Journal Article

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

GRADINGER Abigail B., GRYFE Robert, POLLETT Aaron, SCHWENTER Frank, FAUGHNAN Marie E., COHEN Zane, BERK Terri, GALLINGER Steven, DURNO Carol

2012

Overview

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.

• Publisher: Springer Japan,Springer,Springer Nature B.V
• Subject: Abdominal Surgery / Adolescent / Adult / Age of Onset / Analysis / Anemia / Arteriovenous malformation / Cancer patients / Care and treatment / Child / Colorectal cancer / Colorectal cancer screening / Colorectal Neoplasms - genetics / Colorectal polyps / Colorectal Surgery / Databases, Factual / Development and progression / Gastroenterology / Genetic aspects / Genetic Testing / Hepatology / Hereditary colorectal cancer / Humans / Intestinal Polyposis - congenital / Intestinal Polyposis - genetics / Medicine / Medicine & Public Health / Mutation / Neoplastic Syndromes, Hereditary - genetics / Ontario / Original Article—Alimentary Tract / Prospective Studies / Smad4 Protein - genetics / Surgical Oncology / Telangiectasia, Hereditary Hemorrhagic - genetics / Telangiectasis / Young Adult