FRI0540 A NOVEL AUTOINFLAMMATORY DISEASE CHARACTERIZED BY NEONATAL-ONSET CYTOPENIA WITH AUTOINFLAMMATION, RASH, AND HEMOPHAGOCYTOSIS (NOCARH) DUE TO ABERRANT CDC42 FUNCTION

Background Despite continuous advances in the identification of novel causative genes, several patients with a clinical autoinflammatory phenotype remain unclassifiable Objectives: to describe a novel hematological and autoinflammatory disorder in three unrelated patients caused by a de novo missense mutation of CDC42 Methods Whole exome sequencing was used to identify the novel variant. The functional impact of altered CDC42 function on hematopoiesis and inflammation was assessed through patient peripheral blood and bone marrow analyses, protein behavior and immune and non-immune cell functioning through in vitro biochemical and functional assays and in vivo C. elegans modeling Results Patients shared the same de novo missense mutation of CDC42 (NM_001791, Chr1:22417990, c.556C>T, p.R186C). Disease features included neonatal-onset cytopenia with dyshematopoiesis, autoinflammation, rash, and hemophagocytosis (collectively termed NOCARH syndrome) (Table). An altered hematopoietic compartment (prevalence of early differentiation elements and substantially decreased clonogenic progenitors) was demonstrated. Complementary assays documented the unique consequences of this mutation on CDC42 localization and function, and its disruptive effect on cell behavior and developmental processes, possibly linked to actin dysregulation. Increased secretion of IL-1β, and particularly of IL-18, was observed via ex vivo spontaneous release from unstimulated bone marrow mononuclear cells and by high levels in bone marrow supernatants and plasma. IFNγ was also increased and correlated to CXCL9 levels which were strictly related to ferritin levels. Treatment with anakinra and emapalumab, a monoclonal antibody to iIFNγ, was identified as critical in the survival of one patient, who underwent successful hematopoietic stem cell transplantation Conclusion The p.R186C amino acid substitution in CDC42 underlies a novel, unique syndrome where CDC42 functional dysregulation has pleiotropic effects, causing hematopoietic disturbance, hyperinflammation, and immune impairment. Early recognition and control of HLH, through neutralization of IFNγ, followed by hematopoietic stem cell transplantion, appear to be crucial to survival. Disclosure of Interests Michael T. Lam: None declared, Simona Coppola: None declared, Oliver H. Krumbach: None declared, Giusi Prencipe: None declared, Antonella Insalaco: None declared, Cristina cifaldi: None declared, Immacolata Brigida: None declared, Serena Scala: None declared, Marcello Niceta: None declared, Andrea Ciolfi: None declared, alexandre carisey: None declared, Mohammad Akbarzadeh: None declared, Andrea Finocchi: None declared, Franco Locatelli: None declared, Caterina Cancrini: None declared, Alessandro Aiuti: None declared, Reza Ahmadian: None declared, Jordan S. Orange: None declared, Fabrizio De Benedetti Grant/research support from: Abbvie, SOBI, Novimmune, Roche, Novartis, Sanofi, Pfizer, Marco Tartaglia: None declared