Clinical and molecular spectrum of VEXAS with multiple UBA1 variants: case study and literature review.

Abstract

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a rare adult-onset autoinflammatory disorder, caused by a single somatic UBA1 mutation. We report a novel case with 3 independent UBA1-mutated clones and compare its clinical, hematologic, and laboratory features with those of the only 3 previously reported cases harboring multiple UBA1 mutations. Droplet digital polymerase chain reaction (PCR) and targeted next-generation sequencing of peripheral blood DNA were performed to assess UBA1 variants. Bone marrow specimens were evaluated for morphologic, immunophenotypic, and cytogenetic abnormalities. Clinical and hematologic features included neck swelling, headache, elevated inflammatory markers, leukopenia, macrocytic anemia, and thrombocytopenia. Bone marrow biopsy specimens showed no dysplasia, increased blasts, or cytoplasmic vacuolization. Droplet digital PCR detected atypical positive signals across multiple targets, and next-generation sequencing identified 3 presumed independent UBA1 variants: p.M41V, p.M41L, and c.118-2A > T. Comparison with 3 previously reported VEXAS cases carrying multiple UBA1 variants revealed diverse clinical manifestations, including systemic inflammation, polychondritis, venous thromboembolism, arthritis, and arthralgia, with variable hematologic findings ranging from no neoplasm to myelodysplastic syndrome or multiple myeloma, as well as co-occurring clonal hematopoietic variants. This report describes a novel VEXAS case with multiple UBA1 variants and highlights the clinical and hematologic heterogeneity among patients harboring multiple UBA1 mutations. It also emphasizes the technical challenges in detecting these variants and the importance of sequencing studies for definitive diagnosis in complex or equivocal cases, supporting early identification of UBA1 mutations and closer hematologic surveillance in patients with inflammatory symptoms and cytopenias.