A 64-year-old male, previously healthy, presented in July 2021 with an unprovoked pulmonary embolism and subsequently developed recurrent fevers, myalgias, arthralgias, neck space and orbital inflammation, lymphadenopathy, cutaneous small-vessel vasculitis and panniculitis. Investigations demonstrated a normocytic anaemia (mean corpuscular volume MCV: 87–93 fL) and elevated CRP (45–303 mg/L), but otherwise were non-diagnostic. Positron emission tomography (left panel: PET image of the thorax, abdomen and pelvis) showed fluorodeoxyglucose (FDG) avidity in the bone marrow, lymph nodes, spleen, anterior globes, thyroid and peripheral vasculature. Bone marrow biopsy in December 2021 (middle panel: Initial bone marrow aspirate, 10× objective, May–Grünwald–Giemsa stain) revealed a normocellular marrow with occasional hypolobulated megakaryocytes (circled) and maturing trilineage haematopoiesis; no vacuolisation was noted. Lymph node, tonsillar and thyroid biopsies were also performed and were non-contributory. The patient responded to high-dose prednisone, but would flare if tapered below 20 mg daily. Methotrexate provided minimal benefit. After referrals to Rheumatology and Haematology, genetic testing was performed and confirmed a p.Met41Val UBA1 gene mutation, consistent with a diagnosis of VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome.1 In August 2023, a repeat bone marrow biopsy (right panel: Repeat bone marrow aspirate, 20× objective, May–Grünwald–Giemsa stain) was performed after the patient developed a new progressive macrocytic anaemia (MCV: 95–105 fL). This now revealed trilineage dysplasia with vacuolated erythroid and granulocyte precursors (circled). Treatment was initiated with azacitidine and ruxolitinib, leading to a sustained steroid-free remission. The initial bone marrow biopsy was re-reviewed with again no vacuolisation found. Although rare cases of VEXAS with atypical splice site mutations have presented without vacuoles, this is the first reported case of a classic p.Met41Val mutation with initially absent vacuoles that developed over the patient's disease course.2 A recent study estimated the prevalence of UBA1 pathological variants at 1 in 13 591 for unrelated individuals and 1 in 4269 for men over age 50.3 Given VEXAS may be more prevalent than previously thought, this case emphasises the importance of considering molecular testing for UBA1 mutations in autoinflammatory conditions to avoid underdiagnosis in early disease or atypical clinical phenotypes. Our institution does not require ethics approval when publishing individual case reports (SD, LC, AL, RX). The described patient consents to publication of his clinical information. Documentation available on request from the corresponding author (AL).
Deering et al. (Mon,) studied this question.