Genotype-phenotype analysis and natural history of left ventricular hypertrophy in LEOPARD syndrome

Giuseppe Limongelli, Anna Sarkozy, Giuseppe Pacileo, Paolo Calabrò, Maria Cristina Digilio, Valeria Maddaloni, Giulia Gagliardi, Giovanni Di Salvo, Maria Iacomino, Bruno Marino, Bruno Dallapiccola, Raffaele Calabrò

Research output: Contribution to journalArticlepeer-review


Because it is unclear whether the genotype may influence the clinical course in patients with LEOPARD syndrome (LS), we analyzed clinical and molecular predictors of adverse cardiac events in patients with left ventricular hypertrophy (LVH). A comprehensive cardiovascular evaluation, including baseline electrocardiogram, echocardiography, exercise test and 24 hr Holter monitoring at the time of clinical diagnosis and during follow-up was conducted on 24 patients referred to our departments. Phenotypical examination and diagnosis were performed by expert clinical geneticists. The entire PTPN11 and RAF1 coding regions were screened for mutations by DHPLC analysis, followed by sequencing. Patients without PTPN11 mutations (34%) showed a higher frequency of family history of sudden death (P = 0.007), increased left atrial dimensions (P = 0.05), bradyarrhythmias (P = 0.04), episodes of supraventricular tachycardias (P = 0.06), atrial fibrillation (P = 0.009), and nonsustained ventricular tachycardias (P = 0.05) during Holter monitoring. Six patients (25%) had adverse cardiac events during follow-up (including sudden deaths, resuscitated cardiac arrest, septal myectomy, and heart failure). LVH, New York Heart Association Class, left ventricular outflow tract obstruction, and nonsustained ventricular tachycardias were associated to adverse cardiac events. Of note, three patients with mutations in exon 13 showed a severe obstructive cardiomyopathy, with serious cardiac complications during follow-up (heart failure, septal myectomy, and sudden death). In conclusion, patients with LVH associated with LS seem to carry a relatively high risk of adverse (arrhythmic and nonarrhythmic) events. Further genotype-phenotype studies are warranted to fully elucidate the impact of the genotype on the natural history of patients with LS and LVH.

Original languageEnglish
Pages (from-to)620-628
Number of pages9
JournalAmerican Journal of Medical Genetics, Part A
Issue number5
Publication statusPublished - Mar 1 2008


  • Clinical outcome
  • Left ventricular hypertrophy
  • LEOPARD syndrome
  • PTPN11 mutations

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics
  • Medicine(all)


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