revbrashematolhemoter.2017;39(4):372–374
w w w . r b h h . o r g
Revista
Brasileira
de
Hematologia
e
Hemoterapia
Brazilian
Journal
of
Hematology
and
Hemotherapy
Case
Report
Osteopetrosis
in
twin
infants
mimicking
leukemia
Mili
Jain
∗,
Purvi
Mittal,
Ayush
Shukla,
Ashutosh
Kumar
KingGeorge’sMedicalUniversity,Lucknow,India
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t
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Articlehistory: Received22April2017 Accepted20June2017 Availableonline21July2017
Introduction
Osteopetrosis(OP)variablyreferredtoas‘Marblebonedisease’ or‘AlbersSchonbergdisease’wasfirstdescribedbyaGerman radiologistin1904.Itisagroupofgeneticallyandclinically heterogeneousdisorderscharacterizedbyincreasedskeletal density.Clinicalseverityvariesfromasymptomaticadultsto alife-threateningconditionininfants.Autosomalrecessive osteopetrosishasan incidenceof1in250,000 birthswhile thedominantformhasanincidenceof1in20,000births.1
Wereport on twininfants withosteopetrosis presenting a leukoerythroblasticpictureandhepatosplenomegaly mimick-ingleukemia.
Case
report
Wereportontwomaletwininfantsbornofaconsanguineous Muslimmarriage.Case1wasanine-monthmalewith com-plaintsofrecurrentchestinfectionandfeverforfourmonths. Hehad delayeddevelopmentalmilestones(inabilitytohold neck,inability tosit) along withfailure togain weight. No historyofbleeding,jaundiceandneurologicalsymptomswas
∗ Correspondingauthorat:DepartmentofPathology,KingGeorge’sMedicalUniversity,Lucknow226003,India.
E-mails:milijain@kgmcindia.edu,milijain786@gmail.com(M.Jain).
present. He had received aone-unit packedred blood cell transfusionattheageoffivemonths.Onexamination,hehad pallorandseverewasting.Abdominalexaminationrevealed moderatehepatosplenomegaly.Case2wasthetwinsiblingof Case1whohad similarcomplaintsbutforsixmonths.On examination,hehadpallor,bulginganteriorfontanel along with moderate hepatosplenomegaly. The antenatal period was uneventful. There wasno other similar family history withahealthyelderfemalesibling.
TheperipheralbloodfilmexaminationofCase1showed a leukoerythroblastic blood picture along with anemia (Hb: 7g/dL) and thrombocytopenia (80×109/L). Case 2 had similar findings with severe anemia (Hb: 6.2g/dL) and thrombocytopenia (38×109/L). In view of peripheral blood findings,differentialsofbonemarrowinfiltrationrelatedto possiblehematopoieticmalignancy,metastaticdisease, non-neoplasticstoragedisorderorextramedullaryhematopoiesis (compensatorytomarrowinfiltrationor stress)wascarried out. The bone marrow examination was performed from medialtibialtuberositywithslightdifficulty.Thesmearswere cellular.Megakaryocyteswerereduced.Milderythroid hyper-plasia(M:Eratio1:1)wasseen,howevernoabnormalincrease inimmaturecellswas found.Histiocyticcells werenormal inmorphology.Theonlysignificantfindingwasofincreased
http://dx.doi.org/10.1016/j.bjhh.2017.06.002
revbrashematolhemoter.2017;39(4):372–374
373
Figure1–Bonemarrowaspirate(200×Leishmanstain)–osteoclastscluster-insetosteoclastwithingestedmaterial.
numberofosteoclastsinlargeclusters(Figure1).Considering abnormalosteolyticactivity,anX-rayevaluationwasadvised. X-rayofthe forearmrevealed increasedbone density with characteristicbonein boneappearance ofradiusand ulna (Figure2).OnevaluatingvitaminD,bothhadinsufficientlevels (15.9mg/dLand 21.5mg/dL,respectively).Other parameters ofcalciummetabolism,parathormone,phosphorus,alkaline phosphatase and calcium were withinreference ranges. A headcomputedtomographyscanwasunremarkablewithno evidenceofhydrocephalousorobliterationofopticforamina.
Figure2–X-rayanterior–posteriorviewoftheforearm–
boneinboneappearance.
Nofeaturesofrenaltubularacidosiswerepresent.Liver func-tionandrenalfunctionwerewithinreferenceranges.
Bothsiblingsweremanagedconservativelywithantibiotics andtransfusionsupport.
Discussion
Osteopetrosisisderivedfrom theGreekwordsosteo‘bone’ andpetrosis‘stone’.Itisduetodefectiveosteoclastfunction ordifferentiation.TheNosologyandClassificationofGenetic Skeletal Disorders 20062 categorizes OPinto severe
neona-tal/infantform,intermediateform,andlateonsetform.Also categorizedarevariantsassociatedwithrenaltubular acido-sis (OPwith RTA), withectodermal dysplasia and immune defect (OLEDAID),with leukocyte adhesion deficiency syn-drome(LAD-III).
In autosomal recessive osteopetrosis (AROP), the most commonmutation(60%)isseenintheTCIRG1geneaffecting theprotonpumpfunctioninvolvedinacidificationof resorp-tionlacunae.3Mutationsaffectingthechloridechannel(15%)
andcarbonicanhydrase(<5%)areothersonthelistleadingto AROP.
AROP classically manifests within the first year of life (frequentlywithinthreemonths).Visualimpairmentdueto compression of optic nerve is usually the most common presenting complaint.4 The majorityof casespresent with
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revbrashematolhemoter.2017;39(4):372–374OPwithRTAusuallywithadefectofthecarbonicanhydrase enzyme.3
Ourcasespresentedwithfailuretothrive,recurrent infec-tions and bone marrow failure. Features of cranial nerve involvement,acidosis, andmetabolicabnormalitywere not seenatthetimeofpresentation.
Variable spectrum of osteoclast appearances has been reportedinAROP.5 There arevariable increasesinnumber,
sizeandnucleationofosteoclasts.Electronmicroscopyreveals defectsinruffled border-clearzonecomplex.Ourcasehad increasednumberofosteoclastswithpresenceofclustersin bonemarrowaspiratesmears.
Bone marrow aspirate is usually difficult to obtain; we managed to prepare smears with difficulty. The trephine biopsyshowsinterweavingbonetrabeculaewithplatesof hya-linecartilage withminimalmedullarycavityand markedly reducedhematopoieticprecursors.
The radiological examination is diagnostic showing increasedbonedensitywithdiffuseorfocalsclerosisof vary-ingseverity.Ourcasesrevealedthecharacteristicboneinbone appearance.
Infants with severe OP frequently die during childhood withthemostcommoncauseofdeathbeing bonemarrow failure and infections. Achild oftwo years without trans-fusiondependencyindicatesfavorableprognosis.Anurgent bone marrow transplant is the only curative treatment so far.Patientsreceivinggraftsfromhumanleukocyteantigen (HLA)-identicalsiblingshaveafive-yeardiseasefreesurvival of73–79%.Forcaseswithunrelatedormismatcheddonors, thesurvivalaftertransplantis13–45%.6Otheralternative
ther-apiessuchascalcitriolandinterferon-␥havebeentriedwith minimalsuccess.Targetedgenetherapywithgenetically mod-ifiedretroviralvectorfortheTCIRG1genemutationhasbeen exploredin micemodels,with asurvivalofapproximately 50%.7
Thediseasehasanautosomalrecessiveinheritance pat-tern,implyingariskofphenotypicmanifestationinoneoffour
offspring.Theidentificationofmoleculardefectsinparentsis usefulforantenatalscreeninginsubsequentpregnancies.
AlthoughAROPisararedisorder,itmimicsa hematologi-calmalignancy.Acarefulevaluationofallcomponentsofbone marrowmayprovidecluestothediagnosis.Aradiological sur-veymustbeconsideredininfantswithunexplainedanemia andhepatosplenomegaly.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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1.StarkZ,SavarirayanR.Osteopetrosis.OrphanetJRareDis. 2009;4:5.
2.Superti-FurgaA,UngerS,NosologygroupoftheInternational SkeletalDysplasiaSociety.Nosologyandclassificationof geneticskeletaldisorders:2006revision.AmJMedGenet. 2017;143A:1–18.
3.TolarJ,TeitelbaumSL,OrchardPJ.Osteopetrosis.NEnglJMed. 2004;351(27):2839–49.
4.WilsonCJ,VellodiA.Autosomalrecessiveosteopetrosis: diagnosis,managementandoutcome.ArchDisChild. 2000;83(5):449–52.
5.ShapiroF,KeyLL,AnastC.Variableosteoclastappearancein humaninfantileosteopetrosis.CalcifTissueInt.
1988;43(2):67–76.
6.AskmyrMK,FasthA,RichterJ.Towardsabetterunderstanding andnewtherapeuticsofosteopetrosis.BrJHaematol.
2008;140(6):597–609.
