What is Von Hippel-Lindau Syndrome?
Von Hippel-Lindau (VHL) syndrome is a disease passed down through families that affects numerous parts of the body. It is characterized by the formation of cysts (sac-like structures that may be filled with air, fluid, or other substances) and tumors, which can either be benign (non-cancerous) or malignant (cancerous). A commonly seen type of benign tumor in VHL is hemangioblastoma. This is a benign tumor composed of newly formed blood vessels, typically found in the brain, spinal cord, and retina (the part of the eye responsible for vision). Hemangioblastomas may lead to complications such as issues with balance and coordination (ataxia), and vision loss. Cysts are also frequently associated with VHL and are seen in kidneys, pancreas, and reproductive organs. Furthermore, some patients with VHL experience tumors in the kidney (renal cell carcinoma), pancreas, and the inner ear (endolymphatic sac tumors).
About half of the patients with VHL develop hemangiomas in the retina, a condition called retinal hemangiomas. These benign tumors may leak fluid, resulting in the formation of fibrous bands. These bands can cause the retina to detach or bleed, eventually leading to glaucoma (high pressure in the eye) and/or permanent vision loss.
VHL has different types, with each having unique characteristics:
1. Type 1: This type doesn’t have a certain kind of tumor called pheochromocytoma.
2. Type 2: This type does have pheochromocytomas. From here, it is further divided as:
– Type 2A: Pheochromocytoma along with hemangioblastomas in the central nervous system (CNS) are present, but there are no kidney tumors (RCC).
– Type 2B: Pheochromocytoma, CNS hemangioblastomas, and RCC are all present.
– Type 2C: Only pheochromocytoma is present, but without CNS hemangioblastomas or RCC.
What Causes Von Hippel-Lindau Syndrome?
Von Hippel-Lindau disease, or VHL, is caused by changes, known as mutations, in a gene called the VHL gene, which is found on chromosome 3. These mutations either stop the production of the VHL protein, or make it work improperly. This protein, pVHL, is primarily tasked with breaking down another protein known as hypoxia-inducible factor (HIF) which helps regulate the amount of oxygen in the cells.
When there is a lack of properly working pVHL, HIF isn’t broken down as it should be. This, in turn, leads to an uninhibited surge of HIF and several other growth factors it influences. This surge results in the growth of cysts and blood-rich tumors – hallmark features of VHL disease.
Risk Factors and Frequency for Von Hippel-Lindau Syndrome
VHL, also known as Von Hippel-Lindau syndrome, is a genetic condition that affects both men and women. It’s the most common hereditary type of kidney cancer. Out of every 30,000 to 50,000 people, one person is estimated to have VHL. In the United States, the syndrome affects between 6000 and 7000 people. The typical age when symptoms start to show is 26, but it can begin at any time from infancy to age 70, and is most common between 18 and 30 years old.
Several health conditions can occur as a result of VHL:
- Renal cysts appear in 59% to 63% of patients
- Renal Cell Carcinoma (RCC) occurs in 25% to 45% of patients
- CNS Hemangioblastomas occur in 13% to 72% of patients
- Retinal Hemangioblastomas occur in 45% to 59% of patients
- Endolymphatic Sac Tumors occur in 2% to 11% of patients
- Pancreatic lesions appear in 17% to 56% of patients
- Pheochromocytomas occur in 0% to 60% of patients
Signs and Symptoms of Von Hippel-Lindau Syndrome
Von Hippel-Lindau (VHL) disease is a hereditary condition that can cause various types of tumors. The symptoms a patient experiences can differ greatly based on the size and location of these tumors.
- Tumors in the central nervous system, known as hemangioblastomas, can cause symptoms like headaches, vomiting, issues with senses or movements, and a lack of coordination, also referred to as ataxia.
- Tumors in the retina, referred to as retinal angiomas, may lead to loss of vision.
- Tumors in the adrenal glands, known as pheochromocytomas, can be symptomless. But sometimes, they can cause headaches, panic attacks, excessive sweating, and high blood pressure.
- Patient with tumors in the inner ear, referred to as endolymphatic sac tumors, may experience symptoms such as ringing in the ears (tinnitus), feelings of dizziness (vertigo), or loss of hearing.
Physical examination findings can be minimal, as the diagnosis of VHL is usually based on lab tests and imaging studies. However, for patients with hemangioblastomas in the central nervous system, a physical exam might reveal symptoms such as muscle weakness, sensory issues, and a lack of coordination.
Testing for Von Hippel-Lindau Syndrome
If the diagnosis of Von Hippel-Lindau (VHL) disease isn’t clear through normal clinical tests and imaging, molecular genetic testing can help. This examines for a specific genetic mutation (a damaging change in the DNA) associated with VHL, even if common symptoms or signs aren’t present. Certain clinical clues can also help to establish the diagnosis, such as having more than one CNS hemangioblastoma (a tumor of the blood vessels in the brain), having a certain VHL-related symptom, or any symptom with a family history of VHL.
An eye exam (fundoscopy) can help find retinal hemangioblastomas (tumors in the eye) and other related problems. These include a detached retina (when the tissue at the back of the eye peels away), macular edema (swelling in the center of the retina), or cataracts (cloudy patches in the lens of the eye). Tonometry, a test that measures pressure inside your eyes, can detect glaucoma (a group of eye conditions that damage the optic nerve). An audiological evaluation, a hearing test, can detect hearing loss caused by endolymphatic sac tumors (tumors in the inner ear).
Other laboratory tests can help diagnose particular types of tumors; for instance, checking the levels of certain substances in your blood and urine can assist in diagnosing pheochromocytomas, a rare type of tumor that develops in the adrenal glands.
Imaging studies play a vital role in identifying VHL lesions. Magnetic resonance imaging (MRI) can identify CNS hemangioblastomas in the brain and spinal cord. These usually appear as a cystic lesion (a cavity filled with fluid) with a nodule (a small growth). Approximately 80% will develop in the brain and 20% in the spinal cord. Renal cysts (fluid-filled sacs in the kidneys) can be detected on ultrasound, MRI, or CT and are usually seen in pairs, multiple and of different sizes. CT is the preferred imaging tool for renal cell carcinoma (RCC), a type of kidney cancer that generally occurs in both kidneys and can appear as multiple cysts or solid lumps. CT or MRI can identify pheochromocytomas. Pancreatic cysts and tumors are typically detected on CT, but can also be seen on an ultrasound. MRI and CT through the middle ear can detect endolymphatic sac tumors.
Treatment Options for Von Hippel-Lindau Syndrome
Treatment depends on where and how big the tumors are in VHL syndrome, a genetic disorder that can produce tumors or cysts in various parts of the body. Central nervous system (CNS) hemangioblastomas, which are non-cancerous tumors, can be surgically removed. Gamma-knife surgery, which uses focused radiation beams, may be considered for smaller tumors or those that are difficult to reach surgically. Extensive tumors can be treated with preoperative embolization, a process that blocks the blood supply to the tumors to reduce risk of bleeding, because they have a lot of blood vessels.
Retinal angiomas, which are blood vessel tumors in the eye, are typically treated to prevent vision loss. Treatment options for these tumors could include diathermy – which uses heat from an electric current, xenon or laser treatment, cryocoagulation – which uses extreme cold to destroy tissue, or external beam radiotherapy which uses high-energy beams to destroy cancer cells.
Renal cell carcinoma (RCC), which is a type of kidney cancer, is often best treated by removing the kidney in a procedure known as nephrectomy. Smaller kidney tumors can also be treated with cryoablation (a technique that uses extreme cold to destroy tissue) or radiofrequency ablation (a method that uses heat to destroy cancer cells).
Pheochromocytomas (a rare type of tumor that develops in the adrenal glands) are usually surgically removed. If a child is affected, the preferred method is a partial adrenalectomy, where only a part of the adrenal gland is removed.
If pancreatic tumors pose a high risk of spreading to other parts of the body (metastasis), they should also be considered for surgical removal. A high risk signaled by a tumor that is bigger than 3 cm, increases in size rapidly, or has a specific genetic variant.
Tumors in the endolymphatic sac in the ear should also be considered for surgical removal to prevent hearing loss.
What else can Von Hippel-Lindau Syndrome be?
When diagnosing Von Hippel-Lindau (VHL) disease, doctors would consider a range of specific types of tumors. These tumors are often found in people with VHL but can also occur individually. They include:
- Retinal hemangioblastoma: a blood vessel tumor in the eye
- Renal cell carcinoma: a type of kidney cancer
- CNS hemangioblastoma: a blood vessel tumor in the central nervous system
- Pheochromocytoma: a rare tumor of the adrenal glands
- Pancreatic tumors: cancers that start in the pancreas
- Endolymphatic sac tumors: rare tumors in the inner ear
What to expect with Von Hippel-Lindau Syndrome
Patients with VHL, or von Hippel-Lindau disease, often develop a type of kidney cancer called renal cell cancer, which can shorten their life expectancy. The severity of their disease depends on how many organs are affected.
Another concerning issue is CNS hemangioblastomas, which are benign tumors in the brain and spinal cord. These growths often grow in size, leading to neurological issues. Issues with the retina, such as retinal disease, can lead to complications such as cataracts, glaucoma, retina detachment, or leakage of fluid at the back of the eye (macular exudation), as well as bleeding in the jelly-like substance that fills your eye (vitreous hemorrhage).
Another common issue for these patients includes endolymphatic sac tumors, often affecting both ears. These can cause ringing in the ears (tinnitus), hearing loss, and weakness in the facial muscles. Patients with VHL are also at risk of developing adrenaline-producing tumors known as pheochromocytomas.
Oftentimes, patients have benign pancreatic cystic lesions, fluid-filled sacs in the pancreas. Luckily, these don’t often cause symptoms and are unlikely to become cancerous. Unfortunately, the overall health-related quality of life for patients with VHL can be quite poor due to these complications.
Possible Complications When Diagnosed with Von Hippel-Lindau Syndrome
Without receiving proper treatment, patients with VHL (Von Hippel-Lindau disease) can face severe consequences like vision loss or even irreversible damage to the brain. Sadly, the most common cause of death for these patients tends to be complications from brain tumors or kidney cancer.
Possible Consequences without Treatment:
- Blindness
- Permanent brain damage
- Death due to complications of brain tumors
- Death due to kidney cancer
Preventing Von Hippel-Lindau Syndrome
The treatment for this condition often includes surgery or radiation therapy. It’s important for patients and their loved ones to fully understand the potential risks and benefits involved in these treatments. Apart from these treatments, the condition also needs regular check-ups, so it’s crucial that patients keep up with these appointments. Alongside this, consultation with a genetic counselor could also be beneficial to better understand the condition.
