Abstract Background Ras-associated autoimmune lymphoproliferative syndrome-like disease (RALD) is a rare immune dysregulation disorder characterized by somatic gain-of-function mutations in the KRAS or NRAS genes. It has been linked to various autoimmune conditions; however, reports describing its association with inflammatory bowel disease (IBD) remain limited. This study aimed to elucidate the clinical, endoscopic, and histopathological features of RALD-associated IBD. Methods We retrospectively analyzed four pediatric cases of RALD-associated IBD. Clinical histories, genetic data, endoscopic findings, and histopathological features were collected and reviewed. Results All patients harbored pathogenic KRAS variants (p.G13C, n = 2; p.G12S, n = 1; p.A146T, n = 1), which were detected across various hematopoietic lineages but consistently present in CD3⁺ T cells. Prior to IBD onset, all patients exhibited RALD-related manifestations, including cervical lymphadenopathy, hepatosplenomegaly, and immune thrombocytopenia. The age at IBD diagnosis ranged from 4 to 22 years, with three patients classified as having very-early-onset (VEO) IBD ( 6 years). Three patients presented with Behçet’s disease-like punched-out ulcers in the ileum or colon, while one exhibited features consistent with ulcerative colitis. Histopathological analysis revealed a broad spectrum of findings: some cases showed nonspecific inflammation, whereas others demonstrated classical IBD features such as crypt architectural distortion, basal plasmacytosis, Paneth cell metaplasia, and non-caseating granulomas. Treatment with biologic agents (adalimumab, vedolizumab, and ustekinumab; one case each) led to clinical improvement. Notably, vedolizumab and ustekinumab induced long-term remission with mucosal healing, and no severe adverse events were observed. In contrast, two patients who underwent allogeneic hematopoietic cell transplantation (allo-HCT) succumbed to infectious complications. Conclusion RALD-associated IBD presents with heterogeneous endoscopic and histological features, which may be indistinguishable from classical IBD. Genetic testing for KRAS and NRAS mutations should be actively considered in patients with VEO-IBD or those presenting with autoimmune or hematologic comorbidities. Identifying RALD in IBD cases may facilitate early detection of leukemic transformation and other autoimmune phenomena. Further case accumulation and long-term follow-up are essential to determine optimal biologic therapies, refine indications for allo-HCT, and assess long-term outcomes. Conflict of interest: Dr. Takeuchi, Ichiro: Speaker’s fees from AbbVie GK, Takeda Pharmaceutical Co., Ltd., and EA Pharma Co., Ltd. Akemoto, Yui: No conflict of interest Taniguchi, Kosuke: No conflict of interest Oshina, Kyoko: No conflict of interest Kinjo, Noriko: No conflict of interest Sano, Hideki: No conflict of interest Ishikawa, Takashi: No conflict of interest Kawai, Toshinao: No conflict of interest Uchiyama, Toru: No conflict of interest Hori, Asuka: No conflict of interest Kyodo, Reiko: No conflict of interest Fujikawa, Hiroki: No conflict of interest Shimizu, Hirotaka: No conflict of interest Hata, Kenichiro: No conflict of interest Moritake, Hiroshi: No conflict of interest Takagi, Masatoshi: No conflict of interest Arai, Katsuhiro: No conflict of interest
Takeuchi et al. (Thu,) studied this question.