Cost-effectiveness of prenatal screening and diagnostic strategies for Down syndrome: A microsimulation modeling analysis.

OBJECTIVES: Down syndrome (DS) is the most frequently occurring fetal chromosomal abnormality and different prenatal screening strategies are used for determining risk of DS worldwide. New non-invasive prenatal testing (NIPT), which uses cell-free fetal DNA in maternal blood can provide benefits due to its higher sensitivity and specificity in comparison to conventional screening tests. This study aimed to assess the cost-effectiveness of using population-level NIPT in fetal aneuploidy screening for DS. METHODS: We developed a microsimulation decision-analytic model to perform a probabilistic cost-effectiveness analysis (CEA) of prenatal screening and diagnostic strategies for DS. The model followed individual simulated pregnant women through the pregnancy pathway. The comparators were serum-only screening, contingent NIPT (i.e., NIPT as a second-tier screening test) and universal NIPT (i.e., NIPT as a first-tier screening test). To address uncertainty around the model parameters, the expected values of costs and quality-adjusted life-years (QALYs) in the base case and all scenario analyses were obtained through probabilistic analysis from a Monte Carlo simulation. RESULTS: Base case and scenario analyses were conducted by repeating the micro-simulation 1,000 times for a sample of 45,605 pregnant women per the population of British Columbia, Canada (N = 4.8 million). Preliminary results of the sequential CEAs showed that contingent NIPT was a dominant strategy compared to serum-only screening. Compared with contingent NIPT, universal NIPT at the current test price was not cost-effective with an incremental cost-effectiveness ratio over $100,000/QALY. Contingent NIPT also had the lowest cost per DS case detected among these three strategies. CONCLUSION: Including NIPT in existing prenatal screening for DS is shown to be beneficial over conventional testing. However, at current prices, implementation of NIPT as a second-tier screening test is more cost-effective than deploying it as a universal test.

Methylomic profiling in trisomy 21 identifies cognition- and Alzheimer's disease-related dysregulation.

BACKGROUND: Trisomy 21 (T21) is associated with intellectual disability that ranges from mild to profound with an average intellectual quotient of around 50. Furthermore, T21 patients have a high risk of developing Alzheimer's disease (AD) early in life, characterized by the presence of senile plaques of amyloid protein and neurofibrillary tangles, leading to neuronal loss and cognitive decline. We postulate that epigenetic factors contribute to the observed variability in intellectual disability, as well as at the level of neurodegeneration seen in T21 individuals. MATERIALS AND METHODS: A genome-wide DNA methylation study was performed using Illumina Infinium® MethylationEPIC BeadChips on whole blood DNA of 3 male T21 patients with low IQ, 8 T21 patients with high IQ (4 males and 4 females), and 21 age- and sex-matched control samples (12 males and 9 females) in order to determine whether DNA methylation alterations could help explain variation in cognitive impairment between individuals with T21. In view of the increased risk of developing AD in T21 individuals, we additionally investigated the T21-associated sites in published blood DNA methylation data from the AgeCoDe cohort (German study on Ageing, Cognition, and Dementia). AgeCoDe represents a prospective longitudinal study including non-demented individuals at baseline of which a part develops AD dementia at follow-up. RESULTS: Two thousand seven hundred sixteen differentially methylated sites and regions discriminating T21 and healthy individuals were identified. In the T21 high and low IQ comparison, a single CpG located in the promoter of PELI1 was differentially methylated after multiple testing adjustment. For the same contrast, 69 differentially methylated regions were identified. Performing a targeted association analysis for the significant T21-associated CpG sites in the AgeCoDe cohort, we found that 9 showed significant methylation differences related to AD dementia, including one in the ADAM10 gene. This gene has previously been shown to play a role in the prevention of amyloid plaque formation in the brain. CONCLUSION: The differentially methylated regions may help understand the interaction between methylation alterations and cognitive function. In addition, ADAM10 might be a valuable blood-based biomarker for at least the early detection of AD.

Aberrant Oligodendrogenesis in Down Syndrome: Shift in Gliogenesis?

Down syndrome (DS), or trisomy 21, is the most prevalent chromosomal anomaly accounting for cognitive impairment and intellectual disability (ID). Neuropathological changes of DS brains are characterized by a reduction in the number of neurons and oligodendrocytes, accompanied by hypomyelination and astrogliosis. Recent studies mainly focused on neuronal development in DS, but underestimated the role of glial cells as pathogenic players. Aberrant or impaired differentiation within the oligodendroglial lineage and altered white matter functionality are thought to contribute to central nervous system (CNS) malformations. Given that white matter, comprised of oligodendrocytes and their myelin sheaths, is vital for higher brain function, gathering knowledge about pathways and modulators challenging oligodendrogenesis and cell lineages within DS is essential. This review article discusses to what degree DS-related effects on oligodendroglial cells have been described and presents collected evidence regarding induced cell-fate switches, thereby resulting in an enhanced generation of astrocytes. Moreover, alterations in white matter formation observed in mouse and human post-mortem brains are described. Finally, the rationale for a better understanding of pathways and modulators responsible for the glial cell imbalance as a possible source for future therapeutic interventions is given based on current experience on pro-oligodendroglial treatment approaches developed for demyelinating diseases, such as multiple sclerosis.

A candidate gene analysis and GWAS for genes associated with maternal nondisjunction of chromosome 21.

Human nondisjunction errors in oocytes are the leading cause of pregnancy loss, and for pregnancies that continue to term, the leading cause of intellectual disabilities and birth defects. For the first time, we have conducted a candidate gene and genome-wide association study to identify genes associated with maternal nondisjunction of chromosome 21 as a first step to understand predisposing factors. A total of 2,186 study participants were genotyped on the HumanOmniExpressExome-8v1-2 array. These participants included 749 live birth offspring with standard trisomy 21 and 1,437 parents. Genotypes from the parents and child were then used to identify mothers with nondisjunction errors derived in the oocyte and to establish the type of error (meiosis I or meiosis II). We performed a unique set of subgroup comparisons designed to leverage our previous work suggesting that the etiologies of meiosis I and meiosis II nondisjunction differ for trisomy 21. For the candidate gene analysis, we selected genes associated with chromosome dynamics early in meiosis and genes associated with human global recombination counts. Several candidate genes showed strong associations with maternal nondisjunction of chromosome 21, demonstrating that genetic variants associated with normal variation in meiotic processes can be risk factors for nondisjunction. The genome-wide analysis also suggested several new potentially associated loci, although follow-up studies using independent samples are required.

Epigenome-wide base-resolution profiling of DNA methylation in chorionic villi of fetuses with Down syndrome by methyl-capture sequencing.

BACKGROUND: Epigenetic mechanisms provide an interface between environmental factors and the genome and are influential in various diseases. These mechanisms, including DNA methylation, influence the regulation of development, differentiation, and establishment of cellular identity. Here, we performed high-throughput methylome profiling to determine whether differential patterns of DNA methylation correlate with Down syndrome (DS). MATERIALS AND METHODS: We extracted DNA from the chorionic villi cells of five normal and five DS fetuses at the early developmental stage (12-13 weeks of gestation). Methyl-capture sequencing (MC-Seq) was used to investigate the methylation levels of CpG sites distributed across the whole genome to identify differentially methylated CpG sites (DMCs) and regions (DMRs) in DS. New functional annotations of DMR genes using bioinformatics tools were predicted. RESULTS: DNA hypermethylation was observed in DS fetal chorionic villi cells. Significant differences were evident for 4,439 DMCs, including hypermethylation (n = 4,261) and hypomethylation (n = 178). Among them, 140 hypermethylated DMRs and only 1 hypomethylated DMR were located on 121 genes and 1 gene, respectively. One hundred twenty-two genes, including 141 DMRs, were associated with heart morphogenesis and development of the ear, thyroid gland, and nervous systems. The genes were significantly associated with DS and various diseases, including hepatopulmonary syndrome, conductive hearing loss, holoprosencephaly, heart diseases, glaucoma, and musculoskeletal abnormalities. CONCLUSIONS: This is the first study to compare the whole-epigenome DNA methylation pattern of the chorionic villi cells from normal and DS fetuses at the early developmental-stage using MC-seq. Overall, our results indicate that the chorionic villi cells of DS fetuses are hypermethylated in all autosomes and suggested that altered DNA methylation may be a recurrent and functionally relevant downstream response to DS in human cells. This study provides basic information for future research focused on the pathophysiology of the DS and its potential effects, as well as the role DNA methylation plays in the early developmental stage of DS fetuses.

Adaptation of the Clinical Dementia Rating Scale for adults with Down syndrome.

BACKGROUND: Adults with Down syndrome (DS) are at increased risk for Alzheimer disease dementia, and there is a pressing need for the development of assessment instruments that differentiate chronic cognitive impairment, acute neuropsychiatric symptomatology, and dementia in this population of patients. METHODS: We adapted a widely used instrument, the Clinical Dementia Rating (CDR) Scale, which is a component of the Uniform Data Set used by all federally funded Alzheimer Disease Centers for use in adults with DS, and tested the instrument among 34 DS patients recruited from the community. The participants were assessed using two versions of the modified CDR-a caregiver questionnaire and an in-person interview involving both the caregiver and the DS adult. Assessment also included the Dementia Scale for Down Syndrome (DSDS) and the Raven's Progressive Matrices to estimate IQ. RESULTS: Both modified questionnaire and interview instruments captured a range of cognitive impairments, a majority of which were found to be chronic when accounting for premorbid function. Two individuals in the sample were strongly suspected to have early dementia, both of whom had elevated scores on the modified CDR instruments. Among individuals rated as having no dementia based on the DSDS, about half showed subthreshold impairments on the modified CDR instruments; there was substantial agreement between caregiver questionnaire screening and in-person interview of caregivers and DS adults. CONCLUSIONS: The modified questionnaire and interview instruments capture a range of impairment in DS adults, including subthreshold symptomatology, and the instruments provide complementary information relevant to the ascertainment of dementia in DS. Decline was seen across all cognitive domains and was generally positively related to age and negatively related to IQ. Most importantly, adjusting instrument scores for chronic, premorbid impairment drastically shifted the distribution toward lower (no impairment) scores.

Cerebrospinal fluid and blood Aß levels in Down syndrome patients with and without dementia: a meta-analysis study.

Abnormal ß-amyloid (Aß) levels were found in patients with Down syndrome (DS). However, Aß levels in patients with DS and DS with dementia (DSD) vary considerably across studies. Therefore, we performed a systematic literature review and quantitatively summarized the clinical Aß data on the cerebrospinal fluid (CSF) and blood of patients with DS and those with DSD using a meta-analytical technique. We performed a systematic search of the PubMed and Web of Science and identified 27 studies for inclusion in the meta-analysis. Random-effects meta-analysis indicated that the levels of blood Aß1-40 and Aß1-42 were significantly elevated in patients with DS compared with those in healthy control (HC) subjects. In contrast, there were no significant differences between patients with DS and those with DSD in the blood Aß1-40 and Aß1-42 levels. The CSF Aß1-42 levels were significantly decreased in patients with DS compared to those in HC subjects. Further, CSF Aß1-42 levels were significantly decreased in patients with DSD compared to those with DS, with a large effect size. Taken together, our results demonstrated that blood Aß1-40 and Aß1-42 levels were significantly increased in patients with DS while CSF Aß1-42, but not Aß1-40 levels were significantly decreased in patients with DS.

Tratamiento temprano de alteraciones orofaciales con fisioterapia y placa palatina en niños con síndrome de Down / Early treatment of orofacial alterations with physical therapy and palatal plate in children with Down syndrome

El Síndrome de Down (SD) o trisomía 21, es la anomalía congénita autosómica más frecuente cuya prevalencia mundial es de 10/10.000, en Chile de 2,5/1.000 nacidos vivos. Por trastornos de crecimiento, desarrollo e hipotonía muscular, las personas con SD presentan boca abierta con gran salivación, labio inferior evertido, elevación del labio superior en inactividad y descenso del ángulo de la boca. Objetivo: Evaluar la literatura sobre el tratamiento temprano de alteraciones orofaciales en niños con SD para prevenirlas o minimizarlas. Método: Búsqueda en base de datos PubMed y Scielo, sin discriminar año de publicación, idioma: inglés-español, seleccionando 26 artículos. Resultados: Existen cambios positivos en la función motora orofacial, observando mayores cambios en los casos más severos. Conclusiones: Un niño con SD se beneficia del tratamiento temprano, pero faltan estudios comparables en cuanto a duración, edad y tipo de terapia.

Down syndrome (DS) or trisomy 21 is the most frequent autosomal congenital anomaly, with a worldwide prevalence of 10/10,000; in Chile, the prevalence is 2.5/1,000 live births. People with DS present an open mouth with increased salivation, an everted lower lip, elevated and inactive upper lip, and lowering of the angle of the mouth on account of growth and development disorders, and muscular hypotonia. Objective: To evaluate the literature on the early treatment of orofacial alterations in children with DS to prevent or minimize them. Method: Search in PubMed and Scielo databases, regardless of the year of publication or language; 26 articles were selected. Results: There are positive effects on the orofacial motor function, observing significant changes in the most severe cases. Conclusions: A child with DS can benefit from early treatment, but there are insufficient comparable studies in terms of duration, age and type of therapy

A síndrome de Down (SD) ou a trissomia do cromossomo 21, é a anomalia congênita autossômica mais frequente, com prevalência global de 1 / 1.000, no Chile de 2.5 / 1.000 nascidos vivos. Devido aos distúrbios de crescimento, desenvolvimento e hipotonia muscular, as pessoas com SD apresentam boca aberta com grande salivação, lábio inferior evertido, elevação do lábio superior inativo e ângulo da boca mais baixo. Objetivo: Avaliar a literatura sobre o tratamento precoce dos distúrbios orofaciais em crianças com SD para prevenilas ou minimizá-las. Método: Pesquisa na base de dados PubMed e Scielo, sem discriminar ano de publicação, idioma: inglês-espanhol, selecionando 26 artigos. Resultados: Existem mudanças positivas na função motora orofacial, observando-se grandes alterações nos casos mais graves. Conclusões: Uma criança com SD se beneficia do tratamento precoce, mas faltam estudos comparáveis em termos de duração, idade e tipo de terapia.

Enfermedad celíaca en niños con síndrome de Down / Celiac disease in children with Down syndrome

INTRODUCCIÓN: La enfermedad celíaca (EC) en niños con síndrome de Down (SD) ha sido publicada por varios paí ses, sin que existan datos para Colombia. OBJETIVO: Determinar la frecuencia y factores relacionados de EC en niños con SD, comparado con un grupo de niños sin SD, analizando las manifestaciones clínicas, inmunológicas y genéticas. PACIENTES Y MÉTODO: Fueron estudiados 209 niños, 1-18 años de edad (8,4 ± 4,1 años; 55,5% sexo femenino): 97 con SD y 112 sin SD usando como marcador serológico los anticuerpos anti-transglutaminasa (tTG2); se estudiaron variables de edad, genero, raza, ori gen, peso, talla y síntomas digestivos. A los niños con tTG2 positivos, se les realizó biopsia duodenal y genotipo. Se estimó la proporción de niños con SD, sin SD y EC y su IC95%; medidas de tendencia central, análisis univariado y bivariado, siendo significativa una p < 0,05. RESULTADOS: Ocho niños con SD (8,2%) y 5 niños sin SD (4,5%) fueron tTG2 positivos (p = 0,200). Ninguno presentó deficiencia de IgA sérica. Un niño con SD presentó EC con Marsh II (1,0%); y 2 niños con SD (2,1%) y 2 sin SD (1,8%), presentaron EC potencial (p = 0,432). Tres niños fueron HLA-DQ2. Hubo mayor opor tunidad de presentar EC en el grupo de pre-escolares (OR = 6,14 IC95% = 0,41-87,35 p = 0,0462). CONCLUSIONES: La frecuencia de EC por biopsia intestinal en estos niños con SD es muy inferior a lo relatado en la literatura, estando asociada al pre-escolar, y siendo su principal alelo el DQ2, hallazgos similares a lo descrito a nivel mundial.

INTRODUCTION: Celiac disease (CD) in children with Down syndrome (DS) has been published by several countries, without available data for Colombia. OBJECTIVE: To determine the frequency and related factors of CD in children with DS, compared with a group of children without DS, analyzing the clinical, im munological, and genetic manifestations. PATIENTS AND METHOD: A total of 209 children between 1-18 years of age (8.4 ± 4.1 years, 55.5% female) were studied, 97 with DS and 112 without DS, using anti-transglutaminase antibodies as serological marker (tTG2). Variables of age, gender, race, ori gin, weight, height, and digestive symptoms were studied. Children with positive tTG2 underwent duodenal biopsy and genotype. The proportion of children with DS, without DS, and CD was esti mated and their 95% CI; measures of central tendency, univariate and bivariate analysis, considering a p < 0.05 significant. RESULTS: Eight children with DS (8.2%) and five children without DS (4.5%) were tTG2 positive (p = 0.200). None presented serum IgA deficiency. One child with DS presented CD with Marsh II (1.0%), and two children with DS (2.1%) and two without DS (1.8%), presen ted potential CD (p = 0.432). Three children were HLA-DQ2. CD was more likely in the preschool group (OR = 6.14 95%CI = 0.41-87.35 p = 0.0462). CONCLUSIONS: The CD frequency due to intestinal biopsy in children with DS is much lower than that reported in the literature, being associated with preschool, and having DQ2 as its main allele. These findings are similar to those described worldwide.

Limitaciones sociales en los derechos a la sexualidad de las personas con síndrome de Down / Limitações sociais nos direitos à sexualidade das pessoas com síndrome de Down / Social limitations in the sexuality rights of people with Down syndrome

Resumen La sexualidad es un proceso complejo, especialmente cuando se habla de personas con síndrome de Down. Por ello, el objetivo de este trabajo fue identificar las limitaciones sociales en el ejercicio de los derechos a la sexualidad de esta población. La revisión incluyó información de publicaciones de los años 2006 a 2019, de España, Argentina y Colombia. El análisis arrojó que entre las mayores limitaciones que condicionan la satisfacción de las necesidades afectivas y sexuales de las personas con síndrome de Down, se encuentran el trato infantil, la sobreprotección de sus familias, la reprensión y control excesivo, coerción de su autodeterminación y ausencia de una educación sexual; factores que limitan una inclusión real en la sociedad, pues consideran que son seres asexuados o por el contrario que su exacerbación sexual debe ser inhibida o controlada. Además, varios autores manifiestan que la educación para la sexualidad no se brinda desde la niñez, por miedo a despertar deseos que no se puedan controlar, situación que termina por coaccionar su desarrollo como persona, su inclusión social, el desarrollo de su calidad de vida y ser sujeto de derechos y deberes.

Resumo A sexualidade é um processo complexo, principalmente quando se fala de pessoas com síndrome de Down, portanto, o objetivo deste trabalho é identificar as limitações sociais no exercício dos direitos à sexualidade dessa população. A revisão inclui informações sobre publicações de 2006 a 2019, da Espanha, Argentina e Colômbia. A análise mostra que entre as principais limitações que condicionam a satisfação das necessidades emocionais e sexuais das pessoas com síndrome de Down, estão o tratamento infantil, superproteção de suas famílias, repressão e controle excessivo, coerção de sua autodeterminação e ausência de uma educação sexual; fatores que limitam uma inclusão real na sociedade, que os considera seres assexuais ou, pelo contrário, que sua exacerbação sexual deve ser inibida ou controlada. Além disso, vários autores afirmam que a educação para a sexualidade não é fornecida desde a infância, por medo de despertar desejos que não podem ser controlados, situação que acaba coagindo seu desenvolvimento como pessoa, sua inclusão social, o desenvolvimento de sua qualidade de vida e estar sujeito a direitos e deveres.

Abstract Sexuality is a complex process, especially when related to people with Down syndrome. This work identifies social limitations in this population's exercise of sexual rights. The review includes information from publications of the years 2006-2019 in Spain, Argentina and Colombia. The greatest constraints on the emotional and sexual needs of people with Down syndrome are their infantilization, overprotection from families, excessive repression and control, coercion of self-determination, and absence of sex education; factors that limit their real inclusion in society, which considers them asexual beings or that their sexual exacerbation must be inhibited or controlled. In addition, several authors state that sexual education is not provided, since childhood, for fear of arousing desires that cannot be controlled, a situation that ends up coercing their development as a person, their social inclusion, the development of a quality of life, and being subjects of rights and duties.

Prevalencia al nacimiento de síndrome de Down, según edad materna en Costa Rica, 1996-2016 / Birth prevalence of Down syndrome according maternal age in Costa Rica, 1996-2016

Resumen Justificación: El síndrome de Down es la cromosomopatía más frecuente en Costa Rica y el mundo, así como la principal causa de discapacidad intelectual. La edad materna avanzada es el mayor factor de riesgo conocido para este padecimiento. El objetivo fue conocer la tendencia de síndrome de Down en nacidos vivos, según edad materna en Costa Rica. Métodos: Se realizó un estudio observacional de prevalencias de todos los casos de síndrome de Down nacidos vivos en Costa Rica entre 1996-2016, reportados al Centro Nacional de Registro de Enfermedades Congénitas, programa nacional de vigilancia de los defectos congénitos. Se determinó la tendencia y prevalencia en nacidos vivos según edad materna: < 20, 20-34 y 35 años o más, y según período: 1996-2007 y 2008-2016. Se realizó una regresión de Poisson, tomando como referencias el grupo 20-34 años y 1996-2002, y se compararon estimados mediante chi cuadrado de Wald. Se calculó la razón de prevalencias en madres ≥35 años y la fracción atribuible poblacional para este estrato. Por último, se comparó la tendencia del síndrome de Down con la tendencia de la tasa de fecundidad específica en madres ≥35 años en el país, para el período en estudio. Resultados: Para 1996-2016, la prevalencia de síndrome de Down en nacidos vivos fue de 1,02 x 1000 (IC95 %: 0,97-1,07). Hubo un aumento significativo de 0,91 (1996-2007) a 1,16 x 1000 (2008-2016), a expensas de la prevalencia en madres ≥35 años, la cual aumentó de 4,27 a 5,44 x 1000; mientras que la tasa de fecundidad en estas madres cayó significativamente de 20,15 x 1000 (IC95 %: 20,02-20,28) en 1996-2007, a 15,58 x 1000 (IC95 % 15,46-15,70) para o 2008-2016. La edad materna media en SD fue de 32,2 años, contra 25,5 años para la población general (p≤0,001). La razón de prevalencia ajustada por período, en madres de ≥35 años, contra madres de 20-34 años fue de 8,05 (IC95 % 7,25-8,95) y la fracción atribuible poblacional del 41,22 %. Conclusiones: La prevalencia al nacimiento de síndrome de Down en Costa Rica aumentó a expensas de la prevalencia en madres ≥35 años, pese a que la tasa de fecundidad específica en esas mujeres cayó significativamente. La inclusión del Hospital Nacional de Niños como institución de referencia nacional para este síndrome, dentro de la red de vigilancia de los defectos congénitos, pudo ser un factor determinante en el aumento de la prevalencia.

Abstract Justification: Down syndrome is the most frequent chromosomopathy in Costa Rica and the world, as well as the main cause of intellectual disability. Advanced maternal age is the main known risk factor for this condition. The objective was to know the trend of Down syndrome in live births according to maternal age in Costa Rica. Methods: A prevalence study was made of all Down syndrome cases, born alive in Costa Rica from 1996 to 2016 and reported to the Costa Rican Births Defects Register Center, a national program for the monitoring of congenital defects. The trend and prevalence in live births was determined, according to maternal age: <20, 20-34 and 35 years or more, and according to period: 1996-2007 and 2008-2016. A Poisson regression was carried out, taking as references the group 20-34 years and the period 1996-2002 and the results were compared Wald's chi-square. The prevalence ratio in mothers ≥35 years and the population attributable fraction was calculated for this stratum. Finally, the trend of Down syndrome was compared with the trend of the specific fertility rate in mothers ≥35 years. Results: For 1996-2016 the prevalence of Down syndrome in live births was 1.02 x 1000 (95% CI: 0.97-1.07). There was a significant increase from 0.91 (1996-2007) to 1.16 x 1000 (2008-2016), at the expense of the prevalence in mothers ≥35 years, which increased from 4.27 to 5.44 x 1000; while the fertility rate in these mothers fell significantly from 20.15 x 1000 (95% CI: 20.02-20.28) in 1996-2007, to 15.58 x 1000 (95% CI 15.46-15.70) in 2008-2016. Maternal age mean MS in SD was 32.2 years, versus 25.5 years in the general population (p≤0.001). The prevalence ratio adjusted by period, in mothers of ≥35 years, against mothers of 20-34 years was of 8.05 (95% CI 7.25-8.95) and the population attributable fraction was 41.22%. Conclusions: The livebirth`s prevalence of Down syndrome in Costa Rica increased for the study period, at the expense of prevalence in mothers ≥35 years, although the specific fertility rate in these women fell significantly. The inclusion of the National Children's Hospital - as a national reference institution for this syndrome - within the surveillance network of congenital defects, could be a determining factor in in prevalence rise.

Trisomía del par XXI: Características estomatognáticas / Trisomy pair XXI: Stomatognathic characteristics

El síndrome de Down (SD) es un trastorno genético que se caracteriza por la presencia de un grado variable de discapacidad cognitiva, rasgos y características físicas peculiares, que también, repercuten a nivel estomatognático. Los autores presentamos un estudio clínico y descriptivo, detallando las características odontológicas y estomatognáticas más prevalentemente diagnosticadas en ochenta (80) pacientes que presentan SD, atendidos durante el lapso de 2 años en el consultorio externo del Hospital Bollini, ubicado en el Instituto Psicopedagógico Especial de la Ciudad de La Plata. Nuestro objetivo fue evaluar las manifestaciones clínico­epidemiológicas del paciente con SD, y cómo estas repercuten en el funcionamiento y estructura del sistema estomatognático

Down syndrome (DS) is a genetic disorder characterized by the presence of a variable degree of cognitive disability, features and peculiar physical characteristics, affecting them at the stomatognathic level. We present a clinical and descriptive study, detailing the dental and stomatognathic characteristics most prevalently diagnosed in 80 eighty patients with SD, treated during a period of 2 years in the outpatient clinic of Hospital Bollini, located in The Special Psycopedagogical Institute of the city of La Plata Our the objetive was evaluate the clinical and epidemiological manifestastations of the patient's of SD, and how these affect functioning and structure of the stomatognatic system

Assessment of the Technique of Breastfeeding in Babies with Down Syndrome / Valoración de la técnica de amamantamiento en bebés con síndrome de Down / Avaliação da técnica de amamentação em bebês com síndrome de Down

ABSTRACT Objective: To evaluate the technique and duration of breastfeeding in healthy children and children with Down Syndrome (DS) using the breastfeeding observation form. Materials and methods: An observational study of a prospective cohort was carried out at the Clinical Hospital of Granada during 2015. The Study Group consisted of 40 children with DS and the control group was formed by each new-born with DS and a healthy new-born with the same characteristics of weight and gestational age was selected. The new-borns evaluated shared housing with the mother where the technique was valued during the first 5 days postpartum by a health professional. A bivariable analysis was performed to compare the groups using Student's T test for numerical variables and chi-square for categorical variables. Results: Lactogenesis onset was earlier in the DS group (92.5 % in the first 24 hours vs 20 %; p <0.001). It was observed that 60 % of the healthy children were breastfed for more than three months while in the group of babies with DS this time period was 47.5 %. Conclusions: The results of this study reveal that the breastfeeding technique presented at the beginning more difficulties in mothers of children with DS and it has been shown that technical errors influence the onset and duration of breastfeeding in mothers of these children.

RESUMEN Objetivo: evaluar la técnica y la duración de la lactancia materna (LM) en niños sanos y en niños con síndrome de Down (SD), a través del Formulario de observación del amamantamiento. Materiales y métodos: se realizó un estudio observacional de cohorte prospectivo en el Hospital Clínico de Granada, a finales de 2015. El grupo de estudio estuvo constituido por cuarenta pacientes con SD, y el grupo control se conformó por niños recién nacidos con dicha alteración y, en la misma cantidad, por niños sanos, con las mismas características de peso y edad gestacional. Los recién nacidos evaluados estuvieron en una habitación conjunta con la madre, donde el personal sanitario valoró la técnica durante los primeros cinco días posparto. Se realizó un análisis bivariante para comparar los grupos, utilizando el test t de Student para las variables numéricas, y el chi-cuadrado, para las categóricas. Resultados: la lactogénesis se produjo primero en el grupo sin SD (92,5 % en las primeras 24 horas vs 20 %; p<0,001). Se observó que el 60 % de los niños sanos mantuvieron la LM por más de tres meses, mientras que el grupo de bebés con SD logró en este tiempo el 47,5%. Conclusiones: la LM presentó, al inicio, más dificultades en las madres de niños con SD. Los errores técnicos influyen en el inicio y en el mantenimiento de la LM en las madres de estos niños.

RESUMO Objetivo: avaliar a técnica e a duração do aleitamento materno em crianças saudáveis ​​e crianças com síndrome de Down (SD), com a utilização do formulário de observação do aleitamento materno. Materiais e métodos: estudo de coorte prospectivo observacional, realizado no Hospital Clínico de Granada, em 2015. O grupo de estudo foi composto por 40 pacientes com SD e o grupo controle formado por recém-nascidos com essa alteração e com crianças saudáveis, considerando as mesmas características de peso e idade gestacional. Os recém-nascidos avaliados estavam em um quarto conjunto com a mãe, onde a técnica foi avaliada durante os primeiros cinco dias pós-parto pela equipe médica. Uma análise bivariada foi realizada para comparar os grupos, utilizando o teste t de Student para as variáveis numéricas e o qui-quadrado para as variáveis categóricas. Resultados: a lactogênese ocorreu primeiramente no grupo sem SD (92,5 % nas primeiras 24 horas vs 20 %; p <0,001). Tornou-se evidente que 60 % das crianças saudáveis mantiveram a amamentação por mais de três meses, enquanto no grupo de bebês com SD, esse tempo foi de 47,5 %. Conclusões: os resultados deste estudo revelam que a técnica de amamentação apresentou no início mais dificuldades em mães de crianças com SD e demonstrou que erros técnicos influenciam o início e a manutenção do aleitamento materno em mães dessas crianças.

Síndrome de Down y su pesquisa durante el primer trimestre de la gestación / Down Syndrome and Screening During Pregnancy First Trimester

RESUMEN Introducción: La pesquisa prenatal de anomalías cromosómicas, mediante el uso de marcadores epidemiológicos y ecográficos del primer trimestre permite identificar gestantes con riesgo incrementado de síndrome de Down. Objetivos: Analizar la edad materna, la translucencia nucal, el ductus venoso y el hueso nasal, durante el cribaje del primer trimestre, en las gestantes que se realizaron diagnóstico prenatal citogenético, con el fin de evaluar la efectividad del mismo en la detección temprana del síndrome Down y su utilidad para la reducción del número de pruebas invasivas. Métodos: Se realizó un estudio descriptivo retrospectivo de corte transversal y se analiza una muestra de 3439 gestantes a las que se realizó el estudio citogenético indicado en el Centro Provincial de Genética Médica de La Habana, en el período comprendido entre el 3 de enero de 2006 y el 30 de diciembre de 2008. Resultados: La edad materna avanzada mostró una sensibilidad de un 87 por ciento del test y una tasa de falsos positivos de 99 por ciento. La translucencia nucal se comportó con una sensibilidad de 10 por ciento. El hueso nasal no mostró asociación con los cariotipos positivos para síndrome de Down. Al no realizarse sistemáticamente la presencia del ductus venoso, no se pudo establecer una asociación estadística. La estimación de riesgo de síndrome de Down basada únicamente en la edad materna avanzada determina una alta tasa de falsos positivos. Por lo que este marcador, unido a la evaluación de los marcadores ecográficos del primer trimestre para recalcular el riesgo individual, puede aumentar la efectividad en el diagnóstico y disminuir el número de pruebas invasivas. Conclusiones: La estimación de riesgo de síndrome de Down basada únicamente en la edad materna avanzada determina una alta tasa de falsos positivos. Por lo que este marcador, unido a la evaluación de los marcadores ecográficos del primer trimestre para recalcular el riesgo individual, puede aumentar la efectividad en el diagnóstico y disminuir el número de pruebas invasivas(AU)

ABSTRACT Introduction: The prenatal investigation of chromosomal abnormalities through the use of epidemiological and echographic markers on the first trimester, allows to identify pregnant women with an increased risk of Down syndrome. Objectives: To analyze maternal age, nuchal translucency, venous ductus and nasal bone, during the first trimester screening, in pregnant women who underwent prenatal cytogenetic diagnosis, in order to evaluate effectiveness in early detection of Down syndrome and the value for reducing the number of invasive tests. Methods: A descriptive retrospective cross-sectional study was carried out and a sample of 3439 pregnant women was studied. The cytogenetic study ordered at Havana Provincial Center for Medical Genetics was carried out from January 3, 2006 to December 30, 2008. Results: Advanced maternal age showed 87 percent sensitivity and 99 percent of false positive rate. Nuchal translucency accounted 10 percent of sensitivity. The nasal bone showed no association with positive karyotypes for Down syndrome. A statistical association of the venous ductus presence could not be established since the search was not systematically. Conclusions: The estimation of Down syndrome risk based solely on advanced maternal age determines high false positive rate. Therefore, this marker, together with the evaluation of the first trimester ultrasound markers for recalculating the individual risk, can increase the diagnostic effectiveness and decrease the number of invasive tests(AU)

La ética en la comunicación del diagnóstico de síndrome de Down / Ethics in the communication of down syndrome diagnosis

La comunicación del diagnóstico de síndrome de Down tiene serias implicaciones éticas ya que la finalidad del mismo puede ser eugenésica o terapéutica. El objetivo de este artículo es, por un lado, resaltar el papel fundamental que desempeñan los profesionales sanitarios en la comunicación del diagnóstico y la posterior decisión de la madre. Por otra parte, se exponen las recomendaciones sobre la manera de comunicar un diagnóstico. Por último, se analiza el estado de la cuestión en España, para lo que se exponen los resultados de un estudio descriptivo transversal con una muestra de 352 madres en la que expresan, mediante una encuesta, sus experiencias personales sobre como han recibido la noticia. La conclusión a la que se llega es que la comunicación del diagnóstico de síndrome de Down se puede mejorar en muchos aspectos

Down Syndrome diagnosis communication has got serious ethical implications, since the aim thereof can be either eugenic or therapeutic. The purpose of this paper is, on the one hand, to highlight the fundamental role which sanitary professionals play in diagnosis communication and the subsequent decision of the mother. On the other, recommendations on the way to communicate a diagnosis are set out. Finally, in order to analize the state of play in Spain the results of a cross-sectional descriptive study with a sample of 352 mothers are exposed. In this study the mothers express, by means of a survey, their personal experiences of how they have received the news. It is concluded that the communication of Down syndrome diagnosis can be improved in many aspects

Diagnóstico prenatal de anomalías cromosómicas / Prenatal diagnosis of chromosomal abnormalities

INTRODUCCION: Las anomalías cromosómicas son alteraciones en los cromosomas sexuales o de los autosomas que pueden ser estructurales o numéricas. El Síndrome de Down o trisomía 21 es una de las anomalías cromosómicas más frecuentes, donde el 95% de las afecciones se deben a una trisomía completa. Estas alteraciones generan un importante aumento de la morbimortalidad, por lo cual es importante conocer factores de riesgo y sospecharlas prenatalmente. Los métodos más utilizados para el screening prenatal de estas anomalías son los marcadores serológicos y las pruebas de imágenes ecográficas. Otras pruebas de diagnóstico prenatal no invasivas que se pueden utilizar se basan en la detección ADN fetal que circula libremente en plasma materno. METODOLOGÍA: A partir de un escenario clínico se planteó una pregunta clínica estructurada. Se realizó una búsqueda bibliográfica en Pubmed con el objetivo de encontrar un artículo que pueda responder a nuestro interrogante sobre si el estudio del ADN fetal circulante en comparación con el screening combinado es un método diagnóstico más sensible y específico para puede detectar el Síndrome de Down. Se seleccionó el siguiente artículo: "Cell-free DNA Analysis for Noninvasive Examination of Trisomy". ANALISIS DEL ARTICULO: Para poder responder a nuestra pregunta clínica estructurada, se realizó un análisis secundario de los datos de las distintas variables calculando los valores de sensibilidad (S), especificidad (E), valor predictivo positivo (VPP), valor predictivo negativo (VPN) y su respectivo intervalo de confianza del 95% (IC 95%). Destacamos también el resultado del área bajo la curva (ABC) de la curva ROC (Receiver Operating Characteristic). CONCLUSIÓN: el screening con ADN fetal presenta una mayor sensibilidad y especificidad frente al screening combinado (ecografía y pruebas bioquímicas) para el diagnóstico del Síndrome de Down. Pero su elevado costo implica aún un limitante a resolver. (AU)

INTRODUCTION: Chromosomal abnormalities are alterations in sex or autosomes chromosomes, they can be structural or numerical. Down syndrome or trisomy 21 is one of the most frequent chromosomal abnormalities, where 95% of the conditions are due to a complete trisomy. These alterations produces a significant increase in morbidity and mortality, it is important to know risk factors and suspect them prenatally. The most used methods for prenatal screening of these abnormalities are serological markers and ultrasound imaging tests. The detection of fetal DNA that circulates freely in maternal plasma is an other non-invasive prenatal diagnostic tests that can be used. METHODOLOGY: A structured clinical question was raised from a clinical setting. A bibliographic search was conducted in Pubmed in order to finding an article that could answer our structured question about if the study of circulating fetal DNA compared to combined screening is a more sensitive and specific diagnostic method to detect Down syndrome. The article whose title is: "Cell-free DNA Analysis for Noninvasive Examination of Trisomy", was selected.Analysis of the article: In order to answer our structured clinical question, a secondary analysis was performed to calculate sensitivity (S), specificity (E), positive predictive value (VPP), negative predictive value ( NPV) and its respective 95% confidence interval (95% CI). We also highlight the result of the area under the curve (ABC) of the ROC (Receiver Operating Characteristic) curve. CONCLUSION: fetal DNA screening has higher sensitivity and specificity compared to combined screening (ultrasound and biochemical tests) for the diagnosis of Down syndrome. But its high cost still implies a limitation to solve. (AU)

Down syndrome as a genetic model to evaluate the role of oxidative stress and transsulfuration abnormalities in autism spectrum disorder: A 10-year longitudinal cohort study.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder in which evidence reveals oxidative stress and transsulfuration pathway abnormalities. Down syndrome (DS) is a genetic disorder characterized by similar oxidative stress and transsulfuration pathway abnormalities. This hypothesis-testing longitudinal cohort study determined whether transsulfuration abnormalities and oxidative stress are important susceptibility factors in ASD etiology by evaluating the rate of ASD diagnoses in DS as compared to the general population. The Independent Healthcare Research Database was analyzed for healthcare records prospectively generated in Florida Medicaid. A cohort of 101,736 persons (born: 1990-1999) with ≥10 outpatient office visits and continuously followed for 120 months after birth was examined. There were 942 children in the DS cohort (ICD-9 code: 758.0) and 100,749 children in the undiagnosed cohort (no DS diagnosis). ASD diagnoses were defined as autistic disorder (ICD-9 code: 299.00) or Asperger's disorder/pervasive developmental disorder-not otherwise specified (ICD-9 code: 299.80). ASDs were diagnosed in 5.31% of the DS cohort and 1.34% of the undiagnosed cohort. The risk ratio of being diagnosed with an ASD in the DS cohort as compared to the undiagnosed cohort was 3.97-fold significantly increased with a risk difference of 3.97%. Among children diagnosed with DS, less than 6% were also diagnosed with an ASD. Among children diagnosed with an ASD, less than 5% were also diagnosed with DS. Children diagnosed with DS are apparently more susceptible to ASD diagnosis relative to the general population suggesting oxidative stress and transsulfuration pathway abnormalities are important susceptibility factors in ASD.

TRIDENT-2: National Implementation of Genome-wide Non-invasive Prenatal Testing as a First-Tier Screening Test in the Netherlands.

The Netherlands launched a nationwide implementation study on non-invasive prenatal testing (NIPT) as a first-tier test offered to all pregnant women. This started on April 1, 2017 as the TRIDENT-2 study, licensed by the Dutch Ministry of Health. In the first year, NIPT was performed in 73,239 pregnancies (42% of all pregnancies), 7,239 (4%) chose first-trimester combined testing, and 54% did not participate. The number of trisomies 21 (239, 0.33%), 18 (49, 0.07%), and 13 (55, 0.08%) found in this study is comparable to earlier studies, but the Positive Predictive Values (PPV)-96% for trisomy 21, 98% for trisomy 18, and 53% for trisomy 13-were higher than expected. Findings other than trisomy 21, 18, or 13 were reported on request of the pregnant women; 78% of women chose to have these reported. The number of additional findings was 207 (0.36%); these included other trisomies (101, 0.18%, PPV 6%, many of the remaining 94% of cases are likely confined placental mosaics and possibly clinically significant), structural chromosomal aberrations (95, 0.16%, PPV 32%,) and complex abnormal profiles indicative of maternal malignancies (11, 0.02%, PPV 64%). The implementation of genome-wide NIPT is under debate because the benefits of detecting other fetal chromosomal aberrations must be balanced against the risks of discordant positives, parental anxiety, and a potential increase in (invasive) diagnostic procedures. Our first-year data, including clinical data and laboratory follow-up data, will fuel this debate. Furthermore, we describe how NIPT can successfully be embedded into a national screening program with a single chain for prenatal care including counseling, testing, and follow-up.