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Noonan Syndrome and RAS Signaling Defects 

Noonan Syndrome and RAS Signaling Defects
Noonan Syndrome and RAS Signaling Defects

Marco Tartaglia

and Bruce D. Gelb

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date: 04 March 2021

Noonan syndrome is a pleiomorphic disorder affecting the cardiovascular, craniofacial, skeletal, hematopoietic, lymphatic and central nervous systems. It is clinically variable and genetically heterogeneous. The disorder is transmitted as an autosomal dominant trait, although many cases result from de novo mutations. So far, mutations in nine genes (PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF, SHOC2, MEK1 and CBL) have been documented to underlie Noonan syndrome or closely related phenotypes. Based on these recent discoveries, Noonan syndrome is now regarded as a disorder of upregulated RAS-mitogen-activated protein kinases (MAPK) signal transduction pathway. Mutations in the known disease genes account for approximately 75% of affected individuals. Genotype-phenotype correlation studies have document that the substantial phenotypic variation characterizing Noonan syndrome can be ascribed, in part, to the mutated gene and even the specific molecular lesion. Clinical manifestations of Noonan syndrome include: a typical dysmorphic appearance, congenital heart defects [particularly pulmonic stenosis (PS)] or hypertrophic cardiomyopathy (HCM), webbing of the neck, short stature, cryptorchidism, eye abnormalities, and skeletal anomalies such as pectus deformities, cubitus valgus, and vertebral anomalies. A minority of affected individuals has bleeding diathesis, hearing loss and mental retardation. Diagnosis is made by clinical examination. Prenatal diagnosis of Noonan syndrome may be suspected in the presence of ultrasonographic findings such as nuchal edema or cystic hygroma. Therapy in the neonatal period and infancy involves discovering and treating the cardiac disease and managing the feeding problems. Orchidopexy is indicated for undescended testes. Growth hormone (GH) therapy has been used to ameliorate the short stature. Preventive pediatric care is appropriate for the hematologic and developmental issues.

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