Page 18 - Clinical variability in Noonan syndrome with emphasison ear and eye

CHAPTER 1
causes RTK autophosphorylation and activates an interaction with the adaptor protein growth factor receptor-bound protein 2 (GRB2). GRB2 is bound to son of sevenless (SOS). SOS proteins are guanine nucleotide exchange factors (GEF) that exchange the rate of GDP for GTP. This increases the level of active GTP-bound Ras (67,68).
The first gene discovered to be responsible for NS was PTPN11 on chromosome 12q24.1. PTPN11 encodes the nonreceptor-type tyrosine phosphatase SHP-2, which implicates several signal transduction pathways and therefore the PTPN11 gene influences various developmental processes (69). PTPN11 mutations are seen in approximately 50% of the patients with Noonan syndrome. SHP-2 is required for the function of the RAS-MAPK pathway. It plays an essential role in the response to growth factors, cell adhesion molecules, cytokines and hormones (69,70). After the PTPN11 mutation was discovered, other mutations are found in the coding genes of the proteins that are associated with the function of the RAS-MAPK pathway. KRAS mutations were discovered in 2006 and SOS1 mutations were described in 2007 for the first time (71,72). The Son of Sevenless homolog 1 (SOS1) gene encodes a guanine nucleotide exchange factor (GEF) for RAS proteins. In 70-80% of the Noonan syndrome patients a mutation can be found nowadays. Other mutations of the known Noonan syndrome genes include: RAF1, RIT1, NRAS, BRAF, MAP2K1, SOS2, A2ML1, RASA2, LZTR1, and RRAS (68).
Other RASopathies with mutations in the Ras/MAPK pathway are studied. Due to the same pathway dysregulation, they have numerous overlapping phenotypic features. This can make the clinical diagnoses more challenging and genotypes might be necessary for the correct diagnoses. Neurofibromatosis type 1 (NF1) was the first identified syndrome. Other syndromes in the Ras/MAPK pathway include Noonan syndrome with multiple lentigines, Noonan syndrome with loose anagen hair, Costello syndrome, Cardio-facio-cutaneous syndrome (CFC), and Legius syndrome (67,68).
The group of RASopathies with developmental disorders including Noonan syndrome are caused by germline mutations. The Ras pathway is frequently somatically altered, with somatic mutations, in a broad spectrum of neoplasms. The Ras/MAPK pathway is studied frequently in neoplasms and is an attractive target for small-molecule inhibition to treat varies malignancies. It is suggested that in approximately one third of all human cancers, the Ras/MAPK pathway is deregulated by a somatic mutation. Recent research shows that children with Noonan syndrome have an eight-fold greater risk of developing a childhood cancer compared to children without Noonan syndrome. Correlation between specific types of malignancies and genotypes in Noonan syndrome is not available and therefore cancer surveillance in Noonan syndrome not recommended (58,67).
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