Multiple Endocrine Neoplasia Type 2

  • What is multiple endocrine neoplasia type 2 (MEN2)?

    Multiple endocrine neoplasia type 2 (MEN2) is a rare hereditary cancer syndrome, affecting approximately 1 in 35,000 people. It is associated with the development of:

    • Medullary cancer of the thyroid (MTC)
    • Pheochromocytoma (a tumor of the adrenal gland and neuroendocrine tissues)
    • Other abnormal growths of endocrine tissues 

    Most individuals are diagnosed with MEN2 because they or a close family member develops thyroid cancer. While thyroid cancer is relatively common in adults, medullary thyroid cancer (MTC), one subtype of thyroid cancer, is rare and suggests a diagnosis of MEN2. About 25-30 percent of people with MTC are diagnosed with MEN2 based on confirmatory genetic testing results.

    The true prevalence of the condition is likely underestimated because the disease may go unrecognized in certain individuals. It is important to identify this hereditary cancer syndrome early as it often confers a high risk of tumors, which may occur at younger than expected ages.

  • Types

    MEN2 is classified into three subtypes that vary based on the types of tumors that develop and the age of onset of disease:

    MEN2A

    This subtype of multiple endocrine neoplasia type 2 is associated with an increased risk for medullary cancer of the thyroid (MTC), pheochromocytoma, and primary hyperparathyroidism (PHPT), a condition in which the parathyroid glands secrete extra parathyroid hormone because they contain adenomas (non-cancerous tumors) or hyperplasia (excessive cell growth). The onset of the disease is typically in early adulthood.

    MEN2B

    Multiple endocrine neoplasia type 2B (MEN2B) is characterized by an increased risk for medullary cancer of the thyroid (MTC), pheochromocytoma, mucosal neuromas (benign growths) of the lips and tongue, and distinctive physical characteristics, such as enlarged lips and tall and slender body type. In addition, patients with MEN2B have a higher likelihood of developing ganglioneuromas of the gastrointestinal tract. Ganglioneuromas are rare tumors composed of ganglion cells, nerve fibers and supporting cells. The onset of the disease in MEN2B is generally in infancy or early childhood.

    Familial medullary thyroid cancer (FMTC)

    Familial medullary thyroid cancer (FMTC) is associated with an increased risk of developing medullary thyroid cancer (MTC) in early or middle adulthood, but it is not associated with the development of pheochromocytoma or parathyroid disease. Familial medullary thyroid cancer is now considered a variant of MEN2A with decreased occurrence of pheochromocytoma and parathyroid disease, rather than a distinct subtype of MEN2.

    In small families or those with only a single generation affected with medullary thyroid cancer, caution should be used in the classification of familial medullary thyroid cancer, as this classification can result in the failure to recognize the risks for pheochromocytoma and hyperparathyroidism in these families.

  • Causes

    MEN2 is caused by alterations, also known as “mutations," at specific areas in a person’s genetic information. Each of us has a large amount of genetic information that is organized into smaller segments known as “genes.” Genes provide the instructions that the cells of the body need to perform different functions.

    There is a specific gene known as RET, located on chromosome 10 at position q11.2, that is altered in people with MEN2. The RET gene encodes for a type of protein known as a receptor tyrosine kinase. The normal RET protein interacts with specific factors outside the cell and helps the cell to respond to its environment. When growth factors attach to the RET protein, it triggers biochemical signals inside the cell that can stimulate specific functions such as cell division.

    In MEN2, the RET gene is mutated so the protein that is produced is always “switched on.” When the RET protein is always active, cells receive signals to continuously multiply, which can contribute to cancer development.

    Importance of early detection

    People with MEN2 carry one normal RET gene copy and one abnormal gene copy in all cells of their body. These individuals are born and develop normally, but are at an increased risk of developing benign and/or malignant endocrine tumors over their lifetime.

    Current molecular genetic testing of the RET gene can identify mutations in approximately 98 percent of individuals with MEN2A and MEN2B, and approximately 95 percent of families with familial medullary thyroid cancer. Such testing is available clinically and can be used to identify which individuals in a family are at risk for the disease, even before they become symptomatic. Genetic information can facilitate the initiation of screening measures for early detection of tumors or specific treatments to prevent cancer from occurring.

    How is multiple endocrine neoplasia type 2 (MEN2) inherited?

    With the exception of egg and sperm cells, each cell of the body normally has two working copies of the RET gene. In people with MEN2, however, each cell contains only one working RET gene copy. While the second copy is present, it is altered so it does not function properly.

    A person carrying a mutation in one copy of the RET gene has a 50 percent — or one in two — chance of passing this same alteration onto each of his or her future children. Children who inherit the altered gene copy have MEN2 and carry a higher risk of developing cancers associated with MEN2 over the course of their lives.

    In 95 percent of cases with MEN2A, a person inherits one altered copy of the RET gene from an affected parent. In MEN2B, however, approximately half of the people affected are the first in their families due to the occurrence of a “new” mutation in the RET gene in one of the father’s sperm, mother’s eggs or in a cell of the developing fetus. Since these individuals carry an altered gene copy, each of their future children will have a 50 percent chance of inheriting this genetic mutation.

  • Diagnosis

    Specific biochemical screening and imaging studies can indicate the presence of endocrine tumors associated with the different subtypes of MEN2.

    Clinical indications of MEN2

    MEN2A is diagnosed clinically by the occurrence of two or more endocrine cancers (specifically medullary cancer of the thyroid, pheochromocytoma, and parathyroid adenoma/ hyperplasia) in a person or in close relatives (such as a parent or sibling).

    MEN2B is diagnosed clinically by the presence of mucosal neuromas of the lips and tongue, as well as medullated corneal nerve fibers (a finding seen on eye evaluation by an ophthalmologist), distinctive facial features with full lips, particular physical characteristics such as tall and slender body habitus, and medullary cancer of the thyroid (MTC).

    FMTC is diagnosed in families with four or more cases of MTC in the absence of pheochromocytoma or parathyroid adenoma or hyperplasia, and is considered a variant of MEN2A.

    Symptoms of MEN2-related conditions

    There are certain symptoms that can be associated with the presence of MTC, pheochromocytomas or hyperparathyroidism. It is important to note that these symptoms are not definite signs of MTC, pheochromocytoma or hyperparathyroidism. Evaluation by a specialist is necessary for an accurate diagnosis and treatment.

    MTC

    Early thyroid cancer often does not cause symptoms. But as the cancer grows, symptoms may include:

    • A lump or nodule in front of the neck near the Adam’s apple
    • Hoarseness or difficulty speaking in a normal voice
    • Swollen lymph nodes, especially in the neck
    • Difficulty swallowing or breathing
    • Pain in the throat or neck

    Pheochromocytoma

    Symptoms of pheochromocytomas result from excessive hormone production and can include:

    • High blood pressure
    • Headaches that are typically sudden, severe and of varying duration
    • Excessive sweating
    • Accelerated or racing heartbeat (called tachycardia) and palpitations
    • Feelings of anxiety and/or feelings of extreme fright
    • Pain in the lower chest or upper abdomen
    • Nausea with or without vomiting
    • Weight loss
    • Pale skin
    • Heat intolerance

    Hyperparathyroidism

    A person with hyperparathyroidism may have severe symptoms, subtle ones, or none at all. Symptoms can include:

    • Fatigue or weakness
    • Depression or forgetfulness
    • Bone and joint pain
    • Frequent complaints of illness with no apparent cause
    • Fragile bones that easily fracture (osteoporosis)
    • Kidney stones
    • Increased thirst and excessive urination
    • Abdominal pain
    • Nausea, vomiting or loss of appetite

    Genetic testing 

    In order to determine on a molecular level if a person has multiple endocrine neoplasia type 2 (MEN2), a genetic test must be completed.

    • First, a blood or saliva sample is obtained from the affected individual with a cancer associated with MEN2.
    • DNA is isolated from the blood or saliva sample and the two copies of the RET gene are evaluated using a variety of methods and compared to the normal reference sequence for RET.
    • If an alteration in one of two RET gene copies is identified, the genetic counselor can next examine whether the alteration has been previously reported in other individuals with MEN2.

    It is important to remember that not all patients with MEN2 carry a detectable alteration in the RET gene. Therefore, the failure to identify an alteration in the RET gene does not exclude the diagnosis of MEN2.

    Risk for family members

    RET genetic test results can also provide important information for other family members. Knowing the specific alteration that is present in an individual with MEN2 allows other family members to undergo testing to determine whether they also carry the alteration and could  be at risk to develop the features of MEN2.

    Interestingly, there is a strong correlation between the specific type of RET gene alteration and the subtype of multiple endocrine neoplasia type 2 (MEN2). Some RET mutations may be associated with a milder form of MEN2 while others are associated with more aggressive or recurrent forms of the disease. For example, approximately 95 percent of patients with features of MEN2B have a genetic alteration at a very specific location on the RET gene.

    Monitoring and treating disease

    These correlations between the genetic alteration in RET and their clinical manifestations are helpful because they can help determine the best cancer surveillance plan and provide useful information to guide individualized treatment of the disease. In fact, all children with a family history of MEN2 or clinical exam suggestive of the condition are advised to undergo genetic testing for alterations in RET to guide medical management.

  • Reproductive options 

    Reproductive options exist for an individual with an alteration in the RET gene who does not wish to pass this alteration onto future children:

    • Prenatal diagnosis — DNA is isolated from the cells of the developing baby though one of two procedures (chorionic villus sampling [CVS] or amniocentesis) and is analyzed for alterations in the RET gene. With appropriate counseling, a parent can then decide whether to carry the pregnancy to term or to end the pregnancy.
    • Pre-implantation genetic diagnosis (PGD) — For couples using in vitro fertilization to become pregnant, embryos can be tested for genetic disorders before transferring them into the uterus. Only healthy embryos carrying two working copies of the RET gene would be implanted.

    Before one can proceed with prenatal testing or PGD, a RET mutation must be identified in a parent with MEN2.

  • Cancer risks and screening

    MEN2A, MEN2B and FMTC are each associated with an increased risk of developing thyroid cancer. MEN2A and MEN2B are also associated with a risk of developing pheochromocytoma. MEN2A carries an increased risk for primary hyperparathyroidism (PHPT).

    Individuals with MEN2B have additional physical features associated with a characteristic appearance. The following illustrates the percentage of patients with subtypes of MEN2 who develop certain clinical features:

    MEN2A

    • Medullary thyroid carcinoma — 95 percent
    • Pheochromocytoma — 50 percent
    • Parathyroid disease — 20-30 percent

    FMTC

    • Medullary thyroid carcinoma — 100 percent
    • Pheochromocytoma — 0 percent
    • Parathyroid disease — 0 percent

    MEN2B

    • Medullary thyroid carcinoma — 100 percent
    • Pheochromocytoma — 50 percent
    • Parathyroid disease — uncommon

    Cancer screening

    MTC

    Risk-reducing prophylactic thyroidectomy (surgical removal of the entire thyroid gland) and sometimes parathyroidectomy (surgical removal of the parathyroid glands) may be necessary shortly after birth in children with more severe RET alterations. Surgery can be deferred for a few years for children with more mild alterations. The best timing for surgery varies, depending on the earliest age at which thyroid cancer appears within an affected family and the specific type of RET gene mutation that is present.

    Recent studies suggest that surgery before 6 years of age has a better outcome, with a lower incidence of metastases or recurrent disease. However, the best age at which to perform risk-reducing surgery for MEN2 remains largely controversial.

    Recent 2009 clinical guidelines by the American Thyroid Association recommend thyroidectomy by age 5 in patients with MEN2A and FMTC, though it can be deferred until an abnormal stimulated plasma calcitonin level is detected in individuals with certain low-risk mutations. In patients with MEN2B, surgery is performed within the first 6 months of life (often within the first month), because MTC has been identified in some children with MEN2B as early as shortly after birth.

    All individuals who have undergone removal of the thyroid gland need thyroid hormone replacement and monitoring for possible hypoparathyroidism (American Thyroid Association Guidelines Taskforce, 2009).

    Pheochromocytoma

    Children and adults with MEN2 need to be screened for the presence of a possible pheochromocytoma prior to undergoing any surgeries. This screening can be done through the use of specific blood tests which assess for elevations in the levels of catecholamines, chemicals released by pheochromocytoma tumor cells.

    It is important to distinguish whether a patient with MEN2 has a pheochromocytoma because patients with undiagnosed tumors can develop malignant hypertension (a severe elevation of the blood pressure) following treatment with general anesthesia. Patients with pheochromocytoma who require surgery should undergo evaluation by an anesthesiologist and may require treatment with special medications to prevent the onset of malignant hypertension.

    Patients with MEN2 who have no symptoms should be screened annually for the presence of a pheochromocytoma. This can be done by a physical examination that checks for:

    • Elevated blood pressure
    • Abnormal physical findings such as an abdominal mass
    • Blood and/or urine tests to check for elevations in catecholamines

    Any abnormal examination findings or test results should be followed by specific radiology evaluations such as MRI to look for the presence of a pheochromocytoma tumor. If a pheochromoctyoma is identified, it is generally treated by surgical removal.

    Hyperparathyroidism

    Annual biochemical screening from the time of diagnosis is recommended in individuals with MEN2A who have not undergone parathyroidectomy and parathyroid autotransplantation (placement of removed parathyroid tissue into the muscle of either the neck or forearm). The age at which screening should begin is dependent on the specific RET mutation that is present. For individuals with MEN2B, screening is unnecessary as they are not at increased risk to develop hyperparathyroidism.

    All individuals who have undergone thyroidectomy and autotransplantation of the parathyroids need monitoring for possible hypoparathyroidism (low levels of parathyroid hormone).

  • Adults with MEN2

    Adults who have MEN2 or who would like more information about MEN2 may contact the Medical Genetics Team at the Hospital of the University of Pennsylvania.

  • References

    American Thyroid Association Guidelines Task Force. 2009. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid, 19, 565-612.

    Eng, C. 1996. Seminars in medicine of the Beth Israel Hospital, Boston. The RET proto-oncogene in multiple endocrine neoplasia type 2 and Hirschsprung's disease.  N Engl J Med., 335, 943–51.

Reviewed by Kristin Zelley, MS on September 03, 2012