Downs Syndrome

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Down's Syndrome is a genetic condition caused by three copies of Chromosome 21, 'Trisomy 21', which affects most organ systems in the body. It is the most common and best known chromosomal disorder in humans.

  • First described by british doctor John Down in 1866. Elucidated as trisomy 21 in 1959.


Contents


Incidence and Risk

Risk is proportional to maternal age at conception.

  • However, it remains that most children with Down's Syndrome are born to young mothers since this age group have many more babies.
  • Incidence ~ 1 in 800 live births.
  • Mild male preponderance. (1.15:1).


Table 1 - Age risk of Down's Syndrome [1]

Maternal Age Risk at Birth Risk at 12/40
25 1/1352 1/795
30 1/895 1/526
32 1/659 1/388
34 1/446 1/262
36 1/280 1/165
38 1/167 1/98
40 1/97 1/57
42 1/55 1/32
44 1/30 1/18

Screening

In the UK, it is recommended that all women are offered second trimester screening for Down's Syndrome. The screen is not 'definitive' and provides a "risk assessment". All screens have a false positive rate.


First Trimester screening

  • Combined test (91% detection, 5% false positive)
    • Nuchal translucency - increased in Down's Syndrome (ultrasound screening at 10-14 weeks)
    • Serum tests (10 weeks)
      • serum free ß-HCG
      • Pregnancy Associated Plasma Protein A (PAPP-A)


Second Trimester screening

  • Quadruple test
    • Alpha fetoprotein (aFP): low in Down's syndrome
    • unconjugated oestriol (low)
    • Human chorionic gonadotrophin, hCG (high)
    • Inhibin (high)
  • Triple test (being superceded by quadruple test)
    • Same as quadruple test, but without Inhibin measurement.
  • Integrated test ~ 85% detection rate, 1.2% false positive rate
    • Nuchal translucency at 10 weeks
    • PAPP-A at 10 weeks
    • Quadruple test at 14-16 weeks.


False positives may be due to incorrect dates, normal variation or multiple foetuses (undetected).


A positive screen usually prompts genetic couselling and testing (see #Diagnosis below).

Diagnosis

Antenatal genetic couselling and testing is offered to women at high risk, or where screens have suggested problems. All methods are invasive with a ~1% risk of miscarriage associated

  • Chorionic villous sampling (11-13 weeks) ~ 1% risk miscarriage
  • Amniocentesis (after 14 weeks) ~ 1% risk miscarriage
  • Cordocentesis (after 20 weeks) ~ 1% risk miscarriage


Postnatal

  • Clinical suspicion
  • Karyotyping


Clinical Features

  • Syndromic facies
    • Flat face and nasal bridge
    • Slanting eyes with epicanthic folds
    • protruding tongue (rather than enlarged) due to small oral cavity
    • Small ears
  • Short neck
  • Brachycephaly
  • Hypotonia
  • Single palmar crease (previously described as a 'Simian Crease')
  • Short stubby fingers
  • 'Sandal Gap' (enlarged gap between first and second toes)
  • Brushfield spots (white spots on the Iris)
  • Variable learning difficulties
  • Short stature
  • Atlanto-axial instability ~14% causing spinal cord compression (2%)


Associated conditions:

  • Congenital heart disease ~ 50%
    • Endocardial cushion defects (40%)
    • Ventricular septal defects (30%)
    • Secundum atrial septal defect (10%)
    • Tetralogy of Fallot (6%)
    • Patent Ductus Arteriosus (PDA) (4%)
  • Gastro-oesophageal reflux
  • Oesophageal atresia
  • Duodenal atresia
  • Hirschsprung's disease
  • Impaired immune system
  • Leukaemia
  • Large tonsils / adenoids
  • Glossoptosis / obstructive sleep apnoea
  • Visual and hearing impairments
  • Thyroid dysfunction
  • Epilepsy


Later life

  • Reduced fertility
  • Premature aging
  • Early onset Alzheimer's disease
  • Reduced risk of atherosclerosis and most cancers (not leukaemia or testicular cancer)


Aetiology and Genetics

Down's Syndrome is a genetic condition due to an additional copy (whole or part) of chromosome 21.


  • Full "Trisomy 21" (94%) - Karyotype 47 XY +21
    • Non-disjunction during meiosis I (ie. pre-fertilisation: 88% maternal, 8% paternal)


  • (Robertsonian) Translocation (3.3%):
    • Long arm of chromosome 21 is attached to another chromosome, or itself. eg. 45 XX t(14;21q). These parents will be phenotypically normal, but then normal disjunction events lead to a risk of producing a gamete which could produce a child with an additional copy of chromosome 21; trisomy 21. ("Familial Down's Syndrome")
    • 75% de novo, 25% familial
    • No maternal age effect. Paternal=Maternal incidence


  • Mosaicism - some cells have a normal karyotype, while others have trisomy 21 (2.4%) - 46 XX / 47 XX +21
    • Either a non-disjunction event during cell division in an early embryo (ie. post fertilisation), or
    • A Trisomy 21 embryo undergoes a non-disjunction, resulting in some cells reverting to a normal karyotype


Treatment

Screening for associated medical conditions is important, in particular cardiac and thyroid disease, with treatment as necessary.

Early intervention with appropriate education improves quality of life.


Prognosis

  • 75% of foetuses abort
  • Mortality is initially highest in the first year of life, though modern medicine has reduced this considerably. Important factors:
    • Congenital heart disease
    • Oesophageal atresia
    • Impaired immune response
    • Other associated abnormalities (see above)
  • 50% live beyond 50 years of age.
    • Average life span ~ 49years (2002)


References

  1. Fetal Medicine, St George's Hospital, London
  2. Kumar and Clark, Clinical Medicine, 5th Edition, 2002. ISBN 0-7020-2579-8
  3. Emedicine article
  4. UK resources for patients with Down's Syndrome
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