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CLASSIFICATIONARTICLEpublished:22April2014doi:10.3389/\fmmu.2014.00162 - PPT Presentation

PrimaryimmunodefciencydiseasesanupdateontheclassifcationfromtheInternationalUnionofImmunologicalSocietiesExpertCommitteeforPrimaryWaleedAlHerzAzizBousfhaJeanLaurentCasanovaTalalChatilaMaryEl ID: 293825

Primaryimmunode\fciencydiseases:anupdateontheclassi\fcationfromtheInternationalUnionofImmunologicalSocietiesExpertCommitteeforPrimaryWaleedAl-Herz AzizBous\fha Jean-LaurentCasanova TalalChatila MaryEl

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CLASSIFICATIONARTICLEpublished:22April2014doi:10.3389/\fmmu.2014.00162 Primaryimmunode\fciencydiseases:anupdateontheclassi\fcationfromtheInternationalUnionofImmunologicalSocietiesExpertCommitteeforPrimaryWaleedAl-Herz,AzizBous\fha,Jean-LaurentCasanova,TalalChatila,MaryEllenConleyCharlotteCunningham-Rundles,AmosEtzioni,JoseLuisFranco,H.BobbyGaspar10 www.frontiersin.orgApril2014|Volume5|Article162| Al-Herzetal.PIDIUISclassication Table1|Combinedimmunodeciencies. DiseaseGeneticdefect/presumedpathogenesisInheritanceCirculatingTcellsCirculatingBcellsSerumIgAssociatedfeaturesOMIMnumber 1.T�BCseverecombinedimmunodeciency(SCID)(a)gcdeciencyMutationofIL-2RGXLMarkedlydecreasedNormalorincreasedDecreasedMarkedlydecreasedNKcells300400DefectingchainofreceptorsforIL-2,-4,-7,-9,-15,-21(b)JAK3deciencyMutationofJAK3ARMarkedlydecreasedNormalorincreasedDecreasedMarkedlydecreasedNKcells600173DefectinJanus-activatingkinase3(c)IL7RadeciencyMutationofIL7RAARMarkedlydecreasedNormalorincreasedDecreasedNormalNKcells146661DefectinIL-7receptorachain(d)CD45deciencyaMutationofPTPRCARMarkedlydecreasedNormalDecreasedNormalg/dTcells151460DefectinCD45(e)CD3ddeciencyMutationofCD3DARMarkedlydecreasedNormalDecreasedNormalNKcells186790DefectinCD3dchainofTcellantigenreceptorcomplexNog/dTcells(f)CD3+deciencyaMutationofCD3EARMarkedlydecreasedNormalDecreasedNormalNKcells186830DefectinCD3+chainofTcellantigenreceptorcomplexNog/dTcells(g)CD3zdeciencyaMutationofCD3ZARMarkedlydecreasedNormalDecreasedNormalNKcells186740DefectinCD3zchainofTcellantigenreceptorcomplexNog/dTcells(h)Coronin-1AdeciencyaMutationofCORO1AdefectivethymicegressofTcellsanddefectiveTcelllocomotionARMarkedlydecreasedNormalDecreasedDetectablethymusEBVassociatedBcelllymphoproliferation6050002.T�B�SCID(i)DNArecombinationdefects(a)RAG1deciencyMutationofRAG1ARMarkedlydecreasedMarkedlydecreasedDecreased601457DefectiveVDJrecombination;defectofrecombinaseactivatinggene(RAG)1(a)RAG2deciencyMutationofRAG2ARMarkedlydecreasedMarkedlydecreasedDecreased601457DefectiveVDJrecombination;defectofrecombinaseactivatinggene(RAG)2(b)DCLRE1C(artemis)deciencyMutationofARTEMISARMarkedlydecreasedMarkedlydecreasedDecreasedRadiationsensitivity602450DefectiveVDJrecombination;defectinartemisDNArecombinaserepairprotein(c)DNAPKcsdeciencyaMutationofPRKDC-DefectiveVDJrecombination;defectinDNAPKcsARMarkedlydecreasedMarkedlydecreasedDecreasedRadiationsensitivity,microcephaly,anddevelopmentaldefects600899Recombinaserepairprotein(ii)Reticulardysgenesis,AK2deciencyMutationofAK2ARMarkedlydecreasedDecreasedornormalDecreasedGranulocytopeniaanddeafness103020Defectivematurationoflymphoidandmyeloidcells(stemcelldefect)Defectinmitochondrialadenylatekinase2 (Continued) FrontiersinImmunology|PrimaryImmunodecienciesApril2014|Volume5|Article162|2 Al-Herzetal.PIDIUISclassication Table1|Continued DiseaseGeneticdefect/presumedpathogenesisInheritanceCirculatingTcellsCirculatingBcellsSerumIgAssociatedfeaturesOMIMnumber (iii)Adenosinedeaminase(ADA)deciencyMutationofADAabsentADAactivity,elevatedlymphotoxicmetabolites(dATP,S-adenosylhomocysteine)ARAbsentfrombirth(nullmutations)orprogressivedecreaseAbsentfrombirthofprogressivedecreaseProgressivedecreaseDecreasedNKcells,oftenwithcostochondraljunctionaring,neurologicalfeatures,hearingimpairment,lungandlivermanifestations;partialADAdeciencymayleadtodelayedormilderpresentation102700Combinedimmunodecienciesgenerallylessprofoundthanseverecombinedimmunodeciency3.CD40liganddeciencyMutationofCD40LGdefectsinCD40ligand(CD40L;alsocalledTNFSF5orCD154)causedefectiveisotypeswitchingandimpaireddendriticcellsignalingXLNormal;mayprogressivelydecreasesIgMCandsIgDCBcellspresent,othersurfaceisotypepositiveBcellsabsentIgMincreasedornormal,otherisotypesdecreasedNeutropenia,thrombocytopenia;hemolyticanemia,biliarytractandliverdisease,opportunisticinfections3003864.CD40deciencyaMutationofCD40(alsocalledTNFRSF5)defectsinCD40causedefectiveisotypeswitchingandimpaireddendriticcellsignalingARNormalIgMCandIgDCBcellspresent,otherisotypesabsentIgMincreasedornormal,otherisotypesdecreasedNeutropenia,gastrointestinalandliver/biliarytractdisease,opportunisticinfections1095355.Purinenucleosidephosphorylase(PNP)deciencyMutationofPNP,absentPNP,andTcellandneurologicdefectsfromelevatedtoxicmetabolites,especiallydGTPARProgressivedecreaseNormalNormalordecreasedAutoimmunehemolyticanemia,neurologicalimpairment1640506.CD3gdeciencyaMutationofCD3GdefectinCD3g–componentoftheTcellantigenreceptorcomplexARNormal,butreducedTCRexpressionNormalNormal1867407.CD8deciencyaMutationofCD8A,defectsofCD8achain–importantformaturationandfunctionofCD8TcellsARAbsentCD8,normalCD4cellsNormalNormal1869108.ZAP70deciencyMutationinZAP70intracellularsignalingkinase,actsdownstreamofTCRARDecreasedCD8,normalCD4cellsNormalNormalAutoimmunityinsomecases2698409.MHCclassIdeciencyMutationsinTAP1,TAP2,orTAPBP(tapasin)genesgivingMHCclassIdeciencyARDecreasedCD8,normalCD4NormalNormalVasculitis;pyodermagangrenosum60457110.MHCclassIIdeciencyMutationintranscriptionfactorsforMHCclassIIproteins(CIITA,RFX5,RFXAP,RFXANKgenes)ARNormalnumber,decreasedCD4cellsNormalNormalordecreasedFailuretothrive,diarrhea,respiratorytractinfections,liver/biliarytractdisease20992011.ITKdeciencyaMutationsinITKencodingIL-2-inducibleTcellkinaserequiredforTCR-mediatedactivationARProgressivedecreaseNormalNormalordecreasedEBV-associatedBcelllymphoproliferation,lymphoma613011NormalordecreasedIgG (Continued) www.frontiersin.orgApril2014|Volume5|Article162|3 Al-Herzetal.PIDIUISclassication Table1|Continued DiseaseGeneticdefect/presumedpathogenesisInheritanceCirculatingTcellsCirculatingBcellsSerumIgAssociatedfeaturesOMIMnumber 12.SH2D1Adeciency(XLP1)MutationsinSH2D1AencodinganadaptorproteinregulatingintracellularsignalsXLNormalorincreasedactivatedTcellsReducedmemoryBcellsPartiallydefectiveNKcellandCTLcytotoxicactivityClinicalandimmunologicfeaturestriggeredbyEBVinfection:HLH,lymphoproliferation,aplasticanemia,lymphoma308240HypogammaglobulinemiaAbsentiNKTcells13.CartilagehairhypoplasiaMutationsinRMRP(RNaseMRPRNA)involvedinprocessingofmitochondrialRNAandcellcyclecontrolARVariesfromseverelydecreased(SCID)tonormal;impairedlymphocyteproliferationNormalNormalorreduced.antibodiesvariablydecreasedCanpresentjustascombinedimmunodeciencywithoutotherfeaturesofshort-limbeddwarsm250250AlsoseeTable214.MAGT1deciencyaMutationsinMAGT1,impairedMgCCuxleadingtoimpairedTCRsignalingXLDecreasedCD4cellsreducednumbersofRTE,impairedTcellproliferationinresponsetoCD3NormalNormalEBVinfection,lymphoma;viralinfections,respiratory,andGIinfections30071515.DOCK8deciencyMutationsinDOCK8–regulatorofintracellularactinreorganizationARDecreasedimpairedTlymphocyteproliferationDecreased,lowCD27CmemoryBcellsLowIgM,increasedIgELowNKcellswithimpairedfunction,hypereosinophilia,recurrentinfections;severeatopy,extensivecutaneousviralandbacterial(staph.)infections,susceptibilitytocancer24370016.RhoHdeciencyaMutationsinRHOH–anatypicalRhoGTPasetransducingsignalsdownstreamofvariousmembranereceptorsARNormalNormalNormalHPVinfection,lymphoma,lunggranulomas,molluscumcontagiosum602037LownaïveTcellsandRTE,restrictedTcellrepertoireandimpairedTcellsproliferationinresponsetoCD3stimulation17.MST1deciencyMutationsinSTK4–aserine/threoninekinaseARDecreased/increasedproportionofterminaldifferentiatedeffectormemorycells(TEMRA),lownaïveTcells,restrictedTcellrepertoireintheTEMRApopulation,andimpairedTcellsproliferationDecreasedHighRecurrentbacterial,viral,andcandidalinfections;intermittentneutropenia;EBV-drivenlymphoproliferation;lymphoma;congenitalheartdisease,autoimmunecytopenias;HPVinfection614868 (Continued) FrontiersinImmunology|PrimaryImmunodecienciesApril2014|Volume5|Article162|4 Al-Herzetal.PIDIUISclassication Table1|Continued DiseaseGeneticdefect/presumedpathogenesisInheritanceCirculatingTcellsCirculatingBcellsSerumIgAssociatedfeaturesOMIMnumber 18.TCRadeciencyaMutationsinTRAC–essentialcomponentoftheTcellreceptorARNormalallCD3TcellsexpressedTCRgd(ormaybebettertosay:TCRabTcelldeciency),impairedTcellsproliferationNormalNormalRecurrentviral,bacterial,andfungalinfections,immunedysregulationautoimmunity,anddiarrhea61538719.LCKdeciencyaDefectsinLCK–aproximaltyrosinekinasethatinteractswithTCRARNormaltotalnumbersbutCD4CTcelllymphopenia,lowTregnumbers,restrictedTcellrepertoire,andimpairedTCRsignalingNormalNormalIgGandIgAandincreasedIgMDiarrhea,recurrentinfections,immunedysregulationautoimmunity15339020.MALT1deciencyaMutationsinMALT1–acaspase-likecysteineproteasethatisessentialfornuclearfactorkappaBactivationARNormalimpairedTcellsproliferationNormalNormalBacterial,fungal,andviralinfections604860Impairedantibodyresponse21.IL-21RdeciencyaDefectsinIL-21R–togetherwithcommongammachainbindsIL-21ARAbnormalTcellcytokineproduction;abnormalTcellproliferationtospecicstimuliNormalNormalbutimpairedspecicresponsesSusceptibilitytocryptosporidiumandpneumocystisandcholangitis60538322.UNC119deciencyaDefectsinUNC119–anactivatorofsrctyrosinekinasesADLowTcellsMostlylowNormalRecurrentbacterial,fungal,andviralinfections604011CD4CTcelllymphopenia,impairedTCRsignaling23.CARD11deciencyaDefectsinCARD11–actsasascaffoldforNF-kBactivityintheadaptiveimmuneresponseARNormalpredominanceofnaiveTlymphocyte,impairedTcellsproliferationNormalpredominanceoftransitionalBlymphocytesAbsent/lowPneumocystisjirovecipneumonia,bacterialinfections61520624.OX40deciencyaDefectsinOX40–aco-stimulatorymoleculeexpressedonactivatedTcellsARNormalTcellnumbersNormalBcellnumbersNormalKaposi'ssarcoma;impairedimmunitytoHHV8615593Lowlevelsofantigen-specicmemoryCD4CcellsLowerfrequencyofmemoryBcells25.IKBKBdeciencyaDefectsinIKBKB–encodesIkBkinase2acomponentoftheNF-kBpathwayARNormaltotalTcells;absentregulatoryandgdTcells;impairedTCRactivationNormalBcellnumbers;impairedBCRactivationDecreasedRecurrentbacterial,viral,andfungalinfections;clinicalphenotypeofSCID61559226.ActivatedPI3K-dMutationinPIK3CD,PI3K-dADgain-of-functionDecreasedtotalnumbersofTcellsDecreasedtotalperipheralBcellandswitchedmemoryBcells;increasedtransitionalBcellsReducedIgG2andimpairedantibodytopneumococciandhemophilusRespiratoryinfections,bronchiectasis;autoimmunity;chronicEBV,andCMVinfection602839 (Continued) www.frontiersin.orgApril2014|Volume5|Article162|5 Al-Herzetal.PIDIUISclassication Table1|Continued DiseaseGeneticdefect/presumedpathogenesisInheritanceCirculatingTcellsCirculatingBcellsSerumIgAssociatedfeaturesOMIMnumber 27.LRBAdeciencyMutationsinLRBA(lipopolysaccharideresponsivebeige-likeanchorprotein)ARNormalordecreasedCD4numbers;TcelldysregulationLowornormalnumbersofBcellsReducedIIgGandIgAinmostRecurrentinfections,inammatoryboweldisease,autoimmunity;EBVinfections60645328.CD27deciencyaMutationsinCD27,encodingTNF-Rmembersuperfamilyrequiredforgenerationandlong-termmaintenanceofTcellimmunityARNormalNomemoryBcellsHypogammaglobulinemiafollowingEBVinfectionClinicalandimmunologicfeaturestriggeredbyEBVinfection,HLH615122Aplasticanemia,lymphomaHypogammaglobulinemiaLowiNKTcells29.OmennsyndromeHypomorphicmutationsinRAG1,RAG2,artemis,IL7RA,RMRP,ADA,DNAligaseIV,IL-2RG,AK2,orassociatedwithDiGeorgesyndrome;somecaseshavenodenedgenemutationPresent;restrictedTcellrepertoire,andimpairedfunctionNormalordecreasedDecreased,exceptincreasedIgEErythroderma,eosinophilia,adenopathies,hepatosplenomegaly603554 XL,X-linkedinheritance;AR,autosomalrecessiveinheritance;AD,autosomaldominantinheritance;SCID,severecombinedimmunedeciencies;EBV,Epstein–Barrvirus;CaCC,calcium;MHC,majorhistocompatibilitycomplex,RTE,recentthymicemigrants,HPV,humanpapillomavirus.aTenorfewerunrelatedcasesreportedintheliterature.InfantswithSCIDwhohavematernalTcellsengraftmentmayhaveTcellsthatdonotfunctionnormally;thesecellsmaycauseautoimmunecytopeniasorgraftversushostdisease.HypomorphicmutationsinseveralofthegenesthatcauseSCIDmayresultinOmennsyndrome(OS),or“leaky”SCIDoralessprofoundCIDphenotype.BothOSandleakySCIDcanbeassociatedwithhighernumbersofTcellsandreducedratherthanabsentactivationresponseswhencomparedwithtypicalSCIDcausedbynullmutations.AspectrumofclinicalndingsincludingtypicalSCID,OS,leakySCID,granulomaswithTlymphopenia,autoimmunity,andCD4CTlymphopeniacanbefoundwithRAGgenedefects.RAC2deciencyisadisorderofleukocytemotilityandisreportedinTable5;however,onepatientwithRAC2deciencywasfoundtohaveabsentTcellreceptorexcisioncircles(TRECs)bynewbornscreening,butTcellnumbersandmitogenresponseswerenotimpaired.ForadditionalsyndromicconditionswithTcelllymphopenia,suchasDNArepairdefects,cartilagehairhypoplasia,IKAROSdeciency,andNEMOsyndrome,seeTables2and6;however,itshouldbenotedthatindividualswiththemostseveremanifestationsofthesedisorderscouldhaveclinicalsignsandsymptomsofSCID.Severefolatedeciency(suchaswithmalabsorptionduetodefectsinfolatecarrierortransportergenesSLC10A1orPCFT)andsomemetabolicdisorders,suchasmethylmalonicaciduria,maypresentwithreversibleprofoundlymphopeniainadditiontotheircharacteristicpresentingfeatures.immunodeciencieswithsyndromicfeatures,asincreasingnum-bersofthesearebeingidentied.ThetitleandclassicationofTables3–8presentthesamemajorPIDgroupsasinthepreviousreport.Inthisupdatedversion,wehaveaddedanewcategoryinTable9inwhich“PhenocopiesofPID”arelisted.Thishasresultedfromourunderstandingandstudyofconditionsthatpresentasinheritedimmunodeciencies,butwhicharenotduetogermlinemutationsandinsteadarisefromacquiredmechanisms.Examplesincludesomaticmutationsinspecicimmunecellpopulationsthatgiverisetothephenotypeofautoimmunelymphoprolifer-ativesyndrome(ALPS),andalsoautoantibodiesagainstspeciccytokinesorimmunologicalfactors,withdepletionofthesefactorsleadingtoimmunodeciency.ItislikelythatincreasingnumbersofPIDphenocopieswillbeidentiedinthefuture,andthismaybethestartofamuchlongertable.Aswithallcomplexdiseases,anyclassicationcannotbestrictlyadheredto.Certainconditionsfallintomorethanonecategoryandsoappearinmorethanonetable.Forexample,CD40LliganddeciencyisreportedinbothTables1and3asitwasinitiallyidentiedasadefectofBcellisotypeswitchingbutisnowknowntobeadefectofco-stimulatoryTcellhelpandfunction.Similarly,XLP1duetodefectsinSH2D1AislistedinTable1–combinedimmunodeciencies,duetodefectsofTcellcytotoxicity,Tcellhelp,andBcellmaturation,butalsoinTable4–diseasesofimmunedysregulation,duetothesusceptibilitytohemophago-cytosis.Thereisagrowingappreciationthattherecanbewidephenotypicviabilitywithinaspecicgenotypethatisaprod-uctofvariedspecicmutationsbetweendifferentpatientsaswellasotherhostand/orenvironmentalfactors.Thecomplexitiesoftheseconditionsintermsofclinicalandimmunologicalpresen-tationandheterogeneitycannotbeeasilycapturedinthelimitedspaceofatableformat.Forthisreason,thefurthestleftcolumncontainstheOnlineMendelianInheritanceinMan(OMIM)ref-erenceforeachconditiontoallowaccesstogreaterdetailandupdatedinformation. FrontiersinImmunology|PrimaryImmunodecienciesApril2014|Volume5|Article162|6 Al-Herzetal.PIDIUISclassication Table2|Combinedimmunodeciencieswithassociatedorsyndromicfeatures. DiseaseGeneticdefect/presumedpathogenesisInheritanceCirculatingTcellsCirculatingBcellsSerumIgAssociatedfeaturesOMIMnumber 1.Congenitalthrombocytopenia(a)Wiskott–Aldrichsyndrome(WAS)MutationsinWAS;cytoskeletal,andimmunologicsynapsedefectaffectinghematopoieticstemcellderivativesXLProgressivedecrease,abnormallymphocyteresponsestoanti-CD3NormalDecreasedIgM:antibodytopolysaccha-ridesparticularlydecreased;oftenincreasedIgAandIgEThrombocytopeniawithsmallplatelets;eczema;lymphoma;autoimmunedisease;IgAnephropathy;bacterialandviralinfections.XLthrombocytopeniaisamildformofWAS,andXLneutropeniaiscausedbymissensemutationsintheGTPasebindingdomainofWASP301000(b)WIPdeciencyaMutationsinWIPF1;cytoskeletalandimmunologicsynapsedefectaffectinghematopoieticstemcellderivativesARReduced,defectivelymphocyteresponsestoanti-CD3LowNormal,exceptforincreasedIgERecurrentinfections;eczema;thrombocytopenia.WAS-likephenotype6144932.DNArepairdefects(otherthanthoseinTable1)(a)Ataxia–telangiectasiaMutationsinATM;disorderofcellcyclecheckpoint;andDNAdouble-strandbreakrepairARProgressivedecreaseNormalOftendecreasedIgA,IgE,andIgGsubclasses;increasedIgMmonomers;antibodiesvariablydecreasedAtaxia;telangiectasia;pulmonaryinfections;lymphoreticularandothermalignancies;increasedalphafetoproteinandincreasedradiosensitivity;chromosomalinstability208900(b)Ataxia–telangiectasia-likedisease(ATLD)aHypomorphicmutationsinMRE11;disorderofcellcyclecheckpointandDNAdouble-strandbreakrepairARProgressivedecreaseNormalAntibodiesvariablydecreasedModerateataxia;pulmonaryinfections;severelyincreasedradiosensitivity604391(c)NijmegenbreakagesyndromeHypomorphicmutationsinNBS1(Nibrin);disorderofcellcyclecheckpointandDNAdouble-strandbreakrepairARProgressivedecreaseVariablyreducedOftendecreasedIgA,IgE,andIgGsubclasses;increasedIgM;antibodiesvariablydecreasedMicrocephaly;bird-likeface;lymphomas;solidtumors;increasedradiosensitivity;chromosomalinstability251260(d)BloomsyndromeMutationsinBLM;RecQ-likehelicaseARNormalNormalReducedShortstature;bird-likeface;sun-sensitiveerythema;marrowfailure;leukemia;lymphoma;chromosomalinstability210900 (Continued) www.frontiersin.orgApril2014|Volume5|Article162|7 Al-Herzetal.PIDIUISclassication Table2|Continued DiseaseGeneticdefect/presumedpathogenesisInheritanceCirculatingTcellsCirculatingBcellsSerumIgAssociatedfeaturesOMIMnumber (e)Immunode-ciencywithcentromericinstabilityandfacialanomalies(ICF)MutationsinDNAmethyltransferaseDNMT3B(ICF1)resultingindefectiveDNAmethylationARDecreasedornormal;responsestoPHAmaybedecreasedDecreasedornormalHypogammaglobulinemia;variableantibodydeciencyFacialdysmorphicfeatures;macroglossia;bacterial/opportunisticinfections;malabsorption;cytopenias;malignancies;multiradialcongurationsofchromosomes1,9,16;noDNAbreaks242860(f)Immunode-ciencywithcentromericinstabilityandfacialanomalies(ICF)MutationsinZBTB24(ICF2)ARDecreasedornormal;responsestoPHAmaybedecreasedDecreasedornormalHypogammaglobulinemia;variableantibodydeciencyFacialdysmorphicfeatures;macroglossia;bacterial/opportunisticinfections;malabsorption;cytopenias;malignancies;multiradialcongurationsofchromosomes1,9,16242860(g)PMS2deciencyMutationsinPMS2,resultinginclassswitchrecombinationdeciencyduetoimpairedmismatchrepairARNormalSwitchedandnon-switchedBcellsarereducedLowIgGandIgA,elevatedIgM,abnormalantibodyresponsesRecurrentinfections;café-au-laitspots;lymphoma,colorectalcarcinoma,braintumor600259(h)RNF168deciencyaMutationsinRNF168,resultingindefectiveDNAdouble-strandbreakrepairARNormalNormalLowIgGorlowIgAShortstature;mildmotorcontroltoataxiaandnormalintelligencetolearningdifculties;mildfacialdysmorphismtomicrocephaly;increasedradiosensitivity611943(i)MCM4deciencyMutationsinMCM4(minichromosomemaintenancecomplexcomponent4)geneinvolvedinDNAreplicationandrepairARNormalNormalNormalViralinfections(EBV,HSV,VZV)AdrenalfailureShortstature6099813.Thymicdefectswithadditionalcongenitalanomalies(a)DiGeorgeanomalyContiguousgenedefectin90%affectingthymicdevelopment;mayalsobeduetoheterozygousmutationinTBX1(chromosome22q11.2deletionorTBX1haploinsufcientsyndrome)Denovodefect(majority)orADDecreasedornormal;5%have1500CD3Tcells/mLNormalNormalordecreasedHypoparathyroidism,conotruncalmalformation;abnormalfacies;largedeletion(3Mb)in22q11.2(orrarelyadeletionin10p)188400 (Continued) FrontiersinImmunology|PrimaryImmunodecienciesApril2014|Volume5|Article162|8 Al-Herzetal.PIDIUISclassication Table2|Continued DiseaseGeneticdefect/presumedpathogenesisInheritanceCirculatingTcellsCirculatingBcellsSerumIgAssociatedfeaturesOMIMnumber (b)CHARGEsyndromeVariabledefectsofthethymusandassociatedTcellabnormalitiesoftenduetodeletionsormutationsinCHD7,SEMA3E,orasyetunknowngenesDenovodefect(majority)orADDecreasedornormal;somehave1500CD3Tcells/mLNormalNormalordecreasedColoboma,heartanomaly,choanalatresia,retardation,genitalandearanomalies2148006088924.Immune-osseousdysplasias(a)CartilagehairhypoplasiaMutationsinRMRP(RNaseMRPRNA)involvedinprocessingofmitochondrialRNAandcellcyclecontrolARVariesfromseverelydecreased(SCID)tonormal;impairedlymphocyteproliferationNormalNormalorreduced.AntibodiesvariablydecreasedShort-limbeddwarsmwithmetaphysealdysostosis,sparsehair,bonemarrowfailure,autoimmunity,susceptibilitytolymphomaandothercancers,impairedspermatogenesis,neuronaldysplasiaoftheintestine250250(b)SchimkesyndromeMutationsinSMARCAL1involvedinchromatinremodelingARDecreasedNormalNormalShortstature,spondiloepiphysealdysplasia,intrauterinegrowthretardation,nephropathy;bacterial,viral,andfungalinfections;maypresentasSCID;bonemarrowfailure2429005.Hyper-IgEsyndromes(HIES)(a)AD-HIES(Job'ssyndrome)Dominant-negativeheterozygousmutationsinSTAT3ADOftendenovodefectNormalTh-17andTfollicularhelpercellsdecreasedNormalSwitchedandnon-switchedmemoryBcellsarereduced;BAFFlevelincreasedElevatedIgE;specicantibodyproductiondecreasedDistinctivefacialfeatures(broadnasalbridge),eczema,osteoporosis,andfractures,scoliosis,delayofsheddingprimaryteeth,hyperextensiblejoints,bacterialinfections(skinandpulmonaryabscesses,pneumatoceles)duetoStaphylococcusaureus,candidiasis,aneurysmformation147060(i)Tyk2deciencyaMutationinTYK2ARNormal,butmultiplecytokinesignalingdefectNormal()ElevatedIgESusceptibilitytointracellularbacteria(Mycobacteria,Salmonella),fungi,andviruses611521 (Continued) www.frontiersin.orgApril2014|Volume5|Article162|9 Al-Herzetal.PIDIUISclassication Table2|Continued DiseaseGeneticdefect/presumedpathogenesisInheritanceCirculatingTcellsCirculatingBcellsSerumIgAssociatedfeaturesOMIMnumber (ii)DOCK8deciencyMutationsinDOCK8–regulatorofintracellularactinreorganizationARDecreasedimpairedTlymphocyteproliferationDecreased,lowCD27CmemoryBcellsLowIgM,increasedIgELowNKcellswithimpairedfunction,hypereosinophilia,recurrentinfections;severeatopy,extensivecutaneousviralandbacterial(staph.)infections,susceptibilitytocancer2437006.Dyskeratosiscongenital(DKC)(a)XL-DKCMutationsindyskerin(DKC1)(Hoyeraal–Hreidarssonsyndrome)XLProgressivedecreaseProgressivedecreaseVariableIntrauterinegrowthretardation,microcephaly,naildystrophy,recurrentinfections,digestivetractinvolvement,pancytopenia,reducednumberandfunctionofNKcells305000(b)AR-DKCduetoNHP2deciencyMutationinNOLA2(NHP2)ARDecreasedVariableVariablePancytopenia,sparsescalphairandeyelashes,prominentperiorbitaltelangiectasia,andhypoplastic/dysplasticnails613987(c)AR-DKCduetoNOP10deciencyMutationinNOLA3(NOP10PCFT)ARDecreasedVariableVariablePancytopenia,sparsescalphairandeyelashes,prominentperiorbitaltelangiectasia,andhypoplastic/dysplasticnails224230(d)AR-DKCduetoRTEL1deciencyMutationin(RTEL1)ARDecreasedVariableVariablePancytopenia,sparsescalphairandeyelashes,prominentperiorbitaltelangiectasia,andhypoplastic/dysplasticnails608833(e)AD-DKCduetoTERCdeciencyMutationinTERCADVariableVariableVariableReticularhyperpigmentationoftheskin,dystrophicnails,osteoporosispremalignantleukokeratosisofthemouthmucosa,palmarhyperkeratosis,anemia,pancytopenia127550 (Continued) FrontiersinImmunology|PrimaryImmunodecienciesApril2014|Volume5|Article162|10 Al-Herzetal.PIDIUISclassication Table2|Continued DiseaseGeneticdefect/presumedpathogenesisInheritanceCirculatingTcellsCirculatingBcellsSerumIgAssociatedfeaturesOMIMnumber (f)AD-DKCduetoTERTdeciencyMutationinTERTADVariableVariableVariableReticularhyperpigmentationoftheskin,dystrophicnails,osteoporosispremalignantleukokeratosisofthemouthmucosa,palmarhyperkeratosis,anemia,pancytopenia614742(g)AD-DKCduetoTINF2deciencyMutationinTINF2ADVariableVariableVariableReticularhyperpigmentationoftheskin,dystrophicnails,osteoporosispremalignantleukokeratosisofthemouthmucosa,palmarhyperkeratosis,anemia,pancytopenia6139907.DefectsofvitaminB12andfolatemetabolism(a)TCN2deciencyMutationinTCN2;encodestranscobalamin,atransporterofcobalaminintobloodcellsARNormalVariableDecreasedMegaloblasticanemia,pancytopenia,untreatedforprolongedperiodsresultsinmentalretardation275350(b)SLC46A1deciencyMutationinSLC46A1;aprotoncoupledfolatetransporterARVariablenumbersandactivationproleVariableDecreasedMegaloblasticanemia,failuretothriveuntreatedforprolongedperiodsresultsinmentalretardation229050(c)MTHFD1adeciencyMutationsinMTHFD1;essentialforprocessingofsingle-carbonfolatederivativesARLowLowDecreasedMegaloblasticanemia,failuretothriveneutropenia,seizures,mentalretardation8.Comel–NethertonsyndromeMutationsinSPINK5resultinginlackoftheserineproteaseinhibitorLEKTI,expressedinepithelialcellsARNormalSwitchedandnon-switchedBcellsarereducedElevatedIgEandIgACongenitalichthyosis,bamboohair,atopicdiathesis,increasedbacterialinfections,failuretothrive256500Antibodyvariablydecreased9.Wingedhelixdeciency(Nude)aDefectsinforkheadboxN1transcriptionfactorencodedbyFOXN1ARMarkedlydecreasedNormalDecreasedAlopecia,abnormalthymicepithelium,impairedTcellmaturation60083810.ORAI-IdeciencyaMutationinORAI1,aCaCCrelease-activatedchannel(CRAC)modulatorycomponentARNormalnumber,butdefectiveTCR-mediatedactivationNormalNormalAutoimmunity,anhydroticectodermicdysplasia,non-progressivemyopathydefectiveTCR-mediatedactivation610277 (Continued) www.frontiersin.orgApril2014|Volume5|Article162|11 Al-Herzetal.PIDIUISclassication Table2|Continued DiseaseGeneticdefect/presumedpathogenesisInheritanceCirculatingTcellsCirculatingBcellsSerumIgAssociatedfeaturesOMIMnumber 11.STIM1deciencyaMutationsinSTIM1,astromalinteractionmolecule1ARNormalnumber,butdefectiveTCR-mediatedactivationNormalNormalAutoimmunity,anhydroticectodermaldysplasia,non-progressivemyopathydefectiveTCR-mediatedactivation60592112.STAT5bdeciencyaMutationsinSTAT5B,signaltransducer,andtranscriptionfactor,essentialfornormalsignalingfromIL-2and15,keygrowthfactorsforTandNKcellsARModestlydecreasedNormalNormalGrowth-hormoneinsensitivedwarsm245590DysmorphicfeaturesEczemaLymphocyticinterstitialpneumonitis,autoimmunity13.Hepaticveno-occlusivediseasewithimmunode-ciency(VODI)MutationsinSP110ARNormal(decreasedmemoryTcells)Normal(decreasedmemoryBcells)DecreasedIgG,IgA,IgM,absentgerminalcenters,absenttissueplasmacellsHepaticveno-occlusivedisease;Pneumocystisjirovecipneumonia;susceptibilitytoCMV,Candida;thrombocytopenia;hepatosplenomegaly23555014.IKAROSdeciencyaMutationinIKAROSADdenovoNormal,butimpairedlymphocyteproliferationAbsentPresumablydecreasedAnemia,neutropenia,thrombocytopeniaNotassigned15.FILSsyndromeaMutationinPOLE1;defectiveDNAreplicationARLownaïveTcells;decreasedTcellproliferationLowmemoryBcellsDecreasedIgMandIgG;lackofantibodiestopolysaccha-rideantigensMildfacialdysmorphism(malarhypoplasia,highforehead),livedo,shortstature;recurrentupperandlowerrespiratorytractinfections,recurrentpulmonaryinfections,andrecurrentmeningitis61513916.Immunode-ciencywithmultipleintestinalatresiasMutationinTTC7A[tetratricopeptiderepeat(TPR)domain7A]proteinofunknownfunctionARVariable,butsometimesabsentNormalDecreasedMultipleintestinalatresias,oftenwithintrauterinepolyhydramniosandearlydemise;somewithSCIDphenotype243150 SCID,severecombinedimmunedeciencies;XL,X-linkedinheritance;AR,autosomalrecessiveinheritance;AD,autosomaldominantinheritance;MSMD,Mendeliansusceptibilityofmycobacterialdisease.aTenorfewerunrelatedcasesreportedintheliterature.TandBcellnumberandfunctioninthesedisordersexhibitawiderangeofabnormality;themostseverelyaffectedcasesmeetdiagnosticcriteriaforSCIDorleakySCIDandrequireimmunesystemrestoringtherapysuchasallogeneichematopoieticcelltransplantation.WhilenotallDOCK8-decientpatientshaveelevatedserumIgE,mosthaverecurrentviralinfectionsandmalignanciesasaresultofcombinedimmunodeciency.AR-HIESduetoTyk2deciencyisalsolistedinTable6,becauseofitsassociationwithatypicalmycobacterialdiseaseresultinginMSMD.RiddlesyndromeiscausedbymutationsinageneinvolvedinDNAdouble-strandbreakrepairandisassociatedwithhypogammaglobulinemia.Autosomaldominantandautosomalrecessiveformsofdyskeratosiscongenitaareincludedinthistable.IKAROS-deciencyrepresentsasingleprematurelyborninfantwhodiedattheageof87daysandwhohadabsentBandNKcellsandnon-functionalTcells. FrontiersinImmunology|PrimaryImmunodecienciesApril2014|Volume5|Article162|12 Al-Herzetal.PIDIUISclassication Table3|Predominantlyantibodydeciencies. DiseaseGeneticdefect/presumedpathogenesisInheritanceSerumIgAssociatedfeaturesOMIMnumber 1.SeverereductioninallserumimmunoglobulinisotypeswithprofoundlydecreasedorabsentBcells(a)BTKdeciencyMutationsinBTK,acytoplasmictyrosinekinaseactivatedbycrosslinkingoftheBCRXLAllisotypesdecreasedinmajorityofpatients;somepatientshavedetectableimmunoglobulinsSeverebacterialinfections;normalnumbersofpro-Bcells300300(b)mHeavychaindeciencyMutationsinmheavychain;essentialcomponentofthepre-BCRARAllisotypesdecreasedSeverebacterialinfections;normalnumbersofpro-Bcells147020(c)l5DeciencyaMutationsinl5;partofthesurrogatelightchaininthepre-BCRARAllisotypesdecreasedSeverebacterialinfections;normalnumbersofpro-Bcells146770(d)IgadeciencyaMutationsinIga(CD79a);partofthepre-BCRandBCRARAllisotypesdecreasedSeverebacterialinfections;normalnumbersofpro-Bcells112205(e)IgbdeciencyaMutationsinIgb(CD79b);partofthepre-BCRandBCRARAllisotypesdecreasedSeverebacterialinfections;normalnumbersofpro-Bcells147245(f)BLNKdeciencyaMutationsinBLNK;ascaffoldproteinthatbindstoBTKARAllisotypesdecreasedSeverebacterialinfections;normalnumbersofpro-Bcells604615(g)PI3kinasedeciencyaMutationsinPIK3R1;akinaseinvolvedinsignaltransductioninmultiplecelltypesARAllisotypesdecreasedSeverebacterialinfections;decreasedorabsentpro-Bcells171833(h)E47transcriptionfactordeciencyaMutationsinTCF3;atranscriptionfactorrequiredforcontrolofBcelldevelopmentADAllisotypesdecreasedRecurrentbacterialinfections147141(i)Myelodysplasiawithhypogamma-globulinemiaMayhavemonosomy7,trisomy8,ordyskeratosiscongenitaVariableOneormoreisotypesmaybedecreasedInfections;decreasednumberofpro-BcellsNotassigned(j)ThymomawithimmunodeciencyUnknownNoneOneormoreisotypesmaybedecreasedBacterialandopportunisticinfections;autoimmunity;decreasednumberofpro-BcellsNotassigned2.SeverereductioninatleasttwoserumimmunoglobulinisotypeswithnormalorlownumberofBcells(a)CommonvariableimmunodeciencydisordersUnknownVariableLowIgGandIgAand/orIgMClinicalphenotypesvary:mosthaverecurrentinfections,somehavepolyclonallymphoproliferation,autoimmunecytopenias,and/orgranulomatousdiseaseNotassigned(b)ICOSdeciencyaMutationsinICOS;aco-stimulatorymoleculeexpressedonTcellsARLowIgGandIgAand/orIgMRecurrentinfections;autoimmunity,gastroenteritis,granulomainsome604558(c)CD19deciencyaMutationsinCD19;transmembraneproteinthatampliessignalthroughBCRARLowIgGandIgAand/orIgMRecurrentinfections;mayhaveglomerulonephritis107265(d)CD81deciencyaMutationsinCD81;transmembraneproteinthatampliessignalthroughBCRARLowIgG,lowornormalIgAandIgMRecurrentinfections;mayhaveglomerulonephritis186845 (Continued) www.frontiersin.orgApril2014|Volume5|Article162|13 Al-Herzetal.PIDIUISclassication Table3|Continued DiseaseGeneticdefect/presumedpathogenesisInheritanceSerumIgAssociatedfeaturesOMIMnumber (e)CD20deciencyaMutationsinCD20;aBcellsurfacereceptorinvolvedinBcelldevelopmentandplasmacelldifferentiationARLowIgG,normalorelevatedIgMandIgARecurrentinfections112210(f)CD21deciencyaMutationsinCD21;alsoknownascomplementreceptor2andformspartoftheCD19complexARLowIgG;impairedanti-pneumococcalresponseRecurrentinfections614699(g)TACIdeciencyMutationsinTNFRSF13B(TACI);aTNFreceptorfamilymemberfoundonBcellsandisareceptorforBAFFandAPRILADorARorcomplexLowIgGandIgAand/orIgMVariableclinicalexpression604907(h)LRBAdeciencyMutationsinLRBA(lipopolysaccharideresponsivebeige-likeanchorprotein)ARReducedIIgGandIgAinmostRecurrentinfections,inammatoryboweldisease,autoimmunity;EBVinfections606453(i)BAFFreceptordeciencyaMutationsinTNFRSF13C(BAFF-R);aTNFreceptorfamilymemberfoundonBcellsandisareceptorforBAFFARLowIgGandIgMVariableclinicalexpression606269(j)TWEAKaMutationsinTWEAKADLowIgMandIgA;lackofanti-pneumococcalantibodyPneumonia,bacterialinfections,warts;thrombocytopenia.neutropenia602695(k)NFKB2deciencyaMutationsinNFKB2;anessentialcomponentofthenon-canonicalNF-kBpathwayADLowIgGandIgAandIgMRecurrentinfections615577(l)Warts,hypogam-maglobulinemia,infections,myelokathexis(WHIM)syndromeGain-of-functionmutationsofCXCR4,thereceptorforCXCL12ADPanhypogammaglobulinemia,decreasedBcellsWarts/humanpapillomavirus(HPV)infectionNeutropeniaReducedBcellnumberHypogammaglobulinemia1936703.SeverereductioninserumIgGandIgAwithnormal/elevatedIgMandnormalnumbersofBcells(a)CD40LdeciencyMutationsinCD40LG(alsocalledTNFSF5orCD154)XLIgGandIgAdecreased;IgMmaybenormalorincreased;BcellnumbersmaybenormalorincreasedBacterialandopportunisticinfections,neutropenia,autoimmunedisease300386(b)CD40deciencyaMutationsinCD40(alsocalledTNFRSF5)ARLowIgGandIgA;normalorraisedIgMBacterialandopportunisticinfections,neutropenia,autoimmunedisease109535(c)AIDdeciencyMutationsinAICDAgeneARIgGandIgAdecreased;IgMincreasedBacterialinfections,enlargedlymphnodes,andgerminalcenters605257(d)UNGdeciencyMutationsinUNGARIgGandIgAdecreased;IgMincreasedEnlargedlymphnodesandgerminalcenters1915254.IsotypeorlightchaindeciencieswithgenerallynormalnumbersofBcells(a)IgheavychainmutationsanddeletionsMutationorchromosomaldeletionat14q32AROneormoreIgGand/orIgAsubclassesaswellasIgEmaybeabsentMaybeasymptomaticNotassigned (Continued) FrontiersinImmunology|PrimaryImmunodecienciesApril2014|Volume5|Article162|14 Al-Herzetal.PIDIUISclassication Table3|Continued DiseaseGeneticdefect/presumedpathogenesisInheritanceSerumIgAssociatedfeaturesOMIMnumber (b)kChaindeciencyaMutationsinKappaconstantgeneARAllimmunoglobulinshavelambdalightchainAsymptomatic147200(c)IsolatedIgGsubclassdeciencyUnknownVariableReductioninoneormoreIgGsubclassUsuallyasymptomatic;aminoritymayhavepoorantibodyresponsetospecicantigensandrecurrentviral/bacterialinfectionsNotassigned(d)IgAwithIgGsubclassdeciencyUnknownVariableReducedIgAwithdecreaseinoneormoreIgGsubclassRecurrentbacterialinfectionsNotassigned(e)PRKCddeciencyaMutationinPRKCD;encodingamemberoftheproteinkinaseCfamilycriticalforregulationofcellsurvival,proliferation,andapoptosisARLowIgGlevels;IgAandIgMabovethenormalrangeRecurrentinfections;EBVchronicinfectionLymphoproliferationSLE-likeautoimmunity(nephroticandantiphospholipidsyndromes)615559(f)ActivatedPI3K-dMutationinPIK3CD,PI3K-dADgain-of-functionReducedIgG2andimpairedantibodytopneumococciandhemophilusRespiratoryinfections,bronchiectasis;autoimmunity;chronicEBV,CMVinfection602839(g)SelectiveIgAdeciencyUnknownVariableIgAdecreased/absentUsuallyasymptomatic;mayhaverecurrentinfectionswithpoorantibodyresponsestocarbohydrateantigens;mayhaveallergiesorautoimmunedisease.AveryfewcasesprogresstoCVID,otherscoexistwithCVIDinthefamily1371005.SpecicantibodydeciencywithnormalIgconcen-trationsandnormalnumbersofBcellsUnknownVariableNormalReducedabilitytoproduceantibodiestospecicantigensNotassigned6.Transienthypogammaglobu-linemiaofinfancywithnormalnumbersofBcellsUnknownVariableIgGandIgAdecreasedNormalabilitytoproduceantibodiestovaccineantigens,usuallynotassociatedwithsignicantinfectionsNotassigned XL,X-linkedinheritance;AR,autosomalrecessiveinheritance;AD,autosomaldominantinheritance;BTK,Brutontyrosinekinase;BLNK,Bcelllinkerprotein;AID,activation-inducedcytidinedeaminase;UNG,uracil-DNAglycosylase;ICOS,induciblecostimulator;Ig(k),immunoglobulinorklightchaintype.aTenorfewerunrelatedcasesreportedintheliterature.SeveralautosomalrecessivedisordersthatmightpreviouslyhavebeencalledCVIDhavebeenaddedtoTable3.CD81isnormallyco-expressedwithCD19onthesurfaceofBcells.AsforCD19mutations,mutationsinCD81resultinnormalnumbersofperipheralbloodBcells,lowserumIgG,andanincreasedincidenceofglomerulonephritis.SinglepatientwithahomozygousmutationinCD20andCD21hasbeenreported.Commonvariableimmunodeciencydisorders(CVID)includeseveralclinicalandlaboratoryphenotypesthatmaybecausedbydistinctgeneticand/orenviron-mentalfactors.SomepatientswithCVIDandnoknowngeneticdefecthavemarkedlyreducednumbersofBcellsaswellashypogammaglobulinemia.AlterationsinTNFRSF13B(TACI)andTNFRSF13C(BAFF-R)sequencesmayrepresentdisease-modifyingmutationsratherthandiseasecausingmutations.CD40LandCD40deciencyareincludedinTable1aswellasthistable.AsmallminorityofpatientswithXLP(Table4),WHIMsyndrome(Table6),ICF(Table2),VOD1(Table2),thymomawithimmunodeciency(Goodsyndrome),ormyelodysplasiaarerstseenbyanimmunologistbecauseofrecurrentinfections,hypogammaglobulinemia,andnormalorreducednumbersofBcells.PatientswithGATA2mutations(Table5)mayhavemarkedlyreducednumbersofBcells,aswellasdecreasedmonocytesandNKcells,andapredispositiontomyelodysplasiabuttheydonotusuallyhaveanantibodydeciency. www.frontiersin.orgApril2014|Volume5|Article162|15 Al-Herzetal.PIDIUISclassication Table4|Diseasesofimmunedysregulation. DiseaseGeneticdefect/presumedpathogenesisInheritanceCirculatingTcellsCirculatingBcellsFunctionaldefectAssociatedfeaturesOMIMnumber 1.Familialhemophagocyticlymphohistiocytosis(FHL)syndromes1.1FHLsyndromeswithouthypopigmentation(a)Perforindeciency(FHL2)MutationsinPRF1;perforinisamajorcytolyticproteinARIncreasedactivatedTcellsNormalDecreasedtoabsentNKandCTLactivities(cytotoxicity)Fever,hepatosplenomegaly(HSMG),hemophagocyticlymphohistiocytosis(HLH),cytopenias603553(b)UNC13D/Munc13-4deciency(FHL3)MutationsinUNC13Da;requiredtoprimevesiclesforfusionARIncreasedactivatedTcellsNormalDecreasedtoabsentNKandCTLactivities(cytotoxicityand/ordegranulation)Fever,HSMG,HLH,cytopenias608898(c)Syntaxin11deciency(FHL4)MutationsinSTX11,requiredforsecretoryvesiclefusionwiththecellmembraneARIncreasedactivatedTcellsNormalDecreasedNKactivity(cytotoxicityand/ordegranulation)Fever,HSMG,HLH,cytopenias603552(d)STXBP2/Munc18-2deciency(FHL5)MutationsinSTXBP2,requiredforsecretoryvesiclefusionwiththecellmembraneARIncreasedactivatedTcellsNormalDecreasedNKandCTLactivities(cytotoxicityand/ordegranulation)Fever,HSMG,HLH,cytopenias6131011.2.FHLsyndromeswithhypopigmentation(a)Chediak–HigashisyndromeMutationsinLYSTImpairedlysosomaltrafckingARIncreasedactivatedTcellsNormalDecreasedNKandCTLactivities(cytotoxicityand/ordegranulation)Partialalbinism214500Recurrentinfections,feverHSMG,HLHGiantlysosomes,neutropenia,cytopeniasBleedingtendencyProgressiveneurologicaldysfunction(b)Griscellisyndrome,type2MutationsinRAB27AencodingaGTPasethatpromotesdockingofsecretoryvesiclestothecellmembraneARNormalNormalDecreasedNKandCTLactivities(cytotoxicityand/ordegranulation)Partialalbinism,fever,HSMG,HLH,cytopenias607624(c)Hermansky–Pudlaksyndrome,type2MutationsinAP3B1gene,encodingforthebsubunitoftheAP-3complexARNormalNormalDecreasedNKandCTLactivities(cytotoxicityand/ordegranulation)Partialalbinism608233RecurrentinfectionsPulmonarybrosisIncreasedbleedingNeutropeniaHLH2.Lymphoproliferativesyndromes(a)SH2D1Adeciency(XLP1)MutationsinSH2D1AencodinganadaptorproteinregulatingintracellularsignalingXLNormalorincreasedactivatedTcellsReducedmemoryBcellsPartiallydefectiveNKcellandCTLcytotoxicactivityClinicalandimmunologicalfeaturestriggeredbyEBVinfection:HLH308240Lymphoproliferation,aplasticanemia,lymphomaHypogammaglobulinemiaAbsentiNKTcells (Continued) FrontiersinImmunology|PrimaryImmunodecienciesApril2014|Volume5|Article162|16 Al-Herzetal.PIDIUISclassication Table4|Continued DiseaseGeneticdefect/presumedpathogenesisInheritanceCirculatingTcellsCirculatingBcellsFunctionaldefectAssociatedfeaturesOMIMnumber (b)XIAPdeciency(XLP2)MutationsinXIAP/BIRC4encodinganinhibitorofapoptosisXLNormalorincreasedactivatedTcells;low/normaliNKTcellsNormalorreducedmemoryBcellsIncreasedTcellssusceptibilitytoapoptosistoCD95andenhancedactivation-inducedcelldeath(AICD)EBVinfection,splenomegaly,lymphoproliferationHLH,colitis,IBD,hepatitisLowiNKTcells300635(c)ITKdeciencyaMutationsinITKencodingIL-2inducibleTcellkinaserequiredforTCR-mediatedactivationARProgressivedecreaseNormalDecreasedTcellactivationsEBV-associatedBcelllymphoproliferation,lymphoma613011NormalordecreasedIgG(d)CD27deciencyaMutationsinCD27,encodingTNF-Rmembersuperfamilyrequiredforgenerationandlong-termmaintenanceofTcellimmunityARNormalNomemoryBcellsLowTandNKcellsfunctionsClinicalandimmunologicalfeaturestriggeredbyEBVinfection:HLH615122Aplasticanemia,lymphoma,hypogammaglobulinemiaLowiNKTcells3.GeneticdefectsofregulatoryTcells(a)IPEX,immunedysregulation,polyen-docrinopathy,enteropathyX-linkedMutationsinFOXP3,encodingaTcelltranscriptionfactorXLNormalNormalLackof(and/orimpairedfunctionof)CD4CCD25CFOXP3CregulatoryTcells(Tregs)Autoimmuneenteropathy304790Early-onsetdiabetesThyroiditis,hemolyticanemia,thrombocytopenia,eczemaElevatedIgE,IgA(b)CD25deciencyaMutationsinIL-2RA,encodingIL-2RachainARNormaltodecreasedNormalNoCD4CC25CcellswithimpairedfunctionofTregscellsLymphoproliferation,autoimmunity.ImpairedTcellproliferation606367(c)STAT5bdeciencyaMutationsinSTAT5B,signaltransducer,andtranscriptionfactor,essentialfornormalsignalingfromIL-2and15,keygrowthfactorsforTandNKcellsARModestlydecreasedNormalImpaireddevelopmentandfunctionofgdTcells,Tregs,andNKcellsLowTcellproliferationGrowth-hormoneinsensitivedwarsm245590DysmorphicfeaturesEczemaLymphocyticinterstitialpneumonitis,autoimmunity4.Autoimmunitywithoutlymphoproliferation(a)APECED(APS-1),autoimmunepolyen-docrinopathywithcandidiasisandectodermaldystrophyMutationsinAIRE,encodingatranscriptionregulatorneededtoestablishthymicself-toleranceARNormalNormalAIRE-1servesascheckpointinthethymusfornegativeselectionofautoreactiveTcellsandforgenerationofTregsAutoimmunity:hypoparathyroidismhypothyroidism,adrenalinsufciency,diabetes,gonadaldysfunction,andotherendocrineabnormalities240300ChronicmucocutaneouscandidiasisDentalenamelhypoplasiaAlopeciaareataEnteropathy,perniciousanemia (Continued) www.frontiersin.orgApril2014|Volume5|Article162|17 Al-Herzetal.PIDIUISclassication Table4|Continued DiseaseGeneticdefect/presumedpathogenesisInheritanceCirculatingTcellsCirculatingBcellsFunctionaldefectAssociatedfeaturesOMIMnumber (b)ITCHdeciencyaMutationsinITCH,anE3ubiquitinligasecatalyzesthetransferofubiquitintoasignalingproteininthecellincludingphospholipaseCg1(PLCg1)ARNotassessedNotassessedItchdeciencymaycauseimmunedysregulationbyaffectingbothanergyinductioninautoreactiveeffectorTcellsandgenerationofTregsEarly-onsetchroniclungdisease(interstitialpneumonitis)613385Autoimmunedisorder(thyroiditis,typeIdiabetes,chronicdiarrhea/enteropathy,andhepatitis)Failuretothrive,developmentaldelay,dysmorphicfacialfeatures5.Autoimmunelymphoproliferativesyndrome(ALPS)(a)ALPS–FASGerminalmutationsinTNFRSF6,encodingCD95/FascellsurfaceapoptosisreceptorbADIncreasedCD4�CD8�TCRa/bdoublenegative(DN)TcellsNormal,lowmemoryBcellsApoptosisdefectFASmediatedSplenomegaly,adenopathies,autoimmunecytopenias601859ARcIncreasedlymphomariskIgGandAnormalorincreasedElevatedFasLandIL-10,vitaminB12(b)ALPS–FASLGMutationsinTNFSF6,FasligandforCD95apoptosisARIncreasedDNTcellsNormalApoptosisdefectFASmediatedSplenomegaly,adenopathies,autoimmunecytopenias,SLE134638SolubleFasLisnotelevated(c)ALPS–caspase10aMutationsinCASP10,intracellularapoptosispathwayADIncreasedDNTcellsNormalDefectivelymphocyteapoptosisAdenopathies,splenomegaly,autoimmunity603909(d)ALPS–caspase8aMutationsinCASP8,intracellularapoptosis,andactivationpathwaysARSlightlyincreasedDNTcellsNormalDefectivelymphocyteapoptosisandactivationAdenopathies,splenomegaly,bacterialandviralinfections,hypogammaglobulinemia607271(e)FADDdeciencyaMutationsinFADDencodinganadaptormoleculeinteractingwithFAS,andpromotingapoptosisARIncreasedDNTcellsNormalDefectivelymphocyteapoptosisFunctionalhyposplenism,bacterialandviralinfections613759Recurrentepisodesofencephalopathyandliverdysfunction(f)CARD11gain-of-function(GOF)mutationsaGOFmutationsinCARD11,encodingaproteinrequiredforantigenreceptor–inducedNF-kBactivationinBandTlymphocytesADNormalIncreasedMCDCCD19CCD20CBcellsConstitutiveactivationofNF-kBinB&TLymphoproliferation606445BacterialandviralinfectionsEBVchronicinfectionAutoimmunecytopeniaHypogammaglobulinemia(g)PRKCddeciencyaMutationsinPRKCD,encodingamemberoftheproteinkinaseCfamilycriticalforregulationofcellsurvival,proliferation,andapoptosisARNormalLowmemoryBcellsandelevationofCD5BcellsApoptoticdefectinBcellsRecurrentinfections;EBVchronicinfection615559LymphoproliferationSLE-likeautoimmunity(nephroticandantiphospholipidsyndromes)HypoIgG (Continued) FrontiersinImmunology|PrimaryImmunodecienciesApril2014|Volume5|Article162|18 Al-Herzetal.PIDIUISclassication Table4|Continued DiseaseGeneticdefect/presumedpathogenesisInheritanceCirculatingTcellsCirculatingBcellsFunctionaldefectAssociatedfeaturesOMIMnumber 6.Immunedysregulationwithcolitis(a)IL-10deciencyaMutationsinIL-10,encodingIL-10ARNormalNormalNofunctionalIL-10secretionInammatoryboweldisease(IBD)folliculitisNotassignedRecurrentrespiratorydiseasesArthritis(b)IL-10RadeciencyMutationsinIL-10RA,encodingIL-10R1ARNormalNormalLeukocytes,noresponsetoIL-10IBD,folliculitis613148RecurrentrespiratorydiseasesArthritis,lymphoma(c)IL-10RbdeciencyMutationsinIL-10RB,encodingIL-10R2ARNormalNormalLeukocytes,noresponsetoIL-10,IL-22,IL-26,IL-28A,IL-28B,andIL-29IBD,folliculitis612567RecurrentrespiratorydiseasesArthritis,lymphoma7.Type1interferonopathies(a)TREX1deciency,Aicardi–Goutieressyndrome1(AGS1)MutationsinTREX1,encodingnucleaseinvolvesinclearingcellularnucleicdebrisARNotassessedNotassessedIntracellularaccumulationofabnormalsingle-stranded(ss)DNAspeciesleadingtoincreasedCSFalpha-IFNproductionProgressiveencephalopathyintracranialcalcications606609ADeCerebralatrophy,leukodystrophyHSMG,thrombocytopeniaElevatedhepatictransaminasesChroniccerebrospinaluid(CSF)lymphocytosis(b)RNASEH2Bdeciency,AGS2MutationsinRNASEH2B,encodingnucleasesubunitinvolvesinclearingcellularnucleicdebrisARNotassessedNotassessedIntracellularaccumulationofabnormalss-DNAspeciesleadingtoincreasedCSFalpha-IFNproductionProgressiveencephalopathyintracranialcalcications610326Cerebralatrophy,leukodystrophyHSMG,thrombocytopeniaElevatedhepatictransaminasesChronicCSFlymphocytosis(c)RNASEH2Cdeciency,AGS3MutationsinRNASEH2C,encodingnucleasesubunitinvolvesinclearingcellularnucleicdebrisARNotassessedNotassessedIntracellularaccumulationofabnormalss-DNAspeciesleadingtoincreasedCSFalpha-IFNproductionProgressiveencephalopathyintracranialcalcications610330Cerebralatrophy,leukodystrophyHSMG,thrombocytopeniaElevatedhepatictransaminasesChronicCSFlymphocytosis(d)RNASEH2Adeciency,AGS4aMutationsinRNASEH2A,encodingnucleasesubunitinvolvesinclearingcellularnucleicdebrisARNotassessedNotassessedIntracellularaccumulationofabnormalss-DNAspeciesleadingtoincreasedCSFalpha-IFNproductionProgressiveencephalopathyintracranialcalcications606034Cerebralatrophy,leukodystrophyHSMG,thrombocytopeniaElevatedhepatictransaminasesChronicCSFlymphocytosis (Continued) www.frontiersin.orgApril2014|Volume5|Article162|19 Al-Herzetal.PIDIUISclassication Table4|Continued DiseaseGeneticdefect/presumedpathogenesisInheritanceCirculatingTcellsCirculatingBcellsFunctionaldefectAssociatedfeaturesOMIMnumber (e)SAMHD1deciency,AGS5MutationsinSAMHD1,encodingnegativeregulatoroftheimmunostimulatoryDNAresponseARNotassessedNotassessedInductionofthecellintrinsicantiviralresponse,apoptosis,andmitochondrialDNAdestructionleadingtoincreasedCSFalpha-IFNproductionProgressiveencephalopathyintracranialcalcications612952Cerebralatrophy,leukodystrophyHSMG,thrombocytopenia,anemiaelevatedlactatesChronicCSFlymphocytosisSkinvasculitis,mouthulcers,arthropathy(f)ADAR1deciency,AGS6MutationsinADAR1,encodinganRNA-specicadenosinedeaminaseARNotassessedNotassessedCatalyzesthedeaminationofadenosinetoinosineindsRNAsubstratesmarkedlyelevatedCSFIFN-alphaProgressiveencephalopathyintracranialcalcicationSeveredevelopmentaldelay,leukodystrophy615010(g)Spondyloenchondro-dysplasiawithimmunedysregulation(SPENCD)MutationsinACP5,encodingtartrate-resistantacidphosphatase(TRAP)ARNotassessedNotassessedUpregulationofIFN-alphaandtypeIIFN-stimulatedgenesRecurrentbacterialandviralinfections,intracranialcalcication607944SLE-likeautoimmunity(Sjögren'ssyndrome,hypothyroidism,inammatorymyositis,Raynaud'sdiseaseandvitiligo),hemolyticanemia,thrombocytopenia,skeletaldysplasia,shortstature XL,X-linkedinheritance;AR,autosomalrecessiveinheritance;AD,autosomaldominantinheritance;FHL,familialhemophagocyticlymphohistiocytosis;HLH,hemo-phagocyticlymphohistiocytosis;HSMG,hepatosplenomegaly;DN,doublenegative;SLE,systemiclupuserythematous;IBD,inammatoryboweldisease;CSF,chroniccerebrospinaluid.aTenorfewerunrelatedcasesreportedintheliterature.bSomaticmutationsofTNFRSF6causeasimilarphenotype(ALPS–sFAS),seeTable9.GerminalmutationandsomaticmutationofTNFRSF6canbeassociatedinsomeALPS–FASpatients.cARALPS–FASpatientshaveamostsevereclinicalphenotype.dSomaticmutationsinKRASorNRAScangivethisclinicalphenotypeassociatedautoimmuneleukoproliferativedisease(RALD)andarenowincludedinTable9entitledphenocopiesofPID.eDenovodominantTREX1mutationshavebeenreported.FourteennewdisordershavebeenaddedtoTable4.Twonewentrieshavebeenaddedinthetable,includingimmunedysregulationwithcolitisandType1interferonopathies.EBV-drivenlymphoproliferationisalsoobservedinMAGT1deciency(Table1).Table5|Congenitaldefectsofphagocytenumber,function,orboth. DiseaseGeneticdefect/presumedpathogenesisInheritanceAffectedcellsAffectedfunctionAssociatedfeaturesOMIMnumber 1.Defectsofneutrophilfunction(a)Severecongenitalneutropenia1(ELANEdeciency)MutationinELANE:misfoldedproteinresponse,increasedapoptosisADNMyeloiddifferentiationSusceptibilitytoMDS/leukemia202700(b)SCN2a(GFI1deciency)MutationinGFI1:lossofrepressionofELANEADNMyeloiddifferentiationB/Tlymphopenia613107 (Continued) FrontiersinImmunology|PrimaryImmunodecienciesApril2014|Volume5|Article162|20 Al-Herzetal.PIDIUISclassication Table5|Continued DiseaseGeneticdefect/presumedpathogenesisInheritanceAffectedcellsAffectedfunctionAssociatedfeaturesOMIMnumber (c)SCN3(Kostmanndisease)MutationinHAX1:controlofapoptosisARNMyeloiddifferentiationCognitiveandneurologicaldefectsinpatientswithdefectsinbothHAX1isoforms,susceptibilitytoMDS/leukemia610738(d)SCN4(G6PC3deciency)MutationinG6PC3:abolishedenzymaticactivityofglucose-6-phosphatase,aberrantglycosylation,andenhancedapoptosisofNandFARNCFMyeloiddifferentiation,chemotaxis,O�2productionStructuralheartdefects,urogenitalabnormalities,innereardeafness,andvenousangiectasiasoftrunksandlimbs612541(e)SCN5MutationinVPS45controlsvesiculartrafckingARNCFMyeloiddifferentiation,migrationExtramedullaryhematopoiesis,bonemarrowbrosis,nephromegaly615285(f)Glycogenstoragediseasetype1bMutationinG6PT1:glucose-6-phosphatetransporter1ARNCMMyeloiddifferentiation,chemotaxis,O�2productionFastinghypoglycemia,lacticacidosis,hyperlipidemia,hepatomegaly232220(g)CyclicneutropeniaMutationinELANE:misfoldedproteinresponseADNDifferentiationOscillationsofotherleukocytesandplatelets162800(h)X-linkedneutropenia/amyelodysplasiaMutationinWAS:regulatorofactincytoskeleton(lossofauto-inhibition)XL,gain-of-functionNCMMitosisMonocytopenia300299(i)P14/LAMTOR2deciencyaMutationinROBLD3/LAMTOR2:endosomaladaptorprotein14ARNCLMelEndosomebiogenesisNeutropenia610389Hypogammaglobulinemia#CD8cytotoxicityPartialalbinismGrowthfailure(j)BarthsyndromeMutationintafazzin(TAZ)gene:abnormallipidstructureofmitochondrialmembrane,defectivecarnitinemetabolismXLNMyeloiddifferentiationCardiomyopathy,myopathy,growthretardation302060(k)CohensyndromeMutationinCOH1gene:PgunknownARNMyeloiddifferentiationRetinopathy,developmentaldelay,facialdysmorphisms216550(l)ClericuziosyndromepoikilodermawithneutropeniaMutationinC16ORF57,affectsgenomicintegrityARNMyeloiddifferentiationPoikiloderma,neutropenia,MDS6132762.Defectsofmotility(a)Leukocyteadhesiondeciencytype1(LAD1)MutationinITGB2:adhesionprotein(CD18)ARNCMCLCNKAdherence,chemotaxis,endocytosis,T/NKcytotoxicityDelayedcordseparation,skinulcersPeriodontitisLeukocytosis116920(b)Leukocyteadhesiondeciencytype2(LAD2)aMutationinFUCT1:GDP-fucosetransporterARNCMRolling,chemotaxisMildLADtype1featuresplushh-bloodgroupplusmentalandgrowthretardation266265(c)Leukocyteadhesiondeciencytype3(LAD3)MutationinKINDLIN3:Rap1-activationofb1–3integrinsARNCMCLCNKAdherence,chemotaxisLADtype1plusbleedingtendency612840(d)Rac2deciencyaMutationinRAC2:regulationofactincytoskeletonADNAdherence,chemotaxis,O�2productionPoorwoundhealing,leukocytosis602049 (Continued) www.frontiersin.orgApril2014|Volume5|Article162|21 Al-Herzetal.PIDIUISclassication Table5|Continued DiseaseGeneticdefect/presumedpathogenesisInheritanceAffectedcellsAffectedfunctionAssociatedfeaturesOMIMnumber (e)b-ActindeciencyaMutationinACTB:cytoplasmicactinADNCMMotilityMentalretardation,shortstature102630(f)LocalizedjuvenileperiodontitisMutationinFPR1:chemokinereceptorARNFormylpeptideinducedchemotaxisPeriodontitisonly136537(g)Papillon–LefèvresyndromeMutationinCTSC:cathepsinCactivationofserineproteasesARNCMChemotaxisPeriodontitis,palmoplantarhyperkeratosisinsomepatients245000(h)SpecicgranuledeciencyaMutationinC/EBPE:myeloidtranscriptionfactorARNChemotaxisNeutrophilswithbilobednuclei;absentsecondarygranulesanddefensins245480(i)Shwachman–DiamondsyndromeMutationinSBDS:defectiveribosomesynthesisARNChemotaxisPancytopenia,exocrinepancreaticinsufciency,chondrodysplasia2604003.Defectsofrespiratoryburst(a)X-linkedchronicgranulomatousdisease(CGD)MutationinCYBB:electrontransportprotein(gp91phox)XLNCMKilling(faultyO�2production)Recurrentbacterialinfection,susceptibilitytofungalinfection,inammatorygutmanifestationsMcLeodphenotypeinpatientswithdeletionsextendingintothecontiguousKelllocus306400(b)AutosomalrecessiveCGD–p22phoxdeciencyMutationinCYBA:electrontransportprotein(p22phox)ARNCMKilling(faultyO�2production)Recurrentbacterialinfection,susceptibilitytofungalinfection,andinammatorygutmanifestations233690(c)AutosomalrecessiveCGD–p47phoxdeciencyMutationinNCF1:adapterprotein(p47phox)ARNCMKilling(faultyO�2production)Recurrentbacterialinfection,susceptibilitytofungalinfection,andinammatorygutmanifestations233700(d)AutosomalrecessiveCGD–p67phoxdeciencyMutationinNCF2:activatingprotein(p67phox)ARNCMKilling(faultyO�2production)Recurrentbacterialinfection,susceptibilitytofungalinfection,inammatorygutmanifestations233710(e)AutosomalrecessiveCGD–p40phoxdeciencyaMutationinNCF4:activatingprotein(p40phox)ARNCMKilling(faultyO�2production)Inammatorygutmanifestationsonly6014884.Mendeliansusceptibilitytomycobacterialdisease(MSMD)(a)IL-12andIL-23receptorb1chaindeciencyMutationinIL-12RB1:IL-12andIL-23receptorb1chainARLCNKIFN-gsecretionSusceptibilitytoMycobacteriaandSalmonella209950(b)IL-12p40deciencyMutationinIL-12B:subunitp40ofIL-12/IL-23ARMIFN-gsecretionSusceptibilitytoMycobacteriaandSalmonella161561(c)IFN-greceptor1deciencyMutationinIFNGR1:IFN-gRligandbindingchainAR,ADMCLIFN-gbindingandsignalingSusceptibilitytoMycobacteriaandSalmonella107470(d)IFN-greceptor2deciencyMutationinIFNGR2:IFN-gRaccessorychainARMCLIFN-gsignalingSusceptibilitytoMycobacteriaandSalmonella147569(e)STAT1deciency(ADform)aMutationinSTAT1(lossoffunction)ADMCLIFN-gsignalingSusceptibilitytoMycobacteria600555 (Continued) FrontiersinImmunology|PrimaryImmunodecienciesApril2014|Volume5|Article162|22 Al-Herzetal.PIDIUISclassication Table5|Continued DiseaseGeneticdefect/presumedpathogenesisInheritanceAffectedcellsAffectedfunctionAssociatedfeaturesOMIMnumber (f)Macrophagegp91phoxdeciencyaMutationinCYBB:electrontransportprotein(gp91phox)XLMfonlyKilling(faultyO�2production)IsolatedsusceptibilitytoMycobacteria306400(g)IRF8-deciency(ADform)aMutationinIRF8:IL-12productionbyCD1cCMDCADCD1cCMDCDifferentiationofCD1cCMDCsubgroupSusceptibilitytoMycobacteria601565(h)ISG15MutationinISG15;aninterferon(IFN)a/b-inducible,ubiquitin-likeintracellularproteinARMCNCLIFN-gsecretionSusceptibilitytoMycobacteria147515.Otherdefects(a)IRF8-deciency(ARform)aMutationinIRF8:IL-12productionARMonocytesperiph-eralDCCytopeniasSusceptibilitytoMycobacteria,Candida,myeloproliferation614893(b)GATA2deciency(MonoMACsyndrome)MutationinGATA2:lossofstemcellsADMonocytesperiph-eralDCCNKCBMultilineagecytopeniasSusceptibilitytoMycobacteria,papillomaviruses,histoplasmosis,alveolarproteinosis,MDS/AML/CMML137295(c)PulmonaryalveolarproteinosisaMutationinCSF2RABiallelicmutationsinpseudo-autosomalgeneAlveolarmacro-phagesGM-CSFsignalingAlveolarproteinosis306250 XL,X-linkedinheritance;AR,autosomalrecessiveinheritance;AD,autosomaldominantinheritance;ACTB,actinbeta;B,Blymphocytes;CEBPE,CCAAT/enhancer-bindingproteinepsilon;CMML,chronicmyelomonocyticleukemia;CTSC,cathepsinC;CYBA,cytochromebalphasubunit;CYBB,cytochromebbetasubunit;DC,dendriticcells;ELANE,elastaseneutrophil-expressed;GATA2,GATAbindingprotein2;IFN,interferon;IFNGR1,interferon-gammareceptorsubunit1;IFNGR2,interferon-gammareceptorsubunit2;IL-12B,interleukin-12betasubunit;IL-12RB1,interleukin-12receptorbeta1;IFR8,interferonregulatoryfactor8;F,broblasts;FPR1,formylpeptidereceptor1;FUCT1,fucosetransporter1;GFI1,growthfactorindependent1;HAX1,HLCS1-associatedproteinX1;ITGB2,integrinbeta-2;L,lymphocytes;M,monocytes–macrophages;MDC,myeloiddendriticcells;MDS,myelodysplasia;Mel,melanocytes;M#,macrophages;MSMD,Mendeliansuscepti-bilitytomycobacterialdisease;N,neutrophils;NCF1,neutrophilcytosolicfactor1;NCF2,neutrophilcytosolicfactor2;NCF4,neutrophilcytosolicfactor4;NK,naturalkillercells;ROBLD3:roadblockdomaincontaining3;SBDS,Shwachman–Bodian–Diamondsyndrome;STAT,signaltransducerandactivatoroftranscription.aTenorfewerunrelatedcasesreportedintheliterature.Table5includessevennewlydescribedgeneticdefectsofphagocytenumberand/orfunctionincludingBarthsyndrome,Cohensyndrome,andpoikilodermawithneutropenia.Inthesethreeclinicallywell-knowndiseases,thegeneticdefectshavebeenelucidated,althoughtheirmolecularpathogenesisremainsill-dened.Anewcauseofautosomalrecessivechronicgranulomatousdisease,namelyadeciencyofthecytosolicactivatingproteinp40phox,hasnowbeenfoundintwoCGDpatientsandisincludedunderdefectsofrespiratoryburst.UndertheheadingofMendeliansusceptibilityofmycobacterialdisease(MSMD),twonewentitieswereadded:(a)asubgroupofX-linkedgp91phoxdeciencywithisolatedsusceptibilitytomycobacteriaandadefectoftherespiratoryburstinmacrophagesonly;(b)anautosomaldominantformofIRF8-deciency,resultingfromalackofCD1cCmyeloiddendriticcellsthatwouldnormallysecreteIL-12.TheclinicalphenotypeofMSMDmayvary,dependingonthenatureofthegeneticdefect.Finally,GATA2deciencywasrecentlyidentiedasthecauseoftheMonoMACsyndrome,withmultilineagecytopenias(ofmonocytes,peripheraldendriticcells,NK-andB-lymphocytes)resultinginopportunisticinfections(includingmycobacteria),alveolarproteinosis,andmalignancy. www.frontiersin.orgApril2014|Volume5|Article162|23 Al-Herzetal.PIDIUISclassication Table6|Defectsininnateimmunity. DiseaseGeneticdefect/presumedpathogenesisInheritanceAffectedcellFunctionaldefectAssociatedfeaturesOMIMnumber 1.Anhidroticectodermaldysplasiawithimmunodeciency(EDA-ID)(a)EDA-ID,X-linked(NEMOdeciency)MutationsofNEMO(IKBKG),amodulatorofNF-kBactivationXLLymphocytesCmonocytesNF-kBsignalingpathwayVariousinfections(bacteria,Mycobacteria,viruses,andfungi)300248ColitisEDA(notinallpatients)Hypogammaglobulinemiatospecicantibodypolysaccharidesdeciency(b)EDA-ID,autosomal-dominantaGain-of-functionmutationsofIKBA,resultinginimpairedactivationofNF-kBADLymphocytesCmonocytesNF-kBsignalingpathwayVariousinfections(bacteria,viruses,andfungi)612132EDATcelldefect2.TIRsignalingpathwaydeciency(a)IRAK-4deciencyMutationsofIRAK-4,acomponentofTLR-andIL-1R-signalingpathwayARLymphocytesCgranulocytesCmonocytesTIR–IRAKsignalingpathwayBacterialinfections(pyogenes)607676(b)MyD88deciencyMutationsofMYD88,acomponentoftheTLRandIL-1RsignalingpathwayARLymphocytesCgranulocytesCmonocytesTIR–MyD88signalingpathwayBacterialinfections(pyogenes)6122603.HOIL1deciencyaMutationofHOIL1,acomponentofLUBACARLymphocytesCgranulocytesCmonocytesNF-kBsignalingpathwayBacterialinfections(pyogenes)NotassignedAutoinammationAmylopectinosis4.WHIM(Warts,hypogammaglobu-linemia,infections,myelokathexis)syndromeGain-of-functionmutationsofCXCR4,thereceptorforCXCL12ADGranulocytesClymphocytesIncreasedresponseoftheCXCR4chemokinereceptortoitsligandCXCL12(SDF-1)Warts/humanpapillomavirus(HPV)infection193670NeutropeniaReducedBcellnumberHypogammaglobulinemia5.EpidermodysplasiaverruciformisEVER1deciencyMutationsofEVER1ARKeratinocytesandleukocytesEVERproteinsmaybeinvolvedintheregulationofcellularzinchomeostasisinlymphocytesHPV(groupB1)infectionsandcanceroftheskin(typicalEV)226400EVER2deciencyMutationsofEVER2ARKeratinocytesandleukocytesEVERproteinsmaybeinvolvedintheregulationofcellularzinchomeostasisinlymphocytesHPV(groupB1)infectionsandcanceroftheskin(typicalEV)2264006.Predispositiontosevereviralinfection(a)STAT2deciencyaMutationsofSTAT2ARTandNKcellsSTAT2-dependentSevereviralinfections(disseminatedvaccine-strainmeasles)NotassignedIFN-aand-bresponse (Continued) FrontiersinImmunology|PrimaryImmunodecienciesApril2014|Volume5|Article162|24 Al-Herzetal.PIDIUISclassication Table6|Continued DiseaseGeneticdefect/presumedpathogenesisInheritanceAffectedcellFunctionaldefectAssociatedfeaturesOMIMnumber (b)MCM4deciencyaMutationsinMCM4ARNKcellsDNArepairdisorderViralinfections(EBV,HSV,VZV)609981AdrenalfailureShortstature7.Herpessimplexencephalitis(HSE)(a)TLR3deciencya(b)MutationsofTLR3ADCentralnervoussystem(CNS)residentcellsandbroblastsTLR3-dependentHerpessimplexvirus1encephalitis(incompleteclinicalpenetranceforalletiologieslistedhere)613002ARIFN-a,-b,and-linduction(b)UNC93B1deciencya(a)MutationsofUNC93B1ARCNSresidentcellsandbroblastsUNC-93B-dependentHerpessimplexvirus1encephalitis610551IFN-a,-b,and-linduction(c)TRAF3deciencya(c)MutationsofTRAF3ADCNSresidentcellsandbroblastsTRAF3-dependentHerpessimplexvirus1encephalitis614849IFN-a,-b,and-linduction(d)TRIFdeciencya(c)MutationsofTRIFADCNSresidentcellsandbroblastsTRIF-dependentHerpessimplexvirus1encephalitis614850ARIFN-a,-b,and-linduction(e)TBK1deciencya(c)MutationsofTBK1ADCNSresidentcellsandbroblastsTBK1-dependentHerpessimplexvirus1encephalitisNotassignedIFN-a,-b,and-linduction8.PredispositiontoinvasivefungaldiseasesaCARD9deciencyMutationsofCARD9ARMononuclearphagocytesCARD9signalingpathwayInvasivecandidiasisinfectionDeepdermatophytoses2120509.Chronicmucocutaneouscandidiasis(CMC)(a)IL-17RAdeciencya(a)MutationsinIL-17RAAREpithelialcells,broblasts,mononuclearphagocytesIL-17RAsignalingpathwayCMCFolliculitis605461(b)IL-17Fdeciencya(b)MutationsinIL-17FADTcellsIL-17F-containingdimersCMCFolliculitis606496(c)STAT1gain-of-function(c)Gain-of-functionmutationsinSTAT1ADTcellsGain-of-functionSTAT1mutationsthatimpairthedevelopmentofIL-17-producingTcellsCMC614162Variousfungal,bacterial,andviral(HSV)infectionsAutoimmunity(thyroiditis,diabetes,cytopenia)Enteropathy(d)ACT1deciencya(c)MutationsinACT1ARTcells,broblastsFibroblastsfailtorespondtoIL-17AandIL-17F,andtheirTcellstoIL-17ECMC615527Blepharitis,folliculitis,andmacroglossia10.TrypanosomiasisaMutationsinAPOL-IADAPOL-ITrypanosomiasis603743 (Continued) www.frontiersin.orgApril2014|Volume5|Article162|25 Al-Herzetal.PIDIUISclassication Table6|Continued DiseaseGeneticdefect/presumedpathogenesisInheritanceAffectedcellFunctionaldefectAssociatedfeaturesOMIMnumber 11.Isolatedcongenitalasplenia(ICA)MutationsinRPSAADSpleenRPSAencodesribosomalproteinSA,acomponentofthesmallsubunitoftheribosomeBacteremia(encapsulatedbacteria)Nospleen271400 XL,X-linkedinheritance;AR,autosomalrecessiveinheritance;AD,autosomaldominantinheritance;NF-kB,nuclearfactorkappaB;TIR,Tollandinterleukin1receptor;IFN,interferon;HVP,humanpapillomavirus;TLR,Toll-likereceptor;IL,interleukin.aTenorfewerunrelatedcasesreportedintheliterature.EightnewdisordershavebeenaddedtoTable6.Threenewentrieshavebeenaddedinthetable.OneisanewPIDwiththeassociationofrecurrentbacterialinfections,autoinammation,andamylopectinosiscausedbyARHOIL1mutationsfoundintwokindreds.Thesecondissevereviralinfection,forwhichthreegeneticetiologieshavebeendiscovered.AR-STAT2deciencyandAR-CD16deciencyhavebeenfoundinonekindredeach.ARMCM4deciencyhasbeenfoundinseveralIrishkindreds.Thethirdisisolatedcongenitalaspleniaidentiedin18patientsfrom8kindreds.XR-EDA-IDishighlyheterogeneousclinically,bothintermsofdevelopmentalfeatures(somepatientsdisplayosteopetrosisandlymphedema,inadditiontoEDA,whileothersdonotdisplayanydevelopmentalfeatures)andinfectiousdiseases(somedisplaymultipleinfections,viral,fungal,andbacterial,whileothersdisplayasingletypeofinfection).ThevariousOMIMentriescorrespondtothesedistinctclinicaldiseases.Table7|Autoinammatorydisorders. DiseaseGeneticdefect/presumedpathogenesisInheritanceAffectedcellsFunctionaldefectsAssociatedfeaturesOMIMnumber 1.Defectseffectingtheinammasome(a)FamilialMediterraneanfeverMutationsofMEFV(leadtogainofpyrinfunction,resultingininappropriateIL-1brelease)ARMaturegranulocytes,cytokine-activatedmonocytesDecreasedproductionofpyrinpermitsASC-inducedIL-1processingandinammationfollowingsubclinicalserosalinjury;macrophageapoptosisdecreasedRecurrentfever,serositis,andinammationresponsivetocolchicine.Predisposestovasculitisandinammatoryboweldisease249100(b)Mevalonatekinasedeciency(hyperIgDsyndrome)MutationsofMVK(leadtoablockinthemevalonatepathway).Interleukin-1betamediatestheinammatoryphenotypeARAffectingcholesterolsynthesis;pathogenesisofdiseaseisunclearPeriodicfeverandleukocytosiswithhighIgDlevels260920(c)Muckle–WellssyndromeMutationsofCIAS1(alsocalledPYPAF1orNALP3)leadtoconstitutiveactivationoftheNLRP3inammasomeADPMNsmonocytesDefectincryopyrin,involvedinleukocyteapoptosisandNF-kBsignalingandIL-1processingUrticaria,SNHL,amyloidosis191900(d)FamilialcoldautoinammatorysyndromeMutationsofCIAS1(seeabove)MutationsofNLRP12ADPMNs,monocytesSameasaboveNon-pruriticurticaria,arthritis,chills,fever,andleukocytosisaftercoldexposure120100 (Continued) FrontiersinImmunology|PrimaryImmunodecienciesApril2014|Volume5|Article162|26 Al-Herzetal.PIDIUISclassication Table7|Continued DiseaseGeneticdefect/presumedpathogenesisInheritanceAffectedcellsFunctionaldefectsAssociatedfeaturesOMIMnumber 5.Neonatalonsetmultisysteminammatorydisease(NOMID)orchronicinfantileneurologiccutaneousandarticularsyndrome(CINCA)MutationsofCIAS1(seeabove)ADPMNs,chondrocytesSameasaboveNeonatalonsetrash,chronicmeningitis,andarthropathywithfeverandinammation6071152.Noninammasome-relatedconditions(a)TNFreceptor-associatedperiodicsyndrome(TRAPS)MutationsofTNFRSF1(resultinginincreasedTNFinammatorysignaling)ADPMNs,monocytesMutationsof55-kDaTNFreceptorleadingtointracellularreceptorretentionordiminishedsolublecytokinereceptoravailabletobindTNFRecurrentfever,serositis,rash,andocularorjointinammation142680(b)Early-onsetinammatoryboweldiseaseMutationsinIL-10(resultsinincreasemanyproinammatorycytokines)ARMonocyte/macrophage,activatedTcellsIL-10deciencyleadstoincreaseofTNFgandotherproinammatorycytokinesEarly-onsetenterocolitisentericstulas,perianalabscesses,chronicfolliculitis124092(b)Early-onsetinammatoryboweldiseaseMutationsinIL-10RA(seeabove)ARMonocyte/macrophage,activatedTcellsMutationinIL-10receptoralphaleadstoincreaseofTNFgandotherproinammatorycytokinesEarly-onsetenterocolitisentericstulas,perianalabscesses,chronicfolliculitis146933(b)Early-onsetinammatoryboweldiseaseMutationsinIL-10RB(seeabove)ARMonocyte/macrophage,activatedTcellsMutationinIL-10receptorbetaleadstoincreaseofTNFgandotherproinammatorycytokinesEarly-onsetenterocolitisentericstulas,perianalabscesses,chronicfolliculitis123889(c)Pyogenicsterilearthritis,pyodermagangrenosum,acne(PAPA)syndromeMutationsofPSTPIP1(alsocalledC2BP1)(affectsbothpyrinandproteintyrosinephosphatasetoregulateinnateandadaptiveimmuneresponses)ADHematopoietictissues,upregulatedinactivatedTcellsDisorderedactinreorganizationleadingtocompromisedphysiologicsignalingduringinammatoryresponseDestructivearthritis,inammatoryskinrash,myositis604416(d)BlausyndromeMutationsofNOD2(alsocalledCARD15)(involvedinvariousinammatoryprocesses)ADMonocytesMutationsinnucleotidebindingsiteofCARD15,possiblydisruptinginteractionswithlipopolysaccharidesandNF-kBsignalingUveitis,granulomatoussynovitis,camptodactyly,rash,andcranialneuropathies,30%developCrohn'sdisease18658010.Chronicrecurrentmultifocalosteomyelitisandcongenitaldyserythropoieticanemia(Majeedsyndrome)aMutationsofLPIN2(increasedexpressionoftheproinammatorygenes)ARNeutrophils,bonemarrowcellsUndenedChronicrecurrentmultifocalosteomyelitis,transfusion-dependentanemia,cutaneousinammatorydisorders609628 (Continued) www.frontiersin.orgApril2014|Volume5|Article162|27 Al-Herzetal.PIDIUISclassication Table7|Continued DiseaseGeneticdefect/presumedpathogenesisInheritanceAffectedcellsFunctionaldefectsAssociatedfeaturesOMIMnumber 11.DIRA(deciencyoftheinterleukin1receptorantagonist)aMutationsofIL-1RN(seefunctionaldefect)ARPMNs,monocytesMutationsintheIL-1receptorantagonistallowunopposedactionofInterleukin1Neonatalonsetofsterilemultifocalosteomyelitis,periostitis,andpustulosis61285212.DITRA–deciencyofIL-36receptorantagonistMutationinIL-36RN(seefunctionaldefect)ARKeratinocyteleukocytesMutationsinIL-36RNleadstoincreaseIL-8productionPustularpsoriasis61420413.SLC29A3mutationMutationinSLC29A3(?)ARLeukocyte,bonecellsMacrophageactivation?Hyperpigmentationhypertrichosis60278214.CAMPS(CARD14mediatedpsoriasis)MutationinCARD14(seefunctionaldefect)ADMainlyinkeratinocyteMutationsinCARD14activatetheNF-kBpathwayandproductionofIL-8Psoriasis17320015.CherubismMutationinSH3BP2(seefunctionaldefect)ADStromacells,bonecellsHyperactivatedmacrophageandincreasedNF-kBBonedegenerationinjaws1184016.CANDLE(chronicatypicalneutrophilicdermatitiswithlipodystrophy)MutationinPSMB8(seefunctionaldefect)ADKeratinocyte,BcelladiposecellsMutationscauseincreaseIL-6productionDystrophy,panniculitis25604017.HOIL1deciencyMutationinHOIL1(seefunctionaldefect)ARPMNs,broblastMutationinHOIL1leadstoIL-1bdysfunctionImmunodeciencyautoinammationamylopectinosis61092418.PLAID(PLCg2associatedantibodydeciencyandimmunedysregulation)MutationinPLCG2(seefunctionaldefect)ADBcells,NK,mastcellsMutationscauseactivationofIL-1pathwaysColdurticariahypogam-maglobulinemia614878 AR,autosomalrecessiveinheritance;AD,autosomaldominantinheritance;PMN,polymorphonuclearcells;ASC,apoptosis-associatedspeck-likeproteinwithacas-paserecruitmentdomain;CARD,caspaserecruitmentdomain;CD2BP1,CD2bindingprotein1;PSTPIP1,proline/serine/threoninephosphatase-interactingprotein1;SNHL,sensorineuralhearingloss;CIAS1,cold-inducedautoinammatorysyndrome1.aTenorfewerunrelatedcasesreportedintheliterature.Autoinammatorydiseasesareclinicaldisordersmarkedbyabnormallyincreasedinammation,mediatedpredominantlybythecellsandmoleculesoftheinnateimmunesystem,withasignicanthostpredisposition.Whilethegeneticdefectofoneofthemostcommonautoinammatoryconditions,PFAPA,isnotknown,recentstudiessuggestthatitisassociatedwithactivationofIL-1pathwayandresponsetoIL-1betaantagonists.Muckle–Wellssyndrome,familialcoldautoinammatorysyndromeandneonatalonsetmultisysteminammatorydisease(NOMID),whichisalsocalledchronicinfantileneurologiccutaneousandarticularsyndrome(CINCA)arecausedbysimilarmutationsinCIAS1mutations.Thediseasephenotypeinanyindividualappearstodependonmodifyingeffectsofothergenesandenvironmentalfactors. FrontiersinImmunology|PrimaryImmunodecienciesApril2014|Volume5|Article162|28 Al-Herzetal.PIDIUISclassication Table8|Complementdeciencies. DiseaseGeneticdefect;presumedpathogenesisInheritanceFunctionaldefectAssociatedfeaturesOMIMnumber 1.C1qdeciencyMutationinC1QA,C1QB,C1QC:classicalcomplementpathwaycomponentsARAbsentCH50hemolyticactivity,defectiveactivationoftheclassicalpathwaySLE,infectionswithencapsulatedorganisms120550;601269;120575Diminishedclearanceofapoptoticcells2.C1rdeciencyMutationinC1R:classicalcomplementpathwaycomponentARAbsentCH50hemolyticactivity,defectiveactivationoftheclassicalpathwaySLE,infectionswithencapsulatedorganisms2169503.C1sdeciencyMutationinC1S:classicalcomplementpathwaycomponentARAbsentCH50hemolyticactivity,defectiveactivationoftheclassicalpathwaySLE,infectionswithencapsulatedorganisms1205804.C4deciencyMutationinC4A,C4B:classicalcomplementpathwaycomponentsARAbsentCH50hemolyticactivity,defectiveactivationoftheclassicalpathway,defectivehumoralimmuneresponsetocarbohydrateantigensinsomepatientsSLE,infectionswithencapsulatedorganisms120810;1208205.C2deciencyMutationinC2:classicalcomplementpathwaycomponentARAbsentCH50hemolyticactivity,defectiveactivationoftheclassicalpathwaySLE,infectionswithencapsulatedorganisms,atherosclerosis2170006.C3deciencyMutationinC3:centralcomplementcomponentAR,gain-of-functionADAbsentCH50andAH50hemolyticactivitydefectiveopsonizationInfections;glomerulonephritis120700DefectivehumoralimmuneresponseAtypicalhemolytic–uremicsyndromewithgain-of-functionmutations7.C5deciencyMutationinC5:terminalcomplementcomponentARAbsentCH50andAH50hemolyticactivity;defectivebactericidalactivityNeisserialinfections1209008.C6deciencyMutationinC6:terminalcomplementcomponentARAbsentCH50andAH50hemolyticactivity;defectivebactericidalactivityNeisserialinfections2170509.C7deciencyMutationinC7:terminalcomplementcomponentARAbsentCH50andAH50hemolyticactivity;defectivebactericidalactivityNeisserialinfections21707010.C8a–gdeciencyMutationinC8A,C8G:terminalcomplementcomponentsARAbsentCH50andAH50hemolyticactivity;defectivebactericidalactivityNeisserialinfections12095011.C8bdeciencyMutationinC8B:TerminalcomplementcomponentARAbsentCH50andAH50hemolyticactivity;defectivebactericidalactivityNeisserialinfections12096012.C9deciencyMutationinC9:TerminalcomplementcomponentARReducedCH50andAP50hemolyticactivity;decientbactericidalactivityMildsusceptibilitytoNeisserialinfections613825 (Continued) www.frontiersin.orgApril2014|Volume5|Article162|29 Al-Herzetal.PIDIUISclassication Table8|Continued DiseaseGeneticdefect;presumedpathogenesisInheritanceFunctionaldefectAssociatedfeaturesOMIMnumber 13.C1inhibitordeciencyMutationinSERPING1:regulationofkininsandcomplementactivationADSpontaneousactivationofthecomplementpathwaywithconsumptionofC4/C2Hereditaryangioedema138470Spontaneousactivationofthecontactsystemwithgenerationofbradykininfromhighmolecularweightkininogen14.FactorBaMutationinCFB:activationofthealternativepathwayADGain-of-functionmutationwithincreasedspontaneousAH50aHUS13847015.FactorDdeciencyMutationinCFD:regulationofthealternativecomplementpathwayARAbsentAH50hemolyticactivityNeisserialinfections13435016.ProperdindeciencyMutationinCFP:regulationofthealternativecomplementpathwayXLAbsentAH50hemolyticactivityNeisserialinfections31206017.FactorIdeciencyMutationinCFI:regulationofthealternativecomplementpathwayARSpontaneousactivationofthealternativecomplementpathwaywithconsumptionofC3Infections,Neisserialinfections,aHUS,preeclampsia,membranoproliferativeglomerulonephritis(MPGN)61098418.FactorHdeciencyMutationinCFH:regulationofthealternativecomplementpathwayARSpontaneousactivationofthealternativecomplementpathwaywithconsumptionofC3Infections,Neisserialinfections,aHUS,preeclampsia,membranoproliferativeglomerulonephritis(MPGN)60981419.FactorH-relatedproteindecienciesMutationinCFHR1-5:bindC3bARNormalCH50,AH50,autoantibodiestoFactorHaHUS23540020.ThrombomodulinaMutationinTHBD:regulatescomplementandcoagulantactivationADNormalCH50,AH50aHUS18804021.MASP1deciencyMutationinMASP1:cleavesC2andactivatesMASP2ARDecientactivationofthelectinactivationpathway,cellmigrationInfections,3MCsyndrome60052122.MASP2deciencyaMASP2:cleavageofC2andC4ARDecientactivationofthelectinactivationpathwayPyogenicinfections;inammatorylungdisease,autoimmunity60510223.3MCsyndromeCOLEC11deciencyaMutationinCOLEC11:bindsMASP1,MASP3ARLossofneuralcrestcellmigrationsignalsAdevelopmentalsyndromeoffacialdysmorphism,cleftlipand/orpalate,craniosynostosis,learningdisability,andgenital,limb,andvesicorenalanomalies(3MCsyndrome)612502 (Continued) FrontiersinImmunology|PrimaryImmunodecienciesApril2014|Volume5|Article162|30 Al-Herzetal.PIDIUISclassication Table8|Continued DiseaseGeneticdefect;presumedpathogenesisInheritanceFunctionaldefectAssociatedfeaturesOMIMnumber 24.Complementreceptor2(CR2)deciencyaMutationinCD21ARSeeCD21deciencyinTable312065025.Complementreceptor3(CR3)deciencyMutationinITGB2ARSeeLAD1inTable5116920Membranecofactorprotein(CD46)deciencyMutationinCD46:dissociatesC3bandC4bADInhibitorofcomplementalternatepathway,decreasedC3bbindingaHUS,infections,preeclampsia120920MembraneAttackComplexinhibitor(CD59)deciencyaMutationinCD59:regulatesthemembraneattackcomplexformationARErythrocyteshighlysusceptibletocomplement-mediatedlysisHemolyticanemia,polyneuropathy107271Ficolin3deciencyaMutationinFCN3:activatestheclassicalcomplementpathwayARAbsenceofcomplementactivationbytheFicolin3pathwayRespiratoryinfections,abscesses604973 XL,X-linkedinheritance;AR,autosomalrecessiveinheritance;AD,autosomaldominantinheritance;MAC,membraneattackcomplex;SLE,systemiclupuserythematosus;MBP,mannose-bindingprotein;MASP2,MBP-associatedserineprotease2.aTenorfewerunrelatedcasesreportedintheliterature.NewentitiesaddedtoTable8demonstratetheimportantroleofcomplementregulatorsinagroupofwell-describedinammatorydisorders.Inparticular,wehaveaddedmutationsinmembraneboundaswellassurfaceattachedsolublecomplementregulatoryproteinsrecognizedinhemolytic–uremicsyndrome,age-relatedmaculardegeneration,andpreeclampsia.TheconnectingthemeoftheseotherwiseunrelatedclinicaleventsisexcessiveactivationorinsufcientregulationofC3;theseeventsleadtorecruitmentofleukocytesandpermitsecretionofinammatoryandanti-angiogenicmediatorsthatdisruptthevascularbedofthetargetorgan.AlterationsinthegenesforFactorB(CFB),FactorI(CFI),FactorH(CFH),andCD46actassusceptibilitygenesratherthandiseasecausingmutations.PopulationstudiesrevealnodetectableincreaseininfectionsinMBP(alsoknownatmannose-bindinglectin–MBL)decientadults.The3MCsyndrome,adevelopmentalsyndrome,hasbeenvariouslycalledCarnevale,Mingarelli,Malpuech,andMichelssyndrome.Table9|PhenocopiesofPID. DiseaseGeneticdefect/presumedpathogenesisCirculatingTcellsCirculatingBcellsSerumIgAssociatedfeatures/similarPID Associatedwithsomaticmutations(a)Autoimmunelymphoproliferativesyndrome(ALPS–SFAS)SomaticmutationinTNFRSF6IncreasedCD4�CD8�doublenegative(DN)Talpha/betacellsNormal,butincreasednumberofCD5CBcellsNormalorincreasedSplenomegaly,lymphadenopathy,autoimmunecytopeniasDefectivelymphocyteapoptosis/ALPS–FAS(DALPStypeIm)(b)RAS-associatedautoimmuneleukoproliferativedisease(RALD)SomaticmutationinKRAS(gain-of-function)NormalBcelllymphocytosisNormalorincreasedSplenomegaly,lymphadenopathy,autoimmunecytopenias,granulocytosis,monocytosis/ALPS-like (Continued) www.frontiersin.orgApril2014|Volume5|Article162|31 Al-Herzetal.PIDIUISclassication Table9|Continued DiseaseGeneticdefect/presumedpathogenesisCirculatingTcellsCirculatingBcellsSerumIgAssociatedfeatures/similarPID (c)RAS-associatedautoimmuneleukoproliferativedisease(RALD)SomaticmutationinNRAS(gain-of-function)IncreasedCD4�CD8�doublenegative(DN)Talpha/betacellsLymphocytosisSplenomegaly,lymphadenopathy,autoantibodies/ALPS-likeAssociatedwithautoantibodies(a)Chronicmucocutaneouscandidiasis(isolatedorwithAPECEDsyndrome)GermlinemutationinAIREAutoAbtoIL-17and/orIL-22NormalNormalNormalEndocrinopathy,chronicmucocutaneouscandidiasis/CMC(b)Adult-onsetimmunodeciencyAutoAbtoIFNgammaDecreasednaiveTcellsNormalNormalMycobacterial,fungal,SalmonellaVZVinfections/MSMD,orCID(c)RecurrentskininfectionAutoAbtoIL-6NormalNormalNormalStaphylococcalinfections/STAT3deciency(d)PulmonaryalveolarproteinosisAutoAbtoGM-CSFNormalNormalNormalPulmonaryalveolarproteinosis,cryptococcalmeningitis/CSF2RAdeciency(e)AcquiredangioedemaAutoAbtoCIinhibitorNormalNormalNormalAngioedema/C1INHdeciency(hereditaryangioedema) Therapidadvancesingeneidenticationtechnology,includingthewidespreaduseofwholeexomeandwholegenomesequenc-ing,hasmeantthattheabilitytoidentifygenedefectsinaffectedfamiliesandevensingleindividualswithinheriteddiseaseshasgrownenormously.Inthisreport,over30newgenedefectshavebeenaddedthatwereidentiedsincethepreviousclassicationinNovember,2011.ThesedefectscanbefoundinallmajorgroupsofPIDsincludedinthisreport.Inmanycases,themutationsarenotnecessarilyingenesformallyimplicatedinimmunecellfunc-tionbutaregenesinvolvedinessentialcellprocesses.ThemoredetailedanalysisandfunctionalconsequencesofsuchdefectsasillustratedbythesePIDswillincreaseourunderstandingoftheinterplaybetweendifferentcellularprocessesinthedevelopmentandfunctionoftheimmunesystem.Amongthenewlyidentied,genedefectsaremanythataretodateparticulartoasinglepedigreeorindividual;suchdefectsmayproveexceedinglyrare,orindeedmaynotnecessarilybefoundtorecurinotherindividuals.Wehavemarkedconditionsforwhichthereare10orfewerreportedindividualswithanaster-isk,althoughhistorically,followingthedescriptionoftherstfewcases,additionalindividualswithasimilarPIDphenotypeandgenotypehaveoftenbeenrecognized.Itislikelythatwewilluncovermanymore“personal”orveryraregenedefectsovertimeandthatthespectrumofPIDswillbecomeincreasinglydiverseandcomplex,duetocontributionsofbothenvironmentalexposuresandgeneticmodierstoeachaffectedindividual.Thevalueofthisreportthereforetocaptureandcatalogthefullspectrumatanyonetimepointbecomesincreasinglyimportant.ThegoaloftheIUISExpertCommitteeonPIDsistoincreaseawareness,facilitaterecognition,andpromoteoptimaltreatmentforpatientswithPIDs.Inadditiontothecurrentreportandpre-vious“classicationtable”publications,thecommitteehasalsoproduceda“PhenotypicApproachforIUISPIDClassicationandDiagnosis:GuidelinesforCliniciansattheBedside,”whichaimstoleadphysicianstoparticulargroupsofPIDsstartingfromclinicalfeaturesandcombiningroutineimmunologicalinvestiga-tions.Together,thesecontributionswillhopefullyallowapracticalclinicalframeworkforPIDdiagnosis.ThecommitteealsoaimstoestablishaclassicationofPIDsbasedonotheraspectsandwillworkonpublishingfurtherguidelinesinduecourse.ConictofInterestStatement:Theauthorsdeclarethattheresearchwasconductedintheabsenceofanycommercialornancialrelationshipsthatcouldbeconstruedasapotentialconictofinterest.Received:16December2013;accepted:27March2014;publishedonline:22April2014. FrontiersinImmunology|PrimaryImmunodecienciesApril2014|Volume5|Article162|32 Al-Herzetal.PIDIUISclassication Citation:Al-HerzW,BoushaA,CasanovaJ-L,ChatilaT,ConleyME,Cunningham-RundlesC,EtzioniA,FrancoJL,GasparHB,HollandSM,KleinC,NonoyamaS,OchsHD,OksenhendlerE,PicardC,PuckJM,SullivanKandTangMLK(2014)Pri-maryimmunodeciencydiseases:anupdateontheclassicationfromtheInternationalUnionofImmunologicalSocietiesExpertCommitteeforPrimaryImmunodeciency.Front.Immunol.5:162.doi:10.3389/mmu.2014.00162ThisarticlewassubmittedtoPrimaryImmunodeciencies,asectionofthejournalFrontiersinImmunology.Copyright©2014Al-Herz,Bousha,Casanova,Chatila,Conley,Cunningham-Rundles,Etzioni,Franco,Gaspar,Holland,Klein,Nonoyama,Ochs,Oksenhendler,Picard,Puck,SullivanandTang.Thisisanopen-accessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(CCBY).Theuse,distributionorreproductioninotherforumsispermitted,providedtheoriginalauthor(s)orlicensorarecreditedandthattheoriginalpublicationinthisjournaliscited,inaccordancewithacceptedacademicpractice.Nouse,distributionorreproductionispermittedwhichdoesnotcomplywiththeseterms. www.frontiersin.orgApril2014|Volume5|Article162|33