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中华诊断学电子杂志 ›› 2022, Vol. 10 ›› Issue (02) : 77 -82. doi: 10.3877/cma.j.issn.2095-655X.2022.02.002

超声诊断

Meckel-Gruber综合征的产前诊断学特征及文献复习
黄慧1, 王卫云1, 成晨1, 刘娅1, 陈欣林1,()   
  1. 1. 430070 武汉,湖北省妇幼保健院超声诊断科
  • 收稿日期:2021-08-13 出版日期:2022-04-26
  • 通信作者: 陈欣林
  • 基金资助:
    湖北省卫生计生科研项目(WJ2018H0164,WJ2018H0132)

Prenatal diagnostic characteristics and literature review of Meckel-Gruber syndrome

Hui Huang1, Weiyun Wang1, Chen Cheng1, Ya Liu1, Xinlin Chen1,()   

  1. 1. Department of Ultrasound, Maternal and Child Health Hospital of Hubei Province, Wuhan 430070, China
  • Received:2021-08-13 Published:2022-04-26
  • Corresponding author: Xinlin Chen
引用本文:

黄慧, 王卫云, 成晨, 刘娅, 陈欣林. Meckel-Gruber综合征的产前诊断学特征及文献复习[J/OL]. 中华诊断学电子杂志, 2022, 10(02): 77-82.

Hui Huang, Weiyun Wang, Chen Cheng, Ya Liu, Xinlin Chen. Prenatal diagnostic characteristics and literature review of Meckel-Gruber syndrome[J/OL]. Chinese Journal of Diagnostics(Electronic Edition), 2022, 10(02): 77-82.

目的

探讨Meckel-Gruber综合征(MKS)的产前诊断学特征。

方法

回顾性分析2019年7月5日于湖北省妇幼保健院超声诊断科经产前超声诊断的一例早孕期MKS胎儿的超声影像特征、病理结果及基因检测结果,并复习文献。

结果

孕妇28岁,初产妇,孕11+6周,产前超声图像表现为胎儿颅骨环回声中断,脑膜与脑组织膨出;双肾体积增大伴有细小无回声和小囊肿;双手、双足轴后型多指/趾,诊断为MKS。病理结果显示该胎儿脑膨出,轴后型多指/趾,肾髓质囊性病变及单纯腭裂。全外显子组测序发现,该胎儿携带两个新的CC2D2A基因杂合突变:c.3688 C>T(p.Arg1230*)和c.4314+1-4314+2insT。Sanger测序显示,该两个突变分别遗传自父亲和母亲,为复合杂合突变。该两个基因突变位点均为首次报道,根据美国医学遗传学与基因组学学会(ACMG)变异分类标准与指南,这两个突变位点为疑似致病性突变(PVS1+PM2)。

结论

MKS在早孕期多表现为脑膨出,肾脏体积增大伴有小的囊性病变与轴后型多指/趾。早孕期是产前诊断MKS的最佳时期,高通量测序技术提供了MKS重要的遗传学信息。

Objective

To investigate the diagnostic features of Meckel-Gruber syndrome(MKS).

Methods

The ultrasonographic data, pathological findings and genetic testing results of a fetus with MKS diagnosed prenatally in Department of Ultrasonography, Maternal and Child Health Hospital of Hubei Province on July 5, 2019 were analyzed retrospectively, and the relevant literatures were reviewed.

Results

A 28-year-old healthy Chinese woman presented at the 11+ 6 weeks of gestation underwent the first-trimester ultrasound investigation. The ultrasound examination showed interruption of fetal skull hyperechoic ring with protrusion of meninges and cerebral tissue around occipital region, enlarged kidneys with small anechoic and cysts, postaxial polydactyly of double hands and double feet in this fetus, diagnosed as MKS. The pathological examination of the aborted fetus showed occipital encephalocele, postaxial polydactyly, polycystic kidneys and cleft palate. By whole-exome sequencing, two novel heterozygous mutations [c.3688 C>T(p.Arg1230*), c. 4314+ 1-4314+ 2insT] in the CC2D2A gene were identified. These two mutations had never been described before. Sanger sequencing validated the mutations in the fetus and revealed that they were originated from the father and mother, respectively. These two variants were classified as likely pathogenic mutations (PVS1+ PM2) according to the variation classification criteria and guidelines of American College of Medical Genetics and Genomics (ACMG).

Conclusions

In early pregnancy, MKS is mostly characterized by occipital encephalocele, enlarged kidneys with small pyramidal cysts and postaxial polydactyly. The first trimester of the pregnancy is the earliest and best time for prenatal diagnosis of MKS. High throughput sequencing technology provides important genetic information for the family with fetuses affected by MKS.

图1 Meckel-Gruber综合征胎儿在11+6周时超声检查图像注:a图胎儿三维超声成像图显示胎儿头颅枕部突出(箭头所示);b图为肾脏冠状面图,显示双肾囊状结构(箭头所示);c图显示胎儿左手轴后型多指(6指)
图2 Meckel-Gruber综合征引产胎儿大体及病理检查图像注:a图示枕部脑膜与脑组织膨出(箭头所示);b图示胎儿手轴后型多指(箭头所示);c图示胎儿足轴后型多趾(箭头所示);d图示胎儿腭裂(箭头所示);e图为胎儿肾脏病理检查图像,示肾脏髓质内有大小不一的囊泡状结构(黑色箭头所示),皮质浅层可见发育中的肾小球(蓝色箭头所示)及肾小管(红色箭头所示)
图3 Meckel-Gruber综合征胎儿及其父母CC2D2A基因突变位点测序结果图像注:为Sanger测序峰图,突变位点用方框标志,其中父亲为CC2D2A c.3688 C>T杂合突变,母亲为CC2D2A c.4314+1-4314+2insT杂合突变,患病胎儿为两个突变位点的复合杂合突变
[1]
Meckel JF.Beschreibung zweier,durch sehr aehnliche,bildungsa-bweichungen entsellter Geschwister Dutsch [J].Dtsch Arch Physiol1822:799-172.
[2]
Salonen R, Paavola P.Meckel syndrome [J].J Med Genet199835(6):497-501.DOI:10.1136/jmg.35.6.497.
[3]
Hartill V, Szymanska K, Sharif SM,et al.Meckel-gruber syndrome:an update on diagnosis,clinical management,and research advances[J].Front Pediatr2017(5):244.DOI:10.3389/fped.2017.00244.
[4]
Salonen R.The Meckel syndrome:clinicopathological findings in 67 patients [J].Am J Med Genet198418(4):671-689.DOI:10.1002/ajmg.1320180414.
[5]
Hsia YE, Bratu M, Herbordt A.Genetics of the Meckel syndrome (dysencephalia splanchnocystica) [J].Pediatrics197148(2):237-247.
[6]
Fraser FC, Lytwyn A.Spectrum of anomalies in the Meckel syndrome,or:" Maybe there is a malformation syndrome with at least one constant anomaly" [J].Am J Med Genet19819(1):67-73.DOI:10.1002/ajmg.1320090112.
[7]
Majewski F, Stöss H, Goecke T,et al.Are bowing of long tubular bones and preaxial polydactyly signs of the Meckel syndrome? [J].Hum Genet198365(2):125-133.DOI:10.1007/bf00286648.
[8]
Barisic I, Boban L, Loane M,et al.Meckel-Gruber syndrome:a population-based study on prevalence,prenatal diagnosis,clinical features,and survival in Europe [J].Eur J Hum Genet201523(6):746-752.DOI:10.1038/ejhg.2014.174.
[9]
Ramadani HM, Nasrat HA.Prenatal diagnosis of recurrent Meckel syndrome [J].Int J Gynaecol Obstet199239(4):327-332.DOI:10.1016/0020-7292(92)90265-k.
[10]
Seller MJ.Meckel syndrome and the prenatal diagnosis of neural tube defects [J].J Med Genet197815(6):462-465.DOI:10.1136/jmg.15.6.462.
[11]
Young ID, Rickett AB, Clarke M. High incidence of Meckel′s syndrome in Gujarati Indians [J].J Med Genet198522(4):301-304.DOI:10.1136/jmg.22.4.301.
[12]
Parisi MA.The molecular genetics of Joubert syndrome and related ciliopathies:the challenges of genetic and phenotypic heterogeneity[J].Transl Sci Rare Dis20194(1-2):25-49.DOI:10.3233/trd-190041.
[13]
Zhang M, Chang Z, Tian Y,et al.Two novel TCTN2 mutations cause Meckel-Gruber syndrome[J].J Hum Genet202065(11):1039-1043.DOI:10.1038/s10038-020-0804-0.
[14]
严恺,吕时铭.Meckel-Gruber综合征的诊断与研究 [J].中华检验医学杂志201538(1):7-9.DOI:10.3760/cma.j.issn.1009-9158.2015.01.003.
[15]
张蔓丽,王利群,李晓青,等.6个Meckel-Gruber综合征家系临床和分子遗传学分析 [J].中国生育健康杂志202031(5):449-453,468.DOI:CNKI:SUN:SYJK.0.2020-05-011.
[16]
张靓璠,严恺,王英,等.多种遗传学技术联合运用对疑似Meckel综合征家系进行遗传学分析 [J].温州医科大学学报201949(10):748-752.DOI:10.3969/j.issn.2095-9400.2019.10.009.
[17]
Sepulveda W, Sebire NJ, Souka A,et al.Diagnosis of the Meckel-Gruber syndrome at eleven to fourteen weeks' gestation [J].Am J Obstet Gynecol1997176(2):316-319.DOI:10.1016/s0002-9378(97)70491-5.
[18]
Braithwaite JM, Economides DL.First-trimester diagnosis of Meckel-Gruber syndrome by transabdominal sonography in a low-risk case[J].Prenat Diagn199515(12):1168-1170.DOI:10.1002/pd.1970151215.
[19]
李亚敏,栗河舟,李洁,等.胎儿Meckel-Gruber综合征超声表现[J].中国医学影像技术202137(5):731-734.DOI:10.13929/j.issn.1003-3289.2021.05.022.
[20]
Salomon LJ, Alfirevic Z, Bilardo CM,et al.ISUOG practice guidelines:performance of first-trimester fetal ultrasound scan [J].Ultrasound Obstet Gynecol201341(1):102-113.DOI:10.1002/uog.12342.
[21]
Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform [J].Bioinformatics200925(14):1754-1760.DOI:10.1093/bioinformatics/btp324.
[22]
Van der Auwera GA, Carneiro MO, Hartl C,et al.From FastQ data to high confidence variant calls:the Genome Analysis Toolkit best practices pipeline[J].Curr Protoc Bioinformatics201343(1110):11.10.11-11.10.33.DOI:10.1002/0471250953.bi1110s43.
[23]
Yang H, Wang K.Genomic variant annotation and prioritization with ANNOVAR and wANNOVAR [J].Nat Protoc201510(10):1556-1566.DOI:10.1038/nprot.2015.105.
[24]
Richards S, Aziz N, Bale S,et al.Standards and guidelines for the interpretation of sequence variants:a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology [J].Genet Med201517(5):405-424.DOI:10.1038/gim.2015.30.
[25]
Mecke S, Passarge E. Encephalocele, polycystic kidneys, and polydactyly as an autosomal recessive trait simulating certain other disorders:the Meckel syndrome [J].Ann Genet197114(2):97-103.
[26]
Johnson VP, Holzwarth DR.Prenatal diagnosis of Meckel syndrome:case reports and literature review [J].Am J Med Genet198418(4):699-711.DOI:10.1002/ajmg.1320180416.
[27]
Nyberg DA, Hallesy D, Mahony BS,et al.Meckel-Gruber syndrome.Importance of prenatal diagnosis [J].J Ultrasound Med19909(12):691-696.DOI:10.7863/jum.1990.9.12.691.
[28]
Liu SS, Cheong ML, She BQ,et al.First-trimester ultrasound diagnosis of Meckel-Grüber syndrome [J].Acta Obstet Gynecol Scand200685(6):757-759.DOI:10.1080/00016340600613014.
[29]
Ickowicz V, Eurin D, Maugey-Laulom B,et al.Meckel-Gruber syndrome:sonography and pathology [J].Ultrasound Obstet Gynecol200627(3):296-300.DOI:10.1002/uog.2708.
[30]
Mougou-Zerelli S, Thomas S, Szenker E,et al.CC2D2A mutations in Meckel and Joubert syndromes indicate a genotype-phenotype correlation [J].Hum Mutat200930(11):1574-1582.DOI:10.1002/humu.21116.
[31]
Barroso-Gil M, Olinger E, Ramsbottom SA,et al.Update of genetic variants in CEP120 and CC2D2A-With an emphasis on genotype-phenotype correlations,tissue specific transcripts and exploring mutation specific exon skipping therapies [J].Mol Genet Genomic Med2021:e1603.DOI:10.1002/mgg3.1603.
[32]
郑良楷,田瑞华,孔令员,等.胎儿Meckel-Gruber综合征二例临床病例分析及文献复习[J].中华围产医学杂志201114(6):364-366.DOI:10.3760/cma.j.issn.1007-9408.2011.06.013.
[33]
李志华,陈小兵,刘笑霞,等.连续五次妊娠Meckel-Gruber综合征胎儿一例[J].中华医学遗传学杂志201128(4):474-475.DOI:10.3760/cma.j.issn.1003-9406.2011.04.043.
[34]
Tanriverdi HA, Hendrik HJ, Ertan K, et al. Meckel Gruber syndrome:a first trimester diagnosis of a recurrent case [J].Eur J Ultrasound200215(1-2):69-72.DOI:10.1016/s0929-8266(02)00009-5.
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