Von Hippel-Lindau Syndrome

Overview

The acronym HARP is a helpful mnemonic: Hemangioblastomas, Angiomatosis, Renal cell carcinomas, Pheochromocytomas.

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

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.

From most common to least: Renal (often bilateral and multiple), Pancreatic, Liver
Consider that renal cysts are also a feature of tuberous sclerosis

Note that metastatic renal cell carcinoma is a key cause of mortality in VHL patients (~ 50%)

Diagnosis

References

Image Reference