What is the management and treatment approach for a patient with Von Hippel-Lindau (VHL) disease?

Von Hippel-Lindau Disease: Management and Treatment

Von Hippel-Lindau disease requires lifelong multidisciplinary surveillance starting from birth, with genetic testing for all at-risk individuals, and prompt treatment of retinal hemangioblastomas to prevent vision loss, CNS hemangioblastomas to prevent neurological damage, and renal cell carcinomas which represent the leading cause of mortality. 1, 2

Genetic Diagnosis

• Genetic testing is the gold standard for VHL diagnosis and must be performed in all first-degree relatives of individuals with pathogenic VHL variants. 2
• Patients at risk include first-degree relatives of known VHL patients, or any patient with single or multifocal retinal hemangioblastomas. 1
• Any child diagnosed with retinal angioma/hemangioblastoma, CNS hemangioblastoma, clear cell renal cell carcinoma, pheochromocytoma, endolymphatic sac tumor, or multiple pancreatic cysts should undergo genetic testing. 2
• Up to 20% of VHL cases arise from de novo mutations, so absence of family history does not rule out the diagnosis. 2, 3, 4

Comprehensive Surveillance Protocol

Ocular Surveillance

• Begin ophthalmology examinations within 12 months after birth and continue throughout life. 1, 2
• Perform dilated fundoscopic examinations every 6-12 months until age 30 years, then at least yearly thereafter. 1, 2
• During pregnancy, perform ocular screening before conception and every 6-12 months during pregnancy. 1
• Ultra-widefield color fundus photography and fluorescein angiography may help monitor and detect small retinal hemangioblastomas. 1

Central Nervous System Surveillance

• Begin brain and spine MRI with contrast at age 8 years. 1, 2
• Perform biennial MRI of brain and spine thereafter. 1, 2
• Early detection allows surgical excision with minimal damage to surrounding tissue. 2

Renal and Abdominal Surveillance

• Begin abdominal imaging at age 10 years. 1, 2
• Perform annual abdominal imaging (alternating ultrasound and MRI) starting at age 16 years. 1, 2
• Monitor for renal cysts and renal cell carcinoma, which develops in up to 70% of patients and is a leading cause of death. 2, 5

Pheochromocytoma Surveillance

• Begin screening at age 2 years with blood pressure checks at every medical visit. 1
• Perform annual plasma-free metanephrines or 24-hour urine fractionated metanephrines starting at age 2 years. 1, 2
• Note that younger patients with pheochromocytoma typically have missense variants (type II/III) rather than truncating variants. 1

Endolymphatic Sac Tumor Surveillance

• Begin audiogram screening at age 5 years. 1
• Perform biennial audiology evaluations. 1

Treatment Approaches by Manifestation

Retinal Hemangioblastomas

• Extramacular or extrapapillary retinal hemangioblastomas should be treated promptly, even when small (≤500 μm in diameter). 1, 2
• Laser photocoagulation achieves successful destruction in 100% of retinal hemangioblastomas ≤1.5 mm in diameter, compared to only 47-73% of larger lesions. 2
• Early treatment before symptoms appear maintains good vision. 2
• Spontaneous regression is rare and tumor growth is unpredictable, making observation inappropriate. 2

Juxtapapillary and Macular Lesions

• For juxtapapillary or macular lesions where laser ablation risks vision loss, consider belzutifan as a safer alternative. 2
• Belzutifan is an oral HIF-2α inhibitor approved by the FDA for multiple VHL manifestations. 2, 6
• It avoids direct damage from local ablation and may allow earlier treatment without ablative therapies. 2

CNS Hemangioblastomas

• Surgical excision is recommended when detected early to minimize damage to surrounding tissue. 2
• CNS hemangioblastomas occur in 60-80% of patients and cause significant morbidity through mass effect. 5
• Belzutifan is FDA-approved for CNS hemangioblastomas not requiring immediate surgery. 6

Renal Cell Carcinoma

• Surgical intervention remains the mainstay of treatment. 2
• Belzutifan is FDA-approved for VHL-associated renal cell carcinoma not requiring immediate surgery. 6

Pheochromocytoma

• Surgical removal is the primary treatment. 2
• Occurs in 7-20% of families and is associated with specific missense mutations. 5

Critical Management Principles

Multidisciplinary Care

• Patients should be managed by specialists with experience in VHL disease, ideally within a multidisciplinary center capable of providing multi-organ surveillance and access to genetic testing. 1, 2
• Management requires specialists in ophthalmology, neurosurgery, urology/nephrology, endocrinology, medical genetics, and oncology. 2

Common Pitfalls to Avoid

• Do not delay genetic testing or surveillance based on young age alone, as retinal hemangioblastomas can develop in the first year of life. 5
• Do not assume older age at presentation indicates sporadic disease, as VHL manifestations can first appear in middle or late adulthood. 5
• Even a solitary retinal hemangioblastoma at any age warrants genetic testing and comprehensive evaluation. 5
• Do not wait for multiple manifestations before considering VHL, as 20% of cases arise from de novo mutations without family history. 3

Prognosis

• Historical median life expectancy was only 49 years. 3, 5
• Recent data shows improvement to 60-67 years for those born in 2000 due to comprehensive surveillance and early intervention. 3, 5
• Comprehensive surveillance paradigms have substantially mitigated mortality risks by enabling early tumor recognition and multidisciplinary management. 3, 5
• Lifelong surveillance is required given ongoing risks for tumor development with increasing age. 2