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Hereditary paraganglioma-pheochromocytoma

Reviewed June 2011

What is hereditary paraganglioma-pheochromocytoma?

Hereditary paraganglioma-pheochromocytoma is a condition characterized by the growth of noncancerous (benign) tumors in structures called paraganglia. Paraganglia are groups of cells that are found near nerve cell bunches called ganglia. A tumor involving the paraganglia is known as a paraganglioma. A type of paraganglioma known as a pheochromocytoma develops in the adrenal glands, which are located on top of each kidney and produce hormones in response to stress. Other types of paraganglioma are usually found in the head, neck, or trunk. People with hereditary paraganglioma-pheochromocytoma develop one or more paragangliomas, which may include pheochromocytomas.

Pheochromocytomas and some other paragangliomas are associated with ganglia of the sympathetic nervous system. The sympathetic nervous system controls the "fight-or-flight" response, a series of changes in the body due to hormones released in response to stress. Sympathetic paragangliomas found outside the adrenal glands, usually in the abdomen, are called extra-adrenal paragangliomas. Most sympathetic paragangliomas, including pheochromocytomas, produce hormones called catecholamines, such as epinephrine (adrenaline) or norepinephrine. These excess catecholamines can cause signs and symptoms such as high blood pressure (hypertension), episodes of rapid heartbeat (palpitations), headaches, or sweating.

Most paragangliomas are associated with ganglia of the parasympathetic nervous system, which controls involuntary body functions such as digestion and saliva formation. Parasympathetic paragangliomas, typically found in the head and neck, usually do not produce hormones. However, large tumors may cause signs and symptoms such as coughing, hearing loss in one ear, or difficulty swallowing.

Although most paragangliomas and pheochromocytomas are noncancerous, some can become cancerous (malignant) and spread to other parts of the body (metastasize). Extra-adrenal paragangliomas become malignant more often than other types of paraganglioma or pheochromocytoma.

Researchers have identified four types of hereditary paraganglioma-pheochromocytoma, named types 1 through 4. Each type is distinguished by its genetic cause. People with types 1, 2, and 3 typically develop paragangliomas in the head or neck region. People with type 4 usually develop extra-adrenal paragangliomas in the abdomen and are at higher risk for malignant tumors that metastasize. Hereditary paraganglioma-pheochromocytoma is typically diagnosed in a person's 30s.

How common is hereditary paraganglioma-pheochromocytoma?

Hereditary paraganglioma-pheochromocytoma occurs in approximately 1 in 1 million people.

What genes are related to hereditary paraganglioma-pheochromocytoma?

Mutations in at least four genes increase the risk of developing the different types of hereditary paraganglioma-pheochromocytoma. Mutations in the SDHD gene predispose an individual to hereditary paraganglioma-pheochromocytoma type 1; mutations in the SDHAF2 gene predispose to type 2; mutations in the SDHC gene predispose to type 3; and mutations in the SDHB gene predispose to type 4.

The SDHB, SDHC, and SDHD genes provide instructions for making three of the four subunits of an enzyme called succinate dehydrogenase (SDH). In addition, the protein made by the SDHAF2 gene is required for the SDH enzyme to function. The SDH enzyme links two important cellular pathways called the citric acid cycle (or Krebs cycle) and oxidative phosphorylation. These pathways are critical in converting the energy from food into a form that cells can use.

As part of the citric acid cycle, the SDH enzyme converts a compound called succinate to another compound called fumarate. Succinate acts as an oxygen sensor in the cell and can help turn on specific pathways that stimulate cells to grow in a low-oxygen environment (hypoxia).

Mutations in the SDHB, SDHC, SDHD, and SDHAF2 genes lead to the loss or reduction of SDH enzyme activity. Because the mutated SDH enzyme cannot convert succinate to fumarate, succinate accumulates in the cell. As a result, the hypoxia pathways are triggered in normal oxygen conditions, which lead to abnormal cell growth and tumor formation.

Related Gene(s)

Changes in these genes are associated with hereditary paraganglioma-pheochromocytoma.

  • SDHAF2
  • SDHB
  • SDHC
  • SDHD

How do people inherit hereditary paraganglioma-pheochromocytoma?

Hereditary paraganglioma-pheochromocytoma is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to increase the risk of developing tumors. An additional mutation that deletes the normal copy of the gene is needed to cause the condition. This second mutation, called a somatic mutation, is acquired during a person's lifetime and is present only in tumor cells.

The risk of developing hereditary paraganglioma-pheochromocytoma types 1 and 2 is passed on only if the mutated copy of the gene is inherited from the father. The mechanism of this pattern of inheritance is unknown. The risk of developing types 3 and 4 can be inherited from the mother or the father.

Where can I find information about diagnosis or management of hereditary paraganglioma-pheochromocytoma?

These resources address the diagnosis or management of hereditary paraganglioma-pheochromocytoma and may include treatment providers.

  • American Urological Association Foundation: Pheochromocytoma (http://www.urologyhealth.org/urology/index.cfm?article=14)
  • Gene Review: Hereditary Paraganglioma-Pheochromocytoma Syndromes (http://www.ncbi.nlm.nih.gov/books/NBK1548)
  • Genetic Testing Registry: Paragangliomas 1 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1868633)
  • Genetic Testing Registry: Paragangliomas 2 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1866552)
  • Genetic Testing Registry: Paragangliomas 3 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1854336)
  • Genetic Testing Registry: Paragangliomas 4 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1861848)
  • MedlinePlus Encyclopedia: Pheochromocytoma (http://www.nlm.nih.gov/medlineplus/ency/article/000340.htm)
  • National Cancer Institute: General Information about Pheochromocytoma and Paraganglioma (http://www.cancer.gov/cancertopics/pdq/treatment/pheochromocytoma/HealthProfessional)
  • National Institutes of Health Clinical Center: Patient Education - Pheochromocytoma (http://www.cc.nih.gov/ccc/patient_education/pepubs/pheo.pdf)

You might also find information on the diagnosis or management of hereditary paraganglioma-pheochromocytoma in Educational resources (http://www.ghr.nlm.nih.gov/condition/hereditary-paraganglioma-pheochromocytoma/show/Educational+resources) and Patient support (http://www.ghr.nlm.nih.gov/condition/hereditary-paraganglioma-pheochromocytoma/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about hereditary paraganglioma-pheochromocytoma?

You may find the following resources about hereditary paraganglioma-pheochromocytoma helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for hereditary paraganglioma-pheochromocytoma?

  • familial paraganglioma-pheochromocytoma syndromes
  • hereditary paraganglioma-pheochromocytoma syndromes
  • hereditary pheochromocytoma-paraganglioma
  • paragangliomas 1
  • paragangliomas 2
  • paragangliomas 3
  • paragangliomas 4

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about hereditary paraganglioma-pheochromocytoma?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding hereditary paraganglioma-pheochromocytoma?

adrenal glands ; autosomal ; autosomal dominant ; benign ; cell ; compound ; dehydrogenase ; difficulty swallowing ; digestion ; enzyme ; familial ; gene ; hereditary ; hypertension ; hypoxia ; inheritance ; inherited ; involuntary ; kidney ; metastasize ; mutation ; nerve cell ; nervous system ; oxidative phosphorylation ; oxygen ; palpitations ; pattern of inheritance ; pheochromocytoma ; phosphorylation ; protein ; somatic mutation ; stress ; tumor

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

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  • Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Crespin M, Nau V, Khau Van Kien P, Corvol P, Plouin PF, Jeunemaitre X; COMETE Network. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Res. 2003 Sep 1;63(17):5615-21. (http://www.ncbi.nlm.nih.gov/pubmed/14500403?dopt=Abstract)
  • Hao HX, Khalimonchuk O, Schraders M, Dephoure N, Bayley JP, Kunst H, Devilee P, Cremers CW, Schiffman JD, Bentz BG, Gygi SP, Winge DR, Kremer H, Rutter J. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science. 2009 Aug 28;325(5944):1139-42. doi: 10.1126/science.1175689. Epub 2009 Jul 23. (http://www.ncbi.nlm.nih.gov/pubmed/19628817?dopt=Abstract)
  • Müller U. Pathological mechanisms and parent-of-origin effects in hereditary paraganglioma/pheochromocytoma (PGL/PCC). Neurogenetics. 2011 Aug;12(3):175-81. doi: 10.1007/s10048-011-0280-y. Epub 2011 Mar 9. Review. (http://www.ncbi.nlm.nih.gov/pubmed/21547462?dopt=Abstract)
  • Neumann HP, Pawlu C, Peczkowska M, Bausch B, McWhinney SR, Muresan M, Buchta M, Franke G, Klisch J, Bley TA, Hoegerle S, Boedeker CC, Opocher G, Schipper J, Januszewicz A, Eng C; European-American Paraganglioma Study Group. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA. 2004 Aug 25;292(8):943-51. Erratum in: JAMA. 2004 Oct 13;292(14):1686. (http://www.ncbi.nlm.nih.gov/pubmed/15328326?dopt=Abstract)
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  • Pasini B, Stratakis CA. SDH mutations in tumorigenesis and inherited endocrine tumours: lesson from the phaeochromocytoma-paraganglioma syndromes. J Intern Med. 2009 Jul;266(1):19-42. doi: 10.1111/j.1365-2796.2009.02111.x. Review. (http://www.ncbi.nlm.nih.gov/pubmed/19522823?dopt=Abstract)
  • Pollard PJ, Brière JJ, Alam NA, Barwell J, Barclay E, Wortham NC, Hunt T, Mitchell M, Olpin S, Moat SJ, Hargreaves IP, Heales SJ, Chung YL, Griffiths JR, Dalgleish A, McGrath JA, Gleeson MJ, Hodgson SV, Poulsom R, Rustin P, Tomlinson IP. Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet. 2005 Aug 1;14(15):2231-9. Epub 2005 Jun 29. (http://www.ncbi.nlm.nih.gov/pubmed/15987702?dopt=Abstract)
  • Schiavi F, Boedeker CC, Bausch B, Peçzkowska M, Gomez CF, Strassburg T, Pawlu C, Buchta M, Salzmann M, Hoffmann MM, Berlis A, Brink I, Cybulla M, Muresan M, Walter MA, Forrer F, Välimäki M, Kawecki A, Szutkowski Z, Schipper J, Walz MK, Pigny P, Bauters C, Willet-Brozick JE, Baysal BE, Januszewicz A, Eng C, Opocher G, Neumann HP; European-American Paraganglioma Study Group. Predictors and prevalence of paraganglioma syndrome associated with mutations of the SDHC gene. JAMA. 2005 Oct 26;294(16):2057-63. Erratum in: JAMA. 2006 Feb 8;295(6):628. (http://www.ncbi.nlm.nih.gov/pubmed/16249420?dopt=Abstract)
  • Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, Pan Y, Simon MC, Thompson CB, Gottlieb E. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell. 2005 Jan;7(1):77-85. (http://www.ncbi.nlm.nih.gov/pubmed/15652751?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: June 2011
Published: September 15, 2014