Low-pass whole genome sequencing as a cost-effective alternative to chromosomal microarray analysis for low- and middle-income countries.

Low-pass whole genome sequencing (LP-WGS) has been applied as alternative method to detect copy number variants (CNVs) in the clinical setting. Compared with chromosomal microarray analysis (CMA), the sequencing-based approach provides a similar resolution of CNV detection at a lower cost. In this study, we assessed the efficiency and reliability of LP-WGS as a more affordable alternative to CMA. A total of 1363 patients with unexplained neurodevelopmental delay/intellectual disability, autism spectrum disorders, and/or multiple congenital anomalies were enrolled. Those patients were referred from 15 nonprofit organizations and university centers located in different states in Brazil. The analysis of LP-WGS at 1x coverage (>50kb) revealed a positive testing result in 22% of the cases (304/1363), in which 219 and 85 correspond to pathogenic/likely pathogenic (P/LP) CNVs and variants of uncertain significance (VUS), respectively. The 16% (219/1363) diagnostic yield observed in our cohort is comparable to the 15%-20% reported for CMA in the literature. The use of commercial software, as demonstrated in this study, simplifies the implementation of the test in clinical settings. Particularly for countries like Brazil, where the cost of CMA presents a substantial barrier to most of the population, LP-WGS emerges as a cost-effective alternative for investigating copy number changes in cytogenetics.

[Extremely preterm infants with severe intraventricular hemorrhage: neurological evolution and long term and educational status]. / Niños muy prematuros con hemorragia intraventricular extensa: evolución neurológica y escolaridad a largo plazo.

Extensive intraventricular hemorrhage (IVH) in very preterm newborns (VPNB) is associated with mortality and severe long-term neurological sequelae. OBJECTIVES: To know the most frequent neurological pathologies associated with extensive IVH, to determine the functional outcomes of mobility in the motor area and intellectual capacity in the cognitive area, to analyze the association between both areas and to know the schooling achieved. PATIENTS AND METHOD: Descriptive and longitudinal study in VPNB with extensive IVH born between 2001 and 2014. They underwent protocolized neurological follow-up until school age. The functional outcomes in mobility and intellectual capacity were categorized into 4 levels: level 1 corresponds to good functionality and autonomy; level 2, functionality that allows independence, with support in some tasks; level 3 requires constant external support; and level 4 where there is total dependence. The association was analyzed using Chi-square and Cramer's V coefficient. RESULTS: 74 children completed the follow-up; the most frequent associated neurological pathologies were neurodevelopmental disorders, hypertensive hydrocephalus, and epilepsy. Independent mobility (normal or with limitations) reached 74.4% while 24.3% used wheelchairs. 51.3% was categorized as normal to borderline intellectual range, 12.2% as mild intellectual disability (ID), 17.6% as moderate ID, and 19.9% as severe to profound ID. There was a strong statistical association between functional levels of mobility and intellectual capacity (p < 0.000 and V = 0.62). Schooling was proportional to intellectual capacity: 56.8% attended regular schools, 27.0% attended special schools, and 16.2% had no schooling. CONCLUSIONS: 2/3 VPNB with extensive IVH showed positive functional outcomes, from normal to mild limitations that allow an almost autonomous life; in 1/3 the outcomes were unfavorable in mobility and cognitive performance, and there was a strong statistical correlation between both areas studied. Schooling was consistent with the intellectual level.

[Treatment of sleep disorders in neurodevelopmental disorders]. / Abordaje de los trastornos del sueño en los trastornos del neurodesarrollo.

Sleep disorders are common in children and affect neurological development with important cognitive, emotional and behavioral repercussions. There is a high prevalence of sleep disorders (SD) in neurodevelopmental disorders (NDD) such as autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). Sleep disorders in pediatric population have a prevalence of 6-25%, while in children with NDD this number rises to 50-80%. In NDDs, higher rates of difficulties in falling asleep, nocturnal awakenings and daytime sleepiness are observed. Disturbances in the circadian rhythm as well as respiratory sleep disorders are also observed. Consequently, there is a decrease in alertness for daytime activities with increased behavioral disorders, emotional problems and academic difficulties associated with executive and memory dysfunctions. Sleep assessment has to be a systemic part in the clinical evaluation of children with NDDs, so as to give a convenient diagnosis and treatment in each case, allowing to improve the quality of life of children and their families.

Los trastornos del sueño son frecuentes en niños y afectan al desarrollo neurológico, con importante repercusión cognitiva, emocional y conductual. Existe una alta prevalencia de trastornos del sueño (TS) en los trastornos del neurodesarrollo (TND), como trastorno del espectro autista (TEA) y trastorno por déficit de atención con hiperactividad (TDAH). Los TS en población pediátrica tienen una prevalencia del 6-25%, mientras que en los niños con TND esta cifra asciende al 50-80%. En los TND se observa un incremento de las dificultades para conciliar el sueño, de los despertares nocturnos y de la somnolencia diurna. Así mismo, presentan alteraciones del ritmo circadiano y trastornos respiratorios del sueño. Como consecuencia se produce una reducción de la alerta para las actividades diarias con incremento de trastornos conductuales, problemas emocionales y dificultades académicas asociadas a disfunciones ejecutivas y de memoria. La evaluación del sueño debe formar parte sistemática en la valoración clínica de los niños con TND, con el fin de realizar un diagnóstico y un tratamiento adecuados a cada caso, permitiendo mejorar la calidad de vida del niño y de su familia.

A cohort study of neurodevelopmental disorders and/or congenital anomalies using high resolution chromosomal microarrays in southern Brazil highlighting the significance of ASD.

Chromosomal microarray (CMA) is the reference in evaluation of copy number variations (CNVs) in individuals with neurodevelopmental disorders (NDDs), such as intellectual disability (ID) and/or autism spectrum disorder (ASD), which affect around 3-4% of the world's population. Modern platforms for CMA, also include probes for single nucleotide polymorphisms (SNPs) that detect homozygous regions in the genome, such as long contiguous stretches of homozygosity (LCSH). These regions result from complete or segmental chromosomal homozygosis and may be indicative of uniparental disomy (UPD), inbreeding, population characteristics, as well as replicative DNA repair events. In this retrospective study, we analyzed CMA reading files requested by geneticists and neurologists for diagnostic purposes along with available clinical data. Our objectives were interpreting CNVs and assess the frequencies and implications of LCSH detected by Affymetrix CytoScan HD (41%) or 750K (59%) platforms in 1012 patients from the south of Brazil. The patients were mainly children with NDDs and/or congenital anomalies (CAs). A total of 206 CNVs, comprising 132 deletions and 74 duplications, interpreted as pathogenic, were found in 17% of the patients in the cohort and across all chromosomes. Additionally, 12% presented rare variants of uncertain clinical significance, including LPCNVs, as the only clinically relevant CNV. Within the realm of NDDs, ASD carries a particular importance, owing to its escalating prevalence and its growing repercussions for individuals, families, and communities. ASD was one clinical phenotype, if not the main reason for referral to testing, for about one-third of the cohort, and these patients were further analyzed as a sub-cohort. Considering only the patients with ASD, the diagnostic rate was 10%, within the range reported in the literature (8-21%). It was higher (16%) when associated with dysmorphic features and lower (7%) for "isolated" ASD (without ID and without dysmorphic features). In 953 CMAs of the whole cohort, LCSH (≥ 3 Mbp) were analyzed not only for their potential pathogenic significance but were also explored to identify common LCSH in the South Brazilians population. CMA revealed at least one LCSH in 91% of the patients. For about 11.5% of patients, the LCSH suggested consanguinity from the first to the fifth degree, with a greater probability of clinical impact, and in 2.8%, they revealed a putative UPD. LCSH found at a frequency of 5% or more were considered common LCSH in the general population, allowing us to delineate 10 regions as potentially representing ancestral haplotypes of neglectable clinical significance. The main referrals for CMA were developmental delay (56%), ID (33%), ASD (33%) and syndromic features (56%). Some phenotypes in this population may be predictive of a higher probability of indicating a carrier of a pathogenic CNV. Here, we present the largest report of CMA data in a cohort with NDDs and/or CAs from the South of Brazil. We characterize the rare CNVs found along with the main phenotypes presented by each patient and show the importance and usefulness of LCSH interpretation in CMA results that incorporate SNPs, as well as we illustrate the value of CMA to investigate CNV in ASD.

Clinical Characterization and Underlying Genetic Findings in Brazilian Patients with Syndromic Microcephaly Associated with Neurodevelopmental Disorders.

Microcephaly is characterized by an occipitofrontal circumference at least two standard deviations below the mean for age and sex. Neurodevelopmental disorders (NDD) are commonly associated with microcephaly, due to perturbations in brain development and functioning. Given the extensive genetic heterogeneity of microcephaly, managing patients is hindered by the broad spectrum of diagnostic possibilities that exist before conducting molecular testing. We investigated the genetic basis of syndromic microcephaly accompanied by NDD in a Brazilian cohort of 45 individuals and characterized associated clinical features, as well as evaluated the effectiveness of whole-exome sequencing (WES) as a diagnostic tool for this condition. Patients previously negative for pathogenic copy number variants underwent WES, which was performed using a trio approach for isolated index cases (n = 31), only the index in isolated cases with parental consanguinity (n = 8) or affected siblings in familial cases (n = 3). Pathogenic/likely pathogenic variants were identified in 19 families (18 genes) with a diagnostic yield of approximately 45%. Nearly 86% of the individuals had global developmental delay/intellectual disability and 51% presented with behavioral disturbances. Additional frequent clinical features included facial dysmorphisms (80%), brain malformations (67%), musculoskeletal (71%) or cardiovascular (47%) defects, and short stature (54%). Our findings unraveled the underlying genetic basis of microcephaly in half of the patients, demonstrating a high diagnostic yield of WES for microcephaly and reinforcing its genetic heterogeneity. We expanded the phenotypic spectrum associated with the condition and identified a potentially novel gene (CCDC17) for congenital microcephaly.

Desarrollo infantil y sus principales desafíos en los primeros años de vida: lugar e importancia de los centros de educación y protección del Instituto del Niño y Adolescente del Uruguay / Child development and its main challenges in the first years of life: place and importance of the education and protection centers of the Children and Adolescents Institute of Uruguay

Existe un aumento progresivo de los problemas del neuropsicodesarrollo. Las intervenciones psicoeducativas y sociales oportunas con soporte en evidencias mejoran la evolución a lo largo de la vida de los niños. Los Centros Educativos en Primera Infancia tienen el potencial de identificar precozmente a niños con riesgos de alteraciones en el neuropsicodesarrollo. El Centro de Formación y Estudios del Instituto del Niño y Adolescente del Uruguay convoca a la Unidad Académica de Psiquiatría Pediátrica para la formación y actualización en esta problemática. El objetivo del trabajo es implementar un Programa de Capacitación en desarrollo normal, sus variaciones y desafíos; oportunidades de estimulación, identificación precoz de alteraciones e intervenciones en Centros Educativos en Primera Infancia; simultáneamente capacitar en habilidades de comunicación y trabajo interdisciplinario a posgrados de psiquiatría pediátrica y otras disciplinas de salud mental. Está dirigido a trabajadores del Instituto del Niño y Adolescente del Uruguay que trabajan con niños de 0 a 3 años. La implementación se realiza a través de tres modalidades articuladas, escalando progresivamente en contenidos: 1) Conferencias abiertas. 2) Curso introductorio a través de talleres virtuales sincrónicos. 3) Instancias docentes de profundización con equipos de Centros Educativos en Primera Infancia. Resultados: 2800 inscriptos. Se realizaron dos conferencias (4500 participantes en total), ocho cursos introductorios y se está implementando la modalidad 3 para el año 2024. Las encuestas de satisfacción han sido entre muy buenas-excelente. Se concluye que la implementación de este Programa de Capacitación permite la difusión de conocimientos y el intercambio interdisciplinario, por lo que es necesario continuar la cooperación entre Unidades Académicas, explorar otras modalidades pedagógicas y estudiar el impacto de la capacitación.

A progressive increase in neuro-psycho- developmental problems has taken place; timely evidence-based psycho-educational and social interventions improve children's lifelong development. Early Childhood Educational Centers have the potential for early identification of children at risk for neurodevelopmental disorders. The Training and Studies Center of the Institute of Childhood and Adolescence of Uruguay convenes the Academic Unit of Pediatric Psychiatry for training and updating on this issue. The objective is to implement a Training Program on normal development, its variations and challenges; stimulation opportunities, early identification of changes and interventions in Early Childhood Educational Centers, while training pediatric psychiatry postgraduates and other mental health disciplines in communication skills and interdisciplinary work. Methodology: Aimed at workers of the Institute of Childhood and Adolescence of Uruguay, working with children from 0 to 3 years old. Three articulated modalities, progressively increasing in content: 1) Open lectures. 2) Introductory course: synchronous virtual workshops. 3) Teaching instances with teams from Early Childhood Educational Centers. Results: 2800 participants. Two conferences (4500 participants) and eight introductory courses were held. Modality 3 is being organized for 2024. Satisfaction surveys show very good to excellent results. It is concluded that the implementation of this training Program makes knowledge dissemination and interdisciplinary exchange possible, so it is necessary to continue cooperation between academic units, explore other pedagogical modalities and study training impact.

Las funciones ejecutivas: su significado y aplicación clínica / Executive functions: meaning and clinical application

Las funciones ejecutivas generalmente se conceptualizan como un conjunto de procesos generales de control de orden superior que trabajan juntos para dirigir y gestionar las funciones cognitivas, emocionales y conductuales, especialmente durante la resolución activa de problemas. Su disfunción es frecuente de ser detectada como comorbilidad de otros trastornos del neurodesarrollo, causa o efecto? La detección precoz de la disfunción ejecutiva y su abordaje terapéutico temprano, mejora el pronóstico global madurativo en el periodo infantojuvenil. Esta sucinta revisión de las funciones ejecutivas intenta resaltar su importancia para el pediatra y su mirada de los trastornos del neurodesarrollo (AU)

Executive functions are typically understood as a set of general higher-order control processes that collectively direct and manage cognitive, emotional, and behavioral functions, especially during active problem solving. Their dysfunction is often detected as a comorbidity of other neurodevelopmental disorders; cause or effect? Early detection of executive dysfunction and a prompt therapeutic approach improves the overall developmental prognosis in childhood and adolescence. This brief review of executive functions aims to highlight their importance for the pediatrician and his/her view of neurodevelopmental disorder (AU)

Intervenciones parentales para el desarrollo lingüístico- comunicativo en preescolares con Trastornos del Neurodesarrollo: una revisión sistemática / Parental interventions for linguistic-communicative development in preschoolers with Neurodevelopmental Disorders: a systematic review

Resumen En el actual escenario sociosanitario enfrentado a raíz de la pandemia por SARS-CoV-2, múltiples actividades se han visto mermadas, e incluso, suspendidas por los largos periodos de aislamiento social y las medidas de cuidado para evitar contagios. En este sentido, muchas personas han dejado de recibir con la misma regularidad, o bajo las mismas circunstancias, sus tratamientos, incluyendo a niños con Trastornos del Neurodesarrollo (TND). Es así como surgen las intervenciones Parentales. Estas son programas donde los padres o cuidadores primarios son entrenados para llevar a cabo acciones terapéuticas con el niño y cuyo objetivo puede estar orientado a promover múltiples habilidades. El objetivo de la presente revisión sistemática fue determinar el efecto de estas intervenciones para promover el lenguaje y la comunicación en niños con diagnóstico de TND de entre 2 y 5 años. Se realizó una búsqueda sistemática en las bases de datos ERIC, MEDLINE y PubMed, considerando publicaciones de entre enero del 2010 y marzo de 2022. De las 9885 referencias iniciales, y posterior a las etapas de tamizaje y elegibilidad, 5 fuentes primarias cumplieron con los criterios de selección. Los resultados indican que las intervenciones parentales para habilidades de comunicación serían efectivas e incluso se mantendrían los efectos en medidas de seguimiento. En cuanto a las habilidades de lenguaje, los resultados a través de los estudios son contradictorios. Por otra parte, ninguno de los estudios reporta efectos adversos para los niños. En cuanto a efectos beneficios o adversos para padres o cuidadores primarios, ninguno de los estudios incluidos reporta medidas asociadas.

Abstract In the current socio-sanitary scenario that we are facing as a result of the SARS-CoV-2 Pandemic, there have been many activities that have been reduced and even suspended due to long periods of social isolation and care measures to avoid contagion. In this sense, many people have stopped receiving their treatments with the same regularity or under the same circumstances, including children with Neurodevelopmental Disorders. This is how parental interventions correspond to programs where parents or primary caregivers are trained to carry out therapeutic actions with the child and whose objective may be aimed at promoting multiple skills. The objective of this systematic review was to determine the effect of these interventions to promote language and communication in children diagnosed with Neurodevelopmental Disorders between 2 and 5 years of age. A systematic search was carried out in the ERIC, MEDLINE and PubMed databases including publications between January 2010 and March 2022. Of the 9885 initial references, and after the screening and eligibility stages, 5 primary sources met the selection criteria. The results indicate that parental interventions for communication skills would be effective, and the effects would even be maintained in follow-up measures. Regarding language skills, the results across studies are contradictory. On the other hand, none of the studies reported adverse effects for children. Regarding beneficial or adverse effects for parents or primary caregivers, none of the included studies reported associated measures.

Theophrastus's Anaisthetos Transdiagnostic Presentation: comment on Pehlivanidis and Papanikolaou (2022).

We were pleased to read Pehlivanidis and Papanikolaou's article1 and see that more colleagues are recognizing Theophrastus' text as the first description of Attention Deficit Hyperactivity Disorder (ADHD).2 We agree with the authors' perspective that Theophrastus' description may suggest the presence of more than one neurodevelopmental disorder. In fact, Theophrastus' description aligns with the shared clinical symptoms and underlying neurodevelopmental mechanisms of ADHD and Social Pragmatic Communication Disorder (SPCD). It is fascinating that a description from over 2000 years ago already presented prototypical individual transdiagnostic aspects that are compatible with a modern biological view of psychiatry. Indeed, it is not unexpected that heritable traits with clear biological underpinnings should have been perceived since the dawn of medicine. A significant leap forward in the development of this field came a few decades ago when Clements (1966)3 published a NIH-sponsored project entitled 'Minimal Brain Dysfunction in Children.' This seminal work prepared the terrain for the ongoing understanding of the grouping of signs, symptoms, and biological factors observed across various neurodevelopmental disorders. This grouping can be present in different spectrums, proportions, and nuances, including children and adults with some impairments that are not solely explained by their cognitive abilities. Thus, the characterization of 'The Obtuse Man' by Theophrastus could be considered a prototypical case of this more integrated and less fragmented view of what we call neurodevelopmental disorders.

Consultas de demanda espontánea sobre trastornos del desarrollo en el Hospital Garrahan / Spontaneous consultations for developmental disorders at Garrahan Hospital

Introducción: Los trastornos del desarrollo (TD) constituyen un motivo de consulta muy frecuente en la práctica pediátrica. El Hospital Garrahan recibe por demanda espontánea al servicio de Mediano Riesgo (MR) consultas de cuidadores con preocupaciones sobre el desarrollo de los niños, niñas y adolescentes (NNyA). Allí son valorados por pediatras clínicos, quienes realizan la interconsulta al servicio de Clínicas Interdisciplinarias del Neurodesarrollo (CIND) según necesidad (representan el 10% del total de consultas en MR). El objetivo del trabajo es comparar las características de los pacientes de MR que fueron consultados al área de Maduración de CIND durante el bimestre marzo/abril de 2016, 2021 y 2022. Materiales y métodos: estudio retrospectivo, observacional y comparativo. Se revisaron las historias clínicas analizando las siguientes variables: edad, procedencia, contar con pediatra de cabecera, cobertura de salud, motivo de consulta y sospecha diagnóstica. Resultados: La cantidad de consultas aumentó por encima del 20%, con un descenso en la mediana de edad de alrededor de un año. Aproximadamente el 70% de los pacientes procedían del conurbano en los tres períodos. Observamos un descenso respecto al número de NNyA con seguimiento pediátrico y cobertura social. El lenguaje y la conducta fueron los motivos más frecuentes de consulta y la mayor sospecha diagnóstica fue el Trastorno del Espectro Autista (TEA). Conclusiones: Los datos observados pueden relacionarse con el impacto de la pandemia así como también con las condiciones socio-económicas de los últimos cinco años, con un mayor conocimiento acerca del desarrollo y un probable aumento de la prevalencia de los TD (AU)

Introduction: Developmental disorders (DD) are a frequent reason for consultation in pediatric practice. The Garrahan Hospital receives spontaneous consultations at the department of Intermediate Risk (IR) from caregivers with concerns about the development of children and adolescents. At the IR department, children and adolescents are evaluated by clinical pediatricians, who consult with specialists at the Interdisciplinary Neurodevelopmental Clinic (INDC) as needed (accounting for 10% of the total number of consultations at the IR department). The aim of this study was to compare the characteristics of IR patients who were consulted at the INDC during the bimonthly period March/April 2016, 2021, and 2022. Materials and methods: a retrospective, observational, and comparative study was conducted. Medical records were reviewed analyzing the following variables: age, provenance, having a primary care pediatrician, healthcare insurance, reason for consultation, and diagnostic suspicion. Results: The number of consultations increased by over 20%, with a decrease in median age of around one year. Approximately 70% of the patients came from Greater Buenos Aires in the three periods. A decrease in the number of children and adolescents with pediatric follow-up and a social health insurance was observed. Language and behavior disorders were the most frequent reasons for consultation and autism spectrum disorder (ASD) was most often suspected. Conclusions: The observed data may be related to the impact of the pandemic as well as socio-economic conditions over the last five years, together with increased knowledge about development and a probable increase in the prevalence of ASD (AU)

Detección precoz de desviaciones y promoción de las habilidades sociales del lactante con la escala ADBB durante el seguimiento pediátrico: experiencia en un centro de salud pública de alta vulnerabilidad social / Early detection of deviations and promotion of infant social skills using the ADBB scale during pediatric follow-up: experience at a public health center of high social vulnerability / Detecção precoce de desvios e promoção de habilidades sociais infantis utilizando a escala ADBB durante o acompanhamento pediátrico: experiência num centro público de saúde de alta vulnerabilidade social

Introducción: el retraimiento del lactante es un signo de riesgo de desviaciones en el desarrollo y la salud mental infantil asociado a perturbaciones sostenidas en la interacción padres-bebé. Para este estudio se amplió la formación de un grupo de pediatras, médicos de familia y otros profesionales del primer nivel de un centro de salud de una zona de alta vulnerabildad social en una perspectiva interdisciplinaria del impacto de las interacciones tempranas en el neurodesarrollo y en la salud psicoemocional de los primeros años de vida, junto con la aplicación de un instrumento validado internacionalmente para la detección de retraimiento (escala ADBB, Alarme Détresse Bébé, Guedeney 2001) y estrategias para promover las habilidades sociales del lactante durante el control pediátrico. Objetivo: el estudio fue para evaluar el efecto de este abordaje en el seguimiento pediátrico de un grupo de lactantes a través de la detección de retraimiento y en comparación con otro grupo atendido en el mismo centro de salud sin el abordaje propuesto. Material y métodos: se realizó la detección de retraimiento con ADBB a 101 lactantes de 2 a 11 meses filmados en controles pediátricos durante 2016-2017 en un centro de salud pública de Montevideo. De total, 58 tuvieron seguimiento pediátrico con cuatro pediatras y una médica de familia con el abordaje propuesto y fueron evaluados con ADBB en dos tiempos, entre los 2 y 5 meses y entre los 8 y 11 meses de edad. Los 43 restantes acudieron al control pediátrico habitual en el centro de salud y fueron evaluados con ADBB entre los 8 y 11 meses. Todos los lactantes fueron evaluados con ADBB por expertos independientes. Resultados: de los 58 lactantes atendidos con el abordaje propuesto, 22% presentó retraimiento entre los 2 y 5 meses, y 14% entre los 8 y 11 meses. En el grupo atendido en los controles pediátricos regulares sin el abordaje propuesto, se detectó 53% de retraimiento entre los 8 y 11 meses de edad (p <0,001). Conclusiones: La detección precoz de retraimiento junto con estrategias para la promoción de las habilidades sociales del lactante durante el segui- miento pediátrico podría favorecer una perspectiva más integral y preventiva de la salud, incidiendo en el cuidado del neurodesarrollo y de la salud mental infantil desde el primer nivel.

Introduction: infant withdrawal is a sign of risk for deviations in child development and mental health associated with sustained disturbances in parent-infant interaction. For this study, a group of pediatricians, family doctors and other professionals of the Primary Care Level of a health center in an area of high social vulnerability was trained including an interdisciplinary perspective regarding the impact of early interactions on the neurodevelopment and psychological and emotional health of the first years of life. Similarly, we applied an internationally validated instrument for the detection of withdrawal (ADBB scale, Alarme Détresse Bébé, Guedeney 2001) and strategies to promote infant social skills during the pediatric check-ups. Objective: the study was to evaluate the effect of this approach in the pediatric follow-up of a group of infants through the detection of withdrawal and to compare it with another group assisted in the same center that did not receive the same approach. Material and methods: withdrawal with ADBB was detected in 101 infants aged 2 to 11 months filmed in pediatric controls during 2016-2017 in a public health center in Montevideo. In total, 58 had pediatric follow-up with four pediatricians and one family physician using the approach proposed in this study and were evaluated with ADBB in two stages, between 2 and 5 months and between 8 and 11 months of age. The remaining 43 attended the usual pediatric control at the health center and were evaluated with ADBB between 8 and 11 months. All infants were evaluated with ADBB by independent experts. Results: of the 58 infants treated with the approach proposed in this study, 22% presented withdrawal between 2 and 5 months, and 14% between 8 and 11 months. In the group attended in regular pediatric check-ups without using the proposed approach, 53% of withdrawal was detected between 8 and 11 months of age (p <0.001). Conclusions: the early detection of withdrawal to gether with strategies for the promotion of infant social skills during pediatric follow-up could favor a more comprehensive and preventive health perspective and enable practitioners to focus on the children neurodevelopmental and mental health from primary care assistance.

Introduccion: a abstinencia infantil é um sinal de risco para os desvios no desenvolvimento infantil e na saúde mental associados a distúrbios sustenta- dos na interação pais-bebê. Para este estudo, expandiuse a formação de um grupo de pediatras, médicos de família e outros profissionais do primeiro nível de um centro de saúde numa área de alta vulnerabilidade social, utilizando uma perspectiva interdisciplinar do impacto das interações precoces no neurodesenvolvimento e na saúde psicoemocional dos primeiros anos de vida, juntamente com a aplicação de um instrumento validado internacio- nalmente para a detecção de abstinência (escala ADBB, Alarme Détresse Bébé, Guedeney 2001) e estratégias para promover habilidades sociais infan- tis durante o controle pediátrico. Objetivo: do estudo foi avaliar o efeito dessa abordagem no acompanhamento pediátrico de um grupo de lactentes por meio da detecção de abstinência e comparálo com outro grupo atendido no mesmo centro de saúde, más sem utilizar a abordagem proposta. Material e Métodos: a abstinência com ADBB foi detectada em 101 lactentes com idades entre 2 e 11 meses filmados em controles pediátricos durante 2016-2017 num Centro de Saúde Pública em Montevidéu. No total, 58 tiveram acompanhamento pediátrico com quatro pediatras e um médico de família e receberam a abordagem proposta e foram avaliados com o ADBB em dois estágios, entre 2 e 5 meses e entre 8 e 11 meses de idade. Os 43 restantes compareceram ao controle pediátrico habitual no centro de saúde e foram avaliados com ADBB entre 8 e 11 meses. Todos os lactentes foram avaliados com o ADBB por especialistas independentes. Resultados: dos 58 lactentes tratados com a abordagem proposta, 22% apresentaram abstinência entre 2 e 5 meses e 14% entre 8 e 11 meses. No grupo atendido em check-ups pediátricos regulares sem a abordagem proposta, 53% de desistência (retraimiento) foi detectada entre 8 e 11 meses de idade (p <0,001). Conclusões: a detecção precoce da abstinência, aliada a estratégias de promoção de habilidades sociais infantis durante o acompanhamento pediá- trico, poderia favorecer uma perspectiva de saúde mais abrangente e preventiva, com foco no cuidado do neurodesenvolvimento e da saúde mental infantil desde o primeiro nível de saúde.

Resultados en el neurodesarrollo en la edad preescolar y escolar de los recién nacidos pretérminos asistidos en el CTI neonatal de la Asociación Médica de San José / Neurodevelopmental preschool and school results of preterm newborns assisted at the neonatal ICU of the San José department medical provider in Uruguay / Resultados neuro desenvolvimento em idade pré-escolar e escolar de recém-nascidos pré-termos atendidos na UTI neonatal da assistência médica do departamento do São José no Uruguai

Uruguay acompaña la tendencia mundial al descenso de la natalidad con un descenso de la mortalidad concomitante, siendo la primera causa de mortalidad infantil la prematurez. Enfocados en la prematurez, es de nuestro interés conocer qué ocurre con estos niños luego del alta de la unidad neonatal. Se realizó el estudio de una cohorte de niños entre 4 y 8 años, nacidos con 32 semanas o menos de edad gestacional y/o con pesos al nacer de 1.500 g o menos, asistidos en su período neonatal en la Asociación Médica de San José, a quienes se les realizó el test de Battelle. Se logró identificar las áreas con mayor dificultad en el desarrollo para cada grupo de edad, concluyendo que se pueden realizar planes específicos de acción para promover el desarrollo de estos niños en la edad preescolar y escolar.

Uruguay follows the global declining trend in birth rates along with decreasing mortality, being prematurity the main cause of infant mortality. We studied premature children who had undergone the Battelle Test and had been discharged from the neonatal unit, a cohort of children between 4 and 8 years of age, born at 32 weeks or less of gestational age and/or having a birth weight of 1500g or less, assisted in their neonatal period at the San José Department Medical Center. We could identify the main areas affecting development for each age group, and concluded that specific action plans can be carried out to promote the development of these children at preschool and school age.

O Uruguai acompanha a tendência mundial de declínio das taxas de natalidade com uma concomitante diminuição da mortalidade, sendo a prematuridade a principal causa de mortalidade infantil. Nos focamos na prematuridade e no estudo do que acontece com essas crianças após a alta da unidade neonatal. Realizamos um estudo de uma coorte de crianças entre 4 e 8 anos que tinham sido submetidas ao Teste de Battelle, nascidas com 32 semanas ou menos de idade gestacional e/ou com peso de nascimento igual ou inferior a 1500g, atendidas no período neonatal na Assistência Médica do Departamento de São José no Uruguai. Foi possível identificar as áreas de maior dificuldade de desenvolvimento para cada faixa etária, e concluir que podem se realizar planos de ação específicos para promover o desenvolvimento dessas crianças em idade pré-escolar e escolar.

[Genetics of neurodevelopmental disorders. Practical aspects]. / Genética de los trastornos del neurodesarrollo. Aspectos prácticos.

Neurodevelopmental disorders (NDD) constitute a relevant group of pathologies, of childhood, with a biological basis and totally or partially genetic etiology. The recognition of the causal factors constitutes a challenge that has been perfected over the last decades, until obtaining an increasing diagnostic yield. The implementation of these technological advances can only be achieved through the formation of interdisciplinary work teams, which, following an orderly process, achieve a presumptive diagnosis, which is then certified using the techniques that for each of the cases are more profitable in terms of quality and cost. In this paper we list these procedures, based on different scenarios that highlight the extensive menu of possibilities and the need to manage them in a rational way, on well-founded scientific bases.

Los trastornos del neurodesarrollo (TND) constituyen un grupo relevante de enfermedades, con base biológica y etiología total o parcialmente genética. El reconocimiento de los factores causales constituye un reto cuyos resultados se han perfeccionado a lo largo de las últimas décadas, hasta obtener un rédito diagnóstico cada vez mayor. La implementación de estos avances tecnológicos solo puede lograrse mediante la conformación de equipos de trabajo interdisciplinarios, que siguiendo un proceso ordenado, logran un diagnóstico de presunción, que luego es certificado mediante las técnicas que, para cada uno de los casos, resulta más redituable en calidad y costo. En este trabajo, enumeramos estos procedimientos a partir de diferentes escenarios que ponen de relieve el extenso menú de posibilidades y la necesidad de administrar los mismos de un modo racional, sobre bases científicas debidamente fundadas.

[Neurodevelopmental disorders: from the laboratory to the classroom]. / Desórdenes del neurodesarrollo: del laboratorio al aula de clase.

Neurodevelopmental disorders are the most common diagnosis in the clinical practice in child neurology. Since the 70's the terminology used for the diagnosis of these conditions, was developed with the goal of obtaining better services for those individuals affected. Over the years the classification has changed but the fundamental process for diagnosis continues the same. There is a new movement aiming to change the current classification and propose a new one based in the molecular deficits associated with the clinical phenotype rather than a collection of symptoms. This new approach focusses on the identification of the molecular defectcausing of the specific to design targeted interventions that will promise a curative approach, rather than the current symptom-based interventions available. Important progress has been done alrea dy, given the high association between cognitive/compartmental phenotype in some well-known genetic defects like Neurofibromatosis, TSC, Down syndrome, and the high association between different cognitive/compartmental phenotype in rare diseases. The future will hold opportunities to properly identify the molecular deficit and a tailored intervention for those conditions today called Neurodevelopmental disabilities.

Los desórdenes del Neurodesarrollo son en conjunto los diagnósticos más frecuentes en la práctica clínica en Neurología Infantil. De los años 70', se desarrolló una terminología usada para denominar estos desordenes, con el objetivo de obtener mejor atención en servicios médicos y educativos para los afectados. A lo largo de los años, las clasificaciones han cambiado, pero el proceso fundamental del diagnóstico sigue siendo el mismo. Existe actualmente un movimiento para cambiar y establecer una nueva clasificación, basada en los déficits biológicos asociados con el fenotípico clínico. Esta nueva aproximación diagnóstica tiene como objetivo entre tantos otros, el diseño de intervenciones específicas que prometerían un mayor potencial curativo, a diferencia de las actuales opciones de tratamiento, que se basan en el manejo de síntomas. Importantes progresos se han hecho ya en este campo. Por ejemplo, algunos fenotipos conductuales en condiciones genéticas ampliamente conocidas como el Síndrome de Down, síndrome de X Frágil, neurofibromatosis, esclerosis tuberosa entre otros, han permitido proponer correlaciones biológicas con fenotipos comunes en pacientes con autismo, trastornos por déficit de atención, entre otros. Adicionalmente, el extenso estudio que actualmente se lleva a cabo sobre las denominadas enfermedades raras, que se asocian hasta en un 80% con trastornos del neurodesarrollo, ha abierto la posibilidad para muchas más correlaciones biológicas-comportamentales. En el futuro, será posible esperar oportunidades para la identificación de déficits biológicos moleculares, asociados con fenotipos clínicos cognitivos-conductuales y que, a partir de ellos se puedan diseñar intervenciones individuales a los problemas que hoy conocemos globalmente como los desórdenes del neurodesarrollo.

[New genetic testing algorithm for evaluation of neurodevelopmental disorders]. / Nuevo algoritmo de test genéticos para evaluación de trastornos del neurodesarrollo.

In more than half of neurodevelopmental disorders, a genetic etiology is demonstrated. The detection of these pathogenic variants has a huge impact on the course of the disease of these patients. It allows the acceptance of the disease by the parents of the patients, issue a prognosis, anticipate the future consequences of the disease and in more and more cases establish a treatment or change the one already established. The genetic techniques that allow these etiological diagnoses are very recent therefore not yet fully assumed by neuropediatricians. Even in the diagnostic guides of the different scientific societies, their algorithms are outdated by the quick incorporation of new techniques. This article reviews the current techniques as well as the latest advances in them that are being incorporated into clinical practice.

En más de la mitad de los trastornos del neurodesarrollo se demuestra una etiología genética. La detección de estas variantes patogénicas tiene un impacto enorme en el curso de la enfermedad de estos pacientes. Permite la aceptación de la enfermedad por parte de los padres de los pacientes, emitir un pronóstico, adelantarnos a las futuras consecuencias de la enfermedad y, en cada vez más casos, instaurar un tratamiento o cambiar el ya establecido. Las técnicas genéticas que permiten estos diagnósticos etiológicos son muy jóvenes y por lo tanto todavía no totalmente asumidas por los neuropediatras. Incluso en las guías de diagnóstico de las diferentes sociedades científicas, sus algoritmos están desfasados por la rápida incorporación de nuevas técnicas. En este artículo se revisan las técnicas actuales así como los últimos avances en las mismas, que se están incorporando a la práctica clínica.

Neurodevelopmental Trajectories of Preterm Born Survivors of Twin-Twin Transfusion Syndrome: From Birth to 5 Years of Age.

OBJECTIVE: To investigate the neurodevelopmental outcome at age 2 and 5 years in survivors of twin-twin transfusion syndrome (TTTS) treated with fetoscopic laser surgery and born premature and/or small for gestational age. STUDY DESIGN: At 2 and 5 years of age, standardized neurologic, motor, and cognitive assessments were performed by a neonatologist, a pediatric physical therapist, and a psychologist. Behavior was assessed using a validated questionnaire completed by parents. RESULTS: Neurodevelopmental assessment at both time points was available for 73 survivors of TTTS. Mild to moderate neurodevelopmental impairment (NDI) was detected in 34% of survivors (25 of 73) at 5 years, compared with 25% (18 of 73) at 2 years (P = .178). Severe NDI was observed in 12% (9 of 73) at 5 years and in 3% (2 of 73) at 2 years (P = .035). Mean cognitive score was lower at the 5-year follow-up (90.7 ± 12.3 vs 95.6 ± 13.1 at 2 years; P = .001), and more children were diagnosed with mild cognitive impairment at 5 years (29% vs 11% at 2 years; P = .007). When comparing individual outcomes at both time points, 35% (25 of 71) moved from a normal outcome or mild to moderate impairment at 2 years toward more severe impairment at 5 years. CONCLUSIONS: A high rate of mild to moderate cognitive impairment and severe NDI at age 5 years was not identified at age 2 years. Our data highlight the importance of longitudinal follow-up of survivors of TTTS beyond age 2 years and emphasize the precautions that should be taken when diagnosing an absence of impairment before school age.

A guide for the use of fNIRS in microcephaly associated to congenital Zika virus infection.

Congenital Zika Syndrome (CZS) is characterized by changes in cranial morphology associated with heterogeneous neurological manifestations and cognitive and behavioral impairments. In this syndrome, longitudinal neuroimaging could help clinicians to predict developmental trajectories of children and tailor treatment plans accordingly. However, regularly acquiring magnetic resonance imaging (MRI) has several shortcomings besides cost, particularly those associated with childrens' clinical presentation as sensitivity to environmental stimuli. The indirect monitoring of local neural activity by non-invasive functional near-infrared spectroscopy (fNIRS) technique can be a useful alternative for longitudinally accessing the brain function in children with CZS. In order to provide a common framework for advancing longitudinal neuroimaging assessment, we propose a principled guideline for fNIRS acquisition and analyses in children with neurodevelopmental disorders. Based on our experience on collecting fNIRS data in children with CZS we emphasize the methodological challenges, such as clinical characteristics of the sample, desensitization, movement artifacts and environment control, as well as suggestions for tackling such challenges. Finally, metrics based on fNIRS can be associated with established clinical metrics, thereby opening possibilities for exploring this tool as a long-term predictor when assessing the effectiveness of treatments aimed at children with severe neurodevelopmental disorders.

Behavioral Health Diagnoses in Youth with Differences of Sex Development or Congenital Adrenal Hyperplasia Compared with Controls: A PEDSnet Study.

OBJECTIVE: To evaluate the odds of a behavioral health diagnosis among youth with differences of sex development (DSD) or congenital adrenal hyperplasia (CAH) compared with matched controls in the PEDSnet database. STUDY DESIGN: All youth with a diagnosis of DSD (n = 1216) or CAH (n = 1647) and at least 1 outpatient encounter were extracted from the PEDSnet database and propensity-score matched on 8 variables (1:4) with controls (n = 4864 and 6588, respectively) using multivariable logistic regression. The likelihood of having behavioral health diagnoses was examined using generalized estimating equations. RESULTS: Youth with DSD had higher odds of a behavioral health diagnosis (OR, 1.7; 95% CI, 1.4-2.1; P < .0001) and neurodevelopmental diagnosis (OR, 1.7; 95% CI, 1.4, 2.0; P < .0001) compared with matched controls. Youth with CAH did not have an increased odds of a behavioral health diagnosis (OR, 1.0; 95% CI, 0.9, 1.1; P = .9) compared with matched controls but did have higher odds of developmental delay (OR, 1.8; 95% CI, 1.4, 2.4; P < .0001). CONCLUSIONS: Youth with DSD diagnosis have higher odds of a behavioral health or neurodevelopmental diagnosis compared with matched controls. Youth with CAH have higher odds of developmental delay, highlighting the need for screening in both groups.