Harvey's Garden

Down syndrome

3 min read

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)

  • Flattened facial profile and nasal bridge, upward-slanting palpebral fissures, prominent epicanthal folds, and a small head (brachycephaly). A protruding tongue and small, rounded ears are also common.
  • Eyes: Brushfield spots (small white or grayish spots on the periphery of the iris).

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
  • Early-onset Alzheimer disease (The amyloid precursor protein, which generates amyloid beta, is located on chromosome 21.)

Diagnostics

Treatment

Prenatal testing

Screening Tests (Assess Risk)

  • cffDNA (NIPT): Best screening test (>99% detection rate). Analyzes fetal DNA in maternal blood from 10 wks.
  • 1st Trimester Combined Screen (10-14 wks):
    • ↑ Nuchal Translucency (US)
    • ↑ β-hCG
    • ↓ PAPP-A
  • 2nd Trimester Quad Screen (15-22 wks):
    • ↓ AFP
    • ↑ β-hCG
    • ↓ uE3
    • ↑ Inhibin A
  • US “Soft Markers”: Thickened nuchal fold, absent nasal bone, echogenic intracardiac focus.

Diagnostic Tests (Confirm Dx)

They are offered to women with high-risk screening results or those who desire definitive information

  • Chorionic Villus Sampling (CVS):
    • When: Early (10-13 wks).
    • How: Biopsy of placental tissue.
    • Risk: Higher risk of miscarriage.
  • Amniocentesis:
    • When: Later (15-20 wks).
    • How: Aspirates amniotic fluid.
    • Risk: Lower risk of miscarriage; can also check AFP for neural tube defects.

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