人类遗传病人类遗传病 (3).pdf

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1、The new england journal of medicinen engl j med 362;3 nejm.org january 21,2010239review articleMedical ProgressWilliamsBeuren SyndromeBarbara R.Pober,M.D.From the Center for Human Genetics,Massachusetts General Hospital,Boston.Address reprint requests to Dr.Pober at the Center for Human Genetics,Sim

2、ches Research Bldg.,185 Cambridge St.,Boston,MA 02114,or at pober.barbaramgh.harvard.edu.This article(10.1056/NEJMra0903074)was updated on June 2,2010,at NEJM.org.N Engl J Med 2010;362:239-52.Copyright 2010 Massachusetts Medical Society.WilliamsBeuren syndrome(also known as Williams syndrome;Online

3、Mendelian Inheritance in Man OMIM number,194050),a multisystem disorder,is caused by deletion of the WilliamsBeuren syndrome chromosome region,spanning 1.5 million to 1.8 million base pairs and containing 26 to 28 genes.Exactly how gene loss leads to the characteristic phenotype of WilliamsBeuren sy

4、ndrome is unknown,but hypoexpression of gene products is likely to be involved.Estimated to occur in approximately 1 in 10,000 persons,1 WilliamsBeuren syndrome is a microdeletion disorder,or contiguousgenedeletion disorder,that can serve as a model for the study of genotypephenotype correlations an

5、d potentially reveal genes contributing to diabetes,hypertension,and anxiety.The first cases of WilliamsBeuren syndrome were described as two seemingly unrelated disorders.One presentation was characterized by hypercalcemia plus persistent growth failure,characteristic facial appearance,“mental reta

6、rdation,”heart murmur,and hypertension,2,3 while the other was characterized by supravalvular aortic stenosis(narrowing of the ascending aorta above the aortic valve,involving the sinotubular junction)plus a distinctive facial appearance,“mental retardation,”“friendly”personality,and growth retardat

7、ion.4,5 Subsequent description of a patient with features common to both phenotypes indicated that these were variations of the same disorder,6 now referred to as WilliamsBeuren syndrome.Causes and Current Diagnostic TestsVitamin D teratogenicity was first considered as the cause of WilliamsBeuren s

8、yndrome,on the basis of experiments showing supravalvular aortic stenosis and craniofacial abnormalities in rabbit fetuses exposed to highdose vitamin D.7,8 Two compelling lines of evidence later showed that WilliamsBeuren syndrome was genetic,not teratogenic:transmission of WilliamsBeuren syndrome

9、from parent to child9,10 and characterization of the phenotypically overlapping autosomal dominant familial supravalvular aortic stenosis syndrome(OMIM number,185500).Familial supravalvular aortic stenosis,which is caused by disruption of the elastin gene(ELN),is associated with cardiovascular abnor

10、malities that are characteristic of WilliamsBeuren syndrome but with few of the syndromes other features.11,12 The screening of patients with WilliamsBeuren syndrome for ELN mutations revealed none;rather,one ELN allele was completely lacking,suggesting that WilliamsBeuren syndrome was a microdeleti

11、on disorder,not a pointmutation disorder.13Recognition of WilliamsBeuren syndrome usually starts with the astute clinician.Clinical diagnostic criteria14,15 have only modest usefulness as compared with rapid and accurate laboratory testing.Fluorescence in situ hybridization(FISH)involving ELNspecifi

12、c probes establishes the diagnosis of WilliamsBeuren syndrome by showing the presence of a single ELN allele only rather than two alleles(Fig.1A).Although FISH remains the most widely used laboratory test,the diagnosis can also be established by means of microsatellite marker analysis,multiplex liga

13、tionThe New England Journal of Medicine Downloaded from nejm.org at UNIV OF SOUTHERN CALIF on April 6,2014.For personal use only.No other uses without permission.Copyright 2010 Massachusetts Medical Society.All rights reserved.The new england journal of medicinen engl j med 362;3 nejm.org january 21

14、,2010240dependent probe amplification,quantitative polymerasechainreaction assay,or array comparative genomic hybridization(Fig.1B).Though not yet costcompetitive,array comparative genomic hybridization offers advantages if the clinical impression is not clearly consistent with WilliamsBeuren syndro

15、me or if the patient has an“atypical”deletion,since this method can delineate the deleted genes.COMMON CLINICAL FEATURESWilliamsBeuren syndrome has a characteristic constellation of findings.The facial features range from subtle to dramatic(Fig.2).Young children are often described as cute or pixiel

16、ike,with a flat nasal bridge,short upturned nose,periorbital puffiness,long philtrum,and delicate chin,whereas older patients have slightly coarse features,with full lips,a wide smile,and a full nasal tip.The extent of medical and developmental problems in patients with WilliamsBeuren syndrome is hi

17、ghly variable.Common features affecting each organ system are listed in Table 1.This review emphasizes findings in the cardiovascular,endocrine,and nervous systems that most affect morbidity and mortality.Cardiovascular AbnormalitiesStenosis of medium and large arteries owing to thickening of the va

18、scular media from smoothmuscle overgrowth constitutes the prototypical cardiovascular abnormality of WilliamsBeuren syndrome.Stenosis is most commonly located above the aortic valve at the sinotubular junction(e.g.,supravalvular aortic stenosis)(Fig.2E and 2F).Supravalvular aortic stenosis,the sever

19、ity of which ranges from trivial to severe,is found in approximately 70%of patients and is rare except in WilliamsBeuren syndrome16 and the related familial supravalvular aortic stenosis syndrome.Arterial narrowing may be isolated or may occur simultaneously in numerous locations,including the aorti

20、c arch,the descending aorta(Fig.2G and 2H),and the pulmonary,coronary,renal(Fig.2G),mesenteric(Fig.2H),and intracranial arteries.Noninvasive imaging such as echocardiography17-21 reveals,in most patients,lesions ranging from discrete(e.g.,“hourglass”)narrowing to multiple stenotic areas or,occasiona

21、lly,even diffuse hypoplasia.An increased carotid artery intimamedia thickness,22 consistent with a generalized elastin arteriopathy,is present in all cases.Rarely,patients are found to have“middle aortic syndrome,”in which the thoracic aorta and abdominal aorta and BAAUTHOR:FIGURE:RETAKE:SIZE4-CH/TL

22、ineComboRevisedAUTHOR,PLEASE NOTE:Figure has been redrawn and type has been reset.Please check carefully.1st2nd3rdPober1 of 3ARTIST:TYPE:MRL1-21-10JOB:361xxISSUE:WBSCR deletionFigure 1.Common Laboratory Methods for Diagnosing WilliamsBeuren Syndrome.In patients with WilliamsBeuren syndrome,fluoresce

23、nce in situ hybridization(Panel A)reveals a normal,nondeleted chromosome 7 with two hybridization signals,one of which confirms the presence of the elastin gene(ELN)(red arrow)and the second,the pres-ence of a chromosome 7specific control gene(adjacent green arrow)and a deleted chromosome 7,which sh

24、ows the control hybrid-ization signal only(green arrow,lower right),indicating that ELN is deleted.The results of array comparative genomic hybridization are shown on a schematic of chromosome 7(Panel B,top;from an Agilent 244K microarray),revealing the loss of one copy of the Wil-liamsBeuren syndro

25、me chromosome region(WBSCR),approximately 1.5 Mb in size,as indicated by the cluster of green hybridization signals(Panel B,middle).An enlarged view of the WBSCR is also shown(Panel B,bottom).See Figure 3A and the Supplementary Ap-pendix,available with the full text of this article at NEJM.org,for a

26、dditional details about the genes within the WBSCR.The New England Journal of Medicine Downloaded from nejm.org at UNIV OF SOUTHERN CALIF on April 6,2014.For personal use only.No other uses without permission.Copyright 2010 Massachusetts Medical Society.All rights reserved.Medical Progressn engl j m

27、ed 362;3 nejm.org january 21,2010241its branches are narrowed.23,24 Intracardiac lesions such as ventricular or atrial septal defects are uncommon,whereas myxomatous degeneration of aortic or mitralvalve leaflets,or both,occur in up to 20%of patients.17,25 Leftsided stenoses may remain stable,but ob

28、struction can progress,especially during the first 5 years of life.However,obstruction of right ventricular outflow,particularly peripheral pulmonary stenoses,often resolves spontaneously.21,26 Stenosis or occlusion of coronary ostia can occur in the absence of supravalvular aortic stenosis.27Hypert

29、ension,occasionally beginning in childhood,ultimately develops in approximately 50%of patients.28,29 The basis for hypertension is often not identified;surgically repairable renovascular lesions are infrequent.Animal models suggest that the higher blood pressures in patients with WilliamsBeuren synd

30、rome than in controls may reflect a physiological adaptation to abnormal vasculature.30Cardiovascular complications are the major cause of death in patients with WilliamsBeuren syndrome.A formal assessment of the life expectancy associated with WilliamsBeuren syndrome is lacking.One study of approxi

31、mately 300 patients,1 to 55 years of age,with WilliamsBeuren syndrome showed a cardiovascularassociated mortality 25 to 100 times that among the controls.31 The administration of general anesthesia for cardiac catheterization or for cardiac surgery in patients with WilliamsBeuren syndrome who have b

32、iventricular outflow obstruction,biventricular hypertrophy,or stenosis or occlusion of coronary ABCDEFGHAUTHOR:FIGURE:RETAKE:SIZE4-CH/TLineComboRevisedAUTHOR,PLEASE NOTE:Figure has been redrawn and type has been reset.Please check carefully.1st2nd3rdPober2 of 3ARTIST:TYPE:MRL01-21-10JOB:36203ISSUE:A

33、o rootAo rootLVLVFigure 2.Patients with WilliamsBeuren Syndrome.Four unrelated patients with WilliamsBeuren syndrome are shown in Panels A through D.The young child(Panel A)has a flat nose bridge,upturned tip of nose,long philtrum,mild periorbital puffiness,full cheeks,and a delicate chin.The school

34、-age child(Panel B)has full lips,a wide mouth,and mildly increased interdental spacing.The young adult(Panel C)has a prominent nose and nasal tip,a wide mouth,and a full lower lip.Panel D shows a patient at 12 years of age(left)and at 83 years of age(right).Vascular stenoses in un-related patients a

35、re shown in Panels E through H.Left ventriculography in a 5-year-old boy with WilliamsBeuren syndrome shows a se-vere discrete(so-called hourglass)supravalvular aortic stenosis(Panel E,arrow).The aortic(Ao)root is dilated,and the proximal ascend-ing aorta is mildly hypoplastic.Volume-rendered gadoli

36、nium-enhanced three-dimensional magnetic resonance angiography in a 44-year-old woman with WilliamsBeuren syndrome shows moderate discrete supravalvular aortic stenosis(Panel F,arrow)and post-stenotic dilatation.Panels G and H show the anteroposterior and lateral views,respectively,from computed tom

37、ographic angiography in a 13-year-old boy with hypertension and an abdominal bruit.There is marked tapering of the descending aorta(Panel G,arrowhead)and stenosis at the origin of the renal arteries(arrows);an aberrant course of the renal arteries is also visible.Tapering of the descend-ing aorta(Pa

38、nel H,bracket and arrowhead)with stenosis of celiac and superior mesenteric arteries(arrows)can be seen.LV denotes left ventricle.The New England Journal of Medicine Downloaded from nejm.org at UNIV OF SOUTHERN CALIF on April 6,2014.For personal use only.No other uses without permission.Copyright 20

39、10 Massachusetts Medical Society.All rights reserved.The new england journal of medicinen engl j med 362;3 nejm.org january 21,2010242Table 1.Common Features of WilliamsBeuren Syndrome,According to Organ System.*FeatureCommentsAuditory and ear,nose,and throatHyperacusisNoise sensitivity can negative

40、ly affect quality of lifeMild-to-moderate high-tone sensorineural hearing lossClinically detected in adolescents and adultsRecurrent otitis mediaCardiovascularVascular stenosis(e.g.,SVAS,PPS)Change in stenosis most likely to occur during childhood;surgery often indicated for greater-than-moderate SV

41、ASHypertensionRenovascular cause occasionally foundValve abnormality(e.g.,MVP)Intracardiac lesion(e.g.,VSD)StrokeVery rare;can be secondary to intracranial stenosisSudden deathVery rare;risk factors are use of anesthesia,biventricular outflow obstruction,biventricular hypertrophy,coronary-artery obs

42、tructionDevelopment and cognitionGlobal cognitive impairment(mean IQ,about 55)IQ ranges from 40 to 100;a few patients have IQs within the normal rangeCharacteristic pattern of cognitive strengths and weak-nesses(known as the WilliamsBeuren syndrome cognitive profile)Strengths are in selected languag

43、e skills and weaknesses in visuospatial skillsDentalSmall or unusually shaped primary teethMalocclusionsHypodontiaEndocrineEarly onset of pubertyMenarche occurs about 2 years earlyGlucose intolerance or diabetes mellitusReported in 75%of adultsOsteopenia or osteoporosisVitamin D or calcium supplemen

44、tation should be used with cautionHypothyroidism(subclinical)Can be associated with mild thyroid hypoplasia;drug thera-py required in minorityHypercalcemiaDocumented in a minority of patients;not restricted to infancyGastrointestinal and weight-relatedColic,difficulty feeding,textured-food intoleran

45、ceAbnormal weight gainMany infants gain weight poorly;as adults,two thirds have a body-mass index 25ConstipationGastroesophageal refluxAbdominal pain of unclear causeDiverticular diseasePossibly occurs in up to one third of patients;diverticulitis can occur in young adultsRectal prolapseCeliac disea

46、seThe New England Journal of Medicine Downloaded from nejm.org at UNIV OF SOUTHERN CALIF on April 6,2014.For personal use only.No other uses without permission.Copyright 2010 Massachusetts Medical Society.All rights reserved.Medical Progressn engl j med 362;3 nejm.org january 21,2010243Table 1.(Cont

47、inued.)FeatureCommentsGenitourinaryDelayed toilet trainingVoiding frequency,urgency,enuresisStructural renal anomaliesBladder diverticulaRecurrent urinary tract infectionsNephrocalcinosisMiscellaneousShort statureCommon but not obligatory;cause is probably multifactorialSleep dysregulation,possibly

48、including restless legs syndromePrevalence is currently unknownMusculoskeletalJoint laxityJoint contracturesWorsening lower-extremity contractures with increasing ageLordosisScoliosisNeurologicHypotoniaHyperreflexiaMore prevalent in adolescents and adults than in younger patients,especially in lower

49、 extremitiesCerebellar findingsPoor balance and coordinationType I Chiari malformationOphthalmologicStrabismusAltered visual acuityReduced stereopsisNarrowing of lacrimal ductPersonality,behavior,and emotional well-beingFriendly personalityEndearing,friendly personality that can confer vulnerability

50、 to inappropriate advancesImpulsivity and short attention span(ADHD)Lifelong ADHD,declining hyperactivity after childhoodAnxiety and phobias,obsessivecompulsive traitsAnxiety and other traits develop over time and are present in a majority of adolescents and adultsDysthymiaSkin and integumentSoft sk