What is the management plan for Von Hippel-Lindau (VHL) disease?

Management of Von Hippel-Lindau Disease

Patients with Von Hippel-Lindau disease require comprehensive, lifelong surveillance by a multidisciplinary team at a specialized center to detect and treat tumors early, with specific screening protocols starting from birth and continuing throughout life. 1

Diagnostic Approach

• Genetic testing is the gold standard for diagnosis and should be performed in:
  • First-degree relatives of individuals with pathogenic VHL variants
  • Any patient with single or multifocal retinal hemangioblastomas
  • Any child diagnosed with VHL-associated manifestations 1

Surveillance Recommendations by Age Group

From Birth

• Annual ophthalmologic examination including retinal evaluation 2
• Annual comprehensive physical examination with blood pressure assessment 2

From Age 2 Years

• Blood pressure measurement at all medical visits
• Annual plasma-free metanephrines or 24-hour urine fractionated metanephrines 2

From Age 5 Years

• Biennial audiogram for endolymphatic sac tumor detection 2

From Age 8 Years

• Biennial MRI brain with and without contrast
• Biennial MRI spine with contrast 2

From Age 10 Years

• Annual abdominal MRI for renal cell carcinoma and pancreatic neuroendocrine tumor screening 2, 1

Pregnancy Considerations

• Ocular screening should be performed before planned pregnancy and every 6-12 months during pregnancy 2

Treatment Recommendations

Retinal Hemangioblastomas

• Extramacular or extrapapillary retinal hemangioblastomas should be treated promptly upon detection, even when small (≤500 μm) 2, 1
• Laser photocoagulation is highly effective for small retinal hemangioblastomas (≤1.5 mm) 1

CNS Hemangioblastomas

• Early surgical excision is recommended when detected and before significant neurological damage occurs 1

Renal Cell Carcinoma

• Nephron-sparing surgery is preferred when tumors reach 3 cm 1

Pharmacological Treatment

• Belzutifan (HIF2-α inhibitor) is FDA-approved for treatment of VHL-associated renal cell carcinoma, pancreatic neuroendocrine tumors, and CNS hemangioblastomas 1

Coordination of Care

• A single physician should coordinate the surveillance program and referrals to specialists 1
• Patients should be managed by providers with experience in VHL disease, ideally within multidisciplinary centers 2, 1

Common Pitfalls and Challenges

1. Poor adherence to surveillance protocols: Only 38.9% of mutation carriers continue participating in tumor surveillance programs after five years 3. Being symptomatic at testing time is the strongest predictor of adherence (OR = 5; 95% CI 1.2-20.3) 3.

2. Underdiagnosis: VHL is often underdiagnosed, with prevalence estimated at 1 in 46,900 individuals 4. Increased awareness is needed to identify affected families.

3. Variable penetrance: VHL penetrance at age 60 is approximately 87%, lower than previously estimated (100%), which affects risk assessment in genetic counseling 4.

4. Pregnancy management: Special attention is needed during pregnancy with more frequent ocular examinations 2, though pregnancy is associated with lower frequency of new manifestations 4.

5. Juxtapapillary tumors: These require special consideration due to their proximity to the optic disc and potential vision impact 2, 1.

By implementing these comprehensive surveillance and treatment protocols, the life expectancy of VHL mutation carriers has improved significantly, with those born in 2000 estimated to have a life expectancy of 67 years for men and 60 years for women 4.