism is the most common feature, followed by tumors of the pituitary gland, additional endocrine glands, and other organs.

Multiple endocrine neoplasia type 1 affects about 1 in 30,000 people; multiple endocrine neoplasia type 2 affects an estimated 1 in 35,000 people. Among the subtypes of type 2, type 2A is the most common form, followed by FMTC. Type 2B is relatively uncommon, accounting for about 5 percent of all cases of type 2. The prevalence of multiple endocrine neoplasia type 4 is unknown, although the condition appears to be rare.

Mutations in the MEN1, RET, and CDKN1B genes can cause multiple endocrine neoplasia.

Mutations in the MEN1 gene cause multiple endocrine neoplasia type 1. This gene provides instructions for producing a protein called menin. Menin acts as a tumor suppressor, which means it normally keeps cells from growing and dividing too rapidly or in an uncontrolled way. Although the exact function of menin is unknown, it is likely involved in cell functions such as copying and repairing DNA and regulating the activity of other genes. When mutations inactivate both copies of the MEN1 gene, menin is no longer available to control cell growth and division. The loss of functional menin allows cells to divide too frequently, leading to the formation of tumors characteristic of multiple endocrine neoplasia type 1. It is unclear why these tumors preferentially affect endocrine tissues.

Mutations in the RET gene cause multiple endocrine neoplasia type 2. This gene provides instructions for producing a protein that is involved in signaling within cells. The RET protein triggers chemical reactions that instruct cells to respond to their environment, for example by dividing or maturing. Mutations in the RET gene overactivate the protein's signaling function, which can trigger cell growth and division in the absence of signals from outside the cell. This unchecked cell division can lead to the formation of tumors in endocrine glands and other tissues.

Mutations in the CDKN1B gene cause multiple endocrine neoplasia type 4. This gene provides instructions for making a protein called p27. Like the menin protein, p27 is a tumor suppressor that helps control the growth and division of cells. Mutations in the CDKN1B gene reduce the amount of functional p27, which allows cells to grow and divide unchecked. This unregulated cell division can lead to the development of tumors in endocrine glands and other tissues.

Normal Function

The RET gene provides instructions for producing a protein that is involved in signaling within cells. This protein appears to be essential for the normal development of several kinds of nerve cells, including nerves in the intestine (enteric neurons) and the portion of the nervous system that controls involuntary body functions such as heart rate (the autonomic nervous system). The RET protein is also necessary for normal kidney development and the production of sperm (spermatogenesis).

The RET protein spans the cell membrane, so that one end of the protein remains inside the cell and the other end projects from the outer surface of the cell. This positioning of the protein allows it to interact with specific factors outside the cell and to receive signals that help the cell respond to its environment. When molecules that stimulate growth and development (growth factors) attach to the RET protein, a complex cascade of chemical reactions inside the cell is triggered. These reactions instruct the cell to undergo certain changes, such as dividing or maturing to take on specialized functions.

Health Conditions Related to Genetic Changes

Nonsyndromic paraganglioma

Mutations in the RET gene increase the risk of developing a type of paraganglioma called pheochromocytoma. Paragangliomas are tumors of the nervous system that are usually noncancerous (benign). Pheochromocytomas specifically affect the adrenal glands, which are small hormone-producing glands located on top of each kidney. Pheochromocytomas are a feature of multiple endocrine neoplasia type 2 (described below), but they can also be nonsyndromic, which means they occur without the other signs and symptoms of the syndrome. RET gene mutations associated with nonsyndromic pheochromocytoma change single amino acids in the RET protein. As in multiple endocrine neoplasia type 2, the mutations likely result in an overactive RET protein that can trigger cells to grow and divide uncontrollably and can lead to the formation of tumors.

Hirschsprung disease

Mutations in the RET gene are the most common genetic cause of Hirschsprung disease, a disorder that causes severe constipation or blockage of the intestine. More than 200 RET gene mutations are known to cause this condition. These genetic changes result in a nonfunctional version of the RET protein that cannot interact with growth factors or transmit signals within cells. Without RET protein signaling, enteric nerves do not develop properly. These nerves control contractions that move stool through the intestine, and their absence leads to the intestinal problems characteristic of Hirschsprung disease.

Multiple endocrine neoplasia

More than 25 mutations in the RET gene are known to cause a form of multiple endocrine neoplasia called type 2. Multiple endocrine neoplasia typically involves the development of tumors in two or more of the body's hormone-producing glands, called endocrine glands. These tumors can be noncancerous or cancerous. Multiple endocrine neoplasia type 2 is divided into three subtypes: type 2A, type 2B, and familial medullary thyroid carcinoma. These subtypes are distinguished by their characteristic signs and symptoms and risk of specific tumors.

Most of the RET gene mutations that cause multiple endocrine neoplasia type 2 change single protein building blocks (amino acids) in the RET protein. Type 2A most often results from a mutation that substitutes the amino acid arginine for the amino acid cysteine at position 634 (written as Cys634Arg or C634R). More than 90 percent of cases of type 2B are caused by a mutation that replaces the amino acid methionine with the amino acid threonine at position 918 (written as Met918Thr or M918T). Several amino acid substitutions can cause familial medullary thyroid carcinoma.

The mutations responsible for multiple endocrine neoplasia type 2 result in an overactive RET protein that can transmit signals without first attaching to growth factors outside the cell. The overactive protein likely triggers cells to grow and divide abnormally, which can lead to the formation of tumors in the endocrine system and other tissues. The overactivating RET gene mutations that cause multiple endocrine neoplasia type 2 are very different from the inactivating mutations that cause Hirschsprung disease (described above); these two disorders rarely occur in the same individual.

Lung cancer

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Other cancers

Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes, which are called somatic mutations, are not inherited. Somatic changes in the RET gene have been identified in several nonhereditary (sporadic) cancers. Chromosomal rearrangements involving the RET gene are one of the most common causes of a sporadic form of thyroid cancer called papillary thyroid carcinoma (also known as RET/PTC). Additionally, a nonfamilial form of medullary thyroid carcinoma (a type of thyroid cancer that can also occur as part of multiple endocrine neoplasia, described above) can be caused by somatic mutations in the RET gene.

Other Names for This Gene

• cadherin family member 12
• cadherin-related family member 16
• CDHF12
• CDHR16
• HSCR1
• hydroxyaryl-protein kinase
• MEN2A
• MEN2B
• MTC1
• PTC
• rearranged during transfection
• ret proto-oncogene (multiple endocrine neoplasia and medullary thyroid carcinoma 1, Hirschsprung disease)
• RET-ELE1
• RET/PTC
• RET51
• RET_HUMAN

Genomic Location

Multiple endocrine neoplasia type 1 usually has an autosomal dominant pattern of inheritance. People with this condition are born with one mutated copy of the MEN1 gene in each cell. In most cases, the altered gene is inherited from an affected parent. The remaining cases are a result of new mutations in the MEN1 gene and occur in people with no history of the disorder in their family.

Unlike most other autosomal dominant conditions, in which one altered copy of a gene in each cell is sufficient to cause the disorder, two copies of the MEN1 gene must be altered to trigger tumor formation in multiple endocrine neoplasia type 1. A mutation in the second copy of the MEN1 gene occurs in a small number of cells during a person's lifetime. Almost everyone who is born with one MEN1 mutation acquires a second mutation in certain cells, which can then divide in an unregulated way to form tumors.

Multiple endocrine neoplasia type 2 and type 4 are also inherited in an autosomal dominant pattern. In these cases, one copy of the mutated gene is sufficient to cause the disorder. Affected individuals often inherit an altered RET or CDKN1B gene from one parent with the condition. Some cases, however, result from new mutations in the gene and occur in people without other affected family members.