Williams-Beuren综合征的临床及遗传学特点:2例报道
|
摘要
通过分析2例WBS患儿临床表现,个人史,心脏超声、头颅磁共振成像、脑电图及染色体检测结果的特点,探讨Williams-Beuren综合征(Williams-Beuren syndrome,WBS)的临床及遗传学特点,以提高对该疾病的认识。2例患儿均为男性,就诊年龄分别为11个月1天和9个月9天,均存在心血管畸形,病例1为主动脉瓣上狭窄,病例2为房间隔缺损、动脉导管未闭。患儿具有WBS特征性面容:眶周饱满、球形鼻头、鼻梁低平、长人中、厚嘴唇。精神发育迟滞:病例1为中-重度,病例2为重度。其他表现:病例1合并双侧腹股沟斜疝和鞘膜积液,病例2合并喂养困难、埋藏式阴茎及婴儿痉挛。个人史:病例1孕期曾保胎,后因羊水污染足月剖宫产娩出。辅助检查:2例患儿头颅磁共振成像均未见明显异常,病例2脑电图示高度失律并监测到痉挛发作。染色体检测结果:病例1通过多重连接依赖的探针扩增法确定为染色体7q11.23缺失,其内包含人弹性蛋白(elastin,ELN)基因片段缺失突变;病例2通过高分辨G带法确定为染色体7q11.21q11.23缺失。本组2例WBS患儿均存在心血管畸形、特殊面容、精神发育迟滞及结缔组织或泌尿系统异常,病例1的主动脉瓣上狭窄可能与ELN基因缺失相关,病例2的癫痫发生可能与超出7q11.23区域的q11.21缺失相关。
To explore the clinical and genetic characteristics of Williams-Beuren syndrome( WBS)and to raise awareness of the disease. The characteristics of clinical manifestations,personal history,cardiac ultrasound,brain magnetic resonance imaging( MRI),electroencephalogram( EEG) and chromosome detection results of two cases with WBS were analyzed. The two patients were both male and the age was 11 months and 1 day,and 9 months and 9 days,respectively. They both suffered from cardiovascular malformation: case one presented supravalvular aortic stenosis,and case two showed atrial septal defect and patent ductus arteriosus. Both of the cases were exhibited characteristic facial features of WBS,including full orbital,spherical nose,flat nasal bridge,long philtrum and thick lips. For the mental development,case one displayed moderate to severe developmental retardation,and case two showed severe developmental retardation. In addition,case one presented bilateral indirect inguinal hernia and hydrocele,and case two manifested feeding difficulties,buried penis and infantile spasms. Personal history:case one's mother had tocolytic therapy during pregnancy period,and case one was born at full-term by cesarean section due to amniotic fluid pollution. Supplementary examination: brain MRI of the two cases were no significant abnormalities; the EEG of case two showed hypsarrhythmia,and the epileptic spasms were recorded. Chromosome detection results: case one was identified as 7q11. 23 deletion including the fragment deletion mutation of elastin( ELN) gene by multiplex ligation dependent probe amplification method,and case two was found with 7q11. 21q11. 23 deletion by high resolution G-band method. The two cases with WBS both had cardiovascular malformations,special facial features,mental retardation and connective tissue or urinary system abnormality. The supravalvular aortic stenosis of case one may be associated with the deletion of ELN gene,and the occurrence of epilepsy of case two may be related to the q11. 21 deletion beyond the 7q11. 23 region.
To explore the clinical and genetic characteristics of Williams-Beuren syndrome( WBS)and to raise awareness of the disease. The characteristics of clinical manifestations,personal history,cardiac ultrasound,brain magnetic resonance imaging( MRI),electroencephalogram( EEG) and chromosome detection results of two cases with WBS were analyzed. The two patients were both male and the age was 11 months and 1 day,and 9 months and 9 days,respectively. They both suffered from cardiovascular malformation: case one presented supravalvular aortic stenosis,and case two showed atrial septal defect and patent ductus arteriosus. Both of the cases were exhibited characteristic facial features of WBS,including full orbital,spherical nose,flat nasal bridge,long philtrum and thick lips. For the mental development,case one displayed moderate to severe developmental retardation,and case two showed severe developmental retardation. In addition,case one presented bilateral indirect inguinal hernia and hydrocele,and case two manifested feeding difficulties,buried penis and infantile spasms. Personal history:case one's mother had tocolytic therapy during pregnancy period,and case one was born at full-term by cesarean section due to amniotic fluid pollution. Supplementary examination: brain MRI of the two cases were no significant abnormalities; the EEG of case two showed hypsarrhythmia,and the epileptic spasms were recorded. Chromosome detection results: case one was identified as 7q11. 23 deletion including the fragment deletion mutation of elastin( ELN) gene by multiplex ligation dependent probe amplification method,and case two was found with 7q11. 21q11. 23 deletion by high resolution G-band method. The two cases with WBS both had cardiovascular malformations,special facial features,mental retardation and connective tissue or urinary system abnormality. The supravalvular aortic stenosis of case one may be associated with the deletion of ELN gene,and the occurrence of epilepsy of case two may be related to the q11. 21 deletion beyond the 7q11. 23 region.
引文
[1]Williams JCP,Barratt-Boyes BG,Lowe JB.Supravalvular aortic stenosis[J].Circulation,1961,24(6):1311-1318.
[2]Beuren AJ,Apitz J,Koncz J.Die diagnose und Beurteilung der verschiedenen formen der supravalvulren aortenstenose[J].Zeitschrift Kreislaufforsch,1962,51:829-837.
[3]Stromme P,Bjornstad PG,Ramstad K.Prevalence estimation of Williams syndrome[J].J Child Neurol,2002,17(4):269-271.
[4]Amenta S,Sofocleous C,Kolialexi A,et al.Clinical manifestations and molecular investigation of 50 patients with Williams syndrome in the Greek population[J].Pediatr Res,2005,57(6):789-795.
[5]Li L,Huang L,Luo Y,et al.Differing microdeletion sizes and breakpoints in chromosome 7q11.23 in Williams-Beuren syndrome detected by chromosomal microarray analysis[J].Mol Syndromol,2016,6(6):268-275.
[6]Ewart AK,Morris CA,Atkinson D,et al.Hemizygosity at the elastin locus in a developmental disorder,Williams syndrome[J].Nat Genet,1993,5(1):11-16.
[7]Curran ME,Atkinson DL,Ewart AK,et al.The elastin gene is disrupted by a translocation associated with supravalvular aortic stenosis[J].Cell,1993,73(1):159-168.
[8]Li DY,Toland AE,Boak BB,et al.Elastin point mutations cause an obstructive vascular disease,supravalvular aortic stenosis[J].Hum Mol Genet,1997,6(7):1021-1028.
[9]Tassabehji M,Metcalfe K,Donnai D,et al.Elastin:genomic structure and point mutations in patients with supravalvular aortic stenosis[J].Hum Mol Genet,1997,6(7):1029-1036.
[10]Sugayama SM,Moises RL,Wagenfur J,et al.Williams-Beuren syndrome:cardiovascular abnormalities in 20 patients diagnosed with fluorescence in situ hybridization[J].Arq Bras Cardiol,2003,81(5):462-473.
[11]Committee on Genetics.American Academy of Pediatrics:Health care supervision for children with Williams syndromes[J].Pediatrics,2001,107(5):1192-1204.
[12]吕俊健,周伟,陈珊.以反复心律失常为主要表现的新生儿Williams-Beuren综合征1例[J].中华实用儿科临床杂志,2015,30(20):1593-1594.
[13]Karmiloff-Smith A,Grant J,Ewing S,et al.Using case study comparisons to explore genotype-phenotype correlations in Williams-Beuren syndrome[J].J Med Genet,2003,40(2):136-140.
[14]解春红,杨建滨,邵洁,等.威廉斯综合征25例的荧光原位杂交检测[J].中华医学遗传学杂志,2007,24(1):104-106.
[15]解春红,赵正言.威廉斯综合征的基因型和认知表型研究[J].国际儿科学杂志,2006,33(2):117-119.
[16]Nicita F,Garone G,Spalice A,et al.Epilepsy is a possible feature in Williams-Beuren syndrome patients harboring typical deletions of the 7q11.23 critical region[J].Am J Med Genet A,2016,170A(1):148-155.
[17]Scherer SW,Osborne L.Williams-Beuren syndrome[M]//Lupski J,Stankiewicz P.Genomic disorders:the genomic basis of disease.Totowa NJ:Human Press,2006:221-236.
[18]Tassabehji M.Williams-Beuren syndrome:a challenge for genotype phenotype-correlations[J].Hum Mol Genet,2003,12(2):R229-237.
[19]Fusco C,Micale L,Augello B,et al.Smaller and larger deletions of the Williams Beuren syndrome region implicate genes involved in mild facial phenotype,epilepsy and autistic traits[J].Eur J Hum Genet,2014,22(1):64-70.
[20]Dai L,Bellugi U,Chen XN,et al.Is it Williams syndrome?GTF2IRD1 implicated in visual-spatial construction and GTF2I in sociability revealed by high resolution arrays[J].Am J Med Genet A,2009,149A(3):302-314.
[21]Samanta D.Infantile spasms in Williams-Beuren syndrome with typical deletions of the 7q11.23 critical region and a review of the literature[J].Acta Neurol Belg,2016,117(1):359-362.
[22]Ramocki MB,Bartnik M,Szafranski P,et al.Recurrent distal7q11.23 deletion including HIPI and YWHAG identified in patients with intellectual disabilities,epilepsy,and neurobehavioral problems[J].Am J Hum Genet,2010,87(6):857-865.
[23]Mizugishi K,Yamanaka K,Kuwajima K.Interstitial deletion of chromosome 7q in a patient with Williams syndrome and infantile spasms[J].J Hum Genet,1998,43(3):178-181.
[24]Marshall CR,Young EJ,Pani AM,et al.Infantile spasms is associated with deletion of the MAGI2 gene on chromosome 7q11.23-q21.22[J].Am J Hum Genet,2008,83(1):106-111.
[2]Beuren AJ,Apitz J,Koncz J.Die diagnose und Beurteilung der verschiedenen formen der supravalvulren aortenstenose[J].Zeitschrift Kreislaufforsch,1962,51:829-837.
[3]Stromme P,Bjornstad PG,Ramstad K.Prevalence estimation of Williams syndrome[J].J Child Neurol,2002,17(4):269-271.
[4]Amenta S,Sofocleous C,Kolialexi A,et al.Clinical manifestations and molecular investigation of 50 patients with Williams syndrome in the Greek population[J].Pediatr Res,2005,57(6):789-795.
[5]Li L,Huang L,Luo Y,et al.Differing microdeletion sizes and breakpoints in chromosome 7q11.23 in Williams-Beuren syndrome detected by chromosomal microarray analysis[J].Mol Syndromol,2016,6(6):268-275.
[6]Ewart AK,Morris CA,Atkinson D,et al.Hemizygosity at the elastin locus in a developmental disorder,Williams syndrome[J].Nat Genet,1993,5(1):11-16.
[7]Curran ME,Atkinson DL,Ewart AK,et al.The elastin gene is disrupted by a translocation associated with supravalvular aortic stenosis[J].Cell,1993,73(1):159-168.
[8]Li DY,Toland AE,Boak BB,et al.Elastin point mutations cause an obstructive vascular disease,supravalvular aortic stenosis[J].Hum Mol Genet,1997,6(7):1021-1028.
[9]Tassabehji M,Metcalfe K,Donnai D,et al.Elastin:genomic structure and point mutations in patients with supravalvular aortic stenosis[J].Hum Mol Genet,1997,6(7):1029-1036.
[10]Sugayama SM,Moises RL,Wagenfur J,et al.Williams-Beuren syndrome:cardiovascular abnormalities in 20 patients diagnosed with fluorescence in situ hybridization[J].Arq Bras Cardiol,2003,81(5):462-473.
[11]Committee on Genetics.American Academy of Pediatrics:Health care supervision for children with Williams syndromes[J].Pediatrics,2001,107(5):1192-1204.
[12]吕俊健,周伟,陈珊.以反复心律失常为主要表现的新生儿Williams-Beuren综合征1例[J].中华实用儿科临床杂志,2015,30(20):1593-1594.
[13]Karmiloff-Smith A,Grant J,Ewing S,et al.Using case study comparisons to explore genotype-phenotype correlations in Williams-Beuren syndrome[J].J Med Genet,2003,40(2):136-140.
[14]解春红,杨建滨,邵洁,等.威廉斯综合征25例的荧光原位杂交检测[J].中华医学遗传学杂志,2007,24(1):104-106.
[15]解春红,赵正言.威廉斯综合征的基因型和认知表型研究[J].国际儿科学杂志,2006,33(2):117-119.
[16]Nicita F,Garone G,Spalice A,et al.Epilepsy is a possible feature in Williams-Beuren syndrome patients harboring typical deletions of the 7q11.23 critical region[J].Am J Med Genet A,2016,170A(1):148-155.
[17]Scherer SW,Osborne L.Williams-Beuren syndrome[M]//Lupski J,Stankiewicz P.Genomic disorders:the genomic basis of disease.Totowa NJ:Human Press,2006:221-236.
[18]Tassabehji M.Williams-Beuren syndrome:a challenge for genotype phenotype-correlations[J].Hum Mol Genet,2003,12(2):R229-237.
[19]Fusco C,Micale L,Augello B,et al.Smaller and larger deletions of the Williams Beuren syndrome region implicate genes involved in mild facial phenotype,epilepsy and autistic traits[J].Eur J Hum Genet,2014,22(1):64-70.
[20]Dai L,Bellugi U,Chen XN,et al.Is it Williams syndrome?GTF2IRD1 implicated in visual-spatial construction and GTF2I in sociability revealed by high resolution arrays[J].Am J Med Genet A,2009,149A(3):302-314.
[21]Samanta D.Infantile spasms in Williams-Beuren syndrome with typical deletions of the 7q11.23 critical region and a review of the literature[J].Acta Neurol Belg,2016,117(1):359-362.
[22]Ramocki MB,Bartnik M,Szafranski P,et al.Recurrent distal7q11.23 deletion including HIPI and YWHAG identified in patients with intellectual disabilities,epilepsy,and neurobehavioral problems[J].Am J Hum Genet,2010,87(6):857-865.
[23]Mizugishi K,Yamanaka K,Kuwajima K.Interstitial deletion of chromosome 7q in a patient with Williams syndrome and infantile spasms[J].J Hum Genet,1998,43(3):178-181.
[24]Marshall CR,Young EJ,Pani AM,et al.Infantile spasms is associated with deletion of the MAGI2 gene on chromosome 7q11.23-q21.22[J].Am J Hum Genet,2008,83(1):106-111.