However, not all cases of JPS and HMPS have mutations in SMAD4 and focus has now shifted to other components of the TGF-beta pathway to clarify the genetic mechanisms involved in these conditions.
We examined 29 patients with the clinical diagnosis of JPS for germline mutations in the MADH4 or BMPR1A genes and identified MADH4 mutations in seven (24%) and BMPR1A mutations in five patients (17%).
The Smad4 gene is genetically responsible for familial juvenile polyposis, an autosomal dominant disease characterized by predisposition to gastrointestinal polyps and cancer.
Our findings support that SMAD4 mutations carriers have symptoms of both HHT and JPS and that the frequency of PAVM and gastric involvement with polyps is higher than in patients with HHT or JPS not caused by a SMAD4 mutation.
Juvenile polyposis syndrome (JPS) is a rare autosomal dominant disorder predisposing to gastrointestinal hamartomatous polyps and cancer with a pathogenic SMAD4 or BMPR1A germline mutation (1st-hit) being identified in about 40-50% of patients.
Genetic analysis of the CDC73 gene [for Hyperparathyroidism-jaw tumor (HPT-JT)], MEN1 for Multiple Endocrine Neoplasia Type1, CDKN1B for MEN4, SDHB and SDHD for Paraganglioma/Pheochromocytoma susceptibility, VHL for von Hippel-Lindau Syndrome, BMPR1A and SMAD4 for Juvenile Polyposis Syndrome (JPS) (sequencing and MLPA), karyotype and array CGH (44 K) were all normal.
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.
Pathogenic germline mutations in both the SMAD4 and BMPR1A genes involved in the transforming growth factor beta pathway account for 40% of cases of JPS.
A subset of patients with a mutation in the MADH4 gene on chromosome 18 exhibits an overlapping syndrome of HHT and juvenile polyposis (JPS).We present one such family.
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.
Patients with juvenile polyposis syndrome and germline SMAD4 or BMPR1A mutations were identified from a prospectively maintained institutional registry.
A juvenile polyposis-hereditary hemorrhagic telangiectasia overlap syndrome has previously been reported in 22% of patients with juvenile polyposis due to a SMAD4 mutation.
Although SMAD4 is among several genes in the TGFβ network, and although prior single case reports have described large vessel aneurysms in HHT, this is the first description of aortic and mitral disease presenting with JPS.
It has been suggested that the dpc4 (deleted in pancreatic carcinoma, locus 4) gene, which is located on chromosome 18q21.1, might cause juvenile polyposis.
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.