THE ROLE OF LABORATORY EVALUATION IN THE DIAGNOSIS AND MANAGEMENT OF NLRP12- ASSOCIATED AUTOINFLAMMATORY DISEASE

Abstract

<h3>Introduction</h3> This case highlights the relevance of including autoinflammatory diseases in the differential diagnosis of adults with recurrent fever or episodes of shock. The role of genetic testing and confirmatory functional testing in the diagnosis and therapeutic management of autoinflammatory diseases is also discussed. <h3>Case Description</h3> A 67-year-old man presented with a 2-year history of episodes of shock of unknown etiology. Symptoms included hypotension, fever and abdominal pain requiring vasopressor support and antibiotics. Extensive infectious, autoimmune and rheumatological work-up was negative. Bone marrow biopsy showed chronic myelomonocytic leukemia (CMML) that Oncology determined was non-contributory and did not require treatment. Immunological investigations demonstrated elevated IgE, CD8+ T cell lymphocytosis during episodes of shock and increased sCD163. A targeted NGS panel revealed a heterozygous VUS in the <i>NLRP12</i> gene. Functional studies were performed offline to evaluate inflammasome activity. PBMCs stimulated with LPS for 24h revealed substantially elevated levels of IL-1β, IL-6 and TNF-α compared to healthy controls suggesting inflammasome activation and NFκB dysregulation. This prompted initiation of IL-1β blockade with canakinumab, with symptom resolution. <h3>Discussion</h3> In adults presenting with a hyperinflammatory state of unknown etiology, immunological investigations should be pursued for a possible autoinflammatory syndrome. In this case, genetic testing identified a VUS in <i>NLRP12</i>. NLRP12 is an inflammasome in which LOF and GOF variants have been reported with disease manifestations, including cold-induced autoinflammatory syndrome (FCAS). NLRP12 also regulates NFκB, which may explain some of the observed hyperinflammation. This patient had complete response to IL-1β blockade. Functional evaluation of VUS may provide an opportunity for therapeutic intervention.