Von Hippel-Lindau (VHL) disease is a rare, inherited disorder that causes tumors and fluid-filled sacs (cysts) to develop in various organs. As a multi-system disorder, it often involves the brain, spine, eyes, kidneys, pancreas, and adrenal glands. The tumors associated with VHL disease can be either benign (non-cancerous) or malignant (cancerous), and their growth requires lifelong medical attention. While the disorder is present from birth, its clinical manifestations typically begin to appear in young adulthood, making early detection and management crucial.
The VHL Gene and Its Role in Cellular Regulation
VHL disease is caused by a mutation in the VHL gene, located on chromosome 3. The protein produced by this gene acts as a tumor suppressor, controlling cell growth and division. Its main role involves regulating the cell’s response to varying oxygen levels through a process called the oxygen-sensing pathway.
The VHL protein normally functions as part of a complex that targets a protein called Hypoxia-Inducible Factor (HIF) for degradation. When oxygen is plentiful, the VHL protein binds to HIF, marking it for destruction and keeping its levels low within the cell. This prevents the activation of genes that promote growth and new blood vessel formation.
When a person has a mutated VHL gene, the resulting VHL protein is non-functional or entirely absent. This defect prevents the proper breakdown of the HIF protein, causing it to accumulate even when oxygen is available. The excess HIF then switches on genes that stimulate unchecked cell proliferation and the formation of numerous blood vessels, driving the characteristic tumor growth seen in VHL disease. This mechanism explains why VHL-related tumors are often rich in blood vessels and develop in multiple locations.
How VHL Disease Manifests in the Body
The tumors and cysts arising from VHL disease affect six main organ systems, with symptoms depending on the location and size of the growths. A common manifestation is the formation of hemangioblastomas, which are benign, highly vascular tumors. These are most frequently found in the central nervous system, specifically the cerebellum, brainstem, and spinal cord, where their growth can cause neurological symptoms such as balance problems, weakness, and headaches.
In the retina, these hemangioblastomas, often called retinal angiomas, are common and can lead to significant vision loss if left untreated. They are identified during routine eye examinations and can cause complications like retinal detachment and hemorrhage. The kidneys are frequently affected, developing multiple cysts and facing a high risk for clear cell renal cell carcinoma (RCC), a major cause of mortality for individuals with VHL disease.
Tumors can develop in the adrenal glands, leading to the formation of pheochromocytomas. These growths, though usually benign, can secrete excessive hormones, causing symptoms like high blood pressure, rapid heart rate, and profuse sweating. The pancreas may develop numerous cysts or solid pancreatic neuroendocrine tumors (pNETs), which are often slow-growing. While most pancreatic cysts are benign, the pNETs require careful monitoring due to their potential for malignancy and hormone production.
Inheritance Patterns and Diagnostic Criteria
VHL disease is inherited in an autosomal dominant pattern, meaning a person only needs one copy of the mutated gene from a parent to have the disorder. There is a 50% chance that an affected parent will pass the genetic change on to any child. The condition has high penetrance, meaning the vast majority of individuals who inherit the mutation will eventually develop at least one manifestation of the disease.
While most cases are inherited, approximately 20% of VHL diagnoses are due to a de novo (new) gene mutation that occurs spontaneously and is not inherited. Diagnosis relies on a combination of clinical findings and genetic confirmation. A clinical diagnosis can be made in individuals with a family history of VHL who present with one characteristic tumor, or in those without a family history who present with two or more characteristic tumors.
Genetic testing provides definitive confirmation by identifying the pathogenic change in the VHL gene. This testing is crucial for the affected individual and at-risk family members, as it allows specialized surveillance to begin before symptoms appear. Identifying the mutation allows clinicians to distinguish between inherited VHL and sporadic cases of tumors that might mimic the disease.
Long-Term Surveillance and Treatment Strategies
Management of VHL disease centers on proactive, multidisciplinary surveillance to detect tumors in their earliest stages. Individuals with a confirmed VHL mutation follow a lifelong monitoring schedule that begins in childhood. This protocol includes annual eye examinations to screen for retinal angiomas and periodic magnetic resonance imaging (MRI) of the brain and spine for hemangioblastomas.
Regular imaging, such as MRI or ultrasound, is performed to monitor abdominal organs, including the kidneys and pancreas, for new cysts or tumors. Adrenal gland activity is monitored through annual blood pressure checks and urine tests to screen for hormone metabolites indicative of pheochromocytomas. The goal of surveillance is to intervene when tumors are small, minimizing damage to surrounding tissues.
Treatment for VHL-related tumors is individualized, depending on the tumor type, size, and location. Surgical removal remains the standard of care for most symptomatic or rapidly growing tumors, such as hemangioblastomas and renal cell carcinoma. Non-surgical options include targeted therapies, such as cryotherapy or laser treatment for small retinal angiomas, and radiation therapy for central nervous system tumors. The drug Belzutifan, a targeted therapy that inhibits the HIF-2α pathway, represents a newer option approved for treating some VHL-associated tumors that do not require immediate surgery.