The worldwide prevalence at birth is estimated at 1/4,500-1/10,000.
22q11.2 deletion syndrome shows a variable clinical phenotype that can range from mild to severe. Congenital heart defects (two-thirds of cases) include mainly conotruncal malformations such as ventricular septal defect, truncus arteriosus, tetralogy of Fallot and interrupted aortic arch. Anomalies of the aortic arch and vascular ring are frequent. More than 65% of patients present with palatal anomalies (e.g. velopharyngeal incompetence, submucous cleft palate or bifid uvula) that may lead to hypernasal speech and feeding difficulties. Overt cleft palate and cleft lip are less frequent. Most patients display subtle but recognizable facial features (e.g. ptosis, hypertelorism, epicanthal folds, prominent nasal root, malar flatness, small ears). Immune deficiency is the consequence of thymic aplasia/hypoplasia and improvement in T-cell production occurs over time. Patients have a higher risk of developing an autoimmune disease such as idiopathic thrombocytopenic purpura and juvenile idiopathic arthritis. Hypocalcemia as a consequence of hypoparathyroidism is frequent in the neonatal period and usually resolves but can reappear at any age. Additional clinical findings may include gastrointestinal anomalies (intestinal malrotation, imperforate anus), hearing loss, renal anomalies (renal agenesis), dental anomalies (enamel hypoplasia), and skeletal anomalies (scoliosis, clubfoot). Learning difficulties and developmental delay are almost always present. Psychiatric illness (anxiety, depression, schizophrenia) and Parkinson’s disease are more frequent than in the general population.
In most cases, the syndrome is due to a 3 million base pair (Mb) deletion on the chromosomal region 22q11.2 that is flanked by low copy number repeats. The deletion is due to a non-allelic meiotic recombination during spermatogenesis or oogenesis. In ~15% of cases, the deletion is nested within the 3 Mb DiGeorge critical region and varies in size. Most deletions include the TBX1 gene that has been shown to be implicated in cardiac, parathyroid, thymus and facial structure development. The variable expression of the 22q11.2 phenotype is thought to be due to genetic modifiers on either the other 22q11.2 allele or on other chromosomes.
Diagnosis is suspected upon clinical examination and confirmed by detection of the 22q11.2 deletion, using fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), array comparative genomic hybridization (aCGH) or genome-wide SNP (single nucleotide polymorphism) microarrays.
Differential diagnosis includes Smith-Lemli-Opitz syndrome, CHARGE syndrome, Alagille syndrome, VATER syndrome, Goldenhar syndrome and isotretinoin embryopathy.
Prenatal diagnosis is possible in familial cases by chorionic villus sampling or amniocentesis, and in pregnancies where associated anomalies have been noted by fetal echocardiography. Preimplantation genetic diagnosis is possible.
The deletion arises de novo in ~90% of the cases. The recurrence risk in the sibship of a de novo case is 2-3% due to of low-grade germline parental mosaicism. Affected individuals have a 50% risk of having an affected child.
Management and treatment
Management is symptom-based and requires a multidisciplinary approach. It may consist of heart and/or palate surgery, nasogastric feeding, calcium supplementation, occupational, physical, and speech therapy, educational and behavioral therapy, as well as support and treatment for psychiatric disease. Tonsillectomy is not recommended unless indicated by a center of expertise. A regular surveillance of calcium, thyroid function and blood cell count is necessary. Immune function must be evaluated before administering live vaccines.
The prognosis is variable and depends on the severity of the disease. The infant mortality rate is relatively low (~4%); in adults mortality is higher than that of the rest of the adult population. Most congenital malformations and medical problems can be managed. Prognosis in adults depends on the degree of autonomy.
Expert reviewer(s): Dr Tiffany BUSA | ITHACA* – Pr Nicole PHILIP | ITHACA* – Last update: September 2020