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We describe three cases where Marfan syndrome was suspected, but genetic tests were negative. Two patients, a 38-year-old male and a 45-year-old female, were asymptomatic, but were referred to a clinical geneticist because multiple family members had died of aortic dissections at a young age. The third patient, a 55-year-old female, has been monitored for the past 26 years due to mild aortic dilatation and mitral valve prolapse after three brothers had died suddenly. At screening, all these patients were diagnosed with multiple vascular abnormalities and osteoarthritis. Pathogenic SMAD3 mutations were identified as the cause of the vascular catastrophes in these families. SMAD3 mutations cause aneurysms-osteoarthritis syndrome, an autosomal dominant disorder characterized by aneurysms, dissections and tortuosity throughout the arterial tree, early-onset osteoarthritis and mild craniofacial features. These case descriptions emphasize the importance of timely recognition of aneurysms-osteoarthritis syndrome, as this syndrome causes more aggressive and widespread cardiovascular disease than Marfan syndrome.

Objectives: The purpose of this study was describe the cardiovascular phenotype of the aneurysms-osteoarthritis syndrome (AOS) and to provide clinical recommendations., Background: AOS, caused by pathogenic SMAD3 variants, is a recently described autosomal dominant syndrome characterized by aneurysms and arterial tortuosity in combination with osteoarthritis., Methods: AOS patients in participating centers underwent extensive cardiovascular evaluation, including imaging, arterial stiffness measurements, and biochemical studies., Results: We included 44 AOS patients from 7 families with pathogenic SMAD3 variants (mean age: 42 ± 17 years). In 71%, an aortic root aneurysm was found. In 33%, aneurysms in other arteries in the thorax and abdomen were diagnosed, and in 48%, arterial tortuosity was diagnosed. In 16 patients, cerebrovascular imaging was performed, and cerebrovascular abnormalities were detected in 56% of them. Fifteen deaths occurred at a mean age of 54 ± 15 years. The main cause of death was aortic dissection (9 of 15; 60%), which occurred at mildly increased aortic diameters (range: 40 to 63 mm). Furthermore, cardiac abnormalities were diagnosed, such as congenital heart defects (6%), mitral valve abnormalities (51%), left ventricular hypertrophy (19%), and atrial fibrillation (22%). N-terminal brain natriuretic peptide (NT-proBNP) was significantly higher in AOS patients compared with matched controls (p < 0.001). Aortic pulse wave velocity was high-normal (9.2 ± 2.2 m/s), indicating increased aortic stiffness, which strongly correlated with NT-proBNP (r = 0.731, p = 0.005)., Conclusions: AOS predisposes patients to aggressive and widespread cardiovascular disease and is associated with high mortality. Dissections can occur at relatively mildly increased aortic diameters; therefore, early elective repair of the ascending aorta should be considered. Moreover, cerebrovascular abnormalities were encountered in most patients., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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