What is multiple endocrine neoplasia type 2 (MEN2)?

MEN2 is a hereditary cancer syndrome, affecting approximately 1 in 35,000 people. It is associated with the development of:

• Medullary thyroid cancer (MTC)
• Pheochromocytoma (a tumor of the adrenal gland)
• Hyperparathyroidism (a tumor of the parathyroid glands)
• Other abnormalities of the musculoskeletal and/or gastrointestinal tissues

Most individuals are diagnosed with MEN2 because they or a close family member develops MTC. Although differentiated thyroid cancer is relatively common, MTC, a subtype of thyroid cancer that develops from a different type of cell in the thyroid gland, is less common.

Of adults who develop MTC, about 75 percent have sporadic MTC that is not associated with a risk of the same tumor developing in their children. The remaining 25 percent of adults have MTC associated with the MEN2 syndrome, with a 50 percent chance of passing the risk of developing MTC and the other associated tumors to their children

The true prevalence of MEN2 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 a younger-than-expected age.

Types of MEN2

MEN2 is classified into two subtypes that vary based on the specific genetic abnormality in the RET, the types of tumors that develop, and the age of onset of disease.

MEN2A

Most people with MEN2 have type A. Individuals with MEN2A have an increased risk of MTC, pheochromocytoma (adrenal tumor), and primary hyperparathyroidism (PHPT), a condition in which the parathyroid glands secrete extra parathyroid hormone that results in elevated calcium. The risk and timing for developing the tumors is related to the specific abnormality in the RET proto-oncogene, the genetic abnormality that causes the disease (see Causes of MEN2). All of the tumors may develop during childhood; however, it is more common for pheochromocytoma and hyperparathyroidism to develop during adulthood.

MEN2B

MEN2B is rarer than MEN2A; however, the onset of tumors — particularly MTC, which can be highly aggressive — occurs at a younger age, typically developing in infancy or early childhood. All children with MEN2B will develop MTC within their lifetime, and about half will develop pheochromocytoma.

Causes of MEN2

MEN2 is caused by a mutation in the RET gene located on chromosome 10. These mutations can be hereditary or can occur as a “new” mutation in one of the father’s sperm, mother’s eggs or in a cell of the developing fetus. About 95 percent of individuals with MEN2A inherited the condition from their parents, whereas 50 percent of people with MEN2B are the first in their families to be diagnosed with the disease.

In individuals with either form of MEN2, the RET gene is altered so the protein that is produced is always “switched on.” With the RET protein (receptor) always active, cells continuously grow (multiply), leading to cancer development and over-production of certain proteins and hormones.

People with MEN2 carry one normal copy of the RET gene and one abnormal RET gene in all cells throughout their body. These individuals have a 50 percent chance of passing the same genetic alteration onto each of their future children. A disease that is associated with a 50 percent chance of being passed between generations is described as an “autosomal dominant” condition. Most children who inherit the altered RET gene are born and develop normally, but are at increased risk of developing benign or malignant endocrine tumors during their lifetime.

Signs and symptoms of MEN2

The symptoms of MEN2 — and the age of onset — will depend on the specific genetic abnormality in the RET gene and the location of the tumor.

Most patients with MTC do not have symptoms, but the thyroid tumor (nodule) is visible on a physical exam or on thyroid ultrasound.

Patients with hyperparathyroidism may experience fatigue, weakness, confusion, increased urination, nausea, decreased appetite, constipation and abnormal heart rhythm. They may also develop bone pain and be at increased risk for kidney stones.

Patients with pheochromocytoma may have headaches, flushing, sweating, increased and pounding heart rate (palpitation), tremors, nausea, weakness and anxiety. The headaches, palpitations and sweating are usually present at the same time and may be intermittent (occur as “spells”).

MEN2A

Most pediatric patients are diagnosed based on a parent or family member having MEN2. About 95 percent of people with MEN2A will develop medullary thyroid cancer during their lifetime, but the risk of developing pheochromocytoma and/or hyperparathyroidism range between 10 to 50 percent and depends on the specific RET gene abnormality (codon).

Some people with MEN2A will also develop an itchy skin condition called cutaneous lichen amyloidosis (a raised, itchy area between the shoulder blades of the upper back).  A small percentage (2-5 percent) of families may also have Hirschsprung’s disease, an intestinal disorder that presents with constipation in infancy.

MEN2B

Unlike MEN2A where a tumor may be the first symptom of the syndrome, MEN2B has some early warning symptoms. In infancy, for example, the most common symptoms of MEN2B are the inability to make tears (alacrima) and constipation. Decreased muscular tone, with or without congenital club feet, and failure to thrive are additional early features of MEN2B.

In school-age children, additional signs and symptoms of MEN2B often include:

• A long, thin face (marfanoid facies) and slender body shape (may have short stature)
• Nodules in or on the lips, tongue or on the inside cheeks of the mouth (mucosal neuromas)
• Eyelids that appear to be turned inside out (eyelid eversion), so the side that usually sits against the eyeball is visible
• Scoliosis
• Constipation
• Thyroid nodule(s)

All individuals with MEN2B will develop early onset MTC (often before the child is 1 year old). About half will also develop tumors of the adrenal glands (pheochromocytomas).

In addition, individuals with MEN2B have a greater risk of developing ganglioneuromas of the intestinal tract, rare tumors made of ganglion cells, nerve fibers and supporting cells that result in constipation.

Testing and diagnosis of MEN2

At Children’s Hospital of Philadelphia, a diagnosis of MEN2 begins with a complete medical and family history, as well as a comprehensive physical exam.

In order to determine on a molecular level if your child has MEN2, a genetic test must be performed. A sample of your child’s blood will be collected, then their DNA will be isolated and analyzed to determine if there are any alternations to the RET gene. If there is known family history of MEN2, bringing the previous genetic report will lead to a faster turn-around time for the result of the genetic testing.

Determining the type of mutation will help clinicians better predict the course of your child’s illness, including their risk of developing MTC, hyperparathyroidism and pheochromocytoma, as well as to customize treatment plans and long-term monitoring.

It is important to note that not all patients with MEN2 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.

Treatment of MEN2

If a family member is diagnosed with MEN2, or your child is diagnosed with a cancer associated with MEN2 (MTC, hyperparathyroidism or pheochromocytoma), you should be referred to a dedicated program, like the Pediatric Thyroid Center at Children’s Hospital of Philadelphia (CHOP), which has the experience, expertise and resources to fully evaluate your child. Your family should also be scheduled in the CHOP Cancer Predisposition Program for genetic counseling.

Because many of the symptoms of MEN2 are not apparent until adulthood, screening for the related tumors is critical to optimize a patient’s health. Evaluation by a specialist is necessary for accurate diagnosis and treatment, including knowing when to screen and when to consider surgical treatment.

Although there is no cure for MEN2, there are options to minimize symptoms and decrease your child’s risk of certain cancers. Early and regular screening is the most important path to allow MEN2 patients to lead happy, productive and healthy lives.

At Children’s Hospital of Philadelphia, clinicians from the Pediatric Thyroid Center collaborate with other specialists at the Hospital — depending on which glands are affected — to treat the changes in your child with MEN2.

Treatment often includes:

• Tumor removal
• Medication

When possible, tumors are removed surgically. Medication may be used before and after tumor removal to correct hormone imbalances caused by the glands’ overactivity.

Thyroidectomy

Since there is a high risk for individuals with MEN2 to develop MTC, and MTC is an aggressive type of thyroid cancer, preventative removal of the thyroid gland (thyroidectomy) is generally recommended for individuals with MEN2.

The best timing for this surgery varies depending on the type of MEN2, that is, which RET alteration (codon) is involved, the earliest age at which thyroid cancer appears within an affected family, and the family’s interest in surveillance versus earlier surgery.

A thyroid ultrasound and a blood test to look for two proteins associated with MTC, called calcitonin (Ct) and carcinoembryonic antigen (CEA), will allow your doctor to determine the timing and the extent of surgery.

The goal is to remove the MTC prior to it spreading to lymph nodes in the neck or beyond (lung, liver or bone). Thyroid ultrasound and protein levels, along with fine-needle aspiration of the thyroid and/or lymph nodes, will ensure accurate surgical planning and increase the chances for complete removal of the tumor.

Unfortunately, once MTC spreads (metastasizes) it cannot be cured. However, the tumor grows relatively slowly, and there are an increasing number of medications (systemic therapy) that can be used to slow progression.

For children with MEN2A, some families may elect to remove the thyroid prior to a nodule developing; other families may decide to wait until the blood tests and thyroid ultrasound indicate a small tumor has developed. This second option is safe, but requires the patient and family to undergo annual blood tests and thyroid ultrasound screenings to ensure the tumor is caught early enough in its course to still achieve remission. For some patients, this surgery may not be necessary until they are teenagers, young adults, or even adults.

After surgical removal of the thyroid gland, your child will need to take thyroid hormone replacement (one pill once daily) for the rest of their lives. Learn more about thyroid surgery for children.

Hyperparathyroidism

Hyperparathyroidism is treated with surgical removal of the affected parathyroid gland. The parathyroid glands are small, pea-sized glands, located behind the thyroid gland.

In addition to the signs and symptoms of increased calcium (listed above), patients with hyperparathyroidism have elevated calcium in their blood and urine with a normal or elevated parathyroid hormone level.

Neck ultrasound may be used to find which of the four parathyroid glands is enlarged.

If parathyroid enlargement is detected, minimally invasive surgery may be used — along with intra-operative measurements of parathyroid hormone — to help find and confirm that the affected parathyroid gland was completely removed. Vitamin D and calcium supplementation may be needed for a period of time before and/or after this procedure is performed. 

Pheochromocytoma

The adrenal tumors that develop from the cells that produce epinephrine (adrenaline) — our “fight or flight” hormone — are called pheochromocytomas. These tumors are detected based on signs and symptoms, as well as elevated levels of epinephrine-related hormones in the blood or urine (metanephrines).

Humans have two adrenal glands, one above each kidney, and patients with MEN2 may develop tumors in one or both glands. Adrenal tumors often develop years apart, so ongoing screening is recommended — even after surgical removal of one adrenal gland. Annual urine or blood screening allows clinicians to diagnose adrenal tumors sooner — often when they are smaller — and may be treated with partial removal of the adrenal gland, instead of removing the entire gland.

If your child’s metanephrine levels are very high prior to surgery, then medications to control blood pressure prior to, during and after surgery may be needed. MEN2-associated pheochromocytomas rarely spread (metastasize). However, early detection can reduce the need for lifelong adrenal hormone replacement therapy.

Surgery risks

Children and adults with MEN2 need to be screened for a possible pheochromocytoma prior to any surgery, because patients with undiagnosed adrenal tumors can develop malignant hypertension (a severe elevation of blood pressure) following treatment with general anesthesia. Pheochromocytoma screening is done by a blood or urine test to determine if epinephrine-related hormones (metanephrines) are elevated.

If the metanephrine levels are very high prior to surgery, then medications to control blood pressure prior to, during, and after surgery may be needed.

Follow-up care and cancer screening for MEN2

Children diagnosed with MEN2 will need lifelong follow-up care and cancer screening. In the first few years after thyroidectomy, your child will require physical exams and laboratory tests every three to six months.

As time passes — and if there is no evidence of disease or additional symptoms — follow-up exams may become yearly. Your child’s healthcare team will customize a follow-up plan based on your child’s condition and outcome.

All patients diagnosed with MEN2 — even if they have no symptoms — should be screened annually for the presence of pheochromocytoma and hyperparathyroidism. The American Thyroid Association recommends yearly screening for these tumors beginning at age 11 for patients with MEN2B, and by age 16 for patients with MEN2A.

Reproductive options 

As your child with MEN2 grows into adulthood, they may consider starting a family of their own. Up to 50 percent of children born to a parent with MEN2 may also carry the RET proto-oncogene. However, with early detection and surveillance, children can lead healthy, happy and productive lives. For families that are interested, reproductive options exist for individuals with an alteration in the RET gene who do not wish to pass this alteration onto future children.

Prenatal diagnosis

DNA is isolated from the cells of the developing baby through one of two procedures (chorionic villus sampling [CVS] or amniocentesis) and is analyzed for alterations in the RET gene. With appropriate counseling, a parent can then decide whether to carry the pregnancy to term or to end the pregnancy.

Pre-implantation genetic diagnosis (PGD)

For couples using in vitro fertilization to become pregnant, embryos can be tested for genetic disorders before transferring them into the uterus. Only healthy embryos carrying two working copies of the RET gene would be implanted.

Before one can proceed with prenatal testing or PGD, a RET mutation must be identified in a parent with MEN2.

Care for adults with MEN2

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 or by calling 1-800-789-PENN (7366).