Von Hippel-Lindau disease
Von Hippel-Lindau Disease
Von Hippel-Lindau disease (VHL) is a hereditary condition that involves cancer and can affect people of all ages. It was named after the physicians to first describe aspects of the condition in the early 1900s, German ophthalmologist Eugen von Hippel and Swedish pathologist Arvid Lindau. It was not until 1964 that the term von Hippel-Lindau disease was coined.
VHL often involves symptoms in the central nervous system (CNS) and include hemangioblastomas of the cerebellum , spinal cord, brain stem, and nerve root. Retinal hemangioblastomas and endolymphatic sac tumors are CNS tumors that can also be seen. The kidneys, adrenal gland, pancreas, epididymis, and female broad ligaments may also be affected.
Behavioral and learning problems are not usually associated with VHL, but may be if the CNS tumors are quite significant. Symptoms of VHL do not usually cause concerns in very early childhood. However, VHL is a hereditary cancer syndrome for which screening is appropriate in late childhood and adolescence for those at risk.
Studies from 1991 indicated an incidence of VHL of about one in 36,000 live births in eastern England. The condition affects people of all ethnic groups worldwide, with an equal proportion of males and females.
In 1993, the gene for VHL was identified. The majority of people with VHL also have an affected parent, but in about 20% of cases there is no known family history of VHL.
Causes and symptoms
Mutations in the VHL gene on chromosome 3 are now known to cause the condition. VHL is inherited in an autosomal dominant manner, meaning that an affected individual has a 50% chance to pass a disease-causing mutation to offspring, regardless of their gender.
VHL is a tumor-suppressor gene, or one whose normal function is to prevent cancer by controlling cell growth. Mutations in the VHL gene potentially cause uncontrolled cell growth in the gene, which is why a person with a VHL mutation is prone to developing cancer and other growths.
Hemangioblastomas of the CNS are the most common tumor in VHL; about 60–80% of people with VHL develop these tumors. The average age for CNS hemangioblastomas to develop is 33 years. The tubors are a frequent cause of death in people with VHL because they can disturb normal brain functioning. They can occur anywhere along the brain/spine areas, and swelling or cysts are often associated. The most common locations for CNS hemangioblastomas are in the spinal cord and cerebellum.
Symptoms from CNS hemangioblastomas depend on their size and exact location. Common symptoms include headaches , vomiting, gait disturbances, and ataxia , especially when the cerebellum is involved. Spinal hemangioblastomas often bring pain , but sensory and motor loss
may develop only if the tumor is so large that it is pressing into the spinal cord. Some hemangioblastomas never cause symptoms, and are only seen with special imaging techniques.
Retinal hemangioblastomas are seen in as many as 60% of people, and many times may be the first sign of VHL. There may be multiple hemangioblastomas in one eye, or even in both eyes. The average age for these to develop is about 25 years, but some develop in people younger than 10 years of age. When in the early stages and quite small, retinal hemangioblastomas may not cause symptoms. As they progress, they can cause retinal detachment, with partial or total vision loss.
Endolymphatic sac tumors are seen in about 11% of people with VHL, but are very rare in the general population. The first sign of this form of tumor may be partial hearing loss, which may progress to total hearing loss. Other symptoms can be tinnitus (buzzing in the ear), dizziness , and facial paresis. These tumors often erode or expand the inner bones of the ear, a major reason for the hearing loss.
Kidney involvement occurs in about 60% of people with VHL, which usually includes renal cell carcinoma and kidney cysts. The typical age that these symptoms develop is 39 years. One or both kidneys may be diseased, with multiple cysts or growths that may be seen in each kidney. Renal cell carcinoma is a major cause of death in VHL. Kidney disease may not cause symptoms, or may not cause a reduction in kidney function. In severe cases blood in the urine, a mass or pain may be felt in an affected person's side.
Adrenal gland pheochromocytomas occur in 10–20% of people with VHL; the average age of diagnosis is 30 years, though they have been seen in children under the age of 10. There may be a single tumor present, or multiple tumors. For people with a subset of VHL called type 2C, a pheochromocytoma is the only symptom they have. Five percent of all pheochromocytomas are cancerous, requiring treatment. Symptoms of pheochromocytomas may include intermittent or continuous high blood pressure, heart palpitations, a quickened heart rate, headaches, sweating episodes, nausea, and paleness of the skin. Pheochromocytomas may also cause the level of catecholamines to be elevated in urine.
Of all people with VHL, 35–70% have a pancreatic tumor, cyst, or cystadenoma. The masses often develop in the mid-30s, and are usually without symptoms. Pancreatic involvement is important to diagnose VHL, but is difficult to identify on its own because it may cause no medical problems.
Men with VHL have epididymal cystadenomas 25–60% of the time. There may be multiple masses, occurring in both sides. If occurring in both sides, in rare cases they may lead to infertility. Epididymal cystadenomas are non-cancerous and may show up in the teenage years. In women, a similar tumor to the epididymal cystadenoma in men is that of the broad ligaments. These are not very common, so the true frequency and age of development is unknown in VHL. They are non-cancerous and usually cause no specific symptoms.
Until the discovery of the VHL gene, the diagnosis of the condition was made on a clinical basis. People with a family history of VHL need only have a CNS hemangioblastoma (including retinal), pheochromocytoma, or renal cell carcinoma to be given a diagnosis. Those without a family history must have two or more CNS hemangioblastomas, or one CNS and a visceral finding (with the exception of epididymal and renal cysts) to have a diagnosis.
There has been the creation of subtypes within VHL. Type 1 families are at a very low risk for pheochromocytomas, but have the typical risk for all other tumors that are seen. All type 2 families have a risk for pheochromocytomas; type 2A families have a low risk for renal cell carcinoma, while type 2B families have a high risk for it; type 2C families only have pheochromocytomas and no other signs of VHL.
Hemangioblastomas of the brain and spine are typically found through magnetic resonance imaging (MRI) scans. Those found in the retina can be seen by examination of the dilated eye by an ophthalmologist. Endolymphatic tumors may be visualized using computed tomography (CT ) and MRI scans of the internal ear canals. Audiograms can also be done to identify and track hearing loss.
Renal and pancreatic involvement is often found through abdominal CT scans, MRI scans, or ultrasounds of the kidneys and pancreas. Pheochromocytomas can be seen on CT or MRI scans, and occasionally meta-iodobenzyl-guanidine (MIBG) scintigraphy is required to detect them. Epididymal cystadenomas are usually felt by a physical examination and confirmation through an ultrasound. Broad ligament cystadenomas can be diagnosed by CT scans or an ultrasound.
Genetic testing is available for VHL through gene sequencing and other methods. Testing is useful for confirming a clinical diagnosis or for family testing when there is an identified VHL mutation in the family. Analysis of the VHL gene is not perfect, but it detects about 90% of mutations that cause VHL. An informative test result is one that identifies a known mutation in the gene, and this confirms that the person has VHL. A negative test result means a mutation was not found in the gene. This either means that the tested individual does not have VHL, or instead has a mutation that cannot be found through testing but actually has the diagnosis.
Genetic testing for children at risk for VHL is recommended because some symptoms can show up in childhood. Earlier screening may reduce the chance of serious future complications. As with all genetic testing in people who have no symptoms, the risks, benefits, and limitations of testing should be discussed through proper genetic counseling.
Treatment for people with VHL is often specific to the person. A multi-disciplinary team and approach are essential. A treatment team for someone with VHL may include a neurologist , neurosurgeon, medical geneticist, genetic counselor, endocrinologist, pulmonologist, nephrologist, ophthalmologist, social worker, urologist, and a primary care provider. Often there are pediatric specialists in these fields who aid in the care for children. The key is good communication between the various specialists to coordinate medical care.
There is no cure for von Hippel-Lindau disease. Treatment and management are often based on symptoms. Genetic testing has helped to identify individuals without symptoms, so medical screening may begin earlier than usual.
Most brain and spine hemangioblastomas can be treated by removal through surgery. Radiation therapy is sometimes used, if surgery is not possible. Growth patterns of these tumors can be unpredictable, so monitoring through regular imaging is important. Screening by MRI is recommended yearly, beginning at age 11.
Treatment for retinal tumors varies. Many tumors respond to laser therapy or cryotherapy. In rare cases, removal of the eye is needed to reduce severe pain or the risk for irreversible glaucoma. The key is early diagnosis and monitoring to prevent vision loss or blindness. For this reason, an ophthalmology exam is recommended first in infancy, and yearly thereafter.
Surgery may be quite successful for endolymphatic sac tumors, often preserving the hearing of a person with VHL. Radiation therapy is sometimes used for treatment, but its effectiveness is still unknown. CT and MRI scans of the internal ear canals and audiology exams are recommended if any typical symptoms develop.
Treatment for renal cell carcinoma often includes surgery, depending on the size of the affected area. Percutaneous ablation or cryoablation are experimental treatments that may work well because they are less invasive than other therapies. An abdominal ultrasound is first recommended at age eight, and then an MRI if necessary, and yearly thereafter. An abdominal CT scan is first recommended at age 18 or earlier if needed, and yearly thereafter.
Treatment for pheochromocytomas is most often by surgical removal, with an attempt to keep as much of the adrenal gland as possible. Medications such as corticosteroids are used as a treatment. Since pheochromocytomas can cause significant symptoms, it is important for the person with VHL to be screened prior to any surgery or delivery of a child. Blood or 24-hour checks of urine catecholamine and metanephrine levels are recommended beginning at age two, and yearly thereafter. They are also recommended if a person's blood pressure is raised.
Surgery is the typical treatment for pancreatic growths and cysts, depending on their specific location and size. A goal is to keep as much of the pancreas as possible. If the tumors spread, chemotherapy is sometimes necessary. As with screening of the kidneys, abdominal ultrasounds are recommended beginning at age eight, and yearly thereafter; abdominal CT scans are recommended beginning at age 18, and yearly thereafter.
Both epididymal and broad ligament cystadenomas are non-cancerous and usually cause no symptoms. Therefore, treatment for both is only recommended if symptoms arise. There are no routine screening recommendations for either type. Ultrasounds can be used to find epididymal cystadenomas, and to monitor their growth over time. Ultrasounds or CT scans can be used to identify and monitor broad ligament cystadenomas.
Recovery and rehabilitation
Though VHL typically does not affect a person's thinking, learning, or behavior, the disease can have a significant impact on a person's life. Medical appointments can be frequent, and the pain from tumors may be considerable. Feelings of guilt associated with passing a diseasecausing mutation to children have been reported in families. Professional therapy or family counseling may be helpful for some people.
As of early 2004, there are several clinical studies studying various aspects of VHL. Many are currently recruiting subjects in the United States. Trials are being conducted at several institutions, including the National Cancer Institute and National Institute of Neurological Disorders and Stroke. Further information may be obtained at <http://www.clinicaltrials.gov>.
Prognosis for someone with von Hippel-Lindau disease is highly dependent on symptoms. Those people who die may do so as a result of significant complications with tumors. Renal cell carcinomas and CNS hemangioblastomas have been the greatest causes for death in people with VHL.
The outlook for people with VHL has improved significantly. Before the advent of comprehensive medical screening, the median survival of patients with the condition was less than 50 years of age. Genetic testing now helps identify people at risk before they even develop symptoms, so screening can begin as early as possible. This has helped to reduce the risk of complications and increase the quality of life for many. Medical screening may be further tailored to the individual as scientific studies identify medical complications associated with specific VHL mutations in families.
Couch, Vicki, Noralane M. Lindor, Pamela S. Karnes, and Virginia V. Michels. "Von Hippel-Lindau Disease." Mayo Clinic Proceedings (2000) 75: 265–272.
Hes, F. J., C. J. M Lips, and R. B. van der Luijt. "Molecular Genetic Aspects of von Hippel-Lindau (VHL) Disease and Criteria for DNA Analysis in Subjects at Risk." The Netherlands Journal of Medicine (2001) 59: 235–243.
Lonser, Russell R., et al. "Von Hippel-Lindau Disease." The Lancet 361 (June 14, 2003): 2059–2067.
National Institute of Neurological Disorders and Stroke. (April 27, 2004). <http://www.ninds.nih.gov/index.htm>.
Online Mendelian Inheritance in Man. (April 27, 2004). <http://www.ncbi.nlm.nih.gov/omim/>.
Kidney Cancer Association. 1234 Sherman Avenue, Suite 203, Evanston, IL 60202-1375. (847) 332-1051 or (800) 850-9132; Fax: (847) 332-2978. [email protected] association.org <http://www.kidneycancerassociation.org>.
Deepti Babu, MS, CGC
von Hippel-Lindau Disease
von Hippel-Lindau disease
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.
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. 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 symptoms, such 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 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.
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.
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.
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, ultrasound, 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.
See Also Cancer genetics; Familial cancer syndrome; Kidney cancer
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Couch, V., et al. "von Hippel-Lindau Disease." Mayo Clinic Proceedings 75 (2000): 265-272.
Grimbert, P., et al. "Pregnancy in von Hippel-Lindau disease."American Journal of Obstetrics and Gynecology 180 (1999): 110-111.
Levy, M., and S. Richard. "Attitudes of von Hippel-Lindau disease patients towards presymptomatic genetic diagnosis inchildren and prenatal diagnosis." Journal of Medical Genetics 37 (1 June 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.
VHL Family Alliance. 171 Clinton Road, Brookline, Massachusetts 02445. (617) 277-5667, (800) 767-4VHL.Email: [email protected]. <http://www.vhl.org>. Dedicated toimproving diagnosis, treatment, and quality of life forindividuals and families affected by VHL.
The VHL Handbook: What you Need to Know about VHL. AReference Handbook for people with von Hippel-Lindau Disease, their families, and support personnel. Updated1999. <http://www.vhl.org/handbook/index.html.>.
Laura L. Stein, M.S., C.G.C.
—Not cancerous, not able to spread to new places in the body.
—A fluid filled sac that can be normal or abnormal.
—A benign tumor caused by the abnormal growth of blood vessels.
—Cancerous, able to spread to new places in the body.
—A change in the DNA code.
—An abnormal growth caused by the uncontrolled growth of cells.