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We read with interest the review by Holm Uhlig on monogenic diseases associated with intestinal inflammation.1 XIAP deficiency, caused by X-linked inherited mutations in BIRC4, is highlighted as a mendelian cause of very early onset IBD. Consistently with the observation of Crohn's disease (CD) in XIAP deficiency, the RING activity of XIAP was recently shown to be required for NOD2-dependent immune responses.2 In his review Dr Uhlig suggests to consider monogenetic diseases as causes for IBD particularly in patients younger than 6 years of age. In addition to the reviewed literature, our group has recently reported on the clinical spectrum of 27 patients with XIAP deficiency.3 Seven of these developed severe IBD resembling CD with clinical findings of granulomatous inflammation, recurrent colonic strictures, severe perianal fistulas as well as pancolitis and ulcerations affecting stomach and small bowel. Onset of CD was highly variable in our cohort and ranged from 1 to 18 years (median 7.7 years). We would like to emphasise, that onset of disease was >6 years (8, 11, 12 and 18 years) in four of our patients. In six out of seven patients, CD was the chief complaint at onset of disease and only one patient had previously experienced flares of hemophagocytic lymphohistiocytosis (HLH). Similar to the first description of severe CD in XIAP deficieny,4 IBD was the exclusive disease manifestation in three of our patients. In one patient CD remained the only clinical problem for >25 years of follow up. Treatment regimens varied and included conservative regimens (eg, local or systemic steroids, 5-amino salicylic acid, azathioprine and monoclonal antibodies), bowel resections and haematopoietic stem cell transplantation (HSCT). The indication for HSCT was poor response to conservative IBD management (and not HLH) in three patients. Two of them are alive and cured from IBD, generally documenting efficacy of this treatment for XIAP deficiency associated CD. In addition to the patients with CD, two further patients from our cohort developed bowel symptoms classified as ‘coeliac-like disease’ with blunted villi, lymphocytic infiltrates, but without coeliac disease-associated antibodies. This may indicate that the IBD phenotype of XIAP deficiency may not be restricted to CD. We have also shown that flow cytometry screening for XIAP protein expression in patient derived peripheral blood mononuclear cells allows for a fast and efficient screening. 14 out of 17 patients (82%) were identified, but protein expression can be normal in patients with missense mutations or mutations outside the binding region of the diagnostic antibody (ie, the BIR3 and UBA domain of BIRC4). Considering the possible occurrence of life threatening complications in XIAP deficiency (eg, HLH) and a possible curative (albeit hazardous) treatment option by HSCT, we highly recommend screening for XIAP deficiency in any male patient with severe CD, including those with onset beyond early childhood.
Contributors CS and S E designed the study, recruited patients and wrote the manuscript.
Competing interests None.
Patient consent Obtained.
Ethics approval University of Freiburg Medical Center.
Provenance and peer review Not commissioned; internally peer reviewed.