Retrospective Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 28, 2017; 23(48): 8544-8552
Published online Dec 28, 2017. doi: 10.3748/wjg.v23.i48.8544
Childhood-onset inflammatory bowel diseases associated with mutation of Wiskott-Aldrich syndrome protein gene
Takashi Ohya, Masakatsu Yanagimachi, Kentaro Iwasawa, Shuichiro Umetsu, Tsuyoshi Sogo, Ayano Inui, Tomoo Fujisawa, Shuichi Ito
Takashi Ohya, Masakatsu Yanagimachi, Shuichi Ito, Department of Pediatrics, Yokohama City University, Yokohama, Kanagawa 236-004, Japan
Masakatsu Yanagimachi, Department of Pediatrics, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan
Kentaro Iwasawa, Shuichiro Umetsu, Tsuyoshi Sogo, Ayano Inui, Tomoo Fujisawa, Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohama-shi Tobu Hostopital, Turumi-ku, Yokohama, Kanagawa 230-0012, Japan
Author contributions: Ohya T, Yanagimachi M and Ito S designed the research; Ohya T, Iwasawa K, Umetsu S, Sogo T, Inui A and Fujisawa T performed the research; Ohya T and Yanagimachi M analyzed the data; and Ohya T wrote the paper.
Institutional review board statement: The study was reviewed and approved by the Ethics Committees of the Yokohama City University School of Medicine and Saiseikai Yokohama-shi Tobu Hospital (number: A140724004).
Informed consent statement: All study participants, or their legal guardians, provided written informed consent prior to study enrollment.
Conflict-of-interest statement: All authors have no conflict of interest.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Masakatsu Yanagimachi, MD, PhD, Assistant Professor, Department of Pediatrics, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. myanagimachi.ped@tmd.ac.jp
Telephone: +81-3-58035249 Fax: +81-3-58035246
Received: October 31, 2017
Peer-review started: November 1, 2017
First decision: November 14, 2017
Revised: November 21, 2017
Accepted: November 27, 2017
Article in press: November 27, 2017
Published online: December 28, 2017
Processing time: 57 Days and 3.5 Hours
ARTICLE HIGHLIGHTS
Research background

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a chronic inflammatory disorder of the gastrointestinal tract. Recently, it was discovered that some patients with primary immunodeficiencies initially develop IBD or IBD-like gastroenterocolitis, especially in childhood.

Research motivation

Children with Wiskott-Aldrich syndrome (WAS) and chronic granulomatous disease (CGD) could develop IBD or IBD-like gastroenterocolitis. The diagnosis of underlying primary immunodeficiencies such as WAS and CGD is important for investigating the pathogenesis of IBD, selecting appropriate treatment, taking precautions regarding malignancies and autoimmune diseases, and performing genetic counseling.

Research objectives

To screen primary immunodeficiency, WAS and CGD, among children with inflammatory bowel disease (IBD), and to investigate their clinical features.

Research methods

This was a single-center retrospective study. Eighteen children with IBD were investigated. We performed intracellular staining of Wiskott-Aldrich syndrome protein (WASP) to analyzed their expression in lymphocytes and DHR123 assay to analyze superoxide generation in phagocytes using flow cytometry. When the expression of WASP or superoxide generation was low or absent, we performed direct DNA sequence to determine the cause of this. In silico analysis was performed using PolyPhen-2 (Polymorphism Phenotyping V.2, http://genetics.bwh.harvard.edu/pph2/dbsearch.shtml) and SIFT (http://sift.jcvi.org/), in addition to a literature review of the mutated gene sequence.

Research results

DHR123 assays revealed no patients with abnormal superoxide generation. Three patients (UC, n = 2; CD, n = 1) showed low expression of WASP compared with the healthy controls. WAS gene analysis revealed the same mutation (c.1378C>T, p.Pro460Ser) in all three patients. The mutation was previously reported in four patients with typical WAS or XLT. But, in silico analysis suggested that the mutation would not be pathogenic. Our patients with the mutation did not show thrombocytopenia or recurrent infection despite low WASP expression in their lymphocytes. Only one patient showed refractory eczema.

Research conclusions

We found a WAS c.1378C>T, p.Pro460Ser mutation in three children with IBD, the lymphocytes of whom exhibited low WASP expression. We suggest that low WASP expression has an association with the development of IBD/IBD-like colitis. Therefore, the analysis of WASP expression in children with IBD should be considered even if the triad of WAS symptoms is absent.

Research perspectives

In this study, we found a WAS c.1378C>T, p.Pro460Ser mutation in three children with IBD. These patients did not present typical symptoms of WAS, such as thrombocytopenia and recurrent infection. However, WAS is known to be associated with an increased risk of malignancies including lymphoma, as well as autoimmune diseases. Therefore, in any long-term follow-up, the analysis of WASP expression in children with IBD should be considered even if major symptoms of WAS are absent.