www.rpped.com.br
REVISTA
PAULISTA
DE
PEDIATRIA
REVIEW
ARTICLE
Turner
syndrome
and
genetic
polymorphism:
a
systematic
review
Alessandra
Bernadete
Trovó
de
Marqui
∗UniversidadeFederaldoTriânguloMineiro(UFTM),Uberaba,MG,Brazil
Received18September2014;accepted29November2014 Availableonline29June2015
KEYWORDS Turnersyndrome; Genetic
polymorphism; Growthhormone; Aneuploidy
Abstract
Objective: TopresentthemainresultsoftheliteratureongeneticpolymorphismsinTurner syndromeandtheir associationwiththeclinicalsigns andtheetiologyofthischromosomal disorder.
Datasources:ThereviewwasconductedinthePubMeddatabasewithoutanytimelimit,using thetermsTurnersyndromeandgeneticpolymorphism.Atotalof116articleswerefound,and basedontheestablishedinclusionandexclusioncriteria17wereselectedforthereview.
Datasynthesis: ThepolymorphismsinvestigatedinpatientswithTurnersyndromewere asso-ciatedwithgrowthdeficit,causingshortstature,lowbonemineraldensity,autoimmunityand cardiacabnormalities,whicharefrequentlyfoundinpatientswithTurnersyndrome.Therole ofsinglenucleotidepolymorphismsintheetiologyofTurnersyndrome,i.e.,inchromosomal nondisjunction,wasalsoconfirmed.
Conclusions: GeneticpolymorphismsappeartobeassociatedwithTurnersyndrome.However, inviewofthesmallnumberofpublishedstudiesandtheircontradictoryfindings,furtherstudies indifferentpopulationsareneededinordertoclarifytheroleofgeneticvariantsintheclinical signsandetiologyoftheTurnersyndrome.
© 2015 Sociedadede Pediatriade São Paulo. Publishedby Elsevier Editora Ltda. Allrights reserved.
PALAVRAS-CHAVE SíndromedeTurner; Polimorfismo genético;
SíndromedeTurnerepolimorfismogenético:umarevisãosistemática
Resumo
Objetivo: Apresentar os principais resultados dos estudos que investigaram polimorfismos genéticosemsíndromedeTurner,bemcomosuaassociac¸ãocomalgunssinaisclínicoseetiologia dessedistúrbiocromossômico.
DOIoforiginalarticle:http://dx.doi.org/10.1016/j.rpped.2014.11.014
∗Correspondingauthor.
E-mail:alessandratrovo@hotmail.com
Hormôniodo crescimento; Aneuploidia
Fontesdedados: Revisão bibliográfica feita no PubMed, sem limite de período, com os seguintestermos:Turnersyndromeandgeneticpolymorphism.Foramidentificados116artigos e,deacordocomoscritériosdeinclusãoeexclusão,17foramselecionadosparaleitura.
Síntesedosdados: Os polimorfismos investigados em pacientes com síndrome de Turner estavamrelacionadoscomdéficitdecrescimento,quecausoubaixaestatura,densidademineral ósseabaixa,autoimunidadeeanomaliascardíacas,quepodemestarpresentescom frequên-ciassignificativasnas pacientes. Tambémfoiverificado opapel dos polimorfismosdeúnico nucleotídeo(SNPs)naetiologiadasíndromedeTurner,ouseja,nanãodisjunc¸ãocromossômica.
Conclusões: OspolimorfismosgenéticosparecemestarassociadosàsíndromedeTurner. Entre-tanto,por contadospoucosestudos publicadose dosachadoscontraditórios, pesquisasem diferentespopulac¸õessãonecessáriasparaesclareceropapeldessasvariantesgenéticaspara ossinaisclínicoseaetiologiadodistúrbiocromossômico.
© 2015SociedadedePediatria de SãoPaulo. Publicado porElsevier EditoraLtda. Todosos direitosreservados.
Introduction
The description of female patients with Turnersyndrome (TS) was published in 1938 by Henry Turner1; however,
in1930, German pediatrician Dr.Otto Ullrichhadalready reportedacaseofan8-year-oldgirlwithsignssuggestiveof TS.2 Therefore,thissyndromeisalsocalled Ullrich-Turner
syndrome.
The disorder has an incidence of 1/2500 girls and clinical signs include lymphedema of hands and feet, short and webbed neck, low hairline at the nape of the neck, cubitus valgus, hypoplastic or hyperconvex nails, micrognathia, high-arched palate, short stature, gonadal dysgenesis,primaryamenorrhea,sexualinfantilism, infertil-ity,shieldchest,breasthypertelorism,cardiac(coarctation of the aorta and ventricular septal defects) and renal anomalies(horseshoekidney,urethralduplicationand uni-lateralkidneyagenesis),multiplepigmentednevi,scoliosis, fourth/fifthmetacarpal or metatarsalhypoplasia or both. Thefollowingproblemsmayalsobepresent:hearing impair-ment, arterial hypertension, osteoporosis, obesity, visual disturbances,impaired glucosetolerance,learning disabil-ities, psychosocial problems and thyroid diseases, among otherautoimmunediseases.3
TSischaracterizedbylargephenotypicvariability, rang-ingfromtheclassicalform(girlswithpubertaldevelopment andgrowthdelay)tothosewithfewdysmorphicsigns,which arealmostindistinguishablefromthegeneralpopulation.4
ThedefinitivediagnosisofTSiscarriedoutbyanalyzingthe karyotype,which allows the identification of the individ-ual’s chromosomal constitution. TS chromosomal etiology was only elucidated in 1959, when the first patient was investigated by cytogenetics and showed the 45, X chro-mosomalconstitution.5BrazilianstudiesinpatientswithTS
showedthatthekaryotype45,X,i.e.,monosomyofthesex chromosomeX, wasfound in 40---60% of patients withTS, butmosaicismsandkaryotypeswithstructuralalterations, mainlyisochromosomes,arealsofound.4,6---8Aretrospective
studyindicatedthatbetter-qualitydiagnosishasimproved thequalityofthecytogeneticresultofTS,withmodification oftheproportionbetweenthetypesofkaryotypeobserved,
especiallytheprogressivedecreaseintheidentification of 45,X patientsand increaseddetection ofkaryotypeswith structuralaberrations.6
InBrazil,themeanageofTSdiagnosisisaround12years of age,4,7,9,10 and 25.3% and 51.1% of the patients were
respectively diagnosedinchildhood(1---11years)and ado-lescence (12---18 years),onaccount ofthe shortstature.7
Therefore,itisimportanttoassessgirlswithshortstature, regardlessofthepresenceoftypicaldysmorphicsignsand pubertal delay, by requesting the karyotype analysis to confirm or rule out TS. The authors also point out that neonatologistsandpediatriciansshouldbeawareaboutthe possibilityofgeneticsyndromessuchasTS,consideringthat themainsignsarepresentatbirth,butarenottakeninto accountatthattime.7Thus,medicaltrainingimprovement
aimedtorecognizethespectrumofclinicalmanifestations of thischromosomalsyndromeis necessary.Inadditionto thedifficultyofachievinganearlydiagnosisofthisgenetic condition, other factorsassociated with lateTS diagnosis include lesssevere growth retardation, presence of spon-taneous pubertal signs, socioeconomic determinants and absenceofobviousdysmorphicfeatures.4,10
EarlydiagnosisofTSis vital,asitalsoallowsthe iden-tification of congenital and acquired anomalies, as well as the detection of cases with Y chromosome sequences in the karyotype, which is associated with gonadoblas-toma, a tumor with high malignant potential that can bepreventedthroughprophylacticgonadectomy,11besides
allowing hormonal treatments withgrowth hormone (GH) andoxandrolone12andestrogen/progestogen12,13to
respec-tivelyincreasefinalheightandaccentuatesecondarysexual characteristics at the adequate chronological age, pre-venting further damage to patient health. Therefore, an early and accurate diagnosis is important for a success-ful therapeutic approach. It is noteworthy that there is no classical karyotype or phenotype associated with TS, and the diagnosis is not always evident, but should be activelysought,bothfromaclinicalandcytogeneticpoint ofview.6
etiology.SNPs,whicharedefinedasachangethatcanoccur inoneofevery1000basepairs,arecommoninthehuman genomeandareinvolved inseveralhuman diseases.They correspondtogeneticalterationspresentinmorethan1% of the population andcan belocated in differentregions ofthegene:promoter,codingandnon-coding.SNPsinthe codingandpromoterregionsaremorelikelytoaltergene functionand,consequently,theformedprotein.14
Inthiscontext,thisstudyaimstoreviewthemainresults ofthestudiesinvestigatinggeneticpolymorphismsinTS,as wellastheirassociationwithclinical signsandetiologyof thischromosomaldisorder.
Method
Thepresentstudyisaliteraturereview,withadescriptive approach.AsurveywascarriedoutinPubMed,inJuly2014, without timelimit,usingthe followingterms: Turner syn-dromeandgeneticpolymorphism.ThePubMeddatabasewas chosenforthissystematicreviewbecauseitismore compre-hensiveandinternationallyusedforresearchesinthehealth area.
Inclusion criteria were articles closely related to the topicand selection wasbased ontitles and/or abstracts, fullarticleavailabilityandpublicationinEnglishand/or Por-tuguese.The onesthat didnotmeetthe abovementioned criteriawereexcluded.
A total of 116 articles werefound. Of these, 14 were selectedand102excluded.Oftheexcludedones,21 con-tainedthetermTurnerinthelistofauthors.Thereference lists of the included articles were also assessed to iden-tifyrelevantstudiesnotdetectedbytheelectronicsearch. Based on the established inclusion criteria, we selected threemorestudies,totaling17.
Results
Themainresultsofthe17studies15---31 includedinthis
sys-tematicreviewareshowninTable1.
Discussion
Thepresentstudyisareviewarticleonstudiesabout contri-bution of polymorphisms to the manifestations of TS, its etiologyandresponsetotreatment.SNPsshowninTable1
are related to growth deficit, leading to short stature, low bone mineraldensity,autoimmunityand heart abnor-malities; these characteristics are present at significant frequency in patientswithTS. The roleof polymorphisms in the etiology of TS, namely, the chromosomal non-disjunction,wasalsodemonstrated.
Shortstature
One of the main clinical signs of TS is short stature, which was present in 97% and 100% of patients with TS assessed.7,8 Thus,growth hormonetherapy (GHT)is given
to thesepatients toincrease their final adult height. GH exerts its biological functions by direct binding to the GHR (Growth Hormone Receptor) or indirectly via IGF-1
(Insulin-LikeGrowthFactor) in synergy.32 Therefore,
poly-morphismintheGHRmayaffecttheresponsetoGHtherapy inpatientswithTS.
TheGHRgeneislocatedon5p13.1-p12andhastwo dif-ferentisoforms:acomplete orfull-length(GHRfl)andone withdeletionofexon3(GHRd3).Threepossiblegenotypes canbeobserved:fl/fl,fl/d3andd3/d3,withthelatterbeing the one with the lowest frequency. The GHRd3 polymor-phismwasevaluatedinsevenstudiesregardingitsinfluence on response to therapy with recombinant human growth hormone(rhGH)inpatientswithTS.Fourstudieshave inves-tigatedthis SNPalone15,17,19 andthree, itsrole aloneand
incombination withpolymorphismsin theVDR(vitamin D receptor),IGFBP3 (insulin-like growth factor binding pro-tein)and SOCS2 (suppressorof cytokine signaling) genes, via gene-gene interaction.18,20,21 The results obtained by
the German15,16 and Brazilian groups20,21 reported a
posi-tiveassociationbetweentheinvestigatedSNPsandgrowth responsetorhGH therapy. The VDR geneis important for height because it interferes with calcium and phosphate homeostasis, influencing skeletal growth.18 Additionally,
polymorphismsinheritedfromtheVDRgenecanaffectIGF signalingandinturn,responsetorhGHinpatientswithGH deficiency and TS. The polymorphisms −202 A/C IGFBP3
andSOCS-2areinvolvedin thepharmacogeneticsof rhGH andnegativeregulationofGHRsignaling,respectively.20,21
In one of these studies, the authors suggest the use of thesegeneticmarkers toidentify,amongpatientstreated withrhGH,thosegeneticallypredisposedtohaveless favor-ableresults.21Thehomozygousstateforthed3-GHRallele
wasassociated withweight control and body mass index (BMI) in TS in one study,16 but not in another.17
Regard-inggrowth,polymorphismsintheGHRgenecontributedto therapyresponsealone15 orincombination.20,21 Oneofthe
studies20mentionedthatthepossiblereasonsforthelackof
correlationintwopreviousstudiesincludedthesmall num-berofpatientsevaluated18andthefactthatfewindividuals
arecarriers of the d3 allele.17 The latter study reported
thatthegenotypes ofthe GHRgenecouldnot bedivided inthreegroupsasa consequenceof thelowfrequency of alleled3,which couldhave ledtonegativeresults.17 The
threestudiesthat showednegativeassociation of the d3-GHR polymorphism were carried out in Korea, Venezuela andTurkey.17---19 Oneofthem18reportedthatthestudywas
limitedbysamplesize.However,thefindingswerethe prod-uct of a prospective study18 and the previous researches
were retrospective.15---17 The need for prospective studies
wasreportedbytwostudies.17,20Onewaytoincreasesample
sizeis toperform multicenterstudies, such asthose car-riedoutbyKoetal.17andBas¸etal.,19 bothretrospective.
Inthe first study,the 175 patients with TS were from20 hospitalsinKorea.17Thestudypublishedin2012reportedly
includedthelargestnumberofpatientsamongstudies car-riedout sofar, but only evaluated 43 patientswith TS,19
a number similar to that of non-multicenter studies.15,16
Becauseofthedifficultyinobtaininglargeandhomogeneous samplesof patients with TS andGH deficiency, multicen-ter studies and/or meta-analyses are needed to confirm theroleof thispolymorphism in thepharmacogenetics of rhGH.21 Itisalsonoteworthythat,inrelationtoGH
Table1 Summaryofkeyfindingsof17studiesthatevaluatedgeneticpolymorphismsinTurnersyndrome.
Gene/Reference Samplesize Origin Mainfindingsorconclusion
GHR
Binderetal.15
53girlswithshortstature duetoTS
Germany GirlswithTStreatedwithrhGHtherapy andcarriersofoneortwod3alleles showedincreasedgrowthrate, exceededtheprojectedgrowthand showedagainof1.5cminheight 60childrensmallforGA
62controls
GHR
Binderetal.16
48womenwithTS Germany d3-GHRinhomozygousstatewas associatedwithgaininheightandthe meanweightandBMIwerelowerin Groupd3/d3inpatientsundergoingGH therapy
GHR Koetal.17
175patientswithTS Korea Thed3-GHRgenotypewasnot
associatedwithgrowthandweight(BMI) inTSpatientsundergoingGHtherapy 100controls
GHRandVDR
Alvarez-Navaetal.18
28childrenwithGHD Venezuela Polymorphisms,eitherindividuallyorin combination,didnotcontributetoGH therapyresponse
25patientscomTS 100healthyadults GHR
Bas¸etal.19
218patientswithGHD Turkey ResponsetoGHtherapydoesnotdepend ond3-GHRgenotypes
43patientswithTS 477adultcontrols GHRandIGFBP3
Brazetal.20
112patientswithTS Brazil PatientscarryingatleastoneGHR-d3 alleleor−202AIGFBP3hadhigher
growthrateandbecametalleradults thanthosehomozygousforGHR-flor
−202CIGFBP3,withthetwolatterones
beingassociatedwithlessfavorable growthresultsafterrhGHtreatment
GHR,IGFBP3andSOCS2 Brazetal.21
65patientswithTS
47heightpatientswithGHD
Brazil PolymorphismSOCS2alone (alleleC)showedinfluence onadultheight.SOCS2---T, GHR-fland−202CIGFBP3in
homozygousstatewere unfavorablegenotypesfor adultheight
VDR
Peralta-Lópezetal.22
65womenwithTS 110genotypehealthy
Argentina PolymorphismsBsmIandFokI,genotypes bbandffrespectively,wereassociated withlowerBMD,whereasthe
polymorphicsiteApaIwasnot.
Osteocalcinand-CrossLaps,markersof boneformationandresorption,
respectively,weresimilarinpatients withTS,regardlessofthegenotype VDR
Peralta-Lópezetal.23
55patientswithTS 59controlwomen
Argentina PatientswiththeGGgenotypeof polymorphismCdx2showedhigherlevels ofosteocalcinand-CrossLaps,i.e., markersofboneformationand resorption,respectively ER-␣
Sowinska-Przepiera etal.24
32patientswithTS 82therapyhealthycontrol women
Poland Therecessivehomozygousgenotypes(xx andpp)ofpolymorphismXbaIandPvuII wereconsideredgoodmarkersofbone mineralizationinpatientsundergoing estroprogestagentherapy
VDR
Biancoetal.25
101womenwithTS 133healthyfertilewomen withouthistoryof autoimmunedisease
Table1(Continued)
Gene/Reference Samplesize Origin Mainfindingsorconclusion
PTPN22
Biancoetal.26
142womenwithTS 180healthyandfertile womenwithouthistoryof autoimmunedisease
Brazil Genotypefrequenciesofpolymorphism C1858Twerestatisticallydifferentin TS,suggestingthatthisSNPcouldbea majorgeneticriskfactorthat
predisposestoautoimmunediseasein BrazilianpatientswithTS
AT2R
Struweetal.27
97patientswithCoa Germany A→Gtransitionatposition1675in
intron1ofAT2Rgeneisnotassociated withthepathogenesisofCoAand/orTS 28patientswithTS
10patientswithCoAandTS 96healthychildren MTHFR
Santosetal.28
49patientswithTS 200apparentlyhealthy individuals
Brazil IndividualswithTSshowedanincrease inthefrequencyofhomozygous genotypeC677T,indicatingpossiblerisk factorforchromosomalnon-disjunction asitdecreasestheactivityoftheMTHFR enzyme
MTHFR
Oliveiraetal.29
140patientswithTS Brazil InpatientswithTS,the1298CCgenotype wasmorefrequentandassociatedwith increasedriskofaneuploidy
209healthyfertilewomen withnochildrenwith chromosomalaneuploidy MTHFR
Oliveiraetal.30
78womenwithTS Brazil PolymorphismMTHFRA1298C(alleleC) andthetwohaplotypesCCandTCof SNPsMTHFR,C677TandA1298Cwere alsoassociatedwithTS
372healthyindividuals withoutpersonalorfamily historyofcardiovascular diseaseandcancer EFHC2
Zinnetal.31
97Caucasianpatientswith TS
USA Polymorphismrs7055196wasnot associatedwithfear
TS,Turnersyndrome;rhGH,recombinanthumangrowthhormone;GH,growthhormone;BMI,bodymassindex;GHD,GHdeficiency; BMD,bonemineraldensity;CoA,coarctationoftheaorta;SNPs,singlenucleotidepolymorphisms;GA,gestationalage.
groupofresearchersseekingtoestablish anindividualized therapy.33,34
Positive associations have been reported only for indi-viduals of the same ethnic origin.15,16,20,21 In spite of the
contradictory results regarding GHRd3 polymorphism, a recentreviewshowedtheimplicationsofthisSNPinclinical practiceandconcludeditconstitutesapredictivefactorof betterresponsetohormonereplacementtherapyinpatients with short stature.32 Two other meta-analysis studies35,36
carriedoutbyindependentgroups,alsoconfirmedthe influ-enceofthispolymorphisminresponsetogrowthinchildren withshortstaturetreated withrhGH. However,thesetwo meta-analysesincludedamaximumofthreestudiesofrhGH therapy effectanditsrelation togenotyped3-GHR inTS, whichhighlightstheneedforadditionalinvestigations.35,36
Bonemineraldensity
TS patients have low bone mineral density (BMD), but it can bemaintained at normallevelsif thepatient follows a healthy lifestylewith regularpractice of physical exer-cise,earlyintroductionofanappropriatedoseofestrogens (hormone replacement therapy), as well as calcium and vitamin D.3,37 The VDR gene binds to the active form of
vitamin D to modulate gene transcription. Vitamin D, in turn,isasteroidhormonewhichregulatesbonemetabolism,
immune response,cell proliferation and differentiation.38
Vitamin D deficiency is associated with increased risk of fractures, autoimmune diseases, type 1 and 2 diabetes, hypertension and heart disease,38 clinical characteristics
present in patients with TS.3 Considering the
abovemen-tionedfacts,theVDRgenewasinvestigatedinfourstudies, one of them associated withgrowth,18 two with BMD22,23
andonewiththyroidanomalies.25 TheBsmI,FokIandCdx2
polymorphismswere positively associatedwith bone den-sity,andearly detectionofthese polymorphismscouldbe useful for predicting severe osteopenia in patients with TS.22,23Anotherstudyshowedapositiveassociationbetween
polymorphismsintheER-␣gene(estrogenreceptor-alpha) and BMD in patients with TS undergoing treatment with estroprogestagen.24 Patients with TS have estrogen
defi-ciencyasaresultofovarian failure,andhypoestrogenism playsavitalroleinbonemineralizationdisorders.Thus, hor-monereplacementtherapywithestrogencontributestothe developmentofsecondary sexualcharacteristicsand opti-mizespeakbonemass,preventingosteoporosis.39
Autoimmunity
(45%), otitis (43%), thyroid dysfunction (33%) and hyper-tension(26.6%)werethemostfrequentclinicalalterations observed in 42 patients with TS.8 Polymorphisms in the
VDR and PTPN22 gene (Protein Tyrosine Phosphatase, Non-receptortype22)wereinvestigatedbythesamegroup ofresearcherstoverifytheirassociationwithautoimmune thyroiddiseasesinpatientswithTS.25,26
The allelic variationof the PTPN22 gene,C1858T, was associatedwiththeriskofautoimmunediseasesinBrazilian patients with TS.26 The study published in 2012 reported
that one of its main limitations was the small number of patients with TS and thyroid disorders --- only 22 ---whichreducedthestatisticalpower todetectassociations between polymorphisms of the VDR gene and autoim-mune diseases in TS.25 However, both researches suggest
thatfurther studies involving alarger numberof patients be carried out to assess whether this association exists ornot.
Cardiovascularmalformation
Cardiovascularmalformations arethehighest contributors tomorbidity and mortality in girls withTS, especially as aresult of aortic dissectionrisk and, therefore, theycan changelifeexpectancyofthesepatients.40The most
com-mon are coarctation of the aorta (CoA), bicuspid aortic valve and hypoplastic left heart.3 CoA and bicuspid
aor-tic valve were present in 6.9% and 21%, respectively, of 233 French patients with TS assessed for cardiovascular findings,41 with a 19% frequency being found in another
study.9 One gene associated to cardiovascular diseases is
AT2R(AngiotensinType2Receptor);however,polymorphism A→Gdoes notseemtobeinvolvedinthepathogenesisof
CoA in individuals with and without TS.27 A recent study
showed that 5.3% of girls with CoA were diagnosed with TSwhenkaryotypingwascarriedout.Theauthorsconclude thatallgirls withCoA shouldundergokaryotyping,witha minimum count of 50 cells at the time of heart disease diagnosis.42
Previous studies have demonstrated that: (1) folic acid prevents congenital heart defects; (2) homocysteine levels have a strong correlation with cardiovascular dis-ease genesis, and (3) female sex hormone deficiency is an important factor for homocysteine increase.30,43
How-ever, polymorphisms C677T and A1298C in the MTHFR (5,10-methylenetetrahydrofolatereductase)genewerenot associated with homocysteine levels in Brazilian patients withTS, and these were not higher in patients with the riskhaplotype.30 Alsoin relation tothe risk ofcongenital
heartdefects,disruptionofthefolatepathwaycontributed totheincidenceofatrioventricularseptaldefectin individ-ualswithDownsyndrome.44Itwouldbeinterestingtocarry
out a study focusing onTS, due of the high incidence of cardiacabnormalitiesinthisgroupofpatients.
Chromosomalnondisjunction
TS is an aneuploidy caused by chromosomal nondisjunc-tion,whichoccurswhenhomologouschromosomesorsister chromatids fail toseparate, withadvanced maternal age being a risk factor. Genetic polymorphisms that alter
enzymesinvolvedinfolatemetabolism,suchastheenzyme methylenetetrahydrofolatereductase(MTHFR)canleadto DNA hypomethylation and increase the risk of chromoso-mal nondisjunction and thus, of TS. The MTHFR gene is located on 1p36.3 and includes two polymorphisms: sub-stitutionofcytosinebythymineatnucleotide677(C677T) andadeninebycytosineatnucleotide1298(A1298C), resul-tingindecreasedMTHFRactivity,interferingwiththefolate metabolism.
Three studies analyzed polymorphisms in this gene in Brazilian patients with TS.28---30 The results regarding the
contribution ofthesepolymorphismstotheetiology of TS areconflicting,astheC677TSNPwasassociatedwithTSin onestudy,28whereasintheothersitwasA1298C.29,30Three
independentmeta-analyses45---47positivelyassociatedMTHFR
C677TandDown’sSyndrome:oneofthemincluded28 case-controlstudies,45andtheother,22studiesforMTHFRC677T
and15forMTHFRA1298C.47
Thegeneticpolymorphismsanalyzedhereseemto influ-encetheseverityoftheclinicalmanifestationsofTS,aswell asresponsetotreatment.Inthissense,futurestudiescould indicatetheiruseinclinicalpracticeasmolecularmarkers for diagnosis and prognosis.Another interesting finding is that a detailedanalysis of Table 1 shows that 41% (7/17) of the studies on geneticpolymorphisms in TS were per-formed by Brazilian researchers. Brazil hasa high degree ofmiscegenationandgeneticpolymorphismsarerelatedto ethnicorigin.However,onlyoneofthestudiesbriefly men-tionedthatthecountryisaheterogeneousnationconsisting ofpopulationsdescendedfromdifferentethnicities.30There
isaconsensusintheliteratureontheneedtoanalyzethe same polymorphism in differentpopulations,as agenetic association, although valid for a specific population, may notberelevanttoindividualsfromadifferentethnicgroup. Stratificationofthegroupsregardingethnicityisnotso sim-ple,asneitherskincolornorregionoforigincanadequately differentiateamixedpopulation.48
Another important issue addressed in only a few studies18,25 concernsstudylimitationsinrelationtosample
size.Allofthearticlesincludedinthisreviewreportedthe need for further studies in ‘‘Discussion’’ section, but did not providea description ofpossible sourcesof error and theireffectondata.Regardingthestudysample,research ongeneticpolymorphismsinhumandiseasesmusthavethe statisticalpowerdefinedastheprobabilityofthestudyto detectaneffectwhenitexists.Acritiqueofthe17scientific articlesanalyzedhereisthatonlyoneofthemestablished thestatisticalpower.25
Conclusions
statisticalpower,whichisimportantinstudieswithgenetic polymorphismsinhumandiseases.
Funding
Thisstudydidnotreceivefunding.
Conflicts
of
interest
Theauthordeclaresnoconflictsofinterest.
References
1.TurnerHH.Asyndromeofinfantilism,congenitalwebbedneck, andcubitusvalgus.Endocrinology.1938;23:566---74.
2.UllrichO.ÜbertypischeKombinationsbildermultipler Abartun-gen.EurJPediatr.1930;49:271---6.
3.SantosV,Marc¸alM,AmaralD,PinaR,LopesL,FonsecaG.Turner syndrome.Fromchildto adult.Amultidisciplinaryapproach. ActaMedPort.2010;23:873---82.
4.CarvalhoAB, Guerra-JuniorG, BaptistaMT,Marques-de-Faria AP, Lemos-Marini SH, Maciel-Guerra AT. Turner syndrome: a pediatric diagnosis frequently made by non-pediatricians. J Pediatr(RioJ).2010;86:121---5.
5.FordCE,JonesKW,PolaniPE,deAlmeidaJC,BriggsJH.A sex-chromosomeanomalyinacaseofgonadaldysgenesis(Turner’s syndrome).Lancet.1959;1:711---3.
6.BarrosBA,Maciel-GuerraAT,DeMello MP,CoeliFB,Carvalho AB,Viguetti-CamposN,etal.Theinclusionofnewtechniques ofchromosomeanalysishasimprovedthecytogeneticprofileof Turnersyndrome.ArqBrasEndocrinolMetab.2009;53:1137---42. 7.JungMP,AmaralJL,FontesRG,CostaAT,WuillaumeSM, Car-dosoMH.DiagnosisofTurner’sSyndrome:theexperienceofthe RiodeJaneiro StateInstitute ofDiabetes and Endocrinology between1970and2008.RevBrasMaterInfant.2010;10:117---24. 8.DeAraújo C,Galera BB, GaleraMF, de Medeiros SF. Clinical andcytogeneticaspectsoftheTurnersyndromeintheBrazilian Westernregion.RevBrasGinecolObstet.2010;32:381---5. 9.CarvalhoAB,GuerraJúniorG,BaptistaMT,deFariaAP,Marini
SH,GuerraAT. Cardiovascular and renal anomaliesinTurner syndrome.RevAssocMedBras.2010;56:655---9.
10.MiguelNetoJ,MariniSH,FariaAP,GuerraJúniorG,GuerraAT. VariablesassociatedwithdiagnosticdelayinTurnersyndrome. RevPaulPediatr.2011;29:67---72.
11.OliveiraRM,VerreschiIT,LipayMV,Ec¸aLP,GuedesAD,Bianco B.YchromosomeinTurnersyndrome:reviewoftheliterature. SaoPauloMedJ.2009;127:373---8.
12.Fonteles AV, Dondoni RS, Boguszewski MC, Nesi-Franc¸a S, Marques-PereiraR,SandriniNetoR,etal.Finalheight(FH)in Turnersyndrome(TS):experienceof76casesfollowedatthe PediatricEndocrinologyUnit,HospitaldeClinicas,Federal Uni-versityofParaná.ArqBrasEndocrinolMetabol.2011;55:318---25. 13.NegreirosLP,BolinaER,GuimarãesMM.Pubertaldevelopment profileinpatientswithTurnersyndrome.JPediatrEndocrinol Metab.2014;27:845---9.
14.StrachanT,ReadA.Genéticamolecularhumana.4thed.Porto Alegre:Artmed;2012.
15.Binder G, Baur F, Schweizer R, Ranke MB. The d3-growth hormone (GH) receptor polymorphism is associated with increasedresponsivenesstoGHinTurnersyndromeandshort small-for-gestational-age children. J Clin Endocrinol Metab. 2006;91:659---64.
16.BinderG,TrebarB,BaurF,SchweizerR,Ranke MB. Homozy-gosity of the d3-growth hormone receptor polymorphism is associated witha high total effect of GH on growth and a
lowBMIingirls withTurner syndrome.ClinEndocrinol (Oxf). 2008;68:567---72.
17.KoJM,KimJM,CheonCK,KimDH,LeeDY,CheongWY,etal.The commonexon3polymorphismofthegrowthhormonereceptor geneandtheeffectofgrowthhormonetherapyongrowthin KoreanpatientswithTurnersyndrome.ClinEndocrinol (Oxf). 2010;72:196---202.
18.Alvarez-NavaF,MarcanoH,PardoT,PaoliM,GunczlerP,Soto M,etal.GHRandVDRgenesdonotcontributetothegrowth hormone(GH)responseinGHdeficientandTurner syndrome patients.JPediatrEndocrinolMetab.2010;23:773---82. 19.Bas¸F,DarendelilerF,AycanZ,C¸etinkayaE,Berbero˘gluM,Sıklar
Z,etal.Theexon3-deleted/full-lengthgrowthhormone recep-torpolymorphismandresponsetogrowthhormonetherapyin growthhormonedeficiencyandTurnersyndrome:amulticenter study.HormResPaediatr.2012;77:85---93.
20.BrazAF,CostalongaEF,MontenegroLR,TrarbachEB,Antonini SR,MalaquiasAC,etal.TheinteractiveeffectofGHR-exon3 and−202A/CIGFBP3polymorphismsonrhGHresponsiveness andtreatmentoutcomesinpatientswithTurnersyndrome.J ClinEndocrinolMetab.2012;97:E671---7.
21.Braz AF, Costalonga EF, Trarbach EB, Scalco RC, Malaquias AC,Guerra-Junior G, et al. Genetic predictors oflong-term responsetogrowthhormone(GH)therapyinchildrenwithGH deficiencyandTurnersyndrome:theinfluenceofaSOCS2 poly-morphism.JClinEndocrinolMetab.2014;99:E1808---13. 22.PeraltaLópezM,MirasM,SilvanoL,PérezA,Mu˜nozL,Centeno
V,etal.VitaminDreceptorgenotypesareassociatedwithbone massin patientswithTurner syndrome.JPediatr Endocrinol Metab.2011;24:307---12.
23.PeraltaLópezM,CentenoV,MirasM,SilvanoL,PérezA,Mu˜noz L,etal.AssociationofvitaminDreceptorgeneCdx2 polymor-phismwithbonemarkersinTurnersyndromepatients.JPediatr EndocrinolMetab.2012;25:669---71.
24.Sowi´nska-PrzepieraE,Andrysiak-MamosE,ChełstowskiK,Adler G, Friebe Z,Syrenicz A. Association between ER-␣ polymor-phisms and bone mineral density in patients with Turner syndrome subjectedtoestroprogestagen treatment--- apilot study.JBoneMinerMetab.2011;29:484---92.
25.BiancoB,VerreschiIT,OliveiraKC,GuedesAD,BarbosaCP,Lipay MV.AnalysisofvitaminDreceptorgene(VDR)polymorphismsin Turnersyndromepatients.GynecolEndocrinol.2012;28:326---9. 26.Bianco B, Verreschi IT, Oliveira KC, Guedes AD, Galera BB, GaleraMF,etal.PTPN22 polymorphismis relatedto autoim-mune diseaseriskinpatientswithTurnersyndrome.ScandJ Immunol.2010;72:256---9.
27.StruweE,KrammerK,DötschJ,MetzlerM,DörrHG, Cesnje-varR,etal.Noevidenceforangiotensintype2receptorgene polymorphisminintron 1inpatientswithcoarctationofthe aorta and Ullrich-Turnersyndrome.Pediatr Cardiol. 2006;27: 636---9.
28.Santos K, Lemos-Marini SH, Baptista MT, Bonadia LC, Pinto JúniorW,BertuzzoCS.Frequencyof677C→Tand1298A→C polymorphismsin the5,10-methylenetetrahydrofolate reduc-tase(MTHFR)geneinTurnersyndromeindividuals.GenetMol Biol.2006;29:41---4.
29.Oliveira KC, Bianco B, Verreschi IT, Guedes AD, Galera BB, GaleraMF,etal.PrevalenceofthepolymorphismMTHFRA1298C and notMTHFR C677Tis relatedto chromosomalaneuploidy in Brazilian Turner Syndrome patients. Arq Bras Endocrinol Metabol.2008;52:1374---81.
30.OliveiraKC, Verreschi IT,Sugawara EK,SilvaVC,Galera BB, GaleraMF,etal.C677TandA1298CpolymorphismsofMTHFR geneand theirrelationtohomocysteinelevelsinTurner syn-drome.GenetTestMolBiomarkers.2012;16:396---400. 31.ZinnAR,KushnerH,RossJL.EFHC2SNPrs7055196isnot
32.Andrade RM, Rozza RE, Geller M, Cunha KSG. Polimorfismo GHRd3 e suas implicac¸ões na prática clínica. J Bras Med. 2012;100:41---5.
33.ClaytonP,ChatelainP,TatòL,YooHW,AmblerGR,Belgorosky A,etal.Apharmacogenomicapproachtothetreatmentof chil-drenwithGHdeficiencyorTurnersyndrome.EurJEndocrinol. 2013;169:277---89.
34.Stevens A, ClaytonP, Tatò L, Yoo HW, Rodriguez-Arnao MD, Skorodok J, et al. Pharmacogenomics of insulin-like growth factor-I generationduringGH treatmentin childrenwithGH deficiencyorTurnersyndrome.PharmacogenomicsJ.2014;14: 54---62.
35.Wassenaar MJ, Dekkers OM, Pereira AM, Wit JM, Smit JW, BiermaszNR,etal.Impactoftheexon3-deletedgrowth hor-mone(GH)receptorpolymorphismonbaselineheightandthe growth response to recombinant human GH therapy in GH-deficient (GHD) and non-GHD children withshort stature: a systematicreviewandmeta-analysis.JClinEndocrinolMetab. 2009;94:3721---30.
36.Renehan AG, Solomon M, Zwahlen M, Morjaria R, What-more A, Audí L, et al. Growth hormone receptor poly-morphism and growth hormone therapy response in chil-dren: a Bayesian meta-analysis. Am J Epidemiol. 2012;175: 867---77.
37.CleemannL,HjerrildBE,LauridsenAL,HeickendorffL, Chris-tiansenJS,MosekildeL,etal.Long-termhormonereplacement therapypreservesbonemineraldensityinTurnersyndrome.Eur JEndocrinol.2009;161:251---7.
38.BasitS.VitaminDinhealthanddisease:aliteraturereview.Br JBiomedSci.2013;70:161---72.
39.GallicchioCT,AlvesSTF,GuimarãesMM.Induc¸ãodapuberdadee terapiadereposic¸ãohormonalnasíndromedeTurner.Femina. 2008;36:677---81.
40.MortensenKH,AndersenNH,GravholtCH.Cardiovascular phe-notypeinTurnersyndrome---integratingcardiology,genetics, andendocrinology.EndocrRev.2012;33:677---714.
41.Donadille B, Rousseau A, Zenaty D, Cabrol S, Courtillot C, Samara-BoustaniD,etal.Cardiovascularfindingsand manage-mentinTurnersyndrome:insightsfromaFrenchcohort.EurJ Endocrinol.2012;167:517---22.
42.WongSC, Burgess T, Cheung M, Zacharin M.The prevalence ofturnersyndromeingirlspresentingwithcoarctationofthe aorta.JPediatr.2014;164:259---63.
43.Czeizel AE, Dudás I, Vereczkey A, Bánhidy F. Folate defi-ciency and folic acid supplementation: the prevention of neural-tubedefectsand congenitalheartdefects. Nutrients. 2013;5:4760---75.
44.LockeAE,DooleyKJ,TinkerSW,CheongSY,FeingoldE,Allen EG,etal.Variationinfolatepathwaygenescontributestorisk ofcongenitalheartdefectsamongindividualswithDown syn-drome.GenetEpidemiol.2010;34:613---23.
45.WuX,WangX,ChanY,JiaS,LuoY,TangW.Folatemetabolism gene polymorphismsMTHFR C677T and A1298C and risk for Downsyndromeoffspring:ameta-analysis.EurJObstetGynecol ReprodBiol.2013;167:154---9.
46.YangM,GongT,LinX,QiL,GuoY,CaoZ,etal.Maternalgene polymorphismsinvolvedinfolatemetabolismand theriskof havingaDownsyndromeoffspring:ameta-analysis. Mutagene-sis.2013;28:661---71.
47.VictorinoDB,GodoyMF,Goloni-BertolloEM,PavarinoEC. Meta-analysisofMethylenetetrahydrofolatereductasematernalgene inDownsyndrome:increasedsusceptibilityinwomencarriers oftheMTHFR677Tallele.MolBiolRep.2014;41:5491---504. 48.RochaAP,MagalhãesPK,MaiaAL,MacielLM.Genetic