11例儿童RAS通路病的临床特点和基因突变类型
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摘要
【目的】总结5种亚型儿童RAS通路病的临床特点及基因变异类型,分析Ⅰ型神经纤维腺瘤病(NF1)、努南综合征(NS)、多色素痣型努南综合征(NSML)、科斯特洛综合征(CS)和心-面-皮肤综合征(CFC)的临床共性和特性,提高临床医生对RAS通路病的认识和诊治水平。【方法】回顾性分析我院2015年10月至2018年6月期间确诊的11例RAS通路病患者的临床资料及基因突变类型。【结果】11例RAS通路病患儿的发病年龄为6月～12岁,常见临床表现包括:身材矮小、特殊面容、先天性心脏病、皮肤牛奶咖啡斑、运动发育落后、血小板减少、癫痫、肌张力异常、隐睾等,共检测出5种基因突变类型,包括NF1基因、PTPN11基因、RAF1基因、BRAF基因和HRAS基因。【结论】RAS通路病是丝裂原活化蛋白激酶通路异常引起的一组遗传性生长发育异常综合征。因此,RAS通路病常伴有特殊面容、运动发育落后、心血管、皮肤、骨骼、神经等多系统异常以及肿瘤易感性等共同表现。但因基因突变位点的差异,各类型间亦存在相对特异的表现。另外,因肿瘤易感性是RAS通路病的共性之一,肿瘤监测是随访过程的重要项目。
【Objective】Through summarizing the clinical manifestations and gene mutations of 5 types of RASopathies in childhood including Neurofibromatosis type1(NF1),Noonan syndrome(NS),Noonan syndrome with multiple lentigines(NSML),Costello syndrome(CS)and cardio-facio-cutaneous syndrome(CFC)and analyzing their commonalities and characteristics,to deepen the clinician′s understanding of the RASopathies and improve the domestic doctors′ diagnosis and treatment level of RASopathies.【Methods】The clinical data and gene mutation types of 11 patients of RASopathies who were diagnosed in Sun Yat-Sen Memorial Hospital from January 2015 to May 2018 were retrospectively analyzed.【Results】The age of onset ranged from 6 months to 12 years and the main clinical manifestations of 11 patients included:short stature,craniofacial features,congenital heart defect,café-au-lait macules,developmental delay,thrombocytopenia,seizures and dystonia,cryptorchidism,etc. Five gene mutations were detected including NF1 gene,PTPN11 gene,RAF1 gene,BRAF gene and HRAS gene.【Conclusions】The RASopathies are a clinically defined group of medical genetic syndromes caused by germline mutations in genes that encode components or regulators of the Ras/MAPK pathway.The RAS/MAPK pathway plays an important role in regulating growth development,promoting cell proliferation,differentiation,metabolism,and signal transduction of various hormones. Therefore,they share many overlapping characteristics,including craniofacial features,growth retardation,cardiac malformations,cutaneous and musculoskeletal abnormalities,neurocognitive impairment and tumor susceptibility. However because of mutations at different points in the pathway. In addition features of RASopathies. Therefore,tumor monitoring is one of the most important contents in the follow-up process.
【Objective】Through summarizing the clinical manifestations and gene mutations of 5 types of RASopathies in childhood including Neurofibromatosis type1(NF1),Noonan syndrome(NS),Noonan syndrome with multiple lentigines(NSML),Costello syndrome(CS)and cardio-facio-cutaneous syndrome(CFC)and analyzing their commonalities and characteristics,to deepen the clinician′s understanding of the RASopathies and improve the domestic doctors′ diagnosis and treatment level of RASopathies.【Methods】The clinical data and gene mutation types of 11 patients of RASopathies who were diagnosed in Sun Yat-Sen Memorial Hospital from January 2015 to May 2018 were retrospectively analyzed.【Results】The age of onset ranged from 6 months to 12 years and the main clinical manifestations of 11 patients included:short stature,craniofacial features,congenital heart defect,café-au-lait macules,developmental delay,thrombocytopenia,seizures and dystonia,cryptorchidism,etc. Five gene mutations were detected including NF1 gene,PTPN11 gene,RAF1 gene,BRAF gene and HRAS gene.【Conclusions】The RASopathies are a clinically defined group of medical genetic syndromes caused by germline mutations in genes that encode components or regulators of the Ras/MAPK pathway.The RAS/MAPK pathway plays an important role in regulating growth development,promoting cell proliferation,differentiation,metabolism,and signal transduction of various hormones. Therefore,they share many overlapping characteristics,including craniofacial features,growth retardation,cardiac malformations,cutaneous and musculoskeletal abnormalities,neurocognitive impairment and tumor susceptibility. However because of mutations at different points in the pathway. In addition features of RASopathies. Therefore,tumor monitoring is one of the most important contents in the follow-up process.
引文
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[2]Cao H,Alrejaye N,Klein OD,et al.A review of craniofacial and dental findings of the RASopathies[J].Orthod Craniofac Res,2017,20(S1):32-38.
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[13]Van der Burgt I,Berends E,Lommen E,et al.Clinical and molecular studies in a large Dutch family with Noonan syndrome[J].Am J Med Genet,1994,53(2):187-191.
[14]Digilio MC,Lepri F,Baban A,et al.RASopathies:Clinical diagnosis in the first year of life[J].Mol Syndromol,2011,1(6):282-289.
[15]Gelb BD,Roberts AE,Tartaglia M.Cardiomyopathies in Noonan syndrome and the other RASopathies[J].Progress Pediatric Cardiol,2015,39(1):13-19.
[16]Yohay KH.The genetic and molecular pathogenesis of NF1 and NF2[J].Senmin Pediator Neurol,2006,13(1):21-26.
[17]O′Connell P,Leach RJ,Ledbetter DH,et al.Fine structure DNA mapping studies of the chromosomal region harboring the genetic defect in neurofibromatosis type 1[J].Am J Hum Genet,1989,44(1):51-57.
[18]Wise JB,Cryer JE,Belasco JB,et al.Management of head and neck plexiformneurofibromas in pediatric patients with neurofibromatosis type 1[J].Arch Otolaryngol Head Neck Surg,2005,131(8):712-718.
[19]Needle MN,Cnaan A,Dattilo J,et al.Prognostic signs in the surgical management of plexiformneurofibroma:the Children′s Hospital of Philadelphia experience,1974-1994[J].J Pediatr,1997,131(5):678-682
[20]Gripp KW,Lin AE.Costello syndrome:a Ras/mitogen activated protein kinase pathway syndrome(rasopathy)resulting from HRAS germline mutations[J].Genet Med,2012,14(3):285-292.
[21]Goodwin AF,Oberoi S,Landan M,et al.Craniofacial and Dental Development in Costello Syndrome[J].Am J Med Genet A,2014,164A(6):1425-1430.
[22]Lin AE,O′Brien B,Demmer LA,et al.Prenatal features of Costello syndrome:ultrasonographic findings and atrial tachycardia[J].Prenat Diagn,2009,29(7):682-690.
[23]McCormick EM,Hopkins E,Conway L,et al.Assessing genotype-phenotype correlation in Costello syndrome using a severity score[J].Genet Med,2013,15(7):554-557.
[24]Reynolds JF,Neri G,Herrmann JP,et al.New multiple congenital anomalies/mental retardation syndrome with cardiofacio-cutaneous involvement-the CFC syndrome[J].Am J Med Genet,1986,25(3):413-427.
[25]张欢欢,李牛,郁婷婷,等.Cardio-facio-cutaneous综合征2例报告并文献复习[J].临床儿科杂志,2017,35(4):286-289.Zhang HH,Li N,Yu TT,et al.The clinical feature and gene analysis of Cardio-facio-cutaneous syndrome in children:a report of 2 cases and literature review[J].J Clin Pediatr,2017,35(4):286-289.
[2]Cao H,Alrejaye N,Klein OD,et al.A review of craniofacial and dental findings of the RASopathies[J].Orthod Craniofac Res,2017,20(S1):32-38.
[3]Noonan JA.Hypertelorism with Turner phenotype.A new syndrome with associated congenital heart disease[J].Am J Dis Child,1968,116(4):373-380.
[4]Roberts AE,Allanson JE,Tartaglia M,et al.Noonan syndrome[J].Lancet,2013,381(9863):333-342.
[5]Romano AA,Allanson JE,Dahlgren J,et al.Noonan syndrome:clinical features,diagnosis,and management guidelines[J].Pediatrics,2010,126(4):746-759.
[6]梅玉霞,常国营,庄承,等.SHOC2基因突变致Noonan综合征1例报告[J].临床儿科杂志,2017,35(12):902-905.Mei YX,Chang GY,Zhuang C,et al.Noonan syndrome caused by mutation of SHOC 2 gene:a case report[J].J Clin Pediatr,2017,35(12):902-905.
[7]刘晓亮,傅立军.Noonan综合征的诊治进展[J].临床儿科杂志,2016,34(1):64-67.Liu XL,Fu LJ.Progress in the diagnosis and treatment of Noonan syndrome[J].J Clin Pediatr,2016,34(1):64-67.
[8]Wu X,Yin J,Simpson J,et al.Increased BRAF heterodi merization is the common pathogenic mechanism for Noonan syndrome-associated RAF1 mutants[J].Mol Cell Biol,2012,32(19):3872-3890.
[9]Yoon SR,Choi SK,Eboreime J,et al.Age-dependent germline mosaicism of the most common Noonan syndrome mutation shows the signature of germline selection[J].Am J Hum Genet,2013,92(6):917-926.
[10]Myers A,Bernstein JA,Brennan M,et al.Perinatal features of the RASopathies:Noonan syndrome,Cardiofaciocutaneous syndrome and Costello syndrome[J].Am J Med Genet Part A,2014,164(11):2814-2821.
[11]Aoki Y,Niihori T,Banjo T,et al.Gain-of-function mutations in RIT1 cause Noonan syndrome,a RAS/MAPK pathway syndrome[J].Am J Hum Genet,2013,93(1):173-180.
[12]Aoki Y,Niihori T,Inoue S,et al.Recent advances in RASopathies[J].J Hum Genet,2016,61(1):33-39.
[13]Van der Burgt I,Berends E,Lommen E,et al.Clinical and molecular studies in a large Dutch family with Noonan syndrome[J].Am J Med Genet,1994,53(2):187-191.
[14]Digilio MC,Lepri F,Baban A,et al.RASopathies:Clinical diagnosis in the first year of life[J].Mol Syndromol,2011,1(6):282-289.
[15]Gelb BD,Roberts AE,Tartaglia M.Cardiomyopathies in Noonan syndrome and the other RASopathies[J].Progress Pediatric Cardiol,2015,39(1):13-19.
[16]Yohay KH.The genetic and molecular pathogenesis of NF1 and NF2[J].Senmin Pediator Neurol,2006,13(1):21-26.
[17]O′Connell P,Leach RJ,Ledbetter DH,et al.Fine structure DNA mapping studies of the chromosomal region harboring the genetic defect in neurofibromatosis type 1[J].Am J Hum Genet,1989,44(1):51-57.
[18]Wise JB,Cryer JE,Belasco JB,et al.Management of head and neck plexiformneurofibromas in pediatric patients with neurofibromatosis type 1[J].Arch Otolaryngol Head Neck Surg,2005,131(8):712-718.
[19]Needle MN,Cnaan A,Dattilo J,et al.Prognostic signs in the surgical management of plexiformneurofibroma:the Children′s Hospital of Philadelphia experience,1974-1994[J].J Pediatr,1997,131(5):678-682
[20]Gripp KW,Lin AE.Costello syndrome:a Ras/mitogen activated protein kinase pathway syndrome(rasopathy)resulting from HRAS germline mutations[J].Genet Med,2012,14(3):285-292.
[21]Goodwin AF,Oberoi S,Landan M,et al.Craniofacial and Dental Development in Costello Syndrome[J].Am J Med Genet A,2014,164A(6):1425-1430.
[22]Lin AE,O′Brien B,Demmer LA,et al.Prenatal features of Costello syndrome:ultrasonographic findings and atrial tachycardia[J].Prenat Diagn,2009,29(7):682-690.
[23]McCormick EM,Hopkins E,Conway L,et al.Assessing genotype-phenotype correlation in Costello syndrome using a severity score[J].Genet Med,2013,15(7):554-557.
[24]Reynolds JF,Neri G,Herrmann JP,et al.New multiple congenital anomalies/mental retardation syndrome with cardiofacio-cutaneous involvement-the CFC syndrome[J].Am J Med Genet,1986,25(3):413-427.
[25]张欢欢,李牛,郁婷婷,等.Cardio-facio-cutaneous综合征2例报告并文献复习[J].临床儿科杂志,2017,35(4):286-289.Zhang HH,Li N,Yu TT,et al.The clinical feature and gene analysis of Cardio-facio-cutaneous syndrome in children:a report of 2 cases and literature review[J].J Clin Pediatr,2017,35(4):286-289.