A Patient With LEOPARD Syndrome and PTPN11 Mutation
We present the case of a 37-year-old woman with hypertrophic cardiomyopathy, initially diagnosed at 23 years of age. The leading clinical problem is chest pain and inappropriate shortness of breath under exertion. When the patient was presented to our outpatient clinic for the first time at the age of 34 years, the coincidence of multiple lentigines (Figure 1), ECG changes (Figure 2), deafness, retardation in growth, hypertelorism, and strabism (operation at 21 years of age) were noted. Echocardiography and cardiac magnetic resonance imaging revealed a distinctive biventricular apical hypertrophy (Figures 3A, 3B, and 4⇓A and online-only Data Supplement Movies I and II). Interestingly, cardiac magnetic resonance imaging showed pronounced late gadolinium enhancement (Figure 4B) involving the right ventricle, documenting the extremely rare finding of right ventricular fibrosis, which is seen in <1% of hypertrophic cardiomyopathy patients. The ejection fraction was within the normal range at both cardiac magnetic resonance imaging and echocardiography. The patient showed coronary artery dilatation (Figure 5 and online-only Data Supplement Movies III through V) at coronary angiography, which was performed at initial diagnosis. Chest x-ray revealed no pathological findings (Figure 6). With genetic screening, we were able to detect a heterozygous Gln510Glu mutation in exon 13 of the PTPN11 gene. This mutation was first described in 2005.1
The very rare LEOPARD syndrome (LS, about 200 cases in literature) is an autosomal-dominant multisystem disease,2 which was first described in 1969. LEOPARD is an acronym for lentigines, ECG-changes, ocular changes (mostly hypertelorism), pulmonary stenosis, anomalies in sexual organs, growth retardation, and deafness. Mutations in the protein tyrosine phosphatase, nonreceptor type 11 gene (PTPN11, gene map locus 12q24.1) have been associated with the LS, but distinct mutations within the same gene are related to the Noonan syndrome. The current diagnostic criteria, proposed by Voron et al,3 are fulfilled by lentigines and 2 minor criteria (cardiomyopathy, deafness, ECG-changes, and hypertelorism in our case). Pulmonary stenosis occurs in ≈31% of LS cases4 and was ruled out in our case by Doppler echocardiography and cardiac magnetic resonance imaging (online-only Data Supplement Movie VI). Biventricular involvement occurred in 2 of 3 previously reported patients with Gln510Glu mutation, whereas hypertrophic cardiomyopathy occurs in ≈57% of patients with PTPN11 mutation and LS.5 However, it is still unclear if a specific mutation leads to specific locations of hypertrophic areas. Adverse cardiac events are a major limiting factor for survival of LS patients, predominantly affecting patients with myocardial hypertrophy. A new genetic study emphasizes a possible correlation between the underlying gene mutation and prognosis.4
The onlines only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/119/9/1328/DC1.