Pediatr Cardiol (2014) 35:1309–1320 DOI 10.1007/s00246-014-0998-z
REVIEW ARTICLE
Williams-Beuren Syndrome: Computed Tomography Imaging Review Karuna M. Das • Tarek S. Momenah • Sven G. Larsson • Shehla Jadoon • Abdullah S. Aldosary • Edward Y. Lee
Received: 16 June 2014 / Accepted: 31 July 2014 / Published online: 20 August 2014 Ó Springer Science+Business Media New York 2014
Abstract Williams-Beuren syndrome (WBS) affects young infants and children. The underlying etiopathogenesis of this rare disease is due to the mutation of the elastin gene that is responsible for the elasticity of the arterial wall. As a result of inadequate elastin production, the major systemic arteries become abnormally rigid and can be manifested by an impediment to the blood flow. The most common cardiovascular abnormalities encountered in WBS are supravalvular aortic stenosis, pulmonary arterial stenosis, and mitral valve prolapse. Less frequently observed cardiovascular abnormalities include coarctation of the aorta, ventricular septal defect, patent ductus, subaortic stenosis, and hypertrophic cardiomyopathy. Coronary artery stenosis and severe impediment to the bi-ventricular outflow as a result of supravalvular aortic and pulmonary artery stenosis predispose patients to sudden death. Patients with progressed arterial stenosis and severe stenosis are likely to require intervention to prevent serious complications. Rarely, imaging findings may precede clinical presentation, which allows the radiologist to participate in the patient care. However, to be more prudent, the radiologist must be accustomed to K. M. Das (&) S. G. Larsson A. S. Aldosary Department of Medical Imaging, King Fahad Medical City, Riyadh 11525, Kingdom of Saudi Arabia e-mail: [email protected] T. S. Momenah S. Jadoon Department of Pediatric Cardiology, Prince Salman Heart Center, King Fahad Medical City, Riyadh 11525, Kingdom of Saudi Arabia E. Y. Lee Departments of Radiology and Medicine, Pulmonary Divisions, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA
the imaging characteristics of WBS as well as the patient’s clinical information, which could raise the suspicion of WBS. We performed a retrospective analysis of all the available images from patients diagnosed with WBS in last 4 years at our institution, and present key imaging findings along with a review of the literature to summarize the clinically relevant features as demonstrated by multidetector computed tomography in WBS. Cross-sectional imaging plays a vital role in the diagnosis of WBS cases with equivocal clinical features. MDCT evaluation of complex cardiovascular abnormalities of WBS including coronary artery disease is feasible with modern MDCT scanners and in the future, this approach could provide accurate information for planning, navigation, and noninvasive assessment of the secondary arterial changes in WBS and thus reducing the dependence upon invasive contrast catherization techniques. Keywords Williams-Beuren syndrome Supravalvular aortic stenosis Supravalvular pulmonary artery stenosis Coronary artery disease Pulmonary artery diverticulum MDCT
Introduction Williams-Beuren syndrome (WBS) is a condition that affects young infants and children. Patients present with obstructive lesions of large- and medium-sized arteries due to generalized arteriopathy. WBS is an autosomal dominant inheritance condition characterized by typical facies, mild mental retardation, extroverted personality, growth delay, and congenital disorders involving
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cardiovascular, connective tissue, and central nervous systems [25]. Structural cardiovascular abnormalities are present in 80 % of cases with concomitant systemic arterial stenosis of the neck vessels, abdominal aorta, mesenteric arteries, peripheral and intracranial vessels [10, 43]. The most common cardiovascular abnormalities in WBS are supravalvular aortic stenosis (SVAS), pulmonary arterial stenosis, and mitral valve prolapse. Less frequently observed cardiovascular abnormalities include coarctation of the aorta, ventricular septal defect, patent ductus arteriosus, subaortic stenosis, and hypertrophic cardiomyopathy [9]. In WBS patients with an equivocal clinical examination, modern imaging techniques are highly accurate at detecting structural abnormalities such as coronary artery disease, severe SVAS, and pulmonary artery stenosis (PAS), which can lead to death. The radiologist, therefore, plays a pivotal role in the initial care and appropriate surgical referral of WBS patients. Currently, comprehensive review of multidetector row computed tomography (MDCT) findings of WBS is sparse [23] and, to our knowledge, this is the first complete pictorial review to provide a description of crosssectional imaging findings related to the pathological process of WBS.
Historical Perspective In 1961, J. C. P. Williams first described a small group of patients with SVAS, typical facies, growth delay, mild mental retardation, and extroverted personality [55]. Later, in 1962, A. J. Beuren reported 11 new patients [5] with these symptoms, and the condition has been termed WBS ever since [5]. Equipped with improved molecular genetics diagnostic techniques, Ewart et al. used fluorescent in situ hybridization to explain hemizygosity of the elastin gene locus in patients with WBS, and this is used to confirm a diagnosis of WBS [17]. The current basis for diagnosis is identification of the contiguous gene deletion of the WBS critical region that includes the elastin gene. An overwhelming majority of patients with a clinical diagnosis of WBS have this adjoining gene deletion, which can be detected using fluorescent in situ hybridization or deletion/ duplication testing [37].
Epidemiology WBS occurs in 1 per 7,500–20,000 births, and most cases are sporadic. It is panethnic, and the prevalence of certain clinical features may vary among populations. For example, the incidence of cardiovascular abnormalities is lower in the Greek community [2], and peripheral pulmonary
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stenosis is more common than supra aortic stenosis in the Hong Kong Chinese population [56]. WBS may appear at any age from birth to adulthood. Antenatal diagnosis of WBS can be made by typical cardiovascular lesions in utero [57]. Both sexes are equally affected [47]. If a parent is affected by WBS, the risk of siblings being affected is 50 % [45]; however, in clinically unaffected parents, the risk to siblings of a proband appears to be reduced and only a few familial cases have been reported [37].
Pathogenesis The pathogenesis of WBS vasculopathy is not yet understood. Reduced and abnormal elastin content in the media of developing vessels may lead to recurrent injury and fibrosis. Vascular inelasticity may increase hemodynamic stress to the endothelium leading to intimal proliferation of smooth muscle and fibroblasts, fibrosis, and luminal narrowing of the vessels [28].
Clinical Presentation The clinical features of children with WBS manifest with growth and developmental delay, primarily involving language, auditory function, cognitive development, and visuospatial function [36]. Children with WBS may have mild-to-moderate mental retardation, but the range includes average ability to severe mental retardation [36]. The children often present with failure to thrive and have prenatal and postnatal developmental delay. Some patients present with cardiac murmur because of congenital heart disease and other patients may present with hypertension. Usually, children with WBS are overly friendly, inattentive, hyperactive, and hypersensitive to loud sounds [7, 19]. By contrast, affected adults are passionate with poor societal associations and apprehension, preoccupations and obsessions, phobias, panic attacks, and depression [33]. Unexpected death may occur in such patients, with reported risk 25- to 100-fold higher than in age-matched control subjects [54]. The underlying causes of sudden death in WBS patients include bi-ventricular outflow tract obstruction with ventricular hypertrophy because of severe pulmonary stenosis and SVAS with myocardial ischemia secondary to coronary insufficiency. Rarely, death can occur because of a cerebral stroke occurring at a younger age due to increased stiffness, hypertension, and narrowing of intracranial vessels [31]. Hypercalcemia tends to induce early changes of atherosclerosis with stiffening of the arterial wall in children with WBS, leading to systemic hypertension [12].
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Fig. 1 Supravalvular aortic stenosis of one-month-old girl with WBS. Sagittal oblique contrast-enhanced maximum intensity projection CT image shows hourglass supravalvular stenosis (arrow)
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Fig. 3 Gross hypertrophy of the wall of right and left ventricle in one-month-old girl with SVAS and PAS due to WBS. Short axis view of contrast-enhanced maximum intensity projection CT image shows hypertrophy of right (thin arrow) and left ventricular wall (thick arrow)
Fig. 2 Supravalvular aortic stenosis in a 15-month-old boy with WBS. Sagittal oblique contrast-enhanced maximum intensity projection CT image shows diffuse type of supravalvular stenosis (arrow)
Spectrum of Imaging Features Sinotubular Junction and Aorta
Fig. 4 Distorted aortic root in a 5-month-old boy with WBS. Axial oblique 3D volume-rendered CT endocardial view shows the deformed wall of the aortic root with normal noncoronary sinus (arrow). Distorted right (arrowhead) and left coronary sinus (black arrow)
Supravalvular Aortic Stenosis Supravalvular aortic stenosis is the most common type of arteriopathy in WBS and occurs in 45–75 % of patients [22].
The cardiovascular disease is more severe in males than females [47]. The exact pathogenesis of arteriopathy in WBS is not yet clear. Early studies suggested that excessive
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Fig. 5 Thickened aortic valve in WBS in one-month-old girl. a Coronal oblique contrast-enhanced maximum intensity projection CT image shows hourglass type of supravalvular aortic stenosis (arrowhead). Thickened and stretched dome-shaped aortic valve
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(ECG phase 60 %) seen abutting the wall of the sinotubular junction in an upward direction (arrow). b Static image of echocardiography shows the thick-walled sinotubular junction (thin arrow) with thickened aortic valve (arrow)
deposition of collagen in the elastic sheet during the prenatal period and disorganization of elastic fibers in the aorta may underlie SVAS in WBS [22]. Morphologically, SVAS may be hourglass shaped (Fig. 1), diffuse (Fig. 2), or membranous. Membranous SVAS is rare and presents as constricting semicircular valve-like membranes at the sinotubular junction [40]. The progression of SVAS is most rapid in the first 5 years and then slows down gradually [10]. If left untreated, SVAS may cause an increase in arterial resistance, raised left ventricular pressure, cardiac hypertrophy (Fig. 3), and subsequent cardiac failure [18]. Moreover, the recognition of distorted geometry of the aortic root (Fig. 4) has significant implications for surgical therapy with an aim to reduce the left ventricular pressure overload, by placing simple or elongated patch enlargement of the sinotubular junction above the noncoronary sinus [18]. Aortic Valve Thickening After the first successful surgical relief of SVAS, attention is focused on the influence of SVAS on aortic valve morphology and function [35]. Aortic valve abnormalities are found in 30–45 % of WBS cases with SVAS at surgery or necropsy [27]. A rigid inflexible sinotubular junction during systole restricts straightening the leaflet free edges of the aortic valve and maximizes the fatigue stress, promoting premature degeneration of the leaflets. The aortic valve leaflets are thickened and stretched (Fig. 5) with partial or total adherence to the narrowed sinotubular junction (Fig. 6) [38, 41]. Adhesion of the
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Fig. 6 Thickened and adherent aortic valve cusp to the sinotubular wall in WBS in a 5-month-old boy. Coronal oblique contrastenhanced maximum intensity projection CT image shows nodular thickening of the aortic valve cusp (ECG phase 60 %) adherent to the sinus wall (arrow)
aortic valve leaflet at the sinotubular junction is the most common valve defect in WBS and occurs in approximately 50 % of patients [49]. Although echocardiography is the primary method for evaluating the aortic valve,
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Fig. 7 Aortic diverticulum in WBS in a 5 month-old boy. a 3D Volume rendering contrast-enhanced CT image shows supravalvular aortic stenosis (arrowhead) with a well-defined diverticulum arising from the sinotubular junction (arrow). Origin of RCA (thin arrow).
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b 3D volume rendering contrast-enhanced CT endocardial view reveals the connection of the diverticulum with a narrow neck (arrow) opening into the aortic lumen
computed tomography (CT) and magnetic resonance imaging (MRI) provide substantial information on the function and structure of the aortic valve [2]. Aortic Diverticulum Aortic diverticulum formation at the sinotubular junction (Fig. 7) has not previously been reported in WBS. Deficient elastin of the aortic wall and intraluminal high-pressure hemodynamics because of supra aortic stenosis may be responsible for the formation of aortic diverticulum in WBS [48]. An aortic diverticulum can be documented by two-dimensional contrast-enhanced MDCT, but is more clearly depicted by three-dimensional endocardial view imaging, where full details of the aortic wall can also be seen (Fig. 7b). Aortic Hypoplasia Aorta may be involved in WBS either with minor hypoplasia (Fig. 8) or diffuse narrowing [45]. Middle aortic syndrome with diffuse narrowing of the thoracic and abdominal aorta is present in more than 55 % of WBS patients, as reported by Radford et al. in 10 out of 18 of their WBS patients [45]. Pulmonary Artery Pulmonary Artery Stenosis Pulmonary artery stenosis is the second most common cardiovascular abnormality associated with WBS [9]. The
Fig. 8 Aortic hypoplasia in WBS in a 5-month-old boy. 3D volume rendering contrast-enhanced CT image shows hypoplasia of the proximal thoracic aorta just after branching of the left subclavian artery (arrowhead). Supravalvular aortic stenosis is noted (arrow)
pathological process responsible for pulmonary stenosis is diffuse wall thickening consisting of intimal proliferation, fibrosis, medial dysplasia with hypertrophy, and nonparallel mosaic arrangement of smooth muscle cells [20, 51]. PAS is more common in young WBS patients than in old patients [29]. PAS can be unilateral, bilateral, and multiple (Fig. 9) with hypoplasia of the pulmonary artery bed. Peripheral and branch stenosis of the pulmonary artery are
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Fig. 9 Multiple pulmonary artery stenosis in WBS in a 15-month-old boy. a Coronal oblique contrast-enhanced maximum intensity projection CT image shows two areas of pulmonary artery narrowing (arrowhead) at the origin of the right pulmonary artery and the
beginning of the inferior lobar division of the left pulmonary artery (arrow). Corresponding conventional angiographic anterior posterior image (b) reveals the same areas of narrowing (arrowhead and arrow) corroborating the CT image
Fig. 10 Diffuse pulmonary artery narrowing in WBS in a 5-monthold boy. Axial oblique contrast-enhanced maximum intensity projection CT image shows diffuse narrowing (arrows) of the right pulmonary artery and its branches
Fig. 11 Supravalvular pulmonary artery stenosis in WBS one-monthold girl. Sagittal oblique contrast-enhanced maximum intensity projection CT image shows supravalvular pulmonary artery stenosis (arrowhead) with thin low attenuated pulmonary valve leaflets (black arrow). The right ventricular wall and infundibulum show marked hypertrophy (white arrow)
more common than diffuse stenosis of large segments (Fig. 10) [29].
pulmonic stenosis may cause significant hemodynamic changes due to systemic role of the right ventricle during intrauterine period. Subsequently, after birth, the supravalvular pulmonary stenosis loses its significance and the presence of associated SVAS becomes a dominant feature [16]. Although SVAS progresses with age, pulmonary artery changes improve with time [16]. Pham et al. [42] reported a strong association between PAS and SVAS and
Supravalvular Pulmonary Artery Stenosis Supravalvular pulmonary artery stenosis (Fig. 11) is the least common cardiovascular abnormality associated with WBS and occurs in *12 % of patients [10]. Supravalvular
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Fig. 12 Pulmonary artery diverticulum in WBS in one-month-old girl. a Oblique contrast-enhanced maximum intensity projection CT image shows a bulging vascular structure (arrow) arising from the wall of the left pulmonary artery. b Sagittal oblique contrast-enhanced maximum intensity projection CT image shows nonconfluent pulmonary artery (arrowhead) arising from main pulmonary artery
trunk which ends in a pulmonary artery diverticulum (black arrow) and atrophied PDA (white arrow) as a thin tortuous vessel emerging from the tip of the diverticulum and extending toward the aortic ductal site. Hypertrophy of the infundibulum is noted with supravalvular pulmonic stenosis
Del Pasqua et al. reported of isolated PAS in 45.1 % of 150 patients with WBS [14].
reveals the pulmonary diverticulum, but also provides evidence that persistence of the pulmonary end of the arterial ductus is the cause of diverticulum formation. MDCT can reveal the atrophied ductus as an extension of an irregular contrast-filled tract arising from the tip of the diverticulum and coursing toward the aortic end of the arterial ductus (Fig. 12). Considering the location and direction of the tract, it is obvious that the contrast-filled irregular tract represents the remainder of the atrophied aortic side of the arterial ductus. Unlike angiography, which is a contrast luminography, MDCT has an added benefit of visualizing both the intra- and extra-luminal structure of vessels at the same time.
Pulmonary Artery Diverticulum Rarely, pulmonary artery diverticulum formation (Fig. 12) can be observed with WBS. In a series of 11 cases of WBS, Ahmad et al. documented pulmonary artery diverticulum arising from the bifurcation of the main pulmonary artery by cardiac catheterization in all cases [1], and proposed that pulmonary diverticulum is a pathognomonic marker of WBS. Pulmonary diverticulum may also be associated with tetralogy of Fallot without WBS and is caused by regression of the fourth and sixth brachial arteries [34]. In a review of 110 cases of tetralogy of Fallot, pulmonary diverticulum was noted in 48 % of cases with right-sided aortic arch and 26 % of cases with left-sided arch [34]. Pulmonary Artery Diverticulum and Partially Patent Ductus Arteriosus Although patent ductus arteriosus has been implicated as one of the pathogenesis for the formation of the pulmonary diverticulum, no documentary evidence is available to date to support this theory [1, 34]. Ahmad et al. did not find angiographic evidence of communication between the diverticulum and the aortic end of the ductus in any of their 11 cases of WBS [1]. On the other hand, MDCT not only
Coronary Arteries Abnormalities of the coronary arteries are relatively common in WBS and are found in 25–27 % of patients [15, 51]. In an autopsy series, dysplasia of the coronary arteries was observed in all patients with WBS and was more obstructive proximally than distally [51]. A varying degree of intimal hyperplasia, fibrosis, disruption, and loss of the internal elastic membrane, medial hypertrophy, and adventitial fibroelastosis was noted in the coronary artery [51]. Coronary insufficiency in WBS puts the patient at high risk of death [47]. The thickening of the aortic or sinus wall in WBS is responsible for obstructing the coronary orifice and restricting coronary inflow [44]. Coronary
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Fig. 13 Tortuous course of coronary artery in WBS in one-month-old girl. a Oblique axial contrast-enhanced maximum intensity projection CT image shows tortuous course of the left anterior descending
arteries in WBS are also subjected to elevated prestenotic systolic pressure, resulting in their tortuosity (Fig. 13), dilatation (Fig. 14), and premature arteriosclerosis (Fig. 15) [44, 51]. Kim et al. [29] found SVAS and high intra-aortic intraluminal pressure in seven of 26 patients with WBS and coronary artery disease. These seven patients had a smaller sinotubular ratio (0.46 vs. 0.61, p = 0.021) and a higher pressure gradient between the left ventricle and the aorta (67.6 vs. 42.2, p = 0.023) than WBS patients with normal coronary arteries [29]. An abnormally high systolic pressure in SVAS may increase subepicardial flow but does not alter diastolic coronary flow, which is responsible for the subendocardial perfusion [52]. Subendocardial ischemia in SVAS is primarily caused by a systolic and diastolic supply–demand ratio of \0.7, and blood flow may be further compromised by coronary osteal narrowing due to thickened aortic or sinus wall specially when the coronary orifice is close to the narrowed sinotubular junction or adhesion of the aortic valve leaflet to the edge of the narrowed sinotubular junction (Fig. 16) [52]. Isolated coronary anomalies are rare in WBS but should be suspected, in the presence of ischemia or heart failure in childhood [50]. Sudden death due to drop of coronary perfusion pressure may occur during cardiac catheterization, after induction of anesthesia for minor surgical procedures, and heart surgery [6, 8, 54]; thus, there is a need for a reliable noninvasive imaging test that detects coronary artery lesions. MRI is insufficient for the evaluation of coronary anatomy. MDCT angiography, on the other hand, can be used to obtain all the relevant information of most of the arteries, including the coronary arteries, in the same sitting [39].
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coronary artery (arrow). b Conventional coronary angiography reveals the tortuous course of the left anterior descending artery (arrow)
Fig. 14 Dilated coronary artery in WBS in a 5-month-old boy. Coronal oblique 3D volume-rendered CT endocardial view shows dilated right coronary artery (thick arrow) with normal right coronary sinus (thick black arrow) and relatively smaller diameter at the origin of left main coronary artery (arrowhead) and distally the left coronary artery regained its normal size (white thin arrow). The left coronary sinus is distorted (black thin arrow) compared to right coronary sinus (black thick arrow)
Other Systemic Arteriopathies In 20 % of cases of WBS, arteriopathy involves the elastic arteries and appears as a localized or diffuse narrowing. Pathological studies have demonstrated generalized arterial wall thickening even in nonstenotic areas due to an increased number of lamellar units and expansion of media [32]. It is essential to diagnose concomitant stenosis of
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Fig. 15 Diffuse narrowing of coronary artery in a 15-month-old boy with WBS. Axial oblique contrast-enhanced maximum intensity projection CT image shows (a) markedly irregular beaded appearance of a second branch of left anterior descending artery with multiple narrowing (arrows) and (b) A high-grade narrowing of proximal RCA (arrow) and the rest of the artery is not visualized. c Conventional
coronary angiography anterior posterior image reveals the two branches of left anterior descending artery and the second branch shows several areas of narrowing (arrows). The first branch of the left anterior descending artery is also showing moderate narrowing at the mid part (arrowhead). The RCA is faintly visualized, and only proximal part is seen (black arrow)
other arteries prior to surgery for SVAS, to preclude perior post-operative hypoperfusion of the organs with arterial narrowing. The common sites of arterial involvement are the neck vessels (Fig. 17), abdominal aorta, mesenteric arteries (Fig. 18), celiac arteries (Fig. 18), renal arteries (Fig. 19), and intracranial vessels [10]. Rose et al. [46] reported a high incidence of renal artery stenosis in 15 out of 17 cases of WBS patients with arterial hypertension.
developmental delay, short stature, distinctive faces, and congenital heart disease. Noonan syndrome, DiGeorge syndrome, Smith-Magenis syndrome, and Kabuki syndrome may present with similar features with some distinct differences [11, 13, 26, 30]. Noonan syndrome is characterized by short stature, pulmonary valve stenosis in 20–50 % of cases, hypertrophic cardiomyopathy in 20–30 % of cases, atrial and ventricular septal defects, branch PAS, and tetralogy of Fallot [11]. DiGeorge syndrome has characteristic facial features and is associated with palatal abnormalities in 69 % of cases, congenital heart disease in 74 % of cases, particularly conotruncal malformations with tetralogy of Fallot, interrupted aortic arch, ventricular
Differential Diagnosis Williams-Beuren syndrome must be differentially diagnosed from other diseases that present with
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Fig. 16 Close apposition of aortic valve leaflets to sinotubular junction in 1-month-old girl with WBS. Coronal oblique contrastenhanced maximum intensity projection CT image shows aortic valve leaflet closely apposed to the inner wall (arrows) of the diffusely narrowed of sinotubular junction (ECG phase 75 %) and causing isolation of both coronary sinuses. Both the coronary arteries are noted to emerge from the isolated sinuses (arrowheads)
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Fig. 18 Celiac and mesenteric artery narrowing in a 5-month-old boy with WBS. Sagittal oblique contrast-enhanced maximum intensity projection CT image shows narrowing (arrows) at the origin of both celiac and superior mesenteric artery
Fig. 19 Bilateral renal artery stenosis in a 5-month-old boy with WBS. Axial oblique 3D volume-rendered CT image shows narrowing (arrows) of both the renal arteries at the origin
typical facial features with congenital heart defects in approximately 40–50 % of individuals with obstructive lesions, especially coarctation of the aorta and septal defects [9]. Fig. 17 Multiple neck vessels narrowing in a 15-month-old boy with WBS. Sagittal oblique maximum intensity projection CT image shows narrowing (arrow) at the beginning of all three neck vessels
Radiation Dose Considerations
septal defect, and truncus arteriosus [4]. Smith-Magenis syndrome is characterized by distinctive physical features, developmental delay, cognitive impairment, and behavioral abnormalities without any major cardiovascular defects [13]. Kabuki syndrome is characterized by
Although echocardiography is the mainstay of diagnosis of congenital heart defects in infants and neonates, computed tomographic angiography and cardiac catheterization are utilized as an adjunct in difficult cases for better understanding of the anatomical details. Cardiac CT is
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increasingly being used in children for assessment of intracardiac structures, coronary arteries, ventricular volumetry, and ventricular function [21]. With modern MDCT scanners and dose modulating software, the radiation dose can be reduced significantly (median effective age-adjusted radiation dose of 0.97 ± 1.20 mSv) by various dose reduction strategies with maintenance of diagnostic image quality [21, 24]. Watson et al. [53], in a cohort of 50 children of \1 year of age, reported the effective dose for the CT angiography to be 0.76 mSv compared with 13.4 mSv for the catheterization group (p \ 0.0001). In infants and children, a balance between maintenance of diagnostic accuracy and reduction of radiation exposure remains a difficult decision.
Conclusion Arterial stenosis is a matter of concern for the majority of patients with WBS. Most affected patients experience a mild course, but a small number, especially those with associated coronary artery disease and SVAS, require careful observation either with echocardiography or other noninvasive imaging. MDCT evaluation of complex cardiovascular abnormalities of WBS including coronary artery disease is feasible with modern MDCT scanners and, in the future, this approach could provide accurate information for planning, navigation, and noninvasive assessment of the secondary arterial changes in WBS and thus reducing the dependence upon invasive contrast catherization techniques.
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pulmonary arterial stenosis in Williams’ syndrome. Cardiol Young 9:37–41 Kobayashi D, Sallaam S, Humes RA (2013) Tetralogy of Fallot with complete DiGeorge syndrome: report of a case and a review of the literature. Congenit Heart Dis 8(4):E119–E126 Lee WD, Hsu JJ, Huang FC, Chao MC, Chang YL, Huang MH (2009) Ischemic stroke in Williams-Beuren syndrome: a case report. Kaohsiung J Med Sci 25(4):212–216 Li DY, Faury G, Taylor DG, Davis EC, Boyle WA, Mecham RP et al (1998) Novel arterial pathology in mice and humans hemizygous for elastin. J Clin Invest 102:1783–1787 Lopez-Rangel E, Maurice M, McGillivray B, Friedman JM (1992) Williams syndrome in adults. Am J Med Genet 44(6):720–729 Matsuyama S, Watanabe T, Watabe T, Kuribayashi Y, Tina T, Shohtsu A et al (1977) Pulmonary artery diverticulum associated with tetralogy of Fallot. Tokai J Exp Clin Med 2:113–121 McGoon DC, Mankin HT, Vlad P, Kirklin JW (1961) The surgical treatment of supravalvular aortic stenosis. J Thorac Cardiovasc Surg 41:125–133 Mervis CB, Robinson BF, Bertrand J, Morris CA, Klein-Tasman BP, Armstrong SC (2000) The Williams syndrome cognitive profile. Brain Cogn 44(3):604–628 Morris CA, Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, et al (1999) editors. GeneRevieWBSTM (Internet). Seattle (WA): University of Washington, Seattle; 1993-2013. Morrow AG, Waldhausen JA, Peters RL, Bloodwell RD, Braunwald E (1959) Supravalvular aortic stenosis: clinical, hemodynamic and pathologic observations. Circulation 20:1003–1010 Paul JF, Rohnean A, Sigal-Cinqualbre A (2010) Multidetector CT for congenital heart patients: what a paediatric radiologist should know. Pediatr Radiol 6:869–875 Perou ML (1961) Congenital supravalvular aortic stenosis. A morphological study with attempt at classification. Arch Pathol 71:453–466 Peterson TA, Todd DB, Edwards JE (1965) Supravalvular aortic stenosis. J Thorac Cardiovasc Surg 50:734–741 Pham PP, Moller JH, Hills C, Larson V, Pyles L (2009) Cardiac catheterization and operative outcomes from a multicenter consortium for children with Williams syndrome. Pediatr Cardiol 30:9–14 Pober BR. Williams-Beuren syndrome (2001) N Engl J Med 362:239–252 Pober BR, Johnson M, Urban Z (2008) Mechanisms and treatment of cardiovascular disease in Williams-Beuren syndrome. J Clin Invest 118:1606–1615
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Pediatr Cardiol (2014) 35:1309–1320 45. Radford DJ, Pohlner PG (2000) The middle aortic syndrome: an important feature of Williams’ syndrome. Cardiol Young 10: 597–602 46. Rose C, Wessel A, Pankau R, Partsch CJ, Bu¨rsch J (2001) Anomalies of the Abdominal aorta in Williams-Beuren syndrome—another cause of arterial hypertension. Eur J Pediatr 160:655–658 47. Sadler LS, Pober BR, Grandinetti A, Scheiber D, Fekete G, Sharma AN et al (2001) Differences by sex in cardiovascular disease in Williams syndrome. J Pediatr 139(6):849–853 48. Schaefer BM, Lewin MB, Stout KK, Byers PH, Otto CM (2007) Usefulness of bicuspid aortic valve phenotype to predict elastic properties of the ascending aorta. Am J Cardiol 99(5):686–690 49. Stamm C, Li J, Ho SY, Redington AN, Anderson RH (1997) The aortic root in supravalvular aortic stenosis: the potential surgical relevance of morphologic findings. J Thorac Cardiovasc Surg 114:16–24 50. van Pelt NC, Wilson NJ, Lear G (2005) Severe coronary artery disease in the absence of supravalvular stenosis in a patient with Williams syndrome. Pediatr Cardiol 26(5):665–667 51. van Son JAM, Edwards WD, Danielson GK (1994) Pathology of coronary arteries, myocardium, and great arteries in supravalvular aortic stenosis. J Thorac Cardiovasc Surg 108:21–28 52. Vincent WR, Buckberg GD, Hoffman JI (1974) Left ventricular subendocardial ischemia in severe valvular and supravalvular aortic stenosis: a common mechanism. Circulation 49:326–333 53. Watson TG, Mah E, Joseph Schoepf U, King L, Huda W, Hlavacek AM (2013) Effective radiation dose in computed tomographic angiography of the chest and diagnostic cardiac catheterization in pediatric patients. Pediatr Cardiol 34(3):518–524 54. Wessel A, Gravenhorst V, Buchhorn R (2004) Risk of sudden death in the Williams-Beuren syndrome. Am J Med Genet A 127(3):234–237 55. Williams JC, Barratt-Boyes BG, Lowe JB (1961) Supravalvular aortic stenosis. Circulation 24:1311–1318 56. Yau EK, Lo IF, Lam ST (2004) Williams-Beuren syndrome in the Hong Kong Chinese population: retrospective study. Hong Kong Med J. Feb 10(1):22-27. 57. Zaghloul N, Hutcheon RG, Tepperberg JH (2001) Visual diagnosis: monozygotic twins who have congenital heart disease and distinctive facial features. Pediatr Rev 23(10):365–367
REVIEW ARTICLE
Williams-Beuren Syndrome: Computed Tomography Imaging Review Karuna M. Das • Tarek S. Momenah • Sven G. Larsson • Shehla Jadoon • Abdullah S. Aldosary • Edward Y. Lee
Received: 16 June 2014 / Accepted: 31 July 2014 / Published online: 20 August 2014 Ó Springer Science+Business Media New York 2014
Abstract Williams-Beuren syndrome (WBS) affects young infants and children. The underlying etiopathogenesis of this rare disease is due to the mutation of the elastin gene that is responsible for the elasticity of the arterial wall. As a result of inadequate elastin production, the major systemic arteries become abnormally rigid and can be manifested by an impediment to the blood flow. The most common cardiovascular abnormalities encountered in WBS are supravalvular aortic stenosis, pulmonary arterial stenosis, and mitral valve prolapse. Less frequently observed cardiovascular abnormalities include coarctation of the aorta, ventricular septal defect, patent ductus, subaortic stenosis, and hypertrophic cardiomyopathy. Coronary artery stenosis and severe impediment to the bi-ventricular outflow as a result of supravalvular aortic and pulmonary artery stenosis predispose patients to sudden death. Patients with progressed arterial stenosis and severe stenosis are likely to require intervention to prevent serious complications. Rarely, imaging findings may precede clinical presentation, which allows the radiologist to participate in the patient care. However, to be more prudent, the radiologist must be accustomed to K. M. Das (&) S. G. Larsson A. S. Aldosary Department of Medical Imaging, King Fahad Medical City, Riyadh 11525, Kingdom of Saudi Arabia e-mail: [email protected] T. S. Momenah S. Jadoon Department of Pediatric Cardiology, Prince Salman Heart Center, King Fahad Medical City, Riyadh 11525, Kingdom of Saudi Arabia E. Y. Lee Departments of Radiology and Medicine, Pulmonary Divisions, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA
the imaging characteristics of WBS as well as the patient’s clinical information, which could raise the suspicion of WBS. We performed a retrospective analysis of all the available images from patients diagnosed with WBS in last 4 years at our institution, and present key imaging findings along with a review of the literature to summarize the clinically relevant features as demonstrated by multidetector computed tomography in WBS. Cross-sectional imaging plays a vital role in the diagnosis of WBS cases with equivocal clinical features. MDCT evaluation of complex cardiovascular abnormalities of WBS including coronary artery disease is feasible with modern MDCT scanners and in the future, this approach could provide accurate information for planning, navigation, and noninvasive assessment of the secondary arterial changes in WBS and thus reducing the dependence upon invasive contrast catherization techniques. Keywords Williams-Beuren syndrome Supravalvular aortic stenosis Supravalvular pulmonary artery stenosis Coronary artery disease Pulmonary artery diverticulum MDCT
Introduction Williams-Beuren syndrome (WBS) is a condition that affects young infants and children. Patients present with obstructive lesions of large- and medium-sized arteries due to generalized arteriopathy. WBS is an autosomal dominant inheritance condition characterized by typical facies, mild mental retardation, extroverted personality, growth delay, and congenital disorders involving
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cardiovascular, connective tissue, and central nervous systems [25]. Structural cardiovascular abnormalities are present in 80 % of cases with concomitant systemic arterial stenosis of the neck vessels, abdominal aorta, mesenteric arteries, peripheral and intracranial vessels [10, 43]. The most common cardiovascular abnormalities in WBS are supravalvular aortic stenosis (SVAS), pulmonary arterial stenosis, and mitral valve prolapse. Less frequently observed cardiovascular abnormalities include coarctation of the aorta, ventricular septal defect, patent ductus arteriosus, subaortic stenosis, and hypertrophic cardiomyopathy [9]. In WBS patients with an equivocal clinical examination, modern imaging techniques are highly accurate at detecting structural abnormalities such as coronary artery disease, severe SVAS, and pulmonary artery stenosis (PAS), which can lead to death. The radiologist, therefore, plays a pivotal role in the initial care and appropriate surgical referral of WBS patients. Currently, comprehensive review of multidetector row computed tomography (MDCT) findings of WBS is sparse [23] and, to our knowledge, this is the first complete pictorial review to provide a description of crosssectional imaging findings related to the pathological process of WBS.
Historical Perspective In 1961, J. C. P. Williams first described a small group of patients with SVAS, typical facies, growth delay, mild mental retardation, and extroverted personality [55]. Later, in 1962, A. J. Beuren reported 11 new patients [5] with these symptoms, and the condition has been termed WBS ever since [5]. Equipped with improved molecular genetics diagnostic techniques, Ewart et al. used fluorescent in situ hybridization to explain hemizygosity of the elastin gene locus in patients with WBS, and this is used to confirm a diagnosis of WBS [17]. The current basis for diagnosis is identification of the contiguous gene deletion of the WBS critical region that includes the elastin gene. An overwhelming majority of patients with a clinical diagnosis of WBS have this adjoining gene deletion, which can be detected using fluorescent in situ hybridization or deletion/ duplication testing [37].
Epidemiology WBS occurs in 1 per 7,500–20,000 births, and most cases are sporadic. It is panethnic, and the prevalence of certain clinical features may vary among populations. For example, the incidence of cardiovascular abnormalities is lower in the Greek community [2], and peripheral pulmonary
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stenosis is more common than supra aortic stenosis in the Hong Kong Chinese population [56]. WBS may appear at any age from birth to adulthood. Antenatal diagnosis of WBS can be made by typical cardiovascular lesions in utero [57]. Both sexes are equally affected [47]. If a parent is affected by WBS, the risk of siblings being affected is 50 % [45]; however, in clinically unaffected parents, the risk to siblings of a proband appears to be reduced and only a few familial cases have been reported [37].
Pathogenesis The pathogenesis of WBS vasculopathy is not yet understood. Reduced and abnormal elastin content in the media of developing vessels may lead to recurrent injury and fibrosis. Vascular inelasticity may increase hemodynamic stress to the endothelium leading to intimal proliferation of smooth muscle and fibroblasts, fibrosis, and luminal narrowing of the vessels [28].
Clinical Presentation The clinical features of children with WBS manifest with growth and developmental delay, primarily involving language, auditory function, cognitive development, and visuospatial function [36]. Children with WBS may have mild-to-moderate mental retardation, but the range includes average ability to severe mental retardation [36]. The children often present with failure to thrive and have prenatal and postnatal developmental delay. Some patients present with cardiac murmur because of congenital heart disease and other patients may present with hypertension. Usually, children with WBS are overly friendly, inattentive, hyperactive, and hypersensitive to loud sounds [7, 19]. By contrast, affected adults are passionate with poor societal associations and apprehension, preoccupations and obsessions, phobias, panic attacks, and depression [33]. Unexpected death may occur in such patients, with reported risk 25- to 100-fold higher than in age-matched control subjects [54]. The underlying causes of sudden death in WBS patients include bi-ventricular outflow tract obstruction with ventricular hypertrophy because of severe pulmonary stenosis and SVAS with myocardial ischemia secondary to coronary insufficiency. Rarely, death can occur because of a cerebral stroke occurring at a younger age due to increased stiffness, hypertension, and narrowing of intracranial vessels [31]. Hypercalcemia tends to induce early changes of atherosclerosis with stiffening of the arterial wall in children with WBS, leading to systemic hypertension [12].
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Fig. 1 Supravalvular aortic stenosis of one-month-old girl with WBS. Sagittal oblique contrast-enhanced maximum intensity projection CT image shows hourglass supravalvular stenosis (arrow)
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Fig. 3 Gross hypertrophy of the wall of right and left ventricle in one-month-old girl with SVAS and PAS due to WBS. Short axis view of contrast-enhanced maximum intensity projection CT image shows hypertrophy of right (thin arrow) and left ventricular wall (thick arrow)
Fig. 2 Supravalvular aortic stenosis in a 15-month-old boy with WBS. Sagittal oblique contrast-enhanced maximum intensity projection CT image shows diffuse type of supravalvular stenosis (arrow)
Spectrum of Imaging Features Sinotubular Junction and Aorta
Fig. 4 Distorted aortic root in a 5-month-old boy with WBS. Axial oblique 3D volume-rendered CT endocardial view shows the deformed wall of the aortic root with normal noncoronary sinus (arrow). Distorted right (arrowhead) and left coronary sinus (black arrow)
Supravalvular Aortic Stenosis Supravalvular aortic stenosis is the most common type of arteriopathy in WBS and occurs in 45–75 % of patients [22].
The cardiovascular disease is more severe in males than females [47]. The exact pathogenesis of arteriopathy in WBS is not yet clear. Early studies suggested that excessive
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Fig. 5 Thickened aortic valve in WBS in one-month-old girl. a Coronal oblique contrast-enhanced maximum intensity projection CT image shows hourglass type of supravalvular aortic stenosis (arrowhead). Thickened and stretched dome-shaped aortic valve
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(ECG phase 60 %) seen abutting the wall of the sinotubular junction in an upward direction (arrow). b Static image of echocardiography shows the thick-walled sinotubular junction (thin arrow) with thickened aortic valve (arrow)
deposition of collagen in the elastic sheet during the prenatal period and disorganization of elastic fibers in the aorta may underlie SVAS in WBS [22]. Morphologically, SVAS may be hourglass shaped (Fig. 1), diffuse (Fig. 2), or membranous. Membranous SVAS is rare and presents as constricting semicircular valve-like membranes at the sinotubular junction [40]. The progression of SVAS is most rapid in the first 5 years and then slows down gradually [10]. If left untreated, SVAS may cause an increase in arterial resistance, raised left ventricular pressure, cardiac hypertrophy (Fig. 3), and subsequent cardiac failure [18]. Moreover, the recognition of distorted geometry of the aortic root (Fig. 4) has significant implications for surgical therapy with an aim to reduce the left ventricular pressure overload, by placing simple or elongated patch enlargement of the sinotubular junction above the noncoronary sinus [18]. Aortic Valve Thickening After the first successful surgical relief of SVAS, attention is focused on the influence of SVAS on aortic valve morphology and function [35]. Aortic valve abnormalities are found in 30–45 % of WBS cases with SVAS at surgery or necropsy [27]. A rigid inflexible sinotubular junction during systole restricts straightening the leaflet free edges of the aortic valve and maximizes the fatigue stress, promoting premature degeneration of the leaflets. The aortic valve leaflets are thickened and stretched (Fig. 5) with partial or total adherence to the narrowed sinotubular junction (Fig. 6) [38, 41]. Adhesion of the
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Fig. 6 Thickened and adherent aortic valve cusp to the sinotubular wall in WBS in a 5-month-old boy. Coronal oblique contrastenhanced maximum intensity projection CT image shows nodular thickening of the aortic valve cusp (ECG phase 60 %) adherent to the sinus wall (arrow)
aortic valve leaflet at the sinotubular junction is the most common valve defect in WBS and occurs in approximately 50 % of patients [49]. Although echocardiography is the primary method for evaluating the aortic valve,
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Fig. 7 Aortic diverticulum in WBS in a 5 month-old boy. a 3D Volume rendering contrast-enhanced CT image shows supravalvular aortic stenosis (arrowhead) with a well-defined diverticulum arising from the sinotubular junction (arrow). Origin of RCA (thin arrow).
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b 3D volume rendering contrast-enhanced CT endocardial view reveals the connection of the diverticulum with a narrow neck (arrow) opening into the aortic lumen
computed tomography (CT) and magnetic resonance imaging (MRI) provide substantial information on the function and structure of the aortic valve [2]. Aortic Diverticulum Aortic diverticulum formation at the sinotubular junction (Fig. 7) has not previously been reported in WBS. Deficient elastin of the aortic wall and intraluminal high-pressure hemodynamics because of supra aortic stenosis may be responsible for the formation of aortic diverticulum in WBS [48]. An aortic diverticulum can be documented by two-dimensional contrast-enhanced MDCT, but is more clearly depicted by three-dimensional endocardial view imaging, where full details of the aortic wall can also be seen (Fig. 7b). Aortic Hypoplasia Aorta may be involved in WBS either with minor hypoplasia (Fig. 8) or diffuse narrowing [45]. Middle aortic syndrome with diffuse narrowing of the thoracic and abdominal aorta is present in more than 55 % of WBS patients, as reported by Radford et al. in 10 out of 18 of their WBS patients [45]. Pulmonary Artery Pulmonary Artery Stenosis Pulmonary artery stenosis is the second most common cardiovascular abnormality associated with WBS [9]. The
Fig. 8 Aortic hypoplasia in WBS in a 5-month-old boy. 3D volume rendering contrast-enhanced CT image shows hypoplasia of the proximal thoracic aorta just after branching of the left subclavian artery (arrowhead). Supravalvular aortic stenosis is noted (arrow)
pathological process responsible for pulmonary stenosis is diffuse wall thickening consisting of intimal proliferation, fibrosis, medial dysplasia with hypertrophy, and nonparallel mosaic arrangement of smooth muscle cells [20, 51]. PAS is more common in young WBS patients than in old patients [29]. PAS can be unilateral, bilateral, and multiple (Fig. 9) with hypoplasia of the pulmonary artery bed. Peripheral and branch stenosis of the pulmonary artery are
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Fig. 9 Multiple pulmonary artery stenosis in WBS in a 15-month-old boy. a Coronal oblique contrast-enhanced maximum intensity projection CT image shows two areas of pulmonary artery narrowing (arrowhead) at the origin of the right pulmonary artery and the
beginning of the inferior lobar division of the left pulmonary artery (arrow). Corresponding conventional angiographic anterior posterior image (b) reveals the same areas of narrowing (arrowhead and arrow) corroborating the CT image
Fig. 10 Diffuse pulmonary artery narrowing in WBS in a 5-monthold boy. Axial oblique contrast-enhanced maximum intensity projection CT image shows diffuse narrowing (arrows) of the right pulmonary artery and its branches
Fig. 11 Supravalvular pulmonary artery stenosis in WBS one-monthold girl. Sagittal oblique contrast-enhanced maximum intensity projection CT image shows supravalvular pulmonary artery stenosis (arrowhead) with thin low attenuated pulmonary valve leaflets (black arrow). The right ventricular wall and infundibulum show marked hypertrophy (white arrow)
more common than diffuse stenosis of large segments (Fig. 10) [29].
pulmonic stenosis may cause significant hemodynamic changes due to systemic role of the right ventricle during intrauterine period. Subsequently, after birth, the supravalvular pulmonary stenosis loses its significance and the presence of associated SVAS becomes a dominant feature [16]. Although SVAS progresses with age, pulmonary artery changes improve with time [16]. Pham et al. [42] reported a strong association between PAS and SVAS and
Supravalvular Pulmonary Artery Stenosis Supravalvular pulmonary artery stenosis (Fig. 11) is the least common cardiovascular abnormality associated with WBS and occurs in *12 % of patients [10]. Supravalvular
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Fig. 12 Pulmonary artery diverticulum in WBS in one-month-old girl. a Oblique contrast-enhanced maximum intensity projection CT image shows a bulging vascular structure (arrow) arising from the wall of the left pulmonary artery. b Sagittal oblique contrast-enhanced maximum intensity projection CT image shows nonconfluent pulmonary artery (arrowhead) arising from main pulmonary artery
trunk which ends in a pulmonary artery diverticulum (black arrow) and atrophied PDA (white arrow) as a thin tortuous vessel emerging from the tip of the diverticulum and extending toward the aortic ductal site. Hypertrophy of the infundibulum is noted with supravalvular pulmonic stenosis
Del Pasqua et al. reported of isolated PAS in 45.1 % of 150 patients with WBS [14].
reveals the pulmonary diverticulum, but also provides evidence that persistence of the pulmonary end of the arterial ductus is the cause of diverticulum formation. MDCT can reveal the atrophied ductus as an extension of an irregular contrast-filled tract arising from the tip of the diverticulum and coursing toward the aortic end of the arterial ductus (Fig. 12). Considering the location and direction of the tract, it is obvious that the contrast-filled irregular tract represents the remainder of the atrophied aortic side of the arterial ductus. Unlike angiography, which is a contrast luminography, MDCT has an added benefit of visualizing both the intra- and extra-luminal structure of vessels at the same time.
Pulmonary Artery Diverticulum Rarely, pulmonary artery diverticulum formation (Fig. 12) can be observed with WBS. In a series of 11 cases of WBS, Ahmad et al. documented pulmonary artery diverticulum arising from the bifurcation of the main pulmonary artery by cardiac catheterization in all cases [1], and proposed that pulmonary diverticulum is a pathognomonic marker of WBS. Pulmonary diverticulum may also be associated with tetralogy of Fallot without WBS and is caused by regression of the fourth and sixth brachial arteries [34]. In a review of 110 cases of tetralogy of Fallot, pulmonary diverticulum was noted in 48 % of cases with right-sided aortic arch and 26 % of cases with left-sided arch [34]. Pulmonary Artery Diverticulum and Partially Patent Ductus Arteriosus Although patent ductus arteriosus has been implicated as one of the pathogenesis for the formation of the pulmonary diverticulum, no documentary evidence is available to date to support this theory [1, 34]. Ahmad et al. did not find angiographic evidence of communication between the diverticulum and the aortic end of the ductus in any of their 11 cases of WBS [1]. On the other hand, MDCT not only
Coronary Arteries Abnormalities of the coronary arteries are relatively common in WBS and are found in 25–27 % of patients [15, 51]. In an autopsy series, dysplasia of the coronary arteries was observed in all patients with WBS and was more obstructive proximally than distally [51]. A varying degree of intimal hyperplasia, fibrosis, disruption, and loss of the internal elastic membrane, medial hypertrophy, and adventitial fibroelastosis was noted in the coronary artery [51]. Coronary insufficiency in WBS puts the patient at high risk of death [47]. The thickening of the aortic or sinus wall in WBS is responsible for obstructing the coronary orifice and restricting coronary inflow [44]. Coronary
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Fig. 13 Tortuous course of coronary artery in WBS in one-month-old girl. a Oblique axial contrast-enhanced maximum intensity projection CT image shows tortuous course of the left anterior descending
arteries in WBS are also subjected to elevated prestenotic systolic pressure, resulting in their tortuosity (Fig. 13), dilatation (Fig. 14), and premature arteriosclerosis (Fig. 15) [44, 51]. Kim et al. [29] found SVAS and high intra-aortic intraluminal pressure in seven of 26 patients with WBS and coronary artery disease. These seven patients had a smaller sinotubular ratio (0.46 vs. 0.61, p = 0.021) and a higher pressure gradient between the left ventricle and the aorta (67.6 vs. 42.2, p = 0.023) than WBS patients with normal coronary arteries [29]. An abnormally high systolic pressure in SVAS may increase subepicardial flow but does not alter diastolic coronary flow, which is responsible for the subendocardial perfusion [52]. Subendocardial ischemia in SVAS is primarily caused by a systolic and diastolic supply–demand ratio of \0.7, and blood flow may be further compromised by coronary osteal narrowing due to thickened aortic or sinus wall specially when the coronary orifice is close to the narrowed sinotubular junction or adhesion of the aortic valve leaflet to the edge of the narrowed sinotubular junction (Fig. 16) [52]. Isolated coronary anomalies are rare in WBS but should be suspected, in the presence of ischemia or heart failure in childhood [50]. Sudden death due to drop of coronary perfusion pressure may occur during cardiac catheterization, after induction of anesthesia for minor surgical procedures, and heart surgery [6, 8, 54]; thus, there is a need for a reliable noninvasive imaging test that detects coronary artery lesions. MRI is insufficient for the evaluation of coronary anatomy. MDCT angiography, on the other hand, can be used to obtain all the relevant information of most of the arteries, including the coronary arteries, in the same sitting [39].
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coronary artery (arrow). b Conventional coronary angiography reveals the tortuous course of the left anterior descending artery (arrow)
Fig. 14 Dilated coronary artery in WBS in a 5-month-old boy. Coronal oblique 3D volume-rendered CT endocardial view shows dilated right coronary artery (thick arrow) with normal right coronary sinus (thick black arrow) and relatively smaller diameter at the origin of left main coronary artery (arrowhead) and distally the left coronary artery regained its normal size (white thin arrow). The left coronary sinus is distorted (black thin arrow) compared to right coronary sinus (black thick arrow)
Other Systemic Arteriopathies In 20 % of cases of WBS, arteriopathy involves the elastic arteries and appears as a localized or diffuse narrowing. Pathological studies have demonstrated generalized arterial wall thickening even in nonstenotic areas due to an increased number of lamellar units and expansion of media [32]. It is essential to diagnose concomitant stenosis of
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Fig. 15 Diffuse narrowing of coronary artery in a 15-month-old boy with WBS. Axial oblique contrast-enhanced maximum intensity projection CT image shows (a) markedly irregular beaded appearance of a second branch of left anterior descending artery with multiple narrowing (arrows) and (b) A high-grade narrowing of proximal RCA (arrow) and the rest of the artery is not visualized. c Conventional
coronary angiography anterior posterior image reveals the two branches of left anterior descending artery and the second branch shows several areas of narrowing (arrows). The first branch of the left anterior descending artery is also showing moderate narrowing at the mid part (arrowhead). The RCA is faintly visualized, and only proximal part is seen (black arrow)
other arteries prior to surgery for SVAS, to preclude perior post-operative hypoperfusion of the organs with arterial narrowing. The common sites of arterial involvement are the neck vessels (Fig. 17), abdominal aorta, mesenteric arteries (Fig. 18), celiac arteries (Fig. 18), renal arteries (Fig. 19), and intracranial vessels [10]. Rose et al. [46] reported a high incidence of renal artery stenosis in 15 out of 17 cases of WBS patients with arterial hypertension.
developmental delay, short stature, distinctive faces, and congenital heart disease. Noonan syndrome, DiGeorge syndrome, Smith-Magenis syndrome, and Kabuki syndrome may present with similar features with some distinct differences [11, 13, 26, 30]. Noonan syndrome is characterized by short stature, pulmonary valve stenosis in 20–50 % of cases, hypertrophic cardiomyopathy in 20–30 % of cases, atrial and ventricular septal defects, branch PAS, and tetralogy of Fallot [11]. DiGeorge syndrome has characteristic facial features and is associated with palatal abnormalities in 69 % of cases, congenital heart disease in 74 % of cases, particularly conotruncal malformations with tetralogy of Fallot, interrupted aortic arch, ventricular
Differential Diagnosis Williams-Beuren syndrome must be differentially diagnosed from other diseases that present with
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Fig. 16 Close apposition of aortic valve leaflets to sinotubular junction in 1-month-old girl with WBS. Coronal oblique contrastenhanced maximum intensity projection CT image shows aortic valve leaflet closely apposed to the inner wall (arrows) of the diffusely narrowed of sinotubular junction (ECG phase 75 %) and causing isolation of both coronary sinuses. Both the coronary arteries are noted to emerge from the isolated sinuses (arrowheads)
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Fig. 18 Celiac and mesenteric artery narrowing in a 5-month-old boy with WBS. Sagittal oblique contrast-enhanced maximum intensity projection CT image shows narrowing (arrows) at the origin of both celiac and superior mesenteric artery
Fig. 19 Bilateral renal artery stenosis in a 5-month-old boy with WBS. Axial oblique 3D volume-rendered CT image shows narrowing (arrows) of both the renal arteries at the origin
typical facial features with congenital heart defects in approximately 40–50 % of individuals with obstructive lesions, especially coarctation of the aorta and septal defects [9]. Fig. 17 Multiple neck vessels narrowing in a 15-month-old boy with WBS. Sagittal oblique maximum intensity projection CT image shows narrowing (arrow) at the beginning of all three neck vessels
Radiation Dose Considerations
septal defect, and truncus arteriosus [4]. Smith-Magenis syndrome is characterized by distinctive physical features, developmental delay, cognitive impairment, and behavioral abnormalities without any major cardiovascular defects [13]. Kabuki syndrome is characterized by
Although echocardiography is the mainstay of diagnosis of congenital heart defects in infants and neonates, computed tomographic angiography and cardiac catheterization are utilized as an adjunct in difficult cases for better understanding of the anatomical details. Cardiac CT is
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increasingly being used in children for assessment of intracardiac structures, coronary arteries, ventricular volumetry, and ventricular function [21]. With modern MDCT scanners and dose modulating software, the radiation dose can be reduced significantly (median effective age-adjusted radiation dose of 0.97 ± 1.20 mSv) by various dose reduction strategies with maintenance of diagnostic image quality [21, 24]. Watson et al. [53], in a cohort of 50 children of \1 year of age, reported the effective dose for the CT angiography to be 0.76 mSv compared with 13.4 mSv for the catheterization group (p \ 0.0001). In infants and children, a balance between maintenance of diagnostic accuracy and reduction of radiation exposure remains a difficult decision.
Conclusion Arterial stenosis is a matter of concern for the majority of patients with WBS. Most affected patients experience a mild course, but a small number, especially those with associated coronary artery disease and SVAS, require careful observation either with echocardiography or other noninvasive imaging. MDCT evaluation of complex cardiovascular abnormalities of WBS including coronary artery disease is feasible with modern MDCT scanners and, in the future, this approach could provide accurate information for planning, navigation, and noninvasive assessment of the secondary arterial changes in WBS and thus reducing the dependence upon invasive contrast catherization techniques.
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