title: Can a familial gastrointestinal tumour syndrome be allelic with Waardenburg syndrome?
abstract: Familial gastrointestinal stromal tumours (GISTs) are rare but otherwise well-characterized tumour syndromes, most commonly occurring on a background of germline-activating mutations in the tyrosine kinase receptor c-KIT. The associated clinical spectrum reflects the constitutive activation of this gene product across a number of cell lines, generating gain-of-function phenotypes in interstitial cells of Cajal (GIST and dysphagia), mast cells (mastocytosis) and melanocytes (hyperpigmentation). We report a three-generation kindred harbouring a c-KIT germline-activating mutation resulting in multifocal GISTs, dysphagia and a complex melanocyte hyperpigmentation and hypopigmentation disorder, the latter with features typical of those observed in Waardenburg type 2 syndrome (WS2F). Sequencing of genes known to be causative for WS [microphthalmia transcription factor (MITF), Pax3, Sox10, SNAI2 ] failed to show any candidate mutations to explain this complex cutaneous depigmentation phenotype. Our case report conclusively expands the clinical spectrum of familial GISTs and shows a hitherto unrecognized link to WS. Possible mechanisms responsible for this novel cause of WS2F will be discussed.
authors.affiliation: Hunter Area Pathology Service, Hunter New England Health Service, Newcastle, NSW, Australia. Ricardo.vilain@hnehealth.nsw.gov.au
authors.forename: R E
authors.initials: RE
authors.lastname: Vilain
authors.forename: T
authors.initials: T
authors.lastname: Dudding
authors.forename: S G
authors.initials: SG
authors.lastname: Braye
authors.forename: C
authors.initials: C
authors.lastname: Groombridge
authors.forename: C
authors.initials: C
authors.lastname: Meldrum
authors.forename: A D
authors.initials: AD
authors.lastname: Spigelman
authors.forename: S
authors.initials: S
authors.lastname: Ackland
authors.forename: L
authors.initials: L
authors.lastname: Ashman
authors.forename: R J
authors.initials: RJ
authors.lastname: Scott
mesh_terms: D000483:Alleles; D003680:Deglutition Disorders / Q000235:genetics / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics* / Q000473:pathology; D018095:Germ-Line Mutation; D006801:Humans; D006965:Hyperplasia; D056885:Interstitial Cells of Cajal / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009197:Myenteric Plexus / Q000473:pathology; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D014849:Waardenburg Syndrome / Q000235:genetics* / Q000473:pathology
chemical_list: D019009:Proto-Oncogene Proteins c-kit