Systemic Inflammation and Myelofibrosis in a Patient with Takenouchi-Kosaki Syndrome due to CDC42 Tyr64Cys Mutation
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LETTER TO EDITOR
Systemic Inflammation and Myelofibrosis in a Patient with Takenouchi-Kosaki Syndrome due to CDC42 Tyr64Cys Mutation Giorgia Bucciol 1,2 & Bethany Pillay 3,4 & Jose Casas-Martin 1 & Selket Delafontaine 1,2 & Marijke Proesmans 5 & Natalie Lorent 6 & Johan Coolen 7 & Thomas Tousseyn 8 & Xavier Bossuyt 9,10 & Cindy S. Ma 3,11 & Rik Schrijvers 12,13 & Stuart G. Tangye 3,4 & Leen Moens 1 & Isabelle Meyts 1,2 Received: 26 November 2019 / Accepted: 2 January 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
To the Editor: Heterozygous mutations in CDC42, encoding the small GTP/GDP-binding protein cell division cycle 42 (CDC42) involved in eukaryotic actin cytoskeleton dynamics, cause Takenouchi-Kosaki syndrome, a rare developmental disorder. Hallmarks of Takenouchi-Kosaki syndrome are intellectual and growth delay, dysmorphisms, macrothrombocytopenia, camptodactyly, structural brain abnormalities with sensorineural deafness, hypothyroidism, and frequent infections [1]. The original patient identified with this condition carried a de novo p.Tyr64Cys (c.191A>G) mutation. Five patients with the Tyr64Cys variant and similar clinical phenotypes have now been described [1–5]. Fourteen additional patients with different developmental phenotypes due to autosomal dominant (AD) heterozygous mutations disrupting CDC42 function and downstream signaling were reported by Martinelli et al.
[3]. Recently, Gernez et al. and Lam et al. described a syndrome of immune dysregulation caused by other CDC42 mutations in eight additional patients [6, 7]. These patients presented with neonatal-onset severe auto-inflammation with increased serum inflammatory cytokines and chemokines (IL-6, IL-18, IL-18-binding protein (IL-18BP), CXCL9), as well as hepatosplenomegaly and hemophagocytic lymphohistiocytosis (HLH) [6, 7]. The unrelated patients carried C-terminal CDC42 mutations (p.Arg186Cys in five; p.Cys188Tyr in two; p.*192Cys*24 in one) [6, 7]. The exact pathophysiology of inflammation remains elusive, yet Lam et al. did show that Arg186Cys causes aberrant subcellular localization of CDC42 with impaired cell polarity and migration. In contrast, mutations in the switch II domain of CDC42 underlie Takenouchi-Kosaki syndrome, while mutations within or close to the nucleotide-binding pocket (NBP) cause
Leen Moens and Isabelle Meyts contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10875-020-00742-5) contains supplementary material, which is available to authorized users. * Isabelle Meyts [email protected]
7
Department of Radiology, University Hospitals Leuven, Leuven, Belgium
8
Department of Pathology, University Hospitals Leuven, Leuven, Belgium
9
Clinical and Diagnostic Immunology, KU Leuven, Leuven, Belgium
10
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
Department of Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium
11
St Vincent’s Clinical School, U
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