Molecular and clinical characterization of cardio-facio-cutaneous (CFC) syndrome: overlapping clinical manifestations with Costello syndrome.
Cardio-facio-cutaneous (CFC) syndrome is a multiple congenital anomaly/mental retardation syndrome characterized by heart defects, a distinctive facial appearance, ectodermal abnormalities and mental retardation. Clinically, it overlaps with both Noonan syndrome and Costello syndrome, which are caused by mutations in two genes, PTPN11 and HRAS, respectively. Recently, we identified mutations in KRAS and BRAF in 19 of 43 individuals with CFC syndrome, suggesting that dysregulation of the RAS/RAF/MEK/ERK pathway is a molecular basis for CFC syndrome. The purpose of this study was to perform comprehensive mutation analysis in 56 patients with CFC syndrome and to investigate genotype-phenotype correlation. We analyzed KRAS, BRAF, and MAP2K1/2 (MEK1/2) in 13 new CFC patients and identified five BRAF and one MAP2K1 mutations in nine patients. We detected one MAP2K1 mutation in three patients and four new MAP2K2 mutations in four patients out of 24 patients without KRAS or BRAF mutations in the previous study [Niihori et al., 2006]. No mutations were identified in MAPK3/1 (ERK1/2) in 21 patients without any mutations. In total, 35 of 56 (62.5%) patients with CFC syndrome had mutations (3 in KRAS, 24 in BRAF, and 8 in MAP2K1/2). No significant differences in clinical manifestations were found among 3 KRAS-positive patients, 16 BRAF-positive patients, and 6 MAP2K1/2-positive patients. Wrinkled palms and soles, hyperpigmentation and joint hyperextension, which have been commonly reported in Costello syndrome but not in CFC syndrome, were observed in 30-40% of the mutation-positive CFC patients, suggesting a significant clinical overlap between these two syndromes.
Narumi
Yoko
Y
Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan.
Aoki
Yoko
Y
Niihori
Tetsuya
T
Neri
Giovanni
G
Cavé
Hélène
H
Verloes
Alain
A
Nava
Caroline
C
Kavamura
Maria Ines
MI
Okamoto
Nobuhiko
N
Kurosawa
Kenji
K
Hennekam
Raoul C M
RC
Wilson
Louise C
LC
Gillessen-Kaesbach
Gabriele
G
Wieczorek
Dagmar
D
Lapunzina
Pablo
P
Ohashi
Hirofumi
H
Makita
Yoshio
Y
Kondo
Ikuko
I
Tsuchiya
Shigeru
S
Ito
Etsuro
E
Sameshima
Kiyoko
K
Kato
Kumi
K
Kure
Shigeo
S
Matsubara
Yoichi
Y
D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D019465:Craniofacial Abnormalities / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D005838:Genotype; D006330:Heart Defects, Congenital / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D048369:MAP Kinase Kinase 1 / Q000235:genetics*; D048370:MAP Kinase Kinase 2 / Q000235:genetics*; D017720:Molecular Epidemiology; D010641:Phenotype; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D015398:Signal Transduction; D012868:Skin Abnormalities / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D013577:Syndrome; D018631:ras Proteins / Q000378:metabolism
C482128:MAP2K2 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D018631:ras Proteins