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

The Journal of experimental medicine (2019-10-12)
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 Akbarzadeh, Francesca 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, AnnaCarin Horne, Yenan T Bryceson, Lamberto Torralba-Raga, Kim Ramme, Vittorio Rosti, Claudia Bracaglia, Virginia Messia, Paolo Palma, Andrea Finocchi, Franco Locatelli, Ivan K Chinn, James R Lupski, Emily M Mace, Caterina Cancrini, Alessandro Aiuti, Mohammad R Ahmadian, Jordan S Orange, Fabrizio De Benedetti, Marco Tartaglia
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.

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