A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function

Michael T. Lam, Simona Coppola, Oliver H.F. Krumbach, Giusi Prencipe, Antonella Insalaco, Cristina Cifaldi, Immacolata Brigida, Erika Zara, Serena Scala, Silvia Di Cesare, Simone Martinelli, Martina Di Rocco, Antonia Pascarella, Marcello Niceta, Francesca Pantaleoni, Andrea Ciolfi, Petra Netter, Alexandre F. Carisey, Michael Diehl, Mohammad AkbarzadehFrancesca Conti, Pietro Merli, Anna Pastore, Stefano Levi Mortera, Serena Camerini, Luciapia Farina, Marcel Buchholzer, Luca Pannone, Tram N. Cao, Zeynep H. Coban-Akdemir, Shalini N. Jhangiani, Donna M. Muzny, Richard A. Gibbs, Luca Basso-Ricci, Maria Chiriaco, Radovan Dvorsky, Lorenza Putignani, Rita Carsetti, Petra Janning, Asbjorg Stray-Pedersen, Hans Christian Erichsen, Vittorio Rosti, Claudia Bracaglia, Paolo Palma, Andrea Finocchi, Franco Locatelli, Caterina Cancrini, Alessandro Aiuti, Fabrizio De Benedetti, Marco Tartaglia

Research output: Contribution to journalArticle

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is characterized by immune dysregulation due to inadequate restraint of overactivated immune cells and is associated with a variable clinical spectrum having overlap with more common pathophysiologies. HLH is difficult to diagnose and can be part of inflammatory syndromes. Here, we identify a novel hematological/autoinflammatory condition (NOCARH syndrome) in four unrelated patients with superimposable features, including neonatal-onset cytopenia with dyshematopoiesis, autoinflammation, rash, and HLH. Patients shared the same de novo CDC42 mutation (Chr1:22417990C>T, p.R186C) and altered hematopoietic compartment, immune dysregulation, and inflammation. CDC42 mutations had been associated with syndromic neurodevelopmental disorders. In vitro and in vivo assays documented unique effects of p.R186C on CDC42 localization and function, correlating with the distinctiveness of the trait. Emapalumab was critical to the survival of one patient, who underwent successful bone marrow transplantation. Early recognition of the disorder and establishment of treatment followed by bone marrow transplant are important to survival.

Original languageEnglish
Pages (from-to)2778-2799
Number of pages22
JournalThe Journal of experimental medicine
Volume216
Issue number12
DOIs
Publication statusPublished - Dec 2 2019

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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