{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T22:06:36Z","timestamp":1793916396654,"version":"4.8.0"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Neurological involvement in Wiskott\u2013Aldrich syndrome (WAS) \u2013 an inborn error of immunity caused by mutations in the\n                      <jats:italic>WAS<\/jats:italic>\n                      gene \u2013 is primarily documented through isolated case reports, limiting systematic synthesis and clear characterization of clinical patterns. We conducted a systematic review to characterize central and peripheral nervous system involvement in patients with confirmed WAS.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A systematic search was conducted in PubMed, Embase, Scopus, and Web of Science following the PRISMA 2020 guidelines. Studies reporting neurological manifestations in WAS were eligible. Extracted variables included neurological diagnosis, age at WAS diagnosis, age at neurological onset, hematopoietic stem cell transplantation (HSCT) status, viral associations, and outcomes. Methodological quality was assessed using the Newcastle\u2013Ottawa Scale and Joanna Briggs Institute tools. Analyses were descriptive at the patient level.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Twenty-six studies describing 32 patients were included. Most patients were pediatric (78.1%), with a median age at WAS diagnosis of 0.4 years; neurological manifestations occurred a median of 3.0 years later. Manifestations were classified as brain hemorrhagic (8\/32), immune-mediated (6\/32), infectious (6\/32), or neoplastic (12\/32). Median age at neurological onset differed across categories (p = 0.018): brain hemorrhagic events occurred earliest (1.2 years), immune-mediated events in childhood (3.8 years), infectious events later (14.5 years), and neoplastic events across a broad age range (5.0 years). Infectious cases were predominantly John Cunningham virus\u2013positive progressive multifocal leukoencephalopathy; neoplastic cases involved central nervous system lymphoma or post-transplant lymphoproliferative disorder. Case-fatality varied by phenotype (p = 0.002), reaching 100% in infectious, 75% in neoplastic, 62.5% in hemorrhagic, and 0% in immune-mediated cases. Overall, neurological event\u2013attributed case-fatality was 59.4%. Events occurred both before and after HSCT, with numerically higher mortality among non-transplant patients (63.6% vs 50.0%).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Neurological involvement in WAS exhibits age-dependent phenotypic patterns, with substantial case-fatality particularly in infectious and neoplastic presentations. Although derived from case-based evidence, these findings support heightened neurological vigilance across the disease course and the need for systematic neurological reporting in future registries.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic review registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>https:\/\/www.crd.york.ac.uk\/prospero\/display_record.php?RecordID=1141002<\/jats:ext-link>\n                      , identifier CRD420251141002.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1829058","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T04:54:15Z","timestamp":1778129655000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Neurological manifestations in Wiskott\u2013Aldrich syndrome: a systematic 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Clinics, Fondazione IRCCS San Gerardo dei Tintori","place":["Monza, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Occhino","sequence":"additional","affiliation":[{"name":"Biostatistics and Clinical Epidemiology, Fondazione IRCCS San Gerardo dei Tintori","place":["Monza, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pietro","family":"Invernizzi","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Universit\u00e0 degli Studi Milano-Bicocca","place":["Monza, Italy"]},{"name":"Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori","place":["Monza, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Gasperini","sequence":"additional","affiliation":[{"name":"Paediatric Clinics, Fondazione IRCCS San Gerardo dei 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