Is Von Hippel-Lindau (VHL) disease a genetic disorder?

Is Von Hippel-Lindau Disease Genetic?

Yes, Von Hippel-Lindau (VHL) disease is definitively a genetic disorder caused by mutations in the VHL tumor suppressor gene located on chromosome 3p25-26, inherited in an autosomal dominant pattern. 1

Genetic Basis

VHL disease is caused by germline mutations in the VHL tumor suppressor gene, which was identified in 1993 by Latif et al. 1 The inheritance pattern is autosomal dominant, meaning:

• Approximately 80% of affected individuals inherit the mutation from an affected parent 2, 3
• About 20% of cases arise from de novo (new) mutations, so absence of family history does not rule out the diagnosis 4, 2
• Lifetime penetrance approaches 100% by age 75, meaning nearly all individuals with the mutation will develop manifestations if they live long enough 3

The VHL gene product (VHL protein) plays a critical role in cellular oxygen sensing. When normal VHL protein is absent, hypoxia-inducible factors inappropriately induce expression of genes that coordinate cellular response to hypoxia, leading to tumor formation. 1

Clinical Implications of the Genetic Nature

Genetic testing is the gold standard for VHL diagnosis and should be performed in all first-degree relatives of individuals with pathogenic VHL variants. 4 This is critical because:

• Genetic testing became available in the 1990s, allowing identification of affected individuals before clinical disease develops 1
• Early identification enables institution of surveillance measures at an early age for those harboring VHL gene mutations 1
• Those found not to have inherited the gene do not need lifelong monitoring 5

Mutation Types and Clinical Correlation

The VHL gene contains three exons, and different mutation types predict different tumor spectrums:

• About 20% of patients have large germline mutations detectable by Southern blot analysis 5
• 27% have missense mutations, 27% have nonsense or frameshift mutations 5
• Families are characterized as Type 1 (absence of pheochromocytomas) or Type 2 (presence of pheochromocytomas in 7-20% of families) 5
• Most Type 2 families have missense mutations, whereas most Type 1 families have deletions or premature termination mutations 5

Who Should Undergo Genetic Testing

The American College of Medical Genetics recommends genetic testing for any child or adult diagnosed with:

• Retinal angioma/hemangioblastoma 4
• CNS hemangioblastoma 4
• Clear cell renal cell carcinoma 4
• Pheochromocytoma or paraganglioma 4
• Endolymphatic sac tumor 4
• Epididymal/adnexal papillary cystadenoma 4
• Multiple pancreatic cysts or neuroendocrine tumors 4
• Multiple renal cysts 4

Any young adult with even a single manifestation should undergo VHL genetic testing, as 20% arise without family history. 2

Incidence

The incidence is estimated at 1 in 36,000 live births, making it a rare genetic disorder. 3, 6