Pleomorphic Characteristics of a Germ-Line KIT Mutation in a Large Kindred with Gastrointestinal Stromal Tumors, Hyperpigmentation, and Dysphagia

Abstract

Purpose: 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.Design: 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.Results: 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. Conclusions: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.

Clinical, histopathologic, molecular and therapeutic findings in a large kindred with gastrointestinal stromal tumor

“…For instance, the median age at diagnosis has been described in one study to decrease in successive generations possibly because of better diagnostic imaging or evolving genetic stability. 12 This observation has not been reported in other studies and has not been confirmed in another large kindred. Additionally, histopathologic evaluation of GISTs resected from kindreds has not been evaluated in terms of the consensus criteria for risk stratifications of GIST using mitotic rates and tumor size.…”

“…In contrast to sporadic gastrointestinal tumors that present with a single primary tumor, surgical intervention performed on an individual with a hereditary GIST may reveal tens to hundreds of tumor nodules. 3,5,7,[9][10][11][12][30][31][32] The mitotic rate of the tumors in most of these families (those who were documented) appear to be low suggesting that these tumors appear indolent compared with sporadic GIST. 3,9,10,12,13,30,33 Interestingly, 2 patients in our study presented with metastases at diagnosis despite displaying variable mitotic rates (1 with 5 mitoses per 50 hpf and 1 with 30 mitoses per 50 hpf.…”

“…The median age of diagnosis of all kindreds reported in the literature with GIST is 47 years of age, [3][4][5][6][7][8][9][10][11][12][13] notably earlier in onset than that of patients with the sporadic form of the disease where the median age of diagnosis is 60 years. 24,25 The age at diagnosis of GIST in one affected kindred appears to occur earlier in successive generations as noted by Robson et al 12 The mean age of diagnosis in the 4th generation was 34 years of age when compared with 62 years of age in the 2nd generation in that study. Earlier diagnosis in successive generations may be due to improvement in diagnostic technology 26 or genetic variations such as promoter polymophisms.…”

“…In GIST kindreds, tumor nodules are often contiguous with areas of hyperplastic ICCs on histopathologic analysis 3,4,9,10,12,30,31,36 suggesting that these tumors arise within the hyperplastic ICC. In our study, the tumor nodules appeared to arise from a background of a hyperplastic Auerbach's plexus in the small bowel (Figs.…”

“…3 Most kindreds with familial GIST are stricken with a germ-line mutation in the KIT gene on chromosome 4 but there has been a report of a family with a PDGFRA gene mutation. [3][4][5][6][7][8][9][10][11][12][13] In families with GIST, the mutational site within KIT occurs most commonly in the juxtamembrane domain encoded by exon 11 (Table I). Since most of these kindreds are small and were described before the use of imatinib therapy, there are gaps in the knowledge of this entity.…”