Page 105 - Clinical variability in Noonan syndrome with emphasison ear and eye

Noonan syndrome and related disorders, standard diagnostic testing of all the NS- genes using Sanger sequencing is expensive and a relatively long process. Next generation sequencing, including whole genome sequencing and targeted next generation sequencing, is suggested to be a more accurate and cost-effective genotyping. RASopathies have a high genetic and phenotypic heterogeneity. For an easier and more accurate way of diagnosing Noonan syndrome, we expect next generation sequencing to play a more important role in the nearby future. Molecular characterization that will lead to an early diagnosis, also in patients with mild or atypical clinical features, will improve the clinical care for Noonan syndrome patients (3).
Genotype-phenotype correlations in Noonan syndrome have become a more popular subject in literature since more causative mutations in different genes have been discovered. PTPN11 mutations are found in approximately 50% of the Noonan syndrome patients and therefore play an important role in genotype-phenotype studies. In Noonan syndrome patients with a PTPN11 mutation, frequently described features are short stature, pectus deformities, cardiac abnormalities and facial characteristics (4,5). Very typical facial characteristics are described in patients with KRAS mutations (6) and intellectual disabilities occur more frequent in patients with KRAS mutations (7). Frequent described features in patients with SOS1 mutations are cardiac anomalies, facial characteristics and ectodermal abnormalities (8). Overall in literature, the broad variety of clinical characteristics (from very mild to typical) in both mutation positive and mutation negative Noonan syndrome patients is emphasized.
Noonan syndrome and related disorders
Noonan syndrome and related disorders are caused by germline mutations in distinct genes all leading to dysregulation of components of the RAS-MAPK pathway. They are named together as RASopathies and include among others Noonan syndrome with multiple lentigines (LEOPARD syndrome in the past), cardiofaciocutaneous syndrome, Costello syndrome, and Noonan-like syndrome with loose anagen hair (3). Noonan syndrome is characterized by a broad spectrum of features and shares clinical features with the related disorders. In Chapter 6 we showed hearing impairment in both Noonan syndrome and Noonan syndrome with multiple lentigines, based on different PTPN11 gene mutations.
Monogenic diseases caused by a modification in the DNA sequence of only a single gene, are easier to understand and recognize. It becomes more complicated when mutations occur in genes that encode proteins that have multiple interactions in large protein networks, for example the RAS-MAPK pathway. The fact that the mutated
DISCUSSION AND SUMMARY
103
7