What is Von Hippel Lindau Disease

Von Hippel-Lindau disease (VHL) is a relatively rare genetic disorder, affecting an estimated 10,000 people in the U.S. The inheritance pattern of VHL is autosomal dominant. This means that anyone born with the disease gene has a 50% chance of passing it on to his/her children. VHL is marked by the formation of capillary tumors (hemangioblastomas) in the central nervous system, most often in the cerebellum and retina. Another disease manifestation is the growth of cysts in the liver, kidneys, or pancreas.

In 10% of people with VHL, one or more of the hemangioblastomas release erythropoietin, a hormone that stimulates the production of red blood cells in the bone marrow. The result is a condition called polycythemia vera, an abnormally high number of red blood cells. A notable symptom of polycythemia is intense itching, especially after bathing. Occasionally, the excessive number of red blood cells leads to the formation of blood clots, a potentially fatal complcation.

Individuals with VHL also have an increased risk of developing renal cell carcinoma (cancer of the kidneys) as well as pheochromocytoma, a chromaffin cell tumor of the adrenal medulla that can release high levels of epinephrine and norepinephrine. This can result in sudden surges in blood pressure, leading to dizziness, headaches, and rapid heart rate as well as life threatening complications, especially heart attack and stroke.

The genetic basis of VHL disease involves a mutation of a tumor suppressor gene (also called VHL) located on chromosome 3. The mutant VHL gene encodes an abnormal protein (pVHL) that interferes with the normal elongation step of messenger RNA synthesis. The mutant protein is believed to compete with a normal protein called elongin A, which forms a ternary complex with elongins B and C. The absence of the normal elongation factor complex allows for the production of abnormally long messenger RNA molecules. As large numbers of mutant mRNAs are produced over the course of years, the likelihood that some of them encode oncogenic proteins increases dramatically. Ultimately, this mechanism contributes to the high incidence of tumors seen in VHL. As to why such relatively uncommon tumor types (renal cell and pheochromocytoma) arise, however, no one knows for sure.

Treatment of VHL involves surgical resection of symptomatic hemangioblastomas as well as nephrectomy and/or adrenalectomy (surgical removal of a kidney or adrenal gland), in cases of renal cell carcinoma or pheochromocytoma, respectively. Patients with bilateral tumors of the kidneys can undergo partial nephrectomy, but they tend to have a poorer prognosis. On the other hand, bilateral removal of the adrenal glands can be treated with oral hydrocortisone to replace cortisol and fludricortisone (Florinef) to replace the mineralocorticoid aldosterone.