Variants associated with VEXAS syndrome in p.(Met41) of UBA1 result in reduction of functional cytoplasmic UBA1 resulting in upregulated cellular stress responses and activation of multiple innate immune pathways (such as elevated interferon-γ, TNF, IL-6, IL-8) causing multiorgan involvement as the symptoms progress . The mean age of VEXAS onset is 67 years, ranging from 47 to 79 years with fever being reported as one of the most common symptoms  . Fever in our patient was present only at the beginning of his investigation when CAPS was suspected. In a cohort of 16 patients with VEXAS syndrome, macrocytic anemia was found in all, lymphopenia in twelve individuals, and myelodysplastic syndrome in six individuals . The clinical manifestations exhibited in VEXAS syndrome are notably variable. However, recent cluster analysis has identified a potential phenotype-genotype correlation between the type of UBA1 variants and features exhibited . The presented patient fits within the proposed phenotype of p.(Met41Val) with absence of chondritis, high CRP levels, and increased mortality risk.
VEXAS BM features are characterized by prominent cytoplasmic vacuoles in myeloid and erythroid cells. Even though these findings are not specific of VEXAS syndrome since they are present in other conditions such as myeloid neoplasms, copper deficiency, and alcohol intoxication, almost all of the confirmed cases in the literature have had this alteration [4, 9, 10]. Cytoplasmic vacuolation in hematopoietic cells was initially described for our patient but was not considered specific at the time, given it predated the clinical description of VEXAS syndrome by three years.
Many treatment-related complications have been described for patients with VEXAS syndrome including infections, cardiac involvement, stroke, and intestinal perforation indicating a poor prognosis with a mortality rate of 50% at the mean age of 76 [7, 11]. Our patient developed secondary complications such as cataracts, type 2 diabetes, and disseminated Mycobacterium chelonei infections, during the chronic use of corticosteroids. Sensorineural hearing loss was deemed associated with the use of amikacin, however this may have been due to VEXAS given it has been reported in 9% of the cases . Inhibitors of TNF-alpha, IL-6, IL-1, and Janus Kinase (upregulated in VEXAS syndrome) have demonstrated varying success . In one case series, no subject with VEXAS syndrome responded to disease-modifying anti-inflammatory drugs, while all were high-dose glucocorticoid-dependent . Several immunosuppressive and immunomodulatory agents were used in our patient without adequate control. Stem-cell transplant has been proposed as potential treatment option and has shown preliminary favorable outcomes in case reports [10, 12,13,14,15]. A formal clinical trial evaluating allogeneic stem cell transplant in VEXAS is underway (ClinicalTrials.gov Identifier NCT05027945).
Germline variants in UBA1 are associated with SMAX2 which is characterized by profound proximal hypotonia with muscle biopsy findings of neurogenic atrophy with no clinical overlap with VEXAS syndrome . Germline p.(Met41Val) variant is not yet described to be associated with SMAX2. Sanger technique has been described as the methodology of choice to identify somatic variants in UBA1 in the peripheral blood. Important to note, low-level mosaicism (< 20% of the cells) may be undetectable by Sanger sequencing so a next-generation technology with deeper coverage such as a targeted gene panel or ES might be warranted in some cases . Interestingly, due to the high VAF, the UBA1 pathogenic variant in our case was misinterpreted as being in a hemizygous state. High VAF has been described in the literature to occur in postzygotic event such as clonal hematopoiesis in variants in TP53 with median VAF of 67.7% (range 46.9–84.7%) . Regarding VEXAS, the highest value described in the literature was 83.35% in a patient diagnosed after analysis of peripheral-blood ES data . Due to the absence of clinical features of SMAX2 in our patient, further testing in two different tissues samples through Sanger technique was used to confirm the somatic state of the UBA1 variant. Testing to confirm the presence of somatic UBA1 variant should be pursued, not only when the patient phenotype does not match that reported with SMAX2, but for patients with treatment-refractory inflammation with fever, cytopenia, cutaneous, and rheumatologic symptoms in general.
The present case exemplifies the diagnostic challenge that was imposed by the inaccurate recognition of the UBA1 pathogenic variant as hemizygous on ES due to the VAF of the UBA1 variant in the blood, which in this patient is the highest VAF recorded among VEXAS patients to date [3, 12]. It is important to consider sequencing different tissues when there is conflict between the UBA1 variant status and the patient's clinical presentation. Even though treatment for VEXAS syndrome is still challenging, early diagnosis can be life-changing since there are reports of favorable outcomes after allogeneic stem cell transplant.