Cardiac Imaging Hagspiel et al.

Cardiac Imaging of LEOPARD Syndrome

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Case Report
LEOPARD Syndrome: Cardiac Imaging Findings
Hagspiel KD, Candinas RC, Hagspiel H-J, Amann FW(AQ1)

K. D. Hagspiel1,2,3, R. C. Candinas2,4, H.-J. Hagspiel5,6, F. W. Amann2,4

EOPARD syndrome is a rare autosomal dominant hereditary disorder originally described by Gorlin et al. [1] as multiple lentigines syndrome. For clarification and better memorization of the disorders aspects, the mnemonic aid LEOPARD was introduced: lentigines, multiple; electrocardiographic conduction defects; ocular hypertelorism; pulmonary stenosis; abnormalities of the genitalia; retardation of growth; and deafness, sensorineural. Most cases with this diagnosis have only a few of the features described, and patients with the full clinical spectrum are very rare. We describe the clinical and cardiac imaging findings in a patient with the full syndrome. The patients cardiac involvement was extensively studied, and the following imaging techniques were used: conventional chest Xray, echocardiography, right and left heart catheterization including coronary arteriography, thoracic aortography, and MRI. To our knowledge, this is the first LEOPARD case in the literature that was extensively studied with MRI.

Case Report A 17-year-old boy with known LEOPARD syndrome was referred to our center for evaluation of his cardiac status. The patient had mild exertional dyspnea and central and peripheral cyanosis. The patient also had a minor form of lentiginosis that was especially developed on the left side of the neck and in the right axillary region (Fig. 1A). He had hypertelorism and was deaf, and his genitalia were hypoplastic. His body weight and height were 32.4 kg and 143 cm, values typical for a 10-year-old boy. His ECG showed signs of right ventricular hypertrophy, AV block grade 1, and right axis deviation. The chest X-ray showed a slightly enlarged heart with increased retrosternal contact, indicating the presence of right heart hypertrophy. There was dilatation of the main pulmonary and left pulmonary arteries. No evidence of hypercirculation was found. The peripheral pulmonary vasculature was normal. No abnormality of the chest wall and osseous structures was present (Fig. 1B). Echocardiography showed valvular and infundibular pulmonary stenosis with massive

hypertrophy of the free right ventricular wall and the septum (Fig. 1C). The gradient measured with a Doppler sonogram over the right ventricular outflow tract (RVOT) was 175 mm Hg, and the mean systolic gradient was 87 mm Hg. The left ventricle was small, left ventricular function was normal, and no gradient was present over the left ventricular outflow tract (LVOT), although there was massive hypertrophy of the septum. In addition, there was a patent foramen ovale and minimal aortic and mitral regurgitation, the latter a result of a prolapse of the anterior leaflet of the mitral valve. Cardiac catheterization showed concentric right ventricular hypertrophy with severe systolic infundibular narrowing and the typical doming sign of the pulmonic valve (Fig. 1D). The right ventricular pressures were 220 mm Hg during systole and 4 mm Hg during end-diastole; the pressures in the pulmonary artery were 28 mm Hg and 4 mm Hg, respectively, with a mean of 14 mm Hg. The pulmonary capillary wedge pressure was 11/0/5 mm Hg. The left ventriculogram showed hypertrophy of the septal portion of

Received February 20, 2004; accepted after revision April 16, 2004.
1Department 2Department

of Medical Radiology, University Hospital, Zurich, Switzerland. of Internal Medicine, Division of Cardiology, University Hospital, Zurich, Switzerland.

Division of Cardiac MRI, Department of Radiology, P.O. Box 800170, University of Virginia Health System, 1215 Lee Street, Charlottesville, VA 22908. Address correspondence to K. D. Hagspiel.
4Present address: HerzGefssZentrum, 5Department 6Present

3Present address:

Klinik Im Park, Zrich 8027 , Switzerland.

of Dermatology, Zentralklinikun, Augsburg, Germany.

address: Dermatologische Gemeinschaftspraxis Dr. Wuestner & Dr. Hagspiel, Landsberg 86899, Germany.

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Hagspiel et al. the left ventricular wall without a pressure gradient over the LVOT (Fig. 1E). LV pressure was 130/12 mm Hg. Cardiac index was 2.7 L/min/m2. Coronary angiography showed massively dilated coronary arteries in the typical location, with systolic compression of the left anterior descending artery because of the intramuscular position of parts of it (Figs. 1F and 1G). MRI showed the massive hypertrophy of the right ventricular wall, especially of the septum (Fig. 1H). The RVOT was almost completely obstructed during systole (Fig. 1I). The poststenotic dilatation of the main and left pulmonary arteries was also clearly shown. The pulmonary valve was subsequently replaced and the myocardium in the right ventricular outflow tract was resectioned. Pathologic evaluation of the specimens showed a fibrotic, quadricuspid pulmonary valve with no signs of vascularization or inflammation. The resected myocardium showed irregular interstitial fibrosis and multiple dysplastic vessels (Fig. 1J). Discussion LEOPARD is an acronym for the manifestations of a syndrome first described by Gorlin et al [1]. In only a minority of affected patients are all manifestations present [2]. Lentiginosis is a skin pigmentation disorder of neural crest origin with characteristic findings on skin biopsy. Unlike freckles, they do not become darker or increase in number on exposure to sunlight. Lentigines can be present at birth or develop during childhood. They have a tendency to increase in number and darkness with age. The

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Fig. 1.17-year-old boy with known LEOPARD syndrome. A, Lentiginosis, with typical appearance of multiple lentigines in lateral neck. B, Chest X-ray shows slightly enlarged heart resulting from right heart hypertrophy. There is dilatation of the central pulmonary arteries without hypercirculation. Peripheral pulmonary vasculature is normal. C, B-mode echocardiography shows massive hypertrophy of free right ventricular wall and septum. D, Right ventriculogram shows severe concentric right ventricular hypertrophy with systolic infundibular narrowing. E, Left ventriculogram shows hypertrophy of septal portion of left ventricular wall without pressure gradient over left ventricular outflow tract. (Fig. 1 continues on next page)

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Cardiac Imaging of LEOPARD Syndrome typical appearance of lentigines is shown in Fig. 1A. The coexistence of lentigines and cardiac disease has been recognized previously, and the first description was in 1966 by Walther et al. [3]. Two syndromes have subsequently been postulated: cardiomyopathic lentiginosis, or Moynahan syndrome [4], and LEOPARD syndrome [1]. The most common cardiac involvement described with these two syndromes are hypertrophic obstructive cardiomyopathy (HOCM) and pulmonary valve stenosis [58]. HOCM is usually left-sided in most cases with lentiginosis, but tends to be right-sided in patients with LEOPARD syndrome [5, 6]. LEOPARD patients frequently have valvular and infundibular pulmonary stenosis. A small number of patients with LEOPARD syndrome had an extensive cardiac workup using invasive and noninvasive techniques. In the majority of published patients with the diagnosis and cardiac involvement, echocardiography was the sole cardiac imaging technique. Life expectation is normal in most patients, with cardiac involvement the cause of early death in a small number of affected individuals. The underlying genetic defect has been identified and the entity was assigned an Online Mendelian Inheritance in Man (OMIM) number (LEOPARD syndrome OMIM #151100). Multiple lentigines syndrome (MLS) is now used as a synonym. The defect associated with development of the syndrome has been located on chromosome 12 (gene map locus 12q24.1) and the responsible gene is PTPN11 (protein tyrosine phosphatase nonreceptor type 11, OMIM #176876), which codes for nonreceptor protein tyrosine phosphatase SHP2. Mutations in the same gene are known to lead to a number of congenital heart defects, among them Noonan syndrome, cardiomyopathic lentiginosis, and LEOPARD syndrome. Animal models suggest a role of the SHP2 protein in semilunar valve and myocardial development [6]. In the largest published study on the cardiac anomalies associated with PTPN11 mutations involving 71 patients with Noonan syndrome and 13 patients with multiple lentigines/LEOPARD syndrome, a broad spectrum of congenital heart defects was detected in 5080% of patients [6]. In this study, many patients with Noonan syndrome and most with LEOPARD syndrome had mutations in the PTPN11 gene. The most common defects were pulmonary valve stenosis and hypertrophic cardiomyopathy. The distribution of

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Fig. 1. (continued)17-year-old boy with known LEOPARD syndrome. F and G, Coronary angiography shows massively dilated coronary arteries. Note systolic compression of left anterior descending artery resulting from intramuscular position of its middle portion. End-diastolic frame (F); end-systolic frame (G). H and I, MRI (ECG-gated T1-weighted spin-echo sequence). Axial scan through right ventricle (H) shows massive hypertrophy of right ventricular myocardium, especially in septum. Axial scan somewhat higher (I) shows nearly complete obstruction of right ventricular outflow tract during systole. J, Pathologic evaluation of resected myocardium from right ventricular outflow tract shows irregular interstitial fibrosis and multiple dysplastic vessels (Elastica-van Gieson stain, magnification 50).

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Hagspiel et al. congenital heart defects was markedly different between the two groups. Pulmonary valve stenosis was the most common congenital heart defect in Noonan syndrome and hypertrophic cardiomyopathy was more frequent in LEOPARD syndrome. Other less frequent associated defects were atrial septal defects, atrioventricular canal defects, and mitral valve anomalies. They showed that the different heart defects correlated with different locations of mutations within the PTPN11 gene [6]. In conclusion, we presented the first case of LEOPARD syndrome that had extensive imaging workup, including cardiac MRI, and pathologic correlation. The patient had valvular and infundibular pulmonary stenosis with massive hypertrophy of the free right ventricular wall and the septum due to predominantly rightsided HOCM. Pathologic evaluation showed a dysplastic, fibrotic, quadricuspid pulmonary valve and the resected myocardium showed irregular interstitial fibrosis and multiple dysplastic vessels.
4. Moynahan EJ, Polani P. Progressive diffuse lentiginosis, progressive cardiomyopathy, short stature with delayed puberty, mental retardation or psychic infantilism, and other developmental abnormalities: a new familial syndrome. In: Jadassohn W, Schirren CG, ed. XIII Congressus Internationalis Dermatologiae, vol. 2. Berlin: Springer-Verlag, 1968;15431544 5. Sutton MGStJ, Tajik AJ, Giuliani ER, Gordon H, Su WPD. Hypertrophic obstructive cardiomyopathy and lentiginosis: a little known neuroectodermal syndrome. Am J Cardiol 1981;47:214217 6. Sarkozy A, Conti E, Seripa D, et al. Correlation between PTPN11 gene mutations and congenital heart defects in Noonan and LEOPARD syndromes. J Med Genet 2003;40:704708 7. Voron D, Hatfield H, Kalkhoff M. Multiple lentigines syndrome. Case report and review of the literature. Am J Med 1976;60:447456 8. Senn M, Hess OM, Krayenbuhl HP. Hypertrophe Kardiomyopathie und Lentiginose. Schweiz Med Wschr 1984;114:838841

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References
1. Gorlin RJ, Anderson RC, Blaw M. Multiple lentigines syndrome: complex comprising multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis and other cardiac defects, abnormalities of genitalia, retardation of growth, sensorineural deafness, and autosomal dominant hereditary pattern. Am J Dis Child 1969;117:652662 2. Coppin, BD, Temple IK. Multiple lentigines syndrome (LEOPARD syndrome or progressive cardiomyopathic lentiginosis). J Med Genet 1997; 34:582586 3. Walther RJ, Polanski BJ, Grots IA. Electrocardiographic abnormalities in a family with generalized lentigo. N Engl J Med 1966;275:12201225

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