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European Journal of Endocrinology -18-0712 screening, arewarranted. both thosewithalateclinicaldiagnosisandneonatalobtainedby insufficiency andtheneedforstressdosing.StudiesfocusingonspecificdifficultiespatientswithNCAHface, outcome isrecommended.Itimportanttoacknowledgethatglucocorticoidtreatmentwillleadsecondarycortisol are acommontreatmentoptionforyoungfemaleswithNCAH.Regularclinicalmonitoringtoimprovethe the glucocorticoidtreatment,mayalsobeassociatedwithlong-termandrogenexposure.Oralcontraceptivepills The glucocorticoiddosesshouldbekeptlow.However,complicationsseeninNCAH,assumedtocausedby may resultinlong-termcomplications,suchasobesity,insulinresistance,hypertension,osteoporosisandfractures. time, includingfertilityissues.Long-termtreatmentwithglucocorticoidswillimprovetheandrogensymptomsbut relevant forpreventingandamelioratingthesymptomsconsequencesofandrogenexcessthatdevelopover somewhat controversial,anearlydiagnosisandstartoftreatmentmayhavepositiveimplicationsongrowth be fertility issues.ManymenwithNCAHneverseekmedicalattentionandescapediagnosis.Althoughtreatmentis guidance. Mostpatientsarediagnosedinadolescenceandadultlifewithhirsutism,acne,aPCOS-likepicture CYP21A2 screening, but17-hydroxyprogesteronemeasurementafterACTHstimulationisthegoldstandard.Weadvocate a cases areneverdiagnosed,especiallyinmales.Abaseline17-hydroxyprogesteronemeasurementmaybeused for Non-classic congenitaladrenalhyperplasia(NCAH)isarelativelycommondisorderregardlessofethnicity,butmost Abstract Stockholm, Sweden Diabetes, KarolinskaUniversityHospital,and Astrid LindgrenChildrenHospital,KarolinskaUniversity 1 Anna Nordenström deficiency with non-classicCAHdueto21-hydroxylase Diagnosis andmanagementofthepatient MANAGEMENT OFENDOCRINEDISEASE Department ofWomen’sandChildren’sHealth,KarolinskaInstitutet, https://doi.org/ https://eje.bioscientifica.com Review of disorderssexdevelopment innationalandinternational studies. is another focus. She is involved in long-term follow-up studies of individuals with different forms brain imagingstudiesofindividuals exposedtodexamethasoneprenatally, withandwithoutCAH hyperplasia. Herresearch isfocusedonCAHand disorders ofsexdevelopment.Cognitiveand She is responsiblefor the national neonatal screening programme for congenital adrenal at theAstridLindgrenChildren’s Hospital,Karolinska University HospitalinStockholm,Sweden. Professor AnnaNordenström Invited author’s profile mutationanalysistoverifythediagnosis,forgeneticcounsellingandbetterprognostictreatment 10.1530/EJE -18-0712 1 , 2 and 3 Henrik Falhammar © 2019EuropeanSociety ofEndocrinology H Falhammar A Nordenströmand 4 Department ofMolecularMedicine andSurgery,KarolinskaInstitutet, isaseniorconsultantandteamleaderofPediatricEndocrinology Printed inGreatBritain 3 , 4 3 Department ofEndocrinology,Metabolismand 2 Department ofPaediatricEndocrinology, NCAH Diagnosis andmanagementof Published byBioscientifica Ltd. Downloaded fromBioscientifica.com at10/01/202102:01:27PM (2019) Endocrinology European Journalof [email protected] Email to A Nordenström should be addressed Correspondence 180 180 :3 , R127–R145

R127 –R145 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com organogenesisand for anadequateadrenomedullary local cortisol production in the adrenal cortex is required to the situation for patients with classic CAH. In addition, with NCAHtypicallydonotdevelopsaltcrises, in contrast cortisol productionrate,whichmeansthatindividuals electrolyte homeostasis is 100 times lower than the of thedisease. 17-hydroxyprogesterone (17OHP),isusedasanindicator metabolite just before the21-hydroxylase enzymatic step, synthesis andtheclinicalsymptoms( androgen pathwaysresultintheincreased of enzymekinetics,andtheirmetabolisminthedifferent before the enzymatic block, asdescribed above or because of theadrenals.Accumulationsteroidprecursors ACTH drivesadrenocorticalgrowthandhyperplasia androgen synthesis as the result ( withincreasedACTHproductionandexcess the pituitary and, subsequently, toareducedfeedbackinhibitionon enzyme deficiencymayleadtoamildcortisol in alessseverephenotypethanclassicCAH( 21-hydroxylase enzymeactivity( most common.NCAHtypicallyhas20–70%residual synthesis. Deficiencyofthe21-hydroxylaseisbyfar of onetheenzymesinvolvedinadrenalsteroid an autosomalrecessivedisordercausedbyadeficiency Non-classic congenitaladrenalhyperplasia(NCAH)is Introduction SV CAHwhileV281Listhemost commonmutationinNCAH. I2 splicemutation(I2G)typically resultinSWCAHandI172N completely abolishedenzyme activity (nullmutations)andthe determines thediseaseseverity. Mutationsresultingin deficiency andandrogenexcess. Thelesssevereallele enzyme activityandtheresultingclinicalseverityofcortisol Severity ofthedifferent Figure 1 Review The aldosteroneproductionrequiredfornormal CYP21A2 mutationsinrelationtothe H Falhammar A Nordenströmand 1 ) andthereforeresults 2 , 3 ). The increased i. 2 Fig. Fig. 1 ). The ). The and psychiatric morbidity. However, most studies include cardio-metabolic disorders, tumours, voice, qualityoflife specifically, fertility, pregnancies,bonehealth,mortality, diagnosis, treatment and clinical outcomes: more owing to21-hydroxylasedeficiency:clinicalpresentation, reviewed foradditionalreferences.We focusonNCAH CAH. Articlesretrievedintheinitialsearch werealso or 21-hydroxylasedeficiency/ classic/nonclassical congenitaladrenalhyperplasiaand/ published uptoAugust2018,usingthesearch termsnon- hypoglycaemia ( NCAH should not be at increased risk of developing that innormalcontrols( function inNCAHwasnotsignificantlydifferentfrom both childrenandadults( classic CAHgenotypegroupshasbeendemonstratedin the severityofepinephrineproductionanddifferent epinephrine/adrenaline production.Acorrelationwith more than90%ofthepatients, whichenablesgenotype/ patients. Infact,tenmutations anddeletionrepresent number ofmutationscomprising thevastmajorityof crossing overorgeneconversion hasresultedinalimited patients withCAHarepicked upfromthepseudogeneby The fact that more than 90% of the mutations identified in inactive duetoanumberofmutations( CYP21A2P region onchromosome6intandemwithapseudogene, CYP21A2 has been extensively studied. The gene for 21-hydroxylase, 60 months ofage. clinical definition,thefirstsymptomsshouldoccurafter prenatal virilisation;instead,accordingtotheoriginal external genitaliain46,XXfoetuses.NCAHdoesnotcause both SW and SV CAH cause prenatal virilisation of potentially lethalsaltcrisisintheneonatalperiodand ( (SV) CAH, and the non-classic or late-onset CAH (NCAH) is subdividedintosalt-wasting(SW)andsimplevirilising CAH isclinicallyclassifiedintotheclassicform,which Classification andgenetics attempted toseparateNCAHandclassicCAH. to beofinterestandsimilarNCAH,butwehave from studiesonclassic CAH are presented when assumed CAH patients,andonlyafewincludeNCAH.Data both classicCAHandNCAHpatientsorfocuson NCAH Diagnosis andmanagementof 9 , 10 This reviewisbasedonarticlesidentifiedinPubMed The molecular genetics for 21-hydroxylase deficiency ). UntreatedinfantswithSWCAHwilldevelopa , isacomplicatedgenelocatedclosetotheHLA , with98%homologytheactivegene,but 7 , 8 ). Downloaded fromBioscientifica.com at10/01/202102:01:27PM 4 , 6 5 ). Hence,individualswith ), but the adrenomedullary ), buttheadrenomedullary CYP21A2 180 11 :3 andlate-onset , 12 , 13 , 14 R128 , 15 via freeaccess ). European Journal of Endocrinology simple virilisingformismost oftencausedbytheI172N in about 1% rest activity and is slightly less severe. The neonatal period if untreated. An I2splicemutation results results inthemostseverephenotype withsaltlossinthe of nullmutations,thatis,thegenotypegroup, determines thephenotype( correlation inwhichtheseverityofmildestallele clinically useful.Thereisagoodgenotype/phenotype phenotype correlationsthathavebeenshowntobe dehydroepiandrosterone; DOC,deoxycorticosterone;HSD11B2, 11-OH-steroiddehydrogenase;SRD5A,5alfa-reductase. 11-deoxycorticosterone; AKR1C3,aldo-keto-reductase1C3;CYP17A1, 17alfa-hydroxylaseandlyase;DHEA, converted tothe11oxygentedsteroids,11-ketotestosterone and 11-keto-DHTinperipheraltissues.11DOC, CYP21A2 deficiency,17OHPisconvertedto21-deoxycortisol, bythe11 synthesis oftestosteroneviaandrostenedioneandthe ofdihydrotestosterone(DHT)viathe‘Backdoorpathway’.In deficiency. TheCYP21A2whichisdeficientinCAHdepictedgrey.subsequentincrease17-OHPleadstoincreased Schematic overviewofthesteroidhormonesynthesisfromadrenalandrogensand17OHPinindividualswith Figure 2 Review 14 , 15 H Falhammar A Nordenströmand , 16 , 17 ). Homozygosity heterozygous fortwomild alleles( of thosediagnosedwere homozygous orcompound simple virilisingformand70% forNCAH( CAH, being 100% for the null genotype form, 95% for the phenotype andgenotypevariesinthedifferentforms of V281L ( 20–70% enzyme activity, the most common one being mutation. NCAHtypicallyresultsfrommutationshaving NCAH Diagnosis andmanagementof β -hydroxylase activityofCYP11B1,whichthenmaybe Among thepatientswith NCAH,about25–50% 14 , 15 , 17 , 18 ) ( Downloaded fromBioscientifica.com at10/01/202102:01:27PM Fig. 1 ). Thecorrelationbetween https://eje.bioscientifica.com 180 20 :3 , 19 21 CYP21A2 ). , 22 R129 ). The via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com listed accordingtoprevalenceformalesandfemalesrespectively. Table 1 indistinguishable from adrenarche, sothatthediagnosis symptom intwomaleadolescentswithNCAH( ( pubarche ofageorhirsutismacne(11%) before9 years scarce. Inonereporton45 males,13(29%)hadpremature excess ( to seek medical attention due to symptomsof androgen females, possiblyowingtothefactthattheyarelessprone mutation ( those whoarecompoundheterozygouswithaclassical mild mutationshavelessseveresymptomscomparedto classic mutation,thatis,homozygouspatientswithtwo seen inpatientswhoarecompoundheterozygousfora age andgender. Earlierandmoreseveresymptomsare with the severity of the enzyme deficiency and vary oligo-menorrhea orinfertility. adults, typical presenting symptoms areacne,hirsutism, amenorrhoea(9%)( primary clitoromegaly (11%),irregularmenstruation(56%)oreven present with severe acne, hirsutism, androgen alopecia, was mostcommon(87%),whilefemaleadolescentsmay pretermadrenarchechildren agedyoungerthan10 years, of symptoms at diagnosis is related to age ( start duringchildhoodorlaterinlife.Thespectrum ( on duringchildhoodoradolescenceeveninadulthood Late-onset, nonclassical CAH is usually diagnosed later Clinical presentation (50–75%). a more severe, classic mutation on the other allele remaining patients were compound heterozygous with 18 22 Review Prevalence ). Gynaecomastiahasbeenreportedasthepresenting , The symptomsatpresentationareoften Males arediagnosedconsiderablylessoftenthan In NCAH,thevariationsinphenotypedependon 23 , 18 24 Clinical presentationinindividualswithnon-classiccongenital adrenalhyperplasiadueto21-hydroxylasedeficiency, , 22 , 29 25 , 28 ). Hence,studiesinmenwithNCAHare ). Thesymptomsofandrogenexcessmay ). Clitoromegaly Family screening Growth velocity Increased Acne Premature adrenarche Girls 26 , H Falhammar A Nordenströmand 27 ). Inadolescentsand Short stature Adrenal incidentaloma Clitoromegaly Alopecia Family screening Infertility Acne Menstrual cycledisorders Hirsutism Women al 1 Table 30 ). ). In

not largeenoughforthechildrentobeidentifiedby The increasein17OHPtheneonatalperiodisusually virilisation of the external genitalia in 46,XX foetuses. The androgen excess in NCAH does not cause prenatal Childhood significant alterationsinandrogensynthesis( carriers was1/3.Hence,mayhaveclinically adolescence or as adults, the proportion of heterozygous Among womenwithlate-onsetandrogensymptoms,in allele frequencywas77%forV281Land7%P453S. increased androgenproduction( polymorphism previouslydiscussedwithregardtocausing NCAH, 19 were carriers and 18 were heterozygous for a individuals withandrogensymptomsshowedthat12had CAH ( adrenarche haveshownthat4–25%werediagnosedwith requires investigations.Studiesinchildrenwithpremature age. AlthoughmostchildrenwithNCAHarereported to to estrogensandmaythereforecauseadvancedbone ( excess doesnotaffectgrowthvelocityatsuchanearlyage this cannotbeseenbefore1–2 years ofagesinceandrogen growth indicatesamorepronouncedandrogeneffect,but years of age ( females younger than 10 Clitoromegaly andacnewereeachpresentin20%of type bodyodour, pubarche orpseudopubertaspraecox. identified duringchildhood areoily skin,acne oradult time inCAH( identify NCAHsincethe17OHPleveloftenincreasesover of age are more likely to with a second screen at 14 days identified intheneonatalperiod.Screeningprogrammes 38 pick uppatientsatriskofadrenalcrisis( neonatal screeningprogrammes,whicharedesignedto NCAH Diagnosis andmanagementof 40 ). Therefore,onlyasmallernumberofindividualsare , The mostprevalentearlysymptomsinpatients 41 31 ). The 17OHP and adrenal androgens are converted Gynaecomastia Acne Growth velocity Increased Family screening Premature adrenarche Boys , 32 ). Geneticinvestigationsinacohortof59 35 , 36 , 37 , Downloaded fromBioscientifica.com at10/01/202102:01:27PM 38 , 39 ). 32 Infertility Adrenal incidentaloma Acne Family screening Men ). Intheircohort,the 180 :3 9 26 , 34 ). Accelerated 33 , 35 ). , 36 R130 , 37 via freeaccess , European Journal of Endocrinology levels regardlessoftheACTH increaseowingtothe dihydrotestosterone (DHT)are elevated( usually normal, while androstenedione, testosterone and androgens are increased in NCAH. However, DHEAS is stimulation maybenormalorslightlyimpaired.Adrenal ACTH levelsonassessment.Cortisolproduction The majorityofpatientswithNCAHhavenormal Biochemistry andpathophysiology infertility withaPCOS-likepicture( while beinginvestigatedformenstrualdisturbances or ( age, 50%inadolescenceand70%middle-agedwomen presenting symptom,butnotmoreseverewithincreasing (4%) ( amenorrhoea(4%)andprematurepubarcheprimary infertility (13%),clitoromegaly(10%),alopecia(8%), hirsutism (59%),oligomenorrhoea(54%),acne(33%), ofage,thepresentingclinicalfeatures included 10 years occurred inbothmenandwomen.Amongwomenover stature. Increasedbodyhair, acne,oilyskinandinfertility In adults,theandrogenexcessmayhavecausedshort Adults height. early diagnosisand start oftreatment may improve final all wereabletoreachtheirtargetheight( When treatmentwasstartedbeforeboneageof9 years, a severeallelehadsignificantlyshorterfinalheight( Individuals compoundheterozygousforbothamildand shorter correctedheightthanthosewhodidnot( bone ageadvancementatdiagnosishadasignificantly height SDScorrectedforparentalheight.Thosewhohad ( NCAH thathadnotbeentreated,by2.3 years, onaverage been reportedtostartearlierinthegroupofpatientswith 44 this affects final height and results in short stature ( than theaverageingeneralpopulation,whichcase Untreated patientswithNCAHmayenterpubertyearlier Puberty andgrowth compromised finalheight( and boneageadvancementmay, overtime,leadtoa reach afinalheightwithintheirtarget,acceleratedgrowth 48 26 Review , ). It is notuncommon that women are diagnosed ). Ageatdiagnosiswasnegativelycorrelatedwithfinal 45 The CYP21A2deficiencyresults inincreased17OHP , 26 46 ). Hirsutismwasincreasinglycommonasthe , 47 ). Thepubertalageandpeakvelocityhave 27 , 42 H Falhammar A Nordenströmand ). 22 , 26 27 , 48 , 27 51 ). Hence,an , , 48 52 , ). 50 ). 49 49 43 ). ). , likely tobeduedifferencesin Variations inphenotypeandclinicalsymptomsaremost women. Ithasbeenestimated thatbetween2and11%of the morningandinfollicular phaseinmenstruating It isimportantthatthe17OHP sampleistakenearlyin adults hasbeensuggestedto excludeCAH( than 2.5 17OHP shouldbethefirstinvestigation.Avalueofless childhood orinanadult,screeningwithearlymorning in thescreening( (63%) diagnosedpatientswithNCAHwerenotdetected detected byscreening( ( with NCAH were detected in 2.7 million screened babies it maymisssomepatientswithSVCAHandonly12cases screening in Sweden identifies all cases with SW CAH, but by screening and not by symptoms alone. Neonatal neonatal screening,classicCAHisnowmainlydiagnosed 21-hydroxylase deficiency( in arandombloodsampleisdiagnosticofclassic enzyme ( deficiency andthemainsubstratefor21-hydroxylase ( An elevatedlevelof17OHPisusedasamarkerforCAH Diagnosis in patientswithNCAH. ameliorate oraggravatethesymptomsofandrogenexcess hormone synthesisandmetabolismarelikelytoeither differences inotherenzymeactivitiesinvolvedsteroid neonatal periodandbeforeafteradrenarche ( enzyme activitiesinthedifferentpathwaysdiffer steroidanalysisshouldbedone.The a 24-hurinary perform acompleteassessmentoftheandrogensituation, for the11-ketosteroidsinplasmaarelacking.Inorderto than theconventionalandrogens( of adrenalandrogen production and treatmentresponse 11-oxygenated androgensmayevenbebetterbiomarkers bind equallywelltotheandrogenreceptor( DHT (11-ketotestosteroneand11-ketoDHT),which converted tothe11-ketoformsoftestosteroneand activity, produce21-deoxycortisol,whichisthen addition, elevated17OHPwill,via11-betahydroxylase surpassing theproductionoftestosterone( from testosterone, but also via the ‘back door pathway’, to androgenviaseveralpathways( kinetics intheenzymaticsteps.The17OHPisconverted NCAH Diagnosis andmanagementof 37 56 ). ThemajorityofindividualswithNCAHwillnotbe ). Itisthebiochemicalhallmarkof21-hydroxylase When thediagnosisofCAHissuspectedlaterin nmol/L inchildrenandless than6.0 Fig. 2 ). Aconcentrationof17OHP 36 ). 35 Downloaded fromBioscientifica.com at10/01/202102:01:27PM , 37 57 , 38 , https://eje.bioscientifica.com ). Moreover, 24ofthe38 58 CYP21A2 Fig. 2 ). Incountrieswith 54 180 ). Referencevalues ). DHTisproduced :3 genotype,but 9 > , 23 240 nmol/L 31 54 nmol/L in , , ). These 58 53 R131 , ). In 59 55 via freeaccess ). ). European Journal of Endocrinology https://eje.bioscientifica.com common monogenic disease with a prevalence of 1 in Classic CAHdueto21-hydroxylas deficiencyisarelatively Prevalence and guidanceintreatmentdecisions( equivocal casesandgivesusefulprognosticinformation out NCAH.Genetictestingshouldalwaysbecarried in deficiency ( can beusedina24-hsampletodiagnose21-hydroxylase metabolite of17OHP,addition, pregnanetriol,theurinary a geneticallyconfirmed carrier statusor NCAH( may alsohavelevelsof17OHPabove30 carriers ( 50 not correlatewiththeNCAHgenotype( often seeninNCAH.However, thestimulatedleveldid ( and stimulated17OHPwilltypicallyexceed300 those forNCAH( ( 30 nmol/L some werefoundtohaveastimulated17OHPofabout women respectivelywithgeneticallyconfirmedNCAH, excludes NCAH( suggested thatastimulatedleveloflessthan30 considered tobediagnosticforNCAH( in malesand,femalesduringthefollicularphase,is and/or ACTH-stimulated17OHPofmorethan30 the diagnosis ( 60 cosyntropin i.v.), withameasurementof17OHPat remains is the ACTH stimulation test (250 21-deoxycortisol shouldbecarriedout( measurements ofandrostenedione,testosteroneand such as11-hydroxylaseorP450reductasedeficiency, other enzymedeficienciesthatcancauseelevated17OHP, levels shouldbechangedisnotclear. Inordertoexclude However, itisnotwidelyavailableandifthecut-off assays for measurement of 17OHP level in the circulation. ( homozygous for non-classic mutations, regardless of age a non-classicallele,comparedwiththosewhowere who werecompoundheterozygousforaclassicand level hasbeenshowntobemoreelevatedinindividuals individuals withNCAHandoneclassicallele,the17OHP pattern ofthepresentingsymptomsbeingmoreseverein – atleastamongadults( patients withNCAHwillbemissedusingthisapproach 19 9 , Review nmol/L mayrepresentunaffectedorheterozygous min. Thisisconsideredtobethegoldenstandardfor , 58 The nextdiagnosticstepiftheclinicalsuspicion 22 ). Stimulated levels between 30 and 300 ). LC-MS/MS is more sensitive than the traditional 9 ). Someindividualswithadrenalincidentalomas 63 21 ), butnormalvaluescannotcompletelyrule , 56 22 ). A basal 17OHP of above 15 ). Carriersmayhavelevelsoverlapping 2 22 ). InpatientswithclassicCAH,basal ). Among140and160men 21 , 22 H Falhammar A Nordenströmand , 60 ). Inlinewiththe 9 , 10 64 22 60 nmol/L without , ). ). Levelsbelow 61 ). Ithasbeen ). nmol/L are nmol/L nmol/L nmol/L nmol/L mg of 62 ). In was relativelycommonregardlessofethnicity( believed ( towhathadbeen different populationsand,contrary frequency foraclassicCAHmutationis1in60individuals. than 6.5millionnewborns( from 13neonatalscreeningprogrammesincludingmore 15,000 live-births in most populations, according to data in theAshkenaziJewishpopulationNewYork ( between 2and13.9%,withanespeciallyhighprevalence by farthemostcommonalleleinNCAH( diagnosed withNCAH( Caucasian descentwithandrogenexcess,only1%were 3.2–5.4%) in a meta-analysis including publications for symptomsofandrogenexcesswas4.2%(95%CI: The prevalence among womenseeking medical attention both classicandNCAHarerelativelyuncommon( Caucasians ( ( among theJewishpopulationthanpreviouslythought that is, more commonamong Caucasians and less so 15% amongAshkenaziJewsand9%Caucasians, individuals andCaucasiansshowedacarrierfrequencyof Genotyping performed among 200 Ashkenazi Jewish The recommendedhydrocortisone doseforclassicCAH children becauseithasless negativeeffectongrowth. only beusedinchildrenover 2–3 yearsofage( indication forstartingtreatment ( An acceleratedgrowthvelocityandboneagemaybean severe phenotype, and therefore often starttreatment. develop symptomsrelativelyearly, asasign ofamore children identifiedbyneonatalscreeningseem to for a certain period of time. It is our impression that NCAH willreceivesomekindoftreatment,atleast attention, the majority of individuals diagnosed with for symptoms for which they have sought medical most patientshavebeenidentifiedduringinvestigations patients desiring treatment ( forsymptomatic In general,treatmentshouldbereserved Treatment mutation and,inCyprus,4.3%( respectively ( and non-classic mutations was 4 and 2% (all V281L) study fromNewZealand,thecarrierfrequencyforclassic followed byP30Lwith0.5–2.6%and between 1980and2015( NCAH Diagnosis andmanagementof 68 ). Theestimateddiseasefrequencywas1/200inUS Allele frequencies were investigated in a number of The use of hydrocortisone is recommended in 68 69 ), heterozygosityfornon-classicmutations 72 ). AmongtheAfricanAmericanpopulation, ), whileinSpain,7.5%carriedaV281L Downloaded fromBioscientifica.com at10/01/202102:01:27PM 70 ). TheV281Lmutationwas 27 58 9 , ). InRussianwomenof , 18 18 65 ). , al 2 Table , 27 180 < 66 1% forP453S.Ina ). Since, however, , :3 67 ), butthiscan ). Thecarrier 21 40 ), varying ), varying ). 17 R132 , 71 69 26 via freeaccess ), ). ).

European Journal of Endocrinology

Table 2 Indications for treatment and follow-up of individuals with non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Any symptoms of Review androgen excess in preschool children are indicated a hormonal imbalance and may be indication of treatment. All treatment decisions have to be individualised, in both children and adults.

Indications for treatment Follow-up Preschool children School children Adolescence Women* Men* Children Adults Any symptoms of Oily hair, severe Severe acne Hirsutism, androgen TARTs Every 3–12 months Annually if on treatment, androgen excess acne, hirsutism alopecia, severe depending on otherwise every 2–3 year are indicating an acne symptoms imbalance Apocrine body odour Clitoromegaly Hirsutism or Clitoromegaly Fertility issues Growth velocity, Weight Weight (BMI) alone is not an androgen indication for alopecia, treatment clitoromegaly H Falhammar A Nordenströmand Oily hair, acne, Premature A history of growth Menstrual Severe acne Blood pressure Blood pressure hirsutism adrenarche acceleration in irregularities the absence of central puberty and markedly accelerated bone age Clitoromegaly Growth acceleration Episodes of Fertility issues Episodes of Bone age, every 17-hydroxyprogesterone in the absence of exaggerated exaggerated fatigue 1–3 years depending (if available: 24 h profile, central puberty fatigue during during illnesses on symptoms using dried blood spots) illnesses Growth acceleration, Markedly accelerated Menstrual Episodes of Synacthen/ 17-hydroxyprogesterone Androstenedione NCAH Diagnosis andmanagementof accelerated bone bone age irregularities exaggerated cosynthropin (if available: 24 h age persisting more fatigue during stimulated cortisol profile, using dried than 2 years illnesses <500 nmol/L blood spots) after menarche Episodes with severe Episodes of Primary Synacthen/ Androstenedione Testosterone exaggerated fatigue exaggerated amenorrhea cosynthropin during inter-current fatigue during stimulated cortisol illnesses illnesses <500 nmol/L Synacthen/ Synacthen/ Synacthen/ Testosterone Sexual hormone binding

Downloaded fromBioscientifica.com at10/01/202102:01:27PM cosynthropin cosynthropin cosynthropin globulin stimulated cortisol stimulated cortisol stimulated <500 nmol/L <500 nmol/L cortisol

https://eje.bioscientifica.com <500 nmol/L Sexual hormone-binding Fasting glucose (or HbA1c) globulin 180 Bone mineral density every 3–5 years if on :3 glucocorticoids Testicular ultrasound in males every 5 years R133 *Depending on patients' own decision. via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com preferred optioninNCAH( prescribe dexamethasonemore liberally( foetus ifthewomenbecome pregnant.Incontrast,others dexamethasone passesthe placentaandreachesthe a worsemetabolicand bone profile.Inaddition, altogether ( Some clinicians are cautious and avoid dexamethasone is oftenpreferredinadultsduetosimplerdosing. ( growth suppressionthanthelonger-actingpreparations Hydrocortisone is preferred during childhood due to less are hydrocortisone,prednisoloneanddexamethasone. new therapiesremainsunclear. not there are any benefits regarding NCAH with these circadian rhythm in classic CAH. However, whether or hydrocortisone infusion( experimental studieswithcontinuoussubcutaneous have beenintroducedlately( Newer preparationswithextended-releasehydrocortisone even besubnormalinbothmalesandfemales( changed enzymekinetics( it cannotbeexplainedbycortisoldeficiency, butratherthe normalise theexcessive androgen production, alsowhen By suppressing ACTH production, glucocorticoids can Glucocorticoids stress dosing( and their families are educated regarding treatment and i.v. administration during stress. It is essential that patients a need for increased glucocorticoid doses and sometimes adrenal crisisduringseverestressincreased.Thus,thereis adrenal (HPA) axiswillbesuppressedandtheriskof treatment hasbeeninitiated,thehypothalamic-pituitary- It importanttonotethatwhendailyglucocorticoid at leastforthosewithasuboptimalstimulationresponse. Glucocorticoids canberecommendedduringsevereillness justify dailyglucocorticoidsupplementation( a stimulatedcortisolleveloflessthan500 and 60%below500 with anACTH-stimulatedcortisollevelbelow400 NCAH haveapartialcortisolinsufficiency( contact isusuallytreated. such asacneandhirsutism,promptingthemedical NCAH ( excess areoftensubstantiallylowerforpatientswith ( 10–15 mg/m is 25 86 Review ). Prednisolone (1–5 ). Thedosesrequiredforamelioratingtheandrogen Thus, theglucocorticoidpreparationsnormallyused As manyasone-thirdofthediagnosedpatientswith 25 , 4 73 , 75 2 ). Anadrenarche ofclinicalsignificance, 81 bodysurfaceandishigherinadolescence , 76 , 87 , nmol/L. Ithasbeensuggestedthat 77 , , 88 mg/day divided in twodoses) 78 , 80 90 , 85 89 79 83 ). Theandrogenlevelsmay ). ), bettermimickingthe ), duetoconcernsabout ). , H Falhammar A Nordenströmand 84 ) andtherehavebeen 6 ), evenasthe nmol/L may 21 , 60 81 nmol/L , , 82 29 74 ). ), ). GnRH agonists( androgen secretionbyusingoralcontraceptivepills or androgens with antiandrogens or decrease the ovarian Other treatment options are to block theeffects of Other treatmentoptions especially womenover50 yearsofage. is oflimiteduseinglucocorticoiddoseadjustment( CAH. Inourexperience,asinglemorning17OHPlevel samples, 24-hprofiles,doneathomebythepatientswith ( the follow-upofnotonlyclassicCAH( samples havebeenshowntobereliableandconvenientin NCAH hasnotbeeninvestigated.Driedfilterpaperblood these arenotavailableinclinicalpracticeandtheiruse control andlong-termcomplications( suggested as useful biomarkers in classic CAH for disease 11-oxygenated-C about specific targets ( by theEndocrineSociety, butnoguidanceisgiven (morning 17OHPandandrostenedione)arerecommended annual physicalexaminationandhormonemeasurements ( employed toguideglucocorticoidtreatmentinchildren Growth velocity, weightandboneagearenormally Treatment evaluation NCAH, the antiandrogen, cyproterone acetate, was more comparing theeffectonisolated hirsutisminpatientswith from the liver ( production, togetherwiththe increasedsynthesisofSHBG effectontheovarianandrogen thanks totheinhibitory levels hasbeendemonstratedwithoralcontraceptive pills, to suchadverseeffectsashypertensionandoedema( with NCAHusuallydonottoleratefludrocortisonedue glucocorticoid doses( but hassometimesbeenusedpossiblytominimisethe Fludrocortisone medicationisrarelyusedinNCAH Mineralocorticoids 82 of glucocorticoidsareusedinbothwomenandmen( age-adjusted rangewhennormalsupplementationdoses serum DHEASlevelswillbesuppressedbelowanormal hormone globulin(SHBG)oflessthan0.05( range and,infemales,aratiooftestosteronetosexual and testosteronelevelswithinthenormalage-adjusted 81 NCAH Diagnosis andmanagementof 82 Table 2 ), they can only be used as a marker of non-compliance. , ). Inourpractice,wehavedriedfilterpaperblood 82 ). We besttokeeptheandrostenedione doourvery ), while in adults there is no consensus ( 95 27 19 ). In an old randomised control study andpregnenolonesulphatehavebeen ). A40–60%decreaseintestosterone 4 9 , Downloaded fromBioscientifica.com at10/01/202102:01:27PM ). Recently, metabolites such as 50 , 81 , 90 180 , 93 94 :3 ) butalsoNCAH ). Olderadults 92 ). However, 91 18 ). At least ). Since R134 18 81 64 via freeaccess ), , , European Journal of Endocrinology NCAH hadaPCOmorphology ( 107 which maycontributetothe decreasedfertility( to the subfertility ( androgens mayleadtoendometrial atrophy, whichadds hormonal imbalance, a long-standing excess of adrenal In addition to a possible contraceptive effect caused by the ovulation inductionisusuallysuccessful( 10–30% havefertilitycomplaints( ( women withNCAHareabletoconceivespontaneously the severityofCAHandfertility( less studied,butthereisaclearrelationshipbetween The situationforwomenwithNCAHhasbeenmuch hormonal situationandenablesconception( Treatment withglucocorticoidscanusuallyimprovethe progesterone producesacontraceptiveeffect( cycles( anovulatory and 17OHPlevelsresultinmenstrualirregularities with classicCAH( Fertility hasbeenshowntobecompromisedinwomen Women below. and womenwithNCAHwillbediscussedseparately children ascontrols( women andmenwithNCAHwereaslikelytohave disease. Inanationalepidemiologicalfollow-upstudy, ( Fertility isaffectedinbothmenandwomenwithCAH Fertility issues no improvementofsymptoms( women withNCAH,butnotinPCOS,andlittleor in 17OHPandandrogenlevelsasmallnumberof simvastatin havebeenshowntoproduceimprovements the treatmentofhirsutism( recommended againstowingtotheirinferioreffectin insulin sensitisersincludingmetformininPCOShasbeen as acomplementtomedicaltherapy ( electrolysis and laser therapy may be sufficient or be used of hirsutism,shaving,waxing,bleaching,plucking, not, however, beusedduringpregnancy. Inmildcases (a 5-alpha-reductaseinhibitor)( anti-mineralocorticoid action),flutamideandfinasteride have alsobeenused,suchasspironolactone(inspiteofthe effective thanhydrocortisone( 106 100 Review , , ). This is, however, related totheseverity of the 109 107 ). Sonographyshowedthat 25% ofwomenwith ). Nevertheless,amongwomenwithNCAH, 9 , 105 101 9 ). The clinical picture is PCOS-like, 101 , , 102 23 ). Thefertilityissuesformen 97 ). Continuous elevation of , 103 ). However, metforminand 96 98 , 18 H Falhammar A Nordenströmand 104 22 ). Otherantiandrogens , 110 ). Thesedrugsshould 101 99 , ). Elevatedandrogen 26 ). ). Itisimportant, ). Themajorityof ). Treatment with 97 100 ). Theuseof , 103 100 105 22 , , , 108 105 105 , 26 ). ). ). , pressure andgestationaldiabetes,arerecommended regular clinicalcheck-ups,includingcontrolofblood glucocorticoid doseduringpregnancy( detail forNCAH.Thewomenmayhavetoincrease their and uneventful,althoughthishasnotbeendescribedin factors mayalsoplayarole infertility;forexample, if the TARTs are of limited size. Moreover, psychosexual may, however, stillfather children( of theseminiferoustubules ( may impairgonadalfunction bymechanicalobstruction ( up to86–94%ofalladolescentsandadultswithCAH Testicular adrenalresttumours(TARTs) werepresentin due tohyper-orhypogonadotrophichypogonadism. severely impaired( Fertility inmaleswithCAHhasbeenreportedtobe Men The reasonforthisfindingisnotclear. has beenreported( Caesarean sectionisnotmorecommoninNCAH,butit results, treatmentduringpregnancyisoftenadvised( frequency ofmiscarriage( glucocorticoid treatment did not significantly affect the 107 with glucocorticoidand6%whenontreatment( in twostudieswithsimilarrates:26%ifnottreated ( conception fromabout1 year tolessthan6 months ( ( of mildandseveremutationsbetweenthegroups although therewasnodifferenceinthefrequency had, overall,fewerclinicalsymptomsofandrogenexcess, ( (78%) becamepregnantwithoutovulationstimulation After thestartofhydrocortisonetreatment,mostwomen spontaneously beforediagnosisandtreatment( shown that 53–68% of the women with NCAH conceived the managementdiffers. however, todistinguishbetweenPCOSandNCAHsince population with51%malesand49%females( to 48%,andistheoppositewhatseeningeneral showed aslightpreponderanceoffemalestomales,i.e.,52 NCAH, ashigh14%( have achildwithclassicCAHandofhaving an increased risk (1.4–2.5%) for a woman with NCAH to NCAH Diagnosis andmanagementof 114 100 107 107 ). In contrast, in a retrospective study from Israel, The pregnancieshavebeenreportedtobenormal The outcomeofthechildrenisexcellent( Nevertheless, studies on the fertility outcome have ). Glucocorticoidtreatmentshortenedthetimeto ). Patients who became pregnant spontaneously , ). Anincreasedriskofmiscarriagehasbeenreported 118 ). Thesetumoursarealwaysbenign,butthey 112 89 , ). 113 106 Downloaded fromBioscientifica.com at10/01/202102:01:27PM , 111 , 114 107 ). Despitetheconflicting 119 https://eje.bioscientifica.com , ). Thesexofthechildren 115 ). MaleswithTARTs 180 , 64 116 , :3 114 100 , 117 64 ), especially , 103 106 ). Thereis 112 ), mainly R135 , , ) and 111 111 107 106 27 via freeaccess ). ). ). ). , European Journal of Endocrinology https://eje.bioscientifica.com 73 , reported anincreasedBMI( Most studiesonadultsand childrenwithCAHhave Obesity forms ( appeared tohavefewerfracturesthanthosewithclassic 121 prevalence hassometimesbeenreportedinCAH( compared toclassicCAH( frequency ofosteoporosisordecreasedBMDinNCAH, classic CAH( was normaloratleastbetterthanthatinchildrenwith 122 at leastabetteronethanadultswithclassicCAH( reported thatadultswithNCAHhadanormalBMDor to prolongedperiodsofhyperandrogenism.Somestudies not starttreatment)theirBMDcouldbeincreasedthanks diagnosed firstinyoungadulthood(andeventhen,may start glucocorticoidtreatmentduringchildhoodandare In theory, since many individualswithNCAH do not Bone mineraldensityandfractures Comorbidities significantly increased( risk ofhavingachildwithNCAHorclassicCAHwas with NCAH,butsimilarlytofemalesthe 0.4–19). comparable tothatofcontrols(adjustedOR:2.9,95%CI: increased fatherhood(OR:3.7,95%CI:0.9–15)oratleast 0.2–0.5), while males with NCAH displayed a tendency to of residence,educationandincome)(OR:0.4,95%CI: adjusted for socioeconomic factors (marriage, region CAH was only 0.5 (95% CI: 0.4–0.7) and even less when The odds ratio (OR) for being a father among males with matchedcontrols( 221 maleswithCAHand22 024 largest studyinvestigatingfertilityoutcomesincluding males withNCAH.Thiswasrecentlyconfirmedinthe was assumedthatthefertilitywouldbelessaffectedin in occasionalmaleswithNCAH( ( almost nothingwasknownaboutmalefertilityinNCAH partners throughoutlife( males withCAHwerelesssexuallyactiveandhadfewer 18 131 Review , ) untilrecently( , , 94 Thus, fertilitydoesnotseemtobeimpairedinmales , 122 123 , 132 121 139 , ). Similarly, inchildrenwithNCAH,theBMD , 127 , , 133 122 140 124 , , 128 ). , ). However, otherstudiesfoundasimilar 134 141 , 116 , 129 , 135 142 116 ). TARTs hadonlybeendescribed ) andpatientswithNCAHhave , 6 ). Thefrequencyofobesity did 114 136 ). 6 , , 123 89 , , 120 137 , , H Falhammar A Nordenströmand 124 125 ). Inspiteofallthis, , 114 , 138 , 125 126 , ), butnotall( 117 , , 128 127 ); hence,it , ). Fracture 129 , 116 130 121 82 4 ). , , , , demonstrate an increased frequencyofinsulinresistance another largerstudyonboth childrenandadultsfailedto compliance hadinsulin resistance ( adults with CAH(NCAH, compared tocontrols( SV CAHwhodemonstratedimpairedinsulinsensitivity, adult Chinesewomenwith untreated and non-overweight This isfurthersupportedbyastudyonnewlydiagnosed, insulin sensitivity, whichmayexplainthedifference ( suggested thatpostnatalhyperandrogenismmayimpair fat massthanthosewithclassicCAH( NCAH wereinsulin-resistanteventhoughtheyhadless ( of 75patientswithNCAH,comparedto7500controls type twodiabeteswasfourtimesmorefrequentinastudy gestational diabeteshasbeenreportedinNCAH( only atendencyforanincrease( for heartfailureandvenousthromboembolism,therewas more commonthanincontrols,especiallystroke,while individuals with NCAH, cardiovascular diseases were Cardiovascular diseaseanddiabetes classic CAH( lean, anddecreasedfatmass,comparedtochildrenwith Children withNCAHhavebeenfoundtoincreased assumed that they would have an increased lean mass ( hyperandrogenism duringanextendedperiod,itcanbe ( body mass and underestimation of fat mass if BMI is used glucocorticoid replacementmaycausedecreasedlean or hypoandrogenismowingtosupraphysioloigal of bodyfat.Ontheotherhand,physicalinactivity increased musclemass,ahigherBMIandoverestimation females ( CAH sincephysicalactivity, whichiscommoninCAH has shortcomingsforestimationofbodyfat,especiallyin disease anddiabetesusuallydeveloplaterinlife( than 50 years, thisistobeexpectedbecausecardiovascular most oftheadultsinCAHstudieshavebeenagedless have been performed in children and adolescents and gestational diabetes)( cardiovascular disease( few indicating an increased frequency of established very ( increased cardiometabolic risk, including insulin resistance There havebeenmanystudiesonCAHthatindicatean reported alowerBMIinpatientswithNCAH( in some studies ( not differbetweenpatientswithNCAHandclassicCAH NCAH Diagnosis andmanagementof 151 18 4 , ). Since individuals with NCAHhave been exposed to 6 ). InastudyonchildrenwithCAH,onlythose , 81 , 89 144 , 94 125 ), andhyperandrogenism,mayresultin ). , 6 137 , 94 , , 81 145 137 122 129 Downloaded fromBioscientifica.com at10/01/202102:01:27PM , 103 , ). Moreover, inastudyon26 , , n 146 124

151 = , 8), only thosewith poor 151 , 151 , ) ordiabetes(including 147 125 ). Anoccasionalcaseof ). Sincemoststudies 180 , , 148 143 :3 94 125 , ), while others 149 ). Ithasbeen ). However, , 150 89 50 64 R136 ). BMI ), but ), but ). In 18 18 via freeaccess ). ). European Journal of Endocrinology .–8 years earlier, comparedtocontrols( 6.5–18 an increasedmortalityrate (hazardratio3–5)anddied ( survive increased awareness) more individuals with classicCAH replacement and neonatalscreening in additionto the advanceofmedicine(introductionglucocorticoid Very littleisknownaboutthemortalityinNCAH.With Mortality voice ( NCAH, 50%had,subjectively, a‘dark’(i.e.low-pitched) have a low-pitched voice ( however, 45% ofthepatientsthemselvesclaimedto had given7%ofthewomenwithCAHvoiceproblems; compliance andalatediagnosis( women with CAH had a normal voice in spite of poor with alateCAHdiagnosisandpoorcompliance,butfew women withCAH( voice comparedtocontrols,havebeenidentifiedin frequency ( tissue mass, leading to a lower fundamental voice Prolonged hyperandrogenismmayaffectthelaryngeal Voice pathologyinfemales limited, whichmakesinterpretationsdifficult. the numberofindividualswithNCAHwas,however, disorders inmaleswithNCAHcomparedtocontrols( increased inwomenwithNCAH( suicidality ( 155 increased frequency of psychiatric diseases ( 154 in a few studies, and then mostly in classic CAH ( Psychiatric disordersinCAHhaveonlybeenreported Psychiatric diseases resistance viaandrogenexcess( or toolowglucocorticoiddosesmayalsoresultininsulin for impairedinsulinsensitivityinCAH.Noglucocorticoid the causeofinsulinresistance,maynotbeonlyreason glucocorticoid treatment,whichisoftenassumedtobe insulin sensitivity( in femalesandlowtestosteronelevelsmalescanimpair in NCAH,comparedtoclassicCAH( Review ), depression( , 155 159 36 , ). 156 ). Generallyspeaking,patients withCAHhad 129 157 ). Thesestudieshavegenerallyshownan , ). Morevoiceissues,includingadeeper 154 156 ). Only phobic anxiety disorders were 152 158 ), alcoholmisuse( , ). Theseissueswereassociated 153 170 ). Thus,supraphysiological ). Among the women with 18 158 H Falhammar A Nordenströmand ). ). Hyperandrogenism 155 6 ). Androgenexcess ), andpsychotic 154 , 129 77 155 , , ) and 156 154 154 129 ). ); , , performed ( if aCTormagneticresonancetomographyhasbeen 11–58% will have at leastone adrenal nodule detected ( cortex hyperplasiawithsubsequenttumourformation Chronically elevatedACTHlevelscanresultinadrenal Adrenal tumours patients withNCAHonglucocorticoidtherapy. thereby highlightingtheimportanceofstressdosingin NCAH patientsmayhavebeenrelatedtoanadrenalcrisis, noted onthedeathcertificate( a cardiovascularconditionhadconcurrentinfection condition andone-thirdofanadrenalcrisis,butallwith those with NCAH, two-thirds died of a cardiovascular the NCAHgroup,possiblyduetopowerissues.Among Mortality wasnot significantly increased, however, in CAH and 81% of all cases were associated with NCAH ( (all cases)ofadrenalincidentalomaswereassociatedwith analysis, 0.8%(onlygeneticallyconfirmedcases)and5.9% cohorts ( NCAH, bothincasereportsandadrenalincidentaloma ( than suspectedorknownadrenaldisordermalignancy serendipitously byimaginingperformedforotherreasons adrenal incidentalomas,thatis,lesionsfound in NCAHis,however, unknown.Ontheotherhand, found inanoldercohort(82%)( are inconsistent and indicate varying degreesofimpaired are inconsistentandindicate varying QoL studieshavehadtheclassical phenotype.Thereports study, allorthe majority ofpatientswithCAHincludedin often thanthe7500controls ( had disabilitypensionsand socialwelfarebenefitsmore longer periodsandhadfewersickleaves,butthewomen with NCAH(56females),thepatientshadworkedduring a nationalepidemiologicalstudyincluding75individuals Studies onthequalityoflife(QoL)inNCAHarescarce. In Quality oflife require adrenalectomy( needs tobeperformedexcludeothertumoursthatmay adrenal tumour isdiscoveredaconventional evaluation cancer beingextremelyrareinCAH( with untreatedCAH( the 17OHPlevelandtumoursizeinthesepatients Moreover, therewasapositivelinearrelationshipbetween NCAH Diagnosis andmanagementof 62 164 , ), havesometimesbeentheinitialpresentationof 160 , 62 161 , 162 78 ). InpatientswithknownclassicCAH , , 163 165 ), andanevenhigherprevalencewas , 166 169 18 Downloaded fromBioscientifica.com at10/01/202102:01:27PM ). , ). Inspiteofadrenocortical 167 , https://eje.bioscientifica.com 101 77 168 ). Thus,alldeathsin 160 ). Otherthaninthis 180 ). Inarecentmeta- 18 ). Theprevalence :3 , 169 ), whenan R137 169 via freeaccess ). European Journal of Endocrinology https://eje.bioscientifica.com diagnosis. Although treatment is somewhat controversial, may neverseekmedicalattention andthereforeescape like picture andfertility issues. Many men with NCAH adolescence andadultlifewith hirsutism,acne,aPCOS- treatment guidance.Most patientsarediagnosedin for geneticcounsellingandbetterprognostic a measurement of17OHPisthegoldstandard.We advocate used forscreening,buttheACTHstimulationtestwith a in males. A baseline measurement of 17OHP may be ethnicity, butmostcasesareneverdiagnosed, especially NCAH isarelativelycommondisorderregardless of Conclusion ascertained ( Appropriate transitionintoadultcareneedsshouldbe due tothepotentiallong-termconsequencesofNCAH. even thosewithnoorminimalsymptomssuchasmales individuals withNCAHarefollowedupregularly( in adolescentsandyoungadults.We proposethatall for allhealthcaredecisionsandisevenmoreimportant condition. Informationandpatienteducationisthebasis may notfullyencompassthelong-termeffectsoftheir difficult timeforpatientswithalessseveredisease,who The transitionperiod,intoadultcare,isanespecially Follow-up andtransitionintoadultcare individuals withNCAHorwithouttreatment. our knowledge,therearenostudiescomparingQoLin but therehavebeenconflictingresults( dexamethasone resultinginaworseQoLonestudy, has beenreportedtoaffectQoL,withprednisoloneor ( disorder, incontrasttopatientswithanacquireddisorder because theyhaveneverexperiencedatimewithouttheir CAH werereportedtohaveabetterQoL( adrenal insufficiency,in CAH with primary patients with differ fromthatinclassicCAH.InastudycomparingQoL hence,theirQoLcanbeexpectedto had genitalsurgery; androgen levelsbeforediagnosisbutgenerallyhavenot NCAH haveoftenhadlongperiodsofexposuretoelevated null and I2 splice genotypes ( women withclassicCAH,especiallythe general wellbeingandarelikelytoaffecttheQoLof andsatisfactionwithsexualfunctionaffectthe surgery QoL ( 64 Review CYP21A2 ). Thetypeofglucocorticoidusedfortreatment 18 , 170 mutationanalysistoverifythediagnosis, 171 , 171 ). , 172 , 173 , 174 175 ). Theoutcomeofgenital H Falhammar A Nordenströmand , 176 ). Individuals with 120 177 , ), possibly 178 Table 2 ). To ), The authors declare that there is no conflict of interest that could be could that interest of conflict perceived asprejudicingtheimpartialityofthisreview. no is there that declare authors The Declaration ofinterest obtained byscreening,arewarranted. late clinicaldiagnosis and those with aneonatal diagnosis difficulties patientswithNCAHface,boththosea outcome isrecommended.Studiesfocusingonthespecific monitoring toavoidriskfactorsandimprovetheclinical cortisolinsufficiency.lead toasecondary Regularclinical and fractures.Itisimportanttoknowthattreatmentwill obesity, insulinresistance,hypertension,osteoporosis but theymayresultinlong-termcomplications,suchas will improvesymptomsofandrogenexcessandfertility, androgen excess thatdevelop over time.Glucocorticoids and ameliorating the symptomsandconsequences of implications ongrowthandberelevantforpreventing an earlydiagnosisandstartoftreatmentmayhavepositive References Stockholm CountyCouncil(AN). Swedish Endocrine Society (H F), Karolinska Institutet (H F, A N) and the This work was supported by the Magnus Bergvalls Foundation (H F), the Funding NCAH Diagnosis andmanagementof 7 6 5 4 3 2 1 Odenwald B, Nennstiel-Ratzel U,Dorr HG, Schmidt H,Wildner M Finkielstain GP, Kim MS,Sinaii N,Nishitani M,Van Ryzin C,Hill SC, Charmandari E, Eisenhofer G,Mehlinger SL,Carlson A,Wesley R, Falhammar H, FilipssonNystrom H,Wedell A &Thoren M. Fiet J, Gueux B,Raux-DeMay MC,Kuttenn F, Vexiau P, Brerault JL, New MI. Extensiveclinicalexperience:nonclassical21-hydroxylase Tusie-Luna MT, Traktman P &White PC.Determinationof & Bonfig W. Children with classiccongenitaladrenalhyperplasia doi.org/10.1210/jc.2012-2102) of ClinicalEndocrinologyandMetabolism cohort of244patientswithcongenital adrenalhyperplasia. Reynolds JC, Hanna RM&Merke DP. Clinicalcharacteristicsofa jcem.87.7.8664) and Metabolism 21-hydroxylase deficiency. function maypredictphenotypeandgenotypeinclassic Keil MF, Chrousos GP, New MI&Merke DP. Adrenomedullary (https://doi.org/10.1530/EJE-10-0877) deficiency. males withcongenitaladrenalhyperplasiadueto21-hydroxylase Cardiovascular risk,metabolicprofile,andbodycompositioninadult 542) Metabolism mineralocorticoid pathway. adrenal 21-hydroxylasedeficiencysuggestamilddefectofthe plasma 21-deoxycorticosterone(21-DB)levelsinlate-onset Couillin P, Galons H,Villette JM, Julien R 4205–4214. deficiency. Chemistry (CYP21) usingrecombinantvacciniavirus. functional effectsofmutationsinthesteroid21-hydroxylasegene 1990 1989 European Journal ofEndocrinology European Journal ofClinicalEndocrinologyandMetabolism Journal (https://doi.org/10.1210/jc.2006-1645) 2002 265 68 20916–20922. 542–547. 87 3031–3037. Downloaded fromBioscientifica.com at10/01/202102:01:27PM Journal ofClinicalEndocrinology Journal Journal ofClinicalEndocrinologyand Journal (https://doi.org/10.1210/jcem-68-3- (https://doi.org/10.1210/ 2012 et al 180 2011 Journal ofBiological Journal 97 . Increased :3 4429–4438. 164 285–293. 2006 Journal Journal (https:// R138 91 via freeaccess

European Journal of Endocrinology

20 19 18 17 16 15 14 13 12 11 10 8 9 Review Speiser PW, Knochenhauer ES,Dewailly D,Fruzzetti F, Marcondes JA Dracopoulou-Vabouli M, Maniati-Christidi M&Dacou-Voutetakis C. Falhammar H &Nordenstrom A.Nonclassiccongenitaladrenal New MI, Abraham M,Gonzalez B,Dumic M,Razzaghy-Azar M, Jaaskelainen J, Levo A,Voutilainen R &Partanen J. Population-wide Krone N, Rose IT, Willis DS, Hodson J,Wild SH, Doherty EJ, Wedell A. Moleculargeneticsof21-hydroxylasedeficiency. Speiser PW, Dupont J,Zhu D,Serrat J,Buegeleisen M,Tusie-Luna MT, Krone N &Arlt W. Geneticsofcongenitaladrenalhyperplasia. Wedell A, Ritzen EM,Haglund-Stengler B&Luthman H.Steroid El-Maouche D, Arlt W&Merke DP. Congenitaladrenalhyperplasia. Chrisp GL, Maguire AM,Quartararo M,Falhammar H,King BR, Speiser PW, Azziz R,Baskin LS,Ghizzoni L,Hensle TW, Merke DP, (https://doi.org/10.1006/mgme.2000.3036) phenotype. congenital adrenalhyperplasia:relationship betweengenotypeand & Azziz R.Amulticenterstudyofwomen withnonclassical doi.org/10.1210/jcem.86.6.7574) Clinical EndocrinologyandMetabolism in thedifferentformsofcongenitaladrenalhyperplasia. population: variableconcordancebetweengenotypeandphenotype The spectrumofmoleculardefectstheCYP21geneinHellenic (https://doi.org/10.1007/s12020-015-0656-0) diagnosis, treatment,andoutcome. hyperplasia dueto21-hydroxylasedeficiency:clinicalpresentation, 2611–2616. hyperplasia owingto21-hydroxylasedeficiency. phenotype correlationin1,507familieswithcongenitaladrenal Chitayat D, Sun L,Zaidi M,Wilson RC &Yuen T. Genotype- jcem.82.10.4271) and Metabolism in awelldefinedpopulation. in steroid21-hydroxylase(CYP21)deficiency:goodcorrelation evaluation of diseasemanifestationinrelation to moleculargenotype E346–E354. cohort. Congenital adrenalHyperplasiaAdultStudyExecutive(CaHASE) due to21-hydroxylasedeficiency:analysisoftheUnitedKingdom correlation in153adultpatientswithcongenitaladrenalhyperplasia Hahner S, Parajes S,Stimson RH,Han TS Development doi.org/10.1172/JCI115897) deficiency. genotype incongenitaladrenalhyperplasiadueto21-hydroxylase Lesser M, New MI&White PC.Diseaseexpressionandmolecular 181–192. Practice andResearch: ClinicalEndocrinologyandMetabolism pnas.89.15.7232) mutations. establishment ofphenotype-genotyperelationshipscommon 21-hydroxylase deficiency:threeadditionalmutatedallelesand 6736(17)31431-9) Lancet 2631) Metabolism Society clinicalpracticeguideline. hyperplasia duetosteroid21-hydroxylasedeficiency:anEndocrine Meyer-Bahlburg HF, Miller WL,Montori VM cen.13826) Clinical Endocrinology adrenal hyperplasia:anauditofthreepaediatrichospitals. the managementofacuteillnessinchildrenwithcongenital Munns CF, Torpy DJ, Hameed S &Rushworth RL.Variations in 174 during thefirst6yearsoflife. experience saltlossandhypoglycemia:evaluationofadrenalcrises 177–186. 2017 Journal ofClinicalEndocrinologyandMetabolism Journal (https://doi.org/10.1016/j.beem.2008.10.014) 2010 Journal ofClinicalInvestigation Journal PNAS 2011 Molecular GeneticsandMetabolism (https://doi.org/10.1073/pnas.1300057110) (https://doi.org/10.1210/jc.2012-3343) 390 (https://doi.org/10.1530/EJE-15-0775) 1997 2194–2210. 1992 95 20 4133–4160. 80–87. 82 2018 89 3293–3297. 7232–7236. 89 (https://doi.org/10.1159/000321223) (https://doi.org/10.1016/S0140- Journal ofClinicalEndocrinology Journal European Journal ofEndocrinology European Journal 577–585. (https://doi.org/10.1210/jc.2009- Journal ofClinicalEndocrinology and Journal Endocrine 2001 (https://doi.org/10.1210/ H Falhammar A Nordenströmand (https://doi.org/10.1073/ 1992 (https://doi.org/10.1111/ et al 86 et al . Genotype-phenotype 2015 2000 2845–2848. 90 PNAS . Congenitaladrenal 584–595. 50 71 32–50. 2013 527–534. 2013 Journal of Journal 2009 (https:// Endocrine (https:// 110 98 2016 Best

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NCAH Diagnosis andmanagementof 26 25 24 23 22 21 34 33 32 31 30 29 28 27 Moran C, Azziz R,Carmina E,Dewailly D,Fruzzetti F, Ibanez L, Hindmarsh PC. Managementofthechildwithcongenitaladrenal Witchel SF. Congenitaladrenalhyperplasia. Turcu AF & Auchus RJ.Adrenalsteroidogenesisandcongenital Livadas S, Dracopoulou M,Dastamani A,Sertedaki A,Maniati- Bidet M, Bellanne-Chantelot C,Galand-Portier MB,Tardy V, Nordenstrom A, Thilen A,Hagenfeldt L, Larsson A&Wedell A. Neocleous V, Shammas C,Phedonos AA,Phylactou LA& Skordis N, Shammas C,Phedonos AA,Kyriakou A,Toumba M, Armengaud JB, Charkaluk ML,Trivin C, Tardy V, Breart G,Brauner R Wasniewska M, Raiola G,Galati MC,Salzano G,Rulli I, Zirilli G& Witchel SF. Non-classiccongenitaladrenalhyperplasia. Weintrob N, Brautbar C,Pertzelan A,Josefsberg Z,Dickerman Z, Carmina E, Dewailly D,Escobar-Morreale HF, Kelestimur F, Moran C, Journal ofObstetricsandGynecology Journal Knochenhauer ES, Marcondes JA, Mendonca BB,Pignatelli D, beem.2008.10.010) and Metabolism hyperplasia. jpag.2017.04.001) Adolescent Gynecology America adrenal hyperplasia. cen.12543) Clinical Endocrinology adrenal hyperplasiacausedbymutationsoftheCYP21A2gene. molecular findingsin280individualswithnonclassicalcongenital & Dacou-Voutetakis C. Thespectrumofclinical,hormonaland Christidi M, Magiakou AM,Kanaka-Gantenbein C,Chrousos GP doi.org/10.1210/jc.2008-1582) Clinical EndocrinologyandMetabolism due to21-hydroxylasedeficiencyand330familymembers. unrelated womenwithnonclassicalcongenitaladrenalhyperplasia et al Billaud L, Laborde K,Coussieu C,Morel Y, Vaury C, Golmard JL 21-hydroxylase deficiency. screening forcongenitaladrenalhyperplasia duetosteroid Genotyping isavaluablediagnostic complementtoneonatal 8210.145077) and Metabolism heterozygous forCYP21A2mutations. Skordis N. Phenotypicvariabilityofhyperandrogenemiainfemales 0223-1) Investigation gene ingirlswithprematureadrenarche. Neocleous V &Phylactou LA.GeneticdefectsoftheCYP21A2 doi.org/10.1210/jc.2009-0314) of ClinicalEndocrinologyandMetabolism congenital adrenalhyperplasiafromprematureadrenarche. & Chalumeau M.Precociouspubarche: distinguishing late-onset 2008 prepubertal orpubertalgynecomastia. De Luca F. Non-classical21-hydroxylasedeficiency inboyswith 78 (https://doi.org/10.1530/eje.0.1430397) deficiency. phenotype associationsinnon-classicalsteroid21-hydroxylase Kauschansky A, Lilos P, Peled D,Phillip M&Israel S.Genotype- humupd/dmx014) Reproduction Update with aspecialfocusonadolescentandadultwomen. hyperplasia dueto21-hydroxylasedeficiencyrevisited:anupdate Oberfield S, Witchel SF &Azziz R.Non-classiccongenitaladrenal org/10.1067/mob.2000.108020) hyperplasia isaprogressivedisorder:multicenterstudy. Pugeat M 747–750. . Clinicalandmolecularcharacterizationofacohort161 167 2015 1083–1084. et al European Journal ofEndocrinology European Journal 2015 Best PracticeandResearch: ClinicalEndocrinology (https://doi.org/10.1016/j.steroids.2013.04.010) 44 . 21-Hydroxylase-deficientnonclassicadrenal 2009 2014 275–296. 38 2017 535–539. Endocrinology and Metabolism Clinics of North Endocrinology andMetabolismClinicsofNorth 2017 2015 23 18 (https://doi.org/10.1007/s00431-007-0625-6) 193–208. S72–S79. 23 (https://doi.org/10.1016/j.ecl.2015.02.002) Downloaded fromBioscientifica.com at10/01/202102:01:27PM Journal ofClinicalEndocrinology Journal 30 82 580–599. 520–534. 543–549. (https://doi.org/10.1007/s40618-014- (https://doi.org/10.4103/2230- 2000 (https://doi.org/10.1016/j. https://eje.bioscientifica.com 2009 (https://doi.org/10.1093/ European Journal ofPediatrics European Journal Indian Journal ofEndocrinology Indian Journal 2009 (https://doi.org/10.1016/j. (https://doi.org/10.1111/ 183 Journal ofEndocrinological Journal 94 180 2000 Journal ofPediatricand Journal 1468–1474. 94 1570–1578. :3 2835–2840. 143 397–403. Human Steroids (https://doi. American (https:// Journal of Journal Journal Journal (https:// R139 2013 via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com

49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 Review Eyal O, Tenenbaum-Rakover Y, Shalitin S,Israel S&Weintrob N. Weintrob N, Dickerman Z,Sprecher E,Galatzer A&Pertzelan A. Bonfig W, Pozza SB,Schmidt H,Pagel P, Knorr D&Schwarz HP. Bretones P, Riche B,Pichot E,David M,Roy P, Tardy V, Kassai B, Hargitai G, Solyom J,Battelino T, Lebl J,Pribilincova Z,Hauspie R, Van derKamp HJ,Otten BJ,Buitenweg N,DeMuinckKeizer- Balsamo A, Cicognani A,Baldazzi L,Barbaro M,Baronio F, Trapp CM &Oberfield SE.Recommendationsfortreatment Bonfig W. Growthanddevelopmentinchildrenwithclassic Thilen A, Woods KA, Savage MO,Wedell A Perry LA, &Ritzen EM. Therrell BL. Newbornscreeningforcongenitaladrenalhyperplasia. Witchel SF. Newbornscreeningforcongenitaladrenalhyperplasia: Gidlof S, Wedell A, Guthenberg C,vonDobeln U&Nordenstrom A. Gidlöf S, FalhammarHThilén A,vonDöbeln A,Ritzén M,Wedell A, White PC. Neonatalscreeningforcongenitaladrenalhyperplasia. Adult heightofsubjectswithnonclassical 21-hydroxylasedeficiency. doi.org/10.1530/eje.0.1360188) height. the effectoftimeinitiationtherapy onpubertyandfinal Non-classical 21-hydroxylasedeficiency ininfancyandchildhood: (https://doi.org/10.1210/jc.2009-0942) ofClinicalEndocrinologyandMetabolism Journal congenital adrenalhyperplasia:anevidence-basedrecommendation. Hydrocortisone dosingduringpubertyinpatientswithclassical doi.org/10.1515/jpem-2016-0156) Pediatric EndocrinologyandMetabolism adrenal hyperplasiafromanationalretrospectivecohort. Gaillard S, Bernoux D,Morel Y Research 21-hydroxylase deficiency. Resultsofamulticenterstudy. and finalheightincongenitaladrenalhyperplasiaduetoclassical Kovacs J, Waldhauser F, Frisch H&GroupM-CS.Growthpatterns 2002 21-hydroxylase deficiencypatients. Vulsma T &Wit JM. Longitudinalanalysisofgrowthandpubertyin Schrama SM, Oostdijk W, Jansen M, Delemarre-deWaal HA, jc.2003-030123) and Metabolism treated for21-hydroxylasedeficiency. genotype, adultheight,andpubertaldevelopmentin55patients Gennari M, Bal M,Cassio A,Kontaxaki K&Cacciari E.CYP21 steroids.2011.12.009) update. of nonclassiccongenitaladrenalhyperplasia(NCCAH):an MED.0000000000000308) Diabetes andObesity congenital adrenalhyperplasia. (https://doi.org/10.1111/j.1651-2227.1995.tb13788.x) 21-hydroxylase deficiency. Early growthisnotincreasedinuntreatedmoderatelysevere (https://doi.org/10.1016/S0889-8529(08)70017-3) America Endocrinology andMetabolismClinicsofNorth 2018 Epub. beyond 17-hydroxyprogesteroneconcentrations. jamapediatrics.2013.5321) based study. in Sweden:a26-yearlongitudinalprospectivepopulation- Nationwide neonatalscreeningforcongenitaladrenalhyperplasia org/10.1016/S2213-8587(13)70007-X) study. hyperplasia inSweden:aretrospective,population-basedcohort Nordenström A. Onehundredyearsofcongenitaladrenal org/10.1038/nrendo.2009.148) Nature ReviewsEndocrinology jcem.84.5.5651) and Metabolism 87 Lancet DiabetesandEndocrinology European Journal ofEndocrinology European Journal 2001 Steroids 139–144. (https://doi.org/10.1016/j.jped.2018.06.003) JAMA Pediatrics 55 2003 1999 2012 161–171. (https://doi.org/10.1136/adc.87.2.139) 2017 84 88 77 5680–5688. 1505–1509. 342–346. 24 Acta Paediatrica (https://doi.org/10.1159/000049990) 2009 20141–8. 39–42. et al Current OpinioninEndocrinology, 5 (https://doi.org/10.1016/j. 490–498. . Growth curves forcongenital . Growthcurves Archives ofDiseaseinChildhood (https://doi.org/10.1097/ (https://doi.org/10.1210/ (https://doi.org/10.1210/ 2016 H Falhammar A Nordenströmand Journal ofClinicalEndocrinology Journal (https://doi.org/10.1001/ 2013 1997 1995 29 1 (https://doi. 136 1379–1388. 2009 35–43. 84 Journal ofPediatrics Journal 188–195. 894–898. 2001 94 (https://doi. 3882–3888. Journal of Journal Hormone Hormone 30 (https:// (https:// 15–30.

NCAH Diagnosis andmanagementof 52 51 50 54 53 65 64 63 62 61 60 59 58 57 56 55 Levin JH, Carmina E&Lobo RA.Istheinappropriategonadotropin Carmina E, Gagliano AM,Rosato F, Maggiore M&Janni A.The Falhammar H, Thoren M&Hagenfeldt K.A31-year-oldwoman Kamrath C, Wettstaedt L, Boettcher C, Hartmann MF&Wudy SA. Kamrath C, Hochberg Z,Hartmann MF, Remer T&Wudy SA. Therrell BL Jr, Berenbaum SA,Manter-Kapanke V, Simmank J, Falhammar H &Thoren M.Clinical outcomesinthemanagementof White PC&Speiser PW. Congenitaladrenalhyperplasiadueto Falhammar H. Non-functioningadrenalincidentalomascaused Bulsari K &Falhammar H.Clinicalperspectivesincongenitaladrenal Bachega TA, Billerbeck AE,Marcondes JA, Madureira G, Azziz R, Hincapie LA,Knochenhauer ES,Dewailly D,Fox L& Merke DP &Bornstein SR.Congenitaladrenalhyperplasia. New MI, Lorenzen F, Lerner AJ,Kohn B,Oberfield SE, Pollack MS, Falhammar H, Wedell A &Nordenstrom A. Biochemicalandgenetic Kamrath C, Hartmann MF&Wudy SA. Androgensynthesisin of patientswithadult-onsetcongenitaladrenalhyperplasia? syndromesimilartothat secretion ofpatientswithpolycysticovary (https://doi.org/10.1007/BF03348395) deficiency). endocrine patternoflateonsetadrenalhyperplasia(21-hydroxylase org/10.1007/BF03345586) ofEndocrinologicalInvestigation Journal congenital adrenalhyperplasiaduetoanovelCYP21mutation. with infertilityandpolycysticovariesdiagnosednon-classic apa.12147) Acta Paediatrica doi.org/10.1016/j.jsbmb.2017.12.016) andMolecularBiology Steroid Biochemistry treated childrenwithcongenitaladrenalhyperplasia. Androgen excessisduetoelevated11-oxygenatedandrogensin 2012 hormone analysis. steroid with 21-hydroxylasedeficiency:evidencefromurinary Increased activationofthealternative‘backdoor’pathwayinpatients 0282(16)54592-0) and Sterility 1.9 millionTexas newbornsfor21-hydroxylase-deficient congenital Korman K, Prentice L,Gonzalez J& Gunn S. Resultsofscreening doi.org/10.1007/s12020-011-9591-x) congenital adrenalhyperplasia. 21-hydroxylase deficiency. 308–314. by 21-hydroxylasedeficiencyorcarrierstatus? 19–36. hyperplasia dueto11beta-hydroxylasedeficiency. j.1365-2265.2000.00995.x) Clinical Endocrinology congenital adrenalhyperplasiadueto21-hydroxylasedeficiency. on 17-hydroxyprogesteronelevelsinpatientswithnonclassical Arnhold IJ &Mendonca BB.Influenceofdifferentgenotypes S0015-0282(99)00383-0) andSterility Fertility hyperplasia amonghyperandrogenicwomen:aprospectivestudy. Boots LR. Screeningfor21-hydroxylase-deficientnonclassicadrenal 6736(05)66736-0) Lancet org/10.1210/jcem-57-2-320) Clinical EndocrinologyandMetabolism 21-hydroxylase deficiency:hormonalreferencedata. Dupont B, Stoner E,Levy DJ,Pang S (https://doi.org/10.1007/s12020-015-0731-6) diagnosis of21-hydroxylasedeficiency. doi.org/10.1055/s-0032-1331751) deficiency. patients withcongenitaladrenalhyperplasiadueto21-hydroxylase 97 2005 (https://doi.org/10.1007/s12020-016-1189-x) E367–E375. (https://doi.org/10.1007/s12020-013-0162-1) Hormone andMetabolicResearchHormone 1991 Journal ofEndocrinologicalInvestigation Journal 365 2013 2125–2136. 56 Journal ofClinicalEndocrinologyand Metabolism Journal 1999 635–640. 2000 (https://doi.org/10.1210/jc.2011-1997) 102 72 419–423. Downloaded fromBioscientifica.com at10/01/202102:01:27PM Endocrine Reviews 52 915–925. (https://doi.org/10.1016/S0140- 601–607. (https://doi.org/10.1016/S0015- Endocrine (https://doi.org/10.1111/ 1983 et al 2008 (https://doi.org/10.1016/ Endocrine 2018 (https://doi.org/10.1046/ . Genotypingsteroid 2012 2013 57 180 31 2000 320–326. 178 176–180. Endocrine 41 :3 45 2015 1984 355–373. 21 221–228. Endocrine 86–91. 245–291. Journal of Journal Journal of Journal 50 (https://doi. 2014 7 (https://doi. 89–92. 306–314. (https:// 2017 (https:// (https:// Fertility Fertility R140 47

55 via freeaccess

European Journal of Endocrinology

75 79 78 77 76 74 73 72 71 70 69 68 67 66 Review El-Maouche D, Hargreaves CJ,Sinaii N, Mallappa A,Veeraraghavan P Falhammar H &Torpy DJ. A42-year-oldmanpresentedwithadrenal Falhammar H, Frisen L,Norrby C,Hirschberg AL,Almqvist C, Rushworth RL, Torpy DJ &Falhammar H.Adrenalcrises:perspectives Stoupa A, Gonzalez-Briceno L,Pinto G,Samara-Boustani D, Bachelot A, Golmard JL,Dulon J,Dahmoune N,Leban M, Fitness J, Dixit N,Webster D, Torresani T, Pergolizzi R,Speiser PW Finkielstain GP, Chen W, Mehta SP, Fujimura FK,Hanna RM,Van Grodnitskaya E &Kurtser M.Theprevalenceofnon-classic Hannah-Shmouni F, Morissette R,Sinaii N,Elman M,Prezant TR, Speiser PW, Dupont B,Rubinstein P, Piazza A,Kastelan A&New MI. Heather NL, Seneviratne SN,Webster D, Derraik JG,Jefferies C, Thil’en A, Nordenstrom A,Hagenfeldt L,vonDobeln U, Rushworth RL, Torpy DJ, Stratakis CA&Falhammar H. Journal ofClinicalEndocrinologyandMetabolism Journal illness sequelaeinpatientswithcongenital adrenalhyperplasia. & Merke DP. Longitudinalassessmentof illnesses,stressdosingand 1115–1116. with anovelCYP21A2mutation. incidentaloma duetonon-classiccongenitaladrenalhyperplasia E2715–E2721. deficiency. with congenitaladrenalhyperplasiadueto21-hydroxylase Nordenskjold A &Nordenstrom A.Increasedmortalityinpatients org/10.1007/s12020-016-1204-2) and research directions. org/10.1159/000481660) ResearchHormone inPaediatrics Adrenal crisesinchildren:perspectivesandresearch directions. 262–267. an exceptiontotherule? (Synacthen(R)) testinnon-classiccongenitaladrenalhyperplasia: Piketty M Thalassinos C, Flechtner I,Beltrand J,Bidet M,Simon A, org/10.1530/EJE-14-0978) ofEndocrinology European Journal patients withchildhoodonsetofcongenitaladrenalhyperplasia. clinical andbiologicalindicatorsforhealthoutcomesinadult Bouvattier C, Cabrol S,Leger J,Polak M&Touraine P. Determining 960–966. hyperplasia. and asex-specificgeneinneonatalscreeningforcongenitaladrenal & Day DJ.GenotypingofCYP21,linkedchromosome6pmarkers, org/10.1210/jc.2010-0319) Endocrinology andMetabolism hyperplasia dueto21-hydroxylasedeficiency. analysis of182unrelatedfamilieswithcongenitaladrenal Ryzin C, McDonnell NB&Merke DP. Comprehensivegenetic Russian womenwithhyperandrogenism. congenital adrenalhyperplasiadueto21-hydroxylasedeficiencyin org/10.1038/gim.2017.46) Caucasians. nonclassic congenitaladrenalhyperplasiainUSAshkenaziJewsand Chen W, Pulver A&Merke DP. Revisitingtheprevalenceof ofHumanGenetics American Journal High frequencyofnonclassicalsteroid21-hydroxylasedeficiency. (https://doi.org/10.1210/jc.2014-3168) of ClinicalEndocrinologyandMetabolism congenital adrenalhyperplasiainNewZealand,1994–2013. Carll J, Jiang Y, Cutfield WS&Hofman PL.Newbornscreeningfor peds.101.4.e11) in Sweden. congenital adrenalhyperplasia(21-hydroxylasedeficiency) Guthenberg C &Larsson A.Benefitsofneonatalscreeningfor org/10.1542/peds.101.4.583) adrenal hyperplasia. (https://doi.org/10.1159/000369901) et al Journal ofClinicalEndocrinologyandMetabolism Journal Pediatrics Genetics inMedicine Journal ofClinicalEndocrinologyandMetabolism Journal . Inadequatecortisolresponsetothetetracosactide (https://doi.org/10.1210/jc.2014-2957) 1998 Pediatrics Endocrine Hormone ResearchHormone inPaediatrics 101 2011 1998 2018 E11. 2017 2015 2017 Internal MedicineJournal Internal 1985 96 101 (https://doi.org/10.1542/ 89 E161–E172. 19 H Falhammar A Nordenströmand 173 2015 55 341–351. 583–590. 1276–1279. 37 Human Fertility 175–184. 336–345. 650–667. 100 Journal ofClinical Journal 2018. 1002–1008. (https://doi. (https://doi. (https://doi. (https://doi. (https://doi. (https://doi. 2015 20171–6. 2016 2014 1999 Journal Journal 83 46 99

84

NCAH Diagnosis andmanagementof 85 84 83 82 81 80 93 92 91 90 89 88 87 86 Nella AA, Mallappa A,Perritt AF, Gounden V, Kumar P, Sinaii N, Quinkler M, Dahlqvist P, Husebye ES&Kampe O.AEuropean Mallappa A, Sinaii N,Kumar P, Whitaker MJ,Daley LA,Digweed D, Falhammar H, FilipssonNystrom H,Wedell A, Brismar K& Falhammar H, Filipsson H,Holmdahl G,Janson PO,Nordenskjold A, Weintrob N, Israel S,Lazar L,Lilos P, Brautbar C,Phillip M Wieacker I, Peter M,Borucki K,Empting S,Roehl FW&Mohnike K. Turcu AF, Mallappa A, Elman MS,Avila NA, Marko J,Rao H, Dauber A, Kellogg M&Majzoub JA.Monitoringoftherapyin Parsa AA&New MI.Steroid21-hydroxylasedeficiencyin Arlt W, Willis DS, Wild SH, Krone N,Doherty EJ,Hahner S,Han TS, Ogilvie CM, Crouch NS,Rumsby G,Creighton SM,Liao LM& Nermoen I, Husebye ES,Svartberg J&Lovas K.Subjectivehealth Clayton PE, Miller WL,Oberfield SE,Ritzen EM,Sippell WG& ejim.2014.11.006) Medicine ofInternal Journal Emergency Cardforadrenalinsufficiencycansavelives. (https://doi.org/10.1210/jc.2014-3809) ofClinicalEndocrinologyand Metabolism Journal the treatmentofadultswithclassiccongenitaladrenalhyperplasia. of Chronocort,amodified-releaseformulationhydrocortisone,in Eckland DJ, Van Ryzin C,Nieman LK,Arlt W 0865) Endocrinology adult maleswithcongenitaladrenalhyperplasia. Thoren M. Bonemineraldensity, bonemarkers,andfracturesin Metabolism 21-hydroxylase deficiency. in adultwomenwithcongenitaladrenalhyperplasiadueto Hagenfeldt K &Thoren M.Metabolicprofileandbodycomposition (https://doi.org/10.1515/JPEM.2002.15.7.985) ofPediatricEndocrinologyand Metabolism Journal 21-hydroxylase deficiencybeforeandduringglucocorticoidtherapy. & Pertzelan A.Decreasedcortisolsecretioninnonclassical blood samples. Therapy monitoringincongenitaladrenal hyperplasiabydried 3989) Metabolism in 21-hydroxylasedeficiency. biomarkers ofadrenalvolumeandtesticularresttumors Tsodikov A, Auchus RJ&Merke DP. 11-oxygenatedandrogensare 1245–1251. congenital adrenalhyperplasia. jsbmb.2016.06.015) and MolecularBiology congenital adrenalhyperplasia. (https://doi.org/10.1210/jc.2010-0917) ofClinicalEndocrinologyandMetabolism Journal congenital adrenalhyperplasia:acohortstudyof203patients. Carroll PV, Conway GS, Rees DA 64 medical, surgicalandpsychologicalissues. Conway GS. Congenitaladrenalhyperplasiainadults:areviewof 2010 inNorway.population-based survey status inmenandwomenwithcongenitaladrenalhyperplasia:a 188–195. Wilkins PediatricEndocrineSociety. the EuropeanSocietyforPaediatricEndocrinologyandLawson Speiser PW. Consensusstatementon21-hydroxylasedeficiencyfrom 1916) Metabolism congenital adrenalhyperplasia. continuous subcutaneoushydrocortisoneinfusioninadultswith Daley LA, Ling A,Liu CY, Soldin SJ 28 867–871. 2–11. 163 (https://doi.org/10.1111/j.1365-2265.2005.02410.x) 453–459. (https://doi.org/10.1159/000065490) 2016 2007 2017 (https://doi.org/10.1373/clinchem.2010.146035) 2013 (https://doi.org/10.1515/jpem-2014-0303) Journal ofPediatricEndocrinologyandMetabolism Journal 92 102 101 168 110–116. (https://doi.org/10.1530/EJE-10-0284) 2017 2701–2710. 4690–4698. 331–341. 2015 Downloaded fromBioscientifica.com at10/01/202102:01:27PM 165 Journal ofClinicalEndocrinologyand Journal Journal ofClinicalEndocrinologyand Journal (https://doi.org/10.1210/jc.2006-1350) 2–11. Clinical Chemistry ofSteroid Biochemistry Journal ofClinicalEndocrinologyand Journal 26 et al (https://doi.org/10.1530/EJE-12- (https://doi.org/10.1210/jc.2016- (https://doi.org/10.1210/jc.2016- 75–76. et al https://eje.bioscientifica.com Hormone ResearchHormone European Journal ofEndocrinology European Journal . Healthstatusofadultswith (https://doi.org/10.1016/j. . Aphase2studyof (https://doi.org/10.1016/j. Clinical Endocrinology 180 et al 2015 2010 2002 :3 European Journal of European Journal 2010 . Aphase2study 100 95 15 2002 5110–5121. 56 985–991. 1137–1145. European

58 R141

2015 2006 via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com 107 106 105 104 103 102 101 100 99 98 97 96 95 94 Review Bidet M, Bellanne-Chantelot C,Galand-Portier MB,Golmard JL, Moran C, Azziz R,Weintrob N, Witchel SF, Rohmer V, Dewailly D, Reichman DE, White PC,New MI&Rosenwaks Z.Fertilityin Gastaud F, Bouvattier C,Duranteau L,Brauner R,Thibaud E, Hagenfeldt K, Janson PO,Holmdahl G,Falhammar H,Filipsson H, Jaaskelainen J, Hippelainen M,Kiekara O&Voutilainen R. Child Strandqvist A, Falhammar H,Lichtenstein P, Hirschberg AL, Witchel SF. ManagementofCAHduringpregnancy:optimizing &Okopien B.Theeffectofsimvastatintreatmenton Krysiak R &Okopien B.Theeffectofmetforminonandrogen Krysiak R Escobar-Morreale HF, Carmina E,Dewailly D,Gambineri A, Spritzer P, Billaud L,Thalabard JC,Birman P, Mowszowicz I,Raux- Wiegratz I, Kutschera E,Lee JH,Moore C,Mellinger U,Winkler UH Williams RM, Deeb A,Ong KK,Bich W, Murgatroyd PR,Hughes IA 1383) Metabolism due to21-hydroxylasedeficiency. Fertility inwomenwithnonclassical congenitaladrenalhyperplasia Tardy V, Morel Y, Clauin S, Coussieu C, Boudou P, Mowzowicz I 3451–3456. hyperplasia. outcome ofwomenwith21-hydroxylase-deficientnonclassicadrenal Marcondes JA, Pugeat M,Speiser PW, Pignatelli D 2014 patients withcongenitaladrenalhyperplasia. (https://doi.org/10.1210/jc.2006-1757) ofClinicalEndocrinologyandMetabolism Journal in womenwithclassicalformsofcongenitaladrenalhyperplasia. Kutten F &Bougneres P. Impairedsexualandreproductiveoutcomes (https://doi.org/10.1093/humrep/den118) 21-hydroxylase deficiency. outcome inwomenwithcongenitaladrenalhyperplasiadueto Frisen L, Thoren M&Nordenskjold A.Fertilityandpregnancy Scandinavica classical 21-hydroxylasedeficiency. rate, pregnancyoutcomeandovarianfunctioninfemaleswith 2014 cohort inSweden. adrenal hyperplasia:epidemiologicalstudiesinanonbiasednational Suboptimal psychosocialoutcomesinpatientswithcongenital Wedell A, Norrby C,Nordenskjold A,Frisen L&Nordenstrom A. 19 outcomes. 121 hyperplasia. plasma steroidlevelsinfemaleswithnon-classiccongenitaladrenal 122 hyperplasia. production indiabeticwomenwithnon-classiccongenitaladrenal 18 SyndromeSociety.Polycystic Ovary hirsutism: aconsensusstatementbytheAndrogenExcessand Witchel SF Kelestimur F, Moghetti P, Pugeat M,Qiao J,Wijeyaratne CN, 642–646. hyperplasia. acetate versushydrocortisonetreatmentinlate-onsetadrenal Demay MC, Clair F, Kuttenn F&Mauvais-Jarvis P. Cyproterone 25–32. sex hormonesandserum-bindingglobulins. & Kuhl H.Effectoffourdifferentoralcontraceptivesonvarious j.1365-2265.2009.03587.x) Clinical Endocrinology with classicalandnonclassicalcongenitaladrenalhyperplasia. & Acerini CL.Insulinsensitivityandbodycompositioninchildren 146–170. 489–496. 643–646. 568–571. 101 99 (https://doi.org/10.1016/S0010-7824(02)00436-5) 1425–1432. 301–309. (https://doi.org/10.1210/jcem-70-3-642) Current OpinioninEndocrinology, DiabetesandObesity 2010 et al (https://doi.org/10.1210/jc.2006-0062) 2000 Journal ofClinicalEndocrinologyandMetabolism Journal Experimental andClinicalEndocrinologyDiabetes Experimental andClinicalEndocrinologyDiabetes ofClinicalEndocrinologyand Metabolism Journal (https://doi.org/10.1093/humupd/dmr042) (https://doi.org/10.1097/MED.0b013e32835a1a2e) (https://doi.org/10.1055/s-0033-1355383) (https://doi.org/10.1055/s-0034-1382048) . Epidemiology, diagnosisandmanagementof 95 79 Journal ofClinicalEndocrinologyandMetabolism Journal 1182–1190. (https://doi.org/10.1016/j.fertnstert.2013.11.002) 2010 (https://doi.org/10.1210/jc.2013-3326) 687–692. Human Reproduction 72 155–160. (https://doi.org/10.1210/jc.2009- Journal ofClinicalEndocrinologyand Journal Acta ObstetriciaetGynecologica Human Reproduction Update H Falhammar A Nordenströmand (https://doi.org/10.1111/ Contraception Fertility andSterility Fertility 2007 2008 et al 92 23 . Reproductive 1391–1396. 1607–1613. 2003 1990 2006 2012 2012 2014 2013 et al 67

70 91

.

120 119 118 117 113 112 111 110 109 108 116 115 114 NCAH Diagnosis andmanagementof Falhammar H, Nystrom HF&Thoren M. Qualityoflife,social Claahsen-van derGrinten HL,Otten BJ,Stikkelbroeck MM,Sweep FC Stikkelbroeck NM, Otten BJ,Pasic A,Jager GJ,Sweep CG,Noordam K Engels M, Gehrmann K,Falhammar H,Webb EA, Nordenstrom A, Jaaskelainen J, Kiekara O,Hippelainen M&Voutilainen R. Pituitary Krone N, Wachter I, Stefanidou M,Roscher AA&Schwarz HP. Eyal O, Ayalon-Dangur I, Segev-Becker A,Schachter-Davidov A, Pall M, Azziz R,Beires J&Pignatelli D.Thephenotypeof Stikkelbroeck NM, Hermus AR,Schouten D,Suliman HM,Jager GJ, Casteras A, DeSilva P, Rumsby G&Conway GS.Reassessing Falhammar H, Frisen L,Norrby C,Almqvist C,Hirschberg AL, Bouvattier C, Esterle L,Renoult-Pierre P, delaPerriere AB, Falhammar H, Nystrom HF, Ekstrom U,Granberg S,Wedell A & situation, andsexualsatisfaction,in adultmaleswithcongenital beem.2008.09.007) and Metabolism adrenal hyperplasia. & Hermus AR.Testicular adrenalresttumoursincongenital org/10.1210/jcem.86.12.8090) Endocrinology andMetabolism adult maleswithcongenitaladrenalhyperplasia. impaired spermatogenesis,andLeydigcellfailureinadolescent & Hermus AR.Highprevalenceoftesticularadrenalresttumors, 2018 congenital adrenalhyperplasia. Unruh A Rohayem J,Richter- Sweep FC, Span PN,vanHerwaarden AE, 102 2265.2001.01359.x) Endocrinology children: outcomeofpregnancy, birthandchildhood. Mothers withcongenitaladrenalhyperplasiaandtheir cen.13429) Clinical Endocrinology congenital adrenalhyperplasia:timetoconceiveandoutcome. Israel S &Weintrob N. Pregnancyinwomenwithnonclassic fertnstert.2009.06.025) andSterility Fertility and 21-hydroxylase-deficientnonclassicadrenalhyperplasia. syndrome hirsute women:acomparisonofpolycysticovary 14 results ofultrasonographyandMRimaging. polycystic ovariesinfemaleswithcongenitaladrenalhyperplasia: Braat DD &Otten BJ.Prevalenceofovarianadrenalresttumoursand 2265.2009.03563.x) Endocrinology (CAH): normalpregnancyratebutreducedfertilityrate. fecundity inwomenwithclassicalcongenitaladrenalhyperplasia Cohort Study. 21-hydroxylase deficiency:aSwedishpopulation-basedNational and increasedfrequencyofadoptedchildreninmaleswith Nordenskjold A &Nordenstrom A.Reducedfrequencyofbiological doi.org/10.1210/jc.2014-4124) Clinical EndocrinologyandMetabolism 21-hydroxylase deficiency. aFrenchnationalsurvey. axis, andtesticularfunctionin219adultmenbornwithclassic Galland F Illouz F, Kerlan V, Pascal-Vigneron V, Drui D,Christin-Maitre S, 0828) Endocrinology adult maleswithcongenitaladrenalhyperplasia. Thoren M. Fertility, sexualityandtesticularadrenalresttumorsin (https://doi.org/10.1007/BF03343671) deficiency. gonadal axisandchildrateinmaleswithclassical21-hydroxylase 1802–1806. 4191–4199. 178 et al 285–294. et al Journal ofEndocrinologicalInvestigation Journal 2001 2009 2012 . Gonadalfunctioninadultmalepatientswith . Clinicaloutcome,hormonalstatus,gonadotrope Journal ofClinicalEndocrinologyandMetabolism Journal 2009 (https://doi.org/10.1210/jc.2017-01139) 2010 55 70 166 (https://doi.org/10.1530/EJE-17-0862) Best PracticeandResearch: ClinicalEndocrinology 2017 23 523–529. 833–837. 441–449. 209–220. 94 Downloaded fromBioscientifica.com at10/01/202102:01:27PM 87 684–689. 2001 552–556. European Journal ofEndocrinology European Journal (https://doi.org/10.1046/j.1365- (https://doi.org/10.1111/j.1365- (https://doi.org/10.1530/EJE-11- (https://doi.org/10.1016/j. 86 2015 5721–5728. (https://doi.org/10.1016/j. (https://doi.org/10.1111/ 100 180 European Radiology 2303–2313. :3 2000 Journal ofClinical Journal of European Journal (https://doi. Journal of Journal Clinical 23 Clinical 23–27. (https:// R142 2017 2004 via freeaccess European Journal of Endocrinology 133 132 131 130 129 128 127 126 125 124 123 122 121 Review Helleday J, Siwers B,Ritzen EM&Carlstrom K. Subnormalandrogen Stikkelbroeck NM, Oyen WJ,vanderWilt GJ, Hermus AR&Otten BJ. Hagenfeldt K, MartinRitzen E,Ringertz H,Helleday J&Carlstrom K. Bouvattier C, Esterle L,Renoult-Pierre P, delaPerriere AB, Falhammar H, Claahsen-vanderGrinten H,Reisch N,Slowikowska- Koetz KR, Ventz M, Diederich S&Quinkler M.Bonemineral Ceccato F, Barbot M,Albiger N,Zilio M,DeToni P, Luisetto G, Mora S, Saggion F, Russo G,Weber G, Bellini A,Prinster C& Mnif MF, Kamoun M,Mnif F, Charfi N,Kallel N,BenNaceur B, Paganini C, Radetti G,Livieri C,Braga V, Migliavacca D&Adami S. Chakhtoura Z, Bachelot A,Samara-Boustani D,Ruiz JC,Donadille B, El-Maouche D, Collier S,Prasad M,Reynolds JC&Merke DP. Cortical Falhammar H, Filipsson H,Holmdahl G,Janson PO,Nordenskjold A, virilizing 21-hydroxylasedeficiency. and elevatedprogesteronelevelsin women treatedforcongenital (https://doi.org/10.1210/jc.2002-021074) ofClinicalEndocrinologyandMetabolism Journal mass, inyoungadultpatientswithcongenital adrenalhyperplasia. Normal bonemineraldensityandleanbodymass,butincreasedfat (https://doi.org/10.1530/eje.0.1430667) since infancy. virilizing 21-hydroxylasedeficiencyafterglucocorticoidtreatment Bone massandbodycompositionofadultwomenwithcongenital doi.org/10.1210/jc.2014-4124) Clinical EndocrinologyandMetabolism 21-hydroxylase deficiency. AFrenchnationalsurvey. axis andtesticularfunctionin219adultmenbornwithclassic Galland F Illouz F, Kerlan V, Pascal-Vigneron V, Drui D,Christin-Maitre S, Connections sex development(DSD):aEuropeanmulticenterstudy. Kohler B &dsdLg.Healthstatusin1040adultswithdisordersof Hilczer J, Nordenstrom A,Roehle R,Bouvattier C,Kreukels BPC, 2036) and Metabolism glucocorticoid replacementtherapy. density isnotsignificantlyreducedinadultpatientsonlow-dose org/10.1530/EJE-16-0104) ofEndocrinology European Journal congenital adrenalhyperplasiadueto21-hydroxylasedeficiency. term glucocorticoideffectonbonemineraldensityinpatientswith Zaninotto M, Greggio NA,Boscaro M,Scaroni C&Camozzi V. Long- org/10.1016/8756-3282(96)00003-8) adrenal hyperplasia. Chiumello G. Bonedensityinyoungpatientswithcongenital MAJ.0b013e31824369e4) deficiency. patients withcongenitaladrenalhyperplasiadueto21-hydroxylase Rekik N, Mnif Z,Sfar MH,Sfar MT org/10.1159/000053253) adrenal hyperplasia. Height, bonemineraldensityandmarkersincongenital org/10.1530/EJE-07-0887) ofEndocrinology European Journal bone mineraldensityinpatientswith21-hydroxylasedeficiency. Bouchard P Dulon J, Christin-Maitre S,Bouvattier C,Raux-Demay MC, 330–337. due to21-hydroxylasedeficiency. bone mineraldensityinpatientswithcongenitaladrenalhyperplasia org/10.1210/jc.2007-0744) Endocrinology andMetabolism adult womenwith21-hydroxylasedeficiency. Hagenfeldt K &Thoren M.Fracturesandbonemineraldensityin org/10.1007/s12020-013-0161-2) adrenal hyperplasia. (https://doi.org/10.1111/cen.12507) et al Am JMedSci 2018 et al European Journal ofEndocrinology European Journal . Clinicaloutcome,hormonalstatus,gonadotrope 2012 . Impactoftotalcumulativeglucocorticoiddoseon 7 466–478. Bone ResearchHormone Endocrine 97 2012 85–92. 1996 2007 (https://doi.org/10.1530/EC-18-0031) 344 2014 18 (https://doi.org/10.1210/jc.2011- 2016 2008 363–373. Clinical Endocrinology 337–340. et al 92 47 Journal ofClinicalEndocrinology Journal 2015 Journal ofClinicalEndocrinology Journal 4643–4649. H Falhammar A Nordenströmand 2000 175 158 . Long-termoutcomeof 299–307. 101–106. 879–887. 100 54 (https://doi.org/10.1097/ (https://doi. Journal ofClinical Journal 2000 2003 164–168. 2303–2313. (https://doi. (https://doi. 143 88 (https://doi. (https://doi. Journal of Journal 2015 1036–1042. Endocrine 667–671. (https://doi. (https:// 82

139 138 137 136 135 134 147 146 145 144 143 142 141 140 NCAH Diagnosis andmanagementof Nermoen I, Bronstad I,Fougner KJ,Svartberg J,Oksnes M, Marra AM, Improda N,Capalbo D,Salzano A,Arcopinto M, Zhang HJ, Yang J, Zhang MN,Liu CQ,Xu M,Li XJ,Yang SY &Li XY. Volkl TM, Simm D,Korner A,Rascher W, Kiess W, Kratzsch J Volkl TM, Simm D,Beier C&Dorr HG.Obesityamongchildren Cornean RE, Hindmarsh PC&Brook CG.Obesityin21-hydroxylase Falhammar H, Filipsson H,Holmdahl G, Janson PO,Nordenskjold A, Mooij CF, Pourier MS,Weijers G, de Korte CL,Fejzic Z,Claahsen- Rosenbaum D, Gallo A,Lethielleux G,Bruckert E,Levy BI, Frisen L, Nordenstrom A,Falhammar H,Filipsson H,Holmdahl G, Bachelot A, Plu-Bureau G,Thibaud E,Laborde K,Pinto G,Samara D, Halper A, Sanchez B,Hodges JS,Kelly AS,Dengel D,Nathan BM, Cameron FJ, Kaymakci B,Byrt EA,Ebeling PR,Warne GL &Wark JD. Gussinye M, Carrascosa A,Potau N,Enrubia M,Vicens-Calvet E, org/10.1210/jc.2014-1805) Endocrinology andMetabolism adolescents withcongenitaladrenalhyperplasia. Cardiovascular abnormalitiesandimpairedexercise performancein De Paulis A,Alessio M,Lenzi A,Isidori AM,Cittadini A 260–265. with simplevirilizing21-hydroxylasedeficiency. Metabolic disordersinnewlydiagnosedyoungadultfemalepatients 0770) Endocrinology hyperplasia dueto21-hydroxylasedeficiency? among childrenandadolescentswithclassicalcongenitaladrenal & Dorr HG.Doesanalteredleptinaxisplayaroleinobesity doi.org/10.1542/peds.2005-1005) 21-hydroxylase deficiency. and adolescentswithclassiccongenitaladrenalhyperplasiadueto (https://doi.org/10.1136/adc.78.3.261) deficient patients. jcem.76.4.8473408) and Metabolism Hagenfeldt K &Thoren M.Increased liverenzymesinadult org/10.1111/cen.13529) deficiency. patients withcongenitaladrenalhyperplasia dueto21hydroxylase van derGrinten HL&Kapusta L.Cardiac functioninpaediatric (https://doi.org/10.1097/HJH.0000000000001850) 21-hydroxylase deficiency. Early centralbloodpressureelevationinadultpatientswith Tanguy ML, Dulon J,Dahmoune N, Salem JE,Bittar R 3432–3439. deficiency. women withcongenitaladrenalhyperplasiaduetoCYP21A2 Gender rolebehavior, sexuality, andpsychosocialadaptationin Janson PO, Thoren M,Hagenfeldt K,Moller A&Nordenskjold A. (https://doi.org/10.1159/000098017) 21-hydroxylase deficiency. outcome ofpatientswithcongenitaladrenalhyperplasiadueto Nihoul-Fekete C, Kuttenn F, Polak M&Touraine P. Long-term Endocrinology composition inchildrenwithcongenitaladrenalhyperplasia. &Sarafoglou K.Bonemineraldensityandbody Petryk A 2238–2243. hyperplasia. Bone mineraldensityandbodycompositionincongenitaladrenal (https://doi.org/10.1542/peds.100.4.671) of congenitaladrenalhyperplasia. adolescent andyoungadultpatientswiththesalt-wastingform Ibanez L &Yeste D. Bonemineraldensityinprepubertaland org/10.1530/EJE-12-0196) ofEndocrinology European Journal patientswith21-hydroxylasedeficiency.features ofadultNorwegian Husebye ES &Lovas K.Genetic,anthropometricandmetabolic (https://doi.org/10.1007/s12020-010-9382-9) Clinical Endocrinology ofClinicalEndocrinologyandMetabolism Journal (https://doi.org/10.1210/jc.2009-0636) (https://doi.org/10.1210/jcem.80.7.7608286) Journal ofClinicalEndocrinologyandMetabolism Journal 2009 2018 1993 Archives ofDiseaseinChildhood 160 88 76 813–819. 239–247. 933–936. Downloaded fromBioscientifica.com at10/01/202102:01:27PM Pediatrics Journal ofHypertension Journal ResearchHormone 2015 2012 2018 (https://doi.org/10.1111/cen.13580) (https://doi.org/10.1530/EJE-08- (https://doi.org/10.1210/ Pediatrics 100 2006 https://eje.bioscientifica.com 167 88 644–652. 364–371. 117 507–516. 180 1997 2007 e98–e105. European Journal of European Journal :3 2019 Endocrine 1998 (https://doi. Journal ofClinical Journal 100 67 (https://doi. (https://doi. 268–276. 671–674. et al 37 78 et al (https:// 2009 175–181. 261–263. . 2010 1995 . R143 Clinical 94 38 80 via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com 160 159 158 157 156 155 154 153 152 151 150 149 148 Review Jaresch S, Kornely E,Kley HK&Schlaghecke R. Adrenal Nygren U, Nystrom HF, Falhammar H,Hagenfeldt K,Nordenskjold A Nygren U, Sodersten M,Falhammar H,Thoren M,Hagenfeldt K& Hertegard S,Sodersten M& Nygren U, Isberg B,Arver S, Porter J,Withe M,Jenkins-Jones S, Parviainen L, Whitaker MJ, Engberg H, Butwicka A,Nordenstrom A,Hirschberg AL, Falhammar H, Butwicka A,Landen M,Lichtenstein P, Jones TH. EffectsoftestosteroneonType 2diabetesandcomponents Livingstone C &Collison M.Sexsteroidsandinsulinresistance. Falhammar H, Frisen L,Hirschberg AL,Norrby C,Almqvist C, Bonfig W, Roehl FW, Riedl S,Dorr HG,Bettendorf M,Bramswig J, Ozdemir R, Korkmaz HA,Kucuk M,Karadeniz C,Mese T&Ozkan B. Mooij CF, Sweep F, vanHerwaarden AE, Roeleveld N,deKorte CL, congenital adrenalhyperplasia. incidentaloma andpatientswithhomozygous orheterozygous org/10.1111/cen.12226) deficiency. with congenitaladrenalhyperplasiadueto21-hydroxylase & Sodersten M.Voice problemsduetovirilizationinadultwomen 2265.2008.03347.x) Endocrinology adrenal hyperplasiadueto21-hydroxylasedeficiency. Nordenskjold A. Voice characteristicsinwomenwithcongenital (https://doi.org/10.1044/2016_JSLHR-S-14-0191) ofSpeech,Language,andHearingResearchJournal women withcongenitaladrenalhyperplasiaandvirilizedvoices. Nordenskjold A. Magneticresonanceimagingofthevocalfoldsin 2018 congenital adrenalhyperplasia. increased mortality, depressionandhealthcarecostsinpatientswith Holden SE, Morgan CL,Currie CJ&Ross RJM.Poorcomplianceand org/10.1016/j.psyneuen.2015.06.017) study. girls andwomenbornbetween19152010:atotalpopulation Congenital adrenalhyperplasiaandriskforpsychiatricdisordersin Falhammar H, Lichtenstein P, Nordenskjold A,Frisen L&Landen M. 3707) Metabolism 21-hydroxylase deficiency. morbidity inmenwithcongenitaladrenalhyperplasiadueto Nordenskjold A, Nordenstrom A&Frisen L.Increasedpsychiatric (https://doi.org/10.1111/j.1753-0407.2010.00085.x) of themetabolicsyndrome. cs1020151) Clinical Science org/10.1210/JC.2015-2093) Endocrinology andMetabolism Swedish population-basedNationalCohortStudy. metabolic morbidityinpatientswith21-hydroxylasedeficiency:a Nordenskjold A &Nordenstrom A.IncreasedCardiovascularand Hypertension (CAH) dueto21-hydroxylasedeficiency. cohort ofchildrenandadolescentswithclassicadrenalhyperplasia Schonau E, Riepe F, Hauffa B,Holl RW 2017 in childrenwith21-hydroxylasedeficiency. Assessment ofearlyatherosclerosisandleftventriculardysfunction org/10.1515/jpem-2017-0068) Endocrinology andMetabolism hyperplasia dueto21hydroxylasedeficiency. metabolic riskinpediatricpatientswithcongenitaladrenal Kapusta L &Claahsen-vanderGrinten HL.Cardiovascularand org/10.1507/endocrj.K08E-312) deficiency. women withcongenitaladrenalhyperplasiadueto21-hydroxylase 178 86 Psychoneuroendocrinology 473–479. 309–320. 2014 Endocrine Journal Clinical Endocrinology 2016 2009 2002 99 29 (https://doi.org/10.1111/cen.13275) 70 E554–E560. (https://doi.org/10.1530/EJE-17-0895) 102 266–272. 18–25. 151–166. Journal ofClinicalEndocrinologyand Journal 2009 Journal ofDiabetes Journal 2015 2017 (https://doi.org/10.1111/j.1365- 2015 (https://doi.org/10.1093/ajh/hpv087) Journal ofClinicalEndocrinology Journal ofEndocrinology European Journal 2013 (https://doi.org/10.1210/jc.2013- 56 100 30 (https://doi.org/10.1042/ 601–608. 60 957–966. H Falhammar A Nordenströmand 79 et al 3520–3528. 195–205. American Journal of American Journal 859–866. . Bloodpressureinalarge Clinical Endocrinology 2010 Journal ofPediatric Journal (https://doi. 2016 (https://doi. (https://doi. Journal ofClinical Journal (https://doi. (https://doi. 2 59 146–156. Clinical 713–721.

162 161 166 165 164 163 174 173 172 170 169 168 167 171 NCAH Diagnosis andmanagementof Nermoen I, Rorvik J, Holmedal SH,Hykkerud DL,Fougner KJ, Nermoen I, Rorvik J, Selye H &Stone H.Hormonallyinducedtransformationofadrenal Patocs A, Toth M, Barta C,Sasvari-Szekely M,Varga I, Szucs N, Falhammar H &Thoren M.An88-year-oldwomandiagnosedwith Patrova J, Kjellman M,Wahrenberg H &Falhammar H.Increased Reisch N, Scherr M,Flade L,Bidlingmaier M,Schwarz HP, Muller- Bachelot A, Vialon M, Baptiste A, Tejedor I, Elie C,Polak M& Daae E, Feragen KB,Nermoen I&Falhammar H. Psychological Rapp M, Mueller-Godeffroy E,Lee P, Roehle R,Kreukels BPC, Halper A, Hooke MC,Gonzalez-Bolanos MT, Vanderburg N, Tran TN, Bennecke E, Thyen U,Gruters A,Lux A&Kohler B.Health- Falhammar H &Torpy DJ. Congenitaladrenalhyperplasiadueto Patrova J, Jarocka I,Wahrenberg H &Falhammar H.Clinical Barzon L, Scaroni C,Sonino N,Fallo F, Gregianin M,Macri C& because of21-hydroxylasedeficiency. patientswithclassicalcongenitaladrenalhyperplasia Norwegian myelolipomas andtesticularadrenalresttumoursinadult Svartberg J, Husebye ES&Lovas K.Highfrequencyofadrenal into myeloidtissue. jcem.74.3.1311000) and Metabolism 449–453. or coincidence? adrenal tumorandcongenitalhyperplasia:connection 1400-8) Endocrine cortisol secretion:a13-yearretrospectivestudyfromonecenter. mortality inpatientswithadrenalincidentalomasandautonomous doi.org/10.1210/jc.2009-1929) of ClinicalEndocrinologyandMetabolism hormonal controlinpatientswith21-hydroxylasedeficiency. but nottesticularadrenalresttumorvolumeisassociatedwith Lisse U, Reincke M,Quinkler M&Beuschlein F. Total adrenalvolume 753–759. s12955-018-0881-3) and QualityofLifeOutcomes unilateral andbilateraladrenalincidentalomas. screening forsteroid21-hydroxylasedeficiencyinpatientswith Jakab C, Glaz E&Racz K.Hormonalevaluationandmutation health inmaleswithcongenitaladrenal hyperplasia:asystematic adjustment, qualityoflife,andself-perceptions ofreproductive specific referencepopulations(dsd-LIFE). compared tocountry of lifeinadultswithdisorders/differencessexdevelopment(DSD) Multicentre cross-sectionalclinicalevaluationstudyaboutquality Kohler B, Nordenstrom A,Bouvattier C,Thyen U&dsd-LIFEgroup. Outcomes with congenitaladrenalhyperplasia. Torkelson J &Sarafoglou K. Health-relatedqualityoflifeinchildren Connections congenital adrenalhyperplasiadiagnosedduringchildhood. Touraine P. Impactoftransitiononqualitylifeinpatientswith 86 differences/disorders ofsexdevelopment. related qualityoflifeandpsychologicalwell-beinginadultswith 736–752. a systematicreviewandmeta-analysis. 21-hydroxylase deficiencypresentingasadrenalincidentaloma: EP15618.OR) Endocrine Practice outcomes inadrenalincidentaloma:experiencefromonecenter. Metabolism and scintigraphiccorrelates. Boscaro M. Incidentallydiscoveredadrenaltumors:endocrine eje.0.1470349) of Endocrinology 634–643. 2017 2017 (https://doi.org/10.1007/BF03347226) (https://doi.org/10.1111/j.1365-2265.2011.04151.x) (https://doi.org/10.4158/EP151085.RA) 1998 2017 (https://doi.org/10.1111/cen.13296) 1992 15 58 2002 Journal ofEndocrinologicalInvestigation Journal 2015 83 6 194. 267–275. 422–429. 55–62. American Journal ofPathology American Journal 74 147 21 (https://doi.org/10.1186/s12955-017-0769-7) 685–689. 349–355. 870–877. Downloaded fromBioscientifica.com at10/01/202102:01:27PM 2018 (https://doi.org/10.1007/s12020-017- Journal ofClinicalEndocrinologyand Journal (https://doi.org/10.1530/EC-17-0094) 16 (https://doi.org/10.1210/ (https://doi.org/10.1530/ (https://doi.org/10.4158/ 54. Health andQualityofLife Clinical Endocrinology 2010 Endocrine Practice (https://doi.org/10.1186/ Clinical Endocrinology 180 95 :3 2065–2072. European Journal European Journal 1950 2005 26 2016 211–233. 2011 28 Endocrine Endocrine (https:// R144 Journal Journal 22

2017 Health

75 via freeaccess

European Journal of Endocrinology 176 175 Review Nordenstrom A, Frisen L,Falhammar H,Filipsson H,Holmdahl G, Nordenskjold A, Holmdahl G,Frisen L,Falhammar H,Filipsson H, 2010 patients’ perception. hyperplasia duetoCYP21A2deficiency:clinicalperspectiveandthe function andsurgicaloutcomeinwomenwithcongenitaladrenal Janson PO, Thoren M,Hagenfeldt K&Nordenskjold A.Sexual 2008 adrenal hyperplasia. procedure affectlong-termqualityoflifeforwomenwithcongenital Thoren M, Janson PO&Hagenfeldt K.Type ofmutationandsurgical 1723-0) review. 95 93 Endocrine 3633–3640. 380–386. 2018 (https://doi.org/10.1210/jc.2007-0556) Journal ofClinicalEndocrinologyand Metabolism Journal (https://doi.org/10.1210/jc.2009-2639) Journal ofClinicalEndocrinologyand Metabolism Journal 62 3–13. (https://doi.org/10.1007/s12020-018- H Falhammar A Nordenströmand

Accepted 17December2018 Revised versionreceived14November2018 Received 26August2018 178 177 NCAH Diagnosis andmanagementof Han TS, Krone N,Willis DS, Conway GS,Hahner S,Rees DA, Reisch N, Hahner S,Bleicken B,Flade L,PedrosaGil F, Loeffler M, org/10.1530/EJE-13-0128) ofEndocrinology European Journal Congenital adrenalHyperplasiaAdultStudyExecutive(CaHASE). treatment, adiposityandinsulinresistance:UnitedKingdom with congenitaladrenalhyperplasiarelatestoglucocorticoid Stimson RH, Walker BR, Arlt W&Ross RJ.Qualityoflifeinadults (https://doi.org/10.1111/j.1365-2265.2010.03920.x) adrenal insufficiency. because of21-hydroxylasedeficiencythaninpatientswithprimary of lifeislessimpairedinadultswithcongenitaladrenalhyperplasia Ventz M, Hinz A,Beuschlein F, Allolio B,Reincke M Clinical Endocrinology Downloaded fromBioscientifica.com at10/01/202102:01:27PM 2013 https://eje.bioscientifica.com 168 887–893. 2011 180 :3 74 166–173. et al (https://doi. . Quality R145 via freeaccess