439 VEXAS Syndrome: A vexatious diagnostic entity

Introduction/Objective VEXAS (“vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic mutation”) syndrome is a clonal autoinflammatory disorder characterized by a constellation of overlapping systemic inflammatory and hematologic manifestations. Molecular pathogenesis of VEXAS is driven by somatic mutation in the UBA1 gene encoding a ubiquitin-activating enzyme, with consequent accumulation of misfolded proteins resulting in cellular stress. While not explicitly required per current proposed diagnostic guidelines, cytoplasmic vacuolization of myeloid and erythroid precursors is often – but not always – seen on bone marrow evaluation. VEXAS is reported in a limited demographic, primarily men in their fifth decade or later. Patients present with individually nonspecific manifestations including recurrent fever, lymphadenopathy, polychondritis, arthritis, orbital inflammation, vasculitis, and rash; as such, extensive workup is often undertaken before a specific diagnosis is reached. Hematologic aberrations, including macrocytic anemia and thrombocytopenia, are common, and patients are at elevated risk of developing hematologic – particularly myeloid – malignancies. Morbidity and mortality are high. This case of a 64-year-old patient who underwent two bone marrow biopsies prior to definitive diagnosis demonstrates that accurate and timely diagnosis of VEXAS demands awareness and attention to clinical context. Methods/Case Report A 64-year-old male previously evaluated by rheumatology for pancytopenia, skin changes, chronic sinusitis, orbital inflammation, weight loss, and night sweats, was admitted to our hospital for overall clinical deterioration. Laboratory studies featured anemia and thrombocytopenia with elevated acute phase reactants and c-ANCA. Polytypic hypergammaglobulinemia with elevated IgA and IgG, in addition to free light chains, was also noted. PET imaging revealed diffuse hypermetabolic activity in the bone marrow and spleen. Prior bone marrow biopsies performed at an outside institution were reportedly nondiagnostic. Bone marrow biopsy performed at our institution showed >90% cellular marrow with normal myeloid:erythroid ratio, maturational left-shift, and cytoplasmic vacuolization affecting early granulocytic and erythroid elements. Comprehensive flow cytometry was unrevealing. Karyotyping and chromosomal microarray studies were normal, and no mutations were identified on initial 50-gene molecular NGS panel; however, additional targeted analysis revealed UBA1 mutation. Steroid-based therapy resulted in clinical improvement beyond discharge; however, the patient ultimately died approximately 2 months post-discharge from our hospital, prior to initiating definitive management. Results NA Conclusion The route to diagnosis of VEXAS in this case was long. This rheumatologic patient with VEXAS-suggestive symptomatology underwent three bone marrow biopsies before a unifying diagnosis was rendered. While prior biopsy reports noted scattered cytoplasmic vacuoles within a subset of cells, UBA1 mutational analysis was not pursued. Consideration of VEXAS notwithstanding, findings in this patient’s final bone marrow biopsy were abnormal and would naturally raise myelodysplastic neoplasm as a primary consideration with or without VEXAS-suggestive clinical context. It is therefore not difficult to imagine a scenario wherein VEXAS is not explicitly brought up as a clinical concern, leaving the pathologist to succeed – after exhaustive workup – only in excluding overt neoplastic disease and suggesting etiologies such as nutritional deficiency or a broadly construed inflammatory process.