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GATA2 Deficiency
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Differential diagnoses for GATA2 deficiency (characteristic combination of warts with monocytopenia) include other conditions associated with papillomatosis or generalized verrucosis (e.g., epidermodysplasia verruciformis [EV] warts, hypogammaglobulinemia, immunodeficiency, myelokathexis [WHIM] syndrome warts, immunodeficiency, lymphoedema and anogenital dysplasia [WILD] syndrome, DOCK8 deficiency syndrome, and idiopathic CD4 lymphocytopenia).
Primary immunodeficiency diseases
Published in Gabriel Virella, Medical Immunology, 2019
John W. Sleasman, Gabriel Virella
CARD9 deficiency results in predisposition to invasive fungal infection and deep dermatophytoses. In contrast, increased susceptibility to mycobacterial disease is seen in complete interferon-γ receptor deficiency, manifest by disseminated mycobacterial infection in soft tissue, bone, lung, skin, and lymphoid tissues. Similar clinical phenotypes are seen with IL-12 deficiency and STAT 1 loss of function mutations. Susceptibility to viral infections, particularly human papillomaviruses is seen in WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis) due to an autosomal-dominant gain of function mutation in CXCR4.
Zanubrutinib for the treatment of Waldenström Macroglobulinemia
Published in Expert Review of Hematology, 2020
Kenneth J. C. Lim, Constantine S. Tam
Recent studies have helped shed further light on the pathogenesis of WM through the molecular examination of acquired genetic mutations associated with WM. The identified MYD88 gene was found to encode an adaptor protein involved in Toll-like receptor and interleukin-1 receptor signaling. When these receptors are activated, the MYD88 protein undergoes homodimerization and activates downstream signaling pathways involving the phosphorylation of interleukin-1 receptor-associated kinases (IRAK1 and IRAK 4) followed by IκBα and ultimately the activation of the pro-survival nuclear factor κB (NF-κB) pathway. L265P is a gain in function mutation found in >90% of WM cases. The L265P mutation allows for spontaneous, independent MYD88 homodimerization and subsequent constitutive activation of NF-κB [2,3]. The second gene of interest in WM is the CXCR4 gene with mutations found in approximately 30% of WM cases. These mutations include frameshift and nonsense mutations of CXCR4 similar to those seen in germline mutations associated with the rare congenital immune deficiency condition WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome. Stimulation of CXCR4 by its ligand CXCL12 stimulates WM cell migration, adhesion, and homing. These WHIM-like mutations of CXCR4WHIM promote prolonged activation of CXCR4 by preventing receptor internalization which prolongs CXCR4 stimulation by CXCL12. This promotes the survival, growth, and dissemination of WM cells [4,5]. The presence of these mutations has prognostic implications to therapy and form the basis of current targeted approaches.
CXCR4 mutations affect presentation and outcomes in patients with Waldenström macroglobulinemia: A systematic review
Published in Expert Review of Hematology, 2019
Jorge J. Castillo, David F. Moreno, Maria I. Arbelaez, Zachary R. Hunter, Steven P. Treon
Recent studies have detected recurrent somatic mutations in the carboxyl terminal of the C-X-C chemokine receptor type 4 (CXCR4) gene in patients with WM [6]. These CXCR4 mutations (CXCR4MUT) are similar to the ones described in the congenital WHIM (Warts, Hypogammaglobulinemia, Immunodeficiency, and Myelokathexis) syndrome [7]. Over 30 somatic CXCR4 mutations have been described in patients with WM and can be grouped in frameshift (CXCR4FS) and nonsense (CXCR4NS) mutations [8]. Emerging data suggest that WM patients with CXCR4 mutations not only can have specific clinical features but also different outcomes to standard therapies. Therefore, CXCR4 mutations might need to be considered at the time of the initial evaluation and/or at the time of treatment initiation in patients with WM.
An evaluation of Ibrutinib for the treatment of Waldenstrom macroglobulinaemia
Published in Expert Opinion on Pharmacotherapy, 2020
Kenneth J. C. Lim, Constantine S. Tam
A second crucial set of mutations in WM are those involving the CXCR4 gene in 30% of WM cases. These mutations include frameshift and nonsense mutations similar to those seen in germline mutations of CXCR4 seen in warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome with the most common and established being the nonsense mutation S338X [17]. These mutations promote prolonged activation of CXCR4 via the ligand CXCL12 through blockade of receptor internalization [18]. CXCR4, being a chemokine receptor, promotes cell migration, adhesion to bone marrow stroma, proliferation, and ultimately survival through up-regulation of kinases such as AKT, ERK, and BTK [19,20]. As such CXCR4 WHIM mutations may have a negative impact on the efficacy of BTK-targeted therapies.