SMAD4 Mutations in Juvenile Polyposis Syndrome and Hereditary Hemorrhagic Telangiectasia

Prevalence and Clinical Significance

• SMAD4 mutations cause the juvenile polyposis-HHT overlap syndrome, occurring in 1-2% of all HHT cases, with up to 76% of patients with JPS due to SMAD4 developing features of HHT 1, 2
• The coexistence of JPS and HHT is exclusively due to SMAD4 mutations, not BMPR1A mutations 2, 3
• Among patients with JPS who carry SMAD4 mutations, 76% manifest clinical features of hereditary hemorrhagic telangiectasia 2
• Patients with germline SMAD4 mutations have a more prominent JPS phenotype with significantly higher risk of upper gastrointestinal involvement and gastric cancer compared to BMPR1A mutation carriers 2, 3
• SMAD4 mutation carriers show a higher prevalence of gastric polyposis, with 73% prevalence versus 8% in BMPR1A carriers 3
• All cases of gastric cancer in one cohort occurred exclusively in patients with SMAD4 pathogenic variants 2, 3