Aetiology

PJS is caused by germline mutations in one allele of the STK11 gene on chromosome 19p13.3, which encodes the serine-threonine kinase LKB1.[2][3] The majority of cases are familial with autosomal dominant inheritance, but approximately 25% of newly diagnosed PJS patients have de novo mutations.[4] Germline alterations in the STK11 gene are found in up to 94% of people with the disorder.[5] STK11 is composed of 10 exons, 9 of which are coding. Small and large deletions, insertions, splice site, and missense mutations have all been reported. Subsequent somatic loss or inactivation of the second allele leads to loss of LKB1 tumour suppression function, resulting in the clinical manifestations of PJS.[2][6]

Pathophysiology

The STK11 gene encodes for a serine-threonine kinase, LKB1, that activates, by phosphorylation, many downstream AMP-activated protein kinases (AMPK). The functional consequences of a mutated gene are abnormalities of cell cycle regulation and metabolism, and aberrant transforming growth factor-beta (TGF-beta) signalling. This allows epithelial compartment expansion and loss of cell polarity.[7] COX-2, which is up-regulated early in colorectal carcinogenesis, generates prostaglandins, which promote cell proliferation, inhibit apoptosis, and enhance angiogenesis. COX-2 over-expression has been confirmed in both hamartomatous polyps and carcinomas from patients with PJS.[8][9] The clinical consequences of these molecular changes are a promotion of tumourigenesis in PJS.

Correlations between the presence or type of mutation and risk of disease have been performed. There is no clear genotype-phenotype correlation in PJS.[10][11] In a series of 51 patients, individuals with missense mutations were more likely to have a later age of onset of symptoms and later time to onset of first polypectomy when compared with those with truncating mutations or no identifiable mutation.[12] In another series of 419 individuals (297 with mutations), neither the type nor site of STK11 mutation influenced cancer risk.[11] Cumulative cancer risks were similar in patients with STK11 mutations and those with no detectable mutation.

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