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Histopathological findings of X‐linked inhibitor of apoptosis deficiency‐associated inflammatory bowel disease at onset after the age of 6 years

To the Editor, Conventional inflammatory bowel disease (IBD) is a phenotypically overlapping syndrome in which genetic and environmental factors interact in various ways. However, very early‐onset IBD (VEO‐IBD), which occurs in children younger than 6 years of age, may be caused by mainly genetic factors. Particularly, monogenic IBD, which has a monogenic defect associated with primary immunodeficiencies, has attracted particular attention owing to its severe disease course and the only curative treatment option as allogeneic hematopoietic stem cell transplantation. It is essential to note that not all monogenic IBDs develop before the age of 6. The X‐linked inhibitor of apoptosis (XIAP) deficiency, also known as the X‐linked lymphoproliferative syndrome type 2 (XLP‐2), has sometimes manifested IBD characteristics after the age of 6 (as of late‐onset). The histopathological findings of VEO‐IBD have been gradually accumulated, but the histopathological findings of late‐onset XIAP deficiency‐associated IBD (LO‐XIAP‐IBD) have not been reported. We investigated the histopathological characteristics of lower gastrointestinal lesions in patients with LO‐XIAP‐IBD in this report. We analyzed endoscopic biopsy specimens from the lower gastrointestinal tract (20 sites) of four male patients who were firstly diagnosed with Crohn's disease, followed by a DNA analysis during the clinical course and were finally diagnosed with XIAP deficiency. The ages at the onset of IBD were 8, 8, 11, and 11 years old. Each patient had undergone lower gastrointestinal endoscopy severally, and biopsies had been taken from multiple sites deemed by the endoscopist to be highly variable. Additional eight biopsy specimens from one patient of XIAP deficiency with onset at age 3 was investigated histopathologically, as a comparative control of very early‐onset XIAP deficiency‐associated IBD (VEO‐ XIAP‐IBD) (this patient was previously reported as case No. 25 by Ono S et al. Four patients with LO‐XIAP‐IBD had been clinically and genetically investigated, and reported with a brief pathological report, but in this study, we attempted to compare LO‐XIAP‐IBD with VEO‐XIAP‐IBD by adding more detailed histopathological analysis. The histological evaluation parameters included lymphoplasmacytic inflammation in the lamina propria, eosinophilic infiltration (often into crypt epithelium; so‐ called eosinophilic cryptitis), the degree of apoptosis in the crypt epithelium, neutrophilic cryptitis, crypt abscess, basal plasmacytosis, crypt distortion, epithelioid granuloma, and ileal villous blunting. The above was rated on a 4‐point scale of 0, 1, 2, and 3 determined by the semi‐quantitative evaluation of Conrad et al. All histological examinations were conducted by one pathologist specializing in gastrointestinal tract pathology. The results are shown (Tables 1 and S1). In one case of VEO‐XIAP‐IBD (patient E), eosinophil‐dominant inflammation was more conspicuous than neutrophilic cryptitis, and the presence of eosinophil‐derived granules in the crypt was also shown as a specific finding as previously reported. In contrast, in four cases of LO‐XIAP‐IBD, it was difficult to distinguish from conventional IBD, especially Crohn's disease, although there was a high degree of inflammation (Figure S1). No specimen had a noticeable eosinophilic infiltration, and apoptosis was found in only a few crypts. Villous blunting at the end of the ileum was slightly noticeable in only patient A. Conrad et al. described the diagnostic histopathological findings in patients with VEO‐IBD compared with older children with IBD while reviewing the literature of the past. They highlighted that the characteristic histological features of VEO‐IBD are moderate to severe chronic architectural changes, increased eosinophils within the lamina propria, crypts, and surface epithelium, as well as increased frequency of apoptosis in the crypt epithelium. Additionally, small bowel villous blunting was often observed, and they noted that depending on the type of monogenic defect, granuloma may be a characteristic finding. They conducted whole