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 (Chr1:22417990CT, 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.

A Novel CDC42 Mutation in an 11-Year Old Child Manifesting as Syndromic Immunodeficiency, Autoinflammation, Hemophagocytic Lymphohistiocytosis, and Malignancy: A Case Report

“…In contrast to patients with the classical Takenouchi-Kosaki syndrome and similarly to our patient, systemic autoinflammatory disease and development of HLH were predominating manifestations in four patients with three distinct C-terminal de novo variants (p.C188Y, p.R186C, p. * 192C * 24) in CDC42 reported by Gernez et al (8). Likewise, four patients with disturbed hematopoiesis, rash, autoinflammation, and HLH, reported by Lam et al (9), were sharing the same C-terminal p.R186C variant in the CDC42 gene. The two latter studies point to the unique effect of the C-terminal mutations in CDC42, resulting in neonatal-onset deregulation of the inflammatory response and the development of secondary HLH.…”

“…The signaling and the regulatory function of CDC42 are based on its tightly regulated cycle of activation with GTP binding and an inactive state with GTP hydrolysis, and intricate interactions with multiple proteins that impact on cell functions during its active state (2). It has been shown that CDC42 plays a number of physiologically pivotal, tissuespecific roles in the cardiovascular, genitourinary, respiratory, nervous, and immune systems, and its dysfunction is implicated as a background for syndromic immunodeficiency and immune dysregulation in patients reported so far (3)(4)(5)(6)(7)(8)(9). This is the first report of a pediatric patient with syndromic immunodeficiency, autoinflammation, hemophagocytic lymphohistiocytosis, and malignant lymphoproliferation in whom a novel, heterozygous p.Cys81Tyr mutation in the CDC42 gene was found.…”

Infantile Myelofibrosis and Myeloproliferation with CDC42 Dysfunction

“…The R186 residue is located near the geranylgeranyl moiety and is predicted to alter several key interactions with RhoGDI (Fig. 3a), as has recently been demonstrated through functional analyses [22]. Consistent with this, introduction of either wild type or the R186C mutant CDC42 into 3T3 cells using lentiviral transduction led to abnormal cytoskeletal structure and cell morphology.…”

“…This mutation was located in an evolutionarily conserved C-terminal polybasic region of CDC42 ( Fig. 2d) and was recently described in patients with a distinct disorder characterized by immune dysregulation [14,22].…”

“…Germline mutations of the hematopoietic-specific Rho GTPases RAC2 and RHOH have previously been implicated in inherited immunological conditions, impacting myeloid and lymphoid cell functions [11,50]. Recently, human mutations in CDC42 have presented with diverse developmental phenotypes, and a specific missense mutation, R186C, has been reported in a few patients with a syndrome involving immune dysregulation [14,22,27].…”