- Clinical science
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|
Epidemiological data refers to the US, unless otherwise specified.
Full trisomy 21 (∼ 95% of cases)
- Full trisomy 21 is not a hereditary disease, as the chromosomal aberration occurs spontaneously.
- Meiotic non-disjunction
Translocation trisomy 21 (3–4% of cases)
- Definition: three copies of chromosome 21 are present, of which one is attached to another chromosome (usually chromosome 14)
- Occurrence: independent of maternal age; increased familial incidence (approx. 3–4%); occurs as a spontaneous translocation
In approx. 50% of cases a balanced translocation is inherited from a parent, usually the mother, who does not suffer from trisomy 21. The other 50% of cases are caused by new mutations during meiosis.
Balanced Robertsonian translocation
- Translocation of the long arm of chromosome 21 to the long arm of chromosome 14 with elimination of the respective short arms (fusion of the chromosomes)
- The karyogram shows a total number of 45 chromosomes and may be expressed as either ♀: 45,XX,t(21;14) or ♂: 45,XY,t(21;14).
- Affected individuals only have 45 chromosomes, but possess complete genetic information and therefore a normal phenotype
- Unbalanced translocation: clinical features of trisomy 21 caused by inheritance of a translocation chromosome and a normal chromosome
- Balanced Robertsonian translocation
- In approx. 50% of cases a balanced translocation is inherited from a parent, usually the mother, who does not suffer from trisomy 21. The other 50% of cases are caused by new mutations during meiosis.
- 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
Facial and cranial features (craniofacial dysmorphia)
- Small oral cavity, large tongue
- High arched palate
- Abnormal teeth
- Further features
Extremities, soft tissue, and skeletal features
- Soft tissue: connective tissue deficiency → ↑ increased risk of umbilical and inguinal hernias; marked hyperextension of joints may occur
- Atlantoaxial instability
Organ malformations and associated conditions
- Heart: ; in ∼ 50% of cases – atrioventricular septal defect (∼ 40%); , ventricular septal defect; (∼ 30%), atrial septal defects (∼ 15%), tetralogy of Fallot (∼ 5%)
- Gastrointestinal tract: duodenal atresia/stenosis; , annular pancreas, imperforate anus; , enlargement of the colon, rectal prolapse; , Hirschsprung disease
- Urogenital system: hypogonadism, cryptorchidism, decreased fertility in men
- Further features: hypothyroidism; , celiac disease, sleep apnea; , hearing loss; due to recurrent otitis media, ↑ risk of leukemia (acute lymphoblastic leukemia, acute myeloid leukemia); , ↑ risk of early-onset of Alzheimer disease (75% of individuals affected by age of 40 years), ↑ risk of developing epilepsy
Height and development
- 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
5 A's of Down syndrome: Advanced maternal age, duodenal Atresia, Atrioventricular septal defect, AML/ALL, Alzheimer disease
- The diagnostic approach in Down syndrome is dependent on the week of gestation. It involves an initial screening test
- Standard tests
- Additional tests (usually performed optionally in high-risk pregnancies (e.g, maternal age > 35 years, history of prior pregnancy with trisomy, presence of ultrasound features suggesting aneuploidy) 
- Integrated tests over the first and second trimesters
- Cell-free DNA (10-20 weeks)
- If any of the above screening tests yield an abnormal result, one of the following confirmatory diagnostic tests is performed:
- See for further information.
- Precedes screening procedures
- Provides information that screening is voluntary
- Explains option of terminating the pregnancy if trisomy 21 is diagnosed
- Recommended for all women prior to the 20th week of gestation
First trimester combined test (11–13 weeks)
- First trimester combined test can detect 90% of cases 
- Maternal serum
- Second trimester quadruple test (15–18 weeks)
Additional screening tests: these tests are optionally performed in addition to the above tests and are evaluated along with the results of second trimester quadruple test
- Sequential integrated test
- Full integrated test (10–13 weeks)
Cell-free fetal DNA (10–20 weeks): Fetal DNA is isolated from a maternal blood specimen and evaluated for chromosomal abnormalities. 
- Non-invasive (to the fetus) but expensive test
- More predictive in high-risk women
- The test is currently available but not guideline-recommended
Fetal karyotyping (confirmatory test)
- Procedures 
In the quadruple test, hCG and Inhibin A are both HIgh up (↑) and Estriol and α-fEtoprotein are both dEficient (↓).
- Chromosome analysis
- Screening for associated conditions (see “Clinical findings” above), e.g., echocardiography to detect heart defects
Typical features and malformations are an important indicator, but, on their own, are insufficient for diagnosis!