Article

immunology

Immunologic Aspects of
DiGeorge Syndrome
Nicola A.M. Bobey-

Objectives

Wright, MD,* Haig

Tcheurekdjian, MD,

Diane Wara, MD, David

B. Lewis, MD*

Author Disclosure
Drs Bobey-Wright,

After completing this article, readers should be able to:

1. Describe the immune defects seen in DiGeorge syndrome.

2. Review recommended immune testing and immune follow-up in patients with
DiGeorge syndrome.
3. Review the indications for screening for DiGeorge syndrome.
4. Describe the variety of other congenital defects that can be associated with DiGeorge
syndrome.
5. Review recommended anticipatory guidance for patients with DiGeorge syndrome.

Tcheurekdjian, Wara,
and Lewis did not
disclose any financial
relationships relevant
to this article.

Introduction
DiGeorge syndrome (DGS) is a contiguous field defect of the third and fourth pharyngeal
pouches, most often due to a hemizygous microdeletion in the chromosome 22q11.2
region. Although classically defined as the triad of conotruncal cardiac anomaly, thymic
hypoplasia, and hypocalcemia, the syndrome encompasses a broad spectrum of congenital
defects that have varying degrees of severity. Speech delay and dysmorphic features are two
of the most common and consistent findings. It shares phenotypic features with velocardiofacial syndrome, conotruncal anomaly face syndrome, Opitz-G syndrome, CHARGE
syndrome, and cranio-cerebello-cardiac dysplasia syndrome. In some patients, these other
syndromes are the result of the same 22q11.2 microdeletion and may represent variation
in the presentation of DGS rather than separate syndromes. This review focuses on the
immune defects seen in the patient population with hemizygous 22q11.2 microdeletion.

Causative Factors
The underlying defect of DGS is due to inadequate contribution of neural crest tissue to
the third and fourth pharyngeal pouches that contribute to facial, cardiac, thymic, and
parathyroid tissues. DGS can be caused by either genetic
defects or environmental exposures in utero. Fetal exposure
to ethanol, retinoids, and maternal diabetes can result in a
Abbreviations
clinical DGS phenotype. In more than 90% of patients,
however, the syndrome results from hemizygosity at the
CHD:
congenital heart defect
chromosome 22q11.2 region (del22q11.2). In a small subCMV:
cytomegalovirus
set of patients, a deletion of 10p13 has been identified as the
del22q11.2: microdeletion of the chromosome
causative factor, as has monosomy 18q21.33 and trisomy 18.
22q11.2 region
No genetic or environmental cause can be identified in a
DGS:
DiGeorge syndrome
small percentage of patients.
FISH:
fluorescence in situ hybridization
The specific gene defects that explain the manifestations
Ig:
immunoglobulin
of the DGS phenotype remain poorly understood. Patients
MHC:
major histocompatibility complex
who have del22q11.2 most commonly have a 3-megabase
TCR:
T-cell receptor
deletion involving at least 27 genes, although the smallest
TREC:
T-cell receptor excision circle
deletion reported is 250 kilobases (kb). Severity of phenoVPI:
velopharyngeal insufficiency
type does not correlate with the size of deletion, and patients
VSD:
ventricular septal defect
who have similar phenotypes have been found to have non*Division of Immunology and Transplantation Biology, Department of Pediatrics, Stanford University School of Medicine,
Stanford, Calif.

Division of Allergy and Immunology, Department of Medicine, University of California, San Francisco; Division of Allergy and
Immunology, Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif.

Division of Immunology and Rheumatology, Department of Pediatrics, University of California, San Francisco.

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immunology DiGeorge syndrome

overlapping deletions. A number of candidate genes have

been investigated, but to date, none has been shown
unequivocally to explain the phenotype completely. The
most promising is TBX1, a member of the T-box transcription factor, in which haploinsufficiency in mice
causes a DGS-like phenotype. Three isolated point mutations of TBX1 also recently have been identified in
several patients who have DGS. Nevertheless, it is unlikely that haploinsufficiency of a single gene can explain
completely the DiGeorge phenotype based on the diverse array of deletions in the 22q11.2 region that can
cause the syndrome, the phenotypic variability within the
syndrome, and the discordance seen among patients who
have the same deletion. The full syndrome likely requires
involvement of numerous genes within the microdeletion region and is probably substantially influenced by
modifying genes outside of the microdeletion region.

Incidence
Fluorescence in situ hybridization (FISH) testing in the
last decade has shown that the hemizygous del22q11.2 is
one of the most common genetic defects seen in humans.
The incidence has been found to be as high as 1 in 4,000,
although it is very difficult to estimate due to the extremely variable phenotype and inconsistent screening
practices. Inheritance is autosomal dominant, with most
deletions being spontaneous. Familial transmission is
estimated to occur in only 8% to 28% of cases. The
syndrome occurs equally in males and females and has no
known racial predisposition.

Normal T-cell Ontogeny and Function

Thymocyte development is initiated when prothymocytes derived from bone marrow or fetal liver hematopoietic stem cells enter the thymus. This begins at 7 weeks
gestation. The thymus serves as a site for thymocyte
proliferation and creation of the T-cell receptor (TCR)
repertoire through somatic rearrangement of the TCR
genes. Thymocytes that express surface TCR that can
recognize peptides associated with self major histocompatibility complex (MHC) are selected positively in the
thymic cortex for survival as part of an education
process. This is followed by a negative selection process
in which thymocytes that have too strong an affinity for
self peptide/self MHC complexes are selected negatively
by apoptosis, an important mechanism for limiting autoimmunity. Thymocytes that survive these two selection
mechanisms enter the peripheral blood as recent thymic
emigrant cells and colonize the peripheral lymphoid organs. The end result is that each person has a diverse array
of unique T cells that can recognize the myriad microor-

ganisms and foreign antigens in the environment but

have a limited ability to respond to self-peptides.
T cells are instrumental for appropriate functioning of
the cell-mediated and humoral arms of the immune
system by directing the functioning of other immune
cells (helper functions) and by destroying host cells infected with viruses (cytotoxic functions). Production of
antibodies by B cells to most protein antigens is dependent on CD4 T-cell signals, so severe T-cell disorders
usually result in concomitant abnormalities of humoral
immunity. Furthermore, T cells are intimately involved
in limiting tumor induction by certain viruses, such as
Epstein-Barr virus, as well as the regulation of selfreactive T and B lymphocytes that cause autoimmune
disorders.

Immunodeficiency of DiGeorge Syndrome

The immunodeficiency of DGS is due primarily to reduced production of mature thymocytes from less mature precursors in the thymus. Most results suggest that
the T cells produced and found in the periphery have no
inherent functional defect. The fact that transplantation
of T-cell-depleted allogeneic thymic tissue into DGS
patients can lead to reconstitution of the T-cell compartment is consistent with the deficiency primarily involving
nonhematopoietic cells rather than hematopoietic cells.
Patients who have DGS present with a spectrum of
immunodeficiency ranging from nearly normal to severe,
life-threatening conditions. Although those who have
severe immunodeficiency represent fewer than 1% of all
DGS patients, their early identification is essential to
prevent and treat life-threatening infections and to plan
for immune reconstitution. Affected patients present
with profoundly decreased T-cell numbers (50/mm3),
depressed T-cell function (as measured by lymphocyte
proliferation assays, such as with mitogens), and often
concomitantly low immunoglobulin (Ig) levels. The patients are at high risk for the development of disseminated and life-threatening infections with organisms that
require an intact cell-mediated immune system for eradication, such as cytomegalovirus, adenovirus, or Pneumocystis jiroveci (formerly P carinii). Graft-versus-host disease also may be found due to transplacental transfer and
engraftment of maternal T cells, leading to the typical
rash and diarrhea seen in other forms of graft-versus-host
disease.
A rare subset of DGS patients who have the severe
immunodeficiency phenotype have an atypical presentation of DGS that includes rash, lymphadenopathy, and
oligoclonal T cells. They may have normal or nearnormal T-cell numbers and functional studies that are

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immunology DiGeorge syndrome

not antigen-specific. The T cells in these patients are not

derived from normal maturation and selection in the
thymus, but rather are a result of extrathymic proliferation of a very small number of clonal T cells. Thus, they
exhibit a restricted TCR repertoire and are unable to
recognize and respond appropriately to most microorganisms and antigens. This can be one of the most
difficult presentations of DGS to manage and is associated with significant morbidity and mortality.
In contrast to severely affected patients, most patients
who have DGS present with measurable T-cell numbers
and function ranging from low to near-normal. They
rarely have an increased risk of opportunistic infections,
but are at higher risk for the development of recurrent
sinopulmonary infections such as otitis media, sinusitis,
and bronchitis. Recurrent bacterial infections are likely
due to both anatomic abnormalities of the airway and an
underlying humoral immunodeficiency, but not clinically relevant T-cell dysfunction, as evidenced by the
demonstration of no correlation between measured cellular immune function and number or severity of sinopulmonary infections. Immune function tends to improve through infancy, and by 3 years of age, most
patients tend to have near-normal T-cell counts and
function.
Most patients who have DGS have reduced thymic
production of nave T cells, as assessed by flow cytometric
quantification of CD45RACD62L T cells that have
recently exited the thymus. Thymic function also can be
assessed by measuring peripheral blood TCR excision
circles (TRECs), which are a normal byproduct of somatic recombination of the TCR genes in the thymus.
TRECs persist in newly formed nave T cells and are
diluted by cell division as they undergo replication along
with the cells genomic DNA. TREC content can be
quantitated from peripheral blood by real-time polymerase chain reaction, and DGS patients have lower values
than healthy controls, consistent with reduced thymic
production of peripheral T cells. Decreased thymic output may result in reduced diversity of the TCR repertoire
of nave T cells.

Autoimmunity
Perhaps the most telling sign of a subtly dysfunctional
immune system in patients who have DGS is the high risk
of autoimmune disease evident later in life. More than
10% of patients develop autoimmune disease, most commonly autoimmune cytopenias. The risk of immune
thrombocytopenic purpura is 200 times that of the normal population. Juvenile rheumatoid arthritis may be
20 times more frequent in DGS patients than the general

population, and other autoimmune diseases, including

Graves disease and type 1 diabetes mellitus, also have
been reported. Decreased numbers of CD4CD25
regulatory T cells, which function to suppress autoreactive lymphocytes, have been noted in patients who have
DGS and may contribute to the increased risk of autoimmune disease.

Humoral Immunity
Abnormalities in humoral immunity, as evidenced by
abnormal Ig production, have been identified in up to
40% of patients who have del22q11.2, although this may
predispose to recurrent infections in fewer than one third
of the patients. Ig A deficiency is a common finding, with
a prevalence of 13%. When patients who have recurrent
sinopulmonary infections are evaluated as a separate
group, more than 50% may have poor immune response
to purified polysaccharide antigens such as the 23-valent
Streptococcus pneumoniae vaccine. Restricted Ig repertoire also has been shown, akin to the restricted TCR
repertoire. It is important to identify such patients because they may benefit from antimicrobial prophylaxis or
Ig replacement therapy.

Diagnosis
The diagnosis of DGS is based on the identification of
typical clinical and laboratory features. Genetic analyses
are adjuncts to aid in diagnosis because some patients in
whom a chromosomal abnormality is not identified
clearly fit the DGS phenotype. Because there are no strict
criteria, the diagnosis is based on identifying a constellation of findings generally agreed to encompass the important abnormalities of the syndrome. These include
(to varying degrees): facial dysplasia, cardiac anomalies,
hypoparathyroidism, hypoplastic or absent thymus, and
developmental delay.

Dysmorphic Features
Because the facial dysplasia seen in DGS can be so mild as
to be missed on routine examination, careful physical
examination is important. Dysmorphic features may become more prominent with age. Characteristic features
include low-set, posteriorly rotated, elfinlike ears; bulbous nose with lateral build-up of the nasal bridge (tubelike morphology); hypertelorism; micrognathia; and a
short philtrum).

Cardiac Defects
DGS is the second most common cause of congenital
heart defects (CHDs) after trisomy 21, occurring in 5%
of children who have CHDs. The classic cardiac defects
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immunology DiGeorge syndrome

are conotruncal abnormalities, although it now is recognized that the spectrum of cardiac anomalies is variable,
with only two thirds of patients who have heart abnormalities having a conotruncal defect. Tetralogy of Fallot
is the most common, occurring in nearly 20% of patients.
Approximately 15% of patients have either an interrupted
aortic arch type B or a ventricular septal defect (VSD).
Pulmonary atresia with VSD and truncus arteriosus are
the next most common defects, both with an incidence
of nearly 10%. Patients who test positive for DGS generally also have other features of the disorder. Therefore,
screening of patients who have any type of CHD (other
than isolated secundum type atrioseptal defect or patent
ductus arteriosus, which are not associated with the
syndrome) for other features of DGS is recommended.
Approximately 20% of patients who have the del22q11.2
have no cardiac defect.

ment of T and B lymphocyte populations is imperative,

and lymphocyte proliferation assays to assess T-cell function, including to antigens, is recommended where available. A one-time evaluation rarely is adequate to determine the extent of immunodeficiency. Therefore, serial
clinical and laboratory evaluations, in consultation with
an individual experienced in the care of these patients, are
obligatory.
The humoral immune system should be assessed
through measurement of quantitative Igs (IgG, IgA, and
IgM) and, when indicated, specific antibody responses to
polysaccharide and protein antigens such as the pneumococcal and tetanus vaccines. Care must be taken to interpret these results in relation to the patients age and
corresponding level of immune development; consultation with a pediatric immunologist is recommended.

Otolaryngeal and Airway Abnormalities

Hypoparathyroidism
Hypoparathyroidism is reported in 60% of patients who
have DGS, generally in the neonatal period. Up to 40% of
patients experience seizures due to hypocalcemia. The
hypocalcemia resolves over the first postnatal year in 70%
of patients, although some require long-term calcium
supplementation. It now is recognized that some patients can develop hypocalcemia in adulthood, particularly during times of physiologic stress. Hypoparathyroidism should be confirmed by measurement of
parathyroid hormone concentrations. Challenge with
calcium chelators can unmask latent or subclinical hypoparathyroidism in patients who have normal calcium and
parathyroid hormone concentrations; these patients
eventually may develop episodes of hypocalcemia. Because there are few other causes of hypocalcemia in term
neonates, DGS should be considered in any neonate who
exhibits low calcium values. Recent reports suggest it also
should be considered in adults presenting with hypocalcemia in whom other causes are ruled out.

Immunodeficiency
As previously noted, clinically relevant T-cell dysfunction
is present in only a minority of patients. Severely affected
patients either have profoundly low T-cell numbers and
proportionally poor T-cell function or, rarely, low numbers of recent thymic emigrants and TRECs in the presence of normal-appearing T-cell numbers and function.
Coordination of care with a referral center may be necessary for these specialized studies of thymic function.
Although many patients who have DGS have nearnormal T-cell numbers and function, they must be evaluated thoroughly to ensure immunocompetency. Assess-

Otolaryngeal anomalies are frequent, occurring in almost

50% of patients. A submucosal or overt cleft palate is seen
in 16% and 11% of patients, respectively. These palatal
abnormalities may lead to velopharyngeal insufficiency
(VPI), but even those who do not have an identifiable
cleft palate can have VPI due to poor muscular tone of
the velopharynx. In fact, 38% of individuals who have
VPI of unknown cause and 64% of patients who have VPI
following adenoidectomy have been found to have
del22q11.2. These anomalies can contribute to recurrent
otitis media or sinusitis, poor feeding, and poor speech;
such patients should be referred to an ear-nose-throat
service for evaluation and management.
A strong association recently has been found between
the presence of anterior glottic webs and del22q11.2,
with 65% of children who have anterior glottic webs
having del22q11.2. Other airway abnormalities, including laryngeal webs and tracheomalacia, also can occur.
Finally, hearing deficits are common and multifactorial in this population due to both ear abnormalities and
recurrent otitis media. Audiologic assessment and close
follow-up of hearing is recommended.

Neurologic Abnormalities
Only 20% of patients who have DGS have completely
normal neurologic function. Speech delay is one of the
most common features of the syndrome. Developmental
progress is variable, with 20% of patients having
moderate-to-severe learning difficulties and the remaining 60% having only mild difficulties. Behavior and psychiatric issues are common, occurring in 10% of patients
and including attention-deficit disorder, psychosis, major depressive disorders, and schizophrenia.

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immunology DiGeorge syndrome

Renal and Genitourinary Defects

Renal abnormalities are common, occurring in 36% of
patients, and include absent, dysplastic, or multicystic
kidneys; obstructive abnormalities; and vesicoureteric reflux. Eight percent of males have undescended testes.
Renal imaging, therefore, is recommended for any patient diagnosed with DGS.

Other Abnormalities
Defects have been reported in nearly every organ system
in patients who have DGS, including gastrointestinal
abnormalities, skeletal defects, coloboma, giant platelets
and mild thrombocytopenia, and growth hormone deficiency.

Prenatal Diagnosis
Although the 22q11.2 deletion is frequently a de novo
deletion, it also can be inherited in an autosomal dominant pattern. In some cases, the parent may lack overt
clinical features of DGS. Affected individuals have a 50%
chance of transmitting the deletion to their offspring.
FISH studies can be performed on cells obtained by
chorionic villus sampling between 10 and 12 weeks
gestation or by amniocentesis at later gestational ages. It
should be noted that although prenatal testing can identify affected fetuses accurately, this testing offers no
predictive data on the expected severity of the phenotype.

Management
All patients suspected of having DGS should undergo a
FISH assay to look for hemizygosity at the chromosome
22q11.2 region. If this deletion is not found, a FISH
assay for 10p1314 deletion and high-resolution karyotype should be pursued. Indications for testing are listed
in Table 1.
A multidisciplinary approach is required for the management of neonates who have DGS (Table 2). Because
early mortality is usually due to cardiac disease, early and
aggressive attention must be given to cardiac evaluation.
The most common cause of death after 5 months of age
is infection. Therefore, immune evaluation should occur
promptly after birth to allow rapid initiation of preventive measures and aggressive treatment of possible infections. Although chest radiography frequently is obtained
to assess for the presence of a thymic shadow, absence of
a thymic shadow rarely correlates with the severity of
immunodeficiency due to the presence of functional,
ectopic thymic tissue. Functional studies of thymic function are a more reliable method of assessing immune
function.

Indications for Genetic

Testing for DiGeorge Syndrome

Table 1.

Congenital Heart Disease

Tetralogy of Fallot
Interrupted aortic arch type B
Other conotruncal heart defects
Truncus arteriosus, pulmonary atresia with
ventriculoseptal defect, right-sided aortic arch
Other congenital heart defects except isolated
secundum atrial septal defect or patent ductus
arteriosus*
Hypocalcemia
Immune Defect
T-cell lymphopenia*
Humoral immune defect*
Absent thymus noted on diagnostic imaging studies
or at cardiac surgery
Recurrent sinopulmonary infections or opportunistic
infections*
Autoimmune disease, especially autoimmune
cytopenias*
Airway Abnormalities

Anterior glottic webs

Cleft palate*
Velopharyngeal insufficiency*
Other airway abnormalities*

Dysmorphic Features
Lateral build-up of nasal bridge
Hypertelorism, micrognathia, short philtrum, low-set
posteriorly rotated ears, defective pinna
Developmental Delay*
Speech delay*
Positive Family History
Also consider DGS if history of fetal exposure to
ethanol, retinoids, and maternal diabetes*
Testing should include:

If

FISH for hemizygosity at the 22q11.2 region

strong suspicion and FISH for 22q11.2 is normal:
FISH for 10p13 deletion
High-resolution karyotype of 22q11.2 region

*If associated with other features of the syndrome

FISHfluorescence in situ hybridization

All patients suspected of having DGS should receive

cytomegalovirus (CMV)-negative, irradiated, and
leukocyte-filtered blood products until confirmation of a
competent immune system. There is a potential risk of
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immunology DiGeorge syndrome

Neonatal Management of
DiGeorge Syndrome

Table 2.

All Patients
FISH for 22q11.2 deletion; if negative, karyotype
and FISH for 10p13-14 deletion
Immune assessment
Complete blood count with differential count
T- and B-lymphocyte populations by flow
cytometry
Lymphocyte function (proliferation to mitogens)
IgG, IgA, IgM concentrations
Echocardiography and formal cardiology evaluation
Measurement of calcium, phosphorus, and
parathyroid hormone level
Renal ultrasonography
Ear-nose-throat assessment for airway anomalies,
cleft palate, velopharyngeal insufficiency
Gastrointestinal evaluation if gastroesophageal
reflux or feeding issues as necessary
Central nervous system imaging if defect suspected
Suspected Severe Immunodeficiency
Protective isolation precautions
Pneumocystis prophylaxis
Intravenous immunoglobulin replacement if
indicated
Aggressive treatment of infections, with search for
causative organism
Consultation with regional referral center for thymus
or bone marrow transplantation

immune function within weeks to months posttransplant

has been documented by increased T-cell numbers and
improved function, increased numbers of CD45RA
CD62L nave T cells, increased TRECs, and normalization of the T-cell repertoire. Currently, thymic transplantation is only available on an experimental basis at a
few specialized centers and should be considered only
after consultation with an expert in the field. Thymic
transplantation is recommended for patients who have
severe thymic hypoplasia or aplasia, as evidenced by:
1) significantly decreased T-cell numbers, 2) fewer than
50 nave CD45RA CD62L T cells/mm3; and
3) fewer than 100 TRECs/1105 T cells. The assessment of TRECs is currently only available as a research
test.

Hematopoietic Stem Cell Transplantation

Hematopoietic stem cell transplantation also has been
used in rare cases for immune reconstitution. Bone marrow transplant has been performed on fewer than 10
patients, with only three reported in the literature. Because bone marrow transplant often results in mixed
chimeras, it has been theorized that immune reconstitution was due to infusion of mature T cells from the donor
rather than engraftment of hematopoietic cells. Currently, thymic tissue transplant is performed more frequently than hematopoietic stem cell transplant for rescue of patients who have severe immune defects.

Follow-up Care
graft-versus-host disease due to the presence of a small
number of functional leukocytes in nonirradiated blood
products, and patients are at risk for disseminated CMV
infection if they have a significant defect of cell-mediated
immunity.

Thymic Transplantation
Thymic transplantation has been used experimentally for
the treatment of DGS patients who have severe immunodeficiency. There are several reports of successful
transplant using fetal thymic tissue, but such donor tissue
is obviously difficult to obtain. Alternatively, thymic tissue is obtained from infants who have CHDs in whom a
subtotal thymectomy is performed routinely at the time
of their corrective cardiac surgery. The thymic tissue is
cultured, allowing removal of donor lymphocytes, and
surgically inserted into the quadriceps muscles of the
recipient. The importance of matching of human leukocyte antigen alleles between donor and recipient is currently unknown. Thymopoiesis of host cells has been
demonstrated within the donor tissue, and recovery of

Repeated assessment of the immune system by an immunologist during the first several years after birth is recommended (Table 3). For patients who have severe immunodeficiency, thymic transplantation may be considered.
For patients who have moderate-to-severe immunodeficiency, management may include prophylaxis for P
jiroveci, respiratory syncytial virus prophylaxis, gammaglobulin replacement for significant humoral deficiency,
and possibly prophylactic antibiotics. Live-virus vaccines
should be withheld during the first postnatal year, and
exposure to varicella should be treated with either
varicella-zoster immunoglobulin or acyclovir. For infants
who have significant immunodeficiency, we also recommend avoiding sick contacts; minimizing exposure to
public places and school-age children; and frequent
handwashing for the patient, caregivers, and visitors.
Group child care should be avoided if possible.
Following the first postnatal year, the immune system
improves in many affected children, and restrictions often can be relaxed. If immune re-evaluation results are
normal, live vaccines may be administered. Some pa-

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immunology DiGeorge syndrome

Care Beyond the

Neonatal Period
Table 3.

Immunology
Reassessment of immune function every 3 to 6
months until at least 2 years of age
Testing for adequate response to inactivated
vaccines (eg, tetanus toxoid)
Continuation of prophylactic therapies as necessary
Rapid assessment for possible infections and
aggressive therapy as necessary
Protective precautions: handwashing, avoidance of
sick contacts as necessary
Delayed administration of live-virus vaccines until
immune function is adequate*
Administration of cytomegalovirus-negative,
irradiated, leukocyte-filtered blood products if
needed

diac disease tend to be most troublesome initially, with

other aspects of the syndrome, including problems with
speech delay and developmental delay, gastroesophageal
reflux, and VPI, becoming more problematic in later
infancy. Early enrollment in speech therapy and infant
development programs is recommended; many children
require special education programs at school. Finally,
mental health complications such as schizophrenia may
develop in adolescence or adulthood, requiring psychiatric care.
Genetic counseling should not be neglected, particularly if a chromosomal deletion is identified. FISH testing
should be offered to parents, especially if they plan to
have more children. Testing of siblings may be warranted. Patients themselves should be educated as to the
risk of having affected children once they come of reproductive age.

Development
Early speech therapy
Early developmental assessment and therapy as
required
Ear-Nose-Throat
Follow-up for cleft palate, velopharyngeal
insufficiency, and other airway anomalies
Management of otitis media and sinusitis
Audiology assessment, especially if recurrent otitis
media
Endocrine
Follow-up for hypoparathyroidism as necessary
Cardiology
Follow-up as required for specific congenital defect
Adolescence
Primary physician should watch for late complications:
Autoimmune disease
Mental health complications (eg, schizophrenia)
*Varicella-zoster; measles, mumps, rubella; live polio vaccination; live
flu vaccination

tients, however, continue to have difficulties with recurrent infections and should continue to have an immunologist involved in their care.
As patients grow older, difficulties with infections
tend to resolve, although patients become at risk for
autoimmune disease, which often is seen after the first
decade of life. The threshold for investigation of possible
autoimmune complications should be low.
Patients continue to require multidisciplinary care as
they grow. Complications of immunodeficiency and car-

Suggested Reading
Botto LD, May K, Fernhoff PM, et al. A population-based study of
the 22q11.2 deletion: phenotype, incidence, and contribution
to major birth defects in the population. Pediatrics. 2003;112:
101107
Junker AK, Driscoll DA. Humoral immunity in DiGeorge syndrome. J Pediatr. 1995;127:231237
Gennery AR, Barge D, OSullivan JJ, et al. Antibody deficiency and
autoimmunity in 22q11.2 deletion syndrome. Arch Dis Child.
2002;86:422 425
Goodship J, Cross I, LiLing J, Wren C. A population study of
chromosome 22q11 deletions in infancy. Arch Dis Child. 1998;
79:348 351
Goodship RAK, Wilson JA, Philip DI, et al. Spectrum of clinical
features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet. 1997;34:
798 804
Markert ML, Alexieff MJ, Li J, et al. Complete DiGeorge syndrome: development of rash, lymphadenopathy, and oligoclonal T cells in 5 cases. J Allergy Clin Immunol. 2004;113:
734 741
Markert ML, Boeck A, Hale LP, et al. Transplantation of thymus
tissue in complete DiGeorge syndrome. N Engl J Med. 1999;
341:1180 1189
Markert ML, Sarzotti M, Ozaki DA, et al. Thymus transplantation
in complete DiGeorge syndrome: immunologic and safety evaluation in 12 patients. Blood. 2003;102:11211130
Maynard TM, Haskell GT, Lieberman JA, LaMantia A. 22q11.2
DS: genomic mechanisms and gene function in DiGeorge/
velocardiofacial syndrome. Int J Dev Neurosci. 2002;20:
407 419
Miyamoto RC, Cotton RT, Rope AF, et al. Association of anterior
glottic webs with velocardiofacial syndrome (chromosome
22q11.2 deletion). Otolaryngol Head Neck Surg. 2004;130:
415 417
Perez EE, Bokszczanin A, McDonald-McGinn D, Zackai EH,
Sullivan KE. Safety of live viral vaccines in patients with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/
NeoReviews Vol.6 No.10 October 2005 e477

Downloaded from http://neoreviews.aappublications.org/ at Pakistan:AAP Sponsored on April 21, 2015

immunology DiGeorge syndrome

velocardiofacial syndrome). Pediatrics. 2003;112:e325327.

Available
at:
http://pediatrics.aappublications.org/cgi/
content/full/112/4/e325
Pierdominici M, Mazzetta F, Caprini E, et al. Biased T-cell receptor
repertoires in patients with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Clin
Exp Immunol. 2003;132:323331
Ryan AK, Goodship JA Wilson DI, et al. Spectrum of clinical
features associated with interstitial chromosome 22q11.2 deletions: a European collaborative study. J Med Genet. 1997;34:
798 804
Sullivan KE, McDonald-McGinn D, Driscoll DA, et al. Longitudinal analysis of lymphocyte function and numbers in the first year
of life in chromosome 22q11.2 deletion syndrome (DiGeorge
syndrome/velocardiofacial syndrome). Clin Diagn Lab Immunol. 1999;6:906 911

Yagi H, Furutani Y, Hamada H, et al. Role of TBX1 in human

del22q11.2 syndrome. Lancet. 2003;362:1366 1373
Yamagishi H, Garg V, Matsuoka R, Thomas T, Srivastava D.
A molecular pathway revealing a genetic basis for human cardiac
and craniofacial defects. Science. 1999;283:1158 1161

Other Resources for Families and Physicians

Velocardiofacial Syndrome Educational Foundation
www.vcfsef.org
Primary Immune Deficiency Foundation
www.primaryimmune.org
National Primary Immunodeficiency Resource Center
www.info4pi.org

NeoReviews Quiz
9. The dysfunctional immune system in DiGeorge syndrome renders the affected infant susceptible to the
development of autoimmune disease later in life. Of the following, the risk of autoimmune disease in
DiGeorge syndrome relative to the general population is highest with:
A.
B.
C.
D.
E.

Graves disease.
Immune thrombocytopenic purpura.
Juvenile rheumatoid arthritis.
Multiple sclerosis.
Type 1 diabetes mellitus.

10. Patients who have DiGeorge syndrome present with a spectrum of immunodeficiency ranging from nearly
normal to severe, life-threatening immunodeficiency. Of the following, the immunodeficiency in DiGeorge
syndrome is due primarily to:
A.
B.
C.
D.
E.

Decreased production of mature thymocytes from their precursors.

Deficiency of lymphoid structures necessary for optimal B-cell function.
Dysfunction of B cells in relation to humoral immunity.
Excess production of thymic nave T cells.
Inherent defect in function of T cells in the periphery.

11. DiGeorge syndrome is the second most common cause of congenital heart defects after trisomy 21. Of the
following, the most common congenital heart defect in DiGeorge syndrome is:
A.
B.
C.
D.
E.

Interrupted aortic arch.

Pulmonary atresia.
Tetralogy of Fallot.
Truncus arteriosus.
Ventricular septal defect.

e478 NeoReviews Vol.6 No.10 October 2005

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Immunologic Aspects of DiGeorge Syndrome

Nicola A.M. Bobey-Wright, Haig Tcheurekdjian, Diane Wara and David B. Lewis
NeoReviews 2005;6;e471
DOI: 10.1542/neo.6-10-e471

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Immunologic Aspects of DiGeorge Syndrome

Nicola A.M. Bobey-Wright, Haig Tcheurekdjian, Diane Wara and David B. Lewis
NeoReviews 2005;6;e471
DOI: 10.1542/neo.6-10-e471

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://neoreviews.aappublications.org/content/6/10/e471

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