Von Hippel-Lindau (VHL) disease is a rare, inherited disorder characterized by the abnormal growth of tumors and fluid-filled sacs, known as cysts, across multiple organs. It is classified as a multi-system disorder, affecting the eyes, brain, spinal cord, kidneys, adrenal glands, and pancreas. Although many VHL growths are non-cancerous, their location and tendency to grow can lead to serious health complications, including vision loss and neurological damage. The condition is inherited in an autosomal dominant pattern, meaning a person needs only one copy of the altered gene to inherit the disorder. VHL affects approximately one in every 36,000 people.
The Role of the VHL Gene
The underlying cause of VHL disease is a mutation in the VHL gene, a tumor suppressor gene located on chromosome 3. The protein produced by the gene, called pVHL, normally acts as part of a complex that tags other proteins for degradation, preventing uncontrolled cell growth. This function is important in regulating Hypoxia-Inducible Factor (HIF).
Under normal oxygen conditions, pVHL targets the HIF-alpha subunit for rapid breakdown. When the VHL gene is mutated, the pVHL protein becomes dysfunctional or absent, preventing HIF degradation. The resulting excessive accumulation of HIF within cells triggers the activation of genes involved in cell division and the formation of new blood vessels (angiogenesis). This uncontrolled signaling pathway leads directly to the development of the tumors and cysts characteristic of VHL disease.
Approximately 80% of VHL cases are inherited from a parent who carries the germline mutation. The remaining 20% are caused by a spontaneous, or de novo, mutation in the VHL gene that occurs early in development without a family history. Both inherited and spontaneous mutations result in the same disease mechanism.
How VHL Affects the Body
VHL disease manifests through a spectrum of tumors and cysts across six main organ systems. Hemangioblastomas, which are benign but highly vascular tumors, are the most common manifestation. These growths frequently occur in the Central Nervous System (CNS), specifically the cerebellum, brainstem, and spinal cord. In these sensitive areas, hemangioblastomas can cause neurological symptoms like headaches, balance problems, and muscle weakness as they press against surrounding tissue.
Retinal hemangioblastomas (retinal angiomas) occur in up to 60% of individuals with VHL. These tumors appear in the light-sensitive tissue at the back of the eye and can lead to vision loss or blindness if left untreated. Their growth can cause fluid leakage, resulting in retinal detachment or scarring.
The kidneys are significantly affected, increasing the risk of developing clear cell Renal Cell Carcinoma (RCC). This malignant tumor represents a major cause of mortality in VHL patients. Multiple, benign renal cysts are also frequently observed.
Tumors in the adrenal glands, known as pheochromocytomas, develop in the hormone-producing cells. Pheochromocytomas are usually non-cancerous but can release excessive adrenaline and noradrenaline, leading to symptoms like high blood pressure, rapid heart rate, and excessive sweating. Pancreatic involvement is also common, including benign cysts or neuroendocrine tumors.
Less frequently, VHL can cause endolymphatic sac tumors in the inner ear, which may cause hearing loss, ringing in the ears, and vertigo. Males may develop epididymal cystadenomas, and females may develop similar growths in the broad ligament of the uterus.
Identifying and Monitoring VHL
A definitive diagnosis of VHL disease is established through molecular genetic testing, which involves sequencing the VHL gene. This testing identifies a pathogenic mutation, confirming the diagnosis even if clinical findings are not conclusive. Genetic counseling is recommended for individuals with a family history of VHL or those presenting with characteristic tumors.
For individuals diagnosed with VHL or those at risk, a lifelong surveillance protocol is initiated. This proactive monitoring detects new tumors and cysts at their earliest, most treatable stages. Annual comprehensive physical exams, including blood pressure monitoring, are standard surveillance components.
Regular specialized screenings begin in childhood. Ophthalmic surveillance involves an annual dilated retinal examination to detect retinal hemangioblastomas. To screen for pheochromocytomas, patients undergo annual biochemical testing, typically using 24-hour urine collection or plasma tests to measure catecholamine breakdown products, such as metanephrines. Abdominal imaging (MRI or CT) is performed annually to monitor the kidneys and pancreas. Biennial MRI scans of the brain and spine are also routinely performed to screen for CNS hemangioblastomas.
Current Management Strategies
The management of VHL disease is individualized based on the size, location, and growth rate of the tumors. Active surveillance is a cornerstone of care, involving the monitoring of small, asymptomatic lesions rather than immediate intervention. This approach helps patients avoid unnecessary procedures and preserves organ function, especially in the kidneys, where nephron-sparing surgery is preferred over complete removal.
Surgical intervention remains the primary treatment for tumors that are growing rapidly, causing symptoms, or posing a risk of malignancy, such as Renal Cell Carcinoma. For kidney tumors, surgery is recommended when the lesion reaches three centimeters or more. CNS and retinal hemangioblastomas are surgically removed or treated with focused radiation when they threaten neurological or visual function.
Targeted drug therapies have emerged as a significant advancement. Drugs that specifically inhibit HIF-2α have been developed. The FDA approved the oral HIF2-α inhibitor, belzutifan, for VHL-associated Renal Cell Carcinoma, pancreatic neuroendocrine tumors, and CNS hemangioblastomas that do not require immediate surgery. Other systemic treatments, such as anti-VEGF therapies, are also used to inhibit the new blood vessel formation that fuels tumor growth.