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European Journal of 10.1530/EJE-17-0128 reach aspecificdiagnosisforbettercounselingandtreatment. their suggestedmechanismofdisease.Italsoadvocatesforadvancedgeneticwork-upPAI (especiallyinchildren)to for sphingosine-1-phosphatelyase1( syndrome combiningFGDwithsteroid-resistantnephroticandichthyosiscausedbymutationsinthe IMAGe syndrome( In addition,wholeexomesequencingapproachalsosolvedthegeneticsofsomesyndromicformsPAI including potentialandgenerationofNADPHimportantforsteroidogenesisROSdetoxicationhavebeendiscovered. transhydrogenase ( CYP11A1 ( with isolatedfamilialglucocorticoiddeficiency(FGD),inwhichnomutationsthegenesforACTHreceptor a complexformofcongenitaladrenalhyperplasiawithbroadclinicalphenotypehavecometothefore.Inpatients ofadrenalsteroidogenesis.CofactordisorderssuchasP450oxidoreductase( with theuseofnext-generationsequencingmethodsandnowhasreachedfarbeyondgeneticdefectsinallknown adults suffer moreoftenfromacquiredformsofPAI. Thespectrumof geneticdefectshasincreasedinrecentyears Primary adrenalinsufficiency (PAI) ispotentiallylifethreatening,but rare.Inchildren,geneticdefectsprevailwhereas Abstract Bern, Switzerland Departments ofPediatricsandClinicalResearch,BernUniversityChildren’s HospitalInselspital,UniversityofBern, Christa E Flück adrenal destruction deficiency andautoimmune insufficiency: beyondsteroid Update onpathogenesisofprimaryadrenal MECHANISMS INENDOCRINOLOGY MC2R DOI: 10.1530/EJE-17-0128 www.eje-www.eje-online.org Review using omicsapproaches. controlling humanandrogenproduction andnovelandrogenproducingpathways(e.g.thebackdoor pathway) mechanisms disorders ofsteroidogenesisand disorders ofsexdevelopment.Thegroupalsoinvestigatesregulatory yearsatthe UniversityofBernstudiespatientswithrare hormone biosynthesis.Herresearch groupof13 Hospital, Bern,Switzerland.Shestartedherresearch careerinthefieldofmolecular endocrinology ofsteroid Christa EFlück Invited Author’s profile ) oritsaccessoryproteinMRAPhavebeenfound,non-classicsteroidogenicacuteregulatory( online.org mutationshavebeendescribed;andmorerecentlynovelingenessuchasnicotinamidenucleotide

is Professor for Pediatric Endocrinology and Diabetology at the Bern University Children’s CDKN1C NNT ) andthioredoxinreductase2( ), Irishtravelersyndrome( © 2017EuropeanSociety ofEndocrinology © 2017EuropeanSociety ofEndocrinology C EFlück SGPL1 Printed inGreatBritain ). ThisreviewintendsdogiveanupdateonnovelgeneticformsofPAI and MCM4 TRXR2 ), MIRAGEsyndrome( ) involvedinthemaintenanceofmitochondrial Update primary Published byBioscientifica Ltd. SAMD9 POR Downloaded fromBioscientifica.com at09/29/202105:35:30PM ); andmostrecentlya ) deficiencymanifestingas [email protected] Email to CEFlück should beaddressed Correspondence (2017) Endocrinology European Journal of 177 177 : 3 177 :3 , R99–R111

StAR R99 –R111 ) and via freeaccess European Journal of Endocrinology by RAA. Thus, diagnosis of PAI typically includes elevated production thatwillnotaffectMCregulated is causedbycentraldefectsleadingtoinsufficientACTH AI renin–angiotensin– loop (RAA),secondary (HPA) –pituitary-axis regulatory andthe of theadrenalsandleadstofeedbackstimulation In contrast to PAI wherethe problem occurs at thelevel (GC) and/ormineralocorticoids(MC)intheadrenals. defined asinabilitytoproducesufficientglucocorticoids acquired forms are more prevalent in adults. PAI is PAI ismostlyduetogeneticdefectsinchildren,whereas ( adrenal hyperplasia(CAH)sufferingfrom21-hydroxylase disorder havebeenreportedinpatientswithcongenital yearsagofirstgene mutationsunderlying the only 30 years ago ( by Addison more than 150 manifest at birth orlater in life.PAI was first described isolated formoraspartofasyndromicspectrumandmay or inheritedgeneticdefects( AIisalsoavailable( of secondary ( of PAI havejustbeenpublishedbytheEndocrineSociety .Guidelinesforthediagnosisandtreatment quality oflifeandincreasestheriskforlife-threatening diagnosis ofPAI isassociatedwithlowerhealth-related to thriveanddepressionarecharacteristic.Delayed and other non-specific symptomssuch as fatigue, failure and themucousmembranes;besidesthatsaltcraving peptides, whichleadtohyperpigmentationoftheskin production ofACTHandotherpro-opiomelanocortin and adults,butcanhavefatalconsequences( adrenalinsufficiency(PAI)Primary israreinchildren Introduction www.eje-online.org CYP21A2 3 ), andanexpertreviewondiagnosismanagement Review Both PAI AImaybecausedbysporadic andsecondary ) deficiency, whichistodatethemostcommon 2 C EFlück 4 ). Theybothoccurin ). 5 ). However, 1 , 2 , 3 ). causing genesusingagenetargetedapproach.Infact,over experiments ofnaturetofindandcharacterizenewdisease patients harboringsteroiddisordershavebeenexcellent solved beforetheinvolvedgenesbecameknown( ( classic, late-onset CAH with less severe enzyme inhibition inhibition ofthe21-hydroxylaseenzymeactivity, ornon- salt-wasting orsimplevirilizingCAHwithlosssevere CYP21A2 numerous diseasecausingsequencevariationsinthe soon afterthebirthandwasalsofoundtohave46,XY phenotypically femalebabywasdiagnosedwithPAI harboring animals ( sex reversalinmaleandPAI inbothmaleandfemale of adrenalglandsandgonadsmanifestingascomplete in .Disruption of knockout mousemodelof involvedinadrenaldevelopment( steroidogenesis, butalsorevealedgeneticmutationsin not onlyrevealdefectsingenesinvolvedadrenal were described( of thesteroidbiosyntheticpathwaysadrenalcortex mutationsinalmostallgenesencodingenzymes the yearsandwithgenomeprojectcompletedin2000 complex on 6 in 1985 ( and pseudogeneof 613815, twogroupsofinvestigatorsidentifiedthegene both GCandMCproduction.AccordingtoOMIM This enzyme and thus its gene is essential for inherited formofPAI (about1:10 adrenal insufficiency Update primary 2 , 8 As the biochemistry ofadrenalsteroidogenesiswas As thebiochemistry However, genetic work-up of patient with PAI did , 9 , 10 genehavebeenreported,whichcauseclassic 11 ). NR5A1/SF1 ). Soon afterwards thefirsthumanbeing ). Soonafterwards Table 1 2 (PAPSS2). adenosine-5 SULT2A1 by3 shows cofactorsupportofsulfonyl labeled withayellowstar;the orangestar partner P450oxidoreductase(POR)are Enzymatic reactionssupportedbyredox converting enzymesaredepicted. shown. Metabolitesandinvolvedsteroid andadrenalandrogensis of cholesterolintomineralocorticoids, adult adrenalcortex.Step-wiseconversion Pathway ofsteroidogenesisthehuman Figure 1 CYP21 genemutationswasreported.A ) ( Downloaded fromBioscientifica.com at09/29/202105:35:30PM 2 withintheMHCclassIIIgene , ftz-f1/sf1 ftz-f1/sf1 10 ′ ). -phosphosulfate synthase pioneeredthefinding resulted in agenesis 500 inSwitzerland). 177 6 :3 , ′ -phospho- 7 ). Meanwhile 1 ). Herethe Fig. 1 R100 via freeaccess ), European Journal of Endocrinology have beenidentifiedin several,mostlymultiorgan mitochondrial metabolism and of synthesis ( X-linked peroxisomaldefect causedby neurological deficits seenwith , an cardia andneurologicdeficitsthataresimilartothe FGD typewithalacrima,achalasiaoftheesophageal Allgrove orthetripleAsyndromecombinesPAI ofthe of mitoticspindlesandchromosomealignment( steroidogenesis ( 20 ofthe to thediscovery with PAI inthecontextofAllgrovesyndromeled linkage disequilibriumanalysisoftwocohortsfamilies obvious and thus only revealed by fine-mapping based on mimics thephenotypeoflossMC2Rfunction( which enablesMC2Rtargetingandfunctionthus inthegenefor MRAP, , anaccessory of FGDpatientsnotharboringMC2Rmutationsrevealed well astissuegrowthandmaintenance.Furtherstudies stimulation toadrenalGCandandrogenproductionas expressed in theadrenal cortex that transmits ACTH a Gprotein-coupledreceptorwhichisalmostexclusively ( revealed mutationsintheACTHreceptorgene isolated glucocorticoiddeficiency(FGD)/ACTHresistance due to due to a syndromecomplex,e.g.inthePallister–Hall described withmutationsinseveralothergenesaspartof ( hypogonadotropicaswellprimary and secondary phenotype ofisolated deficiency ( ( together withtheDuchennemusculardystrophygene duplicated, ormaybepartofacontiguousgenesyndrome and maycausedosage-sensitive46,XYsexreversalwhen factor SF1( mutations in (AHC) inchildhoodhavebeenfoundtoharbormostly individuals diagnosed with adrenal hypoplasia congenita finding inpatientswith However, interestingly PAI has been found to be a rare and reproduction that still remains unexplained ( range ofphenotypeswithrespecttosexualdevelopment reported inmanyindividualspresentingwithabroad ( sex reversalduetoaheterozygote DMD 12 23 15 Review ). Aladinseemstoimpairredoxhomeostasisandthus ). Additional mutations in genes of peroxisomal and , ). Meanwhilenumerous Similarly, genetic work-up of patients with familial 16 ; OMIM300679)andthegeneforglycerolkinase DOK7 ), anobviouscandidateforcausingPAI. MC2Ris GLI3 14 GKD mutationsorinthePena–Shokeirsyndrome and/or NR0B1/DAX1 ). DAX1islocatedontheXchromosome ; OMIM307030).However, thetypical 14 21 ). Adrenaldysgenesishasalsobeen ) andisinvolvedintheformation RAPSN aladin DAX1 , acoregulatoroftranscription mutations( SF1 SF1 gene/ mutations.Bycontrast, genemutationsisPAI C EFlück mutationshavebeen NR5A1/SF1 AAAS ABCD1 Table 1 gene( mutations ). 17 18 MC2R ). Less , 13 22 19 ). ). ,

Disorders oftheadrenalcortexhavelatelybeenreviewed mutations in genes thus far unexpected to play a role. forms ofinbornerrorsadrenalGCproductiondueto and molecularmedicinehavestillrevealedseveralnew had beenfoundtocausePAI, recentadvancesingenetics of complexinheritance( contrast, isolatedPAI andAPS-2sharethesamepattern and chronicmucocutaneouscandidiasis( 1, whichtypicallycombinesPAI withhypoparathyroidism gene especially inadults( polyglandular syndromes(APS)havebeendescribed combination withdifferenttypesofautoimmune mediated PAI eitherasisolatedadrenalitisorin (mitDNA del)). Zellweger syndrome( disorders/syndromes includingtheadrenals(e.g. patients ( in P450oxidoreductase( may lieinacofactor( ( (CYP21A2) and17-hydroxylase (CYP17A1)deficiency with abiochemicalprofileofcombined21-hydroxylase remained still unsolved. Some of these patients presented with acomplexprofileofdisturbedsteroidogenesis the adrenalcortex( defects inallenzymesinvolvedsteroidogenesis of deficiency CAH. After having found underlying genetic , butittypicallyelevatedwith21-hydroxylase converted to 11-deoxycortisol by CYP21A2 to finally yield e.g. intermediate17-hydroxyprogesterone(17OHProg) is produce aldosterone,cortisolandandrogens( again as substrates for specific enzymes to finally serve step-wise conversionofcholesteroltointermediatesthat In principal,adrenalsteroidhormonesareproducedby From enzymetocofactordeficiencies will appearonthescenebeforelong. claim tobecompleteandsureenough additional genes complex inthepost-genomicera.Theselectiondoesnot PAI illustrating that the spectrum has become even more their pathomechanismandcharacteristicsofdiseasefor discovered, atfirstglanceunsuspectedgeneticdefectsand Table 1 chapters, e.g.( in journalarticles(fore.g. adrenal insufficiency Update primary 31 ). It was therefore rightly hypothesized that the defect Although sofarnumerousmutationsinmanygenes Finally, geneticdefectscausingautoimmune- . Thisarticleintendstogiveanupdateonrecently 33 , 34 ). 2 , 30 al 1 Table ), andarebrieflysummarizedin PEX1 24 32 Downloaded fromBioscientifica.com at09/29/202105:35:30PM 24 ) ( ). Years latergeneticmutations ). POR ) orKearns–Sayresyndrome ), somepatientsmanifesting al 1 Table AIRE 2 , ) werefoundinthese 3 are responsible forAPS- , 27 ). Mutationsinthe 177 , 28 www.eje-online.org :3 , 29 25 ), andbook , 26 i. 1 Fig. R101 ). By via freeaccess ); European Journal of Endocrinology www.eje-online.org ACTH resistance/FGD Adrenal dysgenesis 11 Defects ofsteroidbiosynthesis Disorder Table 1 FGC –deficiencyofmitochondrialROS 3 AAA syndrome–tripleA(Allgrovesyndrome) FGD –DNArepairdefect Familial glucocorticoiddeficiency(FGD) Galloway–Mowat syndrome Pseudotrisomy 13 Pena–Shokeir syndrome Meckel syndrome Pallister–Hall syndrome MIRAGE syndrome IMAGe syndrome Steroidogenic factor1deficiency X-linked adrenalhypoplasiacongenita(AHC) Apparent cortisonereductasedeficiency Cortisone reductasedeficiency Aldosterone synthasedeficiency P450 oxidoreductasedeficiency(CAH) 17-Hydroxylase deficiency(CAH) 21-Hydroxylase deficiency(CAH) P450 sidechaincleavagesyndrome Congenital lipoidadrenalhyperplasia(CLAH) Review detoxification β (CAH) -Hydroxysteroid dehydrogenasedeficiency β -Hydroxylase deficiency(CAH) Genetic causesofprimaryadrenalinsufficiency. C EFlück PRDX3 GPX1 TXNRD2 NNT AAAS MCM4 MRAP MC2R WDR73 HYLS1 DOK7 MKS1 GLI3 SAMD9 CDKN1C NR5A1 (SF1) NROB1 (DAX1) H6PDH HSD11B1 CYP11B2 POR CYP17A1 CYP11B1 CYP21A2 HSD3B2 CYP11A1 StAR Gene , RAPSN adrenal insufficiency Update primary 184757 300200 604931 614662 124080 613571 202110 202010 201910 201810 118485 606448 614736 231550 609981 607398 202200 251300 236680 264480 208150 249000 165240 617053 300290 201710 OMIM

46,XY DSD,gonadalinsufficiency Hypogonadotropic hypogonadism,insome Androgen excesssyndrome Androgen excesssyndrome Isolated mineralocorticoiddeficiency 46,XY DSD,46,XXgonadalinsufficiency, 46,XY DSD,hypertension,gonadal 46,XX DSD,hypertension,androgenexcess 46,XX DSD,androgenexcesssyndrome, 46,XY DSDand46,XXDSD,gonadal 46,XY DSD,gonadalinsufficiency 46,XY DSD,gonadalinsufficiency Associated clinicalfeatures inadditiontoPAI Only glucocorticoiddeficiency Only glucocorticoiddeficiency Only glucocorticoiddeficiency Only glucocorticoiddeficiency Alacrimia, achalasia,deafness,mental NK celldeficiency, shortstature, Mostly normalproductionof Nephrotic syndrome,microcephaly, Hydrocephaly, micrognathia, Holoprosencephaly, polydactyly, craniofacial Arthrogryposis, facialanomalies,IUGR, Cystic renaldisease,CNSmalformation– Hypothalamic hamartomas,mesoaxialand Myelodysplasia, ,restrictionof IUGR, bonedisordersandanomalies,genital precocious puberty cases gonadotropinindependent syndrome; changesindrugmetabolism Antley–Bixler skeletalmalformation insufficiency syndrome testicular adrenalresttumors insufficiency retardation, hyperkeratosis chromosomal breakage microcephaly, recurrentviralinfections, , tallstature encephalopathy, hiatushernia defects, respiratoryorgandefects abnormal genitalia,congenitalheart anomalies cardial defects,intestinalmalrotation polyhydramnion, pulmonaryhypoplasia, camptodactyly, fetalakinesia, hepatic abnormalities occipital encephalocele,polydactyly, imperforate anus,genitourinaryanomalies postaxial polydactyly, bifidepiglottis, growth, genitalanomalies,enteropathy facial features anomalies, hypercalcemia,dysmorphic Downloaded fromBioscientifica.com at09/29/202105:35:30PM 177 :3 (Continued) R102 via freeaccess European Journal of Endocrinology Autoimmune disorders Metabolic disorders:lysosomal Metabolic disorders:mitochondrialdefect Metabolic disorders:peroxisomaldefects Abeta-lipoproteinemia Cholesterol synthesisdisorders Disorder Table 1

Autoimmune polyglandularsyndrome (APS), Autoimmune polyglandularsyndrome(APS), Autoimmune polyglandularsyndrome(APS), Review Isolated autoimmuneadrenalitis Sphingosine-1-phosphate lyase1deficiency Kearns–Sayre syndrome Infantil Refsumdisease Neonatal adrenoleukodystrophy X-linked adrenoleukodystrophy Sitosterolemia (phytosterolemia) Familial hypercholesterolemia Smith-Lemli Opitzdisease Wolman disease Zellweger syndrome type 4 type 2 type 1(APECED) Continued. C EFlück

SPGL1 mitDNA del PHYH PEX1 ABCD2 ABCD1 ABCG8 ABCG5 LDLR MTP DHCR7 LIPA Gene CLTA-4 CLTA-4 AIRE CLTA-4 PEX1 HLA-DR4 HLA-DR4 HLA-B8 HLA-DR4 PEX andother genes , , , , PEX7 HLA-DR3 HLA-DR3 HLA-DR3 , adrenal insufficiency Update primary

, , , 300371 300100 210250 143890 200100 270400 278000 269200 240300 603723 530000 214100 266500 601539 601081 OMIM

Progressive neurodegeneration,dementia, Short stature,gonadalfailure,xanthomas, Xanthomas, cornealarcus,andcoronary Ataxia, retinopathy, acanthocytosis, Multiple congenitalmalformationand Xanthomatous changesintheliver, adrenal, Associated clinicalfeatures inadditiontoPAI Combination ofautoimmunediseases not Autoimmune thyroiddiseases,T1DM, Hypoparathyroidism, candidiasis, Steroid-resistant nephroticsyndrome, Progressive externalophthalmoplegia, Severe neurologicdysfunctionwith Hypotonia, seizures,diffuse encephalopathy, Anosmia, retinitispigmentosa,neuropathy, accumulation ofverylong-chainfattyacids and hearingloss,spasticityseizures; progressive behavioraldisturbances,vision arthritis, coronaryheartdisease artery disease pathologic fatabsorption mental retardationsyndrome steatorrhea poor weightgain,hypercholesterolemia, adrenal calcification,hepatosplenomegaly, intestine andthymus,diffuse punctate spleen, lymphnodes,bonemarrow, small included inpreviousgroups anemia, celiacdisease premature ovarianfailure,pernicious hepatitis, perniciousanemia, diseases alopecia,chronicautoimmune hypogonadism, autoimmunethyroid autoimmune hypergonadotropic immunodeficiency andneurologicaldefects primary ,cryptorchidism, optionally accompaniedbyichthyosis, pathologies block, cerebellarataxia;otherendocrine pigmented retinopathy, cardiacconduction genitourinary anomalies growth failure,stippledepiphysis, severe mentalretardation,hepatomegaly, handicaps, craniofacialabnormalities, autosomal recessive neuropathy, mildfacialdysmorphism; sensorineural hearingloss,peripheral deafness, ataxia,ichthyosis Downloaded fromBioscientifica.com at09/29/202105:35:30PM 177 www.eje-online.org :3 R103 via freeaccess European Journal of Endocrinology www.eje-online.org have beenfoundtoinhibit someenzymeactivities, all reactionsseverely. Bycontrast,somePORmutations disrupt theelectrontransfer fromFAD toFMNwillaffect function tovariabledegrees. Generally, mutationsthat In addition,differentPORmutations assuchaffectPOR will affectdifferentenzymereactionstovariabledegrees. directly, butratherdisturbtheprotein–protein interaction the electrontransferchainfromFMNtoFAD withinPOR specifically. Therefore,PORmutationsthat donotdisrupt POR proteinseemstointeractwithallitsredoxpartners cytochrome b5,sterolreductaseandmanyothers.The desaturase andelongase,squalene-, also supplies electrons to , fatty acid drug andxenobioticsmetabolism( and cholesterolbiosynthesismetabolismaswell as human P450s,itsimpactmaybevastandincludessteroid As PORistheessentialelectrondonortomorethan50 difficult,butcanbeexplainedbyseveralreasons. very 35 just presentingwithamildPCOS-likephenotype( genital anomaliesandPAI toalmostbeingnormaland and presenting with an Antley–Bixler syndrome with broad phenotype ranging from severely being affected gonadal steroidogenesis ( CYP21A2, CYP17A1andCYP19A1ofadrenal NADPH toallmicrosomaltypeIIP450enzymesincluding low. 17OHP, 17-hydroxyprogesterone;11DOC,11-deoxycortisol;SULT2A1, sulfotransferasefamily2Amember1. sulfate DHEAS.LackofPAPSS2 activityresultsinincreasedDHEAanddownstreamandrostendionelevels,whileDHEASisvery synthesizes PAPS throughitsATP sulfurylaseandAPSkinaseactivitiesforsulfationofdehydroepiandrosterone(DHEA)toits cortisone inmultipletissues.(C)3 11 (B) Hexose-6-phosphate-dehydrogenase (H6PDH)deficiency. InH6PDHDregenerationofNADPHbyH6PDHtosupport steroidogenesis throughPORisinhibitedordisrupted.Thismayaffect adrenalglucocorticoidandandrogenproduction. (PORD). InPORDelectrontransferfromNADPHtodependingP450redoxpartnerssuchasCYP17A1andCYP21A2ofadrenal Schemes ofcofactordisordersaffecting humansteroidbiosynthesisandmetabolism.(A)P450oxidoreductase(POR)deficiency Figure 2 Review β ). Thisbroadphenotypemakestheclinicaldiagnosis -hydroxysteroid dehydrogenasetype1(HSD11B1)activityisdisrupted.Thisleadstoreducedregenerationofcortisolfrom POR is the obligateelectron transfer partner from Fig. 2A ′ -Phospho-adenosine-5 ). It manifests with a very ). It manifests with a very C EFlück 35 ). Intheory, POR ′ -phosphosulfate (PAPS) synthase2(PAPSS2) deficiency. PAPSS2 34 , as apparentcortisonereductase deficiency( mutations. Thiscofactordisorder isthereforealsoknown of hexose-6-phosphate dehydrogenase ( generated depends onahighNADPH/NADP+ratio,which is pseudopuberty ( presenting with hyperandrogenism and premature of HSD11B1havebeendescribedintwounrelatedboys adrenal disorder non-classic, late-onsetCAH,althoughitisnotaprimary the HPA axis.Thisdisorderhasthusasimilarphenotypeas androgen productionduetonegativefeedbackcontrolvia reductase deficiency, andresultsinexcess adrenal to relativecortisoldeficiency, alsoknownascortisone peripheral tissues ( which regeneratescortisolfromcortisoneinmultiple 11 the underlyingcausefordeficientenzymeactivityof as 21-hydroxylaseactivityismostlynotcompletelylost. severewithPORdeficiency insufficiency isoftennotvery partners’ functionremaintobeelucidated.Adrenal well asboneformation,whereaseffectsonotherredox and gonadalsteroidogenesisdrugmetabolismas human whereas theydonotaffectorstimulateothers( adrenal insufficiency Update primary β H6PD -hydroxysteroid dehydrogenasetype1( Similarly, acofactordisorderhasbeendescribedas POR mimic the same clinical picture as in vivo mutationshavebeenshowntoaffectadrenal 37 per se throughtheactivityofmicrosomal ). However, becauseHSD11B1activity i. 2B Fig. . Sofar, heterozygote mutations Downloaded fromBioscientifica.com at09/29/202105:35:30PM ) ( 36 ). Lack of HSD11B1 leads 177 H6PD :3 Fig. 2B ), mutations HSD11B1 35 HSD11B1 ). Sofar, R104 ) ( 36 via freeaccess ). ),

European Journal of Endocrinology were found( which nomutationsin phenotype offamilialglucocorticoid deficiency(FGD),in genetic work-upofindividuals presentingwitha adrenal steroidogenesiscame morerecentlybyadvanced important roleofthecellularredoxhomeostasisfor been illustratedbyH6PDHdeficiency. Evidence forthe the regenerationofcortisolinperipheraltissueshas That awell-balancedredoxpotentialisimportantfor balanceofthecell PAI caused bydisruptingtheoxidative manifests similarly. adrenalproblem,but Also, thisdisorderisnotaprimary fatigue, androgen excess and arterial hypertension. no stigmataofCushing’s, andtheypresentwithchronic inappropriately highserumACTHandcortisollevels,but to cortisolstimulation( in whichtheglucocorticoidreceptordoesnotrespond receptorgene( resistance (OMIM615962)duetomutationsinthe GC deficiencyisalsoseenwithfamilialglucocorticoid androgen excess. to considerinthedifferentialdiagnosisofadrenal may notqualifyforadisorderofPAI, butitisdefinitively production isnormalwithPAPSS2 deficiency. Therefore,it PCOS canhintfor axillarchy inchildrenand aprofileforhyperandrogenic when searched for. Prematureadrenarche, pubarche, lowDHEAS)mayonlybefound elevated DHEAandvery phenotype ofPAPSS2 deficiency(androgenexcessdueto spondyloepimetaphyseal dysplasia( individuals withdisproportionateshortstaturedueto human mutations of formation andtherebybonedevelopmentgrowth, a keytoproteoglycanandthusextracellularmatrix andAPSkinase( sulfurylase of PAPS requiresPAPS synthaseactivities,bothATP is the most abundant steroid in circulation. Generation converts adrenalDHEAtoitssulfateesterDHEASthat human sulfotransferases including SULT2A1, which 612847) ( 5 human mutationsinthecofactor3 homeostasis forcortisolmetabolism. H6PD mutationsillustratetheimportanceofredox ′ -phosphosulfate (PAPS) synthase2( Review A phenotypeofandrogenexcess,butapparent Androgen excessisalsoapossiblephenotypefor 38 ). PAPS istheessentialsulfatedonortoall 27 ). Next-generationsequencing (NGS) PAPSS2 PAPSS2 MC2R 40 mutations.However, cortisol , have been observed first in have been observed , 41 i. 2C Fig. NR3C1 MRAP C EFlück ). Thesepatientshave ′ -phospho-adenosine- 39 orthe , OMIM138040), ). Assulfationis ). Thehormonal PAPSS2 AAAS , OMIM genes forming a1:1complex.Thencferrodoxindissociates then transfers them to the /sulfur protein ferrodoxin located attheinnermitochondrialmembrane,which are acceptedbytheflavoproteinferrodoxinreductase ( supported bythecofactorsystemferrodoxinreductase aldosterone and 11-deoxycortisol to cortisolrespectively, cholesterol topregnenolone,11-deoxycorticosterone CYP11B2/1 dependonNADPHfortheconversionof mitochondria, steroidogenicenzymesCYP11A1and the mitochondrial proton gradient ( for thegenerationofNADPHusingenergyfrom in theinnermitochondrialmembraneandisresponsible accounts forapproximately10%ofFGD.NNTislocated first described in 2012 ( nicotinamide nucleotide transhydrogenase ( a phenotypeofPAI andFGD( revealed mutations in genes so far not suspected to cause of thethioredoxinsystemhave beendescribedinthree ( mutations inothercomponents ofthissystemwerefound Thus, itwasonlyamatter ofshorttimethatgenetic homeostasis ofROSlead to defectivesteroidogenesis. as NNT, which affects NADPH production and the cellular therefore nolongerastonishingthatgeneticdefectssuch initiation ofsteroidhormonebiosynthesis.Overall,it is transporting cholesterolintothemitochondriafor to suppressStARproteinsynthesisthatisessentialfor protein(StAR)( regulatory through negativefeedbacktothesteroidogenicacute production, whereasROSmayinhibitsteroidogenesis high mitochondrial metabolic activity that feeds ROS NADPH. In the , steroidogenesis requires systems andtheirassociatedproteins,whichbothrequire namely theglutathioneperoxidaseorperoxiredoxin superoxides may be detoxified by twoantioxidant systems, mitochondria byelectronleakage.However, produced electron transport chain in the I and III of the respiratory apoptosis ( reactions aswellcellproliferation,differentiationand cellular functionsincludingstressresponse,immune species (ROS).ROSlevelsplayacriticalroleinmany maintaining the right cellular balance of reactive importantin role insteroidogenesis, but arealsovery However, NNTandNADPHdonotonlyplayadirect human mutationsin this electronshuttleseemsratherinefficient. To date,no mitochondrial P450(e.g.CYP11A1,CYP11B1/2).Overall, with theelectronloadtoformanextcomplex adrenal insufficiency Update primary FDXR Fig. 3 FGD duetohumanmutationsinthegenefor ). Recently, human mutationsinthe )/ferrodoxin ( 44 , 45 ). ROS are mainly produced at complex FDX1 FDXR Downloaded fromBioscientifica.com at09/29/202105:35:30PM ) ( 42 10 or 46 ) ( , Fig. 3 43 FDX ). ROShasbeenshown al 1 Table ). ElectronsfromNADPH ). havebeendescribed. 177 www.eje-online.org :3 ). It meanwhile i. 3 Fig. TXNRD2 NNT ). In the R105 ) was gene via freeaccess European Journal of Endocrinology www.eje-online.org CDKN1C, cyclin-dependent kinaseinhibitor1C(IMAGesyndrome). alacrimia (tripleA)syndromegene;MCM4,minichromosome maintenancecomplexcomponent4(Irishtravelerdisease); domain-containing protein9(MIRAGEsyndrome);SGPL1,sphingosine-1-phosphate lyase1;AAAS,achalasia-addisonianism- MRAP, melanocortin receptoraccessoryprotein;StAR,steroidogenicacuteregulatorySMAD9,sterilealphamotif serves asprotonpumpforgeneratingNADPH.SOD,superoxidedismutase.ACTH/MC2R,melanocortinreceptor2; both thethioredoxin(PRDX3)andglutathione(GPX)systemsbyelectrons.Nicotinamidenucleotidetranshydrogenase (NNT) particular, themitochondrialsystemforNADPHandROSproductiondetoxificationisshowninmoredetails.supports perspective oftheircellularlocalization.To illustratetheimportanceofredoxbalanceforcellandsteroidogenesisin defects (abbreviatedgenenamesgiveninredanditalic)underlyingisolatedsyndromicformsofFGDputsthem into Spectrum ofgeneticdisordersassociatedwithfamilialglucocorticoiddeficiency(FGD).Thefiguresummarizestheknown genetic Figure 3 exact pathophysiologylinking thedefectivenuclearpore have bothbeenlinkedtooxidative stress.However, the A syndrome and X-linked adrenoleukodystrophy (ALD) patients ( PRDX3 without anydoubt.Combinedmutationsin of themitochondrialantioxidantsystemwillfollow ( related patientsmanifestingatdifferentageswithFGD 47 Review Matri space Int ) ( Of note, PAI in syndromic disorders such as triple er Mit Table 1 -membrane x SOD have already been identified in the cohort of FGD ochondr 2H 48 H O Electr 2 2 O +½ +H + ). +O ). Geneticmutationsinfurthercomponents on chain H H 2 O ion Tr + + 2 - anspor 2 2 GPX PRDX3 t + GSH GLRX2 TXN2 UCP2 H H C EFlück + + ADP+ P GSR s ynthase AT GSH 1 H P + TXNRD2 AT ANT GPX1 P ADP GSR NADH C StAR NADP YP1 and NNT NADPH H H 1A1 PRDX3 GPX1 TXNRD2 NNT + + + NAD in thisjournalbythegroupofLouMetherell( adrenocortical insufficiencyhasbeenrecentlypublished unclear. Anextensivereviewonoxidative stressand of VLCFAs inALDtoenhancedROSgenerationremains protein complexinAAASandtheabnormalaccumulation of intrauterinegrowthrestriction, metaphysealdysplasia, IMAGe syndromewasfirstdefined in1999bythespectrum Novel syndromic formsofPAI adrenal insufficiency Update primary + Membrane Cy to A CTH/MC2R sol Downloaded fromBioscientifica.com at09/29/202105:35:30PM MRAP CDKN1C MCM4 AAAS GDP α Cell Membr 177 β γ :3 Nuc sub G-pr leus 45 units ane SMAD9 ot ). SGPL1 ein R106 ER via freeaccess European Journal of Endocrinology concurrently theunderlying geneticdefectinthegenefor cohorts withFGDorSRNSrespectively, twogroupsfound and neurological anomalies. Using NGS on patient hypothyroidism, cryptorchidism, immunodeficiency PAI, optionallyaccompaniedbyichthyosis, primary of steroid-resistantnephroticsyndrome(SRNS)and identified inpatientswithasyndromecomprising and thymus. dysgenetic andhypoplasticadrenalglands,ovaries thereby leadtoabnormaltissuedevelopmentincluding to enhanceitsintrinsicendosome-fusingactivityandmay transduction. Thus,heterozygote and isreported to playa role ingrowth factor signaling ( adrenal hypoplasia, genital anomaliesand enteropathy with myelodysplasia,,restrictionofgrowth, the remains unanswered. Why thisleadstoaratherspecificandnarrowphenotype therefore causesdisorderedDNArepairandreplication. a proteincomplexforDNAsynthesisintheSphaseand more susceptibleforneoplasticlesions.MCM4ispartof (e.g. natural killer celldeficiency),which maymakethem chromosomal breakageandimmunologicalanomalies ( consanguinity revealedmutationsinthe suffering fromFGDandgrowthfailurewithfrequent malignancies (e.g.Wilms tumorandhepatoblastoma). with overgrowthandapredispositiontoembryonal Wiedemann syndrome(OMIM130650) manifesting samegeneareknowntocausetheBeckwith– the very the CDK-binding domain and truncating mutations of mechanism. Bycontrast,loss-of-functionmutationsin cause IMAGesyndromelikelythroughagain-of-function the maternallyinheritedalleleof Thus, specific mutations inthe PCNA-binding domain of imprinting andonlythematernalalleleisexpressed. Normally, thepaternalalleleof to playamajorroleininhibitingcell-cycleprogression. prenatal andpostnatalgrowthdevelopment.Itseems gene clusteronchromosome11p15.5,whichregulates CDKN1C identified inarareautosomal-dominantsinglegenedefect, ( hypocalcemia, craniosynostosis,cleftpalateandscoliosis ( congenital adrenalhypoplasiaandgenitalanomalies Table 1 50 49 53 Review ) ( ). UsingaNGSapproach,theunderlyingdefectwas ). Patientsmayalsofeaturehypercalciuria and/or Most recently, novelgeneticmutations were Lately, MIRAGEsyndromeduetogeneticvariantsin Similarly, advancedgeneticwork-upofanIrishcohort SAMD9 al 1 Table ) ( ( 52 Table 1 genewasreportedin11patientspresenting ). Affectedindividualsalsoshowedincreased ). SAMD9isinvolvedinendosomefusion ) ( 51 ). CDKN1Cispartofanimprinted CDKN1C C EFlück SAMD9 CDKN1C mutationsseem isrepressedby werefoundto MCM4 gene

human missensemutationsledtoreducedviability patients comparedtothatincontrols.Also,reconstituted alter ceramidecompositionofculturedfibroblast sphingoids ( enzyme activityandthusdegradationoflong-chain mutations affectingproteinexpressionandlocalization, were showntobehaveasrecessiveloss-of-function the S1Preceptor( other sphingoidbases;and(c)fromS1Psignalingthrough (a) anexcessofintracellularS1P;(b)accumulation SGPL1 deficiencywithinatargetorganmayresultfrom intracellular secondmessenger( mediated by G protein-coupled receptors, or as a direct as anactivator of an extracellular signaling pathway well asangiogenesisanddevelopment.S1Pmayfunction as S1P regulatescellmigration,differentiation,survival responsible forthefinalbreakdownofsphingolipid(S1P). 603723) ( sphingosine-1-phosphate (S1P)lyase1( the classic(salt-vastingand simplevirilizing)andthe activity. Thishas resultedintheclinicaldefinitionof phenotypes duetovariable degreesoflossenzyme as 21-hydroxylasedeficiency canmanifestwithvariable even simplegeneticmutations insteroidenzymessuch help in defining specific enzyme deficiencies. However, with PAI andFGD.Biochemicalsteroidprofilingcan Prediction ofgenotype–phenotypeisnot(always)easy and FGD Phenotype–genotype conundruminPAI been describedforsphingolipidosessofar. been reported.Bycontrast,anadrenalphenotypehasnot disorders andforsomeofthemarenalphenotypehas diseases ( sphingolipidoses suchasNiemann-Pick,GaucherorFabry the sphingolipidmetabolismleadtodisordersknownas infertile. Ofnote,mutationsinupstreamcomponentsof to haveimpairedgonadal steroidogenesis; theyare Sgpl1 adrenal andrenalphenotypefoundinhumans( Thus, theSgpl1 whereas CYP11A1expressionwassignificantlydecreased. revealed marked alterations in adrenocortical zonation, disrupted steroidogenesis( both compromisedadrenaldevelopmentaswell pathomechanism ofPAI inSGPL1deficiencyincludes to thepodocytephenotypeseeninhumans( and nephrocyteanomaliesinDrosophilareminiscent adrenal insufficiency Update primary −/− micediewithinfewweeksandarealsoreported 57 54 ). Theyaremostlyprogressive,multisystemic 54 , 55 ). SGPL1mutationswerealsoshownto −/− ). SGPL1istheintracellularenzyme 54 mousemodelwasfoundtoreflectthe ). Identifiedhuman Downloaded fromBioscientifica.com at09/29/202105:35:30PM 55 ). AdrenalsofSgpl1 56 ). Thepathogenesisof 177 www.eje-online.org :3 SGPL1 SGPL1 mutations 54 , OMIM −/− 54 R107 ). The mice , 55 via freeaccess ). European Journal of Endocrinology www.eje-online.org manifest withanalmostexclusive PAI phenotype? (d) functions incellgrowth,differentiation and metabolism found inFGDpatientsthat areknowntohavebroad FGD patientssofar?(c)How comethatsomenovelgenes 103270) supportingsteroid enzymes suchasCYP11A1in ferrodoxin/-reductase ( Why didwenotfindgeneticmutationsinthecofactors broadrangeofdisorderssex development? (b) very can weexplainthatheterozygotemutationscause a steroidogenesis inmostaffectedindividuals,andhow mutations ofthe currently addressing,areprovided:(a)Whydomost questions concerningPAI, whichweandothersare human biology. mutations have always provided unexcelled insight into ( eventually findingthediseasecausinggeneticvariant(s) to find the ‘needle inthe haystack’ to follow-up for found andaneffectivefilteringstrategymustbeapplied approaches where mostly too many genetic variations are gene functions.ThisisevenmoreofaconcernwithNGS ask fordiseasecausingmechanismsunderstanding gene variants associated with human diseases will always ofnovel forms isstillnotfullyunderstood.Thediscovery PAI aregeneticallysolved,butthepathogenesisofsome approximately two-thirdofpatientsmanifestingwith and understandaboutadrenalsteroidogenesis.To date in thelasttwodecades,thereisstillalotmoretodiscover Although manyquestionsregardingPAI havebeensolved Unsolved questions are generallynotconsideredfirst. appear farbeyondchildhoodonly, whengeneticdisorders manifest earlyinlifeasexpectedforinbornerrors,but FGDs ( ( been suggested to be named non-classical (lipoid) CAH CYP11A1 For instance,mildermutationsofthe discussions about the definition of this group of PAI. several genes( syndromic FGDphenotypemaybecausedbymutationsin manifest withvariablephenotypes.Bycontrast,thenon- this review. Thus,mutationsinasinglespecificgenemay affect allredoxpartnerssimilarlyasdescribedearlierin multipleenzymes,andspecificmutationsmaynot serves phenotypic variability is even broader as this non-classic (late-onset) form of CAH. With PORD, the 58 48 Review ). Incontrast,detailedstudiesofpatientswithgenetic , In thefollowing,fewexamplesofunsolvedspecific 59 27 , 60 , gene,whichcauseaFGD-likephenotype,have 62 , 61 ). In addition, some genetic defects may not Table 1 ) insteadofbeingincludedinthegroup NR5A1/SF1 ) andhasalreadyledtocontroversial FDX1/FDXR genenotaffectadrenal C EFlück , OMIM103260and StAR geneorthe patients withPAI ( genes andhavefinallysolvedthediagnosisinseveral approaches haverevealedgeneticvariationsinnovel indistinguishable ( has increased,butseveraldefectsmanifestphenotypically In recentyearsthespectrumofgeneticdefectscausingPAI of PAI? Conclusion: Whybotherwithgenetics in almost40%ofcases? Finally, whatelsecausesFGDthatstillremainsunsolved published literature and genetic databases. Necessary published literatureandgeneticdatabases.Necessary about diseasespectrumandprognosisaccordingto can beofferedandallowstoprovideclearinformation from PAI bearsseveraladvantages.First,aprecisediagnosis Providing arapidgeneticdiagnosistopatientssuffering in familial cases, syndromic formsand young patients. aim atageneticdiagnosisinpatientswithPAI, especially importantly, analysis ofbigdataobtainedbyWESrequires genome sequencing or array CGH maybeapplied. Most conditions. Forthat,othergenetic analysessuchaswhole transversions, whichareoften associatedwithsyndromic variations, gene conversions or fusions, translocations or is notthefirstchoicefordetectionofcopynumber However, WES doesnotcoverintronicsequencesand at leastinthescreeninganddiagnosticapplication. conditions isoftenwholeexomesequencing(WES), today’s firstapproachforstudyingnon-syndromicgenetic sequencing becomingeasier(available)andcheaper, phenotype suchasPAI areinvestigatedatonce.With which agroupofgenesthatareimplicatedwithspecific candidate analysishasbeenfollowedbygenepanels, in defects characterizedindetailsbysteroidprofiling.The valid forthegeneticwork-upofspecificsteroidenzyme was studiedexonbyexon.Thisapproachmightstillbe by the candidate gene approach, in which a single gene other) disordersincludingPAI. biology andpathomechanismsofendocrine(andmany implications hasprovidedinvaluableinsightintonormal disorders followedbyin-depthstudiesofthebiological unsolved patientsandfamiliesharboringrarecongenital can beoffered.Third,geneticwork-upofgenetically advanced levelandprenatalgenetictestingtreatment affected individualsandtheirfamiliesispossibleatamore disorders maybeinstalled.Second,geneticcounselingof stopped earlier, andscreeningsforaccompanying treatments treatments may be started and unnecessary adrenal insufficiency Update primary In thepast,geneticwork-uphasbeenperformed 27 1 , , 48 2 , Downloaded fromBioscientifica.com at09/29/202105:35:30PM ). Itisthereforerecommendedto 14 , 28 , 48 ). In addition, NGS 177 :3 R108 via freeaccess European Journal of Endocrinology 10 References (current grantID320030–146127). This workissupportedbygrantsoftheSwissNationalScienceFoundation Funding perceived asprejudicingtheimpartialityofthisreview. The authorsdeclarethatthereisnoconflictofinterestcouldbe Declaration ofinterest patients withFGDremainwithoutgeneticdiagnosis. more willfollowcertainlygiventhefactthatstillmany been discoveredrecently( underlying geneticdisordersdescribedinthisreviewhave patients andfamilieswithFGD,mostofthenovel this methodofgeneticanalysistogeneticallyunsolved which thegeneticanalysishasbeeninitiated.Applying disease causingvariantsinthebiologicalcontext,for an educatedfilteringstrategy, whichisabletoscreenfor 2 3 9 8 7 6 5 4 1 Review Miller WL&AuchusRJ.Themolecular biology, biochemistry, and Reviews physiology ofhumansteroidogenesis anditsdisorders. 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