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rev bras hematol hemoter. 2015;37(3):150–152

w w w . r b h h . o r g

Revista

Brasileira

de

Hematologia

e

Hemoterapia

Brazilian

Journal

of

Hematology

and

Hemotherapy

Scientific

Comment

The

compound

state:

Hb

S/beta-thalassemia

夽

Maria

Stella

Figueiredo

∗

UniversidadeFederaldeSãoPaulo(UNIFESP),SãoPaulo,SP,Brazil

Sickle cell disease (SCD) results from a single amino acid substitution in the gene encoding the ␤-globin subunit (␤6Glu>Val) that produces the abnormal hemoglobin (Hb) namedHb S.SCD hasdifferent genotypeswithsubstantial variationsinpresentationandclinicalcourse(Table1).1,2The combinationofthesicklecellmutationandbeta-thalassemia (␤-Thal)mutationgivesrisetoacompoundheterozygous con-ditionknownasHbS/␤thalassemia(HbS/␤-Thal),whichwas firstdescribedin1944bySilvestroniandBianco.3

ThepolymerizationofdeoxygenatedHbS(sickling)isthe primaryeventinthe molecularpathogenesisofSCD. How-ever,thisevent ishighlydependentontheintracellularHb composition;inotherwords,itisdependentonthe concen-trationofHbS,andtypeandconcentrationoftheothertypes ofHb.Therefore, themajorprimarygeneticdeterminantof theseverityofSCDisthegenotype.2,4–6

Many different ␤-Thal mutations have been associated withHbS,andthemolecularbasisofthethalassemiainHb S/␤-Thalindividualsreflectsthespectrumof␤-Thalmutations observedinaparticularpopulation.5,7–12Theheterogeneityof the␤-Thalmutationsleadstoquantitativelydifferent␤-globin synthesisandconsequentlytodifferentamountsofHbA.This factresultsinvariableclinicalmanifestations,rangingfrom nearlyasymptomatictoasevereconditionsimilartosicklecell anemia(homozygousHbS).3,13Thereisnoconsensusabout theclassificationofHbS/␤-Thal,butitisusuallyclassifiedin twotypes:HbS/␤0-ThalandHbS/␤+-Thal.2,4

Hb S/␤0-Thal, inwhich the productionof Hb Ais abol-ished, is often clinically indistinguishable from sickle cell anemia. The thalassemia acts on sickled red blood cells, inducing microcytosis, hypochromia, and sometimes Hb F iselevated.Thisresultinanimprovementofthecirculatory competenceofthesecells,areductionofhemolysis,and a

DOIoforiginalarticle:http://dx.doi.org/10.1016/j.bjhh.2015.03.010. 夽

SeepaperbyBelisárioetal.onpages198-201.

∗ Correspondingauthorat:RuaDr.DiogodeFaria,824,3◦andar,CEP:04037-002,VilaClementino,SãoPaulo,SP,Brazil.

E-mailaddress:stella.figueiredo@unifesp.br

smallincreaseinHbconcentrationandinpackedcellvolume. However,theseeffectsarenotaccompaniedbyanyreduction invaso-occlusiveevents,probablyduetothegreatnumberof HbS-containingredblood cellsresultinginincreasedblood viscosity.4,5

A confusing diagnostic problem is the differentiation of Hb S/␤0-Thal from sickle cell anemia associated with ␣-thalassemia. Table 2 shows that hematologic and elec-trophoreticstudiesareunabletodistinguishbetweenthetwo conditionsandsofamilystudiesandDNAanalysisareneeded toconfirmthediagnosis.5

InHbS/␤+-Thal,variableamountsofHbAdiluteHbSand consequently inhibit polymerization-induced cellular dam-age.TheHbAlevelsvaryfrom<5%to45%ofthehemolysate and higher levels of Hb A are usually associated with a milderphenotype.5,8,12–15However,becauseofthe confound-inginfluencesofothergeneticmodifiers,suchas␥-globingene expression and ␣-thalassemia, arigid genotype–phenotype correlationisdifficulttoestablish.5

AclassificationofHbS/␤+-ThalintoTypesI(HbA:1–7%), II(HbA:7–14%),orIII(HbA:14–25%)accordingtothelevelof HbAhasbeenproposed.3,14However,thisclassificationisnot widelyacceptedandcouldbeconsideredoflittleutility. Nowa-daysit ispossibletodefinethe␤-Thalmutationexactlyby molecularbiologytechniques,anddeterminetherelationship betweenmutationandclinicalmanifestations.5

Thedeterminationofthe␤-ThalmutationinHbS/␤+-Thal individualswasperformedbyBesilarioetal.Theseauthors studiedfourpatientswithanHbAconcentrationabove38% andaverymildformofthedisease,andidentifiedtwo muta-tions for the first time in the Brazilian population.16 It is importanttopointoutthatthesecasescouldbewrongly inter-pretedassicklecelltrait,sincetheyhadnoanemia,despite

http://dx.doi.org/10.1016/j.bjhh.2015.02.008

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revbrashematolhemoter.2015;37(3):150–152

151

Table1–Sicklecelldiseasegenotypes.

Severesicklecelldisease

Sicklecellanemia(HbS/S) ␤6Glu>Val/␤6Glu>Val Themostcommonform

HbS/␤0thalassemia Multiplemutations Mostprevalentintheeastern

MediterraneanregionandIndia

SevereHbS/␤+thalassemia Multiplemutations Mostprevalentintheeastern

MediterraneanregionandIndia HbS/OArab ␤6Glu>Val/␤121Glu>Lys NorthAfrica,theMiddleEast,andthe

Balkans

HbS/DPunjab ␤6Glu>Val/␤121Glu>Gln PredominantinnorthernIndia

HbS/CHarlem ␤6Glu>Val/␤6Glu>Val/␤,␤73Asp>Asn Veryrare

Moderatesicklecelldisease

HbS/C ␤6Glu>Val/␤6Glu>Lys 25–30%casesofsicklecelldiseaseof

Africanorigin

ModerateHbS/␤+thalassemia Multiplemutations MostintheeasternMediterraneanregion

Mildsicklecelldisease

MildHbS/␤++thalassemia Multiplemutations MostlyinpopulationsofAfricanorigin

HbS/E ␤6Glu>Val/␤26Glu>Lys HbEpredominatesinsoutheastAsia

Verymildsicklecelldisease

HbS/HereditaryPersistenceofFetalHemoglobin Largedeletionsofthe␤-globingenecomplex

Source:ModifiedfromReesetal.1

Table2–Laboratorydifferentiationofsicklecellanemia,sicklecellanemia/␣-thalassemia,andHbS/␤0-thalassemia.

Diagnosis Levelvariation MeanHbF(%)

Hemoglobin(g/dL) MCV(fl) HbA2(%)

SCA 7–8 85–95 2.5–3.5 5

SCA/␣-thalassemia 8–10 70–85 3.5–4.5 5

HbS/␤0-thalassemia 8–10 65–75 4–6 9

Source:ModifiedfromSteinbergetal.5

SCA:sicklecellanemia;MCV:meancorpuscularvolume;HbA2:hemoglobinA2;HbF:hemoglobinfetal.

alittlemicrocytosis,andthatthisincorrectdiagnosiswould reflectinthegeneticcounselingprovided.Insummary,this studyreinforcestheimportanceofmolecularstudiesinour population,inordertoenhanceourknowledgeaboutthe dis-easeinBrazilandconsequentlyimprovegeneticcounseling, followup,andtreatment.

Conflicts

of

interest

Theauthordeclaresnoconflictsofinterest

Acknowledgments

TheauthorwishestothankCoordenac¸ãodeAperfeic¸oamento dePessoaldeNivelSuperior(CAPES)andConselhoNacionalde DesenvolvimentoCientíficoeTecnológico(CNPq)forfinancial support.

r

e

f

e

r

e

n

c

e

s

1. ReesDC,GibsonJS.Biomarkersinsicklecelldisease.BrJ Haematol.2012;156(4):433–45.

2. StuartMJ,NagelRL.Sickle-celldisease.Lancet. 2004;364(9442):1343–60.

3.DacieJ.Thehereditaryhaemolyticanaemias.3rded.New York:ChurchillLivingstone;1988.

4.TheinSL.Geneticmodifiersofsicklecelldisease. Hemoglobin.2011;35(5-6):589–606.

5.SteinbergMH.Compoundheterozygousandothersickle hemoglobinopathies.In:SteinbergMH,ForgetBG,HiggsDR, NagelRL,editors.Disordersofhemoglobin:genetics, pathophysiology,andclinicalmanagement.1sted.

Cambridge,UK:CambridgeUniversityPress;2001.p.786–810. 6.ForgetBG,BunnHF.Classificationofthedisordersof

hemoglobin.ColdSpringHarbPerspectMed. 2013;3(2):a011684.

7.RiganoP,RodgersGP,RendaD,RendaMC,AquinoA,Maggio A.Clinicalandhematologicalresponsestohydroxyureain SicilianpatientswithHbS/beta-thalassemia.Hemoglobin. 2001;25(1):9–17.

8.SchmuggeM,WayeJS,BasranRK,ZurbriggenK,Frischknecht H.TheHbS/beta+-thalassemiaphenotypedemonstratesthat theIVS-I(−2)(A>C)mutationisamildbeta-thalassemia

allele.Hemoglobin.2008;32(3):303–7.

9.LacanP,PonceauB,AubryM,FrancinaA.MildHb

S-beta(+)-thalassemiawithadeletionoffivenucleotidesat thepolyadenylationsiteofthebeta-globingene.Hemoglobin. 2003;27(4):257–9.

10. BoletiniE,SvobodovaM,DivokyV,BaysalE,CurukMA, DimovskiAJ,etal.Sicklecellanemia,sicklecell beta-thalassemia,andthalassemiamajorinAlbania: characterizationofmutations.HumGenet.1994;93(2):182–7. 11.Gonzalez-RedondoJM,KutlarA,KutlarF,McKieVC,McKie

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revbrashematolhemoter.2015;37(3):150–152

beta-thalassemiainAmericanblacks.AmJHematol. 1991;38(1):9–14.

12.DivokyV,BaysalE,SchiliroG,DibenedettoSP,HuismanTH.A mildtypeofHbS-beta(+)-thalassemia[−92(C→T)]ina

Sicilianfamily.AmJHematol.1993;42(2):225–6.

13.KinneyTR,WareRE.Compoundheterozygousstates.In: EmburySH,HebbelRP,MohandasN,SteinbergMH,editors. Sicklecelldisease:basicprinciplesandclinicalpractice.1st ed.NewYork:RavenPressLtd.;1994.p.437–51.

14.SerjeantGR,SerjeantBE,FraserRA,HambletonIR,HiggsDR, KulozikAE,etal.HbS-beta-thalassemia:molecular, hematologicalandclinicalcomparisons.Hemoglobin. 2011;35(1):1–12.

15.SerjeantGR.Thenaturalhistoryofsicklecelldisease.Cold SpringHarbPerspectMed.2013;3(10):a011783.

Imagem

Table 2 – Laboratory differentiation of sickle cell anemia, sickle cell anemia/␣-thalassemia, and Hb S/␤ 0 -thalassemia.

Referências

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