Repercussions of inborn errors of immunity on growth

Objectives: This study aimed to review the literature on the repercussions of the different inborn errors of immunity on growth, drawing attention to the diagnosis of this group of diseases in patients with growth disorders, as well as to enable the identification of the different causes of growth disorders in patients with inborn errors of immunity, which can help in their treatment. Data sources: Non-systematic review of the literature, searching articles since 2000 in PubMed with the terms “growth”, “growth disorders”, “failure to thrive”, or “short stature” AND “immunologic deficiency syndromes”, “immune deficiency disease”, or “immune deficiency” NOT HIV. The Online Mendelian Inheritance in Man (OMIN) database was searched for immunodeficiencies and short stature or failure to thrive. Data summary: Inborn errors of immunity can affect growth in different ways, and some of them can change growth through multiple simultaneous mechanisms: genetic syndromes; disorders of the osteoarticular system; disorders of the endocrine system; reduction in caloric intake; catabolic processes; loss of nutrients; and inflammatory and/or infectious conditions. Conclusions: The type of inborn errors of immunity allows anticipating what type of growth disorder can be expected. The type of growth disorder can help in the diagnosis of clinical conditions related to inborn errors of immunity. In many inborn errors of immunity, the causes of poor growth are mixed, involving more than one factor. In many cases, impaired growth can be adjusted with proper inborn errors of immunity treatment or proper approach to the mechanism of growth impairment. Resumo: Objetivos: Revisão da literatura sobre as repercussões dos diferentes erros inatos da imunidade sobre o crescimento, chamar a atenção para o diagnóstico desse grupo de doenças em pacientes que apresentem desordens do crescimento, assim como permitir que se identifiquem as diferentes causas de alterações do crescimento em pacientes com erros inatos da imunidade, o que pode auxiliar em seu manejo. Fonte dos dados: Revisão não sistemática da literatura, com busca de artigos desde 2000 no Pubmed com os termos “growth” ou “growth disorders” ou “failure to thrive” ou “short stature” AND “immunologic deficiency syndromes” ou “immune deficiency disease” ou “imune deficiency” NOT HIV. E buscas na base OMIN (Online Mendelian Inheritance in Man) por imunodeficiências e baixa estatura ou falha no crescimento (“failure to thrive”). Síntese dos dados: Há diferentes modos pelos quais os erros inatos da imunidade podem afetar o crescimento e alguns deles podem alterar o crescimento por múltiplos mecanismos simultâneos: síndromes genéticas; afecções do aparelho osteoarticular; afecções do sistema endócrino; redução de aporte calórico; processos catabólicos: perda de nutrientes, assim como afecções inflamatórias e/ou infecciosas. Conclusões: O tipo de erros inatos da imunidade permite prever que tipo de alteração no crescimento devemos esperar. O tipo de alteração no crescimento pode auxiliar no diagnóstico de condições clínicas associadas aos erros inatos da imunidade. Em muitos erros inatos da imunidade, as causas do crescimento deficiente são mistas, envolvem mais de um fator. Em muitos casos, o prejuízo do crescimento pode ser corrigido com o adequado tratamento dos erros inatos da imunidade ou adequada abordagem do mecanismo que causa o prejuízo do crescimento. Keywords: Diseases of the immune system, Immune deficiency syndromes, Growth, Growth disorders, Palavras-chave: Doenças do sistema imune, Síndromes de imunodeficiência, Crescimento, Transtornos do cresciment

Tecnologias de informação e comunicação e ensino semipresencial na educação médica

O ensino médico vem enfrentando desafios para modificar suas práticas pedagógicas e estrutura curricular. As tecnologias de informação e comunicação (TICs) podem auxiliar no enfrentamento de muitos desses desafios. Tendo em vista esse cenário, este estudo tem como objetivo caracterizar as formas de apropriação de uma Ferramenta de Autoria de cursos na Internet em processos formativos semipresenciais de graduação, pós-graduação, educação continuada e extensão na área médica, no contexto da UFRJ. Com base nas análises, foi possível identificar o perfil de utilização das TICs e discutir os resultados, a partir dos ambientes virtuais de aprendizagem construídos pelos professores, de acordo com as seguintes categorias: unidades acadêmicas de origem; disciplinas e níveis de ensino envolvidos; configuração de áreas de conhecimento dos cursos semipresenciais; conformação das equipes docentes dos cursos; recursos de conteúdo e de comunicação utilizados; e atividades pedagógicas adotadas

Genetic screening in a Brazilian cohort with inborn errors of immunity

Abstract Background Inherited genetic defects in immune system-related genes can result in Inborn Errors of Immunity (IEI), also known as Primary Immunodeficiencies (PID). Diagnosis of IEI disorders is challenging due to overlapping clinical manifestations. Accurate identification of disease-causing germline variants is crucial for appropriate treatment, prognosis, and genetic counseling. However, genetic sequencing is challenging in low-income countries like Brazil. This study aimed to perform genetic screening on patients treated within Brazil's public Unified Health System to identify candidate genetic variants associated with the patient’s phenotype. Methods Thirteen singleton unrelated patients from three hospitals in Rio de Janeiro were enrolled in this study. Genomic DNA was extracted from the peripheral blood lymphocytes of each patient, and whole exome sequencing (WES) analyses were conducted using Illumina NextSeq. Germline genetic variants in IEI-related genes were prioritized using a computational framework considering their molecular consequence in coding regions; minor allele frequency ≤ 0.01; pathogenicity classification based on American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines gathered from the VarSome clinical database; and IEI-related phenotype using the Franklin tool. The genes classification into IEI categories follows internationally recognized guidelines informed by the International Union of Immunological Societies Expert Committee. Additional methods for confirmation of the variant included Sanger sequencing, phasing analysis, and splice site prediction. Results A total of 16 disease-causing variants in nine genes, encompassing six different IEI categories, were identified. X-Linked Agammaglobulinemia, caused by BTK variations, emerged as the most prevalent IEI disorder in the cohort. However, pathogenic and likely pathogenic variants were also reported in other known IEI-related genes, namely CD40LG, CARD11, WAS, CYBB, C6, and LRBA. Interestingly, two patients with suspected IEI exhibited pathogenic variants in non-IEI-related genes, ABCA12 and SLC25A13, potentially explaining their phenotypes. Conclusions Genetic screening through WES enabled the detection of potentially harmful variants associated with IEI disorders. These findings contribute to a better understanding of patients' clinical manifestations by elucidating the genetic basis underlying their phenotypes

Data table 3 - Detailed information of the rare and Pathogenic/Likely pathogenic variants found in the cohort

This work aims (i) to make available genomic data generated from the whole-exome sequencing (WES) of Brazilian patients' suspicion of inborn error of immunity (IEI) without genetic diagnosis; (ii) to improve the diagnostic yield of monogenic disorders by providing a clinically relevant dataset; and (iii) to provide high-throughput data with exploitable potential to gain insights about the genomic population structure of the Brazilians.  We sequenced genomic DNA from twenty unrelated patients treated at four different hospitals in the state of Rio de Janeiro, Brazil. Half of the patients were male with mean ages of 9±3 while females were 12±10  years old. WES were conducted through Illumina NextSeq platform and achieved 90% of the genetic basis coverage by >30 reads. More than 80% of the sequencing reads were uniquely mapped to the reference genome. Each sample had an average of 20,274 variants, being 114 classified as rare pathogenic or likely pathogenic according to ACMG guidelines. Overall, the access to clinical exome sequencing data is limited, challenging exploratory analyses and the understanding of genetic mechanisms underlying disorders. Thus, by making these data available, we foresee increasing the number of WES data from Brazilians despite contributing to the study of  monogenic IEI-disorders. </p

Data table 2 - Overview of the sequencing metrics

This work aims (i) to make available genomic data generated from the whole-exome sequencing (WES) of Brazilian patients' suspicion of inborn error of immunity (IEI) without genetic diagnosis; (ii) to improve the diagnostic yield of monogenic disorders by providing a clinically relevant dataset; and (iii) to provide high-throughput data with exploitable potential to gain insights about the genomic population structure of the Brazilians.  We sequenced genomic DNA from twenty unrelated patients treated at four different hospitals in the state of Rio de Janeiro, Brazil. Half of the patients were male with mean ages of 9±3 while females were 12±10  years old. WES were conducted through Illumina NextSeq platform and achieved 90% of the genetic basis coverage by >30 reads. More than 80% of the sequencing reads were uniquely mapped to the reference genome. Each sample had an average of 20,274 variants, being 114 classified as rare pathogenic or likely pathogenic according to ACMG guidelines. Overall, the access to clinical exome sequencing data is limited, challenging exploratory analyses and the understanding of genetic mechanisms underlying disorders. Thus, by making these data available, we foresee increasing the number of WES data from Brazilians despite contributing to the study of  monogenic IEI-disorders. </p

Data file 1 - Flowchart of the pipeline used to prioritize genetic variants

This work aims (i) to make available genomic data generated from the whole-exome sequencing (WES) of Brazilian patients' suspicion of inborn error of immunity (IEI) without genetic diagnosis; (ii) to improve the diagnostic yield of monogenic disorders by providing a clinically relevant dataset; and (iii) to provide high-throughput data with exploitable potential to gain insights about the genomic population structure of the Brazilians.  We sequenced genomic DNA from twenty unrelated patients treated at four different hospitals in the state of Rio de Janeiro, Brazil. Half of the patients were male with mean ages of 9±3 while females were 12±10  years old. WES were conducted through Illumina NextSeq platform and achieved 90% of the genetic basis coverage by >30 reads. More than 80% of the sequencing reads were uniquely mapped to the reference genome. Each sample had an average of 20,274 variants, being 114 classified as rare pathogenic or likely pathogenic according to ACMG guidelines. Overall, the access to clinical exome sequencing data is limited, challenging exploratory analyses and the understanding of genetic mechanisms underlying disorders. Thus, by making these data available, we foresee increasing the number of WES data from Brazilians despite contributing to the study of  monogenic IEI-disorders. </p

Data table 1 - Demographic characteristics of the cohort

This work aims (i) to make available genomic data generated from the whole-exome sequencing (WES) of Brazilian patients' suspicion of inborn error of immunity (IEI) without genetic diagnosis; (ii) to improve the diagnostic yield of monogenic disorders by providing a clinically relevant dataset; and (iii) to provide high-throughput data with exploitable potential to gain insights about the genomic population structure of the Brazilians.  We sequenced genomic DNA from twenty unrelated patients treated at four different hospitals in the state of Rio de Janeiro, Brazil. Half of the patients were male with mean ages of 9±3 while females were 12±10  years old. WES were conducted through Illumina NextSeq platform and achieved 90% of the genetic basis coverage by >30 reads. More than 80% of the sequencing reads were uniquely mapped to the reference genome. Each sample had an average of 20,274 variants, being 114 classified as rare pathogenic or likely pathogenic according to ACMG guidelines. Overall, the access to clinical exome sequencing data is limited, challenging exploratory analyses and the understanding of genetic mechanisms underlying disorders. Thus, by making these data available, we foresee increasing the number of WES data from Brazilians despite contributing to the study of  monogenic IEI-disorders. </p

II Brazilian Consensus on the use of human immunoglobulin in patients with primary immunodeficiencies

<div><p>ABSTRACT In the last few years, new primary immunodeficiencies and genetic defects have been described. Recently, immunoglobulin products with improved compositions and for subcutaneous use have become available in Brazil. In order to guide physicians on the use of human immunoglobulin to treat primary immunodeficiencies, based on a narrative literature review and their professional experience, the members of the Primary Immunodeficiency Group of the Brazilian Society of Allergy and Immunology prepared an updated document of the 1st Brazilian Consensus, published in 2010. The document presents new knowledge about the indications and efficacy of immunoglobulin therapy in primary immunodeficiencies, relevant production-related aspects, mode of use (routes of administration, pharmacokinetics, doses and intervals), adverse events (major, prevention, treatment and reporting), patient monitoring, presentations available and how to have access to this therapeutic resource in Brazil.</p></div