SMAD4 mutation segregating in a family with juvenile polyposis, aortopathy, and mitral valve dysfunction.

Juvenile polyposis syndrome (JPS) is caused by heterozygous mutations in either SMAD4 or BMPR1A. Individuals with JPS due to mutations in SMAD4 are at greater risk to manifest signs of hereditary hemorrhagic telangiectasia (HHT). HHT is caused by either mutations in SMAD4 or other genes that modulate transforming growth factor-beta (TGFβ) signaling. Additional genes in the TGFβ network include FBN1, TGFBR1, and TGFBR2, mutations of which cause either Marfan syndrome (MFS) or Loeys-Dietz syndrome (LDS), respectively. As SMAD4, FBN1, and TGFBR1/2 map to different regions of the genome, disorders associated with mutations in these genes are not expected to co-segregate in a family. We report an individual whose family history was positive for aortopathy, mitral valve dysfunction, and JPS. Mutation analysis of SMAD4 implicates this gene for these phenotypes in this family. 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. This observation suggests that, in addition to HHT, individuals with SMAD4 mutations may be at risk for aortic dilation and mitral valve dysfunction. We emphasize the importance of comprehensive review of the medical history prior to molecular testing, especially in an asymptomatic patient.