|Embryology - 22 Oct 2021 Expand to Translate|
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| ICD-11 - LD40.0 Complete trisomy 21
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. This can occur during gamete development or following fertilisation during early rounds of mitosis.
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. To help understand these changes with age, you need to study the development of the ovary and the long process of meiosis that commences in the early oocyte.
Australian - Department of Health
- "9.3 Screening tests in the first trimester - Offering the genetic screening test to all women in the first trimester — regardless of maternal age — is recommended in the United Kingdom (NICE 2008), the United States (ACOG 2007) and Australia (HGSA & RANZCOG 2007)."
- "Combined test (nuchal translucency thickness, free beta-human chorionic gonadotrophin, pregnancy-associated plasma protein-A),"
Some Recent Findings
|More recent papers|
This table allows an automated computer search of the external PubMed database using the listed "Search term" text link.
|These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table.
Trisomy 21 (Down Syndrome) Karyotypes
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.
International Classification of Diseases
The International Classification of Diseases (ICD) World Health Organization's classification used worldwide as the standard diagnostic tool for epidemiology, health management and clinical purposes. This includes the analysis of the general health situation of population groups. It is used to monitor the incidence and prevalence of diseases and other health problems. Within this classification "congenital malformations, deformations and chromosomal abnormalities" are (Q00-Q99) but excludes "inborn errors of metabolism" (E70-E90).
Chromosomal abnormalities, not elsewhere classified (Q90-Q99)
- Q90 Down's syndrome
- Q90.0 Trisomy 21, meiotic nondisjunction
- Q90.1 Trisomy 21, mosaicism (mitotic nondisjunction)
- Q90.2 Trisomy 21, translocation
- Q90.9 Down's syndrome, unspecified Trisomy 21 NOS
|21 (Trisomy 21) was identified as the basis of this developmental abnormality. Note that the original paper uses historic terminology that would no longer be considered acceptable in Medicine.|
- 1866 - British physician John Langdon Down was first to describe the syndrome he described as Mongoloid idiocy.
- 1959 - French geneticist Jerome Lejeune discovered the chromosome abnormality.
- 1961 - The Lancet letter to the editor proposed that the name Down's Syndrome. (see reprint Am J Hum Genet. 1961.)
|Letter To The Editor (1961)|
|Reprinted from Lancet, Vol. 1: 775 (Apr. 8) 1961.)
It has long been recognized that the terms “mongolian idiocy”, “mongolism”, “mongoloid”, etc., as applied to a speciﬁc type of mental deﬁciency have misleading connotations. The occurrence of this anomaly among Europeans and their descendents is not related to the segregation of genes derived from Asians; its appearance among members of Asian populations suggests such ambiguous designations as, “mongol Mongoloid” ; and the increasing participation of Chinese and Japanese investigators in the study of the condition imposes on them the use of an embarrassing term. We urge, therefore, that the expressions which imply a racial aspect of the condition be no longer used.
GORDON ALLEN (Bethesda, M d., USA)
C. E. BENDA (Waverly, Mass., USA)
J. A. Bṏṏk (Uppsala, Sweden)
C. O. CARTER (London, England)
C. E. FORD (Harwell, England)
E. H. Y. Chu (Oak Ridge, Tenn., USA)
E. HANHART (Ancona, Switzerland)
GEORGE JERVIS (Letchworth Village, New York, USA)
W. LANGDON-DoWN (Normansﬁeld, England)
J. LEJEUNE (Paris, France)
H1deo NISHIMURA (Kyoto, Japan)
J. OSTER (Randers, Denmark)
L. S. PENROSE (London, England)
P. E. POLANI (London, England)
Edith L. Potter (Chicago, 121., USA)
CURT STERN (Berkeley, Calif, USA)
R. TURPIN (Paris, France)
J. WARKANY (Cincinnati, Ohio, USA)
HERMAN YANNET (Southberry, Conn., USA)
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.
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 Defects (32%)
- Patent Ductus Arteriosus (16%)
- ostium secundum atrial septal defect (10%)
- tetralogy of Fallot (6%)
A Korean study of data from 2005-2006 showed a prevalence of trisomy 21 of 4.4 per 10,000 total births (1.5% of all birth defects). Of the 394 trisomy infants 56.9% (224) had heart defects.
- Atrial septal defects (30.5%)
- Ventricular septal defects (19.3%)
- Patent duct arteriosus (17.5%)
- atrioventricular septal defect (9.4%).
- 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.
Down syndrome cell adhesion molecule (DSCAM, 21q22.2) is a member of the immunoglobulin superfamily and a class of neural cell adhesion molecules. There are several models that suggest that it is required for early neural development and that over-expression may be associated with the mental retardation seen in Trisomy 21.
- Links: OMIM 602523
Australian Clinical Practice Guidelines
The 2018 Australian Clinical Practice Guidelines - Pregnancy Care recommends a combined first trimester test comprising both:
- ultrasound measurement of fetal nuchal translucency thickness between GA 11 weeks and 13 weeks 6 days gestation (when the fetus has a crown-rump length of 45–84 mm)
- maternal plasma testing of pregnancy-associated placental protein-A (PAPP-A) and free beta-human chorionic gonadotrophin (b-hCG) between GA 9 weeks and 13 weeks, 6 days gestation.
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 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
|First trimester screening (10 to 14 weeks):
First trimester double test (PAPP-A, HCG)
First trimester combined test (nuchal translucency, PAPP-A, HCG)
|Second trimester screening (15 to 19 weeks):
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)
Amniocentesis (15 weeks)
Chorionic villus sampling (11-14 weeks)
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.
Second Trimester Ultrasound
Some ultrasound markers have been identified as indicating further testing, but by themselves are not entirely diagnostic. Increased nuchal fold and structural malformation have in some studies been shown to have the highest correlation.
- increased nuchal fold thickness (≥ 6 mm)
- structural fetal malformation
- cardiac hyperechogenic focus
- mild ventriculomegaly
- choroid plexus cysts
- uni- or bilateral renal pyelectasis
- intestinal hyperechogenicity
- single umbilical artery
- short femur and humerus length
- hand/foot alterations
- congenital heart disease
- Links: Ultrasound
Maternal Blood Screening
There have now been reported several non-invasive tests based upon collection and analysis of maternal blood.
- Germany, Austria and Switzerland - PrenaTest detects only trisomy 21 and can be carried out at gestational age 12 to 14 weeks. In Germany, about 50,000 people have Down’s syndrome that is currently detected in one in 800 pregnancies.
- South Korea - The phosphodiesterases gene, PDE9A, located on chromosome 21q22.3, is completely methylated in blood (M-PDE9A) and unmethylated in the placenta (U-PDE9A). Therefore, we estimated the accuracy of non-invasive fetal DS detection during the first trimester of pregnancy using this tissue-specific epigenetic characteristic of PDE9A. "Our findings suggest that U-PDE9A level and the unmethylation index of PDE9A may be useful biomarkers for non-invasive fetal DS detection during the first trimester of pregnancy, regardless of fetal gender."
AMH - A study has shown that maternal blood antimullerian hormone (AMH) 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."
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.
- Clinical application of massively parallel sequencing-based prenatal noninvasive fetal trisomy test for trisomies 21 and 18 in 11,105 pregnancies with mixed risk factors "To report the performance of massively parallel sequencing (MPS) based prenatal noninvasive fetal trisomy test based on cell-free DNA sequencing from maternal plasma in a routine clinical setting in China. One hundred ninety cases were classified as positive, including 143 cases of trisomy 21 and 47 cases of trisomy 18. With the karyotyping results and the feedback of fetal outcome data, we observed one false positive case of trisomy 21, one false positive case of trisomy 18 and no false negative cases, indicating 100% sensitivity and 99.96% specificity for the detection of trisomies 21 and 18. Our large-scale multicenter study proved that the MPS-based test is of high sensitivity and specificity in detecting fetal trisomies 21 and 18. The introduction of this screening test into a routine clinical setting could avoid about 98% of invasive prenatal diagnostic procedures."
- ADAM12-S as a maternal serum marker.<ref>First trimester screening for trisomy 21 in gestational week 8-10 by 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.
- 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
- Canada - all pregnant women in Canada, regardless of age, should be offered, through an informed counselling process, the option of a prenatal screening test for the most common clinically significant fetal aneuploidies in addition to a second trimester ultrasound for dating, assessment of fetal anatomy, and detection of multiples. (see detailed recommendations)
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:
- 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.
- Advanced maternal age was significantly associated with both meiosis I (MI) and meiosis II (MII).
- 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).
- No effect of grand-maternal age on the risk for maternal nondisjunction.
- Links: Cell Division - Meiosis
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.
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
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."
- Bestwick JP, Huttly WJ & Wald NJ. (2010). Evaluation of a proposed mixture model to specify the distributions of nuchal translucency measurements in antenatal screening for Down's syndrome. J Med Screen , 17, 13-8. PMID: 20356940 DOI.
- Down JLH. Observations on an ethnic classification of idiots. (1866) London Hospital Reports, 3:259-262.
- Australian - Department of Health (2013) Clinical Practice Guidelines Antenatal Care - Module I 9.3 Screening tests in the first trimester.
- Sakakibara Y, Hashimoto S, Nakaoka Y, Kouznetsova A, Höög C & Kitajima TS. (2015). Bivalent separation into univalents precedes age-related meiosis I errors in oocytes. Nat Commun , 6, 7550. PMID: 26130582 DOI.
- Sillibourne JE & Bornens M. (2010). Polo-like kinase 4: the odd one out of the family. Cell Div , 5, 25. PMID: 20920249 DOI.
- Prodan N, Wagner P, Sonek J, Hoopmann M, Mutz A, Brucker S & Kagan KO. (2019). First trimester uterine artery pulsatility index levels in euploid and aneuploid pregnancies. Arch. Gynecol. Obstet. , , . PMID: 31616987 DOI.
- Sanchez-Ribas I, Diaz-Gimeno P, Sebastián-León P, Mercader A, Quiñonero A, Ballesteros A, Pellicer A & Domínguez F. (2019). Transcriptomic behavior of genes associated with chromosome 21 aneuploidies in early embryo development. Fertil. Steril. , 111, 991-1001.e2. PMID: 30922649 DOI.
- Wang S, Hassold T, Hunt P, White MA, Zickler D, Kleckner N & Zhang L. (2017). Inefficient Crossover Maturation Underlies Elevated Aneuploidy in Human Female Meiosis. Cell , 168, 977-989.e17. PMID: 28262352 DOI.
- Henneman P, Bouman A, Mul A, Knegt L, van der Kevie-Kersemaekers AM, Zwaveling-Soonawala N, Meijers-Heijboer HEJ, van Trotsenburg ASP & Mannens MM. (2018). Widespread domain-like perturbations of DNA methylation in whole blood of Down syndrome neonates. PLoS ONE , 13, e0194938. PMID: 29601581 DOI.
- Gonzales PK, Roberts CM, Fonte V, Jacobsen C, Stein GH & Link CD. (2018). Transcriptome analysis of genetically matched human induced pluripotent stem cells disomic or trisomic for chromosome 21. PLoS ONE , 13, e0194581. PMID: 29584757 DOI.
- Sullivan KD, Lewis HC, Hill AA, Pandey A, Jackson LP, Cabral JM, Smith KP, Liggett LA, Gomez EB, Galbraith MD, DeGregori J & Espinosa JM. (2016). Trisomy 21 consistently activates the interferon response. Elife , 5, . PMID: 27472900 DOI.
- Chitty LS, Wright D, Hill M, Verhoef TI, Daley R, Lewis C, Mason S, McKay F, Jenkins L, Howarth A, Cameron L, McEwan A, Fisher J, Kroese M & Morris S. (2016). Uptake, outcomes, and costs of implementing non-invasive prenatal testing for Down's syndrome into NHS maternity care: prospective cohort study in eight diverse maternity units. BMJ , 354, i3426. PMID: 27378786
- Deidda G, Parrini M, Naskar S, Bozarth IF, Contestabile A & Cancedda L. (2015). Reversing excitatory GABAAR signaling restores synaptic plasticity and memory in a mouse model of Down syndrome. Nat. Med. , 21, 318-26. PMID: 25774849 DOI.
- McCoy RC, Demko Z, Ryan A, Banjevic M, Hill M, Sigurjonsson S, Rabinowitz M, Fraser HB & Petrov DA. (2015). Common variants spanning PLK4 are associated with mitotic-origin aneuploidy in human embryos. Science , 348, 235-8. PMID: 25859044 DOI.
- Bianchi DW, Parker RL, Wentworth J, Madankumar R, Saffer C, Das AF, Craig JA, Chudova DI, Devers PL, Jones KW, Oliver K, Rava RP & Sehnert AJ. (2014). DNA sequencing versus standard prenatal aneuploidy screening. N. Engl. J. Med. , 370, 799-808. PMID: 24571752 DOI.
- Hollis ND, Allen EG, Oliver TR, Tinker SW, Druschel C, Hobbs CA, O'Leary LA, Romitti PA, Royle MH, Torfs CP, Freeman SB, Sherman SL & Bean LJ. (2013). Preconception folic acid supplementation and risk for chromosome 21 nondisjunction: a report from the National Down Syndrome Project. Am. J. Med. Genet. A , 161A, 438-44. PMID: 23401135 DOI.
- Tringham GM, Nawaz TS, Holding S, Mcfarlane J & Lindow SW. (2011). Introduction of first trimester combined test increases uptake of Down's syndrome screening. Eur. J. Obstet. Gynecol. Reprod. Biol. , 159, 95-8. PMID: 21839574 DOI.
- Chiu RW, Akolekar R, Zheng YW, Leung TY, Sun H, Chan KC, Lun FM, Go AT, Lau ET, To WW, Leung WC, Tang RY, Au-Yeung SK, Lam H, Kung YY, Zhang X, van Vugt JM, Minekawa R, Tang MH, Wang J, Oudejans CB, Lau TK, Nicolaides KH & Lo YM. (2011). Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study. BMJ , 342, c7401. PMID: 21224326
- Ghanta S, Mitchell ME, Ames M, Hidestrand M, Simpson P, Goetsch M, Thilly WG, Struble CA & Tomita-Mitchell A. (2010). Non-invasive prenatal detection of trisomy 21 using tandem single nucleotide polymorphisms. PLoS ONE , 5, e13184. PMID: 20949031 DOI.
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- Allen G, Benda CE, Böök JA, Carter CO, Ford CE, Chu EH, Hanhart E, Jervis G, Langdon-Down W, Lejeune J, Nishimura H, Oster J, Penrose LS, Polani PE, Potter EL, Stern C, Turpin R, Warkany J & Yannet H. (1961). Mongolism. Am. J. Hum. Genet. , 13, 426. PMID: 17948460
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- Cvetkovska V, Hibbert AD, Emran F & Chen BE. (2013). Overexpression of Down syndrome cell adhesion molecule impairs precise synaptic targeting. Nat. Neurosci. , 16, 677-82. PMID: 23666178 DOI.
- Department of Health (2018) Clinical Practice Guidelines: Pregnancy Care. Canberra: Australian Government Department of Health. (5 June 2019)
- New Recommendations for Down Syndrome Call for Screening of All Pregnant Women (press release January 2, 2007)
- Egbe A, Lee S, Ho D, Uppu S & Srivastava S. (2014). Prevalence of congenital anomalies in newborns with congenital heart disease diagnosis. Ann Pediatr Cardiol , 7, 86-91. PMID: 24987252 DOI.
- O'Nualláin S, Flanagan O, Raffat I, Avalos G & Dineen B. (2007). The prevalence of Down syndrome in County Galway. Ir Med J , 100, 329-31. PMID: 17380922
- Siffel C, Correa A, Cragan J & Alverson CJ. (2004). Prenatal diagnosis, pregnancy terminations and prevalence of Down syndrome in Atlanta. Birth Defects Res. Part A Clin. Mol. Teratol. , 70, 565-71. PMID: 15368554 DOI.
- Alphonse J, Cox J, Clarke J, Schluter P & McLennan A. (2013). The Effect of Ethnicity on 2D and 3D Frontomaxillary Facial Angle Measurement in the First Trimester. Obstet Gynecol Int , 2013, 847293. PMID: 24288543 DOI.
- Gilbert RE, Augood C, Gupta R, Ades AE, Logan S, Sculpher M & van Der Meulen JH. (2001). Screening for Down's syndrome: effects, safety, and cost effectiveness of first and second trimester strategies. BMJ , 323, 423-5. PMID: 11520837
- Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L & Mackinson AM. (2003). First and second trimester antenatal screening for Down's syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS). J Med Screen , 10, 56-104. PMID: 14746340 DOI.
- Rumi Kataguiri M, Araujo Júnior E, Silva Bussamra LC, Nardozza LM & Fernandes Moron A. (2014). Influence of second-trimester ultrasound markers for Down syndrome in pregnant women of advanced maternal age. J Pregnancy , 2014, 785730. PMID: 24795825 DOI.
- Tuffs A. (2012). Prenatal blood test for Down's syndrome is to be introduced in Germany despite ethical and legal concerns. BMJ , 345, e4836. PMID: 22809836
- Lim JH, Kim SY, Park SY, Lee SY, Kim MJ, Han YJ, Lee SW, Chung JH, Kim MY, Yang JH & Ryu HM. (2011). Non-invasive epigenetic detection of fetal trisomy 21 in first trimester maternal plasma. PLoS ONE , 6, e27709. PMID: 22132128 DOI.
- Plante BJ, Beamon C, Schmitt CL, Moldenhauer JS & Steiner AZ. (2010). Maternal antimullerian hormone levels do not predict fetal aneuploidy. J. Assist. Reprod. Genet. , 27, 409-14. PMID: 20490648 DOI.
- Dan S, Wang W, Ren J, Li Y, Hu H, Xu Z, Lau TK, Xie J, Zhao W, Huang H, Xie J, Sun L, Zhang X, Wang W, Liao S, Qiang R, Cao J, Zhang Q, Zhou Y, Zhu H, Zhong M, Guo Y, Lin L, Gao Z, Yao H, Zhang H, Zhao L, Jiang F, Chen F, Jiang H, Li S, Li Y, Wang J, Wang J, Duan T, Su Y & Zhang X. (2012). Clinical application of massively parallel sequencing-based prenatal noninvasive fetal trisomy test for trisomies 21 and 18 in 11,105 pregnancies with mixed risk factors. Prenat. Diagn. , 32, 1225-32. PMID: 23138752 DOI.
- Tørring N, Ball S, Wright D, Sarkissian G, Guitton M & Darbouret B. (2010). First trimester screening for trisomy 21 in gestational week 8-10 by ADAM12-S as a maternal serum marker. Reprod. Biol. Endocrinol. , 8, 129. PMID: 21034452 DOI.
- Shanks A & Odibo A. (2010). Nasal bone in prenatal trisomy 21 screening. Obstet Gynecol Surv , 65, 46-52. PMID: 20040129 DOI.
- van Heesch PN, Struijk PC, Brandenburg H, Steegers EA & Wildschut HI. (2008). Jugular lymphatic sacs in the first trimester of pregnancy: the prevalence and the potential value in screening for chromosomal abnormalities. J Perinat Med , 36, 518-22. PMID: 18681837 DOI.
- Kirkegaard I, Petersen OB, Uldbjerg N & Tørring N. (2008). Improved performance of first-trimester combined screening for trisomy 21 with the double test taken before a gestational age of 10 weeks. Prenat. Diagn. , 28, 839-44. PMID: 18677711 DOI.
- Allen EG, Freeman SB, Druschel C, Hobbs CA, O'Leary LA, Romitti PA, Royle MH, Torfs CP & Sherman SL. (2009). Maternal age and risk for trisomy 21 assessed by the origin of chromosome nondisjunction: a report from the Atlanta and National Down Syndrome Projects. Hum. Genet. , 125, 41-52. PMID: 19050929 DOI.
- Rosenbloom ST, McGregor TL, Chen Q, An AQ, Hsu S & Dupont WD. (2010). Specialized Pediatric Growth Charts For Electronic Health Record Systems: the example of Down syndrome. AMIA Annu Symp Proc , 2010, 687-91. PMID: 21347066
- Duchon A, Raveau M, Chevalier C, Nalesso V, Sharp AJ & Herault Y. (2011). Identification of the translocation breakpoints in the Ts65Dn and Ts1Cje mouse lines: relevance for modeling Down syndrome. Mamm. Genome , 22, 674-84. PMID: 21953411 DOI.
- Pennings JL, Rodenburg W, Imholz S, Koster MP, van Oostrom CT, Breit TM, Schielen PC & de Vries A. (2011). Gene expression profiling in a mouse model identifies fetal liver- and placenta-derived potential biomarkers for Down Syndrome screening. PLoS ONE , 6, e18866. PMID: 21533146 DOI.
- Hewitt CA, Ling KH, Merson TD, Simpson KM, Ritchie ME, King SL, Pritchard MA, Smyth GK, Thomas T, Scott HS & Voss AK. (2010). Gene network disruptions and neurogenesis defects in the adult Ts1Cje mouse model of Down syndrome. PLoS ONE , 5, e11561. PMID: 20661276 DOI.
- Down Syndrome Quarterly DSQ - an interdisciplinary journal devoted to advancing the state of knowledge on Down syndrome
- Down Syndrome Research and Practice Archive Homepage
- 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
Dent KM & Carey JC. (2006). Breaking difficult news in a newborn setting: Down syndrome as a paradigm. Am J Med Genet C Semin Med Genet , 142C, 173-9. PMID: 17048355
Benn PA. (2002). Advances in prenatal screening for Down syndrome: II first trimester testing, integrated testing, and future directions. Clin. Chim. Acta , 324, 1-11. PMID: 12204419
Maymon R & Jauniaux E. (2002). Down's syndrome screening in pregnancies after assisted reproductive techniques: an update. Reprod. Biomed. Online , 4, 285-93. PMID: 12709282
Souter VL & Nyberg DA. (2001). Sonographic screening for fetal aneuploidy: first trimester. J Ultrasound Med , 20, 775-90. PMID: 11444737
Jackson M & Rose NC. (1998). Diagnosis and management of fetal nuchal translucency. Semin Roentgenol , 33, 333-8. PMID: 9800243
Zelazowski MJ, Sandoval M, Paniker L, Hamilton HM, Han J, Gribbell MA, Kang R & Cole F. (2017). Age-Dependent Alterations in Meiotic Recombination Cause Chromosome Segregation Errors in Spermatocytes. Cell , 171, 601-614.e13. PMID: 28942922 DOI.
Ren H, Ferguson K, Kirkpatrick G, Vinning T, Chow V & Ma S. (2016). Altered Crossover Distribution and Frequency in Spermatocytes of Infertile Men with Azoospermia. PLoS ONE , 11, e0156817. PMID: 27273078 DOI.
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Gilbert RE, Augood C, Gupta R, Ades AE, Logan S, Sculpher M & van Der Meulen JH. (2001). Screening for Down's syndrome: effects, safety, and cost effectiveness of first and second trimester strategies. BMJ , 323, 423-5. PMID: 11520837
Down JLH. Observations on an ethnic classification of idiots. (1866) London Hospital Reports, 3:259-262.
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. (2005). First-trimester or second-trimester screening, or both, for Down's syndrome. N. Engl. J. Med. , 353, 2001-11. PMID: 16282175 DOI.
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- Department of Health 9.3 Screening tests in the first trimester combined test (nuchal translucency thickness, free beta-human chorionic gonadotrophin, pregnancy-associated plasma protein-A)
- NSW Health (2007) Prenatal Testing/Screening for Down Syndrome & Other Chromosomal Abnormalities PDF.
The Royal Hospital for Women (2014) Trisomy 21 Screening, Including Non-Invasive Prenatal Testing (Nipt) PDF
- Better Health Victoria trisomy disorders
- OMIM Down Syndrome
- Trisomy Organization http://www.trisomy.org/
- CDC USA Facts about Down Syndrome | Pediatric Genetics
- 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:email@example.com
- The ACT Down Syndrome Association P.O. Box 717Mawson ACT 2607Tel: 06 290 1984 Fax: 06 286 4475Email: firstname.lastname@example.org
- The Down Syndrome Association of QueenslandP.O. Box 1293Milton Queensland 4064
- 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)
- Down Syndrome - The historic name used for Trisomy 21, named after the original identifier Down, J.L.H. in a 1866 paper (cited above).
- 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 - neck, anatomically refers to the neck region.
- 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.
- segmental aneuploidies - generated when a small piece of a chromosome is gained or lost during cell division, resulting in subchromosomal copy number (CN) changes.
- 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)
- triple markers - alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol.
|Genetic Terms (expand to view)|
|genetic abnormalities | Molecular Development | meiosis | mitosis
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Cite this page: Hill, M.A. (2021, October 22) Embryology Trisomy 21. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Trisomy_21
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