title: Thoracic aortic aneurysm in infancy in aneurysms-osteoarthritis syndrome due to a novel SMAD3 mutation: further delineation of the phenotype.
abstract: Recently, mutations in the SMAD3 gene were found to cause a new autosomal dominant aneurysm condition similar to Loeys-Dietz syndrome (LDS), mostly with osteoarthritis, called aneurysms-osteoarthritis syndrome (AOS). Our 3-year-old propositus underwent correction of an inguinal hernia at 3 months and substitution of the ascending aorta for pathologic dilation at 12 months of age. Family history reveals aortic dilation in his mother at 30 years, death due to aortic dissection of an 18-year-old maternal aunt, surgical replacement of the ascending aorta because of aneurysm in a maternal uncle at 19 years, postpartum death of the maternal grandmother at 24 years and surgical intervention because of thoracic aortic aneurysm in a brother of the propositus' grandmother at 54 years. The affected individuals present with several other signs of connective tissue disease, but the two adult patients evaluated revealed no radiologic evidence of osteoarthritis. Molecular testing of the TGFBR1 and TGFBR2 genes, involved in LDS, resulted negative, but analysis of SMAD3 disclosed the novel heterozygous loss-of-function mutation c.1170_1179del (p.Ser391AlafsX7) in exon 9 in all affected family members, confirming the diagnosis of AOS. SMAD3 mutations should be considered in patients of all ages with LDS-like phenotypes and negative TGFBR1/2 molecular tests, especially in the presence of aortic root or ascending aortic aneurysms, even though signs of early onset osteoarthritis are absent.
authors.affiliation: Department of Medical Genetics, Policlinico Sant'Orsola-Malpighi, University of Bologna, Bologna, Italy. anita.wischmeijer@unibo.it
authors.forename: Anita
authors.initials: A
authors.lastname: Wischmeijer
authors.forename: Lut
authors.initials: L
authors.lastname: Van Laer
authors.forename: Giada
authors.initials: G
authors.lastname: Tortora
authors.forename: Nikhita Ajit
authors.initials: NA
authors.lastname: Bolar
authors.forename: Guy
authors.initials: G
authors.lastname: Van Camp
authors.forename: Erik
authors.initials: E
authors.lastname: Fransen
authors.forename: Nils
authors.initials: N
authors.lastname: Peeters
authors.forename: Roberto
authors.initials: R
authors.lastname: di Bartolomeo
authors.forename: Davide
authors.initials: D
authors.lastname: Pacini
authors.forename: Gaetano
authors.initials: G
authors.lastname: Gargiulo
authors.forename: Simone
authors.initials: S
authors.lastname: Turci
authors.forename: Marco
authors.initials: M
authors.lastname: Bonvicini
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Mariucci
authors.forename: Luigi
authors.initials: L
authors.lastname: Lovato
authors.forename: Stefano
authors.initials: S
authors.lastname: Brusori
authors.forename: Marco
authors.initials: M
authors.lastname: Ritelli
authors.forename: Marina
authors.initials: M
authors.lastname: Colombi
authors.forename: Livia
authors.initials: L
authors.lastname: Garavelli
authors.forename: Marco
authors.initials: M
authors.lastname: Seri
authors.forename: Bart L
authors.initials: BL
authors.lastname: Loeys
mesh_terms: D000293:Adolescent; D000328:Adult; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics*; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010003:Osteoarthritis / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D051900:Smad3 Protein / Q000235:genetics*; D055815:Young Adult
chemical_list: C497790:SMAD3 protein, human; D051900:Smad3 Protein