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This study systematically evaluates genetic landscape, clinical features, treatment, and transcriptomics in SPENCDI.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Whole\u2010exome sequencing was performed for genetic diagnosis of patients from multiple centers, and tartrate\u2010resistant acid phosphatase (TRAP) activity was measured for novel variants. Previously reported cases were integrated with the current cohort for analysis of genotypes, clinical characteristics, laboratory findings, and treatment responses. Bulk and single\u2010cell RNA sequencing investigated immune signaling alterations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified 17 patients with\n                      <jats:italic>ACP5<\/jats:italic>\n                      deficiency from Egypt and China, discovering five novel pathogenic variants (A260D, L257P, G32D, K190Nfs*22, and T305Nfs*12). Three novel missense variants were detected with loss of TRAP activity. Clinical manifestations involve multiple systems, with the skeletal system most frequently involved (32.31%), in which skeletal dysplasia (94.32%) and short stature (81.82%) are the predominant features. Patients showed elevated inflammatory activity, with enrichment of the NF\u2010\u03baB, MAPK, and cell death pathways, as well as up\u2010regulation of type I interferon (IFN) genes in monocytes. Enhanced IFN\u03b3 signaling interactions between monocytes and natural killer cells were observed. Therapeutically, prednisolone and azathioprine were the most common effective drugs, whereas patients treated with the JAK inhibitors ruxolitinib and upadacitinib achieved a partial response.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This study expanded the genetic and clinical spectrum of\n                      <jats:italic>ACP5<\/jats:italic>\n                      deficiency. An up\u2010regulated IFN signature was revealed, and monocytes were identified as a major cellular source of inflammation. These results provide valuable insights for improving the diagnosis and treatment of SPENCDI.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.70279","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T08:06:17Z","timestamp":1784189177000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Multicenter Integrative Cohort Characterizing the Genetic, Clinical, and Transcriptomic Features of\n                    <scp>\n                      <i>ACP5<\/i>\n                    <\/scp>\n                    Deficiency"],"prefix":"10.1002","author":[{"given":"Shiling","family":"Zhong","sequence":"first","affiliation":[{"name":"Department of Pediatric Rheumatology and Immunology Women and Children's Hospital of Ningbo University, Ningbo Key Laboratory of Prevention and Treatment of Embryo\u2010originated Diseases  Ningbo China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangyue","family":"Ma","sequence":"additional","affiliation":[{"name":"Liangzhu Laboratory of Zhejiang University, Department of Rheumatology Sir Run Run Shaw Hospital, Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmine","family":"El Chazli","sequence":"additional","affiliation":[{"name":"Pediatric Hematology, Department of Pediatrics, Faculty of Medicine Alexandria University  Alexandria Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jika","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Pediatric Rheumatology and Immunology Women and Children's Hospital of Ningbo University, Ningbo Key Laboratory of Prevention and Treatment of Embryo\u2010originated Diseases  Ningbo 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