Down syndrome (or trisomy 21) is the most common trisomy and also the commonest chromosomal disorder. It is a major cause of intellectual disability, and also has numerous multi-system manifestations.
According to the world health organisation (WHO), the approximate worldwide incidence is approximately 1 in 700-1,000 ref live births. The individual risk is strongly dependent on maternal risk, and therefore incidence varies with regional and temporal variation in maternal age distribution and the implementation of antenatal screening.
Diagnosis is often made antenatally and this must occur in conjunction with genetic counselling, which should begin prior to the testing.
In the postnatal period, characteristic phenotypical features point to the diagnosis:
- depressed nasal bridge
- epicanthic folds
- abundant neck skin
- simian crease (single palmar crease)
Intellectual disability becomes evident in early childhood as the failure to reach developmental milestones in an expected timeframe.
In ~95% of cases, the chromosomal abnormality is trisomy of chromosome 21 due to meiotic non-disjunction (i.e. failure of a chromosome pair to separate during meiosis, so that both go to one daughter cell, and none to the other). Thus, the individual’s chromosome count is 47, rather than 46. Maternal non-disjunction accounts for ~95% of such cases.
An alternative chromosomal abnormality that results in the syndrome involves Robertsonian translocation of paternal chromosomal material, such that the overall number of chromosomes remains the same. This happens in ~3% of cases 9. Very rarely (~2%) some individuals have mosaic trisomy 21.
There is an increased incidence with increased maternal age.
Cognitive disability and epilepsy are the most common neurological manifestations 8. Structurally evident abnormalities include:
- cerebellar and vermian hypoplasia
- Moyamoya syndrome
- Alzheimer disease developing in virtually all patients older than 40 years
- hippocampal volume loss: independent of age/dementia 4
- hearing loss
- mental retardation: average IQ ranges ~50-70
Congenital heart disease affects ~40%. In particular, defects affecting the endocardial cushion are common:
- atrioventricular septal defect (AVSD): considered the commonest cardiac defect associated with Down syndrome
- ostium primum atrial septal defect (ASD)
- ventricular septal defect (VSD)
- anal atresia
- coeliac disease 10
- duodenal atresia
- Hirschsprung disease
- diaphragmatic hernia diaphragmatic herniation11
- eleven ribs
- hyper-segmented sternum
- joint laxity/dislocation(s)
- developmental dysplasia of the hip (DDH)
- atlanto-axial subluxation and atlanto-occipital instability 2,3
- hypoplastic posterior arch of C1
- "mickey mouse" pelvis with flaring of iliac wings
- there is a significantly increased incidence of leukaemia (although the individual may be protected against other solid organ tumours)
The manifestations of Down syndrome are protean and can affect multiple systems. Some of these are better discussed under individual features in the wide clinicopathological spectrum of of the condition (listed above).
These are discussed in detail in a separate article.
Treatment and prognosis
Survival can be variable with the mean survival often considered at ~20 years ref.
History and etymology
Down syndrome was named after John Langdon Haydon Down, an English physician who lived from 1828 to 1896.
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