Approach

As there is a reliable diagnostic test for DiGeorge syndrome (22q11.2 deletion syndrome, or 22q11.2DS), the main consideration in the diagnosis of the condition is to determine which patients to test. Presenting signs and symptoms depend on the patient's age at diagnosis and on the organ system affected.[3]​ In young infants, classic or common manifestations include congenital heart disease, hypocalcemia, and gastrointestinal reflux. Mild to moderate T-cell deficiencies are not uncommon; patients with DiGeorge syndrome present with frequent sinopulmonary or viral infections, but opportunistic infections are rare.[41]​ Speech delay and cognitive impairment may be presenting manifestations of DiGeorge syndrome in older children and schizophrenia in young adults.[1][15]

History and exam

  • Children may present with heart failure, cyanosis, and abnormal facial features in infancy. The characteristic facial appearance may provide an indication for further testing. Young patients tend to have prominent, cup-shaped ears and a relatively bulbous nose tip.

  • There may be a family history of DiGeorge syndrome; however, most (90% to 95%) deletions are de novo.[1]

  • Neonates and infants frequently have trouble with feeding, attributed partly to palatal abnormalities. However, feeding difficulty also occurs without associated abnormalities. Consistent reductions in olfaction have also been demonstrated in children with 22q11.2 deletion.[42]

  • Children frequently exhibit speech development delay and learning disorders.[43][44]

  • Syndrome-specific growth charts have now been developed for DiGeorge syndrome.[45][46]​ Growth faltering is common in comparison with World Health Organization standard growth charts.

  • Certain cardiac lesions are characteristic including anomalies of the aortic arch, anomalies of the pulmonary arteries and of the pulmonary blood supply, defects of the infundibular septum and malformations of the semilunar valves.[47]​ A type B interrupted aortic arch is the most suggestive, as around 50% of patients those with this lesion have DiGeorge syndrome.[48]

  • ​Patients with DiGeorge syndrome may present with frequent sinopulmonary or viral infections.[41]

Determining which populations to test

Children of parents with DiGeorge syndrome should be tested as it is passed on in an autosomal dominant fashion; however, most cases are sporadic.

In general, any patient with two or more features associated with DiGeorge syndrome should be tested for the deletion. These features include: any congenital heart defect; signs and symptoms of hypocalcemia/hypoparathyroidism (which can manifest as seizures) in infancy; evidence of any velopharyngeal insufficiency (including cleft palate or hypernasal voice); characteristic facial appearance; and T-cell lymphopenia.[3][48]​​[49]

Cardiologists identify and refer most patients with DiGeorge syndrome, and those who have been trained to recognize the syndrome identify more patients than those who do not have experience with the disorder.[48][50]​​​​ Around 50% of patients with a type B interrupted aortic arch have DiGeorge syndrome, and therefore this feature alone is enough of an indication for testing.​ Patients with tetralogy of Fallot or truncus arteriosus probably also warrant testing, although the yield is lower in these groups.[47]​ Those with more common cardiac lesions, such as ventricular septal defect, should probably be tested only if they have other features of the syndrome.

In addition, patients with CHARGE syndrome (coloboma of the eye, heart defects, atresia of the nasal choanae, retardation of growth and/or development, genital and/or urinary abnormalities, and ear abnormalities and deafness) should be tested for 22q11.2 deletion.

Schizophrenia and other psychiatric disorders typically present in adulthood, although testing these patients without features of DiGeorge syndrome is not practical unless there are other features of the condition.[44]

DiGeorge syndrome is not the only cause of athymia, and other causes of T-cell deficiency should be considered if this is the primary presenting feature.

Because of the great variability in the syndrome, if a patient shows any feature associated with DiGeorge syndrome, it is important they are carefully assessed for other signs to determine whether testing is indicated.

Testing for the deletion

Once tested, evidence of a deletion of 1 copy of 22q11.2 is definitive.

Chromosomal microarray analysis (CMA) is the preferred testing method for patients with suspected DiGeorge syndrome as it can detect small deletions, and can do so across the whole genome.[15][51][52]​​​​ It has an advantage over multiplex ligation-dependent probe amplification (MLPA) and fluorescence in situ hybridization (FISH) which can only detect copy number variants within limited genomic regions.​​ FISH with the TUPLE1 gene probe was historically the most common test used for identifying 22q11.2 deletion, but is now only typically used in settings where CMA and MLPA are both unavailable.[52]

Although deletions in the 22q11.2 region are the primary cause of DiGeorge syndrome, 2% of patients have small atypical 22q11.2 deletions, and a few patients have no deletion at all.[22][23][24][25][26][27]​​​​ Phenocopies of DiGeorge syndrome also exist, such as may be found in infants of diabetic mothers and in patients with retinoic acid embryopathy.​​​​​​[28]​ Some of these patients have been found to have point mutations in TBX1, while others have deletions at 10p or mutations in chromodomain-helicase DNA-binding protein.[23][24]​​[25]​ There is also phenotypic overlap between DiGeorge syndrome and CHARGE syndrome, and distinguishing between them clinically can be challenging.[53]​​ Patients with CHARGE syndrome should therefore also be tested for 22q11.2 deletion.[53]

Karyotyping cannot detect 22q11.2 deletion, except in rare translocations. However, it may support identification and diagnosis of other genetic abnormalities.[15]

If there are existing genetic test results for a patient, do not order a duplicate genetic test unless there is uncertainty about the existing result, e.g., the result is inconsistent with the patient’s clinical presentation or the test methodology has changed.[54]

Other tests

In patients with suspected or confirmed 22q11.2 deletion syndrome, it is crucial to define the extent of the disorder as serious anomalies could be overlooked if not specifically assessed. The initial diagnostic workup is extensive and should include cardiac evaluation with echocardiography, and endocrinologic assessment with serum calcium, parathyroid hormone, and a thyroid function tests. Evaluating immune function is of prime importance and should include a complete blood count with differential and immunophenotyping, serum immunoglobulins (IgG, IgA, and IgM), and, in previously immunized children, levels of specific antibodies.[55]​ Patients frequently have renal anomalies, including obstruction, dysplasia, and reflux. A renal and bladder ultrasound at the time of diagnosis is indicated to screen for these.[56] Dental evaluation and chest x-ray should also be performed together with an evaluation for velopharyngeal insufficiency, cleft palate, or submucous cleft. Nasopharyngeal endoscopy may be required to adequately identify palatal abnormalities.[57] Audiometry and ophthalmologic evaluations should be done.[58]​ Early involvement of developmental specialists and early intervention are important, as the degree of cognitive difficulty is a major factor in the degree of disability patients must contend with.[59]​

While the diagnostic workup slightly differs between children and adults, it should generally include:[15][52]​​

  • Immunologic assessment

  • Complete blood count and differential

  • Endocrinologic assessment

  • Nutritional assessment

  • Neurologic and developmental assessment

  • Cardiac evaluation

  • Referral to cleft-palate team

  • Speech and language evaluation

  • Otolaryngology and audiology assessment

  • Ophthalmology evaluation

  • Dental evaluation

  • Renal, bladder, and abdominal ultrasound

  • Assessment of cognitive and learning capacities

  • Adaptive functioning assessment

  • Psychiatric assessment

  • Other targeted clinical assessment for adults where relevant (e.g., genitourinary, dermatology, gastroenterology, etc.)

Many other types of anomalies have occasionally been associated with DiGeorge syndrome, and the index of suspicion for other congenital malformations should remain high.

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