Anti-TNF-refractory inflammatory bowel disease associated with a novel XIAP frameshift variant successfully treated with ustekinumab.

X-linked inhibitor of apoptosis protein (XIAP) deficiency is a monogenic immunodeficiency disorder with a broad clinical spectrum that includes inflammatory bowel disease (IBD). The inflammatory mechanisms underlying XIAP-associated IBD remain incompletely understood, and resistance to anti-tumor necrosis factor (TNF) therapy represents a significant therapeutic challenge. We report a case of a pediatric patient with XIAP-associated IBD caused by a novel pathogenic frameshift variant in the XIAP gene (c.498dupA, p.Leu167Ilefs*30). The clinical course was characterized by refractoriness to anti-TNF therapy, suggesting a non-TNF-dominant inflammatory phenotype. Although hematopoietic stem cell transplantation represents the only curative option, interleukin-12/23 blockade using ustekinumab (UST) was considered following an inadequate response to standard medical therapies. Subsequent treatment with UST was associated with sustained clinical and endoscopic improvement, supporting the involvement of an IL-12/23-related inflammatory axis in this patient. This case illustrates a distinct phenotype of XIAP-associated IBD, characterized by resistance to TNF inhibition and susceptibility to IL-12/23 blockade using UST, associated with a novel pathogenic XIAP variant. Rather than demonstrating treatment efficacy alone, these findings underscore the value of integrating genetic diagnosis with treatment response to gain insight into disease-driving inflammatory pathways and to guide individualized management strategies in monogenic IBD.