Oral mucosal manifestations with identical mutations to the bone marrow in a patient with VEXAS syndrome

Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome is a recently recognized adult-onset autoinflammatory systemic disease caused by somatic mutations in the X-linked ubiquitin-like modifier activating enzyme 1 (UBA1) gene found in hematopoietic progenitors. This mutation primarily affects men and results in recurring fever, hematological abnormalities, skin lesions, relapsing polychondritis, arthritis, and other inflammatory manifestations.1 UBA1 mutations have also been observed in patients with myelodysplastic syndrome.2 Two studies reported UBA1 mutations in skin biopsies from VEXAS patients with neutrophilic dermatoses.3, 4 It is not known whether UBA1 or other genetic mutations are present in inflammatory changes affecting organs other than the skin and bone marrow in VEXAS patients. We present a patient with mutation in UBA1 detected in the skin and oral mucosa. Additionally, other myeloid mutations were also detected in the patient's oral lesions. A 75-year-old man with pleuritis, polyarthritis, and fever was admitted to Uppsala University Hospital. Inflammatory markers were elevated, while the autoimmune panel (antinuclear antibody, antineutrophil cytoplasmic antibody, anticyclic citrullinated peptide antibody, and rheumatoid factor) was negative, and no evidence of malignancy was found. Initial treatment included low-dose prednisolone and methotrexate to address seronegative polyarthritis and systemic inflammation to which there was partial response. At follow-up visits, the patient continued to have arthritis and suffered widespread pustules on the body, blepharitis, and recurrent chondritis. Hematological tests indicated fluctuating inflammation and macrocytic anemia (a mean corpuscular volume [MCV] of 100 fL) and platelet count under 200 × 109/L. Repeated skin biopsies showed nonspecific neutrophilic inflammation without signs of vasculitis. As the disease progressed, various treatments were administered, including methotrexate, adalimumab, chloroquine phosphate, and colchicine, but none effectively managed his symptoms. Targeted analysis of exon 1 in UBA1 identified the known hotspot mutation (NM_003334.3:c121A>C;p.Met41Leu) in peripheral blood cells, and the patient was diagnosed with VEXAS syndrome. Evaluation of the bone marrow revealed notable dysplastic features of the megakaryocytes exhibiting atypical morphology with bizarre hyperchromatic, hypolobated, or separated nuclei. Vacuoles were observed in some myeloid progenitor cells. Genetic analysis of the bone marrow sample using a targeted droplet digital polymerase chain reaction (ddPCR) assay confirmed the same UBA1 mutation with a variant allele frequency (VAF) of 81%.5 Moreover, pathogenic variants related to clonal hematopoiesis were also detected in DNMT3A (NM_022552.5:c.2204A>C;p.Y735S) and PPM1D (NM_003420.4c.1412del;p.P471Qfs*12) with VAFs of 14% and 6%, respectively in peripheral blood and 39% and 15%, respectively in bone marrow using a customized panel enriched for genes recurrently mutated in myeloid neoplasms.6 Mutations in these genes are not only common in myeloid neoplasms but are also related to clonal hematopoiesis. The DNMT3A (p.Y735S) mutation is a missense variant thought to impair the tumor-suppressing function of its DNA methylation enzyme.7 In contrast, the PPM1D (p.P471Qfs*12) mutation is a truncating, gain-of-function variant that creates a hyper-stable protein, which abrogates the DNA damage signals and allows damaged cells to survive and proliferate.8 Although co-occurring mutations in clonal hematopoiesis driver genes, such as DNMT3A, are associated with a poorer prognosis in VEXAS syndrome, the defining autoinflammatory phenotype is specifically driven by the somatic UBA1 mutation.9 Treatment with low-dose prednisolone and anakinra was initiated with a moderate effect on skin rash, arthritis, and fluctuating inflammatory parameters. The patient developed pulmonary and mesenteric thrombosis and a severe legionella infection with systemic inflammation demanding treatment with high-dose prednisolone. Macrocytic anemia (MCV: 120 fL), thrombocytopenia ([70–80] × 109/L), and pronounced fatigue were persistent. Three years after diagnosis, the patient developed atypical changes in the oral mucosa and on the tongue. The dorsum of the tongue displayed raised, well-defined nodular lesions (up to 1 cm × 1 cm) with papillary atrophy and a dispersed, feather-like pattern. Similar findings were noted along the lateral side of the tongue on the left, extending towards the floor of the mouth, and on the buccal mucosa bilateral, including the inner surfaces of both lips reaching the vermilion (Figure 1A). Additionally, on the buccal mucosa and left labial commissure, hard, gritty lesions lighter than the surrounding mucosa were observed, along with an elongated, whitish-yellow, indurated lesion (approximately 0.5 cm × 1 cm) on the lower lip on the left, with subtle changes in the right labial commissure (Supporting Information: Figure S1). Biopsies from the tongue, inner lower lip, and right buccal mucosa revealed normal stratified squamous epithelium with an edematous stroma containing a diffuse, mild-to-moderate lymphohistiocytic infiltrate, neutrophils, and nuclear dust (Figure 1B,C). Staining with myeloperoxidase confirmed the presence of neutrophil granulocytes (Supporting Information: Figure S1). No granulomas, giant cells, necrosis, vasculitis, or dysplasia were seen. To ascertain whether the cutaneous and oral mucosal findings were associated with the patient's VEXAS syndrome, genetic analysis was performed using ddPCR targeting the UBA1 mutation. This mutation was identified in all skin lesions with VAF ranging from 9% to 20%. In the oral mucosal sample, the mutation was present at a VAF of 86%, and broad genomic profiling further revealed the previously known mutations in DNMT3A (VAF 38%) and PPM1D (VAF 14%) (Figure 1D and Supporting Information: Table S1). Our case highlights that VEXAS patients may have recurrent inflammatory symptoms due to the infiltration of clonal mutated myeloid cells regardless of anti-inflammatory treatment. The targeted ddPCR conducted on peripheral tissue samples may assist in confirming UBA1 and other co-mutations in patients suspected of having VEXAS syndrome. In conclusion, we presented a unique case of a patient with UBA1 mutation in the skin and mucosal lesions consistent with VEXAS syndrome. Moreover, the patient displayed atypical changes in the oral mucosa, harboring additional myeloid mutations identical to those found in the bone marrow. These findings suggest a clonal origin of the extramedullary manifestations in VEXAS. Given the clonal nature of VEXAS syndrome, therapeutic approaches targeting inflammation alone may prove insufficient; combination therapies that simultaneously target the underlying clonal hematopoiesis could theoretically offer additional benefit and should be explored if such treatments become available. Conceptualization: Lilian Vasaitis, Panagiotis Baliakas. Data curation: Lilian Vasaitis, Lena Blomstrand. Formal analysis: Miklos Gulyas, Viktor Ljungström (histopathology), Tatjana Pandzic, Panagiotis Baliakas, Viktor Ljungström (genetic analyses). Investigation: Lilian Vasaitis, Lena Blomstrand, Miklos Gulyas, Tatjana Pandzic, Panagiotis Baliakas, Viktor Ljungström. Methodology: Lilian Vasaitis, Panagiotis Baliakas. Writing, original draft: Lilian Vasaitis, Viktor Ljungström. Writing, review and editing: All authors. We would like to acknowledge Clinical Genomics Uppsala, Science for Life Laboratory, Uppsala University, Sweden, for assisting in sequencing and analysis. The authors declare no conflicts of interest. Written informed consent was obtained from the patient for publication of this case report and accompanying photographs. The patient was informed that information about his case would be published in a medical journal and that complete anonymity could not be guaranteed. A copy of the consent form is available for review upon request. The data that support the findings of this study are available from the corresponding author upon reasonable request. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.