Written and peer-reviewed by physicians—but use at your own risk. Read our disclaimer.

banner image

amboss

Trusted medical answers—in seconds.

Get access to 1,000+ medical articles with instant search
and clinical tools.

Try free for 5 days

Down syndrome

Last updated: June 12, 2020

Summarytoggle arrow icon

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.

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.

References:[1][2][3][4][5][6][7][8]

Epidemiological data refers to the US, unless otherwise specified.

Full trisomy 21 (∼ 95% of cases)

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
  • Pathogenesis

Mosaicism (1–2%)

References:[1][9][10]

Facial and cranial features (craniofacial dysmorphia)

Extremities, soft tissue, and skeletal features

Organ malformations and associated conditions

Height and development

  • Motor skills
  • 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

References:[10][11][12][13]

Diagnostic approach

Prenatal screening

Counseling

  • 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!

References:[7][10][11][22][23][24]

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)

References:[13]

Decreased life expectancy

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

References:[10]

  1. Weremowicz S. Congenital Cytogenetic Abnormalities. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/congenital-cytogenetic-abnormalities.Last updated: August 24, 2016. Accessed: May 10, 2017.
  2. Birth Defects - Data and Statistics. https://www.cdc.gov/ncbddd/birthdefects/data.html. Updated: October 21, 2014. Accessed: May 10, 2017.
  3. Down Syndrome Facts. http://www.ndss.org/Down-Syndrome/Down-Syndrome-Facts/. Updated: January 1, 2017. Accessed: May 11, 2017.
  4. Mai CT, Kucik JE, Isenburg J et al.. Selected birth defects data from population-based birth defects surveillance programs in the United States, 2006 to 2010: Featuring trisomy conditions. Birth Defects Res A Clin Mol Teratol. 2013; 97 (11): p.709-725. doi: 10.1002/bdra.23198 . | Open in Read by QxMD
  5. UpToDate. Maternal age-related risk of common fetal autosomal trisomies at the time of CVS, genetic amniocentesis, and term. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/image?imageKey=OBGYN%2F75423&topicKey=OBGYN%2F426&rank=3~150&source=see_link&search=down+syndrome.Last updated: January 1, 2017. Accessed: May 11, 2017.
  6. Newberger DS. Down Syndrome: Prenatal risk assessment and diagnosis. Am Fam Physician. 2000; 62 (4): p.825-832.
  7. Messerlian GM, Palomaki GE. Down Syndrome: Overview of Prenatal Screening. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/down-syndrome-overview-of-prenatal-screening.Last updated: April 5, 2017. Accessed: May 11, 2017.
  8. Malhotra N, Puri R, Malhotra J. Donald School Manual of Practical Problems in Obstetrics. JAYPEE BROTHERS PUBLISHERS ; 2012
  9. Jorde L, Carey J, Bamshad M. Medical Genetics . Elsevier ; 2015
  10. Mundakel GT. Down Syndrome . In: Descartes M, Down Syndrome . New York, NY: WebMD. http://emedicine.medscape.com/article/943216. Updated: January 17, 2017. Accessed: May 11, 2017.
  11. Ostermaier KK. Down Syndrome: Clinical Features and Diagnosis. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/down-syndrome-clinical-features-and-diagnosis.Last updated: November 23, 2015. Accessed: April 13, 2017.
  12. Haargaard B, Fledelius HC. Down's syndrome and early cataract. Br J Ophthalmol. 2006; 90 (8): p.1024-1027. doi: 10.1136/bjo.2006.090639 . | Open in Read by QxMD
  13. Ostermaier KK. Down Syndrome: Management. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/down-syndrome-management.Last updated: March 21, 2017. Accessed: May 11, 2017.
  14. Bianchi DW, Parker RL, Wentworth J, et al. DNA Sequencing versus Standard Prenatal Aneuploidy Screening. N Engl J Med. 2014; 370 (9): p.799-808. doi: 10.1056/nejmoa1311037 . | Open in Read by QxMD
  15. N.J. Wald, H.C. Watt, A.K. Hackshaw. Integrated Screening for Down's Syndrome Based on Tests Performed during the First and Second Trimesters. N Engl J Med. 1999; 341 (7): p.461-467. doi: 10.1056/nejm199908123410701 . | Open in Read by QxMD
  16. Santorum M, Wright D, Syngelaki A, Karagioti N, Nicolaides KH. Accuracy of first-trimester combined test in screening for trisomies 21, 18 and 13. Ultrasound in Obstetrics & Gynecology. 2017; 49 (6): p.714-720. doi: 10.1002/uog.17283 . | Open in Read by QxMD
  17. Grace MR, Hardisty E, Dotters-Katz SK, Vora NL, Kuller JA. Cell-Free DNA Screening: Complexities and Challenges of Clinical Implementation.. Obstet Gynecol Surv. 2016; 71 (8): p.477-87. doi: 10.1097/OGX.0000000000000342 . | Open in Read by QxMD
  18. Down Syndrome Tests. https://medlineplus.gov/lab-tests/down-syndrome-tests/. Updated: June 1, 2019. Accessed: October 18, 2019.
  19. Ghi T, Sotiriadis A, Calda P, et al. ISUOG Practice Guidelines: invasive procedures for prenatal diagnosis. Ultrasound in Obstetrics & Gynecology. 2016; 48 (2): p.256-268. doi: 10.1002/uog.15945 . | Open in Read by QxMD
  20. Ghidini A. Diagnostic Amniocentesis. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/diagnostic-amniocentesis.Last updated: September 25, 2017. Accessed: November 7, 2017.
  21. Ghidini A. Chorionic villus sampling. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. http://www.uptodate.com/contents/chorionic-villus-sampling.Last updated: August 22, 2016. Accessed: May 2, 2017.
  22. Messerlian GM, Farina A, Palomaki GE. First-Trimester Combined Test and Integrated Tests for Screening for Down Syndrome and Trisomy 18. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/first-trimester-combined-test-and-integrated-tests-for-screening-for-down-syndrome-and-trisomy-18.Last updated: January 18, 2016. Accessed: May 11, 2017.
  23. Graham L. ACOG releases guidelines on screening for fetal chromosomal abnormalities. Am Fam Physician. 2007; 76 (5): p.712-716.
  24. Hsiao C-H, Cheng P-J, Shaw SWS, et al. Extended first-trimester screening using multiple sonographic markers and maternal serum biochemistry: A five-year prospective study. Fetal Diagn Ther. 2014; 35 (4): p.296-301. doi: 10.1159/000357564 . | Open in Read by QxMD
  25. Epocrates - Down Syndrome. https://online.epocrates.com/diseases/70035/Down-syndrome/Differential-Diagnosis. Updated: July 9, 2019. Accessed: October 11, 2019.
  26. Klingel D, Hohoff A, Kwiecien R, Wiechmann D, Stamm T. Growth of the hard palate in infants with Down syndrome compared with healthy infants-A retrospective case control study.. PLoS ONE. 2017; 12 (8): p.e0182728. doi: 10.1371/journal.pone.0182728 . | Open in Read by QxMD
  27. Antonarakis SE, Petersen MB, McInnis MG, et al. The meiotic stage of nondisjunction in trisomy 21: determination by using DNA polymorphisms.. Am J Hum Genet. 1992; 50 (3): p.544-50.
  28. Single Palmar Crease - Medline Plus - U.S. National Library of Medicine (NIH). https://medlineplus.gov/ency/article/003290.htm. Updated: May 17, 2019. Accessed: October 14, 2019.
  29. Colvin KL, Yeager ME. What people with Down Syndrome can teach us about cardiopulmonary disease. European Respiratory Review. 2017; 26 (143): p.160098. doi: 10.1183/16000617.0098-2016 . | Open in Read by QxMD
  30. Alan H. Bittles, Carol Bower, Rafat Hussain, Emma J. Glasson. The four ages of Down syndrome. European Journal of Public Health. 2006 .
  31. Ryu JK, Cho JY, Choi JS. Prenatal sonographic diagnosis of focal musculoskeletal anomalies.. Korean journal of radiology. undefined; 4 (4): p.243-51. doi: 10.3348/kjr.2003.4.4.243 . | Open in Read by QxMD
  32. Priya PK, Mishra VV, Roy P, Patel H. A Study on Balanced Chromosomal Translocations in Couples with Recurrent Pregnancy Loss.. Journal of Human Reproductive Sciences. 2018 .
  33. Shaffer LG, Jackson-Cook CK, Stasiowski BA, Spence JE, Brown JA.. Parental origin determination in thirty de novo Robertsonian translocations.. American Journal of Medical Genetics. 1992 .
  34. Tabor A, Vestergaard CH, Lidegaard Ø. Fetal loss rate after chorionic villus sampling and amniocentesis: an 11-year national registry study.. Ultrasound Obstet Gynecol. 2009; 34 (1): p.19-24. doi: 10.1002/uog.6377 . | Open in Read by QxMD
  35. Data & Statistics on Birth Defects. https://www.cdc.gov/ncbddd/birthdefects/data.html. Updated: January 23, 2020. Accessed: June 29, 2020.
  36. What is Down Syndrome?. https://www.ndss.org/about-down-syndrome/down-syndrome/. Updated: January 1, 2020. Accessed: September 3, 2020.
  37. Bertapelli F, Pitetti K, Agiovlasitis S, Guerra-Junior G. Overweight and obesity in children and adolescents with Down syndrome—prevalence, determinants, consequences, and interventions: A literature review. Res Dev Disabil. 2016; 57 : p.181-192. doi: 10.1016/j.ridd.2016.06.018 . | Open in Read by QxMD
  38. Boleracki M, Farkas F, Meszely A, Szikszai Z, Sik Lányi C. Developing an Animal Counting Game in Second Life for a Young Adult with Down Syndrome.. Stud Health Technol Inform. 2015; 217 : p.71-7.
  39. Winders P, Wolter-Warmerdam K, Hickey F. A schedule of gross motor development for children with Down syndrome. Journal of Intellectual Disability Research. 2018; 63 (4): p.346-356. doi: 10.1111/jir.12580 . | Open in Read by QxMD
  40. Growth Charts for Children with Down Syndrome. https://www.cdc.gov/ncbddd/birthdefects/downsyndrome/growth-charts.html. Updated: December 5, 2019. Accessed: September 4, 2020.