title: Juvenile polyposis, hereditary hemorrhagic telangiectasia, and early onset colorectal cancer in patients with SMAD4 mutation.
abstract: BACKGROUND
  Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder most often caused by mutation in the endoglin or ALK1 genes. A distinct syndrome combines the clinical features of HHT and juvenile polyposis (JP) and has been associated with SMAD4 mutation. The aim of this study was to describe the phenotype of patients with JP-HHT and SMAD4 mutations and to compare this phenotype with HHT or JP patients with mutations other than SMAD4.
  
  
  METHODS
  Patients prospectively enrolled in the Toronto HHT and JP databases who underwent genotyping were included. The phenotypic characteristics of JP-HHT patients with SMAD4 mutations and patients with mutations other than SMAD4 were analyzed and compared.
  
  
  RESULTS
  Three hundred and fifty-eight patients underwent genetic testing (HHT, n = 332; JP, n = 26). Among fourteen patients identified with SMAD4 mutations, ten met the clinical diagnostic criteria for both JP and HHT (71%). Patients with SMAD4 mutations had 100% penetrance of the polyposis phenotype. All patients with JP and SMAD4 mutation had features of HHT. Three JP-HHT patients developed early onset colorectal cancer (CRC) (mean age 28 years). JP-HHT patients with SMAD4 mutation had a significantly higher rate of anemia than HHT patients with mutations other than SMAD4.
  
  
  CONCLUSIONS
  Patients with HHT and SMAD4 mutations are at significant risk of JP and CRC. The gastrointestinal phenotype is similar to JP patients without SMAD4 mutation. It is essential for HHT patients to undergo genetic testing to determine if they have SMAD4 mutations so that appropriate gastrointestinal screening and surveillance for JP and CRC can be completed.
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON M5T 3L9, Canada. frank.schwenter@gmail.com
authors.forename: Frank
authors.initials: F
authors.lastname: Schwenter
authors.forename: Marie E
authors.initials: ME
authors.lastname: Faughnan
authors.forename: Abigail B
authors.initials: AB
authors.lastname: Gradinger
authors.forename: Terri
authors.initials: T
authors.lastname: Berk
authors.forename: Robert
authors.initials: R
authors.lastname: Gryfe
authors.forename: Aaron
authors.initials: A
authors.lastname: Pollett
authors.forename: Zane
authors.initials: Z
authors.lastname: Cohen
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.forename: Carol
authors.initials: C
authors.lastname: Durno
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002648:Child; D015179:Colorectal Neoplasms / Q000235:genetics*; D016208:Databases, Factual; D005820:Genetic Testing; D006801:Humans; D044483:Intestinal Polyposis / Q000151:congenital* / Q000235:genetics; D009154:Mutation; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics*; D009864:Ontario; D011446:Prospective Studies; D051901:Smad4 Protein / Q000235:genetics*; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000235:genetics*; D055815:Young Adult
chemical_list: D051901:Smad4 Protein