title: Phenotypic spectrum of the SMAD3-related aneurysms-osteoarthritis syndrome.
abstract: BACKGROUND
  Aneurysms-osteoarthritis syndrome (AOS) is a new autosomal dominant syndromic form of thoracic aortic aneurysms and dissections characterised by the presence of arterial aneurysms and tortuosity, mild craniofacial, skeletal and cutaneous anomalies, and early-onset osteoarthritis. AOS is caused by mutations in the SMAD3 gene.
  
  
  METHODS
  A cohort of 393 patients with aneurysms without mutation in FBN1, TGFBR1 and TGFBR2 was screened for mutations in SMAD3. The patients originated from The Netherlands, Belgium, Switzerland and USA. The clinical phenotype in a total of 45 patients from eight different AOS families with eight different SMAD3 mutations is described. In all patients with a SMAD3 mutation, clinical records were reviewed and extensive genetic, cardiovascular and orthopaedic examinations were performed.
  
  
  RESULTS
  Five novel SMAD3 mutations (one nonsense, two missense and two frame-shift mutations) were identified in five new AOS families. A follow-up description of the three families with a SMAD3 mutation previously described by the authors was included. In the majority of patients, early-onset joint abnormalities, including osteoarthritis and osteochondritis dissecans, were the initial symptom for which medical advice was sought. Cardiovascular abnormalities were present in almost 90% of patients, and involved mainly aortic aneurysms and dissections. Aneurysms and tortuosity were found in the aorta and other arteries throughout the body, including intracranial arteries. Of the patients who first presented with joint abnormalities, 20% died suddenly from aortic dissection. The presence of mild craniofacial abnormalities including hypertelorism and abnormal uvula may aid the recognition of this syndrome.
  
  
  CONCLUSIONS
  The authors provide further insight into the phenotype of AOS with SMAD3 mutations, and present recommendations for a clinical work-up.
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands. i.vandelaar@erasmusmc.nl
authors.forename: Ingrid M B H
authors.initials: IM
authors.lastname: van de Laar
authors.forename: Denise
authors.initials: D
authors.lastname: van der Linde
authors.forename: Edwin H G
authors.initials: EH
authors.lastname: Oei
authors.forename: Pieter K
authors.initials: PK
authors.lastname: Bos
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Bessems
authors.forename: Sita M
authors.initials: SM
authors.lastname: Bierma-Zeinstra
authors.forename: Belle L
authors.initials: BL
authors.lastname: van Meer
authors.forename: Gerard
authors.initials: G
authors.lastname: Pals
authors.forename: Rogier A
authors.initials: RA
authors.lastname: Oldenburg
authors.forename: Jos A
authors.initials: JA
authors.lastname: Bekkers
authors.forename: Adriaan
authors.initials: A
authors.lastname: Moelker
authors.forename: Bianca M
authors.initials: BM
authors.lastname: de Graaf
authors.forename: Gabor
authors.initials: G
authors.lastname: Matyas
authors.forename: Ingrid M E
authors.initials: IM
authors.lastname: Frohn-Mulder
authors.forename: Janneke
authors.initials: J
authors.lastname: Timmermans
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Hilhorst-Hofstee
authors.forename: Jan M
authors.initials: JM
authors.lastname: Cobben
authors.forename: Hennie T
authors.initials: HT
authors.lastname: Bruggenwirth
authors.forename: Lut
authors.initials: L
authors.lastname: van Laer
authors.forename: Bart
authors.initials: B
authors.lastname: Loeys
authors.forename: Julie
authors.initials: J
authors.lastname: De Backer
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coucke
authors.forename: Harry C
authors.initials: HC
authors.lastname: Dietz
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Willems
authors.forename: Ben A
authors.initials: BA
authors.lastname: Oostra
authors.forename: Anne
authors.initials: A
authors.lastname: De Paepe
authors.forename: Jolien W
authors.initials: JW
authors.lastname: Roos-Hesselink
authors.forename: Aida M
authors.initials: AM
authors.lastname: Bertoli-Avella
authors.forename: Marja W
authors.initials: MW
authors.lastname: Wessels
mesh_terms: D000015:Abnormalities, Multiple / Q000000981:diagnostic imaging / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000783:Aneurysm / Q000000981:diagnostic imaging / Q000235:genetics*; D018376:Cardiovascular Abnormalities / Q000000981:diagnostic imaging / Q000235:genetics; D002648:Child; D018389:Codon, Nonsense; D015331:Cohort Studies; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010003:Osteoarthritis / Q000000981:diagnostic imaging / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011859:Radiography; D051900:Smad3 Protein / Q000235:genetics*; D013577:Syndrome; D055815:Young Adult
chemical_list: D018389:Codon, Nonsense; C497790:SMAD3 protein, human; D051900:Smad3 Protein