{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T21:00:09Z","timestamp":1782421209068,"version":"3.54.5"},"reference-count":30,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2025,8,17]],"date-time":"2025-08-17T00:00:00Z","timestamp":1755388800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>VEXAS syndrome (Vacuoles, E1-enzyme, X-linked, Autoinflammation, and Somatic) is a recently identified late-onset autoinflammatory disorder characterized by a unique interplay between hematological and inflammatory manifestations. It results from somatic mutations in the UBA1 gene, located on the short arm of the X chromosome. Initially, females were considered mere carriers, with the syndrome primarily affecting males over 50. However, recent evidence indicates that heterozygous females can exhibit symptoms as severe as those seen in hemizygous males. The disease manifests as systemic inflammation, macrocytic anemia, thrombocytopenia, chondritis, neutrophilic dermatoses, and steroid-dependent inflammatory symptoms. Due to its overlap with autoimmune and hematologic disorders such as relapsing polychondritis, Still\u2019s disease, and myelodysplastic syndromes, misdiagnosis is common. At the molecular level, VEXAS syndrome is driven by impaired ubiquitination pathways, resulting in dysregulated immune responses and clonal hematopoiesis. A key diagnostic marker is the presence of cytoplasmic vacuoles in myeloid and erythroid precursors, though definitive diagnosis requires genetic testing for UBA1 mutations. Traditional immunosuppressants and TNF inhibitors are generally ineffective, while JAK inhibitors and IL-6 blockade provide partial symptom control. Azacitidine and decitabine have shown promise in reducing disease burden, but hematopoietic stem cell transplantation (HSCT) remains the only curative treatment, albeit with significant risks. This review provides a comprehensive analysis of VEXAS syndrome, examining its clinical features, differential diagnoses, diagnostic challenges, and treatment approaches, including both pharmacological and non-pharmacological strategies. By enhancing clinical awareness and optimizing therapeutic interventions, this article aims to bridge emerging genetic insights with practical patient management, ultimately improving outcomes for those affected by this complex and often life-threatening disease.<\/jats:p>","DOI":"10.3390\/ijms26167931","type":"journal-article","created":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T16:22:33Z","timestamp":1755534153000},"page":"7931","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["VEXAS Syndrome: Genetics, Gender Differences, Clinical Insights, Diagnostic Pitfalls, and Emerging Therapies"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5621-1374","authenticated-orcid":false,"given":"Salvatore","family":"Corrao","sequence":"first","affiliation":[{"name":"Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90133 Palermo, Italy"},{"name":"Department of Internal Medicine, National Relevance and High Specialization Hospital Trust, ARNAS Civico, Di Cristina, Benfratelli, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2119-7988","authenticated-orcid":false,"given":"Marta","family":"Moschetti","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Research and Innovation (IRIB), National Research Council (CNR), 90146 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Scibetta","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Relevance and High Specialization Hospital Trust, ARNAS Civico, Di Cristina, Benfratelli, 90127 Palermo, Italy"},{"name":"Institute for Biomedical Research and Innovation (IRIB), National Research Council (CNR), 90146 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Calvo","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Relevance and High Specialization Hospital Trust, ARNAS Civico, Di Cristina, Benfratelli, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annarita","family":"Giardina","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Relevance and High Specialization Hospital Trust, ARNAS Civico, Di Cristina, Benfratelli, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9426-7798","authenticated-orcid":false,"given":"Ignazio","family":"Cangemi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Relevance and High Specialization Hospital Trust, ARNAS Civico, Di Cristina, Benfratelli, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmela","family":"Zizzo","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Research and Innovation (IRIB), National Research Council (CNR), 90146 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2470-7030","authenticated-orcid":false,"given":"Paolo","family":"Colomba","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Research and Innovation (IRIB), National Research Council (CNR), 90146 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Duro","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Research and Innovation (IRIB), National Research Council (CNR), 90146 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2628","DOI":"10.1056\/NEJMoa2026834","article-title":"Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease","volume":"383","author":"Beck","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1016\/S0140-6736(21)01430-6","article-title":"Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome: Fevers, myalgia, arthralgia, auricular chondritis, and erythema nodosum","volume":"398","author":"Dehghan","year":"2021","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e160","DOI":"10.1016\/S2352-3026(23)00375-7","article-title":"Vacuoles in bone marrow progenitors: VEXAS syndrome and beyond","volume":"11","author":"Lacombe","year":"2024","journal-title":"Lancet Haematol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4690","DOI":"10.1038\/s41467-025-59890-0","article-title":"In depth transcriptomic profiling defines a landscape of dysfunctional immune responses in patients with VEXAS syndrome","volume":"16","author":"Mizumaki","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Alqatari, S., Alqunais, A.A., Alali, S.M., Alharbi, M.A., Hasan, M., and Al Shubbar, M.D. (2024). VEXAS Syndrome: A Comprehensive Review of Current Therapeutic Strategies and Emerging Treatments. J. Clin. Med., 13.","DOI":"10.3390\/jcm13226970"},{"key":"ref_6","unstructured":"ClinVar (2025, May 23). NM_003334.4(UBA1):c.121A>C [p.Met41Leu] and VEXAS syndrome. National Center for Biotechnology Information, U.S. National Library of Medicine: Bethesda, MD, USA, 3 January 2023, Available online: https:\/\/www.ncbi.nlm.nih.gov\/clinvar\/RCV001265108\/."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2694","DOI":"10.1093\/rheumatology\/keae123","article-title":"Comparing clinical features between males and females with VEXAS syndrome: Data from literature analysis of patient reports","volume":"63","author":"Echerbault","year":"2024","journal-title":"Rheumatology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e402","DOI":"10.1093\/rheumatology\/keab392","article-title":"VEXAS syndrome in a woman","volume":"60","author":"Barba","year":"2021","journal-title":"Rheumatology"},{"key":"ref_9","first-page":"47","article-title":"VEXAS syndrome: Clinical manifestations, diagnosis, and treatment","volume":"20","author":"Ferrada","year":"2024","journal-title":"Reumatol. Cl\u00ednica (Engl. Ed.)"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.3324\/haematol.2021.280238","article-title":"VEXAS syndrome in a female patient with constitutional 45,X (Turner syndrome)","volume":"107","author":"Stubbins","year":"2022","journal-title":"Haematologica"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1053\/j.seminhematol.2021.10.004","article-title":"clonal hematopoiesis and VEXAS syndrome: Survival of the fittest clones?","volume":"58","author":"Kusne","year":"2021","journal-title":"Semin. Hematol."},{"key":"ref_12","first-page":"244","article-title":"Spectrum of clonal hematopoiesis in VEXAS syndrome","volume":"142","author":"Kusne","year":"2023","journal-title":"Blood"},{"key":"ref_13","first-page":"S1525","article-title":"Rapid Screening and Monitoring of UBA1 Mutations in VEXAS Syndrome","volume":"14","author":"Mora","year":"2025","journal-title":"J. Mol. Diagn."},{"key":"ref_14","first-page":"s34","article-title":"Detection of UBA1 Mutations Using a Droplet Digital Polymerase Chain Reaction Assay for the Diagnosis of VEXAS Syndrome","volume":"24","author":"Boerger","year":"2022","journal-title":"J. Mol. Diagnostics."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1111\/bjd.20805","article-title":"Further characterization of clinical and laboratory features in VEXAS syndrome: Large-scale analysis of a multicentre case series of 116 French patients","volume":"186","author":"Terrier","year":"2022","journal-title":"Br. J. Dermatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2488","DOI":"10.1056\/NEJMoa1408617","article-title":"Age-related clonal hematopoiesis associated with adverse outcomes","volume":"371","author":"Jaiswal","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1038\/s41375-023-01857-5","article-title":"Novel causative variants of VEXAS in UBA1 detected through whole genome transcriptome sequencing in a large cohort of hematological malignancies","volume":"37","author":"Sakuma","year":"2023","journal-title":"Leukemia"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6061","DOI":"10.1038\/s41467-021-26093-2","article-title":"TET2 mutations are associated with hypermethylation at key regulatory enhancers in normal and malignant hematopoiesis","volume":"12","author":"Tulstrup","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e068044","DOI":"10.1136\/bmj-2021-068044","article-title":"Five strategies for clinicians to advance diagnostic excellence","volume":"376","author":"Singh","year":"2022","journal-title":"BMJ"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1136\/bmjqs-2015-004417","article-title":"Dual-process cognitive interventions to enhance diagnostic reasoning: A systematic review","volume":"25","author":"Lambe","year":"2016","journal-title":"BMJ Qual. Saf."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Ronchetti, S., Ayroldi, E., Ricci, E., Gentili, M., Miglioralti, G., and Riccardi, C. (2021). A Glance at the Use of Glucocorticoids in Rare Inflammatory and Autoimmune Diseases: Still an Indispensable Pharmacological Tool?. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.613435"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1097\/BOR.0000000000001068","article-title":"VEXAS syndrome: An adult-onset autoinflammatory disorder with underlying somatic mutation","volume":"37","author":"Krusche","year":"2025","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1111\/ejh.14441","article-title":"Bone Marrow Vacuolization at the Crossroads of Specialties: Molecular Insights and Diagnostic Challenges","volume":"115","author":"Elbadry","year":"2025","journal-title":"Eur. J. Haematol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/s41409-021-01544-y","article-title":"Allogeneic stem cell transplantation as a curative therapeutic approach for VEXAS syndrome: A case report","volume":"57","author":"Loschi","year":"2022","journal-title":"Bone Marrow Transplant."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1136\/ard-2024-225640","article-title":"Efficacy and safety of targeted therapies in VEXAS syndrome: Retrospective study from the FRENVEX","volume":"83","author":"Hadjadj","year":"2024","journal-title":"Ann. Rheum. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"900543","DOI":"10.3389\/fmed.2022.900543","article-title":"Clinical reasoning: The cornerstone of diagnosis and management","volume":"9","author":"Corrao","year":"2022","journal-title":"Front Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1038\/s41584-024-01113-9","article-title":"Relapsing polychondritis: Clinical updates and new differential diagnoses","volume":"20","author":"Mertz","year":"2024","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1642","DOI":"10.1038\/s41409-022-01774-8","article-title":"Update on VEXAS and role of allogeneic bone marrow transplant: Considerations on behalf of the Chronic Malignancies Working Party of the EBMT","volume":"57","author":"Gurnari","year":"2022","journal-title":"Bone Marrow Transplant."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1177\/15353702231165030","article-title":"JAK inhibitors for the treatment of VEXAS syndrome","volume":"248","author":"Bindoli","year":"2023","journal-title":"Exp. Biol. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"EVIDoa2200034","DOI":"10.1056\/EVIDoa2200034","article-title":"Low-Dose Decitabine versus Low-Dose Azacitidine in Lower-Risk MDS","volume":"1","author":"Sasaki","year":"2022","journal-title":"NEJM Evid."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/16\/7931\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:29:17Z","timestamp":1760034557000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/16\/7931"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,17]]},"references-count":30,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["ijms26167931"],"URL":"https:\/\/doi.org\/10.3390\/ijms26167931","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,17]]}}}