Approach

Given the variable expression of DiGeorge syndrome (22q11.2 deletion syndrome, or 22q11.2DS) and that complications may occur at different stages in a patient’s life, key features of management include treating manifest complications and undertaking multisystem periodical assessments for anticipated features.[16][52][54]​​ Multi-disciplinary care involving consultants and generalists is central to management, as is the involvement of family. 

Birth to 4 months

General care and stabilisation

Treatment of infants is characterised by stabilising life-threatening abnormalities and characterising the extent of disease.[52]

With congenital heart disease

  • About 80% of patients with DiGeorge syndrome have congenital heart disease.[48][90]​ Conotruncal anomalies such as interrupted aortic arch type B and truncus arteriosus are the most characteristic, but tetralogy of Fallot, ventricular septal defect, and others are also common.[91][92]

  • Cardiac anomalies must be managed as appropriate, and echocardiography performed to define the cardiac anatomy and plan surgical repair.[52]​ Infants with cardiac disease secondary to DiGeorge syndrome are managed as other infants with the same cardiac anatomy.

  • ​For children with congenital heart disease those with 22q11.2 deletion may be more likely to need dialysis post cardiac surgery, and have a greater risk of postoperative infection; but this does not seem to increase mortality or length of intensive care or hospital stay.[93]

With hypocalcaemia

  • Hypocalcaemia (secondary to hypoparathyroidism) is present in up to 60% of paediatric patients and hypocalcaemic seizures are common in neonates.[59][94]​​ It often becomes less problematic as the child matures.[59]

  • Hypocalcaemia is managed by calcium and vitamin D (calcitriol) supplementation as necessary.[52]

  • Calcium levels may be corrected orally in most cases, but if there are significant symptoms, such as tetany, seizure, or prolonged QT interval, intravenous correction alongside cardiac monitoring is indicated.

  • Hypercalciuria is a major complication in the treatment of hypocalcaemia. Calcium and calcitriol must be reduced if hypercalciuria is noted. Hydrochlorothiazide may be added to reduce urine calcium excretion if required.

With palatal abnormalities

  • At this age, palatal abnormalities should be managed by adaptive feeding approaches in consultation with nutritionists, occupational therapists, feeding specialists, and orthodontists. Options include specialised nipples, prosthetics, and frequent burping. Otitis media and airway obstruction occur commonly with clefts and should be evaluated. Surgery is an option if other measures are not successful or in the case of overt cleft palates.[52]

  • Growth parameters should be carefully monitored, particularly to allow for early detection of feeding difficulties.

With feeding difficulty

  • Some children may have feeding difficulty, not necessarily due to cleft palate. Modified feeding approaches may be implemented for them and some may require a percutaneous gastrostomy tube.​

With thyroid dysfunction

  • Thyroid function should be assessed regularly by TSH and free T4 monitoring, with replacement therapy started accordingly.

With renal obstruction or hypoplasia

  • Renal ultrasound should be performed to identify renal hypoplasia or obstruction. Speciality consultation is needed for management.

Infants and toddlers (4 months to 5 years)

Many in this age range still require further repair of their cardiac defects. Infants with hypocalcaemia should continue to receive calcium and calcitriol supplementation. Therapy is continued as needed for hypothyroidism.

With palatal abnormalities

  • Surgical repair is required for frank clefts and submucous clefts.[52]​ Patients who have only palatal insufficiency may not need surgical correction, although if speech therapy fails to adequately improve diction and intelligibility, there are surgical options to improve this.

With feeding difficulty

  • Children in this age group routinely have feeding difficulties that may or may not be associated with cleft palate. The first-line therapy is modified feeding approaches to ease feeding, including changing nipples, using bottle feeding if breastfeeding is inadequate, thickening feeds, or changing formulas.

  • Second-line therapy may be required and usually involves placing a percutaneous gastrostomy tube. This should be considered if the child does not gain weight despite other feeding interventions. Feeding difficulties can easily persist for months to years, but generally resolve before school age.

With delayed speech acquisition

  • In older toddlers, delayed acquisition of speech is a characteristic feature.[52]​ This is not due solely to palate defects, but occurs in most children. This should be treated with speech therapy early and use of bridging sign language. Specific recommendations are available for the management of speech therapy in DiGeorge Syndrome.[44]

  • For those with velopharyngeal insufficiency, surgical repair may be indicated to improve speech outcomes.[95]

With immunodeficiency

  • Patients with demonstrated immune dysfunction should be referred to an immunologist. Those with mild to moderate immunodeficiency should be monitored for the presence of infection. Those with significant T-cell deficiency (marked T-cell lymphopenia and absent proliferative responses) should be given trimethoprim/sulfamethoxazole prophylaxis and intravenous immunoglobulin, prepared for thymic transplant, or have adoptive transfer of mature T cells arranged.[17][96] Infants should be monitored for the development of oligoclonal T-cell populations with frequent flow cytometric T-cell counts. Infants with significant T-cell immunodeficiency (<600 T cells/mm^3) should receive no live virus vaccines and should receive only irradiated, filtered (leukodepleted) blood products.[97][98][99][100][101][102][103]

With sinopulmonary infections

  • Sinopulmonary infection and viral infection incidences are increased in this population and occur regardless of detectable immunodeficiency.[42]​[68]​​​ Bacterial infections should be managed with targeted antibiotic therapy.

School age (5 years to 18 years)

By school age, most feeding issues have improved. The primary issues in this age range are learning disorders and behavioural problems.[52]

Monitoring and treatment of sinopulmonary infections is important. Therapy is continued as needed for hypothyroidism or hypoparathyroidism. Patients with congenital heart disease and palatal abnormalities may need continued follow-up.

With learning disorders and behavioural problems

  • DiGeorge syndrome children may be shy, withdrawn, or anxious. Rates of attention-deficit/hyperactivity disorder, oppositional defiant disorder, and autistic spectrum disorders are higher than in the general population.[104]

  • The initial approach should involve standard behavioural modification techniques. Management of these symptoms may require consultation with developmental paediatricians and psychiatrists.

  • Although children have speech delay, their language abilities are relatively preserved later in life when non-verbal learning disorders become predominant. Maths skills may be weak. These aspects should be approached with an individualised education plan.

Adults

Regardless of age at diagnosis, follow-up in adults with DiGeorge syndrome is required. Congenital or early-onset features also require frequent monitoring and management as appropriate.[16]​ Increased risk for sinopulmonary infections persists, and infections should be treated aggressively with appropriate antibiotic therapy. Therapy is continued as needed for hypothyroidism or hypoparathyroidism. Patients with congenital heart disease may continue to need follow-up into adulthood.

With psychiatric disorders

  • Psychiatric disorders comprise the majority of late-onset features.[45]​ Psychiatrists should manage patients with psychosis or schizophrenia with appropriate antipsychotic therapy. Depression, anxiety disorders, and bipolar disorder also occur and are managed as for patients without DiGeorge syndrome.[16]

  • Therapy of schizophrenia is generally typical, but resistance to antipsychotic therapy may be more of an issue. There are few published data on therapeutic recommendations for patients with DiGeorge syndrome, but one case report has successfully used aripiprazole for treatment of resistant psychosis, while another successfully used quetiapine.

  • If hypocalcaemia is present it should be corrected, as hypocalcaemia alone may provoke psychosis.[105]

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