Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV doi: 10.2340/00015555-3123 described below. ting furthergeneticinvestigations andprimarycare,as who have a responsibility in recognizing and facilita patients aregeneralpractitioners anddermatologists, these treat and see to practitioners healthcare first The identify. to slower and difficult more are malignancies Skin symptomsareeasiertorecognize,whereasvisceral and diagnosisiscrucialtotheoutcomeprognosis. potentially affected family members. Early identification of identification for as well as treatment, and diagnosis reness ofthesedisordersisthereforeessentialforearly though with multiplefamilymembersshowingsymptoms,al­ skin conditions,orgenodermatoses,areoftenclustered, associated withinternalmalignancies. These hereditary netically predisposedtodevelopskincancer, sometimes S mark. E-mail:[email protected] Odense University Hospital, Vesterbro 116, 1th, DK-5000 Odense C, Den Corr: Juliane Schierbeck, Department of Dermatology and Allergy Centre, Acta DermVenereol 2019;99:360–369. Accepted Jan16,2019;E-published17,2019 squamous cellcarcinoma;hereditaryskincancer. Key words: genodermatoses; skin cancer; basal cellcarcinoma; noma syndrome. inherited, asinfamilial atypical multiple mole mela dysplasia verruciformis. Malignant melanoma can be Thomson syndrome,Bloom syndrome, andepidermo syndrome,keratitis-ichthyosis-deafness Rothmund- Muir-Torre syndrome, Mibelli-type porokeratosis, related to: xeroderma pigmentosum, Ferguson-Smith, syndrome. Multiple squamous cell carcinomas can be drome, Rombo syndrome, andBazex-Dupré-Christol ciated with basal cell carcinoma are: Gorlin–Goltz syn and management. The most common syndromes asso are described with genetics clinical characteristics, tients with multiple skin cancer lesions. Thedisorders is intended asadiagnostic tool whenencountering pa genetically predisposed to skin cancer and this article and medicaltreatments. Asmall group of patientsare cer worldwide of asaresult environmental exposure Department of Dermatologyand Allergy Centre, Odense University Hospital, Odense, Denmark Juliane SCHIERBECK, Skin CancerAssociatedGenodermatoses:ALiteratureReview 360 Skin cancerhasbecomethe most common typeof can Acta DermVenereol 2019;99: 360–369 or radiotherapy. ultraviolet radiation(UVR),immunosuppressivetherapy Skin cancerisoftencausedbyenvironmentalexposureto Denmark (whichhasapopulationof~5.8million)(1). A small,andoftenoverlooked,groupofpatientsarege wide, withmorethan15,000patientsannuallyin kin canceristhemostcommontypeofworld de novomutationsarealsonotuncommon. Awa Tine VESTERGAARD and Anette BYGUM This isan open access article under the CC BY-NC license. www.medicaljournals.se/acta REVIEW ARTICLE ------­ ­ ­ ­ - bifid rib syndrome, is an autosomal dominant condi dominant autosomal an is syndrome, rib bifid multiple naevoidbasalcellepithelioma,jawcystsand syndrome, naevoidbasalcellcarcinomasyndromeor Gorlin–Goltz syndrome(GGS),alsoknownasGorlin Gorlin–Goltz syndrome HEREDITARY BASALCELLCARCINOMA multiple skincancers. serve as atoolindiagnosingandtreatingpatientswith (SCC) andmalignantmelanoma(MM). The reviewwill basal cellcarcinoma(BCC),squamous on chromosome 10q24-q25, encoding for proteins in the PTCH2 geneonchromosome1p32, ortheSUFUgene mutations inthePTCH1geneon chromosome 9q22, the in moleculargeneticshave proven GGStobecausedby Molecular genetics andpathophysiology bifid ribs(4). multiple naevoidbasalcellepitheliomas,jawcystsand of consists which syndrome, specific the described and the dermatologist Robert Goltz,who, in 1960, published pathologist andhumangeneticistRobertJ.Gorlin adenoides cysticumin1951(3).Itwas,however, theoral callosum, a bifid rib, an ovarian fibroma and epithelioma tion betweendentalcysts,partialagenesisofthecorpus determine thediagnosis,asshowninTable I . criteria or1majorand3minorarenecessaryto miliaandsyndactyly(2). malies, Two majorand1minor kyphoscoliosis, ribanomalies,cleftlip/palate,eyeano medulloblastoma, cerebri, falx the of calcification are and a predisposition for BCC.Other cardinal features frontal andbiparietalbossing),dentalcysts,palmarpits prognathia, lateraldisplacementoftheinnercanthus, tion causing unusual facial appearances (mandibular from our practice. associated withskincancer, and includesclinicalimages and management suggestions for hereditary syndromes This article describes clinicalfeatures, genetic descriptions multiple cancerous lesionswithnoobviousexplanation. hereditary causes, especially when examining patients with portant for physicians treating skincancer tobe aware of an increasedriskof skin cancer development. Itisim This article reviews hereditary skin syndromes that cause SIGNIFICANCE This literaturereviewfocusesonhereditarycausesof Binkley & Johnson were the first to suggest a correla Journal Compilation ©2019ActaDermato-Venereologica. . Recent studies . Recent studies - ­ ­ ­ Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV milia-like papules develop, along with telangiectatic reddening oftheskin.Inadulthood whitish-yellowish, preauricular areaandforehead, alongwithcyanotic with areticularpatternof skin atrophyonthecheeks, Characteristics. The syndromepresents inchildhood mal dominantinheritance(7). autoso suggesting generations, 4 through transmission male transmission has been described ina familywith mutation inRShasyettobedetermined,butmale- - genetic Molecular geneticsandpathophysiology.The rare andonlyafewcaseshavebeenreportedsincethen. vasodilation withcyanosis(6). The conditionisextremely hypotrichosis, trichoepitheliomas,BCCsandperipheral described a family with vermiculate atrophoderma, milia, describe Rombo syndrome (RS), in 1981, when they to first the were Westermark & Olsson Michaelsson, Rombo syndrome B). during theirlifetime(Fig.1A, develop from afew BCCstoseveral hundredsofBCCs bossing andhypertelorism.PatientswithGGSmay frontal ribs, bifid as such abnormalities, skeletal with childhood areconsideredaverystrongindicator, along senteric cysts and ocular abnormalities. Palmarpits in lip and/or palate, ovarian/cardiac fibroma, lymphome skeletal malformationsincludingmacrocephaly, cleft specific other anomalies, rib include criteria Minor first-degree relative with GGS and multiple BCCs (2). a medulloblastoma, cerebri, falx the of calcification criteria are odontogenic keratocysts, palmoplantar pits, should alsoraisesuspicion. The primarydiagnostic but other cutaneous characteristics, such as palmar pits, ping BCCsbetweenpubertyandtheageof35years, Characteristics. PatientswithGGSoftenstartdevelo with anevensexdistribution. prevalence is reported to be 1 in 56,000–164,000 people, of patientswithGGSdonotdevelop BCCs(5). The with completepenetrance,althoughapproximately10% sue development. The condition is autosomal dominant hedgehog signalling pathway, controlling growth and tis Table I.DiagnosticcriteriaforGorlin–Goltzsyndrome • • • • • • • Minor criteria • • • • • • Major criteria glaucoma, coloboma) Ocular abnormalities (i.e. strabismus, hypertelorism, congenital cataracts, Lymphomesenteric cysts Ovarian/cardiac fibroma Cleft lipand/orpalate Macrocephaly anomalies, kyphoscoliosis,shortfourth metacarpals, postaxial polydactyly) Other specific skeletal malformations and radiological changes(i.e. vertebral Rib anomalies First-degree relative withGorlin–Goltzsyndrome Medulloblastoma, typically desmoplastic Lamellar calcification of thefalx cerebri Palmar or plantar pitting Odontogenic keratocysts of thejaws prior to20 years of age exposure andskin type or <20years of age Excessive numbersof basal cell carcinomas out of proportion with prior sun ­ ­ ­ ­ Characteristics. Patients with BDCS are generally diag female tomaleratiois2:1(11). commonly present in the second decade onwards. The most they although life, of decade first the in described the Hedgehogsignallingpathway(10).BCCshavebeen in theARCT1gene,resultinganaberrantactivationof has revealed that BDCS might be caused by mutations . andpathophysiology genetics Molecular A recentstudy 20 familieshavebeenreported(9). BCCs. The conditionisveryrare;onlyapproximately and skin,alongwithanincreasedriskofdeveloping an X-linkeddominantsyndromeaffecting hairfollicles as (BDCS) syndrome Bazex-Dupré-Christol condition the described first Christol & Dupré Bazex, 1964 In Bazex-Dupré-Christol syndrome throughout life(8)(Fig.1C). multiple BCCs.Hypohidrosisandfacialhyperpigmen milia primarilyontheface,follicularatrophodermaand nosed based on a combination ofhypotrichosis, multiple Milia onthecheek,asseeninBazex-Dupré-Christol syndrome. 600 tumours removed.as seen (C) Hypotrichosis in Rombo syndrome. (D) carcinomas (BCC) of the scalp and neck. Thispatient has had more than Fig. 1.(A, B) Patient syndrome with Gorlin–Goltz and multiple basal cell and neck(9,12)(Fig.1D). of life,typicallyinsun-exposedareas,suchasthehead years, butoftendevelopinthesecondorthirddecade appearance. BCCsarereportedasearlytheageof3 dorsa ofthehands,givingacharacteristicorange-peel The follicularatrophodermaislocatedmainlyonthe tation arealsodescribedas early-onset manifestations. 3 eyebrows arealsoseeninadulthood.BCCsdevelopthe vessels. Defectiveorcompletelymissingeyelashesand rd or 4 or th decadeoflifeandareaconsistentcomplication Skin cancerassociatedgenodermatoses Acta DermVenereol 2019 361 ­ ­ Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV www.medicaljournals.se/acta killer cells,macrophagesandB-lymphocytes. This treat Other celltypesactivatedbyimiquimodincludenatural (TNF-α)). factor-α necrosis tumour and interleukin-6, interferon-α, (primarily cytokines secrete TLR-7 via in pathogenrecognition.Cellsactivatedbyimiquimod through toll-likereceptor7(TLR7)commonlyinvolved works by enhancing the innate arm of the immune system Imiquimod isproducedasapatient-appliedcreamand discreet aspossible. in alifetimeandeverytreatmentshouldthereforebeas treatments. SomepatientsdevelophundredsofBCCs first-line as considered be always should cryotherapy, maintain acosmeticallyacceptableoutcomewhiletrea surgical excisionisnecessary. The goalshouldbeto is targeted celldeath. (O are listedinTable II . investigation oftenleadsto thecorrectdiagnosis. These overlap thepreviouslymentioned syndromes,andgenetic risk ofdevelopmentBCC. Their symptoms somewhat There areotherraresyndromes linkedtoanincreased Other rare syndromes linkedtodevelopmentofBCC ting theunderlyingmalignancy. oxygen (O radicals andreactiveoxygenspecies,includingsinglet impaired cells. When exposedtolight,thecells produce applied ontheaffected skinandwillbeabsorbedby the localized BCC, AK andMB. A photosensitizingagentis PDT isusedinavarietyofmedicalconditions,mostly cell apoptosisasaresultofthymidinedepletion. fore causesrapidlydividingcancerouscellstoundergo is anucleosiderequiredforDNA replication.5-FUthere­ of thisenzymeblocksthesynthesisthymidine,which a thymidylatesynthaseinhibitor. Interruptingtheaction 5-FU cream is used for AK and BCC.It acts primarily as (MB) andBCC. ment isusedforactinickeratosis(AK),morbusBowen orouracil (5 of smallerBCCscanimprovethecosmeticoutcome. There arenoperfectsolutions,butpromptmanagement should beoffered patients. andtailoredtoallpredisposed matological treatmentandregulation. Annual check-ups identification and genetic investigation is crucial in der When the suspicion of a genodermatosis arises, clinical ment withahedgehoginhibitormightbeindicated(6). for patientswithmultipleoraggressiveBCCs,treat should primarilyincludenon-surgical methods,and, Since patientsmaydevelopmultipleBCCs,thetreatment and, insomecases,dentistryandotolaryngology(13). including dermatology, plasticsurgery, ophthalmology approach,should beperformedinamultidisciplinary . Management Treatment multipleBCCs with ofpatients 362 For more delimited or larger tumours, curettage or Non-surgical methods, such as imiquimod, 5-flu imiquimod, as such methods, Non-surgical 2 −) ions. With sufficient oxidative damage, the result J. Schierbecketal. 2 ), hydroxylradicals(•OH)andsuperoxide - FU), photo - dynamic therapy (PDT) and ­ ­ ­ ­ ­ non-melanoma skincancer(NMSC)anda2,000foldin patients haveanestimated10,000-foldincreasedriskof XP(14). population general the in than earlier years 50 of BCCandSCCisapproximately8years,morethan XPC, XPD,XPF, XPGorPOLH. The medianageatonset genetic mutations in the following genes: XPA, XPB, is based on family history, clinical findings and biallelic damage, therebypreventingskincancer. The diagnosis an essentialroleinthecorrectionofUV ciated with nucleotide excision repair (NER). NER plays have been identified as the cause of XP, all of them asso Molecular genetics andpathophysiology. countries (15). an ultra-rareconditionwithaveryfewcasesinsmaller dence isapproximately1in250,000newborns,andit able freemargins dueto the highriskofrecurrence.XP surgically, preferablywithMoh’s surgery orwithirrefut­ Larger skin-lesionsandSCCsshouldalways betreated cryotherapy ortopicallywith 5-FUorimiquimod(16). ler pre-neoplasmsandlocalizedBCCs canbetreatedwith and detectingskinchanges in theirearlieststages.Smal the prognosis ofXP depends onminimizing sun -exposure Management. B). is oftenpresent(Fig.2A, telangiectasia canpresentlateron.Opticalphotophobia rough andatrophic(18).Smallhypopigmentedspots Without sunprotection,theskinagesandbecomesdry, neglect or labelled wrongly as cellulitis or impetigo (17). as misinterpreted often is and life, of weeks first the in takes daysorweekstoheal. The reactioncanoccureven seen aftersun-exposure,causingseveresunburn,which XP of indication MM. first and often The SCC is BCC, changes andahighriskofskinmalignancies,suchas sitivity andprematureskinageing,alongwithpigmentary Characteristics. XP ischaracterizedbyseverephotosen translational synthesispastDNA photoproducts(16). this variantischaracterizedbyafailureinerror Europe andtheUSA,butunlikeotherXP mutations, creased risk of melanoma below the age of 20 years (16). the geneticcauseasadefectinDNA repair. The inci a hightumourburden.In1968JamesCleaverdescribed pigmented skin”,isanautosomalrecessivedisorderwith “dry means XP,which (14). Kaposi & Hebra by 1874 in described first was (XP) pigmentosum Xeroderma Xeroderma pigmentosum HEREDITARY SQUAMOUS CELLCARCINOMA carcinoma associated withbasalcell Table II.Listofothergenodermatoses • • • • • • • A clinicallysimilarvariantXP-V isprimarilyfoundin Brooke-Spiegler syndrome Muir-Torre syndrome Hermansky-Pudlak syndrome Cowden syndrome Cartilage-hair hypoplasia Schöpf-Schulz-Passarge syndrome Oley syndrome(possibly a subtype of Bazex-Dupré-Christol syndrome) Although thereareindividualvariations,

-induced DNA Multiple genes Multiple genes -free ­ ­ ­ ­ ­ Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV permission fromTaylor &Francis (50). young a in Poikiloderma F) (E, self-healing. post finger patient Rothmund-Thomsonwith A syndrome. Written permission from the patient isobtained to publish these photos. Figures A and B are published after (D) lip. Upper (C) Ferguson-Smith. with patients in tumours Skin D) (C, Francis. Taylor& Fig. 2.(A, B) Patient with xeroderma pigmentosum with hyperpigmentation of sun-exposed areas, impaired hearing and dry, atrophic skin. Rare diseases, early on,isagoodsolution. However, mutilatingsurgery due tothehistologicalsuspicion ofSCC,andiftreated Management. Surgical interventionis oftenperformed invasion, butwillnevermetastasize (20)(Fig.2C,D). recessed scar. The tumours have atendency to local tissue spontaneously self-heal after 2–3months leaving a small and examinationoftheskinisimportant. The tumours ween SCCandMSSEtumours,thusathoroughhistory a keratoacanthoma. Biopsies cannot differentiate bet a pearlynodulewithcentralkeratosis,visuallyimitating within 3–4 weeks, growing from a 1–2 mm red papule to suspicious ofmalignancy. The tumoursusuallypresent symptoms early in life, presenting skin tumours highly Characteristics. Patients with MSSE often show mechanism of spontaneous healing has yet to be clarified. pathway, triggering uncontrolledcellgrowth(20). The genes. The mutations cause an inactivation of the TGFβ- and mutation wasshown,in2005,toresidetheTGFBR1 genetic Molecular geneticsandpathophysiology.The an autosomaldominantgenodermatosis(19). Ferguson-Smith, ascertained thegeneticinheritance as liomas (MSSE)(17).In1971hisson,geneticistM. early onsetofmultipleself-healingsquamousepithe family ofScottishminers.Hedepictedaconditionwith described acorrelationbetweencertainsymptomsin Ferguson-Smith J. dermatologist Scottish the 1934 In Ferguson-Smith syndrome increase lifeexpectancy(16). can improvethequalityoflifeand,inbestcase,also andmalignancies. changes skin tion ofprecancerous This complete skinexaminationsareessentialinearlydetec specialized investigation at the time ofdiagnosis. Regular along with neurologicaldefects, and should bereferredto patients alsohaveincreasedriskofocularabnormalities, TGFBR2 genes,whicharebothtumoursuppressor ­ ­ ­ painless, slow-growing,pinkoryellownodules, often mas, andcarcinomas.Skin lesionsinitiallypresentas York DermatologicSociety(22). Douglas P. Torre described the same findings at the New age (21).Oneyearlaterthe American dermatologist development of multiple internal malignancies at a young correlation betweenseveralkeratoacanthomasandthe In 1967theBritishphysicianEdgarG.Muirnoted Muir-Torre syndrome cosmetic result. goal istokeepthepatienttumour be doneunderregularclinicalsupervision. Again, the and mouth)canbelefttoself-heal,althoughthisshould Tumours, situated outside the risk areas (eyes, nose, ears ces anddoesnotconcurwithourpersonalexperience. however, hasnotbeensubstantiated byoriginalreferen radiotherapy mightworsenthecondition. This statement, to excision,whereassomestudieshaveproposedthat should beavoided.PDT canbeusedasanalternative amount ofsebaceousneoplasms: adenomas,epithelio Characteristics. PatientswithMTSpresent withahigh an increasedriskofNMSC andvisceralmalignancies. in particularvisceraandskin.Subsequentlyresulting DNA mismatchrepair, affecting rapidlydividingcells, genodermatoses, MTS is caused by a defects in the involved inDNA mismatchrepair(23). for otherAs by mutationsintheMLH1,MSH2,andMSH6genes, Molecular geneticsandpathophysiology. female ratioof3:2. approximately 9.2% of these (22). MTS has a male to in approximately1:350livebirths,andMTSisseen polyposis colorectalcancer(HNPCC).HNPCCoccurs expression, thoughttobeasubtypeofhereditarynon- dominant conditionwithhighpenetranceandvariable Muir -Torre (MTS) isarareautosomal syndrome Skin cancerassociatedgenodermatoses Acta DermVenereol 2019 -free withthebest MTS is caused MTS iscaused 363 ­ ­ Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV www.medicaljournals.se/acta and linearporokeratosis(25). plantaris et palmaris disseminata, punctate porokeratosis minated superficial actinic porokeratosis, porokeratosis disse porokeratosis, superficial disseminated Mibelli, of porokeratosisarenowrecognized: variants clinical Six (25). “porokeratosis” termed he unmarried, of a well-todo family of Parma” with what [years], 21 “age man, young a of report case a blished In 1893theItaliandermatologist Vittorio Mibellipu Mibelli-type hereditary porokeratosis needed forcurativetumourtreatment development (24). Tumour excision or curettage is often isotretinoin, whichhasbeenfoundtopreventtumour oral of consists malignancies skin of Treatment (24). cal evaluation,andimagingoftheabdomenpelvis and early colonoscopies, mammograms, dermatologi cies aspatientswithHNPCC. This includesfrequent screening forcolorectalcarcinomaandothermalignan Management. Patientsshouldbeoffered thesamestrict age of21years(23). neoplasms is 53 years, but it can present as early as the internal malignancy. The meanageofonsetsebaceous tumour (adenoma,epithelioma,orcarcinoma)andone The diagnosis is based on atleast one sebaceous gland nancies ofthecolonandgenitourinarytract(Fig.3D,E). to furtherinvestigation. traits andmultiplekeratoacanthomasshouldgiverise Keratoacanthomas in MTSusuallydisplaysebaceous aggressive, resultinginlocalinvasionandmetastases. mours are benign,but the sebaceouscarcinomacan be with centralumbilicationorulceration.Mostofthetu 364 to publishthesephotos. of the abdomen. (D, E) Pale, keratotic nodule on the columella of a patient with Muir-Torre syndrome. Written permission from the patient is obtained 3. (A, Fig. B) A 31-year-old man with keratitis-ichthyosis-deafness (KID) syndrome, alopecia and keratosis. (C) Mibelli-type hereditary porokeratosis Patients withMTSarealsopronetodevelopmalig J. Schierbecketal. ­ ­ ­ ­ ­ ­ first described the condition as a combination of con of combination a as condition the described first In 1915theCanadiandermatologistFrederickS.Burns Keratitis-ichthyosis-deafness syndrome or contraindicated. difficult is agents topical of use the when preferred be cream (27).Surgical interventionsandcryotherapymay of Mibellicanbetreatedsuccessfullywithimiquimod formation, excisioniscurative.Classicalporokeratosis biopsied. Ifthelesionhasnotundergone malignanttrans excessive sunlight.Uponsuspicion,lesionsshouldbe ups andbeadvisedtousesunprotectionavoid Management. Patientsshouldbeoffered regularcheck- been described(26). butulcerativelesionshave areasymptomatic, lesions involving thedigits,itcaninducepseudoainhum.Most an elevatedkeratoticborder. When circumferentially papules orannular plaques thatexpandcentrifugally with Characteristics. The skinlesionspresentaskeratotic factors (26)(Fig.3C). wounds andexposuretoUVRareallknowncontributing dysplasia. Immunosuppressivediseasesanddrugs,burn be duetocellularclonesexhibitingvaryingdegreesof on histological examination. The lesions are thoughtto All forms share common features ofcornoid lamella commonly, intoSCCandlesscommonlyBCC. keratosis canundergo malignanttransformation, most 18 affected patients and proposed the name keratitis- in a16-year palmoplantar keratosis,andsensorineuralhearingloss genital atypical ichthyosiform erythrokeratoderma, is considered a premalignant condition. All types of poro Molecular geneticsandpathophysiology.Porokeratosis -old boy. In1981Skinneretal.reviewed ­ ­ ­ Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV hypoplastic teethanddisorders ofdentalbreakthrough. Dental aberrationsinclude microdontia, rudimentaryor cally dystrophicwithpachyonychia asafrequentsign. is oftenthin,brittleandsparse, andthenailsaretypi hair alter. The to first are teeth and nails hair, skin, the displayed inindividualpatientsarehighlyvariable,but Characteristics. The severityandamountofsymptoms medical literature(32). only approximately300patientshavebeenrecordedin in there isahomozygousorcompoundheterozygousdefect geneous disorderwithunknownaetiology. InRTS-II DNA damage.RTS-I isanautosomalrecessivehetero loss ofthisgeneleadstoanaccumulationunrepaired sible for correcting double-strandedDNA breaks. The (31). ItencodesfortheRECQhelicase,whichisrespon tion andpossiblegeneticmutationintheRECQL4gene RTS havebeenproposedbasedontheclinicalpresenta Molecular geneticsandpathophysiology. Two typesof sarcoma, poikilodermaandNMSC. be consideredwhenencounteringapatientwithosteo risk ofosteosarcomaandthisdiagnosisshouldalways Thomson added3similarcases. There isanincreased juvenile cataract (31). In 1936 theBritishdermatologist a combinationofpoikiloderma,growthretardationand in 1868bytheGermanophthalmologistRothmundas Rothmund-Thomson syndrome (RTS) was first described Rothmund-Thomson syndrome may reducetheincidenceofskincancer(30). Systemic retinoidscanreducethehyperkeratosisand especially SCCofthehyperkeratoticskinandmucosa. mended toassureearlydiagnosisofmalignanttumours, infections and NMSC. Lifelong follow -up is recom Management. The essentialissueisearlydiagnosisof and SCC(Fig.3 A, B). hidradenitis suppurativa)alongwithfolliculartumours triad (dissectingcellulitisofthescalp,cysticacne,and Patients aresometimesseenwithafollicularocclusion infections, viral, bacterial andfungalarealsocommon. ten keratitis. Alopecia andanincreasedsusceptibilityto deafness, erythroderma,hyperkeratoticplaquesandof Characteristics. KIDsyndromeischaracterizedby explain theconstellationofpathologicalfindings. epithelia oftheinnerear, corneaandepidermis,which are gapjunctionproteinsexpressedinectoderm-derived or theconnexin-30gene,GJB6(29).GJB2andBJB6 mutationsintheconnexin-26 missense gous belongs totheconnexindisorderscausedbyheterozy Molecular geneticsandpathophysiology.KIDsyndrome literature (29). ectoderm withapproximately100reportedcasesinthe main symptoms(28).Itisararecongenitaldisorderof ichthyosis-deafness (KID)syndrometodescribethe3 RECQL4. The condition is considered very rare and gene, GJB2, ­ ­ ­ ­ ­ ­ ­ ­ enzyme RecQL believed tobeamutationintheBMLgene,controlling Molecular genetics and pathophysiology. The cause is of males(35). in 48,000 live births. There seems to be a slight majority Jewish populationitisestimatedtobeapproximately1 The overall prevalence is unknown,but inthe Ashkenazi (34). dwarfism and erythema facial telangiectatic with patients of series a in 1954 in condition the described BS) isarareautosomal recessivedisorder. David Bloom Bloom syndrome(congenitaltelangiectaticerythema, Bloom syndrome (33). same lifespanexpectancyasthebackgroundpopulation regular screeningandtreatment,thesepatientshavethe for SCC/BCC,andadvicewithregardtosuncare. With follow- orthopaedic surgeon. Patientsshouldbeoffered life-long dermatologist, an oncologist, an ophthalmologist and an be managedbyamultidisciplinaryteam,including Management. All patients diagnosedwithRTS should bone lesions(32). osteopaenia, patellar ossification defects and destructive subtle anomalies,suchasradialaplasiaorhypoplasia, rays canbehelpfultovisualizedefectsanddetectmore seen inRTS-II asaresultoftheRECQL4 defects arethesecondmajorcriteria,almostexclusively SCC in young adults (33). Growth deficiency and skeletal defects, increasedriskofosteosarcomainchildhoodand E, F).RTS-II alsocausespoikiloderma,congenitalbone derma, juvenilecataract andectodermaldysplasia(Fig.2 throughout life(32). telangiectatic vesselsandpunctateatrophypersisting kiloderma andlesionsofhypo-hyperpigmentation, tocks. The rash eventually reaches a chronicphase of poi telangiectasia. SCC accounts for 14% of all tumours in tumours all of 14% for accounts SCC telangiectasia. severe photosensitivity, poikilodermaanderythematous to cancer development. Dermatological features include betes, chronicpulmonarydisease andapredisposition seek medicalassistancedue torecurrentinfections,dia muscles toappearmoreprominent. The patientsoften and reducedsubcutaneouslayeroffat,causingtheir zed byseveregrowthretardation,high-pitchedvoices 3 and6months,laterinvolvingtheextremitiesbut blistering facialrashoftenacquiredbetweentheageof A diagnostichallmarkistheerythematous,oedematous, Characteristics. PatientswithBSareoftencharacteri the upperandlowergastrointestinalurinarytract. cancer, mostoftenSCC,butalsoothermalignanciesof which may lead to malignancy (36). This may cause skin logical DNA exchanges between parallel chromatids, consequently causesgeneticinstabilityduetopatho­ replication forksduring DNA replication. This defect The mildest variant is RTS- up, including regular skin examinations to screen Skin cancerassociatedgenodermatoses 3 responsible for restoring malfunctioning responsible forrestoring malfunctioning I, characterized by poikilo Acta DermVenereol 2019 mutation. X- 365 ­ ­ ­ ­ ­ Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV www.medicaljournals.se/acta to publishthesephotos. versicolor-like skin lesions. Written permission from the patient is obtained child withepidermodysplasia verruciformis and plane wart-like or pityriasis verruciformis and squamous cell carcinoma of the scalp. (D) A 2-year-old hair and café-au-lait spots.(C)Male patient with epidermodysplasia Fig. 4.(A, B) A 3-year-old girlwithBloom syndrome. Sparse brittle rous lesionsandSCCs,especiallyinsun-exposedareas. ultimately thepatientsdevelopHPV mechanism ofpathologyhasyettobediscovered,but human papillomavirus(HPV)infections. The precise gene, makingthepatientextraordinarilysusceptibleto transmembrane channelTMC6/EVER1orTMC8/EVER2 somal recessiveskindisordercausedbymutationsinthe . EV andpathophysiology genetics Molecular anauto is 1 in1,000,000(38). rare genodermatosisandhasanestimatedincidenceof dermodysplasia verruciformis(EV)isconsideredavery skin lesions,sometimesalreadyinchildhood(37).Epi present withplanewart-likeorpityriasisversicolor tion andthedevelopmentofskinmalignancies.Patients Lutz in1922,whoobservedacorrelationbetweeninfec & Lewandowsky by described first was condition This Epidermodysplasia verruciformis skin carcinomas(36). patient withpoikiloderma,photosensitivityandmultiple it shouldalwaysbeconsideredwhenencounteringa patients atanearlystage. Although theconditionisrare, these diagnosing and finding in role important an have ting drugsshould be keptto a minimum. Dermatologists DNA damaging therapies, the useofradiation andalkyla skin tumours. As these patients are highly susceptible to exposure andtheyshouldalsoberegularlyscreenedfor Management. Patientsareadvisedtoavoiddirectsun B). (35) (Fig.4A, patients withBSameanageatonsetof31.8years 366 J. Schierbecketal. -induced precance -like ­ ­ ­ ­ ­

development oratleastminimizetheamountofmalig Regular skincheck-upscouldhelppreventmalignant precancerous elementscanbetreatedwithcryotherapy. rently nocurativetreatmentoptions.Earlydetectionof Management. As forothergenodermatoses,therearecur (Fig. 4C,D). typically startinthesecondorthirddecadeoflife(38) transformation andbecomeinvasiveSCC. This will areas, which,ifleftuntreated,oftenundergo malignant quently developprecancerouslesionsonsun-exposed elements onthechestandabdomen.Patientssubse plana, red-brownplaquesandpityriasisversicolor infancy asscalyreddishskinlesionsresemblingverruca Characteristics. The first symptoms often develop during mutations. 8 infections,butgeneticinvestigationsshowno EV (37). These patientsalsotestpositiveforHPV 5and therapy mayalsodevelopaclinicalpicturelikethatof proteins, P16 and P14ARF.and P16 proteins, the of inactivation short, In It islocatedonchromosome 9p21.3andencodesfor2 the on discovered of was mutation FAMMM gene first the Molecular geneticsandpathophysiology.Inthe1990s accounting for47,000deathsworldwideannually(42). ped countries, CMM isthe sixth most common cancer, not detectedandtreatedinitsearlieststages.Indevelo CMM isconsideredthemostdangerousskincancerif in thiscasealongwithanincreasepancreaticcancer. family,but a in features same the observed (41) Krush family historyofthisconstellation.In1968Lynch & a 59-year described He (40). WilliamNorris by 1817 in reported nant melanoma (CMM). The first case of FAMMM was more than50,andafamilyhistoryofcutaneousmalig characterized bymultiple melanocytic naevi, usually syndrome isanautosomaldominantgenodermatosis Familial atypical multiple mole melanoma (FAMMM) Familial atypicalmultiplemolemelanomasyndrome HEREDITARY MALIGNANTMELANOMA spectrum anddonottarget HPV 5or8(39). the currentlyavailablevaccinesaretoonarrowintheir be considered,especiallyinyoungerpatients,although shown promisingresults(38).HPV vaccinationshould ally in relation to verruca plana, and retinoids have also patients withepidermodysplasiaverruciformis,especi nancies. Imiquimod,5-FUandPDT havebeenusedin HIV infection,butpatientsinimmunosuppressive children andadults,isprimarilyassociatedwith (Gardasil 9orCervarix)(39). for HPV 5or8,notincludedin the generalHPV Approximately 90%ofallcutaneousSCCstestpositive An acquired form of EV has been described both in P16/P16INK4A gene,nowknownas CDKN2A (42). -old manwithmelanoma,multiplemolesand -vaccine -like ­ ­ ­ ­ ­ ­

Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV melanocytes extend alone or ingroupsbeyond the main dermal component. intraepidermal wherein phenomenon, the ”shouldering” and infiltration lymphocyte dermal variable bridges; form to ridges rete adjacent with fusing and size variable *Architectural disorder with asymmetry, subepidermal fibroplasia, and lentiginous melanocytic hyperplasia with spindle or epithelioid melanocytes gathering in nests of Table III.Diagnosticcriteriaoffamilial atypicalmultiplemolemelanoma described asadistinctentityin2011 by Wiesner etal. tated atypical intradermal tumours (MBAITs) were first associated protein-1(BAP-1).Melanocyticmu revealed, the most prominent of them being the BRCA1- Other melanoma-predisposinggenemutationshavebeen BAP-1 mutation PET/CT screenings,etc.(45). regards to excision margins, sentinel node diagnostics, with guidelines national follow should MM verified of prophylactic treatmentofthispatientgroup. Treatment selling onsun-exposureandprotectionisessentialinthe introduced toreducediagnosticerrors. Thorough coun tal dermoscopyandcomputerimageanalysis,havebeen digi as such otherobjectivemeasurements, consequently of naevi can be difficult even with regular dermoscopy; can progressevenintheearlyteens.Exactevaluation giventhatCMM genitalareaandnails, oral mucosa, a baselinecompleteskinexaminationincludingscalp, FAMMM patientsshouldbeoffered atanearlyage,with Management. DermatologicalscreeningforCMMin melanoma intheirlifetime(41)(Fig.5). of lifeandpatientsfrequentlyexperiencemorethan1 commonly detectedbetweenthesecondandthirddecade are oftennotawareoftheirownincreasedrisk.CMMis FAMMM patientshaveafamilialhistoryofMM,but The diagnostic criteria are shownin Table III . Most objective findings and only supported by genetic testing. Characteristics. FAMMM is a clinical diagnosisbasedon skin types(42). probably aresultofsharedsunexposureandsusceptible an unknownmutationorhasnogeneticandis majority offamilialMMisthereforeeithercausedby by caused are these of 40% lignant melanomas are hereditary, and approximately FAMMM (44). tations ofCDK4are,however, consideredveryrarein is similartothatofCDKN2A-mutations.Germlinemu andthegeneticoutcome to inhibitionbytheproteinP16, ditary MM (44). This mutation makes CDK4 insensitive coding for cyclin-dependent kinase 4 (CDK4) and here described thecorrelationbetweenmutationsingene geographically variable expressivity. In 2003 Hayward a and penetrance reduced a has mutation (43). The tion apoptosis, increasingtheriskofmalignanttransforma pathways andtherebyenhancesproliferationreduces CDKN2A genedisturbsthe TP53 tumour 3. Naevi with certain histological features on microscopy* 2. High total-body naevi count (often >50), includingsomeof which are clinically atypical (asymmetric, raised, colourvariation present, of variable sizes) 1. Malignant melanoma in 1or more first- or second-degreerelatives It isestimatedthatapproximately5–12%ofallma mutations. The CDKN2A -suppressor ­ ­ ­ ­ ­ ­ ­ familial atypicalmultiplemolemelanomasyndrome Fig. 5.A36-year-old man presentingwithmultiple naevi due to as previouslymentioned. guidelines aspatientswithCDKN2A/CDK4mutations, risk ofmesothelioma. well asannualphysicalexaminationsfocusingonthe imaging (MRI)every2yearscouldbeconsidered,as annual abdominalultrasounds.Magneticresonance gical followupisrecommended,incombinationwith Management. Annual dermatologicalandophthalmolo and ahigherriskofmetastasis. more aggressive cancers, with higher tumour staging have to tend patients These (47). reported been have of onset50years,butpatientsasyoung16years nancy infamilieswithBAP-1mutationsameanage patient. Uvealmelanomaisthemostcommonmalig the numberoftumourscanvarygreatlyfrompatientto of life (48). More tumours often develop over time, but measuring approximately5mm,intheseconddecade develop skin-colouredortanned,elevatedtumours, Characteristics. Patientswiththissyndrometypically senescence, andthecellcycle(47). damage response,aswellinregulationofapoptosis, DNAis notfullyexplained,buthasbeenproposedinthe described as a binding partner of BRCA1 Molecular genetics and pathophysiology. BAP-1 was first renal cellcarcinoma(47). CMM, uvealmelanoma,malignantmesotheliomaand 4 distinct cancers have been linked to by a high penetrance of melanocytic neoplasms.Sofar caused bygermlinemutationsofBAP-1,characterized (46) . It is considered an autosomal dominant syndrome Patients shouldbegiventhesamesun-protection Skin cancerassociatedgenodermatoses Acta DermVenereol 2019 BAP-1 mutations; . Its cellular role . 367 ­ ­ Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV www.medicaljournals.se/acta REFERENCES extracutaneous symptoms. correct diagnosisandtreatment,especiallyinrelationto netic investigationisthereforecrucialinestablishingthe and areoftenthoughtofinthesamecontext.Exactge The above-mentionedsyndromeshavemanysimilarities, mations, neurological deficits and cognitive impairment. gastrointestinal cancer, boneabnormalities, teeth malfor plans. Extracutaneoussymptomsincludepancreaticand early examinationandexecutingappropriatetreatment dermatologists thereforehaveagreaterresponsibilityin and symptoms, display to organ first the often is skin to geneticinvestigationisofutmostimportance. The in general,veryrare,andprompttreatmentreferral Genodermatoses withskincancerpredispositionsare, CONCLUSION 1/2 mutations)(49). (TP53 mutations)andhereditarybreastcancerBRCA syndrome (PTENmutations),Li-Fraumeni xeroderma pigmentosum(describedabove),Cowden noma playsalessdominantrole,exist. These include cell cyclesandmalignanttransformations. genes, andmutationsinthesecancauseuncontrollable transcription factor. lineage-specific melanocytic a represents it as MM, of tations intheMITFgenearethoughttoincreaserisk mu Germline 49). (48, mutations transcriptase (TERT) tion of telomeres 1 (POT-1) andthetelomerasereverse ), protec factor(MITF transcription phthalmia-associated 3 mutationshavebeenassociatedwithMM;micro­ melanoma havebeendiscoveredrecently. Inparticular, Several othermutationsdisposingtobothcancerand Other conditionsassociatedwithmalignantmelanoma 368 6. 5. 4. 3. 7. 2. 1. Other syndromes,wheretheassociationwithmela Both Michaelsson G,Olsson E, Joshi P, Deshmukh V, GolgireS. GorlinGoltzSyndrome. Dent Gorlin RJ, GoltzRW. Multiple nevoid epithelioma, basal-cell Binkley GW, van Steensel MA,JaspersNG,SteijlenPM. A caseof Larsen AK,Mikkelsen DB, JM,Bygum Hertz A.Manifestations Lamberg A, Sølvsten H, Lei U, Vinding GR, Stender IM, Jemec Res J (Isfahan) 2012;9:100–106. 262: 908–912. N Asyndrome. rib. bifid and cysts jaw Syphilol 1951; 63: 73–84. cysts; a clinical and autopsy study. AMA Arch Dermatol basal cellnevi,agenesisof thecorpuscallosumanddental of Gorlin-Goltzsyndrome.Dan MedJ 2014; 61:A4829. GB, etal.TheDanish NonmelanomaSkinCancerDermato bo sis. ActaDerm Venereol 1981; 61: 497–503. cell carcinomas and peripheral vasodilation with cyano derma, drome: a familial disorder with vermiculate logy Database. ClinEpidemiol 2016; 8: 633–636. syndrome. J. Schierbecketal. POT-1 andTERTaretelomerase-controlling milia, Johnson HHJr. Epithelioma adenoides cysticum; Br J

hypotrichosis,trichoepitheliomas, basal Dermatol 2001; 144: 1215–1218. Note: Westermark P. Engl The Md 1960; Med J Rombo atropho Rom syn ­ ­ ­ ­ ­ - - - - - 29. 28. 24. 27. 23. 16. 14. 26. 22. 20. 15. 13. 12. 11. 10. 25. 21. 19. 18. 17. 9. 8. Bygum A, Betz R, Kragballe K, SteinicheT, Peeters N, Wuyts Skinner BA, Greist MC,NorinsAL.Thekeratitis, ichthyosis, Graefe T, Wollina U, SchulzH,Burgdorf W. Muir–Torre syn Gu CY,Gu ZhangCF, ZhengZZ. LH, Xiang Clinical LJ, Chen John AM, Schwartz RA. Muir-Torre syndrome (MTS): An Lehmann AR, SchubertS, EmmertS. Xeroderma Pigmento Hebra Ferreira FR, Santos LD, Tagliarini FA, Lira ML. Porokeratosis Torre D. Multiple sebaceous tumors. Arch Dermatol 1968; Broesby-Olsen S, Bygum A,GerdesAM,Brandrup F. Multi Kraemer DiGiovanna KH, JJ. Forty years ofresearchon Mello RN, Kahn Z, Choudry U. A multidisciplinary approach AlSabbagh M, Baqi M. Bazex-Dupré-Christol syndrome: re Castori M, Castiglia D, Passarelli F, Paradisi M. Bazex-Dupré- Bal E,Park H-S, Belaid-ChoucairZ,Kayserili H,Naville M, Abuzahra F, Frank Parren J. Multiplefamilialandpig LJ, Schamroth JM, Zlotogorski A, Gilead L. Porokeratosis of Muir EG,BellAJ, Barlow KA.Multipleprimarycarcinomata Ferguson-Smith MA, Wallace DC, James RenwickZH, JH. Smith JF. carcino squamous-celled primary Acaseofmultiple Lehmann AR,McGibbonD, Stefanini M.Xeroderma pigmen Bazex A, Dupre A, Christol B. W, Nöthen M. KID Syndrome: report of a Scandinavian pa 285–289. and deafness (KID) syndrome. Arch Dermatol 1981; 117: 8: 737–741. analysis and etiology ofporokeratosis. Acad Dermatol 2016;74: 558–566. update and approach to diagnosis and management. J Am Dermatol 2013;88: 179–182. of Mibelli – literature review and a case report. 98: 549–551. Health. Photochem Photobiol 2015;91: 452–159. xeroderma pigmentosum at the US National Institutes of Case Rep 2017;6: rjw224. to thesuccessfulmanagementofGorlinsyndrome.JSurg Christol syndrome:an ectodermal dysplasiawithskin ap RNA elements lead to aberrant activation of Hedgehog sig Madrange M, et al. Mutations in ACTRT1 and its enhancer Venereol 1997; 77: 207–213. Mibelli. Overview and reviewofthe literature. Acta Derm acanthomata of the face. Br J Surg 1967; 54:191–195. of thecolon,duodenum,and larynxassociatedwithkerato- 1971; 7:157–163. Multiple self-healing squamous epithelioma. Birth Defects Sydenham Soc1874; 61: 252–258. seases oftheskinincludingexanthemata.Volume III.New 57: 1102–1106. view of clinical and molecular aspects. Int J Dermatol 2018; pendage neoplasms.EurJ Med Genet 2009; 52: 250–255. Med 2017;23: 1226–1233. naling in inherited and sporadic basal cell carcinomas. Nat 2012; 26: 117–121. Dupré-Christol syndrome. J Eur Acad Dermatol Venereol mented basal cell carcinomas in early childhood – Bazex- tol Syph 1964; 71: 206. multiples (épithéliomas-basocellulaires). BullSocFrDerma phodermique généralisé et des dégénérescences cutanées 2005; 85: 152–155. tient withconnexin-26genemutation. ActaDerm Venereol 331–333. can prevent tumour development. drome –treatmentwithisotretinoinandinterferon alpha-2a Acta Derm Venereol 2008; 88: 52–56. observations in a Danish family covering four generations. ple self-healing squamous epithelioma of Ferguson-Smith: Br JDermatol 1934;46:267–272. mata of the skin in a young man, with spontaneous healing. tosum. OrphanetJRare Dis 2011; 6: 70. 2014; 12: 867–871. and novel therapeutic approaches.JDtsch Dermatol Ges sum: Diagnostic procedures, interdisciplinary patient care, Erratum: Br J type indétermineassociantunehypotrichose, unétatatro F, Kaposi M. Dermatol 2002;146:715. Xeroderma, parchment skin. In On di Génodermatose complexe de Dermatol 2000; Exp Ther Med2014; An Bras 200: ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV 41. 40. 39. 38. 37. 36. 35. 34. 33. 31. 32. 30. Lynch H.T., KrushA.J. Hereditaryandmalignantmelanoma: Norris W. Vinzón SE,RöslF. HPVvaccination forprevention ofskin Burger B, Itin PH. Epidermodysplasia verruciformis. Curr de Jong SJ, Imahorn E, Itin P, Uitto J, Orth G, Jouanguy Karow JK, Wu L, Hickson ID. RecQ family helicases: roles in Arora H,ChaconAH,ChoudharyS, McLeodMP, Meshkov L, Bloom D.Bloom erythemaresembling telangiectatic Congenital Larizza L,RoversiLarizza G,Volpi L.Rothmund-Thomson syndrome. Rothmund A. UberCataracte inVerbindung mit einereigent Wang LL, Plon SE. Rothmund-Thomson Syndrome. 1999 Oct Chandra S, Bygum A. Successful treatment with alitretinoin implications for early cancer detection. Can Med Assoc J. www.ncbi.nlm.nih.gov/books/NBK7025/. Med SurgJ1820;16:562–565.Available from:https:// melanoma mole syndrome/A case of fungoid disease. cancer. Hum Vaccin Immunother2015;11: 353–357. Probl Dermatol 2014; 45: 123–131. 2018; 9:1222. immunity tohumanbeta-papillomaviruses. FrontMicrobiol E, etal.Epidermodysplasiaverruciformis: inbornerrorsof cancer and aging.CurrOpinGenet Dev 2000;10: 32–38. 798–802. Nouri K,etal.Bloom syndrome.IntJDermatol 2014;53: AMA Am J Dis Child 1954;88:754–758. lupus erythematosus in dwarfs; probably a syndrome entity. Orphanet J Rare Dis 2010; 5: 2. Seattle: GeneReviews®; 1993–2018. RA, et al., editors. Seattle, WA: University of Washington, 6 [updated2016Aug 11].In:Adam MP, Ardinger HH,Pagon deafness syndrome. Acta Derm Venereol 2013; 93: 473–474. keratitis-ichthyosis- in ofthescalp cellulitis of dissecting Klin ExpOphthalmol1868;14: 159–244. huemlichen Hautdegeneration. Albrecht von Graefes Arch The first reported case of familial atypical multiple Edin - 42. 47. 46. 45. 50. 49. 48. 44. 43. Soura E,EliadesPJ, ShannonK,Stratigos AJ, Tsao H.Here Rai K,PilarskiR,CebullaCM,Abdel-Rahman MH.Compre Wiesner T, Obenauf AC, Murali R, Fried I, Griewank KG, Ulz P, Garbe C, Peris K, Hauschild A, Saiag P, Middleton M, Bastholt Kralund Ousager L, HH, Jaspers NG, Raams A, Pedersen Leachman SA, LuceroOM,SampsonJE,Cassidy P, Bruno Soura A,Eliades PJ, ShannonK,Stratigos AJ, Tsao H. Here Hayward Oncogene predisposition. ofmelanoma NK.Genetics Eckerle Mize D, M,Resse Bishop Sluzevich E, J. Familial 1968;99:789–792. tumors. Nat Genet 2011; 43: 1018–1021. et al.GermlinemutationsinBAP1predisposetomelanocytic Eur J Cancer 2016; 63: 201–217. consensus-based interdisciplinaryguideline–update2016. L, et al. Diagnosis and treatment of melanoma. European EB, Gade E, Bygum A. Xeroderma Pigmentosum-Trichothio W, Queirolo P, et al. Identification, genetic testing, and ma 2003; 22: 3053–3062. Atypical MultipleMoleMelanomaSyndrome. Cancer Syn 2017; 36: 77–90. nagement ofhereditarymelanoma.CancerMetastasisRev seling. J Am Acad Dermatol 2016; 74: 411–420. – emergingmelanomacancercomplexes andgeneticcoun ditary melanoma: update on syndromes and management report of two new cases. Clin Genet 2016: 89:285–294. hensive review of BAP1 tumor predisposition syndrome with Information; 2009. dromes. Bethesda, MD: National Center for Biotechnology drome. J Am Acad Dermatol 2016; 74: 395–407. genetics of familialatypical multiplemolemelanomasyn ditary melanoma: Update on syndromes and management: lection 2013. Rare Dis. 2013;1:e24932. doi: 10.4161/rdis.24932. eCol dystrophy overlap patientwithnovel XPD/ERCC2 mutation. Skin cancerassociatedgenodermatoses Acta DermVenereol 2019 369 ------