PJS is caused by pathogenic variants in STK11, which encodes a serine/threonine kinase that phosphorylates and activates AMP-activated protein kinase and related kinases involved in cellular energy sensing and polarity. Loss of STK11 function disrupts downstream signaling that normally suppresses tumor development. The inheritance pattern is autosomal dominant; affected individuals have a 50% probability of transmitting the condition to each offspring. Variable expressivity is a recognized characteristic of PJS. Genotype-phenotype correlations remain incompletely resolved; STK11 variants predicted to cause premature truncation are thought to associate with more severe disease, but published data are conflicting.

PJS is suspected in individuals presenting with two or more PJS-type hamartomatous polyps of the GI tract, characteristic mucocutaneous pigmentation (hyperpigmented macules in the periorbital, perioral, and digital regions), or gynecomastia in males from estrogen-producing Sertoli cell tumors. Diagnosis is confirmed by molecular genetic testing identifying a pathogenic variant in STK11. Evaluations following diagnosis include colonoscopy, upper endoscopy, and small-bowel examination by MR enterography or video capsule endoscopy, beginning at age 8 years or earlier if symptomatic. Female patients undergo clinical breast examination beginning at age 18 and breast MRI and mammography beginning at age 30. Gynecologic surveillance is also initiated. The diagnostic evaluation is guided by the multiorgan cancer risk profile associated with PJS.

No approved pharmacologic treatments are listed in the packet for PJS. Management is surveillance-based and procedural. Endoscopic polypectomy is performed to reduce the risk of obstruction, intussusception, bleeding, and malignant transformation. Regular endoscopic surveillance of the upper and lower GI tract and small bowel is the primary management strategy. Breast and gynecologic surveillance follows structured protocols based on the elevated cancer risks associated with PJS. One orphan drug designation has been granted in this space — BMEDA-chelated Rhenium-186 nanoliposomes — which remains investigational. The GeneReviews therapies-under-investigation section did not identify specific active agents for PJS beyond a general reference to clinical trial resources.

PJS is associated with a substantially elevated lifetime cancer risk across multiple organ systems, with cumulative risk by age 70 being significant. The frequency and severity of GI complications, including recurrent intussusception requiring surgery, influence long-term outcomes. Early and systematic surveillance for GI polyps and cancer, as well as for extraintestinal malignancies, is central to optimizing outcomes. Variable expressivity means that disease burden varies considerably among individuals; some family members may have a relatively mild phenotypic expression with fewer polyps or limited pigmentation. The elevated cancer risk, if unmonitored, represents the principal threat to longevity in PJS.

Five active or recruiting clinical trials are associated with PJS. Research continues to characterize STK11 genotype-phenotype correlations, with studies examining whether specific variant classes (e.g., truncating versus missense) reliably predict phenotypic severity. Given the rarity of PJS, large-scale prospective natural history data are limited, and registry studies are important to the evidence base. The molecular mechanisms of STK11-driven polyposis and cancer susceptibility continue to be investigated in preclinical models as potential therapeutic targets. No approved therapeutics are currently available, making surveillance the primary evidence-based strategy.