An Autoinflammatory Syndrome Caused by PSMB9 Deficiency: The Power of Functional Testing to Guide Therapy

Introduction Proteasome-associated autoinflammatory syndromes (PRAAS) are monogenic systemic autoinflammatory diseases (SAIDs) caused by proteasome mutations. PSMB9 deficiency is classified as an autoinflammatory disease in the IUIS2024. They show a strong type I interferon response, which can be modulated by JAK inhibitors. Case A 9-year-old girl, born to non-consanguineous parents, with no relevant family history. Healthy until age 8, when she developed fever, bicytopenia, hyperferritinemia (20,000 ng/mL), and bone marrow hemophagocytosis; diagnosed with partial hemophagocytic lymphohistiocytosis (HLH), which improved with corticosteroids. After tapering steroids, she had recurrent episodes of systemic hyperinflammation with fever, arthralgias, and shock, requiring ICU admission. Labs showed leukocytosis with neutrophilia, thrombocytosis, anemia, hyperfibrinogenemia, hyperferritinemia, elevated erythrocyte sedimentation rate and C-reactive protein, and high IL-6 (1,336 pg/mL). Immunological tests (CD3, CD4, CD8, CD19, and immunoglobulins) were normal. Symptoms were partially controlled with corticosteroids. She was refractory to cyclosporine after 6 months. No infection, autoimmunity, malignancy, or rheumatologic disease was found. To investigate the disease mechanism, we analyzed the interferon (IFN) pathway in patient cells using droplet digital PCR. Our results showed overexpression of type I (MX1, ISG15, IFIT1, RSAD2) and type II (GBP1, IRF1, IRF8, ICAM1) IFN-inducible genes. IFN-α signature: 19.8 (cutoff: 8.4); IFN-γ signature: 14.6 (cutoff: 3.6). IFN-γ mRNA also elevated. Due to dysregulated type I/II IFN signaling, ruxolitinib (2.5 mg twice a day) was started, leading to clinical/lab improvement after 3 months. Subsequently, gene panel (371 genes) found novel variant of uncertain significance (VUS) heterozygous PSMB9 variant (c.88G>A, p.G30R). Discussion IFN pathway testing guided JAK inhibitor use in suspected monogenic SAID unresponsive to steroids with clinical improvement. Later genetic testing identified a VUS in the PSMB9 gene, which was reclassified to probably pathogenic through functional studies. Together, functional and genetic approaches led to the patient’s definitive diagnosis.