Evaluation of The Infant With Ambiguous Genitalia

14/09/2015
Evaluationoftheinfantwithambiguousgenitalia
OfficialreprintfromUpToDate
www.uptodate.com2015UpToDate
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
http://www.uptodate.com/contents/evaluationoftheinfantwithambiguousgenitalia?topicKey=PEDS%2F5803&elapsedTimeMs=8&source=search_re
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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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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.
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Clitoromegaly
Clitoromegalyina46,XXinfantwith21hydroxylasedeficiency.
CourtesyofChristopherPHouk,MDandLynneLLevitsky,MD
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Clitoromegaly
Clitoralenlargementinaninfantwitha46,XXkaryotype.
Reproducedwithpermissionfrom:ClarkDA.AtlasofNeonatologyA
companiontoDiseaseoftheNewborn,1sted.WBSaundersCo.,Philadelphia
2000.Copyright2000Elsevier.
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Posteriorlabialfusion
Posteriorlabialfusioninthe46,XXpatientwithovotesticulardisorder
ofsexdevelopment(previouslyknownastruehermaphroditism)who
alsohasclitormegalyandgonadspalpapleinthelabioscrotalfolds.
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Perineoscrotalhypospadiaswithpalpablegonads
Thispatienthada46,XYkaryotype,micropenis,palpabletestes,
perineoscrotalhypospadias,andabifidscrotum.
CourtesyChristopherPHouk,MDandLynneLLevitsky,MD.
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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.
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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.
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Phenotypicdifferentiationofthefemaleandmaleurogenital
tracts
Infemales,theMllerianductsgiverisetothefallopiantubes,uterus,andupper
vagina,andtheWolffianductspersistinvestigialform.Inmales,theWolffianducts
giverisetotheepididymides,vasadeferentia,seminalvesicles,andejaculatory
ducts,andtheMllerianductsregress.
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Phenotypicdifferentiationoftheexternalgenitaliain
femaleandmaleembryos
Infemales,thegenitaltuberclebecomestheclitoris,thegenitalswellings
becomethelabiamajora,andthegenitalfoldsbecomethelabiaminora.In
males,thegenitaltuberclebecomestheglanspenis,thegenitalswellings
fusetobecomethescrotum,thegenitalfoldselongateandfusetoformthe
shaftofthepenisandthepenileurethra,andtheprostateformsinthewall
oftheurogenitalsinus.
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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.
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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.
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Virilization(externalview)
Normalandabnormaldifferentiationoftheexternalgenitalia.Diagramsof
normalfemaleandmaleanatomyflankaseriesofschematicrepresentations
ofdifferentdegreesofvirilization,gradedusingthescaledevelopedby
Prader.
Reproducedwithpermissionfrom:WhitePC,SpeiserPW.Congenitaladrenal
hyperplasiadueto21hydroxylasedeficiency.EndocrRev200021:245.
http://edrv.endojournals.org/.Copyright2000TheEndocrineSociety.
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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.
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Algorithmforevaluationofaninfantwithambiguous
genitaliaanda46,XXkaryotype(SRYnegative)*
SRY:sexdeterminingregionontheYchromosomeMIS:Mllerianinhibiting
substance.
*IfSRYispositiveinaninfantwith46XXkaryotype,thisindicatesSRYtranslocation.
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Algorithmforevaluationofaninfantwithambiguousgenitalia
anda46,XYkaryotype(SRYpositive)*
SRY:sexdeterminingregionontheYchromosomeAIS:androgeninsensitivitysyndromeMIS:
MllerianinhibitingsubstanceT:testosteroneDHT:dihydrotestosteroneLH:luteinizing
hormonep450scc:P450sidechaincleavage.
*IfSRYisnegativeinaninfantwitha46XYkaryotype,thisindicatesSRYdeletionormutation.
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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.
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SmithLemliOpitzSyndrome
Immature,ambiguousgenitalia.
Reproducedwithpermissionfrom:ClarkDA.AtlasofNeonatologyA
companiontoDiseaseoftheNewborn,1sted.WBSaundersCo.,Philadelphia
2000.Copyright2000Elsevier.
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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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Evaluation of The Infant With Ambiguous Genitalia

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