Down syndrome

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Down's syndrome (UK and other countries) or Down syndrome (US, Canada and other countries) encompasses a number of chromosomal abnormalities, of which trisomy 21 (an aneuploid) is the most common, causing highly variable degrees of learning difficulties as well as physical disabilities. It is named after John Langdon Down, the British doctor who first described it in 1866.

The incidence of Down syndrome is estimated at 1 per 800 births, making it the most common human aneuploidy. Maternal age influences the chance of conceiving a baby with the syndrome. At age 20 to 24, it is 1/1490, while at age 40 it is 1/106, and at age 49 is 1/11 [1]. Although the chance increases with maternal age, most children with Down syndrome (80%) are born to women under the age of 35, i.e. although the relative risk is higher in older woman, most babies are born to younger mothers.

Because of his perception that Down syndrome children share physical similarities with Mongolians, he used the terms mongolism or mongolian idiocy. At the time, the vast majority of people with Down syndrome were institutionalized.

In 1959, Professor Jérome Lejeune discovered that Down syndrome is a chromosomal irregularity [1]. In 1961, a group of geneticists wrote to the editor of The Lancet suggesting that the name be changed. The World Health Organization (WHO) confirmed the designation Down’s syndrome in 1965. In 1974, the United States National Institute of Health called a conference to standardize the naming of diseases and disorders. They recommended eliminating the possessive form ("The possessive form of an eponym should be discontinued, since the author neither had nor owned the disorder."). Down syndrome is the accepted term in the USA, Canada and other countries, and the possessive form is used in the United Kingdom and other countries.



Down syndrome is a chromosomal abnormality characterized by the presence of an extra copy of genetic material on the 21st chromosome, either in whole (trisomy 21) or part (such as due to translocations). The effects of the extra copy varies greatly from individual to individual, depending on the extent of the extra copy, genetic background, environmental factors, and random chance. Down syndrome can occur in all human populations, and analogous effects have been found in other species, such as chimpanzees and mice.

Down syndrome has four root causes:

  • Trisomy 21 is caused by a meiotic non-disjunction event. In this case, the child has three copies of every gene on chromosome 21. This is the cause of 95% of observed Down syndromes.
  • The extra material is due to a Robertsonian translocation. The long arm of 21 is attached to another chromosome (often chromosome 14 or itself). The parent with the translocation is missing information on the short arm of 21, but this does not have apparent effects. Through normal disjunction during meiosis, gametes are produced with extra copies of the long arm of chromosome 21. There is variability in the extra region. This is the cause of 2-3% of the observed Down syndromes, and is often referred to as 'familial Down syndrome'.
  • The individual is a mosaic of normal chromosomal arrangements and trisomy 21. This can occur in one of two ways: A non-disjunction event during an early cell division leads to a fraction of the cells with trisomy 21; or A Down syndrome embryo undergoes non-disjunction and some of the cells in the embryo revert back to the normal chromosomal arrangement. There is considerable variability in the fraction of trisomy 21, both as a whole and tissue-by-tissue. This is the cause of 1-2% of the observed Down syndromes. Is it likely that all people have an extremely small fraction of their cells that are trisomy 21.
  • Rarely, a region of the 21st chromosome will undergo a duplication event. This will lead to extra copies of some, but not nearly all, of the genes on chromosome 21.



It should be noted (especially following the Bawa Garba case that diagnosing serious disease, including sepsis, may be harder in patients with Down syndrome.



Increased risk of:


Blood tests

For maternal screening see below.



  • Exercise treatments are unproven, but do not appear to be harmful[2].


Clinical trials of memantine
PMID link to reference awaited
and antioxidant supplementation[3] in the dementia associated with the syndrome have shown these to be ineffective. Cholinergic drugs are also probably infective, with the suggestion that donepezil may work in some[4][5][6] tempered by negative evidence[7] and rivastigmine is ineffectual in the long term[8].



Antenatal screening for Down Syndrome

(See also screening article.)

Screening is by means of either:

  1. Triple test (Combined test)
  2. Integrated test
  3. Sequential screening
  4. Contingent screening
  5. Quadruple test

Contingent screening may be the most resource effective. The debate about the best screening strategy is on going.


Low maternal serum alpha fetoprotein (AFP) between 14th and 20th week (second trimester) was associated with risk of Down syndrome in 1984[9][10]. In 1988 the classic triple test was reported to be an effective screening tool[11], the same year as low second trimester estriol was noted to be a marker[12] . In 1992 free β human chorionic gonadotrophin[13] and pregnancy associated plasma protein A[14] were noted as a first-trimester marker and inhibin [15] as a second trimester marker. Nutual translucency was introduced in 1998[16]. The integrated test was first validated in 1999[17]. Absence of the nasal bone during first-trimester scanning was associated with risk of Down syndrome in 2001[18].In 2005 contingent sequential screening was demonstrated to offer potential benefits[19].

External links


  1. Hook EB. Rates of chromosome abnormalities at different maternal ages. Obstetrics and gynecology. 1981 Sep; 58(3):282-5.
  2. Andriolo RB, El Dib RP, Ramos L, Atallah AN, da Silva EM. Aerobic exercise training programmes for improving physical and psychosocial health in adults with Down syndrome. Cochrane database of systematic reviews (Online). 2010; (5):CD005176.(Epub) (Link to article – subscription may be required.)
  3. Lott IT, Doran E, Nguyen VQ, Tournay A, Head E, Gillen DL. Down syndrome and dementia: a randomized, controlled trial of antioxidant supplementation. American journal of medical genetics. Part A. 2011 Aug; 155A(8):1939-48.(Link to article – subscription may be required.)
  4. Prasher VP, Huxley A, Haque MS. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Down syndrome and Alzheimer's disease--pilot study. International journal of geriatric psychiatry. 2002 Mar; 17(3):270-8.
  5. Kishnani PS, Sommer BR, Handen BL, Seltzer B, Capone GT, Spiridigliozzi GA, Heller JH, Richardson S, McRae T. The efficacy, safety, and tolerability of donepezil for the treatment of young adults with Down syndrome. American journal of medical genetics. Part A. 2009 Aug; 149A(8):1641-54.(Link to article – subscription may be required.)
  6. Kondoh T, Kanno A, Itoh H, Nakashima M, Honda R, Kojima M, Noguchi M, Nakane H, Nozaki H, Sasaki H, Nagai T, Kosaki R, Kakee N, Okuyama T, Fukuda M, Ikeda M, Shibata Y, Moriuchi H. Donepezil significantly improves abilities in daily lives of female Down syndrome patients with severe cognitive impairment: a 24-week randomized, double-blind, placebo-controlled trial. International journal of psychiatry in medicine. 2011; 41(1):71-89.
  7. Kishnani PS, Heller JH, Spiridigliozzi GA, Lott I, Escobar L, Richardson S, Zhang R, McRae T. Donepezil for treatment of cognitive dysfunction in children with Down syndrome aged 10-17. American journal of medical genetics. Part A. 2010 Dec; 152A(12):3028-35.(Link to article – subscription may be required.)
  8. Heller JH, Spiridigliozzi GA, Crissman BG, McKillop JA, Yamamoto H, Kishnani PS. Safety and efficacy of rivastigmine in adolescents with Down syndrome: long-term follow-up. Journal of child and adolescent psychopharmacology. 2010 Dec; 20(6):517-20.(Link to article – subscription may be required.)
  9. Cuckle HS, Wald NJ, Lindenbaum RH. Maternal serum alpha-fetoprotein measurement: a screening test for Down syndrome. Lancet. 1984 Apr 28; 1(8383):926-9.
  10. Merkatz IR, Nitowsky HM, Macri JN, Johnson WE. An association between low maternal serum alpha-fetoprotein and fetal chromosomal abnormalities. American journal of obstetrics and gynecology. 1984 Apr 1; 148(7):886-94.
  11. Wald NJ, Cuckle HS, Densem JW, Nanchahal K, Royston P, Chard T, Haddow JE, Knight GJ, Palomaki GE, Canick JA. Maternal serum screening for Down's syndrome in early pregnancy. BMJ (Clinical research ed.). 1988 Oct 8; 297(6653):883-7.
  12. Canick JA, Knight GJ, Palomaki GE, Haddow JE, Cuckle HS, Wald NJ. Low second trimester maternal serum unconjugated oestriol in pregnancies with Down's syndrome. British journal of obstetrics and gynaecology. 1988 Apr; 95(4):330-3.
  13. Spencer K, Macri JN, Aitken DA, Connor JM. Free beta-hCG as first-trimester marker for fetal trisomy. Lancet. 1992 Jun 13; 339(8807):1480.
  14. Wald N, Stone R, Cuckle HS, Grudzinskas JG, Barkai G, Brambati B, Teisner B, Fuhrmann W. First trimester concentrations of pregnancy associated plasma protein A and placental protein 14 in Down's syndrome. BMJ (Clinical research ed.). 1992 Jul 4; 305(6844):28.
  15. Van Lith JM, Pratt JJ, Beekhuis JR, Mantingh A. Second-trimester maternal serum immunoreactive inhibin as a marker for fetal Down's syndrome. Prenatal diagnosis. 1992 Oct; 12(10):801-6.
  16. Snijders RJ, Noble P, Sebire N, Souka A, Nicolaides KH. UK multicentre project on assessment of risk of trisomy 21 by maternal age and fetal nuchal-translucency thickness at 10-14 weeks of gestation. Fetal Medicine Foundation First Trimester Screening Group. Lancet. 1998 Aug 1; 352(9125):343-6.
  17. Wald NJ, Watt HC, Hackshaw AK. Integrated screening for Down's syndrome on the basis of tests performed during the first and second trimesters. The New England journal of medicine. 1999 Aug 12; 341(7):461-7.
  18. Cicero S, Curcio P, Papageorghiou A, Sonek J, Nicolaides K. Absence of nasal bone in fetuses with trisomy 21 at 11-14 weeks of gestation: an observational study. Lancet. 2001 Nov 17; 358(9294):1665-7.(Link to article – subscription may be required.)
  19. Benn P, Wright D, Cuckle H. Practical strategies in contingent sequential screening for Down syndrome. Prenatal diagnosis. 2005 Aug; 25(8):645-52.(Link to article – subscription may be required.)

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