Copper/zinc superoxide dismutase (SOD-1) activity in regular trisomy 21, trisomy 21 by translocation and mosaic trisomy 21.
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Cell Line↗
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Trisomy 21-trisomy 18 mosaicism in a boy with clinical Down's syndrome.
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Chromosomes, Human, Pair 18↗
Health supervision and anticipatory guidance for children with genetic disorders (including specific recommendations for trisomy 21, trisomy 18, and neurofibromatosis I).
A new model for care of children with genetic disorders has emerged from the pediatric and genetic communities in the last decade. This strategy incorporates the basic principles of well-child care, including ongoing psychological support for families, health screening, and prevention, into health supervision visits for children with these conditions. The same types of guidelines that have been developed for well children can also be applied to the routine follow-up and screening of children with these special health care needs. A number of general issues are applicable in the discussion of health supervision guidelines: correct diagnosis, analysis of the natural history of the condition, critical review of screening modalities and interventions, ongoing psychological support, and genetic counseling. With these points in mind and after a thorough review of the natural history of a disorder, guidelines can be developed and often applied to the primary care setting. Down syndrome is an ideal condition to which one can apply such a model because most children are cared for by primary care pediatricians, and the natural history is relatively well studied. Discussion of health provision in Down syndrome brings out some of the controversies regarding routine screening and review of interventions. Discussion of the natural history and uncertainties evident in the care of infants with trisomy 18 exemplifies the important issue of ongoing psychological support. Review of the natural history of neurofibromatosis emphasizes all of the principles involved in providing this model as a framework for health supervision. One of the key identified but unresolved issues is the decision as to when a primary care pediatrician can orchestrate the care on his or her own versus referral to a multidisciplinary team of specialists. In some conditions such as Down syndrome, it seems obvious that the primary care pediatrician can manage most of the care with periodic and appropriate referral to the necessary specialists. On the other hand, children with cystic fibrosis, meningomyelocele, and craniofacial syndromes almost always need referral to the specialist team because of the rarity of the disorder and the complex number of specialists involved in management. A condition such as NF-1 falls somewhere in between. Most children can be cared for in their childhood years by the pediatrician with referral when a symptom or sign emerges, but others would argue that all children with NF-1 need to be seen by a multidisciplinary team.(ABSTRACT TRUNCATED AT 400 WORDS)
Child↗
Risk of recurrence of fetal chromosomal aberrations: analysis of trisomy 21, trisomy 18, trisomy 13, and 45,X in 1,076 Japanese mothers.
OBJECTIVE: To evaluate the risk of recurrence of fetal chromosomal aberrations in women who had offspring with numeric chromosomal abnormalities. SUBJECTS AND METHODS: This collaborative study consisted of 1,076 Japanese women with a history of offspring with trisomy-21, -18, -13, or 45,X. Second-trimester amniocenteses were performed, resulting in 1,248 fetal karyotypes that were analyzed with reference to prior offspring karyotypes and maternal age. RESULTS: Of the 842 women with trisomy-21 offspring, 10 conceived another such fetus. In 2 women with 3 or more such offspring, parental mosaicism of trisomy-21 was suspected. The incidence of recurrence of trisomy-21 increased with age, and significantly exceeded the incidence of trisomy-21 fetuses in the general population. None of the 170 women with trisomy-18 offspring, and none of the 46 women with trisomy-13 offspring, had another such fetus. Of the 18 women with 45,X offspring, 1 with mos 45,X/46,XX had another such fetus. CONCLUSIONS: The risk of recurrence of trisomy-21 is affected by maternal age and parental germline mosaicism. The risk of recurrence of trisomy-18 or -13 appears to be much lower than that of trisomy-21. Women who give birth to more than 1 offspring with 45,X should be examined for mos 45,X/46,XX.
Adult↗
Triple marker screening for trisomy 21, trisomy 18 and open neural tube defects in singleton pregnancies of native Japanese pregnant women.
OBJECTIVE: To report the results of prenatal triple marker screening on a population of Japanese pregnant women. METHODS: From April 1994 through March 1999, a total of 32,925 native Japanese women with singleton pregnancies requested a triple marker-screening test. Multiples of the median values for 3 markers and individual risks for each patient were calculated following adjustment for the Japanese weight correction factor. The risk cut-off values used for Down syndrome (T21), open spina bifida (OSB) and trisomy 18 (T18) were 1: 295, 1: 290, and 1: 100, respectively. Follow-up information was collected postpartum and statistically analyzed. RESULTS: Detection rates (DR) of T21 for women less than 35 years, over 35 years and overall were 58, 94, and 83%, respectively. DR of T18 for women less than 35 years, over 35 years and overall were 75, 79, and 79%, respectively. DR of open neural tube defects (ONTD) was 100%. CONCLUSIONS: The first cumulative data of an intervention program and prospective follow-up studies in Japan have proven to be similar to other published reports. Individual risk values were calculated for each pregnancy for T21, T18 and ONTD. This screening program is more effective than age-dependent screening for detecting T21, T18 and ONTD pregnancies.
Adult↗
Parental origin of the extra chromosome in prenatally diagnosed fetal trisomy 21.
Trisomy 21 (Down syndrome) is one of the most common chromosomal abnormalities. Of cases of free trisomy 21 causing Down syndrome, about 95% result from nondisjunction during meiosis, and about 5% are due to mitotic errors in somatic cells. Previous studies using DNA polymorphisms of chromosome 21 showed that paternal origin of trisomy 21 occurred in only 6.7% of cases. However, these studies were conducted in liveborn trisomy 21-affected infants, and the possible impact of fetal death was not taken into account. Using nine distinct DNA polymorphisms, we tested 110 families with a prenatally diagnosed trisomy 21 fetus. Of the 102 informative cases, parental origin was maternal in 91 cases (89.2%) and paternal in 11 (10.8%). This percentage differs significantly from the 7.0% observed in previous studies (P<0.001). In order to test the influence of genomic parental imprinting, we determined the origin of the extra chromosome 21 in relation to different factors: advanced maternal age, maternal serum human chorionic gonadotropin (hormone of placental origin), severity of the disease, gestational age at diagnosis and fetal gender. We found that the increased frequency of paternal origin of nondisjunction in trisomy 21-affected fetuses cannot obviously be explained by factors leading to selective loss of paternal origin fetuses.
Adult↗
[Placenta and trisomy 21].
Trisomy 21 is the most frequent genetic anomaly leading to mental retardation, and is prenatally diagnosed by fetal karyotyping usually performed on amniotic fluid cells. Amniocentesis is offered to patients according to three criteria: maternal age (over 38 years), fetal anomalies detected by ultrasonography, and abnormal maternal serum markers most of which are produced by the placenta. Placental development in trisomy 21 is poorly understood. We therefore studied the syncytiotrophoblast, which plays a key role in pregnancy through its involvement in fetal-maternal exchanges and in the secretion of pregnancy-specific hormones. The multinucleated syncytiotrophoblast is formed by the differentiation and fusion of mononucleated cytotrophoblasts. We show that in trisomy 21, syncytiotrophoblast formation is defective and/or delayed. This anomaly is associated with defective synthesis and the secretion of pregnancy-specific hormones. These findings enhance the understanding of placental serum markers used in the prenatal screening of trisomy 21 and clarify the impact of placental abnormalities on fetal development in trisomy 21.
Biomarkers↗
Pre-weaning sensorial and motor development in mice transpolygenic for the critical region of trisomy 21.
Trisomy 21 occurs every 1/800 births and is the most frequent genetic cause of mental retardation. Children with trisomy 21 show delayed sensorial and motor development as well as cognitive disorders. We selected a mouse model of trisomy 21 (TRS21): transgenic mice carrying extra copies of a HSA21 region corresponding to the D21S17-ETS2 region (previously referred to as "Down syndrome critical region 1"). Sensorial and motor development was measured in these partially transgenic mice, from birth to weaning. The four HSA21 regions contributed unequally to sensorial and motor development delay. The more centromeric region (230E8) modified 4 of the development indicators plus the size of the effect, indicated by partial eta(2)(eta(p)(2), reached a median value of 14.5%. The neighboring 141G6 region contributed to 5 developmental differences (eta(p)(2) median value 14%). The most telomeric region (285E6) only modified one development indicator. An extra copy of an HSA21 fragment (referred to here as the 152F7 region) induced modifications to 14 of the 18 indicators measured with a eta(2) median value reaching 20%. The results indicate a noticeable contribution of the 152F7 region to sensorial and motor development. The contribution of this region to cognitive functioning and its neurobiological basis has been already reported. This set of result suggests the location in the D21S17-ETS2 region of several genes playing crucial role in cognitive and developmental impairment observed in TRS21.
Aging↗
Rapid prenatal diagnosis of trisomy 21 by real-time quantitative polymerase chain reaction with amplification of small tandem repeats and S100B in chromosome 21.
Trisomy 21 (Down syndrome) is the most common congenital anomaly, and it occurs in one out of 700-1000 births. Current techniques such as amniocentesis and chorionic villi sampling (CVS) require lengthy laboratory culture procedures and high costs. This study was undertaken to establish a rapid prenatal diagnosis of trisomy 21 using real-time quantitative polymerase chain reaction (PCR) of fetal DNA from amniotic fluid. Real-time quantitative PCR was performed with DNA templates obtained from 14 normal blood samples, 10 normal amniotic fluid samples, 14 Down syndrome blood samples, and 7 Down syndrome amniotic fluid samples. Primers for D21S167 and S100B of chromosome 21 were used. Primers that direct the amplification of the 165-bp fragment of the insulin-like growth factor (IGF)-1 gene on chromosome 12 using a PCR primer were included to generate an internal standard for quantitation. The relative levels of D21S167 and S100B were 2.6 and 2.4 times higher in the blood of Down syndrome patients than those in the control group. The differences between these two groups were statistically significant (p-values were 0.0012 and 0.0016, respectively). The relative levels of D21S167 and S100B were 2.1 and 2.7 times higher in the amniotic fluid of Down syndrome fetuses than those in the control group. The difference between these two groups was statistically significant (p-values were 0.0379 and 0.0379, respectively). Prenatal diagnosis of trisomy 21 by real-time quantitative PCR using STR (small tandem repeats) amplification of D21S167 and S100B is a useful, accurate and rapid diagnostic method. Furthermore, it may also be useful for prenatal diagnosis with fetal DNA from maternal blood, and for preimplantation genetic diagnosis and prenatal counseling.
Amniotic Fluid↗
Development of the superior temporal neocortex is anomalous in trisomy 21.
Trisomy 21 (Down syndrome) is the most common inherited form of mental retardation in the United States, however, the basis of impaired cognition is unknown. We have used recently developed stereological cell counting techniques to quantitatively examine the pattern of neuronal migration and maturation in one neocortical area during gestation in normal development and in trisomy 21. Normal development of the cerebral cortex occurs in two general sequences: Beginning at approximately 7-8 weeks gestation, migration of cells destined to become neurons results in the accumulation of cells in the cortical mantle. This process is largely complete by 20-21 weeks. Over the next 7-10 weeks an "inside-out" differentiation into lamina of different neuronal densities occurs. Our data suggest that the second phase of cortical development, the emergence of lamination, is both delayed and disorganized in trisomy 21. The observed pattern of cortical maturation may reflect an abnormality in axonal and dendritic arborization that subsequently subserve the connectional and functional units underlying normal cognition.
Cell Movement↗
First trimester maternal serum placenta growth factor (PIGF)concentrations in pregnancies with fetal trisomy 21 or trisomy 18.
Placenta growth factor (PIGF), an angiogenic factor belonging to the vascular endothelial growth factor family, pregnancy-associated plasma protein A (PAPP-A) and free beta-human chorionic gonadotrophin (beta-hCG) were measured in maternal serum from 45 pregnancies with trisomy 21, 45 with trisomy 18 and 493 normal controls at 10-13 completed weeks of gestation. In the normal pregnancies maternal serum PIGF levels increased exponentially with gestation. The median multiple of the median (MoM) PIGF concentration in the trisomy 21 group (1.26 MoM) was significantly higher (p<0.0001) than in the control group (1.00 MoM). In the trisomy 18 group the median PIGF was lower (0.889 MoM) but this did not quite reach significance (p=0.064). The corresponding median MoM values for PAPP-A were 1.00 MoM for the controls, 0.49 MoM for trisomy 21 and 0.16 MoM for trisomy 18. The median MoM values for free beta-hCG were 1.00 MoM for the controls, 2.05 MoM for trisomy 21 and 0.38 MoM for trisomy 18. In the control group there was a small but significant correlation of PIGF with free beta-hCG (r=+0.1024) and PAPP-A (r=+0.2288). In the trisomy 18 group there was a significant association between PIGF and free beta-hCG (r=+0.2629) but not with PAPP-A (r=+0.0038). In the trisomy 21 group there was a small but significant association with PAPP-A (r=+0.1028) but not with free beta-hCG (r=+0.0339). The separation of affected and unaffected pregnancies in maternal serum PIGF is small, and therefore it is unlikely that measurement of PIGF would improve screening for these abnormalities provided by the combination of fetal nuchal translucency and maternal serum PAPP-A and free beta-hCG.
Adult↗
[Congenital heart diseases and obstructive pulmonary vascular diseases in Down's syndrome. Apropos of 142 children with trisomy 21].
Trisomy 21 accounts for 3 p. 100 of reasons for admission to the Paediatric Cardiology unit of the St Luc University Clinics, Brussels. In a series of 142 cardiac children with trisomy 21 evaluated by catheterization between 1969 and 1987, 54 p. 100 of the cardiac malformations observed consisted of persistent common atrioventricular canal (complete in 45 p. 100 of the cases). The other heart diseases were ventricular septal defect (23 p. 100), atrial septal defect of the ostium secundum type (10 p. 100) and tetralogy of Fallot (9 p. 100). In 40 p. 100 of the patients other cardiovascular abnormalities were associated with these predominant intracardiac shunts. These findings were in agreement with those usually reported in the literature. At the time of investigation (mean age 24 months), pulmonary vascular resistance had already reached a pathological level in 88 p. 100 of the cases. Oxygen tests only slightly improved these results, which suggested that the conditions were favourable to the early development of a pulmonary obstructive vascular disease in Down's syndrome, thus darkening the prognosis of congenital heart disease in mongoloid children. In this series to overall mortality rate of corrective surgery was 23 p. 100. The risk was maximum in infants aged less than 3 months with severe and rapidly symptomatic lesions. The outcome in patients successfully operated upon was satisfactory, with benign residual lesions.(ABSTRACT TRUNCATED AT 250 WORDS)
Child, Preschool↗
[Prenatal diagnosis of trisomy 21].
Trisomy 21 is the most frequent chromosome anomaly found in the living newborns. Prenatal diagnosis by amniocentesis was limited until recently to older pregnant women. Maternal blood biochemical markers (alpha-fetoprotein, unconjugated estriol, human chorionic gonadotropin) and ultrasonographic signs (nuchal fold thickening, femur length to biparietal diameter ratio) can discriminate a group of higher-risk women even though they are not aged. Numerous factors need to be considered when establishing such a screening program including pre-analytical variables (gestational age, diabetes, smoking, race), analytical variables (choice of reagents, quality control) or post-analytical (result reporting, follow-up of abnormal results). Until now the study of these markers has been restricted to the second trimester but they could become useful earlier during pregnancy.
Chorionic Gonadotropin↗
Submicroscopic duplication of chromosome 21 and trisomy 21 phenotype (Down syndrome).
A patient with the phenotype of trisomy 21 (Down syndrome) was found to have a normal karyotype in blood lymphocytes and fibroblasts. Assessment of the chromosome 21 markers SOD1, CBS, ETS2, D21S11, and BCEI showed partial trisomy by duplication of a chromosome segment carrying the SOD1, CBS, and ETS2 loci and flanked by the BCEI and D21S11 loci, which are not duplicated. This submicroscopic duplication at the interface of 21q21 and 21q22.1 reduces to about 2000-3000 kb the critical segment the trisomy of which is responsible for the phenotype of trisomy 21.
Adult↗
The timing of demise in fetuses with trisomy 21 and trisomy 18.
OBJECTIVE: Women with chromosomally abnormal fetuses often choose to continue their pregnancy. However, though they may search for specific details whether their fetus will survive, not much information is available. We sought to determine if there was a pattern for timing of demise and to determine if demise was more likely to occur before viability in fetuses with amniocentesis confirmed trisomy 18 or 21. METHODS: From the California Expanded AFP screening program, 1813 women were identified to have a fetus with trisomy 18 or 21. Of these, 392 women with trisomy 21 and 106 with trisomy 18 continued the pregnancy. Pregnancies ending in fetal demise were analyzed for gestational age at demise. RESULTS: Of the trisomy 21 fetuses, 40 (10.2%) demised and of the trisomy 18 fetuses, 34 (32.1%) demised. The mean gestational age at time of fetal demise was 28.9+/-1.3 weeks SE for trisomy 21 and 32.1+/-1.2 weeks SE for trisomy 18 (p=0.09). There was no clustering of losses as losses were uniformly distributed throughout gestation after 24 weeks. A slightly larger proportion of T-21 (37.1%) losses occurred before viability (24 weeks) compared to those with T-18 (14.8%) (p=0.05). CONCLUSION: It appears that after 24 weeks' gestation, there is no specific time for fetal demise in fetuses affected by trisomy 21 or 18. There may be an association between trisomy 21 and stillbirth prior to viability. This information may be helpful in counseling those patients found to have a chromosomally abnormal fetus who choose to continue their pregnancy.
Adult↗
Cephalic index is not a useful sonographic marker for trisomy 21 and trisomy 18.
OBJECTIVES: To evaluate whether the cephalic index (CI) in trisomy 21 (T21) and trisomy 18 (T18) fetuses is different from that in euploid fetuses, and if so, is this difference of clinical utility. METHODS: Retrospective. Over an 18-month period, patients attending a single centre for routine advanced maternal age amniocentesis were recruited for a prospective study of ultrasound soft markers of aneuploidy. This prospective database was searched for cases with the following criteria: (1) occipitofrontal diameters (OFD) measured at least twice; (2) gestational age between 98 and 126 days either by ultrasound-confirmed menstrual dates or early second- trimester biometry; (3) no major central nervous system abnormalities detected on prenatal ultrasound, and (4) normal fetal karyotype. This constituted the control group. The study group consisted of all cases of prenatally diagnosed T18 and T21 identified in the same time period with criterion 2 as above. The fetuses in the study group had the OFD measured in a blinded fashion from the biparietal diameter images. CI (= mean biparietal diameter/mean OFD) was calculated for all fetuses. Pearson coefficient and regression analysis were used to determine independence of CI to gestational age in the control group. Standard descriptive statistics were used to describe interval data and two-tailed t test was used to compare means between the study and control groups. ROC curves were constructed to evaluate the clinical efficacy of CI for T18 and T21. RESULTS: Five hundred and ninety-seven fetuses were available for analysis. There were 551 fetuses in the control group and 46 in the study group. Within the study group, there were 30 T21 and 16 T18 fetuses. Within the control group, CI was independent of gestational age (R = 0.026, p = 0.922). Mean CI for the control group was 0.802 (SD 0.040) and this was not statistical different from either the T21 group (mean 0.816, SD 0.042, p = 0.067) or the T18 group (mean 0.792, SD 0.057, p = 0.491). Area under the ROC curves was determined for both T18 and T21 and both had poor results (0.545 and 0.598, respectively). When CI was evaluated in the control group according to the two main ethnic groups in the study, there was a trend towards a statistical difference (p = 0.046) between the fetuses of Oriental and Caucasian mothers. CONCLUSIONS: In this retrospective study, CI was not found to be statistically different between the study and control groups. Although a trend towards significance was seen with T21, this difference is not clinically useful. There may be interethnic differences in the CI between fetuses. CI is not useful for aneuploidy screening by ultrasound.
Biomarkers↗
Cardiac expression of sarcoplasmic reticulum calcium ATPase in fetuses with trisomy 21 and trisomy 18 presenting with nuchal translucency.
At 10-14 weeks of gestation about 80% of fetuses with chromosomal defects have abnormal accumulation of subcutaneous fluid in the nuchal region that is visualized by ultrasonography as nuchal translucency. A possible cause for this translucency is cardiac dysfunction due to the associated defects in the heart and great arteries. The aim of this study was to investigate whether in cardiac tissue from trisomic fetuses, compared to normals, there is an alteration in the steady state levels of expression of the genes encoding sarcoplasmic reticulum calcium ATPase (calcium ATPase), which is known to be downregulated in postnatal heart failure. After termination of pregnancy at 10-18 weeks of gestation, mRNA was extracted from cardiac tissue in 11 trisomy 21 and 4 trisomy 18 fetuses. Densitometric analysis of the Northern and slot blots was used to determine the steady state levels of expression of calcium ATPase and the values from the trisomic fetuses were compared to those of 30 normal controls at 10-18 weeks. Calcium ATPase gene expression did not change significantly with gestation at 10-18 weeks. In trisomic fetuses there was no significant decrease in calcium ATPase expression and expression levels of calcium ATPase were not related to increased nuchal translucency. However, the levels expressed in fetuses are already very low and cardiac dysfunction as a potential etiological factor cannot be excluded.
Abortion, Induced↗
Recurrent trisomy 21 in a couple with a child presenting trisomy 21 mosaicism and maternal uniparental disomy for chromosome 21 in the euploid cell line.
Recurrence of trisomy 21 was observed in a family in which both parents had a normal chromosome complement. Mosaic trisomy 21 was found in a blood karyotype of the first child, a second pregnancy ended in spontaneous abortion, and a full trisomy 21 was found at prenatal diagnosis of the third pregnancy of this same couple. Although recurrent trisomy 21 may be due to chance, the possibility of germline mosaicism for trisomy 21 in one of the parents has important implications for recurrence risk. Molecular analysis was therefore undertaken in this family to determine the parental origin and the stage of nondisjunction of the extra chromosome 21 in both cases. Although a maternal origin of both instances of trisomy 21 was observed, the mosaic case showed homozygosity for all markers along the duplicated maternal chromosome. Such a finding would normally suggest a postzygotic origin of the trisomy 21. However, the diploid cell line in this same case showed maternal uniparental disomy 21, implying that it was the result of a trisomic conception. We suggest that a somatic nondisjunction in the maternal germ cells is the most likely explanation for these findings. The apparent meiotic II stage of nondisjunction of the nonmosaic trisomy 21 fetus was consistent with maternal mosaicism. A review of the literature for recurrent trisomy 21 cases studied by molecular means, suggests that mosaicism in germ cells may account for more cases than is detected cytogenetically. These results also show that DNA marker analysis does not provide a valuable tool for patient counseling in case of recurrent trisomy 21.
Child↗