Molecular Cytogenetic Classification of Down Syndrome and Screening of Somatic Aneuploidy in Mothers.

Down Syndrome (DS) caused by trisomy 21 results in various congenital and developmental complications in children. It is crucial to cytogenetically diagnose the DS cases early for their proper health management and to reduce the risk of further DS childbirths in mothers. In this study, we performed a cytogenetic analysis of 436 suspected DS cases using karyotyping and fluorescent in situ hybridization. We detected free trisomies (95.3%), robertsonian translocations (2.4%), isochromosomes (0.6%), and mosaics (1.2%). We observed a slightly higher incidence of DS childbirth in younger mothers compared to mothers with advanced age. We compared the somatic aneuploidy in peripheral blood of mothers having DS children (MDS) and control mothers (CM) to identify biomarkers for predicting the risk for DS childbirths. No significant difference was observed. After induced demethylation in peripheral blood cells, we did not observe a significant difference in the frequency of aneuploidy between MDS and CM. In conclusion, free trisomy 21 is the most common type of chromosomal abnormality in DS. A small number of DS cases have translocations and mosaicism of chromosome 21. Additionally, somatic aneuploidy in the peripheral blood from the mother is not an effective marker to predict DS childbirths.

Analyses stratified by maternal age and recombination further characterize genes associated with maternal nondisjunction of chromosome 21.

OBJECTIVE: In our previous work, we performed the first genome-wide association study to find genetic risk factors for maternal nondisjunction of chromosome 21. The objective of the current work was to perform stratified analyses of the same dataset to further elucidate potential mechanisms of genetic risk factors. METHODS: We focused on loci that were statistically significantly associated with maternal nondisjunction based on this same dataset in our previous study and performed stratified association analyses in seven subgroups defined by age and meiotic recombination profile. In each analysis, we contrasted a different subgroup of mothers with the same set of fathers, the mothers serving as cases (phenotype: meiotic nondisjunction of chromosome 21) and the fathers as controls. RESULTS: Our stratified analyses identified several genes whose patterns of association are consistent with generalized effects across groups, as well as other genes that are consistent with specific effects in certain groups. CONCLUSIONS: While our results are epidemiological in nature and cannot conclusively prove mechanisms, we identified a number of patterns that are consistent with specific mechanisms. In many cases those mechanisms are strongly supported by available literature on the associated genes.

Evaluation of the Z-score accuracy of noninvasive prenatal testing for fetal trisomies 13, 18 and 21 at a single center.

OBJECTIVE: To assess the correlation between Z-scores of positive noninvasive prenatal testing (NIPT) results and the positive predictive value (PPV) of NIPT. METHODS: Pregnancies with positive NIPT results at Guangzhou Women and Children's Medical Centre between July 2017 and May 2020 were included in this study. Fetal karyotyping or microarray analysis was provided to patients with abnormal NIPT results for confirmatory testing. Logistic regression analyses was applied to study the relationship between the Z scores and the PPV performance. The optimal cutoff values for indicating fetal common trisomies were obtained based on receiver operating characteristic (ROC) curve analysis, and then the PPV were calculated in pregnancies with positive NIPT results at Z-score greater than or equal to cutoff value and in patients with a Z-score between 3 and cutoff value respectively. RESULTS: A total of 214 pregnancies with positive NIPT results for fetal common trisomies were validated by invasive prenatal diagnosis and follow up in this study. Of these, NIPT indicated trisomy 13 in 25 cases, trisomy 18 in 54 cases and trisomy 21 in 135 patients. Logistic regression analyses showed a significant association (p < 0.05) between the Z-scores and true positive results for T21 and T18. For T13, the significant association was not observed (p > 0.05). The ROC curve analysis showed that the optimal cutoff Z-score for indicating fetal trisomies 13, 18, and 21 were 6.889, 7.574 and 6.612 respectively, and the corresponding area under curve were 0.706, 0.916, and 0.954. In this cohort with abnormal NIPT results, the cutoff values revealed a sensitivity of 96.8% and a specificity of 90% for indicating trisomies 21, and a sensitivity of 88.9% and a specificity of 92.6% for trisomies 18. However, probably due to the sample size, the sensitivity and specificity for indicating trisomy 13 were lower (85.7% and 61.1%) than that for trisomies 21 and 18. The PPVs in pregnancies with positive NIPT results at Z-score greater than or equal to cutoff value were 99.18% (121/122) for trisomy 21, 92.31% (24/26) for trisomy 18 and 46.15% (6/13) for trisomy 13. In patients with a Z-score between 3 and cutoff Z-score, the PPV of NIPT for trisomies 21, 18, and 13 were 30.77% (4/13), 10.71% (3/28), and 8.33% (1/12) respectively. Moreover, by classifying Z scores as 3 ≤ Z < 5, 5 ≤ Z < 10, and Z ≥ 10, the majority of Z scores were above 10 with a PPV of 99% for T21 and just 5.2% were between 3 and 5 with a PPV of 14.3%. In contrast for T18, over a third of tests had Z scores between 3 and 5. The PPV in this group is just over 5%. CONCLUSIONS: The present results show that the PPV performance of NIPT for fetal trisomies 13, 18, and 21 are closely associated with Z-score. The higher the Z-score, the greater the likelihood that the aneuploidy result is correct. Our experience in evaluating the Z-score accuracy of NIPT in this study could be of use in similar work.

Revised medical criteria for evaluating congenital disorders that affect multiple body systems. Final rule.

We are revising the criteria in the Listing of Impairments (listings) that we use to evaluate cases involving impairments that affect multiple body systems in adults and children under titles II and XVI of the Social Security Act (Act). The revisions reflect our program experience and address adjudicator questions we have received since we last comprehensively revised this body system in 2005. We do not expect any decisional differences due to the revisions in this body system.

Behavioral Phenotyping for Down Syndrome in Mice.

Down syndrome (DS) is the most frequent genetic cause of intellectual disability, characterized by alterations in different behavioral symptom domains: neurodevelopment, motor behavior, and cognition. As mouse models have the potential to generate data regarding the neurological basis for the specific behavioral profile of DS, and may indicate pharmacological treatments with the potential to affect their behavioral phenotype, it is important to be able to assess disease-relevant behavioral traits in animal models in order to provide biological plausibility to the potential findings. The field is at a juncture that requires assessments that may effectively translate the findings acquired in mouse models to humans with DS. In this article, behavioral tests are described that are relevant to the domains affected in DS. A neurodevelopmental behavioral screen, the balance beam test, and the Multivariate Concentric Square Field test to assess multiple behavioral phenotypes and locomotion are described, discussing the ways to merge these findings to more fully understand cognitive strengths and weaknesses in this population. New directions for approaches to cognitive assessment in mice and humans are discussed. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Preweaning neurodevelopmental battery Basic Protocol 2: Balance beam Basic Protocol 3: Multivariate concentric square field test (MCSF).

Systematic Review of Recent Pediatric Down Syndrome Neuropsychology Literature: Considerations for Regression Assessment and Monitoring.

OBJECTIVES: To conduct a systematic review of recent pediatric Down syndrome (DS) neuropsychology research that may be useful to clinicians and researchers examining regression in this population. METHODS: We reviewed original peer-reviewed articles published between 2013 and 2018 studying neuropsychological profiles in DS. RESULTS: Thirty-one articles (of 1231 included in the original search) passed all inclusion criteria, were evaluated for bias, and were included in the analysis. CONCLUSION: Findings argued against a single "DS profile" and revealed multiple within-group differences as well as expected and unexpected differences relative to typically developing children and children with other intellectual and developmental disabilities. Areas identified as most germane to regression monitoring included working memory, inhibition, letter and word identification, navigational route learning, motor skills (when strong at baseline), single word receptive/expressive vocabulary, and adaptive function.

The phenotype of persons having mosaicism for trisomy 21/Down syndrome reflects the percentage of trisomic cells present in different tissues.

Little is known about the pathogenesis of the phenotype in individuals with trisomy 21 mosaicism and Down syndrome. The primary goal of this study was to identify factors contributing to the observed phenotypic variation by evaluating 107 individuals having trisomy 21 mosaicism. To investigate a potential "threshold" effect due to trisomic imbalance, lymphocyte and buccal mucosa nuclei were scored using FISH. Overall, buccal cells showed a significantly higher frequency of trisomy than lymphocytes (P < 0.0001). Using latent class analysis, two phenotypic classes were identified based on the clinical findings of the propositi. Patients from class 1 had significantly fewer traits and a lower percentage of trisomic cells (mean of 37.3% lymphocytes; 34.5% buccal mucosa cells) when compared to those stratified into class 2 (54.0% lymphocytes; 53.4% buccal mucosa cells). Tissue-specific influences were also detected, with buccal mucosa trisomy levels being significantly correlated with IQ (P = 0.0094; both ectodermal derivatives), while congenital heart defects were significantly correlated with lymphocytes (P = 0.0286; both mesodermal embryonic derivatives). In conclusion, allowing for the distinction of two groups, we observed variation in phenotype, associated with the percentage of trisomic cells. We also observed tissue-specific effects on phenotype. The results of this study should enable geneticists and other health care professionals to provide information regarding optimal diagnostic approaches and anticipated clinical outcomes.

Current use of medical eponyms--a need for global uniformity in scientific publications.

BACKGROUND: Although eponyms are widely used in medicine, they arbitrarily alternate between the possessive and nonpossessive forms. As very little is known regarding extent and distribution of this variation, the present study was planned to assess current use of eponymous term taking "Down syndrome" and "Down's syndrome" as an example. METHODS: This study was carried out in two phases - first phase in 1998 and second phase in 2008. In the first phase, we manually searched the terms "Down syndrome" and "Down's syndrome" in the indexes of 70 medical books, and 46 medical journals. In second phase, we performed PubMed search with both the terms, followed by text-word search for the same. RESULTS: In the first phase, there was an overall tilt towards possessive form - 62(53.4%) "Down's syndrome" versus 54(46.6%) "Down syndrome." However, the American publications preferred the nonpossesive form when compared with their European counterpart (40/50 versus 14/66; P < 0.001). In the second phase, PubMed search showed, compared to "Down syndrome," term "Down's syndrome" yielded approximately 5% more articles. The text-word search of both forms between January 1970 and June 2008 showed a gradual shift from "Down's syndrome" to "Down syndrome," and over the last 20 years, the frequency of the former was approximately halved (33.7% versus 16.5%; P < 0.001). The abstracts having possessive form were mostly published from the European countries, while most American publications used nonpossesive form consistently. CONCLUSION: Inconsistency in the use of medical eponyms remains a major problem in literature search. Because of linguistic simplicity and technical advantages, the nonpossessive form should be used uniformly worldwide.

Developing a therapeutic relationship with a blind client with a severe intellectual disability and persistent challenging behaviour.

PURPOSE: A blind, severely intellectually impaired boy aged 17 with Down syndrome and persistent serious challenging behavior received attachment-based behavior modification treatment. The aim was to study the effect of the treatment and the development of the therapeutic attachment relationship. METHOD: In a single-case study, attachment therapy sessions alternated with control sessions. Treatment started with attachment therapy (phase 1), followed by behavior modification (phase 2). The instruments used were: Residential observation lists for challenging behavior, video analyses of attachment behavior in therapy sessions and physiological indicators of affect regulation measuring the pre-ejection period (PEP) and respiratory sinus arrhythmia (RSA) as indices of cardiac sympatho-vagal activity. RESULTS: The client exhibited less frequent and less intensely challenging behavior. The data indicated more appropriate replacement behavior and less PEP arousal during the behavior modification treatment given by the attachment therapist compared to the control therapist who used the same protocol. The client showed more active and longer-lasting attachment behavior, especially proximity seeking, towards the attachment therapist than towards the control therapist. CONCLUSIONS: Attachment-based psychotherapy proved successful in eliciting attachment behavior in a severely intellectually disabled, socially deprived, behaviorally and affectively dysregulated adolescent. The resulting relationship proved to be a therapeutic platform conducive to behavior change.

Preanesthetic evaluation and assessment of children with Down's syndrome.

During preoperative evaluation for anesthesia in the Down patient, it is important to focus attention on the functional conditions of the patient and systems that frequently show anomalies. One of the challenges of evaluating pre-operative conditions and potential risks in the Down patient is the lack of a gold-standard evaluation score; cervical spine abnormalities, reduced dimensions and malformations of the airways, neurological changes, respiratory and cardiac disease, as well as endocrinological and metabolic alterations. We suggest, as a possible method of evaluation for patients with mental retardation and possible malformations, a new scale which takes the functional and mental conditions into account: the Sensorial, Psychological, Anatomical, Biological, Operational and Surgical (SPABOS) Compliance Score.

Functional performance characteristics associated with postponing elementary school entry among children with Down syndrome.

OBJECTIVES: This study investigated the relation between functional performance skills of children with Down syndrome and the age of entry into mainstream elementary education. METHOD: In a cross-sectional study of 70% of the 7-year-old children with Down syndrome in Norway (N = 43), we measured functional performance using the Pediatric Evaluation of Disability Inventory (PEDI). The study was a follow-up of a previous study of the same children at age 5 assessed using the same instrument. Data from both studies were used in the analysis. RESULTS: Forty percent of the sample of children with Down syndrome in Norway had entered elementary school after a 1-year postponement (i.e., at age 7). The functional performance skills of the children, as measured using the PEDI, were significantly lower at both age 5 and age 7 in self-care and social function compared with children with Down syndrome who entered elementary school at the usual time (i.e., at age 6). The main characteristics associated with postponed elementary school entry were found in communication skills and bladder and bowel management. CONCLUSION: A certain level of development and independence seems to be required for a child with Down syndrome to be viewed as ready to enter elementary school, and perceptions of readiness for school may be culturally dependent. In addition to the well-described challenges in language and communication skills, being viewed as ready for school includes having stopped using diapers, a topic not previously mentioned as a factor in postponing elementary school entry for children with Down syndrome. Awareness of culturally influenced performance skills may give direction to parents and professionals in targeting areas in the preschool years that might help promote these children's readiness for school.

Variability of the aging process in dementia-free adults with Down syndrome.

The aim of this cross-sectional study was to analyze the typical aging process in adults with Down syndrome, focusing on its variability. The sample comprised 120 adults with Down syndrome who were free of dementia. Ages ranged from 20 to 69 years. Each participant was assessed on cognitive functioning and social adaptation, and was checked for the presence of psychopathological disorders. Results revealed an age-related deterioration in both cognitive and social adaptation skills, the extent of this decline depending on the dimension under scrutiny, and interindividual variability in aging profiles.

Professionals' prognoses for individuals with mental retardation: search for consensus within interdisciplinary settings.

Previous studies have shown a lack of consensus in professionals' prognoses for individuals with mental retardation. The present study was designed to continue the investigation of professionals' prognoses for the achieved capabilities and residential and vocational placement of individuals with mild, moderate, or severe mental retardation. Four professional groups (N = 567 subjects) from 50 of the 52 University Affiliated Programs throughout the country were surveyed. The Prognostic Beliefs Scale was used. Results showed that physicians had significantly lower expectations and more pessimistic prognoses for children with moderate or severe mental retardation than did the other professionals. The only consensus on prognosis was for children with mild mental retardation. Results call into question one of the assumed benefits of interdisciplinary teams--communication--and its impact on professionals' expectations and prognoses for individuals with mental retardation.

An unclassifiable type of spondylo-peripheral epiphyseal dysplasia associated with 21 trisomy.

We present an unusual type of skeletal dysplasia in a 6 1/2 year-old female child with Down syndrome due to classical 21 trisomy. Differential diagnosis with the pseudoachrondroplastic forms of spondyloepiphyseal dysplasia shows that the epiphyseal changes in the present patient are unique and do not allow to classify the skeletal changes of the present patient in this group of disorders.

Parental perceptions of unmet dental need and cost barriers to care for developmentally disabled children.

PURPOSE: The purpose of this investigation was to describe and assess the disparities, if any, in parental perceived cost barriers to oral health care among developmentally disabled children using a national data set. METHODS: Data from the 1997 National Health Interview Survey (NHIS) were analyzed using a SUDAAN statistical package. RESULTS: After adjusting for age and sex, parental perception of unmet need was significantly associated with developmentally disabled children 2-17 years in lower socioeconomic groups. CONCLUSIONS: Though most children from lower socioeconomic groups are eligible for Medicaid coverage, parents of these children perceive cost barriers to dental care. Children with developmental disabilities face even more perceived barriers to care based on family income.

Factors affecting age of walking by children with mental retardation.

The relationship between age of walking and two factors of severity of intellectual disability and clinical types (autism, Down syndrome, epilepsy, and "residual") in children with mental retardation was investigated. Subjects were 118 children whose disabilities ranged from severe to mild. Measures by clinical type were significant, and the differences of any two clinical types except between children with epilepsy and the "residual" group were significant, but severity of intellectual disability was not significant. Most children with autism (27 subjects, 93%) walked by the normal time limit of 18 months. Only 3 children (11%) with Down syndrome began to walk within that limit, and 9 of them (33%) walked after 2 years of age. In the "residual" group (including children with epilepsy), 37 children (60%) walked within the normal limit but 15 (25%) only after 2 years of age.

Down syndrome diagnosis based on Gabor Wavelet Transform.

Down syndrome is a chromosomal condition caused by the presence of all or part of an extra 21st chromosome. It has different facial symptoms. These symptoms contain distinctive information for face recognition. In this study, a novel method is developed to distinguish Down Syndrome in a custom face database. Gabor Wavelet Transform (GWT) is used as a feature extraction method. Dimension reduction is performed with Principal Component Analysis (PCA). New dimension which has most valuable information is derived with Linear Discriminant Analysis (LDA). Classification process is implemented with k-nearest neighbor (kNN) and Support Vector Machine (SVM) methods. The classification accuracy is carried out 96% and 97,34% with kNN and SVM methods, respectively. Different from the studies related with the Down Sydrome, feature selection process is applied before PCA according to the correlation between components of feature vectors. Best results are achieved with euclidean distance metric for kNN and linear kernel type for SVM. In this way, we developed an efficient system to recognize Down syndrome.