Down syndrome

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 multisystem manifestations.

Epidemiology

The approximate worldwide incidence is approximately 1 in 800live births ¹⁵. 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.

Risk factors

• increased incidence with increasing maternal age

• translocation Down syndrome gene carriers

• previous pregnancy with Down syndrome

Clinical presentation

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

• epicanthal folds

• abundant neck skin

• macroglossia

• simian crease (single palmar crease)

• hypotonia

Intellectual disability becomes evident in early childhood as the failure to reach developmental milestones in an expected timeframe.

Pathology

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.

Clinicopathological spectrum

Neurological manifestations

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 from inner ear anomalies, e.g. semicircular canal dysplasia and dehiscence, narrowed internal acoustic canal, cochlear nerve canal stenosis, enlarged vestibular aqueduct ¹²

• intellectual disability: average IQ ranges ~50-70

Cardiovascular

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

• secundum atrial septal defect (ASD)¹⁶

• ventricular septal defect (VSD)

Respiratory

• pulmonary hypoplasia

• pulmonary cysts

• pig bronchus

Gastrointestinal

• anal atresia

• coeliac disease ¹⁰

• duodenal atresia

• Hirschsprung disease

• omphalocele

• diaphragmatic herniation ¹¹

Musculoskeletal

• eleven ribs

• hypersegmented sternum

• joint laxity and dislocation

• developmental dysplasia of the hip (DDH)

• atlantoaxial subluxation and atlantooccipital instability ^2,3

• hypoplastic posterior arch of C1

• "mickey mouse" pelvis with flaring of iliac wings

• Kirner deformity

Endocrine

• thyroid dysfunction (4-8%)¹⁴

  • hypothyroidism (congenital, subclinical or acquired autoimmune and non-autoimmune)

  • hyperthyroidism

  • thyroid aplasia

Others

• significantly increased incidence of leukaemia (although the individual may be protected against other solid organ tumours)

Radiographic features

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 the condition (listed above).

Antenatal features

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. Respiratory infections stay considerably predominant cause of death. Moreover, other causes of early mortality, include congenital heart defects and dementia ¹⁵.

History and etymology

Down syndrome was named after John Langdon Haydon Down (1828-1896), an English physician ¹³.