P091 XIAP MUTATION IS ASSOCIATED WITH TREATMENT RESISTANT CROHN’S DISEASE: A SINGLE INSTITUTION CASE SERIES
Authors: Tawfik Soliman Hussein Mohamed Sabry , Elkheshen Ahmed , Hashim Mahmoud , Wurth Mark , Perry Courtney , Flomenhoft Deborah 
Published: January 2020

Background

X-linked inhibitor of apoptosis (XIAP) deficiency, also known as X-linked lymphoproliferative syndrome type 2 (XLP2), occurs in about 1 in 5 million males [1] and is associated with development of hemophagocytic lymphohistiocytosis (HLH), splenomegaly and treatment-resistant Crohn’s disease [2][3]. Here we present the cases of two XLP2 siblings with lymphopenia, hepatosplenomegaly, recurrent infections, and refractory Crohn’s disease.

Case Discussions

The first brother was diagnosed with ileocolonic Crohn’s disease at age 8. Lymphopenia and hepatomegaly were present at the time of diagnosis. Initial management with azathioprine resulted in response, but not remission so was switched to MTX. After a year on MTX, CT abd/pelvis demonstrated hepatosplenomegaly concerning for lymphoma. Bone marrow aspiration was remarkable for decreased B-cells without blasts. Liver biopsy demonstrated only sinusoidal dilation. Patient was switched to infliximab + prednisone, but required right hemicolectomy for TI stricture soon after initiation. While on anti-TNF, he suffered multiple viral and bacterial infections, as well as severe psoriasis which did not abate after removing anti-TNF therapy. His CD progressed despite trials of vedolizumab and certolizumab. He underwent diversion loop ileostomy for persistent disease and initiated ustekinumab + MTX. His CD symptoms and psoriatic rash have improved on ustekinumab, but neither are in remission. He still suffers multiple skin infections and infection-induced leukopenia. His most recent immunology evaluation revealed XIAP mutation based on molecular genetic testing, consistent with XLP2. He has been improving with IVIG.

The second brother presented with hepatosplenomegaly in infancy, work-up was unrevealing. He was plagued by recurrent infections, lymphopenia, and hepatosplenomegaly throughout childhood. Soon after his CD diagnosis at age 16, bone marrow aspiration for hepatosplenomegaly was remarkable only for low B-cells. A year later, he underwent diverting loop ileostomy for worsening symptoms. At age 20, he underwent APR with left hemicolectomy/end transverse colostomy. He failed multiple medications including prednisone, infliximab, adalimumab, and vedolizumab. He was recently switched to ustekinumab + MTX and has symptomatically improved. He was referred to our immunologist, who suspects XIAP mutation based on his sibling’s diagnosis and has since begun IVIG.

Discussion

XLP2 is a rare disease that can be challenging to diagnose due to variance in clinical presentation. In this series, our patients presented with refractory, early-onset CD most likely due to XIAP mutation. XIAP deficiency should be suspected in treatment resistant early-onset Crohn’s disease, especially if complicated by recurrent infections or unexplained hepatosplenomegaly. Ustekinumab combined with methotrexate has demonstrated benefit in their CD management, and should be considered in the management of CD associated with XIAP deficiency.