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Evaluationoftheinfantwithambiguousgenitalia

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Evaluationoftheinfantwithambiguousgenitalia
Authors
ChristopherPHouk,MD
LynneLLevitsky,MD

SectionEditors
LaurenceSBaskin,MD,FAAP
MitchellGeffner,MD

DeputyEditor
AlisonGHoppin,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Aug2015.|Thistopiclastupdated:Feb28,2013.
INTRODUCTIONInfantswithacongenitaldiscrepancybetweenexternalgenitalia,gonadaland
chromosomalsexareclassifiedashavingadisorderofsexdevelopment.A2006consensusconference
suggestedthatthepotentiallypejorativeterms"pseudohermaphrodite,""hermaphrodite,"and"intersex"be
replacedbythediagnosticcategory"disordersofsexdevelopment"(DSD)[1].
SomeDSDspresentwithabnormalitiesoftheexternalgenitalia(ambiguousgenitalia).Abnormalitiessufficient
topromptevaluationoccurinapproximatelyonein4500livebirths[2].Manifestationsmayincludebilateral
cryptorchidism(picture1),perinealhypospadiaswithbifidscrotum(picture2),clitoromegaly(picture3AB),
posteriorlabialfusion(picture4),phenotypicfemaleappearancewithapalpablegonad(withorwithoutinguinal
hernia)(picture5),hypospadiasandunilateralnonpalpablegonad(picture6AB).
DSDsalsoincludeinfantswithdiscordantgenitaliaandsexchromosomes(picture7).Turnersyndrome
(45,XO)andKlinefeltersyndrome(47,XXY)arealsoDSDsbutdonotgenerallypresentwithambiguous
genitalia.46,XYinfantswithpalpablegonadsandsimplehypospadiasormicrophallus,althoughundervirilized,
donothavetrulyambiguousgenitaliaandarediscussedseparately.(See"Clinicalfeaturesanddiagnosisof
malehypogonadism"and"Hypospadias".)
TheevaluationoftheinfantwithaDSDispresentedhere.Themanagementofsuchinfants,whichiscritical
andoftencontroversialintheabsenceofwelldefinedoutcomebasedguidelines,isdiscussedseparately.(See
"Managementoftheinfantwithambiguousgenitalia".)
NORMALSEXDEVELOPMENTAlogicalapproachtotheinfantwithadisorderofsexdevelopment(DSD)
requiresabasicunderstandingofnormalhumansexualdifferentiation.Thisprocessisreviewedherebriefly
anddiscussedindetailelsewhere.(See"Normalsexualdevelopment".)
Inearlyfetaldevelopment,bothXXandXYfetuseshavesimilarreproductivestructuralanlagethisperiodis
referredtoasthesexuallyindifferentphaseofsexualdevelopment.Thisambisexualstatecontinuesuntilthe
formationofthebipotentialgonadatsevenweeks,whenfetusesbearingaYchromosomebegindeveloping
testes,therebybecomingsexuallydistinctfromfetuseswithoutaYchromosome.Normalovariandevelopment
alsorequiresactivegeneticpathways.Thereafter,gonadaldifferentiationandfunctiondeterminesthegenital
phenotype.Multiplegenescontributetonormalsexualdifferentiationmutationsinthesegenescanleadto
variousDSDs(table1AB).
GonadsTheinitial,sexuallyindifferentphaseofgonadformationbeginsatfiveweeksofgestationwiththe
developmentofpairedgonadalridges.Theprocessbecomessexuallydimorphicaftergermcellseedingatsix
weeksandbipotentialgonadformationatsevenweeks.
Genesinvolvedingonadaldevelopment
SRYSRYisamasterregulatorofmalesexdetermination.Aroundsixweeksgestation,thosegonads
withaYchromosomebeginexpressingSRY(sexdeterminingregionontheYchromosome)protein,the
transcriptionfactorthoughttoinitiatethedownstreammoleculareventsoftestisformation[35].
SOX9ShortlyafterSRYexpression,theSOX9gene,whichisrequiredforSertolicelldifferentiationand
typeIIcollagenproduction,beginstobeexpressedinthetestes.HaploinsufficiencyofSOX9resultsin
campomelicdysplasia,askeletaldysplasiaassociatedwithsexreversalin75percentofaffectedXY
individuals.FurtherevidencefortheroleofSOX9insexualdifferentiationcomesfromtheobservation
thatSOX9duplicationistheonlyknownautosomalcauseofXXsexreversal(XXkaryotypewithmale
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phenotype).
SF1/NR5A1Steroidogenicfactor1(SF1),alsoknownasNR5A1(MIM184757),isacriticalgonadal
transcriptionfactorwitharoleinsteroidogenesis,fertility,andmalesexualdifferentiation.SF1mutations
causeagonadism,adrenalhypoplasiawithadrenalinsufficiency,hypogonadotropichypogonadism,
cryptorchidism,micropenis,andXYsexreversal[68].(See"Unusualcausesofadrenalinsufficiency",
sectionon'Congenitaladrenalhypoplasia'.)
DHHMutationsinthedeserthedgehoggene(DHH)cancausegonadaldysgenesisandsexreversalin
46,XYindividuals(MIM#233420)[9].DHHsignalingtriggerstesticulardifferentiationbyupregulatingSF
1.
DAX1/NROB1ThedosesensitivesexreversallocusontheXchromosome(formerlyknownasDAX
1andnowreferredtoasNR0B1,MIM300473)isagonadspecifictranscriptionfactorupregulatedinthe
ovary.MutationsinDAX1/NR0B1areresponsibleforadrenalhypoplasiacongenita(AHC),asyndrome
ofadrenalhypoplasiaandhypogonadotropichypogonadismin46,XYmaleswithoutaDSD[5].
DAX1/NR0B1issaidtofunctionasanantitestisfactorintheovarybutisnotrequiredfornormal
testicularfunction.Therefore,DAX1/NR0B1duplicationcanrepressSRYandcauseaDSDwitha
femalephenotypeinanindividualwith46,XYchromosomes.(See"Unusualcausesofadrenal
insufficiency",sectionon'Congenitaladrenalhypoplasia'.)
WT1TheWilmstumor(WT1)geneisatranscriptionfactorinvolvedinbothgonadalandrenal
development.AllWT1mutationsareassociatedwithrenalmalformationordysfunction.Threedistinct
phenotypesareseenwithWT1mutations:
WAGRsyndrome(Wilmstumor,aniridia,genitourinaryanomalies,andmentalretardation,MIM
#194072),causedbyacontiguousdeletionoftheWT1geneandtheadjoiningPAX6gene.
DenysDrashsyndrome(atriadofprogressiverenaldisease,46XYkaryotypewithundervirilization,
andWilmstumor,MIM#194080),inwhichWT1mutationsdisruptDNAbindingabilityintheprotein
[10].Affectedindividualsusuallyhaveambiguousgenitaliaornormalfemaleexternalgenitalia,and
streakgonads[11].Nephroticsyndromepresentswithinthefirsttwoyearsoflifeandprogresses
rapidlytoendstagerenalfailurewithinafewyears.(See"Congenitalandinfantilenephrotic
syndrome".)
Frasiersyndrome(46,XYDSD,gonadaldysgenesis,andrenalfailure,MIM#136680),inwhichthere
isanalteredratioofthetwospliceisoformsoftheWT1protein[12].Affectedindividualshave
normalfemaleexternalgenitaliabutfailtodevelopsecondarysexualcharacteristics[11].Patients
areatriskforgonadoblastomadevelopinginthedysgeneticgonads.Therenaldiseaseisa
glomerulonephropathy,graduallyprogressingfromsteroidresistantnephroticsyndrometorenal
failureinthesecondorthirddecadeoflife.
WT1mutationsinpatientswitha46,XXkaryotypemaycauseisolatednephroticsyndromewithout
abnormalitiesofgenitaldevelopment,butanyoffspringwitha46,XYkaryotypemaybeaffectedby
DenysDrashorFrasiersyndromes[11].
Wnt4andWnt7aWnt4,andWnt7aaresignalingmoleculesfoundinMllerianductsandshowXX
specificgonadalexpression.InSertoliandLeydigcells,Wnt4overexpressionupregulates
DAX1/NR0B1andthismayexplaintheetiologyofhumanXYsexreversalassociatedwith1p35p31
duplicationsyndromes.AnimalmodelshavedemonstratedthattheWnt4genesuppressesmalesexual
differentiationandovarianandrogenproduction[13].AlossoffunctionmutationintheWnt4genewas
reportedinawomanwithprimaryamenorrhea(aresultofMllerianagenesis)andhyperandrogenemia
[14].NoWnt7amutationshavebeenidentifiedinhumanstodate.
Thesetranscriptionfactorsinvolvedinbipotentialgonadformationarenecessaryfordevelopmentalprocesses
inothertissues,andtheirdisruptionoftenisassociatedwithnongonadalmalformationsanddiseases.Other
transcriptionfactorshavebeenassociatedwithsexreversalinanimalsorhumans.MutationsintheFGFr2
geneleadtopartialsexreversalinmalemicehumanlossoftheterminal10q26regionalsohasbeen
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associatedwithDSD,butaspecificassociationwithmutationsinthisgenehasnotbeendescribedin
humans.Similarly,lossofFGF9,aninducerofFGFr2,leadstosexreversalinmalevertebratesbuthasnot
yetbeenreportedinhumanswithDSDs.Thesegenescaninducevariousskeletaldysplasias[15,16].
TranslocationsormutationsinSRYaffectdevelopmentofthegonadsandotherreproductivestructuresbutare
notgenerallyassociatedwithotheranomalies.Defectsofothergonadspecificgeneticfactors,suchas
DAX1/NR0B1,DMRT1/2,orARX/ATRXoftenleadtosyndromicphenotypes[17,18].Becauseagonadism
eliminatesthenormalandrogenproductionrequiredformalegenitaldevelopment,autosomalgenedefects
interferingwithtesticularformationmayappearsexlimited[35].
InternalgenitaliaTheWolffian(mesonephric)andMllerian(paramesonephric)ductsdevelopinboth
sexes.Inmales,atapproximatelytheseventhweekofgestation,testicularSertolicellsbeginsecreting
Mllerianinhibitingsubstance(MIS,alsocalledMllerianinhibitinghormone,andAMH,antiMllerian
hormone),whichinducesMllerianductregression[19].Shortlyafterward,Leydigcellsbeginproducing
testosterone.TestosteronestabilizestheWolffianductandpromotesdevelopmentoftheepididymis,vas
deferens,andseminalvesicle.Infemales,thelackoftestosteroneleadstoWolffianductregressionand,in
responsetothelackofMIS,permitsMllerianductmaturationintooviduct,uterus,cervix,anduppervagina,
respectively(figure1).
ExternalgenitaliaTheexternalgenitaliabecomesexuallydistinctatapproximatelytheninthweekof
gestation,afterLeydigcellshaveproducedsufficienttestosteronetopermitperipheralsynthesisofDHT
(dihydrotestosterone),thepotenttestosteronemetaboliteformedby5alphareductase.
PeripheralsynthesisofDHTinducesposteriorfusionofthegenitalfoldsandgrowthofthegenitaltubercleinto
aphallicstructure(figure2).Differentiationandgrowthoftheexternalgenitaliaareparticularlydependentupon
DHT,and46,XYinfantswholack5alphareductasetype2arebornwithnormallyfunctioningtestesbut
undervirilizedexternalgenitalia.
Maleexternalgenitalmorphogenesisiscompleteby12to16weeks.Afterinitialembryonalstimulationvia
placentalhumanchorionicgonadotropin,subsequentfetalphallicgrowthisaresultoffetalpituitaryluteinizing
hormone(LH)stimulationoftesticularLeydigcelltestosteroneproduction[3].
By12weeks,thenonhormonedependentseparationofvaginaandurethraiscompleteinfemales(figure2).
Excessandrogenexposurebeforethisseparationcancauselabialfusionanddevelopmentofaphallicurethra
orurogenitalsinus,butlaterexposurecausesonlyclitoralenlargementandmasculinization/scrotalizationof
labialfolds.
CLINICALFEATURES
PenilelengthPenilelengthismeasuredonitsdorsalsurfacefromthepubicramustothetipofthepenis
(excludinganyexcessforeskin)afterstretchingthepenistothepointofincreasedresistance.Therulershould
bepresseddownagainsttheramustocompletelydepressthesuprapubicfatpad.Penilewidth(diameter)is
measuredatthemidshaft.
Inaterminfant,atbirth,thenormalpenilelengthis2.5cm,andnormalpenilediameteris0.9cm.These
measurementsshouldbeadjustedforgestationalage(figure3)[20].Smallphallus(micropenis)maybecaused
bydecreasedtestosterone/DHTexposureinthesecondorthirdtrimesterandbydeficienciesofgrowth
hormoneorgonadotropin.Micropeniswithaccompanyinghypospadiasisrarelysecondarytogrowthhormone
orgonadotropindeficiency.Standardsforstretchedpenilelengthofprematureinfantsandolderchildrenand
adultsareavailable[1].
GonadsThescrotum,labiamajora,andinguinalareashouldbecarefullypalpatedtoidentifythepresence
andpositionofthegonads.Ina46,XYchild,bilateralnonpalpabletestesmayarisefromisolated
cryptorchidism,anorchia,oroccurinconjunctionwithpersistentMllerianductsyndrome.Ina46,XXchild,
virilizingcongenitaladrenalhyperplasia(CAH)shouldberuledout.Thisdisorderisusuallyassociatedwith
genitalambiguity,andnotwithmicrophalluswithouthypospadias.(See"Adrenalsteroidbiosynthesis"and
"Undescendedtestes(cryptorchidism)inchildren:Clinicalfeaturesandevaluation",sectionon'Bilateral
nonpalpabletestes'.)
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Gonadspalpablebelowtheinguinalligament(eg,inthelabioscrotalfolds)(picture5)areusuallytestes[21].
Asymmetryofthegonadsorothergenitaliamayindicategonadaldysgenesisordevelopmentofbothgonadal
structuresnamelyovaryandtestis,termedovotesticularDSDunderthenewnomenclature(previouslytermed
"truehermaphroditism").(See'OvotesticularDSD'below.)
UrethralopeningAsingleopeningatthebaseofthephallus(picture2)maybeeitheranincompletely
fusedpenileurethra(hypospadias)oravirilizedurogenitalsinus(eg,internalconnectionbetweenthevagina
andurethra).Accordingly,thesefindingsmustbeconfirmedeitherbycystoscopy/vaginoscopyor
radiographically,becausethephysicalexaminationcanbemisleading.(See'Imaging'below.)
ClitoralsizeClitoralwidthismeasuredbygentlybutfirmlypressingtheshaftoftheclitorisbetweenthe
thumbandforefingertoexcludeexcessskinandsubcutaneoustissue.Normalclitoralwidthinaneonate
rangesfrom2to6mm.Meanclitorallengthinthenewborninfantmayvaryindifferentpopulationgroups,but
lengthsofmorethan9mmareunusualinnormalinfants[22,23].Theclitorismayappeardisproportionately
moreprominentinpreterminfantsbecauseclitoralsizeisfullydevelopedby27weeksgestationandbecause
thereislessfatinthelabiamajora[24].Standardsforclitoralsizethroughinfancyandadulthoodareavailable
[1].
Clitoromegalysecondarytoandrogenexposureina46,XXinfantcanbecausedbyCAH(picture3A),
ovotesticularortesticularDSD,maternalandrogenexposure,or,rarely,bytumorinfiltrationoftheclitoris(eg,
neurofibromatosis)[25].
Someauthorshavesuggestedusingtheclitoralindex(lengthoftheclitoris[mm]multipliedbywidthofthe
clitoris[mm])toassessandrogenexposure[26,27].Asageneralrule,thiscalculationdoesnotcontribute
muchtotheclinicalassessmentandmanagementofinfantswithaDSD.
VirilizationFemalevirilizationstandardsforCAHhavebeenestablishedbyPraderbaseduponthedegree
ofvirilizationoftheurogenitalsinusandtheexternalgenitalia(figure4AB).Forassessingthedevelopmentof
externalgenitaliain46,XYchildrenwithDSD,theQuigleyscaleshavebeenwidelyused(figure5)[28].These
standardscanbeusefulinthediagnosisandtreatmentofchildrenwithDSDasameansofobjectively
documentinggenitalphenotype.
AnogenitalratioTheanogenitalratio,whichisindependentofgestationalageandbodysize,isthe
distancebetweentheanusandposteriorfourchettedividedbythedistancebetweentheanusandthebaseof
theclitoris[29].Aratioof>0.5suggestsvirilizationwithsomeposteriorlabialfusion.
DIAGNOSTICAPPROACHAdiagnosisofadisorderofsexdevelopment(DSD)shouldbeconsideredin
infantswhohave:
Bilaterallynonpalpabletestes(picture1).
Microphallus(stretchedpenilelengthlessthan2.5cminafullterminfant)microphalluswithout
associatedhypospadiasisnot"ambiguous,"butmaybeamarkerofotherdisorders.
Perinealhypospadiaswithbifidscrotum(picture2).
Clitoromegaly(clitoralwidth>6mmorclitorallength>9mm)(picture3AB).
Posteriorlabialfusion(anogenitalratio>0.5)(picture4).
Gonadspalpableinthelabioscrotalfolds(picture5).
Hypospadiasandunilateralnonpalpablegonad(picture6AB).
Discordantgenitaliaandsexchromosomes(picture7).
Theinitialevaluationshouldincludehistory,physicalexamination,karyotype(includingFISHwithSRYprobe),
pelvic/abdominalultrasonography,andassessmentofadrenalandgonadalfunction,asdetailedbelow.(See
'Initialevaluation'below.)
Itisimportanttoevaluateadrenalfunctionpromptlytominimizetheriskofadrenalcrisis.Teststoevaluate
adrenalfunctionincludemeasurementof17hydroxyprogesterone,andmayrequireastimulationtestusing
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adrenocorticotropichormone(ACTH),andsometimesassessmentoftheurinarysteroidexcretionpatternby
gaschromatography/massspectroscopy.Inthenewbornswithcommondisordersofadrenalsteroidogenesis,
adrenalsteroidsareusuallysufficientlyelevatedthatanACTHtestisunnecessary.
TheselectionofsubsequenttestsisdictatedbytheresultsofthekaryotypeandSRYtesting(algorithm1and
algorithm2).TeststoevaluategonadalfunctionincludemeasurementofserumlevelsofMllerianinhibiting
substance(MIS),gonadotropins,andsexsteroids,andhCGstimulationtest.(See'Laboratorytests'below.)
CategorizationTheinformationfromtheinitialevaluationcanbeusedtocategorizetheinfantintooneof
threecategories,assuggestedbyaninternationalconsensusconference[1]:
VirilizedXX
UndervirilizedXY
Mixedsexchromosomepattern
INITIALEVALUATIONTheinitialevaluationoftheinfantwithambiguousgenitaliashouldincludeafamily
history,physicalexamination,evaluationofthesexchromosomes,andassessmentofinternalanatomyby
ultrasound.Next,adrenalandgonadalsteroidsecretionshouldbemeasuredinaspecializedpediatric
endocrinelaboratoryusingagespecificreferencevalues.
HistoryThehistoryinachildwithadisorderofsexdevelopment(DSD)shouldincludethefollowing
information:
Prenatalexposuretoandrogens(eg,progesterones,danazol,testosterone)orendocrinedisrupters
(phenytoin,aminoglutethimide).
Maternalvirilizationinpregnancy(placentalaromatasedeficiency,luteoma).
Familyhistoryoffemaleswhoarechildlessorhaveamenorrhea(androgeninsensitivity).
Familyhistoryofunexplainedinfantdeaths(congenitaladrenalhyperplasia).
Historyofconsanguinity(orhomogeneouspopulation)(recessivedisorders,eg,CAHordisordersof
androgenbiosynthesis).(See"Diagnosisandtreatmentofdisordersoftheandrogenreceptor".)
PhysicalexaminationThephysicalexaminationshouldincludecarefulinspectionandpalpationofthe
genitalia.Thelabioscrotalfoldsandinguinalregionshouldbepalpatedforgonads,andthenumberofurogenital
openingsdocumented.Measuresofthephallus/clitorisandanogenitalratioshouldbedoneforstandardization
(see'Clinicalfeatures'above).
Intheinfantwithambiguousgenitalia,associatednongenitalanomaliesordysmorphicfeaturesshouldbe
documented(table2).Thepresenceofassociatednongenitalanomaliesusuallyexcludescommonformsof
CAH.Genitalmalformationmayoccuraspartofanoverallpatternofmalformation(eg,chromosomal
abnormalitysuchastrisomy21,trisomy18,or13qsyndrome),incompletemasculinization(eg,inadequate
FSH/LHproductionwhichmayleadtomicrophallusandissometimesassociatedwithhypospadias,or
inadequateproductionofthecholesterolprecursorsforsteroidhormonesynthesis).Ifgastrointestinal
anomaliesaccompanygenitalmaldevelopment,adisorderofcloacaldifferentiationshouldbeconsidered.
Asexamples:
Infantswithcongenitalgonadotropinreleasinghormonedeficiencyalsomayhavecleftliporpalateand
othermidlinedefects.(See"Congenitalgonadotropinreleasinghormonedeficiency(idiopathic
hypogonadotropichypogonadism)".)
InfantswithSmithLemliOpitzsyndrome(adisorderofcholesterolbiosynthesiscausedbydeficiencyof
steroldelta7reductase,orDHCR7)mayhaveavarietyofphenotypicabnormalitiesinadditionto
ambiguousgenitalia(picture8).Theseincludemicrocephaly,micrognathia,lowsetandposteriorlyrotated
ears,andsyndactylyofthesecondandthirdtoes[30].(See"Causesandclinicalmanifestationsof
primaryadrenalinsufficiencyinchildren",sectionon'Defectsincholesterolbiochemistry'.)
IndividualswithP450oxidoreductasedeficiency,arareformofcongenitaladrenalhyperplasia,mayhave
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craniofacialandlimbabnormalities(alsoknownasAntleyBixlersyndrome).(See"Geneticsandclinical
presentationofclassiccongenitaladrenalhyperplasiadueto21hydroxylasedeficiency",sectionon
'P450oxidoreductasedeficiency'.)
LaboratorytestsTheinitialevaluationoftheinfantwithaDSDshouldincludedeterminationofsex
chromosomesandassessmentofgonadalandadrenalsteroids.
Akaryotypeisperformed,usuallyusingperipheralleukocytes.Insomecomplicatedpatients,akaryotype
ofthegonadaltissueobtainedwhensurgeryisbeingdoneforotherreasonsmaybehelpfulinidentifying
mosaicism.Becauseofthepossibilityofmosaicism,itissuggestedthatatleast200cellsbeexamined.
Theresultsofthekaryotypepermitclassificationoftheinfantintooneofthreediagnosticcategoriesthat
guidefurtherevaluation,assuggestedbyaconsensusconference[1]:
XXDSD
XYDSD
MixedsexchromosomeDSD
17hydroxyprogesteroneshouldbemeasuredpromptlyinallinfantswithnonpalpablegonadspresenting
withgenitalambiguitytoexcludecongenitaladrenalhyperplasia(CAH)dueto21hydroxylasedeficiency.
Thisisthemostcommoncauseofgenitalambiguityandcanleadtolifethreateningadrenalinsufficiency
withinthefirstweeksoflife.Inaddition,serumelectrolytesshouldalsobemeasuredatthetimeof
presentation,andatleastdailyuntilthereported17hydroxyprogesteronelevelmakesitclearthatsalt
wasting21hydroxylasedeficiencyisnotetiologic.Neonatalscreeningforthisdisorderisroutinely
performedinmanycountriesandallUSstates.However,anyinfantpresentingwithgenitalambiguity
shouldhavearapidandextensiveevaluationforCAHasdescribedabove,withoutwaitingfortheresults
ofthenewbornscreen.Moreover,thereisasubstantialriskoffalsenegativeresultsfortheneonatal
screeningforCAH[31].(See"Diagnosisofclassiccongenitaladrenalhyperplasiadueto21hydroxylase
deficiency".)
Next,evaluationfortheSRYgeneusingfluorescenceinsituhybridization(FISH)andSRYspecific
probesshouldbeperformed,tonarrowthediagnosticpossibilities.TheSRYgeneisacriticalfactorin
testiculardevelopmentandusuallycoincideswiththepresenceofaYchromosome.Thepresenceof
SRYinanindividualwith46XXkaryotypeindicatesSRYtranslocationabsenceofSRYinanindividual
witha46XYkaryotypesuggestsSRYdeletion.
AllinfantswithambiguousgenitaliashouldalsobetestedforlesscommontypesofCAHbymeasuring
dehydroepiandrosterone[DHEA],17hydroxypregnenolone,and11deoxycortisol(preferablybyliquid
chromatographytandemmassspectrometry[LCMSMS]).ThesetestswilldetectCAHcausedbydefects
inadrenalandgonadalsteroidproduction,including11betahydroxylasedeficiencyand3beta
hydroxysteroiddehydrogenasedeficiency(see"Congenitaladrenalhyperplasiadueto11beta
hydroxylasedeficiency"and"Uncommoncausesofcongenitaladrenalhyperplasia").Measurementof
cortisolandACTHcanbeusefulinthediagnosisofACTHdeficiencyrelatedtodefectsinSF1orother
pituitarydisorders,althoughinterpretationofthesetestresultscanbedifficultinstressedorillinfants.
Inthenearfuture,easyavailabilityofgenomewidemicroarraystudies(GWAS)willprobablypermitmolecular
diagnosesofmostchildrenwithgeneticDSD[32].
ImagingUltrasonographyoftheabdomenandpelvisisimportanttodeterminethepresenceofgonads,a
uterus,and/oravagina.Retrogradeurethrogrammaybenecessary,althoughmostsurgeonsfinddirect
visualizationbycystoscopy/vaginoscopytobethesinglebestmethodofassessingtheurethralandvaginal
anatomy.Insomecomplicatedcases(particularlythoseinfantswithelementsofmaleandfemale
gonads/internalreproductivestructures),laparoscopicvisualizationwithgonadalbiopsy,mayberequiredto
completelyinventorythereproductivestructures.
46XXDSDThedifferentialdiagnosisof46,XXDSDincludescongenitaladrenalhyperplasia(CAH),
gestationalhyperandrogenism,testicularDSD,andovotesticularDSD(algorithm1).46,XXDSDwithevidence
offunctioningtesticulartissuemaybecausedbytranslocationoftheSRY(sexdeterminingregionoftheY)
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gene.(See"Normalsexualdevelopment",sectionon'Testiculardetermination'.)
CongenitaladrenalhyperplasiaCAHisthemostcommondiagnosisinvirilizedXXinfants.Dependingon
thesiteofthesteroidbiosyntheticdefect(figure6),patientswithCAHmayunderproduceoroverproduce
mineralocorticoid,typicallyleadingtoabnormalitiesinserumelectrolytesandbloodpressure(table3).
Themostfrequentenzymaticdefects,21alphahydroxylase(CYP21A2)and11betahydroxylase
deficiencies,usuallycanbeexcludedwithbasalmeasurementofserum17hydroxyprogesterone(table
3).Inborderlinecases,anACTHstimulationtestorgenetictestingmaybeneeded.Affectedinfantswith
21alphahydroxylasedeficiencyoftenhavesaltwasting,whichcauseshyponatremiawithhyperkalemia
andhypotension,andtheyareatriskforthelifethreateningcomplicationofadrenalcrisis.(See
"Diagnosisofclassiccongenitaladrenalhyperplasiadueto21hydroxylasedeficiency",sectionon
'Additionallabtesting'.)
Inrareindividuals,21hydroxylasedeficiencymaybecausedbyamutationinP450oxidoreductase,and
hasavariablephenotype.BecauseabnormalelectrontransportcausescombinedP450C17andP450C21
deficiencies,bothgirlsandboysarebornwithambiguousgenitalia,indicatingintrauterineandrogen
excessinfemalesandandrogendeficiencyinmales[33].(See"Geneticsandclinicalpresentationof
classiccongenitaladrenalhyperplasiadueto21hydroxylasedeficiency",sectionon'P450
oxidoreductasedeficiency'.)
Because11betahydroxylasedeficiencyand3betahydroxysteroiddehydrogenasedeficiencyeachhave
theirowncharacteristicserumsteroidpatterns,ACTH,cortisol,dehydroepiandrosterone(DHEA),17
hydroxypregnenolone,and11deoxycortisolalsoshouldbemeasured(table3).(See"Congenitaladrenal
hyperplasiadueto11betahydroxylasedeficiency"and"Uncommoncausesofcongenitaladrenal
hyperplasia".)
Samplesshouldbesenttoaspecializedlaboratorythatiscapableofproperlyextractingandquantitating
serumsteroidsinneonates.Thebestresultsforsteroidsareobtainedusingliquidchromatographytandem
massspectrometry(LCMSMS)methodology.
GestationalhyperandrogenismXXvirilization,withnormalfemaleinternalanatomy,canresultfrom
exposuretomaternalandrogenorsyntheticprogestationalagents.Causesincludematernalluteomaortheca
luteincysts,andplacentalaromataseenzymedeficiency.Thesedisordersaresuggestedbyahistoryof
exogenousprogestinsorandrogenexposure,and/ormaternalvirilizationduringpregnancy[34].(See
"Diagnosisandmanagementofgestationalhyperandrogenism".)
OthercausesOtheruncommoncausesofXXvirilizationincludeSRYtranslocation,SOX9duplication
[4,5,3537],andovotesticularDSD(previouslytermedtruehermaphroditism)[1].Evaluationforthesedisorders
includesmeasurementofMllerianinhibitingsubstance(MIS)orinhibinBandthetestosteroneresponseto
administrationofhCG(algorithm1)[38,39].ThehCGstimulationtestisdescribedbelow.(See'hCG
stimulationtest'below.)
SRYtranslocationcanbediagnosedusingaFISHprobefortheSRYgeneSOX9duplicationcanbe
confirmedwithaSOX9FISHprobe[36].Thesetestsareavailableforeitherresearchorclinicalevaluation
(www.genetests.org).Unfortunately,oncetheseuncommondisordersareexcluded,mostcausesofXX
virilizationremainundefined.
46,XXovotesticularDSDisarareconditioninwhichachildwithanXXchromosomeconstitutionhas
virilizationwithmixedovarianandtesticulartissue(eitherovotestis,orovaryandtestis)thisconditionhas
beentermed"truehermaphroditism"inthepast.Thespecificdiagnosisrequireshistologicalconfirmationofthe
presenceofovarianfolliclesandtesticulartubules.Thedevelopmentoftheinternalandexternalgenitaliain
thesechildrencanbequitevariabledependinguponandrogenproductionandexposure.Theoriginsofthis
DSDarestillnotentirelyclear,althoughithasbeenassociatedwithalossoffunctionmutationintheRSPO1
geneinonepatient[40,41].
46XYDSDThediagnosticprocessinundervirilizedXYinfantswhoexpressSRYismoredifficultbecause
ofthephenotypicvariabilityandthelargenumberofpotentialcauses[3,42].XYinfantswithpalpablegonads
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andsimplehypospadiasormicrophallus,althoughundervirilized,arediscussedelsewhere.(See"Clinical
featuresanddiagnosisofmalehypogonadism"and"Hypospadias".)
Inadditiontotheinformationfromtheinitialevaluation,evaluationofundervirilizedXYinfantsshouldinclude
measurementofserumluteinizinghormone(LH),folliclestimulatinghormone(FSH),Mllerianinhibiting
substance(MIS),testosterone(T),anddihydrotestosterone(DHT)(algorithm2).Gonadotropinsandsex
steroidsshouldbemeasuredatapostnatalagewhentheyarenormallydetectable(eitherinthefirst24hours
oflifeorbetweentwoandsixmonthsofage)[43,44].AdministrationofhCGmayhelptoclarifythesexsteroid
response.
CongenitaladrenalhyperplasiaSeveraltypesofCAHcancauseundervirilizationinanXYinfant:17
alphahydroxylasedeficiency,3betahydroxysteroiddehydrogenasedeficiency,P450sidechaincleavage(scc)
deficiency[45],andStARproteindeficiency(lipoidhyperplasia)(figure6andtable3).Thesedisordersare
discussedindetailseparately.CAHcausedby21hydroxylasedeficiencyisalsoseenin46,XYchildrenbut
doesnotresultingenitalambiguity.(See"Uncommoncausesofcongenitaladrenalhyperplasia"and"Adrenal
steroidbiosynthesis"and'Testingforassociatedadrenalinsufficiency'below.)
EvaluationforuncommoncausesofCAH(eg,StARproteindeficiency,3betahydroxysteroid
dehydrogenasedeficiency,and17alphahydroxylasedeficiency)(figure6)requiresthemeasurementof
additionaladrenalsteroidintermediates(17hydroxypregnenolone,deoxycorticosterone,and
dehydroepiandrosterone[DHEA])(table3).CAHresultingfrom3betahydroxysteroiddehydrogenase
deficiencyusuallyisassociatedwithamodestelevationin17hydroxyprogesteronebecauseofperipheral
conversionofitsprecursor(17hydroxypregnenolone)intheneonatalliver.Becausethe17
hydroxyprogesteroneresultisreadilyandmorerapidlyobtainedthanthe17hydroxypregnenolone,modest
elevationof17hydroxyprogesteroneservesasthefirstcluetothisdiagnosisinagenotypicmaleinfant
[46].(See"Uncommoncausesofcongenitaladrenalhyperplasia".)
For17alphahydroxylasedeficiencyand3betahydroxysteroiddehydrogenasedeficiency,anACTH
stimulationtestmaybenecessarytoconfirmthediagnosis[47].(See'ACTHstimulationtest'below.)
AbnormaltesticularactivitySerumconcentrationsofMISorinhibinB,whicharemarkersofSertolicell
mass,areinthenormalmalerangeforagewhenfunctionaltesticulartissueispresent,andcanserveas
usefulmarkersoftesticularactivityeveniftestesarenotseenwithabdominal/pelvicultrasonography[48].
BecauseMISsecretionbythetestescausesMllerianductregression,decreasedMISsecretionoractionthat
occursearlyindevelopmentischaracterizedbyfullydevelopedMllerianductstructures(gonadaldysgenesis
orpersistentMllerianductsyndrome)[38,39].Defectsthatoccurlaterindevelopmentleadtopartial
regressionoftheMllerianductstructures(testicularregressionsyndrome,vanishingtestessyndromeor
congenitalanorchia).
LowMISlevelsinanindividualwitha46,XYkaryotypesuggestoneofthefollowingdisorders,eachofwhich
ischaracterizedbydiminishedtesticularactivity:
GonadaldysgenesisCompleteXYgonadaldysgenesisisassociatedwithfemaleexternalgenitalia,
intactMllerianducts,andstreakgonads[49].Infantswithdysgeneticgonadsorbothtesticularand
ovariantissuemaydemonstratedisorderedgonadalsteroidsecretionandintactadrenalresponses.An
hCGstimulationtestcannotbeusedtodetectovariantissue,becausehCGalonewillnotstimulatean
estrogenresponsefromovariantissue.46,XYDSDinfantswithandrogeninsensitivitywillalsoshow
normaltesticularresponsesonhCGstimulation.InhibinAissecretedbytheovaryinthefirsttwomonths
oflife.Therefore,measurementofinhibinAmayproveusefulinassessingthepresenceofovariantissue
ininfants,butthismeasurehasnotyetbeenvalidatedinchildrenwithDSDs.
Twopapershavesuggestedthatadministrationofhumanmenopausalgonadotropins(hMG)tostimulate
ovarianfunctionmightbeusedasatesttoidentifyovariantissue,measuringeitheranincreasein
estrogenlevelsorultrasoundevidenceoffolliculardevelopment[50,51].Thisapproachcouldbeusedin
infantswhoareolderthantwoorthreeweeksofage.
TesticularregressionsyndromeLossoftesticularfunctionandtissueearlyindevelopmentmayresultin
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afemalephenotypewithatrophicMllerianducts.
VanishingtestessyndromeLossoftesticularfunctionlateinfetalliferesultsinnormalmalegenitalia,
absentMllerianducts,andanorchia.(See"Etiology,diagnosis,andtreatmentofprimaryamenorrhea",
sectionon'Vanishingtestessyndrome'.)
PersistentMllerianductsyndromeMutationsintheMISgenewithlowserumlevelsofMIS,orinthe
MISreceptor,withlackofresponsetoMISina46,XYindividualcausepersistentMllerianduct
syndrome,withnormalexternalmalegenitaliaandvariabletesticulardescent[5254].
OthercausesofabnormaltesticularactivityinXYinfantsincludeDAX1duplication,whichcausesmaleto
femalesexreversal(dosesensitivesexreversal)throughrepressionofSRY,andSF1mutations[55,56]MIS
levelswillbelowineitherofthesedisorders.MutationsintheMIScognatetypeIIreceptoralsocancause
persistentMllerianductsyndromewithnormalexternalmalegenitaliaandvariabletesticulardescent,but
serumlevelsofMISareappropriateforageandgender,asdescribedbelow.
AbnormalandrogensynthesisCausesofXYundervirilizationinwhichandrogensynthesisisabnormal
include17betahydroxysteroiddehydrogenasetype3deficiency,5alphareductasedeficiency,LHreceptor
defects,andgonadaldysgenesis[5761].Inapatientwhohastesticulartissueonultrasoundand/ornormal
concentrationsofMIS,thehCGstimulationtestcanbeperformedtodistinguishbetweenthesedisordersand
thoseinwhichthereisanabnormalresponsetoandrogen(algorithm2)[62].(See'hCGstimulationtest'
below.)Whenadefectintestosteronebiosynthesisisidentified,adrenalfunctionalsoshouldbeevaluated.
(See'Testingforassociatedadrenalinsufficiency'below.)
PatientswiththefollowingdisorderswillhaveanabnormalresponsetohCGstimulation:
17betahydroxysteroiddehydrogenasetype3deficiencyDefectsintestosteronebiosynthesisusually
causegreaterimpairmentinvirilizationoftheexternalgenitaliathanoftheinternalgenitalia.Themost
commonhereditarydefectintestosteronesynthesisis17betahydroxysteroiddehydrogenasetype3
deficiency,whichcanbecausedbyatleast15differentmutations[61].Inthiscondition,serum
testosteroneconcentrationsareofteninthelowernormalrange,whereasserumconcentrationsof
androstenedione,theprecursorbeforetheenzymaticblock,areelevatedseveralfold(figure7)[59,60].
Theratiooftestosteronetoandrostenedioneisusuallylessthan0.8,whichdistinguishesthisdisorder
fromotherformsofundervirilization[63].(See'Abnormalresponsetoandrogen'below.)
5alphareductasetype2deficiencySteroid5alphareductasetype2deficiencyisanautosomal
recessivedisorderinwhich46,XYsubjectswithbilateraltestesandnormaltestosteroneformationhave
impairedexternalvirilizationduringembryogenesisduetodefectiveconversionoftestosteroneto
dihydrotestosterone(DHT)[6466].Inthisdisorder,theratiooftestosterone:DHTis>10:1(algorithm2).
(See"Steroid5alphareductase2deficiency".)
LHreceptordefectsLHreceptordefects,causedbymutationsintheLHreceptorgeneon
chromosome2p21,cancauseambiguousgenitaliaininfantswitha46,XYkaryotypeandtestes
[57,67,68].Thesepatientscharacteristicallyhavepredominantlyfemaleexternalgenitalia,butlacka
uterusandfallopiantubestheepididymisandvasdeferensmaybepresent[69,70].Laboratory
evaluationrevealslowtestosteroneconcentrationsdespiteelevatedconcentrationofLH,
unresponsivenesstohCG(whichnormallyactsthroughtheLHreceptor),andnormallevelsof
testosteroneprecursors(producedintheadrenalglands).
hCGstimulationtestWeperformthehCGstimulationtestinthefollowingmanner:
BasalLH,FSH,testosterone,androstenedione,andDHTaremeasured.
Humanchorionicgonadotropin(hCG)(1500units/m2SQ)isadministeredondayoneandrepeated
ondaythree.
BetahCG,androstenedione,testosterone,andDHTaremeasuredondaysthreeandsix
measurementofbetahCGconfirmsthemedicationhasbeenadministered.
Adoublingoftestosteronebydaythreeandquadruplingbydaysixisconsideredanormalresponse.The
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normalratiooftestosterone:DHTaftertheadministrationofhCGis<10:1[62].Thenormalratioof
testosterone:androstenedionefollowinghCGstimulationis>0.8[63].
AbnormalresponsetoandrogenCausesof46,XYDSDinwhichandrogensynthesisisnormalinclude
androgeninsensitivity,MISreceptordefect,andexposuretoendocrinedisrupters(algorithm2).
AndrogeninsensitivityAnormalbasalandhCGstimulatedandrogenresponseina46,XYchildwith
undervirilizationraisesthepossibilityofandrogeninsensitivitysyndrome(AIS).(See"Diagnosisand
treatmentofdisordersoftheandrogenreceptor".)
Thediagnosisofandrogenreceptor(AR)insensitivity(AIS)canbedefinitivelyestablishedwithARgene
sequencingorfibroblastARkinetics.Despitetheevidencethatfewerthanhalfofpatientswiththe
clinicaldiagnosisofpartialandrogeninsensitivity(PAIS)showadefinablemutationintheandrogen
receptor,andthelackofclearcutgenotypephenotypecorrelationsinARmutations[71],46,XYDSD
patientswithphenotypicandbiochemicalevidenceofAISshouldundergogenesequencingofthe
androgenreceptor.IfnoARmutationisfound,aprovisionaldiagnosisofAISmaystillbemadeonthe
basisoftheclinicalfindings,butothercausesshouldbeconsidered(eg,SF1mutation).
IninfantswhoseclinicalpresentationisconsistentwithPAISandwhoseparentsstronglydesirethemale
sexofrearing,additionaldiagnosticinformationcanbegainedfromatrialofthreemonthly50mgdepot
testosteroneinjections.AnincreaseinphalliclengthanddecreaseinSHBGsuggestsanandrogenic
responseanddemonstratesthepotentialforadditionalvirilizationduringpubertytheabsenceofa
responsesuggestscompleteandrogeninsensitivity.(See"Diagnosisandtreatmentofdisordersofthe
androgenreceptor".)
MISreceptordefectRegressionoftheMllerianductstructures,whichnormallyoccurswithexposure
toMISinearlygestation,doesnotoccurinindividualswithmutationsinthegenecodingforMISorits
typeIIreceptor.Thesemutationsleadtopersistenceofthefallopiantubesanduterusinindividualswith
a46,XYkaryotypeandnormalmaleexternalgenitaliaandtestes,whichareusuallycryptorchid[54,72].
EndocrinedisrupterOccasionally,boyswithhypospadiasorevenmoreseveregenitalambiguitymay
havehistoriesofinuteroexposureto"endocrine"disrupters.Phenytoinandphenobarbital,aswellas
environmentalexposures,havebeenimplicatedbuttherelationshipofputativeendocrinedisruptorsto
hypospadiasisstillunclear[73,74].Thesechildrenshouldhavenormalphysiologicandanatomic
responsestosexsteroidandgonadotropinstimuliafterbirth.
TestingforassociatedadrenalinsufficiencyIninfantswith17alphahydroxylasedeficiencyand3beta
hydroxysteroiddehydrogenasedeficiency,adrenalfunctionshouldbeevaluatedwithanACTHstimulationtest.
Thistestalsoshouldbeperformedwhenadefectintestosteronebiosynthesisisidentified.Whenthe
diagnosisof17betahydroxysteroiddehydrogenasetype3deficiency,WT1,orLHreceptordefect(which
shownormaladrenalfunction),orCAHhavebeenconfirmedbyotherstudies,anACTHstimulationtestis
unnecessary.(See"Diagnosisofadrenalinsufficiencyinchildren",sectionon'ACTHstimulation'.)
ACTHstimulationtestWeperformtheACTHstimulationtestinthefollowingmanner:
MeasureACTH,cortisol,progesterone,pregnenolone,17alphahydroxyprogesterone,17alpha
hydroxypregnenolone,DHEA,andandrostenedione.
AdministerACTH(250mcg/M2ofsyntheticACTH)[75].
60minutesafteradministrationofACTH,measurecortisol,progesterone,pregnenolone,17alpha
hydroxyprogesterone,17alphahydroxypregnenolone,DHEA,andandrostenedione
Normalvaluesvarydependinguponthelaboratoryperformingthetesting.Thelaboratoryshouldbeconsulted
forageappropriatenormalranges.
FailureofanysteroidogenicresponsesuggestsSF1,DAX1,StAR,orp450sccmutation.MutationsinSF1
canalsocauseagonadism,hypogonadotropichypogonadism,andadrenalhypoplasia.MutationsinStAR
causethelipoidhyperplasiatypeofCAH(table3).(See"Unusualcausesofadrenalinsufficiency"and
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"Uncommoncausesofcongenitaladrenalhyperplasia".)
SEXCHROMOSOMEDSDThissubtypeofDSDincludesmanydisordersthatdonotshowgenital
ambiguitysuchas45,X(TurnerSyndrome)and47,XXY(KlinefelterSyndrome).Thecategoryalsoincludes
somedisordersthatmayincludegenitalambiguity,suchasindividualswithmosaic45X/46,XYkaryotypewith
reproductiveasymmetry(mixedgonadaldysgenesis),orotherindividualswithmosaic46,XX/46,XYcelllines.
MixedgonadaldysgenesisThisdisorderischaracterizedbyasymmetricreproductiveanatomy,generally
withapoorlydevelopedtesticleandWolffianductsononesideandagonadalstreakandincompletely
developedMllerianstructuresontheother.Manyindividualswithmixedgonadaldysgenesishavevariable
degreesofgenitalambiguity.Thepresenceofanyexternalgenitalasymmetry,suchasasinglepalpable
gonad,shouldraisesuspicionofthisdisorder.Thekaryotypecanbequitevariable,andsomaticfeaturesof
Turnersyndromemaybenoted.(See"ClinicalmanifestationsanddiagnosisofTurnersyndrome(gonadal
dysgenesis)".)
Inpatientswithmixedgonadaldysgenesis,theriskofgonadoblastomaisincreasedtheriskisintermediateif
thegonadsareinthescrotum,andhighiftheyareintheabdomen.Managementofthisrisk,including
considerationofgonadectomy,isdiscussedseparately.(See"Managementoftheinfantwithambiguous
genitalia",sectionon'Gonads'.)
OvotesticularDSDOvotesticularDSD(previouslytermedtruehermaphroditism),ischaracterizedbythe
presenceofbothovarianandtesticulartissueinthesameindividual,eitherasaseparateovaryandtestis,or
ovotestis(es).In80percentofcases,itisassociatedwithanXXkaryotype.However,itcanbeseenwithan
XYkaryotype,amixedXX/XYkaryotype,orvariousothersexchromosomepatterns.Amixedovarian
testicularphenotypeinanXYchildhasbeenassociatedwithasmalldeletionintheDMRT1gene,asex
determininggenepresentinmanyvertebratespecies[76].
SUMMARYANDRECOMMENDATIONS
Individualswithacongenitaldiscrepancybetweenexternalgenitalia,andgonadalandchromosomalsex
areclassifiedashavingadisorderofsexdevelopment(DSD).SomeDSDspresentwithagenital
appearancethatdoesnotpermitgenderdeclarationatbirth,andthisphysicalappearanceistermed
ambiguousgenitalia.
Theevaluationofinfantswithambiguousgenitaliashouldbeundertakenassoonaspossible.Thisis
becausecongenitaladrenalhyperplasia,themostcommoncauseofDSD,canbelifethreatening.In
addition,DSDisperceivedasdisturbingbymostfamilies,andcallsforimmediatesensitiveand
professionalcounselingandpsychosocialsupport.(See'Diagnosticapproach'above.)
Onphysicalexamination,keyclinicalfeaturesofinfantswithDSDcanincludebilaterallynonpalpable
testes(picture1),microphallus,perinealhypospadiaswithbifidscrotum(picture2),clitoromegaly(picture
3AB),posteriorlabialfusion(picture4),orpalpablegonadorgonadsinthelabioscrotalfolds(picture5).
(See'Clinicalfeatures'above.)
Initiallaboratorytestingshouldincludemeasurementof17hydroxyprogesteroneasaninitialscreenfor
thepossibilityofcongenitaladrenalhyperplasia(CAH),andakaryotypewithanimmediateprobeforSRY
inordertodirectfurtherstudies.TheSRYgeneisacriticalfactorintesticulardevelopmentandusually
coincideswiththepresenceofaYchromosome.(See'Laboratorytests'above.)
Otherstudiesthatcanbeimportantinearlyevaluationincluderandomserumelectrolytes,cortisol,11
deoxycortisol,17hydroxypregnenolone,dehydroepiandrosterone(DHEA),andadrenocorticotropic
hormone(ACTH)tothoroughlyevaluateforthepossibilityofcongenitaladrenalhyperplasia.Pelvicand
abdominalultrasonographyshouldbeperformedtodeterminewhethergonads,uterus,andvaginaare
present.(Seeaboveandabove.)
Theresultsoftheexaminationandinitiallaboratorytestingshouldpermitclassificationoftheinfantinto
oneofthreebroadcategories:46,XXDSD,46,XYDSD,orsexchromosomeDSD.Theinfantcanthen
befurtherevaluatedtodeterminethenatureoftheunderlyingdisorderwithineachofthesecategories.
(See'46XXDSD'aboveand'46XYDSD'aboveand'SexchromosomeDSD'above.)
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Themanagementoftheseinfants,whichiscriticalandoftencontroversialintheabsenceofwelldefined
outcomebasedguidelines,requiresamultidisciplinaryteamincludingspecialistsfrompediatric
endocrinology,genetics,pediatricsurgery/urology,andpsychologyorsocialwork.(See"Managementof
theinfantwithambiguousgenitalia".)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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45. KimCJ,LinL,HuangN,etal.Severecombinedadrenalandgonadaldeficiencycausedbynovel
mutationsinthecholesterolsidechaincleavageenzyme,P450scc.JClinEndocrinolMetab2008
93:696.
46. CaraJF,MoshangTJr,BongiovanniAM,MarxBS.Elevated17hydroxyprogesteroneandtestosterone
inanewbornwith3betahydroxysteroiddehydrogenasedeficiency.NEnglJMed1985313:618.
47. LutfallahC,WangW,MasonJI,etal.NewlyproposedhormonalcriteriaviagenotypicprooffortypeII
3betahydroxysteroiddehydrogenasedeficiency.JClinEndocrinolMetab200287:2611.
48. MisraM,MacLaughlinDT,DonahoePK,LeeMM.MeasurementofMullerianinhibitingsubstance
facilitatesmanagementofboyswithmicrophallusandcryptorchidism.JClinEndocrinolMetab2002
87:3598.
49. SchnitzerJJ,DonahoePK.Surgicaltreatmentofcongenitaladrenalhyperplasia.EndocrinolMetabClin
NorthAm200130:137.
50. MendezJP,SchiavonR,DiazCuetoL,etal.Areliableendocrinetestwithhumanmenopausal
gonadotropinsfordiagnosisoftruehermaphroditisminearlyinfancy.JClinEndocrinolMetab1998
83:3523.
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51. FrenchS,RodriguezL,SchlesingerA,etal.FSHInjectionsandUltrasonographyDeterminePresenceof
OvarianComponentsintheEvaluationofOvotesticularDisordersofSexDevelopment.IntJPediatr
Endocrinol20092009:507964.
52. KnebelmannB,BoussinL,GuerrierD,etal.AntiMllerianhormoneBruxelles:anonsensemutation
associatedwiththepersistentMllerianductsyndrome.ProcNatlAcadSciUSA199188:3767.
53. ImbeaudS,CarrEusbeD,ReyR,etal.Moleculargeneticsofthepersistentmllerianductsyndrome:
astudyof19families.HumMolGenet19943:125.
54. ImbeaudS,BelvilleC,MessikaZeitounL,etal.A27basepairdeletionoftheantimlleriantypeII
receptorgeneisthemostcommoncauseofthepersistentmllerianductsyndrome.HumMolGenet
19965:1269.
55. SwainA,NarvaezV,BurgoyneP,etal.Dax1antagonizesSryactioninmammaliansexdetermination.
Nature1998391:761.
56. LalliE,SassoneCorsiP.DAX1,anunusualorphanreceptoratthecrossroadsofsteroidogenicfunction
andsexualdifferentiation.MolEndocrinol200317:1445.
57. LatronicoAC,AnastiJ,ArnholdIJ,etal.Briefreport:testicularandovarianresistancetoluteinizing
hormonecausedbyinactivatingmutationsoftheluteinizinghormonereceptorgene.NEnglJMed1996
334:507.
58. LatronicoAC.Naturallyoccurringmutationsoftheluteinizinghormonereceptorgeneaffecting
reproduction.SeminReprodMed200018:17.
59. GivensJR,WiserWL,SummittRL,etal.Familialmalepseudohermaphroditismwithoutgynecomastia
duetodeficienttesticular17ketosteroidreductaseactivity.NEnglJMed1974291:938.
60. MendoncaBB,InacioM,ArnholdIJ,etal.Malepseudohermaphroditismdueto17betahydroxysteroid
dehydrogenase3deficiency.Diagnosis,psychologicalevaluation,andmanagement.Medicine
(Baltimore)200079:299.
61. AnderssonS,MoghrabiN.Physiologyandmoleculargeneticsof17betahydroxysteroid
dehydrogenases.Steroids199762:143.
62. ForestMG.Patternoftheresponseoftestosteroneanditsprecursorstohumanchorionicgonadotropin
stimulationinrelationtoageininfantsandchildren.JClinEndocrinolMetab197949:132.
63. IqbalA,HughesIA.Thetestosterone:androstenedioneratioinmaleundermasculinization.Clin
Endocrinol(Oxf)200053:697.
64. WalshPC,MaddenJD,HarrodMJ,etal.Familialincompletemalepseudohermaphroditism,type2.
Decreaseddihydrotestosteroneformationinpseudovaginalperineoscrotalhypospadias.NEnglJMed
1974291:944.
65. ImperatoMcGinleyJ,GuerreroL,GautierT,PetersonRE.Steroid5alphareductasedeficiencyinman:
aninheritedformofmalepseudohermaphroditism.Science1974186:1213.
66. ImperatoMcGinleyJ,GautierT,PichardoM,ShackletonC.Thediagnosisof5alphareductase
deficiencyininfancy.JClinEndocrinolMetab198663:1313.
67. Luteinizinghormone/chorigonadotropinreceptor.In:OnlineMendelianInheritanceinMan.JohnsHopkins
University,Baltimore,MD,2003.Availableat:www.ncbi.nlm.nih.gov:80/entrez/dispomim.cgi?id=152790
(AccessedonFebruary09,2008).
68. RousseauMerckMF,MisrahiM,AtgerM,etal.Localizationofthehumanluteinizing
hormone/choriogonadotropinreceptorgene(LHCGR)tochromosome2p21.CytogenetCellGenet1990
54:77.
69. BerthezneF,ForestMG,GrimaudJA,etal.Leydigcellagenesis:acauseofmale
pseudohermaphroditism.NEnglJMed1976295:969.
70. PrezPalaciosG,ScagliaHE,KofmanAlfaroS,etal.Inheritedmalepseudohermaphroditismdueto
gonadotrophinunresponsiveness.ActaEndocrinol(Copenh)198198:148.
71. AhmedSF,ChengA,DoveyL,etal.Phenotypicfeatures,androgenreceptorbinding,andmutational
analysisin278clinicalcasesreportedasandrogeninsensitivitysyndrome.JClinEndocrinolMetab
200085:658.
72. JaminSP,ArangoNA,MishinaY,BehringerRR.GeneticstudiesofMISsignallinginsexual
development.NovartisFoundSymp2002244:157.
73. DessensAB,CohenKettenisPT,MellenberghGJ,etal.Associationofprenatalphenobarbitaland
phenytoinexposurewithgenitalanomaliesandmenstrualdisorders.Teratology200164:181.
74. YieeJH,BaskinLS.Environmentalfactorsingenitourinarydevelopment.JUrol2010184:34.
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75. TordjmanK,JaffeA,TrostanetskyY,etal.Lowdose(1microgram)adrenocorticotrophin(ACTH)
stimulationasascreeningtestforimpairedhypothalamopituitaryadrenalaxisfunction:sensitivity,
specificityandaccuracyincomparisonwiththehighdose(250microgram)test.ClinEndocrinol(Oxf)
200052:633.
76. LedigS,HiortO,WnschL,WieackerP.PartialdeletionofDMRT1causes46,XYovotesticulardisorder
ofsexualdevelopment.EurJEndocrinol2012167:119.
Topic5803Version11.0

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GRAPHICS
Bilateralcryptorchidism

Thispatientwithbilateralcryptorchidismhada46,XXkaryotypeand
ovotesticulardisorderofsexdevelopment.
CourtesyofChristopherPHouk,MDandLynneLLevitsky,MD.
Graphic73353Version2.0

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Perinealhypospadias

Perinealhypospadiasandbifidscrotumin46,XYinfantwithDrash
syndrome.
CourtesyofChristopherPHouk,MDandLynneLLevitsky,MD.
Graphic54419Version1.0

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Clitoromegaly

Clitoromegalyina46,XXinfantwith21hydroxylasedeficiency.
CourtesyofChristopherPHouk,MDandLynneLLevitsky,MD
Graphic64870Version1.0

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Clitoromegaly

Clitoralenlargementinaninfantwitha46,XXkaryotype.
Reproducedwithpermissionfrom:ClarkDA.AtlasofNeonatologyA
companiontoDiseaseoftheNewborn,1sted.WBSaundersCo.,Philadelphia
2000.Copyright2000Elsevier.
Graphic76693Version4.0

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Posteriorlabialfusion

Posteriorlabialfusioninthe46,XXpatientwithovotesticulardisorder
ofsexdevelopment(previouslyknownastruehermaphroditism)who
alsohasclitormegalyandgonadspalpapleinthelabioscrotalfolds.
CourtesyofChristopherPHouk,MDandLynneLLevitsky,MD.
Graphic51835Version2.0

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Perineoscrotalhypospadiaswithpalpablegonads

Thispatienthada46,XYkaryotype,micropenis,palpabletestes,
perineoscrotalhypospadias,andabifidscrotum.
CourtesyChristopherPHouk,MDandLynneLLevitsky,MD.
Graphic78743Version1.0

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Mixedgonadaldysgenesis

CourtesyofLaurenceBaskin,MD.
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Mixedgonadaldysgenesis

CourtesyofLaurenceBaskin,MD.
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Sexreversal

Thispatientwithmalephenotypicappearancehada46,XXkaryotype
andsexreversal.
CourtesyChristopherPHouk,MDandLynneLLevitsky,MD.
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Genesknowntobeinvolvedindisordersofsexdevelopment
(DSD)

Gene

Protein

OMIM
No.

Locus

Inheritance

Gonad

Mullerian
structure

46,XYDSD
Disordersofgonadal(testicular)development:singlegenedisorders

WT1

TF

607102

11p13

AD

Dysgenetic
testis

+/

NR5A1(SF1)

Nuclear
receptorTF

184757

9q33

AD/AR

Dysgenetic
testis

+/

SRY

TF

480000

Yp11.3

Dysgenetic
testisor
ovotestis

+/

SOX9

TF

608160

17q24
25

AD

Dysgenetic
testisor
ovotestis

+/

DHH

Signaling
molecule

605423

12q13.1

AR

Dysgenetic
testis

ATRX

Helicase(?
chromatin
remodeling)

300032

Xq13.3

Dysgenetic
testis

ARX

TF

300382

Xp22.13

Dysgenetic
testis

Disordersofgonadal(testicular)development:chromosomalchangesinvolvingkeycandidategenes

DMRT1

TF

602424

9p24.3

Monosomic
deletion

Dysgenetic
testis

+/

NR0B1(DAX1)

Nuclear

300018

Xp21.3

dupXp21

Dysgenetic

+/

receptorTF

testisor
ovary

WNT4

Signaling
molecule

603490

1p35

dup1p35

Dysgenetic
testis

WWOX

Steroid
metabolism

605131

16q23

del16q23

Dysgenetic
testis

2p21

AR

Testis

Disordersinhormonesynthesisoraction

LHGCR

Gprotein

152790

receptor

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DHCR7

Enzyme

602858

11q12
13

AR

Testis

StAR
(steroidogenic
acute
regulatory
protein)

Mitochondrial
membrane
protein

600617

8p11.2

AR

Testis

CYP11A1

Enzyme

118485

15q23
24

AR

Testis

HSD3B2

Enzyme

201810

1p13.1

AR

Testis

CYP17

Enzyme

202110

10q24.3

AR

Testis

POR(P450

CYPenzyme

124015

7q11.2

AR

Testis

oxidoreductase)

electrondonor

HSD17B3

Enzyme

605573

9q22

AR

Testis

SRD5A2

Enzyme

607306

2p23

AR

Testis

AntiMullerian
hormone

Signaling
molecule

600957

19p13.3
13.2

AR

Testis

AntiMullerian
hormone
receptor

Serine
threonine
kinase
transmembrane
receptor

600956

12q13

AR

Testis

Androgen
receptor

Nuclear
receptorTF

313700

Xq1112

Testis

Chromosomalrearrangementslikelytoincludekeygenesareincluded.
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OMIM:OnlineMendelianInheritanceinManTF:transcriptionfactorAD:autosomaldominant(often
donovomutation)AR:autosomalrecessiveY:YchromosomalX:Xchromosomal.
ReproducedwithpermissionfromPediatrics,Vol.118,Pagese488e500,Copyright2006bythe
AAP.
Graphic81145Version14.0

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Genesknowntobeinvolvedindisordersofsexdevelopment
(DSD)(continued)

Gene

Protein

OMIM
No.

Locus

Inheritance

Gonad

Mullerian
structures

46,XXDSD
Disordersofgonadal(ovarian)development

SRY

TF

480000

Yp11.3

Translocation

Testisor
ovotestis

SOX9

TF

608160

17q24

dup17q24

Not
determined

HB2HSD

Enzyme

201810

1p13

AR

Ovary

CYP21A2

Enzyme

201910

6p21
23

AR

Ovary

CYP11B1

Enzyme

202010

8q21
22

AR

Ovary

POR(P450
oxidoreductase)

CYP
enzyme
electron
donor

124015

7q11.2

AR

Ovary

CYP19

Enzyme

107910

15q21

AR

Ovary

Glucocorticoid
receptor

Nuclear
receptor

138040

5q31

AR

Ovary

Androgenexcess

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TF

Chromosomalrearrangementslikelytoincludekeygenesareincluded.
OMIM:OnlineMendelianInheritanceinManTF:transcriptionfactorAD:autosomaldominant(often
donovomutation)AR:autosomalrecessiveY:YchromosomalX:Xchromosomal.
ReproducedwithpermissionfromPediatrics,Vol.118,Pagese488e500,Copyright2006bythe
AAP.
Graphic56975Version11.0

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Phenotypicdifferentiationofthefemaleandmaleurogenital
tracts

Infemales,theMllerianductsgiverisetothefallopiantubes,uterus,andupper
vagina,andtheWolffianductspersistinvestigialform.Inmales,theWolffianducts
giverisetotheepididymides,vasadeferentia,seminalvesicles,andejaculatory
ducts,andtheMllerianductsregress.
Graphic78289Version4.0

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Phenotypicdifferentiationoftheexternalgenitaliain
femaleandmaleembryos

Infemales,thegenitaltuberclebecomestheclitoris,thegenitalswellings
becomethelabiamajora,andthegenitalfoldsbecomethelabiaminora.In
males,thegenitaltuberclebecomestheglanspenis,thegenitalswellings
fusetobecomethescrotum,thegenitalfoldselongateandfusetoformthe
shaftofthepenisandthepenileurethra,andtheprostateformsinthewall
oftheurogenitalsinus.
Graphic65480Version4.0

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Phalliclengthinnewborns

Stretchedphalliclengthof63normalprematureandfulltermmaleinfants().
Themeanfulltermlengthis3.5cmwiththe2standarddeviationrange,from
2.8to4.2cm.Thesolidlineapproximatesthemeanvalues,andthebroken
linesthe2standarddeviationvalues.Superimposedaredatafortwosmall
forgestationalageinfants(),sevenlargeforgestationalageinfants
(closedtriangles),andfourtwins(closedboxes),allofwhichareinthe
normalrange.
Reproducedwithpermissionfrom:FeldmanKW,SmithDW.Fetalphallicgrowthand
penilestandardsfornewbornmaleinfants.JPediatr197586:395.Copyright1975
Elsevier.
Graphic66323Version4.0

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Virilization(crosssectionalview)

Normalandabnormaldifferentiationoftheurogenitalsinusandexternal
genitalia.Diagramsofnormalfemaleandmaleanatomyflankaseriesof
schematicrepresentationsofdifferentdegreesofvirilizationoffemales,graded
usingthescaledevelopedbyPraderforpatientswithcongenitaladrenal
hyperplasia.Notetheuteruspersistsinvirilizedfemalesevenwhentheexternal
genitaliahaveacompletelymasculineappearance(Pradergrade5).
Reproducedwithpermissionfrom:WhitePC,SpeiserPW.Congenitaladrenalhyperplasia
dueto21hydroxylasedeficiency.EndocrRev200021:245.
http://edrv.endojournals.org/.Copyright2000TheEndocrineSociety.
Graphic73502Version6.0

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Virilization(externalview)

Normalandabnormaldifferentiationoftheexternalgenitalia.Diagramsof
normalfemaleandmaleanatomyflankaseriesofschematicrepresentations
ofdifferentdegreesofvirilization,gradedusingthescaledevelopedby
Prader.
Reproducedwithpermissionfrom:WhitePC,SpeiserPW.Congenitaladrenal
hyperplasiadueto21hydroxylasedeficiency.EndocrRev200021:245.
http://edrv.endojournals.org/.Copyright2000TheEndocrineSociety.
Graphic52525Version6.0

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Schematicrepresentationofgradingschemeforclinical
classificationofandrogeninsensitivitysyndromes(AIS)

Gradesarenumbered17inorderofincreasingseverity(moredefectivemasculinization).
Grade1:normalmasculinizationinuterograde2:malephenotypewithmilddefectin
masculinizationeg,isolatedhypospadiasgrade3:malephenotypewithseveredefectin
masculinizationsmallpenis,perineoscrotalhypospadias,bifidscrotumand/or
cryptorchidismgrade4:severegenitalambiguityclitorallikephallus,labioscrotalfolds,
singleperinealorificegrade5:femalephenotypewithposteriorlabialfusionand
clitoromegalygrade6/7:femalephenotype(grade6ifpubichairpresentinadulthood,
grade7ifnopubichairinadulthood).
Reproducedwithpermissionfrom:QuigleyCA,DeBellisA,MarschkeKB,etal.Androgenreceptor
defects:Historical,clinical,andmolecularperspectives.EndocrineReviews199516:271.Copyright
1995TheEndocrineSociety.
Graphic50228Version8.0

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Algorithmforevaluationofaninfantwithambiguous
genitaliaanda46,XXkaryotype(SRYnegative)*

SRY:sexdeterminingregionontheYchromosomeMIS:Mllerianinhibiting
substance.
*IfSRYispositiveinaninfantwith46XXkaryotype,thisindicatesSRYtranslocation.
Graphic70570Version5.0

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Algorithmforevaluationofaninfantwithambiguousgenitalia
anda46,XYkaryotype(SRYpositive)*

SRY:sexdeterminingregionontheYchromosomeAIS:androgeninsensitivitysyndromeMIS:
MllerianinhibitingsubstanceT:testosteroneDHT:dihydrotestosteroneLH:luteinizing
hormonep450scc:P450sidechaincleavage.
*IfSRYisnegativeinaninfantwitha46XYkaryotype,thisindicatesSRYdeletionormutation.
Graphic66241Version5.0

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Disorderswithassociatedgenitalabnormalities
Abnormality
Hypospadias/bifidscrotum

Frequentin:
AniridiaWilmstumorassociation
Deletionof4p,11q,13q
Bladderexstrophysequence
Frasersyndrome
Frynsyndrome
SmithLemliOpitzsyndrome
Triploidysyndrome

Micropenis

Anencephalysequence
Carpentersyndrome
CHARGEassociation
Deletionof9p,18q
4pduplicationsyndrome
Noonansyndrome
PraderWillisyndrome

Cryptorchidism

Aarskogsyndrome
Carpentersyndrome
Deletionof:4p,5p,9p,11q,13q,18q
Duplicationof3q,4p,10q,15q
Distalarthrogryposissyndrome
Cloacalexstrophysequence
Frasersyndrome
FreemanSheldonsyndrome
MillerDiekersyndrome
Noonansyndrome
Robinowsyndrome
RubinsteinTaybisyndrome
SmithLemliOpitzsyndrome
Triploidysyndrome
Trisomy9mosaicsyndrome
Trisomy13
Trisomy18
Weaversyndrome

Hypoplasiaoflabiamajora

Deletionof9p,18q
PraderWillisyndrome
Robinowsyndrome

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Trisomy18syndrome
AdaptedfromJones,KL.Smith'srecognizablepatternsofhumanmalformation,4thed,Saunders,
Philadelphia1998.p.677.
Graphic58766Version1.0

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SmithLemliOpitzSyndrome

Immature,ambiguousgenitalia.
Reproducedwithpermissionfrom:ClarkDA.AtlasofNeonatologyA
companiontoDiseaseoftheNewborn,1sted.WBSaundersCo.,Philadelphia
2000.Copyright2000Elsevier.
Graphic55839Version2.0

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Syntheticpathwaysforadrenalsteroidsynthesis

ThefirststepinadrenalsteroidsynthesisisthecombinationofacetylCoAand
squalenetoformcholesterol,whichisthenconvertedintopregnenolone.The
enclosedareacontainsthecoresteroidogenicpathwayutilizedbytheadrenalglands
andgonads.
17:17alphahydroxylase(CYP17,P450c17)17,20:17,20lyase(alsomediatedbyCYP17)
3:3betahydroxysteroiddehydrogenase21:21hydroxylase(CYP21A2,P450c21)11:11
betahydroxylase(CYP11B1,P450c11)18referstothetwostepprocessofaldosterone
synthase(CYP11B2,P450c11as),resultingintheadditionofanhydroxylgroupthatisthen
oxidizedtoanaldehydegroupatthe18carbonposition17R:17betareductase5R:5
alphareductaseDHEA:dehydroepiandrosteroneDHEAS:DHEAsulfateA:aromatase
(CYP19)SK:sulfokinaseSL:sulfotransferase.
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Characteristicsofdifferentformsofcongenitaladrenal
hyperplasia*
21
hydroxylase
deficiency

11beta
hydroxylase
deficiency

Aldosterone
synthase
deficiency

17alpha
hydroxylase
deficiency

hydroxy
dehydro

Defectivegene

CYP21A2
(P450c21)

CYP11B1
(P450c11)

CYP11B2
(P450aldo)

CYP17
(P450c17)

HSD3B2(
HSD)

Ambiguous
genitalia

+infemales

+infemales

No

+inmales

+inmales

Nopubertyin
females

Mildinfem

Addisoniancrisis

Rare

Saltwastingonly

No

Incidence(general
population)

1:11000
23000

1:100000

Rare

Rare

Rare

Glucocorticoids

Normal

Corticosterone
normal

Mineralocorticoids

Androgens

Normal

inmales

Disease

Hormones

infemale
Estrogens

Relativelyin
females

Relativelyin
females

Normal

Bloodpressure

Nabalance

Kbalance

Acidosis

Alkalosis

Alkalosis

17OHP

DOC,11
deoxycortisol

Corticosterone,
18hydroxy
corticosterone

DOC
corticosterone

DHEA,17

Physiology

Elevatedsteroid
metabolites

17OHP:17hydroxyprogesteroneDOC:deoxycorticosteroneDHEA:dehydroepiandrosterone
175Preg:17delta5hydroxypregnenolone.
Reproducedwithpermissionfrom:WhitePC,SpeiserPW.EndocrRev200021:245.Copyright2000
TheEndocrineSociety.
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Testosteroneformationandmetabolism

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Disclosures
Disclosures:ChristopherPHouk,MDNothingtodisclose.LynneLLevitsky,MDGrant/Research/ClinicalTrialSupport:Novo
Nordisk[growthhormoneregistry(variousinsulins)]EliLilly[growthhormoneregistry(variousinsulins)].Consultant/Advisory
Boards:NovoNordisk[newinsulin(variousinsulins)].LaurenceSBaskin,MD,FAAPNothingtodisclose.MitchellGeffner,MD
Grant/Research/ClinicalTrialSupport:EliLillyInc[growth(Somatotropin/rhGH)]NovoNordisk[growth(Somatotropin/rhGH)]
Verartis[growth(Somatotropin/rhGH)].Consultant/AdvisoryBoards:Ipsen[growth(Mecasermin/rhIGFI)]Pfizer[growth
(Somatotropin/rhGH)]Sandoz[growth(Somatotropin/rhGH)]TolmarDataSafetyMonitoringBoard[puberty(Somatotropin/rhGH)].
OtherFinancialInterest:Sandoz[growth(lecturetocompanyMSL's)]McGrawHill[pediatricendocrinology(textbookroyalties)].
AlisonGHoppin,MDNothingtodisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvetting
throughamultilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.Appropriately
referencedcontentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy

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