PHENOTYPIC CONSEQUENCES AND THE MALIGNANCY RISK IN FAMILIAL NOONAN SYNDROME DUE TO A RARE P.S427G RAF1 MUTATION.

Mutations leading to dysregulation of the Ras/MAPK signal transduction cascade are a common cause of Noonan syndrome (NS) and play a key role in the pathogenesis of many human malignancies. To date, about 24 various RAF1 germline mutations were identified in NS. The incidence of malignancies in NS patients with RAF1 mutations has not been reported so far. However, in a few cases somatic RAF1 mutations were observed in cancer, including two described in therapy-related acute myeloid leukaemia (t-AML). We present a case of an adult female patient with Noonan syndrome and her affected mother with a rare RAF] germline mutation c.1279A>G (p.S427G), located within the highly conserved domain (CR3) of serine/threonine kinase C-RAF. Interestingly, this mutation has been reported for the first time in a patient with t-AML as a somatic change and so far has been identified in only one individual with NS phenotype and his mother. Our report presents the second familial case of Noonan syndrome due to a germline p.S427G substitution in RAF] with no occurrence of a malignant tumor. It may suggest that carrying a germline mutation in the RAF1 oncogene is not associated with an increased risk of tumor development. Since RAF1 mutations have been observed as a somatic event in many types of cancer, this report might be of importance for the genetic counselling and management of patients both with germline and somatic alterations in this gene.