Imad Fadl-Elmula

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DiGeorge Syndrome

Synonyms 1. Chromosome 1. Chromosome

22q11 deletion 22q11 deletion syndrome.syndrome.

2.2. CCAATTCCHH 22. 22. CCardiac anomalies. ardiac anomalies. AAbnormal facies.bnormal facies. TThymic hypoplasia. hymic hypoplasia. CCleft palate. left palate. HHypocalcemia.ypocalcemia.

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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).

Around 1:4.000. Around 1:4.000. Found in 8% of cleft palates, makingFound in 8% of cleft palates, making

it the most commonly associated it the most commonly associated

genetic defect. genetic defect. Constitute 25% of all congenital Constitute 25% of all congenital

cardiac defects. cardiac defects.

Incidence RaceRaceNo racial or ethnic predisposition has been No racial or ethnic predisposition has been identified. identified.

SexSex Males and females appear to be affected equally.Males and females appear to be affected equally.

AgeAgeThis is a congenital condition; therefore, the geneticThis is a congenital condition; therefore, the geneticdefect exists at birth.defect exists at birth.

Arise from an Arise from an unbalanced translocationunbalanced translocation from from

a balanced parent. a balanced parent.

Arise as Arise as de novode novo deletions deletions (although 25% of (although 25% of

parents of children with supposedly parents of children with supposedly de novode novo

deletions are found to carry the same deletions deletions are found to carry the same deletions

themselves). themselves).

Environmental factors, such as Environmental factors, such as maternal maternal

alcoholalcohol use, use, retinoid exposureretinoid exposure, or , or uncontrolled uncontrolled

diabetes diabetes during pregnancy.during pregnancy.

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0%

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90%

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del22q11 point mutation Unbalancedtranslocation

Genetic aberrations associated wit Genetic aberrations associated wit DiGeorge syndromeDiGeorge syndrome

The result of this deletion is:The result of this deletion is:1. 1. Defective migrationDefective migration of the neural crest cells of the neural crest cells

during the fourth week of embryogenesis.during the fourth week of embryogenesis.

2. 2. Developmental field defectDevelopmental field defect involving the involving the

third and fourth pharyngeal pouches portions of: third and fourth pharyngeal pouches portions of: The heart. The heart. Head and neck. Head and neck. Thymus. Thymus. Parathyroid.Parathyroid.

Genetic base

Deletion on the long arm of Ch. 22. Deletion on the long arm of Ch. 22. The deletion is quite long (2-3 Mb) The deletion is quite long (2-3 Mb)

in 95% of patients.in 95% of patients.

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Genetic mechanisms

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Normal Deletion DiGeorge

PresentationPresentationReason to suspect chromosomeReason to suspect chromosome

22q11 deletion syndrome are:22q11 deletion syndrome are:

1. 1. Cleft palate. Cleft palate.

2. Cardiac anomaly.2. Cardiac anomaly.

3. Developmental delays.3. Developmental delays.

4. Neonatal hypocalcaemia. 4. Neonatal hypocalcaemia.

Cytogenetic analysis may detect del22q11. Cytogenetic analysis may detect del22q11.

FISH for suspected submicroscopic deletion.FISH for suspected submicroscopic deletion.

Molecular analysis using DNA probes from Molecular analysis using DNA probes from

the DiGeorge chromosomal region (DGCR). the DiGeorge chromosomal region (DGCR).

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Diagnosis tests

FISHCytogenetic DNA

Probe for the UFD1 gene

Subtelemeric probe

Limitations

5% of patients present with clinical5% of patients present with clinical

symptoms of del 22q11 have normalsymptoms of del 22q11 have normal

cytogenetic studies and negative FISH. cytogenetic studies and negative FISH.

May be a variant of deletions of DGCRMay be a variant of deletions of DGCR

which may be detectable on a researchwhich may be detectable on a research

basis only.basis only.

ConsultationsMultidisciplinary follow-up with:Multidisciplinary follow-up with:

1. Geneticists.1. Geneticists.

2. Psychiatrists. 2. Psychiatrists.

3. Immunologist. 3. Immunologist.

4. Otolaryngologist. 4. Otolaryngologist.

5. Pediatric cardiologist.5. Pediatric cardiologist.

6. Craniofacial specialist.6. Craniofacial specialist.

7. Pediatric endocrinologist. 7. Pediatric endocrinologist.

8. Pediatric thoracic surgeons. 8. Pediatric thoracic surgeons.

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Mortality and Morbidity

1. Failure to thrive.

2. Recurrent infection.

3. Swallowing difficulties.

4. Cardiac defects (80-90%).

5. Immunodeficiency (T-cell lineage).

Genetic CounselingParentsParents     94% have 94% have de novode novo deletion of 22q11. deletion of 22q11. 6% have inherited the 22q11 deletion from a 6% have inherited the 22q11 deletion from a

parent; thus, parent; thus, both parentsboth parents of an individual with of an individual with del 22q11 del 22q11 should have FISH testingshould have FISH testing..

OffspringOffspring     Offspring of individuals with the 22q11 deletion Offspring of individuals with the 22q11 deletion

have a have a 50%50% chance of having 22q11 deletion. chance of having 22q11 deletion. If the parents of an individual with del 22q11 have If the parents of an individual with del 22q11 have

normal FISH studies, the recurrence risk is quite normal FISH studies, the recurrence risk is quite small, assuming a very low, and as yet undefined, small, assuming a very low, and as yet undefined, risk of risk of germ line mosaicismgerm line mosaicism..

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. 22

Imaging StudiesRefer to a pediatric cardiologist for: Refer to a pediatric cardiologist for: ECG.ECG.Chest radiograph (CXR). Chest radiograph (CXR). Cardiac echocardiography.Cardiac echocardiography.Catheterization.Catheterization.Thymus: Thymus:

Chest radiographs can demonstrate a decreased thymic silhouette Chest radiographs can demonstrate a decreased thymic silhouette but are unreliable. MRI is slightly better; however, thymic size is a but are unreliable. MRI is slightly better; however, thymic size is a poor predictor of immune function.poor predictor of immune function.

Head and neck: Magnetic resonance angiography (MRA) or Head and neck: Magnetic resonance angiography (MRA) or conventional angiography is necessary before any neck surgery to conventional angiography is necessary before any neck surgery to identify abnormalities of the internal carotids.identify abnormalities of the internal carotids.

Prenatal Testing

High-risk pregnancies.High-risk pregnancies.     amniocentesis at 14-16 weeks' gestation. amniocentesis at 14-16 weeks' gestation. Prenatal testing using FISH analysis is possible for fetuses at 50% risk. Prenatal testing using FISH analysis is possible for fetuses at 50% risk. high-resolution ultrasound examination for high-risk fetus between 18 high-resolution ultrasound examination for high-risk fetus between 18

and 22 weeks' gestation for palatal anomalies and by echocardiography and 22 weeks' gestation for palatal anomalies and by echocardiography for cardiac anomalies. for cardiac anomalies.

Low-risk pregnancies.Low-risk pregnancies. In some fetuses not known by family history to be at increased risk for 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 del 22q11, findings of congenital heart disease and/or cleft palate detected by routine ultrasound examination may suggest the diagnosis detected by routine ultrasound examination may suggest the diagnosis in particular in those patients with conotruncal cardiac anomalies such in particular in those patients with conotruncal cardiac anomalies such as interrupted aortic arch, truncus arteriosus, tetralogy of Fallot, and as interrupted aortic arch, truncus arteriosus, tetralogy of Fallot, and ventricular septal defect. Chromosome preparations obtained from fetal ventricular septal defect. Chromosome preparations obtained from fetal cells can be analyzed using FISH. Establishing the diagnosis of the cells can be analyzed using FISH. Establishing the diagnosis of the 22q11 deletion even late in gestation can be useful for perinatal 22q11 deletion even late in gestation can be useful for perinatal management. management.

Gestational age is expressed as menstrual weeks calculated either from Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound the first day of the last normal menstrual period or by ultrasound measurements. measurements.