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Phenotypic spectrum of the SMAD3-related aneurysms–osteoarthritis syndrome
  1. Ingrid M B H van de Laar1,
  2. Denise van der Linde2,
  3. Edwin H G Oei3,
  4. Pieter K Bos4,
  5. Johannes H Bessems4,
  6. Sita M Bierma-Zeinstra5,
  7. Belle L van Meer4,
  8. Gerard Pals6,
  9. Rogier A Oldenburg1,
  10. Jos A Bekkers7,
  11. Adriaan Moelker3,
  12. Bianca M de Graaf1,
  13. Gabor Matyas8,
  14. Ingrid M E Frohn-Mulder9,
  15. Janneke Timmermans10,
  16. Yvonne Hilhorst-Hofstee11,
  17. Jan M Cobben12,
  18. Hennie T Bruggenwirth1,
  19. Lut van Laer13,
  20. Bart Loeys13,
  21. Julie De Backer14,
  22. Paul J Coucke14,
  23. Harry C Dietz15,16,17,
  24. Patrick J Willems18,
  25. Ben A Oostra1,
  26. Anne De Paepe14,
  27. Jolien W Roos-Hesselink2,
  28. Aida M Bertoli-Avella1,
  29. Marja W Wessels1
  1. 1Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
  2. 2Department of Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands
  3. 3Department of Radiology, Erasmus Medical Center, Rotterdam, The Netherlands
  4. 4Department of Orthopedic Surgery, Erasmus Medical Center, Rotterdam, Netherlands
  5. 5Department of General Practice, Erasmus Medical Center, Rotterdam, The Netherlands
  6. 6Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands
  7. 7Department of Cardio-Thoracic Surgery, Erasmus Medical Center, Rotterdam, The Netherlands
  8. 8Institute of Medical Molecular Genetics, University of Zurich, Zurich, Switzerland
  9. 9Department of Pediatric Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands
  10. 10Department of Cardiology, Radboud University Hospital Nijmegen, Nijmegen, The Netherlands
  11. 11Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
  12. 12Department of Pediatric Genetics, Academic Medical Center, Amsterdam, The Netherlands
  13. 13Center of Medical Genetics, University and University Hospital of Antwerp, Antwerp, Belgium
  14. 14Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
  15. 15McKusick–Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  16. 16Howard Hughes Medical Institute, Baltimore, Maryland, USA
  17. 17Smilow Center for Marfan Syndrome Research, Baltimore, USA
  18. 18GENetic DIAgnostic Network, GENDIA, Antwerp, Belgium
  1. Correspondence to Ingrid M B H van de Laar, Department of Clinical Genetics, Erasmus MC, PO Box 2040, Rotterdam 3000 CA, The Netherlands; i.vandelaar{at}


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.

Conclusion The authors provide further insight into the phenotype of AOS with SMAD3 mutations, and present recommendations for a clinical work-up.

  • SMAD3
  • TGFβ
  • aortic aneurysm
  • arterial tortuosity
  • osteoarthritis
  • clinical genetics
  • cardiovascular medicine
  • connective tissue disease
  • congenital heart disease
  • diagnosis
  • diagnostics
  • diagnostics tests
  • epidemiology
  • osteoarthritis
  • molecular genetics
  • osteoporosis
  • genetics

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  • Funding This work was partially funded by an Erasmus Fellowship 2009 (Erasmus Medical Center, The Netherlands) to AMB-A, a Research Foundation Flanders grant (Ghent University Hospital, Belgium) to BL, and the Swiss National Science Foundation grant 31003A-120504 to GM.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Medical ethics committee of the Erasmus Medical Center Rotterdam (Erasmus MC) in The Netherlands.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Anonymised clinical records are partially available upon request by physicians, genetic counsellors and other professionals in the field.