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FRI0540 A NOVEL AUTOINFLAMMATORY DISEASE CHARACTERIZED BY NEONATAL-ONSET CYTOPENIA WITH AUTOINFLAMMATION, RASH, AND HEMOPHAGOCYTOSIS (NOCARH) DUE TO ABERRANT CDC42 FUNCTION
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  1. Michael T. Lam1,2,3,
  2. Simona Coppola4,
  3. Oliver H. Krumbach5,
  4. Giusi Prencipe6,
  5. Antonella Insalaco6,
  6. Cristina Cifaldi7,8,
  7. Immacolata Brigida9,
  8. Serena Scala9,
  9. Marcello Niceta10,
  10. Andrea Ciolfi10,
  11. Alexandre Carisey1,2,
  12. Mohammad Akbarzadeh5,
  13. Andrea Finocchi7,8,
  14. Franco Locatelli11,
  15. Caterina Cancrini7,8,
  16. Alessandro Aiuti9,12,13,
  17. Reza Ahmadian5,
  18. Jordan S. Orange2,
  19. Fabrizio De Benedetti6,
  20. Marco Tartaglia10
  1. 1Baylor College of Medicine, Department of Pediatrics, Houston, United States of America
  2. 2Columbia University, Irving Medical Center, Department of Pediatrics, Houston, United States of America
  3. 3Translational Biology and Molecular Medicine Graduate Program and Medical Scientist,Baylor College of Medicine, Houston, United States of America
  4. 4National Center for Rare Diseases, Istituto Superiore di Sanità, Rome, Italy
  5. 5Institute of Biochemistry and Molecular Biology II,Medical Faculty of the Heinrich-Heine, Dusseldorf, Germany
  6. 6Ospedale Pediatrico Bambino Gesù, IRCCS, Division of Rheumatology, Rome, Italy
  7. 7Ospedale Pediatrico Bambino Gesù, IRCCS, Department of Pediatrics, Rome, Italy
  8. 8University of Rome Tor Vergata, Department of Systems Medicine, Rome, Italy
  9. 9San Raffaele Telethon Institute for Gene Therapy (SR-TIGET),IRCCS San Raffaele Scientific Institute, Milan, Italy
  10. 10Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy
  11. 11Ospedale Pediatrico Bambino Gesù, IRCCS, Department of Pediatric Hematology and Oncology, Rome, Italy
  12. 12San Raffaele Scientific Institute, Pediatric Immunohematology, Milan, Italy
  13. 13Vita Salute, San Raffaele University, Milan, Italy

Abstract

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

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