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RESEARCHOpenAccessRenalcelltumourcharacteristicsinpatientswiththeBirt-Hogg-Dubécancersusceptibilitysyndrome:aretrospective,multicentrestudyPatrickRBenusiglio1,2*,SophieGiraud3,SophieDeveaux1,ArnaudMéjean1,4,5,Jean-MichelCorreas1,5,6,DominiqueJoly1,5,7,Marc-OlivierTimsit1,4,5,SophieFerlicot1,8,VirginieVerkarre1,5,9,CarolineAbadie1,10,DominiqueChauveau1,11,DominiqueLeroux1,12,Marie-FranoiseAvril1,5,13,Jean-FranoisCordier14,StéphaneRichard1,15andonbehalfoftheFrenchNationalCancerInstituteInheritedpredispositiontoKidneyCancernetworkAbstractBackground:TheBirt-Hogg-Dubésyndromeisararecancersusceptibilitysyndromecharacterisedbyrenaltumours,lungcystsandpneumothoraces,andfibrofolliculomas.
ItiscausedbydominantlyinheritedmutationsinFLCN.
OurobjectivewastoreportrenaltumourcharacteristicsinalargeseriesofpatientswiththeBirt-Hogg-Dubésyndrome.
Methods:WestudiedFrenchBirt-Hogg-Dubépatientswithahistoryofrenaltumour.
Results:Weincluded33patientswith21distinctgermlineFLCNmutations.
Medianageatdiagnosisoffirstrenaltumourwas46,andagevariedfrom20to83.
Twentycaseshadonerenaltumour,theremainderhadtwoormoretumours.
Mostcases(23/33,70%)hadoncocytomaorrenalcellcarcinomaofthechromophobeorhybridchromophobe-oncocytomatype,threehadclearcellcarcinoma(9%),andtheothersevenhadcarcinomaofpapillary,undifferentiatedorundeterminedhistology.
Fourcaseshadmetastaticdisease,althoughnonediedofit.
Conclusions:Ageatrenaltumourdiagnosiswashighlyvariable,highlightingtheneedforregularsurveillancefromyoungadulthoodtooldage.
MostcaseshadtumourtypesclassicallyassociatedwithBirt-Hogg-Dubé,i.
e.
oncocytomaorrenalcellcarcinomaofthechromophobeorhybridtype.
Nevertheless,9%hadclearcellrenalcellcarcinoma.
Geneticists,urologistsandoncologistsshouldthereforebealerttothepossibilityofBirt-Hogg-Dubéinpatientswithrenalcellcarcinomaofclearcellhistology,especiallyifthereareassociatedmanifestations.
Finally,thebehaviourofmetastaticcarcinomaseemedmoreindolentthaninsporadicrenalcancers.
Keywords:Renalcellcarcinoma,Neoplasticsyndromes,Hereditary,Birt-Hogg-Dubé,Geneticpredispositiontodisease,FolliculinIntroductionTheBirt-Hogg-Dubésyndrome(BHD)isararecancersusceptibilitysyndromecharacterisedmainlybyrenalcelltumours,lungcystsandpneumothoraces,andskinpapulesnamedfibrofolliculomas[1].
ItiscausedbygermlinemutationsintheFLCNgene,whichareinheritedinadominantfashion[1].
FLCNcodesforfolliculin,aproteinthatoperatesinthemTORpathwayandleads,wheninactivated,toincreasedmitochondrialoxidativemetabolism[2,3].
PhenotypeisvariableamongpatientswithBHD.
Indeed,renalcelltumoursaffectsupto34%ofmutationcarriers,andconsistspredominantlyofchromo-phoberenalcellcarcinomas(RCC),benignoncocytomas,andRCCwithhybridchromophobe–oncocytomahist-ology[4-7].
Twenty-fourto37%ofBHDcasespresentwithatleastoneepisodeofpneumothoraxintheirlifetime,and79%to84%haveskinfibrofolliculomas[4,5,8].
*Correspondence:pbenusiglio.
wk@gmail.
com1CentreExpertNationalCancersRaresPREDIR,HpitalBicêtre,AP-HP,BatimentLasjaunias,78rueduGénéralLeclerc,94275LeKremlinBicêtre,France2Consultationd'Oncogénétique,DépartementdeMédecineOncologique,GustaveRoussyCancerCampus,114rueEdouardVaillant,94805Villejuif,FranceFulllistofauthorinformationisavailableattheendofthearticle2014Benusiglioetal.
;licenseeBioMedCentralLtd.
ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(http://creativecommons.
org/licenses/by/4.
0),whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycredited.
TheCreativeCommonsPublicDomainDedicationwaiver(http://creativecommons.
org/publicdomain/zero/1.
0/)appliestothedatamadeavailableinthisarticle,unlessotherwisestated.
Benusiglioetal.
OrphanetJournalofRareDiseases2014,9:163http://www.
ojrd.
com/content/9/1/163Wedescribehereinrenalcelltumourcharacteristicsin33BHDpatients,amongthemfourcaseswithmetastatic,albeitindolentdisease.
PatientsandmethodsInFrance,patientsarereferredtoaccreditedcancergeneticsclinicsthroughoutthecountrywhengeneticsusceptibilitytorenalcelltumoursissuspected.
Notallpatientspresentwithapersonalorfamilyhistoryofrenalcelltumour.
Indeed,somehavenon-renalmanifestationssuggestiveofasyndromeinwhichrenalcelltumourriskisincreased,andothersarehealthyrelativesofindividualswithanestablishedgeneticpredisposition.
ThegenesmostcommonlyanalysedinhereditaryRCCareVHL(associ-atedwithvonHippel-Lindaudisease),FH(HereditaryLeiomyomatosiswithRCC),FLCN(BHD),SDHB(PGL4syndrome),andMET(HereditaryPapillaryRCC)[9].
OnNovember15,2013,weexploredtwooverlappingsources,thePREDIRNationalHereditaryKidneyCancerCentredatabaselocatedatHpitalBicêtrenearParis,andtheMolecularGeneticsLaboratoryattheEdouardHerriotUniversityHospitalinLyon.
ThePREDIRcentrestrivestocollectclinicalandmoleculardataonallFrenchcarriersofamutationpredisposingtorenalcelltumours,whereastheLyonlaboratoryisthemainproviderofFLCNgermlineanalysisinFrance.
Weretrievedclinicaldataforallpatientswithadiagnosisofmolecularly-provenBHD,andselectedthosewithahistoryofrenalcelltumouratthetimeofgenetictesting.
Allpatientshadsignedaninformedconsentformbeforegenetictesting,aslegallyrequired.
Casesreportedintwopreviouspapersareincludedinthisstudy[10,11].
Follow-updataforincludedpatientsareup-to-dateasof29September2014,thedaythefinalversionofthismanuscriptwassubmitted.
MutationswereidentifiedusingbothSangersequencingofexonsandtheirflankingregionsandmultiplexligationprobe-dependentamplification(MLPA)ongenomicDNAextractedfromblood.
Detailedprotocolsareavailableonrequest.
MutationswereconsideredpathogeniciftheyhadbeenreportedandreliablyidentifiedassuchintheFLCNmutationdatabase(http://grenada.
lumc.
nl/LOVD2/shared1),orfornever-reportedmutations,iftheyledtoatruncatedprotein.
ResultsWeascertainedatotalof124BHDpatientsfrom72distinctfamilies.
Thirty-threehadahistoryofrenalcelltumour(Tables1and2).
Twenty-oneweremale,12female.
Medianageatdiagnosisoffirsttumourwas46(agerange20–83).
Twentycaseshadonetumour,fourhadtwotumours,andninehadmultifocal(threeormore)tu-mours.
Mostcases(23/33,70%)hadoncocytomaorRCCofthechromophobeorhybridchromophobe-oncocytomatype,threehadclearcellRCC(9%),onehadpapillaryRCCwithinterspersedeosinophiliccells,andonehadundif-ferentiatedRCC.
Histopathologywasunavailableforfivepatients,mostoftenbecausetheirtumourswereradiologicallycharacteristicbuttoosmalltojustifysur-gery.
ThemostcommonhistologicaltypesareillustratedinFigure1.
Inadditiontorenalcelltumours,29/33casesalsohaddocumentedextra-renalBHDmanifestations.
Twenty-two(67%)hadlungcystsand/orpneumothoraces,and19(58%)hadfibrofolliculomas(twelvecaseshadbothpulmonaryanddermatologicalmanifestations).
Therewere21distinctmutations:frameshift(n=10),missense(n=4),nonsense(n=4),splicesite(n=2)andinframedeletion(n=1).
Amongthose33patients,fourhadmetastaticRCC,eitheratthetimeofdiagnosisorsubsequently.
AllpresentedwithsymptomsthatledtothediagnosisofRCC.
Case13851hadRCCage35,hehadundergonesuccessfulnephrectomyatthetime.
Asolitarylunglesionwasfoundincidentallyage58onaCTscanthatwasprescribedafteranepisodeofmalignanthypertension.
ItwassurgicallyremovedandpathologicalexaminationshoweditwasametastasisfromapoorlydifferentiatedRCC.
Thepatientdiedofischemicstrokefouryearsaftersurgicalresectionofthemetastasis,andtherewasnoevidenceofcancerrelapseatthetime.
Case19398wasdiagnosedage42withbilateralmultifocalhybridchromophobe-oncocytomaRCCandlivermetastases.
Biopsyofaleftrenaltumourledtothepathologicaldiagnosis.
Nofurthersurgicalprocedurewascarriedout.
Forthefirstthreeyears,shewasundersystemictherapywithsunitinib,everolimusandthentemsirolimus,anddiseasestabilitywasachieved.
Alltreatmentswerethenstopped.
Eightyearsaftertheinitialdiagnosis,sheisclinicallywellandthelivermetastasesareradiologicallystable.
Case21310hadleftnephrectomyage46forchro-mophobeRCC,andsubsequentlypresentedwithliverandlungmetastases.
Sheisstillalivefiveyearsafterthemetas-taseswerefirstobserved,eventhoughslowradiologicalandclinicalprogressionhasjustifiedtreatmentwithsuni-tinib,axitinib,everolimus,bevacizumabandpazopanib.
Finally,case22973hadrightnephrectomyage56forachromophobeRCC.
Hereceivedadjuvantradiotherapyformultiple,metastaticretroperitoneallymph-nodesthatcouldnotberemovedsurgically.
Sevenyearslater,therearenoradiologicalorclinicalsignsofdiseaseprogression.
DiscussionOurseriesof33casesisoneofthelargesteverpublished[4-8].
Thisstudyconfirmsthatcasescanhaveeitherunifocaldisease,ormultipletumours,andthatmostrenalcelltumoursareoncocytomasorRCCofchromo-phobeorhybridchromophobe-oncocytomahistology[4-6].
OtherhistologiesarehoweverassociatedwiththeBenusiglioetal.
OrphanetJournalofRareDiseases2014,9:163Page2of6http://www.
ojrd.
com/content/9/1/163syndrome,clearcellinparticular.
Indeed,amongourcases,3(9%)hadclearcellcarcinomas.
GiventhattheyarenottypicalinBHD,allclearcellRCCwerereviewedbyoneofourexpertpathologists,andconfirmationwasobtained.
Thisproportionissimilartowhathasbeenreportedinthepast,andcliniciansshouldthereforeremainalerttothepossibilityofBHDinpatientswithclearcellRCC,especiallyifthereareassociatedmani-festations[6].
Theageatrenalcelltumourdiagnosisvariedbetween20and83,withamedianageof46.
Ofspecialinterestwasthefactthattwopatientspresentedwitharenalcelltumourintheirtwenties,highlightingtheneedforregu-larsurveillancefromanearlyage[12].
Thissurveillanceshouldbecontinuedwithnoupperagelimitandaslongasthepatientsareingoodcondition,asonepatientwithtwotumoursinhiseightieswassuccessfullytreatedbypercutaneousradiofrequencyablation.
Table1Birt-Hogg-DubépatientswithrenaltumoursPatientGenderMutation1strenaltumour,ageNumberofrenaltumoursHistologyOtherBHDmanifestationsDurationofF-U(months)LatestF-Udata11525Mc.
1285dup,p.
His429Profs*2773MultifocalCh,HFF3005/201411528Mc.
1285dup,p.
His429Profs*27832N/AFF,PNO10311/201311545Mc.
1285dup,p.
His429Profs*27391N/ALungcysts6505/201113851Mc.
1285dup,p.
His429Profs*27351(Mt)UndFF22503/2003(D)14381Mc.
755dup,p.
Cys253Valfs*39621CCFF15005/200914840Mc.
1285dup,p.
His429Profs*27201N/AFF,PNO67202/201115842Fc.
828del,p.
Ala277Leufs*16381Ch-17602/201419276Mc.
1062+2T>G562Ch,HFF9605/201119398Fc.
663dup,p.
Met222Aspfs*2642Multifocal(Mt)HPNO11509/201420471Fc.
1285dup,p.
His429Profs*2734MultifocalCh,OFF,PNO24801/201420472Mc.
67G>T,p.
Glu23*431ChPNO13203/201421310Fc.
1198G>A,p.
Val400Ile461(Mt)Ch-9907/201422973Mc.
1523A>G,p.
Lys508Arg561(Mt)ChFF,PNO9603/201425891Fc.
318C>G,p.
Tyr106*251PLungcysts9603/201426016Mc.
1300G>A,p.
Glu434Lys48MultifocalCh,HFF1605/201127674Mc.
616A>T,p.
Lys206*561ChPNO9305/201328190Mc.
1367_1398del,p.
Asp456Glyfs*19531OLungcysts1609/201228535Fc.
1063-2A>G511ChFF,lungcysts7204/201428537Fc.
1300G>A,p.
Glu434Lys472HPNO2002/201428590Mc.
1285dup,p.
His429Profs*27471ChFF,lungcysts1305/201331122Fc.
1285dup,p.
His429Profs*2741MultifocalCCLungcysts,PNO26406/200536616Mc.
1285del,p.
His429Thrfs*39401N/AFF31201/200837644Mc.
958dup,p.
Arg320Profs*70412OFF,PNO607/200837673Mc.
610_611delinsTA,p.
Ala204*44MultifocalCh-907/200840154Fc.
1528_1530del,p.
Glu510del30MultifocalO-N/A02/200940893Mc.
323G>T,p.
Ser108Ile511CCFF,PNO4503/201342207Fc.
1300G>A,p.
Glu434Lys541ChFF,PNO7401/201442337Mc.
1300G>A,p.
Glu434Lys501HFF,lungcysts,PNO6002/201447950Mc.
1458del,p.
Ile486Metfs*544MultifocalOFF2402/201447639Fc.
57_58del,p.
Phe20Leufs*16441HPNO4305/201448746Mc.
1318del,p.
Glu440Argfs*28541ChFF,lungcysts3501/201448781Fc.
1285dup,p.
His429Profs*27551N/AFF,PNO8002/201350335Mc.
958dup,p.
Arg320Profs*7039MultifocalOPNO2406/2014Allpatientswerealiveatlastfollow-up,unlessspecifiedotherwise.
CC,clearcellrenalcellcarcinoma.
Ch,chromophoberenalcellcarcinoma.
D,deceased.
FF,fibrofolliculomas,F-U,follow-up.
H,hybridchromophobe-oncocytomarenalcellcarcinoma.
Mt,metastaticdisease.
N/A,notavailable.
O,oncocytoma.
P,papillaryrenalcellcarcinoma,typeundetermined.
PNO,pneumothorax.
Und,undifferentiated.
Benusiglioetal.
OrphanetJournalofRareDiseases2014,9:163Page3of6http://www.
ojrd.
com/content/9/1/163These33caseswithrenalcelltumoursrepresent27%ofallascertainedBHDpatients(33/124),and34%ofthoseforwhichwehaveevidenceofrenalimaging(33/98).
Thisobservationisremarkablyconsistentwithtwolargestud-iesfromtheUnitedStatesNationalCancerInstitutethatreportedoveralltumourfrequenciesof29%and34%inBHDpatientsevaluatedbyCTscan[4,5].
Weexpecttheproportioninourstudytoberepresentativeofthetruerenalcelltumourriskassociatedwiththesyndrome,asFrenchindexcasesareofferedFLCNgeneticanalysisbecausetheypresentwithalltypesofclinicalmanifesta-tionssuggestiveofBHD.
Anexhaustivedescriptionofextrarenalmanifestationsisbeyondthescopeofthispaper.
Nevertheless,67%and58%ofourcasesalsohadpulmonaryanddermatologicalmanifestationsrespectively,inadditiontoRCC.
ThesefiguresrepresenttheminimalprevalenceaspulmonaryassessmentbyCTscanandexaminationbyadermatologistknowledgeableinthesyndromewasnotsystematic.
Inourseries,fourpatientshadmetastatic,albeitindo-lentRCC.
Comprehensivefamilydatawascollectedforallpatientsinthisseries,andwehavenoknowledgeofotherrelatives(deceasedoralive)withmetastaticRCCwhowerenottestedforFLCNmutations,andwhowerethereforenotincludedinthisstudy.
VeryfewcasesofmetastaticRCCassociatedwithBHDhavebeende-scribed.
Pavlovichetal.
andHouwelingetal.
reportedrespectivelytwoandfivesuchcases;alldiedrapidlyTable2Summaryofclinicalandhistopathologicalcharacteristicsofrenaltumoursamong33patientswithBirt-Hogg-DubéCharacteristicsNumberofpatientsGenderMale21Female12Tumournumber12024Multifocal9TumourhistologyOncocytoma/Chromophobe/Hybridchromophobe-oncocytoma23Clearcell3Papillary(typeundetermined)1Undifferentiated1N/A5Extra-renalmanifestations§Lungcysts/pneumothorax22Fibrofolliculomas19None4§twelvepatientshadbothpulmonaryanddermatologicalmanifestations.
RCC,renalcallcarcinoma.
Figure1MaintypesofrenaltumoursseeninourpatientswithBHD.
Oncocytoma(A),chromophobecarcinoma(B),hybridchromophobe-oncytomacarcinoma(C),andclearcellcarcinoma(D).
Benusiglioetal.
OrphanetJournalofRareDiseases2014,9:163Page4of6http://www.
ojrd.
com/content/9/1/163despitemultidisciplinarymanagementthatincludedsur-gery,radiotherapy,immunotherapyandchemotherapy,andthegoodprognosisassociatedwithmetastaticdiseaseinourstudycontrastswiththeseearlierreports[8,13].
Threeofthefourpatientsreportedherearestillalivemorethanfiveyearsafterthemetastaseswerediagnosed,whilethefourthdiedofunrelatedcausesfouryearsafteralungmetastasishadbeenremoved.
WhethertheseobservationsreflectaspecificbehaviouronlyseeninBHDrequiresfurtherinvestigation.
AnotherhypothesisisthatmetastaticRCCinBHDpatientsismoresensitivetotyrosinekinaseandmTORinhibitorssuchassuniti-nibandeverolimus(tworecently-developeddrugsthatarenowroutinelyusedinthetreatmentofmetastaticRCC),assuggestedforexamplebythemTORsignallingpathwayactivationseeninkidneytumoursassociatedwiththesyndrome,butthatwouldnotaccountforthegoodprognosisofcases13851and22973whoreceivednosystemictreatment[14].
AsshowninTable1,mostpatientsinourstudyarefollowedupmedically,withrelevantinformationbeingcollectedbytheteaminchargeonaregularbasis.
Thereishoweveraminorityfromwhichwehavenotheardinthelastfewyears,andwecannotruleoutwithcertaintythepossibilityofaggressivemetastaticdiseaseinthesepatients.
ConclusionsTheeponymsyndromewasfirstdescribedover35yearsagobyBirt,HoggandDubé[15].
However,theFLCNgenewasonlyidentifiedin2002[16].
Therecentmo-lecularcharacterisationofthesyndrome,addedtothefactthatlikemostgeneticdiseasesBHDisrareinthegeneralpopulation,meansthereareonlylimiteddataonthetopicintheliterature.
Asaresult,thislargeandmulticentricstudywillimproveknowledgeofthesyn-dromeamonggeneticists,urologistsandoncologistsin-volvedintheassessmentandmanagementofpatientswithasuspectedorestablishedgeneticpredispositiontorenalcelltumours.
Itisofutmostimportancetoidentifyindividualswithahighprobabilityofdevelopingrenalcelltumours,sothatthey,andtheirat-riskrelativescanbenefitfrompersonalisedsurveillanceandmanagement.
CompetinginterestsTheauthorsdeclarethattheyhavenocompetinginterests.
Authors'contributionsPRB,SD,AM,JMC,DJ,MOT,CA,DC,DL,MFA,JFCandSRwereinvolvedinthemultidisciplinaryassessementandclinicalmanagementofpatients.
SGperformedFLCNgeneticanalyses.
SFandVVwerethepathologistsofthestudy.
PRBcollectedandanalysedthedata,andwrotethemanuscriptwithsupportfromJFC,SRandJMC.
Allauthorsreadandapprovedthefinalmanuscript.
AcknowledgmentsThisprojectwasfundedbytheLiguenationalecontreleCancer(Comitésdel'IndreetduCher),theMyrovlytisTrust(BHDFoundation)andtheFondationGustaveRoussy.
KamalAchkar,PascalineBerthet,OlivierBinet,VirginieBubien,NaceraBrahimi,OlivierCaron,BertrandCollin,Marie-AgnèsCollonge-Rame,IsabelleCoupier,AlbertDavid,BenedicteDemuynck,YvesDenoux,CatherineDugast,BernardEscudier,ThierryFlam,Jean-MarieFerrière,JeanFriedel,BrigitteGilbert-Dussardier,SophieLejeune-Dumoulin,MichelLongy,GwenaelNadeau,NicolasPoulhalon,OlivierRixe,StanislasRopert,OlivierRouvière,Jean-MichelSalé,AyhanUlusakarya,LaurentYonneau,HélèneZattaraarecontributingcollaborators.
TheyarepartoftheFrenchNationalCancerInstituteInheritedpredispositiontoKidneyCancernetworkandshouldbeacknowledgedassuchintheauthorlist.
WearealsogratefultoHélèneChomarat(Nantes),Jean-FranoisEmile(Boulogne-Billancourt),FranoiseGalateau-Salle(Caen),CatherineMazerolles(Toulouse),andPierreValidire(Paris)whosentusparaffinembeddedtissueuponrequestforpathologicalreview.
Authordetails1CentreExpertNationalCancersRaresPREDIR,HpitalBicêtre,AP-HP,BatimentLasjaunias,78rueduGénéralLeclerc,94275LeKremlinBicêtre,France.
2Consultationd'Oncogénétique,DépartementdeMédecineOncologique,GustaveRoussyCancerCampus,114rueEdouardVaillant,94805Villejuif,France.
3GénétiqueMoléculaireetClinique,HpitalEdouardHerriot,5placed'Arsonval,,69437Lyon,France.
4Serviced'Urologie,HpitaleuropéenGeorges-Pompidou,AP-HP,20rueLeblanc,75908Paris,France.
5UniversitéParis-Descartes,12Ruedel'coledeMédecine,75006Paris,France.
6ServicedeRadiologieAdulte,HpitalNecker-EnfantsMalades,AP-HP,149ruedeSèvres,75743Paris,France.
7ServicedeNéphrologie,HpitalNecker-EnfantsMalades,AP-HP,149ruedeSèvres,75743Paris,France.
8Serviced'AnatomiePathologique,HpitalBicêtre,AP-HP,78rueduGénéralLeclerc,94275LeKremlinBicêtre,France.
9Serviced'AnatomiePathologique,HpitalNecker-EnfantsMalades,AP-HP,149ruedeSèvres,75743Paris,France.
10ServicedeGénétiqueMédicale,CHURennes,16BoulevarddeBulgarie,35203Rennes,France.
11DépartementdeNéphrologieetTransplantationd'Organes,INSERMUMR1048,HpitaldeRangueil,1avenuePoulhès,31059Toulouse,France.
12Départementd'Hématologie,OncogénétiqueetImmunologie,CHUdeGrenoblesiteNord-Institutdebiologieetdepathologie,BoulevarddelaChantourne,38700LaTronche,France.
13ServicedeDermatologie,HpitalCochin,AP-HP,27rueduFaubourgSaint-Jacques,75679Paris,France.
14CentredeRéférencedesMaladiesPulmonairesRares,ServicedePneumologie,HpitalLouisPradel,28avenueduDoyenLépine,69677Lyon,France.
15GénétiqueOncologiqueEPHE,INSERMU743,InstitutdecancérologieGustaveRoussy,94800VillejuifandFacultédeMédecineParis-Sud,94276LeKremlin-Bicêtre,France.
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:RenalcelltumourcharacteristicsinpatientswiththeBirt-Hogg-Dubécancersusceptibilitysyndrome:aretrospective,multicentrestudy.
OrphanetJournalofRareDiseases20149:163.
SubmityournextmanuscripttoBioMedCentralandtakefulladvantageof:ConvenientonlinesubmissionThoroughpeerreviewNospaceconstraintsorcolorgurechargesImmediatepublicationonacceptanceInclusioninPubMed,CAS,ScopusandGoogleScholarResearchwhichisfreelyavailableforredistributionSubmityourmanuscriptatwww.
biomedcentral.
com/submitBenusiglioetal.
OrphanetJournalofRareDiseases2014,9:163Page6of6http://www.
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ItiscausedbydominantlyinheritedmutationsinFLCN.
OurobjectivewastoreportrenaltumourcharacteristicsinalargeseriesofpatientswiththeBirt-Hogg-Dubésyndrome.
Methods:WestudiedFrenchBirt-Hogg-Dubépatientswithahistoryofrenaltumour.
Results:Weincluded33patientswith21distinctgermlineFLCNmutations.
Medianageatdiagnosisoffirstrenaltumourwas46,andagevariedfrom20to83.
Twentycaseshadonerenaltumour,theremainderhadtwoormoretumours.
Mostcases(23/33,70%)hadoncocytomaorrenalcellcarcinomaofthechromophobeorhybridchromophobe-oncocytomatype,threehadclearcellcarcinoma(9%),andtheothersevenhadcarcinomaofpapillary,undifferentiatedorundeterminedhistology.
Fourcaseshadmetastaticdisease,althoughnonediedofit.
Conclusions:Ageatrenaltumourdiagnosiswashighlyvariable,highlightingtheneedforregularsurveillancefromyoungadulthoodtooldage.
MostcaseshadtumourtypesclassicallyassociatedwithBirt-Hogg-Dubé,i.
e.
oncocytomaorrenalcellcarcinomaofthechromophobeorhybridtype.
Nevertheless,9%hadclearcellrenalcellcarcinoma.
Geneticists,urologistsandoncologistsshouldthereforebealerttothepossibilityofBirt-Hogg-Dubéinpatientswithrenalcellcarcinomaofclearcellhistology,especiallyifthereareassociatedmanifestations.
Finally,thebehaviourofmetastaticcarcinomaseemedmoreindolentthaninsporadicrenalcancers.
Keywords:Renalcellcarcinoma,Neoplasticsyndromes,Hereditary,Birt-Hogg-Dubé,Geneticpredispositiontodisease,FolliculinIntroductionTheBirt-Hogg-Dubésyndrome(BHD)isararecancersusceptibilitysyndromecharacterisedmainlybyrenalcelltumours,lungcystsandpneumothoraces,andskinpapulesnamedfibrofolliculomas[1].
ItiscausedbygermlinemutationsintheFLCNgene,whichareinheritedinadominantfashion[1].
FLCNcodesforfolliculin,aproteinthatoperatesinthemTORpathwayandleads,wheninactivated,toincreasedmitochondrialoxidativemetabolism[2,3].
PhenotypeisvariableamongpatientswithBHD.
Indeed,renalcelltumoursaffectsupto34%ofmutationcarriers,andconsistspredominantlyofchromo-phoberenalcellcarcinomas(RCC),benignoncocytomas,andRCCwithhybridchromophobe–oncocytomahist-ology[4-7].
Twenty-fourto37%ofBHDcasespresentwithatleastoneepisodeofpneumothoraxintheirlifetime,and79%to84%haveskinfibrofolliculomas[4,5,8].
*Correspondence:pbenusiglio.
wk@gmail.
com1CentreExpertNationalCancersRaresPREDIR,HpitalBicêtre,AP-HP,BatimentLasjaunias,78rueduGénéralLeclerc,94275LeKremlinBicêtre,France2Consultationd'Oncogénétique,DépartementdeMédecineOncologique,GustaveRoussyCancerCampus,114rueEdouardVaillant,94805Villejuif,FranceFulllistofauthorinformationisavailableattheendofthearticle2014Benusiglioetal.
;licenseeBioMedCentralLtd.
ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(http://creativecommons.
org/licenses/by/4.
0),whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycredited.
TheCreativeCommonsPublicDomainDedicationwaiver(http://creativecommons.
org/publicdomain/zero/1.
0/)appliestothedatamadeavailableinthisarticle,unlessotherwisestated.
Benusiglioetal.
OrphanetJournalofRareDiseases2014,9:163http://www.
ojrd.
com/content/9/1/163Wedescribehereinrenalcelltumourcharacteristicsin33BHDpatients,amongthemfourcaseswithmetastatic,albeitindolentdisease.
PatientsandmethodsInFrance,patientsarereferredtoaccreditedcancergeneticsclinicsthroughoutthecountrywhengeneticsusceptibilitytorenalcelltumoursissuspected.
Notallpatientspresentwithapersonalorfamilyhistoryofrenalcelltumour.
Indeed,somehavenon-renalmanifestationssuggestiveofasyndromeinwhichrenalcelltumourriskisincreased,andothersarehealthyrelativesofindividualswithanestablishedgeneticpredisposition.
ThegenesmostcommonlyanalysedinhereditaryRCCareVHL(associ-atedwithvonHippel-Lindaudisease),FH(HereditaryLeiomyomatosiswithRCC),FLCN(BHD),SDHB(PGL4syndrome),andMET(HereditaryPapillaryRCC)[9].
OnNovember15,2013,weexploredtwooverlappingsources,thePREDIRNationalHereditaryKidneyCancerCentredatabaselocatedatHpitalBicêtrenearParis,andtheMolecularGeneticsLaboratoryattheEdouardHerriotUniversityHospitalinLyon.
ThePREDIRcentrestrivestocollectclinicalandmoleculardataonallFrenchcarriersofamutationpredisposingtorenalcelltumours,whereastheLyonlaboratoryisthemainproviderofFLCNgermlineanalysisinFrance.
Weretrievedclinicaldataforallpatientswithadiagnosisofmolecularly-provenBHD,andselectedthosewithahistoryofrenalcelltumouratthetimeofgenetictesting.
Allpatientshadsignedaninformedconsentformbeforegenetictesting,aslegallyrequired.
Casesreportedintwopreviouspapersareincludedinthisstudy[10,11].
Follow-updataforincludedpatientsareup-to-dateasof29September2014,thedaythefinalversionofthismanuscriptwassubmitted.
MutationswereidentifiedusingbothSangersequencingofexonsandtheirflankingregionsandmultiplexligationprobe-dependentamplification(MLPA)ongenomicDNAextractedfromblood.
Detailedprotocolsareavailableonrequest.
MutationswereconsideredpathogeniciftheyhadbeenreportedandreliablyidentifiedassuchintheFLCNmutationdatabase(http://grenada.
lumc.
nl/LOVD2/shared1),orfornever-reportedmutations,iftheyledtoatruncatedprotein.
ResultsWeascertainedatotalof124BHDpatientsfrom72distinctfamilies.
Thirty-threehadahistoryofrenalcelltumour(Tables1and2).
Twenty-oneweremale,12female.
Medianageatdiagnosisoffirsttumourwas46(agerange20–83).
Twentycaseshadonetumour,fourhadtwotumours,andninehadmultifocal(threeormore)tu-mours.
Mostcases(23/33,70%)hadoncocytomaorRCCofthechromophobeorhybridchromophobe-oncocytomatype,threehadclearcellRCC(9%),onehadpapillaryRCCwithinterspersedeosinophiliccells,andonehadundif-ferentiatedRCC.
Histopathologywasunavailableforfivepatients,mostoftenbecausetheirtumourswereradiologicallycharacteristicbuttoosmalltojustifysur-gery.
ThemostcommonhistologicaltypesareillustratedinFigure1.
Inadditiontorenalcelltumours,29/33casesalsohaddocumentedextra-renalBHDmanifestations.
Twenty-two(67%)hadlungcystsand/orpneumothoraces,and19(58%)hadfibrofolliculomas(twelvecaseshadbothpulmonaryanddermatologicalmanifestations).
Therewere21distinctmutations:frameshift(n=10),missense(n=4),nonsense(n=4),splicesite(n=2)andinframedeletion(n=1).
Amongthose33patients,fourhadmetastaticRCC,eitheratthetimeofdiagnosisorsubsequently.
AllpresentedwithsymptomsthatledtothediagnosisofRCC.
Case13851hadRCCage35,hehadundergonesuccessfulnephrectomyatthetime.
Asolitarylunglesionwasfoundincidentallyage58onaCTscanthatwasprescribedafteranepisodeofmalignanthypertension.
ItwassurgicallyremovedandpathologicalexaminationshoweditwasametastasisfromapoorlydifferentiatedRCC.
Thepatientdiedofischemicstrokefouryearsaftersurgicalresectionofthemetastasis,andtherewasnoevidenceofcancerrelapseatthetime.
Case19398wasdiagnosedage42withbilateralmultifocalhybridchromophobe-oncocytomaRCCandlivermetastases.
Biopsyofaleftrenaltumourledtothepathologicaldiagnosis.
Nofurthersurgicalprocedurewascarriedout.
Forthefirstthreeyears,shewasundersystemictherapywithsunitinib,everolimusandthentemsirolimus,anddiseasestabilitywasachieved.
Alltreatmentswerethenstopped.
Eightyearsaftertheinitialdiagnosis,sheisclinicallywellandthelivermetastasesareradiologicallystable.
Case21310hadleftnephrectomyage46forchro-mophobeRCC,andsubsequentlypresentedwithliverandlungmetastases.
Sheisstillalivefiveyearsafterthemetas-taseswerefirstobserved,eventhoughslowradiologicalandclinicalprogressionhasjustifiedtreatmentwithsuni-tinib,axitinib,everolimus,bevacizumabandpazopanib.
Finally,case22973hadrightnephrectomyage56forachromophobeRCC.
Hereceivedadjuvantradiotherapyformultiple,metastaticretroperitoneallymph-nodesthatcouldnotberemovedsurgically.
Sevenyearslater,therearenoradiologicalorclinicalsignsofdiseaseprogression.
DiscussionOurseriesof33casesisoneofthelargesteverpublished[4-8].
Thisstudyconfirmsthatcasescanhaveeitherunifocaldisease,ormultipletumours,andthatmostrenalcelltumoursareoncocytomasorRCCofchromo-phobeorhybridchromophobe-oncocytomahistology[4-6].
OtherhistologiesarehoweverassociatedwiththeBenusiglioetal.
OrphanetJournalofRareDiseases2014,9:163Page2of6http://www.
ojrd.
com/content/9/1/163syndrome,clearcellinparticular.
Indeed,amongourcases,3(9%)hadclearcellcarcinomas.
GiventhattheyarenottypicalinBHD,allclearcellRCCwerereviewedbyoneofourexpertpathologists,andconfirmationwasobtained.
Thisproportionissimilartowhathasbeenreportedinthepast,andcliniciansshouldthereforeremainalerttothepossibilityofBHDinpatientswithclearcellRCC,especiallyifthereareassociatedmani-festations[6].
Theageatrenalcelltumourdiagnosisvariedbetween20and83,withamedianageof46.
Ofspecialinterestwasthefactthattwopatientspresentedwitharenalcelltumourintheirtwenties,highlightingtheneedforregu-larsurveillancefromanearlyage[12].
Thissurveillanceshouldbecontinuedwithnoupperagelimitandaslongasthepatientsareingoodcondition,asonepatientwithtwotumoursinhiseightieswassuccessfullytreatedbypercutaneousradiofrequencyablation.
Table1Birt-Hogg-DubépatientswithrenaltumoursPatientGenderMutation1strenaltumour,ageNumberofrenaltumoursHistologyOtherBHDmanifestationsDurationofF-U(months)LatestF-Udata11525Mc.
1285dup,p.
His429Profs*2773MultifocalCh,HFF3005/201411528Mc.
1285dup,p.
His429Profs*27832N/AFF,PNO10311/201311545Mc.
1285dup,p.
His429Profs*27391N/ALungcysts6505/201113851Mc.
1285dup,p.
His429Profs*27351(Mt)UndFF22503/2003(D)14381Mc.
755dup,p.
Cys253Valfs*39621CCFF15005/200914840Mc.
1285dup,p.
His429Profs*27201N/AFF,PNO67202/201115842Fc.
828del,p.
Ala277Leufs*16381Ch-17602/201419276Mc.
1062+2T>G562Ch,HFF9605/201119398Fc.
663dup,p.
Met222Aspfs*2642Multifocal(Mt)HPNO11509/201420471Fc.
1285dup,p.
His429Profs*2734MultifocalCh,OFF,PNO24801/201420472Mc.
67G>T,p.
Glu23*431ChPNO13203/201421310Fc.
1198G>A,p.
Val400Ile461(Mt)Ch-9907/201422973Mc.
1523A>G,p.
Lys508Arg561(Mt)ChFF,PNO9603/201425891Fc.
318C>G,p.
Tyr106*251PLungcysts9603/201426016Mc.
1300G>A,p.
Glu434Lys48MultifocalCh,HFF1605/201127674Mc.
616A>T,p.
Lys206*561ChPNO9305/201328190Mc.
1367_1398del,p.
Asp456Glyfs*19531OLungcysts1609/201228535Fc.
1063-2A>G511ChFF,lungcysts7204/201428537Fc.
1300G>A,p.
Glu434Lys472HPNO2002/201428590Mc.
1285dup,p.
His429Profs*27471ChFF,lungcysts1305/201331122Fc.
1285dup,p.
His429Profs*2741MultifocalCCLungcysts,PNO26406/200536616Mc.
1285del,p.
His429Thrfs*39401N/AFF31201/200837644Mc.
958dup,p.
Arg320Profs*70412OFF,PNO607/200837673Mc.
610_611delinsTA,p.
Ala204*44MultifocalCh-907/200840154Fc.
1528_1530del,p.
Glu510del30MultifocalO-N/A02/200940893Mc.
323G>T,p.
Ser108Ile511CCFF,PNO4503/201342207Fc.
1300G>A,p.
Glu434Lys541ChFF,PNO7401/201442337Mc.
1300G>A,p.
Glu434Lys501HFF,lungcysts,PNO6002/201447950Mc.
1458del,p.
Ile486Metfs*544MultifocalOFF2402/201447639Fc.
57_58del,p.
Phe20Leufs*16441HPNO4305/201448746Mc.
1318del,p.
Glu440Argfs*28541ChFF,lungcysts3501/201448781Fc.
1285dup,p.
His429Profs*27551N/AFF,PNO8002/201350335Mc.
958dup,p.
Arg320Profs*7039MultifocalOPNO2406/2014Allpatientswerealiveatlastfollow-up,unlessspecifiedotherwise.
CC,clearcellrenalcellcarcinoma.
Ch,chromophoberenalcellcarcinoma.
D,deceased.
FF,fibrofolliculomas,F-U,follow-up.
H,hybridchromophobe-oncocytomarenalcellcarcinoma.
Mt,metastaticdisease.
N/A,notavailable.
O,oncocytoma.
P,papillaryrenalcellcarcinoma,typeundetermined.
PNO,pneumothorax.
Und,undifferentiated.
Benusiglioetal.
OrphanetJournalofRareDiseases2014,9:163Page3of6http://www.
ojrd.
com/content/9/1/163These33caseswithrenalcelltumoursrepresent27%ofallascertainedBHDpatients(33/124),and34%ofthoseforwhichwehaveevidenceofrenalimaging(33/98).
Thisobservationisremarkablyconsistentwithtwolargestud-iesfromtheUnitedStatesNationalCancerInstitutethatreportedoveralltumourfrequenciesof29%and34%inBHDpatientsevaluatedbyCTscan[4,5].
Weexpecttheproportioninourstudytoberepresentativeofthetruerenalcelltumourriskassociatedwiththesyndrome,asFrenchindexcasesareofferedFLCNgeneticanalysisbecausetheypresentwithalltypesofclinicalmanifesta-tionssuggestiveofBHD.
Anexhaustivedescriptionofextrarenalmanifestationsisbeyondthescopeofthispaper.
Nevertheless,67%and58%ofourcasesalsohadpulmonaryanddermatologicalmanifestationsrespectively,inadditiontoRCC.
ThesefiguresrepresenttheminimalprevalenceaspulmonaryassessmentbyCTscanandexaminationbyadermatologistknowledgeableinthesyndromewasnotsystematic.
Inourseries,fourpatientshadmetastatic,albeitindo-lentRCC.
Comprehensivefamilydatawascollectedforallpatientsinthisseries,andwehavenoknowledgeofotherrelatives(deceasedoralive)withmetastaticRCCwhowerenottestedforFLCNmutations,andwhowerethereforenotincludedinthisstudy.
VeryfewcasesofmetastaticRCCassociatedwithBHDhavebeende-scribed.
Pavlovichetal.
andHouwelingetal.
reportedrespectivelytwoandfivesuchcases;alldiedrapidlyTable2Summaryofclinicalandhistopathologicalcharacteristicsofrenaltumoursamong33patientswithBirt-Hogg-DubéCharacteristicsNumberofpatientsGenderMale21Female12Tumournumber12024Multifocal9TumourhistologyOncocytoma/Chromophobe/Hybridchromophobe-oncocytoma23Clearcell3Papillary(typeundetermined)1Undifferentiated1N/A5Extra-renalmanifestations§Lungcysts/pneumothorax22Fibrofolliculomas19None4§twelvepatientshadbothpulmonaryanddermatologicalmanifestations.
RCC,renalcallcarcinoma.
Figure1MaintypesofrenaltumoursseeninourpatientswithBHD.
Oncocytoma(A),chromophobecarcinoma(B),hybridchromophobe-oncytomacarcinoma(C),andclearcellcarcinoma(D).
Benusiglioetal.
OrphanetJournalofRareDiseases2014,9:163Page4of6http://www.
ojrd.
com/content/9/1/163despitemultidisciplinarymanagementthatincludedsur-gery,radiotherapy,immunotherapyandchemotherapy,andthegoodprognosisassociatedwithmetastaticdiseaseinourstudycontrastswiththeseearlierreports[8,13].
Threeofthefourpatientsreportedherearestillalivemorethanfiveyearsafterthemetastaseswerediagnosed,whilethefourthdiedofunrelatedcausesfouryearsafteralungmetastasishadbeenremoved.
WhethertheseobservationsreflectaspecificbehaviouronlyseeninBHDrequiresfurtherinvestigation.
AnotherhypothesisisthatmetastaticRCCinBHDpatientsismoresensitivetotyrosinekinaseandmTORinhibitorssuchassuniti-nibandeverolimus(tworecently-developeddrugsthatarenowroutinelyusedinthetreatmentofmetastaticRCC),assuggestedforexamplebythemTORsignallingpathwayactivationseeninkidneytumoursassociatedwiththesyndrome,butthatwouldnotaccountforthegoodprognosisofcases13851and22973whoreceivednosystemictreatment[14].
AsshowninTable1,mostpatientsinourstudyarefollowedupmedically,withrelevantinformationbeingcollectedbytheteaminchargeonaregularbasis.
Thereishoweveraminorityfromwhichwehavenotheardinthelastfewyears,andwecannotruleoutwithcertaintythepossibilityofaggressivemetastaticdiseaseinthesepatients.
ConclusionsTheeponymsyndromewasfirstdescribedover35yearsagobyBirt,HoggandDubé[15].
However,theFLCNgenewasonlyidentifiedin2002[16].
Therecentmo-lecularcharacterisationofthesyndrome,addedtothefactthatlikemostgeneticdiseasesBHDisrareinthegeneralpopulation,meansthereareonlylimiteddataonthetopicintheliterature.
Asaresult,thislargeandmulticentricstudywillimproveknowledgeofthesyn-dromeamonggeneticists,urologistsandoncologistsin-volvedintheassessmentandmanagementofpatientswithasuspectedorestablishedgeneticpredispositiontorenalcelltumours.
Itisofutmostimportancetoidentifyindividualswithahighprobabilityofdevelopingrenalcelltumours,sothatthey,andtheirat-riskrelativescanbenefitfrompersonalisedsurveillanceandmanagement.
CompetinginterestsTheauthorsdeclarethattheyhavenocompetinginterests.
Authors'contributionsPRB,SD,AM,JMC,DJ,MOT,CA,DC,DL,MFA,JFCandSRwereinvolvedinthemultidisciplinaryassessementandclinicalmanagementofpatients.
SGperformedFLCNgeneticanalyses.
SFandVVwerethepathologistsofthestudy.
PRBcollectedandanalysedthedata,andwrotethemanuscriptwithsupportfromJFC,SRandJMC.
Allauthorsreadandapprovedthefinalmanuscript.
AcknowledgmentsThisprojectwasfundedbytheLiguenationalecontreleCancer(Comitésdel'IndreetduCher),theMyrovlytisTrust(BHDFoundation)andtheFondationGustaveRoussy.
KamalAchkar,PascalineBerthet,OlivierBinet,VirginieBubien,NaceraBrahimi,OlivierCaron,BertrandCollin,Marie-AgnèsCollonge-Rame,IsabelleCoupier,AlbertDavid,BenedicteDemuynck,YvesDenoux,CatherineDugast,BernardEscudier,ThierryFlam,Jean-MarieFerrière,JeanFriedel,BrigitteGilbert-Dussardier,SophieLejeune-Dumoulin,MichelLongy,GwenaelNadeau,NicolasPoulhalon,OlivierRixe,StanislasRopert,OlivierRouvière,Jean-MichelSalé,AyhanUlusakarya,LaurentYonneau,HélèneZattaraarecontributingcollaborators.
TheyarepartoftheFrenchNationalCancerInstituteInheritedpredispositiontoKidneyCancernetworkandshouldbeacknowledgedassuchintheauthorlist.
WearealsogratefultoHélèneChomarat(Nantes),Jean-FranoisEmile(Boulogne-Billancourt),FranoiseGalateau-Salle(Caen),CatherineMazerolles(Toulouse),andPierreValidire(Paris)whosentusparaffinembeddedtissueuponrequestforpathologicalreview.
Authordetails1CentreExpertNationalCancersRaresPREDIR,HpitalBicêtre,AP-HP,BatimentLasjaunias,78rueduGénéralLeclerc,94275LeKremlinBicêtre,France.
2Consultationd'Oncogénétique,DépartementdeMédecineOncologique,GustaveRoussyCancerCampus,114rueEdouardVaillant,94805Villejuif,France.
3GénétiqueMoléculaireetClinique,HpitalEdouardHerriot,5placed'Arsonval,,69437Lyon,France.
4Serviced'Urologie,HpitaleuropéenGeorges-Pompidou,AP-HP,20rueLeblanc,75908Paris,France.
5UniversitéParis-Descartes,12Ruedel'coledeMédecine,75006Paris,France.
6ServicedeRadiologieAdulte,HpitalNecker-EnfantsMalades,AP-HP,149ruedeSèvres,75743Paris,France.
7ServicedeNéphrologie,HpitalNecker-EnfantsMalades,AP-HP,149ruedeSèvres,75743Paris,France.
8Serviced'AnatomiePathologique,HpitalBicêtre,AP-HP,78rueduGénéralLeclerc,94275LeKremlinBicêtre,France.
9Serviced'AnatomiePathologique,HpitalNecker-EnfantsMalades,AP-HP,149ruedeSèvres,75743Paris,France.
10ServicedeGénétiqueMédicale,CHURennes,16BoulevarddeBulgarie,35203Rennes,France.
11DépartementdeNéphrologieetTransplantationd'Organes,INSERMUMR1048,HpitaldeRangueil,1avenuePoulhès,31059Toulouse,France.
12Départementd'Hématologie,OncogénétiqueetImmunologie,CHUdeGrenoblesiteNord-Institutdebiologieetdepathologie,BoulevarddelaChantourne,38700LaTronche,France.
13ServicedeDermatologie,HpitalCochin,AP-HP,27rueduFaubourgSaint-Jacques,75679Paris,France.
14CentredeRéférencedesMaladiesPulmonairesRares,ServicedePneumologie,HpitalLouisPradel,28avenueduDoyenLépine,69677Lyon,France.
15GénétiqueOncologiqueEPHE,INSERMU743,InstitutdecancérologieGustaveRoussy,94800VillejuifandFacultédeMédecineParis-Sud,94276LeKremlin-Bicêtre,France.
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:RenalcelltumourcharacteristicsinpatientswiththeBirt-Hogg-Dubécancersusceptibilitysyndrome:aretrospective,multicentrestudy.
OrphanetJournalofRareDiseases20149:163.
SubmityournextmanuscripttoBioMedCentralandtakefulladvantageof:ConvenientonlinesubmissionThoroughpeerreviewNospaceconstraintsorcolorgurechargesImmediatepublicationonacceptanceInclusioninPubMed,CAS,ScopusandGoogleScholarResearchwhichisfreelyavailableforredistributionSubmityourmanuscriptatwww.
biomedcentral.
com/submitBenusiglioetal.
OrphanetJournalofRareDiseases2014,9:163Page6of6http://www.
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台湾CN2云服务器 2核2G 5M 5IP 台湾物理服务器 E5x2 64G 20M 5IP
提速啦（www.tisula.com）是赣州王成璟网络科技有限公司旗下云服务器品牌，目前拥有在籍员工40人左右，社保在籍员工30人+，是正规的国内拥有IDC ICP ISP CDN 云牌照资质商家，2018-2021年连续4年获得CTG机房顶级金牌代理商荣誉 2021年赣州市于都县创业大赛三等奖，2020年于都电子商务示范企业，2021年于都县电子商务融合推广大使。资源优势介绍：Ceranetwo...
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