PSTPIP1 (proline-serine-threonine phosphatase-interactive protein 1)–associated myeloid-related proteinemia inflammatory (PAMI) syndrome is a rare autoinflammatory disease caused by heterozygous gain-of-function mutation in PSTPIP1. As one of the PSTPIP1-associated inflammatory diseases (PAIDs), neutropenia is a distinct manifestation to separate PAMI syndrome from other PAIDs. This study aimed to investigate the potential role of neutrophils and inflammatory signatures in the pathogenesis of PAMI. PAMI neutrophils displayed markedly increased production of interleukin-1β (IL-1β) and IL-18 by enzyme linked immunosorbent assay (ELISA) assay and intracellular cytokine staining. ASC speck formation and lactic dehydrogenase (LDH) release are also increased in patient neutrophils suggesting elevated pyrin inflammasome activation followed by upregulated cell death in PAMI neutrophils. RNA sequencing result showed strong inflammatory signals in both nuclear-factor kappa B (NF-κB) pathway and interferon (IFN) pathway in patient neutrophils. This study highlighted that elevated proinflammatory cytokines IL-1β and IL-18, increased pyrin inflammasome activation, and upregulation of NF-κB and IFN signaling pathways in neutrophils play important roles in pathogenicity of PAMI syndrome.

Background: The deficiency of adenosine deaminase 2 (DADA2) is caused by an autosomal recessive bi-allelic loss-of-function mutation in the adenosine deaminase 2 (ADA2) gene. DADA2 is a monogenic inherited autoinflammatory disorder characterized by early-onset vasculopathy for which the symptoms range from skin lesions to very severe multiorgan involvement, including life-threatening ischemia and/or hemorrhagic strokes. Owing to the diversity of clinical presentation and the absence of suggestive features, differentiating DADA2 from other inflammatory disorders in the early stages of disease presentation is difficult. Here, we describe the case of a 3-year-old boy who had been misdiagnosed for nearly 2 years before he was definitively diagnosed with DADA2.Case Description: A previously healthy 3-year-old boy was initially diagnosed with systemic onset juvenile idiopathic arthritis (soJIA) owing to recurrent unprovoked fever and elevated acute phase reactants.He developed intractable hypertension during treatment, which his doctor considered an adverse drug reaction. Monogenic inherited autoinflammatory disorders were not suspected until the patient developed intestinal perforation and ensuing recurrent abdominal pain that coincided with fever. Gene sequence analysis revealed a novel compound heterozygous mutation in ADA2. The ADA2 enzyme activity was almost completely lost in the patient. Conclusions:The broad phenotypic spectrum of DADA2 makes early diagnosis challenging. DADA2 should be considered in case of early-onset vasculitis, which is the most common phenotype of DADA2.Early identification and treatment will result in significant improvement of the disease.