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The prevalence of hereditary hemorrhagic telangiectasia in Juvenile Polyposis syndrome patients with SMAD4 mutations


Juvenile Polyposis Syndrome (JPS) is defined by the presence of ≥ 5 colorectal juvenile polyps or any number of juvenile polyps in an individual with a family history of JPS. Genetic alterations including either point mutations or large rearrangements in BMPR1A or SMAD4 are found in 50% of affected individuals. Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disease diagnosed upon the presence of epistaxis, visceral arteriovenous malformations (AVM) or mucutaneous telangiectasias. HHT is diagnosed when there are ≥ 3 manifestations and is suspected when there are at least 2 manifestations. Most HHT cases are caused by a germline mutation in ALK1 or ENG, members of the TGFβ signaling pathway. Approximately 22% of patients with Juvenile Polyposis Syndrome (JPS) due to a SMAD4 mutation have been reported to also have HHT [1]. Most prior publications have few patients and no systematic approach to screening, so the true incidence of the combined JPS/HHT syndrome is not known. Our aim was to determine the prevalence of HHT in our patients with JPS with a SMAD4 mutation including those who underwent systematic screening for AVM’s.


JPS patients were identified from a comprehensive polyposis database using Cologene© software. Families carrying a germline SMAD4 mutation were studied by screening affected patients for cutaneous telangiectases and with cardiac bubble ECHO, CAT scan chest, or MRI of brain for other AVMs.


Fourteen of 38 JPS families underwent genetic testing. Nine families were identified to have a SMAD4 mutation. These families include 21 affected relatives, 11 men and 10 women, with a current mean age of 36.3 years (range 4 - 70). Fourteen affected relatives, from 6 families, underwent HHT screening (7 men and 7 women, with a mean age of 35.4 years (range 15 -70). Eleven of 14 (79%) had ≥ 3 HHT manifestations and two of 14 (14 %) had at least 2. In addition, 3 of 7 unscreened affected relatives have presented with at least 2 manifestations of HHT. Of the 24 families that have not had genetic testing or HHT screening one affected family member presented with ≥ 3 HHT manifestations, and two had at least 2 manifestations.


Greater than 90% of our patients with JPS due to SMAD4 mutations had clinically diagnosed or suspected HHT. Genetic testing should be performed in all JPS patients. In addition, systematic HHT screening is recommended for JPS patients with SMAD4 mutations.


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Correspondence to Margaret O’Malley.

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This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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O’Malley, M., LaGuardia, L., Kalady, M. et al. The prevalence of hereditary hemorrhagic telangiectasia in Juvenile Polyposis syndrome patients with SMAD4 mutations. Hered Cancer Clin Pract 9, O5 (2011).

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  • Genetic Testing
  • Arteriovenous Malformation
  • Hereditary Hemorrhagic Telangiectasia
  • Autosomal Dominant Disease
  • Affected Family Member