History
The most common reason to suspect 22q11.2DS (chromosome 22q11.2 deletion syndrome; DiGeorge syndrome [DGS]) is a cardiac anomaly, especially a conotruncal one. Neonatal hypocalcemia should also raise suspicion for this syndrome, especially if the hypocalcemia or heart defect is coupled with cleft palate. A picture of severe immune deficiency with low T-cell numbers as compared to age-appropriate controls in early infancy should raise the suspicion of this syndrome as well.
The characteristic facies of this syndrome often are subtle in infancy and not fully manifested until the child is older; therefore, they are not a common indication for a genetic investigation. The distinctive facial features may even be absent or more subtle in people of African-American or in others of nonwhite descent.
Developmental delay may be mild in infancy or may go unnoticed until the child reaches school age. Additional abnormalities of every organ system have been reported, [23] although individually they are rare. Details of the common symptoms/anomalies are described below.
A history of maternal diabetes and/or exposure prenatally to alcohol and other drugs like isotretinoins is relevant because of the overlapping phenotypes associated with fetal alcohol syndrome, diabetic embryopathy, and isotretinoin embryopathy.
Craniofacial features
Characteristic facies of 22q11.2DS are easier to recognize in white children; they consist of a high and broad nasal bridge, long face, narrow palpebral fissures, and micrognathia. Microcephaly, a dimple on the nose, and asymmetrical crying face may be present. Facial features become more pronounced as the children grow into the second decade.
Overall, about 69% of cases have palatal abnormalities. A hypernasal voice indicates velopharyngeal incompetence (VPI). VPI may be due to submucous cleft palate and is more common than an overt cleft of the secondary palate. The presence of an overt cleft palate improves the chances of an earlier diagnosis. There may be a bifid uvula. Rarely, cleft lip and cleft palate occur together. Recurrent episodes of otitis media may be observed. Conductive and/or sensorineural hearing loss may be present. Craniosynostosis occurs on rare occasions.
Immune disorders and recurrent infections
The overall incidence of immune dysfunction in 22q11.2DS is 77%. [23]
However, infections as the first manifestation is unusual, but rather, cardiac malformations and hypocalcemia are the first signs in the neonatal period. Recurrent infections are a major problem and an important cause of later mortality.
Increased susceptibility to infections caused by organisms typically associated with T-cell dysfunction is observed. These include systemic fungal infections, Pneumocystis (carinii) jiroveci infection, other bacterial infections, and disseminated viral infections. [24, 25]
Autoimmune disease such as autoimmune cytopenia, thrombocytopenia, and juvenile rheumatoid arthritis are most common. Autoimmune thyroid disease, autoimmune uveitis, and selective IgA deficiency may occur as well. Atopic disorders of severe eczema [26] and asthma are also seen.
Feeding difficulties
Significant feeding difficulties are present in about 36% of patients. These may be due to poor sucking and nasal regurgitation due to VPI or a submucous cleft palate. The swallowing problem usually resolves by the end of the first year, leaving the child with hypernasal speech as the major remaining manifestation. Abnormal swallowing, with or without aspiration, may occur due to dysmotility and abnormality of the oropharyngeal and cricoesophageal swallowing phase.
Developmental delay/learning difficulties
Developmental delay and learning difficulties are observed in 70-90% of patients with 22q11.2DS. In infancy, developmental milestones are achieved later than expected for age. Delayed language acquisition is often seen in older children.
A frequent pattern of disability is observed, [27] consisting of a low performance on intelligence quotient (IQ) testing compared with verbal IQ, which creates problems with nonverbal learning, abstract reasoning, and math. In school-aged children, full-scale IQ scores can range from average to low average to mild mental retardation. The incidence of mild mental retardation is approximately 30%. Brain anomalies like polymicrogyria and enlarged Sylvian fissures have rarely been noted. [28]
Behavioral and neuropsychiatric problems
Behavioral and psychiatric problems may be observed in patients with 22q11.2DS. [29, 30] Children and adults have high rates of behavioral, psychiatric, and communication disorders. In children, these include attention-deficit/hyperactivity disorder, anxiety, autism spectrum disorder, and affective disorders. Bipolar disorder, autistic spectrum disorder, schizophrenia, and schizoaffective disorder are reported in 10-30% of teenagers and adults with the syndrome. [28, 31] Increased risk for early onset Parkinson disease (younger than 50 years of age) is observed. [32]
Endocrinologic conditions
Main problems are with parathyroid deficiency [33] :
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Hypocalcemia
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Nephrocalcinosis
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Tetany: Neonatal tetany has been reported as a result of hypocalcemia.
Hypocalcemia due to hypoparathyroidism can cause seizures. The incidence of hypocalcemia varies widely, from 17-60%. [34] This is frequently a self-limiting problem, and by age 1 year approximately 50% of patients no longer need calcium supplementation.
Additional endocrine manifestations include hypothyroidism in children and ∼20% of adults, and hyperthyroidism in children. [35] Rarely, growth hormone deficiency has occurred.
Other associated conditions
Other associated conditions include the following:
Physical Examination
There is considerable variability in individual physical findings and in the organ systems that may be involved in 22q11.2DS (chromosome 22q11.2 deletion syndrome; DiGeorge syndrome [DGS]).
Patients usually have characteristic facial features, which become more pronounced as the child grows into the second decade. These are more commonly and easily recognized in white children. Common features include the following (see the images below) [1] :
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Retrognathia or micrognathia
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Long face
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High and broad nasal bridge
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Narrow palpebral fissures
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Small teeth
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Asymmetrical crying face
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Downturned mouth
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Short philtrum
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Low-set, malformed ears
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Hypertelorism
Although VPI is more common, a cleft of the soft palate or a bifid uvula (associated with a submucous cleft palate) may be present. The voice can be hypernasal. [38]
Hypodevelopment of the lingual cusp of the mandibular first premolars and enamel opacities may also exist. [39]
Ocular findings
Ocular features of 22q11.2DS include the following:
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Posterior embryotoxon
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Tortuous retinal vessels
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Eyelid hooding
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Strabismus
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Ptosis
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Amblyopia [40]
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Familial exudative vitreoretinopathy [41]
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Sclerocornea [42]
Skeletal findings
Skeletal features of 22q11.2DS include the following:
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Limb abnormalities: Ectrodactyly, polydactyly and long, tapering fingers [43]
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Craniosynostosis
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Scoliosis: With or without vertebral anomalies
Patients may have short stature; a decrease in the rate of linear growth may suggest a rarely seen growth hormone deficiency.
Pulmonary conditions
Pulmonary features of 22q11.2DS include the following:
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Tracheoesophageal fistula
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Short trachea with a reduced number of tracheal rings
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Abnormal thyroid cartilage
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Laryngomalacia
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Tracheomalacia
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Bronchomalacia
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Congenital anterior glottic web [3]
Cardiac and GI findings
Heart murmur and other cardiac findings would suggest a congenital heart defect. Congenital heart defects are observed in 74-80% of patients. A higher incidence is noted in cases diagnosed during infancy because of the symptomatic nature of the heart lesion. Any conotruncal heart defect can occur. In infancy, tetralogy of Fallot, truncus arteriosus, and interrupted aortic arch are more common; whereas ventricular septal defect (VSD), pulmonary atresia plus VSD, and other conotruncal defects are seen in cases diagnosed after age 2 years. Rare cardiac anomalies in 22q11.2DS include the following:
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Vascular ring anomaly
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Transposition of the great arteries with VSD
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Atrial septal defect (ASD)
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Pulmonary stenosis
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Hypoplastic left heart
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Patent ductus arteriosus.
Anomalies of the carotid arteries should be checked for patients needing pharyngeal surgery.
GI anomalies, such as esophageal atresia and anal atresia or stenosis, intestinal malrotation, tracheoesophageal fistula, have all been reported.
Complications
As described in the initial section, autoimmune complications are common in 22q11.2DS patients, although autoimmune conditions are not typically seen at initial presentation in infants or young children.
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Mother and children with 22q11.2 deletion syndrome.
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An African American girl with 22q11.2 deletion syndrome.
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The same child as in the previous image, showing an asymmetrical crying face.
