Frequently Asked Questions about Hereditary Paraganglioma-Pheochromocytoma Syndrome

What is hereditary paraganglioma-pheochromocytoma syndrome?

Hereditary paraganglioma-pheochromocytoma syndrome is a condition that makes people more likely to develop rare tumors called paragangliomas and pheochromocytomas. Hereditary paraganglioma-pheochromocytoma syndrome can be caused by mutations in any of the following genes: SDHA, SDHB, SDHC, SDHD, and SDHAF2. These genes are collectively known as the SHDx genes. 

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What are paragangliomas and pheochromocytomas?

Paragangliomas are rare tumors that develop in neuroendocrine tissue. Neuroendocrine tissue is made up of cells that make hormones. It is found throughout the body, especially in glands, along the spine in the base of the skull, and in the neck, chest, and abdomen. Paragangliomas often develop in the adrenal glands (small glands that sit above the kidneys). These tumors are called pheochromocytomas.

Paragangliomas and pheochromocytomas are often benign (not cancer) and slow growing, but can sometimes be malignant and metastasize (spread to other parts of the body).

When a tumor grows in neuroendocrine tissue, it can produce too many hormones called catecholamines. These hormones include adrenaline and dopamine. The release of large amounts of these hormones can cause symptoms of the “fight-or-flight” response, including high blood pressure, headaches, profuse sweating, heart palpitations, and feelings of anxiety. It is normal for these symptoms to occur when there is a reason, such as stress or heavy exercise.  However when they are caused by a tumor, there may be no obvious reason. Pheochromocytomas usually cause too many of these hormones to be produced. Paragangliomas may or may not cause these hormones to be produced.

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How common are paragangliomas and pheochromocytomas?

We don’t exactly know how common these tumors are, but they develop in about 1 in 300,000 people per year. About 75% (3 out of 4) of paragangliomas are sporadic, which means they occur by chance. The other 25% (1 in 4) are hereditary. Hereditary paraganglioma-pheochromocytoma syndrome occurs in about 1 in 1 million people; however, the actual rate could be higher.

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What are the chances of inheriting an SDHx gene mutation?

Both males and females can pass down an SDHx gene mutation to their children. All people, whether they have hereditary paraganglioma- and pheochromocytoma syndrome or not, have 2 copies of each SDHx gene (1 copy is from each parent). Only a mutation in 1 of the one changed SDHx genes will cause an increased risk for paragangliomas and pheochromocytomas.

If you have a parent with hereditary paraganglioma-pheochromocytoma syndrome, you may or may not have inherited it. You have a 50% (1 in 2) chance of having inherited the nonworking SDHx gene. If you inherited the nonworking SDHx gene, you have an increased risk of developing paragangliomas and having hereditary paraganglioma-pheochromocytoma syndrome. You also have a 50% chance of having inherited your parent’s working copy of an SDHx gene. If this is the case, you would have the same risk for these tumors as a person in the general population.

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Can I be tested for an SDHx gene mutation?

Mutations in the SDHx genes can be tested for using a blood or saliva sample. It is best to start testing with a person who has already had a paraganglioma or pheochromocytoma. If a mutation is found, other family members can be tested for the same mutation. All genetic testing should be done along with genetic counseling.

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What does a negative SDHx gene test result mean?

A negative result means that no SDHx gene mutation was found. This can happen for several reasons:

  • You could have a mutation in the same gene that is not detectable by the method used. No one gene testing method can find all mutations in that gene. Your genetic counselor may recommend a different test to look for mutations in the SDHx genes.
  • You may have a mutation in a different gene that causes hereditary paraganglioma-pheochromocytoma syndrome. This could be another one of the SDHx genes. For example, even if you tested negative for SDHB gene mutations, your genetic counselor may still recommend testing for SDHD gene mutations. Or it could be a mutation in a less common gene that we do not routinely test or you could carry a mutation in a gene that has not yet been discovered. More genes will probably be discovered in the future.
  • You could have a different syndrome. Other hereditary syndromes that can specifically cause pheochromocytomas are von Hippel Lindau (VHL), neurofibromatosis type 1 (NF1), or multiple endocrine neoplasia type 2 (MEN2). Your genetic counselor may recommend testing for these other syndromes.
  • If only one family member has had a paraganglioma or pheochromocytoma, it could have happened by chance (sporadic). If that is the case, it would not be hereditary.
  • Some people already have a known SDHx gene mutation in their family. If this is the case, a person in the family who does not carry that mutation would have the same risk for paragangliomas and pheochromocytomas as the general population.
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What does a positive SDHB gene test result mean?

A positive test result means that an SDHB gene mutation was found. The exact risks caused by SDHB gene mutations are not yet known. One study of people with SDHB gene mutations found the risk of developing a paraganglioma to be 29% by age 30, 45% by age 40, and 80% by age 80. It is possible that the actual risks are lower. Even with an SDHB mutation, you may never develop a paraganglioma or pheochromocytoma.

Compared to those with SDHD gene mutations, those with SDHB gene mutations may have a higher risk of developing abdominal paragangliomas and a lower risk of developing head and neck paragangliomas (although they may develop either type). Compared with those with SDHD gene mutations, people with SDHB gene mutations may develop paragangliomas later in life, and they may develop more often outside the adrenal glands. They are more likely to metastasize (spread) if not removed.

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What does a positive SDHD test result mean?

A positive test result means that an SDHD gene mutation was found. The exact risks caused by SDHD mutations are not yet known. One study of people with SDHD gene mutations found the risk of developing a paraganglioma or pheochromocytoma to be 48% by age 30, 73% by age 40, and 86% by age 50. It is possible that the actual risks are lower. Even if someone has an SDHD mutation, they may never develop a paraganglioma or pheochromocytoma.

Compared with those with SDHB gene mutations, those with SDHD gene mutations may have a higher risk of developing head and neck paragangliomas and a lower risk of developing abdominal  paragangliomas (although they can develop either type). 

Compared with those with SDHB gene mutations, people with SDHD gene mutations may develop tumors earlier in life, and they occur more often in the adrenal glands (pheochromocytomas).

For people with both SDHB and SDHD gene mutations, a few studies have suggested that they may have lower risks for other cancers, such as kidney cancer, thyroid cancer, and gastrointestinal cancer. These other risks are still being investigated.

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What does it mean if I test positive for a mutation in a different SDHx gene?

Even less is known about SDHx genes other than SDHB and SDHD, such as SDHA, SDHC, and SDHAF2, although the risks may be similar. SDHC gene mutations may mostly cause head and neck paragangliomas.

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If I test positive for an SDHx gene mutation, what are the recommendations for screening?

Doctors believe that routine screening can find paragangliomas and pheochromocytomas early when they are still small and much less likely to cause problems. Screening should be ordered by a specialist who knows about the condition.  Screening should begin around age 10.

Although the best screening for people with a hereditary paraganglioma-pheochromocytoma syndrome is not yet known, the following have been suggested:

  • Annual physical exams, including blood pressure measurement lying down and sitting up.
  • Anyone who has unexplained symptoms such as frequent headaches, sweating, palpitations, severe anxiety with stomach pain, nausea, vomiting or chest pain, should tell his or her doctor.
  • A person should also tell his or her doctor about a neck mass or pressure, trouble swallowing, problems with the voice (hoarseness), or hearing problems such as ringing in the ear.
  • Children or young adults with upper gastrointestinal bleeding, anemia, or any of the symptoms listed above should be evaluated for GastroIntestinal Stromal Tumor (GIST).
  • Blood or urine should be tested yearly for the catecholamine hormones. If the levels are too high, follow-up imaging tests (such as a computed tomography [CT] scan, magnetic resonance imaging [MRI], or positron emission tomography [PET] scan) will be recommended.
  • Routine MRI or CT scans of the head and neck, abdomen, chest, and pelvis every 2 years is recommended. The frequency of screening may be different depending on which gene is affected. Other imaging tests, such as 123I-MIBG scintigraphy, may also be done every 4 years. New screening methods such as fluorodeoxyglucose positron emission tomography [18F] FDG-PET scan (an imaging test that uses a radioactive substance to look for certain types of tumors in the body) may be even more effective.
  • Routine ultrasounds of the kidneys and urine tests may be considered, due to the increased risk of kidney cancer.

If paragangliomas or pheochromocytomas develop, they can be removed with surgery in most cases. Special measures should be taken before surgery to avoid a blood pressure crisis (when a person’s blood pressure becomes dangerously high).  For people at risk, it is important to rule out pheochromocytomas before surgery and before pregnancy. An undiagnosed tumor can cause a life-threatening crisis during surgery or pregnancy.

People with hereditary paraganglioma-pheochromocytoma syndrome should avoid long-term conditions of hypoxia (low oxygen), such as living at high altitudes, and risks for lung disease, such as cigarette smoking.

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If I have an SDHx gene mutation, what are the risks to my children?

If you have an SDHx gene mutation, each of your children will have a 50% (1 in 2) chance of inheriting it. A child who inherits an SDHx gene mutation would inherit the risks. However, the same mutation may cause different problems, or not cause any problems, in different family members.

There is an exception with the SDHD and possibly the SDHAF2 genes. An SDHD gene mutation inherited from one’s father carries the same risks for paragangliomas and pheochromocytomas. If the same mutation is inherited from one’s mother, the risk for paragangliomas and pheochromocytomas is much lower. This is called imprinting. In contrast, with SDHB and SDHC gene mutations, the risk for paragangliomas and pheochromocytomas is the same regardless of whether the mutation came from one’s father or mother.

In this condition, screening for pheochromocytomas and paragangliomas should start at an early age. For this reason, it is a good idea for your children to have genetic counseling and consider genetic testing around the age of 10.

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If I have an SDHx gene mutation, what are my options for having children?

If you have an SDHx gene mutation, you may want to learn about options for family planning (starting a family or having more children). For example, embryos can be tested for the family’s genetic mutation before they are even implanted in a woman’s uterus. This process is called preimplantation genetic diagnosis (PGD). PGD is performed in combination with in vitro fertilization and may be an option for families who wish to have children without the hereditary cancer risk. To learn more, ask for a referral to a PGD-IVF specialist before attempting pregnancy. 

Other possible family planning options include having children with the assistance of donor eggs or sperm or through adoption.

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What if I have questions?

If you have questions or concerns, please contact the MSK Clinical Genetics Service at 646-888-4050.

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