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Genetic Screening

Approximately one-third of pheochromocytomas/paragangliomas are associated with a familial hereditary condition. Multiple genes have been implicated in the predisposition to pheochromocytoma/paraganglioma. Pheochromocytomas/paragangliomas have been linked to patients with von Hippel-Lindau (VHL) syndrome, neurofibromatosis 1 (NF1), and multiple endocrine neoplasia, type II (MEN2). In addition, familial pheochromocytomas/paragangliomas have been linked to mutations in the succinate dehydrogenase (SDH) genes, most commonly SDHB, SDHD, and SDHC. Recently, mutations in the TMEM127 and SDHAF2 genes have also been linked to hereditary pheochromocytomas/paragangliomas.

We accept patients with any pheo/para-related mutations into our protocol. We also may be able to provide genetic testing to family members of patients known to have a mutation in these genes, particularly in the SDH genes.

More pheo/para-related genetic information can be found below.

Basic DNA information

DNA is the molecule that contains the information responsible for much of our development, physical characteristics, and bodily functions. DNA can almost be thought of as an instruction manual found in all of the cells within our body, telling them what to do and how to behave and grow. Information on DNA is contained in units called genes. If DNA is the instruction manual, genes are the words. These genes are translated by the cells into proteins, which actually carry out the functions specified in the DNA. A mutation is a change in one letter of the DNA, like a typo in a word. Since the instructions are different, the protein is often altered, which often affects its ability to function properly. This can have detrimental effects on the cell, which can lead to various symptoms and conditions, depending on the mutation and gene.

Gene mutations occur in two ways:  they can be inherited from a parent or acquired during a person's lifetime.  Mutations that are passed from parent to child are called "hereditary" or "germline" mutations (because they are present in the egg and sperm cells, which are also called germ cells).  This type of mutation is present throughout a person's life in virtually every cell in the body.  Mutations that occur just after fertilization are called "new" or de novo mutations. De novo mutations may explain genetic disorders in which an affected child has a mutation in every cell, but has no family history of the disorder.

Pheo/Para-Related Genes

VHL

Mutations in the VHL gene lead to Von Hippel-Lindau (VHL) syndrome, which affects approximately 1 in 36,000 people. VHL syndrome is characterized by the development of tumors in various locations in the body. VHL syndrome is classified into two types, type 1 and type 2. Patients with VHL type 1 do not develop pheochromocytomas. VHL type 2 is further divided into type 2A (low risk for pheo), type 2B (high risk for pheo), and type 2C (the only symptom is pheo).

NF1

Neurofibromatosis type 1, or von Recklinghausen's disease, is a fairly common disorder, affecting approximately 1 in 4000 people. NF1 has various symptoms, including the development of tumors, but is usually diagnosed at a young age based on the presence of café au lait spots on the skin. The association of NF1 with pheo is fairly small.

MEN2

Multiple endocrine neoplasia type 2 (MEN2) is caused by mutations in the RET gene. It affects approximately 1 in every 40,000 people, and can lead to tumors in the endocrine system, including pheochromocytoma. Patients with MEN2-associated pheo often lack hypertension or other symptoms, and often present with intra-adrenal, bilateral, and/or malignant pheos.

SDHx

Succinate dehydrogenase is a protein associated with metabolism, specifically to the electron transport chain and Krebs cycle. It is located on the inner mitochondrial membrane and is made up of four subunits, SDHA, SDHB, SDHC, and SDHD.

SDHA

SDHA has only recently been linked to pheochromocytoma, and so far only one mutation has been described in one patient. Typically, patients with homozygous SDHA mutations lead to a rare neurological disease, known as Leigh's disease; heterozygous carriers do not seem to be affected.

SDHB

Mutations in SDHB are one of the most common causes of familial pheo/para. Mutations in SDHB are often associated with extra-adrenal pheochromocytomas, parasympathetic paragangliomas, and metastatic pheochromocytomas, particularly metastatic pheos that manifest in younger patients. SDHB mutations are less commonly linked to adrenal pheos. The penetrance of this mutation, that is, the number of people with the mutation who actually develop pheo/para, is still being studied.

SDHC

Mutations in SDHC are much rarer than those in SDHB or SDHD. Patients with SDHC mutations more commonly have head and neck paragangliomas, though some patients with sympathetic paragangliomas have also been identified.

SDHD

Mutations in SDHD were the first SDH mutations to be linked to pheochromcytomas/paragangliomas. Patients with SDHD mutations typically present with head and neck paragangliomas. These tumors are usually benign. Interestingly, SDHD mutations seem to be maternally imprinted, meaning that if the mutation is inherited from the mother, the children never show symptoms of the disease. However, those children can pass it on to their children, who may develop the disease in the future.

New Genes

Mutations in TMEM127 and SDHAF2 have recently been linked to patients with familial pheo/para.

TMEM127 is a tumor suppressor gene, but its function is not completely understood. It may be involved in transport within the cell. TMEM127 seems to be more commonly associated with adrenal and abdominal pheos.

SDHAF2 encodes a protein involved in the assembly of the SDH complex. These mutations have only been identified in a few families, and SDHAF2 mutations are not thought to play a large role in familial pheo/para. Patients with SDHAF2 seem to have head and neck paragangliomas and strong family histories of pheo/para.

Two additional genes, PHD2 and KIF1Bβ, have also been recently associated with pheochromocytoma/paraganglioma. However, the PHD2 mutation has only been found in one patient thus far. The KIF1Bβ encodes a motor protein, and mutations have been described in a few patients with pheochromocytomas and neuroblastomas, as well in one family with hereditary pheo/para.

How to Get Tested

The fastest way to find out whether you have a genetic mutation is through private testing. You can talk to your local doctor about where to get tested. Testing will cost between $500-1000, and may be covered by insurance, depending on your provider and plan.

We can also do genetic testing through our protocol. However, due to limited funding, we can only offer genetic testing to immediate relatives and to patients with financial need. This testing can be done either at the NIH or off-site. For more information on off-site genetic testing, please see our Off-Site Genetic Testing page. To schedule genetic testing at the NIH, please contact Tory Martucci (victoria.martucci@nih.gov).

What if I'm positive?

If you test positive for a mutation, it is very important that you get screened for pheochromocytomas/paragangliomas, even if you are not showing symptoms. Sometimes tumors can be present, but can be biochemically silent (meaning they are not releasing catecholamines) or can be too small to cause symptoms. It is best to catch tumors as early as possible. Screening involves biochemical tests to check for levels of catecholamines and their metabolites, as well as imaging studies, usually a whole body CT scan.

We strongly recommend that patients be screened here at the NIH. We are one of the largest centers in the U.S. and worldwide for the diagnosis and treatment of pheochromocytoma and paraganglioma. Dr. Karel Pacak, our team leader, is a leading expert on pheochromocytoma and paraganglioma, and our team is very experienced in this disease. Screening at the NIH typically takes one day. If a tumor is found, we will invite you back for follow-up.

After the initial screening, we recommend that patients be screened regularly, typically every 6 months to 1 year. The amount of time varies by patient.

If you decide to come to the NIH, please visit our Visitor Information page for important visitor information, including how to get here, where to stay, and what to expect.

More information about the disease, the signs and symptoms, the diagnostic tests, and the treatment options is available here on our website.

Genetics References

The following is a list of references used in the writing of this page. This is no way represents a complete list of articles about pheo/para-related genetics.

  1. Pacak, Karel, Jacques W. M. Lenders, and Graeme Eisenhofer. "Current Trends in Genetics of Pheochromocytoma." Pheochromocytoma: Diagnosis, Localization, and Treatment. Malden, MA: Blackwell Pub., 2007. 30-40
  2. Hensen, Erik F., and Jean-Pierre Bayley. "Recent Advances in the Genetics of SDH-related Paraganglioma and Pheochromocytoma." Familial Cancer (2010): 1-9.
  3. Jiang, Shoulei, and Patricia L.M. Dahia. "Minireview: The Busy Road to Pheochromocytomas and Paragangliomas Has a New Member, TMEM127." Endocrinology 152.6 (2011).
  4. Ladroue, C., R. Carcenac, M. Leporrier, S. Gad, C. Le Hello, F. Galateau-Salle, J. Feunteun, J. Pouyssegur, S. Richard, and B. Gardie. "PHD2 Mutation and Congenital Erythrocytosis with Paraganglioma." New England Journal of Medicine 359.25 (2008): 2685-692.
  5. Schlisio, S., R. S. Kenchappa, L. C.W. Vredeveld, R. E. George, R. Stewart, H. Greulich, K. Shahriari, N. V. Nguyen, P. Pigny, P. L. Dahia, S. L. Pomeroy, J. M. Maris, A. T. Look, M. Meyerson, D. S. Peeper, B. D. Carter, and W. G. Kaelin. "The Kinesin KIF1B  Acts Downstream from EglN3 to Induce Apoptosis and Is a Potential 1p36 Tumor Suppressor." Genes & Development 22.7 (2008): 884-93.
  6. Yeh, I-Tien, Romina E. Lenci, Yuejuan Qin, Kalyan Buddavarapu, Azra H. Ligon, Emmanuelle Leteurtre, Christine Do Cao, Catherine Cardot-Bauters, Pascal Pigny, and Patricia L. M. Dahia. "A Germline Mutation of the KIF1Bβ Gene on 1p36 in a Family with Neural and Nonneural Tumors." Human Genetics 124.3 (2008): 279-85.
  7. Burnichon, Nelly, Jean-Jacques Briere, Rosella Libe, Laure Vescovo, Julie Riviere, Frederique Tissier, Elodie Jouanno, Xavier Jeunemaitre, Pale Benit, Alexander Tzagoloff, Pierre Rustin, Jerome Bertherat, Judith Favier, and Anne-Paule Gimenez-Roqueplo. "SDHA is a tumor suppressor gene causing paraganglioma." Human Molecular Genetics 19.15 (2010): 3011-3020.