Genetic heterogeneity in familial juvenile polyposis

Juvenile polyposis syndrome (JPS) is an autosomal dominant syndrome characterized by multiple gastrointestinal hamartomatous polyps in the absence of the extraintestinal features that are classic for other hamartomatous polyposis syndromes, such as Bannayan-Riley-Ruvalcaba syndrome (BRRS) and Cowden disease (CD). About 50% of BRRS and >80% of CD demonstrate germ-line mutations in the tumor suppressor and dual phosphatase, PTEN. Germ-line mutation of PTEN as a cause for JPS in a child is controversial because extraintestinal manifestations that would exclude JPS could appear after adolescence, altering the clinical diagnosis. Here, we investigated a family in which the 55-year-old father, who lacks thyroid or skin findings characteristic of CD, demonstrated a germ-line mutation in PTEN that was passed to identical twin daughters, who both manifested JPS. The mutation was a deletion of five bases beginning seven bases from the start of exon 4 of PTEN, which caused aberrant transcripts by reverse transcription-PCR that were absent from a normal individual. Thus, mutations in PTEN are associated with JPS in addition to CD and some BRRS families, although the incidence of PTEN germ-line mutations in JPS might be more rare than that reported for SMAD4, a gene found to be mutated in approximately one-half of the JPS families investigated.