Trisomy 21 (Down Syndrome)

 

Epidemiology and Etiology:

    • 1:700 newborns
      • Most common single known cause of mental retardation
    • Meiotic nondisjunction in maternal M1 usually
      • Maternal origin in 95%
    • Trisomy 21 (95%)
    • Translocation resulting in 3 copies of 21q
      • Robertsonian translocation of 21q to another acrocentric chromosome (4% of Down)
      • Often inherited from the mother
      • Risk of recurrence is much lower than the theoretical 1 in 3 chance of passing it on
    • Parts of 21q22.2 and 22q22.3 may be the most critical areas for many of Down Syndrome features
    • Risk factors:
      • Advanced maternal age (1:25 for mothers > 45y)
    • 1% are mosaics
      • Resulting from mitotic nondisjunction at an early stage of embryonic development
      • Milder, variable phenotype

 

Common sites:

    •  

 

Gross features:

    • Hydrops fetalis maybe
    • Facies:
      • Flat nasal bridge
      • Upward slanting palpebral fissures
      • Epicanthal folds
      • Small mouth
      • Thick lips
      • Protruding tongue
      • Flat occiput
      • Small, overfolded ears
    • Abundant nuchal skin
    • Cardiac (40%)
      • Endocardial cushion defects
        • Ostium primum
        • ASD
        • AV valve malformations
        • VSD
        • PDA
    • GI atresias
      • Esophagus
      • Small bowel
    • Annular pancreas
    • Megacolon
    • Choanal atresia
    • Umbilical hernia
    • Hands and feet
      • Small
      • Simian crease
      • Gap between first and second toe
      • Hypoplasia of mid-phalanx of 5th finger
    • Hypotonia
    • Small stature

 

Histologic features:

    •  

 

Immunophenotype:

Marker:

Sensitivity:

Specificity:

 

 

 

 

Molecular features:

    •  

 

Other features:

    • Clinical features:
      • Mental retardation
    • Ultrasounds:
      • Nuchal fold
      • Absent / hypoplastic nasal bone
      • Short long bones
      • Heart defects
      • Hyperechoic bowel
      • Echogenic intracardiac focus
      • Pyelectasis
      • Ventriculomegaly
      • Hypoplasia of 5th digit
      • Wide iliac angle
    • Complications:
      • Hydrops fetalis
      • Increased risk of acute leukemia (10-100x risk)
        • ALL
        • AML (usually acute megakaryoblastic leukemia) (1-2% of DS children during first 5 y)
          • 150x increase in risk < 5y compared to non-DS children
        • Transient myeloproliferative disorder (TMPD)
          • Newborn
          • High spontaneous remission rate
          • Occasional relapse
        • Bimodal age of onset
          • Newborn
          • 3-6 y
      • Death in early infancy or childhood due to cardiac malformations
      • Alzheimer disease (virtually all > 40y)
      • Abnormal immune responses
        • Serious infections
          • Lungs
        • Autoimmunity
          • Thyroid
      • cataracts
      • Median age at death is 47y
    • Councelling:
      • Recurrence risk 1% in women < 30y
        • Including other trisomies
      • Recurrence risk no different from age-specific risk > 30y
      • Gonadal mosaicism in parents is suggested in cases of recurrent trisomy 21

 

References:

    • Robbins & Cotran Pathologic Basis of Disease (2005)
    • Gersen SL, Keagle MB, eds.  The Principles of Clinical Cytogenetics (2005)
    • Evans MI, ed.  Prenatal Diagnosis (2006)