Copyright© ABE&M todos os direitos reservados. compounds. 578 zymes havebeen distinguishedi C INTRODUCTION Campinas, SP, Brazil Médica, FCM-Unicamp, FCM-Unicamp, Campinas,SP, Brazil Disciplina deCirurgia Pediátrica, Unicamp, Campinas,SP, Brazil Engenharia Genética(CBMEG), Unicamp, Campinas,SP, Brazil do Sexo (GIEDDS),FCM- da DeterminaçãoeDiferenciação Unicamp), Campinas,SP, Brazil deCampinas(FCM- Estadual Ciências Médicas,Universidade Pediátrica, Faculdade de Unidade deEndocrinologia 2 1 case report 5 4 3 Accepted onOct/29/2012 Received onJuly/31/2012 [email protected] 13083-100 –Campinas,SP, Brazil FCM-Unicamp dePediatria,Departamento Gil Guerra-Junior Correspondence to: Departamento deGenética Departamento deCirurgia,Departamento Centro deBiologiaMoleculare Grupo InterdisciplinardeEstudos dePediatria,Departamento that catalyze the oxidation of several organic that catalyzetheoxidation ofseveralorganic ytochrome Two biochemicalclassesofP450en

P450 monooxygenases are enzymes enzymes P450 monooxygenases are and and tively tial enzyme activities, as P450 oxidoreductase transfers electronsto asP450oxidoreductase transfers enzyme activities, mother oxidoreductase hyperplasia with cytochrome P450oxidoreductase gene due to novel mutations inthe 46,XX DSDand Antley-Bixler syndrome ano devida,foramobservadoscistoovariano, insuficiênciaadrenalparcialealteraçõesosteoar sem gônadaspalpáveis,comcariótipo46,XXehipogonadismo hipergonadotrófico.Noprimeiro atualmente com9anosdeidade,queapresentavaaonascimento genitaisvirilizados(Prader 5) esqueléticas semelhantes às da síndrome de Antley-Bixley. Relatamos o caso de uma menina, P17A1 eCYP19A1. Essadeficiênciacausaumdistúrbiododesenvolvimento dosexo ealterações enzima P450oxidorredutase participa datransferênciadeelétronsparaasenzimasCYP21A2,CY nal comcaracterísticasdeinibiçãocombinadaeparcialenzimasesteroidogênicas,poisa A deficiênciadaenzimaP450 oxidorredutase éumaformararadehiperplasiacongênitadaadre SUMÁRIO carpal similar Guaragna-FilhoGuilherme mutações nogenedaenzimaP450oxidorredutase DDS 46,XXesíndrome de Antley-Bixler causadapornovas se p.Arg223*edamissensenova p.Met408Lys, herdadasdopaiedamãe, respectivamente. molecular dogeneP450oxidorredutase reveloua heterozigose composta das mutações nonsen dos membrossuperiores.Suamãeapresentouintensavirilização duranteagestação.Oestudo elimitaçãodepronossupinação ticulares comolevecraniossinostose,sinostosecarpaletarsal Lemos-Marini and Deficiency oftheenzymeP450 SUMMARY Bras EndocrinolMetab. 2012;56(8):578-85 with Miranda Fábio CaldasFerraz De Mello Rodrigo RibeiroRodrigo DeCarvalho

n thehuman genome. thenovel missensep.Met408Lys

adrenal insufficiency hypergonadotropic . year During the first

CYP19A1 virilized genitalia .

Arq BrasEndocrinolMetab. 2012;56(8):578-85 and to presented 4 Antley 3 ,Andréa Trevas Maciel-Guerra , LetíciaEsposito Sewaybricker

tarsal . Itresultsin 1 ,Lilia Freire D'Souza-Li Rodrigues

-Bixley gene

characteristics ofcombinedand severe synostosis,

3 revealed

syndrome , ReginaldoJosé Petroli ( Prader stage duringpregnancy. The molecularanalysisofP450 , and - disorders

1,2

and limitedforearm osteoarticular changes,

In the adrenal glands,t In theadrenal spectively, andadrenodoxin; reductase adrenodoxin re called, protein andaniron-sulfur by aflavoprotein tinamide adeninedinucleotide (NADPH)mediated mitochondria, receive electrons electrons mitochondria, receive , Cristina Carla Telles deSousaCastro 3 compound heterozygosisforthenonsense

, Fernanda Borchers Coeli oxidoreductase . We report thecase V)

of sex , inheritedfromthefather , absence ofpalpablegonads 2,5

1,2 development , GilGuerra-Junior , SofiaHelena Valente 3

, Palandi Maricilda is a

partial 1

, Márcio Lopes pron

of a9-year-old girlwhowas born rare form of congenital adrenal rare formofcongenitaladrenal

ype such asmild o

Arq Bras Metab. Endocrinol 2012;56/8 supination impairments

and skeletal malformations and skeletal

I enzymes, located in the I enzymes,locatedinthe 3

, Lúcio and themother, respec- of life 1,2 from reduced nico reduced from CYP21A2,

were observed. Her wereobserved.Her ,

, craniosynostosis ovarian cyst, 46 in ,XX steroidogenic steroidogenic 1,2 , karyotype, p.Arg223*, p.Arg223*, CYP17A1,

par in in Arq ------,

tron gene analysis revealed compoundheterozygo POR gene analysis revealed inwhom manifestations oftheAntley-Bixler syndrome mother, respectively rare and complex form of congenital adrenal hyper ofcongenitaladrenal andcomplexform rare spanning 32 kb sis hepatic squalene with disorders with disorders Arq Bras Metab. Endocrinol 2012;56/8 ied separatelyforeachpotential tivities differently. PORvariants mustbestud Therefore, enzyme activities PORD Maternal of Antley- and 46 identified (4,5).PORDhas 2004, whenmutationsinPORencodinggenewere wasdescribedforthefirsttimeincessive disorder enzymes.Thisautosomalre ment ofsteroidogenic andcombinedimpair partial from plasia thatresults hance PORactivity, b5canen- Association withtheallostericcytochrome coded bythe 17α type IIenzymecomplex and mic reticulum in the endoplas- expressed type II enzymes are turn, cal signs andsymptoms, gene, it may reduce CYP17A1,CYP21A2,CYP19A1ac gene, itmayreduce on thetypeofmutationanditslocationwithinPOR nonsense, splicing,andacoupleofdeletions.Depending missense,followedby POR gene(9).Mostofthemare respectively,Databases report, 57and79mutationsinthe bined tabolism as pregnancy pregnancy reductase droxylase reactions tions POR is an 82-kDa membrane-associated protein en POR isan82-kDamembrane-associatedprotein sense p.Met408Lys a single P450 flavoprotein. Cytochrome Cytochrome a singleP450flavoprotein.

for thenonsense Here, we report a46,XXpatientwithPORDand wereport Here, POR deficiency(OMIM#613571;PORD)is a To date,thepublicandprivateHumanGene Mutation 14α -hydroxylase/17

donor

observed

enzymatic adrenal dysfunction enzymatic adrenal ,XY are drug -lanosterol

and hyperandrogenism

and some epoxidase catalyzed ( (OMIM *124015; CYP21A2), Bixler

individuals can also be observed. can alsobeobserved.

considered flavoprotein

POR gene,which metabolism of on

in

syndrome

sex the

involved

receive electrons from NADPH via NADPHvia from electrons receive many,

demethylase hepatic , inherited from thefather , inheritedfrom ,

by . , as demonstratedby17,20

disruption 20 development p.Arg223* and 7q11.2 and

, and CYP26 to be -

lyase , including including

for the

but not (

8). P450 a (OMIN in

P450 wide

chromosomal band chromosomal

POR) skeletal abnormalities due sterol

is formed by 15 exons by15exons is formed

( isozymes of CYP17A1),

enzymes Skeletal virilization

target enzyme(10).

cytochrome

spectrum ofclini- spectrum to

all, retinoic ( partial and com- partial (DSD the CYP51A1) is

thenovelmis-

( synthesis #201750) impairment

CYP19A1)

the onlyelec- steroidogenic steroidogenic patients P450

associated

) - malforma (6,7 (3).

in 46 acid

and the

during 21-hy-

oxido- ), ,

- P450

such lyase lyase with me- and and (2). ( ,XX (

6). 1). 1). of ------

B A first marriage andahealthyboy.first marriage her girlfrom uneventfulgestations:anormal previous ; balanic urethral openingandcompletefusion gonads; balanicurethral Prader stageVand2.3-cmphallus,withoutpalpable physical examination indicated virilized genitalia with tient was8monthsoldwithmaleassignment.General of 32.5c ference 2,830 gandherheightwas48cm,withheadcircum byvaginaldelivery. sheweighed atterm born Atbirth, childofahealthymother,A girl,whowasthethird was CASE REPORT delivery. Figure 1. Mother´s signs regressed afterdelivery signs regressed megaly, and voice deepening - virilizationwithhirsutism, clitoro severe ported - duringgestation,re who deniedtheuseofdrugs pearance, shewasassignedasamale.Themother, At the first appointment in our service, thepa At thefirstappointmentinourservice, (A) andchild’s (B)externalgenitalia8monthsafter m. Duetothevirilizedgenitalap- POR deficiencyand Antley-Bixler syndrome . She also reported two . Shealsoreported (Figure 1A) (Figure . Allthese 579 - -

Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. 580 * Electrochemiluminescence assay; Table 1. HormonalprofileofthepatientwithPORdeficiencyduringfirst105 monthsoflife indicatedthatthe cing ofthePORgeneherparents a (ATG)from to a lysine (AAG). Sequen­ 408 nucleotide changeleadstoa change in residue thec.1223T>A stopcodon;whereas apremature forms codon 223,causingaCGA>TGAsubstitutionthat 2).Thec.667C>Tnucleotidechangeaffects (Figure in exon6and10,respectively, identified were c.667C>T and c.1223T>A nucleotide changes located investigated.The tions inthePORgenesequencewere ovaries. two normal of thepresence Gonadalbiopsyconfirmed performed. ment ofthefamily, was andfeminizingintroitoplasty maletofemale,withtheagree thesexfrom reassign when thepatientwas18monthsold,itdecidedto undefined, the etiologyofclinicalsignsremained suchdiagnosis.Although gene analysisdidnotconfirm the motherduringpregnancy. However, theCYP19 CYP19 deficiency, virilization of based on the severe forthediagnosiswas the firsthypothesisconsidered deficiencies(Tableor 11b-hydroxylase 1).Therefore, either21-hydroxylase levelsdidnotconfirm tosterone) andtes (DHEA, and lowandrogen a simpleovariancyst. suggestiveof geneous imageintheleftadnexialregion, in30metaphasesanalyzed.A1.1-cm karyotype a46,XX Initialcytogeneticinvestigationrevealed birth. thatthephalluslengthhaddiminishedsince ported Themotherre observed. or physicalalterationswere 1B).Nootherdysmorphic signs (Figure also observed notpigmented,were folds,whichwere of labioscrotal POR deficiencyand Antley-Bixler syndrome upon pelvicultrasonography, withananechoichomo observed and gonadswithtypicalovarianshapewere DHEA (ng/mL) (µg/dL) ACTH (pg/mL) LH (IU/L) (ng/mL) Androstenedione (ng/mL) 17-OH progesterone(ng/mL) FSH (IU/L) Almost oneyearafterthefirstappointment,muta le­ of17-OHprogesterone The moderateincrease *2 *1 *3 #6 #4 *8 *7 #5 # radioimmunoassay;normal range(pre-pubertalgirls): < 0.02 11.6 20.3 13.5 23.3 0.2 0.6 9.0 8 < 0.02 26.8 10.4 2.9 0.5 0.1 0.5 8.8 18 3 uterus uterus vel 1 <0.1-3.8; - - - - - <0.02 Basal < 0.1 20.9 3.8 1.3 0.1 1.0 7.8 p.Arg223* and p.Met408Lys mutations were inher mutationswere p.Arg223* andp.Met408Lys B A in cephalicdiameters, reduction demonstrated discrete until theageof64months,whenX-rayexaminations development andgrowth toneurological ities related anyabnormal tailed intable1.Shehadneverpresented the mutantenzymeandcomparingittoitswildtype. of the enzyme was investigated by modeling structure changeinthe ofp.Met408Lys biological importance the fatherandmother,ited from respectively. The the mother, respectively. p.Arg223* and p.Met408Lys mutations were inherited from the father and substitution incodon408, leadingtothemissensep.Met408Lys. The c.1223T>A nucleotidechangelocatedinexon10causesthe ATG>AAG by astopcodon, representingthenullmutationp.Arg223*. B)The causes the CGA>TGA substitution at codon 223; an is replaced with PORdeficiency. A) The c.667C>T nucleotidechangeinexon6 Figure 2. PartialelectropherogramsofPORgenesequencingapatient 2 <0.1-1.4; Laboratory follow-up from 8to105monthsisde follow-upfrom Laboratory Age (months) Post ACTH 13.3 14.3 0.5 1.1 48 - - - - 3 <46; 4 5.0-22.0; Post hCG 0.09 Codon 408 ------5 0.07-1.5; Codon 223 Arq Bras Metab. Endocrinol 2012;56/8 6 <2.5; < 0.02 < 0.1 35.3 6.6 1.2 0.1 1.1 9.1 67 7 0.05-0.5; 8 <0.2. < 0.02 < 0.1 42.9 105 5.0 1.3 0.2 1.4 8.9 - - -

Arq Bras Metab. Endocrinol 2012;56/8 synostosis (C). and hammered-silverappearance(A) , carpalsynostosis(B), andtarsal the patientwithPORdeficiency, showingashortened diameterofthehead Figure 3. andcols.(11). toKrone was 5,according anomalies ofosteoarticular Thescore pronosupination. despitelimited radiological investigationwasnormal, old, shecomplainedoflimitedmovement of thearms; 3Band3C).Whenshewas7years ostoses (Figures 3A),andcarpaltarsalsyn craniosynostosis (Figure silver”appearance usually associated to “hammered B A C Radiographs of the skull (A), left hand (B) and left foot (C) of - therapy, andafterthetwoadditionalsur exceptbefore (Figure 4B),andshetakesnomedications. (Figure female genitalia with no signs of puberty she has normal age, 4A); herboneage is compatiblewithchronological 51cm(slightlybelowthemean)(Figure circumference 133 cm (z= -0.02, within hertarget height), and head now 9yearsold,herweightis31kg(z=0.32),height attheageof6.Sheis endometritis, andclitoroplasty nal dilationat5yearsofageduetovaginalstenosisand thatshehadbeensubmittedto:vagi gical procedures genitalia aftergenitoplasty (B). Figure 4. PatientwithPORdeficiencyat9years old(A)andherexternal B She had never required hydrocortisone replacement replacement hydrocortisone She hadneverrequired A POR deficiencyand Antley-Bixler syndrome 581 - -

Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. Millennium STING(CNPTIA-Embrapa,Brazil). 582 inthe canbeobserved regions gences intwo disordered folding.However, inprotein diver show differences didnot eled wild-typeandmutated PORstructures 5A).Thealignment ofmod (FMN) domain(Figure gion thatlinksFADdomain toflavinmononucleotide adenine dinucleotide(FAD)domainandahingere offlavin 408. Residue408islocatedattheboundary atcodon lysineresidue by thebasicpolarhydrophilic methionine residue the neutral nonpolar hydrophobic substitution,sinceitreplaces It isanon-conservative forthefirsttime. isdescribedhere The p.Met408Lys most commonPORmutationinCaucasians(14). the whichisconsidered zygosis withp.Arg287Pro, p.Arg223* incompoundhetero patient whocarried ina translation. Thismutationwasdescribedrecently activate nonsense mRNA decay before may probably stopcodonand apremature The p.Arg223* creates isreported. gosis forp.Arg223* andp.Met408Lys A caseofPORDcausedbythecompoundheterozy DISCUSSION MOL version of Py examinedandeditedusingafree were Modelledimages software. MODELLER webserver using 3QE2 (13).Molecularmodelingwasperformed PDBID: PORstructure crystallographically-resolved mutationwasthe modeling analysesforp.Met408Lys spectively, www.ensembl.org). usedin Thestructure the Wizard sequencing, each PCR fragment was purified using fore fragments. Be amplified by PCR in different tions were junc 15 exonsofthePORgene,aswellexon-intron techniques (12).The10exonsofCYP19A1geneandthe bystandard and genomicDNAextractionwasperformed obtained Samples ofperipheralbloodleukocyteswere MATERIALS ANDMETHODS POR deficiencyand Antley-Bixler syndrome ( CYP19A1 andPOR sequenceswith thepublished to analyzeandcompare v.1.5Pro v.6.6.2 andCLCSequence Viewer used were Chromas software (ABI PRISM/PE Biosystems). Free automatic sequencerABIPRISM3130DNAAnalyzer obtained inan antisense primers. The sequences were usingsenseand outinseparatedreactions was carried Kit (ABIPRISM/PEBiosystems,FosterCity, CA,USA) ABI PRISM Big Dye Terminator v3.1 Cycle Sequencing sequencingusing direct Madison, WI,USA).Further ENSG00000137869 ® cts were investigated using the investigated using the contacts were and internal ® SV Gel and PCR clean-up system (Promega, SV Gel and PCR clean-up system (Promega, sequences at Ensembl database sequences at Ensembldatabase andENSG00000127948,re ------418, and 422 are shown in the left (B, D, F, H, J) delimit hingedivergences. Internal contactsforresidues408, 389, 404, normal Met408(purple)andmutated Lys408 (red)residues;dashedlines of thewild-typeandmutantproteins, respectively;blackarrowpointstothe type; greenish-yellow=mutant);redandcyanrepresentthehingeregions mutant); andNADPHdomainisdenotedinyellowishtones(yellow=wild- mutant); FAD domainisdenotedinblue(dark=wild-type;light blue= (A); FMNdomainisdenotedingreen(dark=wild-type;light Figure 5. Alignmentofstructureswild-typeandp.Met408Lys proteins hydrophobic (pink), hydrogenbond(rose), aromaticstacking(grey). and barsbeloweachaminoacidrepresents differentchemicalinteractions: I, K)forthewild-typeandmutantproteins, respectively. The colorof lines W422 (Figure 5C). Those four residues, in turn, estab inturn, 5C).Thosefourresidues, W422 (Figure suchasL389and contacts withneighboringresidues, novelinternal methionine-to-lysine substitutioncreates 5B).The in contactwithLeu404andLeu418(Figure is theMet408residue hinges. Inthewild-typeprotein, be considered based on data in the literature. basedondataintheliterature. be considered investigated.Howeversomepossibilitiescan be further cations cause disturbances in enzymatic activity should 5D-K).Ifsuchmodifi mutation(Figure p.Met408Lys andwiththe lish additionalcontactswithotherresidues A Arq Bras Metab. Endocrinol 2012;56/8 and in the right (C, E, G, - - mutation causes disturbances in the conformational ar mutation causesdisturbancesintheconformational Asp.Met408Lys partners. transfertoitsredox electron changesforproper enzyme mayundergo conformational evidence thatPOR provided theirreport Furthermore, the distanceandorientationoftwoflavincofactors. byadjusting FMNtoCYPsmayberegulated and from FADtoFMN flowfrom They concludethatelectron aligningandorientingthetwoflavindomains. properly FAD to FMNby transferfrom facilitateselectron region Arq Bras Metab. Endocrinol 2012;56/8 (2,11,19,20). Probably, in onlyCYP19A1wasaffected (DHT) to dihydrotestosterone 17OH-progesterone conversionof and AKR1Cpathways,aswell as direct SRD5A1 and activationofthealternative production defective CYP19A1activity with excessive complexmechanisms,mainlythosefrom sult ofmore andgenitalambiguityingirlsmaybethere pairment, CYP17A1 im from resulting production testosterone duetoinadequate undervirilization boys maypresent toamoderategrademalformations. of 5,whichrefers TMS method,ourpatientpresented lowing thisscore 0to16.Fol from (TMS)canvary score malformation tothismethodology,in PORDpatients.According total manifestations fortheevaluationofosteoarticular score a andcols.(11)proposed Krone atbirth. formations virilizitionandnosignsofskeletalmal severe presented pathway thantoskeletaldevelopment,sincethepatient to the androgenic deleterious toPORactivityrelated seemstobemore (6,10,18),p.Met408Lys formations skeletalmal inborn tosevere related patients andare inJapanese observed tions, whichhavebeenfrequently andp.Arg457His muta the moststudiedp.Ala287Pro from lele isdefiningthepatient’sphenotype.Different al missensecarrying activityofp.Met408Lys residual thatthe itcanbeinferred gosis withp.Met408Lys, p.Arg223* is a null allele in the compound heterozy (6,10,11,17,18).Consideringthat necessary were indicating thatperiodicclinicalandimageevaluations pronosupination, niosynostosis), andlimitedforearm appearance(suggestiveofcra and “hammered-silver” skulldiameter as carpalandtarsalsynostosis,reduced such abnormalities, she developedafewosteoarticular however,of skeletalmalformations; duringchildhood, (16). transferisimpaired electron topromote necessary so that theflexibility ofthehingeregion, conformation actions, itmayalterenzymaticactivitybymodifyingthe rangement ofthehingeandestablishesnovellocalinter Hamdane andcols. PORD mayleadtogenitalambiguityinbothsexes: neonatalsigns patientdidnotpresent The reported (15) demonstrated that the hinge (15)demonstratedthatthehinge ------child with low testosterone andhigh17OH-progester child withlowtestosterone virilizationofbothmotherand this case,leadingsevere 17OH-progesterone levels. However,17OH-progesterone dihydroepian moderately elevatedbasal and ACTH-stimulated are UponCYP21A2activity, profile. able hormonal there inavari activitiesandresulting leading themtopartial multipleenzymes, hyperplasiasbecauseitaffects renal (11,24). CYP21A2catalyzedreactions POR activitymayaffect isnotnecessary,ticoid reposition althoughdeficient situations.Mineralocor only administrated upon stress was glucocorticoid patient (11,18,21-25).Therefore, toACTHstimulus,aswasthecaseofour sol response adequate corti for those patients who do not present especially stress, tion onlyincaseofmoderatetosevere administra However, withdrug mostauthorsagree inPORD. replacement need fordailyglucocorticoid one levels. electron transfer from PORforcatalytic activity, transferfrom electron and synthesis and metabolism. CYP51A1 requires on sterol ciency, impact of mutant POR might be the disruptive defi from resulting to high gonadotropins byPORD,inaddition development infemalesaffected (14,18,30). Auniquemechanismdrivingovariancyst (28), CYP19A1(29)and,recently, inPORdeficiency deficiencies ofCYP21A2(26),CYP17A1(27),STAR in havebeenreported disorders, ed bysteroidogenic acommonfindinginfemalesaffect Ovarian cystsare hypogonadism (14,17,18,24). and hypergonadotropic ovariancysts present intheliterature reported puberty age and infants in mini- ity offemale patients in pubertal cases(4,14,17,18,24). ported hypogonadisminallre levels ofhypergonadotropic different female patients,althoughbothsexespresent easily than more to puberty ously begin and progress tally availableyet.Itseemsthatmalepatientsspontane ofpatientswithPORDisnotto profile the hormonal however,ered; itsevolutionand knowledgeregarding activitybyCYP17A1(4,6,18,25). 17-hydroxylation ylation activitybyCYP21A2isasdiminishedthe including thispatient,indicatesthatthe21-hydrox inpatientswithPORD, file, whichisusuallyobserved pro 17,20-lyase activityofCYP17A1.Thishormonal duetothelow generallylowornormal dione levelsare (DHEA),DHEA-sulphateandandrostene drosterone PORD deficiency differs from othercongenitalad from PORD deficiencydiffers the regarding isstillcontroversial The literature Similar to the patient reported here, the great major thegreat here, Similar tothepatientreported aspect tobeconsid isanotherimportant Puberty POR deficiencyand Antley-Bixler syndrome 583 ------

Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. 4. 3. the nonsense 584 1. REFERENCES was reported. relevant tothisarticle nopotentialconflictofinterest Disclosure: with PORDwhois ultrasonography inthefirstmonthsoflife. levels andasuggestiveimageofanovariancystupon elevatedgonadotropin signs,shepresented pubertal (14,18). Althoughourpatientstillhavenotshownany ofpolycysticovaries could amelioratethepresence replacement thathormonal suggested intheliterature at puberty, oocytematuration(31).Itis andtosupport oocytemeiosis toresume have beenshowntobecrucial Follicularfluidmeiosis-activatingsterols vating sterols. tomeiosis-acti lanosterol catalyzes theconversionfrom POR deficiencyand Antley-Bixler syndrome late onset features ofAntley-Bixlersyndrome. late onsetfeatures and ovariancystsduringthefirstyearoflife,aswell 2. coid insufficiency, - glucocorti virilization, 46,XX DSD, partial ternal ma- mutationsassociatedwithsevere p.Met408Lys 11. 8. 7. 6. 5. 10. 9.

Concluding, we present a case report on agirl acasereport Concluding, wepresent Flück CE, transfer. JBiolChem.1998;273:3158-65. 17,20-lyase ofhumanP450c17 withoutdirectelectron activity Auchus RJ, Lee TC, Miller WL. Cytochrome b5augmentsthe transfer. Miller WL. Minireview:regulationofsteroidogenesisbyelectron and itseffect oncoexisting21-hydroxylase deficiency. manifesting heterozygosityinP450oxidoreductase deficiency Scott RR,GomesLG,Huang N, Van Vliet G,Miller WL. Apparent docrinol Metab. P450 P450 al. Mutant Genotype-phenotype analysisincongenitaladrenal hyperplasia Krone N,Reisch N,IdkowiakJ, Dhir V, IvisonHE,Hughes BA, etal. genesis withandwithout Antley-Bixler syndrome. Tomalik-Scharte Commun. 2011;411:490-5. cytochrome P450oxidoreductase (CYPOR).Biochem Biophys Res lation ofgap junctionfunctionandconnexin43expressionby Polusani BS,Panda SR,Kar R,RiquelmeMA,Masters SP. Regu- ductase deficiency. Horm Res. 2008;69:266-75. Scott RR,Miller WL. Genetic andclinicalfeaturesofP450oxidore- 2004;363:2128-35. ductase andhumanandrogensynthesis:analyticalstudy. Lancet. Congenital adrenalhyperplasia causedbymutantP450oxidore- Arlt W, Walker EA,DraperN,IvisonHE,RideJP, HammerF, etal. Flück CE,Pandey AV. Clinical andbiochemical consequencesof cf.ac.uk/ac/index.php. Accessed on: Nov 17, 2012. Human GeneMutationDatabase. Available at:http://www.hgmd. et. 2004 Endocrinol. adrenal hyperplasia duetoP450oxidoreductase deficiency. W. Impairedhepaticdrugandsteroidmetabolism incongenital

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Tajima T, 2010;163:919-24. p.Arg223* and

D, MaiterKirchheiner J, IvisonHE,Fuhr U, Arlt 2007;92:2318-22. 2007;92:2318-22.

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Arlt W, Endocr Dev. 2011;20:63-79. thenovelmissense

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