Abstract

VEXAS syndrome is a rare and severe adult-onset X-linked autoinflammatory disorder and affects mainly adult males. It is caused by a somatic myeloid mutation in the UBA1 gene, which regulates cellular ubiquitylation. The clinical manifestations of VEXAS syndrome are complex and can include recurrent fevers, skin rashes, pulmonary involvement, and hematologic abnormalities. The clinical presentation of the cutaneous lesions is heterogeneous, and the corresponding histologic findings are not specific to this disease. The patient cohort includes a 68-year-old man who presented with intermittently development of subcutaneous nodules, periorbital edema, pulmonary infiltrates, myelodysplastic syndrome, arthritis, fatigue, malaise, and chills. The bone marrow biopsy (BMB) showed mild hypercellularity, with myeloid hyperplasia and morphologically atypical (vacuolated) erythroid and granulocytic precursors. A 71-year-old man presented with fatigue, weakness, diarrhea, pulmonary infiltrates, mild anemia, and thrombocytopenia. Lung biopsy showed infiltrates with vacuolated histiocytes. An 83-year-old man presented with polyarthritis / polyarthralgias, dysphagia, malaise, weight loss and pancytopenia requiring transfusions. BMB showed left-shifted myeloid maturation with an abundance of myelocytes and metamyelocytes containing conspicuous cytoplasmic vacuoles. UBA1 mutations were documented in all three patients, confirming the diagnosis of VEXAS syndrome. Skin biopsies from these patients showed various histopathologic appearances including erythema nodosum, mild chronic inflammation, and Sweet syndrome. In summary, the histopathologic findings of VEXAS are diverse and nonspecific. Awareness for this rare autoinflammatory entity and its diagnostic challenges pertaining to dermatopathology is important, as it is a newly recognized disorder with imperative diagnostic and management implications for patients with unexplained inflammatory, dermatologic, and hematologic manifestations.