Clinical Diagnosis

22q11.2 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])
• Hypocalcemia
• Immune deficiency
• Learning 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 features

Less frequently seen functional differences include:

• Severe dysphagia
• Growth hormone deficiency
• Autoimmune disease (thrombocytopenia, juvenile rheumatoid arthritis, Grave's disease, vitiligo, neutropenia, hemolytic anemia)
• Hearing loss (sensorineural and conductive)
• Psychiatric illness
• Autism

Other 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 cryptorchidism
• Laryngotracheoesophageal abnormalities: vascular ring, laryngeal web, laryngotracheal malacia, and subglottic stenosis
• Ophthalmologic findings: tortuous retinal vessels, ptosis, posterior embryotoxon, sclerocornea, coloboma, cataract, anophthalmia, and strabismus
• CNS abnormalities: cerebellar atrophy, polymicrogyria, enlarged sylvian fissures, neural tube defects, tethered cord, unprovoked seizures, and asymmetric crying facies
• Gastrointestinal anomalies: anteriorly placed/imperforate anus, esophageal atresia, jejunal atresia, accessory spleens, umbilical hernia, diaphragmatic hernia, intestinal malrotation, and Hirschsprung disease
• Preauricular tags and/or pits

Neoplasms:

• Hepatoblastoma, renal cell carcinoma, Wilms tumor, and neuroblastoma

Testing

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).

Figure

Figure 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).

Figure

Figure 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.

Testing Strategy

To 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) Disorders

The 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 History

Findings 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.

Palate. 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.

Feeding. 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].

Genotype-Phenotype Correlations

The great inter- and intrafamilial clinical variability, even among identical twins, makes genotype-phenotype correlations difficult [Driscoll et al 1995, McDonald-McGinn et al 2001]. Anecdotally, developmental delays appear to be more significant in familial cases; however, this may reflect socioeconomic rather than genetic factors.

Penetrance

Penetrance is complete in individuals with 22q112DS; variability is marked.

Anticipation

To date, anticipation has not been observed.

Nomenclature

It is now recognized that 22q11.2DS encompasses the phenotypes previously described as DiGeorge syndrome (DGS) [Kelley et al 1982], velocardiofacial syndrome (VCFS) [Scambler et al 1991, Driscoll et al 1992], conotruncal anomaly face syndrome (CTAF) [Matsuoka et al 1994], some cases of autosomal dominant Opitz G/BBB syndrome [McDonald-McGinn et al 1995, Fryburg et al 1996, LaCassie & Arriaza 1996], and Cayler cardiofacial syndrome (asymmetric crying facies) [Giannotti et al 1994]. The clinical descriptions of these entities resulted from an ascertainment bias.

DGS was originally described as a developmental field defect of the third and fourth pharyngeal pouches, often identified in neonates, with hypoplasia of the thymus gland and parathyroid glands. Later, congenital heart disease, specifically conotruncal cardiac anomalies, was added. The majority of individuals with DGS were identified in the neonatal period with a major congenital heart defect, hypocalcemia, and immunodeficiency.

VCFS, was originally described as the combination of palatal anomalies, often velopharyngeal incompetence (VPI), congenital heart disease (usually a ventricular septal defect or tetralogy of Fallot), characteristic facial features, and developmental delay or learning difficulties. Children with VCFS tended to be diagnosed in cleft palate clinics or craniofacial centers when they reached school age and speech and learning difficulties became evident [Driscoll et al 1993, Wilson et al 1993, Wulfsberg et al 1996, McDonald-McGinn et al 1997b, Thomas & Graham 1997].

Prevalence

Estimates of prevalence vary from one in 4000 [Wilson et al 1994] to one in 6395 [Devriendt et al 1998]. Given the variable expression of 22q11.2DS, the incidence is probably much higher than previously estimated. In a population-based study in Sweden, the mean annual incidence was 14.1 per 100,000 live births [Oskarsdottir et al 2004, Oskarsdottir et al 2005a, Oskarsdottir et al 2005b]. A US population-based study conducted by the Centers for Disease Control (CDC) found an overall prevalence of about one in 6000 in whites, blacks, and Asians, and one in 3800 in Hispanics [Botto et al 2003].

In a recent review of samples submitted to two large reference labs for numerous indications, such as developmental delay or multiple spontaneous abortions, 30,153 individuals underwent array CGH testing. Of these, 274 were found to have a 22q11.2 deletion (~1/100) [McDonald-McGinn et al 2010a] suggesting that, despite bias based on ascertainment, the current prevalence figures may be underestimates. Moreover, newborn screening efforts currently underway in several states will serve to better define these figures over time.

The widespread use of chromosomal microarray technology to detect smaller atypical, “nested” deletions has suggested that the prevalence of 22q11.2DS is even higher than previous estimates. One review evaluated a cohort of 904 affected individuals, of whom 436 had deletion sizing by enhanced FISH or microarray studies. Of these, 63 (15%) had atypical deletions, including 28 A-B (44%), 10 A-C (16%), 17 B-D (27%), 2 C-D (3%), & 6 “other” (10%) (not flanked by LCR blocks) (see Figure 2). The B-D and the less common C-D deletions do not include TBX1 and are not detectable using standard FISH probes. A high incidence of familial deletions was noted among the individuals with these atypical deletions. Many adults therefore go undiagnosed until the deletion is detected in a more dramatically affected child [McDonald-McGinn et al 2010a].

Evaluations Following Initial Diagnosis

Clinical 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 abnormal
• TSH level
• Complete 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 function
• Renal ultrasound examination to evaluate for structural renal defects
• Consideration of ophthalmology evaluation
• Audiology evaluation
• Chest x-ray to evaluate for thoracic vertebral anomalies
• Cervical 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 development
• Assessment for possible feeding problems including significant gastroesophageal reflux; difficulty with sucking/swallowing, advancing feeds, addition of textured foods; vomiting and constipation
• Speech 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 deficiency
• Evaluation by a psychologist or psychiatrist of any person with evidence of anxiety, mood disorder, behavioral differences, or frank psychosis
• Evaluation by a hematologist of any person with a history of a bruising/bleeding disorder

Treatment of Manifestations

Depending 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 Complications

Infants 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 pharynx
• Possible effects on speech prior to adenoidectomy
• Assessment of cervical spine anomalies prior to hyperextension of the neck during surgical procedures/athletic pursuits, such as tumbling
• Pre- and postoperative sleep studies when performing pharyngeal procedures
• Assessment of platelet volume and function prior to surgical procedures

Surveillance

Affected 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 thereafter
• Monitoring of calcium levels preoperatively and postoperatively, and regularly during pregnancy
• Thyroid studies annually
• Reevaluation of immunologic status between age nine and 12 months; consideration of repeat immunologic evaluation prior to any live virus vaccine
• Annual complete blood count and differential
• Repeat ophthalmologic evaluation between age one and five years, or as needed based on symptoms
• Evaluation of nasal speech quality after language emersion to screen for VPI
• Repeat audiology evaluation in infancy and prior to school enrollment
• Routine surveillance for the development of scoliosis
• Routine dental care with consideration of sealants in those individuals with enamel hypoplasia/increased incidence of caries
• Regular 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 Avoid

Carbonated drinks and alcohol consumption may exacerbate hypocalcemia. Caffeine intake may contribute to or worsen anxiety.

Evaluation of Relatives at Risk

See 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 Investigation

Search 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.

Mode of Inheritance

22q11.2DS is a contiguous gene deletion syndrome inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• More than 90% of probands have a de novo deletion of 22q11.2 [McDonald-McGinn et al 2001, Bassett et al 2011].
• About 10% have inherited the deletion from a parent [McDonald-McGinn et al 2001].
• Recommendations for the evaluation of parents of a proband include either FISH or MLPA testing, as mildly affected adults (as well as normal adults with somatic mosaicism) have been identified [McDonald-McGinn et al 2001].

Sibs of a proband

• The risk to the sibs of a proband depends on the status of the parents.
• If the parents of an individual with 22q11.2DS have normal studies, the risk to sibs is low, but greater than that of the general population because parents with germline mosaicism or low-level somatic mosaicism have been identified.
• If a parent is also found to have 22q11.2DS, the risk to each sib is 50%.

Offspring of a proband. Offspring of individuals with 22q11.2DS have a 50% chance of inheriting 22q11.2 deletion syndrome.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent has the deletion, his or her family members are at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

High-risk pregnancies

• Molecular genetic testing. Prenatal testing using FISH, MLPA, or array studies is possible based on family history or findings on ultrasound. Fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or CVS at approximately ten to 12 weeks' gestation can be analyzed.
• Ultrasound evaluation. Pregnancies at increased risk may be evaluated between 18 and 22 weeks' gestation by high-resolution ultrasound examination for palatal and other associated anomalies and by echocardiography for cardiac anomalies.

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

Low-risk pregnancies. In some pregnancies not known by family history to be at increased risk for 22q11.2DS, findings of congenital heart disease and/or cleft palate or cleft lip/palate detected by routine ultrasound examination may suggest the diagnosis, in particular in those individuals with conotruncal cardiac anomalies such as interrupted aortic arch, truncus arteriosus, tetralogy of Fallot, and ventricular septal defect. Additional structural differences which can be associated with 22q11.2DS and may be identified prenatally include: congenital diaphragmatic hernia, umbilical or inguinal hernia, tracheoesophageal fistula/esophageal atresia/laryngeal atresia, polydactyly, craniosynostosis, polymicrogyria, and renal anomalies. In addition, polyhydramnios is frequently present. Chromosome preparations obtained from fetal cells can be analyzed using array studies, MLPA, or FISH. Establishing the diagnosis of 22q11.2DS even late in gestation can be useful for perinatal management.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

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Suggested Reading

1. Alkalay AA, Guo T, Montagna C, Digilio MC, Dallapiccola B, Marino B, Morrow B. Genetic dosage compensation in a family with velo-cardio-facial/DiGeorge/22q11.2 deletion syndrome. Am J Med Genet A. 2011;155A:548–54. [PubMed: 21337693]
2. Bassett AS, Chow EW, Husted J, Hodgkinson KA, Oechslin E, Harris L, Silversides C. Premature death in adults with 22q11.2 deletion syndrome. J Med Genet. 2009;46:324–30. [PMC free article: PMC3188306] [PubMed: 19246480]
3. De Smedt B, Swillen A, Verschaffel L, Ghesquiere P. Mathematical learning disabilities in children with 22q11.2 deletion syndrome: a review. Dev Disabil Res Rev. 2009;15:4–10. [PubMed: 19213009]
4. Fung WLA, McEvilly R, Fong J, Silversides C, Chow E, Bassett AS. Elevated prevalence of generalized anxiety disorder in adults with 22q11.2 deletion syndrome. Am J Psychiatry. 2010;167:998. [PubMed: 20693476]
5. Green T, Gothelf D, Glaser B, Debbane M, Frisch A, Kotler M, Weizman A, Eliez S. Psychiatric disorders and intellectual functioning throughout development in velocardiofacial (22q11.2 deletion) syndrome. J Am Acad Child Adolesc Psychiatry. 2009;48:1060–8. [PubMed: 19797984]
6. Kiehl TR, Chow EW, Mikulis DJ, George SR, Bassett AS. Neuropathologic features in adults with 22q11.2 deletion syndrome. Cereb Cortex. 2009;19:153–64. [PubMed: 18483005]
7. Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, Church DM, Crolla JA, Eichler EE, Epstein CJ, Faucett WA, Feuk L, Friedman JM, Hamosh A, Jackson L, Kaminsky EB, Kok K, Krantz ID, Kuhn RM, Lee C, Ostell JM, Rosenberg C, Scherer SW, Spinner NB, Stavropoulos DJ, Tepperberg JH, Thorland EC, Vermeesch JR, Waggoner DJ, Watson MS, Martin CL, Ledbetter DH. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86:749–64. [PMC free article: PMC2869000] [PubMed: 20466091]
8. Schwinger E, Devriendt K, Rauch A, Philip N. Clinical untility gene card for: DiGeorge syndrome, velocardiofacial syndrome, Shprintzen syndrome, chromosome 22q11.2 deletion syndrome (22q11.2, TBX1). Eur J Hum Genet. 2010;18(9) [PMC free article: PMC2987430] [PubMed: 20125192]
9. Swaby JA, Silversides CK, Bekeschus SC, Piran S, Oechslin EN, Chow EW, Bassett AS. Complex congenital heart disease in unaffected relatives of adults with 22q11.2 deletion syndrome. Am J Cardiol. 2011;107:466–71. [PMC free article: PMC3188300] [PubMed: 21257016]
10. Toriello HV, Goldenberg P. Evidence-based medicine and practice guidelines: application to genetics. Am J Med Genet C Semin Med Genet. 2009;151C:235–40. [PubMed: 19621463]
11. Van Aken K, Swillen A, Beirinckx M, Janssens L, Caevenberghs K, Smits-Engelsman B. Prospective control abilities during visuo-manual tracking in children with 22q11.2 Deletion syndrome compared to age- and IQ-matched controls. Res Dev Disabil. 2010;31:634–41. [PubMed: 20181458]
12. Van Aken K, Swillen A, Beirinckx M, Janssens L, Caevenberghs K, Smits-Engelsman B. Kinematic movement strategies in primary school children with 22q11.2 Deletion syndrome compared to age- and IQ-matched controls during visuo-manual tracking. Res Dev Disabil. 2010;31:768–76. [PubMed: 20181457]

Revision History

• 28 February 2013 (me) Comprehensive update posted live
• 16 December 2005 (me) Comprehensive update posted to live Web site
• 23 July 2003 (me) Comprehensive update posted to live Web site
• 23 September 1999 (me) Review posted to live Web site
• 7 August 1998 (dmm) Original submission