Genotype-phenotype correlations in Noonan syndrome

Objective To study genotype-phenotype correlations in a cohort of clinically well-characterized pediatric patients with Noonan syndrome (NS). Study design Fifty-seven unrelated patients with the clinical diagnosis of NS ascertained according to standardized inclusion criteria were prospectively enrolled. Mutational analysis was performed by direct sequencing of the entire coding sequence of the PTPN11 gene. Results Sixteen known and 3 novel PTPN11 mutations could be detected in 60% of index patients, in all familial and in 52% of the sporadic cases. Presence of pulmonic stenosis, short stature, easy bruising, and thorax deformities was significantly associated with a PTPN11 mutation, whereas cardiomyopathy was more common in patients without a mutation. On average, PTPN11 mutation-negative probands fulfilled fewer clinical criteria of NS, but more than half-among them all with cardiomyopathy-had the full clinical picture of NS indistinguishable from typical cases with PTPN11 mutation. Conclusions The phenotype of NS due to PTPN11 mutations is clinically unambiguous in the majority of patients and represents a highly penetrant trait. Individuals with the clinical diagnosis of NS but without a PTPN11 mutation presumably represent a heterogeneous group in which patients with cardiomyopathy appear to constitute an interesting subgroup for future research.