Down Syndrome (Trisomy 21) - Mechanism of Disease Map

Key Topics

• Etiology
• Pathophysiology
• Manifestations

Legend

• Each box is color coded according to the legend in the top right.

Pathophysiology

Excess Genetic Material from Chromosome 21

• Most common: Full Trisomy 21 (95% of cases)
  • Nondisjunction: Chromosomes fail to separate during meiosis
  • More common in maternal meiosis 1 (70%), less in maternal meiosis 2, least in paternal meiosis 2
  • Higher risk with increased parental age
  • Karyotype: 47 chromosomes
    • Male: 47, XY, +21
    • Female: 47, XX, +21

Translocation Trisomy 21 (3-4% of cases)

• Unbalanced Robertsonian Translocation: Third copy of chromosome 21 attached to another chromosome (usually chromosome 14)
• Balanced Robertsonian Translocation: No Down Syndrome phenotype, can cause miscarriages
  • Karyotype
    • Balanced: 45 chromosomes (extra piece of chromosome 21 on chromosome 14)
    • Unbalanced: Normal number of chromosomes but with extra genetic material from chromosome 21

Mosaic Trisomy 21

• Mosaic Pattern: Both trisomy 21 and normal cell lines
• Result of nondisjunction during mitosis after fertilization
• Karyotype: Varies by cell
  • Normal: 46, XX or 46, XY
  • Trisomy 21: 47, XX, +21 or 47, XY, +21

Manifestations

Characteristic Appearance

• Eyes: Upslanting palpebral fissures, epicanthal folds, Brushfield spots
• Mouth: Small with large, protruding tongue; Smaller teeth with gaps
• Nose: Hypoplastic nasal bone, broad and flat nose with flat nasal bridge
• Ears: Small, low-set, round ears with adherent earlobes
• Neck: Short, predisposing to obstructive sleep apnea
• Extremities: Transverse palmar creases, sandal gap, clinodactyly, shorter limbs and stature

Organ Malformations

• Heart: Atrioventricular septal defects, ASD, VSD, PDA, Tetralogy of Fallot
• GI tract: Duodenal atresia/stenosis, annular pancreas, anal atresia, rectal prolapse, Hirschsprung's disease, celiac disease
• Genitourinary Tract: Hypogonadism, cryptorchidism (undescended testicles), impaired spermatogenesis leading to decreased fertility

Endocrine Disorders

• Higher risk of hypothyroidism, type 1 diabetes, and obesity (due to decreased metabolism, high leptin levels, decreased physical activity)

Behavioral and Intellectual Problems

• Motor: Delayed development, muscle hypotonia
• Intellectual Disability: Severe, average IQ of 50
• Developmental Milestones: Delayed (standing, walking, running at twice normal age)
• Predisposition to ADHD and conduct disorder
• Early onset Alzheimer's (due to amyloid precursor protein on chromosome 21)
• Social: Autism spectrum disorder

Increased Risk of Malignancy

• Acute lymphoblastic leukemia (ALL)
• Acute myeloid leukemia (AML)