A Case of VEXAS Syndrome Initially Masked as Myelodysplastic Syndrome: Importance of Marrow Vacuolization and UBA1 Testing: A Case Report

Introduction

VEXAS syndrome (vacuoles, E1 Enzyme, X-linked, autoinflammatory, somatic) is a recently recognized disorder of adulthood caused by somatic mutations in the UBA1 gene (ubiquitin-like modifier activating enzyme 1) in hematopoietic cells [1]. Since its first description by Beck et al in 2020, population-based and systematic analyses have expanded the understanding of this condition. A genome-first population study [2] estimated a prevalence of approximately 1 in 13 591 individuals and confirmed variable clinical phenotypes spanning hematologic, rheumatologic, pulmonary, and dermatologic manifestations. Moreover, a recent systematic review synthesizing more than 700 genetically confirmed cases [3] reported cutaneous involvement in approximately 82%, constitutional symptoms in approximately 69%, respiratory manifestations in approximately 61%, and myelodysplastic syndrome (MDS) in approximately 36% of patients, thereby underscoring the heterogeneity of the disease and the need for early recognition.

The UBA1 gene encodes the E1 enzyme, which initiates ubiquitylation, a critical process regulating cellular homeostasis and inflammatory pathways. Disruption of this mechanism results in widespread systemic inflammation, the hallmark of VEXAS syndrome. Patients often present with macrocytic anemia, thrombocytopenia, or bone marrow failure, and up to half of cases may meet diagnostic criteria for MDS or plasma cell disorders [1].

Currently, there is no standardized treatment for VEXAS. Glucocorticoids remain the cornerstone of therapy, but their use is limited by long-term toxicity. Promising results have been observed with Janus kinase inhibitors, IL-6 receptor inhibitors, and hypomethylating agents, such as azacitidine and decitabine. VEXAS syndrome is frequently refractory to conventional therapies, and many patients require long-term immunosuppression, most commonly with prolonged high-dose glucocorticoids. This therapeutic dependency substantially increases the risk of opportunistic infections, which have been reported as a major source of morbidity and mortality in affected patients [4]. Allogeneic hematopoietic stem cell transplantation has been reported as the only potentially curative option, although its role and optimal timing remain under investigation [5]. In addition, a recent systematic review of treatment strategies [6] summarized the emerging evidence and highlighted the urgent need for prospective studies to guide management. Notably, azacitidine has been associated with durable remissions and reduction of the UBA1 mutant clone in some patients [7].

The present case is notable because the patient initially presented with hyperchromic macrocytic anemia and suspected MDS, complicating the diagnostic pathway. By reporting this case, we aim to highlight the diagnostic pitfalls and therapeutic considerations associated with VEXAS syndrome and contribute to the growing clinical knowledge of this recently defined condition.

Case Report

The patient was referred for follow-up and further evaluation due to hyperchromic macrocytic anemia (hemoglobin 10.6 g/dL; mean corpuscular volume 103 fL; mean corpuscular hemoglobin 35 pg; Table 1). Several months earlier, an extended diagnostic workup had been initiated following suspicion of monoclonal gammopathy. Serum protein electrophoresis, immunofixation, immunoglobulin levels, and free light chains were normal, thereby excluding a monoclonal gammopathy, although polyclonal hypergammaglobulinemia and an elevated rheumatoid factor were noted. Genetic testing revealed a C282Y mutation but no MYD88 mutation.

Because of the patient’s history of systemic lupus erythematosus, autoimmune serology was performed and showed negative antinuclear antibodies, negative double-stranded DNA, and negative extractable nuclear antigens (ENA panel). Antiphospholipid antibodies were only borderline elevated (cardiolipin IgG and IgM 2.2–2.3 U/mL; phospholipid screen 2.1–2.7 U/mL). Based on these findings, the patient did not fulfil the ACR/EULAR 2019 classification criteria for systemic lupus erythematosus. As the patient was treated with hydroxychloroquine, medication-associated anemia was also considered.

Elevated serum ferritin (950 ng/mL) prompted further evaluation for hereditary hemochromatosis, and a heterozygous HFE gene variant was identified, although this was not considered clinically significant. Additional laboratory investigations, including liver and kidney function tests, electrolytes, thyroid hormones, and viral serologies (HBV, HCV, HIV), were all within normal limits. These findings excluded alternative causes of anemia, such as chronic liver disease, thyroid dysfunction, viral infection, or overt plasma cell dyscrasia.

The initial bone marrow biopsy revealed a hypercellular marrow with dysplastic changes in granulopoiesis and erythropoiesis, left-shifted granulopoiesis, and 8% ring sideroblasts. A small clonal plasma cell population (9%) suggested possible plasma cell myeloma. Enhanced macrophage activity and mast cell proliferation were also noted. However, infiltration by Waldenström macroglobulinemia could not be excluded. Overall, the findings were suggestive of an MDS-like process, although toxic dysplasia due to hydroxychloroquine remained a differential diagnosis.

Immunocytological analysis showed myeloid progenitors and normally granulated granulocytes, with aberrant expression of CD11b and CD13. Monocytes were present without antigen abnormalities. In the erythroid lineage, reduced CD71 expression was observed. Plasma cells accounted for 0.9% of nucleated cells and expressed regular antigens. Mast cells were rare and not aberrant. These findings did not provide definitive evidence for MDS, myeloma, or lymphoma.

Histologic examination demonstrated reactive hyperplastic hematopoiesis, likely secondary to toxic injury, but also revealed a plasma cell increase to approximately 20% of marrow cellularity, suggesting early-stage multiple myeloma. To clarify, a second evaluation at an external laboratory was performed. This showed hypocellular marrow with maturing hematopoiesis, a mild plasma cell increase without aberrant phenotype, and no evidence for myeloma or B-cell non-Hodgkin lymphoma.

Because the cause of anemia remained unclear, a repeat bone marrow biopsy was performed after 11 months. This time, microscopic analysis revealed prominent vacuolization in erythroid and myeloid precursors, particularly proerythroblasts, promyelocytes, and myeloblasts (Figure 1). Molecular genetic testing identified a UBA1 missense mutation in exon 3: c.122T>C (p.Met41Thr), a variant known to be associated with VEXAS syndrome. Additional MDS-like features were also present. Based on these findings, a diagnosis of VEXAS syndrome with concomitant MDS was established.

Given the overlap with MDS and published evidence supporting the efficacy of hypomethylating agents in VEXAS, treatment with azacitidine was initiated. A detailed chronological overview of the patient’s clinical course, diagnostic evaluations, and therapeutic interventions is summarized in Table 2 (Case timeline, CARE Guidelines format).

Discussion

This case adds to the expanding recognition of VEXAS syndrome as a distinct autoinflammatory and hematologic disorder with a remarkably heterogeneous presentation. Since its identification in 2020, subsequent reports have underscored its broad clinical spectrum, characterized by systemic inflammation, macrocytic anemia, and variable overlap with MDS [8–10].

Our patient presented with macrocytic hyperchromic anemia and was initially suspected to have MDS or plasma cell myeloma based on bone marrow findings. Similar diagnostic challenges have been reported in the literature, in which patients with VEXAS were first misclassified as having MDS, monoclonal gammopathy of undetermined significance, or autoimmune disease before the correct diagnosis was established [11,12]. The diagnostic delay in our case was further complicated by the patient’s history of systemic lupus erythematosus and treatment with hydroxychloroquine, which introduced additional differential diagnoses such as drug-induced dysplasia and autoimmune-related cytopenias. This overlap underscores the importance of considering VEXAS syndrome in patients with atypical presentations of MDS, particularly when vacuolization is observed in bone marrow precursors.

Consistent with previous reports, vacuolization in both the erythroid and myeloid precursors proved to be the defining cytomorphological clue, leading to targeted molecular testing. The identification of the UBA1 missense mutation (c.122T>C, p.Met41Thr) confirmed the diagnosis. This variant has been described in other cohorts and is among the most frequently reported pathogenic alterations in VEXAS [13]. Unlike some cases in which additional mutations in DNMT3A or TET2 have been identified [14], no secondary genetic lesions were detected in our patient, which may have implications for prognosis.

Treatment of VEXAS remains challenging due to the lack of standardized protocols. High-dose glucocorticoids are frequently required but are associated with significant toxicity [9]. In our patient, the presence of an MDS component provided the rationale for initiating azacitidine therapy. Reports in the literature suggest that hypomethylating agents such as azacitidine can achieve durable remissions in selected patients, with some cases showing clonal reduction of UBA1 mutant cells [10].

In addition to cases with overlapping MDS, several reports have described clinical improvement with azacitidine in patients with VEXAS lacking definitive myelodysplastic features. In these individuals, azacitidine appears to exert anti-inflammatory and clonal-suppressive effects, leading to reductions in transfusion requirements and inflammatory markers. These findings suggest that hypomethylating therapy may have broader applicability in VEXAS beyond MDS-associated disease, although evidence remains limited to small case series.

In summary, this case illustrates several important lessons for clinical practice and contributes to the growing literature on VEXAS syndrome. It highlights the diagnostic complexity in a patient with pre-existing lupus erythematosus and hydroxychloroquine use, which initially masked the underlying disorder. Clinicians should consider VEXAS in patients with unexplained macrocytic anemia, cytopenias, and systemic inflammation, particularly when bone marrow vacuolization is present. Diagnostic pitfalls may arise in individuals with coexisting autoimmune disease or suspected hematologic malignancies, emphasizing the need for a high index of suspicion. Finally, while therapeutic options remain limited, hypomethylating agents such as azacitidine appear promising in cases with overlapping or even isolated VEXAS, although further studies are required to establish standardized treatment algorithms and clarify prognostic implications of distinct genetic variants.

Conclusions

In conclusion, this case highlights the diagnostic challenges of VEXAS syndrome in a patient with hyperchromic macrocytic anemia initially suspected to have MDS. The presence of vacuolization in hematopoietic precursors and subsequent identification of a UBA1 mutation were decisive for establishing the diagnosis. This report underscores the importance of considering VEXAS in patients with atypical presentations of macrocytic anemia and demonstrates the potential role of hypomethylating therapy with azacitidine in cases with concomitant or isolated VEXAS features.