What are the recommended diagnostic steps and lifelong multidisciplinary management for a patient with 22q11.2 deletion (DiGeorge/velocardiofacial) syndrome?

22q11.2 Deletion Syndrome: Diagnostic and Management Approach

Confirm the diagnosis with chromosomal microarray or FISH testing targeting the 22q11.2 region, then immediately implement lifelong multidisciplinary surveillance across cardiac, immunologic, endocrine, psychiatric, and developmental domains. 1

Initial Diagnostic Evaluation

Genetic Confirmation

• Obtain chromosomal microarray analysis or fluorescence in situ hybridization (FISH) using probes for the 22q11.2 region (LCR22A-LCR22D) to confirm the deletion 1
• Review the genetic test report for specific deletion size (typical 3 Mb LCR22A-D deletion vs. smaller 1.5-2 Mb variants) and any additional clinically relevant variants 1
• The syndrome occurs in approximately 1 in 2,148 live births, making it the most common microdeletion syndrome 1

Immediate Baseline Assessments

Cardiac evaluation (present in ~40% of patients):

• Echocardiography to detect conotruncal defects, especially tetralogy of Fallot, interrupted aortic arch, ventricular septal defects, and vascular rings 1
• ECG to assess for baseline rhythm abnormalities and QT interval 1, 2

Immunologic screening (critical in early infancy):

• Complete blood count with differential to assess lymphocyte populations 1
• T-cell subset analysis (CD3, CD4, CD8 counts) to determine severity of immunodeficiency 1
• Determine immediately if T-cell deficiency is severe enough to require thymus transplant or irradiated blood products 1
• Assess whether T-cell counts are sufficient for live viral vaccines 1
• Immunoglobulin levels (IgG, IgA, IgM) to monitor for progressive antibody deficiency 1

Endocrine evaluation:

• Serum calcium (ionized preferred), phosphorus, magnesium, and parathyroid hormone to detect hypoparathyroidism 1, 2
• Thyroid-stimulating hormone (TSH) and free T4, as hypothyroidism affects >25% of adults 1, 2
• Start prophylactic calcium and vitamin D supplementation in all patients regardless of current calcium levels 1, 2

Renal imaging:

• Renal ultrasound to detect structural anomalies (present in a significant minority) 1

Lifelong Multidisciplinary Surveillance Schedule

Cardiovascular Monitoring

• Annual cardiology follow-up for all patients, even those without congenital heart disease at diagnosis 1
• Adults with repaired tetralogy of Fallot require ongoing surveillance for pulmonary valve regurgitation, ventricular dysfunction, and arrhythmias 1
• Monitor for late-onset aortic root dilation in adulthood 1
• Pregnancy in women with cardiac lesions requires high-risk obstetric care and cardiology co-management 1

Immunology and Infection Management

• Annual complete blood counts to monitor for progressive thrombocytopenia, autoimmune cytopenias, and leukopenia 1
• Recurrent or opportunistic infections warrant repeat immunologic evaluation (T-cell function, specific antibody responses) 1
• Up to 20% develop autoimmune disorders; up to 40% develop allergies 1
• A minority require immunoglobulin replacement therapy in adulthood 1
• Administer all standard vaccinations including COVID-19 and influenza, though antibody response may be reduced 1

Endocrine Surveillance

• Routine thyroid function testing (TSH minimally), as hypothyroidism prevalence exceeds 25% in adults 1, 2
• Serial calcium monitoring throughout life; hypocalcemia affects approximately 80% of adults and can emerge at any age even without prior history 1, 2
• Maintain calcium and vitamin D supplementation lifelong 1, 2
• Obtain 12-lead ECG when hypocalcemia is detected to assess QT prolongation and arrhythmia risk 2

Musculoskeletal Screening

• Scoliosis screening with scoliometer starting at age 6 years, with radiography every 2 years until skeletal maturity 1
• One-time cervical spine radiography (including flexion-extension views with atlas-dens measurements) around age 4 years to detect instability 1
• Evaluate for patellar dislocation, pes planovalgus, and other foot anomalies as clinically indicated 1
• Consider orthotics for frequent nonspecific lower leg/foot pain associated with flat feet 1

Hematology Monitoring

• Annual complete blood counts to track mild-to-moderate thrombocytopenia and increased platelet volume 1
• Perioperative monitoring of CBC and calcium levels before any surgical procedure 1
• Be vigilant for autoimmune thrombocytopenia and hemolytic anemia 1
• No routine cancer surveillance is recommended, but evaluate concerning symptoms promptly given reports of increased pediatric malignancies (Wilms tumor, lymphoma, medullary thyroid carcinoma) 1

Neuropsychiatric and Developmental Management

Cognitive and learning support:

• Comprehensive neuropsychological assessment to establish baseline cognitive functioning and guide individualized educational planning 2
• Most patients require speech therapy for velopharyngeal insufficiency and articulation disorders 1
• Learning disabilities and developmental delays are common; early intervention services are essential 1

Psychiatric surveillance (critical from adolescence onward):

• Psychosis develops in ~10% by late adolescence and 25-40% over the lifespan 2
• Screen routinely for anxiety, depression, ADHD, and autism spectrum features 1
• Avoid cannabis and psychoactive substances, which markedly increase psychosis risk 2
• Implement stress-reduction strategies, as individuals experience greater perceived stress and reduced resilience 2

Seizure monitoring:

• Individuals have a four-fold increased risk of epilepsy; seizures may be precipitated by hypocalcemia, medications, or physiological stress 2
• Hypocalcemic seizures typically resolve after calcium repletion 2
• Consider repeat EEG when neuropsychiatric status deteriorates or seizure activity is suspected 2

Reproductive Health and Genetic Counseling

• Provide developmentally appropriate sex education and contraceptive counseling to all adolescents and adults 1
• Preconception counseling is essential: offspring have 50% risk of inheriting the deletion 1
• Pregnancies require high-risk obstetric care due to elevated maternal and fetal complications 1
• Fetuses with 22q11.2DS have increased risk of intrauterine growth restriction, polyhydramnios, and prematurity regardless of parental affected status 1
• Recommend delivery at a tertiary care facility with neonatal intensive care and pediatric cardiology available 1

Critical Management Pitfalls to Avoid

Medication Safety

• "Start low, go slow" with all psychotropic medications due to heightened drug sensitivity 1, 2
• Avoid initiating antipsychotics during active catatonia, as they can precipitate neuroleptic malignant syndrome 2
• If clozapine is required for treatment-resistant psychosis, co-prescribe prophylactic anticonvulsants due to lowered seizure threshold 2
• Smaller endotracheal tube sizes may be needed for intubation; rarely, cervical spine anomalies require attention 1

Hypocalcemia Management

• Treat hypocalcemic seizures emergently with IV calcium gluconate 50-100 mg/kg over 10 minutes under continuous ECG monitoring 2
• Correct co-existing hypomagnesemia, which frequently accompanies hypocalcemia 2
• Hypocalcemia can manifest with rigidity and altered mental status that mimic psychiatric conditions 2

Catatonia Recognition and Treatment

• If catatonia develops, benzodiazepines (lorazepam ≥6 mg/day) are first-line treatment 2
• ECT is highly effective and safe for catatonia in adolescents with 22q11.2DS if no improvement after 4-6 weeks of adequate-dose lorazepam or if life-threatening complications arise 2
• Intellectual disability is not a contraindication to ECT 2

Care Coordination

• Designate a single clinician to coordinate multidisciplinary care among psychiatry, neurology, endocrinology, cardiology, and primary care 1, 2
• Do not rely exclusively on caregiver reports; direct clinical assessment is essential as discrepancies frequently exist 2
• Initiate transition planning to adult services before age 18, identifying providers experienced with 22q11.2DS 2
• Family and caregiver input is vital, as individuals with intellectual disability may have limited ability to self-report symptoms 2

Sleep Assessment

• Perform polysomnography when sleep quality has not been evaluated, as sleep-disordered breathing is common and worsens neuropsychiatric symptoms 2