AJR 2005; 184:S21-S24
© American Roentgen Ray Society
LEOPARD Syndrome: Cardiac Imaging Findings
K. D. Hagspiel1,2,3,
R. C. Candinas2,4,
H.-J. Hagspiel5,6 and
F. W. Amann2,4
1 Department of Medical Radiology, University Hospital, Zurich,
Switzerland.
2 Department of Internal Medicine, Division of Cardiology, University Hospital,
Zurich, Switzerland.
3 Present address: Division of Cardiac MRI, Department of Radiology, P.O. Box
800170, University of Virginia Health System, 1215 Lee Street,
Charlottesville, VA 22908.
4 Present address: HerzGefässZentrum, Klinik Im Park, Zürich 8027,
Switzerland.
5 Department of Dermatology, Zentralklinikun, Augsburg, Germany.
6 Present address: Dermatologische Gemeinschaftspraxis Dr. Wuestner & Dr.
Hagspiel, Landsberg 86899, Germany.
Received February 20, 2004;
accepted after revision April 16, 2004.
Address correspondence to K. D. Hagspiel.
Introduction
LEOPARD 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 disorder's 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
patient's cardiac involvement was extensively studied, and the following
imaging techniques were used: conventional chest X-ray, 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).
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Fig. 1B. —17-year-old boy with known LEOPARD syndrome. 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.
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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 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).
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Fig. 1E. —17-year-old boy with known LEOPARD syndrome. Left
ventriculogram shows hypertrophy of septal portion of left ventricular wall
without pressure gradient over left ventricular outflow tract.
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Fig. 1F. —17-year-old boy with known LEOPARD syndrome. 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).
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Fig. 1G. —17-year-old boy with known LEOPARD syndrome. 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).
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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).
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Fig. 1H. —17-year-old boy with known LEOPARD syndrome. 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.
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Fig. 1I. —17-year-old boy with known LEOPARD syndrome. 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.
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Fig. 1J. —17-year-old boy with known LEOPARD syndrome. Pathologic
evaluation of resected myocardium from right ventricular outflow tract shows
irregular interstitial fibrosis and multiple dysplastic vessels (Elastica-van
Gieson stain, magnification x 50).
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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 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
[5-8].
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 50-80% 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 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 right-sided HOCM. Pathologic evaluation showed a dysplastic,
fibrotic, quadricuspid pulmonary valve and the resected myocardium showed
irregular interstitial fibrosis and multiple dysplastic vessels.
References
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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
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- Walther RJ, Polanski BJ, Grots IA. Electrocardiographic
abnormalities in a family with generalized lentigo. N Engl J
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-1225
- 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
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J Med Genet2003; 40:704
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Introduction
Case Report
