Down syndrome, also called trisomy 21, is the most common autosomal chromosomal irregularity, occurring in approximately 1:700 live births. The risk of a trisomy 21 pregnancy increases with maternal age. Most individuals with Down syndrome have full trisomy 21, which occurs due to meiotic nondisjunction and results in a genotype with three complete copies of chromosome 21 and a total of 47 chromosomes. Other less common forms of Down syndrome are translocation trisomy 21 and mosaic trisomy 21. Clinically, trisomy 21 manifests as a syndrome involving a characteristic appearance (e.g., upward-slanting palpebral fissures, epicanthal folds, protruding tongue, short stature, transverse palmar crease, sandal gap), organ malformations (e.g., heart defects, duodenal atresia, Hirschsprung disease), and endocrine disorders (e.g., obesity, diabetes mellitus, hypothyroidism). Trisomy 21 is associated with an increased risk of malignancy (e.g., high risk of leukemia) and intellectual disability. Down syndrome is primarily detected in prenatal tests, including ultrasound measurement of nuchal translucency and maternal blood tests for certain hormones (e.g., increased inhibin A and β-hCG; decreased estriol, alpha-fetoprotein, and pregnancy-associated protein A). Fetal karyotyping via chorionic villus sampling or amniocentesis confirm the diagnosis, but these procedures are associated with an increased risk of fetal injury or loss. Management of trisomy 21 involves evaluation, monitoring, and treatment of the symptom complex and malformations as necessary.
- Most common viable autosomal chromosome aberration; (∼ 1:700; live births) and most common genetic cause of cognitive impairment 
- The risk of a Down syndrome pregnancy increases with maternal age. 
Epidemiological data refers to the US, unless otherwise specified.
Full trisomy 21 (∼ 95% of cases)
- Definition: three complete copies of chromosome 21 are present in all cells, with a total of 47 chromosomes
- Occurrence: : Full trisomy 21 is not a hereditary disease; ; the chromosomal irregularity occurs spontaneously.
- Pathogenesis: meiotic 
- Karyotype: ♀: 47,XX,+21 or ♂: 47,XY,+21
Translocation trisomy 21 (3–4% of cases)
- Definition: three copies of chromosome 21 are present, one of which is attached to another chromosome, usually chromosome 14 (less likely attached to chromosomes 13, 15, or 22)
- Occurrence: independent of maternal age; occurs as a spontaneous translocation
Pathogenesis and karyotype: Carriers of have a normal phenotype. Children of a translocation carrier can inherit a normal karyotype, balanced translocation, or unbalanced translocation (trisomy 21).
In approx. 50% of cases, a balanced translocation is inherited from a parent, usually the mother, who does not show phenotypic expression of trisomy 21. 
- Balanced Robertsonian translocation: translocation of the long arm of chromosome 21 to the long arm of chromosome 14
- Unbalanced Robertsonian translocation: clinical features of trisomy 21 caused by inheritance of a translocation chromosome and a normal chromosome
- Pregnancy can end in miscarriage. 
- The other cases of balanced Robertsonian translocation are caused by new translocations during meiosis.
- In approx. 50% of cases, a balanced translocation is inherited from a parent, usually the mother, who does not show phenotypic expression of trisomy 21. 
Mosaic trisomy 21 (1–2% of cases)
- Definition: two cell lines are present, the trisomy 21 cell line and the normal cell line
- Karyotype: either ♀: 46,XX/47,XX,+21 or ♂: 46,XY/47,XY,+21
To remember that Down syndrome is caused by trisomy 21, think of the Drinking age of 21 (in the US).
Facial and cranial features (craniofacial dysmorphia)
- Further features
Extremities, soft tissue, and skeletal features
- Transverse palmar crease: single crease that runs across the palm, along the metacarpophalangeal joints perpendicular to the fingers 
- Sandal gap: a medial displacement of the first toe leading to a large space between the first and second toes 
- Clinodactyly; : abnormal curvature of a finger (typically refers to inward curvature of the 5th finger)
- Soft tissue
- Obesity: prevalence is approx. 50% (higher than in the general population) 
- Skeletal features
Organ malformations and associated conditions
- Heart: congenital heart defects in ∼ 50% of cases 
- Gastrointestinal tract
- Urogenital system
- Type 1 diabetes
- Celiac disease
- Obstructive sleep apnea
- Hearing loss due to recurrent otitis media
- Increased risk of leukemia (acute lymphoblastic leukemia, acute myeloid leukemia)
- Early-onset Alzheimer disease; (The amyloid precursor protein; , which generates amyloid beta, is located on chromosome 21.)
- Increased risk of developing epilepsy
- Delayed motor development
- Muscle hypotonia
- Behavioral and psychiatric disorders
Down syndrome is the most common genetic cause of intellectual disability.
To remember the most important features associated with Down syndrome, think of the 5 A's: Advanced maternal age, duodenal Atresia, Atrioventricular septal defect, AML/ALL, early onset of Alzheimer disease.
- Diagnosis of Down syndrome is primarily prenatal and the diagnostic approach is dependent on the week of gestation.
- Initial screening test
- Standard tests
- First-trimester combined test (11–13 weeks)
- Second-trimester quadruple test (15–18 weeks)
- Additional tests, usually performed optionally in high-risk pregnancies (e.g., maternal age > 35 years, history of prior pregnancy with trisomy, ultrasound features suggesting aneuploidy) 
- Integrated tests over the first and second trimesters
- Cell-free DNA (10–20 weeks)
- Standard tests
- If any of the above screening tests yield an abnormal result, one of the following confirmatory diagnostic tests is performed:
- (15–22 weeks)
- (9–14 weeks)
- (18–22 weeks)
- See “ .”
- Precedes screening procedures
- Provides information that screening is voluntary
- Explains the option of terminating the pregnancy if trisomy 21 is diagnosed
- Indication: recommended for all women prior to the 20th week of gestation
Combined test (first trimester) (11–13 weeks)
- Has a 90% detection rate 
- Maternal serum
- Quadruple test (second trimester) (15–18 weeks)
Additional screening tests: The following tests are optional and performed in addition to the above-mentioned tests, and they are evaluated along with the results of the second-trimester quadruple test.
- Sequential integrated test: combines the results from the first-trimester combined test and second-trimester quadruple test
Cell-free fetal DNA (10–20 weeks): fetal DNA is isolated from a maternal blood specimen and evaluated for chromosomal abnormalities 
- Noninvasive (for the fetus) but expensive test
- More predictive in women with a high risk
- The test is currently available but not guideline-recommended.
In the quadruple test, hCG and Inhibin A are both HIgh up (↑) and Estriol and α-fEtoprotein are both dEficient (↓).
Fetal karyotyping (confirmatory test)
- (9–14 weeks)
- 15–22 weeks
- (18–22 weeks) 
- Chromosome analysis
- Screening for associated conditions (see “Clinical features”), e.g., echocardiography to detect heart defects
Typical features and malformations are important indicators but diagnostic confirmation is still required.
The differential diagnoses listed here are not exhaustive.
- Evaluation, monitoring, and treatment of the symptom complex and malformations as necessary (e.g., cardiac screening with an echocardiogram and heart surgery for cardiac malformations)
- Early, targeted intervention, educational programs, and support
- Decreased life expectancy with an average lifespan of approx. 60 years 
- Common causes of death in individuals with Down syndrome (in decreasing order of incidence)