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.
Description
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.
Demographics
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.
Diagnosis
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 team
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.
Treatment
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.
Clinical trials
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
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.
BOOKS
Parker, James N., and Philip M. Parker. The Official Patient's Sourcebook on von Hippel-Lindau Disease: A Revised and Updated Directory for the Internet Age. San Diego: Icon Health Publishers, 2002.
PERIODICALS
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.
VHL Family Alliance. 171 Clinton Avenue, Brookline, MA 02455-5815. (617) 277-5667 or (800) 767-4VHL; Fax: (617) 734-8233. info@vhl.org. <http://www.vhl.org>.
Kidney Cancer Association. 1234 Sherman Avenue, Suite 203, Evanston, IL 60202-1375. (847) 332-1051 or (800) 850-9132; Fax: (847) 332-2978. office@kidneycancer association.org <http://www.kidneycancerassociation.org>.
