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Von Hippel-Lindau Syndrome
MRI image of hemangioblastoma in von Hippel Lindau

Von Hippel-Lindau Syndrome

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Overview
  • Inherited disorder that manifests with numerous tumors and cysts.
    • The acronym HARP is a helpful mnemonic: Hemangioblastomas, Angiomatosis, Renal cell carcinomas, Pheochromocytomas.
  • Uncommon disorder: 1/36,000.
  • Note that skin manifestations do not occur but the retinal hemangioblastomas make this a neurocutaneous disorder.
Genetics
  • Autosomal dominant disorder
  • High penetrance (90% by age 65) but variable phenotypic expression (various VHL genotypes result in various phenotypic manifestations.
  • Germline mutation of chromosome 3p (3p25); the VHL gene.
    • The mutation is in a tumor suppressor gene for the VHL protein (E3 ubiquitin protein ligase), which is responsible for inhibition of endothelial-derived growth factor: thus one of the characteristic tumors that results, hemangioblastoma, is a vascularized tumor.
    • Mnemonic: VHL (Von Hippel-Lindau) has 3 Letters, which helps us remember the gene mutation is on Chromosome 3.
Pathology
  • The VHL protein promotes the destruction of hypoxia-inducible factor 1 alpha (HIF-1-alpha).
  • In the setting of a loss of VHL protein, there is increased levels of vascular endothelial growth factor (VEGF).
  • Additionally, loss of function promotes renal cyst formation.
  • Disease is triggered via two-hit activation: an acquired VHL mutation combines with an inherited VHL abnormality.
Tumors
  • Hemangioblastomas
    • Most common to least common sites: Cerebellum, Retina, Spinal cord
    • Consider that cerebellar hemangioblastomas can cause obstructive hydrocephalus.
    • Consider that hemangioblastoma is one of the few causes of intramedullary spinal cord tumor. Syringomyelia is a potential pathologic effect of spinal cord tumor.
    • These tumors are rarely, if ever, supratentorial.
    • As a rule, hemangioblastoma is pathognomnic for VHL in children, but in adults, hemangioblastomas can occur sporadically.
    • Retinal capillary hemangioblastoma (aka retinal angioma) is typically the first clinical manifestation of VHL (average age of diagnosis: 25 y.o.). They are most often peripherally located with a subtle red hue and become nodular with dilated and engorged vasculature without hemorrhage. Retinal edema, exudates, and macular invasion are common. Pseudopapilledema from juxtapapillary lesions is far less common.
  • Cysts
    • From most common to least: Renal (often bilateral and multiple), Pancreatic, Liver
    • Consider that renal cysts are also a feature of tuberous sclerosis
  • Pheochromocytoma
  • Renal cell tumors (often bilateral and multiple)
    • Note that metastatic renal cell carcinoma is a key cause of mortality in VHL patients (~ 50%)
Diagnosis
  • If family history of VHL is POSITIVE, one key feature is required.
  • If family history of VHL is NEGATIVE, two key features are required.
References
Image Reference
  • MRI image of hemangioblastoma in von Hippel Lindau
    • Image from Public Library of Science journal

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