Generalized arterial fibromuscular dysplasia and myocardial infarction in familial supravalvular aortic stenosis syndrome

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April, 1969 T h e Journal o[ P E D I A T R I C S

Generalized arterial fibromuscular dyJplasia and myocardial infarction in familial supraralrular aortic stenosis syndrome Postmortem examination o[ two in[ant sisters with findings o[ the supravalvular aortic stenosis syndrome revealed generalized fibromuscular dysplasia o[ the major systemic arteries and o[ the entire pulmonary trunk, without any supravalvular narrowing o[ the aorta. Many in[arcts o[ the myocardium, both old and recent, were [ound in both patients. The vascular lesions were strikingly similar to those [ound in the rubella syndrome and in fibromuscular dysplasia o/the renal arteries.

Roland E. Schmidt, M.D., Enid F. Gilbert, M.D., Thomas C. Amend, M.D., Charles R. Chamberlain, Jr., M.D., and Russell V. Lucas, Jr., M.D. MORGANTOWN,

W.

VA.

S u P R A V A L V U L A R aortic stenosis caused by an obstructing ridge of tissue situated just above the sinuses of Valsalva has been known for more than a century. 1-7 Following Williams and associates 's description of 1961 of its association with a peculiar facies and mental retardation, many cases came to be recognized clinically. The constellation was called the supravalvular aortic stenosis syndrome (SVAS syndrome). Infantile hypercalcemia'has been proved to occur in

From the Departments o/Pediatrics and Pathology, West Virginia University School o[ Medicine. Supported in part by a grant [rom the West Virginia Heart Association, Research Grant No. HE 06456-05:o[ the National Heart Institute, United States Public Health Service, and Research Grant No. HD-9791-04 o[ the Institute o[ Child Health and Human Development, United States Public Health Service. Vol. 74, No. 4, pp. 576-584

some of these patients2 -1~ There has been indirect evidence to suggest hypercalcemia in many others? 6 With few exceptions, TM 17, 18 this variety of SVAS syndrome has been found in isolated individuals. A familial form of SVAS syndrome, in patients with normal facial appearance and normal intelligence, was also described in 1961.10, 19-22 (There had been one earlier report of supravalvular aortic stenosis in a boy and in his grandmother. 7) Thus, the SVAS syndrome has come to embrace two clinically distinct groups of patients. Despite the apparent clinical distinctness of the hypercalcemic and familial groups, the cardiovascular pathology appears identical. A second trend in the evolution of understanding of the SVAS syndrome is recognition of the extreme variability in site, ex-

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tent, a n d severity of c a r d i o v a s c u l a r involvem e n t f r o m case to case. Patients m a y o r m a y not h a v e s u p r a v a l v u l a r aortic stenosis a n d m a y have stenotic lesions of one, several, or all of the following vessels: c o r o n a r y arteries, m a j o r systemic arteries, p u l m o n a r y arteries, a n d systemic veins. O u r purpose in presenting 2 i n f a n t sisters with familial S V A S syndrome is to docum e n t the widespread, severe n a t u r e of their cardiovascular involvement. T h e gross a n d histologic pathological findings in t h e s e sisters strengthen the thesis t h a t the S V A S syndrome is a generalized arterial fibromuscular dysplasia with variable expression. M y o c a r d i a l infarcts, n o t e d at autopsy in both patients, are also of interest. CASE REPORTS

Clinical features. Two infant sisters, aged 10 and 14 months, respectively, at death, had remarkably similar clinical courses. Both had repeated respiratory infections and chronic cough. In each, a heart murmur was noted early in llfe. Only in Patient 1, who was dyspneic one month prior tO admission, were there symptoms of cardiac disease. Neither patient had symptoms suggesting idiopathic hypercalcemia. A brother bad died suddenly at 18 months of age with an "enlarged heart and a murmur," but autopsy was not performed. The parents and 4 siblings were normal. Both infants had normal facies and body habitus and had developed satisfactorily. Blood pressures and respiratory rates were within normal limits. Peripheral pulses were full and symmetrical. Heart rates were 120 to 130 per minute. No thrill, heave, or tap was palpable in either patient. A Grade 3 / 4 harsh systolic murmur was heard best along the left sternal border; in Patient 2, a Grade 1/4 diastolic murmur was heard at the apex. The pulmonary second sounds

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were normal in both girls. Cyanosis and dubbing were not present. Chest roentgenograms revealed globular hearts, evidence of right atrial and right ventricular hypertrophy, prominence of the left ventricle, and normal pulmonary vascular markings. Electrocardiograms showed right atrial and right ventrieular hypertrophy, more prominent in Patient 1. Values obtained at right heart catheterization are summarized in Table I. In neither patient was the pulmonary artery entered. In both patients the presence of severe pulmonary outflow obstruction was suggested by the very high right ventricular pressure. High right atrial V waves in Patient 1 indicated the presence of tricuspid insufficiency, Selective angiography (Fig. 1 ) clearly defined diffuse narrowing of the main pulmonary artery as welI. Right ventricutar hypertrophy and partial obstruction of the pulmonary outflow tract by anomalous muscle bundles were common to both patients. Patient 1 had evidence of tricuspid insufficiency (regurgitation of contrast material across the tricuspid valve, and right atrial enlargement). The pulmonary valve, pulmonary veins, left heart chambers and valves, and the aorta appeared normal in both girls. In Patient 1, the major hemodynamic derangement was thought to be pulmonary outflow obstruction, secondary to infundibular hypertrophy and anomalous muscle bundles. The obstructing muscle was widely resected while using extracorporeal circulation, but the patient died. The second patient died several hours after an uneventful cardiac catheterization, after suddenly having shock, diaphoresis, and restlessness, a symptom complex strongly suggesting an acute myocardial infarction. Pathologic features. Except where noted, the following description applies to both patients. The wall of the aorta throughout its entire length was grossly thickened, averaging 4 mm. (Fig. 2). This process was diffuse and there was no discrete supravalvular narrowing. The major

T a b l e I. H e m o y d n a m i c features Cardiac output RA RV PVW LA SA (L./min./Me ) Patient 1 12/2-20"/2 152/0 25/17 17/6 142/60 4.4 Patient 2 9/2 140/0-12 -17/2 -4.0 RA ~ right atrium; RV = right ventricle; PVW ~ pulmonaryvein wedge; LA = left atrium; SA = systemicartery. * V wave.

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Fig. 1. Selective right ventriculograms. Left: Patient 1. Anteroposterior projection. Following injection into the right ventricle (RV), regurgitation across the tricuspid valve outlines an enlarged right atrium (RA). The right ventricular cavity is filled with contrast material and massive thickness of the right ventricular wall is apparent. T h e filling defect suggests an anomalous muscle mass. T h e pulmonary trunk (PT) appears normal. T h e secondary branches of the pulmonary arteries are significantly narrowed. Center: Patient 2. Anteroposterior projection. T h e r i g h t ventricular cavity (RV) is encroached upon by hypertrophied papillary muscles at the apex and an anomalous muscle bundle below the outflow tract. T h e pulmonary trunk (PT) is hypoplastic, as are the primary branches of the pulmonary artery. T h e more peripheral branches are small. Right: Patient 2. Lateral view, simultaneous with Center. The pulmonary valve appears normal. Supravalvular stenosis is clearly defined.

Fig. 2. T h e heart viewed from in front. Left: Patient 1. The wall of the pulmonary trunk (PT) is thickened, particularly in the supravalvular area. The secondary pulmonary branches are also thick, whereas the tertiary branches exhibit the fusiform dilatation characteristic of a post-stenotic segment. T h e brachiocephalic branches of the aorta (A) have thickened walls. Right: Patient 2. Similar vascular changes are apparent. Pulmonary valve is normal. The arrow indicates the anomalous muscle mass partially subdividing the right ventricle. A similar mass was surgically resected in Patient 1. The fibrous replacement of myocardium in the septal wail of the right ventrlcIe repi~esents a large infarct ( T ~ trachea).

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aortic branches, including the coronary and renal arteries, were extremely thick walled and cordlike but had normal external diameters. On cross section, the lumina of all the aortic branches were markedly encroached upon by hypertrophied medial tissue. This process reduced the lumina of the major coronary vessels to pinpoint dimensions. The pulmonary trunk was extremely thick, particularly in the supravalvular area, where it measured 3 ram. The right and left pulmonary arteries, though smaller in external diameter, had medial hypertrophy as did their primary and secondary branches. Tertiary pulmonary vessels appeared dilated (but had similar medial hypertrophy on microscopic examination). The gross appearance of the myocardium was striking. In both patients, zones of old and relatively recent myocardial infarction were evident within the left ventricular myocardium, including the posterior papillary muscle, which appeared to be totally infarcted. In some areas, there was almost complete

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fibrous replacement of muscle. The endocardium, particularly over the papillary muscles, was pale and had evidence of subendocardial fibrosis. Right ventricular hypertrophy was marked, and left ventricular enlargement was also noted. In both patients, an anomalous muscle bundle originated from the body of the crista supraventricularis and extended anteroinferiorly to attach to the anterior wall of the right ventricle. This resulted in additional obstruction to pulmonary flow. The tricuspid leaflets in Patient 1 showed evidence of fibrous thickening. tIistologic features. These were comparable in both patients and will be considered together. Sections from the aorta, all its major branches, the coronary arteries, and the main pulmonary artery and its branches revealed an extensive fibrous replacement of the media. In some zones the smooth muscle of the media was almost completely replaced by fibrous tissue, as demonstrated by trichrome stains. Elastic tissue stains confirmed marked fraying, fragmentation, and disruption of the internal elastic lamella,

Fig. 3. Low power microscopic section of common carotid artery demonstrating fibrous replacement of the media, disruption of the internal elastic lamella, and marked subintimal fibrosis. The lumen is reduced in size. (Elastic tissue stain. •

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Fig. 4. Left: Microscopic section of the coronary artery. At the upper left is the intact internal elastic lamella which is fragmented in the lower portion of the field. (Elastic tissue stain, xl00.) Right: Higher magnification of the same vessel demonstrating the frayed and fragmented elastic tissue. (Elastic tissue stain. •

Fig. 5. A calcified myocardial infarct, one of many scattered throughout the left ventricle of Patient 2. (Hematoxylin and eosin, x250.)

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which in some areas had completely disappeared (Figs. 3 and 4). In addition to the striking medial changes, there was also variable, sometimes marked, intimal hyperplasia. There was no evidence of an inflammatory reaction, nor were any significant changes seen in the vasa vasorum of the adventitia. Mucopolysaccharide stains (alcian blue and colloidal iron procedures) revealed negligible amounts of neutral and acid mucopolysaccharide material within the dense fibrotic media. Fat stains failed to demonstrate lipid deposits. The lesions in no way resembled arteriosclerotic plaques and there was no medial calcification. The histologic changes were generalized throughout the major systemic and pulmonary vessels and resulted in tubular narrowing of the arterial lumina. A less severe degree of medial fibrosis was present in the medium-sized systemic arteries and the pulmonary branches. Aneurysmal dilatation was not present in any vessel. The myocardium of both ventricles was hypertrophied. The most striking feature was multiple areas of infarction of varying age. Some were densely fibrotic; other areas, of more recent vintage, were composed of somewhat loosely arranged fibrocollagenous tissue. In addition, very recent infarction was demonstrated by myocardial necrosis and polymorphonuclear cell infiltration. In Patient 2, many of the old infarcts were partially calcified (Fig. 5). In each case, permission to examine the brain was denied. However, the carotid arteries as far as they could be dissected were severely narrowed in both patients. With the exception of focal atelectasis and congestion of the lungs and other viscera, there were no other significant pathological lesions.

DISCUSSION Anatomic profile of S V A S . T h e r a n g e of cardiovascular involvement is i d e n t i c a l for the hypercalcemic, familial, a n d sporadic cases of SVAS. A m o n g the a n a t o m i c a n o m alfes described are the following. Supravalvular aortic stenosis. T h e stenosis m a y be one of three a n a t o m i c types: m e m branous, hourglass, o r u n i f o r m hypoplasia of the ascending aorta. 23' 24 Aortic anomalies. O t h e r aortic anomalies r e p o r t e d include coarctations, h y p o p l a s i a of the entire aorta, calcified aneurysm of the ascending aorta, 25 bulging of the a o r t a at

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58 1

the site of the l i g a m e n t u m arteriosum, TM 2~ dissecting aneurysm of the thoracic aorta, 25 a n d t e r m i n a t i o n of the a o r t a in a blind pouch. 4 Systemic arteries. T h e coronary arteries have been described as hypoplastic or stenotic2a, 27 a n d as dilated, tortuous, a n d atherosclerotic.~, 23, 2s A n o m a l o u s origin of the right coronary artery from the pulmon a r y t r u n k has been d o c u m e n t e d . 29 A m o n g the abnormalities of the other systemic arteries are h y p o p l a s i a or localized stenosis of a n y of t h e b r a c h i o c e p h a l i c or a b d o m i n a l branches of the aorta, atresia of the left subclavian artery, 3~ duplication or absence of renal arteries, a n d tortuous cerebral a n d retinal arteries, al Pulmonary arteries. Discrete stenotic lesions m a y be present in a n y o r all portions of the p u l m o n a r y arterial system. T h e main p u l m o n a r y artery a n d its m a j o r branches m a y be diffusely hypoplastic. 1~

Associated

cardiovascular

abnormalities.

T h e aortic valve is c o m m o n l y i n v o l v e d ? a R e p o r t e d lesions include v a l v u l a r stenosis, thickened aortic leaflets, bicuspid aortic valve, a n d a d h e r e n c e of an aortic cusp to the site of the S V A S (usually with fenestration to allow coronary blood flow).4, 5, 19, as P u l m o n a r y outflow obstruction m a y exist in the form of v a l v u l a r stenosis, 9, 13, 1~, a3 inf u n d i b u l a r stenosis,13, 22, 3~ a n d anomalous muscle bundles in the right ventricle. Thickening of the mitral valve 2, 7, 27, 34 a n d its chordae, 27 cleft m i t r a l valve, a4 diverticulum of the left ventricle, 29 a n d fibrosis~' 6, 22, 2s, 32 a n d infarction s of the left ventricle have been reported. T h e c o m m o n d e n o m i n a t o r in m a n y of these a n a t o m i c lesions is arterial medial hyp e r t r o p h y which results in localized or diffuse arterial narrowing. C e r t a i n of the rep o r t e d cardiovascular anomalies are clearly secondary to obstruction, e.g., dilated coron a r y arteries in SVAS, i n f u n d l b u l a r hypertrophy in stenosis of the p u l m o n a r y arteries, a n d m y o c a r d i a l infarction. T h e frequency of involvement of the aortic valve suggests that this m a y be p a r t of the p r i m a r y process. Histology of S V A S . Despite the great

58 2

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diversity of anatomic involvement in the SVAS syndrome, there is remarkable histologic similarity in the various arterial lesions. The arterial media is thickened and has undergone extensive fibrous tissue replacement. The smooth muscle may be almost completeIy replaced by fibrous tissue. The elastic fibers are disrupted and may be absent in smaller vessels. In the larger vessels intensive fraying and fragmentation of the elastic fibers occurs. The lesion appears to be a primary abnormality of elastic tissue involving not only the internal elastic lamella but also the elastica of the media. Consequent to elastic tissue degeneration, medial fibrosis ensues as well as variable degrees of subintimal fibrosis. The abnormalities in the elastic tissue are characteristic of SVAS syndrome, but they are not unique to it. Similar orientation of elastic fibers is seen at the site of coarctation of the aorta. In addition, "the authors have seen this pattern in the pulmonary artery in 2 patients with rubella syndrome and 2 patients with pulmonary valvular stenosis of the dysplastic type. Esterly and Oppenheimer a5 reported a similar histologic picture in the pulmonary arteries, aorta, coronary, renal, and other systemic arteries in 13 patients with the rubella syndrome. One of us (R. V. L.) has seen fibromuscular dysplasia of the renal arteries in 2 nonrubella infants who had positive mumps skin test. Clinical features. SVAS syndrome has a wide spectrum of clinical symptomatology which is related to the extent of the pathological involvement. In its mildest form, the lesion may affect only a small segment of a single vessel and be compatible with freedom of symptoms into adult life. 7 In the most severe form, the entire arterial vascular tree may be involved, and death may occur in infancy. Sudden death has been reported in a number of patients with SVAS, 19-zz probably due to myocardial infarctions similar to those observed in our patients. These infarctions we attributed to an extreme degree of myocardial ischemia produced by severe compromise of the coronary arterial

The Journal o[ Pediatrics April 1969

circulation. Such lesions of the myocardium are reminiscent of tile infarcts seen in cases of anomalous origin of the left coronary artery from the pulmonary artery. 36 The term "SVAS syndrome," though perhaps ineradicably established, has become inappropriate? ~ The term is too limiting" when the entire aorta and pulmonary artery and their branches are affected. It is also inaccurate when no involvement is detectable in the supravalvular portion of the aorta, but only in the pulmonary trunk or branches of the abdominal aorta? 3, 14 Moreover, abnormalities of the venous system have been noted by several authors. 2s, 3T Etiology. In some instances SVAS syndrome appears to be genetically determined. In utero environmental factors' also have been implicated.The correlation of infantile hyperealeemia with SVAS has been noted. Experimentally, administration of excessive vitamin D has produced lesions in the aortas and coronary arteries of mature rats and in the aortas of young rabbits and has caused supravalvular aortic stenosis in the offspring of pregnant rabbits? 8, 39 Absence of evidence of inflammation makes an etiologic relationship with Takayasu's disease unlikely. Intrauterine viral infection must also be considered. T h e fibromuscular dysplasia of the arteries and variability in severity and location of the lesions of patients with rubella syndrome are strikingly comparable with the spectrum seen in the SVAS syndrome? 5' 4 0 - 4 2 We believe that the following hypotheses are worthy of consideration: 1. Arterial fibromuscular dysplasia might be considered a generalized disease with variable expression in terms of location and severity of arterial lesions. 2. The distinctions among the varieties of the SVAS syndrome, the rubella syndrome, and fibromuscular dysplasia of the renal arteries in children are becoming less well defined. While these disease states might be the result of a common response to a variety of intrauterine stresses with or without genetic influence, the clear example of the rubella syndrome suggests that efforts to uncover viral agents in other patients with generalized

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arterial ranted.

fibromuscular

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dysplasia a r e

war7.

SUMMARY

1. H y p e r c a l c e m i c a n d familial varieties have been distinguished as definite ( b u t perhaps o v e r l a p p i n g ~5) entities in the syndrome of s u p r a v a l v u l a r aortic stenosis ( S V A S syndrome). 2. T h e familial variety is described in this paper, w i t h emphasis on abnormalities in the m e d i a of the a o r t a a n d p u l m o n a r y t r u n k a n d on m u l t i p l e m y o c a r d i a l infarctions f o u n d at autopsy. 3. V a s c u l a r involvement in S V A S synd r o m e varies greatly in extent b u t is identical in the hypercalcemic a n d familial forms a n d in the sporadic cases that h a v e been reported. 4. T h e term " s u p r a v a l v u l a r aortic stenosis syndrome" is i n a p p r o p r i a t e . O n the one hand, b o t h g r e a t vessels a n d their m a j o r branches m a y be affected in their entirety. By contrast, o n l y tertiary branches of the p u l m o n a r y trunk or branches of the descending a o r t a m a y be involved. A t either extreme, obstruction is often not detectable in the s u p r a v a l v u l a r aorta. 5. M y o c a r d i a l infarctions m a y be r e s p o n sible for instances of sudden d e a t h in p a tients with S V A S syndrome. 6. T h e close similarity in arterial p a t h o l ogy a m o n g the varieties of t h e S V A S syndrome, the rubella syndrome, a n d fibromuscular dysplasia of the renal arteries in child r e n is noted. REFERENCES

1. Chevers, N.: Observations on tile diseases of the orifice and valves of the aorta, Guy's Hosp. Rep. 7: 387, 1842. 2. Mencarelli, L.: Stenosis sopravalvolare aortica ad anello, Arch. ital. anat. e istol, pat. 1: 829, 1930. 3. Lev, M.: Autopsy diagnosis of congenitally malformed hearts, Springfield, Ill., 1953, Charles C Thomas, Publisher, pp. 53-54. 4. Cheu, S., Fiese, M. J., and Hatayama, E.: Supra-aortic stenosis, Am. J. Clin. Path. 28: 293, 1957. 5. Denie, J. J., and Verheugt, A. P.: Supravalvular aortic stenosis, Circulation 18: 902, 1958. 6. Burry, A. F.: Supra-aortic stenosis associated

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with Marfan's syndrome, Brit. Heart J. 20: 143, 1958. Sissman, N. J., Neill, C. A., Spencer, F. C., and Taussig, H. B.: Congenital aortic stenosis, Circulation 19: 458, 1959. Williams, J. C. P., Barratt-Boyes, B. G., and Lowe, J. B.: Supravalvular aortic stenosis, Circulation 24:1311, 1961. Garcia, R. E., Friedman, W. F., Kaback, M. M., and Rowe, R. D.: Idiopathic hypercalcemia and supravalvular aortic stenosis. Documentation of a new syndrome, New England J. Med. 271: 117, 1964. JSrgensen, G., and Beuren, A. J.: Genetische Untersuchungen bei supravalvul~iren Aortenstenosen, Humangenetik 1: 497, 1965. Jue, K. L., Noren, G. R., and Anderson, R. C.: The syndrome of idiopathic hypercalcemia of infancy with associated congenital heart disease, J. PEDIAT. 67: 1130, 1965. Fraser, D., Kidd, B. S. L., Kooh, S. W., and Paunier, L.: A new look at infantile hypercalcemia, Pedlar. Clin. North America 13: 503, 1966. Chantler, C., Davies, D. H., and Joseph, M. C.: Cardiovascular and other associations of infantile hypercalcaemia, Guy's Hosp. Rep. 115: 221, 1966. Wiltse, H. E., Goldbloom, R. B., Antia, A. U., Ottesen, O. E., Rowe, R. D., and Cooke, R. E.: Infantile hypercalcemia syndrome in twins, New England J. Med. 275: 1157, 1966. Antia, A. U., Wiltse, H. E., Rowe, R. D., Pitt, E. L., Levin, S., Ottesen, O. E., and Cooke, R. E.: Pathogenesis of the supravalvular aortic stenosis syndrome, J. PEDIAT. 71: 431, 1967. Black, J. A., and Bonham Carter, R. E.: Association between aortic stenosis and facies of severe infantile hyperealcaemia, Lancet 2: 745, 1963. Page, H. L., Jr., Vogel, J. H. K., Pryor, R., and Blount, S. G., Jr.: Unusual observations in supravalvular aortic stenosis, Circulation 32 (suppl. 2): 166, 1965. Kurlander, G. J., Petry, E. L., Taybi, H., Lurie, P. R., and Campbell, J. A.: Supravalvular aortic stenosis, Am. J. Roentgenol. 98" 782, 1966. Wooley, C. F., Hosier, D. M., Booth, R. W., Molnar, W., Sirak, H. D., and Ryan, J. M.: Supravalvular aortic stenosis, Am. J. Med. 31- 717, 1961. Eisenberg, R., Young, D., Jacobson, B., and Boito, A.: Familial supravalvular aortic stenosis, Am. J. Dis. Child. 108: 341, 1964. Logan, W. F. W. E., Jones~ E. W., Walker, E., Coulshed, N., and Epstein, E. J.: Familial supravalvular aortic stenosis, Brit. Heart J. 27: 547, 1965. Kahler, R. L., Braunwald, E., Plauth, W. H., Jr., and Morrow, A. G.: Familial congenital heart disease, Am. J. Med. 40" 384, 1966. Peterson, T. A., Todd, D. B., and Edwards, J. E.: Supravalvular aortic stenosls, J. Thoracic & Cardiovas. Surg. 50" 734, 1965. Edwards, J. E.: Pathology of left ventricular

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outflow tract obstruction, Circulation 31: 586, 1965. Morrow, A. G., Waldhausen, J. A., Peters, R. L., Bloodwell, R. D., and Braunwald, E.: Supravalvular aortic stenosis. Clinical, hemodynamic and pathological observations, Circulation 20: 1003, 1959. Beuren, A. J., Schulze, C., Eberle, P., Harmjanz, D., and Apitz, J,: The syndrome of supravalvular aortic stenosis, peripheral pulmonary stenosis, mental retardation and similar facial appearance, Am. J. Cardiol. 13: 471, 1964. Perou, M. L.: Congenital supravalvular aortic stenosis, Arch. Path. 71:453, 1961. Bourassa, M. G., and Campeau, L.: Combined supravalvular aortic and pulmonary stenosis, Circulation 28: 572, 1963. Myers, A. R., and Wiliis, P. W, III: Clinical spectrum of supravalvular aortic stenosis, Arch. Intern. Med. 118: 553, 1966. Ottesen, O. E., Antia, A. U., and Rowe, R. D.: Peripheral vascular anomalies associated with the supravalvular aortic stenosis syndrome, Radiology 86: 430, 1966. Fay, J. E., Lynn, R. B., and Partington, M. W.: Supravalvular aortic stenosis, mental retardation and a characteristic facies, Canad. M. A. J. 9t: 295, 1966. Kreel, I., Relss, R., Strauss, L., Blumenthal, S., and Baronofsky, I. D.: Supra-valvular stenosls of the aorta, Ann. Surg. 149: 519, 1959. Takekawa, S. D., Kineaid, O. W., Titus, J. L., and DuShane, J. W.: Congenital aortic stenosis, Am. J. Roentgenol. 98: 800, 1966.

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34. Neufeld, H. N., Wagenvoort, C. A., Ongley, P. A., and Edwards, J. E.: Hypoplasia of ascending aorta. An unusual form of supravalvular aortic stenosis with special reference to localized coronary arterial hypertension, Am. J. Cardiol. 10: 746, 1962. 35. Esterly, J. R., and Oppenheimer, E. H.: Vascular lesions in infants with congenital rubella, Circulation 36: 544, 1967. 36. Noren, G. R., Raghib, G., Moller, J. H., Amplatz, K., Adams, P., Jr., and Edwards, J. E.: Anomalous origin of the left coronary artery from the pulmonary trunk with special reference to the occurrence of mitral insufficiency, Circulation 30: 171, 1964. 37. Williamson, D. A. J.: Supravalvular aortic stenosis associated with mental and physical retardation and a characteristic facies, Proe. Roy. Soc. Med. 57: 118, 1964. 38. Gillman, J., and Gilbert, C.: Calcium, phosphorus and vitamin D as factors regulating the integrity of the cardiovascular system, Exper. Med. & Surg. 14: 136, 1956. 39. Friedman, W. F., and Roberts, W. C.: Vitamin D and the supravalvular aortic stenosis syndrome, Circulation 34: 77, 1966. 40. Menser, M. A., Dorman, D. C., Reye, R. D. K., and Reid, R, R.: Renal artery stenosis in rubella, Lancet 1: 571, 1967. 41. Way, R. C.: Cardiovascular defects and the rubella syndrome, Canad. M. A. J. 97: 1329, 1967. 42. Campbell, P. E.: Vascular abnormalities following maternal rubella, Brit. Heart J. 27: 134, 1965.