Von Hippel-Lindau (VHL) disease is a rare, inherited condition that predisposes individuals to the development of tumors and fluid-filled sacs, known as cysts, in multiple organs throughout the body. This multisystem genetic disorder affects various organ systems. The growths associated with VHL are often non-cancerous, but they can still cause serious health issues due to their location and tendency to grow large enough to press on surrounding tissues. The condition affects about one in 36,000 people globally.
The VHL Gene and Inheritance
The underlying cause of this condition is a mutation in the \(VHL\) gene, a tumor suppressor gene. This gene normally produces a protein that helps regulate cell growth and division. This protein acts as a component that tags other proteins for degradation, specifically targeting the hypoxia-inducible factors (HIF) 2-alpha protein. Under normal oxygen levels, the VHL protein ensures HIF-alpha subunits are broken down, preventing the cell from activating growth genes. When the \(VHL\) gene is mutated and the protein is non-functional, HIF-alpha accumulates within the cell. This unchecked buildup leads to the continuous activation of genes that promote cell proliferation and the growth of new blood vessels (angiogenesis), resulting in tumor formation. VHL disease is inherited in an autosomal dominant pattern, meaning a person only needs one copy of the mutated gene. While most cases are inherited, some individuals develop a new, or de novo, germline mutation in the \(VHL\) gene.
Specific Organ Involvement and Tumors
The hallmark of VHL disease is the growth of hemangioblastomas, which are benign, highly vascular tumors composed of newly formed blood vessels. These growths most commonly affect the central nervous system (CNS), appearing in the brain (cerebellum and brain stem) and along the spinal cord. Though non-cancerous, these CNS tumors can cause severe neurological symptoms, such as balance problems, headaches, and weakness, by putting pressure on nervous tissue. Retinal hemangioblastomas, which occur in the back of the eye, are often the first sign of the disease and can lead to vision loss or retinal detachment.
The kidneys are a major site of involvement, with clear cell renal cell carcinoma (RCC) being the leading cause of disease-related death for VHL patients. This specific type of kidney cancer develops in up to 70% of affected individuals and frequently presents as multiple tumors in both kidneys.
VHL also causes the growth of pheochromocytomas, which are tumors of the adrenal glands. These tumors produce excessive hormones, leading to symptoms like high blood pressure, rapid heart rate, and severe headaches.
The pancreas is commonly affected by both cysts and pancreatic neuroendocrine tumors (PanNETs), occurring in up to 17% of patients. Pancreatic cysts are usually benign, but PanNETs can sometimes exhibit malignant behavior and may spread to other organs if they grow larger than three centimeters. Less commonly, VHL disease can cause endolymphatic sac tumors (ELSTs) in the inner ear, which can result in hearing loss, dizziness, and ringing in the ears.
Screening and Diagnosis
The diagnosis of VHL disease relies on clinical findings and confirmation through genetic testing. Genetic testing involves DNA sequencing of a blood sample to look for a pathogenic mutation in the \(VHL\) gene. This testing is important for individuals with a family history of the disease or those presenting with characteristic tumors.
Once VHL is confirmed, a lifelong surveillance program is initiated to detect new tumors early. This proactive monitoring schedule involves regular comprehensive physical exams and specific imaging studies:
- Annual dilated eye exams to check for retinal hemangioblastomas.
- Blood or urine tests to screen for hormone-producing adrenal tumors.
- Regular magnetic resonance imaging (MRI) of the brain and spine, often every two years, to check for central nervous system hemangioblastomas.
- Annual abdominal imaging (ultrasound, CT, or MRI) to monitor the kidneys and pancreas for tumors and cysts.
Managing VHL Disease
The management of VHL disease focuses on minimizing the morbidity caused by the tumors through early intervention. The most common treatment strategy for VHL-associated tumors that are growing or causing symptoms is surgical removal. For central nervous system hemangioblastomas, early surgical excision is recommended to prevent permanent neurological damage once the lesions are detected.
For kidney tumors, the goal is nephron-sparing surgery, which removes the tumor while preserving healthy kidney tissue, often when the tumor reaches three centimeters or more. Non-surgical options, such as stereotactic radiosurgery, can treat small hemangioblastomas in the brain by delivering focused, high-dose radiation.
Targeted systemic therapies represent a newer treatment approach. The FDA has approved the oral medication belzutifan, a hypoxia-inducible factor 2-alpha (HIF-2\(\alpha\)) inhibitor, for the treatment of VHL-associated renal cell carcinoma, pancreatic neuroendocrine tumors, and CNS hemangioblastomas that do not require immediate surgery. This targeted drug works by preventing the accumulation of HIF-2\(\alpha\), thereby slowing tumor growth.