Salem Al-Tamemi, Bruce Mazer, David Mitchell, Pedro Albuquerque, Alessandra M.

Complete DiGeorge Anomaly in the Absence of Neonatal Hypocalcemia and
Velofacial and Cardiac Defects
Salem Al-Tamemi, Bruce Mazer, David Mitchell, Pedro Albuquerque, Alessandra M.
V. Duncan, Christine McCusker and Nada Jabado
Pediatrics 2005;116;e457; originally published online August 1, 2005;
DOI: 10.1542/peds.2005-0371
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/116/3/e457.full.html
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2005 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
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Complete DiGeorge Anomaly in the Absence of Neonatal Hypocalcemia
and Velofacial and Cardiac Defects
Salem Al-Tamemi, MD*; Bruce Mazer, MD*; David Mitchell, MD‡; Pedro Albuquerque, MD§;
Alessandra M. V. Duncan, PhD㛳; Christine McCusker, MD*; and Nada Jabado, MD, PhD‡
ABSTRACT. We report an atypical case of complete
DiGeorge (DG) anomaly that presented initially exclusively as severe combined immunodeficiency (SCID).
The child had severe infections at diagnosis, in keeping
with the SCID phenotype; however, normal lymphocyte
counts and immunoglobulin levels were noted at admission, which delayed diagnosis. Importantly, the child
presented without neonatal hypocalcemia or velofacial or
cardiac abnormalities at the time of diagnosis, which
masked underlying DG. This case outlines the difficulties in making the diagnosis of SCID in a timely manner
and illustrates the variation in presentation of the 22q11.2
deletion syndrome. There should be a high index of
suspicion for primary immunodeficiency among children with severe infections and, because management
may vary, DG anomaly should be considered in the differential diagnosis of Tⴚ Bⴙ natural killerⴙ SCID. Pediatrics 2005;116:e457–e460. URL: www.pediatrics.org/cgi/
doi/10.1542/peds.2005-0371; primary immunodeficiency,
stem cell transplant, thymic transplant, fluorescence in
situ hybridization.
ABBREVIATIONS. DG, DiGeorge; PID, primary immunodeficiency; SCID, severe combined immunodeficiency; BMT, bone marrow transplantation; NK, natural killer.
S
evere combined immunodeficiency (SCID) is
life-threatening and usually presents in the first
few months of life. Common manifestations include failure to thrive, recurrent thrush, and respiratory infections. The hallmark of SCID is absent or
poorly functioning T lymphocytes. Although children with SCID often present with lymphopenia,
normal or elevated lymphocyte counts are also seen.
In addition, normal levels of serum immunoglobulins are often found.1,2 Therefore, normal lymphocyte counts or immunoglobulin levels should not
exclude a diagnosis of primary immunodeficiency
(PID) and, among children with recurrent infections,
complete evaluation of the immune system, includ-
From the *Division of Allergy and Immunology, ‡Division of HematoOncology, §Department of Radiology, and 㛳Department of Pathology, Montreal Children’s Hospital, McGill University Health Center, Montreal, Quebec, Canada.
Accepted for publication Apr 8, 2005.
doi:10.1542/peds.2005-0371
No conflict of interest declared.
Address correspondence to Nada Jabado, MD, PhD, 4060 St Catherine West,
PT-239, H3Z 2Z3 Montreal, Quebec, Canada. E-mail: [email protected]
PEDIATRICS (ISSN 0031 4005). Copyright © 2005 by the American Academy of Pediatrics.
ing T, B, and natural killer (NK) cell phenotyping, is
required to ensure prompt diagnosis.
DiGeorge (DG) anomaly (OMIM 188400) is caused
by developmental defects in the third pharyngeal
pouch and fourth pharyngeal arch.3 This disorder is
clinically heterogeneous and is characterized by cardiovascular defects and thymic, parathyroid, and
craniofacial anomalies.4,5 Associated problems include esophageal reflux, laryngomalacia, and delay
in speech acquisition. Phenotypes range from lifethreatening heart defects or T cell immunodeficiency
to mild craniofacial abnormalities and developmental delays. Approximately 80% of DG anomaly cases
are caused by a chromosomal deletion generally referred to as del(22)(q11.2q11.2). In fact, 22q11.2 deletion syndrome6–13 is now used to describe a heterogeneous group of disorders including DG anomaly,
velocardiofacial syndrome,14 and conotruncal anomaly face syndrome and is the most common chromosomal deletion syndrome among humans, occurring
with an incidence of ⬃1 case per 3000 live
births.8,11,12,14–16 Among patients with del(22), 90%
have a virtually identical 3-megabase heterozygous
deletion of 22q11.2 but show great clinical variability,
which suggests the presence of additional genetic
modifiers. Some patients have DG anomaly features
in conjunction with the CHARGE association (association of coloboma, heart defect, agenesis of choanae, retardation of growth or development, genital
hypoplasia, and ear anomalies or deafness)17 or in
association with maternal diabetes mellitus18 and are
more rarely 22q11.2 hemizygous. Others have DG
anomaly features and are hemizygous for 10p13.19
In DG anomaly, the development of thymic tissue
is affected; thymic defects occur for ⬃80% of patients, leading to varying degrees of cellular immunodeficiency.20 DG-SCID describes a small subset of
children with clinical features of DG anomaly and
severe T-cell immunodeficiency (1–2%) attributable
to absent or highly hypoplastic thymic tissue. This
disorder is found often in conjunction with the
CHARGE association, 22q11.2 hemizygosity (50 –
62% in 2 reports),21,22 or diabetic embryopathy. The
profound T-cell immunodeficiency in DG-SCID is
fatal without intervention within the first 2 years of
life.9,23–26 Immune reconstitution is possible through
infusion of peripheral mononuclear cells or bone
marrow transplantation (BMT) from a genotypically
HLA-identical donor or, more recently, through
postnatal thymic tissue transplantation.22,27–29
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e457
We report an unusual case of DG-SCID that presented exclusively as SCID, without neonatal hypocalcemia or velofacial or cardiac abnormalities, at
the time of diagnosis. The child presented with a
SCID phenotype, but normal lymphocyte counts and
immunoglobulin levels were noted at the initial presentation, delaying diagnosis. This case clearly
shows the variation in presentation of DG anomaly,
and we outline difficulties in making the diagnosis of
SCID in a timely manner.
CASE REPORT
A 5-month-old male infant was admitted to our hospital with
severe parainfluenza III virus bronchopneumonitis. He was born
at 41 weeks, after an uneventful normal pregnancy. He had experienced recurrent thrush and more recently failure to thrive. There
was no relevant family history, and there were 2 healthy siblings.
On examination, the patient exhibited marked respiratory symptoms, with a respiratory rate of 70 breaths per minute, intercostal
and abdominal indrawing, and bobbing of the head (evidence of
marked respiratory distress). Growth failure, with height and
weight below the 10th percentile, was also noted. The nasopharyngeal aspirate was exclusively positive for parainfluenza III
virus. Chest radiographs showed marked pulmonary distention,
with flattening of both diaphragms and diffuse bronchoalveolar
infiltrates. There was no evidence of aspiration pneumonia. Biological screening showed normal absolute lymphocyte counts
(9110 cells per mm3) and normal IgG (5.2 g/L), IgA (1.3 g/L), and
IgM levels (0.7 g/L). Three weeks after admission, the patient’s
condition deteriorated rapidly and the immunology service was
consulted. Lymphocyte phenotyping established the diagnosis of
SCID with a T⫺ (150 cells per mm3), B⫹ (3850 cells per mm3), and
NK⫹ (550 cells per mm3) phenotype and absent T cell proliferation
in response to mitogens and anti-CD3 antibody (Fig 1). No obvious dysmorphic features were observed in a thorough physical
examination, including no abnormal implantation of ears or micrognathia. The child had no history of gastroesophageal or nasopharyngeal reflux. His neurocognitive development was concordant with his age. Ionized calcium levels were normal.
Nonmanipulated BMT from a HLA-matched sibling donor was
performed without conditioning and resulted in T-cell engraftment and resolution of pulmonary infection within 2 weeks. On
the basis of the T⫺B⫹NK⫹ lymphocyte phenotype and the absence
of obvious facial, cardiac, and calcium abnormalities, the interleu-
kin-7 receptor genotype was investigated and was found to be
normal.30 CD3 subunits, which could have explained the molecular defect alternately, were not tested at that time.31,32
One month after BMT, the child presented with generalized
seizures secondary to hypocalcemia (ionized Ca2⫹ level of 0.84
mmol/L). Parathyroid hormone was undetectable (⬍10 pg/L). On
the basis of the hypoparathyroidism and SCID, the possibility of
DG anomaly was investigated. Cardiac ultrasound findings were
normal. Chest computed tomographic scans revealed an aberrant
right subclavian artery (an anatomic variation present in 1% of the
population) and the absence of a thymus (Fig 2A). A fluorescence
in situ hybridization study for deletions on chromosome 22q11.2,
performed with fibroblasts from the patient, confirmed the diagnosis of DG anomaly (Fig 2B). Two years after BMT, our patient
exhibits CD3⫹ and CD4⫹ T cell counts of ⬃800 cells per mm3 and
⬃500 cells per mm3, respectively, without additional treatment.
Intravenous immunoglobulin supplementation that was initiated
at the time of BMT was stopped, and the patient’s IgG levels
remain ⬃8 g/L. His IgA and IgM levels are also within normal
ranges (1.25 g/L and 0.75 g/L, respectively). The patient has
normal proliferative responses to phytohemagglutinin and antiCD3. Chimerism studies performed on circulating mononuclear
cells showed that 95% of his CD3⫹ cells were of donor origin. In
a physical examination oriented by the diagnosis of DG anomaly
and performed by the geneticist who is now monitoring the child
jointly, the patient exhibited delayed speech acquisition and very
subtle micrognathia. There were no additional features of DG
anomaly, including no hearing defect and no vertebral, ocular, or
renal abnormalities. The patient’s calcium level is controlled with
vitamin D and calcium supplements. His neurocognitive development cannot be assessed fully at 2.5 years of age, especially in the
presence of delayed speech acquisition, and needs to be reevaluated later in the child’s life.
DISCUSSION
Although lymphopenia is common in SCID, infants presenting with persistent infections and failure to thrive may have normal lymphocyte counts
and immunoglobulin levels, delaying the diagnosis
of PID. We report an unusual case of DG anomaly
presenting exclusively as T⫺B⫹NK⫹ SCID. In the
past decade, many molecular and genetic defects
causing SCID have been identified. Defects that have
been defined genetically for this subset of SCID are
Fig 1. Lymphocyte subsets before and after BMT.
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RECOGNIZING DG-SCID–AFFECTED CHILDREN
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Fig 2. A shows serial axial slices from chest computed tomographic scans performed after BMT, showing the absence of thymus in the
anterior mediastinum and the presence of an aberrant right subclavian artery arising from the aortic cleft behind the tracheal carina
(arrows). B shows fluorescence in situ hybridization analysis of a metaphase preparation from a fibroblast culture, showing 46,XY.ish
del(22)(q11.2q11.2)(TUPLE1,D22S553,D22S609,D22S942⫺). The target probe shows heterozygous deletion of DG region loci on one
chromosome 22 (in red). The control probe hybridizes to both chromosomes 22 (in green).
interleukin-7 receptor ␣ deficiency, which was excluded for our patient, CD3 subunit deficiencies, and
DG anomaly (reviewed in refs 1, 2, and 33). Hypocalcemia and facial or cardiac defects are the hallmarks
of DG-SCID, and ⱖ1 is present in cases reported to
date. For our patient, hypocalcemia was evident only
at 7 months of age. Latent hypoparathyroidism in
DG anomaly has been described and diagnosed even
among adults during evaluation of refractory hypocalcemia.34,35 Cardiac defects may be absent in
DG-SCID; however, severe hypoparathyroidism and
dysmorphic facies have been associated frequently,
allowing early diagnosis.36 In another specialized
center that treats children with SCID routinely (Hoˆpital Necker, Paris, France), one other child with
SCID and isolated labial cleft had del22q11.2 and a
similarly delayed diagnosis (Alain Fischer, MD, PhD,
oral communication, 2004). However, only 50% of
children with DG-SCID have del(22)(q11.2q11.2)21,22
and can thus be diagnosed on the basis of this genetic
characteristic. In all other DG-SCID cases in which
such a deletion is not present, diagnosis is possible
only when all of the other molecular diagnoses of
T⫺B⫹NK⫹ SCID are known and excluded or when
we gain better knowledge of the exact mechanisms
underlying the DG-SCID phenotype.
Several avenues of treatment have been used to
treat the life-threatening immunodeficiency associ-
ated with DG-SCID. Transplantation of fetal thymus
has been used historically and resulted in immune
reconstitution in a few cases.37–39 Genotypically
HLA-identical BMT has also been used successfully
in a few cases.27,28,40 This treatment resulted in restoration of T-cell function, most likely through adoptive transfer of postthymic donor T cells, as was the
case for our patient. Two different groups postulated
that only postthymic lymphocytes, and not stem
cells, were responsible for immune reconstitution
after successful BMT. On the basis of this hypothesis,
they performed peripheral blood mononuclear cell
transplantation from a HLA-identical sibling. This
procedure was followed by partial T-cell engraftment and immune reconstitution through adoptive
transfer of mature T cells among patients.29,36 It is
very likely that children with DG-SCID cannot form
new thymic immigrants from infused stem cells because they have little residual, functional, thymic
tissue. Transplantation of postnatal thymic tissue is a
more recent therapeutic approach and is yielding
very promising results.21,22,25,41 In fact, only after this
procedure did episomal circular DNA excision products of T-cell receptor gene rearrangement analysis
among recipients show evidence of new thymopoiesis. In SCID-DG cases with no genotypically HLAidentical donor, this is the obvious treatment. These
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e459
differences in therapeutic approaches underline the
importance of early diagnosis of DG anomaly.
CONCLUSIONS
There should be a high index of suspicion for PID
among children with severe infections, and this diagnosis is not to be excluded on the basis of normal
lymphocyte counts or immunoglobulin levels. We
recommend strongly performing lymphocyte phenotyping and stimulation tests to ensure diagnosis of
PID. Chromosome 22 deletions are underdiagnosed
among patients with cardiac abnormalities, and
screening with fluorescence in situ hybridization for
chromosome 22 deletion, a widely accessible diagnostic tool in specialized centers, is increasingly part
of the evaluation of congenital cardiac disorders.12,35
Patients with T⫺B⫹NK⫹ SCID may have the molecular defect of DG anomaly even in the absence of
neonatal hypocalcemia or obvious cardiac or facial
defects. Screening for chromosome 22 deletions
among patients with T⫺B⫹NK⫹ SCID should be routine. In the absence of this chromosomal deletion,
enlisting the help of a geneticist and an endocrinologist can prove useful for diagnosis. Ensuring a correct molecular diagnosis has a profound impact on
genetic counseling and, most importantly, on treatment and therapeutic options for affected children.
ACKNOWLEDGMENT
N.J., B.M., and C.M. are recipients of “Chercheur Boursier”
awards from the Fondation de la Recherche en Sante au Quebec.
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RECOGNIZING DG-SCID–AFFECTED CHILDREN
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Complete DiGeorge Anomaly in the Absence of Neonatal Hypocalcemia and
Velofacial and Cardiac Defects
Salem Al-Tamemi, Bruce Mazer, David Mitchell, Pedro Albuquerque, Alessandra M.
V. Duncan, Christine McCusker and Nada Jabado
Pediatrics 2005;116;e457; originally published online August 1, 2005;
DOI: 10.1542/peds.2005-0371
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright © 2005 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
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