Von Hippel-Lindau Syndrome (2022)

What is von Hippel-Lindau disease?

Von Hippel-Lindau syndrome (VHL) is a hereditary condition associated with tumors arising in multiple organs. VHL-related tumors include hemangioblastomas, which are blood vessel tumors of the brain, spinal cord, and retina. The retinal tumors are also called retinal angiomas, which can lead to blindness if not treated in a timely manner. People with VHL also have an increased risk of developingclear cell renal cell carcinoma(ccRCC), which is a specific type of kidney cancer, as well as a type of tumor in the pancreas known aspancreatic neuroendocrine tumor(pNET). Tumors of theadrenal glandorpheochromocytomacan also develop, with a small number becoming metastatic, meaning they spread to other parts of the body.

Other features of VHL include: kidney cysts, which are closed sacs usually filled with fluid; pancreatic cysts, epididymal cystadenomas, which are tumors near a man’s testicles; broad ligament cystadenomas, which occur near the fallopian tubes in women; and endolymphatic sac tumors (ELST), which are tumors of the inner ear that may cause hearing loss.

What causes VHL?

VHL is a genetic condition. This means that the risk of developing certain types of tumors and other features of VHL can be passed from generation to generation. The gene associated with VHL is also calledVHL. Inheriting a deletion or mutation (alteration) in theVHLgene gives a person an increased risk of developing any of the different signs of VHL explained above, called manifestations. Nearly everyone who has VHL syndrome has an identifiableVHLgenetic mutation.

How is VHL inherited?

Normally, every cell has 2 copies of each gene: 1 inherited from the mother and 1 inherited from the father. VHL follows an autosomal dominant inheritance pattern, in which inheriting 1 copy of the altered gene will likely result in a mutation of the second (normal) copy of the gene. This puts the individual at risk for developing cancer.

A parent with a gene mutation may pass along a copy of their normal gene or a copy of the gene with the mutation. Therefore, a child who has a parent with a mutation has a 50% chance of inheriting that mutation. A brother, sister, or parent of a person who has a mutation also has a 50% chance of having the same mutation. Up to 10% of individuals with VHL have no family history. This means that these individuals have ade novomutation and are the first in their family to have this genetic change.

When considering having children, it is advised that a person with VHL discuss future family planning with their partner and make a decision that is the best for them. Some people are more comfortable with the idea of the possible risk of hereditary VHL than others. Some people with VHL feel very worried and anxious about the risk of passing the mutation on. Meeting with a genetic counselor will help you understand all the options available to make the best decision for your family. There are different family planning options available to individuals who have VHL and are considering having children. Some of these options allow someone to have a child unaffected with VHL, and other options simply provide more information about a pregnancy. These options are choices, not a requirement. Many people choose to start a family without doing any genetic or prenatal testing. It is also important to consider that, at this time, there is no clear answer as to whether pregnancy, long term use of hormonal birth control, hormone replacement therapy, or high doses of hormones used for procedures like in vitro fertilization can promote tumor growth for women with VHL.

How common is VHL?

It is estimated that about 1 in 30,000 people has VHL. About 10% of people with VHL do not have any family history of the condition. They have ade novomutation, meaning a new mutation in theVHLgene not present in their parents.

(Video) Medical Marvels - Von Hippel-Lindau Disease

How is VHL diagnosed?

The only way to diagnose VHL is withgenetic testing. Nearly all people with VHL will be found to have a genetic mutation in theirVHLgene once tested.

There are no universal guidelines regarding who should be screened for VHL. However, VHL should be suspected when a person has:

  • Multiple hemangioblastomas of the brain, spinal cord, or eye, or

  • 1 hemangioblastoma and ccRCC, pancreatic cysts, pheochromocytoma, endolymphatic sac tumor, or a epididymal cyst

  • When a younger person has multiple bilateral ccRCC, meaning cancer in both kidneys

If a person has a family history of VHL, they are suspected of also having VHL if the person has any 1 symptom, such as hemangioblastoma of the brain, spine, or eye, kidney cancer, pancreatic cysts, pheochromocytoma, or endolymphatic sac tumor.

A list of signs and symptoms called VHL Referral Criteria can be foundhere. Please note that this link takes you to a separate, independent website.

What are the estimated manifestation risks associated with VHL?

  • Retinal hemangioblastomas: about 60%

  • Cerebellar hemangioblastomas: 44% to 72%

  • Kidney cancer/ccRCC: 25% to 60%

    (Video) Von Hippel-Lindau

  • Epididymal cystadenomas: 25% of 60% of males with VHL

  • Spinal cord hemangioblastomas: 13% to 50%

  • Endolymphatic sac tumors (ELSTs): 10% to 25%

  • Brain stem hemangioblastomas: 10% to 25%

  • Pheochromocytomas/paragangliomas: 10% to 20%

  • Pancreatic neuroendocrine tumors: 9% to 17%

  • Broad ligament cystadenomas: about 10% of females with VHL

Would the treatment of kidney cancer change if I have VHL? (updated 09/2021)

In general, treatment for kidney cancer is similar regardless of whether a patient has VHL. However, there is some evidence about specific VHL considerations regarding surgery. For a person with VHL and kidney cancer, surgery for a kidney tumor is generally considered when the largest tumor reaches 3 centimeters (cm) in size. Preserving the kidney’s function with the intent of preventing or delaying dialysis is an important part of the current surgical approach to VHL, and surgeons generally try to remove kidney tumors while trying to leave as much normal kidney behind as possible (called nephron sparing surgery or partial nephrectomy). This is generally done with enucleative resection, taking zero margins as the tumor capsule is separated from the surrounding adjaent parenchyma. Similarly, the main treatment for tumors arising in other organs is also surgery, which is done when the tumor reaches a specific size or causes symptoms.

For individuals with metastatic kidney cancer,treatment optionsusing systemic therapy with medication are similar to those for patients with ccRCC unrelated to VHL, including tyrosine kinase inhibitors (TKIs) and checkpoint inhibitors (PD-1/PD-L1 and CTLA-4). Researchers are also actively investigating the use of systemic medications earlier in the disease stage when patients cannot have surgery.

There is one approved treatment for people with VHL disease and associated RCC, central nervous system (CNS) hemangioblastoma, or pNET that does not require immediate surgery. Belzutifan (Welireg) is a medication taken by mouth (orally) that targets hypoxia-inducible factor-2 alpha (HIF2a). In people with VHL disease as well as most forms of non-hereditary ccRCC, HIF2a activates more than 100 critical targets that contribute to tumor growth. A recent study (NCT03401788) included 61 people with VHL-associated tumors, mostly in the kidney, that did not need surgery right away. In this study, 27.2% of the kidney tumors responded to the treatment. However, the treatment stopped or stabilized more than 80% of cancerous lesions in the kidney. CNS hemangiomas and pNETs also responded to this medication. The researchers found that belzutifan had manageable side effects, and more than 95% of the study participants have remained on this medication for more than 1 year at the time of approval.

(Video) "von Hippel-Lindau Disease", a scientific lecture by Nobel Laureate William G. Kaelin

What are the suggested screening guidelines for VHL?

Screening for new tumors or active surveillance for known tumors are both very important aspects of VHL care. If tumors are found early, there is a much better chance that treatment will be successful. There are clear recommendations on the frequency and type of screening that should be performed. As VHL manifestations can vary, recommendations for a person's medical surveillance will change over their lifetime. These recommendations are expected to change over time as more information is made available and new technologies are developed specific to VHL. It is important to talk with your health care team about appropriate screening tests.

Learn more about the screening recommendations to detect early disease manifestations onthe VHL Alliance website, which is a separate organization.

Questions to ask the health care team

If you are concerned about your risk for developing cancer, talk with your health care team. It can be helpful to bring someone along to your appointments to take notes. Consider asking your health care team the following questions:

  • What is my risk of developing kidney cancer?

  • What is my risk of developing other types of cancer?

  • What can I do to reduce my risk of cancer?

  • What are my options for cancer screening?

  • When issurgeryneeded to remove tumors?

If you are concerned about your family history and think your family may have VHL, consider asking the following questions:

  • Does my family history increase my risk of developing kidney cancer or other types of tumors?

    (Video) Living with Von Hippel-Lindau Disease

  • Does my family history suggest the need for a cancer risk assessment?

  • Will you refer me to a genetic counselor or other genetics specialist?

  • Should I considergenetic testing?

Related Resources

The Genetics of Cancer

Genetic Testing

What to Expect When You Meet With a Genetic Counselor

Collecting Your Family Cancer History

Sharing Genetic Test Results with Your Family

More Information

VHL AllianceMyVHL: Patient Natural History Study

National Cancer Institute

: Genetics of Kidney Cancer
(Video) Von hipple-Lindau Disease ( VHL ) - Case based discussion USMLE

To find a genetic counselor in your area, ask your health care team or visit the following website:

National Society of Genetic Counselors

FAQs

Can von Hippel-Lindau syndrome be cured? ›

How Is Von Hippel-Lindau Syndrome (VHL) Treated? Although there is no cure for VHL, the associated tumors can be treated. Early detection and treatment of tumors significantly improves a patient's diagnosis. Left untreated, VHL may result in blindness, permanent brain damage, or death.

How long do people with VHL live? ›

Many studies indicated that the survival of VHL disease patients was worse than the general population. A study in 1990 showed that the median survival was 49 years (14). A recent study reported the estimated life expectancy for male and female patients was 67 and 60 years, respectively (15).

How many people get VHL? ›

VHL syndrome affects one in 36,000 people. Because VHL syndrome is genetic, there is a chance that your relatives may have the mutation as well. Eighty percent of cases are inherited from a parent who has VHL syndrome.

Can VHL skip a generation? ›

Some people who have inherited a germline VHL mutation never develop cancer. This is because they never get the second mutation necessary to knock out the function of the gene and start the process of tumor formation. This can make the cancer appear to skip generations in a family.

Can people with VHL have children? ›

If one parent has VHL, the couple has a 50% chance of passing on VHL to any child they have. Whether or not a child has VHL, they will be impacted by VHL because they have a parent with VHL. Additionally, VHL can impact reproductive health for both men and women with VHL.

At what age does VHL present? ›

The mean age of onset of 26 years and 97% of people with a VHL gene mutation have symptoms by the age of 65. VHL disease affects males and females and all ethnic groups equally, and occurs in all parts of the world.

How serious is VHL? ›

Left untreated, even noncancerous tumors can lead to blindness or brain damage. Tumors in the kidneys or pancreas are much more likely to be cancerous. Finding and removing these tumors at their earliest stages can be lifesaving. Careful monitoring and early treatment greatly improve the prognosis for people with VHL.

Is VHL a disability? ›

Malignant VHL that is resistant to treatment, is inoperable, or which recurs following initial treatment, can qualify you for disability benefits. Benign forms of the disease can as well, if they result in such severe limitations that they prevent you from working for a period of one year or are expected to do so.

How do you test for VHL? ›

The only way to diagnose VHL is with genetic testing. Nearly all people with VHL will be found to have a genetic mutation in their VHL gene once tested. There are no universal guidelines regarding who should be screened for VHL.

Is VHL rare? ›

Von Hippel-Lindau disease (VHL) is a rare disease that causes tumors and cysts to grow in your body. They can grow in your brain and spinal cord, kidneys, pancreas, adrenal glands, and reproductive tract. The tumors are usually benign (non-cancerous).

What type of doctor treats Von Hippel-Lindau? ›

Individuals with suspected or confirmed Von Hippel-Lindau (VHL) disease are seen in Mayo's VHL Clinic by a highly skilled team of experts. This experienced team includes a medical geneticist, ophthalmologist, urologist and other specialists as dictated by the particular problem.

What cancers does VHL cause? ›

People with von Hippel-Lindau syndrome commonly develop cysts in the kidneys , pancreas , and 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 pancreatic cancer called a pancreatic neuroendocrine tumor.

Is VHL an autoimmune disease? ›

Von Hippel-Lindau syndrome (VHL) is an autosomal dominant disorder characterized by renal cysts, retinal angiomas, central nervous system hemangioblastomas, and pancreatic cysts. Evan's syndrome is a hematologic disorder characterized by autoimmune thrombocytopenia and autoimmune hemolytic anemia.

Where is VHL located? ›

The VHL gene is a tumor suppressor gene located on chromosome 3, which usually controls cell growth and cell death.

How does the VHL gene work? ›

The VHL gene provides instructions for making a protein that functions as part of a complex (a group of proteins that work together) called the VCB-CUL2 complex. This complex targets other proteins to be broken down (degraded) by the cell when they are no longer needed.

Are there different types of VHL? ›

The differential diagnosis of VHL contains all types of VHL-associated tumors as isolated entities, including retinal hemangioblastoma, renal cell carcinoma, and CNS hemangioblastoma, pheochromocytoma, pancreatic tumors, and endolymphatic sac tumors.

What is Von Hippel-Lindau disease? ›

Von Hippel-Lindau disease (VHL) is a rare disease that causes tumors and cysts to grow in your body. They can grow in your brain and spinal cord, kidneys, pancreas, adrenal glands, and reproductive tract. The tumors are usually benign (non-cancerous).

What is Hemangioblastoma of the brain? ›

A hemangioblastoma is a tumor that grows in the blood vessels of your brain, spinal cord or retina. It isn't cancerous, but it may grow and press on surrounding tissues. Usually, healthcare providers recommend removing a hemangioblastoma with surgery.

Can you have multiple benign tumors? ›

Type 1 (NF-1), also called von Recklinghausen's disease, causes multiple benign (noncancerous) tumors of the nerves and skin.

Videos

1. What is Von Hippel-Lindau Disease?
(CheckRare)
2. von Hippel Lindau Disease (Mnemonic for the USMLE)
(AJmonics)
3. Learn About Ocular von Hippel-Lindau Disease With Dr. Henry Wiley
(National Eye Institute, NIH)
4. Von Hippel Lindau disease - Case based discussion Usmle step 1 Pathology
(Dr.G Bhanu Prakash Animated Medical Videos)
5. Von Hippel Lindau Syndrome
(PATHOLOGY MASTER)
6. Belzutifan for Von Hippel-Lindau syndrome
(VJOncology)

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