What is Von Hippel-Lindau (VHL) disease?

Von Hippel-Lindau Disease: Overview

Von Hippel-Lindau (VHL) disease is a rare autosomal dominant hereditary cancer syndrome caused by mutations in the VHL tumor suppressor gene on chromosome 3p25, characterized by highly vascular tumors affecting multiple organ systems with lifetime penetrance approaching 100% by age 75. 1, 2

Genetic Basis and Inheritance Pattern

The VHL gene mutation disrupts the VHL protein's critical role in cellular oxygen sensing, leading to inappropriate activation of hypoxia-inducible factors that drive tumor development across multiple organs. 1

• Approximately 80% of cases are inherited from an affected parent, while 20% arise from de novo mutations—meaning absence of family history does not exclude the diagnosis. 3, 2
• The incidence is estimated at 1 in 36,000 live births. 2
• Genetic testing detects disease-causing mutations in 95-100% of individuals with clinical VHL, making it the gold standard for diagnosis. 4

Cardinal Clinical Manifestations

The disease presents with multiple tumor types that significantly impact morbidity and mortality:

Ocular Manifestations

• Retinal hemangioblastomas (RHs) occur in 38% of patients, with cumulative probability reaching nearly 80% in those older than 80 years. 2
• Vision loss occurs in approximately 20% of patients if untreated, secondary to tumor-associated exudation, fibrosis, hemorrhage, or retinal detachment. 1, 2
• Extrapapillary RHs (>1.5 mm from optic disc) initially appear as red or grayish pinpoint lesions <500 μm, progressing to larger tumors with dilated, tortuous feeding vessels. 1
• Juxtapapillary RHs (≤1.5 mm from optic disc) exhibit pink-grey localized fullness of the neural rim without visible feeding vessels. 1

Central Nervous System

• CNS hemangioblastomas develop in 60-80% of patients, with the youngest reported diagnosis at age 9 years. 3, 2
• These benign tumors affect the cerebellum, spinal cord, and brain stem, causing significant morbidity through mass effect. 2, 5

Renal Manifestations

• Clear cell renal cell carcinoma develops in up to 70% of patients and represents a leading cause of death. 1, 3, 2
• Multiple renal cysts are common precursors. 1, 5

Endocrine Tumors

• Pheochromocytomas occur in 7-25% of patients, associated with specific missense mutations (Type 2 VHL). 3, 2, 5
• These tumors cluster in certain families based on genotype-phenotype correlations. 5

Other Manifestations

• Endolymphatic sac tumors can cause tinnitus or deafness. 5
• Pancreatic neuroendocrine tumors and cysts occur frequently. 1, 2
• Epididymal and broad ligament cystadenomas are characteristic. 1, 2

Diagnostic Criteria

With Family History

A clinical diagnosis can be established in individuals with a family history of VHL who have any single manifestation: CNS/retinal hemangioblastoma, pheochromocytoma, or renal cell carcinoma. 3

Without Family History

Two or more retinal or cerebellar hemangioblastomas, or one hemangioblastoma with one visceral tumor is required for diagnosis. 5

Genetic Testing Indications

The American College of Medical Genetics recommends genetic testing for any child diagnosed with: 3

• Retinal angioma/hemangioblastoma
• CNS hemangioblastoma
• Clear cell renal cell carcinoma
• Pheochromocytoma or paraganglioma
• Endolymphatic sac tumor
• Multiple pancreatic cysts or neuroendocrine tumors
• Multiple renal cysts

Genetic testing should be performed in all first-degree relatives of individuals with pathogenic VHL variants. 3

Surveillance Protocol

Timing and Frequency

Ocular screening must begin within 12 months after birth and continue throughout life, as tumor development can occur at any age. 1, 3

• Every 6-12 months until age 30 years, then at least yearly thereafter. 1, 3
• During pregnancy: screening before planned pregnancy and every 6-12 months during pregnancy. 1

CNS Surveillance

Brain and spine MRI should begin at age 8 years, allowing early detection and surgical excision with minimal damage to surrounding tissue. 3

Abdominal Surveillance

Abdominal imaging should begin at age 8-10 years, with annual imaging (alternating ultrasound and MRI) starting at age 16 to monitor for renal cysts and renal cell carcinoma. 3

Endocrine Surveillance

Screening for pheochromocytoma should begin at age 5 years with annual plasma or urine metanephrines. 3

Treatment Approaches

Retinal Hemangioblastomas

Extramacular or extrapapillary RHs should be treated promptly, even when small. 1, 3

• Laser photocoagulation achieves 100% successful destruction of RHs ≤1.5 mm in diameter, compared to only 47-73% of larger lesions. 3
• For juxtapapillary or macular lesions where laser ablation is risky, belzutifan represents a safer alternative. 3

Systemic Therapy

Belzutifan, an oral HIF-2α inhibitor, is FDA-approved for multiple VHL manifestations including RCC, CNS hemangioblastomas, and pancreatic neuroendocrine tumors not requiring immediate surgery. 3, 6

• It avoids direct damage from local ablation and may allow earlier treatment without ablative therapies. 3

Surgical Management

Surgical intervention remains the mainstay of treatment for most VHL-related tumors, with CNS hemangioblastomas being surgically excised when detected early. 3

Management Structure

Patients should be managed by specialists with VHL experience, ideally within a multidisciplinary center capable of providing multi-organ surveillance and access to genetic testing. 1, 3

The multidisciplinary team must include: ophthalmology, neurosurgery, urology/nephrology, endocrinology, medical genetics, and oncology. 3

Prognosis

Historical median life expectancy was only 49 years, but recent data shows improvement to 60-67 years for those born in 2000 due to comprehensive surveillance and early intervention. 7, 5

Systematic screening combined with more effective treatments for life-threatening manifestations such as renal cell carcinoma has been credited with improved survival. 1

Critical Pitfalls to Avoid

• Do not wait for multiple manifestations before considering VHL, as 20% of cases arise from de novo mutations without family history. 7
• Do not observe small retinal hemangioblastomas closely, as spontaneous regression is rare and tumor growth is unpredictable—early treatment maintains good vision. 3
• Do not delay genetic testing in first-degree relatives, as those without the mutation can be spared lifelong surveillance. 5