001). No significant difference in the age Oligomycin A chemical structure at gastroscopy was observed between SMAD4 and BMPR1A mutation carriers without gastric polyposis (p=0.15). Gastric cancer Consistent with this over�\representation of gastric polyposis, all seven cases of gastric cancer were reported in families with SMAD4 mutations (index patient JUV�\55; one affected relative in families JUV�\55 and JUV�\37; four affected relatives in family JUV�\4). The brother of index patient JUV�\4 had an early tubular adenocarcinoma diagnosed at 38 years of age; the histology results of the other three affected family members (two uncles and an aunt) were not available. In the relative of JUV�\37, an early gastric cancer of the diffuse�Cinfiltrating type surrounded by hyperplastic tissue was found at 42 years of age.

This woman died from an adenocarcinoma of the small bowel. Index patient JUV�\55 had an adenocarcinoma, and his brother had a well�\differentiated adenocarcinoma diagnosed within a juvenile polyp. To exclude a germline E�\cadherin mutation as underlying cause of gastric cancer, mutation analysis of the CDH1 gene was performed in the affected brother of index patient JUV�\4. No mutation was identified. DNA was not available from the other six patients. Hereditary haemorrhagic telangiectasia In addition to gastrointestinal polyposis, 5 of the 39 index patients with identified germline mutations (JUV 14, 44, 51, 58, 78) had a clinical diagnosis of hereditary haemorrhagic telangiectasia (HHT, Osler�CWeber�CRendu disease).

All five patients belong to the 23 index patients harbouring a SMAD4 mutation, thus the frequency of HHT among SMAD4 mutation carriers is 22% (5/23) in our sample. Large deletions versus point mutations No significant difference with respect in age at diagnosis between carriers of point mutations and large deletions of each gene (SMAD4: p=0.80; BMPR1A: p=0.12) was found; however, the statistical analysis in BMPR1A mutation carriers was limited because of the small number of patients with BMPR1A deletions (n=3). In addition, the difference in presence of gastric polyposis (p=0.3) and HHT (p=1.0) between carriers of SMAD4 deletions and point mutations was not significant. Polyp histology and differential diagnoses The documented histological results of removed colorectal polyps varied considerably among patients as well as between different examinations in the same patient (table 22).). Adenomatous components Cilengitide including dysplasia (intraepithelial neoplasia according to the revised World Health Organization classification) were described in many juvenile polyps.