etas_10 cutaneous
TRANSCRIPT
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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Cutaneous Manifestations of Systemic Disease 355
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
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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
Cutaneous Manifestations of Systemic Disease 357
• 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
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• 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
Cutaneous Manifestations of Systemic Disease 359
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
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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
Cutaneous Manifestations of Systemic Disease 361
• 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
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• 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
Cutaneous Manifestations of Systemic Disease 363
• 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
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• 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
Cutaneous Manifestations of Systemic Disease 365
• 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
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• 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
Cutaneous Manifestations of Systemic Disease 367
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)
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• 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
Cutaneous Manifestations of Systemic Disease 369
• 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
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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
Cutaneous Manifestations of Systemic Disease 371
• 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
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• 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.
Cutaneous Manifestations of Systemic Disease 373
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
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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)
Cutaneous Manifestations of Systemic Disease 375
• 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
376 2011/2012DermatologyIn-ReviewlCommittedtoYourFuture
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)
Cutaneous Manifestations of Systemic Disease 377
Disease Clinical Manifestations Associated Malignancy Diagnosis/Management/Miscellaneous
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.)
378 2011/2012DermatologyIn-ReviewlCommittedtoYourFuture
Disease Clinical Manifestations Associated Malignancy Diagnosis/Management/Miscellaneous
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
Table10-2.ParaneoplasticDiseases(cont.)
Cutaneous Manifestations of Systemic Disease 379
Disease Clinical Manifestations Associated Malignancy Diagnosis/Management/Miscellaneous
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
Table10-2.ParaneoplasticDiseases(cont.)
380 2011/2012DermatologyIn-ReviewlCommittedtoYourFuture
Disease Clinical Manifestations Associated Malignancy Diagnosis/Management/Miscellaneous
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
Table10-2.ParaneoplasticDiseases(cont.)
Cutaneous Manifestations of Systemic Disease 381
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
382 2011/2012DermatologyIn-ReviewlCommittedtoYourFuture
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
Cutaneous Manifestations of Systemic Disease 383
• 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
384 2011/2012DermatologyIn-ReviewlCommittedtoYourFuture
• 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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