What are the common clinical findings in 22q11.2 deletion syndrome?

Common Clinical Findings in 22q11.2 Deletion Syndrome

22q11.2 deletion syndrome (22q11.2DS) presents with a complex multisystem disorder affecting multiple organ systems, with key manifestations including congenital heart defects, palatal abnormalities, immune dysfunction, endocrine disorders, neurological issues, and characteristic facial features. 1

Cardiovascular Manifestations

• Congenital heart defects occur in approximately 25.8% of patients 2
• Common cardiac anomalies include:
  • Tetralogy of Fallot
  • Truncus arteriosus
  • Ventricular septal defects
  • Interrupted aortic arch

Immunological Features

• T-cell deficiency due to thymic hypoplasia or aplasia
• Progressive loss of antibody function with diminished immunoglobulin levels in some children
• Recurrent and prolonged respiratory tract infections (both upper and lower)
• Increased susceptibility to autoimmunity (up to 20%)
• Increased risk of allergies (up to 40%) 1

Endocrine Abnormalities

• Hypocalcemia due to hypoparathyroidism
• Thyroid dysfunction including hypothyroidism
• Hypocalcemia may trigger seizures or worsen movement disorders 1

Neurological Findings

• Seizures (4-fold increased risk of epilepsy in adults) 1
• Movement disorders including early-onset Parkinson's disease in adults
• Structural brain abnormalities may include:
  • Polymicrogyria
  • Gray matter heterotopia
  • Chiari malformation
  • Cervical spine instability (rarely requiring decompression) 1

Palatal and Speech Abnormalities

• Palatal abnormalities in approximately two-thirds of children 1
• Velopharyngeal dysfunction (VPD) with or without submucous cleft palate
• Overt cleft palate less common
• Communication disorders are hallmark features:
  • Delayed speech and language development
  • Both receptive and expressive language delays
  • Speech apraxia
  • Hypernasality and poor intelligibility 1, 3

Musculoskeletal Features

• Scoliosis (adolescent idiopathic type)
• Cervical/occipital anomalies (found in almost all children but rarely consequential)
• Other skeletal issues may include:
  • Joint dislocations
  • Clubfoot
  • Patellar issues
  • Polydactyly
  • Foot anomalies 1

Hematological Findings

• Mild to moderate thrombocytopenia that may progress with age
• Increased platelet volume
• Increased risk for hematologic autoimmunity:
  • Immune thrombocytopenia
  • Autoimmune hemolytic anemia
  • Autoimmune neutropenia 1

Cognitive and Psychiatric Features

• Learning disabilities (77% of patients) 3
• Developmental delay (54% of patients) 3
• Speech delay (57% of patients) 3
• Anxiety disorders (2-3 times higher than general population)
• Increased risk of psychotic disorders (20-fold increased risk of schizophrenia)
• Autism spectrum disorders may persist into adulthood 1

Characteristic Facial Features

• Long face (77% of patients) 3
• Typical nose (69% of patients) 3
• Hooded eyelids (54% of patients) 3
• Other subtle dysmorphic features

Diagnostic Considerations

• Features vary with age, ascertainment, and assessment method 2
• Patients typically have multiple features (median 9, range 3-22) 2
• Number of features correlates with hospitalizations and may accumulate over time 2

Clinical Pitfalls and Caveats

• The phenotype varies significantly between patients, even within families
• Smaller, atypical deletions (central 22q11.2 deletions) may present with different phenotypes:
  • Lower prevalence of congenital heart anomalies
  • Absence of cleft palate
  • Similar frequency of developmental delays and cognitive impairments 4
• Deletions encompassing the MAPK1 gene have a more severe phenotype with higher prevalence of heart anomalies, growth restriction, and microcephaly 4
• Features may accumulate over time, requiring ongoing surveillance throughout the lifespan 1, 2
• Patients with palatal abnormalities and speech delay, learning disabilities, conductive hearing loss, long face, and hooded eyelids should be evaluated for 22q11.2DS 3