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

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

Patients with Von Hippel-Lindau disease require lifelong multidisciplinary surveillance and prompt treatment of manifestations through a coordinated care approach at specialized centers to reduce morbidity and mortality. 1

Diagnosis and Initial Evaluation

• Clinical diagnosis is established by:

  • Individual with family history of VHL and presence of a CNS/retinal hemangioblastoma, pheochromocytoma, or renal cell carcinoma
  • OR individual without family history who has either two hemangioblastomas, two visceral tumors, or one hemangioblastoma and one visceral tumor 1

• Genetic testing is essential for:

  • First-degree relatives of individuals with pathogenic VHL variants
  • Any child diagnosed with VHL-associated manifestations 1

Comprehensive Surveillance Protocol

Ocular Surveillance

• Begin within 12 months after birth and continue throughout life 2
• Frequency:
  • Every 6-12 months until 30 years of age
  • At least yearly thereafter
  • Before planned pregnancy and every 6-12 months during pregnancy 2, 1
• Method: Dilated ophthalmoscopy (ultra-widefield photography and fluorescein angiography may serve as adjuncts but cannot replace detailed examination) 2

Central Nervous System Surveillance

• Biennial MRI of brain and spine with contrast 1
• Consider annual CNS examinations to reduce intercurrent manifestation risk from 7.2% to 2.7% 3

Renal and Abdominal Surveillance

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

Other Essential Surveillance

• Annual comprehensive physical examination with blood pressure assessment 1
• Annual plasma-free metanephrines or 24-hour urine fractionated metanephrines 1
• Biennial audiogram for endolymphatic sac tumor detection 1

Treatment Approach by Manifestation

Retinal Hemangioblastomas

• Extramacular or extrapapillary retinal hemangioblastomas should be treated promptly upon detection, even when small 2, 1
• Treatment options:
  • Laser photocoagulation (highly effective for small tumors ≤1.5 mm, with 100% success rate) 1
  • Belzutifan (HIF2-α inhibitor) may provide options for juxtapapillary and macular tumors 1

CNS Hemangioblastomas

• Early surgical excision is recommended when detected and before significant neurological damage occurs 1
• Belzutifan is FDA-approved for VHL-associated CNS hemangioblastomas not requiring immediate surgery 1, 4

Renal Cell Carcinoma

• Nephron-sparing surgery is preferred when tumors reach 3 cm 1
• Belzutifan is FDA-approved for VHL-associated renal cell carcinoma not requiring immediate surgery 1, 4

Pancreatic Neuroendocrine Tumors

• Belzutifan is FDA-approved for VHL-associated pancreatic neuroendocrine tumors not requiring immediate surgery 1, 4

Pheochromocytomas

• Surgical excision with appropriate pre-operative alpha-blockade 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

Special Considerations

Pregnancy

• More frequent ocular examinations during pregnancy 2, 1
• Pregnancy is associated with lower frequency of new manifestations 1

Prognosis

• Early detection through surveillance allows for more conservative therapy and may enhance length and quality of life 5
• Life expectancy has improved in recent decades due to better surveillance and treatment, but remains lower than the general population 2, 6

Common Pitfalls and Caveats

• Failure to initiate surveillance early in childhood can lead to missed opportunities for early intervention
• Inadequate frequency of surveillance may result in intercurrent manifestations with potential for serious complications
• Lack of coordination between specialists can lead to fragmented care
• Underestimating the importance of lifelong surveillance even in asymptomatic periods

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