Von Hippel-Lindau (VHL) disease is a rare genetic condition that is characterized by the formation of cysts and tumors, both malignant (cancerous) and benign (noncancerous), in multiple sites throughout the body. Some patients will experience a couple of tumors, while others experience many manifestations of the disease. This condition is caused by a specific gene mutation. There are ten known sites of cyst/tumor formation associated with VHL, with some of the most characteristic tumors including hemangioblastomas (tumors arising from blood vessels) and pheochromocytomas (adrenal gland tumors). VHL is also a common cause of hereditary renal cell carcinoma (kidney cancer). Although VHL is currently considered incurable, diligent surveillance and available treatment options will help to manage the disease.
What Mutation Causes VHL?
This genetic condition is caused by a mutation in the VHL gene. DNA is made up of nucleotides (the basic 'building blocks' of DNA). In VHL disease, some of these nucleotides are either dropped or out of their typical sequence. There have been several different types of mutations identified that are known to impact the functioning of the VHL gene. It is an autosomal dominant mutation. In most cases, it is inherited. Less often, the mutation occurs randomly. Each person has two copies, or alleles, of the gene. One allele is inherited from each parent to create the gene. It only takes one mutated copy of the gene to cause von Hippel-Lindau disease. The mutation has a very high penetrance. It is estimated that 97% of people with the VHL mutation will have associated symptoms. The average age for a patient to first start presenting the symptoms of the disease is approximately 26 years of age.
Read MoreHow Does the VHL Gene Work?
The VHL gene is a tumor suppressor gene. It contains the instructions to build certain proteins that will help keep tumor growth 'in check.' When this gene malfunctions, these proteins are not created, and tumors can grow more readily. Specifically, the protein that VHL encodes for targets and degrades a complex called hypoxia-inducible factor (HIF). This HIF complex aids in blood vessel formation, cell division, and gives cells the ability to tolerate changes in oxygen more easily. So, when there is no regulation of HIF, the complex continues unchecked, and tumor growth can occur more freely.
Hereditary VHL
Most often, the von Hippel-Lindau inheritance is through a family member. As mentioned, one copy of the VHL gene is received from each parent. A parent with VHL has a 50% chance of passing the mutation to their child. They can either give their offspring their non-mutated copy of the gene or the germline mutation copy. Once one copy of the gene is mutated, there will likely be a second mutation that causes the VHL gene to malfunction. The second mutation is not able to be inherited or passed to offspring, only the germline mutation.
The germline mutated allele is found in all cells within the body. It is theorized that the second mutation that makes the gene non-functioning would only be found in the tumor cells. When the disease is inherited, the mutation is identical between family members. This makes the diagnosis of the mutation easier. Although the mutation itself is the same, the manifestations may be different. Some families see trends in tumor types, but this is not necessarily always the case. Some family members may experience a few non-problematic tumors, while another family member may have malignant disease.
Inheritance Pattern
Von Hippel-Lindau inheritance is autosomal dominant. This inheritance pattern means that just one copy of the mutation causes the disease. Since the gene is dominant, it would pass from a parent with VHL to their children. It should not skip generations. However, in very unique cases, a patient may have the germline mutation but never acquire the second mutation to make the tumor suppressor gene non-functioning. They would not manifest any of the typical tumors associated with the disease. Although the patient would still have VHL that could be identified by a blood test, the lack of cyst and tumor growth may appear as if the disease had skipped a generation.
Family Planning
Patients with VHL may benefit from meeting with a genetic counselor, prior to conceiving. Due to the autosomal dominant inheritance pattern and high penetrance, the risk of passing the mutation on to offspring and that mutation leading to tumor development is quite high. People may feel differently about this risk.
Genetic counselors can help to guide patients through this decision process. In some instances, patients may choose to have a child via in vitro fertilization, which would allow the opportunity for genetic testing to be done prior to implantation. Genetic testing can also be performed during pregnancy via amniocentesis (amniotic fluid testing) or chorionic villus sampling. There are also safety concerns to address if a pregnant person has VHL. Hormone changes associated with pregnancy may exacerbate tumor growth, which is especially concerning given that treatment options would be limited during this time.
De Novo VHL
In 20% of VHL cases, the patient is the first one in their family to have the disease. This is referred to as a de novo mutation. In this instance, the mutation occurred randomly in the germ cells prior to cell differentiation and was then incorporated into every cell. There are no known causes or environmental factors contributing to this type of mutation. Without a family history of the disease, the patient would likely not be diagnosed until the patient starts showing some symptoms or manifestations. Most people are diagnosed between the ages of 12 and 35 years. Despite the mutation not being acquired through family, patients with de novo VHL would still have a 50% chance of passing on the mutation to their offspring.
Mosaicism
In some rare cases of de novo mutations, the alteration in the DNA occurs during cell differentiation, rather than before, and so the mutation is not found in every cell of the body. Rather, it can only be seen in certain particular tissues. This is called mosaicism. This can make it far more difficult to diagnose since a blood sample will not necessarily reflect the mutation. This type of mutation would only have the potential to be passed down to offspring if there were mutations in the germ cells (egg or sperm cells). If the germ cells are free of DNA alterations, then the alleles available to give to offspring would all be normal.
How is the Mutation Detected?
A blood sample is needed to perform the genetic evaluation of the VHL gene. Genetic testing is the only definitive way to diagnose VHL. If a patient has a known family history of the disease, they will likely be tested during pregnancy or early infancy in order to establish a diligent surveillance plan. The blood sample would be compared to a family member's sample with VHL since the specific mutation should be the same. However, if it is a de novo case, the sample will be compared to a database to determine if there are any similarities with other VHL patients.
As with many other hereditary conditions, genetic counseling is strongly recommended along with genetic testing. Performing a blood test to learn of a VHL diagnosis is very important to develop a surveillance plan. Tumors are easier to remove or treat the earlier they are found. However, the diagnosis is also associated with stress and anxiety. Patients should consider the importance of telling their family about their diagnosis, who may also have the disease, while balancing their own desire for medical privacy. Genetic counselors are trained to help guide patients through these complex decisions while providing necessary support and resources.
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