Trisomy 21

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 is the historic name used for this condition identified by Down, J.L.H. in a 1866 paper where he described the "phenotypic features that includes mental retardation and characteristic facies".

Aneuploidy is the term used to describe any abnormal number of chromosomes either an increase or decrease in total number.

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 genetic risk with maternal age.

| original Trisomy 21 page

Trisomy 21 (Down Syndrome) Karyotypes

Trisomy 21 Male Karyotype

Trisomy 21 Female Karyotype

Trisomy 21 newborn

The normal human karyotypes contain 22 pairs of autosomal chromosomes and one pair of sex chromosomes. The karyotype is the characteristic chromosome complement as identified by staining and can only be identified during cell division when chromosomes are folded. The chromosomes when organised as an image in sequence are called a karyogram or idiogram.

Some Recent Findings

• Discovery of novel serum biomarkers for prenatal Down syndrome screening by integrative data mining. Pennings JL, Koster MP, Rodenburg W, Schielen PC, de Vries A. PLoS One. 2009 Nov 24;4(11):e8010. PMID: 19956656

"To facilitate the experimental search for novel maternal serum biomarkers in prenatal Down Syndrome screening, we aimed to create a set of candidate biomarkers using a data mining approach."

• Maternal age and risk for trisomy 21 assessed by the origin of chromosome nondisjunction: a report from the Atlanta and National Down Syndrome Projects. Allen EG, Freeman SB, Druschel C, Hobbs CA, O'Leary LA, Romitti PA, Royle MH, Torfs CP, Sherman SL. Hum Genet. 2009 Feb;125(1):41-52. Epub 2008 Dec 3. PMID: 19050929

"We examined the association between maternal age and chromosome 21 nondisjunction by origin of the meiotic error. We analyzed data from two population-based, case-control studies: Atlanta Down Syndrome Project (1989-1999) and National Down Syndrome Project (2001-2004). Cases were live born infants with trisomy 21 and controls were infants without trisomy 21 delivered in the same geographical regions. We enrolled 1,215 of 1,881 eligible case families and 1,375 of 2,293 controls. We report four primary findings. First, the significant association between advanced maternal age and chromosome 21 nondisjunction was restricted to meiotic errors in the egg; the association was not observed in sperm or in post-zygotic mitotic errors. Second, advanced maternal age was significantly associated with both meiosis I (MI) and meiosis II (MII). For example, compared to mothers of controls, mothers of infants with trisomy 21 due to MI nondisjunction were 8.5 times more likely to be >or=40 years old than 20-24 years old at the birth of the index case (95% CI=5.6-12.9). Where nondisjunction occurred in MII, mothers were 15.1 times more likely to be >or=40 years (95% CI = 8.4-27.3). Third, the ratio of MI to MII errors differed by maternal age. The ratio was lower among women <19 years of age and those >or=40 years (2.1, 2.3, respectively) and higher in the middle age group (3.6). Lastly, we found no effect of grand-maternal age on the risk for maternal nondisjunction. This study emphasizes the complex association between advanced maternal age and nondisjunction of chromosome 21 during oogenesis."

• Down syndrome—recent progress and future prospects Frances K. Wiseman, Kate A. Alford, Victor L.J. Tybulewicz, and Elizabeth M.C. Fisher Hum Mol Genet. 2009 April 15; 18(R1): R75–R83. doi: 10.1093/hmg/ddp010. PMCID: PMC2657943

• Heterozygosity for a Bub1 mutation causes female-specific germ cell aneuploidy in mice. Leland S, Nagarajan P, Polyzos A, Thomas S, Samaan G, Donnell R, Marchetti F, Venkatachalam S. Proc Natl Acad Sci U S A. 2009 Jul 17. PMID: 19617567

"Aneuploidy, the most common chromosomal abnormality at birth and the main ascertained cause of pregnancy loss in humans, originates primarily from chromosome segregation errors during oogenesis. Here, we report that heterozygosity for a mutation in the mitotic checkpoint kinase gene, Bub1, induces aneuploidy in female germ cells of mice and that the effect increases with advancing maternal age."

Search PubMed Now: Trisomy 21

Associated Congenital Abnormalities

• neurological (mental retardation)
• characteristic facies
• heart (atrioventricular canal)
• gastrointestinal tract (duodenal stenosis or atresia, imperforate anus, and Hirschsprung disease)
• leukemia (ALL and AML)
• hearing loss (90% of all patients)
• musculoskeletal (limb abnormalities, hypotonia, joint hypermobility, ligamentous laxity, spine anomolies, scoliosis)
• 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. PMID: 17048355

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

Trisomy 21 hand features

• 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%).

Other musculoskeletal effects 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. PMID: 17030594

(More? Limb Abnormalities)

American College of Obstetricians and Gynecologists Recommendations

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

• First-trimester screening using both nuchal translucency (NT), an ultrasound exam that measures the thickness at the back of the neck of the fetus, and a blood test is an effective screening test in the general population and is more effective than NT alone.
• Women found to be at increased risk of having a baby with Down syndrome with first-trimester screening should be offered genetic counseling and the option of CVS or mid-trimester amniocentesis.
• Specific training, standardization, use of appropriate ultrasound equipment, and ongoing quality assessment are important to achieve optimal NT measurement for Down syndrome risk assessment, and this procedure should be limited to centers and individuals meeting this criteria.
• Neural tube defect screening should be offered in the mid-trimester to women who elect only first-trimester screening for Down syndrome.

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

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). PMID: 17380922
• 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. PMID: 15368554

Down's syndrome Screening

Screening Strategies

Procedure	Detection rate
First trimester screening (10 to 14 weeks):   Maternal age   Nuchal translucency measurement ([ultrasound.htm 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%

Table data from United Kingdom

AFP = alpha 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.

See also the UK report: Serum, Urine and Ultrasound Screening Study (SURUSS) 1996-2003 published 2006.

(More? Alpha-Fetoprotein | Pregnancy-associated plasma protein-A)

Novel Screening Strategies

There are several additional suggested screening stratagies currently at various stages of development. These techniques should be seen as at the research stage only until data, a clinical concensus and a recommendation has been made.

• Jugular lymphatic sacs in the first trimester of pregnancy
• First-trimester combined screening for trisomy 21 with the double test taken before a gestational age of 10 weeks

Screening By Country

• Spain - all pregnant women aged 35 years and older are offered genetic examination through invasive testing in order to detect fetal trisomy 21 cases

Aneuploidy

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

(More? Genetic Abnormalities)

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. PMID: 17048355
• 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. PMID: 17048355
• Antonarakis SE, Epstein CJ. The challenge of Down syndrome. Trends Mol Med. 2006 Oct;12(10):473-9. Epub 2006 Aug 28. PMID: 16935027
• 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. PMID: 12204419
• 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. PMID: 12709282
• Souter VL, Nyberg DA. Sonographic screening for fetal aneuploidy: first trimester. J Ultrasound Med. 2001 Jul;20(7):775-90. PMID: 11444737
• Jackson M, Rose NC. Diagnosis and management of fetal nuchal translucency. Semin Roentgenol. 1998 Oct;33(4):333-8. Review. PMID: 9800243
• Menendez M. Down syndrome, Alzheimer's disease and seizures. Brain Dev. 2005 Jun;27(4):246-52. PMID: 15862185
• FitzPatrick DR. Transcriptional consequences of autosomal trisomy: primary gene dosage with complex downstream effects. Trends Genet. 2005 May;21(5):249-53. PMID: 15851056

Articles

• Down, JLH Observations on an ethnic classification of idiots. London Hosp. Clin. Lect. Rep. 3: 259 only, 1866.

• 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. PMID: 17382849

• 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. PMID: 16282175 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

• Gilbert RE, Augood C, Gupta R, Ades AE, Logan S, Sculpher M, van Der Meulen JH. Screening for Down's syndrome: effects, safety, and cost effectiveness of first and second trimester strategies. BMJ. 2001 Aug 25;323(7310):423-5. PMID: 11520837 | BMJ link

• Bahado-Singh RO, et al. New triple screen test for Down syndrome: combined urine analytes and serum AFP. J Matern Fetal Med. 1998 May-Jun;7(3):111-4. PMID: 9642606

• 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 Screening for Down's syndrome: effects, safety, and cost effectiveness of first and second trimester strategies BMJ 2001; 323: 423 BMJ link

• Kubas C. J Noninvasive means of identifying fetuses with possible Down syndrome: a review. 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.

Associated Neurological

• Menendez M. Down syndrome, Alzheimer's disease and seizures. Brain Dev. 2005 Jun;27(4):246-52. PMID: 15862185

"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. PMID: 16282175

• Hook EB, Cross PK, Schreinemachers DM. Chromosomal abnormality rates at amniocentesis and in live-born infants. JAMA. 1983 Apr 15;249(15):2034-8. PMID: 6220164
• 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. PMID: 6891368

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

OMIM

• 190685 Down Syndrome

Search PubMed

Search PubMed Now: Trisomy 21 | Down Syndrome | aneuploidy |

WWW Links

• OMIM Down Syndrome
• Trisomy Organization http://www.trisomy.org/
• Better Health Victoria trisomy disorders

Australian Support

• The Australian Down Syndrome Association Inc c/o - Down Syndrome Association of NSW IncPO Box 2356 (31 O'Connell Street)North Parramtta NSW 2151 AustraliaTel. 02 9683 4333 Fax. 02 9683 420E-mail:dsansw@hartingdale.com.au
• The ACT Down Syndrome Association P.O. Box 717Mawson ACT 2607Tel: 06 290 1984 Fax: 06 286 4475Email: ehoek@pcug.org.au
• The Down Syndrome Association of QueenslandP.O. Box 1293Milton Queensland 4064

UNSW Embryology Links

• Abnormal Development - Trisomy 21 (Down Syndrome)

Terms

alpha-fetoprotein - (AFP) A serum fetal glycoprotein produced by both the yolk sac and fetal liver. The presence of the protein in maternal blood is the basis of a test for genetic or developmental problems in the fetus. Low levels of AFP normally occur in the blood of a pregnant woman, high levels may indicate neural tube defects (spina bifida, anencephaly). (More? Abnormal Development- AFP test)

alpha-fetoprotein test (APF test) A prenatal test to measure the amount of a fetal protein in the mother's blood (or amniotic fluid). Abnormal amounts of the protein may indicate genetic or developmental problems in the fetus. Serum alpha-fetoprotein (AFP) is a fetal glycoprotein produced by the yolk sac and fetal liver. Low levels of AFP normally occur in the blood of a pregnant woman, high levels may indicate neural tube defects (spina bifida, anencephaly). (More? Abnormal Development- AFP test)

aneuploidy - Term used to describe an abnormal number of chromosomes mainly (90%) due to chromosome malsegregation mechanisms in maternal meiosis I. (More? Meiosis)

karyotype - (Greek, karyon = kernel or nucleus + typos = stamp) Term used to describe the chromosomal (genetic) makeup (complement) of a cell. (More? Week 1 Notes | Genetic Abnormalities)

single umbilical artery - (SUA) Placental cord with only a single placental artery (normally paired). This abnormality can be detected by ultrasound (colour flow imaging of the fetal pelvis) and is used as an indicator for further prenatal diagnostic testing for chromosomal abnormalities and other systemic defects. (More? Prenatal Diagnosis | Ultrasound)

trimester - Clinical term used to describe and divide human pregnancy period (9 months) into three equal parts of about three calendar months. The first trimester corresponds approximately to embryonic development (week 1 to 8) of organogenesis and early fetal. The second and third trimester correspond to the fetal period of growth in size (second trimester) and weight (third trimester), as well as continued differentiation of existing organs and tissues. (More? Embryo Stages | Human Fetal Period | Development Week by Week)

Glossary Links

Glossary: A | B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q | R | S | T | U | V | W | X | Y | Z | Numbers | Symbols | Term Link

Glossary Comments

Use this page to access brief definitions of specific embryology terms. Additional information can be accessed from links listed at the end of each definition. Glossary from the UNSW Embryology program compiled and written by Dr Mark Hill. Reference material used in preparing this glossary list includes: texts listed on page 1 "Reading" of each notes section, Department of Anatomy Publications, WWW resources from NCBI, NIH, OMIM, NHMRC (Australia), AMA (USA), Office of Rare Diseases (USA), PubMed Medline Dictionaries, MSDS, Merck Manual home edn. and WHO ART terminology (2009).

These notes are for Educational Purposes Only Please email Dr Mark Hill if you wish to make a comment about this current project.