Von Hippel-Lindau (VHL) disease is a rare genetic condition that causes tumors and cysts to grow in multiple organs throughout the body, including the brain, spinal cord, eyes, kidneys, and adrenal glands. It affects roughly 1 in 36,000 people. The tumors are often benign but can become cancerous, and the disease requires lifelong monitoring because new growths can appear at any age.
How VHL Disease Works at the Genetic Level
VHL disease is caused by a mutation in the VHL gene, which normally produces a protein that acts as one of the body’s built-in tumor suppressors. In a healthy cell, the VHL protein works like a quality control system: it tags a molecule called HIF for destruction when oxygen levels are normal. HIF’s job is to trigger the growth of new blood vessels and boost cell survival when oxygen is low, which is useful in certain situations but dangerous when it runs unchecked.
When the VHL protein is missing or broken, HIF accumulates even when oxygen levels are perfectly fine. This tricks the body into constantly producing signals that promote blood vessel growth, cell division, and the production of red blood cells. The result is an overproduction of growth factors, particularly one that drives new blood vessel formation (VEGF) and a hormone that stimulates red blood cell production (erythropoietin). That abnormal signaling is what fuels the tumors and cysts characteristic of VHL disease.
VHL follows an autosomal dominant inheritance pattern, meaning you only need one faulty copy of the gene to be at risk. Most people inherit the mutation from a parent, though about 20% of cases arise as new mutations with no family history. Tumors typically develop when the remaining healthy copy of the gene is lost or damaged in a specific cell, a process known as the “two-hit” model of tumor development.
Types of Tumors and Where They Grow
VHL disease doesn’t produce just one type of tumor. It can affect several organ systems, and the specific combination varies from person to person, even within the same family.
Hemangioblastomas are the hallmark of VHL disease, affecting more than 70% of individuals. These are blood vessel-rich tumors that grow in the central nervous system. About 45% appear in the cerebellum, 36% in the spinal cord, 11% near the base of the spine, and 7% in the brain stem. They’re typically benign but can cause serious problems by pressing on surrounding brain or spinal tissue, leading to headaches, balance issues, weakness, or numbness depending on their location.
Retinal hemangioblastomas are present in more than 50% of VHL patients. These small tumors grow on the blood vessels of the retina and can leak fluid, cause retinal detachment, or lead to vision loss if not caught early. They are one of the earliest manifestations of the disease.
Renal cell carcinoma (RCC) is the most dangerous aspect of VHL for many patients. The clear cell subtype of kidney cancer develops in an estimated 24% to 45% of individuals over their lifetime. It can grow within kidney cysts or in surrounding tissue and is a leading cause of death in people with VHL. Unlike kidney cancer in the general population, VHL-related kidney tumors are often multifocal, meaning they appear in several spots across both kidneys.
Pheochromocytomas are tumors of the adrenal glands that occur in 25% to 30% of VHL patients. These tumors produce excess adrenaline and related hormones, which can cause episodes of high blood pressure, rapid heartbeat, sweating, and headaches. They can appear on one or both adrenal glands and tend to be small and multifocal. VHL is actually classified into subtypes partly based on whether pheochromocytomas are present: type 2 VHL carries a high risk for these tumors, while type 1 does not.
Other possible manifestations include pancreatic cysts and pancreatic neuroendocrine tumors, endolymphatic sac tumors (which can cause hearing loss), and paragangliomas.
How VHL Disease Is Diagnosed
Diagnosis relies on a combination of clinical findings and genetic testing. If you have a first- or second-degree relative with VHL, just one characteristic tumor (such as a hemangioblastoma or clear cell kidney cancer) is enough to make a clinical diagnosis. Without any family history, the bar is higher: you generally need at least two hemangioblastomas, or one hemangioblastoma plus another VHL-related tumor.
Genetic testing for mutations in the VHL gene can confirm the diagnosis and is especially useful for identifying at-risk family members before symptoms appear. Because about 20% of cases have no family history, genetic testing is the only way to establish the diagnosis early in those individuals.
Screening and Surveillance
Because tumors can develop at different ages and in different organs, people with VHL disease follow a structured screening schedule for life. The goal is to catch growths when they’re small and manageable rather than waiting for symptoms.
Eye screening starts remarkably early. Current guidelines recommend ocular exams beginning at 12 months of age, repeated every 6 to 12 months until age 30, then annually after that. This aggressive timeline reflects how common retinal tumors are and how much easier they are to treat when small. Women with VHL should also be screened before any planned pregnancy and every 6 to 12 months during pregnancy, since hormonal changes can accelerate tumor growth.
Brain and spinal MRIs, abdominal imaging for kidney and adrenal tumors, hearing evaluations, and blood or urine tests for excess adrenal hormones round out the surveillance protocol. The exact schedule depends on age and which manifestations have already appeared.
Treatment Options
For decades, managing VHL disease meant surgery: removing tumors as they grew large enough to threaten organ function, while trying to preserve as much healthy tissue as possible. That’s still the case for many patients, particularly those with brain or spinal tumors causing neurological symptoms, or kidney tumors that reach a size threshold where cancer spread becomes a concern.
A significant shift came in 2021 with the FDA approval of belzutifan (sold as Welireg), the first drug designed specifically for VHL disease. It works by blocking the HIF pathway, the same molecular switch that VHL normally controls. By shutting down HIF signaling directly, it addresses the root cause of tumor growth rather than targeting individual tumors.
Belzutifan is approved for adults with VHL-associated kidney cancer, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors that don’t require immediate surgery. It’s taken as a daily oral pill and continued until the disease progresses or side effects become intolerable. For many patients, it offers a way to delay or avoid repeated surgeries, though it doesn’t replace surgery for tumors that are already causing acute problems.
Retinal tumors are typically treated with laser therapy or cryotherapy (freezing) when they’re small. These procedures are highly effective at preserving vision when tumors are caught early, which is why the screening schedule starts so young.
Living With VHL Disease
VHL is a lifelong condition with no cure. The central challenge is that new tumors can appear throughout a person’s life, so even after successful treatment for one growth, continued surveillance is essential. Kidney cancer remains the leading cause of mortality, which is why abdominal imaging and preserving kidney function are high priorities in long-term management.
Life expectancy has improved substantially over the past few decades thanks to earlier detection and better treatment options. Historically, average survival was in the late 40s, but modern surveillance protocols and newer therapies have pushed that figure upward. The introduction of targeted drugs like belzutifan represents a particularly meaningful advance for patients with multiple tumors or those who have already undergone several surgeries.
Because VHL is a dominant genetic condition, each child of an affected person has a 50% chance of inheriting the mutation. Genetic counseling and testing are available for family members, and identifying carriers before symptoms develop allows screening to start on schedule, often years before the first tumor would otherwise be detected.