Monday, June 4, 2012

Von Hippel- Lindau Syndrome

Von Hippel- Lindau, VHL, is a rare genetically inherited disorder. It is estimated that 1 in 32,000 births, approximately 6-7 thousand people in the United States, have VHL.  

VHL is characterized by the abnormal growth of blood vessels. VHL affects many different parts of the body, particularly those rich in blood vessels. Blood vessels in individuals without VHL normally branch out like trees, while the blood vessels of individuals with VHL form into knots. These knots are called angiomas, or hemangioblastomas.

Typically the hemangioblastomas are benign, or non cancerous. However, because of there location they can cause problems.

Hemangioblastomas are typically found in the central nervous system, including the brain, spinal cord, or retina.

Angiomas exert pressure on the spinal cord or retina for example, causing symptoms such as headaches, loss of coordination, or vision loss. Cysts may also form around the angiomas, intensifying the pressure.

VHL varies greatly, affecting several different organs. Even within families, the location and severity of tumors varies greatly. Besides the CNS, cysts and tumors may form in the kidneys, pancreas, liver, or adrenal glands.

VHL is inherited in an autosomal dominant fashion. Children of an individual with VHL have a 50% likelihood of inheriting the syndrome. It is estimated that 80% of individuals with VHL inherited the disorder, which leaves 20% as a result of “de novo,” or new, gene mutation. There is only one gene known to be associated with VHL syndrome.

VHL is the result of an altered VHL gene. The normal function of the VHL gene is tumor suppression. A mutation in the gene allows tumorigenisis, or tumor growth. As long as one copy of the VHL gene is functioning, tumors do not form. It is the alteration of the second copy of the VHL gene (not the inherited gene) that allows the VHL syndrome to develop. The onset of VHL is generally during the second or third decade of life, 20-30 years of age.

In 1993, Latif et al, identified the exact location of the VHL gene. The VHL gene is located on chromosome number three. The site is labeled 3p25-26 locus, which is located on the short arm of the chromosome. The VHL gene codes for 213- amino acid protein.

In a normal VHL gene, DNA would be transformed into RNA, which would create a VHL protein (VHLp). This protein is part of a complex involved in tumor suppression. The complex includes Elongins B and C and CUL2. Together, they control the levels of Hypoxia Inducible Factor (HIF.) There are over 300 germ line mutations that have been identified within families with VHL. They consist of gene frame shift, deletions, nonsense, missense, and splice site mutations. These mutations disrupt the vital process of transcription. The protein created from this mutant is unable to bind to elongin C, resulting in no complex formation. The mutated complex is unable to signal the amount of oxygen available to the cell. The cell believes it is lacking oxygen, even if it is not. The cell then tells the body to build blood vessels to bring more blood and oxygen. These blood vessels continue to grow uncontrollably and form into knots. These knots are known as hemangioblastomas.

There currently is no cure to Von Hippel- Lindau. Surgical removal of lesions and awareness through genetic counseling is currently the method of management.  Advances are being made in genetic research. Although Von Hippel- Lindau is a rare disease, an understanding of the genetic features of the disease could prove useful in understanding and curing sporadic types of cancer.

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