Von Hippel-Lindau syndrome

Von Hippel-Lindau syndrome (VHL) is a rare genetic disorder that increases the risk of developing cancer.

Also known as VHL disease, it causes tumors to grow throughout the body—in areas such as the liver, lungs, brain, spinal cord and retina, and near the inner ear. Some of the tumors are benign (noncancerous), and some become malignant (cancerous) and may spread elsewhere in the body.

People with the VHL gene mutation also are at risk for a type of kidney cancer known as clear cell renal cell carcinoma (ccRCC) and a type of tumor of the pancreas known as a pancreatic neuroendocrine tumor (pNET).

Cysts—fluid-filled sacs—are another common feature of VHL. Cysts may form on or near the:

• Kidneys
• Pancreas
• Reproductive tract
• Inner ear

The disease takes its name from two doctors: Eugen von Hippel, who first described these tumors in the eye, and Arvid Lindau, who described them in the brain and spine.

The disease behaves differently in different patients, depending on the size and location of their tumors. Some people in the same family may have different experiences—VHL manifests as a benign disease for some and a serious illness for others.

It’s impossible to predict how the disease may progress. That’s why it’s extremely important to watch tumors and take action before they cause serious damage to the body.

Many people notice symptoms by age 26, and nearly all people with a VHL gene mutation develop symptoms by the time they’re 65.

How common is VHL?

About one in 36,000 people are born with this genetic disorder, according to the National Organization for Rare Disorders. About 20 percent of VHL patients are the first in their family to develop it, meaning their parents don’t have the VHL mutation. It occurs in both males and females, and doesn’t favor any ethnic group. It occurs in all peoples around the world.

What causes VHL?

This syndrome is caused by a mutation or a deletion in the VHL gene, which is found on the short arm of chromosome 3. If either parent has VHL, every one of their offspring has a 50 percent chance (one in two) of inheriting their mutated gene. It only takes one parent, not both.

When normal, the VHL gene suppresses the formation of tumors. The gene codes for a protein that helps to regulate cell growth. When mutated, the protein allows for increased blood vessel growth (angiogenesis), which may result in the growth of tumors. This is how other, more common tumors—such as those of the kidney, breast, pancreas and adrenal glands—form as well.

Signs and symptoms

Hemangioblastomas, the most common symptom of VHL, are benign tumors that form in the brain, spinal cord and retina. Some are contained within a cyst. When hemangioblastomas, or the cysts that surround them, press on nerve or brain tissue, the patient may experience headaches, unsteadiness when walking or arm/leg weakness. VHL symptoms may be subtle and are often overlooked.

• Adrenal tumors may cause high blood pressure, panic attacks and extreme sweating.
• Pancreatic cysts and tumors may cause digestive disorders, such as bloating and bowel/bladder dysfunction.
• Kidney cysts and tumors may cause loss of kidney function. In the early stages, patients aren’t likely to notice this.
• Inner ear tumors may lead to hearing loss and balance issues.
• Reproductive tract tumors in women may cause difficulty becoming pregnant, and men may not be able to fertilize eggs.
• Tumors that begin in the liver and lungs may not cause symptoms.

Diagnosis

Diagnosis of VHL requires genetic testing. A genetic mutation in the VHL gene will confirm VHL.

Doctors who suspect VHL may order genetic testing if the patient has:

• Many hemangioblastomas of the spinal cord, brain or eye
• A hemangioblastoma and clear cell renal cell carcinoma, pancreatic cyst, epididymal cystadenoma, broad ligament cystadenoma, adrenal gland tumor or endolymphatic sac tumor

Genetic testing also may be ordered for younger people with cancer in both kidneys.

Tests that a doctor may order to aid in a clinical diagnosis include:

• Magnetic resonance imaging (MRI) of the brain and spinal cord
• Ultrasound of the abdomen
• Fundoscopy (when the pupils are dilated to examine the retina)
• Blood test to measure catecholamine (hormones made by the adrenal glands)

Risks

The greatest risk arises from benign tumors that grow and become malignant. Most of the time, the tumors are benign, but they may have the potential to become malignant. According to the American Society of Clinical Oncology, the risks for developing tumors in VHL are: 

• 60 percent for retinal hemangioblastomas
• 44-72 percent for cerebellar hemangioblastomas
• 25-60 percent for kidney cancer and clear cell renal cell carcinoma
• 25-60 percent for epididymal cystadenomas in males with VHL
• 10-25 percent for endolymphatic sac tumors
• 10-25 percent for brain stem hemangioblastomas
• 10-20 percent for pheochromocytomas/paragangliomas
• 13-50 percent for spinal cord hemangioblastomas

Related disorders

Symptoms of VHL overlap with a number of different diseases, including:

• Sporadic kidney cancer
• Birt-Hogg-Dubé syndrome
• Tuberous sclerosis complex
• Adrenal tumor or pheochromocytoma
• Meniere’s disease
• Pancreatic cancer
• Retina hemangioblastomas
• Other spine and brain tumors such as hemangioblastomas

How is VHL treated?

No universal treatment exists for VHL, and a lot depends on a tumor’s size and location. The key is to treat tumors while they’re small and before they’re harmful. For example, tumors on the spinal cord may grow large, putting pressure on it and blocking the flow of cerebrospinal fluid in the nervous system. Tumors of the retina may cause blindness, and tumors of the inner ear may cause deafness.

Often, tumors are removed with surgery, but they also may be treated with focused high-dose radiation.

• Brain and spinal tumors are often removed. If they’re not completely removed, however, the cysts may refill.
• Pancreatic neuroendocrine tumors, cysts and cystadenomas are monitored. PNETs are studied for size and behavior. Cysts and cystadenomas may not require treatment, just surveillance.
• Kidney tumors may be monitored if found in the early stages, when they’re very small. Surgery may be considered depending on size and growth rate of the tumor. Other options may include radiofrequency ablation and cryotherapy. The goal is to save the kidney if possible.
• Retinal hemangioblastomas may be treated with lasers. Larger lesions may be treated with cryotherapy.
• Endolymphatic sac tumors visible through an MRI scan may require surgical removal.

Research is ongoing to find the best ways to treat von Hippel-Lindau syndrome, and patients may be encouraged to sign up for clinical trials.