01). In the entire sample, the frequency was 73% among SMAD4 Imatinib Mesylate clinical trial mutation carriers. The occurrence of gastric cancer in this group of families alone reflects the same trend. The lifetime incidence of gastric polyposis in SMAD4 mutation carriers is probably higher, as the latest gastroscopy in mutation carriers without gastric polyps was performed at a significantly lower age than in mutation carriers with gastric polyps. An underestimation of gastric polyposis in BMPR1A mutation carriers cannot be completely excluded, as age at gastroscopy did not differ significantly between the BMPR1A and SMAD4 mutation carriers without gastric polyps. However, it was clear that no SMAD4 mutation carrier without gastric polyps was older than 33 years, whereas all BMPR1A mutation carriers who underwent gastroscopy at advanced age (42, 48, 52 and 73 years) had no gastric polyps.

The only BMPR1A mutation carrier with positive gastroscopic finding had only two juvenile polyps at 31 years of age. Moreover, there was no family history of gastric polyposis or gastric cancer in any of the BMPR1A mutation carriers. Although HHT, an autosomal dominant disorder of vascular dysplasia, is usually caused by germline mutations in the ENG or ACVRL1 (ALK1) genes,21 there are several case reports of patients with combined symptoms of HHT and JPS.19,22,23,24,25 Recently, mutations in ENG were described in two patients with juvenile polyposis.10 Gallione et al identified SMAD4 mutations in all 14 examined patients from 7 unrelated families with the combined phenotype (JPHT; OMIM 175050).

26 Our findings confirm this result and suggest that the phenotypic overlap of JPS and HHT is more common than previously thought (around a quarter of our index patients with JPS and SMAD4 mutations). Accordingly, JPS patients with SMAD4 mutations should be screened for typical HHT features, particularly vascular lesions, to avoid serious complications such as aortic aneurysm and pulmonary thrombosis. Similarly, patients diagnosed with HHT should be screened for gastrointestinal polyposis to ensure appropriate management. Histopathological results and differential diagnosis The diagnosis of JPS is based mainly on the presence of juvenile polyps in the gastrointestinal tract. Thus, histopathological evaluation is essential for correct classification and analysis of the appropriate genes.

However, the histological findings documented in the medical records of the 80 index patients and their affected relatives encompassed a wide distribution of different polyp types in both SMAD4 and BMPR1A mutation carriers (��mixed polyposis��). Thus, polyp heterogeneity comparable with that described in patients with hereditary mixed polyposis syndromes (HMPS) seems to Cilengitide be a common feature in patients with JPS and reflects both the real occurrence of different polyp types and an uncertainty in histological assessment.