SMAD4 Mutation and the Combined Juvenile Polyposis and Hereditary Hemorrhage Telangiectasia Syndrome: A Single Center Experience

Abstract

Introduction: Juvenile polyposis syndrome (JPS) and hereditary hemorrhagic telangiectasia (HHT) are autosomal dominant disorders with characteristic clinical phenotypes. Mutations of the SMAD4 gene can result in a distinct syndrome with combined clinical features of both HHT and JPS. We aimed to describe the clinical phenotype of patients with the SMAD4 mutations seen at Mayo Clinic Rochester. Methods: Retrospective review of patients with genetically confirmed diagnosis of combined JP-HHT syndrome between January 1998 and January 2018. HHT phenotype was assessed using the Curacao criteria. JPS features were determined by review of endoscopy and pathology reports. Additional outcomes included: incidence of gastrointestinal (GI) malignancies, vascular events, hospitalization for gastrointestinal bleeding (GIB) and overall mortality. Results: A total of 22 patients were identified. Median age was 34 years (1-67) and 41% were males. Median age diagnosis and time of follow-up were 24 (1-66) and 6.5 (0-58) years, respectively. Median Curacao score was 3 (1-4). Seventy-seven percent of patients had a prior episode of epistaxis, 56% skin telangiectasias and 60% visceral arteriovenous malformations (AVM). Common sites for visceral AMV were lower respiratory (45%), liver (27%), GI (10%) and central nervous system (10%). Eighty two percent of patients had family history of HHT. Lower GI polyps (LGP) were found in 86% of patients, most commonly located in the right side of the colon. Upper GI polyps (UGP) were seen in 68% of patients, mainly in the stomach (10/15) and duodenum (5/15). Forty percent of LGP were found to be tubular adenomas compared to 20% of UGP. Family history of polyps and colorectal cancer were present in 91% and 54% of patients, respectively. Two patients had GI malignancies, one rectal and one small bowel adenocarcinoma. One patient had an ischemic cerebellar stroke at age 24 years. A third of the cohort (6/16) had a history of hospitalization for GIB. Overall mortality was 14% with average age of death at 66 years. Conclusion: In our cohort, patients with the combined JP-HHT syndrome had epistaxis and pulmonary AVMs as common manifestations of HHT. Hospitalization for GIB and cerebrovascular events occurred at a rate of 28% and 4%, respectively. Polyps were more commonly seen in the lower GI tract and tubular adenomas were seen in 50%. GI adenocarcinoma occurred at a rate of 10% and overall mortality was 14% within the observed follow-up period.