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A genetic intestinal polyposis syndrome characterized by development of characteristic hamartomatous polyps throughout the gastrointestinal (GI) tract, and by mucocutaneous pigmentation. This disorder carries a considerably increased risk of GI and extra-GI malignancies.
ORPHA:2869Classification level: Disorder
Peutz-Jeghers syndrome (PJS) prevalence estimates range from 1/25,000 to 1/300,000 births.
Despite high variability between families, characteristic PJS polyps generally occur in childhood and early adulthood, with onset often during the first 10 years of life. Hamartomatous polyps can occur at any site in the GI (gastrointestinal tract) tract, but are most frequent in the small intestine. Other sites include the stomach, large intestine, nares, and rarely the renal pelvis, urinary bladder, and lungs. Although benign, polyps can lead to complications including bowel obstruction, rectal prolapse, and severe GI bleeding with secondary anemia, and intussusception. Adenomas and hyperplastic polyps may also occur. During infancy or childhood, patients may develop dark blue to dark brown macules around the mouth, eyes, nares, and in the perianal area and buccal mucosa. Hyperpigmentation may also be found on the fingers and toes. The lesions may fade in adolescence and adulthood but tend to persist in the buccal mucosa. They can cause psychological stress. GI and extra-GI malignancies mainly concern adult patients and include colorectal and gastric cancer (estimated lifetime risk (LTR) of 15% by 50 years of age, and 57% by 70 years), pancreatic cancer (LTR 5% by 50 years of age, and 17% by 70 years), and breast and ovarian cancer in females (LTR 8% by 40 years of age, and 32% by 60 years of age). Female patients may also develop adenoma malignum of the cervix, and typically benign bilateral multifocal sex cord tumors with annular tubules (SCTAT).
The disorder is usually caused by germline mutations in the STK11 gene (19p13.3). Mutations in this tumor suppressor gene are found in more than 80% of affected families. There are no clear genotype-phenotype correlations. One study showed that individuals with missense mutations had a significantly later time to onset of first polypectomy and of other symptoms compared with those either with truncating mutations or no detectable mutation.
Diagnosis is based on clinical findings and can be made in a patient presenting one of the following signs: two or more histologically confirmed PJ polyps, any number of PJ polyps and a family history of PJS, characteristic mucocutaneous pigmentation and a family history, or any number of PJ polyps associated with characteristic mucocutaneous pigmentation. Molecular genetic testing of the STK11 gene confirms the diagnosis and is available clinically. Aside from mutations affecting the STK11 protein, large deletions of STK11 have also been reported to cause PJS and should be considered when sequencing fails to identify a protein coding or splice variant.
Differential diagnoses include juvenile polyposis syndrome, hereditary mixed polyposis syndrome, the PTEN hamartoma tumor syndromes, and Carney complex.
Prenatal diagnosis for increased risk pregnancies is available provided that the disease-causing mutation has been identified in the family.
The syndrome is inherited in an autosomal dominant manner. The number of cases related to de novo gene mutations is not known. A recent report found that 9 of 14 sporadic cases presenting in children were caused by de novo mutations and the cause of the other 5 cases could not be determined. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
Routine treatment methods should be used for polyp resection, intussusception and malignancies. Some evidence indicates routine endoscopy and intraoperative eneteroscopy with polypectomy decreases the requirement for laparotomy and bowel loss. Newer technologies such as video capsule endoscopy, magenetic resonance enterography and balloon-assisted enteroscopy are being suggested to reduce the management burden. Although generally recommended, there is no control data on the value of surveillance strategies for cancer management in PJS patients. The aim of surveillance is to reduce polyp related complications in younger patients and for early detection of malignancies in older patients.
The prognosis depends on the severity of polyp complications and on the development of malignancies. Routine surveillance of polyp growth will lead to better management.