Noonan syndrome, the Ras-MAPK signalling pathway and short stature.
Short stature, with a mean final height almost two standard deviations below the normal mean, is a major feature of Noonan syndrome. The biological basis of the growth failure is not yet clear. The recent detection of mutations in the protein tyrosine phosphatase, non-receptor type 11 gene (PTPN11) in half of all individuals with Noonan syndrome has opened up a new perspective from the endocrine point of view, since the tyrosine phosphatase SHP2 encoded by PTPN11 is implicated in the downregulation of growth hormone (GH) receptor signalling. Current data show decreased insulin-like growth factor (IGF)-I and IGF-binding protein 3 (IGFBP-3) levels in those children with Noonan syndrome who carry PTPN11 mutations. GH responsiveness seems to be reduced in the presence of PTPN11 mutations, but, so far, data are too scarce to draw any final conclusions. Children with Noonan or Noonan-related syndromes carrying mutations in components of the Ras-mitogen-activated protein kinase (MAPK) signalling pathway downstream from SHP2 also have short stature, though less frequently in the case of SOS1 mutations. Therefore, apart from the disturbance of GH signalling, there must be other relevant mechanisms that influence longitudinal growth in Noonan syndrome. In a small subgroup of patients with Noonan syndrome and Noonan-related syndromes, tumour risk is increased. This susceptibility is relevant when GH therapy is considered. Progress in the understanding of cell regulation by Ras-MAPK signalling and its interconnection with other pathways will hopefully provide evidence on which therapy might be helpful and which might be nocuous in the care of children with Noonan syndrome.
Binder
Gerhard
G
Paediatric Endocrinology, University Children's Hospital, Tubingen, Germany. Gerhard.binder@med.uni-tuebingen.de
D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000628:therapy; D009634:Noonan Syndrome / Q000201:enzymology* / Q000235:genetics / Q000628:therapy; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors
D002352:Carrier Proteins; D020929:Mitogen-Activated Protein Kinase Kinases; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D015689:Oncogene Protein p21(ras); C051815:somatotropin-binding protein