Abstract

VEXAS syndrome (Vacuoles, E1 enzyme, X-Linked, Autoinflammatory, Somatic) is a recently described autoinflammatory syndrome caused by a pathogenic mutation of UBA1 (E1 ubiquitin activating enzyme) on the X chromosome. Patients are men in the fifth decade or later with symptoms related to autoinflammation, including fever, chondritis, neutrophilic alveolitis, vasculitis and arthritis; they are also at increased risk of thromboembolism. Patients have macrocytic anemia and cytopenias, and a subset have overt myelodysplastic syndrome or multiple myeloma. VEXAS syndrome frequently has cutaneous manifestations, which often clinically and histopathologically resemble histiocytoid Sweet syndrome. Most patients respond to JAK inhibitors, particularly ruxolitinib. A 64-year-old Caucasian man presented with two years of fever, malaise, and arthralgia, with diffuse, tender, violaceous nodules previously diagnosed as Sweet syndrome. The patient’s course was recalcitrant to concurrent dapsone and prednisone. He had macrocytic anemia,  leukopenia and a history of venous thromboembolism. Repeat skin biopsy revealed a superficial and deep, perivascular and periadnexal atypical histiocytoid infiltrate positive for lysozyme and myeloperoxidase. Tissue cultures for microorganisms were negative. Given the combined clinical and histopathologic features, VEXAS syndrome was suspected. A bone marrow biopsy confirmed a UBA1 mutation without overt evidence of myelodysplastic syndrome. The patient began ruxolitinib with significant improvement. VEXAS syndrome is an emerging entity with important clinical implications. Dermatopathologists play a critical role in making the diagnosis. When evaluating a biopsy suggestive of histiocytoid Sweet syndrome, other related entities should be carefully considered, including myelodysplasia cutis and VEXAS syndrome, with important prognostic and therapeutic implications.