Juvenile Polyposis (JP) and Hereditary Hemorrhagic Telangiectasia (HHT) are two uncommon autosomal dominant disorders characterized by distinct and essentially non-overlapping clinical features. JP, an inherited gastrointestinal malignancy predisposition, is caused by mutations in either SMAD4 or BMPR1A. HHT is a vascular malformation disorder caused by mutations in either Endoglin or ALK1. All four of these genes encode proteins involved in the TGF- β signaling pathway. We recently reported 7 families segregating both JP and HHT phenotypes where all of the affected members have mutations in the COOH-terminus of SMAD4 and none had mutations in either Endoglin or ALK1. This established SMAD4 as the molecular link between these hitherto separate diseases. To further elucidate the clinical and genetic parameters of this syndrome, we collected DNA samples from additional individuals and families exhibiting the combined JP-HHT syndromic phenotype and from patients with only some of the features of each disease. The coding exons of SMAD4, BMPR1A, Endoglin, and ALK1 were sequenced in affected patients. Five more instances of mutations in SMAD4 were found, all in patients exhibiting the full range of JP-HHT symptoms. None of these patients had mutations in any of the other three genes examined. This mirrors the results of our first set of patients both in range of symptoms and types and locations of SMAD4 mutations. Only one family displays the full complement of symptoms found in other JP-HHT families but shows no mutation. It is possible that this family has a SMAD4 mutation, such as is a large deletion which would not be observed by sequencing, or a change within a regulatory region which was not analyzed. In the families and individuals not showing the typical symptoms of JP-HHT, no mutations were found in SMAD4,BMPR1A, Endoglin, or ALK1. At least three of these five new JP-HHT cases are de novo mutations in SMAD4 bringing the total of documented de novo cases of this syndrome to 6 out of our total of 12 instances. This high incidence of de novo cases could have important implications for both genetic screening and counseling of the patients and their families. All of the mutations found to date in this combined syndrome are in the COOH-terminus of the SMAD4 protein. It will be necessary to ascertain JP patients with mutations in other regions of SMAD4 for HHT symptoms to confirm this emerging genotype:phenotype correlation. To begin to establish clinical benchmarks for diagnosis of this syndrome, we have summarized the major symptoms of both diseases found in our SMAD4 mutation positive JP-HHT syndrome patients. We will continue to collect and analyze patients with symptoms of JP and HHT to better delineate the clinical presentation of JP-HHT syndrome.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]