Classical Ehlers-Danlos SyndromeClassical Ehlers-Danlos Syndrome Clair A. Francomano, MD EDS Center...

Classical Ehlers-Danlos Syndrome ClairA.Francomano,MD

EDSCenterforClinicalCareandResearchHarveyIns>tuteforHumanGene>csGreaterBal>moreMedicalCenter

Commi5ee Members

•  JessicaM.Bowen• GlendaJ.Sobey• NigelP.Burrows• MarinaColumbi

• MarkLavallee•  FransiskaMalfait• Chris>naSchwar>ng• ClairA.Francomano

Classical EDS: History

• Beighton,1968:EDSGravisandMi>s• Beighton,1988:EDSTypesIandII• Villefranchenosology,1997:ClassicalEDS

•  1996:Iden>fica>onofmuta>onsinCOL5A1(Nichollsetal.,1996;Wenstrupetal.,1996;DePaepeetal.,1997)

Recommended Naming

• Retainthename“ClassicalEhlers-DanlosSyndrome”• Abbrevia>on:cEDS

Proposed Diagnos@c Criteria

Majorcriteria1.Skinhyperextensibilityandatrophicscarring2.Jointhypermobility

Minor Diagnos@c Criteria

1.Easybruising2.So`,doughyskin3.Skinfragility(ortrauma>csplibng)4.Molluscoidpseudotumours5.Subcutaneousspheroids6.Hernia(orhistorythereof)7.Epicanthalfolds8.Familyhistoryofafirstdegreerela>vewhomeetsclinicalcriteria

To Establish a Clinical Diagnosis

MajorCriterion(1):SkinhyperextensibilityandatrophicscarringPlus•  Either:Majorcriteria(2)–jointhypermobility• Or:threeoftheeightminorcriteria

Clinical considera@ons

Skinisconsideredhyperextensibleifitcanbestretchedoverastandardizedcutoffinthreeofthefollowingareas•  1.5cmforthedistalpartoftheforearmsandthedorsumofthehands•  3cmforneck,elbowandknees

Skin Hyperextensibility

Scarring

• Abnormalscarringcanrangeinseverity.• Mostpa>entshaveextensiveatrophicscarsatanumberofsites.•  Thesecansome>mesbehaemosidero>c.• Aminorityofpa>entsaremoremildlyaffected.

Scarring

Joint Hypermobility

•  JointhypermobilityisassessedthroughtheBeightonscore.Ascoreof5ormoreisconsideredposi>veforthepresenceofjointlaxity

Beighton Scale

Clinical Considera@ons (2)

•  Easybruisingcanoccuranywhereonthebody,includingunusualsites.•  Thepre>bialareao`enremainsstainedwithhemosiderinfrompreviousbruises

Bruising

•  Subjec>veabnormalityoftheskintextureisappreciableonexam

• Molluscoidpseudotumorsarefleshylesionsassociatedwithscars,foundoverpressurepoints(e.g.elbow,fingers)

Molluscoid Pseudotumors

Clinical Considera@ons (3)

•  Subcutaneousspheroidsaresmallsphericalhardbodies,frequentlymobileandpalpableontheforearmsandshins.Spheroidsmaybecalcifiedanddetectableradiologically•  Epicanthalfoldsareo`enseeninchildhoodbutmayalsobeseeninadults.

Verifica@on of Clinical Diagnosis

•  Confirmatoryanalysisisrecommendedforanypa>entmee>ngtherecommendedclinicalcriteria.• MolecularanalysisofCOL5A1andCOL5A2genesiden>fiesacausalmuta>oninmorethan90%ofthepa>entsandshouldbeusedasthestandardconfirmatorytest.•  Incaseofunavailabilityofgene>ctes>ng,electronmicroscopyfindingsofcollagenflowersonskinbiopsycansupporttheclinicaldiagnosis.•  Absenceoftheseconfirmatoryfindingsdoesnotexcludethediagnosis,howeveralterna>vediagnosesshouldbeconsideredintheabsenceofatypeVcollagengenemuta>onorelectronmicroscopyfindings.

HUMANMUTATION,Vol.33,No.10,1485–1493,2012

Organ System Review

• Musculoskeletal•  Skin• Cardiovascular• Gastrointes>nal• Neurologic

Musculoskeletal

•  Jointhypermobility• Complica>onsofjointhypermobility• Mildmusclehypotonia•  Skeletalmorphologyaltera>ons•  Increasedbonefragility(osteopeniaorosteoporosis)

Skin

•  Stretchy•  So`•  Severeatrophicscarring• Hemosidericscarsovertheshinsandextensorsurfacesoftheforearm•  Easybruising

Cardiovascular

• Aor>crootdila>on;rarelyprogresses• Mitralvalveprolapse• Venousinsufficiency

Gastrointes@nal

• Dysphagia• Dyspepsia• Gastro-esophagealreflux• Hiatalhernia•  Irritablebowelsyndrome• Unspecifiedabdominalpain• Cons>pa>on• Diarrhea• Rectocoele

Neurologic

• Pain• Dysautonomia• Headache•  FrequencyofChiariI,craniocervicalinstability,tetheredcordasyetundefined.

Others

• Prolongedbleeding>me• Chronicfa>guesyndrome• Mastcellac>va>on• Giantbladderdiver>culi

Management - Skin

• Avoidanceoftrauma• Closureofwounds–plas>csurgeonifpossible• Ascorbicacid(2gm/dayforadults)• DDAVPmayhelptonormalizebleeding>me• Avoidexcessivesunexposure

Management - Muscloskeletal

• Physiotherapy• Avoidhigh-impactac>vi>es• Avoidexcessivedemonstra>onsofhypermobility• Amul>-disciplinaryteamisveryhelpfulformanagement• Ringsplints,carefullyconsideredbracingandortho>csmaybehelpful• DEXAanalysis

Management – Pain

• Neurologicalassessmentinpa>entswithsymptomssugges>veofneuropathicpain/compressionneuropathy•  Regular,light,non-weight-bearingexercise.•  Physicaltherapyformusclerelaxa>onandmyofascialtriggerpointrelease•  Relaxa>ontechniquesincludingmindfulness-basedstressreduc>onandbiofeedback•  Counsellingsupportincludingcogni>vebehaviouraltherapy•  An>-inflammatorydrugsandpainmedica>ons

Management - Cardiac

•  Echocardiographytolookforaor>crootdila>onandmitralvalveprolapse.•  Aor>crootsizeandmitralvalveprolapseareincreasedinpa>entswithclassicalEDS,buttheytendtobeoflioleclinicalsignificance.•  Echofrequencyinsymptom-freeadultsfrequencycanbereduced(Atzingeretal.,2011).•  Ifechoisnormalinadulthoodnofollowupisrequired(Malfaitetal.,2010).•  Considervascularimaging/agreessivebloodpressurecontrolifthepa>enthasaglycinesubs>tu>oniden>fiedneartheC-terminalendofthetriplehelix,oronthebasisoftheirfamilyhistory(Monroeetal.,2015)

Management - Gastrointes@nal

• Uppergastrointes>nalendoscopyor24hpH-metrytoevaluaterefluxdiseaseinsymptoma>cpa>ents.Treatmentwithproton-pumpinhibitorifneeded• Colonoscopyshouldbeperformedwithcareduetoapossiblyincreasedriskofmucosalbleeding•  Treatmentoffunc>onalgastrointes>nalcomplaintsinEDSpa>entsisproblema>cduetotheabsenceoftailoredstrategiesandanapparentresistancetopharmacologictreatmentsatstandarddosages/regimens.• Pa>enteduca>on,alsocomprisingdietandnutri>onaladvice,seemsatthemomentthemosteffec>vemanagementtool

Management - Pregnancy

•  Followupthroughoutpregnancyiswarranted.• Prematurityhappensmoreo`enwhenthefetusisaffectedandismainlyduetoprematureruptureofthemembranes• Breechpresenta>onismorecommonifthebabyisaffected,duetohypotonia

Differen@al Diagnosis

• Cardiac-valvulartypeEDS•  TenascinXdeficientEDS•  Spondylocheirodysplas>ctypeEDS•  LoeysDietzsyndrome• OI/EDSoverlapsyndrome

Thanks

•  TheClassicalEDScommioee• Ourpa>entsandtheirfamilies•  TheEhlers-DanlosSocietyandEDS-UK•  LaraBloomandShaneRobinson