BACKGROUND: In patients with juvenile polyposis syndrome (JPS) the frequency of 
large genomic deletions in the SMAD4 and BMPR1A genes was unknown.
METHODS: Mutation and phenotype analysis was used in 80 unrelated patients of 
whom 65 met the clinical criteria for JPS (typical JPS) and 15 were suspected to 
have JPS.
RESULTS: By direct sequencing of the two genes, point mutations were identified 
in 30 patients (46% of typical JPS). Using MLPA, large genomic deletions were 
found in 14% of all patients with typical JPS (six deletions in SMAD4 and three 
deletions in BMPR1A). Mutation analysis of the PTEN gene in the remaining 41 
mutation negative cases uncovered a point mutation in two patients (5%). SMAD4 
mutation carriers had a significantly higher frequency of gastric polyposis 
(73%) than did patients with BMPR1A mutations (8%) (p<0.001); all seven cases of 
gastric cancer occurred in families with SMAD4 mutations. SMAD4 mutation 
carriers with gastric polyps were significantly older at gastroscopy than those 
without (p<0.001). In 22% of the 23 unrelated SMAD4 mutation carriers, 
hereditary hemorrhagic telangiectasia (HHT) was also diagnosed clinically. The 
documented histologic findings encompassed a wide distribution of different 
polyp types, comparable with that described in hereditary mixed polyposis 
syndromes (HMPS).
CONCLUSIONS: Screening for large deletions raised the mutation detection rate to 
60% in the 65 patients with typical JPS. A strong genotype-phenotype correlation 
for gastric polyposis, gastric cancer, and HHT was identified, which should have 
implications for counselling and surveillance. Histopathological results in 
hamartomatous polyposis syndromes must be critically interpreted.