McCoy Family Mutation

by Catherine A. Stolle, Ph.D., Director of Molecular Genetics, Children's Hospital of Phildelphia

Many of you have heard the news story about a possible link between the feud between the Hatfields and the McCoys and a VHL gene mutation found in some members of the McCoy family. Concern for your health and that of your family has caused some of you to seek information about the disorder and genetic testing. This message is intended to provide some practical information about VHL disease and suggestions for arranging for genetic testing, if appropriate.

You may wish to print out this page and share it with your doctor, or with a genetic counselor.

VHL is a dominant disorder that can predispose to tumors of the brain, eye, adrenal glands, kidneys and a few other target organs. Affected individuals generally inherit a mutation in the VHL gene from one of their parents and then acquire a second mutation in one of these target organs. In the absence of the VHL protein, highly vascularized tumors can develop. The age of onset is generally between the early 20’s to the late 40’s, however some patients have been diagnosed with the disorder much earlier (~ 5 years of age) or much later (in their 60’s). Most individuals who have a VHL gene mutation will develop symptoms of the disease by the age of 65 years.

A diagnosis of VHL disease is made based on the following clinical criteria. You should consult your physician if you question whether you have any of these symptoms:

In an individual with a positive family history of VHL syndrome, one or more of the following disease manifestations must be present: retinal angioma, spinal or cerebellar hemangioblastoma, pheochromocytoma, multiple pancreatic cysts, epididymal cystadenoma, multiple renal cysts, or renal cell carcinoma before age 60 years.

In an individual with no known family history of VHL, two or more characteristic tumors must be present (for example, multiple hemangioblastomas in the brain or spinal cord, or a single hemangioblastoma in association with a visceral manifestation, such as kidney or pancreatic cysts; renal cell carcinoma; adrenal or extra-adrenal pheochromocytomas, and, less commonly, endolymphatic sac tumors, papillary cystadenomas of the epididymis or broad ligament, or neuroendocrine tumors of the pancreas).

Even if you do not have symptoms of VHL disease, you still may be at risk of developing the disorder if you are directly related to a member of the McCoy kindred who does have the disease. If you have a close relative (mother, father, sister, or brother) with either 1) symptoms of VHL, 2) a clinical diagnosis of VHL, or 3) a positive genetic test for VHL, you may wish to be tested to determine if you have inherited the VHL gene mutation previously identified in the McCoy family.

Molecular diagnostic testing should be arranged through your family doctor and/or a genetic counselor. The genetic counselor will obtain information about your family’s medical history to determine if you are at risk for VHL. They may find that you are NOT at risk for VHL disease if none of your closest relatives have any signs or symptoms of VHL. In this case, molecular diagnostic testing is not necessary.

On the other hand, they may find that you are at risk for VHL disease and that testing is recommended. The genetic counselor will also determine your relationship to other members of the McCoy family who may have been tested for the VHL gene mutation to make sure that the mutation for which you are at risk is actually the McCoy family mutation. The test for the McCoy mutation is ONLY useful to you if you are a direct descendent of a member of the McCoy family with VHL. There are more than 500 recorded ways that the VHL gene may be altered. If you are a member of a different family with VHL, the alteration in the gene will be different.

Molecular diagnostic testing for a VHL gene mutation must be requested by a physician or genetic counselor. The test requires a small amount of blood shipped to the lab by overnight carrier. You may be asked to sign an informed consent to have the test. Test results are usually available within two weeks. The cost for a familial mutation is $313. Your physician or genetic counselor can be enormously helpful in initiating the testing process by filling out the test request and assisting with the other paperwork (including the informed consent and payment information), arranging for a blood draw, and organizing shipment of the sample and paperwork to the lab.

Test results will be returned to your physician or genetic counselor. They will discuss the results with you, and (if the test is positive for the mutation) they may recommend periodic screening (such as an annual eye exam, abdominal ultrasound, or urinary/plasma catecholamines) for early tumor detection and intervention. Other members of your family may also be at risk and could benefit from testing for the mutation as well.

Information for submitting a sample for molecular diagnostic testing for VHL (including sample requirements, shipping instructions, prices, CPT codes, turn-around-times, and other paperwork that must accompany the sample) is available by fax or email on request from the Molecular Genetics Laboratory at the Children’s Hospital of Philadelphia (formerly the Genetic Diagnostic Laboratory at the University of Pennsylvania School of Medicine).

Fax: 215-590 2156