Thoracic aortic disease in two patients with juvenile polyposis syndrome and SMAD4 mutations

Abstract

Dilation or aneurysm of the ascending aorta can progress to acute aortic dissection (Thoracic Aortic Aneurysms and Aortic Dissections, TAAD). Mutations in genes encoding TGF-β related proteins (TGFBR1, TGFBR2, FBN1, and SMAD3) cause syndromic and inherited TAAD. SMAD4 mutations are associated with juvenile polyposis (JPS) and a combined JPS-hereditary hemorrhagic telangiectasia (HHT) known as JPS-HHT. A family with JPS-HHT was reported to have aortic root dilation and mitral valve abnormalities. We report on two patients with JPS-HHT with SMAD4 mutations associated with thoracic aortic disease. The first patient, an 11-year-old boy without Marfan syndrome features, had JPS and an apparently de novo SMAD4 mutation (c.1340_1367dup28). Echocardiography showed mild dilation of the aortic annulus and aortic root, and mild dilation of the sinotubular junction and ascending aorta. Computed tomography confirmed aortic dilation and showed small pulmonary arteriovenous malformations (PAVM). The second patient, a 34-year-old woman with colonic polyposis, HHT, and Marfan syndrome, had a SMAD4 mutation (c.1245_1248delCAGA). Echocardiography showed mild aortic root dilation. She also had PAVM and hepatic focal nodular hyperplasia. Her family history was significant for polyposis, HHT, thoracic aortic aneurysm, and dissection and skeletal features of Marfan syndrome in her father. These two cases confirm the association of thoracic aortic disease with JPS-HHT resulting from SMAD4 mutations. We propose that the thoracic aorta should be screened in patients with SMAD4 mutations to prevent untimely death from dissection. This report also confirms that SMAD4 mutations predispose to TAAD.

Appreciating the broad clinical features of SMAD4 mutation carriers: a multicenter chart review

“…23,24, 31 These include mitral valve prolapse, aortic root dilatation, thoracic aortic dissections, and some skeletal features suggestive of Marfan syndrome. There have also been rare reports of individuals with HHT and large aortic aneurysms 40,41 and a genetic mutation (in ACVRL1 ) was reported for only one of them.…”

“…23,24 Additionally, two individuals with SMAD4 mutations from a series of JP patients had arterial aneurysms, and three individuals (genotype not provided) had mitral valve prolapse. 31 These findings have not been classically associated with the JP or HHT entities.…”

Role of Mechanotransduction in Vascular Biology

“…Aortic tissue from patients undergoing surgical repair of familial TAADs also exhibit increased TGF-β signaling based on immunostaining of phosphorylated SMAD2. It is thus surprising that loss of function mutations in genes encoding proteins critical for TGF-β signaling also predispose to TAADs, including those involving genes that encode type 1 and 2 transforming growth factor receptors ( TGFBR1 and TGFBR2 ), one of the three isoforms of TGF-β ( TGFB2 ), and related signaling molecules, SMAD3 ( SMAD3 ) and SMAD4 ( SMAD4 ) 140,141,144,145,163 . Thus, the paradox of mutations decreasing TGF-β signaling despite evidence of increased TGF-β in end stage aortic tissues raises questions as to the precise role(s) played by TGF-β signaling in thoracic aortic disease.…”

Genetics of Thoracic Aortic Aneurysm

“…Mainly, patients with mutations in SMAD4, associated with juvenile polyposis syndrome (OMIM 174900) and a combined juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia (OMIM 175050), were described to have TAA. 110 Fourth, mutations in other genes encoding collagens or enzymes involved in collagen maturation (COL1A1/A2,…”