Von Hippel-Lindau Disease

Autosomal dominant multiorgan familial cancer syndrome characterized by cerebeller and spinal hemangioblastomas, retinal angiomas, neuroendocrine neoplasms, pheochromocytomas and renal cysts and tumors.

Estimated prevalence 1 in 35-40,000.

The condition is associated with benign and malignant neoplasms, including clear-cell renal carcinoma, pancreatic neuro endocrine tumors, and hemangiomablastomas in the CNS and retina.

VHL gene mutations in 40-60% of patients develop renal cancers.

VHL gene encodes for the VHL proteins which regulates the activity of HIF-alpha, a transcription factor involved in the cellular response to hypoxia.

Renal cell cancer is developed in approximately 70% of patients with VHL disease during their lifetime.

Renal cancers arise from biallelic VHL a gene inactivation.

One of the alleles is inactivated to a deletion as observed in more than 90% of noninherited, sporadic) clear cell renal cell carcinoma.

The remaining VHL a lead held is inactivated flu gene mutation involving approximately 50% of clear cell renal cell cancers, or through gene silencing by methylation in 5 to 10% of cases.

For carcinogenesis to take place alterations and other gene loci other then VHL are probably required.

Renal cancers are clear cell type with a tendency to be bilateral and occur at a young age.

Suppressor gene localized to chromosome region 3p26 →3p25.

VHL gene is any tumor suppressor gene and codes for the VHL protein which is one component of the E3 ubiquitin-ligase complex along with elongin B, elongin C and cullin 2.

A result of a germline mutation of VHL tumor suppressor gene on the short arm of chromosome 3.

Tumor suppressor gene that can be inactivated by various mutations, hypermethylation, alterations in gene modifiers, and by loss of heterozygosity.

While there is a variable expression, VHL has more than a 90% penetrance by 65 years of age.

VHL protein critical to cellular pathway that couples changes in oxygen availability to gene expression via the hypoxia inducible factor (HIF).

Losses of genetic material from the short arm of chromosome 3 (3p) and mutations in the VHL gene seen in virtually all cases.

The VHL gene produces a normal VHL protein which is required to target and degrade HIF in normoxemic states.

Up-regulation of HIF in cells deficient of VHL protein increases angiogenesis and tumorigenesis.

Lack of normal VHL increases HIF-1α levels causing overexpression of endothelial growth factors and a hypervascular state that is seen in most VHL related tumors.

Hypoxia inducible factor is a transcription factor that regulates a program of gene expression that facilitates adaptation to hypoxia.

Most cases of clear cell renal cell cancer the von Hippel-Landau suppressor gene is silenced by mutation or methylation.

Mutations in VHL lead to the accumulation of HIF-alpha and the engagement of hypoxia sensitive genes with tumorigenic effects occur.

VHL disease is associated with the development of tumors in multiple organs including multifocal CNS, hemangiomablastomas, renal cell carcinomas, pheochromocytomas, and pancreatic neuroendocrine tumors.

Most common type of tumor is a hemangioblastomas of the brain and spinal cord, occurring in 40-80% of all patients.

Central nervous system lesions include hemangioblastomas and endolymphatic sac tumors.

Associated with an elevated risk of development of tumors in several organs including the kidneys.

Hemangioblastomas and endolymphatic sac tumors are benign but cause morbidity and mortality in patients with this syndrome.

Prior to present treatments median survival was 50 years of age, with the primary cause of death CNS complications from hemangioblastomas or renal cancers.

Diagnosis based on clinical criteria or genetic testing.

Patients with a family history of VHL with hemangioblastomas, renal cell carcinomas, pheochromocytoma, or endolymphatic sac tumors meet the criteria for diagnosis.

Approximately 20% of individuals do not have a family history of the disease but fulfill diagnostic criteria if they have 2 or more CNS hemangioblastomas and a VHL associated visceral tumor.

Partial nephrectomy is recommended to decrease the risk of metastatic disease in the case of renal tumors that grow beyond 3 cm diameter and in case of renal tumors that grow rapidly.

A nephron sparing approach is used in resection of renal tumors when feasible.

Patients typically undergo several surgical procedures during their lifetime for resection of renal tumors and other VHL disease associated neoplasms.


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