What is Von Hippel-Lindau (VHL) disease?

Von Hippel-Lindau Disease: Definition and Clinical Features

Von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary cancer syndrome caused by pathogenic variants in the VHL tumor suppressor gene on chromosome 3p25, characterized by the development of highly vascular benign and malignant tumors affecting multiple organ systems, with lifetime penetrance approaching 100% by age 75. 1

Genetic Basis and Inheritance

• VHL results from pathogenic variants in the VHL gene, inherited in an autosomal dominant pattern with near-complete penetrance 1, 2
• Approximately 80% of individuals have an affected parent, while 20% arise from de novo mutations 3, 4
• The incidence is estimated at 1 in 36,000 live births 1, 4, 2
• Genetic testing is the gold standard for diagnosis, detecting disease-causing mutations in 95-100% of clinically diagnosed cases 5

Cardinal Tumor Manifestations

VHL is characterized by specific tumor types that develop across multiple organ systems:

Central Nervous System

• CNS hemangioblastomas (cerebellar, spinal cord, brain stem) occur in 60-80% of patients, with youngest reported diagnosis at age 9 years 1
• These are histologically benign but cause significant morbidity through mass effect 1

Ocular

• Retinal hemangioblastomas (retinal angiomas) develop in 38% of patients, with cumulative probability reaching nearly 80% in those older than 80 years 1
• Vision loss occurs in approximately 20% of patients with ocular VHL disease, with 6% having visual acuity <20/200 in both eyes 1

Renal

• Clear cell renal cell carcinoma develops in up to 70% of patients and represents a leading cause of mortality 2
• Multiple renal cysts are common 1

Endocrine

• Pheochromocytomas occur in 7-20% of families (Type 2 VHL), associated with specific missense mutations 1, 2

Other Manifestations

• Pancreatic neuroendocrine tumors and multiple pancreatic cysts 1
• Endolymphatic sac tumors (can cause tinnitus or deafness) 1, 2
• Epididymal and broad ligament cystadenomas 1

Clinical Diagnosis Criteria

A clinical diagnosis can be established in two scenarios 1:

1. With family history: Presence of CNS or retinal hemangioblastoma, pheochromocytoma, or renal cell carcinoma in an individual with a family history of VHL
2. Without family history (simplex case): Two or more hemangioblastomas OR one hemangioblastoma plus one visceral tumor OR two visceral tumors

Important caveat: Renal and epididymal cysts alone are insufficient for diagnosis, as they occur in the general population and can lead to diagnostic errors 6

Clinical Subtypes

VHL is subdivided into five subtypes based on tumor spectrum 1:

• Type 1: Low risk for pheochromocytoma; high risk for renal cell carcinoma
• Type 2: Includes pheochromocytoma, subdivided into:
  • Type 2A: Pheochromocytoma with low risk for renal cell carcinoma
  • Type 2B: Pheochromocytoma with high risk for renal cell carcinoma
  • Type 2C: Pheochromocytoma only

Most Type 2 families have missense mutations, while Type 1 families typically have deletions or premature termination mutations 2

Morbidity and Mortality Impact

• Historically, substantial mortality was attributable to renal cell carcinoma, pancreatic neuroendocrine tumors, and CNS hemangioblastomas 1
• Life expectancy was less than 50 years before comprehensive surveillance protocols were developed 2
• Although many VHL-related tumors are histologically benign, morbidity from mass effect can be profound (vision loss, neurological deficits) 1
• Surgical complications including hemorrhage from large CNS hemangioblastomas contribute to morbidity 1
• These risks have been substantially mitigated through institution of comprehensive surveillance paradigms leading to early tumor recognition and multidisciplinary management 1, 3

Age of Onset and Surveillance Implications

• While many lesions present in the third and fourth decades of life, the age range of initial manifestations is wide 1
• Children are particularly vulnerable, as hemangioblastomas and pheochromocytomas can remain clinically occult until symptoms become severe 1
• Early recognition and testing of at-risk individuals is key to preventing morbidity and mortality 1, 3