The American Association of Endocrine Surgeons, Patient Education Site

Paraganglioma (adrenaline-producing tumor outside the adrenal gland)

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What is the chance that this is genetic?

There are 4 main syndromes associated with paragangliomaParaganglioma - a disease where too much adrenaline is being made by a tumor outside the adrenal glands:

von Hippel-Lindau Syndrome (vHL)
Patients with vHL can develop pheochromocytomas (often bilateral), paragangliomas, retinal angiomas (eye tumors), central nervous system hemangioblastomas (brain tumors), renal cell (kidney) carcinoma, renal and pancreatic cysts, pancreatic endocrine tumors, and epididymal cystadenoma. Many mutations have been identified in the vHL gene which is found on chromosome 3. In some families with vHL, pheochromocytomaPheochromocytoma - a disease where too much adrenaline is being made by an adrenal tumor is the only sign of the syndrome. Overall, about 10 to 20% of vHL patients will develop pheochromocytomas. Bilateral tumors may present synchronously (i.e. at the same time) or separately over the course of many years.

Multiple Endocrine Neoplasia Syndrome type 2A and 2B (MEN2A and 2B)
Mutations in the RET gene are responsible for tumor development in MEN2. There are two forms of MEN2:
In MEN 2A, pheochromocytomas are usually bilateral but may be asynchronous (i.e. develop separately over time). They occur in about 50% of MEN2A patients and are associated with medullary thyroid cancer (MTC) and hyperparathyroidism. (See Parathyroid and Medullary Thyroid Cancer)
In MEN2B (which accounts for 5% of MEN2 cases) syndrome includes pheochromocytomas (usually bilateral), MTC, mucosal neuromas (bumps on the lips, tongue, and eyelids), thickened corneal nerves over the front of the eye, intestinal ganglioneuromatosis, and a marfanoid body habitus (i.e. tall and thin with long hands—Abraham Lincoln likely had Marfan's Disease).

Neurofibromatosis type 1 (NF1)-
NF1 is also known as von Recklinghausen's disease. NF1 is the result of a mutation in chromosome 17 and is characterized by café au lait lesions (i.e. coffee-colored skin spots) and tumors arising from nerve cells in the skin. Pheochromocytoma can occur in up to 5% of cases. They can be both in the adrenal and outside of the adrenal, but are rarely bilateral.

Familial Paraganglioma Syndrome
Pheochromocytomas can also occur (albeit rarely) in association with familial paraganglioma syndromes caused by mutations in the succinate dehydrogenase (SDH) gene. Mutations in the B, C, and D parts of the SDH gene lead to different forms of the disease. The role for routine screening for mutations in the SDH gene is controversial but some have argued for testing for B and D mutations, particularly in the presence of a paraganglioma. Mutations in the C subunit have been reported rarely so it is not routinely tested for.

Many of these syndromes involving paragangliomas are autosomal dominant, which means that offspring (i.e. children) have a 50% chance of developing the disease. For patients with pheochromocytoma, genetic testing should be considered if a patient has one or more of the following:

For family members of patients with paraganglioma, genetic testing should only be done if the family member with the disease has a known genetic mutation. Genetic counseling is strongly urged to help families understand the implications of genetic testing, to coordinate testing of at-risk individuals, and to help families work through the psychosocial issues that may arise before, during, and after the testing process. Genetic testing is expensive and should be performed in a stepwise fashion (i.e. the patient should be tested to identify the genetic mutation and then other family members should be tested for only that genetic mutation) so as to decrease the number of tests performed.

The role for genetic testing in patients with sporadic (i.e. non-familial) paraganglioma remains unclear. It is important to discuss this question with your physician or seek an evaluation by a genetic counselor. In the near future, there may be a role for genetic testing in patients with malignant (i.e. cancerous) paraganglioma to help identify drug therapies that may be effective against their tumor. For example, a drug aimed at RET and HIF1α(genes affected in tumors with vHL and SDH mutations) is in clinical trials for other tumors. For patients with malignant paraganglioma, these types of new drugs hold promise as another way of treating their disease.

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