What is the management and treatment approach for a patient with DiGeorge syndrome?

Management and Treatment of DiGeorge Syndrome

DiGeorge syndrome requires multidisciplinary surveillance and management across cardiovascular, immunologic, endocrine, neuropsychiatric, and developmental domains, with treatment intensity determined by the severity of organ system involvement. 1

Initial Diagnostic Confirmation and Risk Stratification

• Confirm 22q11.2 deletion via chromosomal microarray or FISH testing in patients presenting with the clinical triad: thymic hypoplasia, hypoparathyroidism, and conotruncal cardiac defects 1
• Recognize that approximately 15% of patients with tetralogy of Fallot and other conotruncal defects have 22q11.2 deletion 1
• Identify characteristic facial features: hypertelorism, saddle nose, shortened philtrum, low-set abnormally shaped ears 1
• Screen for associated anomalies including cleft palate, velopharyngeal insufficiency, and renal abnormalities 1

Immunologic Assessment and Management

Perform immediate immunologic evaluation to distinguish partial from complete DiGeorge syndrome, as complete athymia requires urgent T-cell reconstitution to prevent fatal infections. 1

Initial Immunologic Workup

• Measure absolute lymphocyte count with CD3, CD4, and CD8 T-cell subsets 1
• Assess T-cell function via mitogen proliferation assays (PHA response) 1
• Measure immunoglobulin levels (IgG, IgA, IgM, IgE) and vaccine-specific antibody responses 1
• Quantify T-cell receptor excision circles (TRECs) if available 1

Management Based on Immunologic Severity

Partial DiGeorge Syndrome (majority of patients):

• Most patients have mild-to-moderate T-cell lymphopenia with normal T-cell function and do not require immunoglobulin replacement 1
• T-cell counts typically increase over time rather than decrease 1
• Administer non-live vaccines without restriction once normal T-cell responses to mitogens and antigens are documented 1
• Withhold live vaccines until normal T-cell responses are confirmed 1
• Provide IgG replacement therapy if hypogammaglobulinemia develops (occurs in approximately 6% of patients) 1
• Monitor for recurrent sinopulmonary infections and treat aggressively 1

Complete DiGeorge Syndrome (athymia, <1% of 22q11.2DS patients):

• Thymus transplantation is the definitive treatment and should be pursued urgently 1, 2
• Survival with thymus transplantation is approximately 75% 1
• Use irradiated, CMV-negative blood products exclusively to prevent transfusion-associated graft-versus-host disease 1, 3
• Provide prophylaxis against Pneumocystis jirovecii and other opportunistic infections 1
• Avoid all live vaccines 1
• Bone marrow transplantation is an alternative but has higher mortality (53% in combined series) 2

Cardiovascular Management

• Conotruncal cardiac defects occur in approximately 75% of patients, most commonly tetralogy of Fallot, interrupted aortic arch (type B), truncus arteriosus, and ventricular septal defects 1
• Cardiac surgery in DiGeorge patients requires specialized perioperative management due to high rates of complications 3
• Anticipate complex reoperations with potential for vascular injury (occurred in 8 of 62 patients in one series) 3
• Prepare for prolonged mechanical ventilation (required in 35% of procedures) and inotropic support (18% requiring >72 hours) 3
• Monitor closely for postoperative infections (23% incidence) related to immunodeficiency 3
• Coordinate cardiac surgery timing with immunologic status when possible 2

Endocrine Management

Hypoparathyroidism and Hypocalcemia:

• Screen for hypocalcemia at diagnosis and perioperatively 1
• Maintain intravenous calcium chloride infusion readily available during cardiac surgery 3
• Persistent hypocalcemia developed intraoperatively in 2 of 62 surgical patients and postoperatively in 8 patients in one series 3
• Provide long-term calcium and vitamin D supplementation as needed 1
• Monitor for hypothyroidism and other endocrinopathies that develop with age 1

Neuropsychiatric and Developmental Management

Implement early developmental screening and intervention, as neurodevelopmental delays and psychiatric disorders are highly prevalent and often emerge over time. 1

Pediatric Surveillance

• Perform developmental screening at 9,18,30, and 48 months per American Academy of Pediatrics guidelines 1
• Screen for autism spectrum disorders at 18 and 24 months 1
• Refer to early intervention services for any identified delays 1
• Monitor for speech and language deficits, which are extremely common 1
• Assess for learning disabilities and provide educational support 1

Adult Neuropsychiatric Issues

• Screen for schizophrenia and psychotic disorders, which affect up to 25% of adults with 22q11.2DS 1
• Monitor for depression, anxiety disorders, and attention deficit disorders 1
• Provide genetic counseling regarding 50% recurrence risk in offspring 1
• Address psychosocial issues including employment, independent living, and reproductive health 1

Multisystem Surveillance Schedule

Pediatric patients require comprehensive subspecialty evaluation and ongoing surveillance across multiple organ systems. 1

• Cardiology: Baseline echocardiogram and ongoing monitoring based on defect severity 1
• Immunology: Baseline evaluation and periodic reassessment, especially before live vaccines 1
• Endocrinology: Calcium monitoring and thyroid function testing 1
• Genetics: Confirmation testing and family counseling 1
• Otolaryngology: Assessment for velopharyngeal insufficiency, hearing loss 1
• Nephrology: Renal ultrasound to detect structural anomalies 1
• Developmental pediatrics/Neurology: Serial developmental assessments 1

Adult patients require continued multidisciplinary care with attention to late-onset complications. 1

Critical Pitfalls to Avoid

• Never assume immunodeficiency is absent based on normal immunoglobulin levels alone—T-cell function must be directly assessed 1
• Do not delay thymus transplantation evaluation in complete DiGeorge syndrome, as mortality from infection is extremely high without intervention 1, 2
• Recognize that patients with conotruncal defects and complete DiGeorge syndrome have 45% mortality before transplantation 2
• Ensure irradiated blood products are used in patients with severe T-cell deficiency 1, 3
• Do not overlook psychiatric screening in adolescents and adults, as early-onset schizophrenia risk is substantially elevated 1
• Remember that approximately 18% of congenital heart defects are associated with genetic syndromes, making DiGeorge syndrome screening important in this population 1