Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome

Carol Gallione, Arthur S. Aylsworth, Jill Beis, Terri Berk, Barbara Bernhardt, Robin D. Clark, Carol Clericuzio, Cesare Danesino, Joanne Drautz, Jeffrey Fahl, Zheng Fan, Marie E. Faughnan, Arupa Ganguly, John Garvie, Katharine Henderson, Usha Kini, Tracey Leedom, Mark Ludman, Andreas Lux, Melissa MaisenbacherSara Mazzucco, Carla Olivieri, Johannes K. Van Ploos Amstel, Nadia Prigoda-Lee, Reed E. Pyeritz, Willie Reardon, Kirk Vandezande, J. Deane Waldman, Robert I. White, Charles A. Williams, Douglas A. Marchuk

Research output: Contribution to journalArticlepeer-review


Juvenile polyposis (JP) and hereditary hemorrhagic telangiectasia (HHT) are clinically distinct diseases caused by mutations in SMAD4 and BMPR1A (for JP) and endoglin and ALK1 (for HHT). Recently, a combined syndrome of JP-HHT was described that is also caused by mutations in SMAD4. Although both JP and JP-HHT are caused by SMAD4 mutations, a possible genotype:phenotype correlation was noted as all of the SMAD4 mutations in the JP-HHT patients were clustered in the COOH-terminal MH2 domain of the protein. If valid, this correlation would provide a molecular explanation for the phenotypic differences, as well as a pre-symptomatic diagnostic test to distinguish patients at risk for the overlapping but different clinical features of the disorders. In this study, we collected 19 new JP-HHT patients from which we identified 15 additional SMAD4 mutations. We also reviewed the literature for other reports of JP patients with HHT symptoms with confirmed SMAD4 mutations. Our combined results show that although the SMAD4 mutations in JP-HHT patients do show a tendency to cluster in the MH2 domain, mutations in other parts of the gene also cause the combined syndrome. Thus, any mutation in SMAD4 can cause JP-HHT. Any JP patient with a SMAD4 mutation is, therefore, at risk for the visceral manifestations of HHT and any HHT patient with SMAD4 mutation is at risk for early onset gastrointestinal cancer. In conclusion, a patient who tests positive for any SMAD4 mutation must be considered at risk for the combined syndrome of JP-HHT and monitored accordingly.

Original languageEnglish
Pages (from-to)333-339
Number of pages7
JournalAmerican Journal of Medical Genetics, Part A
Issue number2
Publication statusPublished - Feb 2010


  • Allelic series
  • Genotype:phenotype correlation
  • Hereditary hemorrhagic telangiectasia
  • JP-HHT syndrome
  • Juvenile polyposis
  • SMAD4

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics


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