In addition, mutations in mothers against decapentaplegic homolog 4 (SMAD4) are also seen in patients with the combined syndrome of juvenile polyposis and HHT.
We observed that juvenile polyps have a heterogeneous expression of CDX2, MUC2 and SMAD4, with negative areas, and 15 of the 18 solitary polyps and the JP case with SMAD4 mutation exhibit de novo expression of MUC5AC but not MUC6.
The mouse homologue of CDX2 has been shown to give rise to a phenotype which includes hamartomatous-like polyps in the colon and is therefore a good candidate for JPS and PJS cases which are not accounted for by the SMAD4 and LKB1 genes.
Juvenile polyposis syndrome (JPS) is a hereditary condition characterized by development of gastrointestinal polyps, and caused by mutations in SMAD4 or BMPR1A genes.
The identification of SMAD4 mutations in HHT patients without prior diagnosis of JP has significant and immediate clinical implications, as these people are likely to be at risk of having JP-HHT with the associated increased risk of gastrointestinal cancer.
In the proband, the analysis showed the presence of a truncating mutation in the SMAD4 gene (c.1213dupC, a variant previously associated with juvenile polyposis and Hereditary Hemorrhagic Teleangectasia).
Additionally, due to the lack of large pedigrees suitable for linkage analysis, and since SMAD4 germline mutations have been reported in families with combined HHT and juvenile polyposis, we screened this gene and five other genes involved in the TGF-beta/BMP pathway in the patients without mutation of ENG or ACVRL1.
Patients with gastric juvenile polyposis and SMAD4 mutations are at a high risk of developing gastric cancer; hence, early gastrectomy should be considered.
Loss-of-function pathogenic variants in SMAD4 cause juvenile polyposis syndrome and we hypothesize that the gain-of-function pathogenic variants observed in Myhre syndrome may contribute to neoplasia in the patients reported herein.
In addition to this syndrome, gastric cancer risk is elevated in Lynch syndrome associated with germline mutations in DNA mismatch repair genes and microsatellite instability, in hereditary breast and ovarian cancer syndrome due to germline BRCA1 and BRCA2 mutations, in familial adenomatous polyposis caused by germline APC mutations, in Li-Fraumeni syndrome due to germline p53 mutations, in Peutz-Jeghers syndrome associated with germline STK11 mutations, and in juvenile polyposis syndrome associated with germline mutations in the SMAD4 and BMPR1A genes.
In children with SMAD4 mutation and juvenile polyposis, this overlap syndrome needs to be considered in the differential diagnosis and prompt the clinician to look for telangiectasias on examination and consider surveillance imaging to look for arteriovenous malformations.
Juvenile polyposis syndrome (JPS) may coexist with hereditary hemorrhagic telangiectasia (HHT) due to implication of the SMAD4 gene in a subset of both diseases.
Because no common ancestor was suggested by haplotype analysis and the sequence flanking the deletion contains repeats frequently associated with microdeletions, this common SMAD4 deletion in JP most likely represents a mutational hotspot.