Vacuolated Marrow Cytopenias from Copper Deficiency to UBA1‑Mutant VEXAS: Molecular Landscape, Systematic Review, and Cost‑Efficient Diagnostic Algorithm

Vacuolated bone‑marrow precursors are a microscopic hallmark shared by diverse en-tities, from reversible copper deficiency to late‑onset autoinflammatory VEXAS syn-drome driven by somatic UBA1 mosaicism, and, more rarely, by high‑risk myeloid ne-oplasms. This molecular heterogeneity hampers timely diagnosis. We systematically searched PubMed, Web of Science and CENTRAL (December 2020–May 2025) following a PRISMA‑registered protocol (PROSPERO CRD420251082738) and identified 22 eligible series encompassing 818 adults. VEXAS accounted for 89% of cases, copper‑deficiency cytopenia for 9% and vacuolated‑cell MDS/AML for 2%. Median age increased from 58 years (copper deficiency) to 68 years (VEXAS), paralleling a shift from balanced to almost exclusive male prevalence, consistent with the X‑linked UBA1 biology. Inte-grating demographic, biochemical and genomic data, we designed a two‑step molecular screen—serum copper/ceruloplasmin followed, when normal, by hotspot UBA1 se-quencing—that correctly classified 97% of cases in < 5 days at a median laboratory cost of USD 173. Broad myeloid next‑generation sequencing was reserved for the residual 3% of atypical cytopenias. Our review clarifies the molecular landscape of vacuolated marrow cytopenias and delivers a pragmatic algorithm that bridges trace‑metal metabolism and somatic genomics, offering immediate translational value for leukemic and pre‑leukemic conditions.