Hereditary Paraganglioma-Pheochromocytoma Syndrome

Types of paragangliomas and pheochromocytomas

There are 2 types of paragangliomas:

• Sympathetic paragangliomas: These produce and release catecholamines into the bloodstream. Catecholamines are certain kinds of hormones, such as epinephrine, norepinephrine, and dopamine. Hormones are chemical messengers that send important instructions to different parts of the body. Normally, catecholamines are released into the bloodstream by the adrenal glands. The adrenal glands produce catecholamines in response to stress. A pheochromocytoma is a type of sympathetic paraganglioma.
• Parasympathetic paragangliomas: These do not usually release catecholamines into the bloodstream.

Paragangliomas and pheochromocytomas can develop in people without a genetic syndrome. But in families with a history of hereditary paraganglioma-pheochromocytoma syndrome, the risk of developing tumors can be passed from parents to children.

Hereditary paraganglioma-pheochromocytoma syndrome is caused by changes (mutations) in any 1 of a group of genes that includes SDHD, SDHAF2, SDHC, SDHB, SDHA, TMEM127, and MAX. Health care providers should consider a diagnosis of hereditary paraganglioma-pheochromocytoma syndrome for all people with paragangliomas and pheochromocytomas, especially for those who have developed these types of tumors:

• Multiple tumors in different organs, such as bilateral tumors (tumors found in each of a pair of organs, such as 1 in each adrenal gland)
• More than 1 tumor in the same organ (multifocal)
• Tumors that grow back after removal (recurrent)
• Tumors that develop earlier than age 40 (early onset)
• Tumors found in other family members

Not all of these descriptions will apply to every person with hereditary paraganglioma-pheochromocytoma syndrome. Many people with the syndrome may have only 1 tumor in the head, neck, torso, adrenal gland, or pelvis. Many do not have any family history of similar tumors. The age of onset, number, location, and severity of tumors can be very different, even in families that have a history of the syndrome.

Cancer risk with hereditary paraganglioma-pheochromocytoma syndrome

The risk of developing paragangliomas and pheochromocytomas increases as people with the syndrome age. The risk of developing at least 1 tumor if you have the syndrome is:

• About 29–50% (nearly 3 in 10 or 1 in 2) by age 30
• About 45–73% (nearly 1 in 2 or 3 in 10) by age 40
• Up to 86% by age 50

In many cases, paragangliomas and pheochromocytomas are not cancerous (malignant). Sometimes the tumors do become cancerous and spread to other parts of the body (metastasize). The risk varies greatly among different people with this condition.

Doctors have found 7 types of hereditary paraganglioma-pheochromocytoma syndrome. Each has a different risk profile, and each is related to different genes (shown in parentheses):

• Type PGL1 (linked to a mutation in the SDHD gene)
  • Most people with this type have head and neck paragangliomas that are multifocal (several tumors that grow in a single organ).
  • Most of these tumors do not release catecholamines (hormones) into the bloodstream.
  • Some people with Type PGL1 syndrome may have paragangliomas in the adrenal glands, torso, or pelvis that do release catecholamines into the bloodstream.
  • The risk of the tumors becoming cancerous in people with Type PGL1 syndrome is less than 5%.
• Type PGL2 (linked to a mutation in the SDHAF2 gene)
  • People with this rare type typically only have head and neck paragangliomas that do not release catecholamines into the bloodstream.
  • Multifocal tumors and a young age of onset are common.
  • Many people with Type PGL2 syndrome do not have any symptoms.
  • The risk of these tumors becoming cancerous is unknown because the type is so rare. But the risk is very low.
• Type PGL3 (linked to a mutation in the SDHC gene)
  • Most people with this rare syndrome only have head and neck paragangliomas that do not release catecholamines into the bloodstream.
  • The risk of these tumors becoming cancerous is unknown because the type is so rare. But the risk is very low.
• Type PGL4 (linked to a mutation in the SDHB gene)
  • Most people with this type develop paragangliomas that are not in the adrenal glands and do release catecholamines into the bloodstream. These tumors are usually found in the abdomen (belly).
  • Some people with this type also develop pheochromocytomas.
  • The risk of the tumors becoming cancerous in people with this syndrome is high (34% to 97%).
• Type PGL 5 (linked to a mutation in the SDHA gene)
  • This type is rare. People with this type have 1 paraganglioma or 1 pheochromocytoma.
  • The risk of the tumor becoming cancerous is unknown because the type is so rare. But the risk is very low.
• TMEM127-Related PGL
  • In this type, tumors usually develop at older ages than seen with other types. The average age of tumor diagnosis is 42 years.
  • Most people with this type develop pheochromocytomas. Some develop abdominal (belly) or head and neck paragangliomas.
  • The risk of the tumors becoming cancerous in people with this syndrome is less than 5%.
• MAX-Related PGL
  • Only pheochromocytomas have been identified in the few people known to have this type. About 50–70% (1 in 2 or nearly 3 in 10) of people with this type have pheochromocytomas in both adrenal glands.
  • The risk of the tumors becoming cancerous in people with this syndrome is about 25% (1 in 4).

People with hereditary paraganglioma-pheochromocytoma syndrome also have a higher risk of developing other types of tumors, including:

• Gastrointestinal stromal tumors (GIST): a type of tumor found in the digestive tract
• Renal clear cell carcinoma: a type of tumor found in the kidney
• Papillary thyroid carcinoma: a type of tumor found in the thyroid gland

The exact tumor risks depend on which of the 7 types of hereditary paraganglioma-pheochromocytoma syndrome a person has.

Symptoms of paragangliomas and pheochromocytomas

Paragangliomas and pheochromocytomas can cause symptoms if they release catecholamines (hormones) into the bloodstream. These symptoms may include:

• Headache
• High blood pressure
• Excessive sweating
• Heart palpitations (pounding, skipping or fluttering heartbeats)
• Pale skin
• Anxiety

Paragangliomas can also cause symptoms if they become large. These symptoms may include:

• Trouble swallowing
• Coughing
• Hoarse voice
• Hearing loss

Not all patients with hereditary paraganglioma-pheochromocytoma syndrome will have all these symptoms.

How hereditary paraganglioma-pheochromocytoma syndrome is inherited

Hereditary paraganglioma-pheochromocytoma syndrome is caused by changes (mutations) in 1 of the following genes: SDHD, SDHAF2, SDHC, SDHB, SDHA, TMEM127, and MAX.

Most people without hereditary paraganglioma-pheochromocytoma syndrome carry 2 working copies of each of these genes in their cells. One copy of each gene is inherited from the mother and another from the father. Cells from people with hereditary paraganglioma-pheochromocytoma syndrome have a change in 1 copy of these genes that causes it to not work properly.  This gene change is called a mutation. The type of hereditary paraganglioma-pheochromocytoma syndrome someone has depends on which gene has the mutation.

All people with hereditary paraganglioma-pheochromocytoma syndrome have a 50% (1 in 2) chance of passing their gene mutation to their children.

Children who inherit a SDHC, SDHB, SDHA, or TMEM127 gene mutation from either parent will have hereditary paraganglioma-pheochromocytoma syndrome. In most cases, only children who inherit a SDHAF2, SDHD, or MAX mutation from their fathers are at risk of developing paragangliomas or pheochromocytomas.

Hereditary paraganglioma-pheochromocytoma syndrome diagnosis

Health history

A health care provider may suspect that your child has hereditary paraganglioma-pheochromocytoma syndrome after studying their medical and family cancer history.

This information helps the health care provider and the genetic counselor know if:

• There are more cancers than normal in your family
• These cancers happened at a younger age than expected
• The cancers are those that are seen in hereditary paraganglioma-pheochromocytoma syndrome

Your provider or genetics counselor may recommend genetic testing if they suspect hereditary paraganglioma-pheochromocytoma syndrome.

Learn more about types of genetic tests. 

Genetic testing for hereditary paraganglioma-pheochromocytoma syndrome

A blood sample is sent to a genetic testing lab. The lab runs genetic tests that look for changes in the genes related to hereditary paraganglioma-pheochromocytoma syndrome.

If your child has a mutation in 1 or more of these genes, a genetic counselor will work with your family to:

• Find out if other family members should consider testing  
• Help your family understand the increased cancer risk 
• Help with your decisions about prenatal genetic testing

Genetic testing does not always find a mutation in SDHD, SDHAF2, SDHC, SDHB, SDHA, TMEM127, and MAX for all people with hereditary paraganglioma-pheochromocytoma syndrome. A person can still have the syndrome even if no mutations in these genes are found. There are likely to be more, undiscovered genes that play a role in the development of this syndrome.

Genetic testing before or during pregnancy

Parents may choose to do prenatal testing to find out if a pregnancy is affected with a known mutation in SDHD, SDHAF2, SDHC, SDHB, SDHA, TMEM127, or MAX. Testing may take place either before pregnancy occurs or during pregnancy.

You should work with a genetic counselor to review the pros and cons of the test. The genetic counselor can also help you prepare for the test results.

Testing before pregnancy is called preimplantation genetic testing (PGT). This special type of genetic testing is done along with in vitro fertilization (IVF). PGT tests embryos for a known mutation before a provider places the embryo into the uterus.

Testing during pregnancy can help providers see if a pregnancy has a known mutation in SDHD, SDHAF2, SDHC, SDHB, SDHA, TMEM127, or MAX. A doctor gathers cells from the pregnancy in 1 of 2 ways:

• Chorionic villus sampling (CVS) is done during the first 3 months of pregnancy (1^st trimester).
• Amniocentesis is done after the first 3 months of pregnancy (2^nd trimester or later).

After tissue collection, the lab checks the sample for a known mutation in SDHD, SDHAF2, SDHC, SDHB, SDHA, TMEM127, or MAX.

Both tests carry minor risks. Discuss these risks with an experienced health care provider or a genetic counselor.

Special concerns for genetic testing

Take time to think carefully about the benefits and risks of genetic testing. Speak with a genetic counselor before testing. If you decide to get tested, talk with your health care provider or a genetic counselor about your results so you can understand what they mean.

Sometimes, children or adults with hereditary paraganglioma-pheochromocytoma syndrome feel sad, anxious, or angry after getting their test results. Parents may feel guilty if they pass a gene mutation to 1 or more of their children. People with a SDHD, SDHAF2, SDHC, SDHB, SDHA, TMEM127, or MAX gene mutation may also have trouble getting disability or life insurance.

Read more about genetic discrimination.

Monitoring and follow-up care for hereditary paraganglioma-pheochromocytoma syndrome

People with hereditary paraganglioma-pheochromocytoma syndrome should be managed by a health care provider who knows this condition well. Screening is recommended for all people with this condition. The goal of screening is finding and treating tumors early to allow the best outcome for patients.

Screenings usually begin between ages 7–9. If other family members have the syndrome, screenings should begin at least 10 years before the earliest date that tumors developed in those family members.

We recommend the following screenings for children with hereditary paraganglioma-pheochromocytoma syndrome:

• Yearly physical exams by a health care provider who knows this condition well. The health care provider should pay special attention to symptoms such as high blood pressure, heart palpitations, anxiety, headache, coughing, hoarse voice, problems swallowing, and hearing loss.
• Blood tests to screen for abnormally high levels of catecholamines. Repeat these tests every year.
• Whole-body and neck MRIs every 2 years to check for tumors.

These recommended screenings may change over time as health care providers learn more about hereditary paraganglioma-pheochromocytoma syndrome. Discuss all screening options for your child with a health care provider who knows this condition well.

Because hereditary paraganglioma-pheochromocytoma syndrome is a complex condition, it is important to seek an experienced health care provider for your child.

Living with hereditary paraganglioma-pheochromocytoma syndrome

People of any age with hereditary paraganglioma-pheochromocytoma syndrome have a higher risk of cancer. They should monitor their health and adopt healthy habits throughout life. It is important to continue to have regular physical checkups and screenings. That way, any cancer can be found early at the most treatable stage.

Problems to watch for

People with hereditary paraganglioma-pheochromocytoma syndrome should watch closely for general signs or symptoms that could signal cancer:

• Unexplained weight loss
• Excessive sweating or feelings of anxiety
• Racing heartbeat
• Unexplained high blood pressure
• Loss of appetite
• Pain in abdomen (belly)
• Blood in the stool or changes in bowel habits
• Aches, pains, lumps or swelling that cannot be explained
• Headaches or changes in vision or nerve function that do not go away

It is important to seek medical help if anything unusual appears.

Maintain a healthy lifestyle

Habits that will help you maintain a healthy lifestyle include:

• Eat a healthy diet with lots of fruits and vegetables.
• Get regular exercise.
• Avoid smoking or using tobacco products.
• Avoid secondhand smoke.
• Avoid excess sun exposure and always wear sunscreen, a hat and protective clothing when out in the sun.

Hereditary paraganglioma-pheochromocytoma syndrome care at St. Jude

The St. Jude Cancer Predisposition Program is dedicated to diagnosing and screening children with a genetic predisposition for cancer. Our program offers the best clinical care possible. We engage in cutting-edge research to gain more information about genetic disorders and cancer, and to improve the care and treatment for patients who are affected by these conditions. Learn more about the Division of Cancer Predisposition at St. Jude.

Our genetic counselors, clinicians, genetics nurse practitioners, and research assistants work together to provide patients with:

• A complete health history
• A record of cancer that happened over the past 3 generations (family tree or pedigree) to see how diseases were passed down
• Physical exams to check for genetic disease
• Confidential genetic counseling and testing
• Cancer screenings for those with genetic disease to detect and treat cancer as soon as it occurs
• Recommended cancer treatments and ways to reduce cancer risk
• Genetic testing for immediate (1st degree) relatives

Hereditary paraganglioma-pheochromocytoma syndrome increases your child’s risk for many types of cancer. 

If you have questions about the Genetic Predisposition Clinic and care for hereditary paraganglioma-pheochromocytoma syndrome, email our team at GPTeam@stjude.org.

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