Abstract

VEXAS (vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a novel autoinflammatory disease first described in 2020. Patients present later in life due to somatic mutations in UBA1, an X-linked gene which encodes ubiquitin-activating enzyme 1, a key cellular ubiquitinating enzyme in myeloid progenitors. Since the original report, dozens more cases have been published in the literature, and population-based studies have found the prevalence of pathogenic variants of UBA1 associated with clinical phenotypes to be surprisingly high. Loss of UBA1 results in systemic inflammation predominantly affecting the skin, bone marrow, pulmonary system, vasculature, and cartilage. This diagnosis portends a poor prognosis with significant rates in morbidity and mortality. Although further prospective studies investigating treatments are needed, JAK inhibitors represent promising steroid-sparing agents. Cutaneous features are the presenting sign of VEXAS syndrome in over half of cases, so dermatologists may be the first to recognize a patient with the appropriate symptomology. The most common cutaneous manifestation is multiple Sweet-like papules and nodules affecting the trunk and extremities. Distinctive histopathological features of these lesions include neutrophilic and myeloid cell infiltration and leukocytoclastic vasculitis. The hematopoietic population in skin lesions is comprised of bone marrow-derived pathological UBA1-mutated myeloid clones. Herein, we present a case of a 46-year-old man with VEXAS syndrome with characteristic cutaneous features, offer a review of the literature, and highlight the role of the dermatopathologist in recognizing this disease.