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Von Hippel-Lindau, abbreviated VHL, is one of
more than 7000 known inherited disorders. Tumors
will develop in one or more parts of the body. Many of these
tumors involve the abnormal growth of blood vessels in different
organs of the body.
While blood vessels normally branch out like trees,
in people with VHL little knots of blood capillaries
sometimes occur in the brain, spinal cord, or retina. These
little knots are called angiomas,
or hemangioblastomas.
In other parts of the body the tumors of VHL are called by other
names.
These tumors themselves may cause problems, or
problems may develop around them. For this reason they need
to be carefully monitored by your medical team.
VHL is different in every patient. Even in the
same family, people may show only one or several features of
VHL. Since it is impossible to predict exactly which one or
more manifestations of VHL each person will have, it is important
to continue to check for all the possibilities throughout a
person’s lifetime.
Dr. Eugen von Hippel, a German ophthalmologist,
described the angiomas in the eye in 1893-1911. His name was
originally used only in association with VHL in the retina.
Dr. Arvid Lindau, a Swedish pathologist, first
described the angiomas of the cerebellum
and spine in 1926. His description included a systematic compilation
of all other published patients, including those of von Hippel,
and described changes in different abdominal organs. We now
understand that both these physicians were describing different
aspects of the same disease.
Von Hippel-Lindau (VHL) is different from most
other conditions in that it has no single primary symptom,
that it does not occur exclusively in one organ of the body,
and that it does not always occur in a particular age group.
Generally the condition is hereditary, but the health problems
of the involved families and the specialties of the attending
physicians are so varied that the common cause may not be recognized.
In addition, the appearance and severity of the condition are
so variable that many members of the family may have only some
relatively harmless issue, while others may have a serious illness.
With careful monitoring, early detection, and
appropriate treatment, the most harmful consequences of this
gene can be greatly reduced,
or in some cases even prevented entirely.
Researchers are also finding that a significant
number of new cases are occurring. As many as 20 percent of
the families seen at centers around the world are the first
in their family ever to have VHL. We do not yet understand why
this is happening, but it underscores the importance of the
need for careful differential
diagnosis in all people, not just those in families known
to be at risk for VHL.
Angiomas, Hemangioblastomas,
Cysts and Tumors
Angiomas may occur in several parts of the body.
Angiomas in the brain or spinal cord, for example, are called
hemangioblastomas.
The pressure they exert may in itself cause symptoms. They may
press on nerve or brain tissue and cause symptoms such as headaches,
problems with balance when walking, or weakness of arms and
legs.
If the angioma grows, the walls of the blood vessels
may weaken and some blood leakage may occur, which can cause
damage to surrounding tissues. Blood or fluid leakage from angiomas
in the retina, for example, can interfere with vision. Early
detection, careful monitoring of the eye, and treatment when
needed, are very important to maintain healthy vision.
Cysts may grow
up around angiomas. Cysts are fluid-filled sacs which may exert
pressure or create blockages that can cause symptoms.
Some male patients experience tumors in the scrotal
sacs. These tumors are almost always benign,
but should be examined by your urologist.
Similarly, women may have benign cysts and tumors among the
reproductive organs, which need careful monitoring.
Cysts and tumors may occur in the kidney,
pancreas, and adrenal
glands. These cysts frequently cause no symptoms, but must
be monitored for changes. One sign
of adrenal gland tumors may be high blood pressure. Some of
these tumors are benign, while others are cancerous. Early detection
and careful monitoring are particularly important for these
organ systems, usually with yearly CT or MRI, assisted by ultrasound
scanning. (See Figure 1.)
Figure 1: Principal lesions of
VHL and their frequency. People with VHL will
usually experience one or more of the tumors shown. Frequency
varies in different families, and statistics from particular
ethnic groups may differ widely for this reason. French
families are more likely to have CNS lesions, German families
are more likely to have pheochromocytomas, and Japanese
famlies are more likely to have kidney tumors. The ranges
shown here were compiled by the U.S. National Institutes
of Health from a large international pool of patients.
Figure based on an illustration from the U.S. NIH. Data
from Lonser et al., Lancet 2003, 361: 2059-67,
and N. E. J. Med. 2004 350:2481-2486 and G. P.
James, Hastening the Road to Diagnosis, re APMO. |
What is Cancer?
Cancer can be a frightening word. Families need
to know that cancer canoccur with VHL. However, with careful
early monitoring and treatment, the worst possibilities of cancer
may never occur.
Cancer is not one thing, it is a group of more
than 100 different diseases. While each disease differs from
the others in many ways, every cancer is a disease of some of
the body’s cells. Cancer associated with VHL is limited to specific
types.
Healthy cells that make up the body’s tissues
grow, divide, and replace themselves in an orderly way. This
process keeps the body in good repair. Sometimes, however, normal
cells lose their ability to limit and direct their growth. They
divide too rapidly and grow without any order. Too much tissue
is produced, and tumors begin to form. Tumors can be benign
or malignant.
• Benign tumors, such
as VHL tumors of the brain, spine, and retina, are not cancerous
and do not spread.
• Malignant tumors,
like those which may occur in the kidney, are cancerous. They
can invade and destroy nearby healthy tissues and organs.
Cancer cells also can spread, or metastasize,
to other parts of the body and form new tumors.
Because VHL can cause malignant tumors in the
visceral organ systems, it
is considered one of a group of familial
cancer risk factors, which are transmitted genetically. The
objective is to find tumors early, watch for signs that a tumor
is becoming aggressive in its behavior, and to remove the tumor
before it invades other tissues. Since these tumors are inside
the body, you need medical imaging techniques to find and watch
them.
Not all tumors require surgery when they are found.
Research is going on to learn more about how to tell when a
tumor is getting worrisome and requires action. You and your
family can help researchers learn more about how long we can
safely watch tumors by sharing your family’s own experiences.
Please contact the VHL Family Alliance for more information
on researching your family tree.
How Do People get VHL?
Von Hippel-Lindau is caused by an alteration in
one of your two copies of a gene referred to as the VHL gene.
This altered gene may be transmitted genetically, following
a dominant pattern of inheritance. Each child receives one gene
of each pair from each parent. If one parent has an alteration
(mutation) in a dominant
gene, each child has a fifty-fifty chance of inheriting that
gene. One copy of the altered gene is sufficient to produce
the disease. VHL is sometimes referred to as an autosomal
dominant trait, meaning that it is not limited to one sex, but
may occur in both men and women. (See Figure 2.)
Figure 2: Inheritance of a dominant
gene. A child receives one gene in each pair
from each parent. If one parent has a Dominant gene (D),
each child has a fifty-fifty chance of inheriting the
condition. Dominant genes dominate their normal counterparts
(n). A dominant gene can be inherited by either a male
or female child, from an affected mother or father. Illustration
from the March of Dimes. |
Anyone with a parent with VHL and most people
with a brother, or sister with VHL are at 50 percent risk of
having VHL. Anyone with an aunt, uncle, cousin, or grandparent
with VHL may also be at risk. The only way to determine for
sure that someone does not have the VHL gene is through DNA
testing. (See Section 10, Obtaining
DNA Testing.) Even in people who have an alteration in the
VHL gene, however, there is a wide variation in the age at which
angiomas and other VHL tumors begin to grow, the organ system
in which they grow, and the severity of the involvement. Every
person is different.
The booklet Your Family Health Tree,
published by the VHL Family Alliance, discusses the genetics
of VHL in greater detail, and explains how you can compile family
history information, which can be of great help to your medical
team. Family history information is important to understand
your own condition, and to assist researchers in learning more
about VHL.
Early Detection
Because VHL varies so widely, there is no consistent
set of symptoms in each person. Each possible feature of the
disease is detected in a different way.
If you have a family history of VHL, it is important
to tell your doctor, or your child’s pediatrician, and begin
screening early, before any symptoms occur. Most VHL lesions
are much easier to treat when they are small. Confer with your
doctor about the best time to begin screening, and the right
schedule for return visits. We recommend to begin regular screening
of children at risk by age 1-3 years, especially for eye examinations,
and to inform the pediatrician of the family’s history of VHL.
You and your doctor may refer to Section
5, Suggested Screening Guidelines.
Nearly all of us at one time or another have wondered
if it is better not to know — perhaps if we just don’t go through
the testing, we’ll be okay. And for some years, that may seem
to be true. But some of the possible complications of VHL are
sneaky — you may not even have symptoms until the problem has
developed to a critical level. It’s a little like not taking
care of your house or car — you may get away with it for awhile,
and then it all catches up with you and it costs you a great
deal all at once. There is clear, documented evidence
that you will stay healthier longer if you use medical diagnostic
techniques wisely and are watchful.
Detection of affected individuals by DNA analysis of a
blood sample is now possible for nearly all VHL families.
The accuracy of the testing, and its usefulness in more
families, is increasing rapidly. DNA testing can be used
to determine which members of the family need to be followed
closely. It can also determine which members may be reassured
that they do not carry the altered VHL gene. If they do
not have the altered VHL gene, they will not need further
testing, and they cannot pass the altered gene to their
children.
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I explain what’s
going on, how it works and what we’re trying to
fix, what could happen if it isn’t fixed. I’m
educating my patient in a way, but I’m also dispelling
uncertainty. Uncertainty is the worst illness. The fear
of the unknown can really be disabling.
-- Dr. Thomas Delbanco, Beth Israel Hospital, Boston,
Massachusetts, as quoted in Bill Moyers, Healing and the
Mind, Doubleday Books, New York, 1993, p. 18.
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If you are a known VHL gene carrier, or if genetic
testing does not yet work for your family, you will need to
continue regular medical evaluation. One normal screening examination
does not necessarily mean there is no VHL present, since the
first evidence of VHL may occur later in life. Occasionally
a person may be so mildly affected that VHL may seem to skip
a generation. VHL has been diagnosed for the first time in people
as old as 80, often because their children or grandchildren
developed VHL tumors.
Even when only one of the features of VHL is found,
and even if there is no family history of VHL, a diagnosis of
VHL should be considered and a full diagnostic evaluation of
other areas of the body should be carried out. It is quite possible
for someone to be the first in the family to have VHL. In some
studies, twenty percent of the patients were the first in their
family to have VHL.
Depending on the outcome of your screening, your
doctor will tell you what particular signs need to be followed
closely. In general, vision problems, vomiting, headaches, balance
problems, progressive weakness in arms or legs, or persistent
pain lasting more than 1-2 days and that stays in one place,
should be checked by your doctor.
Once VHL has been diagnosed in any one part of
the body, it is important to undergo screening for possible
evidences of the disease in other parts of the body, and to
return for additional screening on the schedule recommended
by your medical team.
General Recommendations
for Screening
Your medical team will work with you to develop
the right screening and monitoring program for you and your
family.
Screening is testing before symptoms appear,
to make sure that any issues are found early. See Section
5, Suggested Screening Guidelines.
Monitoring is checking up on known issues,
to make sure that they are treated at the best time to
insure long-term health. You and your medical team will
work out the right interval for checkups, depending on
your particular situation.
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My family has become
convinced that one should never go alone to a doctor’s
appointment. If the news is difficult to hear, the brain
shuts off at a certain point and just won’t accept
any more information. It helps if there are two people
there, preferably with the unaffected person taking notes.
If you have to go alone, take a tape recorder. You’ll
be amazed when you listen to the tape the next day. --
Darlene Y., Massachusetts |
It is important to begin screening children who
are at risk as early as possible. Using DNA testing, it is possible
to identify which children need screening, and which children
do not carry the VHL mutation and will not need to be screened.
The VHL Family Alliance and its medical advisors
recommend that you begin screening children as early as age
1, especially in the eye. Make sure that the pediatrician knows
that the child is at risk for VHL. We recommend using techniques
that are not painful and do not involve radiation or contrast
dyes: a thorough medical eye examination by a retinal specialist,
and a complete physical examination including blood pressure
and neurological examination, and hearing testing by an audiologist.
Imaging of the brain, ultrasound of the abdomen, and often a
24-hour urine collection usually begin about age 10-12, or sooner
if symptoms or signs occur. (See Figure 3.)
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Figure 3: Ultrasound scanning.
An Ultrasound scan works like the sonar used by
submarines. Sound waves are sent out. A computer analyzes
the reflection of the sound and calculates the depth and
density of the tissue that reflects the sound. Illustration
by Vincent Giovannucci, O.D., Auburn, Massachusetts. |
Included in this booklet is a Reminder
Calendar for you to record your own doctors’ recommendations
for screening, the intervals recommended for repeat testing,
and the date of your next appointments.
A Suggested Screening Protocol, or routine for
checkups and treatment, is included in Section
5.
In British parlance, patients are referred
to as “sufferers.”
We’d like to change the British
language.
We are not sufferers, we are survivors.
We are not victims, we are veterans.
Just as the professionals have experience
and expertise that we need and respect, we too have experience
which is deserving of respect.
Together with the physicians and researchers,
we will succeed in our quest to improve diagnosis, treatment,
and quality of life for people with von Hippel-Lindau.
We are working to find a cure, but a cure will likely
take decades. Meanwhile we are working through early diagnosis
and improving treatment to manage this condition, and
will do all we can to support one another through the
experience.
-- Joyce Graff, Co-Founder of the VHL Family Alliance,
1994
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