What is the management approach for DiGeorge syndrome (22q11.2 deletion syndrome)?

DiGeorge Syndrome (22q11.2 Deletion Syndrome): Comprehensive Management

DiGeorge syndrome requires immediate immunological classification to determine severity, followed by coordinated multidisciplinary care addressing cardiac, endocrine, developmental, and neuropsychiatric manifestations throughout the lifespan. 1, 2

Genetic Foundation and Nomenclature

• DiGeorge syndrome, velocardiofacial syndrome, and conotruncal anomaly face syndrome all represent the same 22q11.2 microdeletion with variable phenotypic expression 1
• The typical deletion spans 2.5 to 3 Mb from LCR22A to LCR22D on chromosome 22q11.2 1
• Incidence is approximately 1 in 2,000 to 1 in 3,000 live births, making it the most common microdeletion syndrome 1, 3
• 90-95% of cases are de novo deletions, while 5-10% are inherited 1, 2
• Affected individuals have 50% recurrence risk for offspring 1, 2

Initial Diagnostic Approach

• Fluorescence in situ hybridization (FISH) and other molecular techniques detect the 22q11.2 deletion with extremely high accuracy 1
• High collective penetrance ensures at least one major phenotypic feature will be present 1
• Immediate immunological assessment is the first critical step after diagnosis to classify severity and guide management 1, 2

Immunological Management: Severity-Based Algorithm

Complete Athymia (CD3+ T lymphocytes <50 cells/μL)

• Thymus transplantation is required for T-cell reconstitution 1, 2
• Do not administer any live vaccines 1, 2
• Implement strict infection prevention protocols 1, 2
• Monitor vigilantly for opportunistic infections including Pneumocystis jirovecii pneumonia, CMV pneumonitis, and persistent candidiasis 1, 2

Partial Thymic Hypoplasia (CD3+ T lymphocytes <1500 cells/μL)

• Periodic immunologic re-evaluation is essential as T-cell numbers typically increase over time 1, 2
• Withhold live vaccines until documented normal T-cell responses to mitogens and antigens 1, 2
• Consider antibiotic prophylaxis for recurrent sinopulmonary infections 1, 2
• Consider IgG replacement therapy if recurrent infections persist 1, 2

Immune Dysregulation (CD3+ T lymphocytes >50 cells/μL with naive T cells <5% of total CD3+)

• Monitor for autoimmunity, particularly hematologic cytopenias 1, 2
• Watch for Omenn syndrome-like features 1, 2
• Assess for IgA deficiency and hypogammaglobulinemia 2

Cardiovascular Management

• Congenital heart defects occur in 68% of patients and are the leading cause of mortality 1
• Conotruncal cardiac anomalies predominate, linked to TBX1 gene haploinsufficiency 1, 4
• Mortality rates range from 5-15%, with most deaths in the first year of life related to complex congenital heart disease 1, 4
• The death rate in children with 22q11.2DS and congenital heart defects exceeds that of children with comparable heart defects without the deletion 4
• All patients require cardiology evaluation and ongoing surveillance 1, 2
• Women planning pregnancy require genetic counseling due to 50% recurrence risk and increased offspring cardiac defect risk 1, 4

Endocrine Management

• Hypoparathyroidism with hypocalcemia occurs in 63% of patients 1
• Regular calcium level monitoring is mandatory, particularly during stress, illness, or surgery 1, 2
• Treat hypocalcemia promptly with calcium and vitamin D supplementation 1, 2
• Monitor calcium levels more frequently during periods of physiologic stress 1, 2

Neuropsychiatric and Developmental Management

Age-Dependent Priorities

Infancy and Preschool Years:

• Focus on acute medical problems including congenital heart disease, immune disorders, feeding problems, cleft palate, and developmental delays 1
• Implement early intervention services for developmental concerns 2

School Years:

• Shift focus to cognitive, behavioral, and learning disorders 1
• Mental impairment affects the majority of patients 1
• Coordinate educational support services 1

Late Adolescence and Adulthood:

• Neuropsychiatric disorders become the most common later-onset conditions and typically of greatest concern to families 5, 1
• Approximately one in four to five adults will develop schizophrenia, usually in late adolescence or early adulthood 5
• This represents a greater than 20-fold increase in schizophrenia risk compared to the general population 5

Schizophrenia Management

• Schizophrenia associated with 22q11.2DS is essentially indistinguishable from idiopathic schizophrenia regarding prodrome, age at onset, presentation, and cognitive profile (apart from lower mean IQ) 5
• Standard management according to clinical practice guidelines for schizophrenia is recommended, including antipsychotic medications 5
• Use a "start low, go slow" approach to antipsychotic dosing 5
• Consider prophylactic anticonvulsant management strategies to ameliorate seizure risk, particularly during clozapine treatment 5
• Informed discussion about schizophrenia as a lifelong but treatable and manageable condition is essential 5
• Place the disease in context of other chronic diseases such as diabetes mellitus 5
• Promptly seek expert help in diagnosis and effective treatment to improve prognosis 5

Coordinated Multidisciplinary Care Structure

Each patient requires tailored care coordinated among multiple specialties: 1, 2

• Immunology: Immune deficiency management and vaccination guidance 1, 2
• Cardiology: Congenital heart defect evaluation and management 1, 2, 4
• Endocrinology: Hypoparathyroidism and calcium monitoring 1, 2
• Developmental Pediatrics: Cognitive and behavioral issues 1, 2
• Genetics: Ongoing counseling and family planning 1, 2
• Psychiatry: Neuropsychiatric disorder screening and management 5, 1
• Additional specialists based on individual manifestations: ENT, nephrology, ophthalmology 1

Critical Management Pitfalls to Avoid

• Never administer live vaccines without documented normal T-cell responses 1, 2
• Do not assume T-cell function is adequate based on standard enumeration alone; the T-cell compartment is often less robust than indicated by standard counts 6
• Do not overlook calcium monitoring during periods of stress, illness, or surgery when hypocalcemia risk increases 1, 2
• Avoid dismissing psychiatric symptoms as "just behavioral"; early recognition and treatment of emerging psychiatric illness improves prognosis 5
• Do not use standard antipsychotic dosing without considering increased seizure risk; start low and go slow 5
• Recognize that all associated conditions in 22q11.2DS respond similarly to idiopathic forms with standard management strategies, but the multisystem nature demands attention from all clinicians regardless of subspecialty 5

Lifespan Surveillance Requirements

• Regular screening for associated comorbidities must continue throughout the lifespan 1, 2
• Monitor for immune dysregulation and autoimmunity 1, 2
• Ongoing psychiatric surveillance, particularly during adolescence and early adulthood 5, 1
• Continuous endocrine monitoring for calcium levels 1, 2
• Cardiac surveillance for both congenital defects and acquired conditions 1, 4