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:
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.
MEN2 is classified into three subtypes that vary based on the types of tumors that develop and the age of onset of disease:
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.
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) 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.
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 their 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 altered so that 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.
People with MEN2 carry one normal RET gene copy and one abnormal gene copy in all the cells of their body. These individuals are born and develop normally, but are at an increased risk to develop 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 thus facilitate the initiation of screening measures for early detection of tumors or specific treatments to prevent cancer from occurring.
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 that it does not fuction properly. A person carrying an alteration in one copy of the RET gene has a 50 percent (or 1 in 2) chance of passing this same alteration on to 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 offspring will have a 50 percent chance of inheriting this genetic alteration.
Specific biochemical screening and imaging studies can indicate the presence of endocrine tumors associated with the different subtypes 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.
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.
Early thyroid cancer often does not cause symptoms. But as the cancer grows, symptoms may include:
Symptoms of pheochromocytomas result from excessive hormone production and can include:
A person with hyperparathyroidism may have severe symptoms, subtle ones, or none at all:
In order to determine on a molecular level if a person has multiple endocrine neoplasia type 2 (MEN2), a genetic test must be completed.
It is important to remember that not all patients with multiple endocrine neoplasia type 2 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.
RET genetic test results can also provide important information for other family members. Knowing the specific alteration that is present in an individual with multiple endocrine neoplasia type 2 allows other family members to undergo testing to determine whether they also carry the alteration and could therefore 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.
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 multiple endocrine neoplasia type 2 (MEN2) or clinical exam suggestive of the condition are advised to undergo genetic testing for alterations in RET to guide medical management.
Reproductive options exist for an individual with an alteration in the RET gene who does not wish to pass this alteration on to future children:
Before one can proceed with prenatal testing or PGD, a RET mutation must be identified in a parent with MEN2.
MEN 2A, MEN 2B and FMTC are each associated with an increased risk of developing thyroid cancer. MEN 2A and MEN 2B are also associated with a risk of developing pheochromocytoma. MEN 2A carries an increased risk for primary hyperparathyroidism (PHPT). Individuals with MEN 2B have additional physical features associated with a characteristic appearance. The following table illustrates the percentage of patients with subtypes of MEN 2 who develop certain clinical features:
|Percent of Patients with MEN2 Who Develop Clinical Features|
|Subtype||Medullary thyroid carcinoma||Pheochromocytoma||Parathyroid disease|
|MEN2A||95%||50%||20% - 30%|
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 suggest thyroidectomy by age 5 years 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).
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:
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.
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. It should also be noted that all individuals who have undergone thyroidectomy and autotransplantation of the parathyroids need monitoring for possible hypoparathyroidism (low levels of parathyroid hormone).
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 at 215-662-4740. Appointments can also be requested online at http://www.uphs.upenn.edu/penngen or by calling 1-800-789-PENN (7366).
National Cancer Institute (NCI)
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.
Written by: Sarah Thornton, MS
Reviewed by: Kim Nichols, MD, Kristin Zelley, MS
Date: January 2012