What is Hereditary Paraganglioma-Pheochromocytoma Syndrome?

Hereditary Paraganglioma-Pheochromocytoma Syndrome is a condition where tumors develop in structures called paraganglia. Paraganglia are bundles of cells of the peripheral nervous system (the nerves outside the brain and spinal cord). A tumor that develops in the paraganglia is called a paraganglioma.

There are two types of paragangliomas:

  • Sympathetic paragangliomas. These produce and release what’s called catecholamines into the bloodstream. Catecholamines are 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, located on top of each kidney, produce catecholamines in response to stress.
  • Parasympathetic paragangliomas. These do not usually release catecholamines into the bloodstream.

Most paragangliomas are usually found in the head, neck, or torso. A specific type of sympathetic paraganglioma, called a pheochromocytoma, develops in the adrenal glands.

Paragangliomas and pheochromocytomas can develop sporadically in people without a genetic syndrome. However, in families with a history of Hereditary Paraganglioma-Pheochromocytoma Syndrome, the risk of developing tumors can be passed from parents to children. Health care providers 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 one in each adrenal gland)
  • Multifocal (more than one tumor in the same organ)
  • Recurrent (tumors that grow back after removal)
  • Early onset (tumors that develop earlier than age 40)
  • 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 one tumor in the head, neck, torso, adrenal gland, or pelvis. Many do not have any family history of similar tumors. Among people that do have a family history of the syndrome, the age of onset, number, location, and severity of the tumors can be very different among family members.

Genes carry information telling cells in the body how to work. Hereditary Paraganglioma-Pheochromocytoma Syndrome is caused by changes in any one of a group of genes that includes SDHD, SDHAF2, SDHC, SDHB, SDHA, TMEM127, and MAX.

Most people without Hereditary Paraganglioma-Pheochromocytoma Syndrome carry two working copies of each of these genes in their cells. One copy of each gene is inherited from each parent. Cells from people with Hereditary Paraganglioma-Pheochromocytoma Syndrome carry two working copies of each of these genes except one. For that one gene, the person’s cells carry one working copy and one copy that is changed. This change causes the gene to not work properly. It is called a variant.

As people with Hereditary Paraganglioma-Pheochromocytoma Syndrome get older, the remaining working copy of the gene with the variant often becomes changed in some of their cells. When both copies of the gene are changed, a tumor can develop. The tumor may become cancerous. That is why people with Hereditary Paraganglioma-Pheochromocytoma Syndrome have a higher risk of developing tumors and cancer than people who do not have this condition.

Currently it is not known how many people with Hereditary Paraganglioma-Pheochromocytoma Syndrome inherit a gene variant from a parent who also has the syndrome. Some people with the syndrome have a new gene variant that did not come from a parent. These children have no history of the syndrome in their families. In these cases, the change either happened in an egg or sperm cell when the child was formed or in one of the child’s cells during pregnancy. These children are the first in their families to have the syndrome.

All people with Hereditary Paraganglioma-Pheochromocytoma Syndrome have a 50% (or 1 in 2) chance of passing their gene variant to their children. Children who inherit a SDHC, SDHB, SDHA, or TMEM127 gene variant from either parent will have Hereditary Paraganglioma-Pheochromocytoma Syndrome. In most cases, only children who inherit a SDHAF2, SDHD, or MAX variant from their fathers will have the syndrome.

A doctor may suspect this diagnosis after looking at a person’s medical or family history. In most cases, a doctor or genetic counselor will ask questions about the person’s health and the health of other family members. Read more about genetic counseling and genetic testing.

Diagnosing this syndrome is usually done by sequencing the SDHD, SDHAF2, SDHC, SDHB, SDHA, TMEM127, and/or MAX genes to find variants (changes in the genes).

Genetic testing does not always find a variant that is responsible for the syndrome. A person can still have the syndrome even if no variants in these genes are found. There are likely to be more undiscovered genes that play a role in the development of this syndrome.

The risk of developing paragangliomas and pheochromocytomas increases as people with the syndrome get older. At 30 years old, about 29–50% of people with the syndrome have developed at least one tumor. This increases to 45–73% at age 40. Up to 86% of patients with the syndrome have developed at least one tumor 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.

The exact tumor risks depend on which of the seven types of Hereditary Paraganglioma-Pheochromocytoma Syndrome a person has, with each type related to a variant in a specific gene (in parentheses below): 

PGL1 (SDHD) 

  • Most people with Type PGL1 Syndrome have multifocal head and neck paragangliomas that 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%.

PGL2 (SDHAF2) 

  • This type is very rare. People with this type typically only have head and neck paragangliomas that do not release catecholamines (hormones) into the bloodstream. Although multifocal tumors and a young age of onset are common, many people with Type PGL2 Syndrome do not have any symptoms.
  • The risk of the tumors becoming cancerous in people with Type PGL2 Syndrome is not known because the type is so rare. However, the risk is probably very low.

PGL3 (SDHC) 

  • This type is also very rare. Most people with Type PGL3 Syndrome only have head and neck paragangliomas that do not release catecholamines (hormones) into the bloodstream.
  • The risk of the tumors becoming cancerous in people with Type PGL3 Syndrome is not known because the type is so rare. However, the risk is probably very low.

PGL4 (SDHB) 

  • Most people with this type develop paragangliomas that are not in the adrenal glands but that do release catecholamines (hormones) into the bloodstream. These tumors are usually found in the abdomen.
  • Some people with this type also develop pheochromocytomas.
  • The risk of the tumors becoming cancerous in people with Type PGL4 Syndrome is high (34– 97%).

PGL 5 (SDHA) 

  • This type is extremely rare. People with this type have had single paragangliomas or single pheochromocytomas.
  • The risk of the tumors becoming cancerous in people with Type PGL5 Syndrome is not known because the type is so rare. However, 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 old.
  • Most people with this type develop pheochromocytomas. Some develop abdominal or head and neck paragangliomas.
  • The risk of the tumors becoming cancerous in people with TMEM127-Related PGL 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% of people with this type have bilateral pheochromocytomas (tumors in both adrenal glands).
  • The risk of the tumors becoming cancerous in people with MAX-Related PGL Syndrome is about 25%.

People with Hereditary Paraganglioma-Pheochromocytoma Syndrome are also at an increased risk to develop 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 in the kidney
  • Papillary thyroid carcinoma, a type of tumor in the thyroid gland

Cancer screening involves tests to check for cancer before symptoms occur. The goal is to find cancer at the earliest and most treatable stage. uidelines for cancer screening are available online. Recommended screenings may change over time as doctors learn more about this syndrome, so these screening tests should be discussed with a health care provider who knows this syndrome well.

Other ideas to reduce the risk of cancer include:

  • Eat a healthful 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, hat, and protective clothing when out in the sun
  • Get medical attention for unusual or ongoing symptoms

Because of the other medical concerns related to this syndrome, specialists in the following areas may need to assess a child with Hereditary Paraganglioma-Pheochromocytoma Syndrome:

  • Endocrinology
  • Gastroenterology

Resources about Hereditary Paraganglioma-Pheochromocytoma Syndrome:

Other resources:

Adapted from educational materials developed by the St. Jude Children’s Research Hospital Cancer Predisposition Program