Beckwith-Wiedemann綜合征1例并文獻(xiàn)復(fù)習(xí)

謝新寶 許 丹 劉仁超 董晨彬 安 宇,4 俞 蕙 張 婷,6

·論著·

Beckwith-Wiedemann綜合征1例并文獻(xiàn)復(fù)習(xí)

謝新寶1,5許 丹1,5劉仁超2董晨彬3安 宇2,4俞 蕙1張 婷1,6

Beckwith-Wiedemann綜合征； 印跡基因； 過度生長； DNA甲基化

1 病例資料

女，5月齡。因“咳嗽4～5 d，偶伴面部發(fā)紺”入復(fù)旦大學(xué)附屬兒科醫(yī)院(我院)。生后因“早產(chǎn)、低血糖、新生兒窒息、新生兒呼吸窘迫綜合征、呼吸暫停”在外院住院，后因頻繁呼吸暫停曾2次轉(zhuǎn)入上一級醫(yī)院NICU住院治療，給予抗感染、輔助支持治療病情穩(wěn)定后出院。

入院查體：T 36.5℃，R 30 ·min-1，P 124 ·min-1，身長60 cm，體重4.5 kg。神志清楚，反應(yīng)可，尖顱，枕骨后凸，前囟平軟。兩側(cè)面頰不對稱，前額可見火焰狀紅斑，壓之不褪色，雙眼外突，口唇紅潤，舌大外凸明顯，不能回納入口腔(圖1A)，雙耳可見折痕及小切跡(圖1B)。雙肺呼吸音粗，可聞及支氣管管狀呼吸音及少許痰鳴音，心音有力，心律齊，胸骨左緣2～3肋間可聞及3/6級收縮期雜音。腹平軟，肝肋下捫及3 cm，劍突下捫及2.5 cm，質(zhì)軟，脾肋下未捫及，可見臍膨出 (圖1C)。女童外陰，大陰唇肥厚，四肢活動自如，神經(jīng)系統(tǒng)查體未見異常。

實(shí)驗(yàn)室檢查：血、尿、糞常規(guī)和肝腎功能指標(biāo)均未見異常，甲狀腺指標(biāo)正常。

影像學(xué)檢查：X線胸片提示肺炎，局限性隔膨升；腹部B超提示肝腫大, 卵巢增大；超聲心動圖提示肺動脈狹窄、卵圓孔未閉。

診治經(jīng)過：住院期間3次呼吸困難發(fā)作，均在劇咳或喂奶時發(fā)生，給予吸氧、對癥處理后可恢復(fù)。入院后結(jié)合患兒特殊面容，臍膨出,肝腫大，考慮Beckwith-Wiedemann綜合征(BWS)可能，取患兒外周靜脈抗凝血提取基因組DNA，應(yīng)用MS-MLPA技術(shù)進(jìn)行11p15.5區(qū)域BWS相關(guān)印跡基因拷貝數(shù)及甲基化狀態(tài)的檢測，結(jié)果顯示印跡中心2區(qū)(IC2)KCNQ1OT1甲基化位點(diǎn)丟失(圖2),確診為BWS。

隨訪：患兒生后體重增加良好，3月齡3.5 kg，4月齡4.5 kg，10月齡9.5 kg，12月齡11.5 kg。運(yùn)動發(fā)育稍落后，4月齡可抬頭，9月齡能坐，10月齡時尚不能翻身。隨訪至13月齡能扶站、扶走。6月齡行DST檢查DQ 42，MI 45，12月齡復(fù)查基本正常 (DQ 83，MI 86)。

9月齡隨訪仍可見巨舌、火焰狀紅斑(圖1D)，臍膨出明顯(圖1E)。巨舌所致喂養(yǎng)困難及反復(fù)呼吸困難發(fā)作較6月齡前明顯好轉(zhuǎn)。12月齡因舌體過大致發(fā)音障礙在我院行舌減容整形術(shù)+臍疝修補(bǔ)術(shù)，術(shù)后傷口愈合良好，舌體明顯縮小(術(shù)后2周，圖1F)，臍部形狀如正常兒童(術(shù)后2周，圖1G)。13月齡隨訪已能發(fā)“ba”等單音節(jié)音，17月齡隨訪可發(fā)雙音節(jié)音，血AFP正常，腹部CT未見腫瘤性病變。目前每3個月隨訪血AFP，腹部B超，并指導(dǎo)喂養(yǎng)。

圖1 本文BWS病例的特殊面容和臍疝

Fig 1 Special facies and umbilical hernia in Beckwith-Wiedemann syndrome (BWS) of the patient

Notes At 5 month-old: A: macroglossia and facial nevus flammeus; B: ear pits; C: exomphalos. At 9 month-old: D: macroglossia and facial nevus flammeus; E: umbilical hernia. At 12 month-old (2 weeks after operation): F: significant improved macroglossia; G: almost normal shape of umbilicus post surgery

圖2 本文BWS病例11p15 BWS相關(guān)區(qū)域異常甲基化檢測結(jié)果

Fig 2 MS-MLPA peak pattern post HhaI digestion showing the typical epigenetic defects of IC2 of the patient

Notes Genomic DNAs extracted from peripheral blood lymphocytes of patient were subjected to detect the molecular alterations by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) using ME030-C1 BWS/RSS purchased from MRC-Holland company (Amsterdam, NL). The results showed that loss of methylation at the 4 methylation sites (shown as black arrows in Fig 2A, B, C and D) of theKCNQ1OT1 promoter (IC2) area in this patient. Red: normal reference signal; Blue: patient′s result

2 討論

BWS(MIM#130650)，又稱臍膨出-巨舌-巨體綜合征，是一種先天性過度生長綜合征,于20世紀(jì)60年代報道[1,2]。據(jù)估計BWS的發(fā)病率至少為1∶13 700[3]。有報道體外人工輔助生育技術(shù)授精兒童BWS的發(fā)生率較正常授精兒童為高[4～6]。國內(nèi)目前報道10余例，均為臨床診斷，且缺乏長期隨訪資料。

BWS由11p15.5區(qū)域母源或父源性印跡基因表達(dá)缺陷所致[7,8]?；蛴≯E是一種表觀遺傳修飾，指體細(xì)胞來源于不同親代的一對等位基因發(fā)生的差異性表達(dá), 即機(jī)體僅表達(dá)來自親本一方的等位基因, 而另一方不表達(dá)或很少表達(dá)。印跡基因最具特征的標(biāo)志是DNA獲得甲基化和去甲基化，其他特點(diǎn)還包括常成簇存在；一般都有印跡中心(imprinting center,IC)又稱差異甲基化區(qū)( differentially methylated region,DMR)；11p15區(qū)域印跡中心有H19 DMR(IC1)和KvDMR(IC2)(圖3)[9]。BWS多為基因變異的偶發(fā)病例，僅少數(shù)病例伴家族遺傳。常見于BWS的11p15.5印跡基因簇異常主要包括：①母源性IC2去甲基化，見于50% BWS病例(本文病例即存在該類異常，圖2和3B)，該甲基化異常會引起KCNQ1QT過度表達(dá), 從而導(dǎo)致KCNQ1和受其調(diào)節(jié)的CDKN1C基因表達(dá)下降(圖3B)。CDKN1C是一種生長抑制基因，其表達(dá)下降會導(dǎo)致臨床出現(xiàn)過度生長、器官增大；②母源性IC1獲得甲基化，該異常約見于5%的BWS病例；③其他還可檢測到父源性單親二聚體、11p15.5區(qū)重復(fù)、倒置、移位、微缺失和微重復(fù)等基因改變[3,10]。應(yīng)用MS-MLPA可檢測到11p15.5區(qū)域微缺失、重復(fù)、基因計量改變、DNA甲基化改變和父源性單親二聚體等[10]。本文病例具有BWS典型臨床表現(xiàn)，基因檢測結(jié)果提示11p15.5 IC2區(qū)低甲基化，因此本例為BWS基因確診。

圖3 11p15 BWS相關(guān)區(qū)域和印跡中心示意圖

Fig 3 Schematic diagram of main target regions and two imprinted domains in the 11p15 region

Notes Genes regulated by imprinted domains were shown in rectangle. IC1(paternal) was associated with the gene H19 and IC2 (maternal) was associated with the maternal geneKCNQ1 andCDKN1C. A: Normal schematic diagram of main target regions and two imprinted domains in the 11p15 region; B: Loss of methylation at the maternal IC2 on 11p15.5 in the case causing low or absent expression ofKCNQ1 andCDKN1Cgenes

就BWS而言，大多數(shù)患兒并無同患此病的父母，對于該癥的同胞以及后代的影響有所不同(表1)。對具于陰性家族史(約占85%)，染色體核型正常的BWS患兒，如分子遺傳學(xué)檢查提示IC2低或高甲基化且無基因異常，以及父源11p15UPD，其同胞和子代患BWS的風(fēng)險較低；如患兒父母一方為CDKN1C基因變異，則其同胞和子代患BWS的風(fēng)險為≤50%。對具有陽性家族史(占10%～15%)。染色體核型正常BWS患兒的同胞及子代患BWS的風(fēng)險為≤50%。對于單卵雙生雙胞胎(約占1%)BWS患兒，其同胞和子代患BWS的風(fēng)險較低。

表1 基于家族史和分子遺傳學(xué)檢測結(jié)果的BWS先證者的同胞和子代患病風(fēng)險

Tab 1 Risk to sibs and offspring of BWS proband based on family history and molecular genetic test results

Moleculargenetic/epigenetictestRisktosibsRisktooffsprings-85%withnegativefamilyhistory，normalkaryotype1，2)IC2hypomethylation；withoutgenomicabnormalityLow LowIC1hypermethylation；withoutgenomicabnormalityLow LowParental11p15UPDdetectedVerylow VerylowCDKN1Cmutationpresentinoneparent≤50%Iftransmittedfrommother：around50%Iftransmittedfromfa?ther：<50%>10%-15%withpositivefamilyhistory，normalkaryotype2)≤50%Iftransmittedfrommother：around50%Iftransmittedfromfa?ther：<50%<1%/MonozygoustwinsLowTheoreticallylow，currentavailabledataareinsufficient

Notes 1) 20% BWS patients without positive family history have parental 11p15 UPD; 2) around 5% BWS patients without abnormal karyotype haveCDKN1Cmutations

關(guān)于BWS至今仍無一致的臨床診斷標(biāo)準(zhǔn)，在正常人中少見的主要臨床表現(xiàn)包括 ：明確的家族史， 巨大兒(身高、體重>P97，耳皺褶及切跡，巨舌，臍疝，內(nèi)臟(肝、脾、胰、腎、腎上腺等)肥大，胚胎類腫瘤，偏身肥大(身體的一個或多個部分不對稱)，腎上腺皮質(zhì)增生，腎臟異常(結(jié)構(gòu)異常、巨大腎、腎鈣質(zhì)沉著、晚發(fā)型髓質(zhì)海綿腎)，腭裂，胎盤間質(zhì)發(fā)育不良，心臟肥大，心肌病(少見)等。在正常人中不少見的次要臨床表現(xiàn)包括：羊水過多，早產(chǎn)，新生兒低血糖，面部火焰狀紅斑及其他的血管畸形，特殊面容(中面部發(fā)育不全、眼眶皺褶)，心臟結(jié)構(gòu)異常，腹直肌分離和骨齡提前等[1,2]。本文病例孕28+5周發(fā)現(xiàn)羊水過多，生后新生兒期低血糖，巨舌，臍疝，雙耳折痕、額部火焰痣，腹部B超提示肝臟和卵巢肥大，超聲心動圖提示肺動脈狹窄、卵圓孔未閉，符合BWS臨床診斷標(biāo)準(zhǔn)。此外，BWS需與其他一些亦具有過度生長表現(xiàn)的疾病相鑒別，包括Simpson-Golabi-Behmel綜合征、Costello綜合征、Perlman綜合征、Sotos綜合征和Maroteaux-Lamy綜合征[4]。

BWS患兒基因型與其表型有一定的相關(guān)性，研究發(fā)現(xiàn)檢測到H19IC1高甲基化和父源UPD嵌合體的BWS患兒，其腎母細(xì)胞瘤和肝母細(xì)胞瘤發(fā)生率明顯高于其他基因變異[5,11～13]；腹壁缺損與CDKN1C和IC2分子變異有關(guān)[14]；IC1/IC2分子變異和父源UPD嵌合體基因變異與偏身肥大有關(guān)[14～16]；所有腎腫大和近半數(shù)集水管系統(tǒng)異常的BWS病例存在IC1基因變異[15,17]；有陽性家族史者(10%～15%的BWS患兒)中可檢測到CDKN1C變異、IC1微缺失和IC2微重復(fù)等[18～22]。腭裂與CDKN1C變異有關(guān)[23,24]；發(fā)育延遲與11p15重復(fù)變異有關(guān)[25]；重型BWS表型與父源11p15UPD嵌合體高變異[26]。本例患兒為IC2異常，表現(xiàn)為臍疝，與文獻(xiàn)報道較為一致。Sasaki等[27]報道日本BWS患兒中H19-DMR(IC1)高甲基化發(fā)生頻率較歐美BWS患兒低，而染色體異常發(fā)生率較高。

BWS患兒的臨床管理主要針對巨舌、腹壁缺損、新生兒低血糖等處理，長期隨訪的目的是為早期發(fā)現(xiàn)腫瘤并干預(yù)。本文病例在12月齡時予臍疝修補(bǔ)術(shù)，術(shù)后臍部形狀如常。50%的BWS患兒新生兒期伴有暫時性低血糖，隨著年齡增長血糖正常。本文病例在新生兒期亦有低血糖，給予鼻飼及輸葡萄糖治療后血糖恢復(fù)正常。BWS患兒巨舌可隨面頜發(fā)育變得不顯著，但某些舌體特別巨大的患兒可能導(dǎo)致呼吸、喂養(yǎng)和發(fā)音困難，影響牙齒的發(fā)育，甚至面容異常等。目前認(rèn)為舌前部菱形切除+后部∧形切除，能明顯減少舌的體積，并保持舌的功能，尤其是味蕾的保存[28,29]。本文病例巨舌明顯，不能回納入口腔，嬰兒早期影響呼吸、進(jìn)食，伴反復(fù)呼吸困難發(fā)作，嬰兒期末則影響發(fā)音，12月齡時外科評估后予舌減容術(shù)，13月齡患兒進(jìn)食及發(fā)音困難明顯改善，舌體明顯縮小變薄，可完全回納入口腔。

大部分BWS患兒預(yù)后良好，與正常兒童相比，一般沒有顯著的智力和體格發(fā)育延遲，但部分BWS患兒可能因巨舌或聽力障礙而存在語言問題。本文病例運(yùn)動發(fā)育稍落后可能與早產(chǎn)、巨舌所致生后反復(fù)呼吸困難發(fā)作和缺氧等因素有關(guān)，需長期隨訪其精神運(yùn)動發(fā)育情況。但BWS患兒兒童期，尤其4歲前罹患胚胎性腫瘤的概率是正常兒童的600倍，主要為腎母細(xì)胞瘤、肝母細(xì)胞瘤，也有腎上腺癌、橫紋肌肉瘤和成纖維細(xì)胞瘤等報道，成人后患腫瘤的風(fēng)險并不增加[30]。此外，也可見腎上腺皮質(zhì)癌、神經(jīng)母細(xì)胞瘤、橫紋肌肉瘤等[31～33]。目前建議BWS患兒每3個月隨訪腹部超聲至6～8歲，每6周進(jìn)行AFP檢查至4歲[3,21,34,35]。本文病例17月齡隨訪血AFP正常，腹部CT未見腫瘤性病變，仍在定期隨訪中。

結(jié)合BWS發(fā)病率不低，臨床表現(xiàn)多樣，總體預(yù)后良好，但仍有兒童期胚胎性腫瘤相對高發(fā)的風(fēng)險，因此臨床醫(yī)生需要對BWS加強(qiáng)認(rèn)識并及時診斷，診治過程中需多學(xué)科合作長期隨訪，可開展基因診斷和產(chǎn)前診斷，對于不典型病例的診治，進(jìn)一步積累基因型與表型的相關(guān)性資料，比較中國BWS患兒與其他國家，尤其是歐美人群的基因異常的發(fā)生頻率，提供遺傳咨詢等方面均具有積極意義。

[1]Beckwith JB, Perrin EV. In situ neuroblastomas: a contribution to the natural history of neural crest tumors. Am J Pathol, 1963, 43:1089-1104

[2]Wiedemann HR. Familial malformation complex with umbilical hernia and macroglossia-A "New syndrome"? J Genet Hum, 1964, 13:223-232

[3]Choufani S, Shuman C, Weksberg R. Beckwith-Wiedemann syndrome. Am J Med Genet C Semin Med Genet, 2010, 154C(3):343-354

[4]Weksberg R, Shuman C, Beckwith JB. Beckwith-Wiedemann syndrome. Eur J Hum Genet, 2010, 18(1):8-14

[5]DeBaun MR, Niemitz EL, Feinberg AP. Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19. Am J Hum Genet, 2003, 72:156-160

[6]Strawn EY, Jr Bick D, Swanson A. Is it the patient or the IVF? Beckwith-Wiedemann syndrome in both spontaneous and assisted reproductive conceptions. Fertil Steril, 2010, 94(2):754. e751-752

[7]Ping AJ, Reeve AE, Law DJ, et al. Genetic linkage of Beckwith-Wiedemann syndrome to 11p15. Am J Hum Genet, 1989, 44(5):720-723

[8]Hirasawa R, Feil R. Genomic imprinting and human disease. Essays Biochem, 2010, 48:187-200

[9]Le Bouc Y, Rossignol S, Azzi S, et al. Epigenetics, genomic imprinting and developmental disorders. Bull Acad Natl Med, 2010, 194(2):287-297

[10]Lukova M, Todorova A, Todorov T, et al. Different methylation patterns in BWS/SRS cases clarified by MS-MLPA. Mol Biol Rep, 2013,40(1):263-268

[11]Gicquel C, Gaston V, Mandelbaum J, et al. In vitro fertilization may increase the risk of Beckwith-Wiedemann syndrome related to the abnormal imprinting of the KCN1OT gene. Am J Hum Genet ,2003, 72:1338-1341

[12]Maher ER, Afnan M, Barratt CL. Epigenetic risks related to assisted reproductive technologies: epigenetics, imprinting, ART and icebergs? Hum Reprod, 2003, 18:2508-2511

[13]Maher ER, Brueton LA, Bowdin SC, et al. Beckwith-Wiedemann syndrome and assisted reproduction technology (ART). J Med Genet 2003, 40(1):62-64

[14]Enklaar T, Zabel BU, Prawitt D. Beckwith-Wiedemann syndrome: multiple molecular mechanisms. Expert Rev Mol Med, 2006, 8(1):1-19

[15]DeBaun MR, Niemitz EL, McNeil DE, et al. Epigenetic alterations of H19 and LIT1 distinguish patients with Beckwith-Wiedemann syndrome with cancer and birth defects. Am J Hum Genet, 2002, 70(3):604-611

[16]Shuman C, Smith AC, Steele L, Ray PN, et al. Constitutional UPD for chromosome 11p15 in individuals with isolated hemihyperplasia is associated with high tumor risk and occurs following assisted reproductive technologies. Am J Med Genet A,2006, 140:1497-1503

[17]Mussa A, Peruzzi L, Chiesa N, et al. Nephrological findings and genotype-phenotype correlation in Beckwith-Wiedemann syndrome. Pediatr Nephrol, 2012, 27(3):397-406

[18]Sparago A, Cerrato F, Vernucci M, et al. Microdeletions in the human H19 DMR result in loss of IGF2 imprinting and Beckwith-Wiedemann syndrome. Nat Genet, 2004, 36(9):958-960

[19]Cooper WN, Luharia A, Evans GA, et al. Molecular subtypes and phenotypic expression of Beckwith-Wiedemann syndrome. Eur J Hum Genet, 2005, 13(9):1025-1032

[20]Prawitt D, Enklaar T, Gartner-Rupprecht B, et al. Microdeletion of target sites for insulator protein CTCF in a chromosome 11p15 imprinting center in Beckwith-Wiedemann syndrome and Wilms′ tumor. Proc Natl Acad Sci U S A, 2005, 102(11):4085-4090

[21]Percesepe A, Bertucci E, Ferrari P, et al. Familial Beckwith-Wiedemann syndrome due to CDKN1C mutation manifesting with recurring omphalocele. Prenat Diagn, 2008, 28(5):447-449

[22]Weksberg R SC. Beckwith-Wiedemann syndrome and hemihypertrophy, Cassidy SB, Allanson JE, eds Management of Genetic Syndromes 2nd ed Hoboken, New Jersey: John Wiley & Sons 2004, 16

[23]Hatada I, Nabetani A, Morisaki H et al. New p57KIP2 mutations in Beckwith-Wiedemann syndrome. Hum Genet, 1997, 100: 681-683

[24]Li M, Squire J, Shuman C et al. Imprinting status of 11p15 genes in Beckwith-Wiedemann syndrome patients with CDKN1C mutations. Genomics, 2001, 74: 370-376

[25]Slavotinek A, Gaunt L, Donnai D. Paternally inherited duplications of 11p15.5 and Beckwith-Wiedemann syndrome. J Med Genet, 1997,34: 819-826

[26]Smith AC, Rubin T, Shuman C et al. New chromosome 11p15 epigenotypes identified in male monozygotic twins with Beckwith-Wiedemann syndrome. Cytogenet Genome Res, 2006,113: 313-317

[27]Sasaki K, Soejima H, Higashimoto K, et al. Japanese and North American/European patients with Beckwith-Wiedemann syndrome have different frequencies of some epigenetic and genetic alterations. Eur J Hum Genet, 2007, 15(12):1205-1210

[28]Kacker A, Honrado C, Martin D, et al. Tongue reduction in Beckwith-Weidemann syndrome. Int J Pediatr Otorhinolaryngol, 2000, 53(1):1-7

[29]Kadouch DJ, Maas SM, Dubois L, et al. Surgical treatment of macroglossia in patients with Beckwith-Wiedemann syndrome: a 20-year experience and review of the literature. Int J Oral Maxillofac Surg, 2012, 41(3):300-308

[30]DeBaun MR, Tucker MA. Risk of cancer during the first four years of life in children from the Beckwith-Wiedemann syndrome registry. J Pediatr, 1998,132(3 pt 1):398-400

[31]Tan TY, Amor DJ. Tumour surveillance in Beckwith-Wiedemann syndrome and hemihyperplasia: a critical review of the evidence and suggested guidelines for local practice.J Paediatr Child Health, 2006, 42(9):486-490

[32]Barlaskar FM, Hammer GD. The molecular genetics of adrenocortical carcinoma. Rev Endocr Metab Disord, 2007, 8(4):343-348

[33]Lapunzina P. Risk of tumorigenesis in overgrowth syndromes: a comprehensive review.Am J Med Genet C Semin Med Genet, 2005, 137C(1):53-71

[34]Clericuzio CL, Chen E, McNeil DE, et al. Serum alpha-fetoprotein screening for hepatoblastoma in children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia. J Pediatr, 2003, 143(2):270-272

[35]Bliek J, Gicquel C, Maas S, et al. Epigenotyping as a tool for the prediction of tumor risk and tumor type in patients with Beckwith-Wiedemann syndrome (BWS). J Pediatr, 2004, 145(5):796-799

Beckwith-Wiedemann syndrome: one case report and literature review

XIEXin-bao1,5,XUDan1,5,LIURen-chao2,DONGChen-bin3,ANYu2,4,YUHui1,ZHANGTing1,6

(1DepartmentofInfectiousDiseases; 2TheResearchCenterforTranslationalMedicineinChildrenDevelopmentandDisease; 3DepartmentofSurgery,Children′sHospitalofFudanUniversity,Shanghai201102,China; 4InstituteofBiomedicalSciencesandMOEKeyLaboratoryofContemporaryAnthropology,Shanghai200433,China; 5Equalcontributiontothestudy; 6NowatShanghaiChildren′sHospital)

ZHANG Ting, E-mail:tingz_shmu@163.com

ObjectiveIn China, Beckwith-Wiedemann syndrome (BWS), a rare pediatric congenital overgrowth disorder, associated with abnormal regulation of gene transcription in an imprinted domain located at chromosome 11p15.5, is still poorly recognized. The purpose of this study was to investigate the clinical features, genetic abnormality, and clinical management of BWS.MethodsClinical manifestations, laboratory examinations and genetic testing of one case of BWS were presented, analyzed and discussed. The related literatures were reviewed.ResultsThe case was female, aged 5 months, presenting typical BWS clinical features, including macroglossia, visceromegaly, ear pits, transient neonatal hypoglycemia, facial nevus flammeus, infraorbital creases, etc. A hypomethylation at IC2 of CDKNIC domain was identified and confirmed by MS-MLPA.Conclusions This case is the first report of BWS in China with epigenetic confirmation, and has typical maternal dysmethylation at ICs. The diagnosis of BWS relies on a combination of clinical features and gene-based tests. The BWS patients need to be long term followed-up.

Beckwith-Wiedemann syndrome; Genomic imprinting; Growth disorders; DNA methylation

上海市科委自然科學(xué)基金：12ZR1403500；國家重點(diǎn)基礎(chǔ)研究發(fā)展計劃(973計劃)：2010CB529601

復(fù)旦大學(xué)附屬兒科醫(yī)院 1 感染科， 2 分子轉(zhuǎn)化中心，3 外科 上海，201102；4 復(fù)旦大學(xué)生物醫(yī)學(xué)研究院現(xiàn)代人類學(xué)教育部重點(diǎn)實(shí)驗(yàn)室 上海，200433；5 共同第一作者；6 現(xiàn)在上海市兒童醫(yī)院工作

張婷，E-mail:tingz_shmu@163.com

10.3969/j.issn.1673-5501.2013.01.011

2012-08-27

2012-12-13)

丁俊杰)