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CongenitalAdrenalHyperplasia:PracticeEssentials,Background,Pathophysiology

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CongenitalAdrenalHyperplasia
Author:ThomasAWilson,MDChiefEditor:StephenKemp,MD,PhDmore...
Updated:Jun23,2016

PracticeEssentials
Thetermcongenitaladrenalhyperplasia(CAH)encompassesagroupofautosomal
recessivedisorders,eachofwhichinvolvesadeficiencyofanenzymeinvolvedin
thesynthesisofcortisol, [1]aldosterone,orboth.Deficiencyof21hydroxylase,
resultingfrommutationsordeletionsofCYP21A,isthemostcommonformof
CAH,accountingformorethan90%ofcases.Seetheimagebelow.

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Steroidogenicpathwayforcortisol,aldosterone,andsexsteroidsynthesis.Amutationor
deletionofanyofthegenesthatcodeforenzymesinvolvedincortisoloraldosteronesynthesis
resultsincongenitaladrenalhyperplasia.Theparticularphenotypethatresultsdependsonthe
sexoftheindividual,thelocationoftheblockinsynthesis,andtheseverityofthegenetic
deletionormutation.

Signsandsymptoms
TheclinicalphenotypeofCAHdependsonthenatureandseverityoftheenzyme
deficiency.Althoughthepresentationvariesaccordingtochromosomalsex,thesex
ofaneonatewithCAHisofteninitiallyunclearbecauseofgenitalambiguity.
Clinicalpresentationinfemales
FemaleswithsevereCAHduetodeficienciesof21hydroxylase,11beta
hydroxylase,or3betahydroxysteroiddehydrogenasehaveambiguous
genitaliaatbirth(classicvirilizingadrenalhyperplasia)genitalanomalies
rangefromcompletefusionofthelabioscrotalfoldsandaphallicurethrato
clitoromegaly,partialfusionofthelabioscrotalfolds,orboth
Femaleswithmild21hydroxylasedeficiencyareidentifiedlaterinchildhood
becauseofprecociouspubichair,clitoromegaly,orboth,oftenaccompanied
byacceleratedgrowthandskeletalmaturation(simplevirilizingadrenal
hyperplasia)
Femaleswithstillmilderdeficienciesof21hydroxylaseor3beta
hydroxysteroiddehydrogenaseactivitymaypresentinadolescenceor
adulthoodwitholigomenorrhea,hirsutism,and/orinfertility(nonclassic
adrenalhyperplasia) [2]
Femaleswith17hydroxylasedeficiencyappearphenotypicallyfemaleatbirth
butdonotdevelopbreastsormenstruateinadolescencetheymaypresent
withhypertension
Clinicalpresentationinmales
Maleswith21hydroxylasedeficiencyhavenormalgenitalia
Ifthedefectissevereandresultsinsaltwasting,thesemaleneonates
presentatage14weekswithfailuretothrive,recurrentvomiting,
dehydration,hypotension,hyponatremia,hyperkalemia,andshock(classic
saltwastingadrenalhyperplasia)
Maleswithlessseveredeficienciesof21hydroxylasepresentlaterin
childhoodwithearlydevelopmentofpubichair,phallicenlargement,orboth,
accompaniedbyacceleratedlineargrowthandadvancementofskeletal
maturation(simplevirilizingadrenalhyperplasia)
Maleswithsteroidogenicacuteregulatory(StAR)deficiency,classic3beta
hydroxysteroiddehydrogenasedeficiency,or17hydroxylasedeficiency
generallyhaveambiguousgenitaliaorfemalegenitaliatheymayberaised
asgirlsandseekmedicalattentionlaterinlifebecauseofhypertensionora
lackofbreastdevelopment
Otherfindings
Patientswithaldosteronedeficiencyofanyetiologymaypresentwith
dehydration,hyponatremia,andhyperkalemia,especiallywiththestressof
illness
Malesorfemaleswith11hydroxylasedeficiencymaypresentinthesecond
orthirdweekoflifewithasaltlosingcrisislaterinlife,thesepatients
develophypertension,hypokalemicalkalosis,orboth
InfantswithStARdeficiency(lipoidadrenalhyperplasia)usuallyhavesigns
ofadrenalinsufficiency(eg,poorfeeding,vomiting,dehydration,
hypotension,hyponatremia,hyperkalemia)
Hyperpigmentation:Occursinpatientswithdeficienciesofenzymeactivity
involvedincortisolsynthesismaybesubtleandisbestobservedinthe
genitaliaandareolae
SeeClinicalPresentationformoredetail.

Diagnosis
ThediagnosisofCAHdependsonthedemonstrationofinadequateproductionof
cortisol,aldosterone,orbothinthepresenceofaccumulationofexcess
concentrationsofprecursorhormones,asfollows:
21hydroxylasedeficiency:Highserumconcentrationof17
hydroxyprogesterone(usually>1000ng/dL)andurinarypregnanetriol

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(metaboliteof17hydroxyprogesterone)inthepresenceofclinicalfeatures
suggestiveofthedisease24hoururinary17ketosteroidlevelsareelevated
11betahydroxylasedeficiency:Excessserumconcentrationsof11
deoxycortisolanddeoxycorticosterone,oranelevationintheratioof24hour
urinarytetrahydrocompoundS(metaboliteof11deoxycortisol)to
tetrahydrocompoundF(metaboliteofcortisol)24hoururinary17ketosteroid
levelsareelevated
3betahydroxysteroiddehydrogenasedeficiency:Anabnormalratioof17
hydroxypregnenoloneto17hydroxyprogesteroneandof
dehydroepiandrosteronetoandrostenedione
SaltwastingformsofCAH:Lowserumaldosteroneconcentrations,
hyponatremia,hyperkalemia,andelevatedplasmareninactivity(PRA),
indicatinghypovolemia
Hypertensiveformsofadrenalhyperplasia(ie,11betahydroxylasedeficiency
and17alphahydroxylasedeficiency)areassociatedwithsuppressedPRA
and,often,hypokalemia
Subtleformsofadrenalhyperplasia(asinnonclassicformsof21hydroxylase
deficiencyandnonclassic3betahydroxysteroiddehydrogenasedeficiency):
Syntheticcorticotropin(Cortrosyn)stimulationtestingdemonstratesthe
abnormalaccumulationofprecursorsteroidsnomogramsareavailablefor
interpretingtheresults [3]
Imagingstudies
CTscanningoftheadrenalglandcanhelpexcludebilateraladrenal
hemorrhageinpatientswithsignsofacuteadrenalfailurewithoutambiguous
genitaliaorothercluestoadrenalhyperplasia [4]
Pelvicultrasonographymaybeperformedinaninfantwithambiguous
genitaliatodemonstrateauterusorassociatedrenalanomalies,whichare
sometimesfoundinotherconditionsthatmayresultinambiguousgenitalia
(eg,mixedgonadaldysgenesis,DenysDrashsyndrome)
Urogenitographyisoftenhelpfulindefiningtheanatomyoftheinternal
genitalia
Aboneagestudyisusefulinevaluatingforadvancedskeletalmaturationin
achildwhodevelopsprecociouspubichair,clitoromegaly,oraccelerated
lineargrowth
Othertests
Akaryotypeisessentialinaninfantwithambiguousgenitalia,toestablish
thechromosomalsex
Genetictestingisessentialforgeneticcounselingandprenataldiagnosisof
adrenalhyperplasia
Newbornscreeningprogramsfor21hydroxylasedeficiencymaybelifesaving
inanaffectedmaleinfantwhowouldotherwisebeundetecteduntil
presentationwithasaltwastingcrisis [5]
SeeWorkupformoredetail.

Management
Newbornswithambiguousgenitaliashouldbecloselyobservedforsymptomsand
signsofsaltwastingwhileadiagnosisisbeingestablished.Clinicalcluesinclude
abnormalweightlossorlackofexpectedweightgain.Electrolyteabnormalities
generallytakefromafewdaysto3weekstoappear,butinmildformsofsalt
wastingadrenalhyperplasia,saltwastingmaynotbecomeapparentuntilanillness
stressesthechild.
Managementisasfollows:
Patientswithdehydration,hyponatremia,orhyperkalemiaandapossible
saltwastingformofCAHshouldreceiveanIVbolusofisotonicsodium
chloridesolution(20mL/kgor450mL/m 2)overthefirsthour,asneeded,to
restoreintravascularvolumeandbloodpressurethismayberepeatedifthe
bloodpressureremainslow
Dextrosemustbeadministeredifthepatientishypoglycemicandmustbe
includedintherehydrationfluidafterthebolusdosetopreventhypoglycemia
Aftersamplesareobtainedtomeasureelectrolyte,bloodsugar,cortisol,
aldosterone,and17hydroxyprogesteroneconcentrations,thepatientshould
betreatedwithglucocorticoidstreatmentshouldnotbewithheldwhile
confirmatoryresultsareawaited
Afterthepatient'sconditionisstabilized,treatallpatientswhohaveadrenal
hyperplasiawithlongtermglucocorticoidoraldosteronereplacement(or
both),dependingonwhichenzymeisinvolvedandonwhethercortisoland/or
aldosteronesynthesisisaffected
Patientswhoaresickandhavesignsofadrenalinsufficiencyshouldreceive
stressdosagesofhydrocortisone(50100mg/m 2or12mg/kgIV
administeredasaninitialdose),followedby50100mg/m 2/dayIVdivided
every6hours
TheEndocrineSociety's2010clinicalpracticeguidelinesnotethefollowing[5]:
PrenataltreatmentforCAHshouldberegardedasexperimental
GlucocorticoidtherapyshouldbecarefullytitratedtoavoidCushingsyndrome
Mineralocorticoidreplacementisencouragedininfants,mineralocorticoid
replacementandsodiumsupplementationareencouraged
Useofagentstodelaypubertyandpromotegrowthareexperimental
Psychiatricsupportshouldbeencouragedforpatientswithadjustment
problems
Medicationshouldbeusedjudiciouslyduringpregnancyandinsymptomatic
patientswithnonclassicalCAH
Surgicalcare

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Infantswithambiguousgenitaliarequiresurgicalevaluationand,ifneeded,plans
forcorrectivesurgery,asfollows:
Thetraditionalapproachtothefemalepatientwithambiguousgenitaliadue
toadrenalhyperplasiaisclitoralrecessionearlyinlifefollowedby
vaginoplastyafterpuberty [6]
Vocalgroupsofpatientswithdisordersofsexualdifferentiation(eg,Intersex
SocietyofNorthAmerica)havechallengedthisapproach
Somefemaleinfantswithadrenalhyperplasiahaveonlymildvirilizationand
maynotrequirecorrectivesurgeryiftheyreceiveadequatemedicaltherapy
topreventfurthervirilization
TheEndocrineSociety's2010clinicalpracticeguidelinesnotethefollowing[5]:
Adrenalectomyshouldbeavoided
Surgicalreconstructionmaynotbenecessaryduringthenewbornperiodin
mildlyvirilizedgirlsbutmaybeappropriateinseverelyvirilizedgirlsitshould
beasinglestagegenitalrepair,performedbyexperiencedsurgeons
SeeTreatmentandMedicationformoredetail.

Background
Thetermcongenitaladrenalhyperplasia(CAH)encompassesagroupofautosomal
recessivedisorders,eachofwhichinvolvesadeficiencyofanenzymeinvolvedin
thesynthesisofcortisol, [1]aldosterone,orboth.

Pathophysiology
Theclinicalmanifestationsofeachformofcongenitaladrenalhyperplasiaare
relatedtothedegreeofcortisoldeficiencyand/orthedegreeofaldosterone
deficiency.Insomecases,thesemanifestationsreflecttheaccumulationof
precursoradrenocorticalhormones.Whenpresentinsupraphysiologic
concentrations,theseprecursorsleadtoexcessandrogenproductionwithresultant
virilization,orbecauseofmineralocorticoidproperties,causesodiumretentionand
hypertension.
Thephenotypedependsonthedegreeortypeofgenedeletionormutationandthe
resultantdeficiencyofthesteroidogenicenzyme.Theenzymesandcorresponding
genesaredisplayedintheimagebelow.

Enzymesandgenesinvolvedinadrenalsteroidogenesis.

Twocopiesofanabnormalgenearerequiredfordiseasetooccur,andnotall
mutationsandpartialdeletionsresultindisease.Thephenotypecanvaryfrom
clinicallyinapparentdisease(occultorcrypticadrenalhyperplasia)toamildformof
diseasethatisexpressedinadolescenceoradulthood(nonclassicadrenal
hyperplasia)toseverediseasethatresultsinadrenalinsufficiencyininfancywithor
withoutvirilizationandsaltwasting(classicadrenalhyperplasia).Themostcommon
formofadrenalhyperplasia(duetoadeficiencyof21hydroxylaseactivity)is
clinicallydividedinto3phenotypes:saltwasting,simplevirilizing,andnonclassic.
CYP21Aisthegenethatcodesfor21hydroxylase,CYP11B1codesfor11beta
hydroxylase,andCYP17codesfor17alphahydroxylase.Manyoftheenzymes
involvedincortisolandaldosteronesynthesesarecytochromeP450(CYP)proteins.

Frequency
UnitedStates
Themostcommonformofcongenitaladrenalhyperplasiaisduetomutationsor
deletionsofCYP21A,resultingin21hydroxylasedeficiency.Thisdeficiency
accountsformorethan90%ofadrenalhyperplasiacases.Mutationsorpartial
deletionsthataffectCYP21Aarecommon,withestimatedfrequenciesashighas1
in3individualsinselectedpopulations(eg,AshkenaziJews)to1in7individualsin
NewYorkCity.Theestimatedprevalenceis1caseper60individualsinthegeneral
population.
Classicadrenalhyperplasiahasanoverallprevalenceof1caseper16,000
populationhowever,inselectedpopulations(eg,theYupikofAlaska),the
prevalenceisashighas1casein400population.Congenitaladrenalhyperplasia
causedby11betahydroxylasedeficiencyaccountsfor58%ofallcongenital
adrenalhyperplasiacases.

International
Congenitaladrenalhyperplasiacausedby21hydroxylasedeficiencyisfoundinall
populations.11betahydroxylasedeficiencyismorecommoninpersonsof
MoroccanorIranianJewishdescent.

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Mortality/Morbidity
Themorbidityofthevariousformsofadrenalhyperplasiaisbestunderstoodinthe
contextofthesteroidogenicpathway,shownbelow,usedbytheadrenalglandsand
gonads.

Steroidogenicpathwayforcortisol,aldosterone,andsexsteroidsynthesis.Amutationor
deletionofanyofthegenesthatcodeforenzymesinvolvedincortisoloraldosteronesynthesis
resultsincongenitaladrenalhyperplasia.Theparticularphenotypethatresultsdependsonthe
sexoftheindividual,thelocationoftheblockinsynthesis,andtheseverityofthegenetic
deletionormutation.

Theclinicalphenotypecanbeunderstoodbyanalyzingthelocationoftheenzyme
deficiency,theaccumulationofprecursorhormones,theproductsofthose
precursorswhenoneenzymepathwayisineffective,andthephysiologicactionof
thosehormones(seeHistory).
Severeformsofcongenitaladrenalhyperplasiaarepotentiallyfatalifunrecognized
anduntreatedbecauseoftheseverecortisolandaldosteronedeficienciesthatresult
insaltwasting,hyponatremia,hyperkalemia,dehydration,andhypotension.

Epidemiology
Race
Congenitaladrenalhyperplasiaoccursamongpeopleofallraces.Congenital
adrenalhyperplasiasecondarytoCYP21A1mutationsanddeletionsisparticularly
commonamongtheYupikEskimos.

Sex
Becauseallformsofcongenitaladrenalhyperplasiaareautosomalrecessive
disorders,bothsexesareaffectedwithequalfrequency.However,because
accumulatedprecursorhormonesorassociatedimpairedtestosteronesynthesis
impactssexualdifferentiation,thephenotypicconsequencesofmutationsor
deletionsofaparticulargenedifferbetweenthesexes.

Age
Classiccongenitaladrenalhyperplasiaisgenerallyrecognizedatbirthorinearly
childhoodbecauseofambiguousgenitalia,saltwasting,orearlyvirilization.
Nonclassicadrenalhyperplasiaisgenerallyrecognizedatorafterpubertybecause
ofoligomenorrheaorvirilizingsignsinfemales.

Prognosis
Withadequatemedicalandsurgicaltherapy,theprognosisisgood.However,
problemswithpsychologicaladjustmentarecommonandusuallystemfromthe
genitalabnormalitythataccompaniessomeformsofcongenitaladrenalhyperplasia.
Shortstatureandinfertilityarecommon.
Genderidentityinfemaleswithvirilizingadrenalhyperplasiaisusually
femaleiffemalegenderassignmentismadeearlyinlife,ifadequate
medicalandsurgicalsupportareprovided,andifthefamily(andeventually
thepatientherself)isgivenadequateeducationtounderstandthedisease.
Femaleswithvirilizingadrenalhyperplasiamayhavemoremasculine
interests.
Femaleswithadrenalhyperplasiahavereducedfertilityrates,butfertilityis
possiblewithgoodmetaboliccontrol.
Earlydeathmayoccurifpatientsarenotprovidedwithstressdosesof
glucocorticoidintimesofillness,trauma,orsurgery.

PatientEducation
Educatethecaretakersandpatientsaboutthenatureofthediseaseinorderfor
themtounderstandtheimportanceofreplacementofthedeficientadrenalcortical
hormones.
Patientsmustalsounderstandtheneedforadditionalglucocorticoidsintimesof
illnessandstressinordertoavoidanadrenalcrisis.

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PatientsmustknowtheimportanceofIMinjectionsofglucocorticoidsandbe
educatedinthetechniqueofIMadministration.
UsefulWebsitesforpatientsandparentsincludetheNationalAdrenalDiseases
FoundationandtheCongenitalAdrenalHyperplasiaResearchEducationand
Support(CARES)Foundation.
ClinicalPresentation

ContributorInformationandDisclosures
Author
ThomasAWilson,MDProfessorofClinicalPediatrics,ChiefandProgramDirector,DivisionofPediatric
Endocrinology,DepartmentofPediatrics,TheSchoolofMedicineatStonyBrookUniversityMedicalCenter
ThomasAWilson,MDisamemberofthefollowingmedicalsocieties:EndocrineSociety,PediatricEndocrine
Society,PhiBetaKappa
Disclosure:Nothingtodisclose.
SpecialtyEditorBoard
MaryLWindle,PharmDAdjunctAssociateProfessor,UniversityofNebraskaMedicalCenterCollegeof
PharmacyEditorinChief,MedscapeDrugReference
Disclosure:Nothingtodisclose.
BarryBBercu,MDProfessor,DepartmentsofPediatrics,MolecularPharmacologyandPhysiology,Universityof
SouthFloridaCollegeofMedicine,AllChildren'sHospital
BarryBBercu,MDisamemberofthefollowingmedicalsocieties:AmericanAcademyofPediatrics,American
AssociationofClinicalEndocrinologists,AmericanMedicalAssociation,AmericanPediatricSociety,Association
ofClinicalScientists,EndocrineSociety,FloridaMedicalAssociation,PediatricEndocrineSociety,Societyfor
PediatricResearch,SouthernSocietyforPediatricResearch,SocietyfortheStudyofReproduction,American
FederationforClinicalResearch,PituitarySociety
Disclosure:Nothingtodisclose.
ChiefEditor
StephenKemp,MD,PhDFormerProfessor,DepartmentofPediatrics,SectionofPediatricEndocrinology,
UniversityofArkansasforMedicalSciencesCollegeofMedicine,ArkansasChildren'sHospital
StephenKemp,MD,PhDisamemberofthefollowingmedicalsocieties:AmericanAcademyofPediatrics,
AmericanAssociationofClinicalEndocrinologists,AmericanPediatricSociety,EndocrineSociety,PhiBeta
Kappa,SouthernMedicalAssociation,SouthernSocietyforPediatricResearch
Disclosure:Nothingtodisclose.
AdditionalContributors
ArlanLRosenbloom,MDAdjunctDistinguishedServiceProfessorEmeritusofPediatrics,UniversityofFlorida
CollegeofMedicineFellowoftheAmericanAcademyofPediatricsFellowoftheAmericanCollegeof
Epidemiology
ArlanLRosenbloom,MDisamemberofthefollowingmedicalsocieties:AmericanAcademyofPediatrics,
AmericanCollegeofEpidemiology,AmericanPediatricSociety,EndocrineSociety,PediatricEndocrineSociety,
SocietyforPediatricResearch,FloridaChapterofTheAmericanAcademyofPediatrics,FloridaPediatric
Society,InternationalSocietyforPediatricandAdolescentDiabetes
Disclosure:Nothingtodisclose.

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