Can a familial gastrointestinal tumour syndrome be allelic with Waardenburg syndrome?

Abstract

Vilain RE, Dudding T, Braye SG, Groombridge C, Meldrum C, Spigelman AD, Ackland S, Ashman L, Scott RJ. Can a familial gastrointestinal tumour syndrome be allelic with Waardenburg syndrome? 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.