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Paraganglioma-Pheochromocytoma Syndrome Diagnosis

Hereditary paraganglioma-pheochromocytoma (PGL-PCC) syndrome is diagnosed by the presence of certain clinical signs, a family history that shows the presence of PGL-PCC, and genetic testing that confirms the gene mutation.

Clinical signs

An individual already has paragangliomas or pheochromocytomas

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 hereditary paraganglioma-pheochromocytoma (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 extend 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 patient's family history shows an increased number of individuals with PGL/PCC

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

• Which members of the family have developed tumors
• Types of tumors
• Ages of onset
• Presence of any clinical manifestations
• If the pattern of clinical features and/or tumors is suggestive of hereditary paraganglioma-pheochromocytoma (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 paraganglioma-pheochromocytoma (PGL/PCC) syndrome, he or she can undergo the process of genetic testing:

• First, a blood sample is obtained from an 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 next 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 percent to 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 paraganglioma-pheochromocytoma (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 paraganglioma-pheochromocytoma syndrome?

People with pheochromocytoma or paraganglioma

Any individual with pheochromocytoma (without evidence of other conditions related to hereditary PGL/PCC — see below) 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 "multi-gene panels" which allow for simultaneous testing of multiple genes at a low cost, these multi-gene panels may eventually repalce 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 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 years, other first-degree relatives of that individual should be tested for the presence of a gene mutation by age 8 years).
• 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) and 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 an individual with an alteration in a PCC/PGL-associated gene who does not wish to pass this alteration on to 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.

References

Gimenez-Roqueplo AP, Lehnert H, Mannelli M, Neumann H, Opocher G, Maher ER,et al. Phaeochromocytoma, new genes and screening strategies. Clin Endocrinol (Oxf). 2006 Dec;65(6):699-705. Cited in PubMed; PMID 17121518. Read the abstract

Hensen EF, Bayley J. Recent advances in the genetics of SDH-related paraganglioma and pheochromocytoma. Fam Cancer. 2011 Jun;10(2):355-63. Cited in PubMed; PMID 21082267. Read the article

Young, WF Jr. Endocrine hypertension. In: Kronenberg HM, Melmed S, Polonsky KS, Larsen PR, editors. Williams textbook of endocrinology. 11 ed. Philadelphia: Saunders Elsevier; 2008. pp 505-37.

Related information

Overview of paraganglioma-pheochromocytoma (PGL-PCC) syndrome 
Paraganglioma-pheochromocytoma (PGL-PCC) syndrome cancer risks and screenings
Resources for people with paraganglioma-pheochromocytoma (PGL-PCC) syndrome

Reviewed by: Kim Nichols, MD, Kristin Zelley, MS
Date: September 2012

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