• Clinical science

Down syndrome


Down syndrome, also known as trisomy 21, is the most common autosomal chromosome aberration, occurring in approximately 1:700 live births. The risk of a trisomy 21 pregnancy rises with increasing maternal age. Clinically, trisomy 21 manifests as a syndrome involving a characteristic appearance, organ malformations, and mental disability. Typical facial features include upward slanting palpebral fissures, epicanthus, a small oral cavity with a large tongue, a flattened nose. Other typical features are disproportionate short stature, a single crease across the palm of the hand (transverse palmar crease), and an enlarged gap between the first two toes (sandal gap). Common organ malformations include heart defects, duodenal stenosis, and a hypoplastic thyroid. Further associated conditions, such as diabetes mellitus, susceptibility to infections, and a higher incidence of leukemia may shorten life expectancy. The degree of intellectual disability varies greatly and may range from mild manifestations to severe impairment with dependence on caregivers. Children with Down syndrome present with a typical appearance at birth although the disease is often detected in prenatal tests. These include ultrasound measurement of nuchal translucency and maternal blood tests for human gonadotropin, estriol, and alpha-fetoprotein. Fetal karyotyping through chorionic villus sampling and amniocentesis confirm the diagnosis but are associated with an increased risk of fetal injury or loss due to the invasive nature of these tests.


  • Most common autosomal chromosome aberration (∼ 1:700 live births).
  • The risk of a Down syndrome pregnancy rises with maternal age
Maternal age (years) Incidence of trisomy 21
20 ∼ 1:1500
30 ∼ 1:900
40 ∼ 1:100
45 ∼ 1:30
50 ∼ 1:6

The general risk of trisomy 21 rises with maternal age. This does not, however, apply to translocation trisomies!

Down syndrome is the most common genetic cause of intellectual disability. Fragile X syndrome is the most common heritable cause of intellectual disability.


Epidemiological data refers to the US, unless otherwise specified.


Full trisomy 21 (∼ 95% of cases)

Translocation trisomy 21 (3–4% of cases)

Mosaicism (1–2%)

  • Mosaic trisomy is caused by non-disjunction during mitosis; . In these cases two cell lines are present, the trisomy 21 cell line and the normal cell line. The resulting karyotypes are either : 46,XX/47,XX,+21 or : 46,XY/47,XY,+21.
  • Depending on the timing of the mitotic error, there is a variable proportion of trisomic and normal cells
    • Phenotypic expression may vary according to the ratio of healthy to trisomic cells


Clinical features

Facial and cranial features (craniofacial dysmorphia)

Extremities, soft tissue, and skeletal features

Organ malformations and associated conditions

Height and development

  • Motor skills
    • Delayed motor development
    • Muscle hypotonia
  • Height: reduced growth with shortening of long bones → average adult height 150 cm (4 ft 11 in)
  • Obesity: prevalence approx. 50% higher than in general population
  • Intelligence

Although symptoms may be less severe in mosaic trisomies, the clinical manifestation generally provides no indication of the underlying genetic mutation!

5 A's of Down syndrome: Advanced maternal age, duodenal Atresia, Atrioventricular septal defect, AML/ALL, Alzheimer disease



Diagnostic approach

Prenatal screening


  • Precedes screening procedures
  • Provides information that screening is voluntary
  • Explains option of terminating the pregnancy if trisomy 21 is diagnosed

Screening procedures

Fetal karyotyping (confirmatory test)

In the quadruple test, hCG and Inhibin A are both HIgh up (↑) and Estriol and α-fEtoprotein are both dEficient (↓).

Postnatal diagnostics

Typical features and malformations are an important indicator, but, on their own, are insufficient for diagnosis!


Differential diagnoses

The differential diagnoses listed here are not exhaustive.


  • Treatment of the symptom complex and malformations as necessary (e.g., heart surgery for cardiac malformations)
  • Early, targeted intervention, educational programs and support (e.g., encourage physical activity to decrease risk of obesity and improve motor control)



Decreased life expectancy

  • Average life expectancy: approx. 50 years
  • Mostly due to organ malformations (especially cardiac) and ↑ susceptibility to infections (immunodeficiency)