Robson Mark E, Glogowski Emily, Sommer Gunhild, Antonescu Cristina R, Nafa Khedoudja, Maki Robert G, Ellis Nathan, Besmer Peter, Brennan Murray, Offit Kenneth
Clinical Genetics and Gastrointestinal Oncology Services, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Clin Cancer Res. 2004 Feb 15;10(4):1250-4. doi: 10.1158/1078-0432.ccr-03-0110.
Somatic mutations that result in the activation of the growth factor receptor KIT are commonly found in gastrointestinal stromal tumors (GISTs). Six families have been reported in which a germ-line mutation in KIT is associated with an autosomal dominant predisposition to the development of GISTs. Hyperpigmentation, urticaria pigmentosa, and dysphagia have been described in some, but not all, families. Preliminary correlations between the site of mutation and the clinical phenotype have been proposed, but the strength of these associations is not defined.
A large kindred with multiple GISTs, hyperpigmentation, and dysphagia was identified after the index case presented with multiple GISTs. A germ-line mutation in KIT (W557R) was identified in an affected cousin, after which a large family meeting was held and testing offered. Clinical data were obtained by interview and, whenever possible, medical record documentation.
To date, 19 individuals have been tested, and the mutation has been shown to cosegregate with the syndrome. The phenotypic expression, however, is variable. GISTs, often presenting as upper gastrointestinal bleeding, and hyperpigmentation are common, but not diagnosed in all documented or obligate carriers. Dysphagia is a less prevalent complaint. The diagnosis of GISTs appears to be made at a younger age in more recent generations. Metastatic disease is uncommon.
A germ-line mutation in KIT resulting in an amino acid substitution in the juxtamembrane region is associated with a syndrome of GIST, hyperpigmentation, and dysphagia, although the prominence of each component varies.
导致生长因子受体KIT激活的体细胞突变常见于胃肠道间质瘤（GIST）。已报道有6个家系，其中KIT基因的种系突变与GIST发生的常染色体显性遗传易感性相关。在部分（而非全部）家系中描述了色素沉着过度、色素性荨麻疹和吞咽困难。已提出突变位点与临床表型之间的初步相关性，但这些关联的强度尚未明确。
在首例病例出现多发性GIST后，识别出一个有多发性GIST、色素沉着过度和吞咽困难的大家系。在一名患病的堂兄弟中识别出KIT基因的种系突变（W557R），之后召开了一次大型家族会议并提供检测。通过访谈并尽可能获取病历记录来获得临床数据。
迄今为止，已对19人进行检测，结果显示该突变与该综合征共分离。然而，表型表达存在差异。GIST通常表现为上消化道出血，色素沉着过度很常见，但并非在所有已记录的或必然携带突变的个体中都能诊断出来。吞咽困难是较少见的主诉。在较近几代人中，GIST的诊断似乎年龄更小。转移性疾病并不常见。
KIT基因的种系突变导致近膜区域的氨基酸替换，与GIST、色素沉着过度和吞咽困难综合征相关，尽管每个组成部分的突出程度有所不同。
