Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2011 Feb;25(1):161-79.
doi: 10.1016/j.beem.2010.09.002.

Noonan syndrome and clinically related disorders

Marco Tartaglia  1 , Bruce D Gelb, Martin Zenker
Affiliations
Review

Noonan syndrome and clinically related disorders

Marco Tartaglia et al. Best Pract Res Clin Endocrinol Metab. 2011 Feb.

Abstract

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.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Facial dysmorphism in Noonan syndrome
Series of affected individuals heterozygous for mutations in different disease genes are shown. (Kindly provided by G. Zampino, M.C. Digilio, B. Dallapiccola and G.B. Ferrero)
Figure 2
Figure 2. Facial dysmorphism in LEOPARD syndrome
Series of affected individuals heterozygous for mutations in PTPN11 are shown. (Kindly provided by M.C. Digilio and B. Dallapiccola)
Figure 3
Figure 3. Facial dysmorphism in Noonan-like syndrome with loose anagen hair
Series of affected individuals heterozygous for the 4A>G missense change (Ser2Gly) in SHOC2 are shown. (Kindly provided by G. Zampino, M.C. Digilio and B. Dallapiccola)
Figure 4
Figure 4. Facial dysmorphism in CBL mutation-associated syndrome and neurobibromatosis-Noonan syndrome
Series of affected individuals heterozygous for germline CBL (above) or NF1 (below) mutations are shown. (Kindly provided by G. Zampino, M.C. Digilio, B. Dallapiccola, M.L. Cavaliere, J.M. van Hagen and R. Savarirayan)
Figure 5
Figure 5. Facial dysmorphism in cardiofaciocutaneous syndrome and Costello syndrome
Series of affected individuals with cardiofaciocutaneous syndrome (above and middle panels) and Costello syndrome (below panel) are shown. (Kindly provided by G. Zampino, M.C. Digilio, B. Dallapiccola and G. Mancini)
Figure 6
Figure 6. The RAS-MAPK signal transduction pathway
Schematic diagram showing the RAS-MAPK cascade and affected disease genes in disorders of the neuro-cardio-facial-cutaneous syndrome family. The double ovals in dark grey and the light grey ovals represent generic dimerized cell-surface receptors binding to their ligand. Abbreviations: CFCS, cardiofaciocutaneous syndrome; CS: Costello syndrome; LS, LEOPARD syndrome; NF1, neurofibromatosis type 1; NFLS, Neurofibromatosis type 1-like syndrome (also termed Legius syndrome); NFNS, neurofibromatosis-Noonan syndrome; NS, Noonan syndrome; NS/LAH, Noonan-like syndrome with loose anagen hair.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Noonan JA. Hypertelorism with Turner phenotype. A new syndrome with associated congenital heart disease. Am. J. Dis. Child. 1968;116:373–380. - PubMed
    1. Nora JJ, Nora AH, Sinha AK, et al. The Ullrich-Noonan syndrome (Turner phenotype). Am J Dis Child. 1974;127:48–55. - PubMed
    1. Bentires-Alj M, Kontaridis MI, Neel BG. Stops along the RAS pathway in human genetic disease. Nat Med. 2006;12:283–285. - PubMed
    1. Tidyman WE, Rauen KA. The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Curr Opin Genet Dev. 2009;19:230–236. - PMC - PubMed
    1. Noonan JA. Noonan syndrome. An update and review for the primary pediatrician. Clin Pediatr (Phila) 1994;33:548–555. - PubMed

Publication types

MeSH terms

Substances

Supplementary concepts

-