Evaluation of the first 5 years of a glutaric aciduria type I neonatal screening programme in Asturias.

INTRODUCTION: . Neonatal screening of glutaric aciduria type 1 (GA-1) has brought radical changes in the course and outcomes of this disease. This study analyses the outcomes of the first 5 years (2015-2019) of the AGA1 neonatal screening programme in our autonomous community. MATERIAL: . We conducted an observational, descriptive and retrospective study. All neonates born between January 1, 2015 and December 31, 2019 that participated in the neonatal screening programme were included in the study. The glutarylcarnitine (C5DC) concentration in dry blood spot samples was measured by means of tandem mass spectrometry applying a cut-off point of 0.25 µmol/L. RESULTS: . A total of 30 120 newborns underwent screening. We found differences in the C5DC concentration based on gestational age, type of feeding and hours of life at sample collection. These differences were not relevant for screening purposes. There were no differences between neonates with weights smaller and greater than 1500 g. Screening identified 2 affected patients and there were 3 false positives. There were no false negatives. The diagnosis was confirmed by genetic testing. Patients have been in treatment since diagnosis and have not developed encephalopathic crises in the first 4 years of life. CONCLUSIONS: . Screening allowed early diagnosis of two cases of GA-1 in the first 5 years since its introduction in our autonomous community. Although there were differences in C5DC levels based on gestational age, type of feeding and hours of life at blood extraction, they were not relevant for screening.

Sospecha clínica y estudios diagnósticos iniciales en enfermedades metabólicas hereditarias / Clinical suspicion and initial diagnostic studies in inherited metabolic diseases

Las enfermedades metabólicas hereditarias (EMH) constituyen un grupo diverso y complejo de trastornos genéticos que, aunque individualmente son poco frecuentes, en su conjunto representan una importante causa de morbilidad y mortalidad. Se lleva a cabo una revisión exhaustiva de la literatura con el objetivo de proporcionar información que oriente la sospecha clínica y el enfoque en los estudios diagnósticos iniciales, cuya clave reside en una anamnesis completa que abarque los antecedentes familiares y obstétricos, junto con una consideración cuidadosa de las manifestaciones clínicas del paciente. Es crucial tener en cuenta la naturaleza multisistémica de estas enfermedades que pueden manifestarse desde el periodo neonatal, generalmente como intoxicaciones agudas, hasta una presentación más insidiosa en adultos jóvenes. Si la evaluación clínica sugiere la posibilidad de una EMH, es fundamental llevar a cabo medidas de apoyo general y realizar investigaciones de laboratorio de manera simultánea. En neonatos, donde la presentación de una EMH puede representar una emergencia médica que requiere una respuesta inmediata, esta acción es especialmente crítica. El diagnóstico de las EMH representa un desafío debido a su variabilidad clínica y sintomatología heterogénea. Sin embargo, la identificación temprana de estas enfermedades es fundamental para iniciar un tratamiento oportuno y mejorar el pronóstico de los pacientes.(AU)

Inherited metabolic diseases (IMDs) constitute a diverse and complex group of genetic disorders that, although individually rare, collectively represent a significant cause of morbidity and mortality. A comprehensive literature review is carried out with the aim of providing information to guide clinical suspicion and the approach to initial diagnostic studies, the key of which lies in a complete medical history encompassing family and obstetric backgrounds, along with careful consideration of the patient’s clinical manifestations. It is crucial to consider the multisystemic nature of these diseases, which can manifest from the neonatal period, usually as acute intoxications, to a more insidious presentation in young adults. If clinical evaluation suggests the possibility of an IMD, it is essential to implement general supportive measures and simultaneously perform laboratory investigations. In neonates, where the presentation of an IMD can represent a medical emergency requiring an immediate response, this action is especially critical. The diagnosis of IMDs poses a challenge due to their clinical variability and heterogeneous symptomatology. However, early identification of these diseases is crucial for initiating timely treatment and improving patient prognosis.(AU)

¿Cómo evaluar la sepsis neonatal de inicio precoz? Estudio comparativo de tres estrategias de detección / How to assess early-onset neonatal sepsis? Comparison of three detection strategies

Introducción: La sepsis neonatal de inicio precoz puede causar morbimortalidad importante, sobre todo si se retrasa su identificación. La disminución de su incidencia en las últimas décadas motiva que sea importante encontrar un equilibrio entre reducir las pruebas complementarias y seguir detectando los pacientes afectos. Comparamos 3 estrategias de detección en pacientes con factores de riesgo: E1. Cribado analítico; E2. Calculadora de riesgo de sepsis neonatal; E3. Observación clínica. Pacientes y métodos: Estudio observacional retrospectivo, en recién nacidos con edad gestacional ≥34 semanas y con factores de riesgo o sintomatología compatible con sepsis neonatal de inicio precoz. Se analizaron los resultados de nuestra unidad con cribado analítico (E1) y se comparó con las otras 2 estrategias (E2 y E3) para valorar modificar nuestro protocolo. Resultados: Se incluyeron 754 pacientes cuyos factores de riesgo más frecuentes fueron la rotura prologada de membranas (35,5%) y la colonización materna por Streptococcus agalactiae (38,5%). Las E2 y E3 disminuirían la realización de analíticas (E1 56,8% de los pacientes; E2 9,9%; E3 22,4%; p<0,01), los ingresos hospitalarios (E1 11%; E2 6,9%; E3 7,9%; p<0,01) y la administración de antibioterapia (E1 8,6%; E2 6,7%; E3 6,4%; p<0,01). Trece pacientes se diagnosticaron de sepsis, las cuales se hubieran detectado con E2 y E3, salvo un paciente con bacteriemia asintomática por Enterococcusfaecalis. Ningún paciente con clínica leve y autolimitada en que no se inició antibioterapia, se diagnosticó posteriormente de sepsis. Conclusiones: La observación clínica estrecha parece una opción segura y podría disminuir la realización de pruebas complementarias, la tasa de hospitalización y el uso de antibioterapia innecesaria. Mantener una conducta expectante en pacientes con sintomatología leve y autolimitada en las primeras horas de vida parece no relacionarse con la no identificación de sepsis. (AU)

Introduction: Early-onset neonatal sepsis can cause significant morbidity and mortality, especially if it is not detected early. Given the decrease in its incidence in the past few decades, it is important to find a balance between reducing the use of diagnostic tests and continuing to detect affected patients. We compared 3 detection strategies in patients with risk factors (RFs) for infection: laboratory screening (S1), the neonatal sepsis risk calculator (S2) and clinical observation (S3). Patients and methods: Retrospective observational study in neonates born at 34 weeks or gestation or later and with RFs or symptoms compatible with early-onset neonatal sepsis. We analysed outcomes in our unit with the use of laboratory screening (S1) and compared them with the other two strategies (S2 and S3) to contemplate whether to modify our protocol. Results: The study included 754 patients, and the most frequent RFs were prolonged rupture of membranes (35.5%) and maternal colonization by Streptococcus agalactiae (38.5%). Strategies S2 and S3 would decrease the performance of laboratory tests (S1, 56.8% of patients; S2, 9.9%; S3, 22.4%; P<.01), hospital admissions (S1, 11%; S2, 6.9%; S3, 7.9%; P<.01) and the use of antibiotherapy (S1, 8.6%; S2, 6.7%; S3, 6.4%; P<.01). Sepsis was diagnosed in 13 patients, and it would have been detected with S2 and S3 except in 1 patient who had asymptomatic bacteriemia by Enterococcusfaecalis. No patient with mild and self-limited symptoms in whom antibiotherapy was not started received a diagnosis of sepsis later on. Conclusions: Close clinical observation seems to be a safe option and could reduce the use of diagnostic tests, hospital admission and unnecessary antibiotherapy. The watchful waiting approach in patients with mild and self-limiting symptoms in the first hours post birth does not appear to be associated with failure to identify sepsis. (AU)

How to assess early-onset neonatal sepsis? Comparison of three detection strategies.

INTRODUCTION: Early-onset neonatal sepsis (EONS) can cause significant morbidity and mortality, especially if it is not detected early. Given the decrease in its incidence in the past few decades, it is important to find a balance between reducing the use of diagnostic tests and continuing to detect affected patients. We compared 3 detection strategies in patients with risk factors (RFs) for infection: laboratory screening (S1), the Neonatal Sepsis Risk Calculator (S2) and clinical observation (S3). PATIENTS AND METHODS: Retrospective observational study in neonates born at 34 weeks of gestation or later and with RFs or symptoms compatible with EONS. We analysed outcomes in our unit with the use of laboratory screening (S1) and compared them with the other two strategies (S2 and S3) to contemplate whether to modify our protocol. RESULTS: The study included 754 patients, and the most frequent RFs were prolonged rupture of membranes (35.5%) and maternal colonization by Streptococcus agalactiae (38.5%). Strategies S2 and S3 would decrease the performance of laboratory tests (S1, 56.8% of patients; S2, 9.9%; S3, 22.4%; P < 0.01), hospital admissions (S1, 11%; S2, 6.9%; S3, 7.9%; P < 0.01) and the use of antibiotherapy (S1, 8.6%; S2, 6.7%; S3, 6.4%; P < 0.01). Sepsis was diagnosed in 13 patients, and it would have been detected with S2 and S3 except in 1 patient who had asymptomatic bacteriemia by Enterococcus faecalis. No patient with mild and self-limited symptoms in whom antibiotherapy was not started received a diagnosis of sepsis later on. CONCLUSION: Close clinical observation seems to be a safe option and could reduce the use of diagnostic tests, hospital admission and unnecessary antibiotherapy. The watchful waiting approach in patients with mild and self-limiting symptoms in the first hours post birth does not appear to be associated with failure to identify sepsis.

Manejo clínico de las complicaciones agudas de la anemia falciforme: 11 años de experiencia en un hospital terciario / Clinical management of the acute complications of sickle cell anemia: 11 years of experience in a tertiary hospital

Introducción: La drepanocitosis es una anemia emergente en Europa que condiciona una elevada morbilidad con complicaciones agudas y crónicas. El manejo de estos pacientes es complejo y requiere atención interdisciplinar. El objetivo del estudio es analizar las características y el manejo de los pacientes con drepanocitosis que ingresan por complicaciones agudas.Métodos: Estudio descriptivo retrospectivo de los ingresos por complicaciones agudas de pacientes con drepanocitosis menores de 16 años en un hospital terciario entre 2010 y 2020. Se revisaron los datos clínicos, analíticos y radiológicos.Resultados: Se incluyeron 71 ingresos correspondientes a 25 pacientes, el 40% diagnosticados por cribado neonatal. Los ingresos se incrementaron de forma progresiva durante este periodo. Los diagnósticos más frecuentes fueron la crisis vasooclusiva (35,2%), el síndrome febril (33,8%) y el síndrome torácico agudo (32,3%). Nueve pacientes precisaron ingreso en cuidados intensivos. En 20 ingresos se obtuvo documentación microbiológica, 60% bacterias. En el 86% se administró antibioterapia y 28% precisaron analgesia con opioides. El 89% cumplían la pauta de vacunación adecuada y el 41% recibían hidroxiurea previo al ingreso.Conclusiones: Las complicaciones agudas que precisan ingreso hospitalario son frecuentes en los pacientes con drepanocitosis, siendo las más habituales la crisis vasooclusiva y el síndrome febril. Esto conlleva un uso elevado de antibioterapia y opioides. El diagnóstico precoz facilita el reconocimiento de complicaciones de riesgo vital como el síndrome torácico agudo y el secuestro esplénico. A pesar de las medidas preventivas y los tratamientos indicados en la actualidad, estas complicaciones agudas precisan manejo hospitalario. (AU)

Introduction: Sickle cell disease is an emerging anemia in Europe leading to high morbidity with severe acute complications requiring hospital admission and chronic consequences. The management of these patients is complex and needs interdisciplinary care. The objective is to analyze clinical characteristics and management of patients with sickle cell disease admitted for acute complications.Methods: Retrospective descriptive study of admissions for acute complications of patients with sickle cell disease under 16 years of age in a tertiary hospital between 2010 and 2020. Clinical, laboratory and radiological data were reviewed.Results: We included 71 admissions corresponding to 25 patients, 40% diagnosed by neonatal screening. Admissions increased during this period. The most frequent diagnoses were vaso-occlusive crisis (35.2%), febrile syndrome (33.8%) and acute chest syndrome (32.3%). Nine patients required critical care at PICU. Positive microbiological results were confirmed in 20 cases, bacterial in 60%. Antibiotic therapy was administered in 86% of cases and the vaccination schedule of asplenia was adequately fulfilled by 89%. Opioid analgesia was required in 28%. Chronic therapy with hydroxyurea prior to admission was used in 41%.Conclusions: Acute complications requiring hospital admission are frequent in patients with sickle cell disease, being vaso-occlusive crisis and febrile syndrome the most common. These patients need a high use of antibiotics and opioid analgesia. Prior diagnosis facilitates the recognition of life-threatening complications such as acute chest syndrome and splenic sequestration. Despite the prophylactic and therapeutic measures currently provided to these patients, many patients suffer acute complications that require hospital management. (AU)

Clinical management of the acute complications of sickle cell anemia: 11 years of experience in a tertiary hospital.

INTRODUCTION: Sickle cell disease is an emerging anemia in Europe leading to high morbidity with severe acute complications requiring hospital admission and chronic consequences. The management of these patients is complex and needs interdisciplinary care. The objective is to analyze clinical characteristics and management of patients with sickle cell disease admitted for acute complications. METHODS: Retrospective descriptive study of admissions for acute complications of patients with sickle cell disease under 16 years of age in a tertiary hospital between 2010 and 2020. Clinical, laboratory and radiological data were reviewed. RESULTS: We included 71 admissions corresponding to 25 patients, 40% diagnosed by neonatal screening. Admissions increased during this period. The most frequent diagnoses were vaso-occlusive crisis (35.2%), febrile syndrome (33.8%) and acute chest syndrome (32.3%). Nine patients required critical care at PICU. Positive microbiological results were confirmed in 20 cases, bacterial in 60%. Antibiotic therapy was administered in 86% of cases and the vaccination schedule of asplenia was adequately fulfilled by 89%. Opioid analgesia was required in 28%. Chronic therapy with hydroxyurea prior to admission was used in 41%. CONCLUSIONS: Acute complications requiring hospital admission are frequent in patients with sickle cell disease, being vaso-occlusive crisis and febrile syndrome the most common. These patients need a high use of antibiotics and opioid analgesia. Prior diagnosis facilitates the recognition of life-threatening complications such as acute chest syndrome and splenic sequestration. Despite the prophylactic and therapeutic measures currently provided to these patients, many patients suffer acute complications that require hospital management.

Papel de la proteína asociada a pancreatitis en el cribado neonatal de la fibrosis quística / [Role of pancreatitis-associated protein in neonatal screening for cystic fibrosis]

Objetivo: El objetivo es comparar la eficacia de dos métodos de cribado de fibrosis quística (FQ) mediante la utilización de la medición del tripsinógeno inmunorreactivo (TIR) y la proteína asociada pancreatitis (PAP) en gota de sangre seca.Métodos: Estudio observacional prospectivo que evaluó a neonatos con niveles de TIR inicial (TIR1) mayor de 50ng/mL a los que se le ha realizado cuantificación de la PAP y una segunda determinación de TIR (TIR2) entre diciembre 2017 y junio 2020. Se comparó la detección de FQ entre dos protocolos de cribado TIR1/ TIR2 vs TIR1/PAP/TIR2.Resultados: Durante el período analizado se sometieron a cribado neonatal 60.399 neonatos, de los que 316 tuvieron TIR1 elevada. Se confirmaron 10 casos de FQ, con una incidencia de 1 caso por cada 6.039 neonatos cribados. El protocolo TIR1/TIR2 identificó 34 casos con una sensibilidad del 88,89%, especificidad 91,53%, valor predictivo positivo 23,53% y valor predictivo negativo de 99,65%. El protocolo TIR1/PAP/TIR2 obtuvo una sensibilidad 88,89 %, especificidad 96,42%, valor predictivo positivo 42,11% y valor predictivo negativo 99,66%. El alelo c.1521_1523delCTT se identificó en el 80% de los casos.Conclusiones: El protocolo TIR1/PAP/TIR2 aumenta la especificidad del cribado neonatal, obteniendo una disminución del 4,89% de la proporción de falsos positivos respecto al protocolo TIR1/TIR2. Este nuevo protocolo de cribado puede permitir hacer un cribado de la FQ más eficiente. (AU)

Objective: The aim is to compare the efficacy of two screening methods for cystic fibrosis (CF) by measuring immunoreactive trypsinogen (IRT) and pancreatitis-associated protein (PAP) in dried blood spots.Methods: Prospective observational study that evaluated neonates with initial IRR levels (IRR1) greater than 50ng/mL who underwent PAP quantification and a second IRR determination (IRR2) between December 2017 and June 2020. The CF detection between two screening protocols TIR1/TIR2 vs TIR1/PAP/TIR2.Results: During the analyzed period, 60,399 neonates underwent neonatal screening, of which 316 had elevated IRR1. 10 cases of CF were confirmed, with an incidence of 1 case per 6,039 newborns screened. The TIR1/TIR2 protocol identified 34 cases with a sensitivity of 88.89%, specificity 91.53%, positive predictive value 23.53%, and negative predictive value 99.65%. The TIR1/PAP/TIR2 protocol obtained a sensitivity of 88.89%, a specificity of 96.42%, a positive predictive value of 42.11%, and a negative predictive value of 99.66%. The c.1521_1523delCTT allele was identified in 80% of cases.Conclusions: The TIR1/PAP/TIR2 protocol increases the specificity of neonatal screening, obtaining a 4.89% decrease in the proportion of false positives compared to the TIR1/TIR2 protocol. This new screening protocol may allow CF screening to be more efficient. (AU)

Cribado neonatal genómico. Perspectiva de la Comisión de ética de la Asociación Española de Genética Humana. Parte II: Aspectos Éticos, Legales y Sociales (AELS) de la Introducción de las Tecnologías de Secuenciación Masiva (NGS) en un programa de cribado neonatal de Salud Pública / Genomic newborn screening. Perspective from the Ethics Commission of the Spanish Society for Human Genetics. Part II: Ethical, legal and social issues (ELSIs) of the introduction of next generation sequencing technologies in a public health newborn screening program

La secuenciación genómica es una tecnología extraordinariamente atractiva, tanto como lo es la idea de poder aplicarla a todos los recién nacidos, estableciendo con ello una etapa de cuidados médicos para toda la vida y acciones preventivas a medida del genoma de cada niño. En la parte I de este artículo se analizaron las limitaciones y oportunidades que presentan las tecnologías de secuenciación de nueva generación (NGS). La parte II relaciona el conocimiento científico con los aspectos éticos, legales y sociales (AELS) de su introducción en un programa de cribado neonatal de salud pública de aplicación universal a población vulnerable y asintomática, que debe ser guiada por los principios fundamentales de “no hacer daño” y de actuar “en el mejor interés del niño”. Para ello se contemplan en primer lugar los principios éticos de la medicina y de la salud pública que rigen el cribado neonatal, a continuación se resumen los principales aspectos de nuestro marco legal al respecto y finalmente en el ámbito social se analizan la influencia del imperativo tecnológico, la de los actores comerciales, los grupos de apoyo de pacientes y por último la perspectiva de los padres y aspectos psicosociales. Las conclusiones son que en este contexto la secuenciación genómica completa no debe ser implementada como cribado neonatal universal, sin embargo el uso de las NGS podría ser una oportunidad para ampliar los programas incluyendo enfermedades infantiles tratables que no pudiesen ser detectadas con otros métodos. Realizando para ello una aproximación dirigida a enfermedades/genes concretos, a fin de identificar variantes genómicas bien conocidas, altamente penetrantes confiriendo riesgo elevado de enfermedad prevenible o tratable, para la cual el tratamiento deba iniciarse en el periodo neonatal.(AU)

Genome sequencing is a very attractive technology as it is also the idea of sequencing children at birth, with the aim to establish medical care and preventive actions during their whole life, tailored to the genome of each newborn. Part I of this article analyses limitations and opportunities of next generation sequencing technologies (NGS). Part II relates scientific knowledge with ethical, legal and social issues (ELSIs) concerning its application to a newborn screening program. This program is offered universally to a vulnerable and asymptomatic population and must be guided by principles of “do not harm” and to act in the “best interest of child”. With this purpose, this article considers, first of all, ethical principles of bioethics and public health that govern newborn screening. Then it summarizes main issues of our legal framework. And finally, in social context, it analyzes influences of technological imperative, commercial actors and patient ́s advocacy groups, as well as parent’s perspective and psychosocial aspects. In this context, conclusion is that whole genome sequencing should not be implemented as universal newborn screening. Nevertheless, the use of NGS could be an opportunity to extend these programs, including treatable infantile diseases that cannot be detected with other technologies. That means realizing a directed approach in order to identify well known genomic variants, highly penetrant, that confer a high risk of preventable or treatable diseases for which treatment must begin at the neonatal period. The implementation of such directed genomic screening should follow current evidence based model for newborn screening.(AU)

Cribado neonatal genómico. Perspectiva de la Comisión de ética de la Asociación Española de Genética Humana. Parte I. Las tecnologías de secuenciación masiva (NGS) y su aplicación al cribado neonatal. Desafíos y oportunidades / Genomic newborn screening. Perspective from the Ethics commission of the Spanish Society for Human Genetics. Part I. Next generation sequencing technologies applied to newborn screening. Challenges and opportunities

En 2003, cuando finalizó el Proyecto Genoma Humano, surgió la idea de secuenciar el genoma a todos los recién nacidos, archivarlo en la historia clínica y usarlo a lo largo de toda la vida para manejar riesgos de enfermedades y respuesta a medicamentos. Dieciocho años más tarde, las promesas de la medicina genómica y el extraordinario abaratamiento de las tecnologías secuenciadoras, siguen alimentando este sueño que todavía plantea grandes desafíos prácticos, éticos y sociales y la secuenciación genómica se presenta como el próximo gran cambio histórico en los programas de cribado neonatal. En el presente artículo, se analizan los retos y oportunidades de las tecnologías secuenciadoras de nueva generación, sus costos reales, la problemática inherente a la gestión, almacenamiento y protección de la enorme cantidad de datos genómicos que generan y finalmente, en base a las conclusiones de investigaciones recientes, se considera el potencial y limitaciones de su aplicación en dos escenarios, el recién nacido enfermo con finalidades diagnósticas y el recién nacido sano, asintomático, con finalidades de salud pública(programas de cribado neonatal). En una segunda parte de este artículo se tendrán en cuenta los aspectos éticos, legales y sociales (AELS). El objetivo final es contribuir al debate científico, profesional, ético y social, promoviendo que la secuenciación genómica en el recién nacido no sea usada indiscriminadamente constituyendo un riesgo, sino que bien empleada sea una aliada en la promoción de la salud y prevención de las consecuencias de las enfermedades genéticas.(AU)

In 2003 at the ending of the Human Genome Project, it aroused the idea that all newborns could be sequenced and its genome archived in the clinical record, in order to manage risks of diseases and response to medicaments along his whole life. Eighteen years later, promises of genomic medicine and tremendous decrease of costs of next generation sequencing technologies, continues feeding this dream that shows important practical, ethical and social challenges and genomic sequencing is presented as the next historical change in newborn screening programs. In this article we analyze challenges and opportunities of next generation sequencing technologies, their real costs, problems associated to management, storage and protection of the enormous amount of genomic data produced and finally, according to conclusions of recent researches, there are considered the conclusions in two contexts, sick newborn with diagnostic purposes and healthy asymptomatic newborns with public health purposes (newborn screening programs). In a second part of this article it will be considered ethical, legal and social issues (ELSI). Final objective is to contribute to scientific, professional, ethics and social debate in order to promote that genome sequencing in newborn don’t be used indiscriminately constituting a risk, but properly done, as a partner in the promotion of health and prevention of consequences of genetic diseases.(AU)

Evaluación de la función tiroidea en el recién nacido pretérmino o de muy bajo peso / Assessment of thyroid function in the preterm and/or very low birth weight newborn

El Programa de cribado o detección precoz del hipotiroidismo congénito es uno de los mayores avances logrados en Pediatría. Las hormonas tiroideas son imprescindibles para el desarrollo y la maduración cerebral, que continúan en la etapa neonatal. Las alteraciones de la función tiroidea en niños prematuros y con bajo peso en los primeros meses de vida origina lesiones irreversibles en el sistema nervioso central y es una de las causas más frecuentes y evitables de retraso mental. El diagnóstico en el periodo neonatal es difícil, por lo que requiere estudio analítico para poder efectuar el tratamiento adecuado.La relevancia de este problema justifica su difusión a todas las áreas de Pediatría. El objetivo principal, evitar el daño cerebral en estos pacientes. Otros aspectos para optimizar el desarrollo adecuado de estos niños con todos los controles periódicos necesarios y lograr la inclusión del diagnóstico de las alteraciones tiroideas durante la estancia en unidades neonatales y en los primeros meses de vida precisan implementar los recursos de los centros sanitarios y continuar avanzando según los conocimientos actuales.En el presente documento nos centraremos en el cribado de los recién nacidos pretérmino (< 32 semanas de gestación) o con muy bajo peso para la edad gestacional (1.500-1.000 g muy bajo peso al nacer, o<1.000 g peso extremadamente bajo al nacer) y la protocolización de evaluación de función tiroidea en prematuros.Actualizamos los procedimientos diagnósticos, las pruebas imprescindibles y complementarias requeridas, la etiología y los diagnósticos diferenciales en esta patología. (AU)

The screening program or early detection of congenital hypothyroidism is one of the greatest advances achieved in Pediatrics. Thyroid hormones are essential for brain development and maturation, which continue into the neonatal stage. Alterations in thyroid function in premature and underweight children in the first months of life causes irreversible damage to the central nervous system and is one of the most frequent and avoidable causes of mental retardation. Diagnosis in the neonatal period is difficult, so it requires an analytical study to be able to carry out the appropriate treatment.The relevance of this problem justifies its communication to all areas of pediatrics. The main objective is to avoid brain damage in these patients. Other aspects to optimize the adequate development of these children with all the necessary periodic controls and to achieve the inclusion of the diagnosis of thyroid alterations during the stay in neonatal units and in the first months of life, need to implement the resources of the health centers and continue advancing according to current knowledge.In this document, we will focus on the screening of preterm newborns VLBW (<32 weeks of gestation) and/or very low weight for gestational age (1500-1000g VLBW or <1000g) and the function evaluation protocol thyroid in premature babies.We update the diagnostic procedures, the essential and complementary tests required, the etiology and the differential diagnoses in this pathology. (AU)

New-born Hearing Screening Programmes in 2020: CODEPEH Recommendations.

Programmes for early detection of congenital hearing loss have been successfully implemented mainly in developed countries, after overcoming some conceptual errors argued against their implementation and some criticism of their efficacy. However, some difficulties and weaknesses are still identified in these programmes: the detection of late-onset hearing loss and the percentage of children who did not pass the screening and did not complete the process of diagnosis and treatment, these being cases that are lost in the process. The purpose of this Document is to analyse these problems to determine areas for improvement and to emphasize one of the basic principles for the success of the programmes: continuous training for the interdisciplinary team. The result of the review process carried out by CODEPEH has been drafted as Recommendations for updating the Programmes with the evidence of the last decade, including advances in screening technology, the impact of the present knowledge on congenital infection by cytomegalovirus, genetic hearing loss research and control systems of lost to follow-up cases, treatment and follow up.

Assessment of thyroid function in the preterm and/or very low birth weight newborn.

The screening program or early detection of congenital hypothyroidism is one of the greatest advances achieved in Pediatrics. Thyroid hormones are essential for brain development and maturation, which continue into the neonatal stage. Alterations in thyroid function in premature and underweight children in the first months of life causes irreversible damage to the central nervous system and is one of the most frequent and avoidable causes of mental retardation. Diagnosis in the neonatal period is difficult, so it requires an analytical study to be able to carry out the appropriate treatment. The relevance of this problem justifies its communication to all areas of pediatrics. The main objective is to avoid brain damage in these patients. Other aspects to optimize the adequate development of these children with all the necessary periodic controls and to achieve the inclusion of the diagnosis of thyroid alterations during the stay in neonatal units and in the first months of life, need to implement the resources of the health centers and continue advancing according to current knowledge. In this document, we will focus on the screening of preterm newborns VLBW (<32 weeks of gestation) and/or very low weight for gestational age (1500-1000 g VLBW or <1000 g) and the function evaluation protocol thyroid in premature babies. We update the diagnostic procedures, the essential and complementary tests required, the etiology and the differential diagnoses in this pathology.

Retinitis pigmentosa as a clinical presentation of LCHAD deficiency: A clinical case and review of the literature.

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency is a rare metabolic disease caused by a specific mutation in the HADHA gene, which leads to an alteration in the metabolic pathway of fatty acids. Its most frequent form of presentation at the ophthalmological level is retinitis pigmentosa, and in some cases the ophthalmologist could be the first one to alert the other paediatric specialties to carry out a multidisciplinary approach to the case. The case is presented of a patient with long-chain 3-hydroxyacyl-CoA dehydrogenase deficit detected in neonatal screening, and which clinically debuted as pigmentary retinosis with no alteration in visual acuity as observed in the fundus images and optical coherence tomography of the retina provided. Finally, a review of the literature of this potentially lethal pathology is presented, and the main pathological and clinical features are highlighted.

Retinosis pigmentaria como clínica de presentación del déficit de LCHAD: caso clínico y revisión de la literatura / Retinitis pigmentosa as a clinical presentation of LCHAD deficiency: A clinical case and review of the literature

El déficit de 3-hidroxiacil CoA-deshidrogenasa de cadena larga es una enfermedad metabólica poco frecuente debido a una mutación específica en el gen HADHA, lo que provoca una alteración en la vía metabólica de los ácidos grasos. Su forma de presentación más frecuente a nivel oftalmológico es la retinosis pigmentaria, y en algunos casos el oftalmólogo podría ser quien alerte a las demás especialidades pediátricas para llevar a cabo un abordaje multidisciplinar del caso. Presentamos el caso de una paciente con déficit de 3-hidroxiacil CoA-deshidrogenasa de cadena larga detectado en el cribado neonatal que inició clínicamente como retinosis pigmentaria sin alteración de la agudeza visual y del que se aportan imágenes de fondo de ojo y de tomografía de coherencia óptica de la retina. Por último, se expone una revisión de la literatura de esta enfermedad potencialmente letal y se destacan las principales características anatomopatológicas y clínicas (AU)

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency is a rare metabolic disease caused by a specific mutation in the HADHA gene, which leads to an alteration in the metabolic pathway of fatty acids. Its most frequent form of presentation at the ophthalmological level is retinitis pigmentosa, and in some cases the ophthalmologist could be the first one to alert the other paediatric specialties to carry out a multidisciplinary approach to the case. The case is presented of a patient with long-chain 3-hydroxyacyl-CoA dehydrogenase deficit detected in neonatal screening, and which clinically debuted as pigmentary retinosis with no alteration in visual acuity as observed in the fundus images and optical coherence tomography of the retina provided. Finally, a review of the literature of this potentially lethal pathology is presented, and the main pathological and clinical features are highlighted (AU)

Programas de cribado de la hipoacusia congénita en 2020: recomendaciones CODEPEH / New-born hearing screening programmes in 2020: CODEPEH recommendations

Los programas de detección precoz de la hipoacusia congénita se han extendido de forma exitosa, especialmente en países desarrollados, superando los errores conceptuales argumentados contra su implantación o las críticas a su eficacia. No obstante, aún se identifican algunas dificultades y debilidades: la detección de la hipoacusia de desarrollo tardío y el porcentaje de niños que no pasaron el cribado y no completan el diagnóstico ni el tratamiento, siendo casos que se pierden en el proceso son algunas de ellas.El objetivo del presente documento es analizar estos problemas para determinar puntos de mejora e incidir en un principio básico del éxito de los programas: la formación continuada del equipo interdisciplinario.El resultado del trabajo de revisión llevado a cabo por la CODEPEH se plasma en la formulación de unas recomendaciones orientadas a actualizar los programas con las evidencias aparecidas en la última década, incorporando los progresos de la tecnología, los conocimientos actuales sobre la infección congénita por citomegalovirus y los estudios genéticos de la hipoacusia en los programas, así como los sistemas de control de la pérdida de casos en el proceso, el tratamiento y el seguimiento. (AU)

Programs for early detection of congenital hearing loss have been successfully implemented mainly in developed countries, after overcoming some conceptual errors argued against their implementation and some criticism of their efficacy. However, some difficulties and weaknesses are still identified in these programs: the detection of late-onset hearing loss and the percentage of children who did not pass the screening and did not complete the process of diagnosis and treatment, these being cases that are lost in the process.The purpose of this Document is to analyse these problems to determine areas for improvement and to emphasize one of the basic principles for the success of the programs: continuous training for the interdisciplinary team.The result of the review process carried out by CODEPEH has been drafted as Recommendations for updating the Programs with the evidence of the last decade, including advances in screening technology, the impact of the present knowledge on congenital infection by cytomegalovirus, genetic hearing loss research and control systems of lost to follow-up cases, treatment and follow up. (AU)

Cribado neonatal de fibrosis quística: análisis y diferencias de los niveles de tripsina inmunorreactiva en recién nacidos con cribado positivo / Neonatal cystic fibrosis screening: Analysis and differences in immunoreactive trypsin levels in newborns with a positive screen

Introducción: El cribado neonatal de fibrosis quística (FQ) ha permitido el diagnóstico precoz de la enfermedad, siendo determinante en el aumento de supervivencia de estos pacientes. Su principal inconveniente es su baja especificidad y elevado número de falsos positivos. El objetivo fue analizar las diferencias de tripsina inmunorreactiva (TIR) entre los diferentes grupos de recién nacidos (RN) con cribado neonatal positivo según fueran sanos, portadores sanos, afectos de FQ o Cystic Fibrosis Screen Positive, Inconclusive Diagnosis (CFSPID). Material: Estudio retrospectivo analítico de las concentraciones de TIR en RN con cribado neonatal positivo para FQ nacidos en un hospital de tercer nivel durante 8 años. Resultados:Se analizaron 790RN con cribado neonatal positivo para FQ, 86,3% a término, 53% niñas y 11,8% ingresados. El valor medio de TIR fue 79,16ng/ml (rango 60-367). Se encontraron concentraciones significativamente más elevadas de TIR en afectos de FQ con respecto a los otros grupos (p<0,001). Existen niveles superiores en grandes prematuros (p=0,007) e ingresados (p=0,002). No difieren en cuanto a sexo o estacionalidad. Existe una correlación directa del 64% (p=0,001) entre TIR y test del sudor en afectos de FQ y CFSPID. Mediante curva ROC se calculó el valor de corte de TIR para el diagnóstico de FQ, que fue 76,2ng/ml (S=95,7%, E=64,5%). Conclusiones: Los RN con FQ presentan cifras significativamente más elevadas de TIR que sanos, portadores o CFSPID. La prematuridad y hospitalización también pueden influir. Un mayor valor de TIR se relaciona con una mayor cifra en el test del sudor. (AU)

Introduction: Neonatal cystic fibrosis (CF) screening has enabled the disease to be diagnosed early, and is a determining factor in the increase in survival of these patients. Its main disadvantage is its low specificity and elevated number of false positives. The aim of this study is to analyse the differences in immunoreactive trypsin (IRT) between the different groups of newborns (NB) with a positive neonatal screen depending on whether they were healthy, healthy carriers, affected by CF, or CFSPID (Cystic Fibrosis Screen Positive, Inconclusive Diagnosis). Material: Retrospective analytical study of the concentrations of IRT in NB with a positive neonatal screen for CF born in a tertiary hospital during an 8-year period. Results: A total of 790 NB with a positive neonatal screen for CF were analysed. Of these 86.3% were term, 53% girls, and 11.8% were admitted. The mean IRT value was 79.16 ng/mL (range 60 – 367). Significantly higher concentrations of IRT were found in those affected by CF compared to the other groups (P<.001). There were higher levels in large prematures (P=.007) and admitted patients (P=.002). There were no differences as regards gender or season. There was a direct correlation of 64% (P=.001) between IRT and sweat test in those affected by CF and CFSPID. A cut-off value of IRT for the diagnosis of CF was calculated from the ROC curve (76.2 ng/mL (S=95.7%, Sp=64.5%). Conclusions: NB with CF have significantly higher levels of IRT than healthy ones, or carriers and CFSPID. Prematurity and hospital admission may also have an influence. A higher IRT value is associated with a higher level in the sweat test.

Neonatal cystic fibrosis screening: Analysis and differences in immunoreactive trypsin levels in newborns with a positive screen.

INTRODUCTION: Neonatal cystic fibrosis (CF) screening has enabled the disease to be diagnosed early, and is a determining factor in the increase in survival of these patients. Its main disadvantage is its low specificity and elevated number of false positives. The aim of this study is to analyse the differences in immunoreactive trypsin (IRT) between the different groups of newborns (NB) with a positive neonatal screen depending on whether they were healthy, healthy carriers, affected by CF, or CFSPID (Cystic Fibrosis Screen Positive, Inconclusive Diagnosis). MATERIAL: Retrospective analytical study of the concentrations of IRT in NB with a positive neonatal screen for CF born in a tertiary hospital during an 8-year period. RESULTS: A total of 790 NB with a positive neonatal screen for CF were analysed. Of these 86.3% were term, 53% girls, and 11.8% were admitted. The mean IRT value was 79.16 ng/mL (range 60-367). Significantly higher concentrations of IRT were found in those affected by CF compared to the other groups (P < .001). There were higher levels in large prematures (P = .007) and admitted patients (P = .002). There were no differences as regards gender or season. There was a direct correlation of 64% (P = .001) between IRT and sweat test in those affected by CF and CFSPID. A cut-off value of IRT for the diagnosis of CF was calculated from the ROC curve (76.2 ng/mL (S = 95.7%, Sp = 64.5%). CONCLUSIONS: NB with CF have significantly higher levels of IRT than healthy ones, or carriers and CFSPID. Prematurity and hospital admission may also have an influence. A higher IRT value is associated with a higher level in the sweat test.

Cribado neonatal de la atrofia muscular espinal: el momento es ahora / Neonatal screening for spinal muscular atrophy: the time is now

La atrofia muscular espinal (AME) es la enfermedad neurodegenerativa más común en la infancia. La aprobación reciente de nuevas terapias efectivas ha justificado la implementación desde hace dos años de un programa piloto de cribado neonatal en la Federación Valonia Bruselas (FWB).Se describe el procedimiento de cribado neonatal utilizado actualmente para detección para la AME en recién nacidos en el sur de Bélgica. El coste del cribado es de 3,10 € por niño. Si se mantiene esta configuración, representa un coste anual de 181 000 € (por aproximadamente 60 000 nacimientos anuales en FWB).En el contexto de contar con un método de cribado neonatal fiable, con un coste económico moderado y la posibilidad de un tratamiento inmediato viable, los autores recomiendan la inclusión y financiación del despistaje de la atrofia muscular espinal en la lista de enfermedades incluidas oficialmente en el marco del cribado neonatal. (AU)

Spinal muscular atrophy (SMA) is the most common neurodegenerative disease in childhood. The recent approval of new effective therapies has justified the implementation of a pilot neonatal screening program in the Federation Wallonia Brussels (FWB).The neonatal screening procedure currently used for screening for SMA in newborns in southern Belgium is described. The cost of screening is € 3.10 per child. If this configuration is maintained, it represents an annual cost of € 181,000 (for approximately 60,000 annual births in FWB).In the context of having a reliable neonatal screening method, with a moderate economic cost and the possibility of a viable immediate treatment, the authors recommend the inclusion and financing of the screening for the spinal muscular atrophy in the list of diseases officially included in the framework of the neonatal screening program. (AU)

[Assessment of thyroid function in the preterm and/or very low birth weight newborn]. / Evaluación de la función tiroidea en el recién nacido pretérmino o de muy bajo peso.

The screening program or early detection of congenital hypothyroidism is one of the greatest advances achieved in Pediatrics. Thyroid hormones are essential for brain development and maturation, which continue into the neonatal stage. Alterations in thyroid function in premature and underweight children in the first months of life causes irreversible damage to the central nervous system and is one of the most frequent and avoidable causes of mental retardation. Diagnosis in the neonatal period is difficult, so it requires an analytical study to be able to carry out the appropriate treatment. The relevance of this problem justifies its communication to all areas of pediatrics. The main objective is to avoid brain damage in these patients. Other aspects to optimize the adequate development of these children with all the necessary periodic controls and to achieve the inclusion of the diagnosis of thyroid alterations during the stay in neonatal units and in the first months of life, need to implement the resources of the health centers and continue advancing according to current knowledge. In this document, we will focus on the screening of preterm newborns VLBW (<32 weeks of gestation) and/or very low weight for gestational age (1500-1000g VLBW or <1000g) and the function evaluation protocol thyroid in premature babies. We update the diagnostic procedures, the essential and complementary tests required, the etiology and the differential diagnoses in this pathology.

Cribado de infección por citomegalovirus congénito en recién nacidos de alto riesgo / Congenital cytomegalovirus infection screening in high risk newborn

INTRODUCCIÓN: La infección congénita por citomegalovirus (CMVc) es la causa más frecuente de infección intrauterina, 90% de los recién nacidos (RN) son asintomáticos al nacer y 6 a 15% desarrollarán secuelas a largo plazo, siendo la principal etiología de hipoacusia sensorio-neural no-genética. OBJETIVO: Determinar la prevalencia de CMVc en RN de alto riesgo. PACIENTES Y MÉTODO: Estudio de cohorte prospectivo, incluyó RN hospitalizados, con uno o más de los siguientes criterios: peso de nacimiento < 1.500 g, < 32 semanas edad gestacional (EG), pequeños para edad gestacional (PEG) severos, sospecha de infección congénita o que "no pasan" en estudio auditivo al nacer, además de hijos de madre con infección por VIH. Se realizó reacción de polimerasa en cadena para CMV en orina antes de 21 días de vida. RESULTADOS: Se enrolaron 193 RN. Prevalencia global CMVc 2,6% (n: 5) y por grupo de riesgo: 1/3 (n: 1) en RN con sospecha activa de infección congénita, 8,3% en RN con resultado "no pasa" en estudio auditivo, 4,9% en hijos de madre con infección por VIH, 3,3% en PEG severo y 1,7% < 1500 g, ninguno con asociación significativa. Sólo un paciente con CMVc fue sintomático, quien falleció en el período neonatal y los restantes RN con CMVc (asintomáticos) tienen seguimiento auditivo normal. DISCUSIÓN: La prevalencia reportada es comparable a las internacionales. Recomendamos cribado de CMVc, al menos en grupos de riesgo, siendo lo ideal el cribado universal. Esto permitiría su tratamiento oportuno y un seguimiento activo.

BACKGROUND: Congenital cytomegalovirus infection (cCMV) is the most frequent cause of congenital infection, 90% of affected newborn (NB) are asymptomatic at birth and 6-15% will develop long term sequalae. It is the main etiology of non-genetic sensorineural hearing loss. AIM: To determine prevalence of CMV in high risk NB. Methods: Cohort prospective study, including inpatient NB with one or more of following criteria: birth weight < 1,500 g, < 32 weeks gestational age (GA), severe small for gestational age (SGA), suspected congenital infection or "refer" in newborn hearing test, also NB to HIV-infected mothers. Urine CMV polymerase chain reaction was performed within 21 day of life. RESULTS: 193 NB were enrolled. Global cCMV prevalence 2.6% (n: 5) and by risk group: one third (n: 1) in NB with suspected congenital infection, 8.3% in NB with "refer" result in hearing test, 4.9% in NB to HIV-infected mothers, 3.3% in severe SGA and 1.7% in < 1,500 g, none with significant association. Only one symptomatic cCMV was detected who died in neonatal period and the remaining (asymptomatic) cCMV patients have normal hearing follow-up. DISCUSSION: Reported prevalence was comparable to international reports. We recommend cCMV screening, at least in risk groups, being ideal the universal screening. This would allow timely treatment and active follow-up.