XIAP Deficiency Caused by a Deletion in the Noncoding Exon 1 Identified by Chromosomal Microarray

X-linked inhibitor of apoptosis (XIAP) is essential for innate and adaptive immune responses, including programmed cell death inhibition, NFkB and MAPK activation, NLRP3 inflammasome activity regulation, and TNFR signaling (1, 2). XIAP deficiency is an immune dysregulation syndrome caused by hemizygous loss-of-function variants in XIAP, with prominent clinical features, including hemophagocytic lymphohistiocytosis, splenomegaly, and inflammatory bowel disease (IBD) (2, 3). A 6-week-old previously healthy term male infant born to nonconsanguineous parents of West African heritage presented to the hospital with bloody diarrhea, hypoalbuminemia, anemia, elevated C-reactive protein (CRP), fever, and growth faltering. The family history was notable for a male sibling’s death at 10 weeks from sepsis following a diarrheal illness. A full septic workup was negative, and the child was empirically treated for culture-negative sepsis with minimal improvement. The working diagnosis was cow’s milk protein-induced allergic proctocolitis, but his severe gastrointestinal symptoms persisted despite dietary modifications, including complete gut rest. Upper and lower endoscopy revealed flat ileal mucosa without villi, and edematous and friable colonic mucosa, while biopsies showed active duodenitis with villous blunting, and chronic active colitis. Screening immune investigations, including neutrophil oxidative burst, were unremarkable. Whole-exome sequencing (WES) was reported as negative; however, chromosomal microarray (CMA) revealed a 5.7 Kb deletion in Xq25, encompassing the noncoding exon 1 of XIAP. Flow cytometry at Cincinnati Children’s Hospital Diagnostic Immunology Lab showed absent XIAP expression in peripheral blood mononuclear cells. A functional defect in XIAP was demonstrated by absent production of TNF-alpha and IL-8 production by monocytes following stimulation with L18-MDP, with intact cytokine response to LPS stimulation. We describe a case of XIAP deficiency resulting from a copy number loss at Xq25 that was functionally supported by absent XIAP expression and NOD2-mediated cytokine production. This case highlights the phenotypic spectrum of XIAP deficiency, whereby IBD can present very early in life, and the importance of a prompt and thorough genetic evaluation for those with suspected monogenic inborn errors of immunity. Any patient suspected of having XIAP deficiency should have a CMA performed, as pathogenic deletions in the noncoding exon 1 of XIAP have been reported (4, 5), and may be missed on gene panels or WES. Figure 1. A. Whole blood from the index case and a healthy control were stained for intracellular XIAP protein and gated for monocytes, lymphocytes, and granulocytes. Histograms show the lack of XIAP protein staining in all leukocyte subsets. B. Isolated peripheral blood mononuclear cells were stimulated with either LPS as a positive control, L18-MDP as the experimental condition, or PBS as an unstimulated control. Gated monocytes from the control show upregulation of both TNF-a or IL-8 expression when stimulated with either LPS or muramyl dipeptide (MDP), but the patient did not show any upregulation with MDP stimulation. Normal responses noted with LPS indicating the patient’s monocytes are viable and responsive.