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

TitleA novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function.
Publication TypeJournal Article
Year of Publication2019
AuthorsLam, 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, SLevi, 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, HChristian, Horne, AC, Bryceson, YT, Torralba-Raga, L, Ramme, K, Rosti, V, Bracaglia, C, Messia, V, Palma, P, Finocchi, A, Locatelli, F, Chinn, IK, Lupski, JR, Mace, EM, Cancrini, C, Aiuti, A, Ahmadian, MR, Orange, JS, De Benedetti, F, Tartaglia, M
JournalJ Exp Med
Date Published2019 12 02
KeywordsAlleles, Amino Acid Substitution, Animals, Binding Sites, cdc42 GTP-Binding Protein, Cell Line, Tumor, Child, Disease Susceptibility, Female, Genetic Association Studies, Genotype, Humans, Infant, Lymphohistiocytosis, Hemophagocytic, Male, Mice, Models, Molecular, Molecular Conformation, Mutation, Phenotype, Protein Binding

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 mutation (Chr1:22417990C>T, p.R186C) and altered hematopoietic compartment, immune dysregulation, and inflammation. 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.

Alternate JournalJ. Exp. Med.
PubMed ID31601675
PubMed Central IDPMC6888978
Grant ListR01 AI067946 / AI / NIAID NIH HHS / United States
R01 AI120989 / AI / NIAID NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States