LEOPARD syndrome (LS) is a congenital developmental disorder named by the acronym of multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness [Gorlin et al., 1969]. This condition is also often associated with other features such as cardiovascular anomalies, hypertrophic cardiomyopathy (HCM), and mental retardation. These clinical features in LS overlap with those in Noonan syndrome (NS). Recently, it has been shown that both NS and LS are caused by heterozygous missense mutations of the gene for protein-tyrosine phosphatase, nonreceptor type 11 (PTPN11)[Tartaglia et al., 2001; Digilio et al., 2002]. PTPN11 encodes cytoplasmic tyrosine phosphatase with two tandemly arranged Src homology 2 (SH2) domains (N-SH2 and C-SH2) on the N-terminal side and a protein-tyrosine phosphatase (PTP) domain on the C-terminal side, and plays a critical role in regulating the responses of eukaryotic cells to multiple extracellular signals in various tissues. Since the missense mutations cause aminoacid substitutions in and around the broad N-SH2/PTP interaction surface, they have been suggested to affect the intramolecular N-SH2/PTP binding in the absence of a phosphopeptide, leading to a gain-of-function effect with an excessive phosphatase activity [Tartaglia et al., 2001]. To date, while various mutations have been found in NS [Tartaglia et al., 2001, 2002], only three mutations have been identified in LS [Digilio et al., 2002; Legius et al., 2002; Conti et al., 2003; Sarkozy et al., 2003]. Here, we report on two novel and one recurrent PTPN11 mutations identified in LS patients.

Six Japanese patients (five males and one female) with LS aged 8.3–26.0 years were studied (Table I). All cases had a normal karyotype. Case 5 had hypochondroplasia resulting from the common Asn540Lys mutation of FGFR3 [Ramaswami et al., 1998]. The mother of case 4 also had LS phenotype and deceased of cardiac failure at 34 years of age. The remaining cases were sporadic.