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 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; Vittorio Rosti; Claudia Bracaglia; Paolo Palma; Andrea Finocchi; Franco Locatelli; Caterina Cancrini; Alessandro Aiuti; Fabrizio De Benedetti; Marco Tartaglia

doi:10.1084/jem.20190147

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

Istituto Superiore di Sanita'

Research output: Contribution to journal › Article › peer-review

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 language	Undefined/Unknown
Pages (from-to)	2778-2799
Number of pages	22
Journal	Journal of Experimental Medicine
Volume	216
Issue number	12
DOIs	https://doi.org/10.1084/jem.20190147
Publication status	Published - Dec 1 2019

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10.1084/jem.20190147

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Lam, M. T., Coppola, S., Krumbach, O. H. F., 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, A. F., Diehl, M., ... Tartaglia, M. (2019). A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function. Journal of Experimental Medicine, 216(12), 2778-2799. https://doi.org/10.1084/jem.20190147

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, Akbarzadeh, M, Conti, F, Merli, P, Pastore, A, Mortera, SL, Camerini, S, Farina, L, Buchholzer, M, Pannone, L, Cao, TN, Coban-Akdemir, ZH, Jhangiani, SN, Muzny, DM, Gibbs, RA, Basso-Ricci, L, Chiriaco, M, Dvorsky, R, Putignani, L, Carsetti, R, Janning, P, Stray-Pedersen, A, Erichsen, HC, Rosti, V, Bracaglia, C, Palma, P, Finocchi, A, Locatelli, F, Cancrini, C, Aiuti, A, De Benedetti, F & Tartaglia, M 2019, 'A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function', Journal of Experimental Medicine, vol. 216, no. 12, pp. 2778-2799. https://doi.org/10.1084/jem.20190147

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

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.",

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

year = "2019",

month = dec,

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doi = "10.1084/jem.20190147",

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volume = "216",

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journal = "Journal of Experimental Medicine",

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publisher = "Rockefeller University Press",

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T1 - A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function

AU - Lam, Michael T.

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 - Mortera, Stefano Levi

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

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

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.

U2 - 10.1084/jem.20190147

DO - 10.1084/jem.20190147

M3 - Articolo

VL - 216

SP - 2778

EP - 2799

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 12

ER -