MEN2B is caused by a specific genetic change (mutation or pathogenic variant) in the RET gene. The disease is inherited in an autosomal dominant manner. A diagnosis of MEN2B is suspected when a person has a personal or family history of medullary thyroid cancer, pheochromocytoma, or physical findings suggestive of MEN2B. The diagnosis can be confirmed with genetic testing. Treatment for MEN2B typically includes removal of the thyroid and screening for the development of additional tumors.

There is another type of multiple endocrine neoplasia type 2 that causes an increased risk for medullary thyroid carcinoma and pheochromocytomas. This disease is known as multiple endocrine neoplasia type 2A (MEN2A).

RET gene. This gene provides instructions to the body to make a protein that helps regulate the growth and division of cells of the endocrine system. This protein is supposed to tell the body when it is appropriate to allow the cells of the endocrine system to divide. When there is a pathogenic variant in the RET gene, the cells of the endocrine system are able to grow and divide out of control. This causes the signs and symptoms of MEN2B, as well as the increased risk for the development of tumors.

About 95% of people who have MEN2B have a pathogenic variant in one particular area of the RET gene known as codon 918. Genetic changes in this region of the RET gene are thought to cause the RET gene to be more highly activated than other genetic changes within the RET gene. This is why MEN2B causes a higher risk for tumor development at a younger age as compared to other pathogenic variants in the RET gene.

RET gene to have a change (mutation or pathogenic variant) causing MEN2B. We inherit one copy of every gene from our mother and the other from our father. When a person who has MEN2B has children, for each child there is a:

• 50% chance that the child will inherit the copy of the RET gene with a pathogenic variant, meaning he or she will have MEN2B
• 50% chance that the child will inherit the working copy of the RET gene, meaning he or she will not have MEN2B

In some cases, people who have MEN2B are the first people to be diagnosed in the family. This may be because they inherited the genetic change from a parent, but the parent was never diagnosed with the disease. In other cases, the genetic change may be new in the person who was diagnosed with MEN2B. Genetic changes that are new in a person are called de novo. It is estimated that about 50% of people with MEN2B have a genetic change that is de novo.

Pheochromocytomas are typically not cancerous (they are usually benign), but they can cause other health problems such as high blood pressure (hypertension). The risk for a person with MEN2B to develop a pheochromocytoma is about 50%.

MEN2B can also cause changes in the skin. People with MEN2B may have lumps and bumps on the lips, eyelids, and tongue. They also may have eyelids and lips that appear thicker than in most people. Children with MEN2B may not have tears when they cry. Some people with MEN2B have growths that can form in the gastrointestinal tract called ganglioneuromas. These growths can cause signs and symptoms including diarrhea or constipation and may present as early as infancy. People with MEN2B are often tall and may have long fingers, toes, arms, and legs (marfanoid habitus). They may have hyperflexible joints, especially during childhood.

RET gene.

After the thyroid is removed, a person with MEN2B may still have tests to make sure a medullary thyroid carcinoma did not develop and spread before the thyroid was removed. If the medullary thyroid carcinoma cannot be completely removed, there are therapies available such as tyrosine kinase inhibitors. These therapies can slow the growth of medullary thyroid carcinomas. People who have thyroidectomies need to take medications that contain the hormones that are normally produced by the thyroid.

People with MEN2B may also be recommended to have frequent tests such as analysis of the blood or urine for signs that there may be a tumor in the adrenal glands(pheochromocytoma). Imaging tests such as MRI or CT scan can also be used to monitor for the development of a pheochromocytoma. If a pheochromocytoma is identified, it may be removed with surgery.

If a person is diagnosed with MEN2B after he or she has already developed medullary thyroid carcinoma, the thyroid can be removed. If the cells of the tumor have already spread to other parts of the body (metastasized), surgery may not be able to remove all of the cancer. This can increase the risk for a person to pass away from the disease.

Other symptoms of MEN2B, such as gastrointestinal symptoms, are not life-threatening but can impact a person’s quality of life.