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 thymus tissue implantation 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 because of 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.