Noonan syndrome is an autosomal dominant dysmorphic syndrome characterized primarily by dysmorphic facial features, cardiac abnormalities, and short stature, among other features (summary by Shah et al., 1999).
For a phenotypic description and a discussion of ... Noonan syndrome is an autosomal dominant dysmorphic syndrome characterized primarily by dysmorphic facial features, cardiac abnormalities, and short stature, among other features (summary by Shah et al., 1999). For a phenotypic description and a discussion of genetic heterogeneity of Noonan syndrome, see NS1 (163950), which is caused by mutations in the PTPN11 gene (176876). Approximately 50% of cases of Noonan syndrome are caused by mutations in PTPN11.
Schubbert et al. (2006) reported a 3-month-old female with Noonan syndrome without mutation in the PTPN11 gene. She had a severe phenotype and presented with a juvenile myelomonocytic leukemia-like (JMML; 607785) myeloproliferative disorder. Clinical features included atrial septal ... Schubbert et al. (2006) reported a 3-month-old female with Noonan syndrome without mutation in the PTPN11 gene. She had a severe phenotype and presented with a juvenile myelomonocytic leukemia-like (JMML; 607785) myeloproliferative disorder. Clinical features included atrial septal defect, ventricular septal defect, valvular pulmonary stenosis, dysmorphic facial features, short stature, webbed neck, severe developmental delay, macrocephaly, and sagittal suture synostosis. Kratz et al. (2009) reported 2 unrelated patients with Noonan syndrome-3 who also had craniosynostosis. In the first patient, polyhydramnios and a cystic hygroma were noted during the first trimester. Craniofacial anomalies included abnormal shape of the skull, frontal bossing, dolichocephaly, hypertelorism, low-set ears, a short nose with anteverted nares, and pterygium colli. Cardiac defects included hypertrophy of the right ventricle and septum, and an open foramen ovale. Skull imaging showed synostosis of the sagittal suture and parts of both coronal sutures, necessitating reconstruction. At age 3 years, 2 months, he was unable to sit independently, made little contact, and had not developed any speech abilities. The second child had a Chiari 1 malformation and closure of the left lamboidal suture that was surgically corrected at 8 months. Other features included reduced growth, hypertelorism, epicanthic folds, ptosis, downslanting palpebral fissures, strabismus, hypoplastic nasal bridge, prominent philtrum, high palate, low-set and posteriorly rotated ears with a thickened helix, and mild pectus excavatum. Cardiac features included a dysplastic pulmonary valve and mild hypertrophy of the interventricular septum. There were mild cognitive deficits. Kratz et al. (2009) noted that craniosynostosis is not a commonly recognized feature of Noonan syndrome.
In a girl with severe Noonan syndrome, Schubbert et al. (2006) identified a heterozygous de novo mutation in the KRAS gene (T58I; 190070.0011). Analysis of 124 patients with Noonan syndrome without PTPN11 mutations demonstrated a heterozygous val14-to-ile substitution ... In a girl with severe Noonan syndrome, Schubbert et al. (2006) identified a heterozygous de novo mutation in the KRAS gene (T58I; 190070.0011). Analysis of 124 patients with Noonan syndrome without PTPN11 mutations demonstrated a heterozygous val14-to-ile substitution in 3 unrelated individuals (V14I; 190070.0012). These individuals showed a milder clinical phenotype that the patient with the T58I mutation, and none had a history of myeloproliferative disorder or cancer. Schubbert et al. (2006) also analyzed 50 additional individuals with Noonan syndrome and 12 with cardiofaciocutaneous syndrome (CFC; 115150) and identified KRAS mutations in 1 individual with Noonan syndrome and 1 with CFC. All of these sequence changes occurred de novo, and none was found in 200 normal European controls. One of the KRAS sequence changes found by Schubbert et al. (2006) in a patient with Noonan syndrome was found by Niihori et al. (2006) in a patient with CFC (190070.0010). In 2 unrelated children with Noonan syndrome and craniosynostosis, Kratz et al. (2009) identified 2 different de novo heterozygous mutations in the KRAS gene (T58I and G60S, 190070.0020). The T58I mutation had previously been observed in a patient with Noonan syndrome and craniosynostosis (Schubbert et al., 2006). The findings indicated that dysregulated RAS signaling may lead to abnormal growth or premature calvarian closure.