title: A Patient with CTLA-4 Haploinsufficiency Presenting Gastric Cancer.
abstract: Cytotoxic T-lymphocyte-antigen 4 (CTLA-4) is an essential negative regulator expressed on regulatory T cells (Tregs) and activated T cells. Germline heterozygous mutations in CTLA4 lead to haploinsufficiency of CTLA-4, resulting in the development of an autosomal dominant immune dysregulation syndrome with incomplete penetrance. We report here a Japanese patient with this disorder who has a novel heterozygous single nucleotide insertion, 76_77insT (p. L28SfsX40), in the CTLA4 gene. Peripheral blood mononuclear cells from the patient showed decreased frequency of CTLA-4(high) cells in CD4(+)FOXP3(+) cells following CD3/CD28 stimulation. The patient experienced hypogammaglobulinemia, recurrent pneumonia, esophageal candidiasis, cytomegalovirus-positive chronic gastritis, chronic and severe diarrhea, and type 1 diabetes mellitus. Moreover, the patient developed multifocal gastric cancer, histologically poorly and well-differentiated adenocarcinomas, associated with chronic atrophic gastritis and intestinal metaplasia. Previously, 23 symptomatic cases with heterozygous CTLA4 mutations have been reported. Including the case presented here, 3 of the 24 cases (12.5%) developed gastric cancer. Notably, 2 of 3 patients presented similarly multifocal adenocarcinomas associated with atrophic gastritis and intestinal metaplasia. Predisposition to gastric cancer has been also reported in CVID patients. These clinical observations suggest that gastric cancer is a disease commonly associated with autosomal dominant immune dysregulation syndrome due to CTLA4 mutation.
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Hayakawa
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan. saok969@gmail.com.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okada
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Tsumura
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
authors.forename: Sonoko
authors.initials: S
authors.lastname: Sakata
authors.affiliation: Department of Gastroenterology and Metabolism, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Ueno
authors.affiliation: Department of Pediatrics, Tokyo Medical and Dental University Graduate School, Tokyo, Japan.
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Imai
authors.affiliation: Department of Pediatrics, Tokyo Medical and Dental University Graduate School, Tokyo, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Morio
authors.affiliation: Department of Technology Development, Kazusa DNA Research Institute, Chiba, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohara
authors.affiliation: Department of Gastroenterology and Metabolism, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Kobayashi
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis* / Q000235:genetics; D000328:Adult; D060908:CTLA-4 Antigen / Q000235:genetics / Q000378:metabolism*; D004252:DNA Mutational Analysis; D017809:Fatal Outcome; D020022:Genetic Predisposition to Disease; D057895:Haploinsufficiency; D006801:Humans; D007239:Infections / Q000175:diagnosis* / Q000235:genetics; D007564:Japan; D008297:Male; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D013274:Stomach Neoplasms / Q000175:diagnosis* / Q000235:genetics
chemical_list: D060908:CTLA-4 Antigen
keywords: Autosomal dominant immune dysregulation syndrome; CTLA-4; FOXP3; Gastric cancer; Regulatory T cells