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

Management and Treatment of Von Hippel-Lindau (VHL) Disease

Genetic Testing and Diagnosis

All patients with suspected VHL disease—including first-degree relatives of known VHL patients and anyone presenting with single or multifocal retinal hemangioblastomas—should undergo genetic testing of the VHL gene as part of their initial evaluation. 1, 2

• Genetic testing is the gold standard for VHL diagnosis and should be performed early in life for at-risk children 2
• Clinical diagnosis can be established in individuals with a family history of VHL who have CNS/retinal hemangioblastoma, pheochromocytoma, or renal cell carcinoma 2
• Up to 20% of VHL cases arise from de novo mutations, so absence of family history does not rule out the diagnosis 2
• The presence of 1 or more retinal hemangioblastomas with a family history of VHL, or 2 or more retinal hemangioblastomas even in asymptomatic patients, should prompt immediate genetic evaluation 1

Ocular Surveillance Protocol

Begin dilated ophthalmoscopic screening within the first 12 months of life and continue throughout the patient's lifetime. 1, 2

Screening Frequency by Age:

• Birth to 30 years: Dilated ophthalmoscopy every 6-12 months 1, 2
• After 30 years: At least annual dilated ophthalmoscopy 1, 2
• During pregnancy: Screen before planned pregnancy and every 6-12 months during pregnancy 1
• Young children: If detailed office examination is not possible, consider examination under anesthesia 1

Imaging Adjuncts:

• Ultra-widefield photography may help monitor retinal hemangioblastomas in certain circumstances 1
• Ultra-widefield fluorescein angiography may help detect small retinal hemangioblastomas 1
• Critical caveat: These imaging methods serve only as adjuncts and cannot replace detailed dilated funduscopic examination 1

Treatment of Retinal Hemangioblastomas

Treat all extramacular or extrapapillary retinal hemangioblastomas immediately upon detection, even when small (≤500 μm diameter), rather than observing them. 1, 2

Rationale for Immediate Treatment:

• Laser photocoagulation achieves 100% successful destruction of retinal hemangioblastomas ≤1.5 mm diameter over an average of 1.3 sessions 1, 2
• In contrast, larger retinal hemangioblastomas have only 47-73% success rates and require an average of 3.5 sessions 1
• Spontaneous regression is uncommon, and most lesions grow at variable and unpredictable rates 1
• Eyes treated before symptoms emerge maintain good vision 1, 2
• This is especially critical for children or patients with poor compliance, where symptom reporting may be unreliable 1

Treatment Modalities:

For small extramacular/extrapapillary lesions (≤1.5 mm):

• Laser photocoagulation is first-line treatment with near-universal success 1, 2

For juxtapapillary or macular lesions:

• Consider belzutifan (oral HIF-2α inhibitor) as a safer alternative to avoid direct ablative damage 1, 2
• Belzutifan is FDA-approved for VHL-related renal cell carcinoma, pancreatic neuroendocrine tumors, and CNS hemangioblastomas 1, 2
• Preliminary findings suggest efficacy for retinal hemangioblastomas 1, 2
• This systemic treatment may allow earlier intervention without ablative therapies and could potentially suppress retinal hemangioblastoma formation 1, 2

For large tumors:

• Belzutifan provides a safer option when effective treatment options are currently lacking 1, 2

Multisystem Surveillance Beyond the Eye

Patients require comprehensive multiorgan surveillance starting in childhood, coordinated through a multidisciplinary team. 2, 3, 4

CNS Surveillance:

• Begin CNS imaging at age 8 years to detect hemangioblastomas early, allowing surgical excision with minimal damage to surrounding tissue 2
• MRI of CNS (including inner ear) every 2 years after age 15 3
• Annual neurological examination after age 15 3

Renal Surveillance:

• Begin abdominal imaging at age 8-10 years 2
• Annual abdominal imaging (alternating ultrasound and MRI) starting at age 16 to monitor for renal cysts and renal cell carcinoma 2, 3
• Renal cell carcinoma has become the first potential cause of mortality in VHL disease 5

Pheochromocytoma Screening:

• Begin screening at age 5 years with annual plasma or urine metanephrines 2
• Continue annual plasma-metanephrine, plasma-normetanephrine, and plasma-chromogranin A tests after age 15 3

Additional Surveillance:

• Annual hearing examinations starting at age 5-14 years to detect endolymphatic sac tumors 3

Multidisciplinary Care Coordination

Patients should be managed by ophthalmologists with specific VHL experience, ideally within a multidisciplinary center capable of providing multiorgan surveillance and genetic testing. 1, 2

Required Specialists:

• Ophthalmology (with VHL experience) 1
• Neurosurgery 2
• Urology/Nephrology 2
• Endocrinology 2
• Medical genetics 2
• Oncology 2

Coordination Strategy:

• One physician should take responsibility for coordinating examinations and communicating with the patient 3
• Care coordination positively affects screening compliance, time to intervention, and treatment adherence 1
• For rare multisystem diseases like VHL, the benefits of care coordination are even greater 1

Common Pitfalls to Avoid

• Do not observe small extramacular/extrapapillary retinal hemangioblastomas: The window of opportunity for successful treatment closes rapidly as lesions grow 1
• Do not delay genetic testing: Early identification enables targeted surveillance before clinical manifestations develop 2
• Do not rely solely on imaging: Ultra-widefield photography and angiography cannot replace dilated ophthalmoscopy 1
• Do not assume absence of family history rules out VHL: 20% of cases are de novo mutations 2
• Do not use only local treatments for retinal hemangioblastomas in isolation: Systemic surveillance for other VHL manifestations is essential 2, 3

Surgical Intervention for Non-Ocular Manifestations

Surgical excision remains the mainstay of treatment for most VHL-related tumors when detected early. 2

• CNS hemangioblastomas should be surgically excised when detected early to minimize damage to surrounding tissue 2
• Early detection through surveillance allows more conservative surgical approaches 4

Lifelong Management

Continue surveillance throughout life, as tumor development can occur at any age due to the two-hit mechanism of VHL tumor suppressor gene inactivation. 2, 6

• Early recognition and intervention limit morbidity and mortality 2
• Most lesions can be treated successfully when diagnosed in time 6