Familial aggregation of genetically heterogeneous hypertrophic cardiomyopathy: a boy with LEOPARD syndrome due to PTPN11 mutation and his nonsyndromic father lacking PTPN11 mutations

Birth Defects Res A Clin Mol Teratol. 2004 Feb;70(2):95-8. doi: 10.1002/bdra.10148.


Background: Nonsyndromic hypertrophic cardiomyopathy (HCM) is a primary cardiac disease transmitted as an autosomal dominant trait. Multiple chromosomal loci have been found to be involved in the etiology of this defect. LEOPARD syndrome is a genetic condition characteristically associated with HCM. Additional features of the syndrome include multiple lentigines, facial anomalies, sensorineural deafness, and growth retardation. Mutations in PTPN11, a gene encoding the protein tyrosine phosphatase SHP-2 located at chromosome 12q24, have been identified in patients with LEOPARD syndrome.

Cases: We report here on a patient with HCM presenting with classic clinical features of LEOPARD syndrome, whose father also has HCM, but lacks phenotypic anomalies of the syndrome. Molecular analysis searching for PTPN11 mutations was performed in this family. A missense mutation (836A-->G; Tyr279Cys) in exon 7 of PTPN11 gene was identified in the patient with LEOPARD syndrome, whereas no mutation in PTPN11 gene was detected in the father or in additional family members.

Conclusions: Aggregation of syndromic and nonsyndromic HCM in the same family is an unusual pattern of recurrence. Although genetic heterogeneity of LEOPARD and nonsyndromic HCM is not disputed, the existence of peculiar interactions linking genes causing nonsyndromic HCM and HCM in LEOPARD syndrome can be hypothesized. Different genes can work together, and a more severe cardiac phenotype can be due to additive effects. The involvement of familial susceptibility to specific cardiac malformations based on the presence of common predisposing factors can also be considered. Further molecular studies may shed light on these observations.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cardiomyopathy, Hypertrophic / diagnosis
  • Cardiomyopathy, Hypertrophic / genetics*
  • Child
  • Child, Preschool
  • Echocardiography
  • Genetic Heterogeneity*
  • Humans
  • Infant
  • Intracellular Signaling Peptides and Proteins
  • LEOPARD Syndrome / diagnosis
  • LEOPARD Syndrome / genetics*
  • Male
  • Mutation, Missense / genetics*
  • Phenotype
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatases / genetics*


  • Intracellular Signaling Peptides and Proteins
  • PTPN11 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatases