NORD gratefully acknowledges the VHL Alliance and their Clinical Advisory Council for assistance in the preparation of this report.
Von Hippel-Lindau disease (VHL) is caused by a gene mutation which frequently induces both nonmalignant tumors and malignant tumors (or cancers) that can spread to other organs (become metastatic). Tumors may develop in up to ten different parts of the body. Many of these tumors involve the abnormal growth of blood vessels in different organs of the body. Most of these tumors are benign, meaning that they stay in the same organ where they began. However, VHL tumors in the kidney and pancreas can grow to a stage where they become “malignant,” meaning that the cancer can spread to other parts of the body.
Because VHL can cause malignant tumors, it is considered one of a group of familial cancer risk factors, which are transmitted genetically. The objective is to find tumors early, watch for signs that a tumor is growing, and to remove or disable the tumor before it invades other tissues. Benign tumors may also need treatment or removal if their growth will cause symptoms.
VHL has no single primary symptom, does not occur exclusively in one organ of the body, and does not always occur in a particular age group. The condition is hereditary, but the health problems of affected families, and the organs involved are so varied, that the common cause may not be recognized for many years. In addition, the appearance and severity of VHL lesions are so variable that many members of the same family may have only some relatively harmless issue, while others may have a serious illness.
If there is a positive DNA diagnosis of VHL, it is important to begin surveillance testing early before any symptoms occur. Most VHL lesions are much easier to treat when they are small. A number of possible complications of VHL are “silent”—there may be no symptoms until the problem has developed to a critical level. Treatment may only be able to stop symptoms that have occurred; it is not always possible to reverse the changes and go back to normal.
Age at onset varies from family to family and from individual to individual. Pheochromocytomas (adrenal tumors) are very common in some families, while clear cell renal cell carcinomas (kidney tumors) are more common in other families. Individuals within a family may differ as to which tumor types they have, although they all share the same VHL gene mutation.
The most common symptom of VHL is hemangioblastomas (also called angiomas). These are benign tumors occurring in the brain, spinal cord and retina (back of the eye) in individuals with VHL and appear as knots formed by tiny blood vessels. Although these tumors are benign, in the brain or spinal cord the pressure they exert may cause symptoms. Hemangioblastomas may press on nerve or brain tissue and cause symptoms such as headaches, problems with balance when walking, or weakness of arms and legs. In the eyes, blood or fluid leakage from hemangioblastomas (also called retinal capillary hemangioblastomas or retinal angiomas) can interfere with vision. Early detection, careful monitoring of the eyes and prompt treatment are very important to maintain healthy vision.
Cysts may grow around hemangioblastomas and other VHL tumors. Cysts are fluid-filled sacs which may exert pressure or create blockages that can cause symptoms. Early signs of adrenal tumors may be high blood pressure, panic attacks, or heavy sweating. Early signs of pancreatic cysts and tumors may include digestive complaints like bloating, or disturbance of bowel and bladder function. Some of these tumors are benign while others may become cancerous. Kidney tumors and cysts (clear cell renal cell carcinoma) may lead to reduced kidney function, but there are usually no symptoms in the early stages. Kidney tumors will metastasize if not removed when they reach approximately 3 cm in diameter.
VHL may also cause a benign tumor behind the inner ear called an endolymphatic sac tumor. If not removed, this tumor can lead to complete loss of hearing in the affected ear as well as balance problems. Less common manifestations of VHL include benign reproductive tract tumors in both men and women, and rare occurrences of hemangioma in the liver, spleen, and lungs.
VHL is caused by an alteration in one of the two copies of a gene referred to as the VHL gene. This altered gene may be transmitted to children following an autosomal dominant pattern of inheritance, meaning that it is not limited to one sex, but may occur in both men and women. It also means that only one gene mutation is needed to produce the disease. Each child receives one gene of each pair from each parent. If one parent has an alteration (mutation) in a dominant gene, each child has a fifty-fifty chance of inheriting that gene and subsequently developing manifestations of the mutated gene.
Although some people with VHL have few tumors and virtually no symptoms, VHL does not skip generations. Unless there is a de novo mutation, every child with VHL must have a parent with VHL. There are certain people, approximately 20%, who are the first in their family to have an alteration in the VHL gene. Neither parent is affected, but these people have VHL. They are considered “de novo,” for the first time. This “new mutation” is caused by a change in the gene in either one sperm from the father, in one egg from the mother, or in the copying of the gene during one of the first stages of division of the embryo. This alteration in the VHL gene can now be passed on to future children of this affected person. It necessitates medical screening of these children as well.
VHL affects males and females equally and all ethnic groups, and countries. The incidence is 1 in 36,000 births.
Detection of affected individuals by DNA analysis of a blood sample is now possible for nearly all VHL families. The accuracy of the testing and its usefulness in most families is increasing rapidly. DNA testing can be used to determine which members of the family need to be followed closely. It can also determine which members may be reassured that they do not carry the VHL gene mutation. If family members do not have the altered VHL gene previously identified in the family, they will not need further testing or annual screening. They also do not have an altered gene to pass to their children.
If you are positive for VHL or if genetic testing is not yet available for your suspected VHL mutation, but you have been clinically diagnosed, you will need to continue regular medical screening tests. One normal screening examination does not necessarily mean there is no VHL present, since the first evidence of VHL may occur later in life. Occasionally a person may be so mildly affected that VHL may seem to skip a generation. VHL has been diagnosed for the first time in people as old as 80, often because their children or grandchildren developed VHL tumors.
Even if there is no family history of VHL, when any suspected VHL tumor is found, a diagnosis of VHL should be considered, and a full diagnostic evaluation of other areas of the body should be carried out. It is quite possible for someone to be the first in their family to have VHL. It is estimated that no DNA mutation or deletion can be found in approximately 10% of people clinically diagnosed with VHL. These people have VHL, but current DNA testing has not been able to find their specific VHL mutation. In some cases, the VHL mutation is present only in certain cells, but not in all cells, making the person “mosaic” for VHL.
Clinical testing and Work-Up
The VHL surveillance guidelines (https://vhl.org/professionals/screening-diagnosis/importance-of-screening/) were developed to prevent VHL tumors from becoming metastatic.
There are no universal treatment recommendations; treatment options can only be determined by careful evaluation of the individual patient’s total situation—symptoms, test results, imaging studies, and general physical condition. The following are offered as general guidelines for possible treatment therapies.
Brain and Spinal Hemangioblastomas
Symptoms related to hemangioblastomas in the brain and spinal cord depend on tumor location, size, and the presence of associated swelling or cysts. Symptomatic lesions grow more rapidly than asymptomatic lesions. Cysts often cause more symptoms than the tumor itself. Once the lesion has been removed, the cyst will collapse. If any portion of the tumor is left in place, the cyst will re-fill. Small hemangioblastomas which are not symptomatic and are not associated with a cyst have sometimes been treated with stereotactic radiosurgery, but this is more a preventive than a treatment, and long-term results seem to show only marginal benefit.
Pancreatic Neuroendocrine Tumors
Careful analysis is required to differentiate between serious cystadenomas and pancreatic neuroendocrine tumors (pancreatic NETs). Cysts and cystadenomas generally do not require treatment. Pancreatic NETs should be rated on size, behavior, and DNA type.
Renal Cell Carcinoma
VHL kidney tumors are often found at very small sizes and at very early stages of development. A strategy for ensuring that an individual will have a sufficient functioning kidney throughout his or her lifetime begins with careful monitoring and choosing to operate only when tumor size or rapid growth rate suggest the tumor may gain metastatic potential (at approximately 3 cm). The technique of kidney-sparing surgery is widely used in this setting. Radio frequency ablation (RFA) or cryosurgery (cryotherapy) may be considered, especially for smaller tumors at earlier stages. Care must be taken not to injure adjacent structures and to limit scarring which may complicate subsequent surgeries.
Small peripheral lesions can be successfully treated with little to no loss of vision using laser. Larger lesions often require cryotherapy. If the hemangioblastoma is on the optic disc, there are few treatment options that will successfully preserve vision. The optimal treatment would be a drug, but to date none has proven successful.
Surgical removal is performed after adequate blocking with medication, and laparoscopic partial adrenalectomy is preferred. Vital signs are carefully monitored for at least a week following surgery while the body readjusts to its “new normal.” Special caution is warranted during surgical procedures of any type and during pregnancy and delivery. Even pheos that do not appear to be active or causing symptoms should be removed, ideally prior to pregnancy or non-emergency surgery.
Endolymphatic Sac Tumors (ELSTs)
Patients who have a tumor or hemorrhage visible on MRI but who can still hear, require surgery to prevent a worsening of their condition. Deaf patients with evidence on imaging of a tumor should undergo surgery if other neurological symptoms are present in order to prevent worsening of balance problems. Not all ELSTs are visible with imaging; some are only found during surgery.
Two types of research are needed to ultimately find a cure for VHL: basic science to understand exactly how a VHL mutation causes a tumor to form in a specific organ, and clinical research to learn which medications, surgeries, and lifestyle interventions prevent tumor formation, or slow or even reverse tumor growth. Everyone with VHL can be an important part of the clinical research effort. Participation is needed in all types of clinical research in order to have enough people tested to draw scientific conclusions. In-person clinical trials are listed here:
The Cancer in our Genes International Patient Databank is an online clinical research study open to everyone diagnosed with VHL or with symptoms of VHL. In 2014, the VHL Alliance, in partnership with NORD, launched a first of its kind patient databank. The Databank is an innovative and comprehensive clinical research study designed through the work of an International Task Force made up of some of the leading VHL researchers and clinicians in the world.
The information from the Databank is helping researchers to:
1. Better understand the natural history of VHL
2. Determine the relationship between lifestyle and VHL progression
3. Identify best practices for VHL treatment and diagnosis
4. Identify patients to participate in future clinical trials—as a means of accelerating a cure.
The Databank also includes conditions similar to VHL including hereditary leiomyomatosis and renal cell cancer (HLRCC), Birt-Hogg-Dubé (BHD), and succinate dehydrogenase complex (SDH). This will allow researchers to learn from the similarities and the differences of these related genetic cancer conditions.
For more information visit:
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
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