This multicenter cohort study systematically evaluated the genetic landscape, clinical features, treatment responses, and transcriptomic signatures of SPENCDI (spondyloenchondrodysplasia with immune dysregulation) caused by biallelic *ACP5* mutations, integrating 17 newly identified patients from Egypt and China with previously reported cases.
Five novel pathogenic *ACP5* variants were identified; skeletal involvement was most common (32.31% of manifestations), with skeletal dysplasia in 94.32% and short stature in 81.82% of patients. Transcriptomics revealed upregulated type I IFN genes in monocytes and enhanced IFNγ signaling between monocytes and NK cells; prednisolone and azathioprine were the most frequently effective treatments, while JAK inhibitors (ruxolitinib, upadacitinib) achieved only partial responses.
Small sample size (17 new patients) limits generalizability; retrospective multicenter design introduces heterogeneity in clinical assessment and treatment protocols; long-term treatment outcome data are not reported.
In patients with SPENCDI, expect predominant skeletal and immune manifestations driven by an elevated interferon signature; conventional immunosuppression (prednisolone, azathioprine) remains the most effective option, while JAK inhibitors may offer only partial benefit and warrant further study.
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