Interval Changes in Hematopoietic Vacuolization in VEXAS Syndrome with M41T Mutation: Insights into Diagnosis and Disease Progression

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is an adult-onset hemato-inflammatory disorder characterized by somatic mutations in the UBA1 gene on Xp11.3. We report a case of VEXAS syndrome in which interval changes were evaluated.

The patient was an 82-year-old man who initially presented with fever, generalized erythematous rash, and sore throat. Despite comprehensive workup, including tests for autoimmune disorders and bone marrow (BM) study, the diagnosis remained unclear. He was managed with prednisolone, but experienced progressive bicytopenia and perichondritis, prompting re-evaluation three years later. Follow-up BM study revealed trilineage dysplasia and vacuoles in hematopoietic cells. Next-generation sequencing using a panel for myeloid neoplasms identified a somatic mutation in UBA1 (p.Met41Thr) with a variant allele frequency (VAF) of 93.6%, leading to a final diagnosis of VEXAS syndrome.

Retrospective evaluation of the initial BM revealed previously overlooked vacuoles. Interestingly, the pro-portion of vacuolated cells significantly increased over time, most notably in early BM precursors (37.0% vs. 58.3%, p < 0.001). Targeted sequencing of an archived BM aspirate specimen identified p.Met41Thr (VAF 88.3%). Immunosuppressive therapy was added to steroid medication, but systemic symptoms improved only par-tially and cytopenia persisted.

This case demonstrates that the proportion of vacuolated hematopoietic precursors increases as VEXAS syndrome progresses. Our findings highlight the importance of suspecting VEXAS syndrome and utilizing UBA1 genetic testing in patients presenting with unexplained fever, multiorgan inflammatory conditions, and cytopenia with vacuolated cells.