BACKGROUND

Down syndrome or trisomy 21, the most common chromosomal disorder, results from the presence of a third copy of chromosome 21 and manifests as mild to moderate intellectual disability, growth retardation, congenital heart defects, gastrointestinal abnormalities, and characteristic facial features. Several methods have been used to screen for Down syndrome in the prenatal period, such as ultrasound, biomarkers, cell-free DNA testing, and combinations of these tests. A positive result from one or more of these screening tests signals the need for confirmatory karyotyping to clinch the diagnosis. Ultrasound between 11 to 14 weeks of gestation can evaluate nuchal translucency (NT) to screen for Down syndrome. During the second trimester, a triple or quadruple test can also be performed alone or in addition to NT to quantify Down syndrome risk. In limited resource settings however, only the measurement of NT via ultrasound can be performed since biomarker tests are either unavailable or inaccessible. While the diagnostic performance of NT measurement alone has been investigated in several observational studies, there is no consensus on its performance as a sole test to screen for Down syndrome.

To determine the diagnostic performance of NT during prenatal first-trimester ultrasound as a screening test for Down syndrome.

We performed a systematic search on the PubMed, ProQuest, and Cochrane Library databases for recent systematic reviews and meta-analyses that addressed the objective. The existing reviews found were then independently appraised by the two reviewers with the AMSTAR-2 checklist. To update the existing reviews, a systematic search was done in the same databases to identify additional primary diagnostic studies, which were appraised using the QUADAS-2 tool. Random-effects univariate meta-analysis and summary receiving operator curve (HSROC) analysis for the outcomes were performed using Review Manager version 5.4 and R version 4.2.2, respectively. Subgroup analysis was performed by stratifying the baseline risk of mothers for fetal anomaly as low- or high-risk. Highrisk mothers were defined as women with risk factors such as advanced age, positive serum screen, presence of other ultrasound anomalies, and history of previous fetus with anomaly.

We found 22 cohort studies (n=225,846) of women at low-risk for fetal anomaly. The pooled sensitivity was 67.8% (95% CI: 61.4%-73.6%, I2=70.4%) and specificity was 96.3% (95% CI: 95.5%-96.9%, I2=96.7%). For low-risk women, the overall certainty of evidence was low, due to different modes of verification and heterogeneity not completely explained by variability in baseline risk or cut-points. Seven studies (n=9,197) were on high-risk women. The pooled sensitivity was 62.2% (95% CI: 54.1%-69.7%, I2=38.8%) and specificity was 96.5% (95% CI: 93.6%-98.1%, I2=95.5%). For women at high-risk, the evidence was rated as moderate due to differential verification.

Our analysis showed that NT measured through first-trimester ultrasound is specific for Down syndrome but has low sensitivity. Despite this, it is a useful screening test for Down syndrome in low-resource settings where other strategies may not be available or accessible. Furthermore, interpretation of NT results must take into consideration its limited sensitivity as this may lead to missed cases.

BACKGROUND

Down syndrome or trisomy 21, the most common chromosomal disorder, results from the presence of a third copy of chromosome 21 and manifests as mild to moderate intellectual disability, growth retardation, congenital heart defects, gastrointestinal abnormalities, and characteristic facial features. Several methods have been used to screen for Down syndrome in the prenatal period, such as ultrasound, biomarkers, cell-free DNA testing, and combinations of these tests. A positive result from one or more of these screening tests signals the need for confirmatory karyotyping to clinch the diagnosis. Ultrasound between 11 to 14 weeks of gestation can evaluate nuchal translucency (NT) to screen for Down syndrome. During the second trimester, a triple or quadruple test can also be performed alone or in addition to NT to quantify Down syndrome risk. In limited resource settings however, only the measurement of NT via ultrasound can be performed since biomarker tests are either unavailable or inaccessible. While the diagnostic performance of NT measurement alone has been investigated in several observational studies, there is no consensus on its performance as a sole test to screen for Down syndrome.

To determine the diagnostic performance of NT during prenatal first-trimester ultrasound as a screening test for Down syndrome.

We performed a systematic search on the PubMed, ProQuest, and Cochrane Library databases for recent systematic reviews and meta-analyses that addressed the objective. The existing reviews found were then independently appraised by the two reviewers with the AMSTAR-2 checklist. To update the existing reviews, a systematic search was done in the same databases to identify additional primary diagnostic studies, which were appraised using the QUADAS-2 tool. Random-effects univariate meta-analysis and summary receiving operator curve (HSROC) analysis for the outcomes were performed using Review Manager version 5.4 and R version 4.2.2, respectively. Subgroup analysis was performed by stratifying the baseline risk of mothers for fetal anomaly as low- or high-risk. Highrisk mothers were defined as women with risk factors such as advanced age, positive serum screen, presence of other ultrasound anomalies, and history of previous fetus with anomaly.

We found 22 cohort studies (n=225,846) of women at low-risk for fetal anomaly. The pooled sensitivity was 67.8% (95% CI: 61.4%-73.6%, I2=70.4%) and specificity was 96.3% (95% CI: 95.5%-96.9%, I2=96.7%). For low-risk women, the overall certainty of evidence was low, due to different modes of verification and heterogeneity not completely explained by variability in baseline risk or cut-points. Seven studies (n=9,197) were on high-risk women. The pooled sensitivity was 62.2% (95% CI: 54.1%-69.7%, I2=38.8%) and specificity was 96.5% (95% CI: 93.6%-98.1%, I2=95.5%). For women at high-risk, the evidence was rated as moderate due to differential verification.

Our analysis showed that NT measured through first-trimester ultrasound is specific for Down syndrome but has low sensitivity. Despite this, it is a useful screening test for Down syndrome in low-resource settings where other strategies may not be available or accessible. Furthermore, interpretation of NT results must take into consideration its limited sensitivity as this may lead to missed cases.

OBJECTIVES: To investigate the clinical features and prognosis of children with non-Down-syndrome-related acute megakaryoblastic leukemia (non-DS-AMKL). METHODS: A retrospective analysis was conducted on the medical data of 17 children with non-DS-AMKL who were admitted to Children's Hospital of The First Affiliated Hospital of Zhengzhou University from January 2013 to December 2023, and their clinical features, treatment, and prognosis were summarized. RESULTS: Among the 17 children with non-DS-AMKL, there were 8 boys and 9 girls. Fourteen patients had an onset age of less than 36 months, with a median age of 21 months (range:13-145 months). Immunophenotyping results showed that 16 children were positive for CD61 and 13 were positive for CD41. The karyotype analysis was performed on 16 children, with normal karyotype in 6 children and abnormal karyotype in 9 children, among whom 5 had complex karyotype and 1 had no mitotic figure. Detected fusion genes included EVI1, NUP98-KDM5A, KDM5A-MIS18BP1, C22orf34-BRD1, WT1, and MLL-AF9. Genetic alterations included TET2, D7S486 deletion (suggesting 7q-), CSF1R deletion, and PIM1. All 17 children received chemotherapy, among whom 16 (94%) achieved complete remission after one course of induction therapy, and 1 child underwent hematopoietic stem cell transplantation (HSCT) and remained alive and disease-free. Of all children, 7 experienced recurrence, among whom 1 child received HSCT and died of graft-versus-host disease. At the last follow-up, six patients remained alive and disease-free. CONCLUSIONS Non-DS-AMKL primarily occurs in children between 1 and 3 years of age. The patients with this disorder have a high incidence rate of chromosomal abnormalities, with complex karyotypes in most patients. Some patients harbor fusion genes or gene mutations. Although the initial remission rate is high, the long-term survival rate remains low.
Humans ; Male ; Female ; Leukemia, Megakaryoblastic, Acute/etiology* ; Child, Preschool ; Infant ; Child ; Retrospective Studies ; Prognosis ; Down Syndrome/complications*

OBJECTIVE: To assess the clinical value of digital PCR (dPCR) for the prenatal diagnosis of common fetal aneuploidies. METHODS: A dPCR-based assay was developed for detecting trisomies 21, 18, and 13. A retrospective analysis was carried out on 173 amniotic fluid samples collected by the Prenatal Diagnosis Center of Taizhou Hospital between January 2017 and December 2023. By using chromosomal karyotyping as the gold standard, the diagnostic performance of the multiplex dPCR system was evaluated in a double-blind manner. This study has been approved by the Ethics Committee of Taizhou Hospital (Ethics No. K20250339). RESULTS: Chromosomal karyotyping has identified 59 cases of trisomy 21, 5 cases of trisomy 18, 2 cases of trisomy 13, 6 cases with chromosomal structural abnormalities or mosaicisms, and 101 cases with a normal karyotype. The dPCR results (Z-score cutoff = 4.0, CI = 99.997%) showed full concordance with karyotyping (sensitivity = 100%, specificity = 100%, Kappa = 1). Among the 6 structurally abnormal or mosaicism samples, dPCR has accurately detected 4 cases, but mis-classified 2 cases of trisomy 21 with very low-level mosaicisms (3.3%, 6.9%, respectively) as normal. CONCLUSION The established multiplex dPCR system demonstrated high diagnostic accuracy for common chromosomal aneuploidies, with results available within 24 hours. It can serve as an efficient supplementary tool to conventional chromosomal karyotyping, providing reliable support for time-sensitive clinical decision-making in prenatal diagnosis.
Humans ; Female ; Pregnancy ; Aneuploidy ; Prenatal Diagnosis/methods* ; Karyotyping ; Retrospective Studies ; Polymerase Chain Reaction/methods* ; Chromosome Disorders/genetics* ; Adult ; Trisomy 13 Syndrome/diagnosis* ; Trisomy 18 Syndrome/genetics* ; Down Syndrome/genetics*

OBJECTIVE: To explore the genetic characteristics and pathogenesis for a child with mosaicism trisomy 21 and Congenital leukemia (CL). METHODS: A child who was admitted to Ningbo Women and Children's Hospital in March 2023 was selected as the study subject. A retrospective analysis was carried out on the clinical data, laboratory test results, immunophenotyping, and genetic characteristics of the child. This study was approved by the Medical Ethics Committee of the Hospital (Ethics No.: EC2024-063). RESULTS: Whole genome sequencing (WGS) revealed that the child has mosaicism trisomy of chromosome 21, with a ratio of approximately 74%. In addition, copy number variations involving multiple OMIM genes that could explain his clinical phenotype were detected and rated as pathogenic based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). No pathogenic variant was detected with the GATA1 gene. Blood immune typing of the child conformed to the immunophenotype of acute myeloid leukemia. CONCLUSION For children with trisomy 21, even in the absence of GATA1 gene variants, the occurrence of CL should be monitored, and early diagnosis and treatment are of great significance for improving the prognosis.
Child, Preschool ; Humans ; DNA Copy Number Variations/genetics* ; Down Syndrome/genetics* ; GATA1 Transcription Factor/genetics* ; Leukemia/congenital* ; Mosaicism ; Mutation ; Retrospective Studies ; Whole Genome Sequencing

OBJECTIVE: To report on a case of mosaicism involving trisomy 21, maternal uniparental isodisomy, and normal diploid cells in uncultured amniocytes, and to explore the discrepancies between conventional cytogenetic and molecular cytogenetic techniques during prenatal diagnosis. METHODS: A 30-year-old pregnant woman who presented to Boai Hospital of Zhongshan on June 27, 2023 has undergone amniocentesis at 16 weeks of gestation. The amniotic fluid sample was subjected to quantitative fluorescent PCR (QF-PCR), G-banded karyotype analysis, and chromosomal microarray analysis (CMA). The discrepancies between the results of each method were analyzed. This study was approved by Medical Ethics Committee of Boai Hospital of Zhongshan (Ethics No.: KY-2024-001-01). RESULTS: Non-invasive prenatal testing (NIPT) at 12 weeks indicated a high risk of trisomy 21. QF-PCR of uncultured amniocytes revealed a pattern of trisomy 21. After one week of cell culture, G-banding analysis showed mos 47,XX,+21[1]/46,XX[72]. CMA revealed a homozygous state of chromosome 21 in cultured cells, while uncultured amniocytes showed mosaic trisomy 21 with an estimated proportion of 50%. These findings suggested a complex chromosomal mosaicism in the fetus, which may result from a trisomy rescue event during early embryogenesis, leading to coexistence of three cell lines including trisomy 21, maternal uniparental isodisomy, and normal diploid cells. CONCLUSION In prenatal diagnosis, discrepancies may arise between QF-PCR and conventional chromosomal karyotyping analysis, particularly in complex genetic phenomena such as trisomy rescue and uniparental disomy. For cases where NIPT indicated a high risk of trisomy 21 but G-banding karyotype analysis yielded a normal result, further molecular genetic testing using uncultured cells is recommended.
Humans ; Female ; Mosaicism ; Pregnancy ; Uniparental Disomy/diagnosis* ; Adult ; Down Syndrome/diagnosis* ; Prenatal Diagnosis/methods* ; Diploidy ; Karyotyping ; Amniocentesis

As the most common chromosomal disorder compatible to life, Down syndrome (DS) is caused by an extra copy of chromosome 21. Almost all DS patients have cognitive dysfunction. Therefore, it is important to study the underlying pathogenetic mechanism to elucidate its molecular basis. This article has provided a review for the molecular mechanisms of NRIP1 and DYRK1A genes, which have been closely associated with the cognitive dysfunctions of DS patients. It has also summarized the research progress on the mechanism of DS and development of new therapeutic strategies based on such studies, with an aim to provide insights into the prevention and treatment for the cognitive dysfunctions in DS patients.
Down Syndrome/psychology* ; Humans ; Protein-Tyrosine Kinases/genetics* ; Dyrk Kinases ; Protein Serine-Threonine Kinases/genetics* ; Cognition Disorders/etiology*

Objective: To describe various local and systemic factors as the cause of gingivitis and to find out the main etiological factors of gingivitis in children with DS. Methods: We searched PubMed and Google Scholar for Indonesian and English references either in the form of textbook, research results, reviews, and internet articles on the topic. We screened and selected the relevant articles for inclusion into the review. Results: In children with DS, apart from poor oral hygiene, the increasing incidence of gingivitis is caused by changes in other local factors related to systemic factors, such as oral dysfunction, dental and gingival abnormalities, changes in the oral microbial profile, and salivary characteristics. Furthermore, systemic immunodeficiency, changes in inflammatory mediators and proteolytic enzymes, and intellectual subnormality are considered as systemic factors. Conclusion There is no main etiological factor of gingivitis in children with DS since various local and systemic factors are interrelated with each other causing gingivitis. The severity of gingivitis in children with DS presumably were caused by the systemic factors. Furthermore, good oral hygiene habits and the dentist's intervention in periodontal health can significantly reduce gingivitis in DS patients.
children ; Down syndrome ; gingivitis ; oral health

Objective To explore the clinical significance of non-invasive prenatal testing(NIPT)for fetal chromosomal abnormalities in the cases of twin pregnancy and its relationship with age and other related factors.Methods A total of 3733 women with twin pregnancy of 12-26⁺⁶ weeks who voluntarily underwent NIPT in the Ningbo Women and Children's Hospital from January 2018 to December 2022 were selected.The results of NIPT and amniocentesis were compared and all the participants were followed up.The detection rate of chromosomal abnormalities by NIPT was calculated,and its correlations with age,gestational weeks,chorionicity,and pregnancy type were analyzed.Results Among the 3733 cases,71 cases of fetal chromosome abnormality were indicated by NIPT,including 13 cases of trisomy 21,19 cases of trisomy 18,5 cases of trisomy 13,18 cases of sex chromosome abnormality,and 16 cases of chromosome microdeletion/duplication(excluding 21,18,13,and sex chromosomes),among which 34 cases were true positive and 37 cases were false positive.The overall sensitivity,specificity,and positive predictive value(PPV)of NIPT for chromosomal abnormalities in the cases of twin pregnancy were 100%,98.99%,and 47.89%(34/71),respectively.NIPT showed the sensitivity,specificity,and PPV of 100%,99.78%,and 78.38%(29/37)for trisomy 21,18,and 13,100%,99.56%,and 16.67%(3/18)for sex chromosome abnormalities,and 100%,99.62%,and 12.5%(2/16)for chromosome microdeletion/duplication,respectively.In the age group of ≥40 years,the NIPT for chromosomal abnormalities showed the PPV of 66.67%,the sensitivity of 100%,and the misdiagnosis rate of 30%。However,the NIPT for trisomy 21,18,and 13 showed the PPV of 100%,the misdiagnosis rate of 0,and the sensitivity and specificity of 100%.In terms of grouping based on gestational weeks,the NIPT for chromosomal abnormalities showed the highest PPV(51.28%)in the women with twin pregnancy for 14-17⁺⁶ weeks,followed by that(50.00%)in the women with twin pregnancy for 22-26⁺⁶ weeks;the NIPT for trisomy 21,18,and 13 showed the highest PPV of 94.74% in the gestation group of 14-17⁺⁶ weeks,followed by that(83.33%)in the gestation group of 18-21⁺⁶ weeks.The rate of dichorionic diamniotic twins was higher in assisted pregnancies than in natural pregnancies,and NIPT showed the same detection efficiency for dichorionic diamniotic twins and monochorionic diamniotic twins and the same detection efficiency for different pregnancy types.Conclusions NIPT has high accuracy in the diagnosis of twin pregnancy and high sensitivity and high specificity for different ages and gestational weeks,especially for trisomy 21,18,and 13.NIPT is suitable for assisted pregnancy and natural pregnancy,and it is of high value in clinical application.However,extensive application needs a large population-based study.
Pregnancy ; Child ; Female ; Humans ; Adult ; Down Syndrome/genetics* ; Pregnancy, Twin ; Prenatal Diagnosis ; Trisomy ; Chromosome Aberrations

OBJECTIVE: To assess the clinical efficacy and health economic value of non-invasive prenatal testing (NIPT) for the prenatal screening of common fetal chromosomal aneuploidies. METHODS: 10 612 pregnant women from October 2017 to December 2019 presented at the antenatal screening clinic of the General Hospital of Tianjin Medical University were selected as the study subjects. Results of NIPT and invasive prenatal diagnosis and follow-up outcome for the 10 612 pregnant women were retrospectively analyzed and compared. Meanwhile, NIPT data for two periods were analyzed for assessing the health economic value of NIPT as the second- or first-tier screening strategy for the prenatal diagnosis of fetal trisomies 21, 18 and 13. RESULTS: The NIPT was successful in 10 528 (99.72%) subjects, with the sensitivity for fetal trisomies 21, 18 and 13 being 100%, 92.86% and 100%, and the positive predictive value (PPV) being 89.74%, 61.90% and 44.44%, respectively. The PPV of NIPT for sex chromosome aneuploidies was 34.21%. Except for one false negative case of trisomy 18, the negative predictive value for trisomy 21, trisomy 13 and other chromosomal abnormalities were 100%. For pregnant women with high risk by serological screening, advanced maternal age or abnormal ultrasound soft markers, NIPT has yielded a significantly increased high risk ratio. There was no statistical difference in the PPV of NIPT among pregnant women from each subgroup. NIPT would have higher health economic value as a second-tier screening until 2019, while compared to 2015 ~ 2017, its incremental cost-effectiveness ratio as a first-tier screening had declined clearly. CONCLUSION The screening efficacy of NIPT for trisomies 21, 18 and 13 for a mixed population is significantly better than conventional serological screening, but it is relatively low for sex chromosomal abnormalities. NIPT can also be recommended for populations with relatively high risks along with detailed pre- and post-test genetic counselling. From the perspective of health economics, except for open neural tube defects, it is possible for NIPT to replace the conventional serological screening in the future as its cost continues to decrease.
Pregnancy ; Female ; Humans ; Trisomy/genetics* ; Retrospective Studies ; Prenatal Diagnosis/methods* ; Down Syndrome/genetics* ; Aneuploidy ; Chromosome Aberrations ; Trisomy 18 Syndrome/genetics* ; Sex Chromosome Aberrations ; Fetus