20,0(QWU\.,1'/(56<1'520(

SNOMEDCT: 238836000 ORPHA: 306539

#173650
KINDLERSYNDROME
Alternativetitles;symbols
POIKILODERMA,HEREDITARYACROKERATOTIC
BULLOUSACROKERATOTICPOIKILODERMAOFKINDLERANDWEARY
POIKILODERMA,CONGENITAL,WITHBULLAE,WEARYTYPE
PhenotypeGeneRelationships
Location Phenotype
20p12.3

Phenotype
Inheritance Phenotype
Gene/Locus Gene/Locus
MIM number (in progress)
mapping key
MIM number

Kindlersyndrome 173650

AR

KIND1

607900

ClinicalSynopsis

TEXT
Anumbersign(#)isusedwiththisentrybecauseKindlersyndromecanbecausedbyhomozygousmutationintheFERMT1(KIND1)gene(607900)
onchromosome20p13.

Description
Kindlersyndromeisanautosomalrecessivedermatosischaracterizedbycongenitalblistering,skinatrophy,photosensitivity,skinfragility,and
scaling(summarybyJobardetal.,2003).

ClinicalFeatures
Kindler(1954)describedanEnglishgirlwithunusualcongenitalblisteringofherhandsandfeet.Laterinchildhood,thepatientdevelopedreticulate
erythemaanddiffusecutaneousatrophy,beginninginsunexposedareas.Hergumsbledeasily,andtheskinofthedorsalhandsandfeethadathin,
wrinkledappearance.By10yearsofage,theblisteringandsunsensitivityhadresolved,buttheskinremainedthinandfragile(Siegeletal.,2003).
Wearyetal.(1971)describedadisorder,whichtheynamedhereditaryacrokeratoticpoikiloderma,in10membersofawhitekindred.Expression
washighlyvariableandfellinto4categories:(1)vesicopustuleformationwhichremainsconfinedtothehandsandfeet,beginningfrom1to3
monthsofageandresolvinginlatechildhood;(2)widespreadeczematoiddermatitissomewhatresemblingatopiceczema,startingbetweenages3
and6monthsandcompletelyresolvingbyage5years;(3)gradualappearanceofdiffusepoikilodermawithstriateandreticulateatrophywhich
sparesonlytheface,scalp,andearsandpersistsintoadulthood;and(4)developmentofkeratoticpapulesonthehands,feet,elbows,andknees,
whichfirstappearatvaryingtimesbefore5yearsofageandpersistindefinitely.Maletomaletransmissionwasobserved.Larregueetal.(1981)
reviewed3pedigreessupportingautosomaldominantinheritance.Theystatedthatapigmentaryanomalyispresentinabout90%ofcases.
HachamZadehandGarfunkel(1985)suggestedautosomalrecessiveinheritance.Theydescribed2relatedKurdishJewishsibships,eachwithfirst
cousinparents;1wasaffectedinthefirstsibshipand3wereaffectedinthesecond.Thepropositahadhadbullaeonpressureareasfrombirth.These
healedwithatrophicscars.Shealsohadseverephotosensitivityonexposedareasanddevelopedwidespreadpoikiloderma.Bullaedidnotoccur
afterage17years.Oralexaminationshowedlimitationofmouthopening,ankyloglossia,dentaloverbite,andatrophyofbuccalmucosawithwhite
spots.
Jobardetal.(2003)described5consanguineousfamiliesfromNorthAfricawithKindlersyndrome.Allaffectedfamilymembersexhibitedcongenital
blistering,progressivepoikiloderma,ichthyosis,andxerosis.Variableclinicalfindingsamongthefamiliesincludedphotosensitivity,palmoplantar
keratoderma,oralmucosalinvolvement,syndactyly,andstenosisofmucosalopenings.
Siegeletal.(2003)identifiedagroupof26NativeAmericanpatientswithKindlersyndrome,allyoungerthan40yearsofage,whoweremembersof
atribeintheBocasdelToroprovinceonthenorthwesternCaribbeancoastofPanama.Thepatientsshowedcongenitalacralblisters,blisteringafter
traumaorsunexposure,erythemaanditchingaftersunexposure,andpatchyhyperandhypopigmentationwithatrophyandtelangiectases
(poikiloderma)developinginearlychildhoodinbothsunexposedandnonexposedskin.Otherfeaturesincludedhyperkeratosisofthepalmsand
solesanddiffusecutaneousatrophyandwrinkling,particularlyonthedorsaofthehandsandfeet.Othermucocutaneousfeaturesincluded
periodontaldisease,dentalcaries,andphimosis.Typically,theblisteringandphotosensitivityimprovedmarkedlyinadulthood,butthe
poikilodermapersisted.Therewassomevariabilityinphenotypicseverity,particularlyinthedegreeofphotosensitivity,ageatonsetof
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poikiloderma,anddegreeofhyperkeratosis.Siegeletal.(2003)notedthatKindlersyndromeclinicallyresemblesbothinheritedblisteringskin
disorderssuchasdystrophicepidermolysisbullosa(226600)andcongenitalpoikilodermassuchasRothmundThomsonsyndrome(268400).

Mapping
Jobardetal.(2003)performedagenomewidelinkageanalysisin5NorthAfricanfamilieswithKindlersyndromeandnarrowedthediseaseinterval
toan834kbregiononchromosome20p12.3.Siegeletal.(2003)confirmedthelocationofthislocusinthePanamanianfamiliesandinindividuals
withKindlersyndromefromdiversegeographicbackgrounds,someofwhomhadpreviouslybeendescribed(Wiebeetal.,1996;Shimizuetal.,1997;
Sugaetal.,2000;AlAboudetal.,2002).
GeneticHeterogeneity
Siegeletal.(2003)studied2familieswithKindlersyndrome,1fromCanada,previouslyreportedbyHaberandHanna(1996),andtheotherfromthe
UnitedStates,with1parentofEuropeandescentandtheotherofAfricandescent,whodidnotshowlinkageto20p12.3.Siegeletal.(2003)noted,
however,thatbothofthesefamiliesshowedclinicaldifferencesfromthePanamaniankindred,suggestingthattheymayhaveadisorderthatis
clinicallysimilarto,butgeneticallydistinctfrom,Kindlersyndrome.

MolecularGenetics
Inaffectedmembersof4consanguineousKindlerkindredsfromNorthAfrica,Jobardetal.(2003)characterized4homozygousmutationsinthe
kindlerin(FERMT1)gene(607900.0001607900.0004).Threeofthe4mutationswerepredictedtoresultintruncationoftheprotein,withlossofFERM
andpleckstrinhomology(PH)domains.Theauthorsdeterminedthatkindlerinisexpressedinmultipletissues,includingskin,andproposedthatit
mayplayaroleincelladhesionprocessesviaintegrinsignaling.
InpatientswithKindlersyndromefromvariousethnicbackgrounds,Siegeletal.(2003)identifiedlossoffunctionmutationsintheKIND1gene
(607900.0005607900.0006).BecauseKIND1isahumanhomologoftheC.elegansproteinUnc112,amembraneassociatedstructural/signaling
proteinthathadbeenimplicatedinlinkingtheactincytoskeletontotheextracellularmatrix(ECM),Siegeletal.(2003)suggestedthatKindler
syndromeisthefirstskinfragilitydisordershowntobecausedbyadefectinactinECMlinkageratherthankeratinECMlinkage.

Pathogenesis
Heinemannetal.(2011)demonstratedthatkindlin1deficientkeratinocytesrespondtocellstressbyupregulatingtheexpressionofseveral
cytokines,which,viaparacrinecommunication,launchaninflammatoryresponseinthedermis,withsubsequentactivationoffibroblastsandtheir
differentiationtomyofibroblasts,whichsecreteanddepositincreasedamountsofextracellularmatrixproteins.Thedatawereconsistentwitha
modelinwhichrepeatedcyclesofepidermalcellstress,cytokinesecretion,dermalinflammation,andprofibroticprocessesunderliethe
mucocutaneousfibrosisinKindlersyndrome.
SeeAlso:
Aguadeetal.(1972);Wallachetal.(1981)

REFERENCES
1.

Aguade,J.P.,Herrero,C.,Castello,C.A.,Grimalt,F.,RuedaPlata,L.A. Congenitalpoikilodermawithvesicobullouslesions:problemsin
classificationofhereditarypoikilodermas. Med.Cutanea6:417435,1972.

2.

AlAboud,K.,AlHawsawi,K.,AlAboud,D.,AlGithami,A. KindlersyndromeinaSaudikindred. Clin.Exp.Derm.27:673676,2002.

[PubMed:12472544,relatedcitations][FullText]

3.

Haber,R.M.,Hanna,W.M. Kindlersyndrome:clinicalandultrastructuralfindings. Arch.Derm.132:14871490,1996. [PubMed:8961879,

relatedcitations][FullText]

4.

HachamZadeh,S.,Garfunkel,A.A. KindlersyndromeintworelatedKurdishfamilies. Am.J.Med.Genet.20:4348,1985. [PubMed:

3970073,relatedcitations]

5.

Heinemann,A.,He,Y.,Zimina,E.,Boerries,M.,Busch,H.,Chmel,N.,Kurz,T.,BrucknerTuderman,L.,Has,C. Inductionofphenotype
modifyingcytokinesbyFERMT1mutations. Hum.Mutat.32:397406,2011. [PubMed:21309038,relatedcitations][FullText]

6.

Jobard,F.,Bouadjar,B.,Caux,F.,HadjRabia,S.,Has,C.,Matsuda,F.,Weissenbach,J.,Lathrop,M.,Prudhomme,J.F.,Fischer,J. Identification
ofmutationsinanewgeneencodingaFERMfamilyproteinwithapleckstrinhomologydomaininKindlersyndrome. Hum.Molec.Genet.
12:925935,2003. [PubMed:12668616,relatedcitations][FullText]

7.

Kindler,T. Congenitalpoikilodermawithtraumaticbullaformationandprogressivecutaneousatrophy. Brit.J.Derm.66:104111,1954.

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[PubMed:13149722,relatedcitations]
8.

Larregue,M.,Prigent,F.,Lorette,G.,Canuel,C.,Ramdenee,P. AcrokeratosepoikilodermiquebulleuseethereditairedeWearyKindler.
Ann.Derm.Venerol.108:6976,1981.

9.

Shimizu,H.,Sato,M.,Ban,M.,Kitajima,Y.,Ishizaki,S.,Harada,T.,BrucknerTuderman,L.,Fine,J.D.,Burgeson,R.,Kon,A.,McGrath,J.A.,
Christiano,A.M.,Uitto,J.,Nishikawa,T. Immunohistochemical,ultrastructural,andmolecularfeaturesofKindlersyndromedistinguishit
fromdystrophicepidermolysisbullosa. Arch.Derm.133:11111117,1997. [PubMed:9301588,relatedcitations][FullText]

10. Siegel,D.H.,Ashton,G.H.S.,Penagos,H.G.,Lee,J.V.,Feiler,H.S.,Wilhelmsen,K.C.,South,A.P.,Smith,F.J.D.,Prescott,A.R.,Wessagowit,
V.,Oyama,N.,Akiyama,M.,and30others. Lossofkindlin1,ahumanhomologoftheCaenorhabditiselegansactinextracellularmatrix
linkerproteinUNC112,causesKindlersyndrome. Am.J.Hum.Genet.73:174187,2003. [PubMed:12789646,images,relatedcitations][Full
Text]
11. Suga,Y.,Tsuboi,R.,Hashimoto,Y.,Yaguchi,H.,Ogawa,H. AJapanesecaseofKindlersyndrome. Int.J.Derm.39:284286,2000. [PubMed:
10809978,relatedcitations][FullText]
12. Wallach,D.,VignonPennamen,M.D.,Cottenot,F. Poikilodermiecongenitaleavecbulles,typeWeary. Ann.Derm.Venerol.108:7983,1981.
13. Weary,P.E.,Manley,W.F.,Jr.,Graham,G.F. Hereditaryacrokeratoticpoikiloderma. Arch.Derm.103:409422,1971. [PubMed:4253719,
relatedcitations][FullText]
14. Wiebe,C.B.,Silver,J.G.,Larjava,H.S. EarlyonsetperiodontitisassociatedwithWearyKindlersyndrome:acasereport. J.Periodont.67:
10041010,1996. [PubMed:8910840,relatedcitations]

Contributors:

MarlaJ.F.ONeillupdated:9/14/2011

CreationDate:

VictorA.McKusick:6/2/1986

EditHistory:

carol:09/14/2011

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