Mutations in SMAD4 have been associated with juvenile polyposis syndrome and combined juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome.SMAD4 is part of the SMAD gene family.
The vascular disorder Hereditary Hemorrhagic Telangiectasia (HHT) is in general an inherited disease caused by mutations in the TGF-β/BMP receptors endoglin or ALK1 or in rare cases by mutations of the TGF-β signal transducer protein Smad4 leading to the combined syndrome of juvenile polyposis and HHT.
The DPC4/SMAD4 gene, lying in close proximity to the DCC gene at 18q21.1, was recently identified as a candidate tumor suppressor for the genesis of pancreatic cancer as well as a predisposing gene for Juvenile Polyposis Syndrome (JPS).
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.
SMAD4 carriers should be managed for juvenile polyposis and hereditary hemorrhagic telangiectasia because symptoms of both conditions are likely yet unpredictable.
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).
Through this case report we aim to discuss the pathophysiology of juvenile polyposis syndrome (JPS), highlight what we believe to be a novel presentation of comorbid BMPR1A mutation and ASD and hypothesise that patients with BMPR1A mutation and JPS may be at risk of previously unrecognised cardiovascular complications analogous to the previous association of SMAD4JPS and cardiac abnormalities.
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.
If no causative ENG or ACVRL1 mutation is found, proband samples are referred for sequence analysis of MADH4 (associated with a combined syndrome of juvenile polyposis and HHT).
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.