Case Report: Genetic Double Strike: VEXAS and TET2-Positive Myelodysplastic Syndrome in a Patient With Long-Standing Refractory Autoinflammatory Disease

Abstract

Somatic genetic mutations involving the innate and inflammasome signaling are key drivers of the pathogenesis of myelodysplastic syndromes (MDS). Herein, we present a patient, who suffered from a long-standing refractory adult-onset autoinflammatory syndrome (AIS), previously interpreted as various distinct rheumatic disorders. Developing pancytopenia and particularly macrocytic anemia prompted the screening for a hematological malignancy, which led to the diagnosis of a TET-2-positive MDS. The impressive and continuously changing range of organ involvement, with remarkable refractoriness to anti-inflammatory treatment, exceeded the common autoinflammatory phenotype of MDS patients. This prompted us to suspect a recently discovered disease, characterized by somatic mutations of the UBA1 gene: the VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome, which was ultimately confirmed by genetic testing. Reevaluation of previous bone marrow biopsies showed the presence of characteristic vacuoles in myeloid- and erythroid progenitor cells. Our case illustrates that the triad of an unresponsive multisystemic autoinflammatory disease, hematological abnormalities and vacuoles in myeloid- and erythroid progenitors in the bone marrow biopsy should prompt screening for the VEXAS syndrome.

Adverse Reaction to COVID-19 mRNA Vaccination in a Patient With VEXAS Syndrome

“…These variations often result in the upregulation of pro-inflammatory cytokines such as IL-6 and IL-1, causing systemic inflammation [ 15 ]. Azacitidine was used with promising results in patients with suspected MDS who tested positive for the DNMT3A and TET2 mutation, making hypomethylating agents efficacious in this subset of VEXAS patients [ 8 - 9 ].…”

“…His DNA analysis came positive for the UBA1 p.Met41 mosaic mutation (exon 3, c.121A>G, pMet41Val). Moreover, given the constant pancytopenia, bone marrow gene testing was advised to check for DNMT3A and TET2 mutations since he may be developing an MDS that could be responsive to current treatment options available on the market [ 8 - 9 ]. At this time, results are not yet available for these two mutations.…”

Vasculitis associated with VEXAS syndrome: A literature review

“…In the initial report, LCV was histologically confirmed in seven of 25 patients (28%) with VEXAS syndrome and in seven of 22 patients (31.8%) with dermatologic manifestations. Although the demographics of patients who developed LCV was unclear in the initial report, an additional nine cases of LCV were identified in our literature review ( Table 1 ) ( 12 , 30 , 37 , 51 , 52 ). The average age at disease onset was 68.3 years (ranging from 55 to 87 years) and all were male.…”

The First Korean Case of VEXAS Syndrome Caused by a UBA1 Somatic Variant

“…The p.Met41Leu variant detected in our case occurred in the most frequent site and is associated with better prognoses [ 4 ]. Co-occurring variants in other genes, such as DNMT3A , TET2 , CSF1R , GNA11 , and EZH2 , which are associated with increased risks of progression to MDS, were not detected [ 10 ]. WES or panel sequencing using peripheral blood or BM should be an appropriate approach for VEXAS syndrome considering the co-occurring variations.…”