MEN2

Multiple Endocrine Neoplasia 2 (MEN2)

Multiple endocrine neoplasia type 2 (MEN2) is characterized by a very high risk of developing medullary thyroid cancer (MTC). Individuals with MEN2 have a greater than 95% chance of developing MTC in their lifetime. MEN2 is divided into three clinical subtypes:

MEN2A is characterized by the presence of medullary thyroid cancer in early adulthood, pheochromocytoma and hyperparathyroidism. About 50% of people with MEN2A will develop a pheochromocytoma and 20-30% will develop hyperparathyroidism.

MEN2B is characterized by medullary thyroid carcinoma in early childhood, and pheochromocytomas (50% frequency). Hyperparathyroidism is almost never seen in people with MEN2B. People with MEN2B often have other physical characteristics, including being tall and slender, having small benign (non-cancerous) tumors on the lips and tongue and a condition where the large intestine becomes enlarged and irritated. 

Familial Medullary Thyroid Carcinoma (FMTC) is medullary thyroid cancer occurring in multiple members of the same family without the presence of pheochromocytoma and/or hyperparathyroidism.

Risk Factors

MEN2 is caused by mutations in the RET gene, which cause affected cells to divide uncontrollably, resulting in tumor formation. Genetic testing can identify RET mutations in approximately 95% of people with clinical symptoms of MEN2A and MEN2B, and in about 88% of families with FMTC. All children of a parent with MEN2 have a 50% chance of getting the disease.

Genetic testing of blood samples can both confirm a diagnosis of MEN2 in individual patients and identify family members who may be at risk of developing the disease. Depending on the specific RET mutation, predicting the severity and progression of the disease to some degree is possible. This is helpful in determining screening recommendations, as well as the appropriate age for performing a prophylactic thyroidectomy (surgery to remove the thyroid before disease strikes). General recommendations are to remove the thyroid gland:

• Within the first six months of life for individuals with MEN2B
• By five to 10 years of age for individuals with MEN2A and FMTC

However, these recommendations ultimately depend on the patient's personal and family history. A genetic counselor can discuss genetic testing with you and your family, answer any questions and help you make an informed decision. 

Adrenal Manifestations of MEN2

A pheochromocytoma is a tumor that occurs in the adrenal medulla that makes excess hormones called catecholamines (such as adrenaline). A pheochromocytoma is diagnosed in about 50% of people with MEN2A and MEN2B, although they do not occur in individuals with true FMTC. Pheochromocytomas may also occur in both adrenal glands in MEN2. Although a pheochromocytoma is a tumor, it is rarely malignant in MEN2.

If detected early, pheochromocytomas are easily treated. However, if not treated, they may be potentially fatal due to dangerously high blood pressures that can occur during accidents, surgery, childbirth or other physically stressful situations.

Regular screening for pheochromocytoma allows for early diagnosis and treatment, often before the tumor becomes symptomatic. Screening should also be done prior to any elective surgery, pregnancy and childbirth. Screening involves either a 24-hour urine collection or a blood test, which measure levels of catecholamines. If screening indicates a pheochromocytoma, an imaging study will be ordered, which may include a CT scan, MRI and/or a special nuclear medicine test called an MIBG study.

All patients with MEN2 should be screened annually, or more often if symptoms develop. Individuals with FMTC should also undergo screening because some families classified as FMTC actually have MEN2A. Pheochromocytoma screening should also be done prior to any elective surgery, pregnancy and childbirth.