What is hereditary paraganglioma-pheochromocytoma syndrome?

Hereditary paraganglioma-pheochromocytoma syndrome (PGL/PCC) is a group of familial cancer syndromes characterized by the presence of:

• Paragangliomas (PGL) — tumors that arise from neuroendocrine tissues symmetrically distributed along the spine from the base of the skull to the pelvis
• Pheochromocytomas (PCC) — a type of paraganglioma that is confined to the adrenal gland, a small hormone-producing organ located on top of each kidney

There are two subtypes of paragangliomas (PGLs):

• Sympathetic paragangliomas — PGLs that produce and secrete catecholamines (specific hormones such as epinephrine, norepinephrine, and dopamine that are released by the adrenal glands in response to stress)
• Parasympathetic paragangliomas — PGLs that usually do not secrete catecholamines

Paragangliomas (PGLs) and pheochromocytomas (PCCs) are rare tumors that occur sporadically or as part of a hereditary cancer predisposing syndrome. Compared to people with sporadic tumors, individuals with hereditary PGL/PCC tend to develop tumors at a younger age and are more likely to have multifocal disease (more than one tumor, all of which have arisen from one original tumor and are often located near each other), bilateral disease (tumors in paired organs, such as both adrenal glands) and/or recurrent disease.

When PGL/PCC is the result of a hereditary predisposition, the risk of developing the features associated with this condition can be passed from generation to generation in a family. The clinical findings associated with PGL/PCC can vary greatly within a family, despite the fact that affected individuals within a given family carry the same genetic alteration.

Causes

PGL/PCC is caused by alterations (mutations) at specific areas within an individual’s genetic information. Hereditary PGL/PCC most often develops as the result of alterations in one of several specific genes, including SDHA, SDHAF2, SDHB, SDHC and SDHD.

With the exception of egg and sperm cells, each cell of the body normally has two working copies of each of the SDH genes. In contrast, a person with hereditary PGL/PCC may carry a mutation in one copy of the SDHAF2, SDHA, SDHB, SDHC or SDHD gene in all the cells of the body.

These people are born and develop normally, but are at an increased risk to develop non-cancerous and cancerous growths. These tumors are believed to develop because, over time, the second copy of the SDH gene becomes altered within one or more cells. Cells in which both SDH gene copies are impaired can divide excessively and ultimately become cancerous.

Testing and diagnosis

Hereditary paraganglioma-pheochromocytoma syndrome is diagnosed by:

• The presence of certain clinical signs
• A family history that shows the presence of PGL/PCC
• Genetic testing that confirms the gene mutation

Clinical signs

The diagnosis of a hereditary paraganglioma-pheochromoctyoma (PGL/PCC) syndrome should be considered in all individuals with PGL and/or PCCs, particularly those where the tumors are:

• Multiple (more than one separate tumor or tumor type), including bilateral tumors (tumors found in each of a pair of organs)
• Multifocal (more than one tumor, all of which have arisen from one original tumor and are often located near each other)
• Recurrent
• Early in onset (i.e. development of a tumor earlier than age 40)
• Linked to a family history of such tumors
• Many individuals with PGL/PCC syndrome may present with a single tumor of the head or neck, thorax, abdomen, adrenal gland or pelvis without any family history of the disorder.

A specific subtype of PGL/PCC types may be suspected based on distinct clinical characteristics that are present in the patient:

• PGL1 (caused by the presence of an SDHD mutation)
  • Typically associated with multifocal, non-secretory, head and neck PGLs and usually benign adrenal and extra-adrenal sympathetic PGLs.
  • Rare cases of metastatic head and neck paragangliomas have been reported.
• PGL2 (caused by the presence of an SDHAF2 mutation)
  • There are few reported cases of families with SDHAF2 mutations, and all currently known affected individuals have head and neck paragangliomas exclusively.
  • Affected individuals often have multifocal tumors and young age of onset; however, many individuals are asymptomatic at the time of mutation testing.
• PGL3 (caused by the presence of an SDHC mutation)
  • Mainly associated with the development of non-secretory head and neck PGLs.
  • There are few reported cases of families with SDHC mutations.
• PGL4 (caused by the presence of an SDHB mutation)
  • Typically individuals develop extra-adrenal tumors and to a lesser extent pheochromocytomas (PCCs) that have increased malignant potential and can lead to metastatic disease.
• PGL/PCC due to TMEM127 mutation
  • Typically associated with an older age of onset of PGL/PCC (with an average age of tumor diagnosis of 42 years) compared to individuals who carry mutations in other PGL/PCC-associated genes.
  • Typically associated with pheochromocytomas and to a lesser extent abdominal or head and neck paragangliomas.
• PGL/PCC due to MAX mutation
  • All currently known affected individuals have pheochromocytomas exclusively.
  • Approximately 50-70 percent of individuals with MAX mutations have bilateral pheochromocytomas.
  • Approximately 35 percent of individuals with MAX mutations developed metastatic disease.

Family history

A detailed review of an individual’s family history is important in diagnosing hereditary PGL/PCC syndrome. A doctor or genetic counselor may construct a pedigree, or a multigenerational family tree, that indicates:

• Which members of the family have developed tumors
• Types of tumors developed
• Ages of onset of tumors
• Presence of any clinical manifestations
• If the pattern of clinical features and/or tumors is suggestive of hereditary PGL/PCC syndrome, the physician or counselor may recommend that genetic testing be performed.

Genetic testing

In order to confirm on a molecular level that an individual has hereditary PGL/PCC syndrome, he or she can undergo the process of genetic testing:

• First, a blood sample is obtained from the affected individual.
• DNA is isolated from the sample and the two copies of specific PGL/PCC-associated genes are evaluated and compared to the normal reference sequence for the PGL/PCC-associated genes.
• If an alteration or a deletion of genetic material in one of the PGL/PCC-associated gene copies is identified, the genetic counselor can examine whether the alteration or deletion has been previously reported in other individuals with hereditary PGL/PCC.
• In patients carrying a clinical diagnosis of hereditary paraganglioma-pheochromocytoma syndrome, approximately 70-90 percent of individuals will have an alteration involving one of the PGL/PCC-associated genes. However, it is important to remember that not all patients with hereditary PGL/PCC syndrome carry a detectable alteration in a PGL/PCC-associated gene. There are likely to be additional, undiscovered genes that play a role in the development of hereditary PGL/PCC, as evidenced by multiple affected members of a family for which no mutation has been identified. Therefore, the failure to identify an alteration in a PGL/PCC-associated gene does not exclude the diagnosis of hereditary PGL/PCC.

Who should consider undergoing genetic testing for hereditary PGL/PCC syndrome?

People with pheochromocytoma or paraganglioma

Any individual with pheochromocytoma (without evidence of other conditions related to hereditary PGL/PCC) or paraganglioma, regardless of family history or age, should be offered genetic testing to identify a possible underlying gene mutation. Since there are several genes that are considered for genetic testing, testing should proceed in a stepwise manner based on:

• Tumor location
• Hormonal status (whether or not the tumor is secreting catecholamines)
• Presence or absence of malignant characteristics
• Existence of multifocal tumors
• Family history

However, as new advances in genetic testing become available, such as "multigene panels" which allow for simultaneous testing of multiple genes at a low cost, these multigene panels may eventually replace stepwise genetic testing for PGL/PCC.

First-degree relatives of someone with a mutation in a PGL/PCC-associated gene

• It is also recommended that all first-degree relatives (parents, siblings, children) of an individual in whom a mutation in one of the PGL/PCC-associated genes has been identified should be offered presymptomatic genetic testing by the age of 10 years, or at least 10 years before the earliest age at diagnosis in the family, whichever comes first (i.e. if an individual in the family was found to have a PGL at age 18, other first-degree relatives of that individual should be tested for the presence of a gene mutation by age 8).
• Genetic test results can provide important information for other family members. Knowing the specific alteration that is present in an individual with PGL/PCC allows for other family members to undergo genetic testing to determine whether they might also carry the alteration and could therefore be at risk to develop the features of PGL/PCC. Asymptomatic individuals found to carry a PGL/PCC predisposing mutation should consider initiating a tumor surveillance protocol.

People with conditions related to hereditary PGL/PCC

There are other genetic conditions in which PCCs and catecholamine-secreting PGLs can be found, including: 

• Neurofibromatosis type 1 (NF1)
• Von Hippel-Lindau disease (VHL)
• Multiple Endocrine Neoplasia type 2 (MEN, Type 2)
• Carney syndrome

However, there are often additional clinical features associated with these conditions and the presence of these features should be considered when outlining a plan for genetic testing.

Reproductive options

Reproductive options exist for people with an alteration in a PCC/PGL-associated gene who does not wish to pass this alteration onto future children:

• Prenatal diagnosis — DNA is isolated from the cells of the developing baby though one of two procedures (chorionic villus sampling [CVS] or amniocentesis) and is analyzed for alterations in the specific gene. With appropriate counseling, a parent can then decide whether to carry the pregnancy to term or to end the pregnancy.
• Preimplantation 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 via PGD. Only healthy embryos carrying two working copies of the specific gene would be implanted.

Follow-up care

The primary risk in hereditary PGL/PCC is the development of paragangliomas and pheochromocytomas. While the majority of these tumors are benign, in certain cases they may be malignant and more likely to spread to other parts of the body.

Individuals with hereditary PGL/PCC are also at an increased risk to develop:

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

The exact tumor risks for individuals with hereditary PGL/PCC are dependent on the specific PGL/PCC-associated gene that is affected.

Recommended cancer screening

Regardless of whether your family decides to pursue testing for PGL/PCC-associated genetic mutations, it is recommended that individuals carrying a clinical diagnosis of hereditary PGL/PCC, individuals without manifestations of the condition but who are known to have a PGL/PCC predisposing mutation, and at-risk relatives who have not undergone genetic testing, consider the following evaluation and surveillance recommendations. 

There is no current medical consensus regarding the optimal surveillance for the development of tumors in individuals with PGL/PCC. These are our recommendations:

• Annual history and physical examination (including blood pressure measurements)
• Annual biochemical testing (i.e., a blood test to assess plasma metanephrines and catecholamines)
• Every 1-2 years, a full-body MRI (for individuals with mutations in the SDHC or SDHAF2 genes, neck MRI may be performed instead of full-body MRI, as these mutations predispose to head and neck tumors)

Screening should begin at age 10 or at least 10 years before the earliest age at diagnosis in the family. For individuals with abnormal test results, further analyses may be warranted to rule-out an underlying PGL/PCC.

In addition to following recommended cancer surveillance guidelines, children and adults with PGL/PCC should:

• Be encouraged to follow-up with physicians familiar with this disease
• Lead as healthy a lifestyle as possible with avoidance of exposure to the sun and ionizing radiation
• Avoid living in places of high altitude
• Avoid participating in activities that promote long-term exposure to hypoxia (where the body as a whole is deprived of adequate oxygen)
• Avoid activities such as cigarette smoking that predispose to chronic lung disease