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Juvenile polyposis, hereditary hemorrhagic telangiectasia, and early onset colorectal cancer in patients with SMAD4 mutation

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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.

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Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, 60 Murray Street, Toronto, ON, M5T 3L9, Canada

    Frank Schwenter & Steven Gallinger

  2. Division of Respirology, Department of Medicine, Toronto HHT Centre, St. Michael’s Hospital, University of Toronto, Toronto, Canada

    Marie E. Faughnan

  3. Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, University of Toronto, Toronto, Canada

    Marie E. Faughnan

  4. Division of Respirology, Department of Medicine, University of Toronto, Toronto, Canada

    Marie E. Faughnan

  5. Zane Cohen Familial Gastro-Intestinal Cancer Registry, Department of Surgery, Mount Sinai Hospital, University of Toronto, Toronto, Canada

    Frank Schwenter, Abigail B. Gradinger, Terri Berk, Robert Gryfe, Zane Cohen, Steven Gallinger & Carol Durno

  6. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Canada

    Aaron Pollett

  7. Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, University of Toronto, Toronto, Canada

    Carol Durno

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  1. Frank Schwenter
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Correspondence to Frank Schwenter.

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Schwenter, F., Faughnan, M.E., Gradinger, A.B. et al. Juvenile polyposis, hereditary hemorrhagic telangiectasia, and early onset colorectal cancer in patients with SMAD4 mutation. J Gastroenterol 47, 795–804 (2012). https://doi.org/10.1007/s00535-012-0545-8

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  • DOI: https://doi.org/10.1007/s00535-012-0545-8

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