Key Terms: Benign, Cyst, Hemangioblastoma, Malignant, Mutation.
Definition
Von Hippel–Lindau disease (VHL) is a rare familial cancer syndrome. A person with VHL can develop both benign and malignant tumors and cysts in many different organs in the body. Tumors and cysts most commonly develop in the brain and spine, eyes, kidneys, adrenal glands, pancreas, and inner ear.
Description
VHL does not have a predictable set of symptoms. VHL affects approximately 1 in 35,000 people, and affects men and women equally. Some families may have different symptoms than other families. Even within a family, there may be people with very mild signs of VHL, and others with more severe medical problems. In one study of a Chinese family with 47 members, four were diagnosed as carriers of the VHL gene while 18 others were diagnosed as having VHL itself. Of these 18 patients, 10 had renal cell carcinoma, 9 had central nervous system hemangioblastomas, and 7 had multiple pancreatic cysts. The age when symptoms develop can range from infancy to late adulthood, although most people with VHL will have some clinical symptoms by age 65. It is important for a person with VHL to have regular physical examinations to check for signs of VHL in all areas of the body that may be affected.
Tumors in the brain and spine, or central nervous system, are called hemangioblastomas. Hemangioblastomas are benign growths (not cancerous), but they may cause such symptoms as headaches and balance problems if they are growing in tight spaces and pressing on surrounding tissues or nerves. The eye tumors in VHL are called retinal angiomas or retinal hemangioblastomas, and may cause vision problems and blindness if they are not treated. Kidney cysts rarely cause problems, but the kidney tumors can be malignant, and are called renal cell carcinoma. Tumors in the adrenal glands are called pheochromocytomas. Pheochromocytomas are usually not malignant, but they can cause serious medical problems if untreated. This is because pheochromocytomas secrete hormones that can raise blood pressure to dangerous levels, causing heart attacks or strokes. Benign cysts can be found in the pancreas, and pancreatic islet cell tumors can also occur. These tumors grow very slowly and are rarely malignant. Tumors that grow in the ear are called endolymphatic sac tumors, which can result in hearing loss if untreated. Occasionally men and women with VHL will have infertility problems if cysts are present in certain places in the reproductive organs, such as the epididymis (a duct in the testes) in men or the fallopian tubes in women. A few male patients with VHL develop large testicular masses that can be treated successfully with steroid therapy.
Diagnosis
A clinical diagnosis of VHL can be made in a person with a family history of VHL if he or she has a single retinal angioma, central nervous system hemangioblastoma, or pheochromocytoma, or if he or she has renal cell carcinoma. If there is no known family history of VHL, two or more retinal or central nervous system hemangioblastomas must be present, or one retinal or central nervous system hemangioblastoma and one other feature of VHL. Melmon and Rosen published these criteria in 1964, when they first described VHL as a disease with a specific set of features. Because not all people with VHL will meet these diagnostic criteria, VHL may be an under–diagnosed disease. Genetic testing can confirm a diagnosis of VHL in a person with clinical symptoms, who may or may not meet the above diagnostic criteria.
Causes
VHL is a genetic disease caused by a mutation of the VHL tumor suppressor gene on chromosome three. It is inherited as an autosomal dominant condition, which means that a person with VHL has a 50% chance of passing it on to each of his or her children. Usually a person with VHL will have a family history of VHL (a parent or sibling who also has VHL), but occasionally he or she is the first person in the family to have VHL. Screening and/or genetic testing of family members can help establish who is at risk for developing VHL. Identification of a person with VHL in a family may result in other family members with more mild symptoms being diagnosed, and subsequently receiving appropriate screening and medical care.
Risks
The United States National Institutes of Health (NIH) has determined risk ranges for a person with VHL to develop certain tumors. Persons with VHL have a 21–72% chance of developing hemangioblastomas of the brain or spinal cord, a 43–60% chance of developing retinal angiomas, a 24–45% chance of developing cysts and tumors of the kidney, an 8–37% chance of developing pancreatic cysts, and an 8–17% chance of developing pancreatic islet cell tumors. It has been proposed that VHL be divided into subtypes depending on the types of tumors present in a family. It is likely that in the future, specific risk figures will be available for the different types of tumors depending on the specific genetic mutation in a family.
Genetic Testing
Almost 100% of people with VHL will have an identifiable mutation in the VHL gene. There have been many different mutations found in the VHL gene, but all persons with VHL in the same family will have the same mutation. If a mutation is known in a family, genetic testing can be done on family members who have not had any symptoms of VHL. A person who tests positive for the family mutation is at risk for developing symptoms of VHL and can pass the mutation on to his or her children. A person who tests negative for the family mutation is not at risk for developing symptoms of VHL, and his or her children are not at risk for developing VHL. Screening is needed for people who test positive for a VHL mutation, and people who are found not to have the family mutation can be spared from lifelong screening procedures. Genetic testing can also be used to determine if a pregnant woman is carrying a fetus affected with VHL. Other techniques may become available which allow selection of an unaffected fetus prior to conception. Families work with a physician, geneticist, or genetic counselor familiar with the most up–to–date information on VHL when having genetic testing, in order to understand the risks, benefits, and current technological limitations prior to testing.
Screening and Treatment
Regular screening and monitoring of tumors in people with VHL allows early detection and treatment, before serious complications can occur. A physician familiar with all aspects of VHL can coordinate screening with a variety of specialists, such as an ophthalmologist for eye examinations. Ultrasounds, computed tomography scans (CT), and magnetic resonance imaging (MRI) may be used to screen and detect tumors and cysts. Whether or not treatment is necessary depends on the size of the tumor, where it is growing, what the symptoms are, and if the tumor is benign or malignant. Treatment for benign tumors may include surgery or laser treatments. Cancer in people with VHL is treated just as it would be in someone in the general population with that type of cancer. People with VHL who develop cancer have a better prognosis if the cancer is detected at an earlier stage before it has spread. Urine tests, ultra-sound, CT and/or MRI screen for pheochromocytomas. It is especially important to screen for pheochromocytomas prior to surgery, because an undiagnosed pheochromocytoma can cause complications during surgery. Prior to becoming pregnant, a woman should have a full physical examination looking for all signs of VHL, but most importantly pheochromocytomas. It is best for a woman to avoid VHL-related surgery while she is pregnant unless medically necessary. Pregnancy itself does not seem to make VHL worse or make the tumors grow faster, but any tumors that are present should be evaluated, and a plan for surgical removal or monitoring should be in place.
Resources
Books
Beers, Mark H., MD, and Robert Berkow, MD, editors. "Adrenal Disorders." Section 2, Chapter 9 In The Merck Manual of Diagnosis and Therapy. Whitehouse Station, NJ: Merck Research Laboratories, 2002.
Beers, Mark H., MD, and Robert Berkow, MD, editors. "Cancer Genetics." Section 21, Chapter 286 In The Merck Manual of Diagnosis and Therapy. Whitehouse Station, NJ: Merck Research Laboratories, 2002.
Periodicals
Huang, Y. R., J. Zhang, J. D. Wang, and X. D. Fan. "Genetic Study of a Large Chinese Kindred with von Hippel-Lindau Disease." Chinese Medical Journal 117 (April 2004): 552–557.
Levy, M., and S. Richard. "Attitudes of von Hippel–Lindau Disease Patients towards Presymptomatic Genetic Diagnosis in Children and Prenatal Diagnosis." Journal of Medical Genetics 37 (June 1, 2000): 476–478.
Sgambati, M.T., et al. "Mosaicism in von Hippel–Lindau Disease: Lessons from Kindreds with Germline Mutations Identified in Offspring with Mosaic Parents." American Journal of Human Genetics 66 (2000): 84–91.
Vortmeyer, A. O., Q. Yuan, Y. S. Lee, et al. "Developmental Effects of von Hippel-Lindau Gene Deficiency." Annals of Neurology 55 (May 2004): 721–728.
Weeks, D. C., M. M. Walther, C. A. Stratakis, et al. "Bilateral Testicular Adrenal Rests after Bilateral Adrenalectomies in a Cushingoid Patient with von Hippel-Lindau Disease." Urology 63 (May 2004): 981–982.
Organizations
VHL Family Alliance. 2001 Beacon St., Suite 28, Boston, Massachusetts 02135. (617) 277–5667, (800) 767–4VHL. Email: info@vhl.org.
Other
The VHL Handbook: What You Need to Know about VHL. A Reference Handbook for people with von Hippel–Lindau Disease, their families, and support personnel. Updated 1999.
Gale Encyclopedia of Cancer. Copyright © 2006 by The Gale Group, Inc. All rights reserved.
