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Down syndrome

Last updated: July 15, 2021

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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.

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

Epidemiological data refers to the US, unless otherwise specified.

Full trisomy 21 (∼ 95% of cases)

Translocation trisomy 21 (3–4% of cases)

Mosaic trisomy 21 (1–2% of cases)

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

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)

Extremities, soft tissue, and skeletal features

Organ malformations and associated conditions

Development

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.

Diagnostic approach

Prenatal screening

Counseling

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

Screening procedures

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

Fetal karyotyping (confirmatory test)

Postnatal diagnostics

Typical features and malformations are important indicators but diagnostic confirmation is still required.

The differential diagnoses listed here are not exhaustive.

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