16p11.2缺失綜合征1例并文獻(xiàn)復(fù)習(xí)

葛 婷 崔 云 肖詠梅 陸燕芬 張育才 張 婷

·論著·

16p11.2缺失綜合征1例并文獻(xiàn)復(fù)習(xí)

葛 婷1崔 云1肖詠梅 陸燕芬 張育才 張 婷

16號(hào)染色體； 16p11.2缺失綜合征； 脊柱側(cè)彎

1 病例資料

男，2月13 d，因“發(fā)熱近20 d伴咳嗽、腹瀉”入住上海市兒童醫(yī)院(我院)。父母非近親婚配，母孕期間和出生史未述不良事件，否認(rèn)家族遺傳疾病史。

圖1為患兒起病后的癥狀、體征、診斷和治療等重要臨床信息時(shí)間軸。

圖1 本文病例重要臨床信息時(shí)間軸

Fig 1 Time shaft of important clinical information of the patient in the study

患兒入我院前2 d頭面部及雙上肢出現(xiàn)少許出血點(diǎn)，伴納差、腹瀉、精神狀態(tài)不佳。

入院查體：T:38.2℃，P 140·min-1，R 40·min-1，BP 76/54 mmHg，神清，氣促，反應(yīng)一般，雙側(cè)瞳孔等大等圓，對(duì)光反射靈敏，全身花紋樣改變，壓之褪色，雙肺呼吸音粗，可聞及少許痰鳴音，心音有力，律齊，未聞及明顯雜音，腹軟不脹，肝肋下2cm，質(zhì)軟，脾肋下未及，四肢肌力肌張力正常。

圖2 本文病例脊柱側(cè)彎及半椎體畸形

Fig 2Scoliosis and half vertebral deformity of the 9thto 12thvertebral body in the case

圖3 CytoOneArray檢測(cè)16號(hào)染色體結(jié)果

Fig 3Results of chromosome 16 detected by GytoOneArray

圖4 CGH Microarray驗(yàn)證Chr 16p11.2缺失區(qū)段結(jié)果

Fig 4 16p11.2 deletion checked by CGH microarray

2 討論

染色體病是由于先天性染色體數(shù)目異?；蚪Y(jié)構(gòu)異常而引起的臨床綜合征。中國(guó)新生兒出生缺陷的發(fā)病率為4%～6%, 其中大部分為染色體異常所致,其中染色體部分缺失的發(fā)生率較低，但種類繁多，癥狀缺乏特異性，患兒多于嬰幼兒期夭折。

16p11.2缺失綜合征指涉及16號(hào)染色體短臂1區(qū)1帶2亞帶上不同大小片段的缺失，該區(qū)域不同程度的缺失所致的臨床表現(xiàn)復(fù)雜多樣，可影響機(jī)體認(rèn)知功能、行為、生長(zhǎng)發(fā)育和BMI等[1～5]。以“16p11.2[All Fields] AND (“sequence deletion”[MeSH Terms] OR (sequence[All Fields] AND deletion[All Fields]) OR “sequence deletion”[All Fields] OR deletion[All Fields])”為檢索式檢索PubMed數(shù)據(jù)庫(kù)，以檢索詞“16p.11.2綜合征”檢索中國(guó)萬(wàn)方數(shù)據(jù)庫(kù)和中國(guó)知網(wǎng)，共復(fù)習(xí)16p.11.2綜合征1 378例，臨床表型涉及到神經(jīng)系統(tǒng)表現(xiàn)547例(39.7%)、內(nèi)分泌系統(tǒng)371例(26.9%)、生長(zhǎng)發(fā)育與骨骼異常84例(6.1%)、泌尿生殖與消化系統(tǒng)10例(0.7%)、心血管系統(tǒng)4例(0.3%)、免疫功能異常1例(0.07%)。

16p11.2區(qū)域中涉及可調(diào)控瘦素和胰島素信號(hào)的SH2B1基因，已有報(bào)道涵蓋該基因片段的16p11.2缺失綜合征患兒中，0.5%患有嚴(yán)重的早發(fā)性肥胖，主要表現(xiàn)為極端的食欲過(guò)盛，嚴(yán)重的胰島素抵抗，最終可致生長(zhǎng)發(fā)育遲緩[6～9]。16p11.2上基因片段的缺失和重復(fù)也是孤獨(dú)癥(ASD)和神經(jīng)發(fā)育障礙最常見(jiàn)的致病基因之一，這可能與該區(qū)域內(nèi)涵蓋了編碼人MAPK3基因，智力低下相關(guān)基因(ALOX5、ACSL4、PTGS2、HPRT1) ，ASD相關(guān)基因(MVP、CDIPT1、SEZ6L2、ASPHD1、KCTD13)有關(guān)，從而導(dǎo)致部分患兒出現(xiàn)智力低下、自閉的神經(jīng)精神發(fā)育異常，但總?cè)巳喊l(fā)生率<0.01%[10～16]。

Nik-Zainal等[17]研究證實(shí)63例苗勒管發(fā)育不全患者中，4例為16p11.2區(qū)域內(nèi)涉及約0.55 Mb基因微缺失造成。16p11.2缺失綜合征與多發(fā)畸形有關(guān)，以骨骼多發(fā)畸形居多，包括頭圍異常、身材矮小、虹膜缺損、小眼畸形、椎骨和脊柱的畸形，還包括脊髓空洞癥，先天性膈疝[4, 16,18～25]。有研究報(bào)道位于16p11.2的TBX6基因的多態(tài)性與漢族人群的脊柱側(cè)彎相關(guān)[26]。本文病例胸部X線可見(jiàn)胸9～12椎體部分呈半椎體畸形，胸骨塑形異常(脊柱側(cè)彎)，符合16p11.2缺失綜合征的表型。

由于16p11.2缺失綜合征患兒缺失片段大小不一，因此該類患兒臨床表型具有較大的異質(zhì)性，臨床表型可為智力障礙、先天發(fā)育異常、ASD、語(yǔ)言障礙，也可為正常表現(xiàn)[35]。目前針對(duì)16p11.2缺失綜合征尚無(wú)有效的治療方法，遺傳咨詢和產(chǎn)前檢查能降低染色體缺陷患兒的出生，本文患兒其遠(yuǎn)期生存情況，精神運(yùn)動(dòng)發(fā)育和骨骼畸形矯正等尚待進(jìn)一步追蹤隨訪。

[1]Walters RG, Jacquemont S, Valsesia A, et al. A new highly penetrant form of obesity due to deletions on chromosome 16p11.2. Nature, 2010, 463(7281): 671-675

[2]Dale RC, Grattan-Smith P, Fung VS, et al. Infantile convulsions and paroxysmal kinesigenic dyskinesia with 16p11.2 microdeletion. Neurology, 2011, 77(14): 1401-1402

[3]Zufferey F, Sherr EH, Beckmann ND, et al. A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders. J Med Genet, 2012, 49(10): 660-668

[4]Mefford HC, Cooper GM, Zerr T, et al. A method for rapid, targeted CNV genotyping identifies rare variants associated with neurocognitive disease. Genome Res, 2009, 19(9): 1579-1585

[5]Bochukova EG, Huang N, Keogh J, et al. Large, rare chromosomal deletions associated with severe early-onset obesity. Nature, 2010, 463(7281): 666-670

[6]Perrone L, Marzuillo P, Grandone A, et al. Chromosome 16p11.2 deletions: another piece in the genetic puzzle of childhood obesity. Ital J Pediatr, 2010, 3643

[7]Bachmann-Gagescu R, Mefford HC, Cowan C, et al. Recurrent 200-kb deletions of 16p11.2 that include the SH2B1 gene are associated with developmental delay and obesity. Genet Med, 2010, 12(10): 641-647

[8]Galioto R, Spitznagel MB, Strain G, et al. Cognitive function in morbidly obese individuals with and without binge eating disorder. Compr Psychiatry,2012, 53(5): 490-495

[9]Jacquemont S, Reymond A, Zufferey F, et al. Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus. Nature, 2011, 478(7367): 97-102

[10]Chen WJ, Lin Y, Xiong ZQ, et al. Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nat Genet, 2011, 43(12): 1252-1255

[11]Weiss LA, Shen Y, Korn JM, et al. Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med, 2008, 358(7): 667-675

[12]McCarthy SE, Makarov V, Kirov G, et al. Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet, 2009, 41(11): 1223-1227

[13]Crepel A, Steyaert J, De la Marche W, et al. Narrowing the critical deletion region for autism spectrum disorders on 16p11.2. Am J Med Genet,2011,156(2): 243-245

[14]Kumar RA, KaraMohamed S , Sudi J, et al. Recurrent 16p11.2 microdeletions in autism. Hum Molec Genet, 2008,17(4):628-638

[15]Marshall CR, Noor A, Vincent JB, et al. Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet, 2008, 82(2): 477-488

[16]Golzio C, Willer J, Talkowski ME, et al. KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant.Nature,2012,485(7398):363-367

[17]Nik-Zainal S, Strick R, Storer M, et al. High incidence of recurrent copy number variants in patients with isolated and syndromic Mullerian aplasia. J Med Genet, 2011, 48(3): 197-204

[18]Finelli P, Natacci F, Bonati MT, et al. FISH characterisation of an identical (16)(p11.2p12.2) tandem duplication in two unrelated patients with autistic behaviour. J Med Genet, 2004,41(7): e90

[19]Bourthoumieu S, Esclaire F, Terro F, et al. First prenatally diagnosed case of 16p11.2p12.1 duplication. Prenat Diagn, 2008, 28(3): 254-256

[20]Bedoyan JK, Kumar RA, Sudi J, et al. Duplication 16p11.2 in a child with infantile seizure disorder. Am J Med Genet A, 2010, 152A(6): 1567-1574

[21]Shinawi M, Liu P, Kang SH,et al. Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size. J Med Genet, 2010,47(5): 332-341

[22]Hernando C, Plaja A, Rigola MA, et al. Comparative genomic hybridisation shows a partial de novo deletion 16p11.2 in a neonate with multiple congenital malformations. J Med Genet,2002, 39(5): E24

[23]Schaaf CP, Goin-Kochel RP, Nowell KP, et al. Expanding the clinical spectrum of the 16p11.2 chromosomal rearrangements: three patients with syringomyelia. Europ J Hum Genet, 2011,19(2): 152-156

[24]Shimojima K, Inoue T, Fujii Y, et al. A familial 593-kb microdeletion of 16p11.2 associated with mental retardation and hemivertebrae. Eur J Med Genet, 2009, 52(6): 433-435

[25]Wat MJ, Veenma D, Hogue J, et al. Genomic alterations that contribute to the development of isolated and non-isolated congenital diaphragmatic hernia. J Med Genet,2011,48(5): 299-307

[26]Fei Q, Wu Z, Wang H, et al. The association analysis of TBX6 polymorphism with susceptibility to congenital scoliosis in a Chinese Han population. Spine (Phila Pa 1976), 2010,35(9): 983-988

[27]Shiow LR, Paris K, Akana MC, et al. Severe combined immunodeficiency (SCID) and attention deficit hyperactivity disorder (ADHD) associated with a Coronin-1A mutation and a chromosome 16p11.2 deletion. Clin Immunol, 2009, 131(1): 24-30

[28]Shiow LR, Roadcap DW, Paris K, et al. The actin regulator coronin 1A is mutant in a thymic egress-deficient mouse strain and in a patient with severe combined immunodeficiency. Nat Immun, 2008, 9(11): 1307-1315

[29]Weber A, K?hler A, Hahn A, et al. Benign infantile convulsions (IC) and subsequent paroxysmal kinesigenic dyskinesia (PKD) in a patient with 16p11.2 microdeletion syndrome. Neurogenetics, 2013, 14(3-4): 251-253

[30] Castro-Gago M, Pérez-Gay L, Gómez-Lado C, et al.16p11.2 microdeletion associated to early onset benign childhood seizures. Rev Neurol, 2013, 56(2): 125-127

[31] Dale RC, Grattan-Smith P, Fung VS, et al.Infantile convulsions and paroxysmal kinesigenic dyskinesia with 16p11.2 microdeletion. Neurology, 2011,77(14): 1401-1402

[32] Battaglia A, Novelli A, Bernardini L, et al. Further characterization of the new microdeletion syndrome of 16p11.2-p12.2. Am J Med Genet A, 2009,149A(6): 1200-1204

[33]Tabet AC, Pilorge M, Delorme R, et al. Autism multiplex family with 16p11.2p12.2 microduplication syndrome in monozygotic twins and distal 16p11.2 deletion in their brother. Eur J Hum Genet, 2012,20(5): 540-546

[34]Shen Y, Chen X, Wang L, et al. Intra-family phenotypic heterogeneity of 16p11.2 deletion carriers in a three-generation Chinese family. Am J Med Genet B Neuropsychiatr Genet, 2011, 156(2): 225-232

[35]Bijlsma EK, Gijsbers AC, Schuurs-Hoeijmakers JH, et al. Extending the phenotype of recurrent rearrangements of 16p11.2: deletions in mentally retarded patients without autism and in normal individuals. Eur J Med Genet, 2009, 52(2-3): 77-87

(本文編輯：丁俊杰)

One case of chromosome 16p11.2 deletion syndrome and literature review

GETing1，CUIYun1，XIAOYong-mei，LUYan-fen，ZHANGYu-cai，ZHANGTing

(ShanghaiChildren′sHospital，ShanghaiJiaoTongUniversity，Shanghai200062，China；1Equalcontributiontothisstudy)

Corresponding Author：ZHANG Ting，E-mail:zhangt@shchildren.com.cn; ZHANG Yu-cai，E-mail:Zhangyc@shchildren.com.cn

ObjectiveTo enhance the understanding of clinical characteristics，diagnosis，follow-up and genetic testing of chromosome 16p11.2 deletion syndrome.Methods The clinical manifestations，laboratory testing，diagnosis，follow-up，and genetic testing of one case with chromosome 16p11.2 deletion syndrome were reviewed，analyzed and summarized. Meanwhile, relevant literatures of chromosome 16p11.2 deletion syndrome were reviewed in this article.Results①A 2-month-and-13-day boy with 20-day fever，cough，and diarrhea was admitted to our hospital. Deformity of six fingers in right palm and scoliosis was found. The total peripheral blood lymphocytes and lymphocyte subsets were lower than the reference levels. Chest X-ray indicated that the sternum shape was abnormal and T9-T12 vertebral bodies were hemivertebrae deformity. The patient was improved with a hyperactive and exciting performance after anti-infection therapy. Follow up after releasing indicated that the count of peripheral blood lymphocytes was improved, however, WBC, N and CD4+T cells remained low levels. The boy was diagnosed as epilepsy at 5 months old and improved after treatment with anti-epileptic drugs. A deletion of 0.545 4 Mb in chromosome 16p11.2 was identified by chromosome chip detection technology and confirmed by high-density oligonucleotide comparative genomic hybridization (CGH) Microarray. The genes located in this deleted region includedSPN,QRRT,C16orf54,KIF22,MAZ,SEZ6L2,CDIPT,ASPHD1,KCTD13,TMEM219,TAOK2,DOC2A,TBX6. The results of Chromosome chip detection were normal in his parents. Thus, this boy was finally diagnosed as chromosome 16p11.2 deletion syndrome. ②1 387cases were reported by 95 published articles related with chromosome 16p11.2 deletion syndrome, involving the nervous system(547,39.7%), endocrine system(371,26.9%), growth and skeletal abnormalities(84，6.1%), urinary and digestive system(10,0.7%)，cardiovascular system(4,0.3%), immune function(1,0.07%). The different size of the deletion region in chromosome 16p11.2 led a high heterogeneity of clinical characteristics.ConclusionChromosome 16p11.2 deletion syndrome has variable clinical manifestations ，including multiple skeletal deformities(such as scoliosis), nervous system abnormalities(such as seizure, autism), other systems(such as repeated infection, endocrine abnormalities). The diagnosis of Chromosome 16p11.2 deletion syndrome relies on chromosome chip detection technology and CGH microarray.

Chromosome 16； Chromosome 16p11.2 deletion syndrome； Gene expression； Scoliosis

上海市兒童醫(yī)院，上海交通大學(xué)附屬兒童醫(yī)院 上海，200062，1 共同第一作者

張婷，E-mail:zhangt@shchildren.com.cn; 張育才，E-mail:Zhangyc@shchildren.com.cn

10.3969/j.issn.1673-5501.2014.06.010

2014-08-20

2014-12-02)