title: Familial gastrointestinal stromal tumors associated with dysphagia and novel type germline mutation of KIT gene.
abstract: A family with multiple gastrointestinal stromal tumors (GISTs), a new type of germline mutation of KIT gene, and dysphagia is reported. The mutation was observed at Asp-820 in tyrosine kinase (TK) II domain. Mutations in TK II domain have been found in mast cell and germ cell tumors but not in GISTs, and the present family members are the first reported cases of GISTs with TK II domain mutations, including sporadic GISTs. Because interleukin 3-dependent Ba/F3 murine lymphoid cells transfected with the mutant KIT complementary DNA grew autonomously without any growth factors and formed tumors in nude mice, the mutation was considered to be gain-of-function type. Family members with the germline KIT mutation reported dysphagia, but those without the mutation did not. The mechanism of dysphagia was examined with gastrointestinal fiberscopy, endoscopic ultrasonography, and esophageal manometry. No mechanical obstruction was found, and the esophagus was not remarkably dilated. In the family members with dysphagia, endoscopic ultrasonography at the esophagocardiac junction showed a thickened hyperechoic layer between the circular and longitudinal muscle layers, suggesting hyperplasia of interstitial cells of Cajal at the myenteric plexus layer. Manometry showed low resting lower esophageal sphincter pressure and abnormal simultaneous contractions of the esophagus without normal peristalsis. These findings indicate that the dysphagia of the present family is different from typical achalasia. This is the first report of familial dysphagia caused by germline gain-of-function mutation of the KIT gene at the TK II domain.
authors: Department of Pathology, Osaka University Medical School, Suita, Japan.
authors: Seiichi
authors: S
authors: Hirota
authors: Toshirou
authors: T
authors: Nishida
authors: Koji
authors: K
authors: Isozaki
authors: Masahiko
authors: M
authors: Taniguchi
authors: Kazuhiro
authors: K
authors: Nishikawa
authors: Akiko
authors: A
authors: Ohashi
authors: Arimichi
authors: A
authors: Takabayashi
authors: Tadashi
authors: T
authors: Obayashi
authors: Tomoko
authors: T
authors: Okuno
authors: Kazuo
authors: K
authors: Kinoshita
authors: Hui
authors: H
authors: Chen
authors: Yasuhisa
authors: Y
authors: Shinomura
authors: Yukihiko
authors: Y
authors: Kitamura
mesh_terms: D000368:Aged; D018952:Antigens, CD34 / Q000032:analysis; D003680:Deglutition Disorders / Q000209:etiology* / Q000235:genetics; D004947:Esophagus / Q000503:physiopathology; D005770:Gastrointestinal Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics*; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis / Q000235:genetics*; D017154:Stromal Cells / Q000473:pathology; D014057:Tomography, X-Ray Computed; D014463:Ultrasonography
chemical_list: D018952:Antigens, CD34; D019009:Proto-Oncogene Proteins c-kit