Pleomorphic characteristics of a germ-line KIT mutation in a large kindred with gastrointestinal stromal tumors, hyperpigmentation, and dysphagia Journal Article


Authors: Robson, M. E.; Glogowski, E.; Sommer, G.; Antonescu, C. R.; Nafa, K.; Maki, R. G.; Ellis, N.; Besmer, P.; Brennan, M.; Offit, K.
Article Title: 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, hyper-pigmentation, 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.
Keywords: adult; middle aged; gene mutation; somatic mutation; mutation; case report; gastrointestinal hemorrhage; phenotype; gastrointestinal stromal tumor; stem cell factor; stem cell factor receptor; cancer susceptibility; familial disease; family health; proto-oncogene proteins c-kit; metastasis; amino acid substitution; genetic association; age factors; time factors; pedigree; gastrointestinal neoplasms; germ line; dysphagia; gene activation; syndrome; cell membrane; hyperpigmentation; deglutition disorders; autosomal dominant disorder; germ-line mutation; rare disease; growth factor receptor; urticaria pigmentosa; humans; human; male; female; priority journal; article
Journal Title: Clinical Cancer Research
Volume: 10
Issue: 4
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2004-02-15
Start Page: 1250
End Page: 1254
Language: English
DOI: 10.1158/1078-0432.ccr-03-0110
PROVIDER: scopus
PUBMED: 14977822
DOI/URL:
Notes: Clin. Cancer Res. -- Cited By (since 1996):70 -- Export Date: 16 June 2014 -- CODEN: CCREF -- Source: Scopus
Altmetric Score
MSK Authors
  1. Murray F Brennan
    759 Brennan
  2. Kenneth Offit
    509 Offit
  3. Khedoudja Nafa
    181 Nafa
  4. Mark E Robson
    365 Robson
  5. Nathan A Ellis
    74 Ellis
  6. Cristina R Antonescu
    606 Antonescu
  7. Robert Maki
    211 Maki
  8. Gunhild Sommer
    6 Sommer
  9. Peter Besmer
    82 Besmer