The primary immunodeficiency
diseases comprise
a family of diseases
which have in
common intrinsic
defects in the
individual components
of the immune
system. There
are over 125 of
these disorders,
most of which
are genetically
determined, with
the most common
clinical presentation
being an increased
susceptibility
to infection.
However, some
of the primary
immunodeficiency
diseases are also
found as part
of a larger clinical
syndrome, and
their initial
clinical presentations
relate to the
other clinical
findings of the
syndrome rather
than to the immunodeficiency
per se. Further,
in addition to
presenting with
clinical manifestations,
many patients
can be ascertained
based exclusively
on a positive
family history
of a previously
affected family
member.
Two of these primary
immunodeficiency
disorders are
of special interest
to the neonatologist:
Severe Combined
Immunodeficiency
describes
over a dozen molecular
genetic defects
which result in
a severe deficiency
of both T and
B lymphocyte number
and function.
In spite of the
different molecular
genetic defects
responsible for
the disorder,
patients are almost
uniformly susceptible
to a wide variety
of common and
opportunistic
infections, and,
if left untreated,
usually succumb
by one year of
age (if not earlier).
Therefore, presymptomatic
diagnosis and
therapy are critical.
The DiGeorge
Syndrome describes
children with
developmental
defects relating
to the 3rd
and 4th
pharyngeal pouch,
which may result
in variable degrees
of hypoparathyroidism,
conotruncal cardiac
defects, thymic
aplasia with T
cell deficiency,
and a variety
of facial, gastrointestinal
and developmental
defects. Infants
with this primary
immunodeficiency
usually present
in the first few
weeks of life
and therefore
are often diagnosed
by the neonatologist.
In this issue
we review important
new contributions
to the understanding
of these two primary
immunodeficiency
diseases as they
relate to neonates.
Commentary
& Reviews: Jerry Winkelstein, MD
Eudowood Professor
of Pediatrics and
Professor of Medicine
and Pathology,
Johns Hopkins University
School of Medicine,
Baltimore, MD
Guest
Faculty Disclosure Jerry
Winkelstein,
MD
Faculty
Disclosure:
No relationship
with commercial
supporters.
Unlabelled/Unapproved Uses:
No faculty member has indicated that their presentation will include information on off label products.
Edward
E, Lawson, M.D.
Professor
Department of
Pediatrics —
Neonatalogy
The Johns Hopkins
University School
of Medicine
Lawrence
M. Nogee, M.D.
Associate
Professor
Department of
Pediatrics —
Neonatalogy
The Johns Hopkins
University School
of Medicine
Christoph
U. Lehmann,
M.D.
Assistant
Professor
Department of
Pediatrics —
Neonatology
The Johns Hopkins
University School
of Medicine
Lorraine
A. Harbold,
R.N., M.S.
The
Johns Hopkins
Hospital
NICU Education
Coordinator
The
Johns Hopkins
University School
of Medicine
and The Institute
for Johns Hopkins
Nursing take
responsibility
for the content,
quality, and
scientific integrity
of this CE activity.
At
the conclusion
of this activity,
participants
should be able
to:
•
Recognize
which primary
immunodeficiency
diseases
may likely
present
in the neonatal
period;
•
Evaluate
the potential
outcomes
advantages
of presymptomatic
diagnosis
of Severe
Combined
Immunodeficiency
disease;
•
Recognize
the clinical
presentation
of the DiGeorge
Syndrome.
The
age at which primary
immunodeficiency
diseases first
present clinically
depends on whether
the deficient
component of the
immune system
crosses the placenta
and is at least
initially supplied
by the mother.
For example, pure
B lymphocyte defects,
such as X-linked
agammaglobulinemia,
usually don't
present until
the second 6 months
of life, since
maternal transfer
of IgG effectively
supplies adequate
replacement therapy
during the prior
6 months. In contrast,
virtually all
phagocytic disorders,
such as Chronic
Granulomatous
Disease and Leukocyte
Adhesion Defect,
can present in
the neonatal period.
Although uncommon,
deficiencies of
the complement
system also can
present in the
neonatal period,
as individual
components of
complement do
not cross the
placenta. In addition,
T cell defects
may also present
in the immediate
neonatal period,
since there is
normally no maternal
transfer of T
cells, or, if
there is, such
maternal transfer
is inadequate
to correct the
infant's deficiency.
Therefore, neonatologists
may be the first
to encounter and
diagnose infants
with these primary
immunodeficiencies.
The critical criteria
in the diagnoses
of these disorders
are knowledge
of the disease
state plus a high
index of suspicion.
In spite of many
advances in the
diagnosis and
therapy of patients
with SCID, a significant
portion of patients
are not diagnosed
until after they
develop serious
infections; their
survival is therefore
compromised even
if they are provided
immune reconstitution
(e.g. via stem
cell transplant).
While obtaining
a positive family
history would
be advantageous
in families with
a previously affected
infant, this is
not always possible.
For example, in
some instances,
the family may
be unaware of
an uncle or great
uncle who died
of the X-linked
recessive form
of the disease
many years before,
while in other
instances an older
sibling may have
died without a
definitive diagnosis.
In addition, over
half of SCID patients
are born into
a family without
a positive family
history for the
disorder because
the molecular
genetic form is
inherited as an
autosomal recessive
trait.
In the absence
of a positive
family history,
the presence of
significant lymphopenia (<3,500 lymphocytes/mm3 for newborns),
a nearly constant
feature of SCID,
can be an important
clue to the presence
of the disorder;
however, not all
newborns have
a CBC and differential
performed, and
not all physicians
are alert to the
significance of
lymphopenia. Thus,
there has been
a great deal of
consideration
given to screening
for SCID, especially
since recent evidence
documents what
seems clinically
intuitive: that
early diagnosis
and therapy improve
survival.
The Buckley, Myers,
and Chan articles
reviewed this
issue provide
important information
about how early
diagnosis and
treatment of SCID
patients can improve
long-term outcomes.
These additions
to our SCID knowledge-base
should help increase
the incidence
of presymptomatic
(before
infection occurs)
identification
and diagnosis,
thereby significantly
improving the
survival of these
infants.
The DiGeorge Syndrome
— with its associated
cardiac abnormalities,
hypocalcemia,
and gastrointestinal
defects usually
presenting in
the first few
weeks of life
— is the most
common primary
immunodeficiency
encountered and
diagnosed by Neonatologists.
Although significant
and persistent
T cell defects
are found in a
small minority
of patients, the
early identification
of the T cell
deficiency, when
it occurs, is
important. These
patients are usually
diagnosed as immunodeficient
before they develop
infections. The
presence of conotruncal
defects, hypoparathyroidism
as a cause of
the hypocalcemia
and/or the abnormal
facies and GI
defects are the
usual clinical
findings that
lead to the diagnosis
of DiGeorge —
which in turn
leads to the presymptomatic
diagnosis of the
immunodeficiency.
While lymphopenia
may be present
in some patients
with the most
severe immunodeficiency,
it should be noted
that only 90-95%
of patients who
have the clinical
syndrome have
a large enough
deletion to be
picked up by Fluorescent
In Situ Hybridization
(FISH). Thus,
a FISH test that
fails to show
the deletion does
not rule out the
diagnosis.
The Sullivan,
Yagi, and Markert
articles reviewed
herein enlarge
and clarify the
clinical and immunologic
findings in this
interesting disorder,
provide insight
into the newest
molecular genetic
analysis, and
offer a new and
novel therapy
that is of benefit
to those patients
with significant
and persistent
T cell defects.
Patients with
primary immunodeficiency
undoubtedly benefit
from early diagnosis
and treatment,
and it is we NICU
providers who
will play a most
critical role
in the diagnosis
and initiation
of therapy.
SEVERE
COMBINED IMMUNODEFICIENCY
(SCID)
Buckley,
RH Molecular
defects in human
severe combined
immunodeficiency
and approaches
to immune reconstitution.
Ann Rev Immunol
2004;22:625-55 (For
non-journal subscribers,
an additional
fee may apply
for full text
articles)
Myers,
LA, Patel, DD,
Puck, JM, Buckley,
RH. Hematopoietic
stem cell transplantation
for severe combined
immunodeficiency
in the neonatal
period leads to
superior thymic
output and improved
survival.
Blood 2002; 99:872-8. (For
non-journal subscribers,
an additional
fee may apply
for full text
articles)
Chan
K, Puck, JM. Development
of population-based
newborn screening
for severe combined
immunodeficiency.
J Allergy Clin
Immunol. 2005;115:391-8. (For
non-journal subscribers,
an additional
fee may apply
for full text
articles)
Reporting
on advances in
understanding,
diagnosing, and
treating this
disorder.
Buckley et
al provide critical
information
about the most
recent advances
on the molecular
genetic bases
of this uncommon
primary immunodeficiency
disease. The
authors report
that there are
at least 9 different
molecular genetic
defects responsible
for this clinical
syndrome, each
of which results
in a severe
deficiency of
both T and B
lymphocyte number
and function.
Three of the
defects affect
important components
of cytokine
receptors, three
are essential
for T cell antigen
receptor rearrangement,
one affects
the delta component
of CD3 antigen
receptor, one
affects the
intracellular
metabolism of
the T cell,
and one affects
the signaling
threshold of
lymphocytes.
The authors
discuss bone
marrow transplantation
(HLA identical
unfractionated
and T cell-depleted
HLA haploidentical),
both of which
have been very
successful in
effecting immune
reconstitution.
They note that
these interventions
produce the
best results
if done in the
first 3.5 months
of life without
pretransplant
chemotherapy.
Of particular
importance is
that, while
gene therapy
had been highly
successful in
nine infants
with X-linked
SCID, trials
have currently
been placed
on hold due
to complications
(leucemia) in
two of the children.
Myers et al
performed a
retrospective
chart review
on SCID patients
transplanted
at a single
center (Duke).
While there
are a variety
of stem cell
transplantation
techniques that
are available
for immune reconstitution
of SCID - HLA
identical (usually
from an HLA
identical sib),
haploidentical
(usually from
a parent), and
matched unrelated
(usually from
and unrelated
but HLA matched
donor entered
into a world
wide computer
data base) —
this review
focused not
on comparing
one technique
to another,
but on determining
whether infants
transplanted
early (<1
month of age)
did better than
those transplanted
later (>1 month of age).
The authors
report that
infants who
received transplants
before 28 days
developed higher
T lymphocyte
counts and higher
lymphocyte responses
to mitogens
than did infants
who were transplanted
after the immediate
neonatal period
of 28 days.
Importantly,
survival of
those patients
transplanted
in the first
28 days of life
was 95% (versus
74% in the >28
day group).
Also noted is
that 6.6 months
is the mean
age at which
children are
diagnosed with
SCIDS, a point
where most of
the patients
have already
suffered from
recurring infections
with weaning
from maternal
antibody protection.
The authors
conclude that
prenatal screen
of affected
families and/or
general screening
of all newborns
using cord-blood
white blood
cell count and
a manual differential
count could
lead to earlier
diagnosis and
therapy and
improved long-term
outcomes.
Seeking to
produce a proof
of principal
that early diagnosis
and therapy
of SCID can
result in improved
survival, the
pilot study
by Chan et al
sought to develop
a screening
method to detect
newborns with
SCID before
they acquired
infections that
could compromise
their survival.
As T lymphocytes
mature, T cell
receptor excision
circles (TRECs)
are produced
as a result
of DNA rearrangement
and excision.
These accumulate
in the T lymphocyte
as it develops
and are an indirect
measure of T
lymphocyte maturation
and development
that can be
analyzed and
quantified by
PCR.
In this study,
dried blood
spots obtained
from normal
neonates and
from 2 patients
with known SCID
were analyzed
for TRECs. Normal
newborns had
an average of
1020 TRECs in
two 3-mm punches,
while infants
with SCID had <30 TRECs. These
results allowed
the authors
to estimate
an incidence
rate for SCIDS
(1/105,000 births);
as importantly,
they were able
to demonstrate
the potential
superiority
of TREC screening
(dried blood)
over lymphocte
count screens
which requires
liquid blood
collection.
AN ADDITIONAL
NOTE: Since
the introduction
of the Guthrie
filter paper
to screen newborns
for phenylketonuria
(PKU), all US
states now mandate
newborn screening
for PKU, hypothyroidism
and galactosemia.
An earlier
edition of eNeonatal
Review discussed
tandem mass
spectrometry
to detect a
large number
of other metabolic
disorders. With
the proven advantages
of early detection
and treatment
of SCID, states
may mandate
the screening
for SCIDS in
the future.
Sullivan
KE. The clinical,
immunological
and molecular
spectrum of chromosome
22q11.2 deletion
syndrome and DiGeorge
Syndrome.
Curr Opin Allergy
Clin Immunol 2004;4:505-12. (For
non-journal subscribers,
an additional
fee may apply
for full text
article)
Yagi,
H, Furutani y,
Hamada H, et al Role of
TBX1 in human
del22q11.2 syndrome.
Lancet 2003; 362:1342-3. (For
non-journal subscribers,
an additional
fee may apply
for full text
article)
Markert
ML, Sarzotti M,
Ozaki DA et al Thymus
transplantation
for complete DiGeorge
Syndrome: Immunologic
and safety evaluation
in 12 patients.
Blood. 2003 Aug
1;102(3):1121-30.
Epub 2003 Apr
17. (For
non-journal subscribers,
an additional
fee may apply
for full text
article)
Exploring
the clinical spectrum
of the disorder,
its genetic determinant,
and a novel therapeutic
approach.
The DiGeorge
Syndrome, or
22q11.2 deletion
syndrome, is
one of the most
common genetic
syndromes found
in the NICU,
with an incidence
(under)estimated
at 1:6000 births.
The disorder
is characterized
by hypoparathyroidism
and hypocalcemia,
conotruncal
cardiac defects,
thymic hypoplasia
or aplasia,
and a variable
concurrent T
cell deficiency
and abnormal
facies. In addition,
affected patients
have a variety
of midline gastrointestinal
defects including
esophageal atresia
and malrotation,
cleft lip and
palate, and
CNS developmental
abnormalities.
The Sullivan
article provides
a thorough overview
of this disorder,
discusses its
variable phenotype
and penetrance,
and presents
a comprehensive
review of its
clinical presentation,
diagnosis, and
therapy. The
author notes
that familarity
of providers
with the disease
doubles the
likelihood of
early detection
and is critical
in the timely
diagnosis and
treatment.
While the DiGeorge Syndrome has
long been appreciated
to involve a
gene residing
on the 22nd
chromosome (since
deletion of
22q11.2 has
led to the clinical
syndrome), the
exact identity
of the gene
responsible
for this complex
developmental
embryonic defect
has been unknown.
Yagi et al explored
the molecular
genetic findings
relating to
this area of
chromosome 22
in 235 patients
with the 22q11.2
deletion syndrome,
examining in
detail the genes
residing in
the area of
chromosome 22
that is commonly
deleted in this
syndrome. As
they could not
examine each
of these genes
for mutations
in those patients
who carried
the deletion
(since the gene
would not be
there!), they
focused on the
relevant genes
in patients
who had classic
DiGeorge Syndrome
but did not
have a deletion.
Based on their
own analysis
of patients
with the deletion,
one specific
candidate gene
was TBX1. They
therefore examined
10 families
with clinical
features of
DiGeorge Syndrome
but no deletion
and found a
strong association
with mutations
in the TBX1
gene. The authors'
results strongly
suggest that
TBX1 is a major
genetic determinant
of the 22q11.2
deletion syndrome,
accounts for
its clinical
presentation
in a significant
number of patients
with DiGeorge
Syndrome, and
is likely responsible
for five major
phenotypes —
abnormal facies
(conotruncal
anomaly face),
cardiac defects,
thymic hypoplasia,
velopharyngeal
insufficiency
with cleft palate,
and parathyroid
dysfunction
with hypocalcaemia.
Further, their
results indicate
that TBX1 mutation
is most likely
not linked
to the mental
retardation
that is commonly
seen in patients
with del22q11.2 syndrome.
The identification
of TBX1 as a
cause of the
DiGeorge Syndrome
is a major step
forward in diagnosis
of these patients,
especially since
between 5 and
10% of patients
with the DiGeorge
Syndrome do
not have a deletion
and therefore
have been diagnosed
purely on clinical
grounds. In
addition, the
identification
of TBX1 will
also contribute
significantly
to our understanding
of the pathogenesis
of this complex
syndrome as
well as to the
role of TBX1
in normal development.
Although thymic
hypoplasia occurs
with some regularity
in the DiGeorge
Syndrome, clinically
significant
T cell deficiency
is relatively
uncommon — nevertheless,
complete T cell
deficiency does
occur in a small
minority of
patients with
the DiGeorge
Syndrome and
can be an important
cause of morbidity
and mortality.
Markert et al
report on the
result of thymic
epithelium transplantation
in the "complete
DiGeorge Syndrome",
a term used
to indicate
T cell deficient
patients with
this disorder.
These patients
possess stem
cells but lack
the thymic epithelium
microenvironment
that is necessary
for the development
of mature and
functionally
competent T
cells. In this
novel therapy,
thymus is cultured
in vitro until
only thymic
epithelium remains
— it is this
thymic epithelium
that is transplanted.
The results
in this first
series of patients
have been very
encouraging,
with over half
of the patients
receiving this
transplant developing
immunologic
function. Deaths
were almost
exclusively
related to non-immunologic
problems associated
with the DiGeorge
Syndrome. As
DiGeoge Syndrome,
if left untreated,
is usually fatal
within 2 to
3 years, the
remarkable survival
rate of 58%
with thymic
epithelium transplant
is a major achievement
in the treatment
of primary immunodeficiency
— especially
considering
the fact that
patients with
DiGeorge often
have other congenital
problems that
impact on overall
survival. Despite
these favorable
outcomes, many
questions remain,
particularly
in regards to
the mechanism
of "thymic education",
and await resolution
through long-term
outcome studies.
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Johns Hopkins
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The Institute
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Nursing take responsibility
for the content,
quality, and scientific
integrity of this
CE activity. At
the conclusion
of this activity,
participants should
be able to:
•
Recognize
which primary
immunodeficiency
diseases may
likely present
in the neonatal
period;
•
Evaluate the
potential
outcomes advantages
of presymptomatic
diagnosis
of Severe
Combined Immunodeficiency
disease;
•
Recognize
the clinical
presentation
of the DiGeorge
Syndrome.
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providers accredited
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