282 The 22q11.2 deletion syndromes are a group of conditions with a deletion in the long arm of chromosome 22. They share a characteristic spectrum of congenital cardiac defects with wide ranging noncardiac congenital anomalies (immune defi- ciencies secondary to aplasia or hypoplasia of the thymus, hypocalcemia due to small or absent parathyroid glands, palatal and speech abnormalities, and congnitive difficulties). The occurrence is approximately 1 in 4000 live births.
Historic overviews of the syndromes associated with 22q11.2 deletion:
1. Congenital thymic hypoplasia associated with hypocal- cemia (1959)
2. DiGeorge syndrome (DGS) (1972) a. Congenital thymic hypoplasia b. Hypocalcemia
c. T-cell dysfunction d. Typical facial anomalies e. Typical cardiac anomalies
3. Takao syndrome (conotruncal anomaly face syndrome) (1976)
a. Conotruncal cardiac anomalies b. Typical facial appearance c. Velopharyngeal insufficiency d. Learning disability
4. Velocardiofacial syndrome (VCFS) (Shprintzen syn- drome) (1978)
a. Velophalangeal abnormalities b. Cardiac abnormalities c. Facial abnormalities
d. The birth incidence of 1/1800–1/400, making VCFS the second most common cause of congenital heart disease after Down syndrome
5. DiGeorge syndrome speculatively linked to chromosome 22 (1981)
6. Partial monosomy of chromosome 22 (1982) 7. “CATCH-22 syndrome” (1989): not a preferred term
a. Cardiac disease b. Abnormal facies c. Thymic hypoplasia d. Cleft palate e. Hypocalcemia
f. Associated with a deletion in chromosome-22 8. Cayler craniofacial syndrome associated with
del(22q11.2) (1994)
a. Asymmetric crying facies
b. Phenotypic spectrum expanded to include extracar- diac anomalies
c. Associated with del(22q11.2)
9. Some cases of autosomal dominant Opitz G/BBB syn- drome (1995)
a. Hypertelorism
b. Laryngotracheoesophageal cleft c. Cleft palate
d. Swallowing difficulty e. Genitourinary defects
f. Mental retardation g. Congenital heart defects
GENETICS/BASIC DEFECTS
1. Inheritance
a. De novo deletions in the majority of cases (93%) b. The deletion can be transmitted as an autosomal dom-
inant trait
c. Familial deletions identified in 7% of probands 2. Cause: hemizygous deletion of 22q11.2
a. Deletions inherited from an affected parent (<14%) b. Up to 89% of patients show a typical phenotype of
DiGeorge syndrome
c. Occupy roughly 15% of the patients with congenital heart disease
d. Microdeletions detected by fluorescence in situ hybridization (FISH) probes
3. Molecular/cytogenetic basis
a. DiGeorge critical region (300–600 kbp containing approximately 25 to 30 candidate genes), mapped to 22q11.2
b. Candidate genes
i. Ubiquitin-fusion-degradation-1-like (UFD1L) gene, located in the DiGeorge critical region, which is most consistently deleted in patients with DGS (88%) or VCFS (76%). A significant percentage of cardiac patients with conotruncal cardiac malformations have a 22q11.2 deletion ii. TBX1 gene (belongs to the T-box family of tran-
scription factors): TBX1 haploinsufficiency is likely the major determinant of aortic arch defects in patients with 22q11.2 deletion syndrome 4. Cardiac embryogenesis and branchial arch abnormalities
a. Cardiac structures (derived from the cardiogenic cord in the embryonic mesoderm during very early embryogenesis)
b. Conotruncus (outflow structures of the heart, derived from branchial arches IV and VI, which differentiate into aorta and pulmonary artery respectively).
Malalignment of these structures and incomplete sep- tation give rise to the following diverse congenital heart disease associated with DiGeorge syndrome:
i. Arch abnormalities (interrupted aortic arch, aortic coarctation)
ii. Conotruncal abnormalities (truncus arteriosus, pulmonary artery atresia)
iii. Malalignment of the interventricular septum with the conotruncus (VSD, ASD, Tetralogy of Fallot, DORV)
iv. Valvular or myocardium abnormalities (unusual)
c. Branchial arches are also the embryological origin of the anterior facial structures, thyroid, thymus, and parathyroids. Their abnormalities are the phenotypic hallmark of the DiGeorge syndrome groups
5. Heterogeneous etiology of congenital heart defects a. Deletion 22q11.2 (the 2nd most common chromoso-
mal cause of significant congenital heart disease) b. Aneuploidy (trisomy 21 remains the most common chro-
mosomal cause of significant congenital heart disease) c. Single gene disorder
d. Multifactorial trait
e. Maternal disease such as diabetes mellitus f. Teratogen exposure
CLINICAL FEATURES
1. Marked variability of phenotype
2. Endocrine abnormalities: common in patients with a 22q11.2 deletion
a. Hypocalcemia (30%)
i. Invariably due to hypoparathyroidism, docu- mented by aplasia or hypoplasia of the parathy- roid glands at surgery or autopsy
ii. Symptoms of hypocalcemia most likely manifest in the neonatal period, because maternal calcium supply by fetal circulation is abruptly interrupted at birth and the calcium intake within the first few days of life is usually insufficient
a) Seizures b) Tremors c) Tetany
iii. Other signs of hypocalcemia a) Paresthesias
b) Muscle cramps c) Rigidity
iv. Prevalence of hypocalcemia by phenotypic char- acteristics
a) DiGeorge syndrome (69–72%) b) Velocardiofacial syndrome (13–22%) c) Conotruncal anomaly face syndrome (10%) d) 22q11.2 deletion (49–60%)
v. Autoimmune enteropathies b. Growth disorders
i. Growth hormone deficiency ii. Short stature
c. Thyroid disorders
i. Congenital hypothyroidism
a) Noted in 7% of patients with VCFS b) Noted in 5% of patients with DGS ii. Hyperthyroidism due to Graves disease 3. Immunodeficiency (highly variable) (77%)
a. Primary T-cell dysfunction (decreased production of T cells caused by impaired formation of thymic tissue) (67%) b. Secondary T-cell functional defects (19%)
c. Humoral immune deficits (23%) d. IgA deficiency (13%)
e. Associated autoimmune disease
i. Polyarticular juvenile rheumatoid arthritis, a frequency 150 times that of the general popula- tion rate
ii. Autoimmune hemolytic anemia
iii. Idiopathic thrombocytopenic purpura iv. Autoimmune enteropathies (celiac disease)
v. Vitiligo
4. Cardiovascular malformations (75%, the most common structural anomaly)
a. Conotruncal heart defects
i. Tetralogy of Fallot (the most common heart anomaly)
ii. Pulmonary atresia with ventricular septal defect iii. Truncus arteriosus (25%)
iv. Interrupted aortic arch type B (30%) v. Atrial septal defect
b. Right-sided, cervical, or double aortic arch/aberrant subclavian artery
c. Pulmonary artery abnormalities
i. Discontinuity of the pulmonary arteries ii. Diffuse hypoplasia
iii. Discrete stenosis iv. Defect of arborization
v. Major aortopulmonary collateral arteries d. Infundibulum abnormalities
i. Malaligned ii. Hypoplastic iii. Absent
e. Semilunar valve abnormalities i. Bicuspid
ii. Severely dysplastic iii. insufficient
iv. Stenotic 5. Craniofacial features
a. Palate
i. Velopharyngeal incompetence (27%) ii. Submucous cleft palate (16%) iii. Overt cleft palate (11%)
iv. Bifid uvula (5%) v. Cleft lip/palate (2%)
vi. Suspected velopharyngeal incompetence vii. Normal
b. Ears
i. Low-set ears ii. Overfolded helices iii. Squared off helices
iv. Cupped, microtic, and protuberant ears v. Preauricular pits/tags
vi. Narrow canals vii. Chronic otitis media viii. Conductive hearing loss c. Nose
i. Prominent nasal root ii. Bulbous nasal tip iii. Hypoplastic alae nasae
iv. Nasal dimple/bifid nasal tip v. Chronic sinusitis
d. Throat
i. Stridor caused by a vascular ring ii. Laryngomalacia
iii. Laryngeal webs e. Eyes
i. Tortuous retinal vessels (58%) ii. Posterior embryotoxon (69%)
iii. Hooding of the upper and/or lower lid (47%) iv. Ptosis (9%)
v. Epicanthal folds (3%) vi. Distichiasis (3%) 6. Skeletal abnormalities
a. Vertebral anomalies (19%) i. Coronal clefts ii. Hemivertebrae iii. Butterfly vertebrae
iv. Scoliosis
b. Rib anomalies including supernumerary ribs (19%) c. Hypoplastic scapulae
d. Upper limb anomalies including pre/postaxial poly- dactyly (6%)
e. Lower limb anomalies (15%) i. Postaxial polydactyly ii. Club foot
iii. Overfolded toes iv. 2, 3 syndactyly f. Craniosynostosis 7. Renal abnormalities (37%)
a. Calculi b. Single kidney c. Small kidneys d. Echogenic kidney e. Horseshoe kidney
f. Bladder wall thickening g. Multicystic dysplastic kidney h. Duplicated collecting system
i. Renal tubular acidosis 8. Neuromuscular development
a. Developmental delays b. Hypotonia
c. Feeding disorders 9. CNS manifestations
a. Mental retardation
b. Seizures (with or without hypocalcemia) c. Asymmetric crying facies
d. Ataxia
e. Cerebellar hypoplasia f. Enlarged Sylvian fissures g. Pituitary abnormalities h. Polymicrogyria
i. Mega cisterna magna j. Neural tube defects 10. Behavior phenotype
a. Attention deficit/hyperactivity disorder b. Autism spectrum disorder
c. Nonverbal learning disability d. Language deficits
e. Social-emotional concern f. Schizophrenia
11. Adult phenotype
a. Lower rates of congenital heart defects
b. Higher rates of palate anomalies, learning disabili- ties/mental retardation, and psychiatric disorders
DIAGNOSTIC INVESTIGATIONS
1. Cytogenetic studies
a. High resolution chromosome analysis to detect del(22q11.2)
b. Fluorescence in situ hybridization (FISH) for the chromosome region 22q11 to detect submicroscopic deletion
2. Molecular analysis: polymerase chain reaction (PCR)- based assays for detection of deletions of 22q11.2 3. Echocardiography for cardiovascular anomalies 4. Chest X-ray
a. Presence of a heart defect b. Absence of thymus shadow
5. Renal ultrasound examination at irregular intervals for the development of renal stones
6. MRI of the brain: detects high prevalence of brain abnor- malities that are most likely neurodevelopmental and may partially explain the high prevalence of learning disability and psychiatric disorder
a. Cerebellar atrophy
b. Agenesis of the corpus callosum c. White matter hyperintensities d. Cavum septum pellucidum e. Cerebral atrophy
f. Widespread differences in white matter bilaterally g. Regional specific differences in grey matter in the left
cerebellum, insula, and frontal and right temporal lobes
7. Blood calcium levels 8. Immunological studies
a. Impaired formation of thymic tissue b. Decreased production of T cells
c. Secondary T-cell functional defects, humoral deficits, or both
GENETIC COUNSELING
1. Recurrence risk a. Patient’s sib
i. Low recurrence risk, provided parents are phe- notypically normal and neither one is a carrier of del(22q11.2)
ii. High recurrence risk in case of a parent with germline mosaicism for a microdeletion syn- drome
b. Patient’s offspring: 50% affected 2. Prenatal diagnosis
a. Indications for prenatal testing for the 22q11.2 deletion i. A previous child with a 22q11.2 deletion or
DiGeorge/velocardiofacial syndrome ii. An affected parent with a 22q11.2 deletion iii. In utero detection of a fetus with a conotruncal
cardiac defect
b. Prenatal ultrasonography and fetal echocardiography for a fetus at risk for the 22q11.2 deletion
i. Conotruncal cardiac defect with associated anomalies
ii. Conotruncal cardiac defect without associated anomalies
iii. Aplasia or hypoplasia of the fetal thymus in the presence of conotruncal cardiac anomalies: very specific for deletion 22q11.2
iv. Cardiac lesions with the deletion a) Interrupted aortic arch (50-80%) b) Truncus arteriosus (35%)
c) Tetralogy of Fallot (15%)
d) Rare in double outlet right ventricle and transposition of the great vessels
v. Sensitivity of different sonographic features allowing discrimination of a subgroup likely to be associated with microdeletion 22q11.2 a) Nuchal translucency (12%)
b) Polyhydramnios (20%) c) IUGR (8%)
d) Extra-cardiac anomalies (36%)
c. Prenatal diagnosis of 21q11.2 deletion by amniocen- tesis or CVS
i. Fluorescence in situ hybridization (FISH) analy- sis with probes from the DiGeorge chromosomal region (DGCR)
ii. Preimplantation genetic diagnosis by FISH reported in an at-risk mother with a 22q11.2 deletion
iii. Occasional detection of an unbalanced transloca- tion or an interstitial deletion of 22q11.2 by cyto- genetic analysis
iv. Molecular genetic analysis
a) Demonstrate failure to inherit a parental allele or hemizygosity in the deleted region b) Restriction fragment length polymorphism
(RFLP) analysis and quantitative hybridiza- tion
c) PCR assays using short tandem repeat poly- morphisms (STRs) within the DGCR v. Limitations of prenatal testing for the 22q11.2
deletion
a) DGS/VCFS, a heterogeneous disorder in which 10–15% of patients do not have the deletion. Therefore, FISH analysis is of lim- ited value in couples who have had a previ- ously affected child without a deletion b) Atypical deletions of 22q11.2, unbalanced
chromosomal translocations, deletions involving other chromosomes have not been detected by FISH using commercially avail- able probes
c) Consider other causes of congenital heart defects such as aneuploidy, single gene defects, maternal diseases such as diabetes, and exposure to teratogens
d) Inability to predict accurately the phenotype prenatally
3. Management a. Medical care
i. Manage the feeding problems
a) Modification of spoon placement when eating b) Treat gastroesophageal reflux with acid blockade, prokinetic agents, postural therapy, and medication to treat gastrointestinal dys- motility and to facilitate bowel evacuation ii. Hypocalcemia
a) Asymptomatic hypocalcemia: treat with oral calcium supplements
b) Severe symptomatic hypocalcemia: treat with prompt administration of parenteral calcium
c) Goal of treatment: maintain calcium in the low-normal range (8–9 mg/dL) to minimize hypercalcinuria
iii. Thyroid hormone for hypothyroidism
iv. Growth hormone therapy in growth hormone deficient children with a 22q11.2: associated with sustained improvements in height and growth velocity
v. Early intervention programs including speech therapy for developmental delay
vi. Management of psychiatric disorder b. Surgical care
i. Congenital heart diseases a) Palliative operation b) Corrective operation ii. Velopharyngeal dysfunction
a) Pharyngoplasty
b) Plastic surgery of cleft lip/palate iii. Surgery
a) Gastrointestinal anomalies b) Renal anomalies
c) Musculoskeletal anomalies
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Fig. 1. An infant (A) with DiGeorge syndrome. The deletion of 22q11.2 was shown by partial karyotype with ideogram (B) and FISH with DiGeorge cosmid probe (C). The FISH in D is a control.
Fig. 2. A newborn infant with conotruncal anomaly facies syndrome.
The radiograph shows a conotruncal heart anomaly and absent thymus.
Fig. 3. A 4-year-6-month old girl with tetralogy of Fallot, growth retardation, developmental delay, and del(22q11.2).
Fig. 4. A 16-year-old boy with tetralogy of Fallot, inguinal hernia, developmental delay, bilateral conductive hearing loss (late onset at 15 years of age), and del(22q11.2) shown in the next figure.
Fig. 5. FISH of the patient in the Fig. 4. showing two green signals (a probe for 22q13 ARSA) and only one red signal (a probe for 22q11.2;
TUPLE1) demonstrating del(22q11.2).
Fig. 6. A mother and daughter both have deletion 22q11.2.
