A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function: The Journal of experimental medicine

MT Lam, S Coppola, OHF Krumbach, G Prencipe, A Insalaco, C Cifaldi, I Brigida, E Zara, S Scala, S Di Cesare, S Martinelli, M Di Rocco, A Pascarella, M Niceta, F Pantaleoni, A Ciolfi, P Netter, AF Carisey, M Diehl, M AkbarzadehF Conti, P Merli, A Pastore, S Levi Mortera, S Camerini, L Farina, M Buchholzer, L Pannone, TN Cao, ZH Coban-Akdemir, SN Jhangiani, DM Muzny, RA Gibbs, L Basso-Ricci, M Chiriaco, R Dvorsky, L Putignani, R Carsetti, P Janning, A Stray-Pedersen, HC Erichsen, A Horne, YT Bryceson, L Torralba-Raga, K Ramme, V Rosti, C Bracaglia, V Messia, P Palma, A Finocchi, F Locatelli, IK Chinn, JR Lupski, EM Mace, C Cancrini, A Aiuti, MR Ahmadian, JS Orange, F De Benedetti, M 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. © 2019 Lam et al.
Original languageEnglish
Pages (from-to)2778-2799
Number of pages22
JournalJournal of Experimental Medicine
Volume216
Issue number12
DOIs
Publication statusPublished - 2019

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    Lam, MT., Coppola, S., Krumbach, OHF., Prencipe, G., Insalaco, A., Cifaldi, C., Brigida, I., Zara, E., Scala, S., Di Cesare, S., Martinelli, S., Di Rocco, M., Pascarella, A., Niceta, M., Pantaleoni, F., Ciolfi, A., Netter, P., Carisey, AF., Diehl, M., ... Tartaglia, M. (2019). A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function: The Journal of experimental medicine. Journal of Experimental Medicine, 216(12), 2778-2799. https://doi.org/10.1084/jem.20190147