VHL (Von Hippel-Lindau Tumor Suppressor)

Von Hippel-Lindau (VHL) is a rare genetic disorder that involves the abnormal proliferation of tumors and cysts that can affect as many as ten different parts of the body. It’s caused by a flaw in the VHL gene which regulates normal cellular growth.

We've reviewed legitimate scientific information to give you the most accurate information available about von Hippel-Lindau Syndrome (VHL).

What Is VHL?

Von Hippel-Lindau Syndrome is known by many synonyms, including “VHL”, “VHL syndrome,” and “VHL disease.” It is also sometimes referred to as “familial cerebello retinal angiomatosis.”

This rare genetic disorder arises from a mutation of the VHL gene which encodes the Von Hippel-Lindau Tumor Suppressor, or pVHL. This is a protein that prevents cells from uncontrolled growth and division and a component of E3 ubiquitin–protein ligase activity ¹.

The most significant characteristic of VHL disease are tumors, which can occur in many organs. Retinal angiomas affect the eyes; endolymphatic sac tumor, the ears; hemangioblastomas, the brain or the spinal cord; pheochromocytoma, the adrenal glands; pancreatic neuroendocrine tumors, the pancreas; and epididymal cystadenomas, the testicles.

If detected and operated on early, the damage caused by these tumors can be prevented. If, however, the tumors are undetected and grow, they can cause permanent damage.

For example, retinal angiomas can cause blindness and endolymphatic sac tumor can cause hearing loss.

People with Von Hippel-Lindau disease also have cysts, which are closed sacs with fluids. Kidney cysts and pancreatic cysts are among the most common.

Although these tumors tend to be benign, certain kinds affecting the kidneys or pancreas can become carcinogenic. A kidney tumor, for example, may be responsible for clear cell renal cell carcinoma.

How Common Is Von Hippel-Lindau Syndrome?

How many people are affected by Von Hippel-Lindau disease? It is a rare condition.

About 1 in 36,000 people have it. What’s more, about 20% of those who have it did not have a family history of it.

These are classified as de novo mutation, meaning they are a new VHL gene mutation.

What Chromosome Is Affected by VHL?

VHL gene mutation occurs on human chromosome 3p25.

(Since it’s identified as number 93300 in the Online Mendelian Inheritance in Man (OMIM), an authoritative compendium of human genes, it is OMIM 19330.)

Causes of VHL

VHL is an autosomal dominant genetic disorder.

It's caused by deletions or mutations of a tumor suppressor gene on human chromosome 3p25.

Is VHL Hereditary?

Von Hippel-Lindau Syndrome is hereditary. Parents pass it down to their biological children.

How Is VHL Inherited?

Those affected by von Hippel-Lindau syndrome inherit an altered copy of the gene from a parent with the disease. This inheritance follows an autosomal pattern.

With this pattern, a single copy of an altered gene in each cell is enough to increase the risk of a person getting VHL disease. Those born with the condition have a working copy and an altered copy, and it this alteration that is the genetic mutation.

Destabilization of the second copy causes the growth of VHL tumors and cysts.

Can VHL Be Prevented?

It is not possible to prevent Von Hippel-Lindau disease because people with VHL inherit it.

Since it’s an autosomal dominant disorder, the offspring inherits the mutation.

What Is the Estimated Cancer Risk Associated with VHL?

VHL has a familial cancer risk factor for clear cell renal cell carcinoma.

Hypoxia-inducible transcription factor ² (HIF) plays an important role in creating clear cell kidney cancer because it decreases the oxygen in the environment of the cells. Angiogenesis ³ also contributes to the proliferation of cancer cells.

This is the biological process of making new blood vessels from existing vessels.

The estimated cancer risk is difficult to estimate for people with VHL. Out of 60,000 people estimated to get kidney cancer each year, 75% will have clear cell renal cell carcinoma.

Out of this population who have clear cell carcinoma, there is not enough data on how many also have VHL because the incidence of VHL disease affects only one person in 36,000.

Diagnosis of VHL

Since VHL is a rare multi-system genetic disorder there are a vast array of symptoms.

When examining a patient for VHL disease, a doctor will ask the patient if they have the following symptoms:

• Frequent headaches.
• Ataxia (impaired coordination, often experienced as problems with balance or walking)
• Nystagmus ( eyes repeatedly move involuntarily)
• Vision problems
• Back pain
• Frequent hiccups
• Numbness in body parts
• Dizziness
• Weakness in the limbs
• Deafness in one ear
• High blood pressure

Sometimes, just a few apparently innocuous symptoms are enough to suggest an underlying cause. For instance, if a person has frequent headaches, hiccups, back pains, and numbness, then it suggests hemangioblastoma affecting the brain or spinal cord.

If the patient has a cluster of symptoms, the doctor may then request scanning for benign tumors and visceral cysts. Non-cancerous tumors grow in many parts of the body.

Hemangioblastomas, for example, are benign tumors with many blood vessels that develop in the brain, in the spinal cord, in the retinas of the eyes, or close to the inner ear. Cysts are fluid-filled sacs that develop around hemangioblastomas.

Other types of tumors are also possible, developing in the adrenal glands, in the kidneys, or in the pancreas.

Although most tumors are benign, they have the potential of a malignant transformation. However, even if the tumor is benign, it must be removed because once it grows it will press against other organs and disrupt their functions.

Incidentally, these tumors and cysts don’t follow a recognizable pattern but vary in size and location between individuals.

Once a diagnosis is made, it should be confirmed through genetic testing.

How Do Doctors Test for VHL?

A doctor may suspect VHL if the patient has a family history of the disease and at least one of the following conditions:

• Kidney cysts
• Pancreatic cysts
• Hemangioblastoma in the eye
• Hemangioblastoma in the cerebellum of the brain
• Hemangioblastoma in the brain stem
• Hemangioblastoma in the spinal cord
• VHL skin manifestations like cold and clammy skin.
• Pheochromocytoma, a rare tumor affecting adrenal gland tissue.
• Kidney cancer.
• Parasympathetic paragangliomas ⁴, a rare neuroendocrine neoplasm associated with parasympathetic nervous system ganglia

One of these alone might be the only sign of VHL. The doctor must confirm a diagnosis through genetic testing.

Genetic Tests for VHL — Are They Available?

Genetic tests are available and they have a high degree of accuracy in detecting a mutation in the VHL gene.

If someone has VHL, testing will discover the genetic mutation.

Genetic testing involves collecting a blood sample, isolating the DNA from the blood samples, and checking both copies of the VHL gene for alterations.

DNA Tests Currently Available for VHL

DNA tests are available for alterations in the VHL gene and include testing before or during pregnancy.

These tests have a high reliability. Once tested, it is easy to confirm if someone has a genetic mutation.

The tests are also getting better in many ways. They can identify which family members need regular medical checkups and which family members do not carry the altered VHL gene.

Occasionally, tests can yield unexpected results:

• A person may have such a mild form of VHL that it skips a generation. People in their 80s might discover they have VHL only after their grandchildren developed tumors and cysts.
• A family member with VHL may only have VHL mutation in some cells, not all cells.
• A person may be the first in their family to have the disease because it is a new mutation of the VHL gene. The identification of VHL mosaic mutations ⁵ is possible through next-generation sequencing (NGS).

Are There Prenatal Tests for Von Hippel-Lindau Syndrome?

Prenatal genetic tests are useful when family medical history shows a known VHL mutation.

A test for genetic information about the baby can be done before the pregnancy or during it.

Before considering testing, it’s advisable to work with a genetic counselor. They can help with the stress of taking the tests and coping with feelings after the results of the tests.

They can also provide any VHL answers when discussing the genetic findings.

Genetic testing can be done for known VHL mutations.

Testing Before Pregnancy

A preimplantation genetic diagnosis (PGD) test is done together with in vitro fertilization (IVF), the process when the egg and sperm are combined outside the body. The embryo is tested for a VHL mutation before it is placed in the uterus.

Testing During Pregnancy

Chorionic villus sampling (CVS) is used for the first three months (first trimester) while amniocentesis is used during the last six months (during or after the second trimester).

After collecting the tissue, a lab will check chromosome 3p25 to see if it has a known VHL mutation in the family.

Before testing during pregnancy, a woman should speak to a genetic counselor or a physician because there is a small risk of a miscarriage.

Treatment Options for Von Hippel-Lindau Syndrome

No cure is available for Von Hippel-Lindau Syndrome (VHL). Early discovery and treatment of tumors are essential.

If undetected or not removed, tumors can grow bigger, causing serious health issues. Tumors have to be cut or shrunk before they grow and cause harm.

A large tumor can put pressure on the brain or on the spinal cord or block cerebrospinal fluid in the central nervous system. It could cause death, brain damage, blindness, or deafness.

Treatments Available for VHL-Related Cancers

Treatment depends on the size and location of the tumor. Here are a few examples of treatments available for different types of hemangioblastomas.

• Hemangioblastomas in the Central Nervous System
  When it comes to Von Hippel-Lindau radiology, doctors prefer to use stereotactic radiology to shrink the tumors. Tumors are less likely to regrow after this safe, non-invasive method. While microsurgery would also remove the tumors, they tend to re-grow.

• Hemangioblastomas in the Retina 
  The best option is laser treatment.

• Hemangioblastomas in the Kidney 
  The best option for renal cell carcinoma is nephron-sparing surgery. It removes the tumor without affecting the healthy parts of the kidney.
  The other, more drastic alternative, is nephrectomy, removing the whole kidney.

Does the Treatment of Certain Cancers Change If a Patient Has VHL?

Someone with VHL is at risk for kidney cancer. Their treatment will be similar to that provided for patients without VHL.

Screening Options for VHL

Screening options depend on VHL patients since each has unique conditions.

However, generally speaking, the patient should get the following annual screening options:

• An eye examination to detect retinal tumors; starting at 2 years of age.
• A physical examination.
• A blood test and urine test to notice elevated catecholamines; starting at 5-years of age.
• An ultrasound to screen kidneys, pancreas, and adrenals; starting at 13- years of age. During adulthood, testing could change to CAT scans or MRIs.
• Hearing assessment.

A doctor may change this yearly screening schedule based on the growth rate of tumors.

The Prognosis for VHL

The prognosis varies on the frequency and complexity of the tumors. In general, regular screening will increase Von Hippel-Lindau syndrome life expectancy, and a doctor familiar with VHL disease will be in the best position to provide Von Hippel-Lindau syndrome differential diagnosis.

At a minimum, yearly screening is essential to improve outcomes because it gives doctors a chance to detect any tumors early before they grow and damage vital organs or cause death from kidney cancer or brain tumors.

Does VHL Go Away?

Since VHL is a hereditary disorder it does not go away. A person cannot outgrow it, nor is there any treatment modality to make it go into remission or fade away over time.

Is There a Cure for VHL?

There is no cure for VHL. So, Von Hippel-Lindau syndrome treatment consists of regular screening. Once detected, tumors should be removed in the least harmful way, like non-invasive procedures to shrink tumors or surgery that spares healthy tissue under the tumor.

Conclusion

VHL disease is a rare genetic disorder characterized by the growth of tumors and cysts. These might grow in almost any organ and show up in the reproductive tract, adrenal glands, pancreas, spinal cord, and brain.

Most are non-cancerous, except those affecting the kidney or pancreas.

The inheritance of VHL is based on autosomal disorder patterns. Normally, every cell has two copies of a gene — one copy comes from the mother, the other from the father.

In an autosomal dominance pattern, getting a single copy of an altered gene is enough to get VHL disease. Since a parent who has a gene mutation may either pass on a normal gene or a copy of the mutated gene, a child has a 50% chance of inheriting the mutation.

A doctor may suggest a genetic test for Von Hippel-Lindau syndrome inheritance for confirmation of a diagnosis. Treatment consists of regular screening by health care teams familiar with the disorder.

Early detection is essential because surgery is necessary to remove tumors before they grow and cause permanent damage.

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