<h4>Clinical characteristics</h4>Peutz-Jeghers syndrome (PJS) is characterized by the association of gastrointestinal (GI) polyposis including distinctive arborized smooth muscle polyps, mucocutaneous pigmentation, and cancer predisposition. PJS-type hamartomatous polyps are most common in the small intestine (in order of prevalence: jejunum, ileum, and duodenum), but can also occur in the stomach, large bowel, and extraintestinal sites including the renal pelvis, bronchi, gall bladder, nasal passages, bladder, and ureters. GI polyps can result in chronic bleeding, anemia, recurrent obstruction, and intussusception requiring repeated laparotomy and bowel resection. Mucocutaneous hyperpigmentation presents in childhood as dark blue to dark brown macules around the mouth, eyes, and nostrils, in the perianal area, and on the buccal intestinal mucosa. Hyperpigmented macules on the fingers and toes are common. The macules may fade in puberty and adulthood. Recognition of the distinctive skin manifestations is important, especially in individuals who have PJS as the result of a de novo pathogenic variant, as these skin findings often predate GI signs and symptoms. Individuals with PJS are at increased risk for a wide variety of epithelial malignancies (colorectal, gastric, pancreatic). Females are at risk for breast cancer, sex cord tumors with annular tubules (SCTATs), a benign neoplasm of the ovaries, and a gastric-type adenocarcinoma (adenoma malignum) of the cervix, a rare aggressive cancer. Males occasionally develop large-cell calcifying Sertoli cell tumors of the testes, which secrete estrogen and can lead to gynecomastia, advanced skeletal age, and, ultimately, short stature if untreated.<h4>Diagnosis/testing</h4>The diagnosis of PJS is based on clinical findings. Identification of a heterozygous pathogenic variant in STK11 by molecular genetic testing confirms the diagnosis and allows for testing of at-risk relatives and prenatal/preimplantation genetic testing.<h4>Management</h4>Treatment of manifestations: Routine endoscopic surveillance with polypectomy decreases the frequency of emergency laparotomy and bowel loss resulting from intussusception. Small bowel imaging includes video capsule endoscopy (VCE) and/or MRI enteroclysis. Magnetic resonance enterography (MRE) may be used if MRI is not tolerated, but MRE is less sensitive than MRI for polyps smaller than 1 cm. Balloon-assisted enteroscopy allows for removal of distal small bowel polyps. Occasionally intraoperative enteroscopy and enterotomy is needed for removal of large distal small bowel polyps. It is advised to remove polyps >15-20 mm or smaller if causing symptoms. Intussusception and malignancies should be treated in the standard manner. Surveillance: Surveillance in people with PJS is preferably done in a center of expertise. Children and adolescents – colonoscopy and upper endoscopy at age eight years; if normal, resume GI surveillance at age 18 years and continue every one to three years. If polyps are detected at initial examination, repeat every one to three years based on size, number, and histopathology of polyps. Small bowel surveillance by VCE or MRI enteroclysis (or MRE if not tolerated) every one to three years based on findings beginning at age eight years. Examination for precocious puberty in females annually beginning at diagnosis or at least by age eight years. Testicular examination and examination for feminizing changes in males annually beginning at diagnosis or at least by age eight years through adulthood. Adults – colonoscopy, upper endoscopy, and small bowel examination by VCE or MRI enteroclysis (or MRE if not tolerated) every one to three years. Clinical breast examination in women every six to 12 months beginning at age 25 years; breast MRI with contrast in women annually from age 25 to 50 years (or if breast MRI with contrast is contraindicated or unavailable, breast ultrasound from age 25 to 30 years and mammography from age 30 to 50 years); consider tomosynthesis and ultrasound for those with dense breast tissue annually from age 30 to 50 years; mammography with consideration of annual breast contrast MRI for dense breasts every one to two years from age 50 to 75 years. Pelvic examination with pap smear and cytology (including those with negative HPV testing) in women annually beginning at age 25 years. Pancreatic imaging with endoscopic ultrasound or MRI is suggested annually beginning at age 40 years in a framework of a study or registry. For lung cancer, provide education regarding signs/symptoms of lung cancer and importance of smoking cessation. Testicular examination and examination for feminizing changes in males annually; testicular ultrasound for those with abnormal findings on examination. Agents/circumstances to avoid: Due to the increased risk for cervical, lung, and pancreatic cancer, smoking should be avoided. Evaluation of relatives at risk: Evaluate apparently asymptomatic older and younger at-risk relatives (including parents, sibs, and children) of an affected individual in order to identify as early as possible those who would benefit from initiation of surveillance, treatment, and preventative measures. If the pathogenic variant in the family is known, offer molecular genetic testing to at-risk relatives. If the pathogenic variant in the family is not known, offer clinical diagnostic evaluations.<h4>Genetic counseling</h4>PJS is inherited in an autosomal dominant manner. Most individuals diagnosed with PJS have an affected parent; some individuals represent apparently simplex cases and may have the disorder as the result of a de novo pathogenic variant. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. To date, all reported individuals with pathogenic variants in STK11 have shown clinical manifestations; however, variable expressivity is common among affected family members. If the STK11 pathogenic variant has been identified in an affected family member, predictive testing for at-risk family members and prenatal/preimplantation genetic testing are possible.