VEXAS: a vivid new syndrome associated with vacuoles in various hematopoietic cells

A 68-year-old man with a history of myeloma, pancytopenia, and relapsing polychondritis presented with macrocytic anemia (8.6 g/dL; mean corpuscular volume, 125 fL). Bone marrow aspirate demonstrated dysmegakaryopoiesis (panel A; Wright-Giemsa stain, 50× objective; original magnification ×500). Increased plasma cells showed vacuolation (panel B; Wright-Giemsa stain, 100× objective; original magnification ×1000), as did dysplastic erythroid precursors and a subset of myeloid precursors (panels C-D and E-F, respectively; Wright-Giemsa stain, 100× objective; original magnification ×1000). Blasts and ring sideroblasts were <5%. The hypercellular bone marrow biopsy revealed dysmegakaryopoiesis (panel G; hematoxylin and eosin stain, 40× objective; original magnification ×400). Serum copper levels were normal. Myelodysplastic syndrome with multilineage dysplasia was diagnosed. κ-restricted CD138⁺ plasma cells comprised 15% of cellularity (panel H; 10× objective; original magnification ×100), confirming residual myeloma. Cytogenetics showed a normal male karyotype, and fluorescence in situ hybridization studies detected CCND1-IGH [t(11;14)]. A 116-gene hematologic malignancy sequencing panel was negative for disease-associated variants. Whole exome sequencing performed at the National Institutes of Health identified a somatic pathologic mutation in UBA1.

Acquired mutations affecting p.Met41 of UBA1 underlie VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, a newly described adult-onset autoinflammatory disease (relapsing polychondritis, polyarteritis nodosa) associated with myelodysplastic syndrome and myeloma. Cytoplasmic vacuoles containing disordered and degenerating organelles and lipid within erythroid and myeloid precursors are characteristic. Vacuolated plasma cells also feature in this case.