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UNSW Embryology

Abnormal Development - Trisomy 21 (Down Syndrome)

© Dr Mark Hill (2008)

Acknowledgements

Introduction

Down syndrome or trisomy 21 is caused by nondisjunction of chromosome 21 in a parent who is chromosomally normal and is one of the most common chromosomal abnormalities in liveborn children. The frequency of trisomy 21 in the population is approximately 1 in 650 to 1,000 live births, in Australia between 1991-97 there were 2,358 Trisomy 21 (Down) infants.

Down Syndrome

The image above showns isolated chromosomes from a male trisomy 21 (red arrow shows extra chromosome 21). Recent attention has focussed on screening for Down's syndrome (mainly in terms of cost and efficiency) during fetal life with over 350 articles in the medical literature in just the past five years.

There is also a high correlation of increased occurance with an increase in maternal age. (see table below) See also local copy of OMIM List for Trisomy 21 and specific Trisomy 21 entry.

Page Links: Introduction | Down Syndrome Newborn | Some Recent Findings | Down Syndrome Newborn | Down Syndrome Karyotype | ACOG Screening Recommendations | Mother's Age and Risk of Having a Baby With a Chromosomal Abnormality | Screening strategies for Down's syndrome | Aneuploidy | Prevalence | Associated Congenital Abnormalities | Heart Defects | Limb Defects | References | Search PubMed | WWW Links | Glossary

Other Pages:AFP | PAPP-A

Some Recent Findings

Breathnach FM, Malone FD. Screening for aneuploidy in first and second trimesters: is there an optimal paradigm? Curr Opin Obstet Gynecol. 2007 Apr;19(2):176-82.

"Screening strategies for aneuploidy continue to evolve, with the most recent evidence favouring a contingent sequential approach."

American College of Obstetricians and Gynecologists New Recommendations for Down Syndrome Call for Screening of All Pregnant Women (January 2, 2007) (More? ACOG Screening Recommendations)

"This new recommendation says that the maternal age of 35 should no longer be used by itself as a cut-off to determine who is offered screening versus who is offered invasive diagnostic testing"

Akiyama T, Nagata M, Aoki F. Inadequate histone deacetylation during oocyte meiosis causes aneuploidy and embryo death in mice. Proc Natl Acad Sci U S A. 2006 May 1;

"It was recently reported that histones are globally deacetylated in mammalian oocytes during meiosis but not mitosis. ... The high incidence of aneuploidy in the embryos of older females may be due to inadequate meiotic histone deacetylation."

Prenatal Diagnosis

Chitty LS, Kagan KO, Molina FS, Waters JJ, Nicolaides KH. Fetal nuchal translucency scan and early prenatal diagnosis of chromosomal abnormalities by rapid aneuploidy screening: observational study. BMJ. 2006 Feb 13

Down Syndrome Karyotype

The images below show both male and female karyotypes for trisomy 21.

Trisomy 21 Male Karyotype

Trisomy 21 Female Karyotype

Down Syndrome Newborn

down syndrome

Trisomy 21 (Down Syndrome) Newborn (Image: CDC/Dr. Godfrey P. Oakley)

American College of Obstetricians and Gynecologists Recommendations

The following ACOG recommendations (January 2007) are based on good and consistent scientific evidence:

(Text extract from: New Recommendations for Down Syndrome Call for Screening of All Pregnant Women (press release January 2, 2007)

Associated Congenital Abnormalities

Acute megakaryocytic leukemia occurs 200 to 400 times more frequently in Down syndrome.

Hearing loss is usually of the conductive type. (More? Hearing Abnormalities)

Musculoskeletal include bony anomalies of the cervical spine (produce atlanto-occipital and cervical instability), scoliosis, hip instability, slipped capital femoral epiphysis, patellar instability, and foot deformities. (modified musculoskeletal list from Caird etal., 2006)

Links: OMIM - Down Syndrome

Mother's Age and Risk of Having a Baby With a Chromosomal Abnormality

(see references)

Age of Mother

Risk of Down Syndrome

Risk of Any Chromosomal Abnormality

20

1 in 1667

1 in 526

21

1 in 1667

1 in 526

22

1 in 1429

1 in 500

23

1 in 1429

1 in 500
24

1 in 1250

1 in 476

25

1 in 1250

1 in 476

26

1 in 1176

1 in 476

27

1 in 1111

1 in 455

28

1 in 1053

1 in 435

29

1 in 1000

1 in 417

30

1 in 952

1 in 384

31

1 in 909

1 in 384

32

1 in 769

1 in 323

33

1 in 625

1 in 286

34

1 in 500

1 in 238

35

1 in 385

1 in 192

36

1 in 294

1 in 156

37

1 in 227

1 in 127

38

1 in 175

1 in 102

39

1 in 137

1 in 83

40

1 in 106

1 in 66

41

1 in 82

1 in 53

42

1 in 64

1 in 42

43

1 in 50

1 in 33

44

1 in 38

1 in 26

45

1 in 30

1 in 21

46

1 in 23

1 in 16

47

1 in 18

1 in 13

48

1 in 14

1 in 10

49

1 in 11

1 in 8

Table References

Hook EB. Rates of chromosome abnormalities at different maternal ages. Obstetrics and Gynecology 58:282-285, 1981 (Data USA sourced)

Hook EB, Cross PK, Schreinemachers DM.Chromosomal abnormality rates at amniocentesis and in live-born infants. JAMA. 1983 Apr 15;249(15):2034-8.

Schreinemachers DM, Cross PK, Hook EB. Rates of trisomies 21, 18, 13 and other chromosome abnormalities in about 20 000 prenatal studies compared with estimated rates in live births. Hum Genet. 1982;61(4):318-24.

Screening strategies for Down's syndrome

  Procedure

  Detection rate

First trimester screening (10 to 14 weeks):

  Maternal age

  Nuchal translucency measurement (by ultrasound)

  First trimester double test (PAPP-A, HCG)

  First trimester combined test (nuchal translucency, PAPP-A, HCG)

 

  32%

  74%

  63%

  86%

Second trimester screening (15 to 19 weeks):

  Maternal age

  Second trimester double test (AFP, HCG)

  Triple test (AFP, HCG, uE3)

  Quadruple test (AFP, HCG, uE3, inhibin A)

  Integrated test (first trimester: nuchal translucency, PAPP-A; second trimester: quadruple test)

 

  32%

  60%

  68%

  79%

  95%

Prenatal diagnosis:

  Amniocentesis (15 weeks)

  Chorionic villus sampling (11-14 weeks)

 

  100%

  100%

Data from United Kingdom: Gilbert etal., British Medical Journal 2001; 323: 423

AFP = fetoprotein, HCG = human chorionic gonadotrophin, PAPP-A = pregnancy associated plasma protein A, uE3 = unconjugated oestriol.

Termination (UK): Surgical dilatation, evacuation (11 to 13 weeks), Medical with mifepristone (14 weeks)

Termination strategies and regulations differ from country to country.

( More? AFP | PAPP-A)

Heart Defects

Congenital heart defects are common (40 to 50%) in Down’s babies and are a common cause of postnatal death.

Approximately 30 to 40% have complete atrioventricular septal defects (early diagnosis generally allows corrective surgery to be performed).

endocardial cushion defect (43%)

ventricular septal defect (32%)

secundum atrial septal defect (10%)

tetralogy of Fallot (6%)

patent ductus arteriosus (16%)

Limb Defects

Hand - features short and broad hands, clinodactyly (curving of the fifth finger, little finger) with a single flexion crease (20%), hyperextensible finger joints.

Foot - space between the great toe (big) and the second toe is increased.

Hip - acquired hip dislocation (6%).

(More? Limb Abnormalities)

Aneuploidy

One of the three main classes of numerical chromosomal abnormalities.

Aneuploidy are chromosome mutations in which chromosome number is abnormal (increased or reduced), nondisjunction in meiosis or mitosis (anaphase of meiosis I, sister chromatids fail to disjoin at either meiosis II or at mitosis) is the cause of most aneuploids.

Polyploidy includes triploidy, usually due to two sperm fertilizing a single egg.

Mixoploidy includes mosaicism, where there are two or more genetically different cell lines in an individual.

Euploidy normal, means having the complete chromosome sets (n, 2n, 3n).

Prevalence

Prevalence is measure of the proportion of a population that are disease cases at a point in time. Generally used to measure only relatively stable conditions, not suitable for acute disorders. Listed below are some sample data from different world regions.

Ireland: county Galway (1981 to 2000) overall prevalence rate was 26.8/10,000 live births for the full period (decade 1991-2000 29.8/10,000; 1981-1990 24.1/10,000). (data: O'Nuallain S, Flanagan O, Raffat I, Avalos G, Dineen B. The prevalence of Down syndrome in County Galway. Ir Med J. 2007 Jan;101(1):329-31.)

USA: Atlanta (1990-1993) 8.4/10,000 live births excluding terminations and 8.8/10,000 including terminations; (1994-1999) 10.1/10,000 excluding terminations and 15.3/10,000 including terminations. (data: Siffel C, Correa A, Cragan J, Alverson CJ. Prenatal diagnosis, pregnancy terminations and prevalence of Down syndrome in Atlanta. Birth Defects Res A Clin Mol Teratol. 2004 Sep;70(9):565-71.)

References

Journals

Down Syndrome Quarterly DSQ - an interdisciplinary journal devoted to advancing the state of knowledge on Down syndrome

Down Syndrome Research and Practice Archive Homepage

NCBI Bookshelf

Modern Genetic Analysis Griffiths, Anthony J.F.; Gelbart, William M.; Miller, Jeffrey H.; Lewontin, Richard C. New York: W. H. Freeman & Co.; c1999. Image - Characteristics of Down syndrome (trisomy 21)

Introduction to Genetic Analysis 7th ed. Griffiths, Anthony J.F.; Miller, Jeffrey H.; Suzuki, David T.; Lewontin, Richard C.; Gelbart, William M. New York: W. H. Freeman & Co.; c1999. Image - Down syndrome in Robertsonian translocation

Clinical Methods 3rd ed. Walker, H.K.; Hall, W.D.; Hurst, J.W.; editors Stoneham (MA): Butterworth Publishers; c1990 Table - Recognizable Genetic Conditions

Reviews

Dent KM, Carey JC. Breaking difficult news in a newborn setting: Down syndrome as a paradigm. Am J Med Genet C Semin Med Genet. 2006 Aug 15;142(3):173-9.

Caird MS, Wills BP, Dormans JP. Down syndrome in children: the role of the orthopaedic surgeon. J Am Acad Orthop Surg. 2006 Oct;14(11):610-9.

Antonarakis SE, Epstein CJ. The challenge of Down syndrome. Trends Mol Med. 2006 Oct;12(10):473-9. Epub 2006 Aug 28.

Benn PA. Advances in prenatal screening for Down syndrome: II first trimester testing, integrated testing, and future directions. Clin Chim Acta. 2002 Oct;324(1-2):1-11.

Maymon R, Jauniaux E. Down's syndrome screening in pregnancies after assisted reproductive techniques: an update. Reprod Biomed Online. 2002 May-Jun;4(3):285-93.

Souter VL, Nyberg DA. Sonographic screening for fetal aneuploidy: first trimester. J Ultrasound Med. 2001 Jul;20(7):775-90.

Jackson M, Rose NC. Diagnosis and management of fetal nuchal translucency. Semin Roentgenol. 1998 Oct;33(4):333-8. Review.

Menendez M. Down syndrome, Alzheimer's disease and seizures. Brain Dev. 2005 Jun;27(4):246-52.

FitzPatrick DR. Transcriptional consequences of autosomal trisomy: primary gene dosage with complex downstream effects. Trends Genet. 2005 May;21(5):249-53.

Articles

Van Riper M. Van Riper M. Families of children with down syndrome: responding to "a change in plans" with resilience. J Pediatr Nurs. 2007 Apr;22(2):116-28.

Malone FD, Canick JA, Ball RH, Nyberg DA, Comstock CH, Bukowski R, Berkowitz RL, Gross SJ, Dugoff L, Craigo SD, Timor-Tritsch IE, Carr SR, Wolfe HM, Dukes K, Bianchi DW, Rudnicka AR, Hackshaw AK, Lambert-Messerlian G, Wald NJ, D'Alton ME. First-Trimester or Second-Trimester Screening, or Both, for Down's Syndrome. N Engl J Med. 2005 Nov 10;353(19):2001-2011. A large team of clinical researchers have compared the effectiveness of first and second trimester screening methods for this chromosome 21 trisomy disorder "First-trimester combined screening at 11 weeks of gestation is better than second-trimester quadruple screening but at 13 weeks has results similar to second-trimester quadruple screening. Both stepwise sequential screening and fully integrated screening have high rates of detection of Down's syndrome, with low false positive rates." First-trimester combined screening - nuchal translucency, pregnancy-associated plasma protein A [PAPP-A], free beta subunit of hCG (10 weeks 3 days through 13 weeks 6 days of gestation) Second-trimester quadruple screening - alpha-fetoprotein, total hCG, unconjugated estriol, and inhibin A at (15 through 18 weeks of gestation). (NEMJ Nov 10) NEMJ - Down's Syndrome Screening Article

Associated Neurological

Menendez M. Down syndrome, Alzheimer's disease and seizures. Brain Dev. 2005 Jun;27(4):246-52. "Neuropathologically, Alzheimer-type abnormalities are demonstrated in patients with Down syndrome (DS), both demented and nondemented and more than a half of patients with DS above 50 years develop Alzheimer's disease (AD)."

Malone FD, Canick JA, Ball RH, Nyberg DA, Comstock CH, Bukowski R, Berkowitz RL, Gross SJ, Dugoff L, Craigo SD, Timor-Tritsch IE, Carr SR, Wolfe HM, Dukes K, Bianchi DW, Rudnicka AR, Hackshaw AK, Lambert-Messerlian G, Wald NJ, D'Alton ME. First-Trimester or Second-Trimester Screening, or Both, for Down's Syndrome. N Engl J Med. 2005 Nov 10;353(19):2001-2011.

Hook EB, Cross PK, Schreinemachers DM.Chromosomal abnormality rates at amniocentesis and in live-born infants. JAMA. 1983 Apr 15;249(15):2034-8.

Schreinemachers DM, Cross PK, Hook EB. Rates of trisomies 21, 18, 13 and other chromosome abnormalities in about 20 000 prenatal studies compared with estimated rates in live births. Hum Genet. 1982;61(4):318-24.

Checking your baby's health before birth. State Health Publication Number (PA) 94-090

New triple screen test for Down syndrome: combined urine analytes and serum AFP. Bahado-Singh RO, et al.J Matern Fetal Med. 1998 May-Jun;7(3):111-4.

Screening for Down's syndrome: effects, safety, and cost effectiveness of first and second trimester strategies R E Gilbert, C Augood, R Gupta, A E Ades, S Logan, M Sculpher, J H P van der Meulen, Euan M Wallace, and Sheila Mulvey BMJ 2001; 323: 423 (link to paper)

Noninvasive means of identifying fetuses with possible Down syndrome: a review. Kubas C. J Perinat Neonatal Nurs 1999 Sep;13(2):27-46 Women who are 35 years or older are offered invasive prenatal testing because of the increased risk of chromosomal abnormalities, especially Down syndrome. In an attempt to increase the number of Down syndrome fetuses being detected and decrease the number of invasive procedures being performed on pregnancies not affected with a chromosome abnormality, both biochemical and ultrasound screening methods are being studied and are summarized in this article.

The ultrasound markers reviewed include increased nuchal thickness, increased nuchal lucency, shortened femur, shortened humerus, pyelectasis, hypoplastic ears, echogenic intracardiac focus, hypoplasia of the fifth middle phalanx, and echogenic bowel.

Books

Note: books are listed for educational and information purposes only and does not suggest a commercial product endorsement.

The Molecular Biology of Down Syndrome

Babies With Down Syndrome: A New Parent's Guide

Search PubMed: term = Trisomy 21 | Down Syndrome | aneuploidy |

WWW Links

OMIM Down Syndrome

Trisomy Organization http://www.trisomy.org/

Better Health Victoria trisomy disorders

See also Virtual Hospital male Karyotype (Virtual Hospital now inactive).

The Australian Down Syndrome Association Inc

c/o - Down Syndrome Association of NSW Inc
PO Box 2356 (31 O'Connell Street)
North Parramtta NSW 2151 Australia
Tel. 02 9683 4333 Fax. 02 9683 420
E-mail:dsansw@hartingdale.com.au

The ACT Down Syndrome Association

P.O. Box 717
Mawson ACT 2607
Tel: 06 290 1984 Fax: 06 286 4475
Email: ehoek@pcug.org.au

The Down Syndrome Association of Queensland
P.O. Box 1293
Milton Queensland 4064

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