title: 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 syndrome (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 features of 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.
authors.affiliation: MassGeneral Hospital for Children, Boston, MA, USA.
authors.forename: Polakit
authors.initials: P
authors.lastname: Teekakirikul
authors.forename: Dianna M
authors.initials: DM
authors.lastname: Milewicz
authors.forename: David T
authors.initials: DT
authors.lastname: Miller
authors.forename: Ronald V
authors.initials: RV
authors.lastname: Lacro
authors.forename: Ellen S
authors.initials: ES
authors.lastname: Regalado
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Rosales
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Ryan
authors.forename: Tomi L
authors.initials: TL
authors.lastname: Toler
authors.forename: Angela E
authors.initials: AE
authors.lastname: Lin
mesh_terms: D000328:Adult; D001011:Aorta / Q000503:physiopathology*; D017545:Aortic Aneurysm, Thoracic / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics; D002648:Child; D004452:Echocardiography; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D006801:Humans; D044483:Intestinal Polyposis / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008382:Marfan Syndrome / Q000235:genetics; D008840:Microfilament Proteins / Q000235:genetics; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics; D051901:Smad4 Protein / Q000235:genetics*; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000235:genetics; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; D051900:Smad3 Protein; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; C000605722:FBN1 protein, human; D054392:Adipokines; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; C000625841:TGFBR1 protein, human