One gene (STK11) has been unequivocally demonstrated to cause PJS. Although earlier estimates using direct DNA sequencing showed a 50% mutation detection rate in STK11, studies adding techniques to detect large deletions have found mutations in up to 94% of individuals meeting clinical criteria for PJS.[40,41,42] Given the results of these studies, it is unlikely that other major genes cause PJS.
(Refer to the Peutz-Jeghers syndrome (PJS) section in the Rare Colon Cancer Syndromes section of this summary for more information.)
Juvenile Polyposis Gene(s)
Juvenile polyposis is defined by the presence of a specific type of hamartomatous polyp called a juvenile polyp, usually in the setting of a family history. The diagnosis of a juvenile polyp is based on its histologic appearance rather than age of onset, and the familial form is caused by mutations in the BMPR1A gene in 20% of cases and by mutations in the SMAD4 gene in another 20%.[43,44]
SMAD4 encodes a protein that is a mediator of the transforming growth factor (TGF)-beta signaling pathway, which mediates growth inhibitory signals from the cell surface to the nucleus. Germline mutations in SMAD4 predispose individuals to forming juvenile polyps and cancer, and germline mutations have been found in 6 of 11 exons. Most mutations are unique, but several recurrent mutations have been identified in multiple independent families.
BMPR1A is a serine-threonine kinase type I receptor of the TGF-beta superfamily that, when activated, leads to phosphorylation of SMAD4. The BMPR1A gene was first identified by linkage analysis in families with juvenile polyposis who did not have identifiable mutations in SMAD4. Mutations in BMPR1A include nonsense, frameshift, missense, and splice-site mutations. Large genomic deletions detected by MLPA have been reported in both BMPR1A and SMAD4 in patients with juvenile polyposis syndrome.[47,48] It was reported that two individuals with mutations in both PTEN and BMPR1A also had phenotypic features of juvenile polyposis syndrome (JPS) and Cowden syndrome (see below). Rare JPS families have demonstrated mutations in the ENG and PTEN genes but these have not been confirmed in other studies.[49,50]
Cowden Syndrome/Bannayan-Riley-Ruvalcaba Syndrome Gene(s)
Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome (BRRS) are part of a spectrum of conditions known collectively as PTEN hamartoma tumor syndromes. Approximately 85% of patients diagnosed with Cowden syndrome and approximately 60% of patients with BRRS have an identifiable mutation of PTEN.
PTEN functions as a dual-specificity phosphatase that removes phosphate groups from tyrosine and serine and threonine. Mutations of PTEN are diverse, including nonsense, missense, frameshift, and splice-variant mutations. Approximately 40% of mutations are found in exon 5, which represents the phosphate core motif, and several recurrent mutations have been observed. Individuals with mutations in the 5' end or within the phosphatase core of PTEN tend to have more organ systems involved.