LEOPARD syndrome (LS) is a rare autosomal dominant disorder characterised by lentigines and café au lait spots, EKG anomalies, ocular hypertelorism, pulmonary stenosis (PS), abnormal genitalia, retardation of growth, and deafness, and has been successively considered as a distinct syndrome and later as a clinical variant of Noonan syndrome (NS). Some months after the discovery of heterozygous mutations in the PTPN11 gene in roughly 40% of clinically typical NS patients,¹ Digilio et al² reported the presence of PTPN11 mutations in nine out of 10 unrelated patients with LS or NS with multiple lentigines or café au lait spots, confirming that both disorders are allelic variants. PTPN11 encodes SHP-2, a ubiquitously expressed non-receptor-type tyrosine phosphatase involved in a variety of cytokine and growth factor initiated signal transduction processes. SHP-2 contains two tandem SH2 domains encoded by exons 1 to 4 at the N terminus, and a phosphatase domain (PTP) encoded by exons 7 to 13 at the C terminus. Three different mutations have been described so far in LS, all located in the PTP domain.^2–4 These mutations are believed to disrupt the interaction between the N-SH2 and PTP domains, leading to increased phosphatase activity as similarly observed in NS. However, mutations described in LS seems to be highly specific for this syndrome.

In an attempt to better define the pattern of PTPN11 mutations responsible for LS and their correlation with clinical presentation, we here report results obtained in 14 families.

METHODS

DNA samples obtained from peripheral leucocytes of 14 unrelated propositi with a clinical diagnosis of LS were referred to our laboratory by confirmed clinician geneticists for PTPN11 mutation screening. For eight of them, parental DNA was also collected. Bi-directional direct sequencing of PTPN11 exons 2, 3, 4, 7, 8, 12, …