Chromosome 22q11 Deletion Syndromes (aka Di George Syndrome, Velocardiofacial Syndrome, Shprintzen Syndrome, Conotruncal Anomaly Face Syndrome, CATCH 22)
Chromosome 22q11.2 Deletion Syndrome History Genetics Features
1968 Di George Conotruncal cardiac anomalies Parathyroid hypoplasia Thymic hypoplasia
1978 Shprintzen Cleft palate – velo Cardiac defects – cardio Similar facial appearance - facio
1991 Cardiac defects Abnormal facies Thymic hypoplasia Cleft palate Scambler Chromosome 22q11.2 deletion Cardiac defects Abnormal facies Thymic hypoplasia Cleft palate Hypocalcaemia 22 deletion
Chromosomes
DNA Structure
Chromosome 22q11.2 Microdeletion
Fluorescent In Situ Hybridisation (FISH) Normal Deleted
Centromere Centromere 22q11.2
Multiplex Ligation-dependent Probe Analysis (MLPA)
Chromosome 22q11.2 Microdeletion
Chromosome 22q11.2 deletion TDR MDGCR CEN HIRA/TUPLE1 NLVCF UFD1L CDC45L CLDN5 PNUTL1 CDCrel-1 GP1bb TBX1 COMT TR ARVCF T10 LAMC1/DGCR6 RANBP1 ZNF74 HCF2 PIK4CA SNAP29 CRKL LZTR1 P2RXL1 SLC7A4 CEN DGCRS PRODH Y191g08 CALS2 DGCR3 IDD STK22A GSCL SLC25A1 DVL1L1 CLTCL1 MDGCR TDR
DNA Structure
22q11.2 Deletion LCR LCR LCR TEL CEN 3Mb 90% 1.5Mb < 5%
Mechanism CEN LCR CEN LCR
Mechanism CEN LCR CEN LCR
Mechanism CEN LCR CEN LCR CEN LCR
Mechanism CEN LCR CEN LCR CEN LCR CEN LCR
Mechanism CEN LCR CEN LCR CEN LCR CEN LCR
Mechanism CEN LCR CEN LCR CEN LCR CEN LCR
Mechanism CEN LCR CEN LCR CEN LCR CEN LCR
Mechanism CEN LCR CEN LCR CEN LCR CEN LCR
Mechanism + + CEN LCR CEN LCR LCR CEN LCR CEN LCR CEN CEN LCR LCR LCR 3Mb Duplication 3Mb Deletion
Mechanism LCR LCR
Mechanism LCR LCR LCR LCR LCR
Mechanism LCR LCR LCR LCR LCR
Mechanism LCR LCR LCR LCR LCR
Mechanism LCR LCR LCR LCR LCR
Mechanism LCR LCR LCR LCR LCR + CEN LCR LCR 3Mb Deletion
Incidence 1:4000 livebirths M = F 5-10% deletions inherited (mat>pat) > 80 associated medical problems
Major Features Characteristic facial appearance 100% Learning difficulties 70 – 90% Congenital heart disease 74% Immune deficiency 77% Palatal problems 69% Low calcium levels 50% Kidney problems 30%
Minor Features Hearing loss (conductive and sensorineural) Feeding problems Laryngotracheoesophageal anomalies Short stature (+/- GH deficiency) Autoimmune disorders Seizures Skeletal problems
Characteristic Facies Long face Hooded eyelids Prominent nasal root Short palpebral fissures Maxillary hypoplasia Bulbous nasal tip Myopathic facies
Characteristic Facies ‘Squared off’ helix Small Overfolding
Chromosome 22q11.2 deletion TDR MDGCR CEN TBX1 HIRA/TUPLE1 NLVCF UFD1L CDC45L CLDN5 PNUTL1 CDCrel-1 GP1bb TBX1 COMT TR ARVCF T10 LAMC1/DGCR6 RANBP1 ZNF74 HCF2 PIK4CA SNAP29 CRKL LZTR1 P2RXL1 SLC7A4 CEN DGCRS PRODH Y191g08 CALS2 DGCR3 IDD STK22A GSCL SLC25A1 DVL1L1 CLTCL1 MDGCR TDR
TBX1 > 20 T-box genes Important for the development of organs of the developing baby during pregnancy Alterations or absence can result in problems especially with the structure of the heart
Cardiac Defects Tetralogy of Fallot 22% Interrupted aortic arch 15% VSD 13% Truncus arteriosus 7% Vascular ring 5% ASD 3% Aortic arch anomaly 4% VSD/ASD 4% Other 4%
Early Development Branchial arch/ Pharyngeal pouch Thymus Parathyroids Branchial arch arteries Face
Immune Function Reduced cells of thymic lineage Improves with age Severe immunodeficiency is extremely rare Impaired T-cell production 67% Impaired T-cell function 19% Humoral defects 23% IgA deficiency 13%
Parathyroid Function Hypocalcaemia 30% Often asymptomatic Improves with age Intermittent recurrences
Chromosome 22q11.2 deletion TDR MDGCR CEN COMT HIRA/TUPLE1 NLVCF UFD1L CDC45L CLDN5 PNUTL1 CDCrel-1 GP1bb TBX1 COMT TR ARVCF T10 LAMC1/DGCR6 RANBP1 ZNF74 HCF2 PIK4CA SNAP29 CRKL LZTR1 P2RXL1 SLC7A4 CEN DGCRS PRODH Y191g08 CALS2 DGCR3 IDD STK22A GSCL SLC25A1 DVL1L1 CLTCL1 MDGCR TDR
Autoimmune Disease Juvenille rheumatoid arthritis Idiopathic thrombocytopenia Hyperthyroidism Hypothyroidism Vitiligo Haemolytic anaemia Coeliac disease
Palate Abnormalities Velopharyngeal Incompetence 27% Submucosal cleft palate 16% Overt cleft palate 11% Bifid uvula 5% Cleft lip +/- palate 2% Infant feeding problems 8%
Growth 40% < 5th centile GH deficiency more common than general population
Kidney Problems Single kidney Echogenic kidneys Multicystic/dysplastic kidneys Small kidneys Horseshoe kidneys Calculi Duplex collecting systems Hydronephrosis Renal Tubular Acidosis
CNS/Development Hypotonia in infancy Seizures (hypocalcaemia) Learning disability Average IQ 75 (range 50-100) Receptive/Expressive language delay Verbal IQ > Performance IQ Psychiatric problems in adulthood are more common than general population