Eisenberg et al. (1964) reported 22 cases of supravalvular aortic stenosis involving 3 generations of each of 2 families. Some had associated pulmonary valvular or peripheral arterial stenosis. None had unusual facies.
Gyllensward et al. (1957) ... Eisenberg et al. (1964) reported 22 cases of supravalvular aortic stenosis involving 3 generations of each of 2 families. Some had associated pulmonary valvular or peripheral arterial stenosis. None had unusual facies. Gyllensward et al. (1957) reported pulmonary artery stenosis in mother and son. Lewis et al. (1969) described a sibship in which 5 of 9 sibs had supravalvar aortic stenosis with peculiar facies but normal intelligence. Schmidt et al. (1989) reevaluated this family and provided examinations of the parents, additional sibs, and offspring of the original 5 patients. Echocardiographic examinations added to the completeness of the survey. The SVAS showed marked variability of expression and was not associated with mental retardation. It also was said not to be associated with the facial manifestations of Williams syndrome, but the photographs seem to belie that conclusion: the configuration of the mouth in patients III-16 and III-18 who had SVAS documented by echocardiogram is very suggestive of the Williams syndrome and is quite different from that in their brother, III-17, who had a normal echocardiogram. Schmidt et al. (1989) concluded that isolated SVAS and Williams syndrome represent 'clinically distinct entities.' They did not commit themselves as to whether there was any genetic relationship between the two. Antia et al. (1967) commented on a lack of clear distinction between the familial supravalvular aortic stenosis with normal facies and mentality and the nonfamilial type with abnormal facies and mental retardation. McDonald et al. (1969) described an arteriopathy, with multiple pulmonary and systemic arterial stenoses, in a mother and 3 daughters. Two had supravalvular aortic stenosis. The familial occurrence of pulmonary arterial stenoses is documented (McCue et al., 1965) and their occurrence after maternal rubella is well established (Rowe, 1963). It can be argued that supravalvular aortic stenosis is an inadequate or inappropriate designation. Strong et al. (1970) observed sudden death following premedication for cardiac catheterization in an 11-month-old male. Postmortem showed severe fibromuscular dysplasia of both systemic and pulmonary arteries. A sister had signs of mild pulmonary artery and supravalvular aortic stenosis. The mother had signs of mild aortic stenosis. Wooley et al. (1961) described sibs with supravalvular aortic stenosis. McKusick (1978) saw a family in which a man, his son and daughter, and his paternal uncle had well-confirmed signs of supravalvular aortic stenosis and/or peripheral pulmonary stenoses. None had manifestations of Williams syndrome. O'Connor et al. (1985) studied 6 patients with supravalvular aortic stenosis; 3 had Williams syndrome, 2 had familial SVAS (presumably without evidence of Williams syndrome), and 1 had sporadic SVAS. The existence of a familial form of SVAS, which might be called the Eisenberg form, separate from the SVAS in the Williams-Beuren syndrome appeared to be established by a study of an extensive kindred with 36 affected persons in 5 generations (Chiarella et al., 1989). The unique study was made possible by the fact that the family had lived in relative isolation on a small island in the Sardinian archipelago for over 200 years and also by the availability of echocardiography, including portable equipment usable in the home, for noninvasive diagnosis. Penetrance was estimated to be 86%. In 5 of 8 patients who underwent cardiac catheterization, multiple pulmonary stenoses were observed. Surgical correction was performed in 4 cases. None of the affected family members had unusual facies or mental retardation. A similar family with the Eisenberg form of SVAS was reported by Ensing et al. (1989). Three members of that family had supravalvular aortic stenosis requiring surgery. Of 22 members examined echocardiographically who had not had prior surgical repair, 13 had supravalvular aortic stenosis. The echocardiographic findings varied widely, from calcification of the ascending aorta in a 71-year-old man with minimally increased flow velocity, to mild narrowing with mildly increased flow velocity in 6 members, to significant narrowing with impressively increased flow velocity in 7. In addition, 4 patients had mild narrowing of pulmonary artery branches and 8 had peak pulmonary artery flow velocities above normal. The family was of Irish-Native American-English descent living in the United States. Kumar et al. (1993) observed 5 affected persons in 1 family; 3 had isolated SVAS, 1 had isolated peripheral pulmonary stenosis (PPS), and 1 had SVAS and PPS.
In a family with SVAS (185500), Ewart et al. (1994) found a heterozygous 100-kb deletion in the 3-prime end of the elastin gene with a breakpoint between elastin exons 27 and 28. The same region was disrupted in ... In a family with SVAS (185500), Ewart et al. (1994) found a heterozygous 100-kb deletion in the 3-prime end of the elastin gene with a breakpoint between elastin exons 27 and 28. The same region was disrupted in the familial reciprocal translocation reported by Morris et al. (1993). Ewart et al. (1993) found that deletion involving 7q11.23 and resulting in hemizygosity of the elastin gene is responsible for the Williams-Beuren syndrome (194050). Deletions limited to the elastin gene appear to result in SVAS, whereas deletions spanning at least 114 kb lead to Williams-Beuren syndrome. Olson et al. (1995) used Southern blot analysis to screen for mutations in the ELN gene in 6 familial and 3 sporadic cases of SVAS. The familial cases included members of the large Middle Eastern pedigree in which linkage to the elastin gene region had been found by Olson et al. (1993). A 30-kb deletion extending from breakpoints in intron 1 and intron 27 (130160.0002) was identified in 2 members of the Middle Eastern family. The proband developed severe SVAS and peripheral pulmonary artery stenosis and underwent aortic operation in early childhood. He had no evidence of Williams syndrome or clinically apparent abnormalities of other elastin-containing tissue. The deletion was also demonstrated in his mother, an obligate carrier with subtle disease (a heart murmur and a nondiagnostic echocardiogram). Blood for DNA analysis was not available from a maternal uncle with SVAS and a sister with isolated peripheral pulmonary artery stenosis. Li et al. (1997) identified a heterozygous nonsense mutation in the ELN gene (130160.0003) in a sporadic case of SVAS. Metcalfe et al. (2000) described the mutation spectrum of the ELN gene in 35 unrelated patients with SVAS and normal karyotypes without major deletions of the ELN gene as determined by FISH. A marked phenotypic intrafamilial variability was illustrated by 2 large families with multiple affected members with disease severity ranging from asymptomatic carriers to mild or severe SVAS requiring surgery, or sudden infant death. No obvious genotype-phenotype correlation was detected; cases with missense or splicing mutations were as likely to have severe SVAS as cases with truncating mutations.