Epidemiology

• Most common viable autosomal chromosome aberration (∼ 1:700 live births) and most common genetic cause of cognitive impairment
• The risk of a Down syndrome pregnancy increases with maternal age.
  • Incidence at 20 years: ∼ 1:2000
  • Incidence at 45 years: ∼ 1:30

Etiology

Full trisomy 21 (∼ 95% of cases)

• Definition: three complete copies of chromosome 21 are present in all cells, with a total of 47 chromosomes
• Pathogenesis: meiotic nondisjunction
• Karyotype: ♀: 47,XX,+21 or ♂: 47,XY,+21

Translocation trisomy 21 (3–4% of cases)

• Definition: three copies of chromosome 21 are present, one of which is attached to another chromosome, usually chromosome 14 (less likely attached to chromosomes 13, 15, or 22)
• Pathogenesis and karyotype
  • Balanced Robertsonian translocation: translocation of the long arm of chromosome 21 to the long arm of chromosome 14. Not symptomatic, but can affect future generations
  • Unbalanced Robertsonian translocation: clinical features of trisomy 21 caused by inheritance of a translocation chromosome and a normal chromosome

Mosaic trisomy 21 (1–2% of cases)

• Definition: two cell lines are present, the trisomy 21 cell line and the normal cell line
• Phenotypic expression varies according to the ratio of healthy to trisomic cells.

Pathophysiology

Clinical features

Facial and cranial features (craniofacial dysmorphia)

• Eyes
  • Upward-slanting palpebral fissures
  • Epicanthal folds
  • Ocular hypertelorism: a distance between the eyes greater than the 95th percentile
  • Brushfield spots: an aggregation of connective tissue in the periphery of the iris, visible as white or grayish-brown spots.
• Hypoplastic nasal bones, broad and flat nasal bridge

Extremities, soft tissue, and skeletal features

• Extremities
  • Transverse palmar crease: single crease that runs across the palm, along the metacarpophalangeal joints perpendicular to the fingers
  • Sandal gap: a medial displacement of the first toe leading to a large space between the first and second toes
  • Clinodactyly: abnormal curvature of a finger (typically refers to inward curvature of the 5th finger)
• Skeletal features
  • Atlantoaxial instability
  • Short stature

Organ malformations and associated conditions

• Heart: congenital heart defects in ∼ 50% of cases
  • Atrioventricular septal defect (endocardial cushion defect) is the most common heart defect in individuals with Down syndrome.
  • Ventricular septal defect
  • Atrial septal defects
• Gastrointestinal tract
  • Duodenal atresia/stenosis
  • Hirschsprung disease
• Early-onset Alzheimer disease (The amyloid precursor protein, which generates amyloid beta, is located on chromosome 21.)

Diagnostics

Treatment