Although the risk of malignancy appears to be exceedingly high in individuals with PJS based on the published literature, the possibility that selection and referral bias have resulted in over-estimates of these risks should be considered.
Table 10. Cumulative Cancer Risks in Peutz-Jeghers Syndrome Up To Specified Agea
GI = Gastrointestinal.
a Reprinted with permission from Macmillan Publishers Ltd: Gastroenterology, copyright 2010.
b All cumulative risks were increased compared to the general population (P < .05) with the exception of cervix and testes.
c GI cancers include colorectal, small intestinal, gastric, esophageal, and pancreatic.
d Westerman et al.: GI cancer does not include pancreatic cancer.
e Did not include adenoma malignum of the cervix or Sertoli cell tumors of the testes.
|Site||Age (y)||Cumulative Riskb||Reference(s)|
Juvenile polyposis syndrome (JPS)
JPS is a genetically heterogeneous, rare, childhood-onset, autosomal dominant disease that presents characteristically as hamartomatous polyposis throughout the GI tract and can present with diarrhea, GI tract hemorrhage, and protein-losing enteropathy.[363,364] While most patients with juvenile polyposis appear to represent sporadic illness, this may be due to reduced penetrance. Juvenile polyposis syndrome is due to germline mutations in the MADH4 gene, also known as SMAD4/DPC4, at chromosome 18q21  in approximately 15% to 20% of cases, and to mutations in the gene-encoding bone morphogenic protein receptor 1A (BMPR1A) residing on chromosome band 10q22 in approximately 25% to 40% of cases.[366,367] The lifetime CRC risk in JPS has been reported to be 39%.
Hereditary mixed polyposis syndrome (HMPS)
HMPS is a rare cancer family syndrome characterized by the development of a variety of colon polyp types, including serrated adenomas; atypical juvenile polyps; and adenomas, and colon adenocarcinoma. Although initially mapped to a locus between 6q16-q21, the HMPS locus is now believed to map to 15q13-q14.[369,370] While there is considerable phenotypic overlap between JPS and HMPS, one large family has been linked to a locus on chromosome 15, raising the possibility that this may be a distinct disorder.
Evidence demonstrates that a subset of families with hereditary breast and colon cancer may have a cancer family syndrome caused by a mutation in the CHEK2 gene.[371,372,373] Although the penetrance of CHEK2 mutations is clearly less than 100%, additional studies are needed to determine the risk of breast, colon, and other cancers associated with CHEK2 germline mutations. One large study showed that truncating mutations in CHEK2 were not significantly associated with CRC; however, a specific missense mutation (I157T) was associated with modest increased risk (odds ratio [OR] = 1.5; 95% CI, 1.2-3.0) of CRC.