How Is Von Hippel-Lindau Disease Diagnosed?

When Is VHL Diagnosed?

People of all ages can be diagnosed with VHL. The average age of onset for the condition is 26 years old, according to the National Organization for Rare Disorders, and 97% of people with the VHL gene mutation will experience symptoms by age 65. "It's usually diagnosed later in life, people will start to develop manifestations of these different tumors," Dr. Rogers said. "For example, if there are tumors affecting the eyes, what we call retinal angiomas, it may affect vision. And they may go to an ophthalmologist and find these tumors."

"If there is a tumor pressing on the brain, it may affect things like their ability to walk or do things or cause headaches. Maybe they're getting a CT scan for something else and they're told they have kidney tumors or pancreas tumors. Some of the adrenal tumors cause symptoms that can affect blood pressure, so maybe their primary care physician is trying to figure out why the blood pressure is so high and why they have headaches." If someone has a family history of VHL, they may learn of their diagnosis at an early age. If that is the case, "it's just a matter of watching them," Dr. Rogers explained, to see when and if treatment is needed.

How Is VHL Diagnosed?

DNA testing via a blood sample is the most conclusive way to determine if someone has VHL. In a conversation with SurvivorNet, Dr. Tobias Else, an endocrinologist who leads the Comprehensive Clinical Care Center for Von Hippel-Lindau disease at the University of Michigan Health Rogel Cancer Center, explains how testing works. "Once we find a change in [the VHL gene] or if there is a described change, we will go back to to basically two big databases," he explains. "One that will describe changes in this gene and in patients with known VHL disease so they will have hallmarks of the disease and then we'll use other databases where basically nobody is assumed to have VHL disease."

What this means is that if testing reveals a mutation or "spelling mistake" in the VHL gene, doctors will turn to their collection of genetic "spelling mistakes," so to speak, to see if it matches up with other patients who have been officially diagnosed with VHL. They'll also see if the "spelling mistake" has occurred in people who don't have VHL. If they find that a person's specific genetic mutation or "spelling mistake" has been seen in patients with VHL but not other syndromes making it a "disease-causing variant," they will officially receive a VHL diagnosis regardless of whether they have manifestations of the disease.

"VHL disease is actually one of those where if you if you carry a variant that is well recognized as disease-causing, then you virtually always will have VHL disease, albeit with a variable expression whether you will develop any of these tumors or all of these tumors or even some," Dr. Else explained. There is, however, sometimes a less common scenario where a variant is found in the VHL gene, but that specific variant is not clearly classified as a disease-causing variant. "It's just a spelling mistake where we don't know. First of all, we'll review the family history, the personal history, whether it actually fits with VHL disease, but we won't necessarily give patients the diagnosis," Dr. Else said.

From there, Dr. Else says they will follow up about whether or not they find other people out there with this specific VHL mutation that never have any issues. If that becomes the case, then that specific mutation would potentially be considered a benign variant or a non-disease-causing variant.

Screening Guidelines

VHL screening is not something the general public should engage in, but if you have a family history, you should. "For the general population, no [recommended screening], because it is such a rare hereditary disease," Dr. Rogers said. "We wouldn't recommend everyone go out and get screened, you know, head to toe for all these tumors, but it becomes very important if… a family member has VHL and there's a potential that they have it.

Knowing your family history of VHL, specifically, is essential. But simply paying attention to a history of cancers or tumors, in general, can be crucial too. "Is there any family history of cancers or tumors that run in the family?" Dr. Rogers recommends the general public ask themselves and their families. "When you start hearing about multiple tumors and tumors affecting multiple organs, that's usually where it's valuable to get checked out and get screened and even genetic testing to see if there's something driving this, whether it's VHL or something else."

Dr. Else also notes that testing for VHL should be done for the following people:

• Patients with pheochromocytoma  a type of neuroendocrine tumor that grows from cells called chromaffin cells, which are found in the adrenal glands.
• Patients who have a known family history of kidney cancer or have multiple kidney cancers in the same person.
• "Pretty much everybody" who has a hemangioblastoma of the retina (in the eye) or of the brain.

Both Dr. Rogers and Dr. Else recommend people visit the VHL Alliance website for guidance on the disease including screening recommendations. Genetic testing can identify which children have VHL and need to undergo surveillance. If a child has a family history of VHL but does not carry the family's VHL gene mutation, they do not need ongoing surveillance.

The VHL Alliance and its Clinical Advisory Council recommend surveillance for affected children to begin before they reach age one.

Early screening includes:

• Eye/retina examination
• A hearing test
• Blood pressure measurement
• Neurological assessment

Finally, it is important to remember that once a specific VHL mutation has been identified within a family, that exact change in the VHL gene will be the same mutation passed through the family if it is inherited. "With this information, another person in the family, who does not have a clinical diagnosis of VHL, can submit a blood sample and the lab can check for the same mutation in this second person's DNA," the VHL Alliance states.

Moving Forward – Questions to Ask Your Doctor

• Should I be screened for VHL?
• If I have VHL, who should be tested for the genetic mutation in my family?
• What should surveillance look like if I test positive for a VHL gene mutation, but I don't have any manifestations of the disease yet?

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