At what age does Von Hippel-Lindau (VHL) disease typically occur?

Age of Onset in Von Hippel-Lindau Disease

Von Hippel-Lindau disease can manifest at any age from infancy through late adulthood, with peak incidence during adolescence and early adulthood (mean age 17-29 years for diagnosis), though manifestations have been documented as early as 2 years of age. 1

Age-Specific Manifestation Patterns

Early Childhood and Infancy

• Retinal hemangioblastomas can develop as early as the first year of life, necessitating screening within 12 months after birth 1
• The youngest documented case of retinal hemangioblastoma in natural history studies was a 2-year-old child 1
• CNS hemangioblastomas have been reported as early as age 9 years 2

Adolescence and Young Adulthood (Peak Period)

• The highest incidence of new manifestations occurs during adolescence and early adulthood, with retinal tumors peaking during teenage years and cerebellar tumors most commonly developing in patients' thirties 3
• Mean age at diagnosis of retinal hemangioblastomas ranges from 17 to 29 years across multiple cohorts 1
• Natural history studies demonstrate that 95% of patients are identified by 37 years of age 1

Middle to Late Adulthood

• The cumulative probability of developing retinal hemangioblastomas reaches nearly 80% in those older than 80 years 2
• Lifetime penetrance approaches 100% by age 75, meaning virtually all mutation carriers will develop manifestations if they live long enough 2, 4
• Sporadic presentations (without family history) become more likely with increasing age at presentation 1

Critical Surveillance Implications

Screening Timeline

The 2024 Ophthalmology consensus guidelines provide the most definitive age-based recommendations:

• Ocular screening must begin within 12 months after birth and continue throughout life 1, 5
• Examinations should occur every 6-12 months until age 30, then at least yearly thereafter 1
• CNS imaging should begin at age 8 years 5
• Abdominal imaging should start at age 8-10 years, with annual imaging (alternating ultrasound and MRI) from age 16 5
• Screening for pheochromocytoma should begin at age 5 years with annual plasma or urine metanephrines 5

Rationale for Early Screening

The recommendation for such early surveillance is based on several critical factors:

• Early detection allows intervention before vision-threatening complications develop, as retinal hemangioblastomas can cause permanent vision loss if untreated 5, 2
• Manifestations can occur unpredictably at very young ages, even though they are less common in early childhood 1
• The benefits of early identification in a small number of infants outweigh the risks and discomforts of examination 1

Common Pitfalls to Avoid

Do not delay genetic testing or surveillance based on young age alone, as cases have been documented in very young children 1. The absence of family history does not exclude the diagnosis, since up to 20% of cases arise from de novo mutations 2, 4, 6.

Do not assume older age at presentation indicates sporadic disease, as VHL manifestations can first appear in middle or late adulthood despite genetic predisposition being present from birth 1. Even a solitary retinal hemangioblastoma at any age warrants genetic testing and comprehensive evaluation 1.

Prognostic Context

Historical data showed median life expectancy of only 49 years 1, 3, 7, but recent improvements in surveillance and treatment have extended mean life expectancy to 60-67 years for individuals born in 2000 1, 4, 3. This improvement underscores the critical importance of age-appropriate surveillance beginning in infancy to detect and treat manifestations early, thereby reducing morbidity and mortality 5, 2, 4.