VEXAS Syndrome with Cutaneous Clues and Rapidly Progressive Multisystem Failure: A Diagnostic Challenge for Pathologists

Summary: VEXAS syndrome, driven by somatic UBA1 mutations, presents with diverse clinical manifestations and rapid disease progression, posing significant diagnostic and therapeutic challenges. We report the case of a 66-year-old male who presented with recurrent infections, erythema, transient cytopenia, and skin lesions. Skin biopsies showed mild acute and chronic inflammation with hemorrhage and sparse interstitial lymphocytic infiltration. A bone marrow biopsy and aspirate revealed vacuoles in the myeloid and occasional erythroid precursors. Hospitalizations for abdominal pain, cellulitis, dyspnea, and deep vein thrombosis followed, with PET/CT imaging demonstrating increased splenic and marrow uptake. A repeat bone marrow biopsy confirmed hypercellularity with vacuolated myeloid precursors, and genomic testing identified a UBA1 mutation (c.121A>G; p.Met41Val, VAF 84%). Despite treatment with steroids, ruxolitinib, and azacytidine, the disease progressed. An allogeneic bone marrow transplant was performed. The patient ultimately succumbed to post-transplant complications, including infections and multiorgan failure. This case underscores the aggressive nature and diagnostic complexity of VEXAS syndrome, highlighting the need for early recognition and novel therapeutic approaches to improve patient outcomes.