Clinical characteristics.

Individuals with 22q11.2 deletion syndrome (22q11.2DS) can present with a wide range of features that are highly variable, even within families. The major clinical manifestations of 22q11.2DS include congenital heart disease, particularly conotruncal malformations (ventricular septal defect, tetralogy of Fallot, interrupted aortic arch, and truncus arteriosus), palatal abnormalities (velopharyngeal incompetence, submucosal cleft palate, bifid uvula, and cleft palate), immune deficiency, characteristic facial features, and learning difficulties. Hearing loss can be sensorineural and/or conductive. Laryngotracheoesophageal, gastrointestinal, ophthalmologic, central nervous system, skeletal, and genitourinary anomalies also occur. Psychiatric illness and autoimmune disorders are more common in individuals with 22q11.2DS.

Diagnosis/testing.

The diagnosis of 22q11.2DS is established by identification of a heterozygous deletion at chromosome 22q11.2 on chromosomal microarray analysis or other genomic analyses.

Management.

Treatment of manifestations: Cardiac anomalies are treated as recommended by cardiologist; surgical repair for palate anomalies as recommended by otolaryngologist; feeding issues are treated with modification of spoon placement; standard treatment for gastroesophageal reflux and gastrointestinal dysmotility; immune deficiency requires aggressive treatment of infections; rarely, prophylactic antibiotics, IVIG therapy, or thymic transplantation are required; irradiated blood products are recommended until normalization of the immune system can be confirmed; treatment of autoimmune disease as per immunologist; calcium supplementation and referral to an endocrinologist and nephrologist due to increased risk of renal calculi if long-term supplementation is required; standard treatment for growth hormone deficiency; standard treatment for ocular anomalies; hearing aids may be helpful for hearing loss; occupational, physical, and speech therapy with introduction of sign language by age one year, educational and behavioral therapy; support and treatment for psychiatric disease as indicated; activity restriction as recommended by an orthopedist for cervical spine anomalies; surgery and treatment as recommended by a nephrologist for renal anomalies; routine dental treatment with consideration of sealants.

Surveillance: Evaluation for nasal speech quality after language emergence; antibody studies to assess seroconversion; reevaluate immune status in childhood before administration of live vaccines; annual complete blood count and differential; serum ionized calcium every three to six months in infancy, every five years through childhood, every one to two years thereafter, preoperatively and postoperatively, and regularly during pregnancy; TSH and free T4 annually; ophthalmologic evaluation between age one and three years or as indicated; audiology evaluation in infancy, at preschool age, and in school age children; developmental assessments annually; annual clinical surveillance for scoliosis; dental examination every six months.

Agents/circumstances to avoid: Infants with lymphocyte abnormalities should not be immunized with live vaccines (e.g., oral polio, MMR). Carbonated drinks and alcohol consumption may exacerbate hypocalcemia. Caffeine intake may contribute to or worsen anxiety.

Genetic counseling.

22q11.2DS is an autosomal dominant contiguous gene deletion syndrome. In 22q11.2DS caused by a 3.0 (2.54)-Mb deletion, the deletion is de novo in more than 90% of individuals and inherited from a heterozygous parent in about 10% of individuals. Sixty percent of individuals with 22q11.2DS caused by a nested 22q11.2 deletion inherited the deletion from an affected parent. Offspring of affected individuals have a 50% chance of inheriting the 22q11.2 deletion. Once the 22q11.2 deletion has been identified in an affected family member, prenatal testing using FISH, MLPA, or array studies for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

22q11.2 deletion syndrome (22q11.2DS) should be suspected in individuals with the following clinical findings.

Clinical features

• Congenital heart disease (in 64% of individuals), particularly conotruncal defects (e.g., ventricular septal defect, tetralogy of Fallot, interrupted aortic arch, truncus arteriosus)
• Palatal abnormalities (in 67%) including velopharyngeal insufficiency, submucosal cleft palate, bifid uvula, cleft palate, and hypernasal speech, dysphagia
• Laryngotracheoesophageal abnormalities including vascular ring, laryngeal web, laryngotracheomalacia, and subglottic stenosis
• Gastrointestinal anomalies including constipation with or without structural gastrointestinal anomalies (e.g., anteriorly placed/imperforate anus, esophageal atresia, jejunal atresia, intestinal malrotation, Hirschsprung disease), accessory spleens, diaphragmatic hernia, umbilical hernia, and inguinal hernia
• Immune deficiency (in 77%) (e.g., frequent infections, thymic hypoplasia)
• Autoimmune disorders (e.g., juvenile rheumatoid arthritis, Grave's disease, vitiligo)
• Ophthalmologic findings including tortuous retinal vessels, ptosis, posterior embryotoxon, sclerocornea, coloboma, cataract, anophthalmia, and strabismus
• Other craniofacial features (e.g., hooded eyelids, ear anomalies, prominent nasal bridge, bulbous nose, micrognathia, asymmetric crying facies, craniosynostosis)
• Hearing loss (sensorineural and/or conductive)
• CNS abnormalities including hypotonia in infancy, microcephaly, polymicrogyria, and seizures (idiopathic or associated with hypocalcemia)
• Developmental delay and/or learning difficulties (in 70%-90%), especially a nonverbal learning disability
• Psychiatric illness including autism spectrum disorder (20% of children), schizophrenia (25% of adults), attention deficit disorder, anxiety, perseveration, and difficulty with social interactions
• Early-onset Parkinson disease
• Skeletal anomalies including occipital-cervical anomaly, scoliosis, rib and vertebral anomalies, clubfoot, and polydactyly
• Genitourinary tract anomalies including renal anomalies (in 16%) (e.g., hydronephrosis, renal agenesis, multicystic/dysplastic kidney), cryptorchidism, and hypospadias

Laboratory features

• Hypoparathyroidism and hypocalcemia (in 50%)
• Growth hormone deficiency
• Hypothyroidism
• Cytopenias (hemolytic anemia, neutropenia, thrombocytopenia)

Establishing the Diagnosis

The diagnosis of 22q11.2DS is established in a proband by identification of a heterozygous deletion at chromosome 22q11.2 (see Table 1). The majority of individuals (~85%) with 22q11.2DS have a heterozygous 2.54-Mb deletion, as described based on chromosomal microarray (CMA) designs, at the approximate position of g. 18,912,231-21,465,672 in the reference genome (NCBI Build GRCh37/ hg19) extending from flanking low copy number repeats (LCRs) A-D and including TBX1 (Figure 1). Note: Historically, the recurrent deletion has been described as a 3-Mb deletion [Guo et al 2016].

Figure 1.

The majority of affected individuals (85%) have a 2.54-Mb deletion encompassing approximately 40 genes; a subset of individuals have a smaller atypical or "nested" deletion. Reprinted from McDonald-McGinn & Zackai [2008] with permission from Wiley (more...)

Note: Approximately 5% of individuals with 22q11.2DS have a heterozygous 1.5-Mb deletion extending from LCRs A-B; about 2% have a deletion extending from LCRs A-C; Approximately 5% have a smaller heterozygous deletion extending from LCRs B-D or C-D.

ISCN nomenclature for this deletion:

• 2.54-Mb del: seq[GRCh37] del(22)(q11.2) chr22:18,912,231-21,465,672
• 1.5-Mb del: seq[GRCh37] del(22)(q11.2) chr22:20,731,986-21,465,672

Note: (1) Since these deletions are recurrent and mediated by segmental duplications, the unique genetic sequence that is deleted is the same in all individuals with each deletion; however, the reported size of the deletion may: (a) may be larger if adjacent segmental duplications are included in the size; and (b) may vary based on the design of the microarray used to detect it (see Molecular Pathogenesis). (2) The phenotype of significantly larger or smaller deletions within this region may be clinically distinct from 22q11.2DS (see Genetically Related Disorders). (3) Although pathogenic variants in a single gene in the 22q11.2 region are not causative of 22q11.2DS, several genes of interest have been identified (see Differential Diagnosis and Molecular Genetics).

Genomic testing methods that determine the copy number of sequences can include chromosomal microarray (CMA) or targeted deletion analysis. Note: The 22q11.2 recurrent deletion cannot be identified by routine analysis of G-banded chromosomes or other conventional cytogenetic banding techniques.

• CMA using oligonucleotide or SNP arrays can detect the recurrent 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.
  Note: (1) Most individuals with a 22q11.2 recurrent deletion are identified by CMA performed in the context of evaluation for developmental delay, intellectual disability, or autism spectrum disorder. (2) Prior to 2004 many CMA platforms did not include coverage for this region and thus may not have detected this deletion. The early arrays used to detect the 22q11.2 deletion were BAC CGH arrays with approximately 25 kb or less for resolution [Mantripragada et al 2004].
• Targeted deletion analysis. FISH analysis, quantitative PCR (qPCR), multiplex ligation-dependent probe amplification (MLPA), or other targeted quantitative methods may be used to test relatives of a proband known to have the 22q11.2 recurrent deletion.
  Note: (1) Targeted deletion testing is not appropriate for an individual in whom the 22q11.2 recurrent deletion was not detected by CMA designed to target this region. (2) It is possible to size the deletion routinely by use of targeted methods; in particular, MLPA can be used to detect the different deletion sizes by LCR.

Table 1.

Genomic Testing Used in 22q11.2 Deletion Syndrome

View in own window

Deletion 1	Method	Sensitivity
		Proband	At-risk family members
2.54-Mb heterozygous deletion at 22q11.2 ISCN: seq[GRCh37] del(22)(q11.2) chr22:18,912,231-21,465,672del 2 ClinGen ID: ISCA-37446	CMA 3	100%	100%
	Targeted deletion analysis 4	~95%-100% 5	100% 6

1.

See Molecular Genetics for details of the deletion and genes of interest included in the region.

2.

Standardized ISCN annotation and interpretation for genomic variants from the Clinical Genome Resource (ClinGen) project (formerly the International Standards for Cytogenomic Arrays (ISCA) Consortium). Genomic coordinates represent the minimum deletion size associated with the 22q11.2 recurrent deletion as designated by ClinGen. Deletion coordinates may vary slightly based on array design used by the testing laboratory. Note that the size of the deletion as calculated from these genomic positions may differ from the expected deletion size due to the presence of segmental duplications near breakpoints. The phenotype of significantly larger or smaller deletions within this region may be clinically distinct from the 22q11.2 recurrent deletion (see Genetically Related Disorders).

3.

Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 22q11.2 region.

4.

Targeted deletion analysis methods can include FISH, quantitative PCR (qPCR), and multiplex ligation-dependent probe amplification (MLPA) as well as other targeted quantitative methods.

5.

The commercially available fluorescence in situ hybridization (FISH) probes, N25 and TUPLE, along with TBX1, are located between low copy number repeat sequences (LCRs) A-B; therefore, the atypical deletions that do not include LCRs A-B are not identifiable using the commercially available FISH probes (Figure 1).

6.

Targeted FISH, MLPA, or other quantitative method analysis may be used to test at-risk relatives of a proband who is known to have the 22q11.2 recurrent deletion.

Evaluating at-risk relatives. FISH, qPCR, MLPA, or other quantitative methods of targeted deletion analysis can be used to identify the 22q11.2 recurrent deletion in at-risk relatives of the proband. Testing of parental samples is important in determining recurrence risk (see Genetic Counseling).

Single-Gene Disorders

Chromosome Disorders

Deletion 10p13-p14. Features overlapping with 22q11.2DS can include cardiac defects, immune deficiency, hypoparathyroidism, cleft palate, developmental delay, microcephaly, and cryptorchidism [Lichtner et al 2000].

Deletion 11q23-ter (Jacobsen syndrome) (OMIM 147791). Features overlapping with 22q11.2DS can include microcephaly, micrognathia, low set ears, ocular manifestations, cardiac defects, hypospadias, cryptorchidism, and immune deficiency.

Other

Disorders of unknown genetic etiology

• VACTERL association (when congenital heart disease, vertebral, renal, and limb anomalies are present). VATER association is a diagnosis of exclusion without an established etiology to date (OMIM 192350).
• Oculoauriculovertebral (Goldenhar) syndrome (OAVS) (when ear anomalies, vertebral defects, heart disease, renal anomalies are present) (OMIM 141400)

Teratogenic exposures. A phenotype similar to 22q11.2DS can be associated with maternal diabetes and maternal retinoic acid exposure [Digilio et al 1995, Coberly et al 1996].

Evaluations Following Initial Diagnosis

Clinical practice guidelines for the evaluation and treatment of individuals with 22q11.2 deletion syndrome (22q11.2DS) have been published. See Bassett et al [2011] (full text) and Fung et al [2015].

To establish the extent of disease and needs of an individual diagnosed with 22q11.2DS, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance