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IDF PATIENT/FAMILY HANDBOOK | CHAPTER IX
The DiGeorge Syndrome
DiGeorge Syndrome is a primary immunodeficiency disease which
is caused by abnormal migration and development of certain cells
and tissues during fetal development. As part of the developmental
defect, the thymus gland may be affected and T-lymphocyte
production may be impaired, resulting in recurrent infections.
 Definition of DiGeorge Syndrome:
The DiGeorge Syndrome is a primary
immunodeficiency disease which is caused by
abnormal migration and development of certain
cells and tissues during growth and differentiation
of the fetus. Different tissues and organs often
arise from a single group of embryonic cells.
Although the tissues and organs that ultimately
develop from a single group of embryonic cells
may appear to be unrelated in the fully formed
child, they are related in that they have developed
from the same embryonic or fetal tissues.
Although many different organs may be involved in
the DiGeorge Syndrome, they all evolve from the
same embryonic cells.
Most, but not all patients with the DiGeorge
Syndrome have a small deletion in a specific
part of chromosome number 22 at position
22q11.2. Another name for this syndrome is the
chromosome 22q11.2 deletion syndrome. Patients
with the DiGeorge Syndrome do not all show the
same organ involvement. A given organ may be
uninvolved, or so mildly involved that the organ
appears to be normal. Thus, patients with the
DiGeorge Syndrome may not all have the same
organs involved or the same severity. Patients
with the DiGeorge Syndrome may have any or all
of the following:
Facial appearance:
Affected children may have an underdeveloped
chin, eyes with heavy eyelids, ears that are rotated
back and defective upper portions of their ear
lobes. These facial characteristics vary greatly from
child to child and may not be very prominent in
many affected children.
Parathyroid gland abnormalities:
Affected children may have underdeveloped
parathyroid glands (hypoparathyroidism). The
parathyroids are small glands found in the front of
the neck near the thyroid gland (hence the name
"parathyroid"). They function to control the normal
metabolism and blood levels of calcium. Children
with the DiGeorge Syndrome may have trouble
maintaining normal levels of calcium, and this
may cause them to have seizures (convulsions).
In some cases, the parathyroid abnormality is
relatively mild or not present at all. The parathyroid
defect often becomes less severe with time.
Heart defects:
Affected children may have a variety of heart
(or cardiac) defects. For the most part, these
anomalies involve the aorta and the part of the
heart from which the aorta develops. As with other
organs affected in the DiGeorge Syndrome, heart
defects vary from child to child. In some children,
heart defects may be very mild or absent.
Thymus gland abnormalities:
Affected infants and children may have
abnormalities of their thymus. The thymus gland
is normally located in the upper area of the front
of the chest. The thymus begins its development
high in the neck during the first three months of
fetal development. As the thymus matures and
gets bigger, it drops down into the chest to its
ultimate location under the breastbone and over
the heart.
The thymus controls the development and
maturation of one kind of lymphocyte, the
T-lymphocyte ("T" for "Thymus") (see chapter
titled The Immune System and Primary Immune
Deficiency Diseases). The size of the thymus
affects the number of T-lymphocytes that can
develop. Patients with a small thymus produce
fewer T-lymphocytes than someone with a
normally sized thymus. T-lymphocytes are
essential for resistance to certain viral and fungal
infections. Some T-lymphocytes, the cytotoxic
T-lymphocytes, directly kill viruses. T-lymphocytes
also help B-lymphocytes to develop into plasma
cells and produce immunoglobulins or antibodies.
Patients with the DiGeorge Syndrome may have
poor T-cell production compared to their peers,
and as a result, they may have an increased
susceptibility to viral, fungal and bacterial infections.
As with the other defects in the DiGeorge
Syndrome, the T-lymphocyte defect varies from
patient to patient. In addition, small or mild
deficiencies may disappear with time.
Miscellaneous clinical features:
In addition to the above features, patients with
the DiGeorge Syndrome may occasionally have
a variety of other developmental abnormalities
including cleft palate, poor function of the palate,
delayed acquisition of speech and difficulty in
feeding and swallowing. In addition, some patients
have learning disabilities, behavioral problems,
and hyperactivity.
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Diagnosis of DiGeorge Syndrome:
The diagnosis of the DiGeorge Syndrome is
usually made on the basis of signs and symptoms
that are present at birth or develop soon
after birth. Some children may have the facial
features that are characteristic of the DiGeorge
Syndrome. Affected children may also show signs
of low blood calcium levels as a result of their
hypoparathyroidism. This may show up as low
blood calcium on a routine blood test, or the infant
may be "jittery" or have seizures (convulsions) as
a result of the low calcium. Affected children may
also show signs and symptoms of a heart defect.
They may have a heart murmur that shows up
on a routine physical exam, they may show signs
of heart failure, or they may have low oxygen
content of their arterial blood and appear "blue" or
cyanotic. Finally, affected children may show signs
of infection because of the underdevelopment of
their thymus gland and low T-lymphocyte levels.
Some children have signs or symptoms at birth or
while they are still in the hospital nursery. Others
may not show signs or symptoms until they are
a few weeks or months older.
Some children and
adults are diagnosed at a much older age due
to speech delay, qualitative speech problems, or
feeding problems.
There is a great deal of variation in the DiGeorge
Syndrome from child to child. In some children,
all of the different organs and tissues are
affected. These children have the characteristic
facial characteristics, low blood calcium from
hypoparathyroidism, heart defects and a
deficiency in their T-lymphocyte number and
function. In other children, all of the different
organs and tissues may not be affected, and
the organs and tissues that are affected may be
affected to different degrees.
Not only do children with the DiGeorge Syndrome
differ in the organs and tissues that are affected,
but they also differ in terms of how severely a
given organ or tissue is affected.
In the past, the diagnosis of the DiGeorge
Syndrome was usually made when at least three
of the characteristic findings described above were
present. Unfortunately, this caused many mild
cases to be missed. In recent years, the genetic
test has been more widely used. Over 90% of
patients with the clinical diagnosis of DiGeorge
Syndrome have a small deletion of a specific
portion of chromosome number 22 at position
22q11.2. This can be identified in a number
of ways, but the most common way is a FISH
analysis (for Fluorescent In Situ Hybridization). Use
of a FISH analysis test has made the diagnosis
of DiGeorge Syndrome more precise and more
common. Approximately 1 in 4000 babies have
DiGeorge Syndrome or chromosome 22q11.2
deletion syndrome. For patients who do not have
the deletion, the diagnosis continues to rely on the
characteristic combination of clinical features.
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Therapy for DiGeorge Syndrome:
Therapy for DiGeorge syndrome is aimed at
correcting the defects in the organs or tissues that
are affected. Therefore, therapy depends on the
nature of the different defects and their severity.
Treatment of the low calcium and
hypoparathyroidism may involve calcium
supplementation and replacement of the missing
parathyroid hormone. A heart (or cardiac) defect
may require medications or corrective surgery
to improve the function of the heart. If surgery is
required, the exact nature of the surgery depends
on the nature of the heart defect. Surgery can
be performed before any immune defects are
corrected. It is important that all the precautions
that are usually taken with children with T-cell
immunodeficiencies be observed, such as
irradiating all blood products to prevent
graft-vs.-host disease and ensuring the blood
products are free of potentially harmful viruses (see
chapter titled Specific Medical Therapy).
As mentioned above, the immunologic defect in
T-lymphocyte function varies from child to child.
Therefore, the need for therapy of the T-lymphocyte
defect also varies. Many children with the
DiGeorge Syndrome have perfectly normal
T-lymphocyte functions and require no therapy for
immunodeficiency. Other children initially have mild
defects in T- lymphocyte function which improve
as they grow older. In most cases of the DiGeorge
Syndrome, the small amount of thymus that is
present provides adequate T-lymphocyte function.
Rarely, the thymus is so small that adequate
numbers of T-cells do not develop. In these cases,
a special form of bone marrow transplantation or a
thymus transplant may be performed.
In some children with the DiGeorge Syndrome,
the T-lymphocyte defect is significant enough to
cause the B-lymphocytes to fail to make sufficient
antibodies. This occurs because antibodies are
produced by B-lymphocytes under the direction
of a specific subset of T-lymphocytes (see
chapter titled The Immune System and Primary
Immunodeficiency). When the B-cells are affected,
this most often results in a delay in the production
of antibodies. Rarely, children may require
immunoglobulin replacement therapy.
As described in the preceding paragraphs, not all
children with DiGeorge Syndrome require therapy
for their immunodeficiency. Approximately 80%
of the patients with the chromosome 22q11.2
deletion have diminished T-cell numbers. However,
less than 0.2% have an immunodeficiency that
requires a bone marrow transplant or a thymus
transplant. The majority of children with an
immunodeficiency have a mild to moderate deficit in
the number of T-cells. These patients usually do not
require transplantation; however, strategies aimed
at prevention of the bacterial infections can often be
quite helpful. This may include antibiotic prophylaxis
and adequate treatment of any allergies. Allergies
appear to be increased in patients with the
DiGeorge Syndrome. They may contribute to
the infections and are treated with the same
medications used in other patients with allergies.
Approximately 10% of patients with the
chromosome 22q11.2 deletion, and an unknown
number of patients with the DiGeorge Syndrome
without the deletion, have an autoimmune
disease. This occurs when the immune system
makes a mistake and tries to fight its own body.
It is not known why this happens in people with
T-lymphocyte problems. The most common
autoimmune diseases in the DiGeorge Syndrome
are idiopathic thrombocytopenia purpura
(antibodies against platelets), autoimmune
hemolytic anemia (antibodies against red blood
cells), juvenile/adult arthritis and autoimmune
disease of the thyroid gland.
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Expectations for the DiGeorge Syndrome Patient:
The outlook for a child with DiGeorge Syndrome
depends on the degree to which the child is
affected in all organ systems. The severity of heart
disease is usually the most important determining
factor. As mentioned above, most children have
a mild to moderate deficit in T-cell production
that often improves with age. Overall, the outlook
for the infection pattern is optimistic as most
patients do not suffer from recurrent infections in
adulthood. Nevertheless, approximately one third
of adults have minor recurrent infections.
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