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European Journal of Endocrinology -18-0279 overproduction ofACTHwithresultingadrenal cortisol biosynthesisisimpairedandthereconsequent refers toanydisorderofsteroidogenesisinwhich The term ‘congenital adrenal hyperplasia’ (CAH) properly Introduction: Overview ofsteroidogenesis recognized. classic’ defectsinallofthesefactorshavebeendescribed.Boththesevereandnon-classicdisorderscanbetreated if synthesis distinguishesitfrom21OHD.Aldosteronesynthasedeficiencyisararesalt-losingdisorder. Mild,‘non- deficiency isthesecond-mostcommonformofCAHinEuropeanpopulationsbutretentionaldosterone aromatase; variousPORdefects,foundindifferent populations,affect theseenzymesdifferently. 11-Hydroxylase different proteins.P450oxidoreductase(POR)isaco-factorusedby21-hydroxylase,17-hydroxylase/17,20-lyaseand are commoninBrazilandChina.Isolated17,20-lyasedeficiencycanbecausedbyraremutationsatleast three in 17-hydroxylase/17,20-lyaseablatesynthesisofsexsteroidsandalsocausemineralocorticoidhypertension;these common, butgeneticanalysesshowthatsteroidmeasurementsaregenerallyunreliableforthisdisorder. Defects 3 the cholesterolside-chaincleavageenzyme,P450scc,areclinicallyindistinguishablefromStARdefects.Defects in disrupt allsteroidogenesisandarethesecond-mostcommonformofCAHinJapanKorea;veryraredefects in on thebasisofbiochemistrysteroidogenesis.Defectsinsteroidogenicacuteregulatoryprotein,StAR, incidences oftherareformsCAHvarywithethnicityandgeography. TheseformsofCAHareeasilyunderstood mean ‘steroid21-hydroxylasedeficiency’(21OHD)as21OHDaccountsforabout95%ofCAHinmostpopulations;the synthesis, withcompensatoryincreasesinACTHleadingtohyperplasticadrenals.Theterm‘CAH’isgenerallyused Congenital adrenalhyperplasia(CAH)isagroupofgeneticdisorderssteroidogenesisthatimpaircortisol Abstract California, SanFrancisco,USA Department ofPediatrics,CenterforReproductiveSciences,andInstituteHumanGenetics,University Walter L Miller Rare defectsinadrenal steroidogenesis MECHANISMS INENDOCRINOLOGY β https://doi.org/ www.eje-online.org Review Review basis ofnumerousdiseases. cloned genesforsteroidogenicenzymesandco-factorselucidated themolecular laboratory Hospitals. Hisworkhascentered onthemolecularbiologyofsteroidhormone synthesis. His San Francisco(UCSF)and Emeritus ChiefofEndocrinologyattheUCSFBenioff Children’s Walter LMiller Invited Author’s profile -hydroxysteroid dehydrogenase,whichalsocausesdisorderedsexualdevelopment,wereoncethoughttobefairly 10.1530/EJE -18-0279 isDistinguishedProfessorofPediatrics,Emeritus,atthe University ofCalifornia, 3 © 2018EuropeanSociety ofEndocrinology W LMiller Printed inGreatBritain The genetics,enzymology, clinicalfindings,hormonal catalyzed bymicrosomalP450c21,encoded CAH haveadisorderinadrenalsteroid21-hydroxylation, hyperplasia. Approximately95%ofallpatientswith Adrenal steroidogenesisdefects Published byBioscientifica Ltd. Downloaded fromBioscientifica.com at09/28/202104:05:24AM (2018) Endocrinology European Journal of [email protected] Email to WLMiller should beaddressed Correspondence 179 179 :3 , R125–R141

R125 CYP21A2 –R141 via freeaccess . European Journal of Endocrinology www.eje-online.org P450c11AS ( P450c11 Oxidoreductase ( P450 17,20-Lyase deficiency P450c17 ( 3 P450scc ( Lipoid CAHStAR( Enzyme Table 1 from infants,isessential.Traditional immunoassaysare smallvolumesofblood hormones, oftenwithvery summarized in therapeutic approachesineachofthesedisordersare in certaingeneticallyisolatedpopulations( these formsofCAHaregenerallyrare,butmaybecommon than 21OHD,whetherornotthereisadrenalhyperplasia; consider alldisordersofadrenalsteroidogenesisother hence thereisnoadrenalhyperplasia.Thisreviewwill steroidogenesis inwhichACTHisnotoverproducedand in detail( deficiency (21OHD) have been studied and discussed patterns, diagnosisandtreatmentof21-hydroxylase syndrome ( β Review HSD ( The clinical and laboratory featuresandkey The clinicalandlaboratory HSD3B2 (gene) β CYP11A1 ( CYP17A1 Clinical andlaboratoryfindingsinuncommonformsofCAH. CYP11B1 1 CYP11B2 CYB5 ). Therearealsosomeadrenaldisorders of ) POR Table 1 ) STAR ) ) ) ) )

) . Accurate measurement of steroid 46,XY DSD Hypertension Sexual infantilism 46,XY DSD 46,XY and46,XXDSD Salt-wasting crisis As inlipoidCAH Mild adrenalinsufficiency Non-classic form: 46,XY DSD Salt-wasting crisis Classic form: Presentation Salt loss Weakness Failure tothrive Occasional saltlossin Postnatal virilizationin 46,XX DSD Infertility inadults Antley-Bixler syndromein 46,XX and46,XYDSD without DSD older childrenandadults newborns; hypertensionin males andfemales infants W LMiller 2 ). Decreased/absent responseto Low/absent levelsofallsteroids Clinical andlaboratoryfindings ↓ ↑ Hyponatremia, hyperkalemia Hypokalemia ↑ Suppression ofelevatedsteroids ↑ ↑ Normal electrolytes ↓ ↑ Low C19steroidswithpoor Hypokalemia ↑ Suppression ofelevatedadrenal Poor responsetohCGin46,XY Low 17OHsteroidswithpoor ↑ ↑ Suppression ofelevatedadrenal ↑ ↑ As inlipoidCAH ↑ Decreased/absent responseto Aldosterone Corticosterone ACTHand Serumandurineandrogens 11-DeoxycortisolandDOC DHEA,Andro,T ACTH,Prog,17OHP ACTHand DOC,18OH-DOC,corticosterone, ACTHandrenin Δ5/Δ54serumsteroids Δ5steroidsbeforeandafter ACTHandrenin administration after glucocorticoid before andafterACTH responses tohCG administration steroids afterglucocorticoid responses toACTH 18OH-corticosterone administration steroids afterglucocorticoid ACTH hCG in46,XYDSD ACTH and itslimitations. whatever assaytechnologyisusedforclinicaldiagnosis, is theclinician’s responsibilitytobecomefamiliarwith research ( be processed,sothatthisprocedureislargelyusedfor (GC/MS),butfewersamplescan by massspectrometry and theirmetabolitesbygaschromatographyfollowed ( problems ofsteroidcross-reactivityinimmunoassays (LC-MS/MS),whicheliminatesthe spectrometry by liquidchromatographyfollowedtandemmass age andsex.Immunoassaysarerapidlybeingsupplanted reference laboratories with well-established standards by widely usedforthispurposeandcanbequitereliablein Adrenal steroidogenesisdefects 3 , ↓ ↓ 4 Renin Renin ). Some laboratories also assess urinary steroids ). Somelaboratoriesalsoassessurinary ↑ Renin 5 ). Irrespectiveoftheassaytechnologyused,it Downloaded fromBioscientifica.com at09/28/202104:05:24AM Glucocorticoid and Treatment Salt supplementationininfancy Mineralocorticoid replacement Surgical correctionofgenitaliaand Glucocorticoid administration Surgical correctionofskeletal Glucocorticoid andsexsteroid Testosterone replacementinmales Estrogen replacementinfemalesat Testosterone replacementifreared Estrogen replacementinfemalesat Surgical correctionofgenitaliaand Glucocorticoid administration Surgical correctionofgenitaliaand Salt supplementationininfancy Glucocorticoid and As inlipoidCAH Consider gonadectomyof46,XY Estrogen replacementat mineralocorticoid replacement, DSD consistentwithsexofrearing sex steroidreplacementin46,XX anomalies replacement ≥ as male(rare) ≥ DSD consistentwithsexofrearing sex steroidreplacementin46,XY consonant withsexofrearing sex steroidreplacement mineralocorticoid replacement salt supplementationininfancy 12 years 12 years 179 :3 ≥ 12 year R126 via freeaccess European Journal of Endocrinology mechanisms maynotbereadilyapparent.Thefirstand transport mechanisms;consequently, disordersinthese There areredundanciesintheintracellularcholesterol disease rather than as forms of adrenal hyperplasia ( are typicallyconsideredasgeneticformsofAddison’s cholesterol side-chaincleavageenzyme,cytochrome of cholesteroltopregnenolonebythemitochondrial rate-limiting step in steroidogenesis is the conversion the fetaltestis,5 and testosteronetoestradiol;in estrogenictissues(ovary, breastfat),17 zona reticularisproducesmall amounts oftestosterone.Inovariangranulosacells,P450aro convertsandrostenedionetoestrone 17 convert 17OH-PregtoDHEA,so thatmosthumanandrogensynthesisproceedsviaDHEA,not viaandrostenedione.Testicular P450c17 converting17OH-PregtoDHEA;humanconverts 17OHPtoandrostenedionewithonly~2%ofitsactivity P450c11 fasciculata, expressionofmicrosomalP450c17permitssynthesis of17OHP, whichisconvertedtocortisolbymitochondrial P450c11AS catalyzes11-hydroxylase,18-hydroxylaseand18-methyl oxidaseactivities,toyieldaldosterone(Aldo).Inthezona glomerulosa, progesterone,thefirst corresponding P450scc removesthecholesterolsidechaintoyieldpregnenolone, thefirstC21steroid. facilitates mostcholesterolinfluxintosteroidogenicmitochondria, butsomesteroidogenesisoccursinitsabsence.Mitochondrial Principal pathwaysofsteroidogenesis.Thefigureincorporates pathwaysfromadrenalandgonadalsteroidogenesis.StAR Figure 1 disorders thatmayincludeadrenalinsufficiency( mechanisms ( the intracellulartransportofcholesterolinvolvescomplex essentially insolubleinwaterandcytoplasm;hence, disorders arealsowellcharacterized( de novo lipidsorbesynthesized which canderivefromdietary All steroidhormonesynthesisbeginsfromcholesterol, steroid biosynthesisarenowwellunderstood( Review β HSD3 convertsDHEAtoandrostenediol andandrostenedionetotestosterone;lowlevelsof adrenal17 The pathways, enzymology and disorders of human ; thepathwaysofcholesterolbiosynthesisandits β . InthezonareticularisandtesticularLeydigcells,expression ofcytochromeb5facilitatesthe17,20-lyaseactivity ∆ 8 4-steroids by3 α ), disruptionofwhichcanleadtorare -reductase type2furtheractivates testosteronetodihydrotestosterone.(CopyrightWLMiller.) β HSD2 intheadrenalandgonadorby3 W LMiller ∆ 4-steroid, is21-hydroxylatedbymicrosomalP450c21toyield DOC, thenmitochondrial 7 ). Cholesterolis Fig. 1 9 ); these ) ( 10 6 ). ). pathway stopswitha17-hydroxy21-carbon(C21)steroid CYP17A1 activities ofP450c17,amicrosomalenzymeencodedby to DHEAbythesequential17-hydroxylaseand17,20-lyase converted to17OH-pregnenolone(17OH-Preg)andthence whereas disorderedP450sccisnot.Pregnenolonemaybe but disordered StAR is associated with adrenal enlargement, P450scc areclinicallyandhormonallyindistinguishable, to pregnenolonebyP450scc( into steroidogenicmitochondria,whereitisconverted the protein, StAR (encoded by steroidogenic acute regulatory understood, butiscriticallydependentonthe Mitochondrial cholesterolimportremainsincompletely cholesterol importisratelimitinginsteroidogenesis. littlecholesterol;hence,mitochondrial there isvery located ontheinnermitochondrialmembrane,where P450scc, encodedbythe Adrenal steroidogenesisdefects β STAR β HSD1 intheplacentaandperipheraltissues.Inzona HSD1 convertsestronetoestradiol. Ingenitalskinandin gene),whichfacilitatesrapidfluxofcholesterol . Thedeterminationofwhetherasteroidogenic ∆ 5-steroids areconvertedtothe Downloaded fromBioscientifica.com at09/28/202104:05:24AM CYP11A1 9 ). DisordersinStARand β gene( HSD5 (AKR1C3)inthe 179 www.eje-online.org :3 11 ). P450sccis R127 via freeaccess European Journal of Endocrinology www.eje-online.org outer mitochondrialmembrane (OMM)totheinner StAR facilitatestheinflux ofcholesterolfromthe protein: classicandnon-classiclipoidCAH StAR: thesteroidogenic acuteregulatory dihydrotestosterone. encoded by lesser extent in the testis), 5 converts estronetoestradiol.Ingenitalskin(and a also express17 in ovariangranulosacells(andadipocytes).Thesetissues androstenedione toestroneandtestosteroneestradiol P450aro (aromatase,encodedby (encoded by in thetestis,thisreactioniscatalyzedby17 amounts ofandrostenedionetotestosterone,whereas reticularis, 17 animals catalyzesthisstepefficiently. Intheadrenalzona contrast, theP450c17ofrodents,cattleandmanyother proceeds viaDHEA,andnotandrostenedione;by to DHEA,sothatmosthumantestosteronesynthesis with only~2%ofitsactivitytoconvert17OH-Preg b5, humanP450c17converts17OHPtoandrostenedione androgen precursors.However, evenwiththeassistanceof the steroidsidechainthusconvertingC21steroidstoC19 catalyzes 17,20-lyaseactivity, removingtwocarbonsfrom action ofcytochrome encoded by cortisol bymitochondrialP450c11 of 17OH-progesterone(17OHP),whichisconvertedto P450c17 intheadrenalzonafasciculatapermitssynthesis oxidase activities,yieldingaldosterone.Expressionof catalyzes 11-hydroxylase,18-hydroxylaseand18-methyl ‘aldosterone synthase’,encodedby glomerulosa, mitochondrialP450c11AS(‘AS’designates be 21-hydroxylatedbymicrosomalP450c21.Inthe does notexpressP450c17,permittingprogesteroneto liver and elsewhere. The adrenal zona glomerulosa gonad orbythecloselyrelated3 2 (3 ∆ inactive atoms 5and6inthesteroidB-ring.Thesehormonally ∆ by NADPH ( availability of reducingequivalentssuppliedtoP450c17 19-carbon (C19)androgenprecursorsdependsonthe or undergoessubsequent17,20-lyaseactivitytoyield 4-steroids by3 5 steroids,retainingthedoublebondbetweencarbon Review β HSD2, encodedby ∆ 5-steroids canbeconvertedtothecorresponding 12 CYP11B1 β SRD5A2 HSD17B3 HSD5 (encodedby ). Pregnenolone, 17OH-Preg and DHEA are β HSD1 (encodedby β -hydroxysteroid dehydrogenasetype ) further activates testosterone to ). Whenfacilitatedbytheallosteric b 5 ) and proceeds very efficiently.) andproceedsvery (b5,encodedby HSD3B2 α -reductase type 2 (5 W LMiller AKR1C3 ) intheadrenaland CYP11B2 β β CYP19A1 HSD1 inplacenta, (11 HSD17B1 CYB5 ) convertssmall β -hydroxylase, ) sequentially ) converts ), P450c17 ), which β α HSD3 Red2, year of life with salt loss, very lowserumsteroids,high year oflifewithsaltloss,very severe steroidogenic disorder, typically presents in the first hyperplasia (lipoidCAH)( some roleinthisprocess. 16 protein (TSPO)hasbeendisproven,atleastinmice( ( the mechanism by which this happens remains unknown the importationof100–200moleculescholesterol,but ( is inactivebecauseofitsintramitochondriallocation 37 biologically activeformofStARistheextra-mitochondrial facilitated byStARactingexclusivelyontheOMM; steroidogenesis is import of cholesterol into mitochondria, steroidogenic enzyme,butthetruerate-limitingstepin to pregnenolonebyP450scc. P450scc istheslowest mitochondrial membrane,whereitmaybeconverted Leydig cellsaredestroyedearly ingestation,eliminating knockout mice ( ( observations ( destroys residualStAR-independent steroidogenesis auto-oxidation products;this‘secondhit’eventually accumulated cholesterol,cholesterolestersandtheir causing mitochondrialandcellulardamagefromthe Over time,thisintracellularcholesterolaccumulates, of LDLcholesteroland of receptorsforlow-densitylipoproteins(LDLs),uptake increases inACTHandLH,whichincreasebiosynthesis and testicularsteroidogenesisleadstocompensatory most (but not all) steroidogenesis. Diminished adrenal The absenceofStARisthefirsthit,resultinginaloss of model forthepathophysiologyoflipoidCAH( seen intheabsenceofStAR,whichsuggestedatwo-hit characterized bygrossadrenalenlargement(seebelow). indistinguishable fromlipoidCAH,butarenot causing P450sccdeficiencyareclinicallyandhormonally mutated inthesepatients( pregnenolone, butthe an outmodedtermforconversionofcholesterolto was formerlymisnamed‘20,22-desmolasedeficiency’, conversion ofcholesteroltopregnenolone,lipoidCAH ( adrenals laden withcholesteroland esters chorionic gonadotropin(hCG)andgrosslyenlarged long-term treatmentwithhighdosesofACTHorhuman ACTH andplasmarenin,minimalsteroidalresponsesto Adrenal steroidogenesisdefects 14 8 20 20 , , kDa protein, while the intramitochondrial 30 ). TheviewthatStAR’s actionrequiresthetranslocator ). Becausethesefindingsindicatedisruptioninthe ). Thistwo-hitmodelhasbeen confirmedbyclinical 9 17 StAR mutationscausecongenitallipoidadrenal Low levelsofStAR-independentsteroidogenesisare , 13 , 18 ). Each molecule of StAR on the OMM facilitates ), although it remains possible that it may serve ), althoughitremainspossiblethatmayserve 22 , 24 23 , 25 ) andbyexperimentsin StAR- CYP11A1 Downloaded fromBioscientifica.com at09/28/202104:05:24AM ). In the affected 46,XY fetus, de novo 19 21 , ). Rare 20 geneforP450sccisnot ). LipoidCAH,themost cholesterolsynthesis. 179 CYP11A1 :3 20 mutations kDa StAR ) ( R128 Fig. 2 15 via freeaccess ). ). ,

European Journal of Endocrinology manifested atalmostanytime fromthenewbornperiod is severelyimpaired,causing saltloss,butthismaybe feto-placental estriolproduction. Aldosteronesynthesis severely impairedsynthesis ofDHEA,whicheliminates cortisol synthesisresultsinelevatedACTHsecretionand uterus andfallopiantubes.Intheadrenal,defective that thephenotypicallyfemale46,XYfetuslacksacervix, hormone appropriately,produce Müllerianinhibitory so external genitalia. However, the Sertoli cells continue to sexual development(DSD),withfemale-appearing biosynthesis oftestosterone,resultingindisordered anovulatory cycles.(From( recruited atthebeginningofeachcycle,whenproducesmall amountsofestradiol,asinpanelB,leadingtofeminizationand steroidogenic capacity. Intheovariesofaffected females,follicularcellsremainunstimulatedandundamageduntiltheyare cholesterol thenaccumulatesinlipiddroplets.(C)Accumulatingdropletsdamagethecell,eventuallydestroyingall independent mechanisms.DecreasedcortisolsecretionleadstoincreasedACTHandcholesteroluptakesynthesis; absent StARreducesmitochondrialcholesterolimportandsteroidogenesis,butsomesteroidogenesispersistsbyStAR- travels fromtheOMMtoIMMbybothStAR-dependentandStAR-independentmechanisms( acetyl CoA.Cholesterolisstoredinlipiddroplets,reachesthemitochondriabybothvesicularandnon-vesicularmeans, then LDL cholesterolisprocessedinlysosomesbeforeenteringthecellularpool;canalsobesynthesized Two-hit modeloflipoidCAH.(A)NormaladrenalcellsderivecholesterolprimarilyfromLDLbyreceptor-mediated endocytosis. Figure 2 Review 20 ) withpermission.) W LMiller female. Continuedgonadotropin stimulationinduces results insufficientestrogen tofeminizeanadolescent time ofpuberty, whenStAR-independentsteroidogenesis undamaged untilitisstimulated bygonadotropinsatthe littlesteroidandhence remains largely makes very bleeding inearlyadolescence( puberty, withbreastdevelopmentand cyclic vaginal normal genitaliaatbirthandappeartogothrough ( indicating variabledestructionofthezonaglomerulosa to ayearofage,irrespectivethe Adrenal steroidogenesisdefects 20 , 26 ). Genetic 46,XX females with lipoid CAH have Downloaded fromBioscientifica.com at09/28/202104:05:24AM 9 ). (B)EarlyinlipoidCAH, 22 , STAR 23 179 ). The fetal ovary ). Thefetalovary www.eje-online.org de novo :3 genemutation, from R129 via freeaccess European Journal of Endocrinology www.eje-online.org is variableandshouldbetitrated tothebloodpressure contain moresodium.Thus, mineralocorticoiddosing because thedietsofolder children andadultstendto receptors intherenalepithelium increaseswithage,and are weaned thereafter, as the density of mineralocorticoid ofage,andmineralocorticoiddoses weaned after1 year and areraisedasfemales.Saltsupplementationistypically female externalgenitaliausuallyundergoorchiectomy production. Growthshouldbenormal.46,XYmaleswith tosuppressexcess adrenal androgen it isnotnecessary insufficiency andarelessthanthosein21OHDbecause adrenal glucocorticoid dosesarethoseusedinprimary saltinthenewborn period. The with supplementary replacement ofglucocorticoidsandmineralocorticoids, disorders ofStARmaymanifestatanyage. may havemildhypergonadotropichypogonadism.Thus, serum electrolytesandelevatedplasmarenin,some compromised mineralocorticoidsecretion,withnormal appearing external genitalia. Patients may have mildly non-classic 46,XYgeneticmalestypicallyhavenormal- glucocorticoid deficiency ( these patientshavebeenmistakenforhavingfamilial any timefromchildhoodtoadulthood,sothatsomeof CAH havemildadrenalinsufficiencythatmaypresentat lipoid CAH( especially p.R188C,causeamild‘non-classical’formof age ( of severe StARmutationshavepresentedaslate1 year salt lossinthefirstweeksoflife,butsomeinfantswith phenotypically femaleinfantwithfailuretothriveand Switzerland ( among Arabpopulations( mutations includep.R182L,p.R182Handc.201_202delCT for most alleles ( about 1in300,withthemutationp.Q258Xaccounting Korea andJapanwheretheheterozygouscarrierrateis Lipoid CAHisthesecond-mostcommonformofin patients havebeenreportedwith cycles ( monthly estrogenwithdrawalbleedingandanovulatory undamaged follicle is recruitedineachcycle,resulting hence, mostfolliclesremainundamagedsothatan stimulation sequentiallyrecruitsindividualfollicles; synthesis lateinthecycleisimpaired.Gonadotropin at thebeginningofmenstrualcycle,progesterone estrogen ismadebyStAR-independentsteroidogenesis cholesterol accumulationandcellulardamage;although Review The classicalpatientwithlipoidCAHisa Treatment of lipoid CAH consists of physiological Lipoid CAH is rare in most populations, but 26 ). StAR mutations that retain about 20% activity, 22 , 23 33 32 ). , ). 34 , 20 35 , , 36 27 ). Patientswithnon-classiclipoid , 34 2 28 , ). UnlikeclassiclipoidCAH, 20 , 29 , W LMiller > 26 , 40 StARmutations( 30 , 31 ). Other recurrent ) andp.L260Pin > 100 9 ). electrons fromadrenodoxinreductase. (CopyrightWLMiller.) adrenodoxin canthenrecycleand receiveanotherpairof available mitochondrialcytochrome P450suchasP450scc.The electron shuttlemechanismthat candonateelectronstoany mitochondrial matrixthatfunctions asafreelydiffusable ferredoxin (adrenodoxin,Adx),aniron–sulfurproteininthe and convertsittoNADP+.Theelectronsarepassed mitochondrial membrane,acceptselectrons(e reductase (AdRed),islooselyboundtotheinner flavoprotein, termedferredoxinreductaseoradrenodoxin Electron transporttomitochondrialP450enzymes.A Figure 3 also typeIP450enzymes( below), and thevitamin D 1 ( transfer proteins–ferredoxinreductaseand donated byNADPHviatheintermediacyoftwoelectron in mitochondriaandmediatecatalysisutilizingelectrons human ‘typeI’P450enzymes,includingP450scc,arefound cytochrome P450scc,encodedby scission ofthe20-22carbonbond;allarecatalyzedby involved: 20-hydroxylation,22-hydroxylationand side chain to yield pregnenolone. Three reactions are The firststepinsteroidogenesisiscleavageofthecholesterol cleavage enzyme(P450scc) CYP11A1 females withlipoidCAH( and plasmarenin.Pregnancyhasbeeninducedin46,XX deficiency havebeenreported,includingseveralwith lethality.embryonic However, ~30 patients with P450scc it waslaterthoughtthatP450sccdeficiencywouldcause suppress uterinecontractilitytopermittermgestation, placental productionofprogesterone,whichisneededto cause lipoidCAH,butbecauseP450sccisneededforthe Adrenal steroidogenesisdefects i. 3 Fig. Deficient P450sccactivitywasinitiallythoughtto ) ( 39 : thecholesterol side-chain ); thetwoisozymesof11 Downloaded fromBioscientifica.com at09/28/202104:05:24AM 37 40 , ). 38 α - and 24-hydroxylases are ). CYP11A1 179 β -hydroxylase (see :3 − ) fromNADPH . Theseven R130 via freeaccess European Journal of Endocrinology pregnenolone, 17OH-Preg, DHEA andandrostenediol, ∆ reactions, 3 dehydrogenase (3 Using NADasaco-factor, 3 dehydrogenase deficiency HSD3B2 substantial interest. mitochondrial P450enzymes.Suchstudieswouldbe of examined functionally not examinedinthesepatients,norwerethemutants proteins inneurologicfunction,butadrenalfunctionwas findings apparentlyreflecttheessentialroleofiron–sulfur reported inchildrenfrom17families( hearing lossandvisualimpairmenthaverecentlybeen acid replacement) reported. Forferredoxinreductase,15missense(amino arrest ( inhibiting cortisolsynthesisandcausingdevelopmental corresponding FDX1 isespeciallyabundantintheadrenalcortex; iron-sulfur clusters,butnotinsteroidogenesis( mitochondrial P450s;FDX2participatesinsynthesisof of ferredoxin,FDX1andFDX2:interactswith utilized bysomeenzymes( also participateinthesynthesisofiron–sulfurcenters ferredoxin reductase or ferredoxin; these two proteins suggests thatmutationsmightbefoundinthegenesfor compatible withtermgestationinsomeaffected fetuses with non-classiclipoidCAH. hormonally andclinicallyindistinguishablefromthose about 10–20% of WT activity ( is foundinpatientswhoseP450sccmutationsretain ( in SoutheasternTurkey, apparentlyduetoafoundereffect A geneticisolateof P450scc deficiency has beenreported the onlydefinitivewaytodifferentiatethesetwodisorders. consequently, sequencingthe adrenal enlargement that is characteristic of lipoid CAH; lipoid CAH, although they typically lack the massive and hormonallyindistinguishablefromthosewith not been studied directly. These patients are clinically produce progesteroneintolatepregnancy, butthishas the maternal corpus luteum of pregnancy continues to with P450scc mutations probably reach term only when complete loss-of-function mutations ( 42 5– Review ). A milder, ‘non-classic’ form of P450scc deficiency ∆ The discovery thatcompletedeficiencyofP450sccis The discovery 4-isomerization, offour adrenal 49 ), but no human or mouse mutations have been : 3 β β -hydroxysteroid -hydroxysteroid dehydrogenation and Fdx1 β HSD) catalyzestworapidly sequential FDXR genehasbeendisruptedinzebrafish, mutationscausingneuropathic in vitro 45 STAR , 43 46 withP450sccorother W LMiller , ). Therearetwoforms and 44 ); these patients are CYP11A1 β 9 -hydroxysteroid 50 , , 41 ∆ 51 5-steroids, ). Fetuses ). These genesis 47 , 48 ). pregnenolone to progesterone. Nevertheless, the the preferredlocation( the mitochondrial intramembranous space appearstobe reticulum, cytoplasmandmitochondrialmatrix( immunoreactivity has been found in the endoplasmic distribution of3 downstream cortisolandsexsteroids.Thesubcellular ( 3 10-fold higherthanthatof3 ( same reactions;however, theMichaelis–Mentenconstant isoforms share 93.5% sequence identity and catalyze the expressed in the adrenals and gonads ( peripheral tissues,and (encoding 3 3 testosterone, respectively. Therearetwoformsofhuman yielding progesterone,17OHP, androstenedioneand are typicallyyoungfemales withprematureadrenarche, many reportsof‘partial3 standard deviations following an ACTH test have ledto 3 ACTH cannot reliably identify heterozygous carriers of corresponding of pregnenolone,17OH-PregandDHEAtheir intravenous administrationofACTHwithmeasurement ( approaching thoseseeninpatientswithclassical21OHD 3 thus complicatingthediagnosis;somenewbornswith produce some in 3 not beappropriate( patients with3 thus, DSDisseeninbothsexes.Gonadectomyof46,XY are insufficient forcompletemalegenital development, of adrenalandtesticularDHEA,buttheconcentrations also synthesizesomeandrogensbyperipheralconversion is convertedtotestosteronevia3 and mildvirilizationbecausesomefetaladrenalDHEA abortion. Affected 46,XX infants have clitoromegaly progesterone, resultinginaspontaneousfirst-trimester presumably wouldpreventplacentalbiosynthesisof in the deficiency. Allreportedcasesof3 with glucocorticoid, mineralocorticoid and sex steroid Adrenal steroidogenesisdefects 58 K 62 β β β β m HSD2 ismuchhigherthanthatofP450c17(~0.8 similargenes: HSD, encodedbytwovery HSD deficiency( HSD2 deficiencyhaveserumconcentrationsof17OHP ), whichwouldfavorproductionof17OH-Pregand ). Theprincipaldiagnostictestin3 ) for3 β Ratios of HSD3B1 3 HSD2 deficiency; thelow β HSD deficiencyisarare,severeformofCAH HSD3B2 β HSD2 isabout5.5 expressionintheliverandelsewherepersists β HSD1) isexpressedintheplacentaand ∆ ∆ β 5 to gene ( ∆ 4-steroids fromcirculating β HSD deficiencyiscontroversialandmay HSD isanactiveareaofresearch ( 4 compounds.Steroidalresponsesto 63 61 ∆ ). 4 steroids that areelevated by 2–3 ). 2 Downloaded fromBioscientifica.com at09/28/202104:05:24AM , 57 HSD3B2 β 59 HSD deficiency’.Thesepatients ), favoringtheconversionof , 60 K m β μ ); mutations in 3 (encoding3 HSD1 ( of 3 M ( β HSD1. Geneticmales β 179 HSD deficiencyare 54 β β HSD1 permits it to 52 www.eje-online.org HSD deficiencyis :3 ), approximately 53 , 53 ∆ , 5-precursors, ). These two 55 β ). 3 HSD2) is HSD3B1 R131 β 14 K HSD1 β HSD m μ ). 56 of M) via freeaccess );

European Journal of Endocrinology www.eje-online.org androgen synthesis,inwhich 17OHPis3 is alsoessentialinthealternative ‘backdoor’pathwayof p38 ( serine/threonine phosphorylation activity ofhumanP450c17 can alsobeaugmentedbyits but notinthezonafasciculata( b5 isabundantly expressed inthe adrenal zona reticularis Consistent withitsessentialrolein17,20-lyase activity, allosteric factor rather than as anelectron donor ( 17OH-Preg isstimulated10-foldbyb5,actingasan reaction easily ( DHEA, eventhoughcattleandrodentscatalyzethis with only~2%oftheactivitytoconvert17OH-Preg to human P450c17 converts 17OHP to androstenedione pathway pregnenolone Thus, mosthumansexsteroidsynthesisproceedsviathe of C21steroidstoC19onlywith17OH-Preg. with equalefficiency, butefficientlycatalyzesthecleavage the 17-hydroxylationofpregnenoloneandprogesterone synthesis andreproduction.HumanP450c17catalyzes and androgens;thus,P450c17isessentialforbothcortisol C21, 17-hydroxysteroidstoC19precursorsofestrogens 16-hydroxylation and the17,20-lyase activity thatconverts ( involved indrugmetabolismandleukotrienesynthesis include P450c21,P450aroandmostoftheenzymes oxidoreductase (POR)( P450 enzymesreceiveelectronsfromNADPHvia the expressed intheadrenalsandgonads and isencoded by P450c17 isatype2(microsomal)P450enzymethat CYP17A1 final adultheight. contraindicated ingirlswhohavenotyetreachedtheir with lowdosesofglucocorticoids,butsuchtreatmentis elevated ratiosof and regularmensescanberestoredinadultwomenwith requires further study ( individuals withnormal3 mildly elevatedratiosof with aprofoundrisein 3 ∆ exceed 8SDabovethemean( In true 3 HSD3B1 hirsutism, virilismandoligomenorrhea.However, the 40 β 4 steroidsarenotreliableandcannotbeusedtodiagnose Review HSD deficiency;thediagnosisrequiresanACTHtest ). P450c17 catalyzes steroid 17 α CYP17A1 (MAPK14)( and β HSD deficiency, the ratios of : 17 HSD3B2 gene( α 73 58 -hydroxylase deficiency ∆ 5 to ). The17,20-lyaseactivityof P450c17 ). Human17,20-lyase activity with 66 genesinthesepatientsarenormal. , 14 ⟶ ∆ ∆ ∆ 67 39 4 steroidsbysuppressingACTH ). Hirsutism can be ameliorated 5 steroids( 5 to 17OH-Preg ). The50humanmicrosomal β ); othermicrosomalP450s HSD genesisunknownand 64 ∆ , 4 steroidsinthesehirsute W LMiller 65 69 α -hydroxylation, steroid ). Thus,ratiosof , 71 65 70 ⟶ , ). Thebasisofthe ). The17,20-lyase α ∆ 72 - and5 DHEA ( 5 to ), catalyzedby ∆ α 4 steroids -reduced, 58 , ∆ 58 68 5 to ). ); are phenotypicallynormalinchildhoodbutdonot consequently, 46,XXpatientslackingallactivity Absent 17,20-lyase activity prevents sexsteroidsynthesis; replacement therapytypicallynormalizesthesefindings. and variablysuppressedaldosterone); glucocorticoid sodium retention,hypokalemia,suppressedplasmarenin (which oftencausesmineralocorticoidhypertensionwith cortisol deficiency)and11-deoxycorticosterone(DOC) overproduce corticosterone (which compensates for the ACTH andgonadotropins.Affectedpatientstypically sex steroidsynthesis,withcompensatorilyelevated 21OHD ( This pathwayparticipatesinthevirilizationseen about equally. Two studies have associated while someotherspartially affect bothactivities,usually Most reported of PortugueseandSpanish descent,respectively( the mutationsp.R362Cand p.W406Rtrackwithpersons appears to be the second most common form of CAH, Korea ( frameshift mutation is common in Northern China and throughout Southeast Asia and China ( a ThaipatientofChinesedescent( ( Dutch Mennonites and their Canadian descendants The first-describedmutationwasa4-baseinsertionamong with adistinctethno-geographicdistribution( sex ofrearing. appropriate sexsteroidreplacementconcordantwiththe to suppressthe mineralocorticoid hypertension, and age- Treatment consists of glucocorticoid replacement therapy 17-hydroxylated steroids, which respond poorlytoACTH. are hyperresponsivetoACTH,andlowconcentrationsof corticosterone, 18OH-corticosterone and 18OH-DOCthat diagnosis isestablishedbyfindingelevatedlevelsofDOC, or 46,XY)withmineralocorticoidhypertension.The infantile adolescent phenotypic female (either 46,XX The mostcommonclinicalpresentationisasexually development andbothsexesmaypresentwithDSD( retain partialactivity, femalesmayhavemodestbreast external genitalia.Amongpatientswithmutationsthat while 46,XYpatientshavefemaleorundervirilized undergo adrenarche or feminize at the timeof puberty, (DHEA, androstenedione,testosterone)( without goingthroughtheconventionalintermediates to yieldthemost potent androgen, dihydrotestosterone, 17 cleaved toaC19steroidby17,20-lyaseactivityandthen Adrenal steroidogenesisdefects 78 β ); adeletionofaminoacids487-489,firstreportedin -reduced toandrostanediol,whichisthen3 Deficient P450c17 activity impairs cortisoland Many 77 75 , CYP17A1 80 ). , 81 CYP17A1 , 82 mutationshavebeenreported, often , 83 Downloaded fromBioscientifica.com at09/28/202104:05:24AM mutationsablateallactivity, ); andinBrazil,where17OHD 79 179 80 ), hasbeenfound :3 ), the p.Y329Kfs 6 , 74 α ) ( CYP17A1 -oxidized 76 i. 4 Fig. R132 , 84 77 76 via freeaccess ). ). ). ).

European Journal of Endocrinology mutations inP450c17;these aremostcommonlyfound First, 17,20-lyasedeficiency maybecausedbyspecific be causedbymutationsin severaldifferentgenes( ( alternative, ‘backdoor’ pathway of androgen synthesis mutations intwoenzymes(AKR1C2andAKR1C4)the reported tohave17,20-lyasedeficiencyinstead P450c17 catalyzesbothactivities.Thepatientsoriginally 17,20-lyase wereseparateenzymes,butitisnowclearthat patients incorrectlysuggestedthat17-hydroxylaseand Early reportsofisolated17,20-lyasedeficiencyinsome Preg most humansexsteroidsaremadeviathepathway the conversionof17OHPtoandrostenedione;hence, that ofmostnon-primatemammals,doesnotcatalyze to C19precursorsofsexsteroids.HumanP450c17,unlike The 17,20-lyase activity ofP450c17convertsC21steroids lyase deficiency CYB5 mild, unrecognizedP450c17deficiencies. is responsive to mineralocorticoid-antagonists may have that someindividualswithlow-reninhypertension polymorphisms with hypertension ( substrate withouttheallostericactionofb5;thisreactionyieldsandrosterone,whichthencanbeactedonbytesticular17 by AKR1C2,toyield17 that 17OHPissequentially5 The backdoorpathwayofandrogensynthesis.issimilartothegeneralshowninFig. 1,except Figure 4 under investigation.(CopyrightWLMiller.) as retinoldehydrogenase,RoDH)orpossiblybyAKR1C4.Theidentitiesoftheenzymescatalyzing3 or adrenal17 87 Review ). Itisnowapparentthat17,20-lyase deficiencycan ⟶ , 17OH-Preg CYP17A1 β HSD5 (AKR1C3)toyieldandrostanediol.Androstanediolmaythenbe3 ⟶ andothers:17,20 OH DHEA -allopregnanolone. P450c17cancatalyze17,20lyaseactivityusing17 α - and3 ⟶ androstenedione ( W LMiller α -reduced, firstby5 85 , 86 ), suggesting 58 α , Red1 to5 88 68 ). ). α ( reticularis andcoincideswiththeonsetofadrenarche In theadrenal,b5expressionisconfinedtozona been foundinthecatalyticactivesite( but mutations causing 17,20-lyase deficiency have also 17 canbeseenincomplete with 46,XX,asbothkaryotypes the DSDphenotyperather than geneticincompatibility been 46,XY; thisprobablyrepresentsascertainmentfrom all reportedpatientswith 17,20-lyase deficiencyhave but mightalsocause17,20-lyasedeficiency( ofP450c17havenot(yet)been described, phosphorylation in p38 the efficiencyofelectrontransfertoP450c17;mutations 17,20-lyase deficiencyiscausedbymutationsaffecting P450c17 mayalsocause17,20-lyasedeficiency( the electron-donating domain of POR that interacts with methemoglobinemia ( and testicularandrogendeficiency, with associated thus increasing17,20-lyaseactivityabout10-fold( factor topromotetheinteractionofP450c17withPOR, reduction of methemoglobin, but also acts asan allosteric is asmallhemoproteinthatprincipallyparticipatesinthe deficiency causes17,20-lyasedeficiency. Cytochromeb5 interacts withandreceiveselectronsfromPOR( in the‘redoxpartner-bindingsite’ofenzyme,which Adrenal steroidogenesisdefects -Pregnan-17 69 α , -hydroxylase deficiency. 93 α orotherkinasesthatmightparticipateinthe ). Cytochromeb5deficiency causesadrenal α -ol-3,20-dione, andthen3 α -oxidized, possiblyby17 94 Downloaded fromBioscientifica.com at09/28/202104:05:24AM , OH 95 -allopregnanolone asthe , 96 ). Third,raremutationsin α HSD reactionsremain α 179 -reduced, probably 91 www.eje-online.org β :3 HSD6 (alsoknown , 92 ). Second,b5 14 ). To date, 97 89 ). Thus, R133 β HSD3 , 58 90 via freeaccess ). ), European Journal of Endocrinology www.eje-online.org P450c17. (CopyrightWLMiller.) action ofcytochromeb of humanP450c17andPORis facilitated bytheallosteric opposite fromtheredoxpartner bindingsite.Theinteraction on thesideofhemeringcontaining theironatom(Fe) mediate catalysis.Thesubstrate-bindingsiteoftheP450lies interactions, andtheelectronsreachP450hemegroupto redox partnerbindingsiteoftheP450bycharge-charge orientation. TheFMNdomainofPORthen‘docks’withthe conformational changethatreturnstheproteintoitsoriginal electrons passfromtheFAD totheFMN,elicitinganother brings theFAD andFMNmoietiesclosetogether. The FAD moietyofPOR,elicitingaconformationalchangethat receives electrons(e oxidoreductase (POR),boundtotheendoplasmicreticulum, Electron transporttomicrosomalP450enzymes. Figure 5 ranges fromnewbornmaleswithandrogendeficiency ( associated deficientactivityofP450c21andP450aro by partiallydeficientP450c17activity, withorwithout steroidsshowthatPORdeficiencyischaracterized urinary in bothsexes( POR activitycausesanunusualformofCAHwithDSD the P450( transfers themtotheFMN,whichthen them to other wing;theFAD receivestwoelectronsfromNADPH, wing andanflavinmononucleotide(FMN)moietyinthe has a flavin adeninedinucleotide (FAD) moietyin one POR isamembrane-bound,butterfly-shapedproteinthat step. electron flowfromPORisanimportantregulatory catalysis ( P450s mustreceiveelectronsfromPORtomediate P450c17, P450c21,P450aroandallothermicrosomal POR: P450oxidoreductase deficiency 99 Review , Although POR-knockoutmicedie 100 , 101 40 39 ). Asillustratedwith17,20-lyasedeficiency, , , 98 102 ) ( 99 − Fig. 5 ). The spectrum of endocrine findings , ) fromNADPHanddonatesthemtothe 100 5 , andbyserinephosphorylation of ). ). Measurementsofserumand W LMiller in utero , deficient strongly dependsonthecausativePORmutation( males. The phenotypic outcome in genetic females to incompletelydeveloped external genitalia inaffected transport, defective fetal testicular steroidogenesis leads is especiallysensitivetoperturbationsinelectron ( detected by newborn screening of 17OHP for 21OHD deficiency ( ‘backdoor’ pathwaymayassistinthediagnosisofPOR in some of the steroids (and their metabolites) from the of C19 precursors of sex steroids. Abnormal elevations 17OHP that respond variably to ACTH and low levels that respondpoorlytoACTH,highconcentrationsof mineralocorticoid function, nearly-normal cortisollevels deficient patientsusuallyhavenormalelectrolytesand syndrome( and womenwithpolycysticovary to P450c21 deficiency) to men with infertility (secondary (impaired P450c17activity)andvirilizednewbornfemales ( function mutationsinfibroblast growthfactorreceptor 2 in steroidogenesis, ABSis caused by dominant,gain-of- deficiency ( DSD ineithersex,thecause isautosomalrecessivePOR seen in association with disordered steroidogenesis and proptosis andchoanalstenosis.ABShastwocauses:when bowed femora,arachnodactyly, midface hypoplasia, brachycephaly, radio-ulnarorradio-humeral synostosis, syndrome (ABS),characterizedbycraniosynostosis, associated skeletaldefectknownasAntley–Bixler similarly( the incidencesofSNPsvary butrareamongpeopleofAfricanancestry,ancestry and P450 activities( sequence variantp.A503V, whichmildlyaffectsmany furthermore, thePORgeneishighlypolymorphic: phenotype of POR deficiencyvarieswithethnicity; of affectedfemales( production also contributes to the prenatal virilization addition, thealternative‘backdoorpathway’ofandrogen afetuswithsomePORmutations.In women carrying 101 For example,PORp.A287P, thepredominantmutation often experiencevirilizationduringpregnancy( afetuswithPORp.R457H(butnotp.A287P) carrying enter andvirilizethemother;hence,pregnantwomen placental P450aroactivitypermitsfetalC19steroidsto disrupts placentalP450aroactivity( is commoninJapan( P450c21 ( in Europe( Adrenal steroidogenesisdefects 99 100 , , Newborns withPORdeficiencyoftenhavean ). PORdeficiencyimpairs CYP26B1 activity, causing 105 108 ). Because the 17,20-lyase activity of P450c17 ), as evidenced by the low estriol values seen in 107 99 104 99 , ), and the POR mutation p.R457H, which , 102 106 ). SomepatientswithPORdeficiencyare 100 ), disruptsactivityofP450c17butnot ), iscommonamongpeopleofChinese , 101 103 100 Downloaded fromBioscientifica.com at09/28/202104:05:24AM ). Asnoted,theincidenceand ); whenseenwithoutalesion , 101 ), butnotPORp.A287P, 179 109 :3 108 ). ). Defective 103 99 ). POR- R134 , 106 100 via freeaccess ). , European Journal of Endocrinology 117 non-classic form of 11OHD has alsobeen described ( secretion, causingvirilization ofaffectedfemales.Arare, consequent ACTHexcesscauses fetaladrenalandrogen (11OHD) disrupt synthesis of cortisol but not aldosterone; CYP11B1 synthesize aldosteronefrom18OH-corticosterone( weak 18-hydroxylase activity, but onlyP450c11AS can can convertDOCtocorticosterone;P450c11 DOC toaldosterone. Both P450c11 and 18-methyloxidaseactivitiesneededtoconvert and catalyzesthe11-hydroxylation,18-hydroxylation glomerulosa inresponsetoangiotensinIIandpotassium cortisol. P450c11ASisexpressedatlowlevelsinthezona 11-hydroxylase activity, converting 11-deoxycortisol to the zonafasciculatainresponsetoACTHandcatalyzes and ferredoxin( electron transportfromNADPHviaferredoxinreductase these aremitochondrialP450enzymesthatrequire CYP11B2 encoded bythetandemlyduplicated are catalyzed by P450c11 The final steps in the synthesis of cortisol and aldosterone CYP11B1 cortisol responsetoACTH. this shouldbedeterminedindividuallybyassessingthe replacement therapy, especially during severe illness; Some patients may require low-dose glucocorticoid therapy shouldbestartedatpubertalageinbothsexes. surgeons andfamilysupport;sexhormonereplacement endocrinologists, geneticists,orthopedicandcranio-facial teamof POR deficiencyrequiresamultidisciplinary in POR-deficientpatientsarerare( impairment byPORmutations( in vitro been describedinpatientswithPORdeficiency. Numerous accumulate hepatic lipids, but similar problems have not specific PORknockoutsmetabolizedrugspoorlyand metabolizing enzymes( role ( affecting signalingby ( their prematurefusionandtheABSskeletalphenotype normally formskeletaljointsandsutures,leadingto sitesthat retinoic acidaccumulationatembryonic 110 Review ). POR is required by the principal hepatic drug- ). POR-associateddefectsincholesterolsynthesis 6 CYP11B2 , studiesofdrug-metabolizingenzymesshowmajor 103 mutationscausing11-hydroxylasedeficiency genes( : 11-hydroxylase deficiency ). mutationscause forms ofaldosterone 39 113 ). P450c11 , 114 hedgehog 98 ). LikeP450sccdiscussedearlier, β and P450c11AS, respectively, , 106 β isabundantlyexpressedin proteinsmayalsoplaya 98 , W LMiller 111 , 106 112 ). Micewithliver- β andP450c11AS , 111 ). Treatment of CYP11B1 ), buteffects β alsohas and 115 116 ). , salt loss( to mineralocorticoids, they may havemild,transient Nevertheless, because newborns are relatively resistant in newbornscreeningfor21OHD( concentrations of 17OHP, sothat 11OHD maybe detected and hypertensioninolderchildrenadults( high levelsproducedin11OHDcancausesaltretention is alesspotentmineralocorticoidthanaldosterone,the to mineralocorticoid-based hypertension. Although DOC also resultsinoverproductionofDOC,potentiallyleading steroid usedfordiagnosis;defectivecorticosteronesynthesis hyperresponsive to ACTH administration and is the key 11-deoxycortisol (Reichstein’s compound S), which is defective cortisolsynthesisresultsinaccumulationof virilization ofaffectedfemales.Inthezonafasciculata, (see below). deficiency inwhichcortisolproductionisunaffected 18 methyloxidaseactivities impairbiosynthesisof P450c11AS activity;thedisrupted 18-hydroxylaseand forms ( oxidase’ (CMO)deficiency, clinicallydescribedastwo deficiency, alsoknownas‘corticosterone methyl P450c11AS disorderscausealdosteronesynthase hyperaldosteronism and glucocorticoid-remediable CYP11B2 needed. used in21OHD,butmineralocorticoidreplacementisnot is glucocorticoidreplacementwithdosessimilartothose retained partialactivity( were foundamong28patientsfrom25families( patients). InTurkey, 13different andp.Q356Xp.G379VamongTunisianancestry CYP11B1 p.R448HamongSephardicJewsofMoroccan genetically isolatedgroupshavinghighincidences(e.g. mutations have been reported ( established its general incidence, but over 100 about 13.5%inTurkey ( percentage in Middle Eastern populations ( 5% ofCAHinpersonsEuropeanancestry, ahigher sexual precocityinmenwith asymptomaticwomenor irregularities inotherwise reported manifestingashirsutism,virilismandmenstrual A rare,mild,non-classicformof11OHDhasbeen Adrenal steroidogenesisdefects It iswidelystatedthat11OHDaccountsforabout 11OHD impairs cortisol secretion, causing CAH with 114 118 , : aldosterone synthase deficiency 128 , 119 ). ‘CMOIdeficiency’results fromabsent ). Newbornsmayalsohaveelevated Downloaded fromBioscientifica.com at09/28/202104:05:24AM 126 123 , ). Noprospectivestudyhas 127 CYP11B1 ). Treatment of11OHD 116 120 CYP11B1 179 , ). www.eje-online.org 124 :3

mutationsthat 121 ), with some mutations , CYP11B1 122 R135 ) and 125 114 via freeaccess ). ).

European Journal of Endocrinology www.eje-online.org correct diagnosisandtreatment ofthesedisorders; steroid assaysandDNAsequencing nowpermitthe The availabilityofaccurate, inexpensiveLC-MS/MS abnormal steroidmetabolomes seeninthesedisorders. and pathwaysofsteroidogenesis permitonetopredictthe new disorders.Knowledgeofthesteroidogenicenzymes genetic causesofknowndiseasesandtheprediction of transforming enzymeshaspermittedidentificationofthe ofthegenes encoding steroid- and POR).Thediscovery have beendescribedrecently(deficienciesofP450scc 11OHD) have been known since the 1950s, while others Some raredisordersofsteroidogenesis(3 Conclusions form ofhyperaldosteronism( causing afairlycommon,glucocorticoid-suppressible of achimericproteinwithaldosteronesynthaseactivity, coding regions, resulting in the ACTH-induced expression portions of CYP11B the activity is increased. Genetic recombination between opposite ofaldosteronesynthasedeficiency, asP450c11AS forms of21OHD. and ‘CMOII’overlap( unaffected ( homozygous foronlyoneofthesemutationsareclinically mutations p.R181Wandp.V386A,whereasindividuals Jews: affectedindividualsarehomozygousforthetwo ( 18OH-corticosterone is high and aldosterone is low mutations thatretainpartialactivitysoserum with age ( mineralocorticoid sensitivityandsodiumintakeincrease andreachadulthoodwithouttherapy,may survive as but maybenormalinaffectedadults.Thesepatients renin activityismarkedlyelevatedinaffected children the newborn'smineralocorticoidrequirements.Plasma as thesecretionof DOC maybeinsufficient tomeet toabsentaldosteronebiosynthesis salt losssecondary missense mutationp.R384P. Infantsmayexperience frameshift mutations,prematurestopcodonsandthe plasma reninactivity. of corticosteroneto18OH-corticosteroneandelevated Thus, thereissuppressedaldosterone,increasedratio corticosterone and cortisol by P450c11 18OH-corticosterone andaldosterone,butsynthesisof 114 Review Glucocorticoid-remediable hypertension isthe CYP11B1 , 128 geneinwhichtheACTH-regulatedupstream ). CMOIIdeficiencyiscommonamongIranian 129 130 CYP11B1 and ). ‘CMOII deficiency’ results from ). However, theclinicalfindingsin‘CMOI’ CYP11B2 arefusedinframetothe 131 , CYP11B2 genescreatesathird,hybrid 132 133 ), similarlytothevarious W LMiller , 134 mutationsinclude ). β β remains intact. HSD deficiency, CYP11B2- CYP11B2

References NIH andfromTheMarchofDimes. performed intheauthor'slaboratorywassupportedbygrantsfrom agency inthepublic,commercialornot-for-profit sector. Research Writing thisreview didnotreceiveanyspecificgrantfromfunding Funding perceived asprejudicingtheimpartialityofthisreview. The authordeclaresthatthereisnoconflictofinterestcouldbe Declaration ofinterest these disordersarenotsorareasoncethought. improved diagnostictacticsarerevealingthatsomeof

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