Echocardiographic Features of Genetic Diseases: Part 6. Complex Cardiovascular Defects

SPECIAL REPORT

Echocardiographic Features of Genetic Diseases: Part 6. Complex Cardiovascular Defects Azra Alizad, MD, and James B. Seward, MD, Rochester, Minnesota

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chocardiographic features of complex cardiovascular defects are described in this sixth in a series of 8 articles. Down Syndrome Shone’s Syndrome Turner’s Syndrome Williams Syndrome

DOWN SYNDROME Pathologic Features Down syndrome (trisomy 21) is the most common phenotype caused by a human chromosome abnormality, occurring approximately once in every 500 to 600 births.The condition is caused by either the presence of an extra chromosome 21 or the presence of only the distal half of chromosome 21, band q22. The gene or genes responsible for Down syndrome are unknown, but the severity of the disease is believed to depend on the extent of the region q22 and beyond that is triplicated.1 Forty to sixty percent of patients with Down syndrome have congenital heart disease, most characteristically the endocardial cushion defect or atrioventricular (AV) canal defect. Fifty to seventy-five percent of patients with the complete form of AV canal defect have associated Down syndrome.2 Tetralogy of Fallot is also a common congenital heart defect in Down syndrome.3 Recently, the region of chromosome 21 related to heart disease was localized.1 Peculiar anatomic cardiac patterns are present in children with tetralogy of Fallot associated with genetic conFrom the Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minn. Reprint requests: James B. Seward, MD, Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. J Am Soc Echocardiogr 2000;13:637-43. Copyright © 2000 by the American Society of Echocardiography. 0894-7317/2000/$12.00 + 0 27/1/102342 doi:10.1067/mje.2000.102342

ditions.An accurate phenotypic analysis is essential in all patients with tetralogy of Fallot and may alert the cardiologist to look for additional cardiac anomalies. Atrioventricular canal defect is associated with tetralogy of Fallot in patients with Down syndrome.4 Clinical Manifestations In addition to the morphologic characteristics and mental retardation, among the most important abnormalities are cardiac defects (Figure 1). In the absence of severe pulmonary vascular obstructive disease, there may be no clinical evidence of systemic arterial oxygen desaturation. The symptoms and signs are similar to those of ventricular septal defect. Cardiac failure, repeated respiratory infections, and failure to thrive are frequent when pulmonary vascular obstruction is present.The electrocardiogram shows a prolonged PR interval and abnormal vectorcardiographic results, both indicators of right ventricular hypertrophy.7 Early recognition and correction of significant cardiac abnormalities reduce cardiorespiratory complications and improve lifestyle. Echocardiographic Features (Figures 2 and 3) The echocardiographic features of cardiac defects in Down syndrome have been described.8-11 Twodimensional echocardiography is an excellent noninvasive method for diagnosing cardiac malformations in Down syndrome. The endocardial cushion defect is the most common anomaly.9 The typical echocardiographic finding is type A complete AV defect (large primum atrial septal defect, common AV valve, insertion of anterior bridging leaflet on the crest of the ventricular septum, and an inflow ventricular septal defect).8,11 Other incomplete forms of AV canal are also encountered, including partial AV canal (primum atrial septal defect).Tetralogy of Fallot is the second most common lesion and can occur in conjunction with AV canal defect. Other complex cardiac abnormalities are less frequent.5,6

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Figure 1 Down syndrome. All patients with Down syndrome should have echocardiographic assessment shortly after birth to assess for the presence of congenital heart disease. Other clinical and diagnostic methods are much less suitable. Early and late complications are affected by the presence of associated cardiovascular abnormalities.5,6 Shown is a child with the classic physical features of Down syndrome.

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Figure 2 Down syndrome. This is an example of type A complete atrioventricular canal defect in patients with Down syndrome. The primum atrial septal defect (arrows) is best imaged in the 4-chamber plane. The distinguishing feature of this form of complete atrioventricular canal is that the insertions of the anterior components of the atrioventricular valve are to the crest of the ventricular septum (arrowhead). The ventricular septal defect may be partially obscured by chordae. The canal defect and associations are very predictable in Down syndrome. Two-dimensional echocardiography can aid diagnosis of atrioventricular canal and its variations in virtually 100% of patients. RA, Right atrium; LA, left atrium; LV, left ventricle; RV, right ventricle; VS, ventricular septum.

SHONE’S SYNDROME Pathologic Features This relatively rare disease usually is diagnosed during infancy or childhood. Shone’s syndrome includes at least 2 anomalies from the 4 potential obstructive anomalies that may coexist: parachute mitral valve, supravalvular ring of the left atrium, subaortic valve stenosis, and aortic coarctation.12-14 There is not enough information about the natural history of the disease;its origin and pathogenesis are poorly understood.

valve, and coarctation of the aorta.The syndrome usually presents with 2 or 3 of the 5 features.18 Other findings include dilatation and hypertrophy of the right ventricle and left atrium and enlarged left atrium with a normal or small left ventricle.17 Paramembranous-type ventricular septal defect and patent ductus arteriosus also have been reported.16

TURNER’S SYNDROME

Clinical Manifestations

Pathologic Features

The symptoms usually appear within the first 2 years of life. Affected infants are underdeveloped and often have dyspnea caused by congestive heart failure; cyanosis and pallor are common. Electrocardiography shows right ventricular hypertrophy with normal, bifid, or spiked P waves.15

Cardiovascular anomalies occur in 45% of patients with Turner’s syndrome, a condition that affects 1 in 2500 females as a result of a loss of some X-chromosome material, and thus patients most commonly have a karyotype of XO.1,19 Many cases are mosaic for cell lines with normal 46,XX or 46,XY makeup. The most common cardiac defect is coarctation of the aorta (COA). Various other cardiac defects also may occur, either singly or in combination with COA. Most of these include other left heart abnormalities, including bicuspid aortic valve, aortic stenosis, dilated ascending aorta, and hypoplastic left heart syndrome. Atrial and ventricular septal defects and

Echocardiographic Features (Figure 4) The echocardiographic features of cardiac defects in Shone’s syndrome have been described.16-18 The characteristic findings include a discrete subaortic membrane, single mitral papillary muscle (parachute valve), hypoplastic and stenotic mitral orifice, bicuspid aortic

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Figure 3 Down syndrome, tetralogy of Fallot. These are echocardiographic images of tetralogy of Fallot in an infant with Down syndrome. This patient did not also have atrioventricular canal defect. A, Subcostal 4-chamber plane showing the aorta (Ao) overriding the plane of the ventricular septum (VS) (arrow) and a large subaortic ventricular septal defect. B, Parasternal short-axis view at the level of the ascending aorta (Ao) and the hypoplastic and stenotic pulmonary valve and pulmonary outflow (arrows). This child underwent successful surgical correction. RV, Right ventricle; LV, left ventricle; LA, left atrium.

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Figure 4 Shone’s syndrome. Multiple associations of Shone’s syndrome are shown in these echocardiographic examples. A, Tunnel subaortic stenosis with fibrous plaque (arrow) in the left ventricular outflow beneath the aortic valve (AV). The left ventricular outflow is narrowed and hyper-refractile (fibrotic). Also note the thickened anterior leaflet of the mitral valve. B, A supravalvular mitral ring (arrows). Note that the MV annulus is small and the left atrium (LA) is enlarged. This patient had discrete subaortic stenosis. C, A more complex abnormality with a domed and bicuspid aortic valve (arrows) and tunnel subaortic stenosis with a markedly thickened anterior leaflet of the mitral valve (MV) (arrowheads). This patient also had a congenitally stenotic MV caused by parachute deformity. D, Suprasternal view of the descending thoracic aorta. A discrete coarctation is visualized (arrows) just after the takeoff of the left subclavian artery. Shone’s syndrome is multifaceted, and complete anatomical and hemodynamic assessment requires a meticulous noninvasive examination. ARCH, Aortic arch; Desc Ao, descending aorta; LPA, left pulmonary artery; LVO, left ventricular outflow; RV, right ventricle; RVO, right ventricular outflow; VS, ventricular septum.

partial anomalous pulmonary venous connection also have been reported. Postmortem examination of midtrimester abortuses with cytogenetic evidence of Turner’s syndrome has demonstrated a higher inci-

dence of left-sided flow lesions than found at birth, and an association between the pathogenesis of cardiovascular abnormalities and lymphatic obstruction may be important.1,20

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Figure 5 Turner’s syndrome. A, This 16-year-old patient had short stature with typical webbed posterior neck and broad chest. B, Other features included low posterior hairline (upper left), short fourth metacarpal and metatarsal (upper right and lower left), and deep-set nails (lower left and lower right).

Clinical Manifestations The clinical findings of Turner’s syndrome include lymphedema of the hands and feet, inguinal hernias, short stature, primary amenorrhea, webbed neck,

small chin, and other skeletal abnormalities (Figure 5).1 Coarctation of the aorta may be part of Turner’s syndrome. Patients with COA have systolic hypertension in the left ventricle and upper body, from

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Figure 6 Turner’s syndrome. Two cardiovascular anomalies commonly associated with Turner’s syndrome are shown in these echocardiograms. The 2 upper panels show the bicuspid aortic valve in diastole (left) and systole (right). The commissure between the right and left coronary cusp (arrow) is fused. In systole, the aortic orifice appears ovoid and does not open completely. These valves tend to degenerate with age. The bottom panel is a high parasternal view of the upper descending aorta (Desc Ao), showing a discrete juxtaductal coarctation. The aorta below the coarctation is mildly dilated (poststenotic dilatation). AV, Aortic valve; L, left-aortic sinus; LPA, left pulmonary artery; N, nonaortic sinus; R, rightaortic sinus; RVO, right ventricular outflow.

Figure 7 Williams syndrome. The typical appearance of Williams syndrome is elfin facies: prominent forehead, epicanthal folds, underdeveloped bridge of the nose and mandible, overhanging upper lip, strabismus, and abnormal dentition (widely spaced teeth).

which several complications may develop. These include heart failure, which may develop at any time from infancy to adulthood; cerebral hemorrhage, which may be from a berry aneurysm, aortic rup-

Figure 8 Williams syndrome. Supravalvular aortic stenosis is the most common cardiovascular accompaniment. This echocardiogram in an affected child shows diffuse hypoplasia of the ascending aorta (ASC Ao), particularly at the sinotubular junction (arrows). Discrete supravalvular stenosis is infrequent. In addition, the aortic wall is increased in thickness. AV, Aortic valve; RPA, right pulmonary artery; LA, left atrium.

ture, or dissection; and infective endocarditis or endarteritis. The usual electrocardiographic findings are left ventricular hypertrophy and left atrial enlargement.21

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Figure 9 Williams syndrome. A 7-year-old boy with severe and diffuse thoracic and abdominal aortic hypoplasia. The left panel shows a turbulent color flow Doppler signal in the abdominal aorta. However, velocities in the upper thoracic aorta were near normal. In the right panel, pulsed Doppler in the abdominal aorta shows prolongation of the signal consistent with severe coarctation. In this patient, Williams syndrome was diagnosed by anatomic and hemodynamic assessment. Patient had severe abdominal coarctation. RA, Right atrium; LA, left atrium.

Echocardiographic Findings (Figure 6) The most characteristic of the echocardiographic features of cardiovascular anomalies in Turner’s syndrome include bicuspid aortic valve and aortic coarctation. Echocardiographic visualization of the entire aorta can be complemented with magnetic resonance imaging and transesophageal echocardiography.22 Doppler echocardiography is superior for recognition of the hemodynamic and functional consequences of coarctation. Echocardiography is used to determine the associated abnormalities, including the status of the aortic and mitral valves and the presence or absence of ventricular septal defect.23,24 Other echocardiographic findings include aortic dilatation, mitral valve prolapse, mitral stenosis, hypoplastic left heart syndrome, and hyperdynamic systolic function.

WILLIAMS SYNDROME Pathologic Features Williams syndrome is a relatively rare autosomal dominant disorder characterized by dysmorphic facies, growth deficiency, mental retardation, microcephaly, occasionally idiopathic infantile hypercalcemia, and variable cardiovascular abnormalities.1,25,26 The characteristic cardiovascular defects include stenosis, hypoplasia or atresia of major vessels, mainly supravalvular aortic stenosis, and peripheral pulmonary artery stenosis.25 Occasionally, there are other manifestations, including mitral valve prolapse, bicuspid aortic valve, and hypertension.Williams syndrome results from submicroscopic deletion involv-

ing chromosome 7q11.23 in the region of the elastin gene. Elastin gene deletion is found in 90% to 95% of patients with Williams syndrome, and translocations also occur.27 The disorder is usually sporadic but may be a highly variable autosomal dominant condition.1 Clinical Manifestations The full spectrum of Williams syndrome includes mental retardation and typical appearance, similar to elfin facies, characterized by a high, prominent forehead, epicanthal folds, underdeveloped bridge of the nose and mandible, overhanging upper lips, strabismus, short stature, and anomalies of dentition (Figure 7).26-29 Recognition of this distinctive appearance, especially in association with a positive family history, should lead to suspicion of underlying multiplesystem disease. The most important problem is cardiovascular abnormality. Unexpected sudden death and endocarditis are reported. With a few exceptions, the physical findings are similar to those in patients with valvular aortic stenosis.The narrowing of the peripheral pulmonary arteries that frequently coexists in patients with Williams syndrome may produce a continuous murmur, which helps distinguish this anomaly from valvular aortic stenosis. Electrocardiography generally reveals left ventricular hypertrophy. However, biventricular hypertrophy or even right ventricular hypertrophy may be present if significant narrowing of peripheral pulmonary arteries coexists.28 Echocardiographic Features (Figures 8 and 9) The echocardiographic features of Williams syndrome have been reported.27 The M-mode echocardiography features of supravalvular aortic stenosis

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have been described30 but have been of limited help in localizing obstruction to the supravalvular aorta. The level of narrowing of the outflow tract can be visualized by two-dimensional echocardiography, and the pressure gradient can be determined by Doppler examination.28 Two-dimensional echocardiographic and Doppler evaluation findings include supra-aortic narrowing, thickening of the aortic valve, tricuspid aortic valve, increased aortic flow velocities, mitral valve and tricuspid valve prolapse, atrial septal defect, and left ventricular hypertrophy.25,31 Echocardiographic and Doppler evaluation provide useful information regarding the anatomic and hemodynamic spectrum of cardiovascular abnormalities associated with Williams syndrome.

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