Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndrome
What is hereditary paraganglioma-pheochromocytoma syndrome?
The following text is taken from the Genetics Home Reference (update pending):
Hereditary paraganglioma-pheochromocytoma is an inherited 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 several types of hereditary paraganglioma-pheochromocytoma. 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. The other types are very rare. Hereditary paraganglioma-pheochromocytoma is typically diagnosed in a person's 30s.
Paragangliomas and pheochromocytomas can occur in individuals with other inherited disorders, such as von-Hippel Lindau syndrome, Carney-Stratakis syndrome, and certain types of multiple endocrine neoplasia. These other disorders feature additional tumor types and have different genetic causes. Some paragangliomas and pheochromocytomas occur in people with no history of the tumors in their families and appear not to be inherited. These cases are designated as sporadic.
Hereditary paraganglioma-pheochromocytoma occurs in approximately 1 in 1 million people.
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.
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INFORMATION ABOUT GENETICS AND GENETIC TESTING:
Genetics Home Reference
Consumer-friendly information about the effects of genetic variations on human health. Federally-supported resources, include reviews of more than 800 genetic diseases and more than 1000 genes.
Learning Resources from the NHGRI
Lots of very good resources from the NHGRI, including major sections about The Human Genome Project, Facts Sheets, and educational resources for teachers and students.
Find a Genetic Counselor
The National Society of Genetic Counselors have a searchable database of genetic counselors. Their website also includes some education materials for patients and healthcare professionals.
NHGRI Talking Glossary
Talking glossary of genetic terms developed by the National Human Genome Research Institute. A huge range of definitions is provided by researchers from around the world.
Help Me Understand Genetics
Help Me Understand Genetics is a handbook from the National Institutes of Health that contain useful information about genetics in clear language and provides links to even more online resources. The entire handbook can also be downloaded as a pdf.
Genetic and Rare Diseases Information Center (GARD)
A joint project from The Office of Rare Diseases Research (ORDR) and the National Human Genome Research Institute (NHGRI) that provides searchable information about genetic conditions and rare diseases. It also includes a list of FDA-Approved drugs and other medical products for treating rare disease.
National Organization for Rare Disorders - Resources for Parents/Families
The National Organization for Rare Disorders (NORD) is a volunteer organization dedicated to empowering the rare disease community. Again, they have some very nice web resources.
Ethical, Legal and Social Implications Research Program
The ELSI Research Program supports examinations and investigations of the ethical, legal and social implications of genetics research.
Genetic Information Nondiscrimination Act of 2008
The Genetic Information Nondiscrimination Act of 2008, also referred to as GINA, is a new federal law that protects Americans from being treated unfairly because of differences in their DNA that may affect their health.
Learn.Genetics, University of Utah
Excellent resources, especially for those involved in education. Includes a catalog of animations, videos, interactive features, and virtual labs.
Dolan DNA Leaning Center
The DNALC provides genetics learning resources for teachers and students.
INFORMATION FOR RESEARCHERS:
ClinVar: ACMG Recommendations for Reporting of Incidental Findings in Clinical Exome and Genome Sequencing
Clinvar's dedicated ACMG page - a useful jumping-off point to the Genetic Testing Registry, OMIM, MedGen, and local ClinVar pages for each gene.
Gene Reviews (updated September, 2018)
What is the purpose of this information?
Our aim is to provide information about why we do genetic testing. We try to answer some common questions and offer guidance on some personal and practical issues. This information is for anybody with questions about genetic testing for any of the diseases and drugs listed in this site.
Are there geographical differences in testing, service or treatment?
Different centers have different policies in terms of how tests are administered and results shared. However, the results discussed in this document should be relevant to most individuals tested for risk of developing genetic disease.
How is this paid for?
If you received this test as part of the eMERGE research study, neither you nor your insurance company will have to pay anything toward this test
When was this content last updated?
October 10, 2018.