Due to the chromosome 10 deletion involving contiguous portions of BMPR1A and PTEN in our patient, he may be at risk for CS associated cancers and features, in addition to the polyps associated with JPS.
Alternatively, because simultaneous disruption of both the PTEN and TGF-β/SMAD4 pathways is associated with development of esophageal cancer in a mouse model and because SMAD4 mutations cause gastrointestinal hamartomas in juvenile polyposis syndrome, the SMAD7 mutation may represent an additional modifier of these individuals' PTEN-mutant phenotype.
The current clinical findings and deletion of BMPR1A indicate a diagnosis of severe juvenile polyposis, but the existing macrocephaly and PTEN deletion also point to either CS or BRRS, which cannot be ruled out at the moment because of their clinical manifestation later in life and the de novo character of the deletion.
Contiguous gene deletion within chromosome arm 10q is associated with juvenile polyposis of infancy, reflecting cooperation between the BMPR1A and PTEN tumor-suppressor genes.
The entire coding region of PTEN was screened by single strand conformational polymorphism or direct sequencing for somatic mutations in 16 gingival papillomas, 4 juvenile polyps, 10 esophageal papillomas, and 20 colorectal cancers and for germline mutations in three patients with Cowden disease (including one with Lhermitte-Duclos disease) and one patient each with juvenile polyposis syndrome, Turcot's syndrome, and Cronkhite-Canada syndrome.
Thus, mutations in PTEN are associated with JPS in addition to CD and some BRRS families, although the incidence of PTEN germ-line mutations in JPS might be more rare than that reported for SMAD4, a gene found to be mutated in approximately one-half of the JPS families investigated.