ARCHIVESOFDISEASEINCHILDHOODTABLE1BLOODEXAMINATIONSHbRBCYmillionmm3WBCpermm3StabCellsPolymorphonuclearNeutrophilsEosinophilsBasophilsLymphocytesMonocytesPlatelets ID: 949923
Download Pdf The PPT/PDF document "INFANTILECONGENITALANEUTROCYTOSISBYDAGFI..." is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
INFANTILECONGENITALANEUTROCYTOSISBYDAGFINNAARSKOGFromtheSchoolofMedicine,PaediatricDepartment,UniversityofBergen,Norway(RECEIVEDFORPUBLICATIONMARCH22,1961)In1956Kostmannreportedanewdiseaseofinfancywhichhetermed'infantilegeneticagranulo-cytosis'.Hedescribed14childrenofbothsexesinninefamilies.Allbuttwoofthechildrendiedasaresultofthedisease.Forsixofthemdetailedclinicalandhistologicaldatawerereported.Thediseaseoccursduringearlyinfancywithinfectionsparticularlyoftheskin.Thereisacompleteoralmostcompletelackofpolymorphonuclearneutro-philleucocytesintheperipheralblood,andthebonemarrowshowsamarkedretardationorblockinthematurationofthemyelopoieticcells.AlloftheaffectedchildreninhisreportlivedinthenorthernpartofSweden.Closeconsanguinitybetweentheparentswasestablishedinfiveoftheninefamilies.Kostmannpresentedageneticanalysiswhichsup-portedtheconclusionthatthediseasewasprimarilycausedbyasinglerecessiveautosomalgene(asimplerecessivemutation).SinceKostmann'soriginalreportthreeadditionalcasesbelongingtothesamefamilieshavebeenexamined(Kostmann,1960).Hedenberg(1959)describedacaseofagranulo-cytosisdiscoveredinagirlattheageof1week.Hefoundgoodagreementwithinfantilegeneticagranulocytosis.Inhiscasetherewasnocon-sanguinitybetweentheparents.ThefamilylivedinthesouthernpartofSweden,andtherewasnorelationshiptothefamiliesdescribedbyKostmann.OutsideSweden,Luhby,Speer,LeeandShapiro(1957)describedaninfantwhopresentedwithagranulocytosisat2weeksofage;itpersisteduntilthechilddiedofanoverwhelminginfectionwhen7monthsold.Theauthorsconcludedthatthecaserepresentedacongenitalgeneticagranulocytosisduetoaninbornerrorofdevelopmentandmatura-tionoftheneutrophils.TheyfoundtheconditionapparentlyidenticaltothatdescribedbyKostmann.KnikerandPanos(1957)studiedtwoinfantsaged7and30months,bothofwhomhadfatalagranulo-cytosis.Theystatedthattheclinical,laboratoryandpathologicalfeaturescloselyfittedthesyndromedescribedbyKostmann.However,allcasesonrecordoutsidethosebelongingtothefamiliesreportedbyKostmannhavefailedtoshowhere-ditaryorgeneticfactors.Thenumberofreportedcasesofthissyndromeisstillsmall,althoughthisdeleteriousmutationseemsnowtooccurindifferentareas.Thepurposeofthispaperistopresentafurthercasewithtypicalclinicalandlaboratoryfindings.CaseReportThepatientwasa2-month-oldgirladmittedtotheChildren'sHospital,Bergen,onJune4,1960,becauseofjaundice,pyodermiaandotitis.Therewasnoconsanguinitybetweentheparents,andthepatientwasthefourthchild.Asisterdiedofmeningitisattheageof2months.Therewasnoknowncaseofblooddisorderinthefamily.Themotherdidnotuseanymedicamentsduringthepregnancywhichwasuneventful.ThedeliverywasspontaneousattermonApril4,1960,andthechild'sbirthweightwas2,870g.Attheageof1weekshedevelopedpyodermia,andwhen10daysoldaslightjaundicewasobserved.Attheageof6weeksshehadanotitisandwastreatedwithaureomycin,120mg.daily.UponadmissiontotheChildren'sHospitalshelookedill,buthergeneralconditionwasnotseverelyaffected.Shewasthin,paleandslightlyicteric.Temperature37-70C.Ontheabdomenshehadseveralpea-size
d,bluish-redinfiltrations.Theliverwasfeltabout2cm.belowtherightcostalmarginandthespleenjustbelowtheleft.Shehadsignsofanotitiswithaclear,viscoiddischarge.ThebloodexaminationsaresummarizedinTable1.Examinationofthebonemarrowbyneedleaspirationrevealedacellularmarrowwithastrikingabsenceofneutrophilicmyeloidelements(Table2).Thetotalserumproteinwas6g.per100ml.withdecreasedalbuminfractionandelevatedgamma-globulinlevel.Examinationoftheserumforleucocyteantibodieswasnegative.Abloodculturewasnegative.CulturesfromtheearrevealedcoagulasepositiveStaphylococcusaureus,andfromthecutaneousinfiltrationstherewasgrowthofEscherichiacoli,ProteusvulgarisandEnterococcus.Shewastreatedwithlargedosesofpenicillinandwithstreptomycin,erythromycin,chloramphenicoland511 ARCHIVESOFDISEASEINCHILDHOODTABLE1BLOODEXAMINATIONSHbR.B.C.(Y.)(million/mm.3)W.B.C.(permm.3)StabCells(%Poly-morpho-nuclearNeutro-phils(%)Eosino-phils(%Baso-phils(%Lympho-cytes(%Mono-cytes(%)Platelets(permm.3X103)Reticulo-cytes(per1,000)Sedimen-tationRate4/6624-0113,300-2-465292241256/620,800--1505633113/6482-9217,800050545821251705013/6Bloodtransfusion20/6713-8214,700--9*5141*5481425227/6693*3618,700--8-50*57714121264/7683-3811,800--317719107/7549/716,200--9*55253823/7Bloodtransfusion27/77831529/7653-8230,800--20563-534288/8653-8015,300--12152352483015/86335336,100--815054053629/8Bloodtransfusion9/9854-8723,800--95414951214/9Bloodtransfusion15/9874-8218,000--8-56625*5619/918,000--20572255vancomycininappropriatedoses.Shealsoreceivedrepeatedbloodtransfusions.However,theclinicalcoursewasmarkedbyintermittentfeverandanewout-breakofcutaneousinfiltrations.Smearsofthelattershowedthecellularreactiontobemonocyticandlymphoid.ThroughoutthewholecourseonlyoccasionalTABLE2BONEMARROWEXAMINATION*neutrophilicgranulocyteswerefoundinsmearsfromtheperipheralblood.Plateletandreticulocytecountswerewithinnormallimits(Table1).AttemptstoimprovethebonemarrowwithvitaminB12andfolicacidwereofnoeffect.OnAugust30,1960,physicalexaminationrevealedsignsofpneumonia,andaradiographshowedmassiveconsolidationsinbothlungs.Despitemassiveanti-biotictherapyshediedonSeptember19,1960,ofanoverwhelminglunginfection.BloodbasophilsBasophilicmyelocytesSegmentedbasophilsEosinophils.EosinophilicmyelocytesEosinophilicmetamyelocytesStabeosinophils.Neutrophils.NeutrophilicpromyelocytesIIMonocytesMonoblastsPromonocytesMonocytes.Athrophagocytes.Lymphocytes.Plasmacells.PlasmoblastsProplasmocytesPlasmocytesMegakaryocyte-plateletsystemMegakaryocytesNormocytes.BasophilicnormoblastsPolychromatophilicnormoblastsOxyphilicnormoblastsIOxyphilicnormoblastsItNon-haemopoieticcellsOsteoblasts0*8Autopsy.Atautopsyscatteredpleuraladhesions02werefound.Intherightlungthereweretwolarge9*8abscesses,andintheleftlungseveralbronchopneumonic390foci.Microscopicallythewallofthelungabscesses1-6wasinfiltratedbymononuclearcellswithmanyplasma5-2cells.Thespleenwasalsorichinplasmacellsand0-8containedlargeamountsofhaemosiderin.Thebonemarrowshowedpronouncedmyelofibrosiswithdeposits26-8ofhaem
osiderin.Itcontainedmanyeosinophilic3°4granulocytesandplasmacells.Inthekidneysthere22-8werescatteredfociofcellularinfiltrationscontaining0-2mainlylymphoidcells,butalsomanyplasmacellsand44-8someeosinophilicgranulocytes.17-0Definitepolymorphonuclearneutrophilicleucocytes1-2werenotfound.9-26-604048-01*6302-41*004*ExaminationcarriedoutonAugust8,1960(500cellswerecounted).DiscussionAgranulocytosisafterdrugtherapyisawell-knownfeatureinadults,andisalsoknownasararecomplicationininfancyandchildhood.Thepresentpatientdidnotreceivemedicamentsknowntocauseagranulocytosis,neitherdidthemotheruseanydrugduringthepregnancy.Itisalsoawell-knownclinicalfactthatsevereinfections,especiallysepsis,maybeassociatedwith512Date(1960) INFANTILECONGENITALANEUTROCYTOSIS513leucopeniaandarelativegranulocytopenia.How-ever,leucopeniaisnotacommonfeatureinsepsis.RecentlyNyhanandFousek(1958)reportedaseriesof106newborninfantswithsepsis.Leucopeniawasnotedinfiveinfants.Persistentabsenceofpolymorphonuclearneutrophilleucocytessimilartothatobservedinthispatienthardlyoccursinsepsis.Duringthepastfewdecadesanumberofotherconditionsoccurringininfancyandchildhoodhavebeenobservedinwhichthereisanisolatedreductionorcompleteabsenceofpolymorpho-nuclearneutrophilleucocytes.Transitorygranulo-cytopeniaofthenewbornwasdescribedbySlobody,AbramsonandLoizeaux(1950)andLehndorff(1951).Inthisconditionthereisapronouncedgranulocytopeniawithadurationofseveraldaysuptofourweeks.Duringthegranulocytopenicphasethereisapatternofmaturationarrestattheneutrophilmyelocytestageinthebonemarrow.Thepersistentnatureoftheaneutrocytosisinthepresentcaserulesoutthispossibility.ChronicgranulocytopeniainchildrenwasfirstdescribedbyFanconi(1941),butSalomonsen(1948)firstputforwardtheopinionthatthesyndromerepresentedadistinctclinicalentity.Stahlie(1956)reportedacaseandcollected15casesfromtheliterature.Thesyndromeischaracterizedbyachronic,marked,selectivegranulocytopeniawithacorrespondingleucopenia.Thebonemarrowisnormal.Thediseaseusuallystartsaftertheageof6months,runsabenignprotractedcoursewithatendencytoinfectionsandspontaneouscure.Thisclinicalentitydiffersfromthecasereportedinthepatient'sageatonset,thepathologicalbonemarrow,thegravecourseandfataloutcome.ThepresentcaseseemstocorrespondcloselywithKostmann'ssyndrome.However,therewasnoconsanguinitybetweentheparentsandtodatenootherconclusivecaseofthediseasehasbeenfoundinthefamily.Itisnoteworthythatthepatienthadasisterwhodiedofmeningitisattheageof2months.Unfortunatelyherbloodwasnotexamined.Theearlyonsetintheneonatalperiodwithskinmanifestations,therelentlessclinicalcourseaswellasthefindingsintheperipheralbloodandbonemarrowareingoodagreementwiththefindingsinKostmann'scases.Themonocytosisaccompanyingtheaneutro-cytosisinthepatientresemblesthatseeninseveralpreviouslyreportedcases.IntwoofKostmann'scasesthemonocytesmadeup50%ofthetotalnumberofwhitecells.Monocytosisofmoderatedegreewasalsoobservedinanothercase.AmoderateincreaseinthetotalnumberofmonocyteswasnotedinthecasereportedbyLuhbyetal.(
1957).Hedenbergalsonotedmonocytosis,andinhiscaseavaryingconnexionbetweentheinfectionsandmonocytosiscouldbeobserved.ToblerandBuser-Pluss(1942)demonstratedexperimentallythatthemonocytesinapatientwithagranulocytosishadaconsiderablystrongerphagocyticfunctionthanthoseofcontrols.Themonocytosismaythereforerepresentacompensatorymechanismfortheimpairedphagoeyticfunctioninthispatient.Theelevatedserumgamma-globulinlevelfoundinthepresentpatientmayalsobecompensatoryasanattempttoraisetheimmunobiologicalprotectivemechanismsagainstinfection.Hypergammaglobu-linaemiawasalsonotedbyKostmanninonecaseandwasmarkedinbothcasesreportedbyKnikerandPanos(1957).Thelatterauthorsalsofoundeosinophiliaandplasmocytosisinthebonemarrow,findingssimilartothoseinthepresentpatient.Inviewoftheroleplayedbyplasmaandeosino-philiccellsintheimmunobiologicalresponsetoinfection,itseemsjustifiabletolookupontheplasmocytosisandeosinophiliaalsoassecondaryphenomena.Consideringtheterminologyofthissyndromeitseemsmorereasonabletousethetermaneutro-cytosisthanagranulocytosis,sinceonlythepoly-morphonuclearneutrophilicleucocytesareaffected.Theeosinophilicandbasophilicleucocytesmayactuallybeincreased.SummaryAcaseofinfantilecongenitalaneutrocytosisispresented.A2-month-oldgirlwhosufferedfrominfectionsstartingsoonafterbirth,revealedanalmostcompleteabsenceofneutrophilicmyelo-genouselementsintheperipheralbloodandbonemarrow.Thispersisteduntilshediedattheageof5monthsofanoverwhelmingpulmonaryinfection.ThecaseseemedtocorrespondcloselywithKostmann'ssyndrome,buttherewasnoevi-denceofgeneticbackground.IamindebtedtoEhrendozentDr.med.E.Undritz,Basel,Switzerland,forexaminingthebonemarrowsmear,andtoDr.P.Lexow,UniversityofBergen,forthepost-mortemexamination.IwishtoexpressmyappreciationtoProf.A.SundalandtoDr.0.K.Harlemfortheirvaluablehelpandcriticism.REFERENCESFanconi,G.(1941).KlinischeDemonstrationen.Ann.paediat.(Basel),157,317.Hedenberg,F.(1959).Infantileagranulocytosisofprobablycon-genitalorigin.Actapaediat.(Uppsala),48,77.Kniker,W.T.andPanos,T.C.(1957).Idiopathicinfantileagranulo-cytosiswithhypergammaglobulinemia.A.M.A.J.Dis.Child.,94,549. 514ARCHIVESOFDISEASEINCHILDHOODKostmann,R.(1956).Infantilegeneticagranulocytosis.Actapaediat.(Uppsala)45,suppl.105.-(1960).Personalcommunication.Lehndorff,H.(1951).TransitorischeGranulocytopeniebeimNeugeborenen.Helv.paediat.Acta,6,173.Luhby,A.L.,Speer,F.D.,Lee,R.andShapiro,A.D.(1957).Congeritalgeneticagranulocytosis.A.M.A.J.Dis.Child.,94,552.Nyhan,W.L.andFousek,M.D.(1958).Septicemiaofthenew-born.Pediatrics,22,268.Salomonsen,L.(1948).Granulocytopeniainchildren.Actapaediat.(Uppsala),35,189.Slobody,L.B.,Abramson,H.andLoizeaux,L.S.,Jr.(1950).Agranulocytosisinthenewborninfant.J.Amer.med.Ass.,142,25.Stahlie,T.D.(1956).Chronicbenignneutropeniaininfancyandearlychildhood.Reportofacasewithareviewoftheliterature.J.Pediat.,48,710.Tobler,W.andBuser-Pluss,E.(1942).BeobachtungenineinemFallevonchronischer,myelogener,hochgradigerNeutropeniemitmonocytarerReaktion.Ann.paediat.(Basel),159,25