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A 25 year old male with left ventricular hypertrophy and widespread lentigines

The patient was referred for cardiac evaluation because of palpitations during physical exercise. There were no known inherited disease in the family and the patient was physically very active with no feeling of dyspnea or syncope.
Upon physical examination the patient had a systolic murmur and an abnormal ECG.
Myocardial Disease

Figure 1: ECG in sinus rhythm with widespread inversion of the T waves.

Echocardiography revealed a moderately hypertrophic left ventricle with very long anterior and posterior mitral leaflets and systolic anterior movement of the mitral valve with a resting gradient of the left ventricular outflow tract of 40 mmHg.

Figure 2: Apical 4 chamber view showing a moderately hypertrophic left ventricle and long anterior and posterior mitral leaflets (A) diastole, (B) systole with systolic anterior movement (SAM) of the mitral valve.

Furthermore he had widespread lentigines all over the body including his cheeks where they were confluent. 

Figure 3: Photograph of the patient’s left arm (A) and back (B) with widespread lentigines.

Treatment with a beta blocker was initiated and the patient was referred to an exercise test and 24-hour Holter monitoring. Both were normal without arrhythmias .
At follow up 1 month later the patient reported significantly less palpitations and was able to perform better physically.


1: What could be the explanation for the disease presentation?

The patient had hypertrophic cardiomyopathy and widespread lentigenes. There was no family history of sudden cardiac death but the patient reported that his father and grandfather also had widespread lentigenes.
The patient presented clinical characteristics consistent with a diagnosis of LEOPARD syndrome, which was first described by Gorlin et al. in 1969 and initially named “The multiple lentigenes syndrome”. The condition was renamed in 1971 using the acronym LEOPARD (Lentigines, Electrocardiographic abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormalities of the genitalia, Retardation of growth and Deafness) (1).
Voron et al. further developed the diagnostic criteria in 1976 to include multiple lentigenes plus two additional recognized features or a first-degree relative with LEOPARD syndrome and lentigenes plus three additional features in the patient (2).
The most common features for LEOPARD syndrome are mulitiple lentigenes and structural heart defects such as left ventricular hypertrophy, right ventricular hypertrophy, coronary abnormalities and/or pulmonary stenosis. Facial dysmorphisms are also prevalent and the patients often suffer from short stature, retarded growth and sensorineural deafness. Genital abnormalities can also be present (3).
In 2002 mutations in the gene encoding the protein tyrosine phosphatase SHP-2, PTPN11, were identified as the cause of LEOPARD syndrome in 90% of patients. In the majority of cases LEOPARD occurs sporadic and is caused by de novo mutations in PTPN11 (3). Interestingly it has previously been shown that mutations in the same gene caused Noonan Syndrome, which is a condition sharing several of the same clinical manifestations as seen in LEOPARD (4). Subsequent studies have shown that mutations in the RAF1 gene and BRAF gene are less frequent causes of LEOPARD syndrome (5).

2: What additional tests would you order to confirm your diagnosis?

Genetic investigations of the patient in the gene for PTPN11 identified a novel missense mutation (A461S), which was most likely to be disease associated.

The LEOPARD syndrome is quite rare and it is therefore difficult to assess the long-term prognosis of the condition although it is generally believed to be benign, especially with only mild cardiac abnormalities. However in a study of 26 LEOPARD patients, 2 patients died suddenly and 2 patients had a cardiac arrest (average follow-up 9.1 years).
The majority of LEOPARD patients have left ventricular hypertrophy, which may be accompanied by left ventricular outflow tract obstruction, and the risk of sudden cardiac death may be higher in this group.  Careful risk assessment is therefore indicated. It has been suggested to use the same algorithms as for familial hypertrophic cardiomyopathy, but careful consideration is needed as it is unknown if the pathophysiological background of these 2 diseases are comparable (3).



LEOPARD syndrome is a rare genetic disease, which should be considered in patients with structural heart disease – in particular left ventricular hypertrophy – and widespread lentigenes. The diagnosis is based on clinical examination and genetic testing. Cascade clinical screening of relatives is recommended. The prognosis is mostly benign in the absence of left ventricular hypertrophy. In patients with left ventricular hypertrophy, risk stratification is recommended using the same algorithms as in hypertrophic cardiomyopathy.


1) Gorlin RJ, Anderson RC, Moller JH. The leopard (multiple lentigines) syndrome revisited. Laryngoscope. 1971;81:1674-81.
2) Voron DA, Hatfield HH, Kalkhoff RK. Multiple lentigines syndrome. Case report and review of the literature. Am J Med 1976;60:447-56.
3) Limongelli G, Pacileo G, Marino B, Digilio MC, Sarkozy A, Elliott P, Versacci P, Calabro P, De Zorzi A, Di Salvo G, Syrris P, Patton M, McKenna WJ, Dallapiccola B, Calabro R. Prevalence and clinical significance of cardiovascular abnormalities in patients with the LEOPARD syndrome. Am J Cardiol;100:736-41.
4) Digilio MC, Conti E, Sarkozy A, Manganelli R, Dottorini T, Marino B, Pizzuti A, Dallapiccola B. Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet 2002;71:389-94.
5) Online Mendelian Inheritance in Man #151100 (

Notes to editor

L.D. Vestergaard, T. Hey, J. Mogensen 
Department of Cardiology, Odense University Hospital, Sonder Boulevard, 5000 Odense C, Denmark
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.