Clinical characteristics: Peutz-Jeghers syndrome (PJS) is characterized by the association of gastrointestinal (GI) polyposis, 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, bronchus, gall bladder, nasal passages, urinary bladder, and ureters. GI polyps can result in chronic bleeding, anemia, and 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 mucosa. Hyperpigmented macules on the fingers 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, breast, and ovarian cancers). Females are at risk for sex cord tumors with annular tubules (SCTAT), a benign neoplasm of the ovaries, and adenoma malignum of the cervix, a rare aggressive cancer. Males occasionally develop large calcifying Sertoli cell tumors of the testes, which secrete estrogen and can lead to gynecomastia, advanced skeletal age, and ultimately short stature, if untreated.
Diagnosis/testing: 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.
Management: 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), CT enterography, and/or magnetic resonance enterography (MRE). Balloon-assisted enteroscopy allows for removal of deep small-bowel polyps. Occasionally intraoperative enteroscopy and enterotomy is needed for removal of large distal small-bowel polyps. Intussusception and malignancies should be treated in the standard manner.
Prevention of primary manifestations: Although not specifically studied in individuals with PJS, prophylactic mastectomy to decrease the risk of breast cancer could be considered based on family history or other clinical factors. Similarly, there is no prospective data on gynecologic prophylactic surgery for the elevated gynecologic cancer risk in females with PJS.
Surveillance: In children and adolescents: colonoscopy and upper endoscopy at age eight years; if negative, follow up at age 18 years. If polyps are detected repeat every one to three years based on size, number, and histopathology of polyps. Small-bowel surveillance by MRE or VCE every one to three years beginning at age eight years. Examination for precocious puberty in females annually beginning at age eight years. Testicular examination and examination for feminizing changes in males annually beginning at age ten years.
In adults: Colonoscopy, upper endoscopy, and small-bowel examination by MRE or VCE every two to three years beginning at age 18 years; clinical breast examination in women every six months beginning at age 30 years; mammogram and breast MRI in women annually beginning at age 30 years; pelvic examination and pap smear in women annually beginning at age 18 to 20 years. Pancreatic imaging with endoscopic ultrasound or MRI/MRCP annually beginning at age 30 to 35 years.
Evaluation of relatives at risk: If the pathogenic variant in the family is known, offer molecular genetic testing to at-risk relatives so that morbidity and mortality can be reduced by early diagnosis and prevention of disease through appropriate surveillance and consideration of prophylactic measures in affected family members. If the family variant is not known, offer clinical diagnostic evaluations to all at-risk family members, who will benefit from early treatment and appropriate surveillance.
Genetic counseling: PJS is inherited in an autosomal dominant manner. The majority of individuals diagnosed with PJS have an affected parent; however, many individuals with PJS represent apparently simplex cases. The exact proportion of individuals who have PJS as the result of a de novo pathogenic variant is unknown. If a parent of the proband is affected and/or is known to have the STK11 pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Once the STK11 pathogenic variant has been identified in an affected family member, predictive testing for at-risk family members, prenatal testing, and preimplantation genetic testing are possible.
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