Von Hippel-Lindau syndrome

Definition

Von Hippel-Lindau (VHL) syndrome is an inherited condition characterized by tumors that arise in multiple locations in the body. Some of these tumors cause cancer and some do not. Many of the tumors seen in VHL are vascular, meaning that they have a rich supply of blood vessels.

Description

In the mid-1800s, ophthalmologists described vascular tumors in the retina, the light-sensitive layer that lines the interior of the eye. These tumors, called angiomas, were not cancerous but were associated with vision loss. In 1904, a German ophthalmologist named Eugen von Hippel noted that these retinal angiomas seemed to run in families. Twenty-three years later, Arvid Lindau, a Swedish pathologist, reported a connection between these retinal angiomas and similar tumors in the brain, called hemangioblastomas. Like angiomas, hemangioblastomas are vascular tumors as well. After Lindau noted this association, there were many more reports describing families in which there was an association of retinal angiomas and central nervous system (CNS) hemangioblastomas. Other findings were found to be common in these families as well. These findings included cysts and/or tumors in the kidney, pancreas, adrenal gland, and various other organs. In 1964, Melmon and Rosen wrote a review of the current knowledge of this condition and named the disorder von Hippel-Lindau disease. More recently, the tumors in the retina were determined to be identical to those in the CNS. They are now referred to as hemangioblastomas, rather than angiomas.

There are four distinct types of VHL, based on the manifestations of the disorder. Type 1 is characterized by all VHL-related tumors except those in the adrenal gland. Type 2 includes tumors of the adrenal gland and is subdivided into type 2A (without kidney tumors or cysts in the pancreas), type 2B (with kidney tumors and cysts in the pancreas), and type 2C (adrenal gland tumors only).

Genetic profile

VHL is inherited in an autosomal dominant manner. This means that an affected person has a 50% chance of passing the disease on to each of his or her children. Nearly everyone who carries the mutation in the VHL gene will show signs of the disorder, usually by the age of 65.

VHL is caused by a change or mutation in the VHL gene. This gene is located on chromosome 3 and produces the VHL protein. The VHL protein is a tumor suppressor, meaning that it controls cell growth. When the VHL gene is changed, the VHL protein does not function correctly and allows cells to grow out of control. This uncontrolled cell growth forms tumors and these tumors may lead to cancer.

People without VHL have two working copies of the VHL gene, one on each chromosome 3. Each of these copies produces the VHL protein. People affected with VHL inherit one working copy and one non-working copy of the gene. Thus, one gene does not make the VHL protein but the corresponding gene on the other chromosome continues to make the functional protein. In this case, cell growth will still be controlled because the VHL protein is available. However, as this person lives, another mutation may occur in the working gene. If this happens, the VHL protein can no longer be made. Cell growth cannot be controlled and tumors develop. Mutations like this occur in various organs at various times, leading to multiple tumors forming in distinct parts of the body over a period of time.

The majority of patients with VHL syndrome inherited the mutation from one of their parents. In approximately 1–3% of cases, there is no family history of the disorder and VHL occurs because of a new mutation in the affected individual. If a person appears to be an isolated case, it is important that the parents have genetic testing . It is possible that a parent could carry the mutation in the VHL gene but have tumors that do not cause any noticeable symptoms. If a parent is affected, each of his or her future children would have a 50% of being affected with VHL. If both parents test negative for the VHL gene mutation, each future child has a 5% risk of inheriting VHL. This small risk is to account for the rare possibility that one parent carries the mutation in his or her sex cells (egg or sperm) but does not express the disorder in any of the other cells of the body.

Demographics

VHL occurs in approximately one in 36,000 live births. It is seen in all ethnic groups and both sexes are affected equally.

Signs and symptoms

There are several characteristic features of VHL but no single, unique finding. Thus, it is necessary that many different specialties be involved in the diagnosis and management of the disease. This approach will ensure proper, thorough care for these patients.

VHL is characterized by hemangioblastomas, tumors that arise in the blood vessel. These tumors are found in the central nervous system, or the brain and spinal cord. They most commonly present between the ages of 25 and 40 years and are the first symptom of VHL in 40% of cases. It is common to see multiple tumors. They may appear at the same time or at different times. These tumors generally grow slowly but, in some cases, may enlarge more rapidly. Hemangioblastomas seen in VHL are benign (non-cancerous) but may produce symptoms depending on their size, site, and number. Hemangioblastomas in the brain may lead to headache, vomiting, slurred speech, or unsteady and uncoordinated movements. These symptoms are usually due to the tumors disrupting brain function or causing increased pressure in the brain. Hemangioblastomas of the spine are usually accompanied by pain and can lead to loss of sensation and motor skills. Some of these tumors may fail to cause any observable symptoms.

In patients with VHL, hemangioblastomas also appear in the retina, the light-sensitive layer that lines the interior of the eye. These tumors occur in approximately half the cases of VHL and may be the first sign that a person is affected. It is common to see numerous retinal hemangioblastomas develop throughout a person's lifetime. They often can be found in both eyes. These tumors have been detected as early as the age of four years but are more typically found between the ages of 21 and 28 years. They often occur without symptoms, but can be detected on a routine eye exam. If untreated or undetected, they may cause the retina to detach from the eye. This condition is accompanied by bleeding and leads to vision loss and possibly blindness.

Approximately 50–70% of individuals with VHL also have numerous cysts on their kidneys. Cysts are sacs or closed cavities filled with liquid. In VHL, these cysts are vascular and frequently occur in both kidneys; however, they rarely result in noticeable symptoms. In some cases, these cysts may develop into renal cell carcinomas. These are cancerous tumors that are composed of kidney cells. Seventy percent of people affected with VHL will develop this type of kidney tumor during their lifetime. This type of cancer is generally diagnosed between the ages of 41 and 45 years. By the time this condition produces symptoms, it is likely that the cancer has already spread to other parts of the body. If this is the case, the tumors will respond poorly to chemotherapy and radiation, two common cancer treatments.

VHL can also cause multiple cysts in the pancreas. These occur at the average age of 41 years and are vascular in nature. Pancreatic cysts rarely cause problems and tend to grow fairly slowly. Pancreatic islet cell tumors can occur as well but are unrelated to the cysts. Islet cells in the pancreas produce hormones. Hormones are substances that are produced in one organ and then carried through the bloodstream to another organ where they perform a variety of functions. When tumors occur in the islet cells of the pancreas, these cells secrete too many hormones. This increase in hormones rarely leads to recognizable symptoms. Pancreatic islet cell tumors grow slowly and are non-cancerous.

Additionally, tumors in the adrenal gland, called pheochromocytomas, are common in VHL. The adrenal glands are located on top of each kidney. They secrete various hormones into the bloodstream. Pheochromocytomas are made of cells from the inner region of the adrenal gland. These tumors are benign but can be numerous and are often located in both adrenal glands. They can be confined to the inside of the adrenal gland or they can travel and appear outside of it. Some do not cause any observable symptoms. Others can lead to high blood pressure, sweating, and headaches.

In approximately 10% of cases, tumors can also be found in the inner ear. Most often, these tumors occur in both ears. They may lead to hearing loss of varying severity. This hearing loss may be one of the first signs that an individual is affected with VHL. Less commonly, a person may complain of dizziness or a ringing in the ear due to these inner ear tumors.

Men with VHL commonly have tumors in the epididymus. The epididymus is a structure that lies on top of the testis and serves as the site for sperm storage and maturation for motility and fertility. If these tumors occur bilaterally, they can lead to infertility. However, as a general rule, they do not result in any health problems. The equivalent tumor in females is one that occurs in the broad ligament. This ligament connects the ovaries to the uterus. These tumors, however, are much less common than those in the epididymus.

It is important to note that wide variation exists amoung all individuals affected with VHL in regards to the age of onset of the symptoms, the organ systems involved, and the severity of disease.

Diagnosis

VHL can be diagnosed clinically, without genetic testing, in some cases. If a person has no family history of the disorder, a diagnosis of VHL can be made if one of the following criteria are met:

• the patient has two or more hemangioblastomas of the retina or CNS
• the patient has a single hemangioblastoma along with one of the other tumors or cysts that are commonly associated with the disorder.

A diagnosis of VHL can also be established in a person who has a positive a family history of the disorder if they show one or more of the following before the age of 60:

• retinal hemangioblastoma
• CNS hemangioblastoma
• pheochromocytoma
• multiple pancreatic cysts
• tumor of the epididymus
• multiple renal cysts
• renal cell carcinoma

Several tests are available that can assist in the diagnosis of VHL. They can also determine the extent of symptoms if the diagnosis has already been made. A computed tomography (CT) scan or magnetic resonance imaging (MRI) are often utilized for these purposes. These procedures serve to produce images of various

soft tissues in the body, such as the brain and abdominal area. In someone with VHL, they are used to assess for the presence of CNS hemangioblastomas and other tumors associated with the disorder, such as pheochromocytomas and inner ear tumors. Pheochromocytomas may also cause abnormal substances to be released into the urine. A urinalysis can detect these substances and, therefore, suggest the existence of these tumors. Additionally, ultrasound examination can assist in evaluating the epididymus, broad ligament, and kidneys. Ultrasound examination involves the use of high frequency sound waves. These sound waves are directed into the body and the echoes of reflected sound are used to form an electronic image of various internal structures.

VHL can also be diagnosed via examination of the VHL gene on the molecular level. This type of testing detects approximately 100% of people who are affected with the disorder and is indicated for confirmation of the diagnosis in cases of suspected or known VHL. Molecular genetic testing examines the VHL gene and detects any mutations, or changes in the gene. Most often, in this disorder, the gene change involves a deletion of a part of the gene or a change in one of the bases that makes up the genetic code.

Since molecular testing is so accurate, it is recommended even in cases where the clinical criteria for diagnosis are not met. It is possible that the tumors associated with VHL are present but are not causing any observable symptoms. Thus, even if a person does not meet the diagnostic criteria mentioned above, molecular testing can be used as a means of "ruling out" VHL with a high degree of certainty. For patients with numerous, bilateral pheochromocytomas or for those who have a family history of these tumors, molecular testing is strongly suggested since these tumors may be the only signs of the disorder in those with VHL type 2C.

VHL can be diagnosed at various ages, ranging from infancy to the seventh decade of life or later. The age of diagnosis depends on the expression of the condition within the family and whether or not asymptomatic lesions are detected.

Treatment and management

There is no treatment for VHL because the genetic defect cannot be fixed. Management focuses on routine surveillance of at-risk and affected individuals for early detection and treatment of tumors.

For at-risk relatives of individuals diagnosed with VHL, molecular genetic testing is recommended as part of the standard management. If a person tests negative for the mutation, costly screening procedures can be avoided. If an at-risk relative has not been tested for the mutation, surveillance is essential for the early detection of signs of VHL.

The following groups of people should be routinely monitored by a physician familiar with VHL:

• individuals diagnosed with VHL
• individuals who are asymptomatic but who have tested positive for a mutation in the VHL gene
• individuals who are at-risk due to a family history of the disorder but have not undergone molecular testing

For these groups of people, annual physical examinations are recommended, along with neurologic evaluation for signs of brain or spinal cord tumors. Additionally, an eye exam should be completed annually, beginning around the age of five years. These exams can detect retinal hemangioblastomas, which often produce no clinical symptoms until serious damage occurs. When a person reaches the age of 16, an abdominal ultrasound should be completed annually as well. Any suspicious findings should be followed up with a CT scan or MRI. If pheochromocytomas are in the family history, blood pressure should be monitored annually. A urinalysis should be completed annually as well, beginning at the age of five. Although the majority of tumors associated with VHL are benign in nature, they all have a small possibility of becoming cancerous. For this reason, surveillance and early detection is very important to the health of those affected with VHL.

If any tumors are identified by the above surveillance, close monitoring is necessary and surgical intervention may be recommended. Hemangioblastomas of the brain or spine may be removed before they cause symptoms. They may also be followed with yearly imaging studies and removed only after they begin to cause problems. Most of these tumors require surgical removal at some point and results are generally good. Retinal hemangioblastomas can be treated with various techniques that serve to decrease the size and number of these tumors.

Early surgery is recommended for renal cell carcinoma. Extreme cases may require removal of one or both kidneys, followed by a transplant. Additionally, pheochromocytomas should be surgically removed if they are causing symptoms. Inner ear tumors, however, generally are slow-growing. The benefit of removing one of these tumors must be carefully compared to the risk of deafness, which may result from the surgery. Epididymal and broad ligament tumors generally do not require surgery.

Prognosis

The average life expectancy of an individual with VHL is 49 years. Renal cell carcinoma is the leading cause of death for affected individuals. If an affected person is diagnosed with renal cell carcinoma, their average life expectancy decreases to 44.5 years. CNS hemangioblastomas are responsible for a significant proportion of deaths in affected individuals as well, due to the effects of the tumor on the brain.

Resources

BOOKS

The VHL Handbook: What You Need to Know About VHL. Brookline, MA: VHL Family Alliance, 1999.

PERIODICALS

Couch, Vicki, et al. "Von Hippel-Lindau Disease." Mayo Clinic Proceedings 75 (March 2000): 265-272.

Friedrich, Christopher A. "Von Hippel-Lindau Syndrome: A Pleiomorphic Condition." Cancer 86, no. 11 Supplement (December 1, 1999): 2478-2482.

ORGANIZATIONS

VHL Family Alliance. 171 Clinton Ave., Brookline, MA 02455-5815. (800) 767-4VHL. <http://www.vhl.org>.

WEBSITES

Schimke, R. Neil, Debra Collins, and Catharine A. Stolle. "Von Hippel-Lindau Syndrome." GeneClinics. http://www.geneclinics.org/profiles/vhl/index.html.

"Von Hippel-Lindau Syndrome." Genes and Disease. http://www.ncbi.nlm.nih.gov/disease/VHL.html.

Mary E. Freivogel, MS