Correlation between PTPN11 gene mutations and congenital heart defects in Noonan and LEOPARD syndromes.

N oonan syndrome (MIM 163950), an autosomal dominant disorder with an estimated prevalence of 1/1000– 2500 at birth, is characterised by short stature, facial anomalies, pterygium colli, and congenital heart disease. 2 Although pulmonary valve stenosis with dysplastic leaflets, hypertrophic cardiomyopathy, and atrial septal defects (ASD) are the most common congenital heart defects in Noonan syndrome, a broad spectrum of cardiac phenotypes has been recognised. About half the affected individuals have PTPN11 gene mutations. This gene, which maps to chromosome 12q22-qter, encodes for the human SH2 domain containing protein tyrosine phosphatase (SHP2). PTPN11 gene mutations have also been detected in multiple lentigines/LEOPARD syndrome (multiple lentigines, ECG conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth and sensorineural deafness; ML/LS, MIM 151100), 13 in Noonan-like/multiple giant cell lesion syndrome (MIM 163955), in two families presumably affected by cardiofacio-cutaneous syndrome (CFCS, MIM 115150), but not in sporadic CFCS. The clinical and genetic heterogeneity of these disorders suggests a possible relation between different PTPN11 gene mutations and distinct clinical features. A genotype–phenotype correlation study in Noonan syndrome found an association between pulmonary stenosis and PTPN11 mutations. Our aim in this study was to screen a large cohort of patients with Noonan syndrome and ML/LS in order to expand the genotype–phenotype correlation analysis, with particular emphasis on cardiac diseases.