Von Hippel-Lindau (VHL) syndrome is a hereditary condition characterized by the presence of benign and malignant tumors, including:
Because Von Hippel-Lindau syndrome is hereditary, the risk of developing features associated with VHL may be passed from generation to generation in a family. However, the type and severity of Von Hippel-Lindau syndrome can vary widely between family members.
Von Hippel-Lindau syndrome is caused by alterations, also known as mutations, at specific areas within an individual’s genetic information. Each of us has a large amount of genetic information that is organized into smaller segments known as “genes.” Genes provide the necessary instructions that our cells require to perform their different functions within our bodies.
In almost 100 percent of patients with Von Hippel-Lindau syndrome, the disorder develops as the result of alterations in a specific gene known as VHL, which is located on chromosome 3 at position p26-p25. VHL is the only gene known to be associated with Von Hippel-Lindau syndrome. The protein produced by the VHL gene acts as a “tumor suppressor," which means that it helps to keep cells from growing and dividing too quickly and it promotes cell death. It also has a fundamental role in regulating the biological pathways involved with normal blood vessel growth.
With the exception of egg and sperm cells, each cell of the body normally has two working copies of the VHL gene. Patients with Von Hippel-Lindau syndrome generally carry an alteration in one copy of the VHL gene in all the cells of their body. Von Hippel-Lindau syndrome patients are born and develop normally, but are at an increased risk of developing benign and malignant tumors. These tumors are believed to develop because, over time, the second working copy of the VHL gene may become altered within one or more cells. The loss of function of the second VHL gene copy leads to abnormal growth of the affected cells, increasing their chance to become cancerous.
Approximately 80 percent of patients with Von Hippel-Lindau syndrome inherit an altered copy of the VHL gene from a parent who also has Von Hippel-Lindau syndrome. In the remaining 20 percent of patients, Von Hippel-Lindau syndrome results from the development of a “new” mutation in the VHL gene in one of the father’s sperm, mother’s eggs, or in a cell of the developing fetus. In the latter scenario, the affected individuals will be the first ones in their family to carry this genetic change. Individuals who carry an alteration in one copy of the VHL gene in all the cells of their body have a 50 percent (or 1 in 2) chance of passing this same alteration on to each of his or her children. Children who inherit the altered gene copy will have Von Hippel-Lindau syndrome and will therefore be at risk to develop the features associated with this disease.
In about 5 percent of cases, an individual is a genetic “mosaic” for a VHL mutation. A person with VHL mosaicism has two different populations of cells that make up the body. One population contains two working copies of the VHL gene (these cells are normal) and a second population contains one working and one non-working VHL gene copy (these cells are abnormal).
The phenomenon of mosaicism may occur in the following way:
The clinical diagnosis of Von Hippel-Lindau syndrome relies on the presence of certain clinical findings. For an individual with no known family history of Von Hippel-Lindau syndrome, the occurrence of two or more characteristic lesions (a change in body tissue or an organ caused by disease) confirms a clinical diagnosis of the syndrome. Characteristic lesions may include:
For an individual with a positive family history of Von Hippel-Lindau syndrome, a clinical diagnosis of the syndrome is established by the presence of one or more of the following:
A detailed review of an individual’s medical and family history becomes important in diagnosing Von Hippel-Lindau syndrome. A doctor or genetic counselor may construct a pedigree, or a multi-generation family tree, that indicates which members of the family have developed cancer, the types of cancer and the ages of onset, as well as the presence of any clinical manifestations, such as benign tumors. If the pattern of clinical features and/or cancers is suggestive of Von Hippel-Lindau syndrome, the physician or counselor may recommend that genetic testing be performed.
In order to confirm on a molecular level that an individual has Von Hippel-Lindau syndrome, he or she can undergo genetic testing:
It is estimated that close to 100 percent of individuals carrying a clinical diagnosis of Von Hippel-Lindau syndrome will have a mutation involving VHL. Some individuals may be mosaic and not have a detectable alteration of VHL in their blood cells. Therefore, the failure to identify an alteration in the VHL gene does not exclude the clinical diagnosis of Von Hippel-Lindau syndrome.
VHL genetic test results can also provide important information for other family members. If a mutation responsible for Von Hippel-Lindau syndrome is identified, at-risk relatives (first or second degree relatives) can be tested for the same genetic alteration. Almost every individual with a mutated VHL gene displays symptoms of Von Hippel-Lindau syndrome by the age of 65 years.
A person with Von Hippel-Lindau syndrome who does not wish to pass this disease on to future children has several options, including:
Before one can proceed with prenatal testing or PGD, a VHL mutation must be identified in a parent with Von Hippel-Lindau syndrome. Using either method, a parent can work with a genetic counselor and/or physician to decide whether to carry the pregnancy to term or to end the pregnancy.
Individuals with an altered VHL gene are at increased risk to develop tumors in areas of the body that contain blood vessels. Most commonly, Von Hippel-Lindau patients develop tumors in the brain, retina, spinal cord, inner ear, and pancreas. Often, these tumors must be removed to prevent medical problems, but they are usually benign (non-cancerous). About 15 percent of patients with Von Hippel-Lindau syndrome develop neuroendocrine tumors of the pancreas, which behave like cancers. Individuals with Von Hippel-Lindau syndrome are also at a high risk for renal cell carcinoma (malignant kidney cancer) which occurs in 40 percent of affected individuals. Pheochromocytomas are usually benign, but malignant behavior has been documented.
|Occurrence and age of onset in VHL syndrome|
|CNS||Ages at diagnosis||Most common ages at diagnosis||Frequency in patients|
|Retinal hemangioblastomas||0-68 yrs||12-25 yrs||25-60%|
|Endolymphatic sac tumors||1-50 yrs||16-28 yrs||11-16%|
|Cerebellar hemangioblastomas||9-78 yrs||18-25 yrs||44-72%|
|Brainstem hemangioblastomas||12-46 yrs||24-35 yrs||10-25%|
|Spinal cord hemangioblastomas||12-66 yrs||24-35 yrs||13-50%|
|Renal cell carcinoma or cysts||16-67 yrs||25-50 yrs||25-60 %|
|Pheochromocytomas||4-58 yrs||12-25 yrs||10-20%*|
|Pancreatic tumor or cyst||5-70 yrs||24-35 yrs||35-70%|
|Epididymal cystadenomas||17-43 yrs||14-40 yrs||25-60% of males|
|APMO or broad ligament cystadenoma||16-46 yrs||16-46 yrs||Estimated 10% of females|
*Compiled from a survey of papers from 1976 - 2004, including data from the VHL Family Alliance. Frequency of pheochromocytoma varies widely depending on genotype.
"VHLFA Handbook." VHL Family Alliance. Last revised: 01/2005
Regardless of whether an at-risk individual decides to pursue genetic testing, he or she should be regularly monitored for the development of benign and malignant tumors associated with Von Hippel-Lindau syndrome.
While many of the tumors associated with Von Hippel-Lindau are benign, they should be followed closely or treated as their growth can cause other problems. For example, retinal hemangioblastomas can lead to loss of vision and pheochromocytomas can cause high blood pressure. Regular screening and appropriate management has been shown to reduce mortality and morbidity from this condition.
It is important for VHL patients to be screened regularly for these issues through:
It is important to note that management of tumors differs depending on whether an individual develops a tumor as a result of having VHL as opposed to developing a sporadic tumor that is not caused by VHL. An individual with VHL who develops a tumor should consult a physician with expertise in the management of this condition.
Adults and older children and adolescents should avoid the use of tobacco products, which increase the risk for kidney cancer.
Adults who have VHL or who would like more information about VHL may contact the Medical Genetics Team at the Hospital of the University of Pennsylvania at 215-662-4740. Appointments can also be requested online at https://www.pennmedicine.org/request-appointment/ or by calling 1-800-789-PENN(7366).
VHL Family Alliance
2001 Beacon Street, Suite 208
Boston, MA 02135-7787 USA
Phone: 1-800-767-4845 or 1-617-277-5667
American Cancer Society
1599 Clifton Road NE.
Atlanta, GA 30329
National Library of Medicine Genetics Home Reference- VHL syndrome
Gene Reviews- VHL syndrome
Written by: Sarah Thornton, MS
Reviewed by: Kim Nichols, MD, Kristin Zelley, MS
Date: September 2012