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 aneuploidy 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.

Some Recent Findings

Trisomy 21 newborn

Introduction of first trimester combined test increases uptake of Down's syndrome screening "Addition of the earlier first trimester combined test has increased uptake of antenatal screening for Down's syndrome in women of all ages. This is most likely due to the advantages this test gives women such as earlier decision making, earlier further invasive diagnostic testing and earlier termination, if necessary." Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study. "Multiplexed maternal plasma DNA sequencing analysis could be used to rule out fetal trisomy 21 among high risk pregnancies. If referrals for amniocentesis or chorionic villus sampling were based on the sequencing test results, about 98% of the invasive diagnostic procedures could be avoided." Non-invasive prenatal detection of trisomy 21 using tandem single nucleotide polymorphisms "We outline a novel, rapid, highly sensitive, and targeted approach to non-invasively detect fetal T21 using maternal plasma DNA. ...a targeted approach, based on calculation of Haplotype Ratios from tandem SNP sequences combined with a sensitive and quantitative DNA measurement technology can be used to accurately detect fetal T21 in maternal plasma when sufficient fetal DNA is present in maternal plasma." Maternal antimullerian hormone levels do not predict fetal aneuploidy "Maternal AMH does not appear to be a marker of fetal aneuploidy in ongoing pregnancies. Contrary to previous reports, we found a significant decline in maternal AMH levels with advancing gestational age."

Recent References | References | PubMed

Trisomy 21 (Down Syndrome) Karyotypes

Trisomy 21 Male Karyotype	Trisomy 21 Female Karyotype

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.

Associated Congenital Abnormalities

• neurological (mental retardation)
• characteristic facies
• heart (atrioventricular canal)
• gastrointestinal tract (duodenal stenosis or atresia, imperforate anus, and Hirschsprung disease)
• leukemia - Acute lymphocytic (lymphoblastic) leukemia (ALL) and Acute megakaryocytic leukemia (AML). AML occurs 200 to 400 times more frequently in Down syndrome.
• hearing loss (90% of all patients) - usually of the conductive type. (More? Hearing Abnormalities)
• musculoskeletal (limb abnormalities, hypotonia, joint hypermobility, ligamentous laxity, spine anomolies, scoliosis) - 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.

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%)
• patent ductus arteriosus (16%)
• ostium secundum atrial septal defect (10%)
• tetralogy of Fallot (6%)

Links: Cardiovascular System Development | Cardiac Tutorial | Lecture - Heart

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.

Links: Limb Abnormalities | Musculoskeletal System Development

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.

Prevalence

John Langdon Down (1828 – 1896) was a British physician who in 1866 was first to describe the syndrome.

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).
• 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.

Down's syndrome Screening

Screening Strategies

Nuchal translucency 11, 12, 13 weeks

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%

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.

Links: 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.

• ADAM12-S as a maternal serum marker.
  • " The data show moderately decreased levels of ADAM12-S in cases of fetal aneuploidy in gestational weeks 8-11. However, including ADAM12-S in the routine risk does not improve the performance of first trimester screening for fetal trisomy 21."
• Nasal bone measurement
• 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

Detection using Tandem Single Nucleotide Polymorphisms

Trisomy 21 detection using tandem single nucleotide polymorphisms

DNA obtained from maternal buccal swab represent maternal germinal DNA. Tandem Single Nucleotide Polymorphism (SNP) sequences on chromosome 21 are amplified by Multiplexed Linear Amplification (MLA) followed by High-Fidelity Polymerase Chain Reaction (HiFi PCR) and Cycling Temperature Capillary Electrophoresis (CTCE) analysis. DNA obtained from maternal plasma represents a mixture of fetal and maternal DNA. Tandem SNP sequences identified as heterozygous on maternal buccal swab are amplified on maternal plasma by MLA followed by High-Fidelity PCR (HiFi PCR) and CTCE analysis. CTCE analysis is followed by Tandem SNP evaluation to check for informativeness. Results with 3 peaks are subjected to Haplotype Ratio (HR) analysis.

Terms

• Buccal swab is a simple technique used to collect cheek cells from inside your mouth.
• Cycling Temperature Capillary Electrophoresis is a molecular biology technique for detecting DNA variation by DNA sequencing.
• Haplotype is a genetic term for a combination of alleles (DNA sequences) at different places (loci) on the chromosome that are transmitted together.
• Polymerase Chain Reaction is a molecular biology technique for amplifying, making many copies of, a short sequence of DNA.
• Single Nucleotide Polymorphism is a genetic term for a variation in single nucleotide in a DNA sequence differing between individuals or paired chromosomes in an individual.

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

Meiosis I and Meiosis II

A recent study has analysed two large USA studies (1,215 of 1,881 eligible case families and 1,375 of 2,293 controls) the Atlanta Down Syndrome Project (1989-1999) and National Down Syndrome Project (2001-2004), looking for an association between maternal age and chromosome 21 nondisjunction by origin of the meiotic error.

Four key findings:

1. Significant association between advanced maternal age and chromosome 21 nondisjunction was restricted to meiotic errors in the oocyte. The association was not observed in sperm or in post-zygotic mitotic errors.
2. Advanced maternal age was significantly associated with both meiosis I (MI) and meiosis II (MII).
3. The ratio of MI to MII errors differed by maternal age. (ratio lower among young and older women and higher in the middle age group).
4. No effect of grand-maternal age on the risk for maternal nondisjunction.

Links: Cell Division - Meiosis

Aneuploidy

Ploidy refers to the chromosomal genetic content of cells and there are a range of terms used to describe variations that may occur:

• 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.

Links: Abnormal Development - Genetic

Trisomy 21 Growth Charts

Data from this paper "describes an approach for generating subpopulation-specific growth charts meeting requirements for implementation into Electronic health record (EHR) systems, using as an example weights for children with Down syndrome. Gender-specific growth curves were generated from 2358 weight values obtained from 331 patients with Down syndrome from July 2001 until March 2005. The project generated printable curves and computable data tables formatted according to growth chart standards set forth by the Centers for Disease Control and Prevention to facilitate implementation into EHR systems."

Links: Growth Charts

Mouse Model

The following are some recent articles using the Ts65Dn and Ts1Cje mouse models.

Identification of the translocation breakpoints in the Ts65Dn and Ts1Cje mouse lines: relevance for modeling Down syndrome.

"Down syndrome (DS) is the most frequent genetic disorder leading to intellectual disabilities and is caused by three copies of human chromosome 21. Mouse models are widely used to better understand the physiopathology in DS or to test new therapeutic approaches. The older and the most widely used mouse models are the trisomic Ts65Dn and the Ts1Cje mice. They display deficits similar to those observed in DS people, such as those in behavior and cognition or in neuronal abnormalities. The Ts65Dn model is currently used for further therapeutic assessment of candidate drugs."

Gene expression profiling in a mouse model identifies fetal liver- and placenta-derived potential biomarkers for Down Syndrome screening.

"Placenta and fetal liver at 15.5 days gestation were analyzed by microarray profiling. We confirmed increased expression of genes located at the trisomic chromosomal region. Overall, between the two genotypes more differentially expressed genes were found in fetal liver than in placenta. Furthermore, the fetal liver data are in line with the hematological aberrations found in humans with Down Syndrome as well as Ts1Cje mice. Together, we found 25 targets that are predicted (by Gene Ontology, UniProt, or the Human Plasma Proteome project) to be detectable in human serum."

Gene Network Disruptions and Neurogenesis Defects in the Adult Ts1Cje Mouse Model of Down Syndrome

"We have shown that trisomy affects a number of elements of adult neurogenesis likely to result in a progressive pathogenesis and consequently providing the potential for the development of therapies to slow progression of, or even ameliorate the neuronal deficits suffered by DS individuals."

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

<pubmed>17048355</pubmed> <pubmed>17048355</pubmed> <pubmed>16935027</pubmed> <pubmed>12204419</pubmed> <pubmed>12709282</pubmed> <pubmed>11444737</pubmed> <pubmed>9800243</pubmed> <pubmed>15862185</pubmed> <pubmed>15851056</pubmed>

Articles

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

<pubmed>17382849</pubmed> <pubmed>16282175</pubmed>| NEMJ - Down's Syndrome Screening Article

<pubmed>11520837</pubmed>| BMJ link

<pubmed>9642606</pubmed>

Associated Neurological

<pubmed>15862185</pubmed> <pubmed>16282175</pubmed> <pubmed>6220164</pubmed> <pubmed>6891368</pubmed>

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 |

External Links

External Links Notice - The dynamic nature of the internet may mean that some of these listed links may no longer function. If the link no longer works search the web with the link text or name. Links to any external commercial sites are provided for information purposes only and should never be considered an endorsement. UNSW Embryology is provided as an educational resource with no clinical information or commercial affiliation.

• Original UNSW Embryology Abnormal Development - Trisomy 21 (Down Syndrome)
• OMIM Down Syndrome
• Trisomy Organization http://www.trisomy.org/
• Better Health Victoria trisomy disorders
• Growth Charts
  • Growth Charts for USA Children with Down Syndrome
  • Growth Charts for UK Children with Down Syndrome

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

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? Alpha-Fetoprotein 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? Alpha-Fetoprotein Test)
• aneuploidy - Term used to describe an abnormal number of chromosomes mainly (90%) due to chromosome malsegregation mechanisms in maternal meiosis I. (More? Prenatal Diagnosis | Abnormal Development - Genetic | Cell Division - Meiosis)
• karyotype - (Greek, karyon = kernel or nucleus + typos = stamp) Term used to describe the chromosomal (genetic) makeup (complement) of a cell. (More? Abnormal Development - Genetic)
• nuchal translucency - (fetal nuchal-translucency thickness) An initial diagnostic ultrasound measurement in the fetal neck region carried out by trans-abdominal ultrasound at gestational age (GA) 10–14 weeks. Fetal sagittal section scan at a magnification that the fetus occupied at least 75% of the image. Measured is the maximum thickness of the subcutaneous translucency between the skin and the soft tissue overlying the cervical spine.
• 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? Timeline human development)

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Cite this page: Hill, M.A. (2024, May 1) Embryology Trisomy 21. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Trisomy_21

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