Von Hippel Lindau (VHL) disease is considered a rare genetic condition that impacts an estimated 200,000 people across the globe. Caused by a mutation on the VHL gene, the disease can prevent the body’s normal tumor-suppressing capabilities from working correctly. Patients born with this mutation on one gene will likely have a mutation develop on the corresponding normal gene, resulting in a higher risk of developing multiple tumors throughout their lives. These growths can impact normal organ function and, in some cases, can be cancerous. Because of this, it is important for patients who are at risk to know the first signs of Von Hippel Lindau disease.
What is a Differentiated Cell?
In the body, cells begin as unspecialized cells that do not have a specific function. As they mature, they undergo cellular differentiation, where they follow a specific path of growth to achieve a specific function and ultimately become a differentiated cell. In patients with a VHL mutation, the VHL gene can disrupt the cellular differentiation of cells that are found within blood vessels. Because of this, many cancers related to the disease causes abnormal growth of blood vessels within different parts of the body.Read More
First Signs of Von Hippel Lindau DiseaseThe average age for VHL to first present itself is 26 years of age. Because the location and extent of the tumor(s) can differ, there is not a specific set of symptoms experienced by most patients. The symptom burden will vary between individuals. Some families may see a predominant tumor type; however, this is not always the case. Even though the inherited mutation is the same, the manifestation of the condition can be different between family members. One person in the family may even have manifestations that do not harm anything and just need to be monitored, while another has a malignant disease. Since there are no specific symptoms to monitor, patients with VHL should continually have routine surveillance to check for new tumor growth. Common tumors that arise include the following:
- Brain and Spinal Cord: Hemangioblastomas
- Eye: Retinal Hemangioblastoma
- Adrenal Glands: Pheochromocytomas and paragangliomas
- Kidneys: Benign cysts and malignant renal cell carcinoma
- Ear: Endolymphatic sac tumors
- Pancreas: Benign cysts and pancreatic neuroendocrine tumors
Each patient’s clinical presentation is different from others due to the wide variety of tumors and manifestations that can occur due to the disease. There are a few signs physicians look out for to identify VHL disease and/or tumors related to the disease.
Dr. Craig Rogers, Chair of Urology, Henry Ford Health, says that the disease can present at any point in life, which makes regular surveillance exceedingly important for people living with VHL.
The average age of onset for the condition is 26 years old, according to the National Organization for Rare Disorders, and 97% of people with the VHL gene mutation will experience symptoms by age 65. VHL can look very different as far as symptoms and manifestations of the disease.
“It varies in how it is expressed in different patients and families,” Dr. Rogers explained.
Signs of the disease may differ significantly depending on how many tumor(s) arise – there can be one or multiple – and where those tumors are exactly located.
“If there are tumors affecting the eyes – what we call retinal angiomas – it may affect vision, and they may need to go to an ophthalmologist and find these tumors,” Dr. Rogers said. “If there is a tumor pressing on the brain, it may affect things like their ability to walk (gait), do things like perform normal daily activities, or cause headaches.”
Although VHL tumors can be either cancerous or benign (noncancerous), even benign tumors can lead to severe unwanted health problems.
The tumors that occur in the eyes and the brain are pretty much always benign, according to Dr. Rogers.
“They are what we call hemangioblastomas, which are blood vessel based benign tumors. So, they cause harm by pushing on things, not by spreading,” he said. “They may eventually lead to blindness or someone could be wheelchair bound or have issues with walking because of these brain tumors that have been removed or are pushing on things.”
Some people with VHL develop tumors in their adrenal glands – small, triangular-shaped glands located on top of both kidneys – which can cause issues with their blood pressure and even lead to stroke or heart attacks.
“Maybe their primary care physician is trying to figure out why their blood pressure is so high and why they suffer from occurring headaches,” Dr. Rogers said. “So, you can see multiple sorts of portals of entry where somebody could have symptoms.”
Kidney and pancreas tumors from Von Hippel-Lindau Disease, on the other hand, are less likely to cause symptoms, according to Dr. Else. He says a little bit of blood in the urine (hematuria) can be a sign of cancerous kidney tumors, but usually, only once the tumor “has become bigger.” Please note that if you notice blood in your urine, this is always abnormal, and you should be evaluated by your physician as soon as possible. “The kidney tumors, those are cancerous tumors called renal cell carcinoma that can lead to metastasis and even death,” Dr. Rogers explained.
Dr. Tobias Else, an endocrinologist who leads the Comprehensive Clinical Care Center for Von Hippel-Lindau disease at the University of Michigan Health Rogel Cancer Center, discussed VHL further with SurvivorNet.
“In Von Hippel-Lindau disease, we also see a good proportion of what we call de novo mutation, so meaning you are the first one in the family, it just happened during development or prior to fertilization at some point, but you are just the first one,” Dr. Tobias Else told us.
Central Nervous System Hemangioblastoma
The central nervous system (CNS) is made up of the spinal cord and brain. Patients with hemangioblastoma of the CNS typically present with headaches, nausea, and vomiting. Patients can also experience issues with coordination, including difficulties walking (gait) and decreased muscle function.
Routine surveillance will be performed in patients with established or suspected VHL disease to identify any new tumor growth. As a result, many diagnoses of CNS hemangioblastoma may occur with standard MRI scans before any symptoms even occur.
The retina allows your eye to convert light into images to allow you to see. One of the main symptoms reported to providers that point to potential retinal hemangioblastoma in VHL disease patients is the complaint of vision loss. While this is the primary symptom reported, retinal detachment can also be observed.
Pheochromocytoma and Paraganglioma
One of the main signs of pheochromocytomas (PCC) or paragangliomas in patients with VHL disease is an increase in blood pressure and heart rate that can last for minutes or even hours. If frequent episodes of high blood pressure, heart rate, and palpitations occur, your provider may look at metanephrine levels within your body.
Metanephrine is a byproduct that is made whenever norepinephrine and epinephrine breakdown. High levels of metanephrine may indicate an adrenal gland tumor, such as a PCC. Extremely elevated levels may also point to new adrenal tumor development.
Endolymphatic Sac Tumors
Within the inner ear, there is a structure called an endolymphatic sac, which is responsible for protecting parts of the ear that contribute to hearing and balance. If a mutation of the VHL gene occurs, patients may develop an endolymphatic sac tumor (ESLT).
Patients that have tumors related to VHL disease within the ears may initially report hearing loss, ringing in the ears, or vertigo. Sometimes patients may also have earache or loss of facial muscle movement, although this generally does not occur until later in a diagnosis of an ESLT.
Other Cysts and Tumors Related to VHL Disease
Patients with VHL can also experience cysts or tumors within their kidneys and pancreas. Signs of tumor or cyst growth in the kidneys may include blood in urine and a lump or mass in the patient’s back. Patients with pancreatic cyst or tumor growth may experience dark urine, yellowing of the skin or eyes, or abdominal pain.
Although these symptoms can occur with the growths, they typically do not present until the patient has advanced disease or until the tumors have grown large enough to press on other organs. Instead, the first sign of kidney or pancreatic tumor growth is usually seen on an abdominal MRI or CT diagnostic scan. For newly diagnosed patients, these scans are usually ordered for unrelated reasons.
Diagnosing VHL from the First Signs and Symptoms
Most tumors that occur in patients with VHL are considered rare. As a result, any patient that presents with these tumors should be screened for potential disease. Your healthcare team will review your personal medical history, as well as your family history, to identify any cancer diagnoses that may be related to VHL disease.
If your provider believes you may have VHL disease, you will undergo genetic testing. Genetic testing will look at your DNA to determine if you carry the VHL gene mutation and is the only way to diagnose Von Hippel-Lindau disease definitively.
VHL Syndrome Surveillance Screening
Once you are diagnosed with VHL disease, you have an approximate 50% chance of passing the condition down to your children. Because Von Hippel-Lindau disease is a genetic condition, one of the first signs of the disease may be a positive diagnosis.
Children with a family history can undergo genetic testing during pregnancy or shortly after birth to identify if they carry the VHL mutation. Identifying VHL mutations in children that are at risk due to family history is an integral part of beginning screening as early as possible.
Routine surveillance screening is performed with the goal of identifying signs of new growth before a patient becomes symptomatic. Surveillance screening includes an overall physical, eye exams, blood pressure checks, hearing exams, and MRI imaging of the brain, spine, and abdomen. While most of the screening is performed on an annual basis, your provider may decide to screen more or less frequently based on your individual signs and symptoms to keep you on track to better health. Other resources are available at VHL Alliance.
Moving Forward – Questions to Ask Your Doctor
- If I plan to become pregnant, what genetic testing options are available for my child?
- What are the available treatment options for VHL?
- I have not experienced symptoms of VHL yet but have the VHL mutation; what screening or surveillance do I need?