Hirota Seiichi, Nishida Toshirou, Isozaki Koji, Taniguchi Masahiko, Nishikawa Kazuhiro, Ohashi Akiko, Takabayashi Arimichi, Obayashi Tadashi, Okuno Tomoko, Kinoshita Kazuo, Chen Hui, Shinomura Yasuhisa, Kitamura Yukihiko
Department of Pathology, Osaka University Medical School, Suita, Japan.
Gastroenterology. 2002 May;122(5):1493-9. doi: 10.1053/gast.2002.33024.
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.
报道了一个患有多发性胃肠道间质瘤（GIST）、携带KIT基因新型种系突变且有吞咽困难症状的家族。该突变发生在酪氨酸激酶（TK）II结构域的Asp-820位点。TK II结构域的突变已在肥大细胞和生殖细胞肿瘤中发现，但在GIST中未发现，而本家族成员是首例报道的携带TK II结构域突变的GIST病例，包括散发性GIST。由于用突变型KIT互补DNA转染的依赖白细胞介素3的Ba/F3小鼠淋巴细胞在无任何生长因子的情况下自主生长并在裸鼠中形成肿瘤，因此该突变被认为是功能获得型。携带种系KIT突变的家族成员报告有吞咽困难，而未携带该突变的成员则没有。通过胃肠纤维内镜检查、内镜超声检查和食管测压来研究吞咽困难的机制。未发现机械性梗阻，食管也未明显扩张。在有吞咽困难的家族成员中，食管贲门交界处的内镜超声检查显示环形肌层和纵行肌层之间有增厚的高回声层，提示肌间神经丛层的 Cajal 间质细胞增生。测压显示食管下括约肌静息压力低，食管出现异常同步收缩且无正常蠕动。这些发现表明本家族的吞咽困难不同于典型的贲门失弛缓症。这是关于由TK II结构域KIT基因种系功能获得性突变引起的家族性吞咽困难的首例报道。
