Germline SMAD4 or BMPR1A mutations and phenotype of juvenile polyposis

Background: Juvenile polyposis (JP) is an inherited condition predisposing to upper gastrointestinal (UGI) polyps and colorectal cancer. Two genes are known to predisose to JP, SMAD4 and bone morphogenetic protein receptor type 1A (BMPRIA). The object of this study was to determine the differences in phenotype of patients with SMAD4 or BMPRIA mutations (MUT+) compared with those without (MUT-). Methods: DNA was extracted from 54 JP probands and used for polymerase chain reaction of all exons of SMAD4 and BMPRIA. Products were then sequenced and analyzed for mutations. Medical record data were used to create a JP database, and statistical analysis was performed using Fisher's exact and unpaired t-tests. Results: Nine of 54 patients had germline SMAD4 mutations, 13 had BMPRIA mutations, and 32 had neither. There were no significant differences between SMAD4 + and BMPRIA + cases in terms of clinical factors examined, except for a family history of UGI involvement (P < .01). There was a higher prevalence of familial cases in MUT+ patients (P = .09), >10 lower gastrointestinal polyps (P = .06), and frequency of family history of gastrointestinal cancer compared with MUT-patients (P = .01). Conclusions: Patients with germline SMAD4 or BMPRIA mutations have a more prominent JP phenotype than those without, and SMAD4 mutations predispose to UGI polyposis.