What’s the Skinny on Elastin Deficiency and Supravalvular Aortic Stenosis?

Supravalvular aortic stenosis (SVAS), a localized narrowing of the aorta just distal to the aortic valve, has been encountered sporadically for over 130 years.1,2 In 1961, reported 4 patients with SVAS who shared syndromic features, including short stature, mental retardation, peripheral pulmonary artery stenoses, and a characteristic facies.3 Beuren et al4 reported additional cases, and this syndrome is now known both as syndrome (WS) and Williams–Beuren syndrome. Familial clustering of nonsyndromic SVAS5,6 and WS7 was later identified, bolstering the notion that both WS and SVAS are genetically based.See accompanying article on page 930 Williams hypothesized that SVAS was caused by a combination of medial hypertrophy and aortic wall constriction, but proposed no underlying mechanisms. Others proposed intimal fibrous thickening, due to hyperplasia and excessive collagen deposition (Figure [A]), as potential pathogeneses.9,10 However, the mechanisms that might account for cell proliferation and fibrosis remained uncertain. In 1993, Keating’s group discovered that (1) individuals with both familial and sporadic WS were hemizygous at the elastin locus11 and (2) members of a family with SVAS had a balanced translocation that disrupted the elastin gene and cosegregated with the SVAS phenotype.12 Because elastin is a major component of the aortic wall, comprising ≈50% of total protein,13 and because aortas of individuals with SVAS have decreased elastin content and abnormal elastin architecture,10 elastin deficiency seemed the obvious underlying cause of SVAS. This conclusion was solidified by detection of elastin point mutations in individuals with SVAS.14 Keating’s group speculated that SVAS associated with elastin deficiency was caused by decreased aortic elasticity leading to endothelial dysfunction, and that this nondenuding endothelial injury led to intimal proliferation, fibrosis, and stenosis (Figure [B]).12Figure. Models of pathogenesis of aortic …