Autoimmune Lymphoproliferative Syndrome (ALPS): NIAID
Article title: Autoimmune Lymphoproliferative Syndrome (ALPS): NIAID
Conditions: Autoimmune Lymphoproliferative Syndrome
Autoimmune Lymphoproliferative Syndrome
FOUND OUT SO FAR AT THE NIH
INTRODUCTION TO IMMUNOLOGY
MANAGE ENLARGED SPLEENS IN ALPS
MANAGE AUTOIMMUNE PROBLEMS IN ALPS
DOES ALPS RUN
INTRODUCTION TO GENETICS
CHILDREN AT RISK IF I HAVE A FAS GENE MUTATION?
QUESTIONS AND PROBLEMS PEOPLE WITH ALPS FACE
THE ALPS TEAM
AT THE NIH
IN OUR STUDY
Clinical Features of ALPSSome signs of
ALPS are ones that people can feel or see, and some of them can be
detected only by laboratory tests. Not all people with ALPS will
have all of its possible symptoms. Some people have only a few. Some
things that are seen most often in people with ALPS include:
- an enlarged spleen
- enlarged lymph nodes, especially in the neck and underarms
- an enlarged liver
- skin rashes
- frequent nose bleeds
- anemia (low blood counts)
- an increase in certain types of white blood cells (including
double-negative T cells)
- an increased life-span of some white blood cells that are no
- an alteration in a gene
ONE OF YOUR RELATIVES has been invited to visit doctors at the National
Institutes of Health (NIH) because of health problems related to the
immune system. We first began to study these problems in 1990, when we saw
a child who had immune system symptoms that did not fit any previously
known disorders. Since then, dozens of other children and adults with
similar problems have been identified and followed at the NIH.
1995, we gave this newly identified condition a name - ALPS. By August
1999, we diagnosed ALPS in 58 individuals from 35 families. These families
come from all over the country and are of many different racial
We hope that this brochure will help answer some of
your questions about ALPS. Share it with your family, physicians, members
of your community, and your children's teachers so that they can
understand ALPS better, too.
ALPS-WHAT IS IT?
ALPS is a rare disease that affects
both children and adults. ALPS stands for A
yndrome. Each of these three
words helps describe the main features of this condition. The word
identifies ALPS as a disease of the
immune system. The tools used to fight germs turn against our own cells
and cause problems. The word lymphoproliferative
unusually large numbers of white blood cells (called lymphocytes
(lim'-fo-sites)) stored in the lymph nodes and spleens of people with
ALPS. The word syndrome
refers to the many common symptoms shared
by ALPS patients.
WHAT WE'VE FOUND OUT SO FAR AT THE NIH
At this time we
are still learning about ALPS. Based on our experience, we believe the
following to be true:
Types of Autoimmune
- ALPS is a disorder that develops in early childhood.
- ALPS is not cancer; it is not contagious; it is not AIDS.
- There is a wide spectrum of illness in ALPS. For some, it is very
mild; for others, it is more severe.
- Once a person has ALPS, he or she does not become sicker and sicker
over time. In fact, the problems seem to improve as children get to be
teenagers and young adults.
- Most people with ALPS have episodes of autoimmune problems. These
can happen at any age, but they appear worse in childhood.
Common autoimmune problems in ALPS
- Very low red blood cell counts (hemolytic anemia) that can make one
- Very low platelet counts (immune-mediated thrombocytopenia,
or ITP) that cause bruises and nose bleeds, and may pose a risk
for hemorrhage (excessive bleeding). Little spots called petechiae
(pet-eek'-ia) may also show up on the skin when platelets are low.
- Very low white blood cell counts (autoimmune neutropenia), creating
a risk for bacterial infection.
- Less often, other autoimmune problems can occur in almost any organ
- skin, liver, kidney and nerves are examples.
A BRIEF INTRODUCTION TO IMMUNOLOGY
You may wonder what
the connection is between the findings in ALPS and the immune system. To
understand what happens in ALPS, we would like to review some basic
information about the immune system. It is the immune system that defends
our bodies against germs. There are many components of the immune system.
Two major components are the spleen and white blood cells. The spleen is a
fist-sized organ found to the left of your stomach. It has a special job
of filtering the blood, by cleaning out dead blood cells that arenŐt
needed any more. The blood contains many types of cells:
- red blood cells help transport oxygen to your tissues
- platelets help to form blood clots
- white blood cells are the soldiers in your immune
One major class of white blood cells is called
. There are many kinds of lymphocytes to combat the
variety of germs in the world. B cells
and T cells
two major kinds of lymphocytes.
There are many kinds of T cells.
Some of these direct our immune response to infections, and others kill
infected cells. Each T cell is named for the markers found on its surface.
There are over 100 different markers. For example, some T cells are called
CD4 cells because they have the type 4 chemical marker coating their
surfaces. Other T cells are named CD8 cells because they are coated by the
type 8 marker. Almost all T cells of healthy people have either the type 4
or the type 8 marker. Those with neither type 4 nor type 8 markers are
called double-negative T cells. People with ALPS often have increased
numbers of double-negative T cells
People with ALPS often
have extra B cells, too. The B cells produce immunoglobulins
(Ig's, also called antibodies). The antibodies are custom-fit to stick to
specific germs. There are thousands of different antibodies in the body.
Each is molded for a specific germ. Because ALPS patients have more B
cells than normal, they produce more antibodies, including ones that cause
WHAT HAPPENS IN ALPS
To better understand how ALPS
works, imagine that you have a respiratory infection, perhaps the flu. The
cells in the nose and throat send out a message to the immune system to
start making more lymphocytes to fight the flu. New troops of lymphocytes
come to the nose and throat to seek out and destroy the cells infected
with the flu virus. Once the virus is conquered, the lymphocytes get a
message that their job is done and they are no longer needed. At this
point, it is normal for most of the fighter cells to disintegrate through
a process called apoptosis
systems of people with ALPS are efficient in fighting germs. The problem
in ALPS happens after an infection is gone. In ALPS, apoptosis does not
work as well as it should. In other words, the troops (lymphocytes) donŐt
hear the message that the war is over. As a result, excess T and B cells
gather in the lymph glands, liver and spleen. We can detect the extra
cells in people with ALPS by looking for high numbers of double-negative T
cells. In general, these extra T cells donŐt cause a
Sometimes in ALPS, the B cells make a mistake. Instead of
making antibodies to be custom-designed against germs, the B cells make
antibodies against platelets, red blood cells, or other cells. This causes
autoimmune problems. The antibodies become stuck to the platelets and red
blood cells, which then get stuck in the spleen. The spleen has to work
extra hard to filter out the sticky cells. This is another reason why the
spleen gets so big.
MANAGEMENT OF ALPS
There is no cure for ALPS. However,
we can treat and prevent most
of its complications. Management of
- Diagnosis. You probably know from experience that this may
take months or years until you find a doctor who recognizes the features
- Counseling and education. The more you know about ALPS and
how to recognize its symptoms and signs, the better you will be able to
- Knowing what's treatable. Unfortunately, we have not found
ways to permanently make the swelling of lymph nodes go down or to fix
the problem with apoptosis (see WHAT HAPPENS IN ALPS).
- Therapies. Complications of ALPS, including the many
different autoimmune problems, can be treated successfully. ALPS can be
managed through close communication with doctors as symptoms and signs
WAYS TO MANAGE ENLARGED SPLEENS IN ALPS
people with ALPS have an oversized spleen. Usually, it is not necessary to
remove the spleen unless there are severe problems like anemia. However,
removing a spleen carries both risks and benefits, which doctors and
patients must carefully consider before deciding what to do.BENEFITS OF SPLENECTOMY
You will be missing an organ which helps protect against infection.
Your chances of getting certain bacterial infections increase. You must
get some vaccines to avoid these infections.
After your spleen is removed, you may need to take antibiotics for
many years to help prevent specific bacterial infections.
- It will be easier to regulate and control blood counts.
- You will feel less discomfort.
- There is no longer a risk of spleen rupture, a very serious problem,
should it occur.
WAYS TO MANAGE AUTOIMMUNE PROBLEMS IN ALPSSteroids are
the first line of treatment for autoimmune episodes, like hemolytic anemia
and ITP. One common steroid is prednisone. It is often given for
a short time, but sometimes it is needed for longer periods. When
prednisone is not enough to treat the episode, other drugs, such as Imuran
and cyclosporin, may also be prescribed. Steroids have saved lives and
have dramatically reduced the complications in some people with ALPS.
However, like all treatments, steroids have some disadvantages, so they
should not be used too much or for too long.
POSSIBLE LONG-TERM SIDE EFFECTS OF
- Thinning of bones
- Poor wound healing
- Difficulty in fighting infection
- Cataracts of the eyes
- Mood swings
- Weight gain
- The body starts to rely on the steroids and the amount has to be
- Blood Transfusions are useful to replace red blood cells
when anemia is severe.
- Vaccines are important to help prevent infections. The
fewer infections you have, the less often you will need to "call in the
troops." In addition to all the childhood vaccinations, it is important
to get a yearly flu shot and boosters as needed. People with allergies
to eggs should discuss this with their doctor prior to receiving a flu
- Gene Therapy is unfortunately not likely to work for
DOES ALPS RUN IN FAMILIES?Children can inherit ALPS
from one of their parents. The process of apoptosis is controlled by
several genes. Most people with ALPS have an altered gene that plays a
major role in apoptosis. The altered gene may be passed from one
generation to the next. Before discussing what this gene does, we need to
describe some basic information about genes and how they work.
A BRIEF INTRODUCTION TO GENETICSGenes, which
are made of DNA, are located on chromosomes in the cells of our body. We
have two copies of each gene, except for the genes on the sex chromosomes.
Genes act as the blueprint for the development and operation of our
bodies. Each gene contains the instructions for making one of the building
blocks of a cell. We each have around 100,000 genes that determine who we
are, what we look like, and how our bodies work. By chance, every person
has approximately 10-12 genes that donŐt work as well as they should or
donŐt work at all. These genes are mutated. That is, the DNA is slightly
different in mutated genes. Not all changes, or mutations, are harmful.
Sometimes these changes cause no problems at all, but sometimes they cause
human disease. Sometimes it takes alterations in several genes to cause
problems. Other times the genetic mutation interacts with the environment
to cause health problems.
THE FAS GENEWe have found genetic changes or
mutations that seem to be factors in the development of ALPS. In
over 83% of the ALPS patients, we have found an alteration in a gene that
encodes a cell component, or protein, called Fas. This alteration
causes the gene to produce abnormal Fas protein. We do not
completely understand how abnormal Fas protein leads to ALPS, but
it clearly does. We still need to identify other genetic and non-genetic
factors that contribute to the development of ALPS.
Fas protein is one of several proteins that are important for
apoptosis, the normal process through which cells die. Fas
controls the life span of certain cells, particularly the lymphocytes.
Like people, cells have a normal life span in which they grow, do their
job, and then die. The mutated Fas protein does not work well,
and can't give the cells the message that it is time to die. Although most
ALPS patients have one normal and one altered copy of the Fas gene, the
altered protein is able to interfere with the function of the normal
However, Fas mutations do not explain all cases of
ALPS. About 17% of people with ALPS do not have a Fas mutation. In some of
them there are alterations in other proteins known as Fas-ligand and
Caspase-10. In some ALPS patients a genetic alteration has not yet been
found. Also, there are many relatives of ALPS patients who have a
Fas mutation and do not have ALPS. We believe that other
genes and environmental factors also play a role determining which people
ARE MY CHILDREN AT RISK IF I HAVE A FAS GENE
MUTATION?There are many people who have no signs of ALPS,
yet have a Fas mutation. Individuals with a Fas mutation have a
50/50 chance of passing the Fas mutation on to their children.
That means that each child has a 50% chance of inheriting the unaffected
gene and a 50% chance of inheriting the altered gene. This chance is the
same for each child. In other words, if you have 5 children and they have
each inherited the Fas mutation, the sixth child still has the
same 50/50 risk of inheriting the Fas mutation. Of the children
who inherit the Fas mutation, approximately half of them will
develop some features of ALPS. This figure is based on the 98 people we
have studied so far at NIH who have a Fas gene mutation. Of these
98 people with the Fas gene mutation, 48 have enough symptoms to
be diagnosed with ALPS and additional persons have some features of ALPS.
Children who have inherited the unaltered Fas gene have almost no
chance of developing ALPS.
HOW TO EXPLAIN ALPS TO YOUR KIDSIt may seem easier not to
tell your children anything about ALPS, but children, like adults, often
want to know "why?" and don't like to be left in the dark. The more
children understand about ALPS, the fewer fears and misunderstandings they
may have. The following is one way we have explained ALPS to a child. You
may find these ideas helpful for your family.
|ALPS IS A PROBLEM WITH THE
Usually, the immune system attacks
germs, as an army would attack its enemy. The soldiers are called
lymphocytes. They go around the blood stream and find germs. After
the soldiers kill the germs, their job is done and it is time for
them to go away and die. In ALPS, the soldiers don’t hear the
message to die. They stay and hang out in places like your spleen
and the lymph nodes found under your cheeks, making them really big.
Sometimes, the soldiers become confused and they attack members of
their own side, such as the red blood cells and platelets in your
body. Without enough red blood cells, you may feel tired. Without
enough platelets, you may get nosebleeds, red spots on your skin and
bruises. Sometimes you may need to take medicine or get a
transfusion of new blood. Sometimes you have to be extra careful not
to bump your belly because your spleen is fragile. Even though
living with ALPS can be hard, all kids still go to school, and most
adults work. All have responsibilities, contribute to their
communities in many ways, have friends, and have
SOME COMMON QUESTIONS AND PROBLEMS PEOPLE WITH ALPS
FACEDo you have the mumps? No! People
with mumps have a very different condition, even though both involve
swelling of the sides of your face. Some people who ask questions are
well-meaning, some are curious, and some are just plain rude. You don't
have to answer if you don't want to. You can just ignore the question. A
simple answer, such as "I was born this way" or "God made me this way" is
often enough to satisfy curiosity. People tend to say different things
depending on their mood. The important thing is to find an answer that
feels comfortable to you.
Why is your face so
round? If you are taking steroids, you may gain weight quickly.
Some parents talk to teachers about the side effects of steroids in
advance, so that the class knows what to expect. Try to remember that the
swelling is temporary. It goes away once you stop taking the
Are you contagious? People often worry
that ALPS is catching. It is important that people understand that ALPS is
Stares from strangers: It's a fact
of life that people will stare at people who look different. Often there
are good days when stares don't seem to matter, and bad days when you feel
like crawling under the bed. Parents of children with ALPS have to work
extra hard to develop their child's self-confidence and sense of security.
The important thing is to let them know that you love them no matter how
they look. Children and adults with ALPS need to be reminded that they
have many positive characteristics.
sports: Sometimes doctors recommend that people with enlarged
spleens not play contact sports. When the spleen is large, it is fragile
and there is a risk of rupture. This can be hard for many to accept. We at
the NIH encourage people with large spleens to wear spleen guards. A
spleen guard is a piece of fiberglass that is molded to a person's
stomach. It is easily wrapped around your stomach and held in place under
your shirt. In general, the spleen guard is worn whenever someone is
involved in an activity at high risk for stomach injury, such as contact
sports. Other people choose different sports, such as swimming, track, or
Relatives who do not have ALPS:
Brothers and sisters or other relatives who don't have ALPS are still
affected by the condition. Some worry that their brother or sister will
die. Some think they will develop ALPS because they look or act like their
brother or sister. Some children struggle with how much of their parents'
time is spent with their sick brother or sister. Relatives who have a
Fas mutation but do not have ALPS may feel guilty that they are
not sick. It is important for families to talk openly about ALPS so that
any misconceptions can be explained and feelings can be expressed. Family
counseling is often helpful.
The positive side:
Many families say that ALPS has brought them closer together. Family
members learn that they can rely on each other for support. Children learn
from their parents' open and honest communication, and the experience
teaches them how to solve problems.
THE ALPS TEAM AT THE NIHThe team at the NIH is
composed of doctors, scientists, nurses, genetic counselors, and several
students and scientists in training. Physicians from around the country
refer families suspected of having ALPS to us. We study their blood for
specific laboratory findings related to ALPS. After reviewing the medical
records and lab results, the team invites those who we think have ALPS to
NIH for evaluation and follow-up. With the many referrals we have been
getting recently, we are beginning to think that ALPS is more common than
WHAT'S THE PURPOSE OF OUR STUDY AT THE NIH?We are trying
to better understand this rare disease, to find the cause and hopefully to
find improved ways to treat ALPS. Of course, the ultimate hope is to find
WHY WE WANT TO INVOLVE OTHER MEMBERS OF YOUR FAMILY IN OUR
STUDYWe know there is a genetic component to ALPS. However,
the development of ALPS in families with mutations in apoptosis genes is
not straightforward. For example, we want to know why some family members
have an alteration in Fas and no sign of ALPS. Therefore, we would like to
study this gene, and other genes, in your family. We have other research
questions that may be helped by studying other members of your family.
Therefore, we are inviting your family members to join our study by
providing us with a small sample of their blood in order to help us answer
our research questions.
PARTICIPATING IN OUR STUDYEach person who is
interested in participating will have a chance to discuss study details
with the investigators. We will ask each person to read and sign a consent
form. All of the tests, evaluations and treatments at the NIH are
free. Family members who participate will be helping us better understand
We hope that you found this information helpful. Since 1990,
we have moved from identifying and treating one child to dozens of
families. We look forward to learning more about ALPS so that we can learn
better ways to manage the condition.
Please call either,
Straus (301-496-5221) or
Janet Dale, RN, MPH (301-496-1699) or
Jennifer Puck (301-402-2194).
Stephen Straus, M.D. | Michael
Sneller, M.D. | Janet Dale, RN, MPH
Jennifer Puck, M.D. | Michael