What are the symptoms of Von Hippel-Lindau (VHL) disease?

Symptoms of Von Hippel-Lindau (VHL) Disease

Von Hippel-Lindau disease is often asymptomatic in early stages, but manifests through symptoms related to tumor development in multiple organ systems, with ocular and neurological symptoms being among the earliest presentations. 1, 2

Ocular Manifestations

Retinal hemangioblastomas are frequently the first manifestation and can appear as early as the first year of life. 2

Early-Stage Ocular Symptoms

• Most retinal hemangioblastomas are asymptomatic initially, which is why surveillance screening is critical rather than waiting for symptoms 1
• Vision changes may not occur until complications develop 1

Advanced Ocular Symptoms (When Complications Arise)

• Vision loss occurs in approximately 20% of patients when retinal hemangioblastomas progress untreated 2, 3
• Symptoms develop from tumor-associated exudation causing fibrosis, hemorrhage, or retinal detachment 1
• Epiretinal membrane formation 1
• Retinal vascular proliferation 1

Central Nervous System Symptoms

CNS hemangioblastomas occur in 60-80% of patients and cause symptoms through mass effect. 2, 4

• Headaches from increased intracranial pressure 2
• Ataxia and balance problems (cerebellar lesions) 2
• Neurological deficits depending on tumor location (brain stem or spinal cord) 2, 5
• The youngest documented CNS hemangioblastoma was diagnosed at age 9 years 2, 4

Renal Symptoms

Renal manifestations develop in up to 70% of patients and represent a leading cause of mortality. 2, 4

• Most renal cysts and early renal cell carcinomas are asymptomatic 5, 6
• Hematuria (blood in urine) in advanced cases 5
• Flank pain when tumors become large 5
• Abdominal mass (palpable in advanced disease) 5

Endocrine Symptoms (Pheochromocytoma)

Pheochromocytomas occur in 7-20% of families, associated with specific missense mutations. 2

• Episodic hypertension 5, 6
• Headaches 5
• Palpitations 5
• Excessive sweating 5
• Anxiety or panic attacks 5

Inner Ear Symptoms

Endolymphatic sac tumors can cause auditory symptoms. 5, 6

• Tinnitus (ringing in ears) 5
• Progressive hearing loss or deafness 5, 6
• Vertigo 6

Pancreatic Manifestations

Pancreatic neuroendocrine tumors and cysts develop but are often asymptomatic. 2, 5

• Most pancreatic lesions are discovered on surveillance imaging rather than through symptoms 5, 6
• Abdominal pain (when tumors become large) 6

Reproductive System Symptoms

• Epididymal cystadenomas in males are typically asymptomatic 2, 5
• Broad ligament cystadenomas in females are usually asymptomatic 2, 5

Critical Clinical Pitfalls

The asymptomatic nature of early VHL manifestations is the most dangerous pitfall—waiting for symptoms before screening leads to preventable morbidity and mortality. 2, 4

• Do not rely on symptoms for diagnosis; retinal hemangioblastomas can develop in the first year of life before any symptoms appear 2
• A single retinal or CNS hemangioblastoma at any age warrants immediate genetic testing, even without family history, as 20% of cases arise from de novo mutations 2, 4
• Historical median life expectancy was only 49 years, but comprehensive surveillance has improved this to 60-67 years for those born in 2000, demonstrating the critical importance of early detection before symptoms develop 2, 3

Surveillance must begin within 12 months after birth and continue throughout life, regardless of symptom presence. 1, 2, 4