Von Hippel-Lindau Disease (VHL)

von Hippel-Lindau disease (VHL) is a rare, genetic multi-system disorder characterized by the abnormal growth of tumors in certain parts of the body (angiomatosis). The tumors of the central nervous system (CNS) are benign and are comprised of a nest of blood vessels and are called hemangioblastomas (or angiomas in the eye). Hemangioblastomas may develop in the brain, the retina of the eyes, and other areas of the nervous system. Other types of tumors develop in the adrenal glands, the kidneys, or the pancreas. Symptoms of VHL vary among patients and depend on the size and location of the tumors.

Other Names

• Angiomatosis retinae
• Cerebelloretinal Angiomatosis, Familial
• Hippel-Lindau Diseae
• VHL syndrome
• von Hippel-Lindau Syndrome

Types

VHL can be divided into two major types based on the risk of developing pheochromocytomas. Type 1 VHL is associated with a low risk of these tumors, and type 2 is characterized by a much higher risk. Type 2 can be further divided into types 2A, 2B, and 2C, depending on the probability of developing renal cell carcinoma and hemangioblastomas.

Signs and Symptoms

Symptoms may include headaches, problems with balance and walking, dizziness, weakness of the limbs, vision problems, and high blood pressure. Cysts (fluid-filled sacs) and/or tumors (benign or cancerous) may develop around the hemangioblastomas and cause the symptoms listed above. Individuals with VHL are also at a higher risk than normal for certain types of cancer, especially kidney cancer.

Causes

Mutations in the VHL gene cause von Hippel-Lindau syndrome. The VHL gene is a tumor suppressor gene, which means it keeps cells from growing and dividing too rapidly or in an uncontrolled way. Mutations in this gene prevent production of the VHL protein or lead to the production of an abnormal version of the protein. An altered or missing VHL protein cannot effectively regulate cell survival and division. As a result, cells grow and divide uncontrollably to form the tumors and cysts that are characteristic of von Hippel-Lindau syndrome.^[1]

Treatment

Treatment for VHL varies according to the location and size of the tumor and its associated cyst. In general, the objective of treatment is to treat the growths when they are causing symptoms but while they are still small so that they do not cause permanent problems by putting pressure on the brain or spine, blocking the flow of cerebrospinal fluid in the nervous system, or impairing vision. Treatment of most cases of VHL usually involves surgery to remove the tumors before they become harmful. Certain tumors can be treated with focused high-dose irradiation. Individuals with VHL need careful monitoring by a physician and/or medical team familiar with the disorder.

Chances of Developing Von Hippel-Lindau Disease (VHL)

This condition occurs in about 1 in 32,000 individuals. ^[2]

Genetics

Mutations in the VHL gene cause von Hippel-Lindau syndrome.^[3]

Heredity

Mutations in the VHL gene are inherited in an autosomal dominant pattern, which means that one copy of the altered gene in each cell is sufficient to increase the risk of developing tumors and cysts. 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 in early fetal development. Unlike most autosomal dominant conditions, in which one altered copy of a gene in each cell is sufficient to cause the disorder, two copies of the VHL gene must be altered to trigger tumor and cyst formation in von Hippel-Lindau syndrome. A mutation in the second copy of the VHL gene occurs during a person's lifetime in organs such as the brain, retina, and kidneys. Cells with two altered copies of this gene make no functional VHL protein, which allows tumors and cysts to develop. ^[4]

Related Problems

People with von Hippel-Lindau syndrome commonly develop cysts in the kidneys, pancreas, and male genital tract. They are also at an increased risk of developing a type of kidney cancer called clear cell renal cell carcinoma and a type of noncancerous tumor called a pheochromocytoma. Pheochromocytomas affect the adrenal glands, which are small hormone-producing glands located on top of each kidney. These tumors often cause no symptoms, but in some cases can lead to dangerously high blood pressure. About 10 percent of people with von Hippel-Lindau syndrome develop noncancerous tumors (called endolymphatic sac tumors) in the inner ear. These growths can cause hearing loss in one or both ears, as well as ringing in the ears (tinnitus) and problems with balance. ^[5]

Clinical Trials

Select this link to view a list of clinical trials and studies currently seeking patients with VHL.

Research

The NINDS pursues a vigorous program of research aimed at preventing and treating disorders that cause tumors in the brain and spinal cord such as VHL.

Expected Outcome

The prognosis for patients with VHL depends on the location and complications of the tumors. Untreated, VHL may result in blindness and/or permanent brain damage. With early detection and treatment the prognosis is significantly improved. Death is usually caused by complications of brain tumors or kidney cancer.

Other Resources

• Educational resources
• Patient support.

References

1. ↑ Kuehn EW, Walz G, Benzing T. Von hippel-lindau: a tumor suppressor links microtubules to ciliogenesis and cancer development. Cancer Res. 2007 May 15;67(10):4537-40. Abstract | PDF
2. ↑ Gordeuk VR, Stockton DW, Prchal JT. Congenital polycythemias/erythrocytoses. Haematologica. 2005 Jan;90(1):109-16. Abstract | PDF
3. ↑ Friedrich CA. Genotype-phenotype correlation in von Hippel-Lindau syndrome. Hum Mol Genet. 2001 Apr;10(7):763-7. Abstract | PDF
4. ↑ Genetics Home Reference, NIH
5. ↑ Friedrich CA. Von Hippel-Lindau syndrome. A pleomorphic condition. Cancer. 1999 Dec 1;86(11 Suppl):2478-82. Abstract | PDF