Von Hippel-Lindau disease
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Von Hippel-Lindau disease (VHL) is a rare inherited genetic condition involving the abnormal growth of tumors in parts of the body which are particularly rich in blood supply.
Features
Features of VHL are:- angiomatosis - little knots of capillaries in various organs. These tend to be cavernous hemangiomas, which are sharply defined, sponge-like tumors composed of large, dilated, cavernous vascular spaces.
- hemangioblastomas - tumors of the central nervous system (CNS, especially the cerebellum). These tumors, whether benign (usual) or malignant (rarer), may cause problems, for example angiomas in the brain or spinal cord may press on nerve or brain tissue. As an angioma grows, the walls of the blood vessels may weaken and leak, causing damage to surrounding tissues. Blood leakage from angiomas in the retina can interfere with vision. Cysts may also grow around angiomas.
- pheochromocytoma - tumors of the adrenal medulla that often produce catecholamines
- renal cell carcinoma - in some forms
Types
There are various subtypes:- Type 1 (angiomatosis without pheochromocytoma)
- Type 2 (angiomatosis with pheochromocytoma)
- * Type 2A (with renal cell carcinoma)
- * Type 2B (without renal cell carcinoma)
- * Type 2C (only pheochromocytoma and no angiomatosis or renal cell carcinoma)
Genetics
The disease is caused by mutations of the VHL gene on the short arm of the third chromosome (3p26-p25). The resultant protein is produced in two forms, an 18 kDa and a 30 kDa protein that functions as a tumor suppressor gene. The main action of the VHL protein is thought to be its E3 ubiquitin ligase activity that results in specific target proteins being 'marked' for degradation. The most researched of these targets is hypoxia inducible factor 1a (HIF1a), a transcription factor that induces the expression of a number of angiogenesis related factors. It stands to reason that the loss of VHL protein activity results in an increased amount of HIF1a, and thus increased levels of angiongenic factors. In turn, this leads to unregulated blood vessel growth, one of the prerequesites of a tumour.VHL is an autosomal dominant disorder, but there is a wide variation in the age of onset of the disease, the organ system affected and the severity of effect. Most people with von Hippel-Lindau syndrome inherit an altered copy of the gene from one parent. In about 20 percent of cases, however, the altered gene is the result of a new mutation that occurred during the formation of reproductive cells (eggs or sperm) or early in fetal development.
As long as one copy of the VHL gene is producing functional VHL protein in each cell, tumors do not form. If a mutation occurs in the second copy of the VHL gene during a person's lifetime, the cell will have no working copies of the gene and will produce no functional VHL protein. A lack of this protein allows tumors characteristic of von Hippel-Lindau syndrome to develop.
History
Eugen von Hippel described the angiomas in the eye in 1904.Von Hippel E. Ueber eine sehr seltene Erkrankung der Netzhaut. Albrecht von Graefes Arch Ophthal 1904;59:83-106.. Arvid Lindau described the angiomas of the cerebellum and spine in 1927.Lindau A. Zur Frage der Angiomatosis Retinae und Ihrer Hirncomplikation. Acta Ophthal 1927;4:193-226.Nomenclature
Other names are: angiomatosis retinae, angiophakomatosis retinae et cerebelli, familial cerebello-retinal angiomatosis, cerebelloretinal hemangioblastomatosis, Hippel Disease, Hippel-Lindau syndrome, HLS, Lindau disease or retinocerebellar angiomatosis.References
External links
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