Roberts et al. (2007) and Tartaglia et al. (2007) delineated a Noonan syndrome phenotype caused by mutation in the SOS1 gene that lies within the Noonan syndrome spectrum but is distinctive. Roberts et al. (2007) noted 2 significant ... Roberts et al. (2007) and Tartaglia et al. (2007) delineated a Noonan syndrome phenotype caused by mutation in the SOS1 gene that lies within the Noonan syndrome spectrum but is distinctive. Roberts et al. (2007) noted 2 significant differences: pulmonic stenosis was more frequent in patients with SOS1 mutations than in those without SOS1 or PTPN11 mutations, and atrial septal defect was relatively rare in affected individuals with SOS1 mutations compared to those with PTPN11 mutations. Tartaglia et al. (2007) noted ectodermal features including keratosis pilaris and curly hair that were significantly more prevalent among individuals with an SOS1 mutation compared with the general Noonan population. They observed height below the third percentile in only 2 of 15 individuals with an SOS1 mutation, whereas the prevalence is approximately 70% among patients with Noonan syndrome in general and among those with a PTPN11 mutation. In contrast, macrocephaly was overrepresented among those with SOS1 mutations. Only one individual with an SOS1 mutation had mental retardation, potentially attributable to critical illness as a newborn. In comparison, 30% of all children with Noonan syndrome require special education. Zenker et al. (2007) reported that Noonan syndrome patients with SOS1 mutations commonly had ectodermal manifestations including keratosis pilaris of the face, sparse eyebrows, curly hair, and, in 1 patient, ichthyosiform skin changes. By comparing clinical features of a cohort of 42 patients with PTPN11 mutations derived from a previous study with those of their current study of 28 patients with SOS1 mutations, Zenker et al. (2007) confirmed a significantly higher prevalence of keratosis pilaris/hyperkeratotic skin and curly hair in patients with SOS1 mutations compared with those with PTP11 alterations (58% vs 6% and 78% vs 34%, respectively). Moreover, ocular ptosis was observed more frequently in patients with NS with SOS1 mutations than in patients with a PTPN11 mutation (80% vs 54%). Ferrero et al. (2008) reported a newborn with Noonan syndrome due to SOS1 mutation (T266K; 182530.0002). He presented with facial dysmorphisms and prenatal anomalies, not associated with other congenital defects. The pregnancy was characterized by polyhydramnios and increased fetal nuchal translucency. Dysmorphic facial features included hypertelorism, epicanthal folds, flat nasal bridge, low-set posteriorly rotated ears, and short neck. Other features included moderated pulmonic stenosis and bilateral cryptorchidism. Developmental milestones were normal at 24 months of age. There were no coagulation abnormalities.
Roberts et al. (2007) and Tartaglia et al. (2007) found mutation in the SOS1 gene (182530) in Noonan syndrome patients without mutation in PTPN11 (176876) or KRAS2 (190070). Gain-of-function mutations in PTPN11, which encodes the tyrosine phosphatase SHP2, ... Roberts et al. (2007) and Tartaglia et al. (2007) found mutation in the SOS1 gene (182530) in Noonan syndrome patients without mutation in PTPN11 (176876) or KRAS2 (190070). Gain-of-function mutations in PTPN11, which encodes the tyrosine phosphatase SHP2, cause approximately 50% of Noonan syndrome cases, and less than 5% of cases are caused by mutations in KRAS2. SHP2 is required for RAS-ERK MAP kinase (MAPK; see 176948) cascade activation, and Noonan syndrome mutants enhance ERK activation ex vivo and in mice. The phenotypically related cardiofaciocutaneous syndrome (CFCS; 115150) is caused by gain-of-function mutations in 1 of 4 different genes: KRAS, BRAF (164757), MEK1 (176872), or MEK2 (601263). The common features of these disorders probably result from increased ERK activation (Roberts et al., 2007). Discovery of these disease genes have established Noonan syndrome and related traits as disorders of dysregulated RAS-MAPK signaling (Tartaglia et al., 2007). Noonan syndrome-associated SOS1 mutations are hypermorphs encoding products that enhance RAS and ERK activation. They represent a major cause of Noonan syndrome and the first example of activating mutations in a RAS guanine nucleotide exchange factor (GEF) associated with human disease. Zenker et al. (2007) investigated SOS1 in a large cohort of patients with disorders of the NS-CFCS spectrum, who had previously tested negative for mutations in PTPN11, KRAS, BRAF, MEK1, and MEK2. Missense mutations of SOS1 were discovered in 28% of patients with Noonan syndrome, thus confirming SOS1 as the second major gene for that disorder.