The Neurologic Face of X-Linked Lymphoproliferative Syndrome Type 1: A Systematic Review Publisher Pubmed



Rajabi E ; Gharagozlou S ; Farhadi K ; Safavi M ; Zamani F ; Javadi A ; Rahemi Z ; Rostami P ; Parvaneh N
Source: Orphanet Journal of Rare Diseases Published:2025

Abstract

Background: X-linked lymphoproliferative syndrome type 1 (XLP1) is a rare inborn error of immunity with high mortality rates. Neurological manifestations may be the presenting features and are often fatal; however, their characterization is insufficient, hindering optimal clinical management. The aim of this study is to systematically review the neurological characteristics, outcomes, and survival in XLP1 patients and identify parameters associated with improved prognosis. A PRISMA-guided analysis of PubMed, Web of Science, Scopus, and Embase (up to March 2025) identified studies documenting neurological involvement in genetically verified XLP1 patients. We extracted data on clinical features, neuroimaging findings, therapeutic interventions, and survival. Results: We identified 42 genetically verified XLP1 patients with neurological involvement. Central nervous system (CNS) involvement comprised hemophagocytic lymphohistiocytosis (HLH) in 38.1%, vasculitis in 28.6%, and lymphoma in 19% of them. The development of brain vasculitis several months after Burkitt’s lymphoma was a specific presentation. The median age of neurological onset was 5 years. The predominant presenting symptoms were seizures (47.6%), altered consciousness (35.7%), and headaches (21.4%). Neuroimaging frequently revealed abnormalities in the temporal lobe and basal ganglia, often with hemorrhage and edema. Epstein-Barr virus (EBV) was identified in 54.8% of cases, sometimes limited to brain tissue. CSF analysis frequently showed elevated protein and pleocytosis. SH2D1A mutations were diverse, with Arg55 and Trp64 identified as recurrent hot spots. The overall mortality reached 52.4%, with most deaths occurring within five years of neurological onset. Conventional immunosuppressive and cytotoxic treatments were largely ineffective in changing the disease course. In exploratory analysis, hematopoietic stem cell transplantation (HSCT) did not significantly improve survival in the primary dataset, although sensitivity analysis suggested a possible benefit. Conclusions: Neurological involvement in XLP1 exhibits clinical heterogeneity and carries a high mortality rate. Early recognition and timely HSCT may improve survival, demonstrating the importance of vigilant neurological monitoring in affected individuals. © 2025 Elsevier B.V., All rights reserved.