Von Hippel-Lindau disease
Von Hippel-Lindau disease is an autosomal dominant tumor-suppressor syndrome in which loss of functional pVHL causes accumulation of hypoxia-inducible factor and a lifelong predisposition to hemangioblastomas, clear-cell renal cell carcinoma, pheochromocytoma, and pancreatic cysts and neuroendocrine tumors. Diagnosis is clinical or by VHL germline testing, and management is a lifelong, age-staged surveillance program combined with nephron-sparing or HIF-2 alpha-directed treatment of lesions as they arise.
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What this article covers
- Overview
Definition: von Hippel-Lindau (VHL) disease is an autosomal dominant tumor-suppressor syndrome caused by germline loss-of-function mutation or deletion of the VHL gene, producing a lifelong…
- Epidemiology
Rare autosomal dominant disorder: near-complete penetrance by mid-adulthood, so nearly all gene carriers develop at least one characteristic lesion.
- Risk factors
Germline VHL mutation or deletion (chromosome 3p): the only risk factor; a two-hit mechanism in which the inherited mutation is followed by somatic loss of the remaining allele in a susceptible cell.
- Pathophysiology
Tumor-suppressor loss: a classic Knudson two-hit mechanism; the germline mutation is present in every cell, and somatic inactivation of the remaining allele in a target tissue initiates clonal tumor formation.
- Clinical features
CNS hemangioblastoma: the most common and often earliest lesion; cerebellar tumors cause headache, ataxia, nausea, and vomiting from mass effect or hydrocephalus, spinal cord tumors cause radicular…
- Differential diagnosis
Multiple endocrine neoplasia type 2: bilateral pheochromocytoma with medullary thyroid carcinoma and hyperparathyroidism, no hemangioblastoma or clear-cell renal cell carcinoma (multiple endocrine neoplasia (MEN)).
- Diagnosis
Establish the diagnosis by clinical criteria or germline testing: a clinical diagnosis requires one characteristic VHL-associated tumor (CNS or retinal hemangioblastoma, clear-cell renal cell…
- Management
Stage disease burden first: obtain baseline MRI brain and total spine, dilated retinal exam, abdominal MRI, and metanephrines before deciding which lesions need treatment.
- Complications
Metastatic clear-cell renal cell carcinoma: the leading cause of death; risk rises with tumor size, which is why size-triggered nephron-sparing intervention is central to management.
- Prognosis
Renal cell carcinoma drives overall survival: metastatic clear-cell renal cell carcinoma is the leading cause of death, so lifelong renal surveillance and size-triggered treatment are the single most survival-relevant components of care.
- Prevention
Lifelong, age-staged surveillance is the core preventive strategy: annual biochemical monitoring for pheochromocytoma (metanephrines) starting at age 5 to 10 years, and biennial contrast-enhanced MRI…
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