Multiple Endocrine Neoplasia Type 2

Approved by the Cancer.Net Editorial Board, 05/2019

What is multiple endocrine neoplasia type 2?

Multiple endocrine neoplasia type 2 (MEN2) is a hereditary condition associated with 3 primary types of tumors: medullary thyroid cancer, parathyroid tumors, and pheochromocytoma. MEN2 is classified into subtypes based on clinical features.

  • MEN2A, which affects 95% of MEN2 families. There are 4 variants:

    1. Classical MEN2A

      1. Medullary thyroid cancer: 98% to 100% with MEN2A are affected

      2. Pheochromocytoma, a typically benign (noncancerous) tumor of the adrenal glands: 50% with MEN2A affected

      3. Parathyroid adenoma (a benign tumor) or hyperplasia, meaning increased size of the parathyroid gland: 5% to 10% with MEN2A affected

    2. MEN2A with cutaneous lichen amyloidosis (CLA)

    3. MEN2A with Hirschsprung disease (HD)

    4. Familial medullary thyroid cancer (FMTC).

  • MEN2B, which affects 5% of MEN2 families

    • Medullary thyroid cancer: 98% to 100% with MEN2B affected

    • Pheochromocytoma: 50% with MEN2B affected

    • Mucosal neuromas, which is a benign tumor of nerve tissue on the tongue, lips and throughout the gastrointestinal tract: 95% to 98% affected

    • Digestive problems caused by nerve problems in the gastrointestinal tract: 75% to 90% affected

    • Muscle, joint, and spinal problems: 95% affected

    • Typical facial features, including swollen lips and thick eyelids: 75% to 90% affected

Sources:  Gagel RF, Marx SJ. “Multiple endocrine neoplasia.” Williams Textbook of Endocrinology, Chapter 40, 11th ed., Philadelphia, 2008, and Eng C, Clayton D, et al. Grubbs EG, Gagel RF. My, How Things Have Changed in Multiple Endocrine Neoplasia Type 2A! J Clin Endocrinol Metab 100(7):2532-5, 7/2015. PMID: 26151398.

What causes MEN2?

MEN2 is a genetic condition. This means that the cancer risk and other features of MEN2 can be passed from generation to generation in a family. The gene associated with MEN2 is called RET. A mutation (alteration) in the RET gene gives a person an increased risk of developing medullary thyroid cancer and other tumors associated with MEN2.

How is MEN2 inherited?

Normally, every cell has 2 copies of each gene: 1 inherited from the mother and 1 from the father. MEN2 follows an autosomal dominant inheritance pattern, in which a mutation, a change in the DNA sequence that alters the protein sequence, happens in only 1 copy of the gene. This means that a parent with a gene mutation may pass along a copy of their normal gene or a copy of the gene with the mutation. Therefore, a child who has a parent with a mutation causing MEN2 has a 50% chance of inheriting that mutation. A brother, sister, or parent of a person who has a mutation also has a 50% chance of having the same mutation. However, if the parents test negative for the mutation, the risk to the siblings significantly decreases but their risk may still be higher than an average risk. If a child inherits the mutated RET gene from an affected parent, there is almost a 100% chance of developing medullary thyroid cancer and lower probabilities of developing other features of this syndrome during his or her lifetime.

Options exist for people interested in having a child when a prospective parent carries a gene mutation that increases the risk for this hereditary cancer syndrome. For more information, talk with an assisted reproduction specialist at a fertility clinic.

How common is MEN2?

It is estimated that about 1 in 30,000 people has MEN2. Most people with MEN2B do not have any family history of the condition. They have a de novo (new) mutation in the RET gene. Fewer than 5% of people with MEN2A are thought to have a de novo mutation in the RET gene.

How is MEN2 diagnosed?

FMTC is suspected in families with 2 or more cases of medullary thyroid cancer and no evidence of parathyroid or adrenal gland problems.

MEN2A is suspected when there are at least 2 of the 3 common tumors, such as medullary thyroid cancer, pheochromocytoma, or parathyroid adenoma, in 1 person or a close relative. Close relatives are generally considered to be parents, siblings, and children. Medullary thyroid carcinoma has been reported in children as young as 2 years of age, although it more commonly develops between the ages of 5 and 18 years.

MEN2B is suspected in children with mucosal neuromas, meaning lumps on the tip of the tongue, and typical facial features, such as thickened lips. Medullary thyroid cancer can occur very early in childhood.

Genetic testing for mutations in the RET gene is available. It is recommended for people with a family history of FMTC, MEN2A, and MEN2B, and anyone diagnosed with medullary thyroid cancer. Mutations in the RET gene are found in more than 95% of families with MEN2A or MEN2B, and in more than 85% of families with FMTC. 

What are the estimated cancer risks associated with MEN2?

The risk of medullary thyroid cancer in people with MEN2 is nearly 100% for all subtypes.

What are the screening options for MEN2?

Due to the high risk of medullary thyroid cancer, RET gene testing is recommended for children at risk for any of the MEN2 subtypes. If a high-risk mutation is found, the thyroid gland should be surgically removed to prevent cancer from developing. Depending on the type of mutation, the timing of surgery could be as early as first months of life to childhood or young adulthood. This surgery is recommended in the first months of life to first year in children with MEN2B and by age 5 in children with MEN2A. For patients with MEN2A with moderate risk mutations, surgery can be postponed until calcitonin becomes elevated or in childhood. However, close monitoring by an experienced medical professional is important. Surgical procedures should be performed by a surgeon with experience in thyroid surgery in children and with the management of medullary thyroid cancer.

Additional screening recommendations may include:

  • Yearly blood tests for ionized calcium and parathyroid hormone levels, beginning in childhood (for people with MEN2A)

  • Yearly blood tests for catecholamines and catecholamine metabolites (metanephrine and normetanephrine), beginning in childhood (for people with MEN2A and MEN2B)

  • Magnetic resonance imaging (MRI) or computerized tomography (CT or CAT) scan of the abdomen to detect pheochromocytomas, every 4 to 5 years or when abnormal catecholamine or metanephrine levels are detected.

Screening guidelines may change over time as new technologies are developed and more is learned about MEN2. It is important to talk with your health care team about appropriate screening tests.

Learn more about what to expect when having common tests, procedures, and scans.

What is the treatment for medullary thyroid cancer that has spread to the lymph nodes of the neck or beyond?

Surgical resection (removal) of lymph nodes in the neck and upper chest, performed by a surgeon experienced with this technique, can result in cure in 10% to 20% of cases where there is spread to neck lymph nodes. Learn more about treatment options for thyroid cancer.

Recent studies of drugs that target the RET gene have shown promise for the treatment of medullary thyroid cancer that has spread to the lymph nodes, liver, lung or other places in the body. Two of these compounds, vandetanib and cabozantinib, are available as a treatment option for people with progressive, metastatic medullary thyroid cancer.  The risks and benefits of additional surgery should be discussed with a surgeon or endocrinologist experienced with this disease. Other promising therapies are available through participation in a clinical trial, which is a research study. To find clinical trials specific to your diagnosis, talk with your health care team or search online clinical trial databases now.

What are the risks associated with pheochromocytoma?

Pheochromocytoma associated with MEN2 is almost always a benign tumor. However, such tumors commonly produce abnormally high levels of adrenalin and noradrenalin and may cause high blood pressure, a rapid or irregular heart rate, tremulousness, meaning tremors or involuntary muscular contractions, and cardiac arrest, which can result in sudden death. Medical treatments to prevent these symptoms are highly effective and should be started at the time of diagnosis and before the surgical removal of the tumor. Learn more about pheochromocytoma.

What is the typical treatment for a parathyroid tumor?

Increased production of parathyroid hormone by a benign parathyroid tumor can cause hypercalcemia, meaning high blood calcium, kidney stones, and osteoporosis, meaning the loss of bone mass causing fracture. Surgical removal of the parathyroid tumor often cures the problem. Learn more about parathyroid tumors.

Questions to ask the health care team

If you are concerned about your risk of thyroid cancer or other tumors, talk with your health care team. It can be helpful to bring someone along to your appointments to take notes. Consider asking your health care team the following questions:

  • What is my risk of developing thyroid cancer?

  • What is my risk of developing other types of tumors?

  • What can I do to reduce my risk of cancer?

  • What are my options for cancer screening?

If you are concerned about your family history and think you or other family members may have MEN2, consider asking the following questions:

  • Does my family history increase my risk of developing thyroid cancer?

  • Does it suggest the need for a cancer risk assessment?

  • Will you refer me to a genetic counselor or other genetics specialist?

  • Should I consider genetic testing?

Related Resources

The Genetics of Cancer

Genetic Testing

What to Expect When You Meet With a Genetic Counselor

Collecting Your Family Cancer History

Sharing Genetic Test Results with Your Family

Family Genetic Testing Q&A

More Information

Thyroid Cancer Survivors Association
www.thyca.org

American Multiple Endocrine Neoplasia Support
http://amensupport.org/  

Association for Multiple Endocrine Neoplasia Disorders (AMEND)
www.amend.org.uk

American Thyroid Association
www.thyroid.org

International Thyroid Oncology Group (ITOG)
www.itog.org

National Cancer Institute
www.cancer.gov  

To find a genetic counselor in your area, ask your doctor or visit these websites: 

National Society of Genetic Counselors 
www.nsgc.org

National Cancer Institute
www.cancer.gov/cancertopics/genetics/directory