Aortic Regurgitation Due to Aortic Root Dilation with Aneurysms-osteoarthritis Syndrome Caused by SMAD3 Variant

Aneurysms-osteoarthritis syndrome (AOS) is a recently characterized syndrome caused by SMAD3 mutations and represents a unique cardiovascular and orthopedic phenotype. A 73-year-old man presented with progressive shortness of breath on exertion. He had had a diagnosis of aortic regurgitation due to dilated aortic root 5 years earlier and had been thereafter followed up at outpatient department. The size of aortic root was progressively increased to 61 mm. Concomitantly, he was found to have osteoarthrosis of interphalangeal and shoulder joints, interocular dehiscence, scoliosis, funnel chest and thin skin. From his characteristic facial appearance and skeletal abnormalities, we suspected connective tissue disorder as underlying pathogenesis. A new type of missense variants in SMAD3 gene, which has been suggested to play a pathogenetic role in Loeys-Dietz syndrome (LDS), was identified. The patient underwent a Bentall procedure, and post-operative course was uneventful. Marfan syndrome, LDS and arterial tortuosity syndrome are characterized by increased transforming growth factor (TGF)-β signaling in the arterial wall, thus suggesting a central role of TGF-β signaling in the pathogenesis of arterial aneurysms. Previous studies have demonstrated that mutations in SMAD3, a key regulator of TGF-β signal transduction, contribute to AOS. Thus, SMAD3-related AOS can be a cause of ascending aortic aneurysm and resultant aortic regurgitation, even in elderly subjects, as in our patient.