DiagnosisClinical Diagnosis22q11.2 deletion syndrome (22q11.2DS) is suspected in individuals with a range of findings including:Congenital heart disease (particularly conotruncal defects)Palatal abnormalities (especially velopharyngeal insufficiency [VPI])HypocalcemiaImmune deficiencyLearning difficulties (especially a non-verbal learning disability, with a greater than ten-point split between the verbal intelligence quotient [VIQ] and the performance intelligence quotient [PIQ]: VIQ>PIQ)Characteristic facial featuresLess frequently seen functional differences include:Severe dysphagiaGrowth hormone deficiencyAutoimmune disease (thrombocytopenia, juvenile rheumatoid arthritis, Grave's disease, vitiligo, neutropenia, hemolytic anemia)Hearing loss (sensorineural and conductive)Psychiatric illnessAutismOther important structural anomalies contributing to diagnosis:Skeletal findings: pre- and postaxial polydactyly of the hands, postaxial polydactyly of the feet, supernumerary ribs, hemivertebrae, and craniosynostosis (coronal, lambdoidal)Genitourinary tract anomalies: renal agenesis, hydronephrosis, multicystic/dysplastic kidneys, duplicated kidney, horseshoe kidney, absent uterus, hypospadias, inguinal hernia, and cryptorchidismLaryngotracheoesophageal abnormalities: vascular ring, laryngeal web, laryngotracheal malacia, and subglottic stenosisOphthalmologic findings: tortuous retinal vessels, ptosis, posterior embryotoxon, sclerocornea, coloboma, cataract, anophthalmia, and strabismusCNS abnormalities: cerebellar atrophy, polymicrogyria, enlarged sylvian fissures, neural tube defects, tethered cord, unprovoked seizures, and asymmetric crying faciesGastrointestinal anomalies: anteriorly placed/imperforate anus, esophageal atresia, jejunal atresia, accessory spleens, umbilical hernia, diaphragmatic hernia, intestinal malrotation, and Hirschsprung diseasePreauricular tags and/or pitsNeoplasms:Hepatoblastoma, renal cell carcinoma, Wilms tumor, and neuroblastomaTesting Cytogenetic testing. The syndrome most often results from a three million-base pair (Mb) deletion on the chromosomal region 22q11.2 that is flanked by low copy number repeats (LCRs), labeled A-D (see Molecular Genetics ). The deletion is caused by a non-allelic meiotic recombination event during spermatogenesis or oogenesis (see Figure 1).FigureFigure 1. 22q11.2DS is thought to result from non-allelic homologous recombination due to the presence of segmental duplications (SD) which flank the region and lead to aberrant interchromosomal exchanges. These SDs, referred to as A, B, C, and D here, (more...)The most common deletion, present in 85% of individuals, extends from A to D and includes TBX1 (Figure 2), a gene deemed responsible for typically associated features, in particular conotruncal cardiac anomalies. The remaining 15% of affected individuals have atypical “nested” deletions. To date, atypical deletions include A-B, B-D, or C-D deletions. These latter deletions are being identified using higher-resolution techniques including chromosomal microarray (CMA) or multiplex ligation-dependent probe amplification (MLPA). Of the atypical deletions, 34% do not include the A-B region. The commercially available fluorescence in situ hybridization (FISH) probes, N25 and TUPLE, along with TBX1, are located within A-B; therefore, the atypical deletions that do not include A-B are not identifiable using the commercially available FISH probes (Figure 2). FigureFigure 2. The majority of affected individuals (85%) have a large (3-Mb) deletion encompassing approximately 40 genes; a subset of individuals have a smaller atypical or ‘‘nested’’ deletion.
Reprinted (more...)A small percentage (<1%) of individuals with clinical findings of 22q11.2DS have chromosomal rearrangements involving 22q11.2, such as a translocation between chromosome 22 and another autosome. Molecular Genetic TestingGene. Deletion of genes within the DiGeorge chromosomal region (DGCR) is the only genetic abnormality known to be associated with 22q11.2DS [Driscoll et al 1992, Wilson et al 1992, Desmaze et al 1993, Driscoll et al 1993]. Clinical testingFISH. The two probes commercially available for 22q11.2 FISH analysis are TUPLE1 and N25. The detection rate of FISH analysis using either probe is thought to be equivalent. However, FISH with either probe is not sensitive enough to detect smaller deletions (<40 kb) within 22q11.2. Most deletions are now being identified by the use of CMA or MLPA, either of which will detect the smaller deletions missed by FISH. These studies will not detect mutations in any of the genes within the deleted region, however.Note: The probe ARSA, which hybridizes to chromosomal locus 22q13.3, may also be used in testing, but only for control purposes.Duplication/deletion analysis is testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA. The 2.54-Mb A-D common deletion can be detected by any molecular method that determines the copy number of genomic sequences within the deleted region (see Table 1, footnote 2). Either whole-genome or targeted approaches can be applied (see Molecular Genetics for details of the deleted region):Chromosomal microarray (CMA) technologies are the most appropriate test to identify the 22q11.2 deletion in a proband because the phenotype is nonspecific and often performed as part of the evaluation of developmental delay or intellectual disability. CMA can detect many chromosomal abnormalities that may be causal. CMA analysis using arrays of BACs, oligonucleotides, or SNPs (single-nucleotide polymorphisms) can detect the 2.54-Mb deletion in a proband. The ability to size the deletion depends on the type of microarray used and the density of probes in the 22q11.2 region.Targeted deletion analysis. Targeted methods including for example, FISH and MLPA, can be used for rapid diagnosis if the syndrome is suspected clinically or for confirmation of the deletion after CMA analysis. Targeted approaches can also be used for evaluating relatives of the proband for presence of the deletion. Note: Whether or not it is possible to size the deletion depends on the number and distribution of probes in the 22q11.2 region. The deletion cannot be sized using a single FISH probe (as is customary in commercial laboratories). Table 1. Summary of Molecular Genetic Testing Used in the 22q11.2 Deletion SyndromeView in own windowChromosomal RegionTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityDGCRDeletion / duplication analysis 2: FISHDeletion of 22q11.2 DGCR~95%ClinicalDeletion / duplication analysis 2: chromosomal microarray or targeted analysisThe common A-D deletion 85%Atypical / nested deletions15%1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.Interpretation of test resultsDeletion analysis. Depending on the type of initial testing, validation of the deletion by an independent method could be warranted. If high-density genomic microarray platforms have been used for the identification of the deletion, validation of the deletion may not be necessary, as it is unlikely that more than 50-100 adjacent targets show an abnormal copy number by chance.Testing StrategyTo establish the diagnosis in a proband requires detection of a deletion on the q arm of chromosome 22, within the 11.2 region. Most deletions are detected by chromosomal microarray (CMA) analysis performed as part of the evaluation of developmental delay or intellectual disability. If the 22q11.2 microdeletion is suspected based on the clinical features, a targeted technique (e.g., FISH, MLPA) can be employed for rapid diagnosis; however, both CMA and MLPA have a higher sensitivity for detection of atypical deletions and will allow for determination of the size of the deletion.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for pregnancies known to be at risk require prior identification of the 22q11.2 deletion in the proband and/or demonstration that a parent carries a balanced or unbalanced chromosomal rearrangement involving 22q11.2.Genetically Related (Allelic) DisordersThe 22q11.2DS is associated with the phenotypes described in this GeneReview. No other phenotypes are associated with deletion of 22q11.2. See Nomenclature for a discussion of previous clinically defined syndromes that have now all been found to be due to the 22q11.2DS.}

Natural HistoryFindings in 250 individuals (48% male; 52% female) with 22q11.2 deletion syndrome (DS) are summarized below [McDonald-McGinn et al 1999]. In unpublished data on an additional 750 individuals evaluated through a large multidisciplinary 22q11 deletion syndrome center, the percentages for the following findings remain the same [Author, unpublished data (2012)]. Heart. Congenital heart defects are present in 74% of affected individuals and are the major cause of mortality (>90% of all deaths) in this diagnosis [McDonald-McGinn et al 2001]. The most frequent anomalies are conotruncal defects of the outflow tract, as shown in Table 2. Of note, a subset of affected individuals are found to have dilated aortic root [John et al 2009]. The natural history of affected individuals who have aortic root dilatation is unknown but under investigation. Table 2. Cardiac Findings in 222 Individuals with 22q11.2 Deletion SyndromeView in own windowCardiac Finding % of Affected IndividualsTetralogy of Fallot (TOF)20%Interrupted aortic arch (IAA)13%Ventricular septal defect (VSD)14%Truncus arteriosus (TA)6%Vascular ring5.5%Atrial septal defect3.5%VSD; ASD4%Other ^{110%Normal24%McDonald-McGinn et al [2010b]1. Hypoplastic left heart syndrome; pulmonary valve stenosis; double outlet right ventricle; bicuspid aortic valve; heterotaxy/A-V canal, transposition of the great vessels; isolated right pulmonary artery atresia; aortic root dilatation; aberrant subclavian arteriesPalate. Sixty-nine percent of individuals with deletion 22q11.2 have a palatal abnormality (Table 3). The most common, velopharyngeal incompetence (VPI), may be a structural problem (short palate), a functional problem (hypotonia of the velophayrngeal musculature), or a combination of the two. Submucosal cleft palate and/or a bifid uvula are also fairly prevalent, whereas overt cleft palate and cleft lip/palate are less frequently observed. Often children initially diagnosed with deletion 22q11.2 because of a cardiac defect are subsequently found to have unrecognized but clinically significant VPI [McDonald-McGinn et al 1997a]. It is important to note that the reported incidence of palatal abnormalities varies widely, depending on numerous factors including the reporting technique, the diligence with which the diagnosis is sought, the age at which the individual is evaluated, and the inherent ascertainment bias of any single center [Kirschner 2005]. About 17% of persons have no palatal involvement.Table 3. Palatal Findings with 22q11.2 Deletion SyndromeView in own windowPalatal Finding % of Affected IndividualsVelopharyngeal incompetence (VPI)27%Submucosal cleft palate (SMCP)16%Overt cleft palate11%Bifid uvula5%Cleft lip/cleft lip and palate 12%Infantile VPI 2 8%Need follow-up/too young to assess adequately 314%Normal17%From McDonald-McGinn et al [1999]1. Either unilateral or bilateral2. ‘Infantile VPI’ or occult submucosal cleft palate diagnosed by history (nasal regurgitation and frequent otitis media), physical examination, or nasendoscopy (to detect incomplete closure of the velopharyngeal mechanism during crying and swallowing) in children too young to provide an adequate speech sample for definitive diagnosis3. No overt abnormality, but children too young to provide an adequate speech sampleFeeding. About 36% of children have significant feeding difficulties, often severe dysphagia requiring nasogastric tube feedings and/or gastrostomy tube placement. Feeding difficulties are independent of cardiac defects and palatal anomalies. Further evaluation of such children often reveals a preponderance of nasopharyngeal reflux, prominence of the cricopharyngeal muscle, abnormal cricopharyngeal closure, and/or diverticulum. Thus, the underlying feeding problem in many children appears to be dysmotility in the pharyngoesophageal area, which is derived from the third and fourth pharyngeal pouches. Abnormal swallowing, with or without aspiration, may be erroneously attributed to palatal or cardiac abnormalities, rather than to dysphagia related to dysmotility and abnormality of the orophayrngeal and cricoesophageal swallowing phase. Aspiration should be considered a possible cause for respiratory compromise or recurrent pulmonary infections and reactive airway disease [Eicher et al 2000]. Constipation is a chronic feature in the majority of individuals. In addition, structural anomalies such as imperforate anus, intestinal malrotation, intestinal non-rotation, congenital diaphragmatic hernia, esophageal atresia, tracheoesophageal fistula, Hirschsprung disease, and feeding difficulties secondary to a vascular ring have all been reported and can contribute to significant feeding and swallowing problems and in some instances to constipation [Digilio et al 1999; Kilic et al 2003; D McDonald-McGinn, unpublished data (2010)]. Immune function. Immunodeficiency occurs as a result of thymic hypoplasia. Impaired T-cell production is the primary defect because the role of the thymus is to support the maturation of T cells. T-cell functional defects and antibody defects are less common and are secondary to the T-cell production abnormality [Sullivan 2004].Compared to control individuals without the deletion, newborns with the 22q11.2DS have significantly fewer cells of thymic lineage; however, improvement in T-cell production occurs over time. In one study, children with the most significant deficiencies in T-cell production improved most in the first year of life [Sullivan et al 1999]. Thus, individuals with slight decreases in T-cell numbers typically have normal defenses against pathogens [Sullivan 2004].In a study of immune function in 60 affected children over age six months, 77% were considered to be immunodeficient regardless of their clinical presentation. Sixty-seven percent had impaired T-cell production, 19% had impaired T-cell function, 23% had humoral defects, and 13% had IgA deficiency [Smith et al 1998, Sullivan et al 1998, Sullivan 2004].Additional phenotypic features associated with 22q11.2DS such as aspiration pneumonia, palatal dysfunction, and gastroesophageal reflux can all contribute to recurrent infection, especially in persons with congenital heart disease. Furthermore, dysphagia can lead to poor nutrition which further impairs cellular immunity. Thus, older children and adults do in fact continue to have infections, including 25%-33% with recurrent sinusitis or otitis media and 4%-7% with recurrent lower respiratory infections [Jawad et al 2001]. However, despite these issues, very few school-aged children require active management for their immunodeficiency [Sullivan 2004]. Immunoglobulin levels are usually normal in individuals with the 22q11.2 deletion syndrome, although subtle immunoglobulin abnormalities may be noted. Hypogammaglobulinemia present in the first year of life usually resolves and hypergammaglobulinemia may occur after age five. Although the majority of affected individuals have normal antibody function and antibody avidity, some have functional antibody defects. Those with recurrent sinopulmonary infections frequently have immunoglobulin abnormalities, in particular impaired antibody responses to pneumococcal polysaccharide vaccine [Gennery et al 2002, Sullivan 2004].Autoimmune disease in 22q11.2DS is common. However, it does not correlate with severe T-cell dysfunction and it includes a range of pediatric diseases. Autoimmune cytopenias and juvenile rheumatoid arthritis (JRA) appear to be the most common and may occur 20-100 times more frequently than in the general population. JRA is often polyarticular and may be difficult to manage. Autoimmune thyroid disease and other autoimmune abnormalities have also been described and it is likely that the T-cell defect acts synergistically with other predisposing factors (e.g., major histocompatibility complexes) to cause autoimmune disease. Selective IgA deficiency may occur in up to 10% of individuals with a deletion, and seems to be particularly common in those with autoimmune problems including JRA [Kawame et al 2001, Sullivan 2004].Parathyroid function. Hypocalcemia is present in 17%-60% of persons with 22q11.2DS and is typically most serious in the neonatal period. Calcium homeostasis typically normalizes with age, although recurrence of hypocalcemia in later childhood and adulthood has been reported during illness and/or puberty or during pregnancy. In some instances, children receiving ongoing care for infantile hypocalcemia may not be diagnosed with 22q11.2DS until school age, while at least one otherwise asymptomatic adult came to attention following onset of hypoparathroidism in the fourth decade [Kapadia et al 2008; M Eagen, personal communication]. Craniofacial. Craniofacial findings include auricular abnormalities, nasal abnormalities, ‘hooded eyelids,’ ocular hypertelorism, cleft lip and palate, asymmetric crying facies, and craniosynostosis [Gripp et al 1997, McDonald-McGinn et al 2001]. However, the presence of these features as well as other facial findings, such as a long face and malar flatness, is variable. In fact, some individuals offer no clues to their underlying diagnosis based on their facial features, especially persons of African-American heritage [McDonald-McGinn et al 1996, McDonald-McGinn et al 2005].Eyes. A prospective evaluation for ocular abnormalities in 33 individuals revealed hooding of the upper lids (41%), ptosis (9%), hooding of the lower lids (6%), epicanthal folds (3%), and distichiasis (abnormal growth of lashes from the orifices of the meibomian glands) (3%). Other findings included posterior embryotoxon (69%), isolated corneal nerves (3%), sclerocornea (3%), deep iris crypts (10%), tortuous retinal vessels (58%), small optic nerves (7%), and tilted discs (3%). Strabismus was observed in 13% and amblyopia in 6%. While posterior embryotoxon was observed in 12%-32% of controls, the incidence in individuals with 22q11.2DS was almost as high as that seen in Alagille syndrome (89%) [Krantz et al 1997]. The incidence of astigmatism, myopia, and hyperopia was comparable to that in the general population. A small number of persons have cataracts and colobomas [Forbes et al 2007]; anophthalmia has recently been observed in a very small subset of individuals [unpublished data].Ear, nose, and throat. Ear abnormalities include overfolded or squared off helices; cupped, microtic, and protuberant ears; preauricular pits or tags, and narrow external auditory meati. A prominent nasal root, bulbous nasal tip, hypoplastic alae nasae, and a nasal dimple/bifid nasal tip are common [Gripp et al 1997]. Stridor resulting from vascular ring, laryngomalacia, and laryngeal web, laryngeal atresia, and subglottic stenosis can occur. Chronic otitis media and chronic sinusitis are common. Sensorineural and conductive hearing loss have both been reported. Incidents of trachea-esophageal fistula and esophageal atresia have also been observed [M Digilio, unpublished data (1999)].Central nervous system. Although the majority of individuals with 22q11.2DS have a history of hypotonia in infancy and learning disabilities [Moss et al 1995], specific neurologic manifestations are uncommon. Microcephaly has been reported in nearly 50% of affected individuals in some studies [Kobrynski & Sullivan 2007] but in the authors’ experience was seen in only 18% of 129 individuals with significant CNS findings [Author, unpublished observation]. Seizures are seen in some individuals and are most often, but not always, associated with hypocalcemia. In one study, 7% (27/383) of persons with 22q11.2DS had unprovoked seizures [Kao et al 2004].Several individuals have asymmetric crying facies [Cayler 1969, Levin et al 1982, Silengo et al 1986, Sanklecha et al 1992, Giannotti et al 1994], which may be an independent clue to the diagnosis.Rarely, ataxia and atrophy of the cerebellum are observed [Lynch et al 1995].Additional CNS abnormalities include multicystic white matter lesions of unknown significance and perisylvian dysplasia [Bingham et al 1997], hypoplastic pituitary gland, and polymicrogyria (see Polymicrogyria Overview).Recent investigations utilizing functional MRI scans revealed significantly reduced posterior brain volumes relative to age- and sex-matched controls with more significant white matter loss in the left occipital and left parietal regions than in the frontal lobes [Barnea-Goraly et al 2003, Bearden et al 2004, Bish et al 2004, Kates et al 2004]. Many of these changes in brain structure can be postulated to relate to the specific cognitive deficits exhibited in the area of working memory, executive function, visuospatial skill, language, and math performance.Overall, the pattern of CNS abnormalities is broad and overlaps with that seen in some cases of Opitz G/BBB syndrome [Neri et al 1987, Guion-Almeida & Richieri-Costa 1992, MacDonald et al 1993].Psychosocial development and cognitive function. In general, young children with 22q11.2DS have delays in motor milestones (walking at 18 months mean age), delay in emergence of language (many are nonverbal at age 2-3 years), and autism/autistic spectrum disorders in approximately 20% [Fine et al 2005].Specifically, in a study of 28 toddlers assessed with standardized tests, mental development was average in 21%, mildly delayed in 32%, and significantly delayed in 46%; in motor development, 8% were average, 13% were mildly delayed, and 79% were significantly delayed.In a group of 12 preschoolers assessed using the WPPSI-R, the full scale IQ was 78±11, the mean performance IQ was 78±14, and the mean verbal IQ was 82±15. In total language, 16% were average, 44% were mildly delayed, and 40% were significantly delayed [Solot et al 1998].In a group of 80 school-aged children assessed with the age-appropriate Weschler IQ test, the mean IQ score was 76; 18% attained full scale IQ scores in the average range, 20% in the low-average range, 32% in the borderline range, and 30% in the intellectually disabled range.Older individuals with 22q11.2DS generally have an atypical neuropsychologic profile across multiple domains, the most striking aspect of which is a significantly higher verbal IQ score than performance IQ score. Moss et al [1995] observed a mean split between the verbal IQ and performance IQ in 66% of 80 school-age children consistent with a nonverbal learning disability that is rare in the general population [Wang et al 1998]. Because the full scale IQ score alone does not accurately represent the abilities of many individuals with 22q11.2DS, verbal and performance IQ scores need to be considered separately. In addition, affected individuals exhibit relative strengths in the areas of rote verbal learning and memory, reading decoding, and spelling. Deficits are found in the areas of nonverbal processing, visual-spatial skills, complex verbal memory, attention, working memory, visual-spatial memory, and mathematics. This evidence of stronger verbal than visual memory skills and stronger reading than math skills also supports the presence of a nonverbal learning disorder that requires specific cognitive remediation, behavior management, and parental counseling.Psychiatric illness. Behavior and temperament observed in some individuals with 22q11.2DS include disinhibition and impulsiveness on the one hand and shyness and withdrawal on the other [Swillen et al 1999]. Attention deficit, anxiety, perseveration, and difficulty with social interactions are also common, along with autism and autistic spectrum disorders [Swillen et al 1999, Niklasson et al 2001, Vorstman et al 2006]. The incidence of psychiatric disorders, including schizophrenia, bipolar disorder, anxiety, and depression, is increased. The prevalence and exact nature of these psychiatric disorders has been a subject of investigation [Shprintzen et al 1992, Chow et al 1994, Bassett et al 1998, Yan et al 1998, Murphy et al 1999, Baker & Skuse 2005, Bassett et al 2005, Oskarsdottir et al 2005a]. It has been suggested that 60% of adults have a psychiatric disorder. Most notably, schizophrenia is identified in approximately 25% of individuals, however, anxiety and depressive disorders are also quite common [Bassett et al 2011]. Behavioral differences may begin at a young age; screening children with 22q11.2DS for psychiatric issues before age ten years may provide an opportunity for early intervention [Vorstman et al 2006].Growth. Most adults with 22q11.2DS are of normal stature; however, in 95 children between age one and 15 years, 41% were below the fifth percentile in height. Of these, four were significantly below the fifth percentile; all had low concentrations of growth factors IGF1 and IGFBP3. Three had evidence of growth hormone deficiency; three had a small pituitary gland on MRI; and two responded to human growth hormone therapy [Weinzimer et al 1998]. More recently, growth charts specific to 22q11.2DS have been developed [Habel et al 2012]. Autoimmune disease. Polyarticular juvenile rheumatoid arthritis (JRA) occurs in children with 22q11.2DS at a frequency 20 times that in the general population. The age of onset of JRA ranges from 17 months to five years. HLA types permissive for the development of JRA are observed [Keenan et al 1997, Sullivan et al 1997]. Other autoimmune disorders associated with 22q11.2DS include: idiopathic thrombocytopenia purpura (ITP), hyperthyroidism (Grave's disease), hypothyroidism, vitiligo, hemolytic anemia, autoimmune neutropenia, aplastic anemia, and celiac disease. ITP is seen 200 times more frequently in individuals with 22q11.2DS than in the general population [Sullivan et al 1997, Jawad et al 2001, Kawame et al 2001].Musculoskeletal system. Of 108 individuals evaluated for skeletal abnormalities, 6% had upper-extremity anomalies, including pre- and postaxial polydactyly, and 15% had lower-extremity anomalies including postaxial polydactyly, club foot, overfolded toes, and syndactyly of toes 2 and 3 [Ming et al 1997].Of 63 individuals on whom chest films were examined, 19% had vertebral anomalies including butterfly vertebrae, hemivertebrae, and coronal clefts; 19% had rib anomalies, most commonly supernumerary or absent ribs. Hypoplastic scapulae were seen in 1.5% [Ming et al 1997]. Significant cervical spine abnormalities observed in 50% of 79 persons studied prospectively included posterior fusion of vertebrae C2-C3 without block vertebrae in 21%, hypoplastic/anomalous C1 in 75%, dysmorphic C2 in 59%, and posterior element fusion with block vertebrae of C2-C3 in 13% [Ricchetti et al 2004]. In addition, 56% of persons with cervical spine anomalies had instability on flexion and extension radiographs; 33% had increased motion at more than one vertebral level; of these, four children had abnormalities including increased C2-C3 segmental motion with anterior and posterior narrowing of the spinal canal on further examination with cervical CT scan and/or MRI. Two of the four had surgical stabilization; one of the two required an emergency procedure following onset of symptoms of spinal cord compression. More recently, scoliosis has been identified in 15% of 1067 patients evaluated [D Colo, personal communication].Kidneys. A prospective evaluation using renal ultrasonography in 80 individuals with 22q11.2DS who had no prior history of uropathy revealed renal or other GU abnormalities in 31% [Wu et al 2002]. These included single kidney, echogenic kidney, multicystic dysplastic kidney/small kidneys, calculi, bladder wall thickening, horseshoe kidney, duplicated collecting system, renal tubular acidosis, hydronephrosis (5%), and enuresis. The high incidence of renal abnormalities is similar to that reported by Devriendt et al [1996]. In addition, hypospadias, undescended testes [McDonald-McGinn et al 1995] and absent uterus have been observed [Sundaram et al 2007]. More recently, records on 859 individuals with 22q11.2DS were reviewed for renal anomalies, single umbilical artery, polyhydramnios, and genitourinary abnormalities. Of these, 677 individuals had genitourinary evaluations, of whom 45% had abnormalities present including: umbilical hernia, inguinal hernia, chordee, phimosis, undescended testes, and hypospadias. Renal data was available on 530 individuals, of whom 24.5% had anomalies, including hydronephrosis and unilateral renal agenesis [Amlie-Wolf et al, in preparation].Other. Other findings observed in individuals with 22q11.2DS include:Abnormal lung lobation [McDonald-McGinn et al 1995]Bernard-Soulier syndrome (BSS) [Budarf et al 1995], an autosomal recessive disorder of thrombocytopenia and giant platelets caused by a mutation in one of four genes. One of the four genes is GP1BB, at chromosomal locus 22q11.2. BSS is associated with 22q11.2DS in persons whose non-deleted chromosome 22 has a mutation in GP1BB. Individuals with both 22q11.2DS and BSS are particularly susceptible to bleeding secondary to surgical procedures.Malignancies including hepatoblastoma [Patrone et al 1990, Scattone et al 2003, McDonald-McGinn et al 2006], renal cell carcinoma [Scattone et al 2003], Wilms tumor [McDonald-McGinn et al 2006], and neuroblastoma. Based on these reports a causal relationship between 22q11.2DS and hepatoblastoma seems likely as the population incidence of hepatoblastoma is 1:1,000,000. It is theorized that the absence of COMT, which is located within the area of the deletion, causes this increase in incidence of hepatoblastoma as COMT usually allows for the effective detoxification of environmental carcinogens, the early exposure to which is believed to cause such malignancies [McDonald-McGinn et al 2006].CEDNIK syndrome, an autosomal recessive disorder of cerebral dysgenesis (polymicrogyria), neuropathy, ichthyosis, and keratoderma caused by mutations in SNAP29 (chromosomal locus 22q11.2). Two individuals with 22q11.2DS who had a 22q11.2 deletion on one 22q homologue and a mutation in SNAP29 on the remaining 22q11.2 homologue were recently reported [McDonald-McGinn et al 2013].}

Differential DiagnosisAll of the findings appreciated in association with 22q11.2DS can also be found as an isolated anomaly in an otherwise normal individual.Up to11% of individuals with an apparently isolated cleft palate, including submucosal cleft, may have 22q11.2DS, making this the most common genetic syndrome associated with palatal clefts. 22q11.2DS is also the most common genetic cause of congenital velopharyngeal incompetence.TBX1. Mutations in TBX1, a gene located within the A-B region of chromosome 22q11.2, have been found in individuals with clinical features of 22q11.2 deletion syndrome, primarily congenital cardiac anomalies, who do not have a deletion [Gong et al 2001, Yagi et al 2003]; at least one of these mutations affects function [Stoller & Epstein 2005]. It is still uncertain what other genes must be deleted, since mutations in TBX1 do not account for all of the features of deletion 22q11.2 syndrome. Moreover, affected individuals with atypical nested deletions which do not include TBX1 (B-D deletions; Figure 2) have now been reported, including individuals with typical conotruncal cardiac defects such TOF, IAA, and truncus arteriosus, thus suggesting either a downstream effect or the involvement of CRKL (see Figure 2) [McDonald-McGinn et al 2010a]. Furthermore, some individuals with features of the 22q11.2 deletion syndrome, including typical conotruncal cardiac anomalies, have neither an identifiable deletion nor a TBX1 mutation. However, many of these individuals were subsequently found to have CHARGE syndrome, caused by mutations in CHD7 [Jyonouchi et al 2009]. Disorders with overlapping features:Smith-Lemli-Opitz syndrome (when polydactyly and cleft palate are present). Smith-Lemli-Opitz syndrome, an autosomal recessive inborn error of metabolism is associated with elevated serum concentration of 7-dehydrocholesterol (7-DHC) or an elevated 7-dehydrocholesterol:cholesterol ratio. Mutations in DHCR7 are causative.Alagille syndrome (when butterfly vertebrae, congenital heart disease, and posterior embryotoxon are present). Alagille syndrome is an autosomal dominant condition where sequence analysis of the JAG1 gene detects mutations in approximately 88% of individuals who meet clinical diagnostic criteria. FISH detects a microdeletion of 20p12, including the entire JAG1 gene, in approximately 7% of affected individuals. Mutations in NOTCH2 are observed in fewer than 1% of individuals with Alagille syndrome. VATER association (when heart disease, vertebral, renal, and limb anomalies are present). VATER association is a diagnosis of exclusion without an established etiology to date.Oculo-auriculo vertebral (Goldenhar) syndrome (OAVS) (when ear anomalies, vertebral defects, heart disease, renal anomalies are present). OAVS is often a sporadic condition.CHARGE syndrome (when any combination of congenital heart disease, palatal differences, coloboma, atresia choanae, renal, growth deficiency, ear anomalies/hearing loss, developmental differences, facial palsy GU anomalies,and immunodeficiency are present). Mutations in CHD7 are found in about 65%-70% of affected individuals. CHARGE syndrome is inherited in an autosomal dominant fashion, although most affected individuals represent simplex cases (i.e., a single occurrence in a family).Individuals with normal FISH studies suspected of having 22q11.2DS may have (a) an atypical nested 22q11.2 deletion which would not include the A-B region of chromosome 22q11.2 or (b) a chromosome abnormality involving some other chromosomal region including deletion 10p13-p14 (although (b) is believed to be a distinct entity).Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisClinical practice guidelines for the evaluation and treatment of individuals with 22q11.2 deletion syndrome have been published [Bassett et al 2011 (click here for full text)].To establish the extent of disease and the needs of an individual diagnosed with 22q11.2DS, the following evaluations are recommended (if not performed as part of the evaluation that led to the diagnosis): A baseline cardiac evaluation by a cardiologist that includes a chest x-ray, ECG, and echocardiogram; a chest MRI may be required if a vascular ring is suspected. Measurement of serum ionized calcium concentration and intact parathyroid hormone level to assess for hypoparathyroidism, followed by a formal endocrinology evaluation if abnormalTSH levelComplete blood cell count with differential. A low absolute lymphocyte count necessitates evaluation of T- and B-cell subsets and referral to an immunologist.Immunologic evaluation, which may include flow cytometry, immunoglobulins, and T-cell functionRenal ultrasound examination to evaluate for structural renal defectsConsideration of ophthalmology evaluationAudiology evaluationChest x-ray to evaluate for thoracic vertebral anomaliesCervical spine films (six views: flexion, extension, AP, lateral, open mouth, skull base) in all individuals over age four years (the age that the cervical spine becomes better ossified)Clinical evaluation of the palate to screen for palatal anomalies which may affect feeding and speech developmentAssessment for possible feeding problems including significant gastroesophageal reflux; difficulty with sucking/swallowing, advancing feeds, addition of textured foods; vomiting and constipationSpeech and language assessment by age one year given that almost all children with 22q11.2 deletion syndrome have delay in emergence of language and would benefit from early intervention strategies. In addition, such an evaluation aids in the diagnosis of a palatal abnormality/VPI.As needed:Evaluation of children with short stature (height below the 2nd percentile) by an endocrinologist for possible growth hormone deficiencyEvaluation by a psychologist or psychiatrist of any person with evidence of anxiety, mood disorder, behavioral differences, or frank psychosisEvaluation by a hematologist of any person with a history of a bruising/bleeding disorderTreatment of ManifestationsDepending on the age and presenting problems of the individual with the 22q11.2 deletion syndrome, a multidisciplinary evaluation involving healthcare providers from the following specialties is often necessary: allergy, audiology, cardiology, cardiac surgery, child development / psychology, dental, endocrine, ENT, feeding, gastroenterology, general pediatrics, general surgery, immunology, medical genetics, neurology, neurosurgery, ophthalmology, orthopedics, otolaryngology, plastic surgery, psychiatry, pulmonary, rheumatology, speech, and urology.Low serum calcium concentration warrants calcium supplementation in a standard manner and, when possible, referral to an endocrinologist/nephrologist because of the increased risk of renal calculi in individuals on long-term calcium supplementation.Feeding difficulties should be evaluated by a gastroenterologist to assess for possible structural abnormalities such as intestinal malrotation/nonrotation, Hirschsprung disease, and late-onset diaphragmatic hernia [McDonald-McGinn et al 2004].Strategies for addressing feeding difficulties include: modification of spoon placement when eating; treatment for gastroesophageal reflux with acid blockade, prokinetic agents, postural therapy; and medication to treat gastrointestinal dysmotility and to facilitate bowel evacuation [Dinulos & Graf 1998, Eicher et al 2000].Early intervention (occupational therapy, physical therapy) and speech therapy/the introduction of sign language should be instituted by age one year or at presentation in childhood because of the high risk for motor, cognitive, speech, and language delay. Later, educational and behavioral therapy are often warranted.Growth hormone deficiency, if present, should be treated as in the general population.Immune deficiency generally requires no specific intervention except treating infections aggressively. Rarely, prophylactic antibiotics, IVIG therapy, or thymic transplantation are required.Early diagnosis and early intervention for psychiatric illnesses improve long-term prognosis in individuals with schizophrenia and bipolar disorder [Clarke & O'Callaghan 2003] and other disorders including autism, anxiety, obsessive compulsive disorder (OCD), and attention deficit hyperactivity disorder/attention deficit disorder (ADHD/ADD) [Vorstman et al 2006, Bassett et al 2011].Prevention of Secondary ComplicationsInfants with lymphocyte abnormalities should not be immunized with live vaccines (i.e., oral polio, MMR). Their immune status should be reevaluated in childhood before receiving live vaccines. Antibody studies to assess results of immunizations are warranted. Irradiated blood products are recommended until normalization of the immune system can be confirmed.Serum ionized calcium concentration should be measured pre- and postoperatively to avoid hypocalcemic seizures due to physical stress. Consider the following:Assessment of carotid arteries prior to surgical procedures involving the pharynxPossible effects on speech prior to adenoidectomyAssessment of cervical spine anomalies prior to hyperextension of the neck during surgical procedures/athletic pursuits, such as tumblingPre- and postoperative sleep studies when performing pharyngeal proceduresAssessment of platelet volume and function prior to surgical proceduresSurveillanceAffected individuals require follow up as needed on a "system by system" basis:Monitoring for hypocalcemia, including ionized calcium level every three to six months in infancy, every five years through childhood, and every one to two years thereafterMonitoring of calcium levels preoperatively and postoperatively, and regularly during pregnancyThyroid studies annuallyReevaluation of immunologic status between age nine and 12 months; consideration of repeat immunologic evaluation prior to any live virus vaccineAnnual complete blood count and differentialRepeat ophthalmologic evaluation between age one and five years, or as needed based on symptomsEvaluation of nasal speech quality after language emersion to screen for VPIRepeat audiology evaluation in infancy and prior to school enrollmentRoutine surveillance for the development of scoliosisRoutine dental care with consideration of sealants in those individuals with enamel hypoplasia/increased incidence of cariesRegular developmental assessments benefit the child and assist the school in providing appropriate remediation.Periodic reevaluation by a medical geneticist can apprise the family of new developments and/or recommendations.Agents/Circumstances to AvoidCarbonated drinks and alcohol consumption may exacerbate hypocalcemia. Caffeine intake may contribute to or worsen anxiety.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management Pregnant women must be monitored medically, taking into account any preexisting conditions including congenital heart disease, scoliosis, and asthma. Additional surveillance should include calcium, thyroid, and platelet levels. In addition, changes in mental status/behavior should be referred for immediate evaluation by a mental health care provider. A fetus at high risk of having the condition should undergo a level II ultrasound with fetal echocardiogram to evaluate for the following anomalies : congenital heart disease; airway, palate, swallowing, and gastrointestinal differences possibly leading to polyhydramnios (congenital diaphragmatic hernia, tracheoesophageal fistula, subglottic stenosis, vascular ring, laryngeal web, and cleft palate/cleft lip/palate); renal anomalies; skeletal differences such as club foot and craniosynostosis; and umbilical and inguinal hernia.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. 22q11.2 Deletion Syndrome: Genes and DatabasesView in own windowCritical RegionGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDDGCRNot applicable22q11​.2Not applicable TBX122q11​.21T-box transcription factor TBX1TBX1 homepage - Mendelian genesTBX1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for 22q11.2 Deletion Syndrome (View All in OMIM) View in own window 188400DIGEORGE SYNDROME; DGS 192430VELOCARDIOFACIAL SYNDROME 600594DIGEORGE SYNDROME CRITICAL REGION GENE 2; DGCR2 601279DIGEORGE SYNDROME CRITICAL REGION GENE 6; DGCR6 601755DIGEORGE SYNDROME CRITICAL REGION GENE 14; DGCR14 602054T-BOX 1; TBX1 609030DIGEORGE SYNDROME CRITICAL REGION GENE 8; DGCR8Normal allelic variants. A number of genes have been mapped within the DGCR (DiGeorge chromosomal region) on 22q11.2 (see Table 4 [pdf]).Pathologic allelic variants. More than 85% of individuals with a 22q11.2 deletion have deletions in the same approximately 2.54-Mb region; the remainder have either variant deletion endpoints or recurrent, atypical shorter deleted segments nested within the large typically deleted region (TDR) (see Figure 2) [Levy et al 1995, Kurahashi et al 1996, O'Donnell et al 1997, McQuade et al 1999]. A small 20-kb deletion within the TDR was reported in an individual with a classic VCFS/DGS phenotype [Yamagishi et al 1999]. This smaller deletion disrupts UFD1L and CDC45L. In several additional affected individuals, the deletions do not overlap the typically deleted region in that they begin distal to it and extend toward the telomere. The location of duplicated sequence blocks in the vicinity of the 22q11.2 deletion endpoints strongly implicates them in the events leading to the typical and atypical deletions.A small number of individuals have the deletion as the result of unbalanced translocations that delete the 22pter →q11 region. (For more information, see Table A, Locus Specific)Normal gene product. Several of the gene products from within the deletion have been identified and are being further characterized. See Table 4 for a list of genes and their relevant gene products.Abnormal gene product. Unknown