etas_10 cutaneous

Cutaneous Manifestations of Systemic Disease 353

10 Cutaneous Manifestations of Systemic Disease

Dori Rausch, MD

Valerie Harvey, MD

Anthony Gaspari, MD

C o n t e n t s

10.1 Cutaneous Manifestations of Hepatitis C Virus . . 355

10.2 Cutaneous Manifestations of Thyroid Disease . . . 357

10.3 Cutaneous Manifestations of Renal Disease . . . . . 359

10.4 Cutaneous Manifestations of Gastrointestinal Disorders . . . . . . . . . . . . . . . . . . . . . . 362

10.5 Cutaneous Manifestations of Neurologic Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367

10.6 Cutaneous Manifestations of Diabetes Mellitus . . . . 371

10.7 Cutaneous Manifestations of Cardiac Disease . . . . 373

10.8 Porphyrias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381

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10.1 CUTANEOUS MANIFESTATIONS OF HEPATITIS C VIRUSMorphology and Epidemiology

• Single-strandedRNAvirus,memberoftheflaviviridaefamily• Sixmajorgenotypesallwithanumberofsubtypes.Types1aand1baccountfor75%ofinfectionsintheUnitedStates

• IndevelopednationstheprevalenceofHCVantibodies<3%comparedwith10-30%inhighlyendemicareassuchasEgyptandJapan

• 3.9millionpeopleinfectedinU.S.

Risk Factors• Intravenousdruguseaccountsfortwo-thirdsofthecases• Transfusionofbloodorbloodproducts• Nosocomialinfection• Casesfromsexualtransmission,verticaltransmissionandbreast-feedingarerare

Disease Course/Diagnosis• 20-30%ofdevelopsymptomswithacuteinfection• Chronicdiseasecourse:70%ofpatientswillprogresstochronichepatitis;cirrhosiswilldevelopin20%-30%ofthepatientswithchronicdiseaseand4-11%ofcirrhoticpatientswilldevelophepatocellularcancer

• DiagnosisismadebyELISA

Extra Hepatic Systemic Manifestations• Autoimmunethyroiditis(mostcommonassociatedautoimmunedisorder)• Pulmonaryfibrosis• Aplasticanemia,autoimmunethrombocytopenicpurpura,peripheralneuropathies,arthralgias,systemicsclerosis,andlymphocyticsialadenitis.Mostofthesearebelievedtobeimmunemediated

Cutaneous ManifestationsCryoglobulinemia• Systemicvasculitisofsmall-sizedarteriesinvolvingmultipleorgans

• Cryoglobulins:Immunoglobulinsthatreversiblyprecipitateinthecold.Therearethreemajortypesofcryoglobulins.Type1iscomposedofmonoclonalimmunoglobulins,type2iscomposedofpolyclonalIgGandmonoclonalIgM(rheumatoidfactoractivity)andintype3therearepolyclonalIgGandpolyclonalIgM

• 80percentofcasesofmixedcryoglobulinemiaareassociatedwithHCVinfection• Classicalclinicalpresentationincludespalpablepurpura(mostcommonfinding),arthralgiasandglomerulonephritis.Livedoreticularis,hemmorhagicbullae,acrocyanosisandurticarialplaquescanalsobefound

• Lababnormalitiesincludeanelevationofliverenzymes,positiverheumatoidfactor(70-90%)anddepressedC3levels

• Histopathologydemonstratesaleukocytoclasticvasculitis• Cutaneouslesionsrespondtoalphainterferontherapy,butthereisahighrelapserateafterstoppingthedrug

uTIP Cryoglobulinemia Immunoglobulin

Type 1 Monoclonal IgG or IgM

Type 2 Polyclonal IgG and monoclonal IgM

Type 3 Polyclonal IgG and polyclonal IgM

356 2011/2012DermatologyIn-ReviewlCommittedtoYourFuture

Porphyria Cutanea Tarda (PCT)• Causedbyadeficiencyinuropoprhyrinogendecarboxylase(UROD);maybeinherited,sporadicorassociatedwithHepatitisC

• SporadicformmayoccurinassociationwithHCV;inonestudy82%ofpatientswithPCThadHCV-antibodies

• Otherenvironmentaltriggersincludealcohol,estrogens,andpolyhalogenatedhydrocarbons • Skinfindingsincludevesiclesandbullaeonsun-exposedareas,atrophicscarringwithmiliaformation,facialhypertrichosis,hyper/hypopigmentation,skinfragilityandsclerodermoidchanges.Pathdemonstratesasubepidermalbullalinedbywell-preserveddermalpapillae(festooning),thickeningofbasementmembranezoneandvessels

• ThepathogenesisofHCVrelatedPCTmightberelatedtodecompartmentalizationofironstoresresultinginformationoffreeironradicalsandoxidationofUROD

• Treatmentincludesphlebotomytodecreaseironload,interferonbasedregimensandavoidanceoftriggeringfactors

Lichen Planus• IncidenceofHCVinpatientswithlichenplanusvariesfrom0.1%to35%,dependingonregion

• Thepathogenesisoftheskinlesionsisunclearbutmaybesecondaryto proliferationoftheviruswithinlymphocytes

• Treatmentwithinterferonhascausedbothworseningandimprovementoftheskinlesions

Polyarteritis Nodosa• Multisystemsegmentalnecrotizingvasculitisaffectingmedium-andsmall-sizedarteries• Cutaneouslesionsoccurringin25-50%ofpatientsincludesubcutaneousnodulesthatcoursealongbloodvesselswithvariableoverlyingerythema.Nodulesmaybepainful,pulsatileandaremostcommonlylocatedonthelowerlegs

• Invariousstudies12-31%ofpatientswereHCV+• PolyarteritisnodosaisalsoassociatedwithHepatitisB

Pruritus• CommoncomplaintofpatientswithchronicHCVinfection• Patientswillpresentwithexcoriations,lichenificationandprurigonodularislesions• Tendstobegeneralizedandnotrelievedwithscratching• Thepathogenesismayberelatedtoelevatedbilesaltlevelsthatoccurinthesettingofliverfailure.However,thereisnotalwaysadirectcorrelationbetweenserumbilesaltlevelanddegreeofpruritus

• Treatmentregimensincludecholestyramine,ursodeoxycholicacid,rifampin,naltrexone,thalidomide,andUVA,UVBandinterferonalpha

Uncommon AssociationsMostofthesearefromanecdotalcasereports,thereforefurtherepidemiologicalstudiesare

neededtoclarifywhetherthesearetrueassociations.• Erythemanodosum• Erythemamultiforme• Unilateralnevoidtelangiectasia• Pyodermagangrenosum• Vitiligo• Psoriasis

uTIPa

Erosive mucosal variant of LP has the strongest association with HCV


• Behçet’ssyndrome• Moorencornealulcers• Granulomaannulare• Disseminatedsuperficialactinicporokeratosis

Adverse Skin Reactions Secondary to TreatmentCurrentlythebestmanagementofHepatitisCisthecombina-

tionofinterferonαandribavirin.Themajorsystemicsideeffectsofinterferontherapyincludeaflu-likeillnessconsistingoffatigue,neutropenia,fever,myalgia,anorexia,vomiting,andheadaches.Asmallstudycomparingpatientstreatedwithinterferon/ribavirinto controlsoninterferonalonefoundthatcutaneousreactionsweremorecommoninthegrouponcombinationtherapy.

10.2 CUTANEOUS MANIFESTATIONS OF THYROID DISEASEThyroid-Specific Diseases

Thyroglossal Duct Cyst• Remnantofembryonicduct• Mostcommoncysticabnormalityofneck• Presentsasmobilenontendermass,midlineanteriorneck• Path:Cystwalllinedbycuboidal,columnarorstratifiedsquamousepithelium.Characteristichistologicfeatureispresenceofthyroidfolliclesincystwall

Thyroid Malignancies• Metastasestotheskinfromathyroidmalignancyisrare• Mostreportedcasesoccurwithpapillaryadenocarcinoma• Multipleendocrineneoplasia(MEN)2a,Sipplesyndrome,isautosomaldominantandischaracterizedbymedullarythyroidcarcinoma,pheochromocytoma,andparathyroidhyperplasia/adenomas.ThegenedefectliesintheRETproto-oncogene,whichencodesatyrosinereceptorkinase.Skinfindingsarerarebutmayincludelichenormacularamyloidosis

• MEN2b/IIIisalsoautosomaldominantandcharacterizedbymedullarythyroidcarcinoma,pheochromocytoma,marfanoidfeatures,andgastrointestinalganglioneuromatosis.Themostcommonskinfindingismucosalneuromas.Otherassociatedcutaneousfindingsincludeperioralandacralhypopigmentation,café-au-laitmacules,andcirumorallentigines

• Cowden’ssyndrome(multiplehamartomasyndrome)autosomaldominantduetoadefectinthePTENtumorsupressorgene,whichencodesaproteinphosphatase.Thisconditionischaracterizedbytrichilemmomas,acralkeratoses,oralpapillomas,acanthosisnigricans,lipomas,facialdysmorphismandbonyabnormalitiesandmacrocephaly.Inaddition,patientsmaydevelopthyroidadenomas,thyroidgoiter,thyroglossalductcyst,andareatanincreasedriskofdevelopingthefolliculartypeofthyroidcarcinoma.Patientsarealsoatriskforfibrocysticbreastdisease,breastcancerandLhermiteDuclosdisease(dysplasticgangliocytomaofcerebellum)

Cutaneous Manifestations of HyperthyroidismGraves Disease• Ahypermetabolicstatecharacterizedbythyrotoxicosis,diffusegoiter,infiltrativeopthalmopathy.Aninfiltrativedermopathyispresentinasubsetofpatients

uTIPa�The most frequently reported

cutaneous findings with interferon were alopecia, lichenoid eruption, eczema, malar erythema, and local cutaneous necrosis

uTIPa�Malignant degeneration to

papillary adenocarcinoma rare


• Clinicalmanifestationsincludenon-specificsignsseenwithhyperthyroidism,goiter,pretibialmyxedema(thyroiddermopathy)

• Thyroid dermopathy:Bilaterallysymmetric,non-pittingyellowish-browntoredwaxypapules,nodulesandplaquesonlowerextremities>ankles,arms,andshoulders.Mayprogresstoresembleelephantiasisverrucosanostra.Canoccurintheeuthyroid,hypothyroid,orhyperthyroidstate.Theclinicalfindingsareduetoanincreaseinhyaluronicacidindermis.Thepathogenesisofhowthisoccursisunknown.Treatmentregimensincludehighpotencytopicalsteroidsandintralesionaltriamcinolone

• CutaneousconditionsassociatedwithGrave’sdiseaseincludevitiligo,anetoderma,dermatitisherpetiformis,mid-dermalelastolysis,herpesgestationis,pemphigusvulgaris,andSweet’ssyndrome

Non-specific Manifestations of HyperthyroidismSkin

• Warm,andmoist

• Localizedorgeneralizedhypertrichosis • Palmarerythema • Erythemaoverlyingelbows

• Flushingofhead/neck,trunk

Hair • Soft/fine/straight • Diffusereversiblealopecia

Nails • Fasterrateofgrowth • Onycholysis

• Plummernails:concavedeformitywithdistalonycholysisPigmentation

• Focalorgeneralizedhyperpigmentation

• Vitiligo

Cutaneous Manifestations of Hypothyroidism• Theseskinfindingsresultfromtheinadequatecirculationofthyroidhormone,targetorganresistance,oraniatrogeniccause

• Congenitalhypothyroidism:rareinU.S.,asitispartofneonatalscreening.Clinicalfindingsincludecool,dry,pastyskin,andthick,paleprotuberantlips,delayeddentition,anenlargedtongue,wideseteyes,abroadflatnose,dwarfism,cutismarmorata,cardiacdefects,gastrointestinalandskeletaldefects

• PotassiumIodide(KI)andWolff-Chaikoffeffect(WCE):TheWCEisdescribedasthebindingofexcessorganiciodideinthethyroidglandwithresultantinhibitionofthyroidhormonesynthesis.Thiscanoccurinthesettingofpatientswitherythemanodosum(orotherinflammatorydermatoses)beingtreatedwithpotassiumiodide

uTIPa Thyroidacropachy:clubbingof

fingersassociatedwithsofttissueswellingandperiostealnewboneformation


Non-specific Manifestations of HypothyroidismSkin

• Cool,dry,pale• Xerosis• Hypohidrosis

• Yellowishhuesecondarytocarotenemia • Generalizedmyxedema:swollenwaxyappearance

• Swollenlips,broadnose,macroglossia• Purpurasecondarytoimpairedwoundhealing

Hair• Dry,brittle,coarse• Increaseinpercentageoftelogenhairs• Diffusealopecia

• Lossoflateralthirdofeyebrow(madarosis)

10.3 CUTANEOUS MANIFESTATIONS OF RENAL DISEASEDiseasesthateitherindirectlyordirectlyimpairrenalfunctioncanmanifestintheformofcuta-

neouspathology.Thissectionwillhighlightthekeyclinical,serologicalandhistopathologicalfea-turesoftheacquiredandhereditaryconditionsthathavebothcutaneousandrenalmanifestations.

Genetic Disorders with Cutaneous and Renal InvolvementTuberous Sclerosis (Bourneville’sDisease)• Autosomaldominantneurocutaneousdisorderclassifiedbyseizures,mentalretardation,andcharacteristicskinfindings

• DuetomutationsintheTSC1andTSC2genes,which codeforthetumorsuppressorproteinshamartin (TSC1)andtuberin(TSC2)

• Renalinvolvementincludesthedevelopmentofrenalangiomyolipomas,polycysticrenaldisease(associatedwithTSC2)andrarelyrenalcellcarcinoma

Fabry’s Disease • X-linkedrecessiveconditionduetoadeficiencyofalpha-galactosidase-A.Absence

ofthisenzymeleadstoaccumulationofglycosphingolipids(globotriaosylceramide,galabiosylcermide)withinthevascularendothelium

• Classiccutaneousfindingsincludehypohidrosis,andangiokeratomacorporisdiffusuminabathingtrunkdistribution.Extracutaneousfindingsincludewhorl-likecorneal/lenticularopacities,acralparesthesias,myocardialinfarctionsandcerebrovasculardisease

• Patientscandevelopproteinuria.Diagnosisisconfirmedbydecreasedlevelsofalpha-galactosidaseinwhitebloodcells,serum,fibroblasts,andamnioticfluid.Treatmentwithenzymereplacementisavailable;renalfailureisduetoaccumulationofceramidetrihexoside.Diagnosisisconfirmedbydecreasedlevelsofalpha-galactosidaseinwhitebloodcells,serum,fibroblasts,andamnioticfluid.Treatmentwithenzymereplacementisavailable

uTIPa Hypopigmentedmaculesaretheearliest

cutaneousfinding.Othercharacteristicskinlesionsincludefacialangiofibromas(adenomasebaceum),collagenomas(shagreenpatch),periungualfibromas(Koenen’stumors),foreheadplaques,gingivalfibromas,anddentalpitting


Birt-Hogg-Dube Syndrome (BHDS)• Autosomaldominant,duetodefectintheBHDgenethatencodesthetumorsuppressorprotein,folliculin.Thefunctionofthisproteinisunknown

• Triadoftrichodiscomas,fibrofolliculomasandacrochordons• Clinicallypatientsdisplaynumerousfirmflesh-coloredpapulesoverthehead,neckanduppertrunk

• StrongevidencesuggestingthatBHDSandbilateralrenaltumors,co-segregateinanautosomaldominantfashion.Histologically,theserenaltumorsareoncocytomas,chromophobeadenomasandpapillaryrenalcellcarcinoma

•Periodicsurveillanceofpatientsandtheirrelativesforrenalcellcarcinomaisrecommended.Patientsarealsoatriskforpulmonarycystsandpneumothorax

Nail-Patella Syndrome• Autosomaldominant

• ThedefecthasbeenidentifiedintheLMX1Bgene,whichencodesatranscriptionfactor involvedincollagensynthesis

• Patientsdevelopdystrophicnails(thumbnailmostcommonlyinvolved),triangularlunulae,hypoplasticorabsentpatellae,dislocationofthemradialhead,andposterioriliachorns

•Patientsmaydevelophyperpigmentationofthepapillarymarginoftheiris(Lesteriris) • Renalinvolvementincludes:glomerulonephritis,hemolyticuremicsyndromeandrarely,

renalfailure

Pseudoxanthoma Elasticum (PXE)• Autosomalrecessive• �Fragmentationandcalcificationofelasticfibersintheskin,Bruch’smembraneoftheeye(angioidstreaks)andvasculatureleadstotheclinicalmanifestations

• Yellowpapulesandplaquesintheflexuralareasgivetheappearanceof“pluckedchickenskin.”Patientsmayalsodevelopclaudication,lossofperipheralpulsesandangina

• InactivatingmutationintheABCC6gene,whichencodestheMRP6protein(functionsas effluxpump) expressedinhepatocytesandrenalcells

• Histopathology:fragmentedelasticfibersinthemidanddeepreticulardermis• Hypertensionfrequentlydevelopsinthesepatientssecondarytoinvolvementofrenalvasculature

End Stage Renal Disease (ESRD) and DialysisTherearemanydermatologicalmanifestationsofESRD.Manypatientsdevelopachronicane-

miaresultinginskinpallor.Depositionofcarotenoidsandurochromegivestheskinayellowishhue.Photo-distributedhyperpigmentation,andecchymoses(secondarytouremicplateletdys-function)arealsocommonlyseen.

• Halfandhalf(Lindsay’s)nailsresultfromedemaofthenailbedandcapillarynetworkandgivetheproximalhalfofthenailanopaquewhiteappearance.Incontrast,patientswithcirrhosisorhypoalbuminemiahavewhiteningoftheproximaltwothirds,whilethedistal1/3isred(Terry’snails)

Pruritus• ThemostcommoncutaneousmanifestationofESRD• Seeninbothperitonealorhemodialysispatients


• Patientscanpresentwithlocalizedorgeneralizedsymptoms.Physicalexaminationoftheskinwilloftenrevealexcoriations,lichenificationandprurigonodularis

• Thepathogenesisisnotwellunderstoodandmostlikelymultifactorial.ProposedtheoriesincludehypervitaminosisA,accumulationoftoxicsubstanceswithexcitationofcutaneousnerveendings,andincreasednumberofmastcellswithinlesionalskin.Noneofthesetheorieshavebeensubstantiatedinstudiesyet

• Themanagementischallenging,andoftenunsatisfactory.Treatmentregimensincludetopicalsteroids,lubricants,keratolytics,oralantihistamines,activatedcharcoal,andcholestyramine.UVBphototherapyisthemosteffectiveformoftreatmentforpatientswhoarenottransplantcandidates.Renaltransplantationiscurative

Acquired Perforating Dermatosis of ESRD• Similartoprimaryperforatingdisordersinthattheyareallcharacterizedbytransepidermaleliminationofaltereddermalsubstances.ShareoverlappingclinicalfeaturesofKyrle’sdisease,perforatingfolliculitisandreactiveperforatingcollagenosis

• Etiologyisunknown,butmayberelatedtothedermalaccumulationofmicro-depositsofcalciumwithsubsequentevacuationthroughtheepidermis

• Patientspresentwithflesh-coloredorhyperpigmentedumbilicatedpapules/nodules/plaqueswithacentralkeratoticcore

• Treatmentpossibilitiesincludetopicalsteroids,intralesionalcorticosteroids,topical/oralretinoids,cryotherapyandUVB

Metastatic Calcification• Depositionofcalciumwithintissuesecondarytoabnormalcalciumandorphosphatemetabolism

• Itcanmanifestintheskinasbenignnodularcalcifications(calcinosiscutis)orasamoreseriouscondition(calciphylaxis)withanassociatedmortalityratebetween60-80%

•Calciphylaxispresentsaspainfulpurpuricplaquesandretiformpupurawithprogressiontoulcerationandnecrosis.Distributionofthelesionsmaypredictprognosis;patientswithacrallesionshaveabetteroutcomethatthosewithproximallylocatedlesions

• Histologicalfindingofmedialcalcification/intimalhyperplasiaofsmallarteriesandarteri-olespointstoanabnormalityofcalcium/phosphatemetabolism

• Managementofthesepatientsincludestotalorsubtotalparathyroidectomy(ifPTHlevelsareelevated),woundcare,andavoidanceorprecipitatingfactors.MortalityisrelatedtoStaphylococcalsuperinfectionofulcerswithresultantsepsis

Nephrogenic Systemic Fibrosis (NSF)• Nephrogenicfibrosingdermopathy(NFD).Itisanewlyrecognizedfibrosingdisorderthatoccursinthesettingofchronicandacuterenalfailureduetoavarietyofrenaldiseases

• RecentreportssuggestgadoliniumcontainingMRIcontrastisatriggerinsuchpredisposedindividuals

• Patientspresentwithwoodyinduratednodules/plaqueswithapeaud’orangeappearance.Thelesionsareusuallyconfinedtotheextremitiesbutcanoccasionallyappearonthetrunk.Besidesrenaldisease,otherassociatedconditionsincludecoagulationabnormalities,DVT,andrecentsurgery(especiallyvascularsurgery)

• Noserologicalevidenceofparaproteinemia,peripheraleosinophilia,thyroiddiseaseorcollagen-vasculardisease

uTIPa�More commonly seen in darker skin types,

and in patients with ESRD secondary to diabetic nephropathy


• Histopathologydemonstratesadiffusefibroblasticproliferationinthedermiswithminimaltoslightincreaseindermalmucin

• Thediseasecourseisvariable.Lessthan5%havefulminantandfataldisease.Thisiscausedbyimpairedventilationduetofibrosisofrespiratorymuscles

• Treatmentisusuallynotsatisfactory.Correctionofkidneyfunctionviahemodialysisortransplantproducesvariableimprovement

Porphyria Cutanea Tarda (PCT)• Thepathogenesismayberelatedtothesuboptimalclearanceofuroporhyrinsfromthecirculation

• HasanidenticalclinicalpresentationtosporadicPCT• Patientsmaypresentwithbullae,skinfragility,photodistributedhyperpigmentationandhypertrichosis

• Pathdemonstratesasubepidermalbullalinedbywell-preserveddermalpapillae(festooning),thickeningofbasementmembranezoneandvessels

• Treatmentincludeserythropoietintoraisehemoglobinfollowedbyphlebotomytodecreaseironload

Pseudo-PCT • SimilarclinicalandhistologicalfindingsofPCT,insettingofnormalporphyrinprofile • Usuallyduetocertainmedicationssuchasfurosemide,naproxen,tetracycline,nalidixic

acid,oramiodarone

Acquired Disorders with Renal and Cutaneous ManifestationsTherearemanyacquireddisordersthathavebothrenalandcutaneousfindings.Someofthe

moreimportantoneswillbebrieflyreviewedbelow.• Insystemiclupuserythematosuspatientsdevelopmalarerythema,photosensitivity,andoralulcers.Renalbiopsywillrevealfocalproliferative,diffuseproliferativeormembranousglomerulonephritis

• SystemicsclerosisischaracterizedbyRaynaud’sphenomenonacralordiffusesclerosis,esophagealdysmotilityandpulmonarydisease.Rarely,patientscandeveloprenalfailure

• Henoch-Schonleinpurpura(HSP)isanIgAmediatedsmallvesselvasculitis.Clinically,patientspresentwithpalpablepurpuraofthelowerextremitiesandbuttocks,GIvasculitisandglomerulonephritis.DirectimmunofluorescenceoflesionalandperilesionalskinwilldemonstrateIgA,C3,andfibrindepositsinsmallvesselwalls

• Wegener’sgranulomatosisischaracterizedbynecrotizinggranulomasandvasculitisoftheupper/lowerrespiratorytractandkidneys.Dermatologicalmanifestationsincludepalpablepurpura,oralulcers,nodules,gingivalhyperplasia,andlivedoreticularis.Renalinvolvementcanleadtohypertensionandedema;renalfailureisuncommonbutamajorcauseofmorbidity

10.4 CUTANEOUS MANIFESTATIONS OF GASTROINTESTINAL DISORDERS Hereditary Hemorrhagic Telangiectasia (Osler-WeberRendu)

• AutosomaldominantdisordercausedbymutationsinEndoglin(ENG)orActivinreceptor-likeKinase-1(ACK1,ACVRLI)genesresultinginHHT1orHHT2,repsectively.BothgenesencodeproteinsthatbelongtoTGF-breceptorcomplexandplayaroleinformationofvascularsystem

• Characteristicfindingsincludemaculartelangiectasiasontheoralmucosa,faceandacralsurfaces.Thesepatientshavedirectarteriovenousconnectionwithoutaninterveningcapillary


• Typicalinitialsymptomisepistaxis.Melena,relatedtoangiomasintheGItract,isthepresentingsignin25%.AVmalformationsmaydevelopintheliver,lungandCNS.Treatmentwithsystemicestrogenmayreduceepistaxis.LaserisalsobeneficialfornasalandGIbleeding.Usuallypresentingsignisepistaxis;painlessgastrointestinal(GI)bleeding,mostlyfromnodularangiomasinstomachorduodenum;AVmalformationsofliver,lung,andeye

Blue Rubber Bleb Nevus Syndrome

•Autosomaldominantorsporadiccondition,causedbymutationsinVMCM1gene(unknownprotein)

• Softcompressiblebluetumorsdevelopusuallyonthetrunkandarms.Nocturnalpainischaracteristic

• Melenaoccurswhengastointestinalhemangiomasrupture.Lesscommonsitesofinvolvementarethelung,eyeandCNS.Disseminatedintravascularcoagulationhasbeenreported

Kaposi’s Sarcoma (KS)• Pathogenesis:HHV-8infectioncausesabnormalvascularproliferation(otherHHV-8associatedconditionsinclude:primaryeffusionlymphoma,solidlymphoma,andCastleman’sdisease).TypesincludeClassic,Africanendemic,AfricanLymphadenopathic,drug-inducedimmunosuppression,andHIV-associated

• ClassicformisseeninmiddleagedmenofSouthern-EasternEuropeanheritage.Typically,patientspresentwithredtoblue-blackpatches,plaquesornodulesonthefeet

• AfricanendemicKSisalocallyaggressiveprocessthataffectsmiddleagedmeninNortheastCongo,andRwanda-Burundi

• AfricanlymphadenopathicKSisanaggressivediseasewhichaffectschildrenyoungerthantenyears.Lymphnodeinvolvementmaypreceedskin.Eyelidandconjunctivallesionsarecharacteristic.Deathoccurswithinonetotwoyears

• Drug-inducedimmunosuppressionKSissimilartoclassicKSbutlocationofthelesionsismorevariable

• HIVassociatedKSisanaggressiveform.Thereisatendencytowardupperbodyandfacialdistributionofskinlesions.Visceraisinvolvedin70%ofcases

• Radiationtherapy,localexcision,cryotherapy,alitretinoingel,intralesionalvincristineorinterferonandlaserablationhaveallbeensuccessfulintreatinglocaldisease

• HAARTiseffectiveinHIVassociatedKS,irrespectiveofwhethermedicationisaproteaseinhibitorornon-nucleosidereversetranscriptaseinhibitor

Henoch-Schonlein Purpura (HSP)• Precededbyupperrespiratoryinfection.Otherproposedtriggersincludebacterialinfections,medications,foodsandlymphoma.Ittypicallyaffectsyoungstersundertheageof20.However,adultvariantsexist

•Palpablepurpura,urticaria,andnecroticulcersonbuttock,distallegs,extensorextremitiessymmetrically.Histologyshowsleukocytoclasticvasculitis.DirectimmunofluoresenceshowsperivascularIgA,C3andfibrindeposits


• Constitutionalsymptomssuchaslowgradefever,headacheandjointachesmaypreceedskineruption.Arthralgiasandarthritisofthekneeandanklescandevelop.GIinvolvementpresentsasabdominalpain,vomitting,distension,GIbleeding,orileus.Renalinvolvementintheformofgrossormicroscopichematuriaoccursinmorethan25%ofpatients.Treatmentissupportive.Systemiccorticosteroidsisquiteeffectiveforabdominalpain,althoughcontroversialforrenaldisease.Longtermsequelaeincludehypertensionandrenalinvolvement

Malignant Atrophic Papulosis of Degos• Aconditionofunknownetiologywhichtypicallyaffectsmen>women

• Pinkdome-shapedpapulesonthetrunk,bulbarconjunctiva,andoralmucosaaretheinitialmanifestations.Lesionsbecomeumbilicatedandultimatelyatrophytocreateawhitecenterwithtelangiectaticrim.Subsequently,GIinvolvementensues,producinghematemasis,cramping,andfever.Deathisrelatedtoperforationandperitonitis.CNSinvolvementoccurstoalesserextentandpresentsasheadache,hemiparesis,aphasia,andcranialnerveinvolvement

•Histologyshowsepidermalatrophyoverlyingwedge-shapeddermalnecrosisandmucinousdegenerationoverlyingthromboticvasculitiswithminimalinflammation

Gardner’s Syndrome •AutosomaldominantdisordercausedbymutationsintumorsuppressorAPCgeneleadingtodisturbedsignaltransductionanduninhibitedgrowth • Epidermalcystsin50-100%ofpatientsandoccurmostlyonthefaceandscalp.Histology

oftenshowspilomatricoma-likefeaturesfoci.Otherfindingsinclude:desmoidtumors,fibromas,lipomas,leiomyomas,osteomasofmandible/maxilla,impactedteeth,supranum-meryteeth,dentalcysts,andearlytoothloss

• Allpatientsdevelopadenenomatouspolyposisofcolonandrectumwith100%transformationtocarcinomabyage30in50%

Peutz-Jeghers Syndrome • Autosomaldominantdisorderinwhich50%ofpatientshavemuta-

tionsinSTK11gene.Thisgeneencodesaserinethreoninekinasethatisimportantforsignaltransduction

•Hyperpigmentedmaculesmaydevelopanywhereintheoralmucosa,onthegenitaliaanddorsalacralsurfaces.Oncetheclinicalpatternisrecognized,thenendoscopyshouldbeperformedtodetecthamartomatouspolypsoftheGItract.Frequencyofinvolvementis:smallintestines>stomach>colon>rectum

• Thesepolypscanprogresstocancerandthusscreeningeverytwoyearsisrecommended.Inaddition,screeningforpancreaticcancershouldbeconsideredsincethelifetimeriskofdevelopingsuchis10%.Malignanciescanalsodevelopinthegallbladder,breast,ovary,andtestes

• Laugier-Hunziker(LH)andCronkhite-Canadasyndromeshouldalsobeconsideredinthedifferentialdiagnosis. PatientswithLHpresentwithmucosalpigmentationandpigmented

nailstreaksonly

Cronkhite-Canada Syndrome • Clinically,patientspresentwithmelanoticmaculesofthe

fingersandGIpolyps.MostaffectedpatientsareJapanese.Extensivealopeciaandonychodytrophyarealsocharacteristic

uTIPa�Hyperpigmentation of

the lip begins in infancy

uTIPa� Unlike Peutz-Jegher syndrome,

onset is in adulthood

uTIPa Congenital hypertrophy of

retinal epithelium (CHRPE) is an early sign of Gardner’s syndrome


• TheGIpolypsarebenign,althoughtheymayresultinprotein-losingenteropathy,bleeding,andasmallriskofmalignanttransformation

Muir-Torre Syndrome (MTS) • AutosomaldominantdisordercausedbymutationsineitherMSH2orMLH1genes.Thelatter

encodesamismatchrepairenzyme • Characteristicfeaturesaresebaceousneoplasms,(especiallyadenomas),multiplekeratoac-

anthomataandinternalmalignancy.Theseinternalmalignanciesoftenpreceedcutaneouslesionsby10-20years

• Themostcommonmalignancyiscoloncancer,butlaryngeal,uterine,andbreastcancercanalsodevelop

Bannayan-Riley-Ruvalcaba Syndrome • AutosomaldominantdisordercausedbymutationsinPTENgenein60%ofcases.PTENis

alsomutatedinCowden’ssyndrome•Clinically,patientpresentwithmacrocephaly,genitallentigines(Bannayansyndromeaffectsthe“banana”akapenis),developmentaldelay,GIhamartomatouspolyps,lipomas,myopathiesandhemangiomas

Multiple Endocrine Neoplasia (MEN)•MucocutaneousfindingsaremorecommonintypesIandIIB•Type I “Wermers’s syndrome”: AutosomaldominantdisorderinvolvingmutationsinMENIgene,whichencodesmenin,anuclearprotein.Theyinclude:facialangiofibromas,collagenomas,lipomas,hypopigmentedmacules,andcafé-au-laitmacules.Sytemicfindingsarerelatedtoparathyroid,pancreatic,andpituitarytumors

•Type IIA “Sipple’s syndrome”: AutosomaldominantdisordercausedbymutationsinRETgene,whichencodesatyrosinekinasereceptor.Itisasyndromeofcutaneousamyloidosis,pancreatictumors,parathyroidtumors,pheochromocytomaandmedullarythyroidcarcinoma.Clinically,patientspresentinchildhoodwithnotalgiaparesthetica,macularorlichenamyloidosis.Workupshouldincludecalcitonin,calcium,PTH,andurinecatecholamines

•Type IIB: Autosomal dominant disorder involving RET gene.Characteristicfeaturesaremultiplemucosalneuromas,marfanoidbodyhabitus,andprotrudinglips.Thesepatientsarealsoatriskformedullarythyroidcarcinoma,pheochromocytoma,andGIganglioneuromas

Bowel-Associated Dermatosis-Arthritis Syndrome•Occursinthosewithulcerativecolitis(UC),Crohn’sdisease(CD),s/pbypasssurgery,orblindloopsyndrome.Involvesbowelbacterialovergrowthcausingcomplementactivationwithsubsequentdepositionofantibodycomplexesinskin/synovium

• Clinically,patientspresentwithcropsofredandpurpuricpapulovesiclesonproximalextremitiesortrunkassociatedwithfevers,chills,malaise,andarthritis

• Histologyshowsaperivascularlymphocyticinfiltrateandaleukocytoclasticvasculitisofdermalcapillaries.DirectIFispositivewithimmunoglobulinsandcomplementatDEjunctionandaroundvessels

•Pustularpyodermagangrenosumshouldbeconsideredinthedifferentialdiagnosis

Dermatitis Herpetiformis or “Duhring’s Disease”• VirtuallyallpatientswithDHhavegluten-sensitiveenteropathy,althoughmostareasymptomatic


• ThereisahighincidenceofHLA-B8,DR3andDQw2haplotypes• Pathogenesisisunclear.Themajorproblemliesinthedevelopmentofantibodiestotissuetransglutaminase(thisenzymemetabolizesgliadinproteinfoundingluten-richfoodssuchaswheat,barley,andrye).Theseantibodiescross-reactwithepidermaltransglutaminaseandcausethecutaneousfindings.PatientsalsohavecirculatingIgAantibodiesagainstsmoothmuscleendomysium

• Severelypruriticgroupedvesiclesoccurontheextensorsurfaces,scalp,neckandbuttocks.Lesionsare“herpetiform”becausetheystartasgroupedandarisefromanerythematousbase

• Histologyoflesionalskinshowssubepidermalclefting.IndirectIFisnegative• Oraliodidesshouldbeavoided

Table10-1.ManifestationsofInflammatoryBowelDisease(IBD)

Association Cutaneous Findings

FissuresandFistulas CD>UC Commonlyinvolvesperineum Associatedwithedemaandinflammation

OralCrohn’s CD Edema,cobblestone,ulcerations,nodules

MetastaticCrohn’s CD Nodules,plaques,ulcerations;commonlyonextremitiesorintertrigenousregionsMimicsErythemaNodosum

ErythemaNodosum UC>CDFemales>males

Tenderrednodulesonanteriorlowerlegs;precedesoroccurssimultaneouswithIBDflare

PyodermaGangrenosum(PG) UC>CDClinicalcoursefollowGIdisease

Papules,pustules,hemorrhagicblisters→ enlarge,ulceratewithduskyunderminededges;exacerbatedbytrauma;frequentlyonlegs

PyodermaVegetans UC Vegetatingplaques,vesiculopustulesofintertrigenousareas;healwithhyperpigmentation;whenprocessinvolvesmucosa=Pyostomatitsvegetans

ChronicApthousUlcers UC>CD Identicaltocommonaphthousulcers;developwithIBDflares

PolyarteritisNodosa(PAN) CD Tenderrednodulesthatmayulcerateonlegs;associatedwithstarburstlivedoreticularis,peripheralneuropathy,arthralgias,myalgias

Otherlesscommonmanifestations:Epidermolysisbullosaacquisita,erythemamultiforme,urticaria,clubbing,psoriasis,vitiligo.Note:CD=Crohn’sdisease UC=UlcerativeColitis


10.5 CUTANEOUS MANIFESTATIONS OF NEUROLOGIC DISEASENeurofibromatosis 1 (NF1)

• AutosomaldominantdisorderinvolvingmutationsintumorsuppressorgeneNF1,whichencodesneurofibromin.Thisproteinisthoughttodownregulateproto-oncogeneras

• Theinitialpresentingsignisthecafé-au-laitmacule(CALM).Theybegintodeveloppriorto,orshortlyafterbirth

• Axillaryoringuinalfreckling(Crowe’ssign)ispathognomonicforNF• IfNFissuspectedinachild,aslitlampexamshouldbeperformedsinceLischnodules(pigmentedirishamartomas)arepresentinthisagegroupandcanconfirmthediagnosis

• Neurofibromastypicallyappearafterpubertyandoccurin3differentforms: 1.)Thefirstispedunculated.Thesehaveapositivebutton-holesign 2.)Plexiformneuromasdevelopalongthecourseofaperipheralnerve 3.)Diffuseneuromascancausegrossdeformity.TheElephantMan,JosephMerrickofLondon,haddiffuseneuromas

• Otherassociatedfindingsinclude: 1.)Skeletal:macrocephaly,kyphoscoliosis,lordosis,spinalbifida,sphenoidwingdysplasia,pseudoarthrosisofthelongbones 2.)CNS:Learningdisabilities,opticgliomas,seizures,unidentifiedbrightobjects(UBO)inthebasalganglia,brainstem,andcerebellumvisualizedbyT2-weightedMRI

3.) Malignancy:patientswithNF1whodevelopjuvenilexanthogranulomasareat20-30timesgreaterriskforjuvenilechronicmyelogenousleukemia(“tripleassociation”),pheo-chromocytoma

Segmental Neurofibromatosis or NF5• SegmentaldistributionofCALMSandneurofibromas• Arisefromapost-zygoticmutation.MostofthesepatientsdoNOThaveafamilyhistoryofNF1

• TransmissionofNFtooffspringisrare,butpossible

Basal Cell Nevus Syndrome (BCNS,GorlinSyndrome)

•AutosomaldominantdisordercausedbymutationsinPATCHgenethatencodesPTCpro-teininvolvedinsonichedgehogpathway.InactivatingPATCHmutationsleadstolossof inhibitionofsmoothen(SMO)andsuqsequentincreasedexpressionofothergenes

•�Multiplebasalcellcarcinomasbegininearlyadulthood(20-30s)•Palmoplantarpitsoccurinnearlyallpatient.Histologically,theyshowbasaloidproliferationbutdonotprogresstoBCC

• �SkeletaldefectsthatharehighlysuggestiveofBCNSinclude:bifidribsandshortenedmetacarpalandmetatarsalbones.Thisresultsindimplingoftheoverlyingskin(Albright’ssign). Characteristicfaciesarerelatedtofrontalbossing,hypoplasticmaxilla,abroadnasal

root,andocularhypertelorism• Jawcystsarecommonanddevelopinthefirstdecadeoflife• CNSabnormalitiesinclude:falxcerebricalcifications,agenesisofthecorpuscallosum,mentalretardation,andmedulloblastoma

uTIPa Plexiform lesions can transform

into neurofibrosarcoma or malignant peripheral nerve sheath tumor (MPNST)


• OthersyndromeswithdevelopmentofmultipleBCCs: 1.)Bazexsyndrome:ThisisanX-linkeddominantdisordercharacterizedbyhypotrichosis,hypohidrosis,andfollicularatrophodermaoftheextremities 2.)Rombosyndromeisdistinguishedbythevermiculateatrophodermaandhypotrichosis

Xeroderma Pigmentosum (XP)

• AnautosomalrecessivedisordercausedbymutationsinDNAexcisionrepairenzymesinvolvedinUVinduced-thymidinedimers.Thereareeightcomplementationgroups(XPAthruG)thathavedifferentmoleculardefects,someinvolvehelicase.Complementationgroupsaredefinedbythecorrectionofexcisionrepairwhenfibroblastsfromdifferentpatientsarefused

• Itischaracterizedbyacutesunsensitivityandprematureagingbyage1-2years.Skincan-cers(BCC>SCC>melanoma)developbyage20

• Ocularabnormalitiesdevelopin40%andinclude:conjunctivitis,keratitis,cornealopacitiesorulcerations,blepharitis,symblepharon,andectropion

Cockayne Syndrome

• Autosomalrecessivedisorderassociatedwithdefectsinnucleotideexcisionrepair.SomehavemutationsintheXPGgene.OthershavemutationintheCSAorCSAgeneswhichencodeproteinsthatassociatewithRNApolymerase

• SimilartoXP,photosensitivityandneurologicdegenerationoccurs

• Deafness,retinalatrophy,basalgangliacalcifications,andperipheralneuropathyaretheCNSabnormalities

IBIDS Syndrome (Ichthyosis,BrittleHair,IntellectualImpairment,DecreasedFertility,ShortStature) or Tay’s Syndrome

• AutosomalrecessivedisordercausedbymutationsinXPD/ERCC2orXPB/ERCC3genes.(SamegenesasXP)

• Hairissparsehairanddemonstratesareducedsulfurcontent(50%ofnormal).Thissulfurdeficiencyresultsinthefollowingpatternsnotedonpolaroscopy:trichoschisis,pilitorti,trichor-rhexisnodosaandtrichothiodystrophy(“tigertail”oralternatingbrightanddarkbands)

• Systemicfindingsinclude:impairedintelligence,cataracts,shortstature,jointcontractures,osteosclerosis,decreasedfertility,andhypogonadism

• PIBIDSsyndrome=photosensitivity+IBIDSsyndrome.ConditionisverysimilartoIBIDSbutgonadsizeisnormal,andphotosensitivityispresent

Ataxia-Telangiectasia (AT) or Louis-Bar Syndrome

• AutosomalrecessivedisorderassociatedwithmutationsinATMgeneencodingphosphatidylinositol3-kinase-likeproteinthatsensesDNAdamageattheG1/Scheckpoint.ItinitiatesDNRrepair.Cellsarehypersensitivetoionizingradiation

• Theinitialfindingisataxia.Thisisnotedwhenchildstartstowalk.Ultimately,patientsarewheelchairboundbyageten

uTIPa De-Sanctis-Cachione syndrome = XP

plus mental retardation, dwarfism, and gonadal hypoplasia

uTIPa In contrast to XP, there is neither

premature aging nor skin cancer development in Cockayne syndrome. Bird-headed facies, “Mickey-Mouse” ears, and dwarfism are hallmarks of Cockayne syndrome

uTIPa Photosensitivity is prominent,

as in XP. However, there is no

increased risk for skin cancer

uTIPa��Patients are at risk for B-cell

lymphomas, leukemias, and

breast cancer


• Byagethree,therearetelangiectasiasoftheconjunctiva.Latertelangiectasisdeveloponthemalarface,ears,roofofthemouth,chest,flexures,anddorsalhandsandfeet

• Eyeabnormalitiesarepseudopalsyandnystagmus• Recurrentsinopulmonaryinfectionsbeginbetweenthreetoeightyearsofage.SusceptibilitytoinfectionisrelatedtoIgAdeficiency,lymphopeniaandhypoplasticthymus

• Diagnosisismadebyradiosensitivitystudyoffibroblasts.ElevatedalphafetoproteinandCEAarealsosupportiveofAT

Incontinentia Pigmenti or Bloch-Sulzberger Disease

• X-linkeddominantdisordercausedbymutationsofNEMOgene.TheproteinproductisasubunitofakinasethatactivatesNFkBtherebyprotectingagainstTNFinducedapoptosis.VariablephenotypesoccuringirlsduetoXlyonization.IPislethalinmales

• Girlspresentwithinafewweeksofbirthwithablaschkoidpatternofvesicles(stage1).Overthefollowingweekstomonths,hyperkeratoticverrucouslesionsdevelop(stage2).Hyperpigmentationthenensues(stage3).Thismayfadeorbecomeatrophic(stage4)

• CNSfindingsare:psychomotorretardation,microcephaly,seizures,spasticity,andcerebellarataxia

• Ocularabnormalitiesincludecolobomas,retinaldetachment,strabismus,cataracts,opticatrophy,cornealopacities

• Dentalfindingsmaypresentasabsentteeth,smallteeth,andpeg-shapedteeth• Skeletalchangesinclude:syndactyly,skulldeformity,dwarfism,spinabifida,clubfoot,supernummaryribs,hemiatrophyandshorteningofthelimbs

• IPshouldbedistinguishedfromIncontinentiaPigmentiAchromicans(HypomelanosisofIto).Inthelattercondition,thepredominantfindingishypopigmentationalongBlaschkoslines.AbnormalitiesoftheCNS,skeletalsystem,eyesandteethmayalsooccur

Piebaldism

•Anautosomaldominantdisordercausedbydefectsinthepro- to-oncogenec-KIT.Thegeneencodestyrosinekinasereceptoronmelanocytes

•AssociatedCNSabnormalitiesareimpairedmotorcoordina-tion,cerebellarataxia,mentalretardation,anddeafness

Waardenburg Syndrome

• Thisisaheterogeneousgroupofdisorders.Allmanifestawhiteforelock,prematuregray-ing,leukoderma,synophrys,deafness,dystopiacanthorum,heterochromiairides,andabroadnasalroot

• Inheritanceisautosomaldominantforalltypesexcepttype4,whichhasbothADandARinheritance

• Type 1: Defects in PAX 3 gene.Patientspresentwithwhiteforelock,prematuregraying,leukoderma,synophrys,deafness,dystopiacanthorum,heterochromiairides,andabroadnasalroot

• Type 2: Defects in MITF gene. Phenotypeissimilartotype1,butdystopiacanthorumisabsentanddeafnessismorecommon

• Type 3: Defects in PAX 3 gene. Phenotypeissimilartotype1,butlimbabnormalitiesarepresent

• Type 4: Defects in SOX10, EDN3, and EDNRB genes. Similartotype1alongwithHirschsprungdisease(congenitalmegacolon)

uTIPa�Patchy leukoderma containing

smaller spots of hyperpigmenta-tion and a white forelock are present at birth


KID Syndrome (Keratitis-Ichthyosis-Deafness)

• Inheritanceisbothautosomaldominantandautosomalrecessive.ItiscausedbymutationsinGJB2gene,whichencodesthegapjunctionprotein,connexin26 •Thisdisorderischaracterizedbyvascularizingkeratitis,transienterythrodermaatbirthfol-lowedbyerythrokeratoderma,reticulatedpalmoplantarkeratoderma,hypotrichosis,partialanhidrosisanddystrophicnails

• DeafnessisthemajorCNSfinding

•Thefaceandearshaveadistinctappearance.Thereisaleatherytexture,absenteyebrowsandprominentperioralfurrows

Vohwinkel Syndrome

• Autosomaldominantdisordercausedby mutationofGJB2gene,whichencodes Connexin26(sameasKIDsyndrome)

• DeafnessisthemajorCNSabnormality

Sjorgen-Larsson Syndrome• AutsomalrecessivedisordercausedbyadeficiencyofFALDH(fattyaldehydedehydrogenase).Phenotypeisrelatedtoaccumulationoffattyalcoholorfattyaldehydelipids

• MorecommoninNorthernSweeden

• Clinicaltriadofcongenitalichthyosis,di-ortetraplegia,mentalretardation.Theichthyosisisnotableinthatthereisaccentuationoftheflexuresandlowerabdomen

• Perifovealglisteningwhitedotsoftheeyearecharacteristic.Grandmalseizuresalsooccur

Refsum Disease• AutosomalrecessivedisordercommoninNorthernEuropeans.Itinvolvestheperoxisomalenzyme,phytanoyl-CoAhydroxylase(PhyH).OthermutationsinvolvethePEX7gene

• Phenotypeisrelatedtoimpairedmetabolismofphytanicacid(foundindairyandchlorophyll-richfoods),withresultantaccumulationofphytanicacid

• Thecharacteristicfeaturesinclude:adultonsetofmildichthyosiswithaccentuatedpalmarcreases,atypicalretinitispigmentosa,EKGchanges,cardiomy-opathy,andrenaltubulardysfunction

• Diagnosismadebyelevatedserumphytanicacid• TreatmentinvolvesdietaryrestrictionofphytanicacidandextracorporealLDL-aphoresis

Bjornstad’s Syndrome

• Adisordercharacterizedbypilitortianddeafness.Inheritancecanbebothautosomaldom-inantandrecessive

Menkes Disease • X-linkedrecessivedisordercausedbymuta- tionsofATP7Agene(encodescopper-trans-portingATPase).Thediseaseislethalinmales

uTIPa Helpful hint: a seizing, spastic,

scaly Swede has Sjogren-Larsson syndrome

uTIPa CNS abnormalities are deafness,

anosmia, peripheral neuropathy, decreased deep tendon reflexes, and cerebellar ataxia

uTIPa Girls develop variably depigmented lusterless hair.

Polaroscopy reveals monilethrix, pili torti, trichorrhexis nodosa. In addition, there is diffuse cutaneous hypopig-mentation, doughy skin, and an exaggerated cupid bow

uTIPa Cutaneous features are mutilating, honeycombed palmo-

plantar keratoderma, constricting bands around the digits (pseudoainhum) resulting in autoamputation, star-shaped keratosis over the knuckles, nail dystrophy, and alopecia


• CNSabnormalitiesinclude:severepsychomotorretardation,seizures,andgrowthfailure• Diagnosismadebylowserumcopperandcerruloplasmin

10.6 CUTANEOUS MANIFESTATIONS OF DIABETES MELLITUSDiabetesMellitus,themostcommonendocrinedisorder,affectsanestimated11millionindi-

vidualsintheUnitedStates.Atleast30%ofdiabeticshavecutaneousmanifestationsoftheirdis-ease;thesefindingsmayappearbeforeorafterthedevelopmentofdiabetes.

Diseases Associated with DiabetesAcanthosis Nigricans• AfricanAmericansandHispanicsareaffectedmorefrequentlythanCaucasians.Thisfindingisassociatedwithobesity,insulinresistance,totallipodystrophy,malignancy,medicationsandHAIRANsyndrome(hyperandrogen,insulinresistance,acanthosisnigricans)

• Hyperpigmentedvelvetyplaquesoftheflexures.Theface,externalgenitalia,medialthighs,dorsaljoints,conjunctiva,lipsandumbilicuscanbeinvolvedinextensivecases

• Pathogenesisinvolves:– Geneticsensitivityoftheskintohyperinsulinemia– Aberrantkeratinocyteandfibroblastproliferationstimulatedbyexcessgrowthfactor(e.g.,IGF-1,TGF-b)

• Treatment:Tightbloodglucosecontrol,treatmentofunderlyingmalignancy,weightcontrol,anddiscontinuationofoffendingagent

Diabetic Limited Joint Mobility (LJM)= Cheiroarthropathy• Incidenceisproportionaltodurationofdiabetesandpoorglucosecontrol;correlatedwithmicrovasculardisease

• Patientsdeveloptightnessandthickeningoftheskinandperiarticulartissueofthefingerswithresultantpainlesslossofjointmobility.Patientsareunabletoapproximatethepalmarsurfacesandinterphalangealjointspaceswiththehandspressedtogetherandfingersseparate(prayersign)

• Tightglucosecontrolandphysicaltherapyhelptopreserverangeofmotion

Scleroderma-like Syndrome• Adisorderinvolvingthickenedwaxyskinoverthedorsalhandsandfeet,usuallyinconjunctionwithLJM.Nospecifictreatment

Scleredema Diabeticorum• Occursmorecommonlyintype2diabetics,long-standingdisease,andobesemen• Painless,symmetricwoody“peaud’orange”indurationtheupperbackandneck.Nospecifictreatmentisavailable

Necrobiosis Lipoidica Diabeticorum (NLD)• Patientsclassicallypresentwithsingleormultiplered-brownpapules,whichprogresstosharplydemarcatedyellow-brownatrophic,telangiectaticplaqueswithaviolaceous,irregularborder.Commonsitesincludeshinsfollowedbyankles,calves,thighsandfeet.Ulcerationoccursinabout35%ofcases.Cutaneousanesthesia,hypohidrosisandpartialalopeciacanbefound

• Pathology:Palisadinggranulomascontainingdegeneratingcollagen(necrobiosis).Inflammatoryinfiltratecontainsplasmacellsandmultinucleatedhistocytes.Involvesentiredermis.MucinisNOTincreased


• Approximately20%ofNLDpatientshavediabetesorglucoseintolerance.Conversely,upto3%ofdiabeticshaveNLD.Womenaremoreaffectedthanmen.Pathogenesisisthoughttoinvolvethenonenzymaticglycosylationofdermalcollagenandelastin

• Treatment:Ulcerprevention.NoimpactoftightglucosecontrolonlikelihoodofdevelopingNLDbutdiabeticswithNLDhavehigherrateofmicrovascularcomplicationsandlimitedjointmobility

Diabetic Bullae or Bullosis Diabeticorum• Rarestcutaneouscomplicationsofdiabetes;M>F,longstandingdiabetics.Mostmicrovascularcomplications.Traumaandmicroangiopathymayplayarole

• Presentswithdiffuseorange-yellowskinwithsparingofthesclera(distinguishesfromjaundice)

• Clinical: Rapidonsetofpainlesstenseblistersonthehandsandfeet• Pathology: Intraepidermaland/orsubepidermalsplitwithoutacantholysis.DIFisnegative• Pathogenesis: Traumaandmicroangiopathymayplayarole• Treatment:Spontaneoushealingintwotofiveweeks

Yellow Skin or Carotenosis• Affectsabout10%ofdiabetics.Halfhaveelevatedserumcarotene• ProposedPathogenesis:Involveshighyellowfruit/vegetablediet,impairedhepaticmetabolismofcarotene,andnon-enzymaticglycosylationofdermalcollagen

Diabetic Dermopathy or “Shin Spots” or Pigmented Pretibial Papules• Mostcommoncutaneousmanifestationofdiabetes;M>F,malesoverage50yearswithlongstandingdiabetes

• Therearebilateralasymptomaticred-brownatrophicmaculesonshins• Thereisnoeffectivetreatment

Eruptive Xanthomas• Occursinsettingofuncontrolleddiabetes.Alsoassociatedwithhypertriglyceridemia(>2000mg/dl),medications(retinoids,estrogens),andalcohol

• Suddencropsoffirmnon-tenderyellowpapuleswitharedrimonextensorsurfaces• Tightglucosecontrolandlipidreductionresultsinregressionoflesions

Granuloma Annulare (GA)• Associationbetweengranulomaannulareanddiabetesiscontroversial.GeneralizedandperforatingformsofGAaremostcloselyassociatedwithDM.Thesevariantsoftenhaveachronicandrelapsingcourse

• Asymptomaticred-purpledomeshapedpapulesarrangedinannularconfiguration• Treatmentisdifficult.Screenfordiabeteswithpatientswithchronicrelapsing,perforatedorgeneralizedGA

Other Conditions associated with Diabetes• Neurotrophiculcers,lichenplanus,lipodystrophy,Dupuytren’scontractures,vitiligo,rubeosisoftheface,skintags,andclearcellsyringomata

Cutaneous InfectionsDiabeticpatientsarepredisposedtodevelopingcutaneousinfectionsduetopoormicro-

circulation,hypohidrosis,impairedphagocytosis,killing,leukocyteadhesionandchemotaxis.Theincidenceofinfectionscorrelateswithserumglucoselevels.


Candida• Candidainfections,usuallyduetoC. albicans,occurwithincreasedfrequencyandseverityindiabetics.Theycantakemanyforms:1.)Angular cheilitis:Aclassiccomplicationofchildhooddiabetes,presentsasawhitecurd-likematerialadherenttored,fissuredoralcommissures

2.)Medianrhomboidglossitis3.)Chronic paronychia:Involvestheproximalnailfold;erythema,swelling,separationfromthenailmarginwithnaildystrophy.Superinfectionbybacterialorganismsmayoccur

4.)Erosio interdigitale blastomycetica:Interdigitalinfectionbetweenthe3rdand4thfingersor4thand5thtoes

5.)Genital infections: Vulvovaginitisandcandidaintertrigooftheinframmamaryregionin women.Incontrast,balanitisandphimosisinmenarerelativelylesscommon

• Treatmentincludescontrolofbloodsugarandtopicalorsystemicantifungals

Bacterial InfectionsDiabeticsareatgreaterriskforGroupAandBstreptococcal,staphylococcalinfections,

necrotizingfasciitis,malignantotitisexterna(Pseudomonas aerugenosa),anderythrasma(Corynebacterium minutissimum).

Fungal Infections• Dermatophyteinfectionsdonotoccurwithgreaterfrequencyinthispopulation,buttineapedismayserveasaportalofentryforsuperinfectionandcellulitis

• Rhinocerebralmucormycosesoccursinuncontrolleddiabeticswithketosis.Thisconditioninvolvestheterbinates,septum,palate,maxillaryandethmoidsinuses.Symptomsincludeheadache,fever,lethargy,nasalcongestionandfacialocularpain,swelling,unilateralptosis,andophthalmoplegia.Treatmentinvolvescorrectionofketosis,debridement,andintravenousantifungalagents.Mortalityrangesfrom15-34%

Cutaneous Reactions to Diabetic Treatment• 1stgenerationsulfonylureas(chlorpropamideandtolbutamide)-Allergicreactionsoccur<5%ofpatients.Themostcommoncutaneousreactionisamaculopapulareruption.Chlorpropamidecausesadisulfiram-likereactioncharacterizedbyflushing,headache,tachycardia,andshortnessofbreathoccurringafteralcoholconsumption

• Insulin-allergicreactionsoccurinupto50%.Theyarerelatedtoimpurities,beeforporkproteins,preservativesorzincadditives.Systemicallergicreactions(generalizedurticaria,angioedema,oranaphylaxis)areuncommon.Otherreactionsincludelipoatrophyandlipohypertrophy

10.7 CUTANEOUS MANIFESTATIONS OF CARDIAC DISEASEMarfan’s Syndrome

• AutosomaldominantdisordercausedbymutationsinFibrillin1,amajorcomponentofintermediatefibrilsfoundinskin,skeletal,ocularandcardiovascularsystem

• Characterizedbyextensivestriaedistensae,abdominalwallhernias,elastosisperforansser-piginosa,andupwardlensdislocation

• Skeletalfindingsinclude:tallstature,alonghead(dolicocephalic),longears,hyperextensible joints,pectusexcavatum,arachnodactyly,kyphoscoloiosis,andflatfeet

• Cardiacirregulatiesinclude:aorticrootaneurysms,rupture,anddissection.Mitralvalvepro-lapse(MVP)canalsooccur

• Occasionallyemphysemaandpneumothoraxcandevelop


Homocystinuria

• Thisconditionisautosomalrecessiveinheritanceinmostcases.Phenotypeisrelatedtoelevatedserumhomocys-teineandmethioninelevelsduetoadeficiencyofcysta-thioninebetasynthase.Elevatedhomocysteineisthoughttoinhibitcollagencross-linking

•Treatmentinvolvesavoidanceofmethionineandhomocysteine.Supplementationwithcysteine,pyridoxine,folateandvitaminB12hasproducedvariableresults

Ehlers-Danlos Type IV, Vascular Type

• AutosomaldominantdisordercausedbymutationsinCOL3A1,whichencodesprocollagentype3.Thiscollagentypeisabundantinskin,lungandvasculature

• Cutaneousfeaturesinclude:thintranslucentskin,easybruisability,thinnose,andthinupperlip • Thereisapredispositiontoarterial,bowelanduterinerupture

• Jointmobilityisnormal,althoughthereatlantoaxialsubluxationcanoccur

Cutis Laxa (GeneralizedElastolysis)• Type I: Disorderthancanbeinheritedinanautosomaldominantorrecessivemanner.Itiscausedbymutationsineitherelastinorfibulin5.Mutationsinfibulin4canleadtotherecessiveform.CutaneousfindingsofTypeIcutislaxaincludeloosewrinkledskincausing

“bloodhound”facies,andlargependulousfoldsoftheabdomen.Cardiacmanifestationsaremitralvalveprolapse,aorticaneurysms,andcar-diomegaly.Pulmonaryemphysema,corpulmonaleandrightsidedheartfailureareoftennotedininfancy.Othersystemicfeaturesinclude:GIorGUdiverticula,dentalcavities,andosteoporosis

• Type II or “Congenital Horn syndrome”: ThisconditionwasformerlycategorizedastypeIXEhlersDanlos.ItisanX-linkedrecessivedisordercausedbyadefectinthecopperbindingtransportATPase,ATP7A.ItisallelictoMenkesdisease.FeaturesofTypeIIincludemild

skinlaxity,hookednose,longphiltrum,invertednostrils,jointhypermobility,andlow-pitchedvoice

• Type III or Acquired Form: ThegeneralizedformissimilartoTypeI.Itisassociatedwithpenicillamine,penicillin,complementdeficiency,SLE,andamyloidosis.Thelocalizedformispreceededbyerythemamultiforme,contactdermatitis,andSweet’ssyndrome

• Costellosyndromeischaracterizedbycoarsefacies,cardiomyopathy,growthretardation,andanoutgoingpersonality.Patientsarepronetoabdominalrhabdomyosarcomasduringchildhood.PatientswithdeBarsysyndromehavementalandgrowthretardation,jointlaxity,oculardefectsandskeletalabnormalities

•OtherconditionswithlooseskinareCostellosyndromeanddeBarsysyndrome

Osteogenesis Imperfecta (OI)

• TherearesevendifferentformsofOI.AllareassociatedwithdefectsintypeIcollagen

• Thepredominantfindingisbrittleboneswithatendencytowardfractures.Thereisalsojointlaxity,bluesclerae,deafness,scoliosisandabnormalteeth

• Cutaneousfindingsarethintranslucentskin,easybruising,andwideatrophicscars • Cardiacdiseasemanifestsasaorticregurgitation,mitralregurgitation,andlargevesselfragility

• TreatmentinvolvedsurgicalstabilizationoffracturesaswellasbisphosphonatesandVitaminDtoimprovebonedensity

uTIPa In contrast to Marfans, Homocystinuria

presents with arterial and venous thromboses, generalized osteoporosis, and mental retardation. In addition, the lens displacement in Homocystinuria is downward (whereas Marfan’s is upward)


• Mortalityisrelatedtoimpairedventilationsecondarytokyphoscoliosis• Bracksyndrome=OIplusarthrogryposismultiplex

Werner Syndrome(AdultProgeria)

• Autosomalrecessivedisordercausedbymuta-tionsinWRN(Recql2)gene,whichencodesDNAhelicase

• Mostfindingsaremanifestatedbymiddleage• Thereisgrowtharrestatpubertyandcataractsbyage30

• Prematurecardiacatherosclerosisaccountsforearlydeath• ThereisalsoatendencytowardtypeIIDM,andtumorsoftheuterus,breast,liverandthyroid

Progeria or Hutchinson-Guilford Syndrome• ThisisarareautosomaldominantdisordercausedbymutationsintheLMNAgenewhichencodeslaminAandC

• Itisdistinguishedfromadultprogeriabyitsearlieronsetandcharacteristicfacies.Patientshavealargebaldhead,prominentscalpveins,andlackofeyebrowsandeyelashes

• Similartoadultprogeria,prematuredeathisrelatedtocardiacdisease

Noonan’s Syndrome

• AutosomaldominantdisorderthatresemblesTurnerssyndrome.Menandwomenareequallyaffected.ItiscausedbymutationsinthePTPN11gene,whichencodesaproteintyrosinephosphatase

• Patientshaveacharacteristicfacewithhypertelorism,prominentears,webbedneck,shortstature,andlostposteriorhairline

•Somehavecutaneousmanifestationssuchas:curlyorwoollyhair,lymphedema,elasticskin,multiplemelanocyticnevi,keratosispilarisatrophicans,dystrophicnails,abnormalfingerprintsandatendencytowardkeloids

• Typicalcardiacabnormalitiesinclude:hypertrophiccardiomyopathy,pulmonicvalvestenosis,andseptaldefects

• Cryptorchidisminboys

LEOPARD Syndrome (MultipleLentiginesSyndrome)• AutosomaldominantdisordercausedbymutationsinPTPN11gene.LeopardsyndromeisallelictoNoonan’ssyndrome

• Otherfindingsinclude:Café-au-laitmacules,melanoma,localhypopigmentation,triangularface,frontalbossing,lowears,jointhypermobility,scapulawinging,andpectusdeformity

Carney Complex includes LAMB and NAME Sydromes

• Autosomaldominantdisorder.MostcasesarecausedbymutationsinPRKAR1Agene.AvariantformofCarneycomplexassociatedwithdistalarthrogryposisisassociatedwithmutationsintheMYH8genethatencodesperinatalmyosin

• Multiplemyxomasarethehallmarkofthiscondition

• Earlydiagnosisandremovalofatrialmyxomacanbelifesaving

MNEMONICLEOPARD Syndrome

ClassicFeaturesare: Lentigines EKGchanges(includingAVblock,arrhythmias,bundlebranchblock,ven-tricularhypertrophy) Ocularhypertelorism Pulmonicstenosis Abnormalgenitals(hypoplasia,cryp torchidism) Retardationofgrowth Deafness

uTIPa�Characteristic features include premature aging,

balding, and graying. Other skin changes include: a sclerodermoid appearance, poikeloderma, leg ulcers, and painful callosities of the feet and ankles


Naxos Disease

• Autosomalrecessivedisordercausedbydefectsin plakoglobin

• Itischaracterizedbynon-transgradientpalmoplantarkeratodermaandwoolyhairininfancy

• Cardiacdiseaseismanifestedasarrhythmogenicrightventricularcardiomyopathy(ARVC)andsuddencar-diacdeathinpuberty

• CarvajalsyndromeissimilartoNaxosinthatbothdemonstratepalmoplantarkeratodermaandwoolyhair.Incontrast,thecardiomyopathyofCarvajalisleftsided.Itiscausedbyautosomalrecessivemutationsindesmoplakin

Conradi-Hunermann-Happle Syndrome

• Aformofchondrodysplasiapunctatawhichonly affectsgirls.ItisanX-linkeddominantdisordercausedbymutationsinEBPgeneencodingemopamilbindingprotein.Thephenotypeisrelatedtoimpairedcholesterolsynthesis

• Characteristicfeaturesarecongenitalichthyosiformerythrodermaalongblaschko’slineswhichresolvesandisreplacedbyfollicularatrophoderma

• Cardiacanomaliesinclude:ventricularseptaldefectandpatentductusarteriosus• Chondrodysplasiapunctata(stippledepiphysesduetobonycalcifications)canbeappreci-

atedwithX-rayuntiltheageof4• Asymmetriclimbshorteningandcataractscanoccur

Table10-2.ParaneoplasticDiseases

Disease Clinical Manifestations Associated Malignancy Diagnosis/Management/Miscellaneous

Hypertrichosis Lanuginosa Acquisita

Abruptonsetofdowny,soft non-pigmented hair on face →trunkandextremities

Mayhaveanassociated glossitis. Lung carcinoma

Ruleoutunderlyingcausesofhypertrichosis,i.e.,thy-rotoxicosis,corticosteroids,phenytoin,andspirono-lactone.Mayresolvewithtreatmentofunderlyingmalignancy

AcquiredIchthyosis Similartoautosomaldominantform,withinvolvementofexten-sorsandsparingofflex-uralcreases.Diagnosis is usually made after malignancy

Hodgkins lymphoma, breastandlungcarci-noma

Courseparallelsthatofunderlyingmalignancy

MNEMONICLAMB

Lentigines(faceandmucoas) Atrialmyxoma(complicatedbyCHF,angina,pulmonaryedema,andembolicevents) Mucocutaneousmyxoma Bluenevi(spareshandandfeet)

MNEMONICNAME

Nentigines(faceandmucoas) Atrialmyxoma Myxoidneurofibromata EphilidesandEndocrineneoplasms (Cushing’ssyndrome,testiculartumors, growth-hormonesecretingpituitarytumors)



BazexSyndrome(AcrokeratosisParaneoplastica)

Erythematous/viola-ceous psoriasiform dermatitis affecting ears, nose, hands and feet. Naildystrophy,andaquiredkeratodermamaybefound.Skinfind-ingsusuallypreceedtheunderlyingmalignancy

Squamous cell carci-noma of larynx, orophar-ynx, esophagous and tongue

Skindiseasefollowscourseofunderlyingmalignancy.Ageappropriatecancerscreeninginsuspectedpatientsisrecommended

ErythemaGyratumRepens

Men>women.Concentricerythema-tousringswithtrail-ingscaleontrunkandproximalextremities.Skindescribedashavinga “wood grain appear-ance.” Intense pruritus. Skin findings precede the diagnosis

Lung carcinoma most common. Alsoreportedinassociationwithbreast,cervical,bowel,andbladdercancer

Path:hyperkeratosis,parakeratosis,hydropicdegeneration,andpigmentincontinence.Symptomsimprovewithtreatmentofunderlyingmalignancy

MulticentricReticulohistiocytosis

Non-tenderreddishbrownnodularlesionsmostcommonlylocatedondorsalhandsandnailfolds,alsofoundinpara-nasalareas,ears,fore-arms,cornea,andtrunk.Mucosallesionscanalsooccur.Symmetric arthri-tis of interphalangeal, knee, elbow, vertebral and temporomandib ular joints. Can progress to a mutilating form in 50% ofpatients.Weaknessandweightlossalsopresent

20% of patients develop malignancy, no predom-inant type

Pathology:nodularinfiltratecomposedofmultinucle-atedoncocyticgiantcellswitheosinophilliccyto-plasmdisplayingagroundglassappearance

NecrolyticMigratory Erythema(GlucagonomaSyndrome)

Erythema, vescicles, pustules and erosions in periorificial, acral flex-ural distribution. Lesionshaveacircinatepatternduetoperipheralspread.Canalsodevelopaglos-sitisandchelitis.Adultonsetdiabetes,glucoseintolerance,weightloss.75%ofcasesaremeta-staticbytimeofdiag-nosis

Alpha 2 glucagon pro-ducing islet cell pancre-atic carcinoma

Path: necrosis of keratino-cytes in granular layer, acanthosis and parakera-totic scale.Elevatedserumglucagon.CTtolocalizetumor.Mainstayofman-agementissurgicalresec-tionoftumor.SomatostatinandIVaminoacidshelpfulin some cases

Table10-2.ParaneoplasticDiseases(cont.)



Cushing’s Syndrome

Skinfindings:hirsut-ism,hyperpigmentation,facialplethora,buffalohump,striae,telangi-ectasiaandatrophy.Hypertension,kypokale-mia,hypoglycemia

Glucorcorticoidexcessduetounderlyingoatcelllungcarcinoma

Elevatedurinecortisollev-els.Corticortopinnotsup-pressedw/administrationofdexamethasone

Carcinoid Syndrome

Facial flushing that spreads to neck and upper trunk, diarrhea, and intermittent bron-chospasm. Patientscanalsodeveloptelangi-ectasia,pellagra-likeorsclerodermoid-likeerup-tion. Symptoms develop after liver metastases or if the primary tumor does not involve the GI tract

Neoplasmoriginatingintheendocrineargentaf-fincells.80-85%foundintheGItract:appendix

g smallbowelg rectum.Mediatorsinvolvedinproducingsymptomsarebradykinin,serotonin,his-taminesubstance-P,andprostaglandins

Test urine for elevated 5-hydroxyindole-acetic acid (5-HIAA). Chest/abdominal/pelvicCT.Surgicalremovaloftumor.Medicaltreatmentincludessomatostatin,methly-sergide,cyproheptadine,beta-blockers,andpheno-thiazinederivatives

Acanthosisnigricans

Rapidonsetofhyperpig-mentedvelvetyplaquesinvolvingtheinter-triginousareas.Unusuallocationsincludedorsalhandsandlips.May be seen in association with tripe palms and florid oral papillomatosis

Most commonly seen with gastric carcinoma. Alsoseenwithlung,breast,uterine,ovariancarcinomas,lymphomaandmycosisfungoi-des.Mayberesultofincreasedgrowthhor-moneproducedbythetumor

Canimprovewithtreat-mentofunderlying malignancy

Sweet’sSyndrome(Febrileneutrophilicdermatosis)

Males=Femalesincasesassociatedwithunderly-ingmalignancy.Tendererythematousplaquesthatmaydevel-oppustulesorvesiclesdistributedonface,neck,uppertrunk,and extremities.Accompaniedbyfever,possiblyarthritis,con-junctivitis,episcleritis,andoralulcers.+/–pul-monaryinfiltrates

Acute myelogenous leu-kemia = most common. Alsolymphoma,polycy-themiavera

Anemia,leukocytosis,neu-trophilia,elevatedESR.Pathology:Prominentedemainthesuperficialdermis,dermalinfiltraterichinneutrophilswithleukocy-toclasis.Leukocytoclasticvasculitisisabsent.Treatment:prednisone,SSKI,andmanagementofUnderlyingmalignancy

Cryoglobulinemia Type I cryoglobulins (monoclonal IgM)Palpable purpura, Raynaud, livedo reticu-laris

Multiple myelomaWaldenstroms macro-globulinemia

ElevatedcryoglobulinsPathology:eosinophilic,intravasculardeposits




SignofLesser-Trelat Rapidincreaseinsizeand/ornumberofseb-orrheickeratosis.Canbeseeninassociationwithacanthosisnigri-cansandtripepalms.Appearsbeforeoraftermalignancy.Canhaveanassociatedgeneralizedpruritus

Gastric or colon carcinoma

Mayimprovewithtreat-mentofunderlyingmalig-nancy

ParaneoplasticPemphigus

Painfuloralerosions/sto-matitis.Polymorphousskineruption:withlichenoidlesions,ery-thema-multiforme-likelesionsorflaccidortensebullae.Most patients die from complications of underlying malignancy. Bronchiolitis obliterans also a reported com-plication and cause of death

Non-Hodgkins lymphomaChronic lymphocytic leukemiaThymomaCastleman’s tumorSarcoma

Pathology:suprabasalacantholysis,dyskeratosis.Vacuolarinterfacedermati-tiswithlichenoidinfiltrate.Directimmunofluoresenceofperlesionalskindemon-strates intercellular IgG and granular C3 at the DEJ. Indirect immunofluo-rescence with rat bladder substrate shows intercel-lular IgG.Targetantigensincludedesmoplakin(250KD),envoplakin(210KD),BPAg-1(230KD),periplakin(190KD),desmogleins3and1.Treatmentincludesman-agementofunderlyingmalignancy,prednisoneorotherimmunosuppressiveagents

Dermatomyositis ProximalsymmetricalmuscleweaknessPeriorbitaledemaw/heliotropediscolorationGottron’spapules/Gottron’ssign.Periungaltelangiecta-sia,cuticulardystrophy.Violaceouserythemainshawlorphotodistribu-tion.Poikilodermavascu-lareatrophicans,hyper-keratosis/scaleoverpalmsandsoles,andpsoriasiformscalpder-matitis.Calcinosiscutisinpediatricpatients

Riskofmalignancygreaterinpatientsolderthan40.Morelikelytooccurwithinfirstthreeyearsofdiagnosis.Women: ovarian and breast carcinomaMen: gastric carcinoma and lymphoma

Elevatedmuscleenzymes(CPKmorespecificthanaldolase).Musclebiopsywithevi-denceofinflammation.AbnormalEMG.Thoroughhistoryandphysicalexam.Ageappropriatecancer screening.Treatmentincludescor-ticorsteroids,methotrex-ate,othersteroidsparingagents




Howell-EvansSyndrome

Autosomal dominantDiffuse waxy keratoder-ma of palms and soles.Otherfeaturesinclude oral hairy leukoplakia, and squamous cell car-cinoma arising from keratodermic skin

Esophageal carcinoma Cancerscreeninginfamilymembers

Amyloidosis Patientsdevelopshiny, firm translucent pap-ules/nodules distributed around mouth, nose, and eyes. Pinch purpura. Glossitis, macroglossia. Diffusepatchyalopeciaandcutisverticesgyrata.Nailfindingincludesatrophyofproximalnailplate.Extracutaneous findings include carpal tunnel syndrome and periph-eral neuropathy. Cardiac arrythmias and conges-tive heart failure are the most common causes of death

MultiplemyelomaPlasmacelldyscrasia

Pathology:eosinophilic,amorphicfissuredglobulesinthedermisandsubcuta-neous tissues.The amyloid is composed of immunoglobulin lambda light chains.Diagnosisismadebydem-ostrationofamyloiddepos-itswithintissues,monoclo-nalproteininserumandurine

Erythroderma Widespreaderythemaandscalingoftheskinwithsparingofthepalmsandsoles.Mayormaynotbeaccom-paniedbyalopeciaandnaildystrophy.Ectropionmaybepresent

Leukemiasandlymphomas

Searchforevidenceofunderlyinginflammatoryskinconditionssuchasatopicdermatitis,psoriasis,erythrodermicdrugerup-tion.Path:maynotbehelpfulwiththeexceptionofcasesassociatedwithmycosisfungoides.Treatment:skindirectedtherapywithlukewarmsoaks,topicalemollients,topicalsteroids,antihista-mines,inadditiontotreat-ingtheunderlyingcondi-tion.Supportivecarewiththermoregulation,electro-lyteandfluidbalance



10.8 PORPHYRIASPorphyrinogens

• Buildingblocksofhemoglobinandcytochromeenzymes• Inporphyrias,intermediatemetabolitesofhemoglobinsynthesisareincreased

• PhotosensitivityinporphyriacausedbyabsorptionofUVRinSoretband(400-410nm)byincreasedporphyrins→activatedporphyrinsunstableandtransferenergytooxygen,creatingreactiveoxygenspecies

Pathway• Delta-aminolevulinicacid(dALA)madeinmitochondriaviadALAsynthetase• FromdALAareformed(successively)porphobilinogen,uroporphyrinIII,coproporphyrinIII,andprotoporphyrinIX,whichentersmitochondrionandconvertedtohemebyferrochelatase

• Heme,bynegativefeedback,repressesactivityofdALAsynthetase• Ifhemeinadequate,dALAsynthetaseactivityincreases• Medicationsthatincreasecytochromedrugmetabolizingsystemintheliverexacerbateporphyriasbyincreasingproductionofporphyrinintermediates

Porphyria Cutanea Tarda

• Uroporphyrinogendecarboxylasedeficiency(sporadicin80%),enzymaticactivityabnormalonlyinliverandwithoutmutationsinthegene

• FamilialPCTshowsdecreaseinactivityandamountofenzymeandpresentsearlierinlife(beforeageof20)

•Mostcommontypeofporphyria• Photosensitivityresultinginbullaeespeciallyonsun-exposedparts• Bullaenotsurroundedbyerythema• Bullaehealwithscarring,milia,anddyspigmentation• Hypertrichosisontheface• Sclerodermatousthickeningsmaydeveloponthebackoftheneck,preauricularareas,thorax,fingers,andscalp

• Directrelationshipbetweenlevelsofuroporphyrinsintheurineandsclerodermatouschanges• Liverdiseasefrequentlypresent:alcoholism,HepatitisC;ironoverloadintheliverfromhemochromatosiscarriers

• Associateddiseases:diabetesin15%;lupuserythematosus,HIV;treatmentwithestrogens

Testing • Urine:pink/coral-redunderWood’slamp

• 4hrurine:elevatedporphyrins→uroporphyrins:coproporphyrins3:1orgreater• Lowcoproinstool

Treatment• Removalofallprecipitatingenvironmentalagentssuchasalcoholandmedications

• Sunprotection;chemicalsunscreenshelplittleastheydon’tabsorbatnecessarywavelengths;physicalsunscreensmaybemorehelpful

• Phlebotomy(2weekintervals),toreduceironlevels•Antimalarials

• TreatmentofHCVwithinterferon


Pseudoporphyria

• Normalurineandserumporphyrins • Nohypertrichosis,dyspigmentation,andsclerodermoidchanges • Mostcommonlycausedbymedications:naproxen,other

NSAIDs,tetracycline,furosemide,sunbeds,patientsonhemodialysis

• Treatwithdiscontinuationofmedication

Hepatoerythropoietic Porphyria• Autosomalrecessive

• HomozygousformofPCT • Homozygousorcompoundheterozygousdeficiencyofuroporphyrinogendecarboxylase

• Clinicallysimilartocongenitalerythropoieticporphyria• Dark,redurineatbirth• Vesiclesatinfancy,followedbysclerodermoidscarring,hypertrichosis,pigmentation,redfluorescenceofteethunderWood’slamp,naildamage

• Notreatmentexceptsunscreen/sunavoidance

Test • CEPhaselevateduroporphyrinsintheRBC’s,andHEPdoesn’t,butHEPhaselevatedRBCprotoporphyrins

• AbnormalurinaryuroporphyrinsasinPCT• Elevatederythrocyteprotoporphyrins• Increasedcoproporhyrinsinfeces

Acute Intermittent Porphyria

• Deficiencyinporphobilinogendeaminase,whichhas50%activityinaffectedindividuals• Secondmostcommonformofporphyria

• Periodicattacksofcolic,paralyses(motorneuropathy),andpsychiatricdisorders • Attacksprecipitatedbydrugs:barbiturates,estrogen,griseofulvin,sulfonamides

• Attacksalsoprecipitatedbyinfection,fever,decreasedcaloricintake,alcohol,pregnancy,andmenses

• Noskinlesions • Only10%ofthosewithgeneticdefectdevelopthedisease,butallatriskforprimarylivercancer

Test • Elevatedurinaryporphobilinogen(Watson-Schwartztest)

• IncreaseddALAinplasmaandurineTreatment• Avoidprecipitatingmedications,starvation• Glucoseloading• Oralcontraceptives• Painmedicationslikephenothiazines,opiates,propoxyphene

Hereditary Coproporphyria• Coproporphyrinogenoxidasedeficiency

• Photosensitivityin1/3 • AttacksofneurologicalandGIsymptomslikeAIP

MNEMONIC

Pseudoporphyria Drugs

Not Till After Last

Night’sPartyDude

NalidixicAcid Tetracycline Lasix Naproxen Pyridoxine

Dapsone


• AcuteattacksprecipitatedbysamefactorsasAIPandVP• Autosomaldominant

Test • Fecalcoproporphyrinalwaysincreased • Urinarycopro,ALA,andPBGincreasedonlyduringattacks

Variegate Porphyria

• Protoporphyrinogenoxidasedecreasedinactivity• Autosomaldominantwithhighpenetrance• Mostpeoplehavesilentdisease

•CombinationofskinlesionsofPCTandGI/neurodiseaseofAIP,mustbecomparedtoPCT • SouthAfricanancestry • Attackslife-threatening

• Aggravatedbydrugs:barbiturates,estrogen,griseofulvin,sulfonamides• Aggravatedbyinfection,alcohol,pregnancy,anddecreasedcaloricintake• Treatwithglucoseloading,hematininfusionduringattack,avoidanceofdrugprecipitators,andsunscreen/sunavoidance

Test• Fecalcoproporphyrinsandprotoporphyrinsarealwayselevated,withproto>copro

• Urinarycoproporphyrinsincreasedoveruroporphyrins,distinguishingdiseasefromPCT • Plasmafluorescesat626nm→diagnostic

Erythropoietic Protoporphyria

• Ferrochelatasedeficiency • Usuallypresentsinearlychildhood

• ADandARinheritance

• Immediateburningofskinonsunexposure→elevatedprotoporphyrinIXabsorbsintheSoretbandandat500-600nm,andthusvisiblelightthroughwindowglasscanprecipitatesymptoms;protoporphyrinIXistheonlyoxidizedporphyrininthehemepathway

• Erythema,plaque-likeedema,wheals,andpurpuracanbeseeninphoto-distribution• Repeatedexposuregivesskin“weather-beaten”look

• Excessiveporphyrinsdepositedintheliver,porphyringallstonesarefound,andliversarecirrhotic–mayrequirelivertransplantation

Test• Urineporphyrinsnormal• Erythrocyteprotoporphyrinelevated

Differential Dx• Hydroavacciniforme,XP,solarurticaria

Treatment• Sunprotectionwithbarriers• Betacarotene• PUVAorUVBNBtoincreaseskinthicknessandepidermalmelanin

Congenital Erythropoietic Porphyria• Gunther’s

• UroporphyrinogenIIIsynthasehomozygousdefect

MNEMONIC

EPP

Empty Pee Pee


• Presentssoonafterbirthwithredurine• Severephotosensitivity• Redness,swelling,andblisteringinsun-exposedareaswithresultantscarring

• Erythrodontiaofbothdeciduousandpermanentteeth,andteethfluorescecoral-redinWood’slamp

• Hypertrichosis(werewolf) • Otherfeatures:growthretardation,hemolyticanemia,thrombocytopenia,porphyrin

gallstones,osteopenia,andincreasedbonefractures

Test• Darkurineandseverephotosensitivity

• ElevateduroporphyrinIandcoproporphyrinIinurine,stool,andredcells→distinguishesitfromHEP

• Stableredfluorescenceoferythrocytes

Transient Erythroporphyria of Infancy• Infantsexposedtobluelightsfortreatmentofhyperbilirubinemia• Markedpurpurainexposedskin• Allinfantsreceivedbloodtransfusions

The Basic Heme Synthesis Pathway (distilleddownabit)1.) Glycine+succinylCoA2.) Aminolevulinicacid(viaALAsynthase)3.) Porphobilinogen(viaALAdehydratase)4.) Hydroxymethylbilane(viaporphobilinogendeaminase)5.) CoproporphyrinogenIII(viaurodecarboxylase)6.) Protoporphyrinogen(viacoprooxidase)7.) ProtoporphyrinIX(viaprotooxidase)8.) Heme(viaferrochetalase)

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NOTES

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