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Noonan and Cardio-facio-cutaneous syndromes: Two Clinically and Genetically Overlapping Disorders
  1. Anna-Maja Nyström (maja.nystrom{at}
  1. Uppsala University, Sweden
    1. Sara Ekvall (sara.ekvall{at}
    1. Uppsala University, Sweden
      1. Erna Berglund
      1. Central hospital, Skellefteå, Sweden
        1. Maria Björkqvist
        1. University hospital Örebro, Sweden
          1. Gunnar Braathen
          1. Sahlgrenska university hospital, Göteborg, Sweden
            1. Karel Duchen
            1. University hospital Linköping, Sweden
              1. Henrik Enell
              1. Regional hospital of Halmstad, Sweden
                1. Eva Holmberg
                1. Sahlgrenska University hospital, Göteborg, Sweden
                  1. Ulrika Holmlund
                  1. Central hospital, Västerås, Sweden
                    1. Mia Olsson-Engman
                    1. Regional hospital of Karlskrona, Sweden
                      1. Göran Annerén (goran.anneren{at}
                      1. Uppsala University, Sweden
                        1. Marie-Louise Bondeson (marielouise.bondeson{at}
                        1. Uppsala University, Sweden


                          Background: Noonan and Cardio-facio-cutaneous syndromes are related disorders associated with dysregulated RAS/RAF/MEK/ERK signalling. Noonan syndrome (NS), characterized by facial dysmorphism, congenital heart defects and short stature, is caused by mutations in the genes PTPN11, SOS1, KRAS and RAF1. The Cardio-facio-cutaneous syndrome (CFC) is distinguished from NS by the presence of ectodermal abnormalities and more severe mental retardation in addition to the NS phenotype. The genetic aetiology of CFC was recently assigned to four genes: BRAF, KRAS, MEK1 and MEK2.

                          Methods and results: Here, we present a comprehensive mutation analysis of BRAF, KRAS, MEK1, MEK2 and SOS1 in 31 unrelated patients without mutations in PTPN11. Mutations were identified in 7 CFC patients (2 in BRAF, 1 in KRAS, 1 in MEK1, 2 in MEK2 and 1 in SOS1) .Two mutations were novel: MEK1 E203Q and MEK2 F57L. The SOS1 E433K mutation, identified in a patient diagnosed as CFC, has previously been reported in patients with NS. In one NS patient, we also identified a BRAF K499E that previously has been reported in patients with CFC. We thus suggest involvement also of BRAF in the pathogenesis of NS.

                          Conclusions: Taken together, our results indicate that the molecular and clinical overlap between CFC and NS is more complex than previously suggested and that the syndromes might even present as allelic disorders. Furthermore, we suggest that the diagnosis should be refined to, e.g., NS-PTPN11-associated or CFC- BRAF-associated after the genetic defect has been established since this may have an impact on prognosis and treatment of the patients.

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