DP22 VEXAS syndrome presenting with histiocytoid Sweet syndrome-like skin changes

Abstract

VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a recently recognized adult-onset autoinflammatory disorder caused by somatic UBA1 mutations. It is associated with systemic inflammation, macrocytic anaemia and a wide range of cutaneous manifestations. Histopathological assessment and genetic testing are often central to diagnosis, as skin lesions may resemble other neutrophilic dermatoses, including Sweet syndrome. We report the case of a 68-year-old man with seronegative rheumatoid arthritis, pulmonary embolism and a previous atypical fibroxanthoma, who presented with recurrent febrile skin eruptions and transfusion-dependent macrocytic anaemia. Skin biopsy showed a dense dermal infiltrate composed predominantly of immature myeloid and histiocytoid-appearing cells, with leucocytoclasia and occasional neutrophils. There was no evidence of vasculitis or fibrosis. Immunohistochemistry demonstrated strong CD68 and myeloperoxidase positivity, supporting a myeloid and histiocytoid phenotype, while other lineage markers were negative. These findings were initially interpreted as histiocytoid Sweet syndrome. Bone marrow examination revealed hypercellularity, reticulin fibrosis and cytoplasmic vacuolation of myeloid and erythroid precursors. Subsequent genetic testing identified a pathogenic UBA1 mutation together with a CUX1 variant, confirming a diagnosis of VEXAS syndrome. The clinical course was complicated by progressive myelofibrosis and ongoing dependence on transfusion. This case illustrates the close histopathological overlap between VEXAS syndrome and histiocytoid Sweet syndrome. The presence of immature myeloid infiltrates and atypical neutrophilic patterns in skin biopsies should prompt consideration of VEXAS as a differential alongside histiocytoid Sweet syndrome, particularly in older men with systemic inflammation and macrocytic anaemia. In such cases, early testing for somatic UBA1 mutations, using bone marrow or skin-derived tissue where appropriate, is important to establish the diagnosis and guide clinical management.