Von Hippel-Lindau syndrome (VHL)

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Von Hippel-Lindau syndrome, usually shortened to VHL, is an inherited condition that causes tumors and cysts to develop in several organs. It is caused by a change in a single gene, also called VHL. It affects roughly 1 in 36,000 people.

The tumors it causes share an unusual feature: nearly all of them are built from abnormal blood vessels or occur in tissues rich in them. The main ones are hemangioblastomas in the brain, spinal cord, and retina, clear cell renal cell carcinoma in the kidneys, pheochromocytoma in the adrenal glands, and tumors and cysts in the pancreas.

Two features set VHL apart from the other conditions in this section. Nearly everyone who carries a VHL change develops something, with penetrance approaching 100% by age 60 to 75. And unlike most hereditary cancer syndromes, VHL has an approved targeted drug. Belzutifan blocks the exact protein that becomes overactive when the gene stops working, and it can shrink tumors across several organs at once without surgery.

This article is written for people who carry a VHL change, whether or not any tumors have been found.

What does the VHL gene do?

The VHL gene makes a protein that senses how much oxygen a cell is receiving. When oxygen is plentiful, the VHL protein tags a second protein called HIF for destruction. When oxygen is scarce, that tagging stops, HIF survives, and it switches on genes that help the cell cope, including genes that tell the body to grow new blood vessels.

This is a normal and useful system. It is how tissue responds to poor blood supply.

VHL is a tumor suppressor gene, and everyone carries two copies. A person with VHL syndrome is born with one working copy and one that does not work. If the remaining copy is lost in any individual cell, that cell can no longer tag HIF for destruction. HIF accumulates permanently, and the cell behaves as though it were starved of oxygen even when it is not. It grows, and it recruits a dense new blood supply.

This single mechanism explains almost everything about the condition. It explains why the tumors are so rich in blood vessels that some are named for it. It explains why they arise in tissues where this oxygen-sensing pathway matters most. And it explains why a drug works: belzutifan blocks HIF directly, replacing the function the missing gene can no longer perform.

Tumors associated with VHL

Hemangioblastomas of the brain and spinal cord

These benign tumors are made of abnormal blood vessels and occur in roughly 60% to 80% of people with VHL, most often in the cerebellum at the back of the brain, the brainstem, and the spinal cord. They typically appear in the twenties and thirties.

Although they do not spread, they cause serious problems by growing in a confined space and pressing on the brain or spinal cord, and by developing fluid-filled cysts alongside them that enlarge faster than the tumor itself. Symptoms depend on location and include headache, unsteadiness, coordination difficulty, and weakness or numbness. These tumors and their complications are a leading cause of death in VHL, which is why brain and spine imaging is central to surveillance.

Hemangioblastomas of the retina

The same tumors occur at the back of the eye in roughly 50% to 80% of carriers, and they are often the earliest feature of the condition, sometimes appearing in childhood. They are often found on a routine eye exam before causing symptoms.

Finding them early matters. Small retinal hemangioblastomas can be treated with laser or freezing before they damage vision, while larger ones can cause bleeding, retinal detachment, and permanent sight loss. This is one of the clearest examples in medicine of surveillance preventing disability rather than simply detecting disease.

Kidney cancer and kidney cysts

Clear cell renal cell carcinoma develops in roughly 30% to 70% of people with VHL, usually from the late thirties, compared with a lifetime risk of under 2% in the general population. As with the other tumors in this condition, they are typically multiple and affect both kidneys, and new ones continue to appear over a lifetime. Kidney cysts are extremely common and are generally harmless.

Kidney cancer is one of the two leading causes of death in VHL, and the way it is managed follows directly from the fact that it keeps recurring. Removing a kidney at the first tumor would lead to dialysis within a few decades, so small tumors are watched and treatment is timed instead.

Pheochromocytoma

These tumors of the adrenal gland occur in roughly 10% to 20% of carriers overall, though the figure is far higher in some families. They release hormones that cause episodes of high blood pressure, headache, sweating, and palpitations, and blood or urine testing often detects them before symptoms appear.

They appear earlier in VHL than most of the other tumors, with an average age around 12 to 30, and in children they may be the first sign of the condition. Related tumors called paragangliomas can also occur outside the adrenal gland. An unrecognized pheochromocytoma can cause a dangerous rise in blood pressure during surgery or pregnancy, so it is checked before any operation is planned.

Pancreatic tumors and cysts

Two quite different things occur in the pancreas. Serous cystadenomas and simple cysts are common, benign, and generally need no treatment. Well differentiated neuroendocrine tumors occur in roughly 10% to 17% and can spread, so these are watched and treated when they reach a certain size.

Other tumors

Endolymphatic sac tumors — Slow-growing tumors of the inner ear, occurring in around 10%, which can cause hearing loss, ringing in the ears, and dizziness. Hearing loss from these is often permanent once it occurs, so clinicians investigate any new hearing symptoms in a carrier promptly.
Cystadenomas of the epididymis and broad ligament — Benign growths near the testicle in men and near the ovary in women. They are common in VHL and rarely cause problems, though they can occasionally affect fertility in men when both sides are involved.

How lifetime risk is estimated and why the numbers vary

Overall penetrance in VHL is genuinely very high. Close to everyone who carries a VHL change develops at least one feature, with the first tumor usually appearing in the mid-twenties and penetrance approaching 100% by age 60 to 75. Unlike most conditions in this section, that figure has not fallen substantially as testing has widened.

What varies considerably is which tumors develop, and here VHL differs from most hereditary syndromes in a useful way: the specific gene change predicts the pattern reasonably well. Families are traditionally divided into types based on whether pheochromocytoma occurs:

Type 1 — Hemangioblastomas, kidney cancer, and pancreatic tumors, with a low risk of pheochromocytoma. Usually caused by changes that remove or truncate the gene.
Type 2 — Pheochromocytoma is a prominent feature. Usually caused by single-letter changes. This group is subdivided further by whether kidney cancer risk is low (type 2A), high (type 2B), or whether pheochromocytoma occurs essentially alone (type 2C).

These categories help anticipate what to watch for, but they are not precise enough to narrow surveillance. Families with the same change can differ, and surveillance therefore covers all the at-risk organs in everyone.

Two further points affect how to read the numbers. The ranges quoted for individual tumors are wide partly because sensitive imaging finds small lesions that older studies would not have counted. And these figures describe the natural course of the condition. Median survival in VHL has historically been around 60 to 66 years, driven mainly by brain hemangioblastomas and kidney cancer, and both surveillance programs and belzutifan are recent enough that their full effect on that figure is not yet known.

Who should be tested?

Genetic testing for VHL is generally offered when:

A hemangioblastoma is diagnosed in the brain, spinal cord, or retina, at any age. These tumors are uncommon enough that a single case prompts testing.
Clear cell renal cell carcinoma occurs at a young age (generally under 46), affects both kidneys, or occurs alongside a family history.
Pheochromocytoma is diagnosed at any age, particularly when it is bilateral, occurs in a child, or is accompanied by other VHL features.
An endolymphatic sac tumor is found, or multiple pancreatic neuroendocrine tumors or cysts are present.
A known gene change has already been identified in the family.

Roughly 20% of people with VHL have a new gene change rather than an inherited one, so an absent family history does not exclude the diagnosis.

How the test is performed

Germline testing uses a blood or saliva sample and examines the DNA a person was born with. The laboratory sequences the VHL gene using next-generation sequencing and a method that detects large deletions, since a substantial proportion of VHL changes involve missing sections of the gene rather than single-letter changes. Testing detects a change in close to all people who meet the clinical criteria.

Some people carry the change in only a proportion of their cells, a situation called mosaicism, which can produce features of VHL while a standard blood test appears normal or shows the change at a lower level than expected. When the clinical picture is convincing, and blood testing is negative, more sensitive testing or testing of tumor tissue may clarify the result.

How results are reported

Pathogenic or likely pathogenic variant — A change known, or strongly expected, to stop the gene working. This confirms VHL syndrome.
Variant of uncertain significance — A change was found,d but its effect is unknown. This is not a positive result. It is managed as though negative, with monitoring guided by the clinical picture and family history, and it is never a basis for preventive surgery. Our article on variants of uncertain significance explains this result in detail.
Benign or likely benign variant — A harmless difference, usually not reported.
No variant identified — No change was found in the gene.

What the result means

A pathogenic or likely pathogenic variant confirms VHL syndrome and begins lifelong surveillance across several organs. Each child, sibling, and parent has a 50% chance of carrying the same change.

A negative result means two different things:

True negative — A specific change is already known in your family, and you tested negative for that exact change. You did not inherit it, you do not need VHL surveillance, and your children cannot inherit it from you. In a VHL family, this result releases a person from decades of annual scans and eye examinations.
Uninformative negative — No change has been identified in anyone in the family. Because testing finds a change in nearly everyone who truly has VHL, a negative result in someone with clear features raises the possibility of mosaicism or of a different condition. Several other inherited conditions cause kidney cancer or pheochromocytoma, and testing usually extends to those genes.

Germline versus somatic VHL changes

A germline change is present in the DNA a person was born with, exists in every cell, and can be passed to children. That is the syndrome.

A somatic change arises within a tumor during life, exists only in the tumor cells, and cannot be inherited.

This distinction matters unusually often for VHL, because somatic VHL changes are found in the large majority of ordinary clear cell renal cell carcinomas. Loss of this gene within a tumor is the usual first step in that cancer, whether or not anything was inherited. A pathology report or tumor sequencing panel describing a VHL change in a kidney cancer is therefore an expected finding and does not suggest the syndrome. What suggests VHL syndrome is the pattern: tumors in more than one organ, cancer in both kidneys, a young age at diagnosis, or a hemangioblastoma anywhere.

Surveillance and management

VHL surveillance is lifelong, covers several organs, and begins in childhood. It has changed the condition substantially: tumors that once caused permanent damage are now often found early, when they can still be treated.

What surveillance involves

Eye examination — Annually from early childhood, generally from around age one to five. This is the earliest surveillance to begin, because retinal tumors appear young and treating them early preserves sight.
Blood pressure and adrenal hormone testing — Annually from around age five, to detect pheochromocytoma before it causes problems.
MRI of the brain and spine — Every one to two years from adolescence.
Abdominal MRI — Every one to two years from adolescence, covering the kidneys, adrenal glands, and pancreas. MRI is preferred over CT because of the number of scans accumulated over a lifetime.
Hearing assessment — Periodically, with imaging of the inner ear if hearing changes or dizziness develops.

This is a considerable amount of medical contact sustained from childhood onward. Scans frequently find small lesions that are then watched rather than treated, and living with known tumors that are being monitored rather than removed is its own difficulty. Centers experienced in VHL are generally better placed to judge which findings need action.

The three centimeter rule for the kidney

Kidney tumors in VHL are managed by a principle that surprises people used to hearing that cancer should be removed promptly. Small tumors are watched, and surgery is generally undertaken when the largest reaches about 3 cm.

The reasoning rests on two observations. Tumors below this size have very rarely been found to spread, and new tumors keep appearing throughout life. Operating on every small tumor would mean repeated surgery and progressive loss of kidney function, ending in dialysis. Waiting until 3 cm, then removing the tumor while sparing as much kidney as possible, has been shown to control the cancer while preserving kidney function for decades. Being told that a known cancer is being watched is unsettling, and understanding why makes it easier to live with.

Treating the other tumors

Hemangioblastomas — Treated when they cause symptoms or grow, usually by surgery, sometimes by focused radiation. Those found on a scan and causing no symptoms are commonly watched, since many remain stable for years.
Retinal tumors — Treated with laser or freezing while small.
Pheochromocytoma — Removed surgically, with the surgeon aiming to preserve part of the adrenal gland, since these tumors often affect both sides and losing both glands means lifelong steroid replacement.
Pancreatic neuroendocrine tumors — Watched while small, with treatment considered as they grow.

Belzutifan

Belzutifan is a tablet that blocks HIF, the protein that accumulates when the VHL gene stops working. It is approved for adults with VHL syndrome who need treatment for kidney cancer, hemangioblastomas of the brain or spinal cord, or pancreatic neuroendocrine tumors, where immediate surgery is not required.

What makes it notable is that it treats several tumors at once and can shrink them without an operation. In the trial that led to approval, roughly half of participants had their kidney tumors shrink substantially, with responses also seen in hemangioblastomas and pancreatic tumors. For a condition in which people have historically faced repeated surgery across several organs, a medication that reduces the need for some of that surgery is a meaningful change.

It is not a cure, and it has side effects including anemia and fatigue that require monitoring. Its long-term role, including whether to start it earlier, is still being worked out. Your team can tell you whether it applies to your situation and whether you’re eligible for a clinical trial.

Testing family members

VHL is inherited in an autosomal dominant pattern, meaning a single altered copy causes it. Each child, sibling, and parent of a carrier has a 50% chance of carrying the same change, and it passes through fathers as well as mothers.

Once a specific change is identified, relatives are tested for that exact change through cascade testing.

Children are tested in infancy or early childhood. The reason is that surveillance begins earlier in VHL than in almost any other hereditary cancer syndrome: eye examinations start around age one to five, and pheochromocytoma has been found in children under ten. A child who carries the change needs annual eye examinations from the preschool years, and a child who tests negative needs none. Testing shortly after birth is common where a parent is known to carry a change.

Because roughly 20% of cases arise from a new gene change, an affected person’s parents are often unaffected. Testing may still be offered, since a parent can occasionally carry the change in only some of their cells.

Carriers planning a family sometimes ask whether they can avoid the change in their children. Preimplantation genetic testing, in which embryos created through IVF are tested before transfer, and prenatal testing are available in many places. A genetics service and a fertility specialist can work through these options together.

What happens next

For someone newly diagnosed, the first step is a full assessment of all the organs involved, since more than one is often already affected when the diagnosis is made. A surveillance schedule follows, along with referral for family testing.

For a carrier identified through family testing, the work is establishing that schedule and keeping to it across decades.

Care involves an unusually wide range of specialists, including neurosurgery, ophthalmology, urology, endocrinology, ear, nose, and throat surgery, oncology, and genetics. Coordinating them is difficult enough that referral to a designated VHL center is strongly preferred where one is available, and outcomes are better in centers that see the condition regularly.

Living with VHL means an ongoing relationship with the health system from childhood, often while carrying known tumors that are being watched. Experienced centers include psychological support as part of care, and the VHL Alliance and similar organizations connect families and maintain lists of specialist centers.

Questions to ask your doctor

Which specific VHL change was found, and does it suggest a particular pattern of tumors?
Which of my organs are currently affected, and which are being watched?
What surveillance schedule do you suggest, and which tests will I have each year?
Will my scans use MRI rather than CT, given how many I will have over a lifetime?
If a kidney tumor has been found, how large is it, and at what size would you consider treating it?
Why is a tumor being watched rather than removed?
Have my eyes been examined by an ophthalmologist familiar with this condition?
Have I been checked for a pheochromocytoma, and should that be repeated before any surgery or pregnancy?
Would belzutifan be an option for me, and what would it involve?
Should I be seen at a designated VHL center?
Which of my relatives should be tested, and at what age should my children be tested?
What surveillance would my children need, and when would it start?
What reproductive options are available if I want to avoid passing this on?
Is psychological support or a patient organization available to my family?