case_images: PMC10859398_01
case_images: Genetic and clinical characteristics of SPENCDI patients. (A) Xray of the left hand (patient #1). Well-defined metaphyseal irregularity (indicated by red arrow) and sclerosis of the distal radius and ulna consistent with bone growth abnormality. Brain MRI (patient #1): nonspecific calcifications of the globus pallidus bilaterally without acute intracranial abnormality (indicated by red arrow). Xray of spine (patient #1): Multilevel compression deformities of the thoraco-lumbar spine (indicated by red arrows). Nd: not determined. (B) Family pedigree for patient #1 and patient #2. (C) Diagram illustrates the distribution of the reported ACP5 variants for patient #1 and patient #2. * : stop codon.
case_images: fimmu-14-1328005-g002.jpg
case_images: PMC10859398_02_fimmu-14-1328005-g002.jpg
case_images: f2
case_images: Both parents were identified as heterozygous asymptomatic carriers of one of these variants establishing that the patient was compound heterozygote for these two variants ( Figures 2B, C ;  Supplementary Materials ;  Supplementary Table 1 ).
case_images: Laboratory parameters and interferon scores pre- and post-ruxolitinib therapy. (A) Hemoglobin and platelet count pre and post therapy with ruxolitinib in patient #1 and patient #2. Asterix (*) indicates time of hospital admission for acute viral and bacterial pneumonia complicated by acute SPENCDI flare. Asterix (**) indicates ISG expression in patient #1 transiently spiked during an infectious trigger while he remained clinically symptom free (B) Interferon Score of a panel of interferon stimulated genes in 4 SPENCDI patients at various time points throughout treatment, three subjects with IPEX and eight healthy donors. Dashed lines indicate the start of ruxolitinib. HD: healthy donors, Pat: patient, pre: pre ruxolitinib, post: post ruxolitinib, ruxo: ruxolitinib, IS: Interferon Score. Grouped statistical analysis performed using One-Way ANOVA (Kruskal-Wallis test) with Dunn's multiple comparison test. p-value between groups indicated on the graph. Overall p-value: <0.0001. Level of significance (p)=0.05. Additional information on ACP patient #3 and #4 is detailed in 
  Supplementary Table 3
  .
case_images: fimmu-14-1328005-g003.jpg
case_images: PMC10859398_02_fimmu-14-1328005-g003.jpg
case_images: f3
case_images: After resolution of sepsis and following the reinitiation of ruxolitinib therapy, the patient's platelet count improved within 4 weeks ( Figure 3A ). The interferon score of both patients with SPENCDI in our study (patient 1 and 2) was significantly elevated at baseline compared to healthy controls and patients with IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome, where autoimmunity is caused by a regulatory T cell defect ( Figure 3B ;  Supplementary Figure 1 ). As previously reported by Fremond et al., we only observed a minimal decrease in interferon score in patient #1 following the initiation of ruxolitinib therapy ( Figure 3B ). Notably, ISG expression in patient #1 transiently spiked during an infectious trigger while he remained clinically symptom free ( Figures 3A, B ;  Supplementary Figure 1 ).
case_images: PMC10859398_02
case_images: Model for the disease mechanism in SPENCDI, adapted from. ACP5 encodes for tartrate-resistant acid phosphatase (TRAP). Lack of TRAP phosphatase activity results in hyperphosphorylation of OPN. Increased OPN phosphorylation has been linked to increased osteoclast activity, which is believed to contribute to the observed bone and cartilage defects in this disease. In antigen presenting cells of the immune system, increased OPN phosphorylation has been associated with increased interferon (IFN)-alpha release. This figure was created using .
case_images: fimmu-14-1328005-g001.jpg
case_images: PMC10859398_02_fimmu-14-1328005-g001.jpg
case_images: f1
case_images: The interferon score of both patients with SPENCDI in our study (patient 1 and 2) was significantly elevated at baseline compared to healthy controls and patients with IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome, where autoimmunity is caused by a regulatory T cell defect ( Figure 3B ;  Supplementary Figure 1 ). Notably, ISG expression in patient #1 transiently spiked during an infectious trigger while he remained clinically symptom free ( Figures 3A, B ;  Supplementary Figure 1 ).
case_images: Genetic and clinical characteristics of SPENCDI patients. (A) Xray of the left hand (patient #1). Well-defined metaphyseal irregularity (indicated by red arrow) and sclerosis of the distal radius and ulna consistent with bone growth abnormality. Brain MRI (patient #1): nonspecific calcifications of the globus pallidus bilaterally without acute intracranial abnormality (indicated by red arrow). Xray of spine (patient #1): Multilevel compression deformities of the thoraco-lumbar spine (indicated by red arrows). Nd: not determined. (B) Family pedigree for patient #1 and patient #2. (C) Diagram illustrates the distribution of the reported ACP5 variants for patient #1 and patient #2. * : stop codon.
case_images: fimmu-14-1328005-g002.jpg
case_images: PMC10859398_02_fimmu-14-1328005-g002.jpg
case_images: f2
case_images: Both parents were identified as heterozygous asymptomatic carriers of one of these variants establishing that the patient was compound heterozygote for these two variants ( Figures 2B, C ;  Supplementary Materials ;  Supplementary Table 1 ).
case_images: Laboratory parameters and interferon scores pre- and post-ruxolitinib therapy. (A) Hemoglobin and platelet count pre and post therapy with ruxolitinib in patient #1 and patient #2. Asterix (*) indicates time of hospital admission for acute viral and bacterial pneumonia complicated by acute SPENCDI flare. Asterix (**) indicates ISG expression in patient #1 transiently spiked during an infectious trigger while he remained clinically symptom free (B) Interferon Score of a panel of interferon stimulated genes in 4 SPENCDI patients at various time points throughout treatment, three subjects with IPEX and eight healthy donors. Dashed lines indicate the start of ruxolitinib. HD: healthy donors, Pat: patient, pre: pre ruxolitinib, post: post ruxolitinib, ruxo: ruxolitinib, IS: Interferon Score. Grouped statistical analysis performed using One-Way ANOVA (Kruskal-Wallis test) with Dunn's multiple comparison test. p-value between groups indicated on the graph. Overall p-value: <0.0001. Level of significance (p)=0.05. Additional information on ACP patient #3 and #4 is detailed in 
  Supplementary Table 3
  .
case_images: fimmu-14-1328005-g003.jpg
case_images: PMC10859398_02_fimmu-14-1328005-g003.jpg
case_images: f3
case_images: After resolution of sepsis and following the reinitiation of ruxolitinib therapy, the patient's platelet count improved within 4 weeks ( Figure 3A ). The interferon score of both patients with SPENCDI in our study (patient 1 and 2) was significantly elevated at baseline compared to healthy controls and patients with IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome, where autoimmunity is caused by a regulatory T cell defect ( Figure 3B ;  Supplementary Figure 1 ). As previously reported by Fremond et al., we only observed a minimal decrease in interferon score in patient #1 following the initiation of ruxolitinib therapy ( Figure 3B ). Notably, ISG expression in patient #1 transiently spiked during an infectious trigger while he remained clinically symptom free ( Figures 3A, B ;  Supplementary Figure 1 ).