Splenectomy revisited in Wiskott–Aldrich syndrome in the era of HSCT and gene therapy: a bridge, a rescue, or simply obsolete?

Figures

• 

  Figure 1. Pathogenesis of Wiskott-Aldrich syndrome. The WAS gene, located at Xp11.23, encodes the WASp. Upon T-cell receptor (TCR) engagement with peptide–MHC complexes, downstream signaling activates LAT and SLP-76, which recruit adaptor proteins (e.g., Nck and WIP) and facilitate Cdc42-GTP binding alongside Src kinase–mediated phosphorylation at Y291 of WASp. This conformational change exposes the VCA domain, allowing WASp to interact with the Arp2/3 complex by delivering actin monomers and promoting nucleation of branched actin filaments, thereby generating a dynamic actin network that stabilizes the immunological synapse and sustains signaling. In WAS, loss-of-function mutations impair VCA–Arp2/3 interactions, leading to defective actin polymerization, unstable synapse formation, and reduced nuclear translocation of NFAT, NF-κB, and Elk-1, resulting in impaired transcription of IL-2 and AP-1–dependent genes. Clinically, this manifests as microthrombocytopenia, recurrent infections, eczema, autoimmunity, and an increased risk of malignancy.

• 

  Figure 2. Geographic mapping of cases across the included studies. Geographic distribution of reported cases across the included studies, demonstrating a predominance of cases reported from the United States and Europe, with additional concentrations in East Asia and Australia. Countries are shaded according to the number of reported Wiskott–Aldrich syndrome cases identified in the literature search, with warmer colors indicating a greater number of reported cases. Data were extracted from the studies summarized in Table 1. This distribution reflects study reporting patterns rather than true disease epidemiology, as there is no established geographical, ethnic, or regional predominance for Wiskott–Aldrich syndrome.

• 

  Figure 3. Therapeutic evolution in Wiskott–Aldrich syndrome from splenectomy to curative therapies (Pre 1968–2025). This schematic timeline illustrates the transition from symptomatic management to curative treatment strategies. The red trajectory represents the declining utilization of splenectomy, whereas the green trajectory represents improving survival outcomes following hematopoietic stem cell transplantation (HSCT) and, more recently, gene therapy. Based on historical developments and outcome trends reported in the studies included in this review, the figure highlights the progressive shift from supportive interventions toward curative therapies, culminating in the 2025 FDA approval of Waskyra.

• 

  Figure 4. Age-related immune deficits contributing to post-splenectomy infection risk in Wiskott-Aldrich syndrome. In early childhood, incomplete marginal zone development and impaired T-independent antibody responses limit recognition of polysaccharide-encapsulated bacteria. Concurrently, immature B-cell function and delayed IgG2 class switching reduce effective opsonization, impairing phagocytic clearance. Underdeveloped germinal center architecture further results in reduced somatic hypermutation and production of low-affinity, short-lived antibodies. Collectively, these factors contribute to increased susceptibility to severe infections following splenectomy in young patients.

• 

  Figure 5. Clinical consequences of mixed donor chimerism following HSCT in Wiskott–Aldrich syndrome. (A) Incomplete donor engraftment with persistence of recipient WAS-defective immune cells results in mixed chimerism associated with immune dysregulation, autoimmunity, and ongoing peripheral platelet destruction, leading to persistent thrombocytopenia. (B) Stable mixed chimerism with sufficient donor-derived hematopoietic and immune cell contribution supports effective hematopoiesis and partial but clinically adequate immune competence, allowing control of thrombocytopenia despite incomplete donor dominance.

• 

  Figure 6. Physician-perceived distribution of quality of life (QoL) outcomes among splenectomized Wiskott–Aldrich syndrome patients (Glasmacher et al., 2016) (60). The figure illustrates that most patients were perceived by their physician to have good or very good quality of life following splenectomy.

• 

  Figure 7. Evidence-based management algorithm for Wiskott–Aldrich syndrome. This proposed algorithm is based on the evidence synthesized in this review and is intended as a conceptual management framework; prospective studies and standardized clinical guidelines remain needed. (A) Phenotype-based management pathway prioritizing HSCT or gene therapy as definitive treatment; when delayed or unavailable, care is guided by bleeding severity and response to supportive therapy, with splenectomy reserved for selected refractory cases requiring strict lifelong prophylaxis. (B) Post-HSCT management of persistent thrombocytopenia based on donor chimerism, where mixed chimerism may warrant splenectomy for optimization and full donor chimerism prompts evaluation of alternative causes.