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Paraganglioma-Pheochromocytoma Syndrome

What is hereditary paraganglioma-pheochromocytoma syndrome?

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

There are two subtypes of paragangliomas (PGLs):

Typical symptoms associated with the excess production of catecholamines include:

These signs and symptoms are often referred to a “paroxysmal," which means that they appear suddenly and without warning. The symptoms may also go away but then reoccur in an unpredictable fashion.

Paragangliomas (PGLs) and pheochromocytomas (PCCs) are rare tumors that occur sporadically or as part of a hereditary cancer predisposing syndrome. Compared to persons 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.

What causes paraganglioma-pheochromocytoma syndromes?

PGL/PCC is caused by alterations (mutations) at specific areas within an individual’s genetic information. Each of us has a large amount of genetic information that is organized into smaller segments known as “genes.” Genes provide the necessary instructions that our cells require to perform their different functions within our bodies.

Hereditary PGL/PCC most often develops as the result of alterations in one of several specific genes, including SDHAF2, SDHB, SDHC and SDHD. An alteration in SDHA, another member of this group of genes, has thus far been identified in six patients with PGL or PCC. SDHA, SDHB, SDHC and SDHD encode protein subunits for the mitochondrial enzyme succinate dehydrogenase (SDH). SDHAF2 encodes an SDH co-factor. The normal role of the SDH proteins is to regulate specific metabolic functions in living cells.

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 patient with hereditary PGL/PCC may carry an alteration in one copy of the SDHAF2, SDHA, SDHB, SDHC or SDHD gene in all the cells of the body. These patients 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.

More recently, genetic alterations in two other genes have been identified in individuals with PGL or PCC:

How paraganglioma-pheochromocytoma syndromes are inherited

A patient with hereditary paraganglioma-pheochromocytoma syndrome usually inherits the condition from an affected parent who similarly carries an altered gene copy. An individual with one altered gene copy has a 50 percent (or 1 in 2) chance of passing this same alteration on to each of his or her future children. However, the hereditary paraganglioma-pheochromocytoma syndrome may manifest differently in children who inherit the mutation, depending on the specific gene that is affected and from which parent the mutation is inherited.

Children who inherit an alteration in the SDHA, SDHB, SDHC or TMEM127 gene will have hereditary PGL/PCC, regardless of which parent they inherited the mutation from. Therefore, they will be at increased risk to develop tumors and other features associated with the hereditary PGL/PCC syndrome.

When a child inherits an alteration in one copy of the SDHD, SDHAF2 or MAX gene, there are some differences in how the disease might manifest itself in the child, based on which parent passed the mutation to the child. This is known as a “parent-of-origin effect.”

Less commonly, patients with hereditary PGL/PCC may not have a family history of the disease. In these individuals, hereditary PGL/PCC likely results from presence of a “new mutation” in one copy of one of the PGL/PCC-associated genes. Although these individuals will be the first ones in their family to carry the genetic change, each of their future offspring will have a 50 percent chance of inheriting the genetic alteration. Another possibility is that the family history may appear to be negative due to the parent-of-origin effects described above or incomplete penetrance (meaning that other individuals in the family may carry the genetic mutation but do not develop PGL/PCC).

Related information

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

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.

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

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