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What is Von Hippel-Lindau Syndrome?

written by: dgemmellaro•edited by: Paul Arnold•updated: 10/13/2009

Von Hippel-Lindau syndrome, known as VHL, is an inherited autosomal dominant disease that causes tumors throughout various regions of the body. The symptoms and the characteristics of VHL are actually quite different from patient to patient, making the diagnosis of this disease often problematic.

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    The Mutation at the Heart of the Disease

    The cause of Von Hippel-Lindau Syndrome, or VHL, can be found in a mutation of one of the two copies of the so-called VHL gene, which is located on the short arm of chromosome 3. The full name of the VHL gene is the Von Hippel-Lindau tumor suppressor gene. As the name suggests, the function of this gene is to control and limit (to “suppress”) the growth and the reproduction of cells, which would otherwise reproduce continuously and indiscriminately.

    The VHL gene exerts its function by producing a protein that plays a role in the VCB-CUL2 complex, a group of proteins that act together to perform a specific job or jobs. This particular complex targets and breaks down large proteins that are no longer necessary to the cell. Among these proteins there is the hypoxia-inducible factor, or HIF, whose function is to control genes involved in cell division and in the formation of blood vessels. When the VHL gene is mutated, the VCB-CUL2 complex can no longer perform its job properly and, consequently, the regulation of cell growth and cell replication is no longer possible. This is why cells will continue to divide and multiply, forming cysts, as well as cancerous and non-cancerous tumors.

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    The Effects of the Mutation and Von Hippel-Lindau Symptoms

    Because the VCB-CLU2 complex under normal conditions has an effect on a number of different proteins, alterations of the VHL gene can trigger several different conditions, whose timing and severity differ from individual to individual.

    Eugen v. Hippel - described the angiomas in the eye - image released into the public domain The lack of control in the formation of blood vessels can cause the creation of hemangioblastomas, which are non-cancerous tumors made of “knots” of blood vessels. Even though these growths are benign, when hemangioblastomas develop in the central nervous system they can exert pressure on nerves, causing headaches, loss of coordination or vomiting. At times, the uncontrolled growth of blood vessels can develop in the retina and may even cause loss of vision. In such cases, the growths are called retinal angiomas.

    It has also been observed that alterations in the VHL gene can be the cause of a blood disorder called Chuvash polycythemia, also known as congenital polycythemia. Characteristics of this disease include the excessive formation of red blood cells, which may cause excessive bleeding, formation of blood clots or even strokes.

    In other cases, VHL can cause tumors in the kidneys, called clear cell renal cell carcinomas, or in the adrenal glands, called pheochromocytomas, or pheos. Pheos are very rarely cancerous, and, when detected early, they are not difficult to treat. Nevertheless, these tumors can still be lethal to an individual if they are left untreated. In fact, the presence of pheos causes an uncontrolled production of noradrenalin and adrenaline, which are hormones that the body uses during stressful situations. The secretion of these hormones causes a serious rise in blood pressure that could lead to heart attack or a stroke.

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    Disease Transmission

    Genetically, VHL is a very peculiar disease in terms of transmission. In order for the disease to be present, it is necessary for both alleles, or copies, of the VHL gene to be altered. Normally, in genetic terms, the requirement for two mutated alleles for disease occurrence is a characteristic of a recessive trait. This is not the case regarding Von Hippel-Lindau disease. Autosomal dominant patterns of inheritance characterize the disease, so it is an autosomal dominant disorder.

    In other words, one good copy of the VHL gene means that an individual will not develop the benign or cancerous tumors associated with the disease. However, individuals who inherit one single copy of the defective VHL gene are at a much greater risk for developing a second copy of the mutated VHL gene. Once that second mutation develops, there will be two altered copies and the disease will be triggered. This second mutation tends to occur during an individual's lifetime.

    Usually, in 80% of cases, the presence of the altered VHL gene is due to transmission from parent to child. Since it is a dominant disease, if even one parent has one mutated gene, each child will have a 50% risk of being affected by VHL. In 20% of cases, the mutation of the VHL gene is not inherited from either parent, but instead it occurs as reproductive cells form or while a fetus is developing.

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    DNA Testing

    There is no cure for Von Hippel-Lindau Syndrome, though treatment is available. Treatment involves the removal of tumors while they are still small and have not caused damage to sensitive areas, like the brain, eyes and kidneys. If left undetected and untreated, blindness and brain damage could result. DNA tests are available today to detect the presence of VHL. This allows people who are at risk of developing the disease to be closely monitored, so that growths can be caught early.