PTPN11 analysis for the prenatal diagnosis of Noonan syndrome in fetuses with abnormal ultrasound findings.

Noonan syndrome (NS) is an autosomal dominant disorder characterized by short stature, congenital heart defects and distinctive facies. The disorder is genetically heterogeneous with approximately 50% of patients having PTPN11 mutations. Prenatally, the diagnosis of NS has been suspected following certain ultrasound findings, such as cystic hygroma, increased nuchal translucency (NT) and hydrops fetalis. Studies of fetuses with cystic hygroma have suggested an NS prevalence of 1-3%. A retrospective review was performed to assess the utility of PTPN11 testing based on prenatal sonographic findings (n = 134). The most commonly reported indications for testing were increased NT and cystic hygroma. Analysis showed heterozygous missense mutations in 12 fetuses, corresponding to a positive test rate of 9%. PTPN11 mutations were identified in 16% and 2% of fetuses with cystic hygroma and increased NT, respectively. Among fetuses with isolated cystic hygroma, PTPN11 mutation prevalence was 11%. The mutations observed in the three fetuses with hydrops fetalis had previously been reported as somatic cancer mutations. Prenatal PTPN11 testing has diagnostic and possible prognostic properties that can aid in risk assessment and genetic counseling. As NS is genetically heterogeneous, negative PTPN11 testing cannot exclude the diagnosis and further study is warranted regarding the other NS genes.