Phenotypic spectrum of the SMAD3-related aneurysms–osteoarthritis syndrome

• Published in: Journal of medical genetics Vol. 49; no. 1; pp. 47 - 57
• Main Authors: van de Laar, Ingrid M B H, van der Linde, Denise, Oei, Edwin H G, Bos, Pieter K, Bessems, Johannes H, Bierma-Zeinstra, Sita M, van Meer, Belle L, Pals, Gerard, Oldenburg, Rogier A, Bekkers, Jos A, Moelker, Adriaan, de Graaf, Bianca M, Matyas, Gabor, Frohn-Mulder, Ingrid M E, Timmermans, Janneke, Hilhorst-Hofstee, Yvonne, Cobben, Jan M, Bruggenwirth, Hennie T, van Laer, Lut, Loeys, Bart, De Backer, Julie, Coucke, Paul J, Dietz, Harry C, Willems, Patrick J, Oostra, Ben A, De Paepe, Anne, Roos-Hesselink, Jolien W, Bertoli-Avella, Aida M, Wessels, Marja W
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.01.2012; BMJ Publishing Group; BMJ Publishing Group LTD
• Subjects: Abdomen; Abnormalities, Multiple - diagnostic imaging; Abnormalities, Multiple - genetics; Adolescent; Adult; Aged; Aneurysm - diagnostic imaging; Aneurysm - genetics; Aneurysms; aortic aneurysm; arterial tortuosity; Arthritis; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiovascular Abnormalities - diagnostic imaging; Cardiovascular Abnormalities - genetics; cardiovascular medicine; Child; clinical genetics; Codon, Nonsense; Cohort Studies; Congenital diseases; congenital heart disease; connective tissue disease; Deoxyribonucleic acid; diagnosis; diagnostics; diagnostics tests; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Dissection; DNA; epidemiology; Family medical history; Female; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genetic Association Studies; Genetic testing; genetics; Genetics of eukaryotes. Biological and molecular evolution; Humans; Male; Medical genetics; Medical imaging; Medical sciences; Middle Aged; Molecular and cellular biology; molecular genetics; Mortality; Mutation; osteoarthritis; Osteoarthritis - diagnostic imaging; Osteoarthritis - genetics; osteoporosis; Pedigree; Phenotype; Radiography; SMAD3; Smad3 Protein - genetics; Studies; Syndrome; TGFβ; Veins & arteries; Young Adult; Human; Diseases of the osteoarticular system; Aneurysm; Cardiovascular disease; Genetic disease; Spectrum; Vascular disease; Phenotype; Arthropathy; Genetics; Degenerative disease; Complex syndrome; Osteoarthritis
• ISSN: 0022-2593; 1468-6244
• DOI: 10.1136/jmedgenet-2011-100382

BackgroundAneurysms–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.MethodsA 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.ResultsFive 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.ConclusionThe authors provide further insight into the phenotype of AOS with SMAD3 mutations, and present recommendations for a clinical work-up.