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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.