Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV of patientswithichthyosishaveonlymildtomoderate including oral therapy. Yet, the vast majority This isan open access article under the CC BY-NC license.www.medicaljournals.se/acta Typically, the skin problems begin at birth or shortly the skin, sometimesalsoassociatedwithsyndromicfeatures. by widespreadhyperkeratosis,xerosisandscalingofthe Annual Meeting of the Japanese Dermatological Association in Nagoya, June 2019. 2 1 S1 occur, such aspruritus,ectropionandanhidrosis(Fig. in life, less severe, but more common, complications and certaintypesofsyndromicichthyosis(2,3).Later harlequin ichthyosis(HI),epidermolytic(EI) threatening consequences; for example, in neonates with patients’ qualityoflife (1).Onlyrarelyaretherelife- mild tosevere,inthelattercasemarkedlyreducing on theunderlyinggenotype,diseaseintensityrangesfrom reafter and usually show lifelong persistence. Depending I [email protected], [email protected] anders.vahl- E-mails: Sweden. Uppsala, 85 SE-751 University, Uppsala Corr: Acta DermVenereol 2020;100:adv00097. Accepted Feb 12,2020;EpubaheadofprintMar9,2020 des; therapy; epidermolytic;congenital;keratinocytes. Key words: skin pH; ARCI;human epidermis; keratins; cerami - mate goal of and better findingnew treatments. different ulti the with diseases related and ichthyosis, of types of consequences clinical and pathobiology highlights a series of approaches used to elucidate the review This unsatisfactory. remains often ichthyosis new knowledge about pathomechanisms, treatment of other and this Despite symptoms. skin patient’s the to contributing potentially hyperkeratosis, and feration hyperproli inflammation, epidermal elicit may per se abnormality barrier The function. barrier skin normal for essential structural or lipids epidermal of almost invariably uncovered errors in the biosynthesis the aetiology of more than 50 types of ichthyosis have of Studies years. recent in greatly expanded has ses, fication, including the group of diseases called ichthyo The understandingofmonogenetic disordersofcorni Journal Compilation ©2020ActaDermato-Venereologica. Department of MedicalSciences, UppsalaUniversity,Uppsala, Sweden Anders VAHLQUISTand HansTÖRMÄ Ichthyosis: ARoad ModelforSkin Research https://www.medicaljournals.se/acta/content/abstract/10.2340/00015555-3433 This article is based partly on the Dohi Memorial Lecture presented at the 118 of, usuallymonogenetic,diseases,allcharacterized chthyosis isanumbrellatermformorethan50types 2 ). Carefulmedicalattentionisfrequentlyrequired, Anders Vahlquist and Hans Törmä, Department of Medical Sciences, REVIEW ARTICLE - - - - th - Centenary theme section:GENODERMATOSES

new ideasaboutdermatotherapy (Fig.1). understanding ofnormalhuman skinbiologyandyields of ichthyosis, research that concurently results ina better used to elucidate the aetiopathogenesis of various types ichthyosis usuallyhavevariablyincreasedtransepider applications ofcream(2,3). skin symptoms,whicharereadilycontrolledbydaily types ofnon-syndromicichthyosis(4): normal barrier formation, specific for each of the 4 main in thebiosynthesisofproteinsandlipidsessentialfor mal waterloss(TEWL). This isduetovariousdefects • • • • better care and treatments. causes and consequences of ichthyosis, which may lead to view highlights recent progress in the understanding of the common (prevalence < thyosis, ranging inseverity and frequency from mildand more than 50 genetic types of, mostly non-syndromic, ich­ (Greek: scales fish of reminiscent Ichthyosis refers to skin diseases with scaling somewhat SIGNIFICANCE oeie cmlmne wt rtni tbes Ti re This tablets. retinoid with complemented sometimes patients with ichthyosis require daily applications of cream, barrier function, requiring intensive medical care. Nearly all skin impaired and inflammation dermal (collodion), layer In the latter case, babies are often bornwitha thick horny This overview exemplifies a wide range of approaches Despite a thick stratum corneum (SC), patients with differentiated keratinocytes. or 10, impairing the structural integrity of terminally caused bydominant negative mutations in keratin 1, 2 EI) including (1:300,000, Keratinopathic ichthyosis lipid envelopes(CLE). acylceramides (acylCer), lipid lamellae and cornified in anyof>10genesinvolvedthebiosynthesis prevalence 1:100,000, including HI) due to mutations Autosomal recessive congenital ichthyosis(ARCI; the SC. in accumulation of cholesterol sulphate (CSO caused by a deficiency of steroid sulphatase, resulting X-linked recessive ichthyosis (XRI; 1:3000 in males) of hydrophilicmoleculesinthecorneocytes. filaggrin’s compaction of keratin filaments and release due to semi-dominant 1:300) prevalence vulgaris; (I. Ichthyosis vulgaris 1 Acta DermVenereol 2020;100: adv00097 1%) to severe and rare (< FLG mutations abolishing doi: 10.2340/00015555-3433 =fish). There are There ichthus=fish). 0.001%). 4 ) in - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV was eventuallyshowntobecausedbyrecessive muta massively enlarged keratohyalin granules(18).KLICK keratoderma (KLICK),which ultrastructurallyexhibits Theme issue:Genodermatoses disorder rare the concerns example Another (17). deficiency allergy andmetabolicwasting) causedbydesmoglein with amildformofSAMsyndrome(severedermatitis, revealed novelmutationsintheDSG1gene,consistent few andabnormallylooking(16).Genomicscreening signs of EM types 1–4, but the corneodesmosomes were believed tohaveanatypicalformof ARCI, showedno nostic teameffort 2Scandinavianhalf-brothers,initially ARCI fromotherconditions.Forexample,inadiag of theskinspecimen(10). CLEs areattenuated,best seen afterrutheniumstaining common to most types of ARCI, the lipid bilayers and distortions ofthelamellarbodies(11, 15).Finally, and tions duetoABCA12mutationsoftenshowprominent condi related and HI Furthermore, 14). (13, mutations lipid membranes), exclusively associated with SCL27A4 with bodies andelongatedmembranes(7)),oftenassociated TGM1 mutations(12);EMtype3(abnormallamellar 2 (“cholesterol clefts”(6)), typicallyassociatedwith typerelated toepidermalhyperproliferation(5);EM probably droplets), (lipid 1 type EM epidermis: the of layers corneal and granular the in identifiable are terns (5–11). thehistopathologicalhallmarks quired todisclose other types of ichthyosis, electron microscopy (EM) isre cytolysis ofsuprabasalkeratinocytes.However, inmost of intermediate filaments is seen, occasionally leading to with confettiduetovariouskeratinmutationsaclumping stratum granulosum(belowSC)andinEIichthyosis light microscopy, anabsenceof I.vulgarisdisplays causing clearcutstructuralabnormalities. Thus, under also makesitvulnerabletogeneticdefects,frequently many disparatefunctionsandconstantrenewalofcells, The ingenious construction of human epidermis,withits MICROSCOPIC EXPLORATION OFICHTHYOSIS research. Fig. 1. Examples of scientific issues and methodological approaches in ichthyosis 198 EM analysisisclinicallyusefulfordifferentiating In ARCI, for example, 4 distinctive ultrastructural pat NIPAL4 mutations (9); and, EM type 4 (aggregated A. VahlquistandH.Törmä NGS: nextgeneration sequencing;LC: liquidchromatography. k eratosis eratosis l inearis, inearis, i chthyosis c ongenita with - - - - -

possibly reflecting its master role during barrier repair. barrier during role master its reflecting possibly pH appearstonormalize more quicklythan TEWL, one week before the full restoration of SC (28). Indeed, normal surfacevalueswithin 5–7days,approximately SC, pHand TEWL willstarttodecrease again,reaching increase dramatically(27).Forobviousreasons,acon down totheglisteninglayerofepidermis, TEWL will influx oftoxicsubstancesviatheskin. or water of losses harmful any preventing for sufficient remaining amounts ofSCseems nearly always to be inadvertedly enhance the pathomechanism ofichthyosis, treatment with topical keratolytics (26). While this might untreated ARCI skin and increases further after efficient in elevated is TEWL that is studies these from finding Another 25). (24, barrier skin the affecting potentially studying the effects of various drugs and noxious agents in both healthy and diseased skin; for instance, when surface pHispossible. This low-techapproachisuseful measurement of TEWL, skinhydration(capacitance)and evaporimeter and a flat glass electrode to the intact skin, in vivoinformationaboutSC.Bysimplyapplyingan Invasive techniquesarenotalwaysrequiredforobtaining FUNCTION CORNEUM INRELATION TOITS BARRIER BIOPHYSICAL PROPERTIES OFSTRATUM bullosa simplex,anotherkeratinopathicdisorder(23). was disappointinginarecentstudyofepidermolysis circumspection because the efficacy of topical chaperon (21), any extrapolation to the lecular chaperondesignedtostabilizeproteinpolymers Fig. S3 details ofthiseventforlongremainedunexplored(28). although occur, also then must epidermis viable in 7.4 current increaseinpHfrom~5ontheskinsurfaceto aggregates wasdiminishedbypre-treatmentwithamo cells (22).However, althoughthenumberofcellular filaments to a much higher extent than in healthy control heat. Clearly, heat stress causes aggregation of keratin However, whenSCismechanicallyremovedintoto 2 showsthat,soonafteracomplete removalof EI (21).Regardingthe latter, studies ofculturedcellsfrompatientswith osis withconfetti(20)orforexperimental keletal abnormalitiesinpatientswithichthy­ can be used, for example, for detecting cytos alternative, immunofluorescence (IF) analysis only availableincertainlaboratories. As an of ichthyosis,itisatediousandcostlymethod dation ofnumerousepidermalproteins(19). gene interferingwiththeproteasomedegra tions intheregulatoryelementsofPOMP mutation beforeandafterinvitro exposureto keratinocytes from a patient with IF stainings ofkeratin 10indifferentiated Although EM is invaluable in many studies Although EMisinvaluableinmanystudies in vivo situation demands Fig. S2 2 KRT10 shows - - - -

Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV and -hydrogenexchanger-1(NHE-1),allaccu in normalSCappeartobeurocanicacid,freefattyacids SULT2B1 mutationsmayalsocauseichthyosis(34). 28 and30withpermission). refs. from (modified skin. normal to compared left the to shifted be case former the in will gradient pH the XRI), (and vulgaris I. in SC remove to each group). When adjusting for the higher number of strippings required vulgaris) and patients with X-linked ichthyosis (XRI) or ichthyosis vulgaris Fig. 2. The pH (I. gradients over stratum corneum in healthy controls degradation involvedincorneodesmosome proteases mes operating in SC are kallikrein 5 and 7, the principal fication (35–37). Examples of two pH-dependent enzy creams anintriguingoptionforsomedisordersofcorni of SC.Indeed,thismakestreatmentwithpH-adjusting lipid organization and structure at different depths of SC)isbiologicallyhuge,andprobablyaffects both over adistanceofonly10–20µm(thenormalthickness (35). Clearly, areductionofapproximately2pH units mulating inacidicmicrodomainsneartheskinsurface dentally, CSO and anaccumulationofacidicCSO vulgaris I. in acid) urocanic (e.g. filaggrin of products for thisdifference isapaucityofacidicbreak-down posite istrueforXRI(Fig.2). The proposedexplanation towards less acidic valuesis observed, whereas the op ferent inI.vulgarisandXRI(30);theformerashift both humanandmouseskin(29). in techniques sophisticated more using confirmed been of pH in thecourseof>100tapestrippings,hassince This gradient, first demonstrated by repeated monitoring between stratumgranulosumandtheskinsurface(28). over human SC, with its steepest slope occurring midway highlighted bythediscoveryofasigmoidalpHgradient The importanceofpHforSChomeostasishasalsobeen fact, a deficiency of CSO molecule duringkeratinocytematuration(32,33).In an inhibitorofSCdesquamation(31)andasasignalling The keycomponentscontributingtothepHgradient Interestingly, thepHgradientinSClooksquitedif . Mean pH values revealed by tape-stripping (n 4 isafascinatingmolecule,actingbothas 4 inepidermisduetorecessive 4 inXRI(30).Inci = 10–11 males in ------in XRIisduetoCSO DEGs (Fig. S4 patients withI.vulgarisshowedupto120timesasmany (44, 45). While patients with XRI showed only 27 DEGs, or I.vulgarisduetomono-bi-allelicFLGmutations healthy controlsanduntreatedpatientswitheitherXRI 22,000 geneswereappliedtopooledskinextractsfrom ichthyosis comparedwithnormalskin. searching fordifferently expressedgenes(DEGs)in of transcriptomes extracted from tissue biopsies and expression inepidermis,usingmicroarrayanalysis of testingthishypothesisistostudytheglobalmRNA way One causes. it insufficiency barrier of extent the in epidermiswilldiffer dependingonthegenotype and it isnotfar-fetched toassumethathomeostatic responses Considering themanydifferent aetiologiesofichthyosis, BARRIER RESPONSES REPAIR ANDGENOMIC enzymes fromthelamellarbodies(42,43). be associatedwithdecreasedsecretionofproteolytic hyperkeratotic conditions,suchasHIandEI,knownto it mightbepossibletoincrease desquamationinsome tion in the opposite direction, e.g.by blocking LEKTI, LEKTI (41). Hypothetically, by modulating desquama of deficiency secondary a with associated frequently is treatments forNSandpossiblyatopicdermatitis,which application ofsyntheticinhibitorsmayleadtonew topical with trials clinical Ongoing 40). (39, TEWL thickness toalmostnil,hencedramaticallyincreasing circumflexa), acceleratesdesquamationandreducesSC of LEKTI,asinNethertonsyndrome(NS;Ichthyosis (39). deficiency ALEKTI genetic is which of one tors, repair. However, in ARCI patientswithtruncatingTGM1 aimed atgeneratingmoreomega-O-acylCer forbarrier of several ARCI genes reflects a positive feedback loop up-regulation marked a Speculatively, (48). aetiology “ARCI genes”because of theirinvolvement inthe ARCI as known arealso ofwhich thelast acylCer biosynthesis, zation and cell mobility, 46 in immune response and 8 in spectrum of 256 DEGs appeared; 25 involved in keratini TGM1 mutationsweresimilarlyinvestigated,abroad eczema (24,44). FLG mutationswhoarealsonotoriouslypronetodevelop response isparticularlyevidentinpatientswithbiallelic flammation, lipid and hyperproliferation; the enzymes dependsontheamountofendogenousinhibi and desquamation(38).BesidespH,theactivityofthese showing activationofnumerousgenesinvolvedin support fromourgeneontologyandqPCRanalyses, explain the abundance of DEGs. This hypothesis gains occurs, a chronic repair process takes place that might I. vulgaris, sinceno“silent”generationofhyperkeratosis In 47). (46, repair barrier active more for need the In sucharecent study, microarrays consisting of When skin samples from patients with ARCI with Ichthyosis: aroadmodelforskinresearch 2 ). Speculatively, thelownumberofDEGs 4 -induced hyperkeratosisreducing Theme issue:Genodermatoses 199 - - - -

Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Genodermatoses diagram correspond tostratum corneum(modified fromref. (48)withpermission). with immuno­ of Examples 3. Fig. plies thatichthyin(atentativetransporterofMg mutations inNIPAL4 (encodingichthyin)(52). This im­ epidermis, butnotin ARCI epidermiswithinactivating 12R-LOX andeLOX-3 in stratum granulosum of normal (51). TGm-1 hasalsobeenfoundtoco-localizewith a chainofeventsleadingtoproperformationCLE with a close interaction between TGm-1 and SDR9C7 in duced astrongsignalinstratumgranulosumconsistent with eitherofthe2 ARCI proteins,togethertheypro (50). While filaggrin did not produce any teins areatadistanceoflessthan30nmfromeachother ( healthy control skin using in situ proximity ligation assay teins, TGm-1 andSDR9C7,wasstudiedinmoredetail microarray data. The co-localizationof2other ARCI pro is muchhigherinthepatients,thuscorroborating both patientsand controls,but the protein expression CerS3, co-localizeinthegranularlayerofepidermis controls. Clearly 2 of the studied proteins, CYP4F22 and sies from5patientswithTGM1 mutations and 4 healthy (48). the proteinexpressionatdifferent depthsofepidermis filer imaging, allowing semi-quantitative comparisons of recent studiesusingIFstainingcombinedwithCellPro rating inafeedbackregulatedpathwaycomesfromour prevent apropercrosslinkingofCEandCLE(49). cells theabsenceoftransglutaminase-1(TGm-1)will how manylipidprecursorsareavailableinthegranular mutations sucharesponseisprobablyuseless;nomatter 200 wild-type ARCI genes,numerousothergenesinvolved proximity toother ARCI proteins. also essentialforacylceramidesynthesis,actinginclose isPLA), whichgeneratesasignalwhen2different pro Further supportforaconceptof ARCI proteinsope In additiontoanincreasedexpressionofseveral TGM1 Fig. 3showsexamplesofresultsobtainedinbiop A. VahlquistandH.Törmä mutations versus healthy controls. fluorescence staining (left) and CellProfiler analysis (right) of the CYP4F22 and CERS3 proteins in patients in proteins CERS3 and CYP4F22 the of (right) analysis CellProfiler and (left) staining fluorescence The increased expression in patients’ skin extends beyond the granular layer. The shaded area in the isPLA signals 2+ (53)) is (53))is ------samples ofSCcanbecollectedforanalysisof,ex By simply scraping the skin surface with a sharp blade, EPIDERMIS ANDGENETICSTUDIES OF BIOCHEMICAL contributing factor. case skin erosions andblisteringarecertainlyamajor deposition and AMP release (43, 58, 59), although in this intrinsic defectsinbarrierrepair, inter-corneocyte lipid skininfectionsarefrequentinEIwithFurthermore, (43). bodies lamellar the from of AMPs release fective and septicaemia; inthis case possibly related to a de HI andIPSoftenexperienceneonatalskininfections against bacterial infections. For example, patients with inflammatory reactions(57). this caseonabackgroundofmuchstrongerimmuneand psoriatic lesionsexpresshighlevelsof AMPs, albeitin ichthyosis despite a fissured and scaly skin. Analogously, microbial infectionsarerareinpatientswithlamellar tally, increasedexpressionof AMPs mightexplainwhy and drugs, such asvitamin such and drugs, A andretinoids.Forexample, allow quantitationofnumerousendogenouscompounds high-performanceliquidchromatography(HPLC),as of suchsamples,sensitiveanalyticaltechniques, ofscarring. risk homogenization andextractionAfter samples of epidermis are obtainable without significant full-thickness biopsies, shave superficial as such ques, ample, CSO factors (NMFs)(60).Usingslightlymoreinvasivetechni upregulated in ARCI epidermis (48, 54–56). Inciden 54–56). (48, epidermis ARCI in upregulated anti-microbial peptides (AMPs) defence are also heavily and inflammation biosynthesis, lipid repair, barrier in However, not all subtypes of ARCI exhibit a resilience 4 (46), urocanic acid and natural moisturizing - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV ( in I. vulgaris and increased levels of 3,4-didehydroretinol hence constitutingCer. This highlyhydrophobicmo (ULCFA) formamid-linkageswithsphingosines, chains ultra-long the (FA)ELOVL4, acids by fatty of elongation enzymatic the to Subsequent 70)). 69, (4, positioning ofseveral ARCI proteins(forreviewsee of lipidbarrierformationinepidermisandthecritical hunting. gene via confirmed later was which (68), biosynthesis early cluestotheexistenceofinbornerrorsacylCer of variousceramidesfoundin ARCI epidermisgave levels abnormal the Indeed, (65–67). specificity and sensitivity high with quantifiable are (Cer) ceramides different chainlengths,squaleneandvarioustypesof spectrum detection, the skin levels offatty acids of as ultra-performanceliquidchromatographyandmass- be measuredinshavebiopsies(63,64). assay, therapeuticlevelsofisotretinoinandacitretincan epidermis usuallyfallbelowthedetectionlimitof endogenous concentrationsofall-transretinoicacidin Although significance. known without yet as 62), (61, tive moiety known for its non-enzymatic coupling to oxidated linoleatemoleculeintoa13-ketone,reac (67). SDR9C7is a dehydrogenase, that converts the implicates analternativepathwayinvolvingSDR9C7 transacylation ofinvolucrin.However, arecentreport thought tobecatalysedby TGm-1, analogoustothe previously was formation CLE in step final (72). This and eLOX-3,asubsequentcovalentbindingtoCE dation ofthelinoleatemoiety, catalyzedby12R-LOX A significant fraction of acylCer undergoes further oxi essential fortheformationoflipidbilayersinSC. acylCer (71). The latterstep, enhanced by PNPLA1,is and subsequent transacylation with linoleic acid to form CYP4F22-mediated lecule undergoes a series of modifications, including a reduced concentrations of (vitamin A Using moresophisticateddetectionmethods,such Fig. 4summarizesourcurrentunderstanding 2 ) in some types of hyperproliferative keratosis w -hydroxylation oftheFA moiety 1 ) were found ) were found - - - ARCI, therearealreadygoodarguments fordistinguis in process pathogenic other the and this about clarified lipid bilayers and CLE. Although much remains to be levels andthusimpairtheformationofbothintercellular or blockages of acylCer biosynthesis, e.g. due to TGM1-associated ARCI (6).Conversely, moreupstream this might explain some of the EM characteristics of cytes aslipidaggregatesormembranes.Speculatively, converted toCLEby TGm-1, accumulatesinthecorneo (48) imply that lipoxygenated acylCer, instead of being the skinofpatientswithinactivatingTGM1mutations several of upregulation an of findings in proteins ARCI a possible extension to this “blockage theory”, our own downstream blockadeintheacylCerpathway(70). As free FA accumulating in the keratinocytes owing to a features in ARCI areactuallycausedbytoxic levels of gested that some previously unexplained ultrastructural the intercellularspaceviaexocytosis.Itwasalsosug vering preformedCLEscaffolds andlipidbilayersto and (30–35%), zygous orcompoundheterozygousmutationsinTGM1 leading causesof ARCI inNorthernEuropearehomo review see (4)). With respect to the latter diagnosis, the nopathic ichthyosis, and 85–90% of cases with ARCI (for to genetically diagnose all forms of common and kerati Japan, Scandinavia,UKandtheUSA,itisnowpossible tic”, forthisgroupsofdisorders(48,70). synthe “lipid or “lipodysgenic” as such prefixes, using metabolism fromothercausesof ARCI; forexample,by hing aetiologiesrelatedtoinbornerrorsoftheacylCer place within the lamellar bodies, subsequently deli that virtuallyalltheabove-mentionedprocessestake examination (67). EM on CLEs absent by characterized is deficiency protein (67). As acorollary, ARCI causedbySDR9C7 Thanks toresearchmainlyfromFrance,Germany, Interestingly, Crumrineetal.(70)recentlyproposed CERS3 mutations,mightinsteadreducetheacylCer NIPAL4 (12–15%) (4, 73–76). Detailed discussions ALOX12B orALOXE3(combined15–20%) Ichthyosis: aroadmodelforskinresearch dehydrogenase/reductase family 9C member 7. LIPN: lipase member N, (ichthyin), NIPA4 transporter ALOXE3, TGm-1: transglutaminase-1, NIPAL4: isomerase hydroperoxide eLOX-3: 12R-type, 12-lipoxygenase, arachidonate 12R-LOX: 1, PNPLA1: patatin-like 3,phospholipase domain containing synthase ceramide CERS3: 4, member 22, FATP4: fatty acid transport protein CYP4F22: cytochrome P450 family 4 subfamily F ceramide, ELOVL4: ELOVL fatty acid acyl elongase AcylCer: acid, 4, fatty chain ultra-long FA: cornified envelope, FFA: free fatty acids, ULC- CE: matrix; extracellular ECM: granulosum, (4) with Derm Clin J permission). SC: Am stratum corneum, SG: stratum from formation (modified (CLE) envelope lipid cornified in pathways alternative two indicate box the in barrier. lipid epidermal an of formation the in steps Fig. 4. Crucial components and biosynthetic Theme issue:Genodermatoses

Light green (hatched) arrows SDR9C7 CYP4F22 : short-chain 201 ------

Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Genodermatoses from refs.(4,75)withpermission). with partially overlapping phenotypes and culprit genes. erythema and severity ichthyosis 4 types between of correlation autosomal recessive Tentative congenital 5. ichthyosis (ARCI) Fig. identified at first examination, i.e. before the genetic re seemingly correspondingtothemajorclinicalsubtypes circles overlapping partially 4 into distributed roughly against oneanotherinadiagram,theindividualratios the ISandESvaluesrecordedatage>1yearwereplotted summation of individual score values (4, 73, 80). When 10 different bodyregions,followedbyanarea-adjusted ichthyosis (IS)anderythema(ES)severityweremadein of (0–4) scorings separate ARCI, with patients 132 of models may still beuseful. Forexample, in a recent study trials (forreviewsee(79)) about thebestseverityscoringsystemtouseinclinical of theyear. Nowonderthenaconsensusisstilllacking or environmentalfactors,e.g.work,climateandseason time, eitherspontaneouslyorastheresultoftreatment over occur often fluctuations phenotypic complexity, pain, all with a variable degree of severity. Adding to this as xerosis, palmoplantar keratoderma, erythema, itch and Furthermore, aplethoraofothersymptomsoccurs,such etc. white, and fine brownish, cobblestone-like, like, with scalestypicallydescribedaslamellar, collodion- the intensityofscalingmayrangefrommildtosevere, skin lesionsmaybegeneralizedoronlyoccurfocally, and Characteristically, study. scientific a to relation in e.g. to describeinaconcisewayorscoreforseveritygrade, symptoms that may be difficult for the examining doctor Patients withichthyosisfrequentlyexhibit skinsignsand AS RESEARCH TOOLS ANDSERENDIPITY CLINICAL EXAMINATION papers (77,78). about thegeneticsofichthyosisareavailablein2other 202 In clinicalpractice,however, lesssophisticatedscoring A. VahlquistandH.Törmä (modified - pleomorphism, “aconditioninwhichanindividualas of severalweeks. This alteringpatternisconsistentwith symptoms atbirth,healingspontaneouslyoveraperiod IS andES,althoughmostofthepatientshadsevereskin mutations) and IPS (specifically caused by caused (specifically IPS and mutations) suit ichthyosis (dueto temperature-sensitive TGM1 (mostly due to mild ALOX12B conditions, suchasself-improvingcollodionichthyosis as “non-LI/non-CIE”(80).Itcomprisesseveraldistinct new nameforthissubgroupof ARCI previously known Accordingly, pleomorphicichthyosis(PI)isasuggested sumes anumberofdifferent formsduringitslife-cycle”. of either IS or ES. The 4 overlapping phenotypes and genotypes, show high values dermic ichthyosis (CIE), with more varied and partially highest ISandESvalues.Lamellar(LI)erythro ARCI due to truncating ichthyosis (HI),therarestandmostseveresubtypeof sults becameknown(Fig.5).Unsurprisingly, harlequin oai (iecn) uain n n lee ih germline with allele an on mutation (silencing) somatic patient’s the of effects (B) and thigh, the on areas erythrokeratodermic in spots white appearing Gradually (A) keratinocytes. of phenotype showing spontaneous revertant Fig. 6. Patient with keratitis-ichthyosis-deafness (KID) syndrome quencing ofDNA fromthehealedspots revealedseveral histopathologically “non-lesional”. A subsequent se skin, whichgraduallygrewinsizeandnumber, were started inher20stodevelopspotsofnormal-looking syndrome due to a recurrent mutation in GJB2 in childhoodwithkeratitis,ichthyosis,deafness(KID) diagnosed 45-year-oldwoman, a case: a such lustrates healed spots(modifiedfromref. (83)withpermission). skin, are restored by the The blurred gap junctions (top panel wt-GJB2 with together cells HeLa to transfected when (EGFP) chance of making serendipitous findings. serendipitous making of chance the varioustypesofichthyosis. for teaching medical students how to distinguish between diagnosing ARCI withoutavailablegeneticexpertiseor genetic diagnosing,itis still useful; for instance, when exact of era an in superfluous seem may subgroups appear tobesecondarytheskinmalfunction.) misnomer for IPS, because all extra-cutaneoussymptoms a probably is “syndrome” mutations) (73,80,81).(Nb: Another bonusofadetailed skin examinationis the major 4 into ARCI of classification crude a While de novo th entity, shows low values of both ABCA12 mutations, shows the ) as in as (bottom panel) mutation somatic GJB2 mutation restoring the normal ), resembling the situation in lesional mutations), bathing- GJB2 Fig. 6Ail SLC27A4 (82). She (Cherry). mutation - - - -

Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV results, atleastinpachyonychia congenita, of mutatedmRNA hasshown promising antisense therapyblockingthetranslation as successfulinitially hoped, topical therapy forskindiseaseshas notyetproved tion andhyperproliferation. Although gene but also secondary events, such as inflamma targeting notonly thecausative mechanisms, ichthyosis treatment are in the pipeline, (94). are knowntorespondmostfavourably with itsheterodimerizationtokeratin9, caused bykeratin2mutationsthatinterfere ichthyosis, superficial of type Siemens the keratin 10 (93). Conversely, patients with placer ofmutatedkeratin1duringitsdimerizationwith with KRT10-mutated epidermis,butdeleteriousinpatients by retinoids;thiseffect isharmlessinbothnormal and explanation istheubiquitousdown-regulationofKRT2 more blisters during retinoid therapy (91). A proposed tients withKRT1mutationsoftengetworseanddevelop tent withadown-regulationofmutatedKRT10(92),pa respond quitewelltolow-doseretinoidtherapy, consis or in patientswithepidermolyticichthyosisduetoKRT10 example isthedifferent outcomeofretinoidtreatment on ichthyosispathogenesisarealsotobeexpected.One rous genes expressed in epidermis, more specific effects transcription factors and regulate the expression of nume because many retinoids bind to specific ligand-activated have anti-keratinizingandkeratolyticeffects. However, ally available (90).Broadly speaking, vitamin A agonists agents (RAMBAs),such as liarozole, not yet commerci benefit ratio (89), and metabolism blocking as ,probablyhavingalessfavourablerisk/ preferred drugsforsystemicuse,withnewcomers,such forms of ichthyosis. and are the retinoids remain mainstay therapy formoderate to severe Besides emollientsandkeratolyticcreams(2,3,26), NEW THERAPEUTIC DEVELOPMENTS tive genodermatoses(87,88). therapy”) aninterestingpossibilityfordominantnega makes drugenhancementofrevertance(“naturalgene with confetti(85)andloricrinkeratoderma(86). This been described in epidermolysis bullosa (84), ichthyosis lar examplesofspontaneousrevertantsintheskinhave 26intothegap-junctions(Fig.6B)(83).Simi thus allowinganunopposedincorporationofwild-type that thedenovogeneproductremainedintracellular, mutations togetherwithwt-GJB2inHeLacellsshowed allele. Co-transfectionofgermlineanddenovo(somatic) de novo mutations restricted to the disease-causing GJB2 Encouragingly, manynewideasfor KRT1 mutations(91). Whereas theformerpatients KRT1 mutationswhodependonkeratin2asare - enzyme replacementtherapy. ERT:therapy. ichthyosis of development future about ideas of Summary 7. Fig. ------

ichthyosis inthefuture(97,98). situ, holds promise for a more specific gene therapy for editing, aimedatcorrectingtheunderlyingmutationin These andotherapproaches,suchasCRISPR/Cas9gene fragility filament intermediate the reverts activator-like effector nuclease(TALEN) technology mutated dermolytic ichthyosis (EI)(95).Moreover, disruption of mutations willremainunresponsive.Inthiscontext,en implying that lipodysgenic ARCI due to truncating CLE formationmustremainatleastmarginally intact, treatment to be effective in ARCI, all genes involved in cardiovascular disease.However, forthishypothetical veral PPAR agonistsarealreadyinusefordiabetes and the expressionofmany ARCI genesinvitro (100).Se (PPARs) expressedinepidermisandknowntoaffect such asperoxisome proliferator activating receptors pathway vialigandstimulationoftranscriptionfactors, still preclinical, approach is to enhance the acylCer candidates for testing topically in ARCI (99). Another, now besynthetizedinlarge amounts,theyareobvious resting approaches.Sincevarioustypesofceramidescan lief tothepatient. Whether thisgoalisattainablethrough intrinsic responses,whichoftencausemoreharmthanre ways torestoretheskinbarrieranddampenexcessive therapies inichthyosisshouldalsofocusonalternative of ichthyosis(56).Inthelongterm,searchfornew ved biologicaltherapiesfeasibletotestinseverecases many similaritiestopsoriasis,makingalreadyappro has ARCI in inflammation skin that noteworthy is it mains tobestudied. would provemostversatile,althoughthisapproachre of ERT andsupplementationwithsyntheticceramides TGM1-associated ARCI (101). Perhaps a combination (but expensive) future option, especially for patients with recombinant transglutaminasemaybecomeanattractive zyme replacementtherapy(ERT) withtopicallyapplied a keratinopathicdisordermechanisticallysimilartoepi Substitution andreplacementtherapyareotherinte As regardstreatmentofsecondarypathogenicevents, KRT10 in EI keratinocytes using a transcription Ichthyosis: aroadmodelforskinresearch Theme issue:Genodermatoses in vitro (96). 203 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Genodermatoses REFERENCES cation ofActaDermato-Venereologica. Conflicts of interest: AV istheChairmanofSocietyforPubli studies. laboratory staff, andfundersforall theirsupportinthepresented We thank ourco-authorsandtheparticipatingpatients,health& ACKNOWLEDGEMENTS barrier. also characterized by inflammation and a perturbed skin to ichthyosis,suchaseczemaandpsoriasis,whichare many other skindiseases with biological features similar this research,newknowledgemayalsobegainedabout aimed at improving the patients’ qualityof life. Through the years,thereisstillagreatneedfornewdevelopments genetic counsellingshouldnearlyalwaysbefeasible. establishment ofmodeinheritance,andanaccurate definite a life, in early diagnosis exact an level, tural been characterized at both the genomic and ultrastruc logy ofmanyskindiseases,notleastichthyosis. skin, muchinformationisattainableabout the pathobio invasive skinbiopsies,orinvitro culturesofreconstituted tech biochemicalandgenomicanalysesofminimally vivo measurementsof TEWL and surfacepH,tohigh- gative methods,rangingincomplexityfromsimple friendly” organ. Bycombiningawidevarietyofinvesti The skinis,bothclinicallyandpre-clinically, a“research- CONCLUSION other prospectsforichthyosistreatment. to bedetermined.Fig.7givesasummaryoftheseand tailored moleculesandsubstitutiontherapies,remains specifically by or biologics, new and technology gene 204 Though thetreatmentoptionshavealsoevolvedover Today, whenalmost100subtypesofichthyosishave 7. 6. 5. 4. 3. 2. 1. congenita type III. 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