{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T17:53:01Z","timestamp":1776361981937,"version":"3.51.2"},"reference-count":56,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T00:00:00Z","timestamp":1755648000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grant-in-Aid for Scientific Research","award":["KAKENHI 24K11527"],"award-info":[{"award-number":["KAKENHI 24K11527"]}]},{"name":"Grant-in-Aid for Scientific Research","award":["23KC2009"],"award-info":[{"award-number":["23KC2009"]}]},{"name":"Health and Labour Sciences Research Grant","award":["KAKENHI 24K11527"],"award-info":[{"award-number":["KAKENHI 24K11527"]}]},{"name":"Health and Labour Sciences Research Grant","award":["23KC2009"],"award-info":[{"award-number":["23KC2009"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Although cytoplasmic vacuoles are instantly recognizable on bone marrow smears, their etiologic significance remains a diagnostic dilemma in everyday practice. We conducted a PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) aligned systematic review with narrative synthesis registered in PROSPERO and refrained from meta-analysis owing to high between-study heterogeneity (I2 &gt; 80%). Across 22 studies, we identified 818 unique adults with vacuolated marrow cytopenias. A stepwise diagnostic algorithm\u2014serum copper\/ceruloplasmin followed, when non-diagnostic, by UBA1 hotspot sequencing in adults meeting clinical \u201cred flags\u201d\u2014correctly classified 97% of cases within &lt;5 days at a median laboratory cost of ~USD 173, reserving broad myeloid next-generation sequencing for the atypical minority. This synthesis clarifies the relative frequency of major etiologies and provides a cost-efficient, practice-ready pathway that bridges trace-metal metabolism and somatic genomics.<\/jats:p>","DOI":"10.3390\/ijms26168044","type":"journal-article","created":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T08:02:44Z","timestamp":1755763364000},"page":"8044","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Vacuolated Marrow Cytopenias from Copper Deficiency to UBA1-Mutant VEXAS: Molecular Landscape, Systematic Review, and Cost-Efficient Diagnostic Algorithm"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1822-9976","authenticated-orcid":false,"given":"Akiyoshi","family":"Takami","sequence":"first","affiliation":[{"name":"Division of Hematology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2983-2129","authenticated-orcid":false,"given":"Kaori","family":"Uchino","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mai","family":"Terashima","sequence":"additional","affiliation":[{"name":"Department of Central Clinical Laboratory, Aichi Medical University Hospital, Nagakute 480-1195, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seiko","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Fujita Health University Hospital, Toyoake 470-1192, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuka","family":"Kondo","sequence":"additional","affiliation":[{"name":"Department of Central Clinical Laboratory, Toyohashi Municipal Hospital, Toyohashi 441-8570, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1794-6666","authenticated-orcid":false,"given":"J. Luis","family":"Espinoza","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, Kanazawa University, Kanazawa 920-0942, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megumi","family":"Enomoto","sequence":"additional","affiliation":[{"name":"Department of Central Clinical Laboratory, Aichi Medical University Hospital, Nagakute 480-1195, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,20]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1002\/ajh.20864","article-title":"Copper deficiency causes reversible myelodysplasia","volume":"82","author":"Huff","year":"2007","journal-title":"Am. J. Hematol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1182\/blood-2002-01-0256","article-title":"Copper deficiency masquerading as myelodysplastic syndrome","volume":"100","author":"Gregg","year":"2002","journal-title":"Blood"},{"key":"ref_4","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_5","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_6","unstructured":"NIHR (2025, June 01). PROSPERO: International Prospective Register of Systematic Reviews. Available online: https:\/\/www.crd.york.ac.uk\/PROSPERO\/home."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"i4919","DOI":"10.1136\/bmj.i4919","article-title":"ROBINS-I: A tool for assessing risk of bias in non-randomised studies of interventions","volume":"355","author":"Sterne","year":"2016","journal-title":"BMJ"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1038\/bmt.2012.244","article-title":"Investigation of the freely available easy-to-use software \u2018EZR\u2019 for medical statistics","volume":"48","author":"Kanda","year":"2013","journal-title":"Bone Marrow Transplant."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3685","DOI":"10.1182\/blood.2021010811","article-title":"Vacuolization of hematopoietic precursors: An enigma with multiple etiologies","volume":"137","author":"Gurnari","year":"2021","journal-title":"Blood"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1002\/jha2.278","article-title":"Cytopenia associated with copper deficiency","volume":"2","author":"Uchino","year":"2021","journal-title":"EJHaem"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1097\/MCG.0b013e3181354294","article-title":"Copper deficiency in celiac disease","volume":"43","author":"Halfdanarson","year":"2009","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1111\/j.1600-0609.2008.01050.x","article-title":"Hematological manifestations of copper deficiency: A retrospective review","volume":"80","author":"Halfdanarson","year":"2008","journal-title":"Eur. J. Haematol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Vitale, A., Leone, F., Caggiano, V., Hinojosa-Azaola, A., Martin-Nares, E., Guaracha-Basanez, G.A., Torres-Ruiz, J., Ayumi Kawakami-Campos, P., Hissaria, P., and Callisto, A. (2025). Efficacy and safety of conventional disease-modifying antirheumatic drugs in VEXAS syndrome: Real-world data from the international AIDA network. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1539756"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1093\/rheumatology\/kead697","article-title":"Treatment experiences with focus on IL-6R inhibition in patients with VEXAS syndrome and a case of remission with azacytidine treatment","volume":"64","author":"Johansen","year":"2025","journal-title":"Rheumatology"},{"key":"ref_15","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_16","doi-asserted-by":"crossref","first-page":"2056","DOI":"10.1093\/rheumatology\/kead425","article-title":"Efficient detection of somatic UBA1 variants and clinical scoring system predicting patients with variants in VEXAS syndrome","volume":"63","author":"Maeda","year":"2024","journal-title":"Rheumatology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2190","DOI":"10.1182\/blood.2023022329","article-title":"Venous and arterial thrombosis in patients with VEXAS syndrome","volume":"143","author":"Kusne","year":"2024","journal-title":"Blood"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3879","DOI":"10.57187\/s.3879","article-title":"VEXAS syndrome: A Swiss national retrospective cohort study","volume":"155","author":"Wolff","year":"2024","journal-title":"Swiss Med. Wkly."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1001\/jama.2022.24836","article-title":"Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population","volume":"329","author":"Beck","year":"2023","journal-title":"JAMA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1136\/ard-2023-224460","article-title":"Spanish cohort of VEXAS syndrome: Clinical manifestations, outcome of treatments and novel evidences about UBA1 mosaicism","volume":"82","author":"Mascaro","year":"2023","journal-title":"Ann. Rheum. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3947","DOI":"10.1093\/rheumatology\/kead245","article-title":"Targeted testing of bone marrow specimens with cytoplasmic vacuolization to identify previously undiagnosed cases of VEXAS syndrome","volume":"62","author":"Hines","year":"2023","journal-title":"Rheumatology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1111\/imj.15742","article-title":"VEXAS syndrome: Lessons learnt from an early Australian case series","volume":"52","author":"Islam","year":"2022","journal-title":"Intern. Med. J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2739","DOI":"10.1038\/s41375-022-01698-8","article-title":"A Phase II prospective trial of azacitidine in steroid-dependent or refractory systemic autoimmune\/inflammatory disorders and VEXAS syndrome associated with MDS and CMML","volume":"36","author":"Mekinian","year":"2022","journal-title":"Leukemia"},{"key":"ref_24","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_25","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1111\/bjh.17893","article-title":"Azacitidine for patients with Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic syndrome (VEXAS) and myelodysplastic syndrome: Data from the French VEXAS registry","volume":"196","author":"Comont","year":"2022","journal-title":"Br. J. Haematol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1182\/blood.2022016985","article-title":"Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis","volume":"140","author":"Ferrada","year":"2022","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1136\/annrheumdis-2021-220089","article-title":"Pathogenic UBA1 variants associated with VEXAS syndrome in Japanese patients with relapsing polychondritis","volume":"80","author":"Tsuchida","year":"2021","journal-title":"Ann. Rheum. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1886","DOI":"10.1002\/art.41743","article-title":"Somatic Mutations in UBA1 Define a Distinct Subset of Relapsing Polychondritis Patients With VEXAS","volume":"73","author":"Ferrada","year":"2021","journal-title":"Arthritis Rheumatol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Takami, A., and Uchino, K. (2025). Discovering the hidden link: Hematological disorders caused by copper deficiency. Int. J. Hematol.","DOI":"10.1007\/s12185-025-04036-7"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.4161\/cc.10.11.15673","article-title":"Autophagy in the pathogenesis of myelodysplastic syndrome and acute myeloid leukemia","volume":"10","author":"Watson","year":"2011","journal-title":"Cell Cycle"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Pierro, F., Fazio, M., Murdaca, G., Stagno, F., Gangemi, S., and Allegra, A. (2025). Oxidative Stress and Mitochondrial Dysfunction in Myelodysplastic Syndrome: Roles in Development, Diagnosis, Prognosis, and Treatment. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26136415"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Savy, C., Bourgoin, M., Cluzeau, T., Jacquel, A., Robert, G., and Auberger, P. (2025). VEXAS, Chediak-Higashi syndrome and Danon disease: Myeloid cell endo-lysosomal pathway dysfunction as a common denominator?. Cell Mol. Biol. Lett., 30.","DOI":"10.1186\/s11658-025-00691-0"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1039\/C8MT00224J","article-title":"Copper deficiency-induced anemia is caused by a mitochondrial metabolic reprograming in erythropoietic cells","volume":"11","author":"Jensen","year":"2019","journal-title":"Metallomics"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1111\/j.1365-2141.2004.05192.x","article-title":"Vacuolated neutrophils in ethanol toxicity","volume":"127","author":"Cook","year":"2004","journal-title":"Br. J. Haematol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1111\/bjh.16795","article-title":"Vacuolation of early erythroblasts with ring sideroblasts: A clue to the diagnosis of linezolid toxicity","volume":"190","author":"Liapis","year":"2020","journal-title":"Br. J. Haematol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1056\/NEJM196010132631503","article-title":"Chloramphenicol toxicity. Reversible vacuolization of erythroid cells","volume":"263","author":"Rosenbach","year":"1960","journal-title":"N. Engl. J. Med."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Ballo, O., Stratmann, J., Serve, H., Steffen, B., Finkelmeier, F., and Brandts, C. (2019). Blast vacuolization in AML patients indicates adverse-risk AML and is associated with impaired survival after intensive induction chemotherapy. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0223013"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.humpath.2020.02.003","article-title":"Unique morphologic and genetic characteristics of acute myeloid leukemia with chromothripsis: A clinicopathologic study from a single institution","volume":"98","author":"Gao","year":"2020","journal-title":"Hum. Pathol."},{"key":"ref_39","first-page":"42","article-title":"The hematological complications of alcoholism","volume":"21","author":"Ballard","year":"1997","journal-title":"Alcohol. Health Res. World"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"106638","DOI":"10.1016\/j.leukres.2021.106638","article-title":"A higher percentage of leukemic blasts with vacuoles predicts unfavorable outcomes in patients with acute myeloid leukemia","volume":"109","author":"Song","year":"2021","journal-title":"Leuk. Res."},{"key":"ref_41","first-page":"325","article-title":"Kearns-Sayre syndrome: A case series of 35 adults and children","volume":"7","author":"Khambatta","year":"2014","journal-title":"Int. J. Gen. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1182\/blood-2017-12-820308","article-title":"Mutations in the SRP54 gene cause severe congenital neutropenia as well as Shwachman-Diamond-like syndrome","volume":"132","author":"Marty","year":"2018","journal-title":"Blood"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1038\/35022595","article-title":"Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice","volume":"406","author":"Tanaka","year":"2000","journal-title":"Nature"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e2021026","DOI":"10.4084\/mjhid.2021.026","article-title":"Parvovirus B19 Infection in a Patient with Common Variable Immunodeficiency","volume":"13","author":"Zanelli","year":"2021","journal-title":"Mediterr. J. Hematol. Infect. Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/s00428-014-1592-8","article-title":"Risk factor analysis for bone marrow histiocytic hyperplasia with hemophagocytosis: An autopsy study","volume":"465","author":"Inai","year":"2014","journal-title":"Virchows Arch."},{"key":"ref_46","unstructured":"CMS (2025, July 03). 25CLABQ2, Available online: https:\/\/www.cms.gov\/medicare\/payment\/fee-schedules\/clinical-laboratory-fee-schedule-clfs\/files\/25CLABQ2."},{"key":"ref_47","unstructured":"UNC (2025, July 03). UBA1Q Mutation Quantitative Detection, DDPCR (VEXAS Syndrome). Available online: https:\/\/www.uncmedicalcenter.org\/mclendon-clinical-laboratories\/available-tests\/uba1q-mutation-quantitative-detection-ddpcr-vexas-syndrome\/."},{"key":"ref_48","unstructured":"University, J.H. (2025, June 27). Myeloid Panel, NGS, Blood. Available online: https:\/\/pathology.jhu.edu\/test-directory\/leukemia-panel-ngs-blood-2."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1182\/blood-2019-124445","article-title":"Clinical Utility of a Multi-Gene Next-Generation Sequencing Myeloid Panel in an Academic Hematology Practice","volume":"134","author":"Vianna","year":"2019","journal-title":"Blood"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1002\/ajh.27156","article-title":"VEXAS syndrome: Clinical, hematologic features and a practical approach to diagnosis and management","volume":"99","author":"Koster","year":"2024","journal-title":"Am. J. Hematol."},{"key":"ref_51","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_52","doi-asserted-by":"crossref","first-page":"e472","DOI":"10.1016\/S2665-9913(25)00034-7","article-title":"Treatment outcomes in patients with VEXAS syndrome: A retrospective cohort study","volume":"7","author":"Trikha","year":"2025","journal-title":"Lancet Rheumatol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"101160","DOI":"10.1016\/j.xcrm.2023.101160","article-title":"Early activation of inflammatory pathways in UBA1-mutated hematopoietic stem and progenitor cells in VEXAS","volume":"4","author":"Wu","year":"2023","journal-title":"Cell Rep. Med."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Cardoneanu, A., Rezus, I.I., Burlui, A.M., Richter, P., Bratoiu, I., Mihai, I.R., Macovei, L.A., and Rezus, E. (2024). Autoimmunity and Autoinflammation: Relapsing Polychondritis and VEXAS Syndrome Challenge. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25042261"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"7445","DOI":"10.1182\/bloodadvances.2023010531","article-title":"Sensitivity to targeted UBA1 inhibition in a myeloid cell line model of VEXAS syndrome","volume":"7","author":"Chiaramida","year":"2023","journal-title":"Blood Adv."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Lin, J.F., Chi, C.W., Huang, Y.C., Tsai, T.H., and Chen, Y.J. (2023). Anti-Cancer Effects of Oxygen-Atom-Modified Derivatives of Wasabi Components on Human Leukemia Cells. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24076823"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/16\/8044\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:31:53Z","timestamp":1760034713000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/16\/8044"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,20]]},"references-count":56,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["ijms26168044"],"URL":"https:\/\/doi.org\/10.3390\/ijms26168044","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,20]]}}}