DiGeorge syndrome:
Chromosome 22q11.2 deletion
Kate Sullivan MD PhD
The Children’s Hospital of Philadelphia
Johnson City 2012
Disclosure Statement of Financial Interest
I, Kate Sullivan
DO NOT have a financial interest/arrangement or affiliation
with one or more organizations that could be perceived
as a real or apparent conflict of interest in the context of
the subject of this presentation.
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A word about nomenclature
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Chromosome 22q11.2 deletion syndrome
DiGeorge syndrome
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Clinical triad: cardiac, thymus, parathyroid
Etiologies
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Velocardiofacial syndrome
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CH22q11.2 hemizygous deletion
CHD7 mutations
Maternal diabetes
Maternal isotretinoin
Chromosome 10 deletions
Clinical triad
Some CHARGE
The Phenotype of Chromosome 22q11.2 Deletion
Syndrome
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Cardiac anomaly 75%
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TOF 20%
IAA 15%
Truncus arteriosus 8%
Palatal anomaly 69-100%
Hypocalcemia 17-60%
Speech delay 75%
Renal anomaly 36-37%
Skeletal anomaly 17-19%
Immunodeficiency 60-77%
Where to look for the deletion?
Cardiac Diseases
Any cardiac lesion
Interrupted aortic arch B
Pulmonary atresia
Aberrant subclavian
Tetralogy of Fallot
1.1%
50-60%
33-45%
25%
11-17%
Where to look for the deletion?
Velopharyngeal insufficiency following adnoidectomy 64%
Isolated velopharyngeal insufficiency
37%
Neonatal hypocalcemia
74%
Schizophrenia
0.3-6.4%
Any other clues?
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Speech delay
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Almost universal if you do formal testing
75% fail the rapid Denver speech criteria
Dysmorphic facies
Notice preauricular pit
Father/Daughter
Posteriorly rotated ears
Simple helices
Many other features
The diagnosis is established by FISH,
multiplex ligation-dependent probe
amplification (MLPA), or SNP array
The deletion has many genes
Tbx-1
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Expressed in developing mesenchyme
Expressed in pharyngeal arches, otic vesicle
Part of a cascade of transcription factors
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Parathyroid
Thymus
Anterior heart field
TBX1 mutations in humans look like Ch22qD
Yagi, H 2003
The significance of the diagnosis
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Toddlers
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79% significant motor delay
53% significant expressive delay
26% significant receptive delay
School-age
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12.7% average IQ (Weschler)
25.5% low average
34.5% borderline
27.3% retarded
Behavior/School issues
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65.5% have a nonverbal learning disability
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25% have ADHD
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6-30% will develop psychiatric diseases
Obviously not all patients are the same…
The Immunodeficiency
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60-77% of patients have quantitative T cell defects
Only ≈0.2% have absent T cells
2-4% IgA deficiency
6% Hypogammaglobulinemia
The Role of the Thymus
15-20% of patients
have an absent anatomic
thymus
Thymic tissue is found in
aberrant locations
Only ≈0.2% of patients
have no T cells and truly
have thymic aplasia
Hypoplasia
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Restricts T cell output
Movies courtesy of Richard Lewis, Stanford
Early thymic development
Human=6wk
Ectoderm
Endoderm
Thymic tissue is derived from pharyngeal pouch endoderm
Hollander Imm Rev 209:28
Clinical Immunodeficiency
7% of all ages have significant, serious infections
9% of kids have autoimmune disease
(may be ≈25% in adults- Bassett 2005)
Older children continue to get infections
27% recurrent sinusitis
25% recurrent otitis media
7% recurrent bronchitis
4% recurrent pneumonia
Sullivan J. Ped. 2001
P=0.0006
P=0.05
Staple Ped All Imm 2005
Autoimmunity
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Juvenile arthritis is seen 20X more frequently (2%)
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ITP is seen 200X more frequently (4%)
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AHA, IBD are seen in about 1%
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Older patients develop autoimmune diseases of adults
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6% ITP
20% Thyroid disease
CD3 T cells
Homeostatic proliferation
Thymus
2 cells exported
Thymus
Peripheral proliferation
10 cells total
Only two T cell receptors
10 cells exported
Ten different T cell receptors
Evidence of homeostatic expansion
Adult
Controls
Adult
Patients
P value
Oligoclonal
1.55
8.6
0.0001
Absent
1.44
7.1
0.0009
TREC circles
Piliero Blood 2004
Zemble Clin Imm 2010
T cells default to Th2 with homeostatic expansion
P=0.07
P=0.0014
Zemble Clin Imm 2010
T cell summary
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Quantitative defects most apparent in infancy
T cell numbers normalize with age
Qualitative T cell defects accrue with age
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Repertoire degradation
Poor proliferation
Th2 skewing
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??? Poor support for B cell development/differentiation
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B cells
P=0.01
P=0.02
P=0.001
Immunoglobulin Levels:
ESID, USIDNET, LASID collaboration
IgG vs Age
3000
IgG mg/dl
2500
2000
1500
1000
500
0
0
10
20
30
40
50
Age (y)
IgM vs Age
IgA vs Age
500
1000
400
IgM mg/dl
IgA mg/dl
800
600
400
300
200
100
200
0
0
0
10
20
30
Age (y)
40
50
0
10
20
30
Age (y)
40
50
What to do?
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Prophylactic antibiotics
Immunoglobulin replacement
Thymus transplant
Peripheral blood T cells
Thymus enhancement
Thymus transplants
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Surgical thymectomy specimens
Screened for infection
Not HLA matched
0.5mm thick slices of 15mm X 15mm
Cultured for 12-21d to remove donor T cells
Implanted into the quadriceps
>70% survival (n=60)
Markert Clin Imm 135:236
T cell recovery is adequate but not robust
B cell function
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Normal immunoglobulin levels
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100% normal IgG
91% normal IgA
77% normal IgM
100% normal tetanus titers
Markert Clin Imm 135:236
Can thymic function be enhanced?
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Fibroblast growth factor 7-TEC expansion
Estrogen-expands thymic tissue
Summary
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Developmental delay/Behavioral problems are the biggest
long term challenges
Cardiac anomalies
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Most common cause of death
Monitor calcium carefully
The immune deficiency ranges from none to profound
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Most kids have recurrent sinopulmonary infections
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Prophylactic antibiotics
Immunoglobulin for hypogammaglobulinemia
Rarely, thymus transplants are required
Thank you!