RESUMO
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.
Assuntos
Anormalidades Múltiplas/genética , Deficiência Intelectual/genética , MAP Quinase Quinase 1/genética , MAP Quinase Quinase 2/genética , Proteínas Proto-Oncogênicas B-raf/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/epidemiologia , Estudos de Casos e Controles , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/epidemiologia , Anormalidades Craniofaciais/genética , Análise Mutacional de DNA , Diagnóstico Diferencial , Genótipo , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/genética , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/epidemiologia , Epidemiologia Molecular , Fenótipo , Transdução de Sinais , Anormalidades da Pele/diagnóstico , Anormalidades da Pele/epidemiologia , Anormalidades da Pele/genética , Síndrome , Proteínas ras/metabolismoRESUMO
Cardio-facio-cutaneous (CFC) syndrome is characterized by a distinctive facial appearance, heart defects and mental retardation. It phenotypically overlaps with Noonan and Costello syndrome, which are caused by mutations in PTPN11 and HRAS, respectively. In 43 individuals with CFC, we identified two heterozygous KRAS mutations in three individuals and eight BRAF mutations in 16 individuals, suggesting that dysregulation of the RAS-RAF-ERK pathway is a common molecular basis for the three related disorders.
Assuntos
Face/anormalidades , Cardiopatias Congênitas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas/genética , Anormalidades da Pele/genética , Sequência de Aminoácidos , Humanos , Deficiência Intelectual/genética , Dados de Sequência Molecular , Proteínas Proto-Oncogênicas p21(ras) , Valores de Referência , Síndrome , Proteínas rasRESUMO
Costello syndrome is a multiple congenital anomaly and mental retardation syndrome characterized by coarse face, loose skin, cardiomyopathy and predisposition to tumors. We identified four heterozygous de novo mutations of HRAS in 12 of 13 affected individuals, all of which were previously reported as somatic and oncogenic mutations in various tumors. Our observations suggest that germline mutations in HRAS perturb human development and increase susceptibility to tumors.
Assuntos
Anormalidades Múltiplas/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Deficiência Intelectual/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Sequência de Aminoácidos , Cardiomiopatias/genética , Face/anormalidades , Feminino , Humanos , Dados de Sequência Molecular , Neoplasias/genética , Proto-Oncogene Mas , Anormalidades da Pele/genética , SíndromeRESUMO
In Japan, transdermal fentanyl (Durotep Patch) was launched in March 2002, and it was regarded as making opioid rotation possible. When changing from morphine to transdermal fentanyl, the efficacy ratio of 1:150 is used in Japan as well as in many other countries. However, the ratio of 1:100 is used in Germany. As a result, a dose increase in transdermal fentanyl is often required to control pain. We studied transdermal fentanyl use in the Aichi Cancer Center (ACC) to investigate the actual conversion ratio and appropriate switching by following up 144 patients (81 men, 63 women) who had received transdermal fentanyl in the ACC from March 19, 2002, to April 30, 2003. Transdermal fentanyl improved pain control in patients who had difficulty in tolerating oral medication or in continuing morphine because of side effects. Regression analysis indicated that the efficacy ratio of oral morphine to transdermal fentanyl was 1:78. As the fentanyl dosage was excessive even in some patients who followed the recommended morphine/fentanyl conversion of 150:1, it is dangerous to use the conversion ratio of 78:1 at first. Morphine side effects were reduced in some patients who changed to transdermal fentanyl, but there was no reduction in those who needed high-dose morphine for rescue analgesia. Therefore it is safe and effective to use low-dose transdermal fentanyl in the beginning and to control pain promptly using rescue morphine based on the present recommended dosage. For opioid rotation, quick-acting opioids other than morphine are expected to be launched in Japan.