Multiple endocrine neoplasia type 2B

Multiple endocrine neoplasia type 2B is an inherited genetic disease that causes multiple tumors on the mouth, eyes, and endocrine glands.

Alternate Names

MEN 2B; Mucosal neuroma syndrome; Multiple endocrine neoplasia, type 3 (formerly); Wagenmann-froboese syndrome

Clinical features

Multiple endocrine neoplasia type 2B (MEN2B) is a genetic disease in which one or more of the endocrine glands are overactive and form a tumor (neoplasia).

Common tumors that may be associated with MEN2B include medullary thyroid carcinoma (MTC) and tumors of the adrenal glands called pheochromocytomas. Other features of MEN2B can include having bumps on the lips, eyelids, and tongue. People with MEN2B typically have a body type with long arms, legs, and fingers. They may also have joints that are very loose (hyperextensible).

Cause

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).

Signs and symptoms

Signs and symptoms of multiple endocrine neoplasia type 2B (MEN2B) include the development of tumors (neoplasias) of the endocrine glands. Endocrine glands are located throughout the body and are responsible for secreting hormones.

Tumors

The most common tumors that are found in people with MEN2B are medullary thyroid carcinoma (MTC) and tumors of the adrenal glands called pheochromocytomas. MTC is a type of thyroid cancer. In addition, tumor cells from medullary thyroid carcinomas can spread (metastasize) to other parts of the body.

The risk for a person with MEN2B to develop a medullary thyroid carcinoma or changes in the production of the cells of the thyroid gland (hyperplasia) is nearly 100%. People with MEN2B are most likely to develop medullary thyroid carcinomas in childhood or early adulthood.

Pheochromocytomas

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%.

Skin changes

MEN2B can also cause changes in the skin.

Lips

People with MEN2B may have lumps and bumps on the lips, eyelids, and tongue.

Eyes

They also may have eyelids and lips that appear thicker than in most people. Children with MEN2B may not have tears when they cry.

Ganglioneuromas

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.

Physical features

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.

Symptoms

• Aganglionic megacolon
• Autosomal dominant inheritance
• Colonic diverticula
• Constipation
• Disproportionate tall stature
• Elevated calcitonin
• Elevated urinary epinephrine
• Failure to thrive in infancy
• Flushing
• Ganglioneuroma
• Generalized hypotonia
• Decreased muscle tone
• Global developmental delay
• High palate
• Elevated palate
• High, narrow palate
• Narrow, high-arched roof of mouth
• Hyperlordosis
• Prominent swayback
• Joint laxity
• Joint instability
• Kyphosis
• Hunched back
• Medullary thyroid carcinoma
• Muscular hypotonia
• Myopathy
• Muscle tissue disease
• Nodular goiter
• Parathyroid hyperplasia
• Enlarged parathyroid glands
• Pectus excavatum
• Funnel chest
• Pes cavus
• High-arched foot
• Pheochromocytoma
• Proximal femoral epiphysiolysis
• Slipped end part of innermost thighbone
• Scoliosis
• Thick eyebrow
• Thick lower lip vermilion

Inheritance

Multiple endocrine neoplasia type 2B (MEN2B) is caused by certain genetic changes (mutations or pathogenic variants) in the 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.

Autosomal dominant Heredity

Multiple endocrine neoplasia type 2B (MEN2B) is inherited in an autosomal dominant manner. This means that a person only needs one copy of the 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.

Diagnosis

Multiple endocrine neoplasia type 2B (MEN2B) is suspected when a doctor sees a person who has a personal or family history of medullary thyroid carcinoma or pheochromocytoma. The diagnosis may also be suspected based on physical features suggestive of MEN2B such as having bumps on the eyelids or lips and long arms, legs, fingers, and toes.[2] The diagnosis of MEN2B can be confirmed with genetic testing of the RET gene.

Treatment

People with multiple endocrine neoplasia type 2B (MEN2B) are recommended to have their thyroid removed (thyroidectomy) as soon as they are diagnosed. This is because the risk for medullary thyroid carcinoma is nearly 100% in people who have MEN2B, and a thyroidectomy can prevent a person from ever developing medullary thyroid carcinoma.

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.

Prognosis

The long-term outlook for people with multiple endocrine neoplasia type 2B (MEN2B) may depend upon when a person with the disease was diagnosed. If the disease is identified early, prior to the development of a medullary thyroid carcinoma, the thyroid can be removed. Because medullary thyroid cancer often metastasizes, spreading cancer to other tissues in the body, removal of the thyroid (thyroidectomy) greatly reduces the chances that a person with MEN2B develops cancer. The other types of tumors which develop in people with MEN2B are usually not cancerous (benign) and therefore do not tend to be life-threatening.

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.

Thyroidectomy is the mainstay of treatment, and should be performed without delay as soon as a diagnosis of MEN2B is made, even if no malignancy is detectable in the thyroid. Without thyroidectomy, almost all patients with MEN2B develop medullary thyroid cancer, in a more aggressive form than MEN 2A.

Pheochromocytoma - a hormone secreting tumor of the adrenal glands - is also present in 50% of cases. Affected individuals are encouraged to get yearly screenings for thyroid and adrenal cancer.

Because prophylactic thyroidectomy improves survival, blood relatives of a person with MEN2B should be evaluated for MEN2B, even if lacking the typical signs and symptoms of the disorder. The mucosal neuromas of this syndrome are asymptomatic and self-limiting, and present no problem requiring treatment. They may, however, be surgically removed for aesthetic purposes or if they are being constantly traumatized.

See also

• Multiple endocrine neoplasia
• Multiple endocrine neoplasia type 1
• Multiple endocrine neoplasia type 2a

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