Myeloid and lymphoid vacuolation in <scp>VEXAS</scp> syndrome
Authors: Bingwen E. Fan, Ling Cao, Christian A. Gallardo, Shang M. S. Lee, Li W. Koh, Liuh L. Goh, Kiat H. Ong, Ponnudurai Kuperan
Journal: American Journal of Hematology (2021)

A 70-year-old Chinese male presented with unexplained fever, relapsing polychondritis, macrocytic anemia, acute necrotising lymphadenitis, skin papules that were in keeping histologically with Kikuchi-Fujimoto disease, and pulmonary embolism secondary to extensive unprovoked right lower limb deep vein thrombosis. Given the recent discovery of VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome,1 Sanger sequencing was performed on the patient's peripheral blood and buccal swab specimens, where p.Met41Leu missense mutation [NM_153280.3:c.121A➔C; ClinVar accession number SCV001450457] was detected in the blood but not buccal swab, consistent with a somatic X-linked mutation in codon 41 of the UBA1 gene which confirmed the diagnosis. He was subsequently treated with hydroxychloroquine, methotrexate and prednisolone with improvement of his autoimmune features. A retrospective review of the patient's bone marrow examination, previously ordered in July 2019 to exclude haematologic disease due to his constitutional symptoms, was performed. The full blood count showed hemoglobin concentration of 9.5 g/dL, white blood cell count of 6.3 x 109/L and platelet count of 351 × 109/L. Peripheral blood film examination showed dysplastic neutrophils with occasional forms showing vacuolation. Bone marrow aspirate showed moderately hypocellular marrow fragments with adequate trilineage hematopoiesis. Dysplastic features were seen in both the myeloid and erythroid series with no increased blasts. Iron stores were markedly increased but no ringed sideroblasts were seen. In the myeloid series, cytoplasmic vacuolation was observed predominantly in the myelomonocytic precursors (Image top left (A), top center left (B), top center right (C)) and to a lesser extent in the erythroid precursors (Image top right (D)) and in giant platelets (Image bottom left (E), bottom center left (F)). Interestingly, vacuolation was observed in plasma cells as well (Image bottom center right (G), bottom right (H)). Cancer cytogenetics revealed a normal 46XY karyotype. Other causes for vacuolation in hematopoietic cells including copper deficiency,2 zinc excess3 and a history of alcohol use4 were excluded. While in a previous report,5 vacuolation in hematopoietic cells were observed occurring exclusively in the myeloid and erythroid cells, vacuolation was seen in the plasma cells of our patient. This observation is plausible, given the findings of Beck et al.1 that UBA1 mutation in the early progenitor cells which show mosaicism where apart from myeloid and erythroid precursors, abundant mutant cells were seen in the lymphoid progenitors isolated from the bone marrow. Dysfunction in the UBA1, specifically the E1 enzyme, may affect the first step in ubiquitin conjugation (ubiquitination) that targets cellular proteins for degradation via proteasomes and accumulation of intracellular vacuoles may ensue in hematopoietic cells with the p.Met41Leu missense mutation. In contrast, in a study of vacuolation in myelodysplastic syndrome by the International Working Group on Morphology of MDS,6 the vacuoles were observed to be generally irregular in shape, a tendency to coalesce, with indistinct outlines, which suggest the presence of glycogen (rather than lipids which causes round vacuoles). The study also emphasized that vacuoles in hematopoietic cells were rarely recorded in non-neoplastic conditions. Hematologists and haematopathologists should be mindful that vacuolation in hematopoietic cells with dysplastic features may be seen in a spectrum of disorders, ranging from commoner causes such as myelodysplastic syndrome to heavy alcohol intake, as well as rarer cases of copper deficiencies or zinc excess. While not pathognomic for VEXAS syndrome, vacuolation in both the myeloid and lymphoid hematopoietic cells in elderly male patients with unexplained autoimmune features should raise a clinical suspicion for VEXAS syndrome and warrant further genetic sequencing for somatic UBA1 mutations. The data that support the findings of this study are available from the corresponding author upon reasonable request.