Noonan syndrome (NS) is a genetic disorder characterized by short stature, typical facial dysmorphology, and congenital heart defects. Noonan syndrome may occur on a sporadic basis or in a pattern consistent with autosomal dominant inheritance, with a predominance of maternal transmission (Noonan 1994). In approximately 50% of the patients with definite NS, a missense mutation is found in the PTPN11 gene on chromosome 12. PTPN11 is one of the genes of the Ras-MAPK pathway, a signal transduction cascade that has been studied extensively for its role in human oncogenesis. The signaling cascade regulates cell proliferation, differentiation, and survival. PTPN11 encodes the nonreceptor protein tyrosine phosphatase SHP-2. The mutations associated with NS result in a gain of function of SHP-2 (Tartaglia and Gelb 2005). Recently, activating mutations in other genes of the Ras-MAPK pathway (SOS1, KRAS, RAF1) were found as the causative dominant mutations in NS. These findings establish hyperactive Ras as a cause of the developmental abnormalities seen in NS (Schubbert et al. 2007). The diagnosis is made on clinical grounds, by observation of key features. Establishing the diagnosis can be very difficult, especially at an older age. There is great variability in expression, and mild expression is likely to be overlooked. Improvement of the phenotype occurs with increasing age. The age-related change of facial appearance can be subtle, especially at older age. Several scoring systems have been devised to guide the diagnostic process). The most recent scoring system was developed in 1994 (Van der Burgt et al. 1994). The incidence of NS is estimated to be between 1:1,000 and 1:2,500 live births (Mendez and Opitz 1985). Further details on the various medical aspects of NS (e.g., congenital heart defects, skeletal and urethrogenital abnormalities, growth delay) can be found in Van der Burgt (2007). A number of conditions have phenotypes strikingly similar to NS. The first is Turner syndrome (45, X0), a well-known chromosomal abnormality in girls. A group of distinct syndromes with partially overlapping phenotypes also exist in which causative mutations are also found in genes of the RAS-MAPK pathway.
A Rare Mutation In Noonan Syndrome
