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Background
This is the most common serious disorder of the autosomal chromosomes. The overall incidence in the United States is 1 in 700 live births. Most cases result from an extra copy of the long arm region of q22.1 to q22.3 on chromosome 21, resulting in a trisomy 21. In 95% of cases of Trisomy 21, the extra chromosome is of maternal origin. It results from meiotic nondisjunction but the reason for this is still unknown. In a smaller percentage, there are a normal number of chromosomes (46) but extra chromosomal material is present as a translocation, such as a Robertsonian translocation. In these cases, the translocated chromosome is inherited from one of the parents, usually the mother. The fertilized egg has two copies of chromosome 21 and the extra translocated material acts as a triple gene dosage. Mosaics result form mitotic nondisjunction of chromosome 21 during an early stage.
OUTLINE
PATHOGENESIS CHARACTERIZATION CHROMOSOMAL ABNORAMALITY Percentage of Cases
47, XX, +21 (female)94%
46, XX,der(14;21)(q10;q10),+21 (female)5%
46,XX/47,XX,+21
1%
Annotation of human chromosome 21 for relevance to Down syndrome: gene structure and expression analysis.Gardiner K, Slavov D, Bechtel L, Davisson M.
Eleanor Roosevelt Institute, 1899 Gaylord Street, Denver, CO 80206, USA.
Genomics 2002 Jun;79(6):833-43 Abstract quote Down syndrome is caused by an extra copy of human chromosome 21 and the resultant dosage-related overexpression of genes contained within it.
To efficiently direct experiments to determine specific gene-phenotype correlations, it is necessary to identify all genes within 21q and assess their functional associations and expression patterns. Analysis of the complete finished sequence of 21q resulted in annotated 225 genes and gene models, most of which were incomplete and/or had little or no experimental verification.
Here we correct or complete the genomic structures of 16 genes, 4 of which were not reported in the annotation of the complete sequence. Our data include the identification of six genes encoding short or ambiguous open reading frames; the identification of three cases in which alternative splicing produces two structurally unrelated protein sequences; and the identification of six genes encoding proteins with functional motifs, two genes with unusually low similarity to their orthologous mouse proteins, and four genes with significant conservation in Drosophila melanogaster.
We further demonstrate that an additional nine gene models represent bona fide transcripts and develop expression patterns for these genes plus nine additional novel chromosome 21 genes and four paralogous genes mapping elsewhere in the human genome.
These data have implications for generating complete transcript maps of chromosome 21 and for the entire human genome, and for defining expression abnormalities in Down syndrome and mouse models.
Cytogenetic and epidemiological findings in Down syndrome, England and Wales 1989 to 1993. National Down Syndrome Cytogenetic Register and the Association of Clinical Cytogeneticists.
Mutton D, Alberman E, Hook EB.
Wolfson Institute of Preventive Medicine, Medical College of St Bartholomew's Hospital, London.
J Med Genet 1996 May;33(5):387-94 Abstract quote Data from the National Down Syndrome Cytogenetic Register is used to describe the cytogenetics and epidemiology of registered cases. The register comprises notifications from cytogenetics laboratories in England and Wales.
This report is of 5737 cases registered between 1989 and 1993: 2169 prenatal and 3436 postnatal diagnoses, and 132 spontaneous abortions. Eighty eight registrations were from multiple pregnancies. Ninety five percent had regular trisomy 21. In 4% there was a translocation, mostly Robertsonian t(14;21) or t(21;21). One percent were mosaics with one normal cell line. Mean maternal age was raised in free trisomy 21, but not in translocations.
Where families had been investigated, about a third of translocations were inherited, six to seven times more often from the mother than the father. Associations between free trisomy 21 and structural chromosomal defects in the births were no more common than expected from newborn series.
The overall sex ratio was raised (male to female: 1.23 to 1), and there was an excess of associated male sex chromosomal aneuploidy. However, in mosaics with one normal cell line the male to female ratio was 0.8 to 1, and in twins discordant for trisomy 21 there was also a female excess.
MOUSE ANIMAL MODEL (Ts65Dn)
Neuroscience Graduate Program, USUHS, Bethesda, Maryland, United States.
Down syndrome (DS) is the most common nonheritable cause of mental retardation. DS is the result of the presence of an extra chromosome 21 and its phenotype may be a consequence of overexpressed genes from that chromosome. One such gene is Kcnj6/Girk2, which encodes the G-protein coupled inward rectifying potassium channel subunit 2 (GIRK2). We have recently shown that the DS mouse model, Ts65Dn, overexpresses GIRK2 throughout the brain and in particular the hippocampus.
Here, we report that this overexpression leads to a significant increase (~2 fold) in GABAB-mediated GIRK current in primary cultured hippocampal neurons. The dose response curves for peak and steady state GIRK current density is significantly shifted left towards lower concentrations of baclofen in Ts65Dn neurons compared to diploid controls, consistent with increased functional expression of GIRK channels. Stationary fluctuation analysis of baclofen-induced GIRK current from Ts65Dn neurons indicated no significant change in single channel conductance compared to diploid. However, significant increases in GIRK channel density was found in Ts65Dn neurons. In normalized baclofen-induced GIRK current and GIRK current kinetics no difference was found between diploid and Ts65Dn neurons, which suggest unimpaired mechanisms of interaction between GIRK channel and GABAB receptor.
These results indicate that increased expression of GIRK2 containing channels have functional consequences which likely affect the balance between excitatory and inhibitory neuronal transmission.
Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, F Edward Herbert School, Bethesda, Maryland 20814, USA.
The Ts65Dn mouse model of Down syndrome (DS) has an extra segment of chromosome (Chr.) 16 exhibits abnormal behavior, synaptic plasticity and altered function of several signaling molecules. We have further investigated signaling pathways that may be responsible for the impaired hippocampal plasticity in the Ts65Dn mouse.
Here we report that calcium/calmodulin-dependent protein kinase II (CaMKII), phosphatidylinositol 3-kinase (PI3K)/Akt, extracellular signal-regulated kinase (ERK), protein kinase A (PKA) and protein kinase C (PKC), all of which have been shown to be involved in synaptic plasticity, are altered in the Ts65Dn hippocampus.
We found that the phosphorylation of CaMKII and protein kinase Akt was increased, whereas ERK was decreased. Activities of PKA and PKC were decreased. Furthermore, abnormal PKC activity and an absence of the increase in Akt phosphorylation were demonstrated in the Ts65Dn hippocampus after high-frequency stimulation that induces long-term potentiation.
Our findings suggest that abnormal synaptic plasticity in the Ts65Dn hippocampus is the result of compensatory alterations involving the glutamate receptor subunit GluR1 in either one or more of these signaling cascades caused by the expression of genes located on the extra segment of Chr. 16.ROBERTSONIAN TRANSLOCATION
Preimplantation genetic diagnosis for couples at high risk of Down syndrome pregnancy owing to parental translocation or mosaicism.Conn CM, Cozzi J, Harper JC, Winston RM, Delhanty JD.
The Galton Laboratory, University College London, UK.
J Med Genet 1999 Jan;36(1):45-50 Abstract quote The population risk for trisomy 21 is 1 in 700 births but some couples are at a much higher risk owing to parental translocation or mosaicism.
We report on the first attempt to carry out preimplantation genetic diagnosis for two such couples using cleavage stage embryo biopsy and dual colour FISH analysis. Each couple underwent two treatment cycles. Couple 1 (suspected gonadal mosaicism for trisomy 21) had two embryos normal for chromosome 21 transferred, but no pregnancy resulted; 64% (7/11) unfertilised oocytes/embryos showed chromosome 21 aneuploidy. Couple 2 (46,XX,t(6;21)(q13;q22.3)) had a single embryo transferred resulting in a biochemical pregnancy; 91% (10/11) oocytes/embryos showed chromosome 21 imbalance, most resulting from 3:1 segregation of this translocation at gametogenesis.
The opportunity to test embryos before implantation enables the outcome of female meiosis to be studied for the first time and the recurrence risk for a Down syndrome pregnancy to be assessed.
LABORATORY/
RADIOLOGIC/
OTHER TESTSCHARACTERIZATION INHIBIN-A
Evaluation of a dimeric inhibin-A assay for assessing fetal Down syndrome: establishment, comparison, and monitoring of median concentrations for normal pregnancies.
Erickson JA, Ashwood ER, Gin CA.
ARUP Institute for Clinical and Experimental Pathology, LLC, Salt Lake City, Utah 84108, USA.
Arch Pathol Lab Med. 2004 Apr;128(4):415-20 Abstract quote.
CONTEXT: Several studies report the role of dimeric inhibin-A in assessing risk for fetal Down syndrome. The majority, however, use the Serotec inhibin-A assay and not the newer Diagnostic Systems Laboratories inhibin-A enzyme-linked immunosorbent assay (ELISA).
OBJECTIVES: To establish normal gestational age day-specific medians, to compare our results against previous studies pertaining to the inhibin-A ELISA, and to evaluate long-term assay performance.
DESIGN: Using the inhibin-A ELISA, 100 specimens were assayed for each completed week of gestation for weeks 15 to 20, 50 specimens for 14 weeks, and 54 specimens for 21 weeks or older. Regressed inhibin-A medians were calculated employing a second-degree polynomial fit of the arithmetic medians. Thereafter, inhibin-A ELISA lot comparisons were performed to evaluate consistency.
RESULTS: Regressed values of 182, 174, 175, 184, 201, and 226 pg/mL resulted for weeks 15 to 20, respectively [pg/mL inhibin-A = 4.1528(gestational age)2 - 136.49(gestational age) + 1294.9]. A comparison with 2 other studies shows our values to be lower overall by 15 +/- 11.4% and 16 +/- 2.6%. However, variability between kit lots was as high as 30%.
CONCLUSIONS: The equation derived provides for the calculation of gestational age day-specific inhibin-A medians for integration into maternal serum screening programs with a subsequent decrease in false-positives expected and observed. Our medians differ considerably from those of other studies, with limited data, using the Diagnostic Systems assay. However, lot changes since the initial analysis have exhibited similar inconsistencies. Therefore, we recommend that others incorporating the assay into their screening programs carefully establish, monitor, and adjust their medians accordingly as a result of potential variations.ULTRASOUND
Down syndrome risk estimation after normal genetic sonography.Vintzileos AM, Guzman ER, Smulian JC, Yeo L, Scorza WE, Knuppel RA.
Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Medicine and Dentistry of New Jersey--Robert Wood Johnson Medical School/St Peter's University Hospital, New Brunswick, NJ, USA.
Am J Obstet Gynecol 2002 Nov;187(5):1226-9 Abstract quote OBJECTIVE: The objective of this study was to determine whether there are any indication-specific variations in risk reduction for fetal Down syndrome after a normal genetic sonogram.
STUDY DESIGN: A second-trimester genetic sonogram was offered to all pregnant women who were at increased risk for fetal Down syndrome (>/=1:274) because of either advanced maternal age (>/=35 years), an abnormal triple screen, or both. Outcome information included the results of genetic amniocentesis (if performed), the results of pediatric assessment, and follow-up after birth. Normal genetic sonography was defined as the absence of all ultrasound aneuploidy markers.
RESULTS: The overall prevalence of fetal Down syndrome in the tested population was 1.41% (53/3,753 pregnancies); however, in the presence of normal genetic sonography, the overall prevalence of fetal Down syndrome was 0.21% (7/3,291 pregnancies). The overall risk reduction for fetal Down syndrome in the presence of normal genetic sonography was 6.64-fold (95% CI, 3.01-14.62); the overall negative likelihood ratio was 0.15 (95% CI, 0.07-0.33). In the presence of normal genetic sonography, the risk for fetal Down syndrome was reduced by 83% in patients with advanced maternal age, 88% in patients with abnormal triple screen, 89% in patients with abnormal triple screen who were <35 years old, and 84% in patients who had both abnormal triple screen and advanced maternal age.
CONCLUSION: There were no significant variations in the risk reduction for fetal Down syndrome in the presence of normal genetic sonography. Regardless of the indication for testing, the likelihood for fetal Down syndrome was reduced by 83% to 89%. This information will be useful in counseling pregnant women who are at high risk for fetal Down syndrome and who prefer to undergo genetic sonography before deciding about genetic amniocentesis.
NUCHAL TRANSLUCENCY/
THICKNESS BY ULTRASOUND
Measurement of nuchal translucency as a single strategy in trisomy 21 screening: should we use any other marker?Comas C, Torrents M, Munoz A, Antolin E, Figueras F, Echevarria M.
Fetal Medicine Unit, Department of Obstetrics and Gynecology, Institut Universitari Dexeus, Barcelona, Spain.
Obstet Gynecol 2002 Oct;100(4):648-54 Abstract quote OBJECTIVE: To evaluate the role of nuchal translucency thickness as a single marker in screening for trisomy 21 at 10-16 weeks' gestation.
METHODS: From December 1996 to October 2001, nuchal translucency was measured in 11,281 consecutive early second trimester fetuses referred to our unit for prenatal care and delivery. Scans were performed by eight experienced ultrasonographers, under strict methodological criteria.
RESULTS: Chromosomal abnormalities were found in 118 cases (52 trisomy 21). Using nuchal translucency greater than the 95th centile as a cut-off, the overall detection rate was 71.2% with a specificity of 95.4%, and a positive predictive value of 14%. In the trisomy 21 selected group, detection rate, specificity, and positive predictive value for nuchal translucency were 92.3%, 95.4%, and 8.5%, respectively. The detection rate of trisomy 21 reached 100% when nuchal translucency was measured between 10 and 14 weeks' gestation, maintaining the same specificity.
CONCLUSION: Early second trimester nuchal translucency measurement can achieve prenatal detection rates of trisomy 21 greater than 95% with a 5% false-positive rate. With a detection rate so high, the benefits of using additional markers may be less than previously considered. Although maternal age, other sonographic or Doppler markers, and maternal serum biochemistry might play a role in prenatal strategies to detect fetal chromosomal abnormalities, the high detection rate of trisomy 21 fetuses using nuchal translucency as a single parameter suggests that early nuchal translucency measurement between 10 and 14 weeks' gestation can be a simple screening strategy for this condition.
Fetal nuchal translucency screening in 12495 pregnancies in Sardinia.Zoppi MA, Ibba RM, Floris M, Monni G.
Department of Obstetrics and Gynecology, Prenatal and Preimplantation Genetic Diagnosis, Fetal Therapy, Ospedale Microcitemico, Via Jenner, 09125 Cagliari, Italy.
Ultrasound Obstet Gynecol 2001 Dec;18(6):649-51 Abstract quote OBJECTIVE: To examine the distribution of fetal nuchal translucency thickness in normal and chromosomally abnormal fetuses in Sardinia and to determine the effectiveness of screening by a combination of fetal nuchal translucency and maternal age.
METHODS: Fetal nuchal translucency thickness and crown-rump length were measured at 10-14 weeks of gestation in 12 495 pregnancies. A reference range of fetal nuchal translucency thickness for crown-rump length was determined from the 10 001 singleton pregnancies with known normal pregnancy outcome. The median nuchal translucency thickness for crown-rump length was determined by regression analysis of the calculated median values of nuchal translucency thickness for each 0.1 mm interval in crown-rump length. The proportions of unaffected fetuses and those with trisomy 21 or other chromosomal defects with nuchal translucency thickness > 1.5 and 2.0 multiples of the regressed normal median for crown-rump length were calculated. The distribution of estimated risks based on maternal age and fetal nuchal translucency thickness according to The Fetal Medicine Foundation software were also determined and the sensitivity and false-positive rates were calculated.
RESULTS: In the 10 001 normal pregnancies, the median fetal nuchal translucency thickness increased with crown-rump length (median nuchal translucency thickness = 0.3496 + 0.018 x crown-rump length) (r2 = 0.4411). In the singleton pregnancies, there were 64 fetuses with trisomy 21 and 46 with other chromosomal defects. The fetal nuchal translucency thickness was > 1.5 multiples of the median in 510 (5%) of the normal fetuses, in 52 (81%) of the trisomy 21 fetuses and in 33 (72%) of those with other chromosomal defects. The respective values for nuchal translucency thickness > 2.0 multiples of the median were 195 (2%), 41 (64%) and 32 (70%). In 184 multiple pregnancies, there were four fetuses with chromosomal abnormalities and in three of these the nuchal translucency thickness was > 1.5 multiples of the median. Screening by a combination of maternal age and fetal nuchal translucency thickness with a risk cut-off of 1 in 300 identified 90% of trisomy 21 pregnancies and 85% of all other chromosomal defects for a false-positive rate of 9%.
CONCLUSION: Screening for chromosomal defects by measurement of nuchal translucency thickness identifies 80% of fetuses with trisomy 21 for a false-positive rate of 5%. In our population with a median maternal age of 33 years, screening by a combination of maternal age and fetal nuchal translucency thickness with a risk cut-off of 1 in 300 identified 90% of trisomy 21 pregnancies for a false-positive rate of 9%.
Four years experience of first-trimester nuchal translucency screening for fetal aneuploidies with increasing regional availability.Wayda K, Kereszturi A, Orvos H, Horvath E, PAl A, Kovacs L, Szabo J.
Department of Medical Genetics, Albert Szent-Gyorgyi Medical and Pharmaceutical Center, University of Szeged, Szeged, Hungary.
Acta Obstet Gynecol Scand 2001 Dec;80(12):1104-9 Abstract quote BACKGROUND: A prospective screening study was carried out at the regional genetic and perinatal center in South Hungary in order to determine the efficiency of first-trimester nuchal translucency screening for fetal aneuploidies, following augmentation of the availability of nuchal translucency screening in the region by the inclusion of newly-trained hospital sonographers.
METHODS: Nuchal translucency thickness was measured by transvaginal sonography in 7,044 women with singleton or multiple pregnancies at weeks 10-12. Fetal karyotyping was performed when the nuchal translucency was . or = 2.5 mm, and in women with fetuses at high cytogenetic risk.
RESULTS: Follow-up was performed in 6,841 of the 7,044 screened women. An abnormal karyotype was found in 33 cases (0.48%). The level of increased nuchal translucency was 4.5% at a cutoff of > or = 2.5 mm, and 2.8% at a cutoff of > or = 3 mm. Seventeen cases of trisomy 21, eight of trisomy 18, four of trisomy 13, one of 45,X, one of triploidy and two cases with other chromosomal abnormalities were detected. In the 33 fetuses with a chromosomal abnormality, the nuchal translucency thickness was <2.5 mm in a case of trisomy 18, > or = 2.5 mm in 32 cases and > or = 3 mm in 28 cases. With cutoffs of 2.5 mm and 3 mm, the sensitivity was 96.97% and 84.85%, respectively.
CONCLUSIONS: Application of a nuchal translucency thickness cutoff of 2.5 mm is highly efficient for the screening of fetal aneuploidies at 10-12 weeks. This efficiency can be maintained by increasing the regional availability of nuchal translucency screening through the inclusion of newly-trained hospital sonographers.
Screening for trisomy 21 by fetal nuchal translucency and maternal age: a multicenter project in Germany, Austria and Switzerland.Gasiorek-Wiens A, Tercanli S, Kozlowski P, Kossakiewicz A, Minderer S, Meyberg H, Kamin G, Germer U, Bielicki M, Hackeloer BJ, Sarlay D, Kuhn P, Klapp J, Bahlmann F, Pruggmayer M, Schneider KT, Seefried W, Fritzer E, von Kaisenberg CS; German-Speaking Down Syndrome Screening Group.
Department of Obstetrics and Gynaecology, Kiel University Hospital, Michaelisstrasse 16, 24105 Kiel, Germany.
Ultrasound Obstet Gynecol 2001 Dec;18(6):645-8 Abstract quote OBJECTIVE: To examine the effectiveness of screening for trisomy 21 by a combination of maternal age and fetal nuchal translucency thickness at 10-14 weeks of gestation in Germany, Austria and Switzerland.
METHODS: This was a multicenter study of screening for trisomy 21 by a combination of maternal age and fetal nuchal translucency thickness at 10-14 weeks of gestation. All the sonographers involved in the study had received The Fetal Medicine Foundation Certificate of Competence in the 10-14-week scan. Fetal nuchal translucency thickness and crown-rump length were measured in 23 805 singleton pregnancies with live fetuses. In each case the risk for trisomy 21 was estimated on the basis of maternal age and fetal nuchal translucency thickness for crown-rump length with the use of The Fetal Medicine Foundation's software. The distribution of estimated risk was determined and the sensitivity and false-positive rate for a risk cut-off of 1 in 300 was calculated.
RESULTS: Fetal nuchal translucency thickness was successfully measured in all 23 805 pregnancies and outcome was available in 21 959. The median maternal age was 33 (range 15-49) years and in 7935 (36.1%) the age was 35 years or greater. The median gestation at screening was 12 (10-14) weeks and the median fetal crown-rump length was 61 (range 38-84) mm. The estimated risk for trisomy 21 based on maternal age and fetal nuchal translucency thickness for crown-rump length was 1 in 300 or greater in 13.0% (2800 of 21 475) normal pregnancies, in 87.6% (184 of 210) of those with trisomy 21 and in 87.2% (239 of 274) with other chromosomal defects.
CONCLUSIONS: In Germany, Austria and Switzerland the results of screening for chromosomal defects by measurement of fetal nuchal translucency thickness, in centers with appropriately qualified sonographers and using The Fetal Medicine Foundation's software, are similar to those reported in the UK using the same methodology.
Screening for Down syndrome using first-trimester ultrasound and second-trimester maternal serum markers in a low-risk population: a prospective longitudinal study.Audibert F, Dommergues M, Benattar C, Taieb J, Thalabard JC, Frydman R.
Department of Obstetrics and Gynecology, Hopital Antoine Beclere, Universite Paris XI, Paris, France.
Ultrasound Obstet Gynecol 2001 Jul;18(1):26-31 Abstract quote OBJECTIVES: To compare nuchal translucency and second-trimester maternal serum measurements as alternative methods of antenatal screening for Down syndrome in a low-risk population and to evaluate the consequence of combining the results in the estimation of risk.
DESIGN: In a consecutive series of 4130 women aged less than 38 years with a singleton pregnancy, we examined both the detection rate of Down syndrome by nuchal translucency measurement at 10-14 weeks and maternal serum screening by human chorionic gonadotrophin and alpha-fetoprotein at 14-18 weeks. Women with a nuchal translucency measurement of > or = 3 mm and women with a maternal serum screening-derived risk > or = 1/250 were recommended to have amniocentesis. A second-trimester detailed ultrasound scan was also performed in all women. The outcome of all pregnancies was recorded prospectively and the detection rate and false-positive rate of different screening strategies were retrospectively analyzed.
RESULTS: Out of the 4130 pregnancies that were followed (mean maternal age, 30.1 years), 12 cases of Down syndrome were observed (0.28%), all detected prenatally. Seven of 12 cases had a nuchal translucency measurement of > or = 3 mm (58%), and six out of 10 cases with available maternal serum screening had a calculated risk of > or = 1/250 (60%). Four of the five Down syndrome cases with a nuchal translucency measurement of < 3 mm were detected by subsequent maternal serum screening. At a threshold giving 5% of positive tests, the sensitivity of nuchal translucency, maternal serum screening and combined risk screening were 75%, 60% and 90%, respectively.
CONCLUSIONS: In screening for Down syndrome, an approach which combines the results from first-trimester nuchal translucency and second-trimester biochemistry is effective and increases the detection rate compared to the use of any single test. However, this strategy is likely to raise the false-positive rate and the interpretation of maternal serum screening-derived risk should be combined with the first-trimester nuchal translucency measurement.
Critical appraisal of the use of nuchal fold thickness measurements for the prediction of Down syndrome.Locatelli A, Piccoli MG, Vergani P, Mariani E, Ghidini A, Mariani S, Pezzullo JC.
Divisione di Ostetricia e Ginecologia, Istituto di Scienze Biomediche San Gerardo, Monza, Italy.
Am J Obstet Gynecol 2000 Jan;182(1 Pt 1):192-7 Abstract quote OBJECTIVE: Nuchal fold thickness is the best ultrasonographic predictor of fetal trisomy 21. However, the risk assigned on the basis of the commonly used threshold of nuchal fold thickness >/=6 mm does not take into consideration the significant associations between nuchal fold thickness and gestational age and between maternal age and Down syndrome. We propose a new method of calculating Down syndrome probability that takes into account both gestational age at examination and previously assessed probability of Down syndrome.
STUDY DESIGN: Nuchal fold thickness was measured at ultrasonographic examination at 14 to 22 weeks' gestation without previous knowledge of the fetal karyotype. Nuchal cystic hygromas were excluded from analysis. Statistical analyses included correlation, logistic regression to control for other ultrasonographic predictors of trisomy 21 and for maternal age, receiver operating characteristic curve, and likelihood ratios (defined as the ratio of the sensitivity to the false-positive rate). P <.05 was considered significant.
RESULTS: Mean gestational age at ultrasonography was 16.9 weeks' gestation (range, 14-22 weeks' gestation). Mean (+/-SD) nuchal fold thickness in fetuses with trisomy 21 (4.7 +/- 1.6 mm; n = 29) was greater than in euploid fetuses (3.2 +/- 0.9; n = 780; P <.001). Logistic regression analysis established that nuchal fold thickness was a significant predictor of trisomy 21 independent both of the other ultrasonographic markers and of maternal age (P <.001). Regression analysis showed that nuchal fold thickness was significantly correlated with gestational age among both fetuses with trisomy 21 and euploid fetuses and that the regression line of fetuses with trisomy 21 had a slope similar to that of euploid fetuses. The difference between observed and expected nuchal fold thicknesses on the basis of the biparietal diameter (as a function of gestational age) was used to obviate the confounding effect of gestational age. Differences between observed and expected nuchal fold thicknesses were then used to calculate likelihood ratios. These likelihood ratios could then be multiplied by the individual prior probability to obtain a patient-specific Down syndrome probability.
CONCLUSION: Nuchal fold thickness is correlated with gestational age in both euploid fetuses and fetuses with Down syndrome. Use of the difference between observed and expected nuchal fold thicknesses to determine likelihood ratios allows the calculation of individual posterior probabilities of Down syndrome that take into consideration both gestational age and maternal age.
Gestational age standardized nuchal thickness values for estimating mid-trimester Down's syndrome risk.Bahado-Singh RO, Oz UA, Kovanci E, Deren O, Feather M, Hsu CD, Copel JA, Mahoney MJ.
Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut 06520-8063, USA.
J Matern Fetal Med 1999 Mar-Apr;8(2):37-43 Abstract quote OBJECTIVE: Our aim was to develop gestational age standardized indices of fetal nuchal thickening. In addition, we wanted to develop a method for combining nuchal thickness data with maternal age for calculating individual Down's syndrome risk.
METHODS: Nuchal thickness was measured prospectively in pregnancies undergoing genetic amniocentesis. A regression equation for expected median nuchal thickness based on the biparietal diameter (BPD) was developed. Nuchal thickness values were expressed as multiples of the median (MoM). Additionally, a new parameter, percentage increase in nuchal thickness (PIN) (measured minus expected nuchal thickness) X100/expected nuchal thickness, was used. Receiver operator characteristics curves for Down's syndrome detection based on nuchal thickness values expressed as MoM, PIN, and in mm were compared. Log10 transformation of MoM data resulted in a Gaussian distribution, and the Down's syndrome likelihood ratios were calculated based on the heights of the Gaussian curves. Likelihood ratios were also calculated based on PIN values. The screening efficiency of maternal age alone was compared to age plus MoM, and age plus PIN values by multiplying age-related risk by the likelihood ratio corresponding to the given nuchal thickness MoM or PIN values.
RESULTS: There were 3,574 chromosomally normal and 50 Down's syndrome fetuses in the study. Both PIN and MoM values for nuchal thickness were closely correlated (R = 1.00, P<0.001) and each was poorly correlated with gestational age (R = 0.018, P = 0.28). The Down's syndrome screening efficiency of PIN, MoM, and nuchal thickness values in mm were not significantly different. The addition of nuchal thickness data to maternal age-related risk significantly improved the Down's syndrome screening efficiency: Area under the ROC curve for maternal age risk = 0.58, maternal age + PIN area = 0.79 (P<0.001 compared to maternal age alone) and for maternal age + MoM = 0.77 (P<0.005 compared to maternal age alone).
CONCLUSIONS: The development of gestational age standardized nuchal thickness indices makes it possible to combine ultrasound and maternal age-related risk to derive individual Down's syndrome odds.
Screening for Down's syndrome by fetal nuchal translucency measurement in a high-risk population.Pajkrt E, Mol BW, van Lith JM, Bleker OP, Bilardo CM.
Department of Obstetrics and Gynecology, University of Amsterdam, The Netherlands.
Ultrasound Obstet Gynecol 1998 Sep;12(3):156-62 Abstract quote OBJECTIVE: To examine the discriminative capacity of nuchal translucency measurement in the detection of trisomy 21 and other chromosomal anomalies.
DESIGN: Prospective cohort study.
SUBJECTS: A total of 2247 women with viable singleton pregnancies between 10 and 14 weeks' gestation attending a prenatal diagnosis center for fetal karyotyping.
METHODS: The fetal nuchal translucency was measured transabdominally in all women before invasive prenatal testing.
RESULTS: Chromosomal abnormalities were found in 63 fetuses, including 36 with Down's syndrome. The likelihood of the presence of chromosomal abnormalities increased with larger nuchal translucency thickness. A nuchal translucency of 3 mm or more identified 25 out of 36 fetuses (69%) with trisomy 21 at the expense of a 4.0% false-positive rate. Correction of nuchal translucency measurements for differences due to variation of the measurement with gestational age, either by using the 'delta-value' or multiples of the median (MoM), did not improve the detection rate in our patient data set.
CONCLUSIONS: The discriminative capacity of nuchal translucency measurement makes it a useful tool in screening for trisomy 21 and other chromosomal anomalies.
Subtle ultrasonographic anomalies: do they improve the Down syndrome detection rate?Deren O, Mahoney MJ, Copel JA, Bahado-Singh RO.
Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut 06520-8063, USA.
Am J Obstet Gynecol 1998 Mar;178(3):441-5 Abstract quote OBJECTIVE: Our purpose was to determine whether the identification of subtle anomalies further improves Down syndrome detection over standard ultrasonographic biometry and the detection of gross morphologic defects.
STUDY DESIGN: The screening efficiency of clinodactyly, dilated renal pelvis (> or =4 mm), echogenic bowel, mild ventriculomegaly (> or =10 to 15 mm), and two-vessel cord was determined prospectively in midtrimester fetuses at amniocentesis. The screening efficiency of increased nuchal thickness and shortened long-bone length (standard biometry) and gross morphologic defects was determined for comparison. Multiple backward stepwise regression analysis was used to determine which subtle anomalies significantly correlated with Down syndrome detection rate and whether they increased Down syndrome detection over that with standard biometry and morphologic defects.
RESULTS: Although all subtle anomalies except two-vessel cord correlated with the presence of Down syndrome on univariate analysis, only echogenic bowel (Wald chi2 = 15.0211, p = 0.0001) and clinodactyly (Wald chi2 = 9.4273, p = 0.002) persisted in regression analysis of the subtle anomaly group. When either of the above-described anomalies was present, the detection rate for Down syndrome was 28.6%, p < 0.00001. For the combination of standard biometry (either increased nuchal thickness or short humerus) or gross anatomic defect, Down syndrome detection rate was 53.3% (p < 0.00000001). This increased to 63.2% (p < 0.00000001) when subtle anatomic defects (either echogenic bowel or clinodactyly) were included in the definition of an abnormal sonogram.
CONCLUSION: Subtle anomalies, of which echogenic bowel and clinodactyly are the most significant, further increase Down syndrome screening efficiency over standard biometry or the finding of gross anatomic defect. Our data appear to support the addition of subtle anomaly findings to ultrasonographic screening for Down syndrome.
Risk of Down syndrome and any clinically significant chromosome defect in pregnancies with abnormal triple-screen and normal targeted ultrasonographic results.Bahado-Singh RO, Tan A, Deren O, Hunter D, Copel J, Mahoney MJ.
Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT 06520-8063, USA
Am J Obstet Gynecol 1996 Oct;175(4 Pt 1):824-9 Abstract quote OBJECTIVE: Our purpose was to study prospectively the use of ultrasonographic biometry to refine the risk estimates for both Down syndrome and any clinically significant chromosome defect in women with abnormal biochemical triple-screen results.
STUDY DESIGN: Ultrasonographic biometry and anatomic survey were performed on study and control cases. Expected values for humerus, femur, combined humerus plus femur lengths, and abdominal circumference were generated on the basis of biparietal diameter obtained from a normal group. Threshold observed/expected values of each measurement for screening for Down syndrome and clinically significant chromosome defects were determined with receiver-operator characteristic curves. By stepwise logistic regression analysis the optimal screening parameters, including nuchal thickness, for detection of Down syndrome and clinically significant chromosome defect were determined. Risk tables for chromosome anomalies were developed on the basis of ultrasonography and triple-screen values.
RESULTS: Of 1034 cases at risk for Down syndrome (risk > or = 1/270) or trisomy 18 on the basis of triple-screen results, there were 11 cases of Down syndrome, 1 of trisomy 18, and 17 clinically significant chromosome defects. Abnormal nuchal thickness or observed/expected humerus length < 0.92 was the most sensitive parameter for Down syndrome detection. Abnormal nuchal thickness or observed/expected combined femur and humerus length < 0.90 was the most sensitive for significant chromosome defects. With abnormal biometry or anatomy the Down syndrome risk was 8 of 127 versus 1 of 753 in normals, odds ratio 50.4 (95% confidence interval 6.4 to 90.2), p < 0.00001, and the risk of significant defects was 11 of 90 versus 6 of 830 in normals, odds ratio 19.3 (95% confidence interval 6.4 to 60.5), p < 0.00001. In a pregnancy with a 1 in 270 triple-screen risk for Down syndrome, normal biometric and anatomic results reduce the risk to 1 in 2100.
CONCLUSION: Normal ultrasonographic anatomy and biometry significantly reduces the risk of both Down syndrome and any significant chromosome defects in pregnancies with abnormal triple-screen results.
Normal nuchal thickness in the midtrimester indicates reduced risk of Down syndrome in pregnancies with abnormal triple-screen results.Bahado-Singh RO, Goldstein I, Uerpairojkit B, Copel JA, Mahoney MJ, Baumgarten A.
Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT 06520-8063, USA.
Am J Obstet Gynecol 1995 Oct;173(4):1106-10 Abstract quote OBJECTIVE: Our purpose was to determine whether nuchal thickness measurement can identify the euploid fetuses in midtrimester pregnancies at increased risk for Down syndrome on the basis of maternal age and serum screening.
STUDY DESIGN: Nuchal thickness was obtained prospectively in 651 consecutive fetuses at 14 to 21 weeks' gestation and at > or = 1:270 risk for Down syndrome on the basis of unconjugated estriol, alpha-fetoprotein, and human chorionic gonadotropin levels. The risk of Down syndrome with a normal nuchal thickness was determined. A receiver-operator characteristic curve was used to determine a serum-based risk threshold below which the risk for Down syndrome was low. The prevalence of Down syndrome in fetuses with both a normal nuchal thickness and a below-serum-risk threshold was compared with prevalence in either those above threshold risk or with an abnormal nuchal thickness.
RESULTS: There were eight cases of trisomy 21 and one case each of 46,XX/47,XXX, 46,XY/47,XY, +7, and 46,XX, 11q-. The sensitivity of an abnormal nuchal thickness (> or = 6 mm) for detecting Down syndrome was four in eight (50%) (95%) confidence interval 15.3% to 84.6%). The risk of Down syndrome was significantly increased with an abnormal compared with a normal nuchal thickness, four in 13 (30.8%) versus four in 638 (0.6%), p < 0.0001. A risk threshold was defined at > or = 1:100 on the basis of the receiver-operator characteristic plot. Of 390 cases with a normal nuchal thickness and a serum risk estimate < 1:100, there were no cases of Down syndrome (0/390 vs 8/253, p = 0.002).
CONCLUSION: Normal nuchal thickness significantly reduces the risk of Down syndrome and may help reduce the number of amniocenteses done for abnormal triple screen results.
Prospective multicenter study of second-trimester nuchal skinfold thickness in unaffected and Down syndrome pregnancies.Donnenfeld AE, Carlson DE, Palomaki GE, Librizzi RJ, Weiner S, Platt LD.
Department of Obstetrics and Gynecology, Pennsylvania Hospital, Philadelphia.
Obstet Gynecol 1994 Nov;84(5):844-7 Abstract quote OBJECTIVE: To determine the distribution of nuchal skinfold thickness in normal and Down syndrome pregnancies and to evaluate the use of this sonographic measurement as a screening test for fetal Down syndrome.
METHODS: A prospective, multicenter, population-based study was performed by experienced obstetric sonographers on 1382 women with sonographically normal fetuses undergoing second-trimester amniocentesis for the indication of advanced maternal age. A standard, well-defined sonographic image was obtained at all collaborating centers. The distributions of nuchal skinfold thickness were compared between euploid and Down syndrome fetuses.
RESULTS: There were 1346 chromosomally normal pregnancies, 13 fetuses with Down syndrome (1:106), and 23 other chromosome abnormalities. Seventeen fetuses had measurements of 6 mm or greater, and one of these had Down syndrome. The median nuchal skinfold thickness in Down syndrome was 3.2 mm and in euploid fetuses was 3.1 mm. By the Mann-Whitney rank-sum test, there was no statistically significant difference in nuchal skinfold between the euploid and Down syndrome fetuses (P = .5). Overall, using a nuchal skinfold thickness of 6 mm or greater as a screening test, the detection rate for Down syndrome was one of 13 (8%), the false-positive rate was 16 of 1382 (1.2%), the positive predictive value was one of 17 (6%), and the probability of detecting Down syndrome was 6.5%.
CONCLUSION: In this investigation, excess nuchal skinfold thickness was a poor and unreliable screening test for Down syndrome.
CT scan and MRI Value Decreased Increased Decreased LABORATORY TESTING FOR PREGNANCY
HISTOLOGICAL TYPES CHARACTERIZATION VARIANTS ACUTE LEUKEMIA
- Acute leukaemia in children with Down syndrome: a population-based Nordic study.
Zeller B, Gustafsson G, Forestier E, Abrahamsson J, Clausen N, Heldrup J, Hovi L, Jonmundsson G, Lie SO, Glomstein A, Hasle H; Nordic Society of Paediatric Haematology and Oncology (NOPHO).
Department of Paediatrics, National Hospital of Norway, N-0027 Oslo, Norway.
Br J Haematol. 2005 Mar;128(6):797-804. Abstract quote
To determine the epidemiology and outcome of children with Down syndrome (DS) diagnosed with acute leukaemia in the Nordic countries, data registered in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) population-based leukaemia registry were analysed.
Of 3494 children with acute leukaemia diagnosed between July 1984 and December 2001, 136 patients (3.9%) with DS were identified. 2.1% of the children with acute lymphoid leukaemia (ALL) and 14.0% of the children with acute myeloid leukaemia (AML) had DS. In ALL, DS patients had similar age and sex distribution and no major differences in blood counts compared with non-DS children. None of the DS patients had T cell leukaemia. Outcome was inferior to that of non-DS children and treatment results did not improve over time.
In AML, DS patients showed a significant female predominance and all but one were <5 years old. DS patients with AML had significantly lower platelet and white blood cell counts and two-thirds were type M7 as according to the French-American-British classification. None of the patients <5 years of age had typical AML cytogenetic aberrations. Outcome was far better in the DS group.
DS patients treated for AML after 1992 had an excellent outcome (probability of event-free survival, 83 +/- 6%). The high proportion of female DS patients with AML is unexplained. The differing treatment results in AML versus ALL need further evaluation and represent a challenge for the coming years.
Leukemia in Down syndrome: a review.Zipursky A, Poon A, Doyle J.
Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada
Pediatr Hematol Oncol 1992 Apr-Jun;9(2):139-49 Abstract quote The incidence of leukemia is higher in children with Down syndrome (DS) than in normals. In approximately 50% of cases the type of leukemia is acute megakaryoblastic leukemia (AMKL) and it occurs during the first 4 years of life.
The leukemic cell also has features of erythroid progenitors and therefore appears to be a precursor cell with biphenotypic properties. In addition, newborns with DS frequently develop transient leukemia (TL), which is characterized by the presence of megakaryoblasts in the blood which disappear during the first 1-3 months of life.
The incidence of this disorder is unknown although preliminary studies suggest that megakaryoblasts may be found frequently in the blood of DS newborns. TL does not occur in normal newborn infants. Although TL disappears spontaneously, many of these children will develop AMKL at 1-4 years of age.
Recent surveys suggest that 20-30% of newborns with TL will develop AMKL. Preliminary evidence suggests that TL is a clonal proliferation, can be fatal, and may occur in a specific subgroup of DS children.
The observations in this report are drawn from our own experience, reports in the literature, and data accumulated in the Canadian Down Syndrome Leukemia Registry.
TRANSIENT ABNORMAL MYELOPOIESIS (TAM)/TRANSIENT LEUKEMIA/TRANSIENT MYELOPROLIFERATIVE DISORDER
Departments of Pathology and Pediatrics, Saint Louis University School of Medicine, Saint Louis, MO.
Transient leukemia of Down syndrome (DS-TL), also known as transient myeloproliferative disorder of Down syndrome (DS) and transient abnormal myelopoiesis of DS, occurs in approximately 10% of DS neonates and in phenotypically normal neonates with trisomy 21 mosaicism. In DS-TL, peripheral blood analysis shows variable numbers of blasts and, usually, thrombocytopenia; other cytopenias are uncommon.
Bone marrow characteristics of DS-TL are, likewise, variable, though (in contrast to other leukemias) the bone marrow blast differential can be lower than the peripheral blood blast differential.
The blasts of DS-TL typically show light microscopic, ultrastructural, and flow cytometric evidence of megakaryocyte differentiation. DS-TL neonates have a approximately 15% risk of developing potentially fatal liver disease and show <10% incidence of hydrops fetalis. Additional manifestations of DS-TL include cutaneous involvement, hyperviscosity, myelofibrosis, cardiopulmonary failure, splenomegaly, and spleen necrosis. Despite its typical transient nature, 20% to 30% of DS-TL patients develop overt (nontransient) acute leukemia, usually within 3 years and typically of the M7 phenotype (acute megakaryoblastic leukemia).
The pathogenesis of DS-TL (and of subsequent acute leukemia) involves mutation of GATA1 (on chromosome X), which normally encodes a transcription factor integral to normal development of erythroid, megakaryocytic, and basophilic/mast cell lines. The pathogenetic role of trisomy 21 in DS-TL is unclear.
Though indications for chemotherapy in DS-TL have not been firmly established, the blasts of DS-TL are sensitive to low-dose cytosine arabinoside.
Telomerase and the benign and malignant megakaryoblastic leukemias of Down syndrome.Holt SE, Brown EJ, Zipursky A.
Department of Pathology, Medical College of Virginia, Virginia Commonwealth University, Richmond, USA.
J Pediatr Hematol Oncol 2002 Jan;24(1):14-7 Abstract quote The most common form of leukemia in Down syndrome patients is megakaryoblastic leukemia. There are two forms of the disease. Transient leukemia (TL) is a form of megakaryoblastic leukemia that occurs in newborns with Down syndrome and usually disappears spontaneously within the first 3 months of life. Acute megakaryoblastic leukemia (AMKL) occurs in Down syndrome children within the first 4 years of life and is fatal without treatment. The megakaryoblasts of TL and AMKL are indistinguishable by light and electron microscopy; yet, TL is benign and AMKL is malignant. One of the hallmarks of many malignancies is the expression of telomerase. It is therefore hypothesized that the transient, benign form of megakaryoblastic leukemia (TL) would not contain telomerase activity, whereas telomerase would be demonstrable in the malignant form of the disease.
Telomerase activity was determined in the blood and/or bone marrow aspirates in 29 cases of AMKL and 34 cases of TL. The authors found telomerase activity in 15 of 29 (52%) cases, of AMKL and in only 4 of 34 (12%) cases of TL (P < 0.001). Furthermore, three of the four telomerase-positive TL cases were particularly severe, of which two were fatal.
Telomerase activity is found frequently in the leukemic cells of the malignant form of megakaryoblastic leukemia but rarely in the benign form of the disease (TL). Observations provide evidence that telomerase may be a critical factor for the malignant conversion of leukemic cells.
Incidence and treatment of potentially lethal diseases in transient leukemia of Down syndrome: Pediatric Oncology Group Study.Al-Kasim F, Doyle JJ, Massey GV, Weinstein HJ, Zipursky A; Pediatric Oncology Group.
Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.
J Pediatr Hematol Oncol 2002 Jan;24(1):9-13 Abstract quote Transient leukemia (TL or transient myeloproliferative disorder) occurs in approximately 10% of newborn infants with Down syndrome.
The disorder is characterized by the presence of megakaryoblasts in the peripheral blood; most cases resolve spontaneously within the first 3 months of life, and the child is well thereafter. However, there are cases in which a severe, potentially lethal form of disease develops, manifesting as hepatic fibrosis or cardiopulmonary failure. Hitherto, the incidence of these severe forms of the disease has not been reported.
A prospective study of TL was conducted by the Pediatric Oncology Group (POG Study 9481) in which 48 children with TL were identified. Life-threatening disease occurred in nine patients (19%); seven had hepatic fibrosis and two had cardiopulmonary failure. Five children died of the disease within the first 3 months of life, none of whom received antileukemic therapy. One patient died on day 31 after receiving minimal therapy within 1 day of death.
Three children received low-dose cytosine arabinoside (Ara-C) (0.4-1.5 mg/kg every 12 hours for 5 or 7 days). In all these patients, the disease resolved. It is concluded that potentially lethal disease is relatively common in TL, and the available evidence suggests that these diseases are responsive to low-dose Ara-C therapy.
Acute megakaryoblastic leukemia after transient myeloproliferative disorder with clonal karyotype evolution in a phenotypically normal neonate.Polski JM, Galambos C, Gale GB, Dunphy CH, Evans HL, Batanian JR.
Department of Pathology, University of South Alabama College of Medicine, Mobile, USA.
J Pediatr Hematol Oncol 2002 Jan;24(1):50-4 Abstract quote We report a case of transient myeloproliferative disorder (TMD) in a neonate without features of Down syndrome (DS) with clonal karyotype evolution, after apparent spontaneous resolution of TMD, but eventually progressing to acute megakaryoblastic leukemia (AMKL).
The patient had petechiae, thrombocytopenia, and blastemia. Trisomy 21 with a satellited Y chromosome (Yqs) was found in proliferating blasts. A stimulated peripheral blood culture confirmed the constitutional origin of the Yqs, but did not reveal the presence of any trisomic 21 cell. By the age of 3 months, clonal chromosome evolution in the form of an interstitial deletion of the long-arm of chromosome 13 [del(13)(q13q31)] was detected along with trisomy 21 in unstimulated bone marrow cultures. However, remission was achieved without treatment at the age of 4 months. Trisomy 21 and del(13)(q13q31) were not identified in either cytogenetics or fluorescence in situ hybridization studies at that time.
The child was asymptomatic until the age of 20 months when anemia and thrombocytopenia prompted a bone marrow biopsy, revealing changes consistent with AMKL. The remission proceeded by clonal karyotype evolution in a neonate with TMD demonstrates that clonal karyotype evolution does not indicate an immediately progressive disease. However, the development of AMKL after TMD in this case illustrates the increased risk for leukemia in TMD cases, even without DS.
The gradual clonal evolution of the blasts in our patient suggests that "multiple hits" oncogenesis applies to TMD progression to acute leukemia.
Transient Myeloproliferative Disorder and Acute Myeloid Leukemia in Down Syndrome An Immunophenotypic Analysis
Nitin J. Karandikar, MD, PhD, Deborah B. Aquino, MD, Robert W. McKenna, MD, and Steven H. Kroft, MD
Am J Clin Pathol 2001;116:204-210 Abstract quote
Immunophenotypic analysis of transient myeloproliferative disorder (TMD) and acute myeloid leukemia (AML) using multiparameter flow cytometry might provide insight into their relationship.
We retrospectively analyzed the expression of multiple lymphoid, myelomonocytic, and megakaryocytic antigens on blast proliferations in 18 patients with Down syndrome (DS; AML, 9; TMD, 9). The AMLs and TMDs shared several immunophenotypic characteristics. Blasts in all expressed CD45, CD38, and CD33; most AMLs and all TMDs were CD36+; and the majority expressed CD41 and CD61, suggesting megakaryocytic differentiation. The majority of cases were CD34+, CD14–, and CD64–. There was aberrant expression of the T-cell–associated antigen CD7 in most AMLs and TMDs. CD56 was expressed aberrantly in 5 AMLs and 7 TMDs.
The major difference between the disorders was the pattern of expression of myeloid markers CD11b and CD13; each was expressed in 8 AMLs but only 2 TMDs. Blasts were HLA-DR–positive in 3 AMLs vs 7 TMDs. Blasts in TMD and AML in DS have a characteristic immunophenotype distinct from AML in other settings. The immunophenotypic similarities suggest a biologic relationship between the disorders; however, distinct immunophenotypic differences also were observed.
Transient myeloproliferative disorder (transient leukemia) and hematologic manifestations of Down syndrome.Zipursky A, Brown EJ, Christensen H, Doyle J.
Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada.
Clin Lab Med 1999 Mar;19(1):157-67 Abstract quote Transient Myeloproliferative Disorder (Transient Leukemia) is found in approximately 10% of newborn infants with Down Syndrome.
It is characterized by the large numbers of megakaryoblasts in the peripheral blood, variable thrombocytopenia and, in a minority of cases, by a lethal course with hydrops fetalis or progressive hepatic fibrosis. Evidence is presented that this disease is truly leukemia, which, in most cases, recovers spontaneously.
There is evidence that hematopoiesis is abnormal in Down Syndrome children who do not have leukemia. These abnormalities of red cells, platelets, and granulocytes are reviewed.
Leukemia and/or myeloproliferative syndrome in neonates with Down syndrome.Zipursky A, Brown E, Christensen H, Sutherland R, Doyle J.
Department of Pediatrics, Hospital for Sick Children, University of Toronto, Ontario, Canada.
Semin Perinatol 1997 Feb;21(1):97-101 Abstract quote Approximately 10% of newborn infants with Down Syndrome develop a form of megakaryoblastic leukemia which usually disappears spontaneously during the first months of life.
The evidence that this "Transient Leukemia" is truly leukemia includes the following: it is clonal proliferation, it can be fatal and tissue infiltration of leukemic cells occurs. Also in approximately 25% of cases that recover, Acute Megakaryoblastic Leukemia will develop in the first four years of life, which, if not treated, is fatal. Evidence regarding the megakaryoblastic nature of the leukemic cells is presented as well as a description of the lethal forms of the disease.
The study of Transient Leukemia is of considerable importance because it can provide insight into both the nature of leukemia and its relation to trisomy 21.
Transient abnormal myelopoiesis of infancy associated with trisomy 21.
Homans AC, Verissimo AM, Vlacha V.
Department of Pediatrics, University of Vermont College of Medicine, Burlington 05405.
Am J Pediatr Hematol Oncol 1993 Nov;15(4):392-9 Abstract quote PURPOSE: A unique myelodysplastic syndrome referred to as transient abnormal myelopoiesis (TAM) has been reported to occur primarily in infants with Down's syndrome (DS) or other abnormalities of chromosome 21. This disorder raises basic questions regarding the pathogenesis of leukemia, yet its natural history is poorly documented and derives from small series and isolated case reports.
PATIENTS AND METHODS: To better characterize TAM, we accumulated data on 35 cases identified through a questionnaire mailed to pediatric oncologists in the United States. These cases, pooled with two that we recently encountered, and 58 comparable cases reported in the literature comprise a series of 95 cases of TAM in DS.
RESULTS: The patients in this series were notable for the high morbidity and mortality of this reportedly benign condition. Eleven percent of the patients died during the initial event, and the overall mortality for the entire series was 27%. Twenty-eight of the 85 patients (33%) who survived the initial event developed a subsequent hematologic disorder, most often acute nonlymphocytic leukemia, at a median age of 16 months.
CONCLUSIONS: No initial clinical or hematologic features predicted the development of a subsequent hematologic disorder. However, those patients initially mosaic for the presence of trisomy 21 did not develop subsequent abnormalities. This series reviews questions regarding leukemogenesis in DS and underscores the importance of conducting future prospective studies of this unique hematologic disorder.
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