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

1 Citation (Scopus)

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

Cite this

A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function. / Lam, Michael T.; Coppola, Simona; Krumbach, Oliver H.F.; Prencipe, Giusi; Insalaco, Antonella; Cifaldi, Cristina; Brigida, Immacolata; Zara, Erika; Scala, Serena; Di Cesare, Silvia; Martinelli, Simone; Di Rocco, Martina; Pascarella, Antonia; Niceta, Marcello; Pantaleoni, Francesca; Ciolfi, Andrea; Netter, Petra; Carisey, Alexandre F.; Diehl, Michael; Akbarzadeh, Mohammad; Conti, Francesca; Merli, Pietro; Pastore, Anna; Levi Mortera, Stefano; Camerini, Serena; Farina, Luciapia; Buchholzer, Marcel; Pannone, Luca; Cao, Tram N.; Coban-Akdemir, Zeynep H.; Jhangiani, Shalini N.; Muzny, Donna M.; Gibbs, Richard A.; Basso-Ricci, Luca; Chiriaco, Maria; Dvorsky, Radovan; Putignani, Lorenza; Carsetti, Rita; Janning, Petra; Stray-Pedersen, Asbjorg; Erichsen, Hans Christian; Rosti, Vittorio; Bracaglia, Claudia; Palma, Paolo; Finocchi, Andrea; Locatelli, Franco; Cancrini, Caterina; Aiuti, Alessandro; De Benedetti, Fabrizio; Tartaglia, Marco.

In: The Journal of experimental medicine, Vol. 216, No. 12, 02.12.2019, p. 2778-2799.

Research output: Contribution to journalArticle

Lam, Michael T. ; Coppola, Simona ; Krumbach, Oliver H.F. ; Prencipe, Giusi ; Insalaco, Antonella ; Cifaldi, Cristina ; Brigida, Immacolata ; Zara, Erika ; Scala, Serena ; Di Cesare, Silvia ; Martinelli, Simone ; Di Rocco, Martina ; Pascarella, Antonia ; Niceta, Marcello ; Pantaleoni, Francesca ; Ciolfi, Andrea ; Netter, Petra ; Carisey, Alexandre F. ; Diehl, Michael ; Akbarzadeh, Mohammad ; Conti, Francesca ; Merli, Pietro ; Pastore, Anna ; Levi Mortera, Stefano ; Camerini, Serena ; Farina, Luciapia ; Buchholzer, Marcel ; Pannone, Luca ; Cao, Tram N. ; Coban-Akdemir, Zeynep H. ; Jhangiani, Shalini N. ; Muzny, Donna M. ; Gibbs, Richard A. ; Basso-Ricci, Luca ; Chiriaco, Maria ; Dvorsky, Radovan ; Putignani, Lorenza ; Carsetti, Rita ; Janning, Petra ; Stray-Pedersen, Asbjorg ; Erichsen, Hans Christian ; Rosti, Vittorio ; Bracaglia, Claudia ; Palma, Paolo ; Finocchi, Andrea ; Locatelli, Franco ; Cancrini, Caterina ; Aiuti, Alessandro ; De Benedetti, Fabrizio ; Tartaglia, Marco. / A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function. In: The Journal of experimental medicine. 2019 ; Vol. 216, No. 12. pp. 2778-2799.
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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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AU - Coppola, Simona

AU - Krumbach, Oliver H.F.

AU - Prencipe, Giusi

AU - Insalaco, Antonella

AU - Cifaldi, Cristina

AU - Brigida, Immacolata

AU - Zara, Erika

AU - Scala, Serena

AU - Di Cesare, Silvia

AU - Martinelli, Simone

AU - Di Rocco, Martina

AU - Pascarella, Antonia

AU - Niceta, Marcello

AU - Pantaleoni, Francesca

AU - Ciolfi, Andrea

AU - Netter, Petra

AU - Carisey, Alexandre F.

AU - Diehl, Michael

AU - Akbarzadeh, Mohammad

AU - Conti, Francesca

AU - Merli, Pietro

AU - Pastore, Anna

AU - Levi Mortera, Stefano

AU - Camerini, Serena

AU - Farina, Luciapia

AU - Buchholzer, Marcel

AU - Pannone, Luca

AU - Cao, Tram N.

AU - Coban-Akdemir, Zeynep H.

AU - Jhangiani, Shalini N.

AU - Muzny, Donna M.

AU - Gibbs, Richard A.

AU - Basso-Ricci, Luca

AU - Chiriaco, Maria

AU - Dvorsky, Radovan

AU - Putignani, Lorenza

AU - Carsetti, Rita

AU - Janning, Petra

AU - Stray-Pedersen, Asbjorg

AU - Erichsen, Hans Christian

AU - Rosti, Vittorio

AU - Bracaglia, Claudia

AU - Palma, Paolo

AU - Finocchi, Andrea

AU - Locatelli, Franco

AU - Cancrini, Caterina

AU - Aiuti, Alessandro

AU - De Benedetti, Fabrizio

AU - Tartaglia, Marco

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AB - 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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