Noonan syndrome (NS) is a genetic multisystem disorder characterized by recognizable facial features, developmental delay, learning issues, short stature, congenital heart disease, renal anomalies, lymphatic malformations, and/or bleeding problems. NS-causing mutations alter genes encoding proteins with roles in the Ras/mitogen-activated protein kinase (Ras/MAPK) pathway, leading to pathway dysregulation. Thus far, eight genes have been shown to cause NS or closely related conditions (PTPN11
, RAF1, BRAF
, and CBL
). There are multiple clinically relevant genotype-phenotype correlations that aid in risk assessment and patient management. Genotype phenotype correlation with regard to cardiovascular, growth, development, cutaneous, and hematological features will be discussed. Features of Cardiofaciocutaneous (CFC) syndrome include multiple congenital anomalies and intellectual disabilities, failure to thrive and short stature, congenital heart defects, and a characteristic facial appearance. The phenotypic presentation of CFCS significantly overlaps that of NS and mutations in four Ras/MAPK genes, BRAF
, and MEK2
, have been found to cause CFC. The dysmorphic facial features, skin abnormalities, short stature, and cardiac abnormalities in Costello syndrome (CS) have prompted comparison to NSand CFC. Mutations in the Ras/MAPK gene HRAS
have been identified as the cause of approximately 85% of cases of CS. Genotype phenotype correlations, as they relate to Cardiofaciocutaneous (CFC) syndrome and Costello syndrome (CS) will be reviewed. Detailed assessment of the phenotype may be helpful in guiding molecular genetic diagnostic testing for an individual.
<—Back to Abstracts