Journal
BEST PRACTICE & RESEARCH CLINICAL ENDOCRINOLOGY & METABOLISM
Volume 25, Issue 1, Pages 161-179Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.beem.2010.09.002
Keywords
Noonan syndrome; LEOPARD syndrome; Noonan-like syndrome with loose anagen hair; CBL mutation-associated syndrome; RAS signaling; pathogenetic mechanisms; diagnosis; patient management; genotype-phenotype correlations
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Funding
- Telethon-Italy [GGP10020]
- Associazione Italiana Sindromi di Costello e Cardiofaciocutanea
- ERARE (NSEuroNet)
- DFG [ZE 524/4-1]
- National Institutes of Health [HL71207]
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Noonan syndrome is a relatively common, clinically variable developmental disorder. Cardinal features include postnatally reduced growth, distinctive facial dysmorphism, congenital heart defects and hypertrophic cardiomyopathy, variable cognitive deficit and skeletal, ectodermal and hematologic anomalies. Noonan syndrome is transmitted as an autosomal dominant trait, and is genetically heterogeneous. So far, heterozygous mutations in nine genes (PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF, SHOC2, MEK1 and CBL) have been documented to underlie this disorder or clinically related phenotypes. Based on these recent discoveries, the diagnosis can now be confirmed molecularly in approximately 75% of affected individuals. Affected genes encode for proteins participating in the RAS-mitogen-activated protein kinases (MAPK) signal transduction pathway, which is implicated in several developmental processes controlling morphology determination, organogenesis, synaptic plasticity and growth. Here, we provide an overview of clinical aspects of this disorder and closely related conditions, the molecular mechanisms underlying pathogenesis, and major genotype-phenotype correlations. (C) 2010 Elsevier Ltd. All rights reserved.
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