Wednesday, July 4, 2012

Von Hippel-Lindau (VHL) Disease

Introduction


Von Hippel-Lindau (VHL) disease is characterized by tumors or growths in multiple body systems. Typically, these growths or lesions begin as blood vessel hypertrophy in the central nervous system (CNS) and eyes. These VHL lesions can cause symptoms such as headaches, nausea or balance issues. The VHL disease can progress into other body systems such as the renal system where cysts form as a potential precursor to renal cancer. VHL also affects the body's adrenal glands and pancreas, causing cysts to form within the gland that prevent proper functioning. Approximately one in 36,000 individuals is affected by VHL, making it a relatively rare disease.

Symptoms and Diagnosis


Diagnosis of VHL often occurs only after the patient begins to exhibit symptoms, which can be latent and present until well into adulthood. Symptoms include dizziness, ataxia, and tinnitus, hearing loss, vision disturbances and hypertension. Because these symptoms can also be attributed to other causes, the patient's course of treatment can be compromised. Treatment and excision of the VHL tumors should begin as expediently as possible. Diagnosis can be definitively made upon the revelation of one's genotype, for those with VHL often have a genetic mutation.

VHL and Genetics


VHL disease follows an autosomal dominant inheritance pattern where the VHL genetic mutation must be present on only one set of chromosomes from either parent. The VHL gene resides on chromosome 3's short arm. In individuals who do not have a VHL mutation, the VHL gene codes for a specific messenger RNA (mRNA) sequence that creates Von Hippel-Lindau proteins (pVHL) that the cell then uses for a variety of cellular functions, including tumor suppression. A mutation in the VHL gene changes the individual's genetic blueprint to mutate mRNA so that pVHL is suppressed or defective. The manner by which the suppression of pVHL affects the body systems allows the disease to be made manifest.

Pathophysiology of VHL Disease


While it might seem that the suppression of pVHL would not seriously affect the mechanism of action within the cell, pVHL is a potent protein that regulates a cell's activity in numerous ways. First, the suppression of pVHL cells' cytoplasm causes marked changes in the cells' recycling program. Essentially, pVHL pairs with other proteins and begins to ubiquitinate other materials, which marks them to be deconstructed. The marker indicates which materials are no longer crucial to the cell's actions, thereby preventing the cell from engaging in unrestricted growth.

(Image from: HIF Biology)


Defective pVHL allows the cell to continue its growth without restraint


A major cytoplasmic constituent that is targeted for destruction includes a factor that should degrade in the presence of oxygen. These factors, hypoxia-inducible factors 1 (HIF1) and hypoxia-inducible factors 2 (HIF2), play an enormous role in how the cell chooses to differentiate its growth. In low-oxygen environments, HIF encourages the cell to create more blood vessels in order to relieve the cell or tissue of hypoxia. If the HIF does not become targets for recycling by the pVHL, then the HIF continues to signal to the cell that it needs to create blood vessels even if the cell is properly oxygenated. These blood vessels form the tumors that are the foundation of the VHL disease state.

Genetic testing for VHL can greatly improve an affected individual's prognosis. Because VHL can be present for years before symptoms become tiresome enough to go to the physician, genetic testing and subsequent counseling can prove to be life-saving. Proper medical imaging and surgical options can not only reduce the severity of bothersome symptoms, they can also slow the progression of VHL into deadly carcinomas.


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