Familial Mediterranean fever in the pediatric population

Familial Mediterranean fever; Amyloid A; ColchicineFebre mediterrània familiar; Amiloide A; ColchicinaFiebre mediterránea familiar; Amiloide A; ColchicinaFamilial Mediterranean fever (FMF) is the most frequent autoinflammatory disorder characterized by short, repeated, and self-limiting crises of fever and serositis. The disease was described as autosomal recessive hereditary transmission secondary to variants of the MEFV (MEditerranean FeVer) gene, even though a variable proportion of patients only present a heterozygous variant. FMF is very common in certain ethnic groups (Turkish, Armenian, Arab, and Jewish), even though it has been described throughout the Mediterranean and elsewhere in the world. The clinical manifestations are variable, with secondary amyloidosis being the most serious complication of the disorder. Treatment and prophylaxis are mainly based on the administration of colchicine, which prevents the crises and avoids complications in most cases. This study reviews the course of seven pediatric patients diagnosed with FMF during the period 2010-2018 at a district hospital. Most of the patients were of Caucasian origin, with onset at an early age in the form of fever as the main symptom, and some patients moreover presented less frequent manifestations (pericardial effusion, sensorineural hearing loss). Two cases presented plasmatic amyloid A protein elevation that subsided with the treatment. All the patients initially received colchicine, and one of them required prescription of anakinra, which was replaced by canakinumab due to a serious adverse reaction. There were no cases of consanguinity, and all the patients were of Mediterranean origin. The subjects showed a favorable course over the years, which was attributed to the early diagnosis and treatment provided

Classification criteria for autoinflammatory recurrent fevers.

BACKGROUND: Different diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)-familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS)-and for the non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis (PFAPA). We aimed to develop and validate new evidence-based classification criteria for HRF/PFAPA. METHODS: Step 1: selection of clinical, laboratory and genetic candidate variables; step 2: classification of 360 random patients from the Eurofever Registry by a panel of 25 clinicians and 8 geneticists blinded to patients\u27 diagnosis (consensus ≥80%); step 3: statistical analysis for the selection of the best candidate classification criteria; step 4: nominal group technique consensus conference with 33 panellists for the discussion and selection of the final classification criteria; step 5: cross-sectional validation of the novel criteria. RESULTS: The panellists achieved consensus to classify 281 of 360 (78%) patients (32 CAPS, 36 FMF, 56 MKD, 37 PFAPA, 39 TRAPS, 81 undefined recurrent fever). Consensus was reached for two sets of criteria for each HRF, one including genetic and clinical variables, the other with clinical variables only, plus new criteria for PFAPA. The four HRF criteria demonstrated sensitivity of 0.94-1 and specificity of 0.95-1; for PFAPA, criteria sensitivity and specificity were 0.97 and 0.93, respectively. Validation of these criteria in an independent data set of 1018 patients shows a high accuracy (from 0.81 to 0.98). CONCLUSION: Eurofever proposes a novel set of validated classification criteria for HRF and PFAPA with high sensitivity and specificity

Evaluation and Management of Deficiency of Adenosine Deaminase 2: An International Consensus Statement

IMPORTANCE: Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited disease characterized by systemic vasculitis, early-onset stroke, bone marrow failure, and/or immunodeficiency affecting both children and adults. DADA2 is among the more common monogenic autoinflammatory diseases, with an estimate of more than 35 000 cases worldwide, but currently, there are no guidelines for diagnostic evaluation or management. OBJECTIVE: To review the available evidence and develop multidisciplinary consensus statements for the evaluation and management of DADA2. EVIDENCE REVIEW: The DADA2 Consensus Committee developed research questions based on data collected from the International Meetings on DADA2 organized by the DADA2 Foundation in 2016, 2018, and 2020. A comprehensive literature review was performed for articles published prior to 2022. Thirty-two consensus statements were generated using a modified Delphi process, and evidence was graded using the Oxford Center for Evidence-Based Medicine Levels of Evidence. FINDINGS: The DADA2 Consensus Committee, comprising 3 patient representatives and 35 international experts from 18 countries, developed consensus statements for (1) diagnostic testing, (2) screening, (3) clinical and laboratory evaluation, and (4) management of DADA2 based on disease phenotype. Additional consensus statements related to the evaluation and treatment of individuals with DADA2 who are presymptomatic and carriers were generated. Areas with insufficient evidence were identified, and questions for future research were outlined. CONCLUSIONS AND RELEVANCE: DADA2 is a potentially fatal disease that requires early diagnosis and treatment. By summarizing key evidence and expert opinions, these consensus statements provide a framework to facilitate diagnostic evaluation and management of DADA2

Evaluation and Management of Deficiency of Adenosine Deaminase 2: An International Consensus Statement

Importance: Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited disease characterized by systemic vasculitis, early-onset stroke, bone marrow failure, and/or immunodeficiency affecting both children and adults. DADA2 is among the more common monogenic autoinflammatory diseases, with an estimate of more than 35000 cases worldwide, but currently, there are no guidelines for diagnostic evaluation or management. Objective: To review the available evidence and develop multidisciplinary consensus statements for the evaluation and management of DADA2. Evidence Review: The DADA2 Consensus Committee developed research questions based on data collected from the International Meetings on DADA2 organized by the DADA2 Foundation in 2016, 2018, and 2020. A comprehensive literature review was performed for articles published prior to 2022. Thirty-two consensus statements were generated using a modified Delphi process, and evidence was graded using the Oxford Center for Evidence-Based Medicine Levels of Evidence. Findings: The DADA2 Consensus Committee, comprising 3 patient representatives and 35 international experts from 18 countries, developed consensus statements for (1) diagnostic testing, (2) screening, (3) clinical and laboratory evaluation, and (4) management of DADA2 based on disease phenotype. Additional consensus statements related to the evaluation and treatment of individuals with DADA2 who are presymptomatic and carriers were generated. Areas with insufficient evidence were identified, and questions for future research were outlined. Conclusions and Relevance: DADA2 is a potentially fatal disease that requires early diagnosis and treatment. By summarizing key evidence and expert opinions, these consensus statements provide a framework to facilitate diagnostic evaluation and management of DADA2

Somatic genetic variation in healthy tissue and non-cancer diseases

© The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Somatic genetic variants have been studied for several years mostly concerning cancer, where they contribute to its origin and development. It is also clear that the somatic variants load is greater in aged individuals in comparison to younger ones, pointing to a cause/consequence of the senescence process. More recently, researchers have focused on the role of this type of variation in healthy tissue and its dynamics in cell lineages and different organs. In addition, somatic variants have been described to contribute to monogenic diseases, and the number of evidences of their role in complex disorders is also increasing. Thanks to recent advances in next-generation sequencing technologies, this type of genetic variation can be now more easily studied than in the past, although we still face some important limitations. Novel strategies for sampling, sequencing and filtering are being investigated to detect these variants, although validating them with an orthogonal approach will most likely still be needed. In this review, we aim to update our knowledge of somatic variation detection and its relation to healthy tissue and non-cancer diseases.This study was funded by grants PID2021-125106OB-C32 (FC), RTI2018-096824-B-C22 (FC), RTI2018-096824-B-C21 (JIA) and PID2021-125106OB-C31 (JIA) funded by MCIN/ AEI /10.13039/501100011033/ and FEDER Una manera de hacer Europa; Direcció General de Recerca- Generalitat de Catalunya (2017SGR-702) (FC); and CERCA Programme/Generalitat de Catalunya (JIA). MS-M was supported by the Ministerio de Economía y Competitividad, Spain (Maria de Maetzu grant MDM-2014-0370-16-3).Peer reviewe

Assessing the digenic model in rare disorders using population sequencing data

An important fraction of patients with rare disorders remains with no clear genetic diagnostic, even after whole-exome or whole-genome sequencing, posing a difficulty in giving adequate treatment and genetic counseling. The analysis of genomic data in rare disorders mostly considers the presence of single gene variants in coding regions that follow a concrete monogenic mode of inheritance. A digenic inheritance, with variants in two functionally-related genes in the same individual, is a plausible alternative that might explain the genetic basis of the disease in some cases. In this case, digenic disease combinations should be absent or underrepresented in healthy individuals. We develop a framework to evaluate the significance of digenic combinations and test its statistical power in different scenarios. We suggest that this approach will be relevant with the advent of new sequencing efforts including hundreds of thousands of samples.This study was funded by grants RTI2018-096824-B-C22 (FC), PID2021-125106OB-C32 (FC), RTI2018-096824-B-C21 (JIA) and PID2021-125106OB-C31 (JIA) funded by MCIN/ AEI /10.13039/501100011033/ and FEDER Una manera de hacer Europa; Direcció General de Recerca- Generalitat de Catalunya (2017SGR-702) (FC); and CERCA Programme/Generalitat de Catalunya (JIA). NMR was supported by grant 2021 FI_B_00296 from Agència de Gestió d’Ajuts Universitaris i de Recerca, Generalitat de Catalunya. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support.Peer reviewe

Executive Summary of the Consensus Document on the Diagnosis and Management of Patients with Primary Immunodeficiencies

Primary immunodeficiencies (PIDs) are rare, undiagnosed and potentially fatal diseases. Clinical manifestations of PID can be fatal or leave sequelae that worsen the quality of life of patients. Traditionally, the treatment of PIDs has been largely supportive, with the exception of bone marrow transplantation and, more recently, gene therapy. The discovering of new affected pathways, the development of new molecules and biologics, and the increasing understanding of the molecular basis of these disorders have created opportunities in PIDs therapy. This document aims to review current knowledge and to provide recommendations about the diagnosis and clinical management of adults and childre with PIDs based on the available scientific evidence taking in to account current practice and future challenges. A systematic review was conducted, and evidence levels based on the available literature are given for each recommendation where available. � 2020 American Academy of Allergy, Asthma & Immunology; Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica [Published by Elsevier Inc./Elsevier Espana]. All rights reserved

Resumen ejecutivo del Documento de consenso sobre diagnóstico y manejo de pacientes con inmunodeficiencias primarias

[EN] Primary immunodeficiencies (PIDs) are rare, undiagnosed and potentially fatal diseases. Clinical manifestations of PID can be fatal or leave sequelae that worsen the quality of life of patients. Traditionally, the treatment of PIDs has been largely supportive, with the exception of bone marrow transplantation and, more recently, gene therapy. The discovering of new affected pathways, the development of new molecules and biologics, and the increasing understanding of the molecular basis of these disorders have created opportunities in PIDs therapy. This document aims to review current knowledge and to provide recommendations about the diagnosis and clinical management of adults and children with PIDs based on the available scientific evidence taking in to account current practice and future challenges. A systematic review was conducted, and evidence levels based on the available literature are given for each recommendation where available.[ES] Las inmunodeficiencias primarias (IDP) son unas enfermedades raras, frecuentemente infradiagnosticadas y potencialmente fatales. Las manifestaciones clínicas de las IDP pueden ser muy graves y ocasionar secuelas que empeoran la calidad de vida de los pacientes. Tradicionalmente, el tratamiento de las IDP ha sido fundamentalmente de soporte, con excepción del trasplante de progenitores hematopoyéticos y, más recientemente, la terapia génica. El descubrimiento de nuevos mecanismos patogénicos, el desarrollo de nuevas moléculas y fármacos biológicos y los avances en el conocimiento de las bases moleculares de estas enfermedades han abierto oportunidades para el tratamiento de esta afección. El objetivo de este documento es revisar el conocimiento actual y aportar recomendaciones para el diagnóstico y el tratamiento clínico de los pacientes adultos y pediátricos con IDP basado en la evidencia científica disponible y teniendo en cuenta la actual práctica y los retos futuros. Se realizó una revisión sistemática, que justifica los niveles de evidencia para cada recomendación

Evaluation and Management of Deficiency of Adenosine Deaminase 2 An International Consensus Statement

IMPORTANCE Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited disease characterized by systemic vasculitis, early-onset stroke, bone marrow failure, and/or immunodeficiency affecting both children and adults. DADA2 is among the more common monogenic autoinflammatory diseases, with an estimate of more than 35 000 cases worldwide, but currently, there are no guidelines for diagnostic evaluation or management.OBJECTIVE To review the available evidence and develop multidisciplinary consensus statements for the evaluation and management of DADA2.EVIDENCE REVIEW The DADA2 Consensus Committee developed research questions based on data collected from the International Meetings on DADA2 organized by the DADA2 Foundation in 2016, 2018, and 2020. A comprehensive literature review was performed for articles published prior to 2022. Thirty-two consensus statements were generated using a modified Delphi process, and evidence was graded using the Oxford Center for Evidence-Based Medicine Levels of Evidence.FINDINGS The DADA2 Consensus Committee, comprising 3 patient representatives and 35 international experts from 18 countries, developed consensus statements for (1) diagnostic testing, (2) screening, (3) clinical and laboratory evaluation, and (4) management of DADA2 based on disease phenotype. Additional consensus statements related to the evaluation and treatment of individuals with DADA2 who are presymptomatic and carriers were generated. Areas with insufficient evidence were identified, and questions for future research were outlined.CONCLUSIONS AND RELEVANCE DADA2 is a potentially fatal disease that requires early diagnosis and treatment. By summarizing key evidence and expert opinions, these consensus statements provide a framework to facilitate diagnostic evaluation and management of DADA2.Peer reviewe