What are the features of 22q11.2 deletion syndrome?

Features of 22q11.2 Deletion Syndrome

22q11.2 deletion syndrome is characterized by multisystem involvement including congenital heart defects, palatal abnormalities, immune dysfunction, hypocalcemia, and neuropsychiatric disorders, with variable expressivity even within families. 1

Genetic Basis

• Heterozygous deletion of chromosome 22q11.2 region (typically 2.5-3 Mb)
• Most deletions (85%) involve the typical LCR22A-LCR22D region containing ~50 genes 1, 2
• Majority (93%) occur as de novo events; ~7% are inherited from an affected parent 2
• TBX1 gene deletion is particularly associated with cardiac and other physical anomalies 3

Major Clinical Features by System

Cardiovascular (64-91%)

• Conotruncal cardiac anomalies:
  • Tetralogy of Fallot
  • Ventricular septal defects
  • Truncus arteriosus
  • Aortic arch anomalies 1, 2
• EKG abnormalities and arrhythmias may develop over time 1

Palatal/Craniofacial (67%)

• Velopharyngeal dysfunction
• Submucous cleft palate
• Overt cleft palate/lip (less common)
• Characteristic facial features:
  • Malar flatness
  • Hooded eyelids
  • Upslanting palpebral fissures
  • Bulbous nasal tip
  • Overfolded helices of ears 1

Immune System (77%)

• T-cell deficiency due to thymic hypoplasia
• Recurrent infections (particularly respiratory)
• Autoimmune disorders
• Allergies 1, 2, 3

Endocrine (>50%)

• Hypocalcemia due to hypoparathyroidism
  • Can cause seizures, tetany, and cardiac arrhythmias 4
• Thyroid dysfunction
• Growth hormone deficiency 1, 3

Neuropsychiatric

• Developmental delay/intellectual disability (median IQ ~76) 2
• Learning disabilities
• Speech and language delays
• Increased risk for psychiatric disorders:
  • Attention deficit hyperactivity disorder
  • Anxiety disorders
  • Schizophrenia (20-25% of adults) 1

Gastrointestinal (65%)

• Feeding difficulties in infancy
• Gastroesophageal reflux disease
• Constipation
• Structural anomalies (less common) 1, 2

Airway (71% of those assessed)

• Tracheomalacia (36%)
• Subglottic stenosis (28%)
• Laryngomalacia (26%)
• Glottic web (21%)
• May require tracheostomy in severe cases 5

Skeletal

• Scoliosis (50%)
• Vertebral anomalies
• Limb differences (e.g., arachnodactyly, syndactyly) 1, 2

Genitourinary

• Renal anomalies (16%)
• Genitourinary malformations 2, 3

Age-Related Manifestations

Neonatal/Infancy

• Congenital heart defects
• Hypocalcemia
• Feeding difficulties
• Immunodeficiency
• Polyhydramnios during pregnancy (16%) 1, 5

Childhood

• Speech and language delays
• Developmental delays
• Recurrent infections
• Learning disabilities 1

Adolescence/Adulthood

• Psychiatric disorders emerge (especially schizophrenia)
• Endocrine disorders may develop or worsen
• Scoliosis progression
• Additional medical problems accumulate with age 1, 6

Management Considerations

Diagnostic Testing

• Chromosomal microarray analysis (CMA) is preferred
• FISH testing may miss smaller or atypical deletions (6% of cases) 1, 2

Surveillance Recommendations

• Regular cardiac evaluations
• Calcium, PTH, and thyroid function monitoring
• Immunologic assessment
• Developmental/neuropsychiatric evaluations
• Speech and feeding assessments 1

Treatment Approach

• Multidisciplinary care coordination is essential
• Cardiac surgical repair when indicated
• Calcium and vitamin D supplementation for hypocalcemia
• Speech therapy for velopharyngeal dysfunction
• Early intervention for developmental delays 1, 4

Important Considerations

• Features accumulate over time - median of 9 features per patient (range 3-22) 6
• Phenotypic variability is significant, even within families
• Many treatable conditions may be anticipated with appropriate surveillance
• Early diagnosis allows for better anticipatory care and improved outcomes 1