Noonan, Cardiofaciocutaneous and Costello syndromes and the RAS-MAPK pathway
Noonan syndrome is a common autosomal dominant disorder whose characteristic features include congenital heart defects, short stature, pectus deformity of the chest, bleeding diathesis, variable differences in learning and development, and a particular facial appearance that changes with age. While genetically heterogeneous, up to 60% of affected individuals have a mutation in PTPN11, which encodes SHP-2, a key molecule in the cellular response to growth factors, hormones, cytokines and cell adhesion molecules. PTPN11 mutations are gain of function, with enhanced phosphatase activity and activation of the RAS/MAPK (mitogen-activated protein kinase) cascade in a cell-specific manner.
Noonan, Cardiofaciocutaneous and Costello syndromes have overlapping phenotypes, although one can usually distinguish between them. Nonetheless, even the experts may have differences of opinion. Within the last six months, mutations in HRAS have been found to cause Costello syndrome. These mutations activate downstream effectors such as MAPK. Just last week, missense mutations in three additional genes in the MAPK pathway, BRAF, MEK1 and MEK2, have been shown to cause cardiofaciocutaneous syndrome.
This complex pathway has a central role in cell growth and disruptions in the pathway can lead to tumour development. Individuals with cardiofaciocutaneous syndrome do not seem to be prone to cancer, however, a number of different malignancies have been described in Costello syndrome, including embryonal rhabdomyosarcoma, ganglioblastoma and bladder cancer. Juvenile myelomonocytic leukemia is an infrequent finding in Noonan syndrome and other cancers, such as neuroblastoma, Wilms’ tumour and non-Hodgkins lymphoma, have been rarely reported. Genotype-phenotype correlations will be explored.