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

Management Plan for Von Hippel-Lindau (VHL) Disease

The management of Von Hippel-Lindau disease requires comprehensive surveillance starting in early childhood, with genetic testing for all at-risk individuals and lifelong monitoring for multiple organ manifestations to prevent morbidity and mortality through early detection and intervention.

Diagnosis and Genetic Testing

• Genetic testing is the gold standard for VHL diagnosis and should be performed in all first-degree relatives of individuals with pathogenic VHL variants 1
• Clinical diagnosis can be established in two scenarios:
  • Individual with family history of VHL who has CNS/retinal hemangioblastoma, pheochromocytoma, or renal cell carcinoma 1
  • Individual without family history (simplex case) who has 2 hemangioblastomas, 2 visceral tumors, or one of each 1
• Genetic testing is indicated for any child diagnosed with:
  • Retinal angioma/hemangioblastoma
  • CNS hemangioblastoma
  • Clear cell renal cell carcinoma
  • Pheochromocytoma or paraganglioma
  • Endolymphatic sac tumor
  • Epididymal/adnexal papillary cystadenoma
  • Multiple pancreatic cysts or neuroendocrine tumors
  • Multiple renal cysts 1

Surveillance Recommendations

Ocular Surveillance

• Begin ocular screening within 12 months after birth and continue throughout life 1
• Perform examinations every 6-12 months until age 30, then at least yearly thereafter 1
• Conduct examinations before planned pregnancy and every 6-12 months during pregnancy 1
• Treat extramacular or extrapapillary retinal hemangioblastomas promptly, even when small 1
• Refer to ophthalmologists with subspecialty training and experience with VHL 1

CNS Surveillance

• Begin CNS imaging at age 8 years 1
• Annual MRI of brain and spine is recommended rather than biennial, as annual imaging reduces intercurrent manifestation risk from 7.2% to 2.7% 2
• Early detection of CNS hemangioblastomas allows surgical excision with minimal damage to surrounding tissue 1

Renal Surveillance

• Begin abdominal imaging at age 8-10 years 1
• Annual abdominal imaging (alternating ultrasound and MRI) starting at age 16 1
• Monitor for renal cysts and renal cell carcinoma, which affect 25-75% of patients 1

Endocrine Surveillance

• Begin screening for pheochromocytoma at age 5 years with annual plasma or urine metanephrines 1, 3
• Annual blood pressure monitoring starting at age 2 years 3
• Monitor for pancreatic neuroendocrine tumors and cysts starting at age 5 1

Other Surveillance

• Audiology evaluation every 2-3 years starting at age 5-15 years for endolymphatic sac tumors 1
• For males, monitor for epididymal cystadenomas (25-60% risk) 1
• For females, monitor for broad ligament cystadenomas (10% risk) 1

Treatment Approaches

• Surgical intervention remains the mainstay of treatment for most VHL-related tumors 4
• Retinal hemangioblastomas should be treated promptly to prevent vision loss 1
• CNS hemangioblastomas should be surgically excised when detected early 1
• Renal tumors typically require surgical management when they reach appropriate size 1
• Belzutifan (HIF-2α inhibitor) has been approved by the FDA for adult patients with VHL-associated renal cell carcinoma, CNS hemangioblastomas, or pancreatic neuroendocrine tumors not requiring immediate surgery 4

Multidisciplinary Approach

• Management should involve specialists in:
  • Ophthalmology
  • Neurosurgery
  • Urology/Nephrology
  • Endocrinology
  • Medical genetics
  • Oncology 4
• Patients should be managed at centers capable of providing multiorgan surveillance and access to genetic testing 1

Prognosis and Follow-up

• Life expectancy for VHL patients has improved over time, with estimated mean life expectancy for those born in 2000 of 67 years for men and 60 years for women 5
• Lifelong surveillance is mandatory given ongoing risks for tumor development with increasing age 1
• Early recognition and intervention have been shown to limit morbidity and mortality in VHL 1, 2
• Pregnancy may be associated with a lower frequency of new manifestations 5

Common Pitfalls and Caveats

• Up to 20% of VHL cases arise from de novo mutations, so absence of family history does not rule out the diagnosis 1
• Patients may develop multiple tumors simultaneously in different organs, requiring comprehensive rather than focused surveillance 1
• Children are particularly vulnerable to visual loss from undetected retinal hemangiomas 1
• Pheochromocytomas can remain clinically occult until symptoms become severe 1
• Even though most VHL-related tumors are histologically benign, they can cause significant morbidity due to mass effect 1