Noonan syndrome-8 is an autosomal dominant disorder characterized by short stature, distinctive facial features, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. A subset of patients show intellectual disabilities (summary by Aoki et al., 2013). ... Noonan syndrome-8 is an autosomal dominant disorder characterized by short stature, distinctive facial features, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. A subset of patients show intellectual disabilities (summary by Aoki et al., 2013). For a phenotypic description and a discussion of genetic heterogeneity of Noonan syndrome, see NS1 (163950).
Aoki et al. (2013) reported 17 unrelated individuals with Noonan syndrome-8 ranging in age from a few months to 15 years. Patients had a distinctive facial appearance with relative macrocephaly, hypertelorism, downslanting palpebral fissures, ptosis, epicanthal folds, and ... Aoki et al. (2013) reported 17 unrelated individuals with Noonan syndrome-8 ranging in age from a few months to 15 years. Patients had a distinctive facial appearance with relative macrocephaly, hypertelorism, downslanting palpebral fissures, ptosis, epicanthal folds, and low-set ears. Many had skin and hair anomalies, such as curly hair, hyperelastic skin, and hyperkeratosis. Other features included short stature and short or webbed neck. Twelve individuals (71%) developed hypertrophic cardiomyopathy, 11 (65%) had pulmonic stenosis, and 5 (29%) had atrial septal defects. At least 4 patients had documented intellectual disability. Nine patients showed perinatal abnormalities, including polyhydramnios, nuchal translucency, and chylothorax. One infant with cardiomyopathy and pleural effusion died at age 53 days, and 1 child developed acute lymphoblastic leukemia at age 5 years.
In 17 (9%) of 180 unrelated patients suspected of having Noonan syndrome but without mutation in any known Noonan syndrome-causing genes, Aoki et al. (2013) identified heterozygous mutations in the RIT1 gene (see, e.g., 609591.0001-609591.0004). The first mutations ... In 17 (9%) of 180 unrelated patients suspected of having Noonan syndrome but without mutation in any known Noonan syndrome-causing genes, Aoki et al. (2013) identified heterozygous mutations in the RIT1 gene (see, e.g., 609591.0001-609591.0004). The first mutations were found by exome sequencing and subsequent mutations were identified from a larger cohort of patients screened for the RIT1 gene. A total of 9 missense mutations were found. The mutations tended to cluster in the switch II region, and in vitro functional expression studies of 3 of the mutations showed that they resulted in a gain of function. Transfection of 2 of the mutations into zebrafish embryos resulted in a variety of developmental defects, including gastrulation defects, craniofacial abnormalities, pericardial edema, and elongated yolk sac. A smaller percentage of mutant embryos showed even more disorganized growth and abnormal cardiogenesis. The findings were similar to those observed with mutations in other RAS genes (see, e.g., PTPN11, 176876; SOS1, 182530; NRAS, 164790) causing other forms of Noonan syndrome.