C h a p t e r 1 6
Disorders of the Immune Response
361
Thymic Hypoplasia: DiGeorge Syndrome.
DiGeorge
syndrome stems from an embryonic developmental
defect.
35
The defect is thought to occur before the 12th
week of gestation, when the thymus gland, parathyroid
gland, and parts of the head, neck, and heart are devel-
oping. The disorder affects both males and females and
is relatively more common than other T cell immuno-
deficiencies. Formerly thought to be caused by a vari-
ety of factors, including extrinsic teratogens, this defect
has been traced to microdeletion of specific deoxyribo-
nucleic acid (DNA) sequences from chromosome 22
(22q11).
1,35,39
Infants born with this defect have partial or com-
plete failure in development of the thymus and para-
thyroid glands and have congenital defects of the
head, neck, and/or heart. The extent of immune and
parathyroid abnormalities is highly variable, as are
the other defects. In some children, the thymus is not
absent but is in an abnormal location and is extremely
small. These infants can have partial DiGeorge syn-
drome, in which hypertrophy of the thymus occurs
with development of normal immune function. The
facial disorders can include hypertelorism (increased
distance between the eyes); micrognathia (abnormally
small jaw); low-set, posteriorly angulated ears; split
uvula; and high-arched palate (Fig. 16-7). Urinary
tract abnormalities also are common. The most fre-
quent presenting sign is hypocalcemia and tetany that
develop within the first 24 hours of life. It is caused by
the absence of the parathyroid gland and is resistant
to standard therapy.
Children who survive the immediate neonatal period
may have recurrent or chronic infections because of
impaired T-cell immunity. Children also may have an
absence of immunoglobulin production, caused by a lack
of helper T-cell function. For children who do require
treatment, thymus transplantation can be performed to
reconstitute T-cell immunity. Bone marrow transplanta-
tion also has been successfully used to restore normal
T-cell populations. If blood transfusions are needed,
as during corrective heart surgery, special processing is
required to prevent graft-versus-host disease.
Severe Combined Immunodeficiency
Disorders
Severe combined immunodeficiency (SCID) is a syn-
drome of diverse genetic causes characterized by pro-
found deficiencies in T- and B-cell function, and in
some cases NK cells and function.
1,35
Mutations in
13 different genes have been found to cause the condi-
tion, which is usually fatal in the first 2 years of life
unless reconstitution of the immune system can be
accomplished. Although they appear normal at birth,
affected infants begin to develop frequent episodes of
diarrhea, pneumonia, otitis media, sepsis, and cutane-
ous lesions within the first few months of life. Growth
may appear normal, but extreme wasting develops
after infections and diarrhea begin. Exposure to live
vaccines, nonirradiated blood products, and infections
can prove life threatening.
Pathogenesis and Etiology.
The most common form
of SCID, accounting for about half of all cases in the
United States, is X-linked, and hence is more common
in boys than girls. These mutations are recessive so that
heterozygous girls are usually normal carriers of the
gene, whereas boys who inherit the abnormal chromo-
some manifest the disease.
40,41
The genetic defect in the
X-linked form of SCID is due to a mutation in a trans-
membrane protein that is responsible for the survival and
proliferation of T-lymphocyte precursors. T-cell numbers
are greatly reduced in number and, although B cells are
normal, antibody synthesis is greatly impaired because of
a T–cell help. There may also be a deficiency in NK cells.
The remaining cases of SCID show an autosomal
recessive pattern of inheritance, with the most common
cause being mutations in the gene encoding adenos-
ine deaminase (ADA), an enzyme involved in purine
FIGURE 16-7.
An infant with DiGeorge syndrome.The surgical
scar on the chest indicates repair of heart disease caused by
truncus arteriosus or interrupted aortic arch, which is common
in this syndrome.The infant also has the facial features of a
child with DiGeorge syndrome, as illustrated by hypertelorism,
low-set ears, hypoplastic mandible, and bowing upward of
the upper lip. (From Roberts R. Atlas of Infectious Diseases.
Edited by Gerald Mandell [series editor], Catherine M. Wilfert.
© 1998 Current Medicine, Inc. With kind permission of Springer
Science + Business Media.)
