Noonan syndrome and clinically related disorders

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.

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. 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. 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. 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. 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. 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.