Inborn Error of WAS Presenting with SARS-CoV-2-Related Multisystem Inflammatory Syndrome in Children

• Published in: Journal of clinical immunology Vol. 45; no. 1; p. 49
• Main Authors: Drago, Enrico, Fioredda, Francesca, Penco, Federica, Prigione, Ignazia, Bertoni, Arinna, Del Zotto, Genny, Bocca, Paola, Massaccesi, Erika, Lanciotti, Marina, Moratto, Daniele, Thurner, Lorenz, Caorsi, Roberta, Gattorno, Marco, Volpi, Stefano
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.12.2025; Springer Nature B.V
• Subjects: Apoptosis; Biomedical and Life Sciences; Biomedicine; Child; Child, Preschool; children; COVID-19 - complications; COVID-19 - diagnosis; COVID-19 - genetics; COVID-19 - immunology; Female; Frameshift mutation; genes; Genetic analysis; Humans; Immune response; immunity; Immunology; Infectious Diseases; Inflammasomes; Inflammation; Interferon; interferons; Interleukin-1beta; Internal Medicine; Leukocytes (mononuclear); Male; Medical Microbiology; Monocytes; Multisystem inflammatory syndrome in children; mutation; pathogenesis; patients; Peripheral blood mononuclear cells; phenotype; Phenotypes; Point mutation; protein synthesis; SARS-CoV-2 - immunology; secretion; Severe acute respiratory syndrome coronavirus 2; Systemic Inflammatory Response Syndrome - diagnosis; Systemic Inflammatory Response Syndrome - genetics; Systemic Inflammatory Response Syndrome - immunology; Thrombocytopenia; Wiskott-Aldrich syndrome; Wiskott-Aldrich Syndrome - diagnosis; Wiskott-Aldrich Syndrome - genetics; Wiskott-Aldrich Syndrome - immunology; Wiskott-Aldrich Syndrome Protein; XLT; MIS-C; SARS-CoV-2; WAS; NLRP3; Inflammasome; Interferon; IEI
• ISSN: 0271-9142; 1573-2592; 1573-2592
• DOI: 10.1007/s10875-024-01840-4

Multisystem inflammatory syndrome in children (MIS-C) has been reported in patients with inborn errors of immunity (IEI), providing insights into disease pathogenesis. Here, we present the first case of MIS-C in a child affected by Wiskott-Aldrich syndrome (WAS) gene mutation, elucidating underlying predisposing factors and the involved inflammatory pathways. Genetic analysis revealed a frameshift truncating variant in the WAS gene, resulting in WAS protein expression between mild and severe forms, despite a clinical phenotype resembling X-linked thrombocytopenia (XLT). IL-1β secretion by LPS-stimulated peripheral blood mononuclear cells from patient during MIS-C was lower compared to healthy subjects but increased during follow-up. Conversely, the percentage of ASC (apoptosis-associated speck-like protein containing a CARD) specks in the patient’s circulating monocytes during the acute phase was higher than in healthy subjects. The type I interferon (IFN) signature during MIS-C was normal, in contrast to the raised IFN signature measured far from the acute event. This case supports the association of IEI with MIS-C, potentially linked to delayed immune responses to SARS-CoV-2. The XLT phenotype underlies a subclinical immunodysregulation involving the NLRP3 inflammasome and the type-I IFN response.