A word about nomenclature
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Chromosome 22q11.2 deletion syndrome
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DiGeorge syndrome
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Velocardiofacial syndrome
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Conotruncal anomaly face
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Some CHARGE
The majority of patients with DiGeorge syndrome, VCFS, CTAF have
hemizygous deletions of chromosome 22q11.2.
The nomenclature is not synonymous.
The Phenotype of Chromosome 22q11.2 Deletion Syndrome
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Cardiac anomaly 75%
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TOF-20%
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IAA-15%
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Truncus arteriosus-8%
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Palatal anomaly-69-100%
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Hypocalcemia-17-60%
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Speech delay-75%
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Renal anomaly-36-37%
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Skeletal anomaly-17-19%
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Immunodeficiency-60-77%
Where to look for the
deletion?
Cardiac Diseases
Any cardiac lesion-1.1%
Interrupted aortic arch-50-60%
Pulmonary atresia-33-45%
Aberrant subclavian-25%
Tetralogy of Fallot-11-17%
Others
Velopharyngeal insufficiency
following adnoidectomy-64%
Isolated velopharyngeal
insufficiency-37%
Neonatal hypocalcemia-74%
Schizophrenia-0.3-6.4%
The diagnosis is established
by FISH
22 well-characterized genes
The critical region was
established by generating mice with comparable deletions
The Heterozygous Murine
Deletion
25-50% of mice have
cardiovascular anomalies
o
Aberrant great vessels (right subclavian, IAAB)
o
VSDs
o
Conotruncal anomalies rare
Thymus was variably effected
depending on background strain
Parathyroid gland variable
Homozygous mice have additional
features of Ch22q11.2 D
Tbx-1
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Expressed in developing mesenchyme
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Expressed in pharyngeal arches, otic vesicle,
tooth buds, sclerotome
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Heterozygous mutations of Tbx-1 are associated
with great vessel defects in mice
• Homozygous deficient mice have a small mandible,
low set ears, a single cardiac outflow tract, deficient
thymus/parathyroid/salivary glands
TBX1 in humans
More than TBX1?
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COMT, GPIBB may modify the phenotype
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Background genes outside the deleted region may
modify the phenotype
The significance of
establishing the diagnosis
Toddlers
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79% significant motor delay
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53% significant expressive delay
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26% significant receptive delay
School-age
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12.7% average IQ (Weschler)
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25.5% low average
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34.5% borderline
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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 schizophrenia
The Immunodeficiency of
Chromosome 22q11.2 Deletion Syndrome
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60-77% of patients have laboratory evidence of
quantitative T cell defects
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Only 0.5-1.0% have absent T cells
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T cell proliferation is usually normal
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2-4% are IgA deficient
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10% have delayed production of IgG
The Role of the Thymus in the
Immunodeficiency
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15-20% of patients have an absent anatomic thymus
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Thymic tissue is found in aberrant locations
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Only 0.5-1.0% of patients have no T cells and
truly have thymic aplasia
80% of patients have thymic
hypoplasia
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Restricts T cell output
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T cells are qualitatively normal
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CD4/CD25 T cells are markedly decreased
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There can be secondary effects on antibody
production
Clinical Immunodeficiency
7% of all ages have significant,
serious infections
9% have autoimmune disease
Older children and adults
continue to get infections
27%
recurrent sinusitis
25%
recurrent otitis media
7%
recurrent bronchitis
4%
recurrent pneumonia
Autoimmunity
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JRA 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
T cell findings
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The mean T cell number is about 50% of normal in
infancy
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The mean T cell number is about 80% of normal in
adulthood
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Why are the adults sick so much?
