Anais
Brasileiros
de
Dermatologia
www.anaisdedermatologia.org.br
CONTINUING
MEDICAL
EDUCATION
Albinism:
epidemiology,
genetics,
cutaneous
characterization,
psychosocial
factors
夽,夽夽
Carolina
Reato
Marc
¸on
a,∗,
Marcus
Maia
baPro-AlbinoProgramDermatologyClinic,DepartmentofMedicine,SantaCasadeMisericórdiadeSãoPaulo,SãoPaulo,SP,Brazil bDepartmentofOncologyDermatologyClinic,SchoolofMedicalSciences,SantaCasadeMisericórdiadeSãoPaulo,SãoPaulo,SP,
Brazil
Received14April2019;accepted9September2019 Availableonline30September2019
KEYWORDS Albinism; Albinism, oculocutaneous; Keratosis,actinic; Sunscreeningagents; Skinneoplasms; Socialstigma
Abstract Oculocutaneousalbinismisanautosomalrecessivediseasecausedbythecomplete absenceordecreaseofmelaninbiosynthesisinmelanocytes.Duetothereductionorabsence ofmelanin,albinosarehighlysusceptibletotheharmfuleffectsofultravioletradiationand are atincreasedrisk ofactinic damage andskin cancer.In Brazil,asin otherpartsofthe world,albinismremainsalittleknowndisorder,bothinrelationtoepidemiologicaldataandto phenotypicandgenotypicvariation.Inseveralregionsofthecountry,individualswithalbinism havenoaccesstoresourcesorspecializedmedicalcare,andareoftenneglectedanddeprived ofsocialinclusion.Brazilisatropicalcountry,withahighincidenceofsolarradiationduring theyearnationwide.Consequently,actinicdamageandskincanceroccurearlyandhaveahigh incidenceinthispopulation,oftenleadingtoprematuredeath.Skinmonitoringofthesepatients andimmediatetherapeuticinterventionshaveapositiveimpactinreducingthemorbidityand mortalityassociatedwiththiscondition.Healtheducationisimportanttoinformalbinosand theirfamilies,thegeneralpopulation,educators,medicalprofessionals,andpublicagencies abouttheparticularitiesofthisgeneticcondition.Theaimofthisarticleistopresentareview oftheepidemiological,clinical,genetic,andpsychosocialcharacteristicsofalbinism,witha focusinskinchangescausedbythisrarepigmentationdisorder.
©2019SociedadeBrasileira deDermatologia.PublishedbyElsevierEspa˜na,S.L.U.Thisisan openaccessarticleundertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/).
夽 Howtocitethisarticle:Marc¸onCR,MaiaM.Albinism:epidemiology,genetics,cutaneouscharacterization,psychosocialfactors.AnBras
Dermatol.2019;94:503---20.
夽夽StudyconductedattheAlbinismOutpatientClinic,ClinicofDermatology,DepartmentofMedicine,SantaCasadeMisericórdiadeSão
Paulo,SãoPaulo,SP,Brazil.
∗Correspondingauthor.
E-mail:[email protected](C.R.Marc¸on).
https://doi.org/10.1016/j.abd.2019.09.023
0365-0596/©2019SociedadeBrasileiradeDermatologia.PublishedbyElsevierEspa˜na,S.L.U.ThisisanopenaccessarticleundertheCC BYlicense(http://creativecommons.org/licenses/by/4.0/).
Introduction
Etiology,definition,andclinicalcondition
Oculocutaneous albinism (OCA) is an autosomal recessive disorder caused by the complete absence or reduction of biosynthesis of melanin in melanocytes. Patients with albinismhave anormalnumberofmelanocytesinthe epi-dermisandfollicles,but themelaninpigmentistotallyor partiallyabsent.1---4Individualswithoculocutaneousalbinism
areunabletooxidizetyrosineintodopathroughtyrosinase. Thisinabilitytoproducepigmentcausespalecomplexion, whiteorfairhair,andredeyes,aslightreflectsblood ves-selsinthe retina,or greenish-blueorlight brown eyes,if thereis pigmentformation intheiris. Infact,the pheno-typicvariabilityofalbinismisbroad,rangingfromcomplete absenceofpigmentationofthehair,skin,andeyestomild depigmentation(Figs.1---3).5---7
Duetothereductionorabsenceofmelanin,albinosare highlysusceptibletotheharmfuleffectsofultraviolet(UV) radiationandareatgreaterriskofactinicdamage.5,8,9
Clin-icalmanagement shouldinclude educationof albinos and familymembersontheimportanceofpreventingsun expo-sureandaboutmethodstoprotectagainstUVradiation.
Many albinos develop actinic keratosis or skin cancers beforereachingtheage of30 years.5,8---12 The sequelaeof
skin cancer areamong the leading causes of early death in albino patients.11,12 Skin cancer occursin young adults
amongalbino patients with non-photoprotected exposure tosun.Inthosepatients,skincancerisinvariablymultiple andbiologicallyaggressiveinnature,althoughmelanomais rare.5,8,9 Thecancer typicallyoccursonthehead orneck,
areasusuallymoreexposedtosolarradiation. Giventheir highsensitivitytoUVlight,albinosneedtotalsunprotection andshouldundergoregularskinexamseverysixmonthsor less.5,8,9
Reducedvisualacuity,refractiveerrors,iristranslucency, nystagmus, foveal hypoplasia, fundus hypopigmentation, andabnormaldecussationofopticnervefibersatthechiasm arealsocommonfeaturesinalbinos.Thismisroutingis cha-racterizedbyexcessivecrossingoffibersattheopticchiasm, which can result in strabismus and reduced stereoscopic vision.Inaddition,photophobiamaybesevere.Albinosare alsoocularlymoresusceptibletotheharmfuleffectsofUV radiation5---7 andmost individualswithalbinismhave some
degreeoflowvisualacuity.
Albinism
types
and
epidemiology
Albinismcanoccurinsyndromicandnon-syndromicforms. In syndromic forms of albinism such as the Hermansky-Pudlak and Chediak-Higashi subtypes, hypopigmentation andvisualimpairmentscoexistwithmoresevere pathologi-calabnormalities.Hermansky-Pudlaksyndromecanpresent withimmunologicalchanges,interstitialpulmonaryfibrosis, granulomatouscolitis,andhemorrhagicdiathesissecondary toplateletalterations.Chediak-Higashisyndrome,besides hypopigmentation,canmanifestwithhematologicchanges, high susceptibility to infections, bleeding, and neurologi-cal problems.13---17 Albinism can also be expressed by the
exclusivelyocularform(OA1andFHONDAsyndrome).5,18,19
To date, 19 genes have been linked to the different clinicalpresentationsofalbinism,includingsevenforOCA. Four main types of non-syndromic albinism were initially described:fromOCAType1(AandB)toOCA4.TheOCA1A typeisthemostsevere,withatotalabsenceofmelanin pro-ductionthroughoutlife,whereastheotherforms---OCA1B, OCA2, OCA3, and OCA4 --- exhibit some accumulation of pigments over time. Mutations in the TYR, OCA2, TYRP1, andSLC45A2 genes arethe maincause ofoculocutaneous albinism.2,5,10 Recently, another two new genes, SLC24A5
andC10orf11,20havebeenidentifiedasresponsiblefor
caus-ing OCA6 and OCA7, respectively, giving a total of seven differenttypesofalbinism.Alocuswasalsomappedinthe regionofthehuman chromosome4q24,thegeneticcause ofOCA5.21
However,thereremainasubstantialnumberofalbinism caseswithoutmolecularidentification,suggestingthatmore genes are associated with the condition. In addition, the lackofknowledgeoftheunderlyingmechanismsbywhicha geneticmutationinducesadeleteriousfunctionaleffecton thegene’sproductimpliesthatthedisordercannotyetbe fullyunderstood.21
In Brazil, albinism is clinically diagnosed basedon the presence of typical cutaneous abnormalities and ocular findings.The distinctionbetween albinismsubtypesbased on clinical characteristics and the broad phenotypic het-erogeneity of the disorder hinders the establishment of phenotypic and genetic correlations, and there is exten-siveoverlappingofdifferentformsofthedisease.Molecular studiestodefine theexacttypeofmutationaretherefore necessary.However,thistestiscurrentlynotavailableunder theBrazilianpublichealthsystem.2---4
Albinismisageneticdisorderthataffectsindividualsof allsocialclassesandcountriesworldwide,albeitat differ-ent prevalence rates. The global incidence of albinism is 1:20,000individuals,withalowerrateintheUnitedStates (1:37,000),1,7,22 whilethe highest ratereportedinthe
lit-eraturetodateisamongst theCunaindigenouspeople(in Panamaand Colombia),whohave an estimated incidence of 6.3 per 1000 population.23 High rates have also been
reportedinAfrica.22,23InTanzania,Luandeetal.24estimated
therewere700albinosliving inDaresSalaam, represent-ing aprevalence of 1:1500. In sub-SaharanAfrica, 1:5000 to1:15,000areaffectedbyalbinism.25Areviewstudy
pub-lished in 2006 revealed that sevenpublications contained epidemiologicaldataontheprevalenceofalbinisminSouth Africa,Zimbabwe,Tanzania,andNigeria.26 Theprevalence
ofalbinisminthesestudiesrangedfrom1:15,000inthe mid-easternstateofNigeria27to1:1000amongtheTongatribeof
Zimbabwe,anisolatedruralcommunity.28 Albinismis
con-sidered a relatively common hereditary condition among populationsofSouthAfrica.Besidesthelimitedgeographical mobility,consanguinity,togetherwithothertraditional mar-riagepractices,mayalsobepertinentfactorsinassessments ofcurrentandfuturetrendsofalbinismprevalence.22,27---29
ThefrequencyofdifferenttypesofOCAdiffersaccording tothepopulation.OCA1isthemostcommonlyfoundsubtype inCaucasians,accountingfor50%ofallcasesworldwide.30,31
OCA2,orbrownOCA,isresponsiblefor30%ofcases world-wide and is more common in Africa,where it affects an estimated 1:10,000 and more than 1:1000 among certain populations.27,32 This is largely due to a highly frequent
Figure1 Phenotypeinalbinism.Widephenotypicvariabilityamongchildrenwithalbinism.
Figure2 Phenotypeinalbinism.Widephenotypicvariabilityamongwomenwithalbinism.
deletionofOCA2foundintheAfricanpopulation.32---35OCA3,
or red OCA, is practically nonexistent in Caucasians, but affectsapproximately1:8500individualsinSouthAfrica,or 3%of allcasesglobally.31 OCA4is alsorareinCaucasians,
and likewise amongAfricans, but accounts for 17% of all casesworldwideand,inJapan,is diagnosedinoneoutof
every four people affected by OCA. In Japan and China, thepredominantformisOCA1,followedbyOCA4.31,36New
genesandmutationarebeingdiscoveredaroundtheworld, suchasthatresponsiblefor OCA5 identifiedinPakistan,37
thatfor OCA6, firstidentified inChina, butnow reported in other populations,38,39 and that for OCA7, identified in
Figure3 Phenotypeinalbinism.Widephenotypevariabilityamongmenwithalbinism.
a family from the Faroe islands and in Denmark.20 The
Hermansky-Pudlaksyndromicformhasahigh incidencein the Puerto Rican population40,41 and is relatively
preva-lentinsome populations:for example,a recentEuropean prospectivestudyassessingtheclinicalandgenetic charac-teristicsofagroupofpatients (33childrenand31adults) seenataspecializeddayhospitalrevealedaprevalenceof 7.8%.42Chediak-Higashisyndromeisuniversallyrareandis
describedinsomeEuropeanregionsandAsia.16,17
In Brazil, the epidemiology of albinism has not been mapped. There are scant epidemiological studies and no informationisheldingovernmentdatabases(thecensusof theBrazilianInstituteofGeographyandStatistics[IBGE],or theNationalHealthSystemDatabase[DATASUS])onthe inci-denceofthegeneticdisorderinthecountry.Theincidence isthoughttobehigherinregionswithagreaterprevalence Africandescent,suchastheNortheast.The populationof Bahia,Brazil’sthirdmostpopulousstate,ismostlyofAfrican or mixed descent.Owing to the high presence of African ancestryandthefacttheregionwasthepointofentryfor Africanslavesduringthecolonialperiod,Bahiaisbelieved tohavethehighestincidenceofalbinosinthecountry.43,44
Inastudyontheprofileofalbinismin thestateofBahia, 70%ofthealbinosdeclaredtheywereofAfricanor mixed ethnicity.44AnotherstudyconductedinthecityofSalvador
(capitalofBahia)revealedcasesofalbinismin44%ofthe163 districtsandlocationsofSalvador,where17%ofplaceshada prevalenceofmorethan1:10,000and8.5%ofover2:10,000. Thedistrictswithhigheralbinismrates hadahigh propor-tionofAfricandescent.Theproportionofalbinosinoneof theregions investigated,called Ilha deMaré, whose pop-ulation descended from Quilombos (former escaped-slave communities),exceeded1:1000.43
AnotherareaofBrazil studiedfor itshighincidence of albinism is the city of Lenc¸óis, in the north of Maranhão state.Givenitssmallpopulationandremotelocation, con-sanguinity is high and the supposed rate of albinism in the1970sand 1980swasconsidered oneof thehighest in the world.The region nowhasfewer albinos,since many migratedtoother regionsand/or metearly deathsdueto skin cancer (according non-published reports). There are alsoisolatedreportsofalbinisminmanyindigenous commu-nitiesofBrazil(instatesofPará,Acre,Paraná,SãoPaulo, MatoGrosso;datareportedfromtheinternet).45---47
The few studies and reports available in the scien-tific literature suggest that figures for albinism in Brazil resemble thoseof Africa.However, it is unclear whether these numbers reflect the true situation in the country, highlighting the need for the government to register albinism inofficialdatabasesorconduct population-based studies that provide a reliable estimate of these figures. Thus,thereisageneralpaucityofstudiesmappingthe epi-demiologyofalbinisminBrazil.Furtherstudiesareneeded toprovideadeeperunderstanding onthedistributionand incidenceofthisgeneticdisorderinthecountryandthe con-sequentdevisingofmoreobjectiveandassertivestrategies forthecondition.
Theoccurrenceofalbinismisassociatedwithdifficulties and disadvantages, resulting from the genetic disorder and social segregation. There is stigma related to the disease thataffects albinos andtheir families.Reports of studies carried out in Bahia, data from the Association of Persons Living with Albinism in Bahia* State [APALBA] (*http://apalba-albinosdabahia.blogspot.com), informal global references, and the practical experience of the authorsindicatethatalbinosinBrazil,eveninmajorurban
centers, suffer prejudice and social exclusion, as well as limited access to specialized medical healthcare and resources. These factors contribute to an increase in the morbimortality associated with the condition, including actinicdamageandskincancer.44---48
Physiopathology
---
albinism,
actinic
damage,
and
skin
cancer
Physiopathologyofmelaninbiosynthesisand
oculocutaneousalbinism
Skin pigmentation varies among individuals and is deter-mined by multiple factors, including the number and metabolicactivityofmelanocytes inthebaselayerof the epidermis,themelanogenicactivityofmelanosomeswithin these melanocytes, and variations in the number, size, and distribution of melanosomes. Differences in types of melanin,the degree ofbranching ofthe dendritic protru-sionsofmelanocytes,andinthetransportofmelanosomes from these protrusions to keratinocytes also affect skin pigmentation.49,50
Melanocytes have an ectodermic origin in the neural crest,evolvingwithcutaneous(hair,skin)orextracutaneous (eyes,cochlea,leptomeninges)migration.Somegenes con-trol the proliferation and differentiation of cells from the neural crest and regulate the migration of precursor melanocytes to their final positions. The microphthalmia transcriptionfactor(MITF)isthemasterregulatorof devel-opment, function, and survival of melanocytes51 and is
responsible for modulating the expression of some spe-cific proteins in these cells.52 After differentiation of
melanocytes,MITFregulatestheexpressionofgenesduring exposuretoultravioletradiation(UVR),promotingtanning oftheskin.53
Melaninisapolymerpigmentproducedinmelanocytes. Itssynthesisoccursthroughenzymereactions, which con-verttyrosine intomelaninthroughthe tyrosinaseenzyme. Melanin biosynthesis is regulated by a number of fac-tors, particularly the melanocortin-1 receptor (MC1R) in melanocytes and its ligand, the alpha-melanocyte stim-ulating hormone (␣-MSH). Cytokines and growth factors fromthe environmentand thedegree of basal activityof tyrosinase, of tyrosinase-relatedprotein 1 (TRP1), andof membrane-associated transporter proteins are additional factorsregulatingthisbiosynthesis.50---54
One of the important functions of melanin is to pro-tecttheskinandeyesfromtheharmfuleffectsofUV.The melanin produced through this modulation is transferred to adjacent keratinocytes, where a covering around the nucleus is thus formed, protecting the DNAfrom damage induced by UV radiation.50,55 The degree of skin
pigmen-tationis inverselycorrelatedwithriskof sun-inducedskin cancer.53
Geneticmutationsinvolvedinalbinism
Genetically,albinism isclassified accordingtothetypeof genetic mutationpresent. There are seven types of non-syndromic OCA identified to date; of these, Type 1 OCA
(OCA1)andType2OCA(OCA2)arethemostcommon.OCA1 isconsideredthemost prevalenttypeglobally,56 affecting
differentethnicgroupsandcharacterizedbylossoffunction ofthetyrosinaseenzyme,asaresultofamutationinthe TYRgene.Tyrosineisthecriticalenzymeinthebiosynthesis ofthebrownish-blackeumelaninandyellowpheomelanin. IndividualswithOCA1Ahavenon-functionalTYRwithtotal absence of melanin production, whereas individuals with OCA1Bhavesomefunctionoftyrosinaseactivitywithlimited productionofmelanin.57OCA2isthemostprevalentformof
albinisminAfrica.5,35,53ThedisorderaffectsthoseofAfrican
descentmoreoftenthanCaucasiansandischaracterizedby mutationintheOCA2gene(previouslyknownasthePgene), whichencodesthePprotein.5,57 Itsexactfunctionsarenot
fullyunderstood,butthePproteinappearstobeinvolved withthetransportofproteins tomelanosomes,stabilizing themelanosomalproteincomplexandtheregulationofthe pHof themelanosome and/ormetabolism ofglutathione, allofwhicharekeyformelaninproduction.5,34,57---59Albinos
withtheOCA2phenotypehavenoeumelanin,buthavesome degree of pheomelanin, which can progressively increase withage.57---60
TheOCA3andOCA4phenotypesofalbinismarecaused bymutationsin genesencoding tyrosinase-relatedprotein 1 (TYRP1) and membrane-associated transporter protein (MATP), respectively.60 TYPR1 is an enzyme that
stabi-lizes tyrosinase. Mutations in TYPR1 are associated with the early degradation of tyrosinase and late maturation ofmelanosomes.7MATP acts asamelanosomalmembrane
transporter protein necessary for melanin biosynthesis. MutationsintheMATPgenecausehypopigmentationandthe OCA4phenotypeofalbinism.7TheOCA5phenotypeislinked
toaspecific,asyetunidentifiedgene,mappedtotheregion ofthe4q24chromosome,whichwasdiscoveredinmembers ofaconsanguineousPakistanifamily.37,61
In early 2013, a teamof Chineseresearchers reported theuseofexomesequencingtorevealthemolecularbasis of albinism in an affected family. They discovered that mutationsinSLC24A5, agenethatencodesasolute trans-porter protein, was associated with a new form of OCA, denominated OCA6. SLC24A5 mutations were detected in patients of different ethnicities, indicating that OCA6 is not confined to the Chinese population. Recent results indicate an important role of SLC24A5 in the maturation ofmelanosomes,melanosomalarchitecture,andinproper melanin biosynthesis. Animal studies have revealed that mutation of this gene leads to a reduction in the size anddensityofmelanosomes.38,39 Alsoin2013,anewgene
associatedwithalbinismwasdiscoveredamongindividuals withOCA fromthe FaroeIslands. The C10orf11gene was identified using gene mapping of a consanguineous fam-ily. In addition, a mutation in the same C10orf11 gene wasfoundinanalbinofromLithuania.Thesedatastrongly suggest a role of this new gene in the differentiation of melanocytes.5,21
Atbirth,peoplewithdifferentphenotypicformsofOCA present, in general, white hair and very fair or whitish-pink skin. Individuals with OCA1B, OCA2, OCA3, OCA4, OCA5,OCA6,orOCA7goontoacquiresomepigmentation throughoutlife, but thosewithOCA1A remaincompletely depigmented.37,60,61
Melaninandskincancer
Skin melanin, particularly eumelanin (brown/black), pro-vides protection against solar radiation and oxidative damagetoDNAinducedbystress,wherebyindividualswith darkskinhavealowerrateofskincancerthanthosewith fairskin.However,photoprotectionconferredbymelaninis nottotal,evenindark-skinnedindividuals,whoalsosuffer solar radiation-inducedDNA damage. This damage gener-allyoccursatadegreethatisreversiblebythemechanisms ofcellularDNArepair, thusreducing theriskofmalignant transformation.Bycontrast,infair-skinnedindividualswith insufficientmelanintoprovideeffectiveprotectionagainst solarradiation,theextentofDNAdamagecanexceedthe repairabilityofthesemechanisms,withmajorriskof malig-nanttransformation.62,63 Albinoswhohavelittleor noskin
melaninarethereforehighlysusceptibletoUV-induced can-cers.
The melanin present inOCA is predominantly pheome-lanin(yellow/red),withminimalproductionofeumelanin.64
Eumelanin plays an important photoprotective role. Althoughpheomelaninofferssomephotoprotectionagainst solarradiation,carcinogenicreactiveoxygenspecies(ROS) aregeneratedduringitsbiosynthesis.Inalbinos,areduction inphotoprotectiondue tothesmallamount of eumelanin present---aswellasanincreaseinROSderivedfrom pheome-lanin---areimplicatedinkeratinocytecancers.60
Thebiosynthesisofbothtypesofmelanin,brown/black eumelanin and yellow/red pheomelanin, is controlled largely by the melanocortin-1 receptor (MC1R) in melanocytes. Albinos with the OCA2 phenotype who havepolymorphicgeneticvariantsofMC1R, incontrastto the majority of other albinos, can have reddish hair and a yellowed skin tone.65 The activity of some variants of
MC1Rcan neutralizeapoptosisand reduce theDNArepair ability in melanocytes. It can also, indirectly, reduce the protection of keratinocytes against DNA damage induced by solar radiation, due to the reduced production of eumelanin,therebyincreasingtheriskof skincancer. The variantsoftheMC1Rgeneareassociatednotonlywiththe dysregulated production of melanin and reduced tanning ability, but also with the modulation of immune inflam-matory responses important in immunologic surveillance and destruction of keratinocytes transformed by solar radiation.49,64,66 Hence, genetic polymorphisms of other
codinggenes involvedin thebiosynthesisof melanin(TYR and TYRP1), besides determining skin pigmentation, are indeedfactors contributing tothe risk of developing skin cancer.49Ithasbeensuggestedthatthefunctionallyactive
tyrosinase has the ability to protect against oxidative damagetoDNA.67 Thus, insummary, lack of melaninand
exposure to intense UVR increase the risk of developing skin-cancer.68---70
Differencesinsensitivitytocarcinogenesisoftheskincan beexpecteddependingonthemutationinOCA.Thereisno convincingevidence supporting differences in risksacross thevarioustypesofalbinism.Theassumptionthatthe pres-enceoflowlevelsofpigmentconferssomephotoprotection, loweringthe riskofdeveloping skincancer inalbinos,has beenputindoubt.60 Reportsintheliteraturesuggestthat
patientswith OCA1Ahave alower risk of developing skin
cancercomparedwithothertypesofOCA.Thisissupported bythe factthatthemelanin polymerpheomelaninis pro-duced mainly when melanogenesis remains at base level, such asin OCA1B,2, 3,4, 5, 6,and 7.Pheomelanin pro-motes theproductionofROS.Thedamaging effectofROS onDNAiswellknown.71BecausepatientswithOCA1Adonot
synthesizepheomelanin,theriskofproducingROSinduced by UVR is lower. Another argument that suggests OCA1A patientsmaybelessvulnerabletoskincancersstemsfrom comparisonswithvitiligo.Inpatientswhose whitepatches have no melanin, a negative correlation between vitiligo andskin cancer hasbeen reported.72 Anotherexplanation
for this might be that the elevated levels of glutathione peroxidaseandsuperoxidedismutase(SOD)inactivateROS, conferring protection against oxidative damage and, con-sequently reducing the risk of skin cancer.73 It would be
worthwhile examining this in the white skin of patients with OCA1Ato distinguish between thesusceptibilities to skin cancer induced by UVR; the various mutations that causeOCAshouldbeconsideredtogetherinstudieson sin-glenucleotidepolymorphisms(SNPs),showingasignificant association with risk of skin cancer.74 In conclusion, the
absenceofpheomelaninandthepossibleinactivationofROS by antioxidant enzymes means that the risk of skin can-cer induced by UV radiation in patients OCA1A may well belowerthaninothertypesOCA.Studiesinvestigatingthe differences inROS concentrationshouldbe carriedoutto provideavalidcomparisonoftheriskofskincancerbetween OCA1Aandothertypesofalbinism.Additionally,information obtainedfromSNPsshouldbetakenintoaccount,providing additionaldataonthemolecularmechanismsofskincancer inalbinism.60
Malignanttransformationinducedbysolar
radiationinalbinism
OCA predisposes tokeratinocyte skin cancers, i.e., basal cell carcinoma(BCC) andsquamouscell carcinoma(SCC), particularlyinmoresun-exposedareas.11,75Giventhat
indi-viduals with OCA are typically more prone to sunburn,5
the progenitor keratinocytesof basal cells of the skin of albinos exposed to sun are at greater risk of undergoing malignanttransformationinducedbyUVradiation.SCCsin albinosmaydevelop denovoor frompremalignantactinic lesions,suchasactinickeratosis,inwhichkeratinocytescan undergo initial transformationinduced by solarradiation. ThekeratinocytesexhibitdifferentdegreesofDNAdamage, dependingontheintensityanddurationofexposureto sun-light.Normally,thesuppressorgeneofp53tumorsdisrupts thecellcycle,allowing therepairofthedamaged DNAor promotionofapoptosisifthedamagetotheDNAis irrepara-ble.However,ifthesolarradiationinducesmutationinthe p53itself,renderingit dysfunctional,therewillbe propa-gationofthe damagedDNAby celldivision,resultingin a pre-cancerous epithelial field composedof a cloneof ini-tially transformed keratinocytes with genomic instability. Thisgenomicinstabilitypredisposestheinitial transforma-tionofthekeratinocytestofurthergeneticalterationsand can leadtoclonal divergence processes,withconsequent expansionofkeratinocyteswithselectivegrowthadvantage, ultimatelygivingrisetoafull-blownSCC.50,62,76,77
Theriskofskincancerisproportionaltotheaccumulated amount of UV radiation absorbed by the keratinocytes78;
thepotentialformalignantalterationisdeterminedbythe numberofgeneticinsults.Thus,ahighfrequencyofshorter exposures to sunlight are more likely to be carcinogenic thanlessfrequentlongerexposures,78 sinceeachexposure
event can potentially cause a change. The more genetic alterationsthatoccur,thegreaterthechanceofmalignant transformation.
Asalbinosarephotosensitiveandtendtoburneasily,the localinflammationinducedbythesolarradiationintheskin canbeanadditionalfactorcontributingtoincreased prolif-erationandlongevity ofkeratinocytes, favoringmalignant transformation. Following sunburn, the ROS derived from localinflammatorycells candirectly damageDNA,and/or dysregulate the mechanisms, not only of DNA repair and cell cycle control, but also of apoptosis, thus promoting evolutiontoskincancer.79
Atamolecularlevel,DNAdamageinducedbyUV radia-tionischaracterizedbysubstitutionofspecificnucleotides, particularlythesubstitutionsC>TandCC>TTfoundinthe p53 gene that encode the p53 protein, which normally regulate the cell cycle, apoptosis, and DNA repair. Solar radiationregularlyprovokesthesegeneticchanges,referred to as ‘‘signatures’’ associated with UV exposition; these ‘‘signed’’mutationsleadtomalignanttransformationfrom solarradiationcausingskincancer.78,80
Theinitiallytransformedkeratinocytesareimmunogenic andproduceimmuneresponsesthatcanmodulateor con-trol tumorigenesis; however, immunosuppression induced by solar radiation can critically disrupt this protection mechanism.81Therefore,exposuretoUVraysisveryharmful
tohypopigmentedskinofalbinos. Lackof melanin predis-posesthispopulationtoseverecutaneousdamage.Mostof this damage occursin the body regions most exposed to thesun,suchastheface, ears,neck,andshoulders.Skin lesionsincludesunburns,blisters,solarelastosis/keratosis, ephelides,lentigo,andskincancer.24,68,82,83
Climatic
factors
and
skin
cancer
in
albinism
ClimaticfactorsinBrazil
Brazil is transected in the North by the Equator and in theSouthby theTropicofCapricorn, thus92% ofitsarea is within the tropics, providing very high levels of solar radiation. Despite some variations in latitude, altitude, andatmosphericcharacteristicsindifferentregions, mete-orological studies show that UVR tends to be very high throughoutthecountry.Thisholdstrueevenduringthe win-terseasonandoutsidethehoursconsideredcriticalforsolar exposure,typicallyattaininghigh levelsontheultraviolet indexscale(UIV) publishedbytheWorldHealth Organiza-tion(WHO),i.e.,fromveryhigh(UIV8---10)toextreme(UVI 11+).Dailydosesofradiationare,onaverage,higherinthe Northand Northeastregions, reaching20times the doses recommendedbytheWHOeveninwinter,butcriticallevels ofover15arealsorecordedintheSoutheastofthecountry during the summer.84,85 Studies have shown that the
inci-denceofsquamouscellcarcinomadoublesfor everyeight totendegreedecreaseinlatitude,peakingattheEquator.86
TheUVdosepertimeunitintheEquatorisaround200%of the dose in Europe or the NorthernUnited States.87 This
accumulationofUVradiationoccursmorereadilyinalbino skinowing tomelanin deficiency, makingBrazilextremely unfavorableforthishighlyvulnerablepopulation.
Solarradiation,actinicdamage,andskincancer
Theprevalence of actinickeratosisdepends onskintype, geographic location, and length of exposure to sunlight. Left untreated, these lesions can evolve to SCC.88,89 As
previouslyoutlined, Brazil hasa high UVR index,favoring theemergenceofskin cancerin itspopulation withlower phototypes.90 AstudyinAustraliaconductedbyGreenand
Batistutta91showedthatfairskinisthemostimportantrisk
factor for developing cancer. Maia et al.92 classified the
skintypeof259patientswithSCCaccordingtoFitzpatrick’s criteria.93Thefair-skintypesIandII,theleastpigmentedof
thesixtypesclassified,havegreaterriskofdevelopingthe cancer.Thesestudiesindicateadirectrelationshipbetween fair-skinandgreateroccurrenceofskincancer,agroupthat includesthosewithalbinism.
Actinicandskincancersaregenerallyfound in middle-aged and elderly fair-skinned individuals living in sunny areas,suchasAustraliaandSouthAfrica.94Anestimated80%
ofskincancersarediagnosedinthoseagedover55years.95
Arecent study performed at the Skin Oncology Sector of theDermatologyOutpatientClinicoftheSantaCasade Mis-ericórdiade São Paulo (not yet published), revealed that theage of945patientswithfirst-time non-melanomaskin cancer (NMSC)averaged68 years, while 1.7% wereunder 40 years of age and 90.3% were over 50 years. A similar study(alsoyetunpublished),composedof146patientsona pro-albinocareprogramseenbythesameinstitution,found thatthemeanageofalbinopatientswithskin cancerwas 47years.Asexpected,failuretousesunprotectionand sun-burnweresignificantlyassociatedwithcanceroccurrence. Thepopulationstudiedalsoexhibitedahighrateofactinic damage (Fig. 4): sunburn (72%), actinic keratosis (45%), elastosis(57%),lentigo(25%),andskincancer(26%). Unfor-tunately,these injuries were highly prevalent,with rates similartothosereportedinAfricanstudies.27Theselesions
leadtotheneedforalbinostoundergomultipletreatments, surgeries,andevendisfigurements,whichcouldbeaverted through prevention or early intervention (Fig. 5). The minimumagesatwhichthisdamageoccurredwasalsofound tobeprecocious,asreportedinAfrica,83withthelowestage
foractinickeratosisbeing21years,solarelastosisobserved ina6-year-oldpatient,andskincancerat23yearsofage.
Inthenegro populationwithalbinismin Africa,actinic damagecanbeseeninyoungchildren.Non-melanomaskin cancer,includingbasalcellandsquamouscellcarcinomas, arecommoninthissusceptiblegroupwithalbinism.Studies inWest,East,andSouthAfricarevealtheextentof vulner-abilityofthoseaffectedbyalbinism.27,96Manystudieshave
documentedahigh rateof actinickeratosisandskin can-cersinthesepatients,24,27,68,82,97especiallywhencompared
tothelow prevalence of skin cancer inthe normally pig-mentednegropopulationfromAfrica,inwhichskincancers arerare.98---103Thehotclimateandfarmingactivitiesinthis
Figure4 Actinicdamageinalbinism.Albinopatientspresentingactinicdamageinphotoexposedareas.
Figure5 Sequelaeofskincancer.Albinopatientswithmultiplescarsandmutilationsduetoprevioussurgeriesforexcisionof skincancers.
sunprotection; this factor alonecan increase therate of skin cancer87,88 Alsohighlighted in previous reports,24,27,98
thisrelationshipcanbeconfirmedbystudiesofpopulation ofalbinosinwhichthefrequencyofmalignantskin abnor-malitiesismuchhigherinthoselivinginequatorialregions thanthoselivingfartherfromtheEquator.
A study by Lookingbill et al. of 164 albinos fromrural equatorialAfrica(NorthTanzania) revealedthat, withthe exceptionof fourbabies,all patientshadsunburn. Ahigh rateofactinickeratosis andskin cancerwasfound inthe adults,butactinicskindamagewasalsoobservedinyoung children. Wrinkling on the back of hands and solar elas-tosis on the back of the neck was present in virtually all patients agedover 10 years.Actinic cheilitiswas also present in many children andin 93% of patients over the ageof10.Theyoungestpatientwithactiniccheilitiswas8 yearsold.In patientsagedover 20years,91%had actinic keratosis,whereasamongpatientsover 30years,thisrate was100%.83
A recent study conducted in Kenya (located along the Equator) involving 151 albinos revealed the presence of serious skin lesions in 80% of patients. Most patients were in the age group of 21---30 years. The frequency of
premalignantandmalignantlesionswasasfollows:actinic cheilitis(18%),solarelastosis(12%),actinickeratosis(37%), and skin cancer (13%).104 A prospective assessment of 64
Frenchalbino patientsrevealed amedicalhistoryof prior skin cancer in three adults (4.6%). Actinic keratosis was detected in 9% of the patients.42 Very few patients in
this European study reported sunburns, confirming a sat-isfactory levelofsun protection.Similarly, dermatological characterization in Italian albinos involving 200 patients revealedthepresenceofactinickeratosisinthreepatients (1.5%) and skin cancer (melanoma) in one.105 This
find-ingmightbeexplainedbylowersunexposureatEuropean latitudes.
Skincancerinalbinos
Skin cancer is the most common malignancy among Cau-casians. The condition accounts for around 20---30% of all cancers in Caucasians and 1---2% in those with pigmented skin.101Skincancerisoneoftheleadingcausesofmorbidity
andmortalityamongalbinoswhodeveloppremalignantand malignantlesionsatayoungerageandwhohaveadvanced
skincancerbythethirdandfourthdecadesoflife.27,27
Pre-viousstudiesinNigeria97andTanzania102reportthatonlya
fewalbinossurvivebeyondtheageof30years.Bythethird decadeoflife,manynegroalbinosinAfricawillhave devel-opedpotentiallyfatalSCCs,7,69butifdiagnosedatanearly
stage,SCCiscurablebysurgicalexcision.
StudiesshowthatSCCriskinalbinonegroesis1000times greaterthanforthegeneralpopulation,withtheheadand neck being themost commonly affected areas.63,69,75 SCC
ismorefrequent,hasamoreaggressivecourse,andtends tohave a higherrecurrence ratein negro albinos thanin normallypigmentedindividuals.7,8,103
A study carried out in Nigeria revealed albinos repre-sented67%ofpatientstreatedforprimaryskincancersata universityteachinghospital,61%ofwhomwereagedunder 40 years.12 The presence of skin cancer was investigated
in111albinosfromanegropopulationfromJohannesburg, SouthAfrica.Theoverallratewas23%,withincreasedrisk with age.68 In a review involving 1000 Nigerian albinos,
Okorofoundnoneovertheageof20freeofpre-malignant ormalignantskinlesionsinducedbysolarradiation.27A
sim-ilarfindingwasalsoreportedbyLuandeetal.intheirreview of350albinosinDar-es-Salam.Inthecitedstudy,thepeak age ofpatients withadvancedskin cancer wasthefourth decade of life.24 Another study wascarried out in
Tanza-niainvolving ahistologicalreview of134biopsies from86 albinopatientsdiagnosedwithskincancerseenata derma-tologiccenterinTanzania.Theageoftheyoungestpatient was18 and the oldest68 years,while themean age was 35years.88
In Brazil, there arescant studies withclinical data on albinism,andtheonlytwosuchstudiesavailablewere con-ductedinBahia.Onewaspublishedin2007andinvolved40 albinos affiliatedwiththeAPALPA.The studyshowed that 42%ofthealbinoshadskinlesionsand47%didnotuse sun-screenregularly.Asubstantialproportionofthealbinoswho developedskinlesionsdidnotusesunscreensorseldomused them.44Aretrospectivestudywaspublishedin2013ofdata
collectedfrom22albinosand30non-albinos(24---89years) withcancerouslesionsand24albinoswithoutskinlesions. Themeanageofthealbinoswithcancerswas34yearsvs.
65yearsfornon-albinos.UsingtheYatestest,asignificant relationshipbetweenuseofsunscreenandabsenceof devel-opmentofskintumorswasdetermined.Amongthosealbinos whohadusedsunscreenssincechildhood,onlytwo(11%)had developedskincancer.48
The prevalence ofskin cancer inpatientsstudied from the Pro-Albino Program (Brazil, n=146) (26%) was similar tothatfoundinalbinosbyresearchersinTanzania(25%),83
SouthAfrica(23%),68andmuchhigherthantheratesfound
inEuropeof 6%inFranceandof0.5% inItaly.42,105
There-fore, comparison of the present results with data in the literaturerevealsagreatsimilaritywithreportsofstudiesin Africa,butamajordifferencewiththefindingsofEuropean groups.Thisillustratesthemajorinfluenceof environmen-tal factors and socioeconomic and cultural conditions on themorbimortalityassociatedwithalbinism.Specialfocus and approaches willbe needed when considering preven-tive measures. Those data make clear the fundamental importance of effective guidance and attitudes regarding sun protection in regions with a high incidence of solar radiation.
Typesofskincancerinalbinism
NMSCaccountsfor 90%ofallskin cancers.The most com-monskintumorsinBrazilandgloballyareBCC(70---80%of diagnosedcases)andSCC(20---25% of cases).BCCis three tofourtimesmorecommonthanSCCinthewhite popula-tion.Bothhavehigh cureratesifdetected earlyandonly asmallproportionof cases arefatal. These cancershave the highest incidence and lowest lethality of all the skin cancers.89,106---109
A retrospective study involving a review of medical recordsof 945patientswithfirst-timeNMSCconductedat theSantaCasadeSãoPaulofoundthat82%hadadiagnosis ofBCCand18%hadSCC.Thebodysitesmostaffectedwere the head and neck (81% of cases), followed by the trunk (11%)andthelimbs(8%;datanotpublished).By contrast, SCCwasthemostcommoncutaneousmalignancyobserved inAfricanstudies.11,12,27,68,69,97,110AstudyofAfricanalbinos
reportedaSCCtoBCCprevalenceratioof1.2:1.Thehead andneckwerethesitesmostcommonlyaffectedbytheskin cancer(56%).88 Previousstudieshave alsoreporteda
pre-dominanceofSCCin albinos,withSCCsoccurringat rates threetosixtimeshigherthanBCCs.11,12,68,97,111Areviewof
775normally-pigmentedAfricansand18albinoAfricanswith malignanttumorsshowedthatSCCwasthemostcommon tumortype,withtheheadandneckregionsmostaffected.97
InanotherstudycarriedoutinSouthAfricaof111negro albi-nos,theheadwasthemostcommonlyaffectedsiteandSCC wasmorefrequentthanbasalcellcarcinoma.Nomelanoma casesweredetected.68
InthecitedstudyofpatientsinthePro-AlbinoProgram, of the 37 (26% of sample; n=146) patients with previous orcurrenthistoryofskincancer, thehistologicaltypewas identified in 29, comprising 62% BCC, 51% SCC, and 7% melanoma,ataBCC/SCCratioof1.2:1.Thisproportion dif-fersslightlytothatreportedforthenon-albinopopulation, albeitwithBCCstillpredominatingoverSCCcases.Ofthese patients,14%hadbothcarcinomatypes(BCCandSCC).Some patients had multiple ulcerated tumors (Figs. 6---8). The siteoftumorswaspreferentiallytheheadandneck(43%), followed by the trunk (37%) and limbs (20%), mirror-ing the tendency of greater prevalence in areas most exposed to the sun.11,12,24,68,83,96,97,104,110 Reporting similar
results to those of the present study, another investi-gation carried out in Bahia, Brazil showed that of the albinos with skin cancer (n=22), 56% had basal cell carcinoma.48
The relativelyhigh predominance ofSCCs overBCCs in the African studies may have been due to small sample sizes,fourofwhichcomprisedfewerthan20patients.The majority of these studies were also based on excisional biopsiesof advancedtumors.The smallslow-growingBCC may have been missed in earlier studies. Biopsies were taken from patients submitted to routine dermatological examsin onlyoneofthestudies, whichshowedan essen-tiallybalanced rate of SCC and BCC (1.2:1),88 asseen in
thepresentstudy,inwhichtheproportionofSCCandBCC wasinverted (1:1.2), butvery similarfromaquantitative standpoint.Basedonthisinformation,ithasbeensuggested thatnon-melanomaskincancersarepredominantinalbinos andthattheproportionofSCCsandBCCsisalmost identi-cal.
Figure6 Morbimortalityassociatedwithskincancer.Youngalbinopatient,presentingmultipleulceratedtumors.Hediedatage 27duetometastaticsquamouscellcarcinoma.
Figure7 Morbimortalityassociatedwithskincancer.Youngalbinopatientwithmultipletumors(BCCandSCC)andsurgicalscars frompreviousexcisions.
InAfrica,negroalbinosareoftensubjectedto discrim-inationdue to superstitiousbeliefs and stigmaassociated with the condition.62 Albinos are often shunned by their
communities,withconsequentdelaysinseekingand receiv-ingmedicaltreatment. Thus,bythe timethe conditionis diagnosed, the SCCs in African albinos are often already advanced.12,62 Reports indicate that, on average, negro
albinos in Africa seek treatment 14---26 months after the onset of actinic lesions.12,69,88,97,111 Unfortunately, around
40%ofthesealbinoswithskincancerdonotconclude treat-mentduetofinancialproblems11 ormissfollow-upsessions
becauseofdistancefrommedicalfacilities.Thesereasons mightexplainwhySCCsaremorefrequentandtendtohave greaterrecurrenceratesinnegroalbinos inAfricathanin normally-pigmentedindividuals.7,8,103
ArecentstudyinKenyafoundthatBCCwasmorecommon thanSCCinalbinos.104ThelowerSCCrateswereattributed
to early treatment of actinic keratoses, preventing their transformationintomalignantSCCs.Thereisnoknown cor-relationbetweenactinickeratosisandBCC.Thesefindings
highlight theimportanceof earlydiagnosis andtreatment ofpremalignantlesions,whichcouldbeeasilyachievedvia
careprogramsaimedattreatingthispopulation.The treat-mentsofchoiceundertheauthors’Pro-AlbinoProgramfor premalignantlesions(actinickeratoses)arecryotherapyand topicalchemotherapy with5-fluorouracil (Figs.9 and10),
i.e.,relativelysimple,effective,low-costinterventions.
Alternatives
for
minimizing
skin
cancer
risk
in
albinos
The goals of skin cancer management in public health are to reduce incidence and provide early detection and immediatetreatmentofthediseasewhenitoccurs. Univer-sal precautionsagainstsunexposure shouldbeintroduced during early childhood, continue through life, and should include reducing outdoor activities during peak sunlight hours (10---16h), the use of protective clothing to cover asmuchskin aspossible, widebrimhats, sunglasses,and
Figure8 Cumulativesolardamage---unprotectedexposure. Elderlyalbinopatientwithmultipleactinicdamagein photoex-posedareas.Historyofbasalcellcarcinomaandsquamouscell carcinoma.
sunscreenfor exposedskinandlips.62,76,112 Basedonthese
considerations,thecrucialroleofthedermatologistisclear in the management of this condition and particularly in screeningtodetectearlyskincancers.
StudiesinAfricahaveshownthattheprevalenceofskin cancerscouldbereducedinalbinos12ifhealthteamswere
regularlydeployedtoremotevillagestoscreenfor malig-nantandpremalignantlesionsinthealbinopopulationand toeducatethemontheharmfuleffectsofexposuretosolar radiation. This wouldneed tobecomplementedby medi-calcenters,whereearlytreatmentofthecancercouldbe provided,26andbyestablishingeducationalsupportgroups.
Otherstudiesassessingtheimpactofalbinocareprograms in Africa have shown an increase in life expectancy as a result of greater awareness and early treatment of skin cancer.83,113
The sustaineduseofsunscreen andother photoprotec-tivemeasures is pivotal inthepreventive managementof actinicdamageandofskincancerinalbinos.76,112Theuseof
sunscreenfromchildhoodreducesthechancesofdeveloping skincancerinthegeneralpopulationbyaround78%,114a
fig-urelikelyevengreaterinalbinos.Inpractice,thereismajor difficultyinacquiringtheseproductsduetoatotallackof accessandresources.Itisofvitalimportancethatthe gov-ernmentprovidestheseproductsfreeofchargetothealbino population,becausethiswouldreducethesecondarycosts of treatingskin cancer, loss of workproductivity, and the morbimortalityassociatedwiththecondition.
Healthcommunicationhasalsoproveneffectivein redu-cing the morbimortality associated with albinism.26,102,113
Pertinent information on preventive measures should be givenateach visit.Organizingmeetingswithpatientscan alsobe useful, in which these issues and other problems relatedtoalbinismcanberaisedanddiscussed. Communica-tioninschoolsandspecificguidanceonprofessionalpursuits inabidtominimizesunexposureareimportant.Thepresent authorsadvocateaninteractivesociallearningapproachfor extensionprograms,supportgroups,andworkshopsfocused onthemanagementofalbinism.
Estimatesofalbinismprevalencesuggestthatthereare a significant number of individuals living with albinism in Brazil.Theevidenceshowsthatalargeproportionofthese individualsliveinpoorsocioeconomicconditionsandrequire socialandhealthcareservicesthatarelacking.Thisscenario reiteratestheneedforgreaterawarenessandpublichealth interventionforalbinism.
Psychological
and
social
issues:
stigma,
prejudice,
and
discrimination
Besides concerns over physical health, individuals with albinism also have to cope with psychological and social challenges.InNigeria,astudycollectedreportsfrom albi-nos, showing that they avoided social situations so as not tobe noticed. They were more emotionally unstable and had less assertive personalities than people without albinism. In addition, they deemed society as insensitive and felt rejected, even when they had close friends.112
Mostsocial discriminationin Africa appears tostem from alackofeducationamongcommunitiesaboutthecausesof albinism.There is limited awareness of its genetic inher-itance, giving rise to numerous deep-rooted myths and superstitions.22 Forexample,somebeliefslinkalbinism to
conceptionduringmenstruation(culturallyunacceptable)or consideralbinism a punishment by the gods for mistakes made by an ancestor.27 This socially-entrenched
discrimi-nationcan negativelyimpactthequality oflife ofpeople withalbinism.Forexample,thisgroupismorelikelytodrop outofschoolandencounterdifficultiesinemploymentand marriagecompared tothe population at large. Moreover, thefamiliesof albinosmay alsobesubjected to discrimi-nationby thecommunity. As aresultof traditionalmyths surroundingthecauseofalbinism,mothersofaffected off-springmaybesubjectedtomajorstigmaandpsychological distress.22,26,28,102,115,116InBrazil,owingtototalignoranceof
thecondition,thisdistressinvolves,forinstance,questions regardingpaternityatthetimeofbirthofanalbinoinfant withinafamilyof Africanor mixeddescent,whereby the motherand baby suffer prejudicefrom within the family andthegeneralcommunity.
Individualswithalbinismalsofacesocial discrimination asaresultoftheirdifferentappearance.Studiesshowthat mostcountriesreportlackofknowledgebythegeneral pub-lic.Thestudiesalsorevealthatmanypeoplewithalbinism donotfullyunderstandtheircondition.Thissocial discrim-inationis viewedasabarriertobuildingrelationshipsand tofindingandholdingdownajob.Therefore,mostpeople withalbinismgenerallyhavelowereconomicstatusintheir society.Inlightof thesedifficulties,itis unsurprisingthat
Figure9 Treatmentofthecancerizationfield.Albinopatientwithmultipleactinickeratosesontheface.Theimageshowsthe resultoftreatmentofthecancerizationfieldwith5-fluorouracil.
Figure10 Treatmentofactinicdamage.Albinopatientwithmultipleactinickeratosesandsolarlentiginestreatedwith cryother-apy.
manystudieshavereportedabuseandpsychological prob-lemsinthispopulation.26Nospecificstudiesonthesefactors
areavailableforBrazil;however,theexperiencesacquired fromthePro-Albino Programandfromnumerous personal accountsindicatethat Brazilian albinosface similar prob-lems.OneoftheProgram’sgoalsistoaddresstheseissues inordertoeliminatestigmaandprejudice,andtopromote socialinclusion.
Albinismis adisorderthat affectsindividualsandtheir familiesfromamedical,social,andpsychological perspec-tive.Formany,thesocialandpsychologicalaspectscanbe agreater burden than the medicalissues. Although small compared with other major public health problems, the numberof individualsaffectedbythecondition---andthe evengreaternumberindirectlyimpacted---makealbinisma publichealthproblemthatwarrantsgreaterattention, par-ticularly toincrease awareness and knowledge about the condition.
Diagnosis
Albinism is diagnosed based on clinical observations and moleculargeneticanalysisconsideringthefollowingfactors:
• Full physical exam, including checkingpigmentation of theskin,hair,andeyes4,5;
• Thoroughocular exam,includingassessmentof possible nystagmus,strabismus,refractivedeficits,photophobia, andiristransillumination.Avisualinspectionoftheretina isalsocarriedouttodeterminewhethertherearesigns ofabnormaldevelopment117;
• Comparisonofpigmentationofthealbinopatientagainst thatofotherfamilymembers;
• Review of family and personal history, including the existence of prolonged bleeding, excessive bruising, intestinal,pulmonary, or neurological abnormalities, or repeatedinfections.
Differentialdiagnosis
Basedonhairandcutaneousfindings(hypopigmentation):
• OCAsyndromes;
• Hermansky-Pudlaksyndrome; • Chediak-Higashisyndrome;
• Vici syndrome: autosomal recessive disorder characte-rizedbyagenesisofthecorpuscollosum; hypopigmenta-tionofthehairandskin,microcephaly,immunodeficiency, heartdefects,growthdeficit,cataracts,cleftlip/palate, andneurologicalabnormalities;
• Waardenburg syndrometype II:Mutation of the autoso-maldominantMITFgene,characterizedbyheterogeneous hypopigmentationoftheskin,whitelocksorprematurely gray hair, heterochromia of the iris and sensorineural hearingloss;
• Albinism-deafness of Tietz syndrome: mutation of the autosomal dominantMITF gene,characterizedby white eyebrows and eyelashes,iris hypopigmentation, normal visualacuity,andsensorineuralhearingloss;
• Griscelli syndrome: autosomal recessive mutation in myosin, together with its receptors and ligands; melanocytes do not transfer melanosomesto dendrites and peripheral keratinocytes, leading to attenuation of skin and hair color; presents with hypopigmen-tation, silvery-gray hair, immunodeficiency, reduced visual acuity with abnormal ocular movements, pancytopenia, hemophagocytic syndrome, and cerebral demyelination.118
Geneticdiagnosis
Thetypeofalbinismandgeneticinheritancecanbe deter-minedthroughmoleculargeneticdiagnosis.Geneticanalysis alsoallowspropergeneticcounselingandearlydiagnosisof syndromicforms(Hermansky-PudlakandChediak-Higashi), which can present initially as non-syndromic forms and develop serious complications at a later age. These complications can be prevented with guidance and early therapeuticinterventions.4,5,119,120
Genetic counseling prior to the fertile yearsis benefi-cialtoparentsofalbinochildrenconsideringhavingfurther children,aswellasfor thealbinismpatientandtheir sib-lings. Albinism is an obligate homozygote condition with 100%chanceoftransmissionofthedefectivegene. Coordi-natedgenetictesting oftheunaffectedpartnerispossible ifthe pathogenic variant is known. This willconfirm that descendantshavethepotentialtoinheritthecondition,if thepartneris acarrierofthe samepathogenicvariant or onlyobligatecarriersifthepartneronlyhaswildtypegenes. Acouple whoalready hasan albino childwill have a25% chanceofhavinganotherchildwithalbinism,a50%chance ofhavingchildrenwhoarecarriersofthegene,and25%of havingnon-carrieroffspring.Therefore,itisassumedthatif oneoftheparentsisnon-albino,thechanceofhavinga sec-ondalbinochildis50%afterconfirmedalbinodescendancy. Itisimportanttoadvisethatnon-albinosiblingshavea67% chance ofbeingcarriers beforetheyconsiderhaving chil-dren.Also,ifboth parentscarrygenes fordifferenttypes of albinism, nochild will be born with albinism, but the childrenruntheriskofbeingheterozygousforbothmutant alleles.118
Insummary, geneticdiagnosis isoffundamental impor-tanceinthemanagementofalbinopatients.Molecularstudy enables classificationof subtypes(not possible by pheno-typicclinicalassessmentalone),diagnosisofnon-clinically
evidentcases,provisionofgeneticcounseling,and identifi-cationofsyndromicforms.
Treatment
Given that the condition is a genetic disorder, albinism has no cure. Treatment centers on administering proper ophthalmologic care and on skin monitoring for signs of abnormalities and prevention of sun damage. Treatment generallyencompassesthefollowing:
• Eyecare:ophthalmologicassessmentinthefirstmonthsof life,regularophthalmologicexam,correctivelenses, ocu-larphysiotherapy,surgicalinterventionswhennecessary, guidanceforlearning---learningaidsandspecial consid-erationintheclassroom(high-contrastreadingmaterial, printed textsand spreadsheets, large scale display set-tingsoncomputers,amongothers).Thisapproachhelps overcomethelearningdisabilitiesassociatedwithvisual deficits117,118,121;
• Skin care and prevention of skin cancer: guidance on actinic damage prevention and regular clinical and cutaneousdermatoscopyassessment todetect skin can-cerorprecursorlesions.Interventionssuchasapplication of liquid nitrogen, topical chemotherapy, curettage, electrocauterization, and surgery are performed when needed.
Thereisnosubstituteforsunprotectionthroughoutthe lifespan in albinism and its importancecannot be under-estimated.Individualsshouldbeinformedaboutavoidance ofprolongedexposuretoUVlight,directexposurein criti-calhoursofhighincidenceofradiation(10:00---15:00),and avoidanceofmedicationsthatcanincreasephotosensitivity. Anyoutdooractivity,howevershort,shouldbeprecededby applyingsunscreen (SPF 30+) withcopious frequent reap-plication (every two hours) when in the sun. Additional protectivemeasuresshouldbetaken,suchastheuseof pro-tectiveclothing,hats,andsunglasses.Self-examinationand self-educationaboutthecriteriaforskincancerand imme-diatereferraltoadermatologistintheeventofanysuspect lesionmustbeemphasized.Monitoringwithadermatologist shouldcommenceearly(childhood)toexplainthebenefits andoptionsregardingsunprotection.11,104,118
Syndromic forms: patients with the Hermansky-Pudlak or Chediak-Higashi syndromes generally require regular specialized care to meet medical needs and prevent complications.5,21,118
Direct therapeutic modalities (in process of investiga-tionandratification):Nitisinonepromotestheaccumulation of tyrosine in blood and rat models, suggesting that it mayimprovepigmentationin OCA1Bpatients, buta clini-caltrial is stillunderway.Aminoglycosidesareapotential unconfirmed therapy. Despite reports, L-DOPA led to no improvement in vision in a study of 45 patients. Adeno-associatedvirus(AAV)vectorsareapotentialgenetherapy thatintroducesafunctionalcopyofthegenetyrosinasein OCA1andOA1patients.122,123
Prognosis
Thelife expectancyof thepopulation withnon-syndromic OCAis similartothat of thegeneral population.There is anincreasedriskofmortalityduetoskincancer. Thisrisk changesbasedontheamountofrelativesunexposureina givengeographicareaandcertainsocioeconomicproblems. Thesocioeconomicissuesincluderestrictedaccessto sun-screen;limited educationabout sunprotection measures; culturaldifferencesinclothing;limitedaccesstohealth pro-fessionalsformonitoring,leadingtolatepresentationand delayed treatment; aswell asinability tocomply withor concludeacourseoftreatment.
Inregions withsocioeconomicproblems, thereis often a palpablestigma associatedwith albinism, and individu-alswiththegeneticdisordercanbevictimsofpersecution, prejudice,violence,andsocialexclusion.
Albinos havenormalintelligence comparedtothe gen-eralpopulation. Thereissomedelay invisualmaturation, andthiscanleadtolearningdisabilitiesiftheocularissues arenotaddressedinatimelymanner.Inaddition,low self-esteemandsocialalienationcanleadtofeelingsofisolation anddepression.Albinoshaveahighrateofattentiondeficit disorder.11,118,121
Final
considerations
Measurestopreventandcontrolskincancerinalbinosshould includetheimplementationofmedicalscreeningprograms to identify potentially malignant actinic skin lesions and allowearlydetectionofcancer,andalsotomakeavailable effectiveandimmediatepsychologicalanddermatological treatment measures.63 Although skin cancer is the most
commoncauseofearlydeathinalbinos,affectedpatients can have a normal life expectancy with the provision of adequateskincare.7
Irrespective of the geographic location, patients with albinism can feel stigmatized and isolated. Initiatives to raise awareness of albinism are extremely important in all places worldwide. The quality of life of patients can be markedly improved with access to health, support, and adequate guidance. Care with regard to oculocuta-neous albinism seeks to reduce morbimortality due to advanced skin cancer and ocular diseases. This is pos-sible through primary dermatologic and ophthalmologic prevention and secondary prevention measures. Through theprovisionofadequatecareforalbinopatients,the dis-ease course can be changed, and the comorbidities can betreated whenpresent.Additionally, thediseaseandits distribution in Brazil can be better understood, thereby promoting benefits for the patient and the family mem-bers, who often lack adequate information and have no knowledgeabout the condition. This informationcan also helpeliminatethestigmaandprejudiceassociatedwiththe disease.
Financial
support
Nonedeclared.
Authors’s
contribution
Carolina Reato Marc¸on: Statistical analysis; approval of thefinal versionofthemanuscript;conceptualization and planningofthestudy;compositionofthemanuscript; pro-curement,analysis,andinterpretationofdata;intellectual participationinthepropedeuticand/ortherapeuticconduct inthestudiedcases;criticalreviewoftheliterature;critical reviewofthemanuscript.
MarcusAntonioMaiadeOlivasFerreira:Guidanceofthe study,intellectualparticipationinthe propedeuticand/or therapeuticconductinthecasesstudied,criticalreviewof themanuscript.
Conflicts
of
interest
Nonedeclared.
Questions
1. Themain causeofmorbimortalityforalbinosliving in geographicregionswithahighsolarradiationindexis: a) Melanoma
b) Lowvisualacuity c) Keratinocytecancer d) Systemiccomplications
2. Themainsyndromicformsofalbinismare: a) WaardenburgandPrader-Willi
b) Hermansky-PudlakandChediak-Higashi c) Chediak-HigashiandAngelman
d) Hermansky-PudlakandWaardenburg
3. There are 19 genes related to the different clinical presentationsofalbinism,includingsevenfor oculocu-taneous albinism. The genes responsible for the four main typesof non-syndromicalbinism ---OCA1, OCA2, OCA3,OCA4,arerespectively:
a) TYR,OCA2,TYRP1,andSLC45A2 b) TYRP1,OCA2,SLC24A5,andC10orf1 c) TYR,OCA2,SLC45A2,andC10orf1 d) TYR,OCA2,TYRP1,andSLC24A5
4. The epidemiologic datacurrently available show that the incidence of albinism is probably highest on the followingcontinent:
a) SouthAmerica b) Asia
c) Africa(correct) d) NorthAmerica
5. Withregardtothemostprevalentgenetictypesof ocu-locutaneousalbinism(OCA)globally,wemayconsider: a) OCA1andOCA3
b) OCA3andOCA4 c) OCA2andOCA4 d) OCA1andOCA2
6. Melanocytes have an ectodermic origin, in the neu-ral crest, evolving with cutaneous or extracutaneous migration. Some genes control the proliferation and differentiation ofcellsfromtheneuralcrest and reg-ulatethemigrationof precursormelanocytes totheir final positions. The sites of extracutaneous migration ofmelanocytesandthemastergeneregulating
devel-opment, function and survival of melanocytes, are respectively:
a) Eyes,leptomeninges,pleura,andMC1R. b) Eyes,leptomeninges,hypothalamus,andMITF c) Eyes,cochlea,leptomeninges,andMITF d) Eyes,adrenal,leptomeninges,andSCF/KIT
7. Regarding the physiology of skin cancer in albinism, thefactorsdirectlyinvolvedandcorrelatedwithgene mutationanditsinteractionwithultravioletradiation are:
a) Reducedquantityofmelanin,proportionaldecrease or absence of eumelanin, p53 dysfunction, and oxidativestress
b) Reducedquantityofmelanin,proportionaldecrease or absence of pheomelanin, oxidative stress, and immunosuppression
c) Reducedquantityofmelanin,proportionalincrease of eumelanin,inflammation, anddisruptionof the cellcycle/apoptosis
d) Reducedquantityofmelanin,proportionalincrease inpheomelanin,p53hyperfunction,and ineffective-nessofDNArepairmechanisms
8. ThemostcommonactinicdamagereportedinBrazilian albinosis:
a) Actinickeratoses,lentigo,andsquamouscell carci-noma
b) Actinickeratoses,solarelastosis,andbasalcell car-cinoma
c) Solar elastosis, squamous cell carcinoma, and melanoma
d) Solarelastosis,actinickeratoses,andmelanoma 9. Riskfactorscurrentlyconsideredforskincancerin
albi-nos:
a) Sunexposurewithoutprotection,historyofsunburn, andage
b) Sun exposure without protection, tonality of the hair,andage
c) Historyofsunburn,coloroftheiris,andethnicity d) Genetictype,sunburn,andage
10. Concerninggeneticcounseling, thechances ofa non-albinocouplewithanalbinochildhavinganotherchild withalbinismandthechances oftheirchildren being carriersofthegeneare,respectively:
a) 50%and50% b) 50%and67% c) 75%and50% d) 25%and50%
Answers:
Paraneoplasticpemphigus:aclinical,laboratorial,and therapeuticoverview.AnBrasDermatol.2019;94(4):388---98.
1.c 3.b 5.d 7.a 9.b
2.d 4.b 6.a 8.d 10.d
Acknowledgements
TheauthorswouldliketothanktheSantaCasade Misericór-diadeSãoPauloandtheBrazilianSocietyofDermatologyfor thesupportinthedevelopment,operation,andexpansion ofthePro-AlbinoProgramandfortheunconditionalsupport
foralltheinitiativestopromotethealbinocause,reduce morbimortality,andimprovethequalityoflifeofBrazilian albinopatients.
References
1.Bolognia J, Jorizzo J, Schaffer J. Dermatology. 3rd ed. Philadelphia,PA:SaundersElsevier;2012.
2.James WD,BergerTG, ElstonDM. Andrews’diseasesofthe skclinical dermatology. Philadelphia, PA: Saunders Elsevier; 2011.
3.SummersCG.Albinism:classification,clinicalcharacteristics, andrecentfindings.OptomVisSci.2009;86:659---62.
4.OkuliczJF,ShahRS,SchwartzRA,JannigerCK.Oculocutaneous albinism.JEurAcadDermatolVenereol.2003;17:251---6.
5.Grønskov K, Ek J, Brondum-Nielsen K. Oculocutaneous albinism.OrphanetJRareDis.2007;2:43.
6.KirkwoodBJ.Albinismanditsimplicationswithvision.Insight. 2009;34:13---6.
7.DavidCV.Oculocutaneousalbinism.Cutis.2013;91:E1---4.
8.CastoriM,MorroneA,KanitakisJ,GrammaticoP.Geneticskin diseasespredisposingtobasalcellcarcinoma.EurJDermatol. 2012;22:299---309.
9.Dessinioti C, Stratigos AJ, Rigopoulos D, Katsambas AD. A review of genetic disorders of hypopigmentation: lessons learned from the biology of melanocytes. Exp Dermatol. 2009;18:741---9.
10.ZühlkeC,StellA,Kasmann-KellnerB.Geneticsof oculocuta-neousalbinism.Ophthalmologe.2007;104:674---80.
11.MabulaJB,ChalyaPL,MchembeMD,JakaH,GiitiG,Rambau P,etal.Skincancersamongalbinosatauniversityteaching hospitalinNorthwesternTanzania:aretrospectivereviewof 64cases.BMCDermatol.2012;12:5.
12.OparaKO,JiburumBC.Skincancersinalbinosinateaching HospitalinEasternNigeria---presentationandchallengesof care.WorldJSurgOncol.2010;8:73.
13.Brandt A, Offner F, Quatacker J, Phillipe J, Meire F. TheHermansky-Pudlaksyndrome.BullSocBelgeOphtalmol. 1997;267:99---105.
14.Oh J, Ho L, Ala-Mello S, Amato D, Armstrong L, Bellucci S, et al. Mutation analysis of patients with Hermansky-Pudlaksyndrome:aframeshifthotspotintheHPSgeneand apparent locus heterogeneity. Am J Hum Genet. 1998;62: 593---8.
15.IannelloS,FabbriG,BoscoP,CavaleriA,CantarellaS,Camuto M,etal.AclinicalvariantoffamilialHermansky-Pudlak syn-drome.MedGenMed.2003;5:3.
16.FukaiK,IshiiM,Kadoya A, ChanokiM,Hamada T. Chédiak-Higashisyndrome:reportofacaseandreviewoftheJapanese literature.JDermatol.1993;20:231---7.
17.Möttönen M, Lanning M, Baumann P, Saarinen-Pihkala UM. Chediak-Higashisyndrome:fourcasesfromNorthernFinland. ActaPaediatr.2003;92:51---1047.
18.KingR,HearingV,CreelD,OettingW.Albinism.In:ScriverC, BeaudetA,SlyW,ValleD,editors.Themetabolicand molecu-larbasesofinheriteddisease.8thed.NewYork:McGraw-Hill; 2001.p.5587---627.
19.KingOW.Oculocutanneousalbinism.In:NordlundJ,BoissyR, HearingV,KingR,OettingW,OrtonneJ,editors.The pigmen-tarysystem.2nded.Malden,MA:Wiley-Blackwell;2006.p. 599---613.
20.Grønskov K,Dooley CM, Østergaard E,KelshRN, HansenL, Levesque MP, et al. Mutations in c10orf11, a melanocyte-differentiationgene,causeautosomal-recessivealbinism.Am JHumGenet.2013;92:415---21.