Received: 7 July 2017 | Revised: 6 October 2017 | Accepted: 8 October 2017

DOI: 10.1002/ajmg.c.31594

RESEARCH REVIEW

Immunodeficiency in CHARGE syndrome

Sam Mehr1,2 | Peter Hsu2 | Dianne Campbell2,3

1 Department of Allergy and Immunology,

Royal Children's Hospital, Melbourne, Victoria, Immunodeficiency can occur in CHARGE syndrome, with immunophenotypes
Australia
including reduction in T-cell counts, combined T-B cell defects rarely requiring
2 Department of Allergy and Immunology,
Children's Hospital at Westmead, Sydney,
antibiotic prophylaxis or immunoglobulin replacement, and severe combined
New South Wales, Australia immunodeficiency, which is fatal without immune reconstitution. However, the
3 TheDiscipline of Paediatrics and Child
prevalence of immunodeficiency in CHARGE syndrome remains unclear with few
Health, University of Sydney, Sydney, New
South Wales, Australia prospective studies. In this review, we examine the existing literature covering
immunodeficiency associated with CHARGE syndrome, compare these with
Correspondence
Dr. Sam Mehr, Department of Allergy and immunodeficiencies reported in 22q11.2 deletion syndrome (a condition that shares
Immunology, Royal Children's Hospital, many phenotypic characteristics with CHARGE syndrome) and suggest future research
Melbourne, Victoria, Australia.
Email: sam.mehr@rch.org.au priorities.

KEYWORDS
CHARGE syndrome, complete Di George, immunodeficiency

1 | INTRODUCTION compares the immune defects in CHARGE with those reported in

CHARGE is an acronym that classically describes a syndrome which is
comprised of Coloboma, Heart defects, Atresia of the choanae,
Retardation of growth and/or development, Genitourinary abnormali-
ties, and Ear anomalies (Pagon, Zonana, & Yong, 1981). The disorder is
more complex than the acronym suggests, with other systems
potentially involved including the immune system. Mutations in the
chromodomain helicase DNA-binding 7 (CHD7) gene have been
identified in up to 90% of patients with CHARGE syndrome (Bergman
et al., 2011; Janssen et al., 2012). CHD7 is essential for multi-potent
neural crest cell migration, which differentiates into a variety of
tissues, including neural, cardiac, genitourinary, craniofacial, and
thymic/parathyroid structures. Immunodeficiency in individuals with
CHARGE syndrome is not unexpected given the potential for thymic
maldevelopment; however, its prevalence and severity remain poorly
defined because of a general lack of published systemic assessment
from large CHARGE cohorts. Most reports are of single case
descriptions or retrospective series, invariably resulting in a publication
bias of more severe phenotypes. However the severity of immunode-
ficiency in CHARGE syndrome can vary from asymptomatic derange-
ments in absolute T-cells to life threatening severe combined
immunodeficiency (SCID), also termed complete Di George anomaly.
This review summarizes the immune defects reported in CHARGE,
22q11.2 deletion syndrome and discusses future research priorities.
2 | TH E I MM UN E SY ST EM I N CHA RGE
SYNDROM E
The immune system has two broad divisions, the innate and adaptive
arms. The first line of defense against invading pathogens is the innate
system which does not rely on specific antigen/allergen recognition or
memory responses and includes functions of cells such as neutrophils,
macrophages, and natural killer (NK) cells and of a group of proteins such
as complement, toll like protein receptors and other pathogen pattern
recognition receptors. To date, no defects in this system have been
reported in those with CHARGE syndrome. The adaptive arm principally
comprises of T-cells (CD4 and CD8 cells) and B-cells. T-cells are essential
in initiating, coordinating and then dampening the adaptive immune
response to pathogens. They assist B-cells in producing immunoglobu-
lins essential for the pathogen removal. The thymus is essential for T-cell
maturation, self and non-self-programming and T cell regulation. In
essence it is where T cells are educated after they are produced in the
bone marrow.
Immunodeficiency in CHARGE syndrome is rare, and occurs
largely due to impairment in thymic development, and thus functional

516 | © 2017 Wiley Periodicals, Inc. wileyonlinelibrary.com/journal/ajmgc Am J Med Genet. 2017;175C:516–523.


MEHR ET AL.
T-cell production. The severity of the immunodeficiency relates to
the degree of thymic maldevelopment. Complete thymic aplasia,
although very rare, results in a severe immunodeficiency with
complete/near complete absence of T-cells and abnormal B-cell
function with associated hypogammaglobulinaemia. Without effec-
tive immune reconstitution these children will die from infection.
Partial thymic aplasia may result in no detectable defect at all, mild
reduction in T-cells with no clinical consequence, or more significant
reduction in T-cells with associated B-cell function impairment,
resulting in recurrent infections which will require prophylactic
antibiotics and/or immunoglobulin infusions but not immune
reconstitution. Pure B-cell or antibody defects are rarely described
in CHARGE syndrome.
2.1 | Presentations with infections
The vast majority of children with CHARGE syndrome do not appear to
have an immune defect on functional in vitro immune assessment, yet,
have a propensity for chest and ear infections. This is primarily due to
underlying anatomical and functional abnormalities, with increased
risks of aspiration from bulbar dysfunction and altered eustachian tube
anatomy. In the combined published paediatric cohorts of Hsu et al.
(2016) and Wong, Lambeck, et al. (2015), no child had a significant
immune defect, yet two thirds of cases had a prior history of otitis
media (often requiring tympanostomy tubes) and one quarter had
pneumonia. Although other invasive infections were not documented,
both cohorts typically included older children presenting to specialized
outpatient clinics. Recurrent suppurative sinopulmonary or life-
threatening infections, however, have been reported in cases of
CHARGE with concurrent immunodeficiency (reviewed in Wong,
Scholvinck, et al., 2015).
2.2 | Partial thymic hypoplasia
There is no universally accepted definition for partial thymic
hypoplasia. In conditions such as CHARGE and 22q11.2 deletion
syndromes where thymic hypoplasia is reported, reduced T-cell (CD3)
or naïve CD4/CD8 cell counts are used as surrogate markers for a small
thymus. Partial thymic hypoplasia may result in lymphopenia, reduced
CD3 counts, and/or reduced CD4 or CD8 counts.
2.3 | Lymphopenia
The two studies of Hsu et al. (2016) and Wong, Lambeck, et al. (2015)
are the only published prospective studies that have reported detailed
immune-phenotypes in children with CHARGE syndrome. Of the
combined cohort of 44 children, none were lymphopenic at the time of
evaluation (in four cases, CD3 counts were only mildly reduced). In
contrast, Jyonouchi et al. (2009) reported that in their retrospective
study, 15 out of 25 children with CHARGE syndrome (60%) were
lymphopenic, despite using the same reference ranges as Hsu et al.
(2016) and Wong, Lambeck, et al. (2015). Nine patients had T-cell
enumeration, with four having very low CD3 cells (two of whom had a
15524876, 2017, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ajmg.c.31594 by CochraneArgentina, Wiley Online Library on [11/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
| 517
complete Di George anomaly). The differences between the studies
likely relates to the populations studied, with Hsu et al. (2016) and
Wong, Lambeck, et al. (2015) predominately studying older children
attending specialized outpatient clinics over a short period of time,
while Jyonouchi, McDonald-McGinn, Bale, Zackai, and Sullivan (2009)
included much younger infants attending a tertiary hospital over
10 years.
When Hsu et al. (2016) evaluated lymphocyte counts in children
with CHARGE who had a full blood count within the first 72 months of
life, they found 4 out of the 14 patients evaluated (30%) were
lymphopenic, but these counts had normalized in later childhood,
suggesting the lymophenia in this cohort was transient. Similarly,
Assing et al. (2013) reported a child with CHARGE who was
lymphopenic at birth but had a normal lymphocyte count by 6 months
of age. Thus lymphopenia in CHARGE syndrome appears to be more
common in early infancy, and may normalise over time. Persistent
lymphopenia is always of concern in any infant with CHARGE due to
the possibility of complete Di George anomaly.
2.4 | Reduced CD3 T-cells
Wong, Lambeck, et al. (2015) reported 5 out of 24 children had
mild-moderately reduced CD3 counts (another three patients had
normal CD3 counts, but reduced naïve CD4/CD8 counts indicating
probable thymic hypoplasia). Despite the mild-moderate reduced
T-cell numbers, the cells appeared to function normally, with normal
lymphocyte mitogen proliferation responses and appropriate cytokine
secretary function. Nineteen out of 23 children (83%) were reported to
have a suboptimal serological response following tetanus, diphtheria
and/or H.influenza B vaccination. However, it is important to note that
(i) antibody levels were not measured in healthy children to determine
the rate of suboptimal response in this group; (ii) no booster was
administered to determine if responses remained inadequate; (iii) no
child had a poor response to all three vaccines (which would be more
immunological significant); and (iv) no child had an antibody defect
requiring immunoglobulin infusions with all cases having normal IgG
and IgM levels and only one child a reduced IgA level (who responded
to two of the three vaccines).
Children with CHARGE syndrome and partial thymic hypoplasia can
present with more significant reductions in T-cell number, not profound
enough to result in complete Di George anomaly, but substantial enough
to warrant prophylactic antibiotic therapy or rarely immunoglobulin
replacement therapy (Assing et al., 2013; Chopra, Baretto, Duddridge, &
Browning, 2009; Jyonouchi et al., 2009; Theodoropoulos, 2003). In all of
these cases, although total immunoglobulin levels were normal,
assessment of antibody vaccine responses, and thus the B-cell function,
was inadequate. Either functional responses were not performed by
vaccination with pure polysaccharide vaccines, or vaccine protein
responses were not assessed following revaccination. There has been a
single case of common variable immunodeficiency in a child with
CHARGE syndrome (CHD7 mutation positive) (Martire, Panza, Pillon, &
Delvecchio, 2016). The child presented with recurrent infections,
haemolytic anaemia, and had reduced naïve CD4 and CD8 cells, low IgG

518 | MEHR
and A levels and impaired baseline responses to routine vaccination with
tetanus, diphtheria and H.influenza B. The child required immunoglobulin
infusions.
2.5 | Reduced CD8 T-cell
Wong, Lambeck, et al. (2015) reported reduced CD8 T cells in 11 out of
24 patients (46%; in five cases the reduced CD8 count was the sole
T-cell aberration) by applying standard laboratory reference ranges
(Comans-Bitter et al., 1997). The same group reported that a higher
proportion of children with CHARGE had reduced CD8 T cells when
compared to healthy controls (using the same reference ranges for
both groups (Comans-Bitter et al., 1997)). In contrast, Hsu et al. (2016)
found that no child had reduced CD8 counts (nor CD4, or NK cell
counts) using the same reference ranges as Wong, Lambeck, et al.
(2015). The differences between the two studies are not explained by
differences in age, given the median age of the cohorts were similar.
When Hsu et al. (2016) compared CD8 cells in CHARGE patients to
their own age matched healthy controls, they found CD8 counts were
lower in the CHARGE group, but this did not reach statistical
significance. Overall, further data is required across a broad range of
ages in larger cohorts to clarify whether CD8-penia is a common
feature of CHARGE syndrome.
2.6 | Complete thymic aplasia
Profound T-cell deficiency due to complete thymic aplasia is the most
common immunodeficiency reported in CHARGE syndrome (Table 1),
reflecting a reporting bias of more severe cases.. The term complete Di
George is used to describe this phenotype, describing infants with a Di
George anomaly (characterized by defects of the heart, thyroid and
parathyroid glands) who are athymic (Markert et al., 2007). Complete
Di George anomaly can occur in association with CHARGE, 22q11.2
deletion and diabetic embryopathy (Markert et al., 2007). Infants with
complete Di George syndrome can be further subdivided into typical or
atypical (also termed Omenn-like syndrome). Both subtypes can occur
in CHARGE and the typical phenotype can evolve into the atypical
subtype with the expansion of oligoclonal dysregulated T-cells. The
atypical phenotype can be clinically differentiated by the presence of
erythroderma, hepatosplenomegaly, lymphadenopathy, elevated IgE,
and/or peripheral blood eosinophilia. These patients do not have these
clinical features immediately after birth but rather evolve into this
phenotype with the expansion of dysregulated oligoclonal T cells
within the first months of life. Thus, these infants may initially be
profoundly lymphopenic with lymphocyte numbers “normalizing” over
time (Gennery et al., 2008).
The thymus and parathyroid develop from the same pharayngeal
pouches, and therefore hypocalcaemia is almost always reported in
complete Di George anomaly, suggesting a close correlation between
lymphopenia (i.e., and thymic aplasia) and hypocalcaemia (i.e., and
hypoparathyroidism) (Table 1). Jyonouchi et al., 2009 reported
combined hypocalcaemia and lymphopaenia in 14 of 18 CHARGE
patients. In contrast only one out of nine patients with normal calcium
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ET AL.
levels was lymphopenic. Markert et al. (2007) reported 44 children
with complete Di George syndrome (due to CHARGE, 22q11.2
deletion and diabetic embryopathy), of whom 36 (82%) had
hypocalcaemia requiring supplementation. Hsu et al. (2016) reported
a positive correlation between ionized calcium levels and total
lymphocyte counts in children with 22q11.2 deletion syndrome but
not in those with CHARGE syndrome. However, only 30% of this
CHARGE cohort had a calcium level performed and 22q11.2 deletion
children were more likely to be lymphopenic (60%) compared to
children with CHARGE syndrome (30%). We therefore propose that
persistent hypocalcaemia in neonates and infants with CHARGE is a
risk factor for thymic hypoplasia/aplasia, and an urgent full blood count
and T-B, and NK subsets is required to exclude complete Di George.
The management of an individual with complete Di George anomaly
follows the basic management tenants of any child with SCID, including
no live viral vaccines, cytomegalovirus (CMV) negative and irradiated
blood products (if required), anti-fungal and pneumocystis pneumonia
prophylaxis, commencement of immunoglobulin replacement, and
urgent need to reconstitute the immune system. Without treatment,
the condition is uniformly fatal. However, unlike other forms of SCID
where the primary defect lies within the immune cell lineage pathways
(and thus bone marrow transplantation is the cornerstone of therapy) in
complete Di George, stem cells are produced in normal numbers but
cannot undergo thymic education and maturation.
Thymic transplantation is regarded as the most suitable therapy in
complete Di George anomaly. The thymus does not need to be HLA
matched, but those with the atypical phenotype do need pre-graft
conditioning due to the presence of reactive oligoclonal T cells. Overall
graft versus host disease was rare in those undergoing thymic
transplantation and overall survival was 75% (Markert et al., 2007).
Naïve T-cells are generally detected within 6 months of thymic transplant
and by 2 years, most children can cease immunoglobulin infusions
(Markert et al., 2007). However, such specialized therapy is currently only
available in two centers in the world (Great Ormond St Hospital, London,
United Kingdom and Duke University Hospital, Durham, USA).
Consequently, other centers have had to rely on bone marrow
reconstitution (either bone marrow transplant or cord transplants) or
infusion of peripherally harvested lymphocytes with the view that
sufficient mature post-thymic naïve T-cells would be needed to expand
and rescue the immunological defect (Table 1). However, the outcome of
such transplants is less clear; 3/6 cases had graft vs. host disease, 3/6 died
post-transplant, and there is always the risk of graft failure (Gennery et al.,
2008; Hoover-Fong et al., 2009; Inoue et al., 2010; Janda et al., 2007).
2.7 | Isolated antibody deficiency
Although co-associated antibody defects occur in infants with the
complete Di George phenotype, there have been very few cases of
isolated antibody defects. Isolated IgA deficiency has been reported
(Jyonouchi et al., 2009), although IgA deficiency is the most common
primary immunodeficiency with a prevalence in healthy blood donors
ranging from 1:403 to 1:983 (Urbonas et al., 2016), so reports may
reflect chance associations rather than real relationship.
 TABLE 1 Published cases of complete Di George in CHARGE syndrome
MEHR

22q11.2 CD3 Outcome (and

ET AL.

CHD7 deletion Neonatal count Mitogen Transplant if died cause

Reference Sex C H A R G E mutation excluded ↓ Ca+2 T, B, NK cells per µl response Immunoglobulins performed death)
Kim, Kim, F + + − − + + − No U + (T − B + NK +) 6 ND IgG ↓, IgA ↓, Nil Died; BCG
and Park (2017) IgM ↓ pneumonitis
Kaliakatsos et al. M + + + U + + + Yes Yes + (T − B + NK +) 239 ↓ IgG N*, IgA N, Nil Died; infection
(2010) Atyp IgM N
Inoue et al. (2010) M + + + U − + + Yes Yes + (T − B + NK +) 8 ↓ IgG N*, IgA ↓, MUD CBT Alive
IgM N
Chopra et al. F + + − − − + Not done Yes Yes + (T − B + NK +) 2 ND IgG N*, IgA ↓, Nil Died; cause?
(2009) IgM ↓
M + + − − − + + Yes ND + (T − B + NK +) 0 ND IgG N*, IgA ↓, Thymic Alive
IgM N
Jyonouchi et al. U U U U U U U + Yes U + (T − B + NK +) 3 ↓ IgG N*, IgA ↓, Nil Died; infection
(2009) IgM N
U U U U U U U + Yes U + (T − B + NK +) 34 ↓ IgG ↓, IgA ↓, Nil Died; infection
I
gM ↓
Hoover-Fong M − + + U + + + Yes Yes + (T − B + NK +) 4 ↓ Not recorded Unrelated Died; acute
et al. (2009) 10/10 renal failure
matched
PBMC
infusion
Gennery et al. F + + U U U + + Yes Yes + (T − B + NK +) 0 ↓ IgG N*, IgA ↓, MUD BMT Alive
(2008) IgM N
M + + + U + U + Yes Yes + (T − B + NK +) 0 ↓ IgG ↓, IgA ↓, MUD CBT Died
IgM N
M + + + U + + + Yes Yes + (T − B + NK +) 142 ↓ IgG N, IgA ↓, MUD CBT Died; infection
Atyp IgM N
F − + U U U + + Yes Yes + (T − B + NK +) 0** ↓ IgG N, IgA ↓, Nil Died; cause
Atyp IgM N ND
Sanka, F + + U U + U + Yes Yes + (T − B + NK +) 0 ↓ IgG N*, IgA N, U U
Tangsinmankong, Loscalzo, Sleasman, and Dorsey (2007) IgM N

Janda et al. (2007) M + + + + + + Not done Yes Yes + (T − B + NK +) 2 ↓ IgG N*, IgA ↓, MUD BMT Alive
IgM ↓
Writzl et al. (2007) M − + + + + + + Yes Yes + (T − B + NK +) 0 ↓ IgG↓, IgA ↑, Nil Died; cause
IgM ↑ ND
M − + − + + + + + (T − B + NK +) 3 ↓ Not stated Nil Died; cause
|

(Continues)
519

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 520

TABLE 1 (Continued)
|

22q11.2 CD3 Outcome (and

CHD7 deletion Neonatal count Mitogen Transplant if died cause
Reference Sex C H A R G E mutation excluded ↓ Ca+2 T, B, NK cells per µl response Immunoglobulins performed death)
ND
Boudny, Kurrer, F + + + U U U Not done No No + (T − B + NK +) U ↓ IgG ↓, IgA ↓, Nil Died;
Stamm, and Atyp IgM ↓ respiratory
Laeng (2000) failure,
infection
Markert et al. U U U U U U U U U Yes (44/ 14 cases CHARGE <50 naïve Flat to U Thymic (in 33/44 cases
(2007)# 54 of complete Di T-cells reduced 44 cases) complete Di
cases George anomaly (? total George
complete Di CD3 anomaly
George count) survived
anomaly) (number
with
CHARGE
unknown)
Wood, David, M − + + + − + Not done No Yes + (T − B + NK +) 3 ↓ Not recorded Nil Died (ND)
Chrystie, and (but treated
Totterdell with IVIg)
(1988)
de Lonlay- M + + − + + + Not done Yes Yes + (T−; B/NK ND) 0 U U Nil U
Debeney et al.
(1997)##

Atyp, Atypical complete Di George, BMT, bone marrow transplant, CBT, cord blood transplant, F, Female, IVIg, intravenous immunoglobulin G, M, Male, MUD, matched unrelated, N, normal, ND, not documented, SC,
stem cells, U, Unknown.
N* = Normal IgG due to transplacental transfer of maternal IgG.
**At birth the CD3 count was 0/μl but by 3.5 months of age with the development of atypical complete Di George it was 11,368/μl
#
There were 54 cases of complete Di George (of which 14 were due to CHARGE), and a number cases had been previously published in other papers. 44 cases went on to thymic transplant (but it is unclear how many
of these had CHARGE syndrome). The T-cell counts were not provided but all cases included had to have a naïve T cell count <50/μl (which would indicate the presence of complete thymic aplasia)
##
There were another 2 children who died (one had hypocalcaemia, the lymphocyte count was not presented, and the cause of death was unclear; the other case had hypocalcaemia reduced T-cell counts and died of
sepsis/hepatic abscess at day 13 of life)
MEHR
ET AL.

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MEHR ET AL.
IgG subclass deficiency alone has been reported in CHARGE-
(Theodoropoulos, 2003), but this is not considered immunologically
significant without an accompanying functional antibody defect. One
child with CHARGE and recurrent respiratory/ear infections did have
IgG1 subclass deficiency, associated with reduced titers of Hib and
pneumococcal antibodies following routine vaccination (Theodoropoulos,
2003). The child also had low CD3 counts, impaired mitogen stimulation
(Theodoropoulos, 2003), and required prophylactic antibiotics.
There has been a single case report of a girl with presumed
CHARGE (no CHD7 mutation analysis) with hyperIgM syndrome
(Bahillo et al., 2003). However, her clinical features would neither
satisfy the current definitions used for hyperIgM (http://www.esid.
org) nor CHARGE syndrome (Blake et al., 1998; Verloes, 2005).
There have been no convincing cases of specific antibody
deficiency (SAD) in CHARGE. In almost every case report or series,
polysaccharide responses were either based on protein conjugated
pneumococcal vaccination (Jyonouchi et al., 2009; Wong, Scholvinck,
et al., 2015) or the type of vaccine administered was not mentioned
(Jyonouchi et al., 2009). Hsu et al. (2016) is the only study to date to
systematically examine polysacharride vaccine responses, and found
no child had SAD. In this cohort, the children were on average older,
with no current history of recurrent suppurative infections. Given SAD
appears more likely to occur in infants/younger children, and the
condition can spontaneously resolve over time, evaluation of
polysaccharide responses in a younger cohort of patients in CHARGE
syndrome is required to confirm the findings of Hsu et al. (2016).
2.8 | Comparison of the immune phenotype between
CHARGE and 22q11.2 deletion syndrome
CHARGE and 22q11.2 deletion syndromes share significant pheno-
typic similarities, given that both disorders are associated with
impaired development of the pharyngeal arch structures, from which
thymic stromal cells are derived (Randall et al., 2009). CHARGE is much
less common (estimated incidence 1:10,000–17,000) (Janssen et al.,
2012) than 22q11.2 deletion syndrome (estimated incidence 1:4000)
(McDonald-McGinn & Sullivan, 2011) and notable phenotypic differ-
ences exist between the two conditions (Jyonouchi et al., 2009).
Although Jyonouchi et al., 2009 compared the phenotypic features
of CHARGE with 22q11.2 deletion syndrome, they did not compare
their immune phenotype. Hsu et al. (2016) did compare the two immune
phenotypes, and found that 22q11.2 deletion patients had lower total
lymphocyte, CD3 and CD4 counts, as well as a higher rate of
immunoglobulin (especially IgM) and specific antibody deficiency.
However, data from 22q11.2 deletion patients was collected retro-
spectively and was incomplete, and thus subject to selection bias.
In studies examining 22q11.2 deletion syndrome alone, in addition
to the rare but well recognized complete Di George presentation
(discussed above), lymphopenia due to reduced T cell numbers is a
common feature, but the natural age-related decline in peripheral T cells
appears to be blunted in these patients (Jawad, McDonald-Mcginn,
Zackai, & Sullivan, 2001). Antibody deficiencies, including isolated low
IgM, IgG, and IgA are also reported in 22q11.2 deletion syndrome. The
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| 521
prevalence of such defects was up to 50% in one study (Gennery, 2012);
however, in a larger cohort of 855 patients, Patel et al. (2012) found that
only 6% of patients had hypogammaglobulinemia. Additionally, SAD has
been reported in up to 55% of children with 22q11.2 deletion (Gennery
et al., 2002) but Hsu et al. (2016) found that no child with CHARGE had
SAD. Overall, 22q11.2 deletion syndrome appears more likely to be
associated with immunodeficiency than CHARGE syndrome, with its
increased likelihood of lymphopenia and prevalence of antibody
deficiencies. However, prospective head to head comparison of these
two patient cohorts is required to confirm these observations.
3 | RECOMMENDATIONS FOR IMMUNE
SCREENING I N C HAR GE
There is no consensus regarding whether all patients with CHARGE
syndrome should be screened for immune deficiency upon diagnosis.
Chopra et al., 2009 recommended lymphocyte subset analysis for all
patients in their report of 4 children with CHARGE syndrome with
moderate to severe T cell deficiency and infection. Jyonouchi et al. (2009)
recommended that all children with CHARGE syndrome be evaluated for
T cell and humoral immune deficiency. Wong, Scholvinck, et al. (2015)
proposed that specialized immunological tests (such as lymphocyte subset
analysis and vaccine responses) should be performed in patients with
persistent infections requiring prophylactic antibiotics.
Given the small but real risk of complete Di George in CHARGE
syndrome, and in light of published data to date, we recommend that a full
blood count with a lymphocyte differential and calcium level should be
performed in the neonatal period in all patients with CHARGE syndrome.
Complete Di George must also be considered in any infant with persistent
lymphopenia (particularly in the presence of hypocalcaemia), but also in infants
with signs of an Omenn-like phenotype or those with normal lymphocyte
count and presenting with unusual or invasive infections (e.g., CMV, PCP).
For older children with CHARGE syndrome who present with
recurrent sino-pulmonary infections, further immune testing (full
blood count, lymphocyte subsets, naïve T cells, B-cell memory
phenotype, immunoglobulin levels and protein/polysaccharide vaccine
responses) should be performed to detect a more subtle cellular or
humoral immune deficiency. While this approach may miss some of the
milder immune deficits in asymptomatic patients (such as mild T cell
lymphopenia), the clinical relevance of such defects remains unclear.
4 | FUTURE DIRECTIONS AND
RECOMMENDATIONS
There remains a paucity of information with respect to the immune
function of patients with CHARGE syndrome. Further areas of
potential interest include:
 Systematic assessment and characterisation of immunological
phenotype in younger and adult cohorts with CHARGE syndrome
and comparison to age matched healthy controls and patients with
22q11.2 deletion syndrome.

522 | MEHR
 Standardisation of assessment for humoral defects (i.e., boosting if
routine vaccination titres are reduced; assessing for SAD by
vaccination with 23 valent pneumococcal vaccine and performing
memory B-cell phenotyping).
 Determining if additional genetic mutations are responsible for
thymic aplasia in those with complete Di George anomaly, given
there is no clear CHD7 genotype-phenotype correlation.
 Addressing the need for other countries to be able to provide thymic
transplantation outside of the US and UK. This is particularly
required in regions where neonatal SCID screening is being
implemented. Otherwise, a situation will arise where an early
diagnosis of complete Di-George anomaly will be made but thymic
transplantation cannot be offered.
These areas of ongoing need can only be addressed by
collaboration between multiple centers currently managing children
with CHARGE syndrome. Overall, based upon current reports, we
suggest significant immune defects in CHARGE are rare but if missed,
have potential devastating consequences.
ORCID
Sam Mehr http://orcid.org/0000-0003-2483-917X
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MEHR ET AL.
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Theodoropoulos, D. S. (2003). Immune deficiency in CHARGE association. PETER HSU is a Consultant Paediatric Immu-
Clinical Medicine & Research, 1(1), 43–48. nologist and Allergist at the Children's
Urbonas, V., Sadauskaite, J., Cerkauskiene, R., Kaminskas, A., Maki, M., &
Hospital at Westmead, Australia, and a
Kurppa, K. (2016). Population-Based screening for selective immuno-
globulin a (IgA) deficiency in lithuanian children using a rapid antibody- senior lecturer at the University of Sydney.
Based fingertip test. Medical Science Monitor, 22, 4773–4778. His research interests include immune
Verloes, A. (2005). Updated diagnostic criteria for CHARGE syndrome: A regulatory mechanisms in allergy and
proposal. American Journal of Medical Genetics Part A, 133A(3), 306–308.
immunodeficiency.
Wong, M. T., Lambeck, A. J., van der Burg, M., la Bastide-van Gemert, S., Hogendorf,
L. A., van Ravenswaaij-Art, C. M., . . . Scholvinck, E. H. (2015). Immune
dysfunction in children with CHARGE syndrome: A cross-Sectional study. PLoS DIANNE CAMPBELL is the Chair and Co-head of
ONE, 10(11), e0142350. the Department of Allergy and Clinical
Wong, M. T., Scholvinck, E. H., Lambeck, A. J., & van Ravenswaaij-Arts,
Immunology at the Children's Hospital,
C. M. (2015). CHARGE syndrome: A review of the immunological
aspects. European Journal of Human Genetics, 23(11), 1451–1459. Westmead, Australia. She has active roles
Wood, D. J., David, T. J., Chrystie, I. L., & Totterdell, B. (1988). Chronic in Allergy and Immunology research, and
enteric virus infection in two T-cell immunodeficient children. Journal of has published >90 peer reviewed papers.
Medical Virology, 24(4), 435–444.
Writzl, K., Cale, C. M., Pierce, C. M., Wilson, L. C., & Hennekam, R. C. (2007).
Immunological abnormalities in CHARGE syndrome. European Journal of
Medical Genetics, 50(5), 338–345.
How to cite this article: Mehr S, Hsu P, Campbell D.
Immunodeficiency in CHARGE syndrome. Am J Med Genet
SAM MEHR is a Consultant Paediatric Immu-
Part C Semin Med Genet. 2017;175C:516–523.
nologist, Allergist and Immunopathologist
https://doi.org/10.1002/ajmg.c.31594
at the Royal Children's Hospital Melbourne,
Australia. He has a clinical and research
interest in allergy, autoinflammation and
paediatric immunodeficiency.