Comprehensive mutation analysis in Costello syndrome, CFC syndrome and Noonan syndrome : clinical and genetic overlap among three disorders. Y. Aoki¹, T. Niihori¹, Y. Narumi¹, H. Kawame², K. Kurosawa³, H. Ohashi⁴, M. Filocamo⁵, G. Neri⁶, H. Cavé⁷, A. Verloes⁷, N. Okamoto⁸, R.C.M Hennekam⁹, G. Gillessen-Kaesbach¹⁰, D. Wieczorek¹⁰, M.I. Kavamura⁶, L. Wilson⁹, Y. Suzuki¹, S. Kure¹, Y. Matsubara¹. 1) Dept Medical Genetics, Tohoku Univ Sch Medicine, Sendai; 2) Nagano Childrens Hosp, Nagano; 3) Kanagawa Childrens Med Ctr, Yokohama; 4) Saitama Childrens Med Ctr, Saitama, Japan; 5) IRCCS. G.Gaslini, Genova; 6) Istituto di Genetica Medica, Rome, Italy; 7) Hôpital Robert Debré (APHP), Paris, France; 8) Osaka Med Ctr & Res Inst for Maternal & Child Health, Osaka, Japan; 9) Inst of Child Health, London, UK; 10) Univ Essen, Essen, Germany.
   Costello syndrome and cardio-facio-cutaneous (CFC) syndrome are Noonan-related syndromes characterized by heart defects, facial dysmorphism, ectodermal abnormalities and mental retardation. Recently we discovered proto-oncogene HRAS mutations in Costello syndrome and KRAS and BRAF mutations in CFC syndrome, establishing a new role of RAS/RAF/MEK/ERK pathway in human development. To elucidate the clinical and molecular characteristics of Noonan, Costello and CFC syndromes, we have analyzed PTPN11, HRAS, KRAS, BRAF and MAP2K1/2 (MEK1/2) in 50 patients with Noonan syndrome, 35 patients with Costello syndrome and 59 patients with CFC syndrome. Mutations in PTPN11 were identified in 42% of patients with Noonan syndrome, two patients with Costello phenotype and three patients firstly diagnosed as having CFC syndrome. HRAS mutations were detected in 57% of Costello patients. Mutations in KRAS, BRAF and MAP2K1/2 were found in 61% of patients with CFC syndrome. Mutations in BRAF or MAP2K1 were detected in two patients with Costello phenotype. No mutations were found in MAPK3/1 (ERK1/2), downstream of MEK1/2, in mutation-negative CFC patients. The analysis of 81 clinical manifestations in 25 mutation-positive CFC patients showed that wrinkled palms and soles, hyperkeratosis and joint hyperextension, which are important diagnostic features in Costello syndrome, were present in 30-40% of CFC patients. These results suggest that there is significant clinical and molecular overlap among these three syndromes.