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Von Hippel – Lindau disease (VHL) is a rare, autosomal dominant genetic condition^[1]:555 in which hemangioblastomas are found in the cerebellum, spinal cord, kidney and retina. These are associated with several pathologies including renal angioma, renal cell carcinoma and phaeochromocytoma. VHL results from a mutation in the Von Hippel-Lindau tumor suppressor gene on chromosome 3p25.3.^[2]

[edit] Signs and symptoms

VHL may be diagnosed when one of its associated diseases starts to cause discomfort in the person suffering from the disease. Angiomatosis, hemangioblastomas, pheochromocytoma, renal cell carcinoma, pancreatic cysts and café au lait spots are all associated with VHL.^[3] Angiomatosis occurs in 37.2% of patients presenting with VHL and usually occurs in the retina, however other organs can be affected. As a result, loss of vision is very common.^[2]

[edit] Genetics

The disease is caused by mutations of the Von Hippel-Lindau tumor suppressor (VHL) gene on the short arm of chromosome 3 (3p25-26).

Von Hippel – Lindau disease is inherited in an autosomal dominant pattern.

As long as one copy of the VHL gene is producing functional VHL protein in each cell, tumors do not form. Since both alleles need to be mutated in order for the disorder to develop, it would be easy to assume that the mutation is recessive. However, studying the patterns of heredity, we see that VHL is, paradoxically, an autosomal dominant disorder. This is because people who have already inherited one mutated copy of the gene have an extremely high probability of developing the second mutation in at least one other cell in their bodies. This is known as the two-hit hypothesis. If a mutation occurs in the second copy of the VHL gene, 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.

An inherited mutation of the VHL gene is responsible for about 80 percent of cases. 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. This is quite rare because the probability of a mutation occurring in a cell where both alleles are previously normal is quite small. Whether by new mutation or inherited mutation, the aforementioned second hit still needs to occur in order for a tumor to appear.

There is a wide variation in the age of onset of the disease, the organ system affected and the severity of effect. This suggests that the second mutation can occur in different types of cells and at various times of a person's life.

[edit] History

Eugen von Hippel described the angiomas in the eye in 1904.^[4]. Arvid Lindau described the angiomas of the cerebellum and spine in 1927.^[5]

[edit] People

Some descendants of the McCoy family (involved in the Hatfield-McCoy feud of Appalachia, USA) have VHL. In an article appearing in the Associated Press, it has been speculated by a Vanderbilt University endocrinologist that the hostility underlying the Hatfield–McCoy feud may have been partly due to the consequences of von Hippel – Lindau disease. The article suggests that the McCoy family was predisposed to bad tempers because many of them had a pheochromocytoma, which produced excess adrenaline and a tendency toward explosive tempers.^[6] Pheochromocytomas produce surges of adrenaline which are more often perceived as panic attacks than rage attacks. Left untreated, they will cause serious cardiovascular disease, heart attack, and stroke. Only about 20% of people with VHL get pheochromocytomas.^[7]

The Bray family mainly of North Carolina is also known to have Von Hippels disease. Tony Bray's(founder of T.V. Now) mother died from Von Hippels and her body was donated to Duke for research because it is such a rare disease. The Bray family still carries the gene in the family.

[edit] Nomenclature

Other uncommon names are: angiomatosis retinae, angiophakomatosis retinae et cerebelli, familial cerebello-retinal angiomatosis, cerebelloretinal hemangioblastomatosis, Hippel Disease, Hippel–Lindau syndrome, HLS, VHL, Lindau disease or retinocerebellar angiomatosis.

[edit] See also

• Haemangioblastoma

[edit] References

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[edit] External links

• Clinical Description of VHL
• The VHL Handbook
• Von Hippel – Lindau Disease (VHL) at NINDS
• Von Hippel – Lindau syndrome at NLM Genetics Home Reference
• von Hippel – Lindau syndrome at CHORUS
• Hippel–Lindau disease at Who Named It?
• Online 'Mendelian Inheritance in Man' (OMIM) 608537 (VHL gene)
• VHL Family Alliance support group