DiGeorge Syndrome Imad Fadl-Elmula 1

Synonyms 2. CATCH 22. 1. Chromosome 22q11 deletion syndrome. Cardiac anomalies. Abnormal facies. Thymic hypoplasia. Cleft palate. Hypocalcemia.

History 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). 3

Incidence 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 Sex Age 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.

Causes Arise from an unbalanced translocation from a balanced parent. Arise as de novo deletions (although 25% of parents of children with supposedly de novo deletions are found to carry the same deletions themselves). Environmental factors, such as maternal alcohol use, retinoid exposure, or uncontrolled diabetes during pregnancy.

Genetic aberrations associated wit FISH testing because a small percentage Of patients with clinical findings of del 22q11 have chromosomal rearrangements involving 22q11, such as a translocation between chromosome 22 and another chromosome. Genetic aberrations associated wit DiGeorge syndrome 7

Pathogenesis 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: The heart. Head and neck. Thymus. Parathyroid.

Genetic base Deletion on the long arm of Ch. 22. The deletion is quite long (2-3 Mb) in 95% of patients.

Genetic mechanisms Normal Deletion DiGeorge 22 22 22 1 1 1 1 1 1 2 2 2 3 3 3 22 22 22 Normal Deletion DiGeorge 1 1 3 2 1 1 2 3 1 1 3 2 1 1 2 3 1 1 3 2 1 1 2 3 22 10

Presentation Reason to suspect chromosome 22q11 deletion syndrome are: 1. Cleft palate. 2. Cardiac anomaly. 3. Developmental delays. 4. Neonatal hypocalcaemia.

Diagnosis tests Cytogenetic analysis may detect del22q11. FISH for suspected submicroscopic deletion. Molecular analysis using DNA probes from the DiGeorge chromosomal region (DGCR). Cytogenetic FISH DNA 13

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 Failure to thrive. Recurrent infection. Swallowing difficulties. Cardiac defects (80-90%). 5. Immunodeficiency (T-cell lineage). 20

Genetic Counseling Parents Offspring 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. 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.

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

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Imaging Studies 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.