Von Hippel-Lindau Disease

Von Hippel-Lindau disease is a rare genetic disorder that causes tumors and cysts to develop in multiple organs throughout a person’s life, requiring lifelong monitoring and often multiple surgeries, but new treatments are bringing hope to patients who once faced a lifetime of repeated operations.

Table of contents

• What is von Hippel-Lindau disease?
• What causes this condition
• Tumors and cancers associated with VHL
• Signs and symptoms
• Diagnosis and testing
• Treatment options
• Monitoring and surveillance
• Living with VHL

What is von Hippel-Lindau disease?

Von Hippel-Lindau disease (VHL) is a rare genetic disorder that significantly increases the chance that you’ll develop certain kinds of tumors and cysts throughout your body. These growths can be either cancerous (malignant) or noncancerous (benign), and they can appear in many different organs at various times during your life.^[1]

VHL Disease, VHL Syndrome, Familial cerebello retinal angiomatosis

ORPHA:892
OMIM-number 193300

The condition affects about 1 in 36,000 people worldwide. It affects males and females equally, and there are no known differences based on ethnicity or where people live.^[4] Research shows that by the time they’re 65 years old, 97% of people who carry the genetic change that causes VHL will develop tumors and other conditions.^[1]

The disease is named after two doctors—Eugen von Hippel, a German eye doctor, and Arvid Lindau, a Swedish specialist—who were the first to describe tumors in people’s eyes and brains, which are characteristic features of this condition. In the 1960s, the disease was named von Hippel-Lindau syndrome to recognize their contributions.^[8]

What causes this condition

Von Hippel-Lindau disease is caused by changes (mutations) in the VHL gene, which is located on chromosome 3. This gene is a tumor suppressor gene, which means it normally keeps cells from growing and dividing too rapidly or in an uncontrolled way.^[2]

Everyone is born with two copies of the VHL gene. The VHL gene produces a protein called von Hippel-Lindau tumor suppressor protein (pVHL). This protein helps cells respond properly to oxygen levels and use nutrients correctly. When the VHL gene is mutated, the protein cannot do its job properly, leading to uncontrolled cell growth and the formation of tumors and cysts.^[4]

The disease is inherited in an autosomal dominant pattern, which means that having just one copy of the mutated gene in each cell is enough to increase the risk of developing tumors and cysts. Most people with VHL inherit the altered gene from an affected parent. However, in about 20% of cases, the mutation occurs for the first time in that person and is not inherited from either parent. This is called a “de novo” mutation.^[2]

What makes VHL disease unique is that even though you’re born with one mutated copy of the gene, a second mutation must occur in the other copy within specific cells for tumors to form. This second mutation happens during a person’s lifetime in certain cells within organs such as the brain, retina, and kidneys. This explains why tumors develop at different times and in different locations throughout a person’s life.^[2]

If you have VHL disease, each of your children has a 50% chance of inheriting the mutated gene. The VHL gene is not located on the sex chromosomes, so mutations can be inherited from either the mother’s or father’s side of the family.^[8]

Tumors and cancers associated with VHL

Cancerous tumors

Having von Hippel-Lindau disease increases your chance of developing one or more of the following types of cancer:^[1]

• Clear cell renal cell carcinoma (ccRCC): This is the most common form of kidney cancer. Experts estimate that 25% to 60% of people with VHL develop this cancer. It occurs in about 70% of individuals with VHL and is the leading cause of death from this condition.^[13]
• Pancreatic neuroendocrine tumors: These are rare tumors that start in the hormone-producing cells of the pancreas. Between 9% and 17% of people with VHL develop these tumors.^[1]
• Pheochromocytoma: This is a rare tumor that starts in the adrenal gland. These tumors usually start as noncancerous but can sometimes be cancerous. Between 10% and 20% of people with VHL develop pheochromocytomas.^[1]
• Broad ligament cystadenomas: This condition affects 10% of females who have VHL. These tumors develop near the fallopian tubes.^[1]

Noncancerous tumors

Hemangioblastomas are the most common noncancerous tumors in people with VHL. A hemangioblastoma is a tumor made of newly formed blood vessels. Although they are typically noncancerous, they can cause serious or life-threatening complications because they can grow large enough to affect nearby tissue.^[1]

Hemangioblastomas associated with VHL include:

• Retinal hemangioblastomas: These are tumors in the light-sensitive tissue at the back of the eye. They may cause vision loss and occur in about 60% of people with VHL. These may be the first sign of VHL.^[1]
• Brain and cerebellar hemangioblastomas: These brain tumors may affect balance and cause other issues. They affect 13% to 72% of people with VHL.^[1]
• Spinal cord hemangioblastomas: Between 13% and 50% of people with VHL have this type of hemangioblastoma.^[1]

Other noncancerous tumors and cysts associated with VHL include:^[1]

• Epididymal cystadenomas: These tumors affect males and develop in the small tube-like structure near the testicles that stores sperm. Between 25% and 60% of males with VHL develop this type of tumor.
• Endolymphatic sac tumors (ELST): These very rare tumors develop in the inner ear. Between 10% and 25% of people with VHL have this condition. About 10% of people with VHL develop these tumors, which can cause hearing loss in one or both ears, ringing in the ears, and problems with balance.^[2]
• Cysts: These are fluid-filled growths. People with VHL may have cysts on or in their kidneys and pancreas. Pancreatic cysts occur in 50-91% of people with VHL.^[3]

• Brain
• Spinal cord
• Retina (eye)
• Kidneys
• Pancreas
• Adrenal glands
• Inner ear
• Epididymis
• Fallopian tubes

Signs and symptoms

Tumors associated with VHL most commonly appear between ages 18 and 30, although they can occur at any age. Most people with VHL develop symptoms in their mid-twenties.^[3]

Signs and symptoms vary depending on where tumors develop in the body. Common symptoms include:^[3]

• Headaches
• Problems with balance and walking
• Dizziness
• Weakness of the limbs
• Vision problems
• High blood pressure

Hemangioblastomas that develop in the brain and spinal cord can cause headaches, vomiting, weakness, and a loss of muscle coordination (ataxia). Hemangioblastomas in the retina can cause vision loss.^[2]

Spinal hemangioblastomas and related fluid-filled cavities (syrinx) usually present with pain. Sensory and motor loss may develop with spinal cord compression.^[13]

Pheochromocytomas can be asymptomatic but may cause sustained or episodic high blood pressure. In some cases, they are associated with headaches, panic attacks, or excess sweating. Pheochromocytomas are particularly dangerous during times of stress or trauma, such as when undergoing surgery or during pregnancy.^[2]

Endolymphatic sac tumors can cause hearing loss of varying severity, which can be a presenting symptom. Without treatment, these tumors can cause sudden profound deafness.^[13]

Pancreatic lesions often remain asymptomatic and rarely cause problems with hormone production or digestive function.^[13]

Diagnosis and testing

The diagnosis of VHL can be established in two ways:^[13]

First, a person can be diagnosed based on clinical criteria—meaning the presence of certain tumors. A person may be diagnosed with VHL if they have specific types and numbers of tumors characteristic of the condition.

Second, the diagnosis can be confirmed through genetic testing. Identification of a mutation in the VHL gene on molecular genetic testing establishes the diagnosis if clinical features are inconclusive.^[13]

Genetic testing of unaffected family members is useful only if a mutation has already been identified in an affected family member. For first-degree relatives (parents, siblings, children) of affected people, genetic testing is considered part of standard management.^[8]

Once a diagnosis is made, various imaging tests and examinations are used to look for tumors in different parts of the body. These may include MRI scans, CT scans, ultrasounds, and eye examinations.^[4]

Treatment options

Surgical treatment

Surgery is the most common treatment for conditions that von Hippel-Lindau disease causes. Different types of surgery may be used depending on where tumors are located:^[1]

• Surgical resection for most brain and spinal cord hemangioblastomas
• Early treatment for retinal hemangioblastomas to prevent vision loss
• Removal of kidney tumors or, in some cases, kidney transplantation following removal of both kidneys
• Removal of pheochromocytomas, with partial removal of the adrenal gland when possible
• Removal of pancreatic neuroendocrine tumors in some cases
• Surgical removal of endolymphatic sac tumors, particularly small tumors, to preserve hearing

For kidney tumors, doctors may use cryoablation or radiofrequency ablation, which are procedures that destroy tumors without surgery using extreme cold or heat.^[13]

Managing VHL has traditionally involved frequent body scans to look for and monitor tumors, along with surgical interventions to treat symptoms and prevent cancer from spreading. Doctors typically perform surgery when tumors grow to a size that increases the risk of spread and may begin to affect organ function. Each successive surgery increases the risk of complications.^[15]

Targeted drug therapy

New drug treatments are changing the approach to VHL. Belzutifan (Welireg) was approved by the Food and Drug Administration (FDA) in August 2021 to treat adults with VHL who have certain tumors that don’t require immediate surgery. Specifically, it is approved for VHL-associated kidney cancer, brain and spinal cord hemangioblastomas, and pancreatic neuroendocrine tumors.^[12]

Belzutifan works by binding to a specific protein called HIF-2α and blocking its tumor-promoting activity. This drug has shown the ability to shrink tumors in people with VHL. In a clinical trial, after 18 months, nearly half of participants had kidney tumor shrinkage of at least 30%, and a majority of those people’s tumors were still responding after one year. The drug also shrank tumors in the brain, pancreas, and eyes.^[12]

This treatment represents a major advance because it can help patients avoid or delay surgery by shrinking their tumors. The drug is taken as a daily pill and has relatively mild side effects compared to repeated surgeries.^[15]

Another drug, pazopanib, is an FDA-approved treatment for advanced kidney cancer and may be used in some people with VHL-associated kidney tumors.^[13]

Monitoring and surveillance

People with VHL require lifelong monitoring to detect and treat tumors before severe complications occur. Annual screening to find tumors before they cause serious problems is recommended for people who are mutation-positive.^[8]

According to guidelines endorsed by medical experts, surveillance is recommended for individuals who fulfill the diagnostic criteria for VHL and/or carry a mutation in the VHL gene, as well as for first-degree relatives of affected individuals when an underlying genetic cause cannot be identified.^[4]

Recommended surveillance includes:^[4]

For children ages 0-4 years:

• Annual retinal (eye) examination
• Annual general pediatric examination including growth measurements

For children ages 5-14 years:

• Annual retinal examination
• Annual general pediatric examination including growth measurements
• Annual blood tests for hormones produced by pheochromocytomas
• Baseline MRI scan of the brain, spine, and inner ear at age 10 years
• Annual hearing examination

From age 15 years onward:

• Annual retinal examination
• Annual neurological evaluation
• Every two years: MRI of the brain, spine, and inner ear
• Every two years: Imaging of the abdomen focused on the kidneys, pancreas, and adrenal glands
• Every two years: Hearing examination

Living with VHL

Von Hippel-Lindau disease is a lifelong condition that requires ongoing medical care and monitoring. The outlook varies greatly depending on which tumors develop and how early they are detected and treated. Kidney cancer is the leading cause of death in people with VHL.^[13]

With proper monitoring and treatment, many people with VHL can lead active, fulfilling lives. The development of new targeted therapies like belzutifan is improving quality of life by reducing the need for repeated surgeries. Some patients have reported being able to travel, work, and maintain normal family lives while taking these medications.^[15]

Early detection through regular screening is crucial. When tumors are found and treated early, complications can often be prevented or minimized. People with VHL benefit from care by a multidisciplinary team of specialists who understand the condition, including experts in urology, ophthalmology, neurosurgery, genetics, and other fields.^[14]

Support groups and patient organizations, such as the VHL Alliance, provide resources, education, and community support for people living with VHL and their families.^[16]

Genetic counseling is recommended for people with VHL and their families to understand inheritance patterns, discuss family planning options, and make informed decisions about testing for other family members.^[13]