PSTPIP1 is a cytoskeleton-associated adapter protein that regulates actin dynamics and innate immunity 1. Functionally, PSTPIP1 bridges interactions between phosphatases (PTPN18, PTPN12) and their substrates including WAS and ABL1, modulating actin polymerization critical for T-cell synapse formation [UniProt data]. In innate immunity, PSTPIP1 is recruited to inflammasomes by MEFV, promoting pyroptosome formation and inflammatory responses [UniProt data]. Pathogenic variants in PSTPIP1 cause PAPA spectrum disorders—a group of autosomal dominant autoinflammatory syndromes characterized by cutaneous manifestations (pyoderma gangrenosum, acne, hidradenitis suppurativa) and articular involvement 2. PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome represents a distinct clinical phenotype marked by early-onset systemic inflammation, cytopenia (anemia, neutropenia), elevated serum myeloid-related proteins (S100A8/A9), and hyperzincemia, caused by specific missense variants (p.E250K, p.E257K) 3. Disease severity varies; only 18% of identified PSTPIP1 variants are pathogenic 4. Clinically, IL-1 pathway inhibitors (anakinra, canakinumab) show promise in managing PAPA and PAMI syndromes 5, though evidence remains limited to observational studies. Systemic corticosteroids and immunosuppressants remain first-line treatments, with hematopoietic stem cell transplantation showing recent success in select cases 3.