Transcript Di George

DiGeorge Syndrome
Imad Fadl-Elmula
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Synonyms
1. Chromosome
22q11 deletion
syndrome.
2. CATCH 22.
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Cardiac anomalies.
Abnormal facies.
Thymic hypoplasia.
Cleft palate.
Hypocalcemia.
 Described by Angelo DiGeorge, in 1965.
 Thymic hypoplasia.
 Congenital cardiac anomalies.
 Kinouchi et al, in 1975 described the
 Conotruncal anomalies face.
 Shprintzen et al, in 1977 described.
 Velocardiofacial syndrome (VCFS).
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Around 1:4.000.
Found in 8% of cleft palates, making
it the most commonly associated
genetic defect.
Constitute 25% of all congenital
cardiac defects.
Incidence
Race
No racial or ethnic predisposition has been
identified.
Sex
Males and females appear to be affected equally.
Age
This is a congenital condition; therefore, the genetic
defect exists at birth.
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Arise from an unbalanced translocation from
a balanced parent.
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Arise as de novo deletions (although 25% of
parents of children with supposedly de novo
deletions are found to carry the same deletions
themselves).
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Environmental factors, such as maternal
alcohol use, retinoid exposure, or uncontrolled
diabetes during pregnancy.
Genetic aberrations associated wit
DiGeorge syndrome
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del22q11
point mutation
Unbalanced
translocation
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The result of this deletion is:
1. Defective migration of the neural crest cells
during the fourth week of embryogenesis.
2. Developmental field defect involving the
third and fourth pharyngeal pouches portions of:
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The heart.
Head and neck.
Thymus.
Parathyroid.
Genetic base
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Deletion on the long arm of Ch. 22.
The deletion is quite long (2-3 Mb)
in 95% of patients.
Genetic mechanisms
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DiGeorge
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Deletion
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Presentation
Reason to suspect chromosome
22q11 deletion syndrome are:
1. Cleft palate.
2. Cardiac anomaly.
3. Developmental delays.
4. Neonatal hypocalcaemia.
Diagnosis tests
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Cytogenetic analysis may detect del22q11.
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FISH for suspected submicroscopic deletion.
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Molecular analysis using DNA probes from
the DiGeorge chromosomal region (DGCR).
Cytogenetic
FISH
DNA
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Subtelemeric probe
Probe for the UFD1 gene
Limitations
 5% of patients present with clinical
symptoms of del 22q11 have normal
cytogenetic studies and negative FISH.
 May be a variant of deletions of DGCR
which may be detectable on a research
basis only.
Consultations
Multidisciplinary follow-up with:
1. Geneticists.
2. Psychiatrists.
3. Immunologist.
4. Otolaryngologist.
5. Pediatric cardiologist.
6. Craniofacial specialist.
7. Pediatric endocrinologist.
8. Pediatric thoracic surgeons.
Mortality and Morbidity
1. Failure to thrive.
2. Recurrent infection.
3. Swallowing difficulties.
4. Cardiac defects (80-90%).
5. Immunodeficiency (T-cell lineage).
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Genetic Counseling
Parents
94% have de novo deletion of 22q11.
 6% have inherited the 22q11 deletion from a
parent; thus, both parents of an individual with
del 22q11 should have FISH testing.
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Offspring
Offspring of individuals with the 22q11 deletion
have a 50% chance of having 22q11 deletion.
 If the parents of an individual with del 22q11 have
normal FISH studies, the recurrence risk is quite
small, assuming a very low, and as yet undefined,
risk of germ line mosaicism.
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Genetic counseling
 Del 22q11 is inherited as a deletion
syndrome.
 About 94% of probands have a de
novo deletion of 22q11.
 6% have inherited the 22q11
deletion from a parent.
 Prenatal testing is possible for
fetuses determined to be at 50%
risk by family history.
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Imaging Studies
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Refer to a pediatric cardiologist for:
ECG.
Chest radiograph (CXR).
Cardiac echocardiography.
Catheterization.
Thymus:
Chest radiographs can demonstrate a decreased thymic silhouette
but are unreliable. MRI is slightly better; however, thymic size is a
poor predictor of immune function.
Head and neck: Magnetic resonance angiography (MRA) or
conventional angiography is necessary before any neck surgery to
identify abnormalities of the internal carotids.
Prenatal Testing
High-risk pregnancies.
amniocentesis at 14-16 weeks' gestation.
 Prenatal testing using FISH analysis is possible for fetuses at 50% risk.
 high-resolution ultrasound examination for high-risk fetus between 18
and 22 weeks' gestation for palatal anomalies and by echocardiography
for cardiac anomalies.
Low-risk pregnancies.
 In some fetuses not known by family history to be at increased risk for
del 22q11, findings of congenital heart disease and/or cleft palate
detected by routine ultrasound examination may suggest the diagnosis
in particular in those patients with conotruncal cardiac anomalies such
as interrupted aortic arch, truncus arteriosus, tetralogy of Fallot, and
ventricular septal defect. Chromosome preparations obtained from fetal
cells can be analyzed using FISH. Establishing the diagnosis of the
22q11 deletion even late in gestation can be useful for perinatal
management.
 Gestational age is expressed as menstrual weeks calculated either from
the first day of the last normal menstrual period or by ultrasound
measurements.
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