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Tumor necrosis factor receptor–associated factor 3 (TRAF3) is a central regulator of immunity. TRAF3 is often somatically mutated in B cell malignancies, but its role in human immunity is not defined. Here, in five unrelated families, we describe an immune dysregulation syndrome of recurrent bacterial infections, autoimmunity, systemic inflammation, B cell lymphoproliferation, and hypergammaglobulinemia. Affected individuals each had monoallelic mutations in TRAF3 that reduced TRAF3 expression. Immunophenotyping showed that patients’ B cells were dysregulated, exhibiting increased nuclear factor-κB 2 activation, elevated mitochondrial respiration, and heightened inflammatory responses. Patients had mild CD4 + T cell lymphopenia, with a reduced proportion of naïve T cells but increased regulatory T cells and circulating T follicular helper cells. Guided by this clinical phenotype, targeted analyses demonstrated that common genetic variants, which also reduce TRAF3 expression, are associated with an increased risk of B cell malignancies, systemic lupus erythematosus, higher immunoglobulin levels, and bacterial infections in the wider population. Reduced TRAF3 conveys disease risks by driving B cell hyperactivity via intrinsic activation of multiple intracellular proinflammatory pathways and increased mitochondrial respiration, with a likely contribution from dysregulated T cell help. Thus, we define monogenic TRAF3 haploinsufficiency syndrome and demonstrate how common TRAF3 variants affect a range of human diseases.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, characterized predominantly by respiratory symptoms, has affected a small subset of children. Neurologic manifestations have been described in adults, including encephalitis/meningitis, encephalopathy, strokes, seizures, and anosmia,1,2 but there are few reports of neurologic manifestations in children with SARS-CoV-2.3

Made available in DSpace on 2022-04-29T08:30:47Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-07-01 Objective: Sjögren syndrome in children is a poorly understood autoimmune disease. We aimed to describe the clinical and diagnostic features of children diagnosed with Sjögren syndrome and explore how the 2016 ACR/EULAR classification criteria apply to this population. Methods: An international workgroup retrospectively collected cases of Sjögren syndrome diagnosed under 18 years of age from 23 centres across eight nations. We analysed patterns of symptoms, diagnostic workup, and applied the 2016 ACR/EULAR classification criteria. Results: We identified 300 children with Sjögren syndrome. The majority of patients n = 232 (77%) did not meet 2016 ACR/EULAR classification criteria, but n = 110 (37%) did not have sufficient testing done to even possibly achieve the score necessary to meet criteria. Even among those children with all criteria items tested, only 36% met criteria. The most common non-sicca symptoms were arthralgia [n = 161 (54%)] and parotitis [n = 140 (47%)] with parotitis inversely correlating with age. Conclusion: Sjögren syndrome in children can present at any age. Recurrent or persistent parotitis and arthralgias are common symptoms that should prompt clinicians to consider the possibility of Sjögren syndrome. The majority of children diagnosed with Sjögren syndromes did not meet 2016 ACR/EULAR classification criteria. Comprehensive diagnostic testing from the 2016 ACR/EULAR criteria are not universally performed. This may lead to under-recognition and emphasizes a need for further research including creation of paediatric-specific classification criteria. Division of Pediatric Rheumatology Department of Pediatric and Adolescent Medicine Mayo Clinic Division of Rheumatology Department of Pediatrics University of Utah School of Medicine Division of Rheumatology The Children's Hospital of Philadelphia Department of Internal Medicine and Pediatrics The University of Chicago Medical Center Department of Pediatrics Duke University School of Medicine Department of Pediatrics Hematology and Oncology Medical University of Gdansk Children's Mercy Hospital University of Missouri-Kansas City Division of Rheumatology Irccs Ospedale Pediatrico Bambino Gesù Department of Pediatric Rheumatology Institute of Rheumatology Department of Pediatrics Columbia University Medical Center Division of Rheumatology Children's National Hospital George Washington University School of Medicine and Health Sciences National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases Department of Pediatrics University of Texas McGovern Medical School at Houston Division of Pediatric Rheumatology Children's Healthcare of Atlanta Emory University School of Medicine Instituto de Puericultura e Pediatria Martagão Gesteira Universidade Federal Do Rio de Janeiro Pediatric Rheumatology Hospital Sant Joan de Déu Universitat de Barcelona Barcelona Rheumatology Unit Department of Medicine School of Medical Science University of Campinas Division of Rheumatology Department of Pediatrics University of Indiana School of Medicine Riley Hospital for Children at Indiana University Health Pediatric Rheumatology Unit São Paulo State University (UNESP), Botucatu Rheumatology Service Royal Children's Hospital Melbourne and Murdoch Children's Research Institute Division of Pediatric Allergy Immunology and Rheumatology Department of Pediatrics College of Medicine University of Florida Division of Oral Medicine Department of Oral and Maxillofacial Diagnostic Sciences College of Dentistry University of Florida Rheumatology Department Hospital General Universitario Gregorio Marañón Division of Immunology Boston Children's Hospital Department of Pediatrics Harvard Medical School Department of Rheumatic Diseases Tokyo Metropolitan Tama Medical Center Division of Rheumatology Allergy and Immunology Stead Family Department of Pediatrics Carver College of Medicine University of Iowa Pediatric Rheumatology Unit São Paulo State University (UNESP), Botucatu

Supplemental Digital Content is available in the text., Objectives: The disease caused by severe acute respiratory syndrome coronavirus 2, known as coronavirus disease 2019, has resulted in a global pandemic. Reports are emerging of a new severe hyperinflammatory syndrome related to coronavirus disease 2019 in children and adolescents. The Centers for Disease Control and Prevention has designated this disease multisystem inflammatory syndrome in children. Our objective was to develop a clinical inpatient protocol for the evaluation, management, and follow-up of patients with this syndrome. Data Sources: The protocol was developed by a multidisciplinary team based on relevant literature related to coronavirus disease 2019, multisystem inflammatory syndrome in children, and related inflammatory syndromes, as well as our experience caring for children with multisystem inflammatory syndrome in children. Data were obtained on patients with multisystem inflammatory syndrome in children at our institution from the pre-protocol and post-protocol periods. Data Synthesis: Our protocol was developed in order to identify cases of multisystem inflammatory syndrome in children with high sensitivity, stratify risk to guide treatment, recognize co-infectious or co-inflammatory processes, mitigate coronary artery abnormalities, and manage hyperinflammatory shock. Key elements of evaluation include case identification using broad clinical characteristics and comprehensive laboratory and imaging investigations. Treatment centers around glucocorticoids and IV immunoglobulin with biologic immunomodulators as adjuncts. Multidisciplinary follow-up after discharge is indicated to manage continued outpatient therapy and evaluate for disease sequelae. In nearly 2 months, we admitted 54 patients with multisystem inflammatory syndrome in children, all of whom survived without the need for invasive ventilatory or mechanical circulatory support. After institution of this protocol, patients received earlier treatment and had shorter lengths of hospital stay. Conclusions: This report provides guidance to clinicians on evaluation, management, and follow-up of patients with a novel hyperinflammatory syndrome related to coronavirus disease 2019 known as multisystem inflammatory syndrome in children. It is based on the relevant literature and our experience. Instituting such a protocol during a global pandemic is feasible and is associated with patients receiving treatment and returning home more quickly.

This case series describes clinical characteristics, treatment, and outcomes of 17 previously healthy SARS-CoV-2-infected children and adolescents with an inflammatory phenotype overlapping with but distinct from Kawasaki disease and toxic shock syndrome admitted to a New York City hospital in late April and early May 2020.