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

Although cytoplasmic vacuoles are instantly recognizable on bone marrow smears, their etiologic significance remains a diagnostic dilemma in everyday practice. We conducted a PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) aligned systematic review with narrative synthesis registered in PROSPERO and refrained from meta-analysis owing to high between-study heterogeneity (I2 > 80%). Across 22 studies, we identified 818 unique adults with vacuolated marrow cytopenias. A stepwise diagnostic algorithm-serum copper/ceruloplasmin followed, when non-diagnostic, by UBA1 hotspot sequencing in adults meeting clinical "red flags"-correctly classified 97% of cases within <5 days at a median laboratory cost of ~USD 173, reserving broad myeloid next-generation sequencing for the atypical minority. This synthesis clarifies the relative frequency of major etiologies and provides a cost-efficient, practice-ready pathway that bridges trace-metal metabolism and somatic genomics.