Von Hippel–Lindau disease

Von Hippel–Lindau (VHL) is a rare, autosomal dominant genetic condition 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 pheochromocytoma. VHL results from a mutation in the von Hippel–Lindau tumor suppressor gene on chromosome 3p25.3.

Signs and symptoms
Signs and symptoms associated with VHL include angiomatosis, hemangioblastomas, pheochromocytoma, renal cell carcinoma, pancreatic cysts (pancreatic serous cystadenoma) and café au lait spots. Angiomatosis occurs in 37.2% of patients presenting with VHL and usually occurs in the retina. As a result, loss of vision is very common. However, other organs can be affected: strokes, heart attacks, and cardiovascular disease are common additional symptoms.

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).



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, the second allele must develop the 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.

Treatment
There is no current way to reverse the presence of the VHL mutation in patients. Nonetheless, early recognition and treatment of specific manifestations of VHL can substantially decrease complications and improve quality of life.

History
The German ophthalmologist, Eugen von Hippel first described the angiomas in the eye in 1904. Arvid Lindau described the angiomas of the cerebellum and spine in 1927.

People
Some descendants of the McCoy family (involved in the Hatfield-McCoy feud of Appalachia, USA) as well as the Elliotts 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. 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.

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.