A Female Patient with Incomplete Hemophagocytic Lymphohistiocytosis Caused by a Heterozygous XIAP Mutation Associated with Non-Random X-Chromosome Inactivation Skewed Towards the Wild-Type XIAP Allele

Abstract

X-linked lymphoproliferative disease (XLP) is a rare inherited immunodeficiency that often leads to hemophagocytic lymphohistiocytosis (HLH). XLP can be classified as XLP1 or XLP2, caused by mutations in SH2D1A and XIAP, respectively. In women, X-chromosome inactivation (XCI) of most X-linked genes occurs on one of the X chromosomes in each cell. The choice of which X chromosome remains activated is generally random, although genetic differences and selective advantage may cause one of the X chromosomes to be preferentially inactivated. Here we describe three patients with pancytopenia, including one female patient, in a Japanese family with a novel XIAP mutation. All three patients exhibited deficient XIAP protein expression, impaired NOD2/XIAP signaling, and augmented activation-induced cell death. In the female patient, the paternally derived X chromosome was non-randomly and exclusively inactivated in her peripheral blood and hair root cells. In contrast to asymptomatic females, this patient exhibied non-random XCI skewed towards the wild-type XIAP allele. This is the first report of a female patient with incomplete HLH resulting from a heterozygous XIAP mutation in association with non-random XCI.

Advances in the pathogenesis of primary and secondary haemophagocytic lymphohistiocytosis: differences and similarities

“…This was corroborated by the generation of polygenic mouse models, in which the accumulation of heterozygous mutations in Rab27a, Prf1 and/or Stx11 reduced cytotoxic function and increased the risk of developing virus-induced HLH (Sepulveda et al, 2016). Heterozygous mutations in X-linked genes may also cause HLH in female patients, depending on the percentage of wild-type X-chromosome inactivation (Holle et al, 2015;Yang et al, 2015). Moreover, monoallelic missense mutations in STXBP2 or RAB27A have been described to cause late-onset FHL in a (partial) dominantnegative manner (Spessott et al, 2015;Zhang et al, 2016).…”

“…Since XIAP-deficient T and NK cells display apparently normal in vitro cytotoxic functions, HLH development in XLP-2 may be linked to other pathogenic processes, such as accumulating apoptotic cells and persisting EBV-infected cells, triggering excessive immune activation (Marsh et al, 2010;de Saint Basile et al, 2015). XLP-associated HLH was previously assumed to occur only in males, however, two HLH cases have recently been reported in female patients carrying a heterozygous XIAP mutation that significantly reduced XIAP expression due to highly skewed X-chromosome inactivation of the wild-type allele (Holle et al, 2015;Yang et al, 2015).…”

Epstein–Barr Virus and Hemophagocytic Lymphohistiocytosis

“…Of note, flow cytometric screening tests are also available to screen patients for XLP1 and XLP2 ( 55 ). XLP1 and XLP2 should be considered in male patients with HLH, and even in female patients in whom other genetic causes of HLH have been excluded, due to the observation that females with abnormal skewing of lionization toward XIAP-deficient cells can be symptomatic ( 56 , 57 ). A functional screen for XIAP deficiency is available via evaluation of NOD2 signaling ( 58 ), and IL-18 levels can be helpful as a screening tool for patients with XIAP deficiency or NLRC4 mutations.…”

Inflammatory bowel diseases and primary immunodeficiency diseases

“…Pathway genes in IBD-associated loci Epithelial barrier function and repair CDH1, ERRFI1, GNA12, HNF4A, ITLN1, MUC19, NKX2-3, PLA2G2E, PTGER4, REL, STAT3 Innate mucosal defence CARD9, FCGR2A, IL18RAP, ITLN1, NOD2, REL, SLC11A1 Autophagy ATG16L1, CUL2, DAP, IRGM, LRRK2, NOD2, PARK7 Apoptosis/necroptosis DAP, FASLG, MST1, PUS10, THADA Activation of adaptive immune response IL23R response pathway CCR6, IL12B, IL21, IL23R, JAK2, STAT3, STAT4, TYK2 NF-jB NFKB1, REL, TNFAIP3, TNIP1 Aminopeptidases ERAP1, ERAP2 IL-2 and IL-21 T-cell activation IL2, IL21, IL2RA Regulation of adaptive immune response TH17 cell differentiation AHR, CCR6, IL2, IL21, IL23R, IRF4, JAK2, RORC, STAT3, TNFSF15, TYK2 T-cell activation ICOSLG, IFNG, IL12B, IL2, IL21, IL23R, IL2RA, IL7R, NDFIP1, PIM3, PRDM1, TAGAP, TNFRSF9, TNFSF8 B-cell [16,17]. XIAP expression is decreased in lymphocytes and monocytes of some patients with XIAP deficiency (Figure 4(a)) [17,18], and muramyl dipeptide signaling is selectively defective in patients with XIAP deficiency (Figure 4(b)) [19]. IL-10 receptor deficiency can also be detected using assays that determine whether exogenous IL-10 suppresses lipopolysaccharide-induced cytokine production in peripheral blood mononuclear cells [20,21].…”