Von Hippel-Lindau Syndrome
What is von Hippel-Lindau syndrome (VHL)?
Two eye care providers—von Hippel in Germany and Lindau in Sweden—were the first to
describe tumors in people's eyes and brains, hallmarks of this genetic condition.
In the 1960s, the disease was named von Hippel-Lindau syndrome to recognize their
Von Hippel-Lindau syndrome is a rare genetic disorder. A person with VHL has an increased
risk of developing pockets of fluid (cysts) or tumors in many parts of the body. The
more common tumors to occur are:
Hemangioblastomas. These are noncancerous (benign) tumors made up of nests of blood vessels of the brain
Hemangioblastomas of the retina. These benign tumors are found in the retina of the eye.
Pheochromocytomas. This neuroendocrine tumor is usually benign. It occurs within or outside of the adrenal
Renal cell carcinoma. This cancerous tumor of the kidney happens in about 7 in 10 people with VHL.
Less often, some people develop endolymphatic sac tumors. These are ear tumors that
can cause deafness if undetected. People with VHL may also develop pancreatic tumors
and cystadenomas of the epididymis or broad ligament. Other signs include cysts in
the kidney and pancreas.
The VHL gene is a tumor suppressor gene located on chromosome 3. This usually controls
cell growth and cell death. Both copies of a tumor suppressor gene must be changed,
or mutated, before a person will develop cancer. In about 4 in 5 VHL cases, the first
mutation is inherited from either the mother or the father. It is present in all cells
of the body at birth. This is called a germline mutation. Whether a person who has
a germline mutation will develop a tumor and where the tumor or tumors will develop
depends on where (in which cell type) the second mutation happens. For example, if
the second mutation is in the retina, then a retinal hemangioblastoma may develop.
If it is in the adrenal gland, then a pheochromocytoma may develop. The process of
tumor development actually needs mutations in multiple growth control genes. Loss
of both copies of the VHL gene is just the first step in the process. What causes
these additional mutations is unknown. Possible causes include chemical, physical,
or biological environmental exposures or chance errors in cell replication.
Some people who have inherited a germline VHL mutation never develop cancer. This
is because they never get the second mutation necessary to knock out the function
of the gene and start the process of tumor formation. This can make the cancer appear
to skip generations in a family. But, in reality, the mutation is present. People
with a VHL mutation, regardless of whether they develop cancer, have a 50/50 chance
to pass the mutation on to each of their children. About 1 in 5 VHL cases are new
mutations, and not inherited from a parent.
It is also important to remember that the VHL gene is not located on the sex chromosomes.
Therefore, mutations can be inherited from either the mother's side or the father's
side of the family.
Molecular genetic testing of VHL is available and can find a mutation in about 9 in
10 to 10 in 10 affected people. Genetic testing is also considered part of the standard
management for first-degree relatives (parent, siblings, children) of affected people.
For people who are mutation-positive, annual screening to find tumors before severe
complications develop is recommended. Genetic testing of unaffected relatives is useful
only if a germline mutation has already been identified in an affected family member.