LIPOEDEMA ADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FATDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSA

A GIVING SMARTER GUIDE

AUTHORS

LEADAUTHOR

ErikLontok,PhD

CONTRIBUTINGAUTHORS

LaTeseBriggs,PhDMauraDonlanYooRiKim,MS

EbonyMosleyEkeminiA.U.Riley,PhDMelissaStevens,MBA

LIPEDEMASCIENTIFICADVISORYGROUP

WegraciouslythankthemembersoftheLipedemaScientificAdvisoryGroupfortheirparticipationandcontributiontotheLipedemaResearchProjectandGivingSmarterGuide.Theinformativediscussionsbefore,during,andaftertheLipedemaScientificRetreatwerecriticaltoidentifyingtheunmetneedsandphilanthropicopportunitiestodevelopthelipedemaresearchspaceandultimatelybenefitlipedemapatients.SaraAl-Ghadban,PhDPostdoctoralResearchFellow,DepartmentofMedicineTREATProgramUniversityofArizonaTobiasBertsch,MD,PhDSeniorLecturer,DepartmentofHealthEducation,UniversityofFreiburgSeniorConsultant,FoeldiClinic,GermanyEchoeBouta,PhDResearchFellow,RadiationOncologyMassachusettsGeneralHospitalGlenBriceGeneticCounselor,ClinicalGeneticsSt.George’s,UniversityofLondonBruceA.Bunnell,PhDProfessor,DepartmentofPharmacologyDirector,TulaneCenterforStemCellResearchChairman,DivisionofGeneTherapy,TulaneNationalPrimateResearchCenterTulaneUniversitySchoolofMedicine

DeborahClegg,PhDProfessor,DepartmentofBiomedicalResearchCedars-SinaiDiabetesandObesityResearchInstituteRachelleCrescenzi,PhDResearchFellow,InstituteofImagingScienceVanderbiltUniversityWalterCromer,PhDAssistantResearchScientist,Immunology,VascularPhysiology,andLymphaticBiologyTexasA&MHealthScienceCenterKristianaGordon,MBBS,MRCP,CLT,MD(Res)ConsultantinDermatologyandLymphovascularMedicine,St.George’s,UniversityofLondonCarolHaft,PhDProgramDirector,DivisionofDiabetes,Endocrinology,andMetabolicDiseasesNationalInstituteofDiabetesandDigestiveandKidneyDiseases,NationalInstitutesofHealth`

NatashaHarvey,PhDHead,LymphaticDevelopmentLaboratoryCentreforCancerBiologyUniversityofSouthAustraliaAdHendrickx,BHS,PhysicalTherapistDoctoralCandidate,HanzeUniversityofAppliedSciences,GroningenHead,DepartmentofPhysicalTherapy,ExpertCentreforLymphovascularMedicineNijSmellingheHospitalKarenHerbst,PhD,MDAssociateProfessorofMedicine,DivisionofEndocrinologyDirectoroftheTREATProgramUniversityofArizonaYannKlimentidis,PhDAssistantProfessor,DepartmentofEpidemiologyandBiostatisticsUniversityofArizonaAmiraKlip,PhDSeniorScientist,CellBiologyProgram,TheHospitalforSickChildren,ProfessorofBiochemistry,PhysiologyandPaediatrics,TheUniversityofTorontoBabakMehrara,MDPhysician-scientist,PlasticandReconstructiveSurgeryMemorialSloanKetteringCancerCenterChia-LingNhan-Chang,MD,MS,FACOGAssistantClinicalProfessorofObstetricsandGynecology,DivisionofMaternalFetalMedicineDepartmentofObstetrics&GynecologyColumbiaUniversityMedicalCenterPiaOstergaard,PhDSeniorLecturerinHumanGenetics,InstituteofCardiovascularandCellSciencesSt.George’s,UniversityofLondon

TimPadera,PhDAssociateProfessor,RadiationOncology,MassachusettsGeneralHospitalandHarvardMedicalSchoolNeilPiller,PhD,FACPDirector,LymphoedemaClinicalResearchUnitProfessor,DepartmentofSurgeryFlindersMedicalCentreJosephRutkowski,PhDAssistantProfessor,MedicalPhysiologyTexasA&MCollegeofMedicinePhilippScherer,PhDProfessor,DepartmentofInternalMedicineDirector,TouchstoneDiabetesCenterTheUniversityofTexasSouthwesternMedicalCenterHamishScott,PhDHead,DepartmentofMolecularPathologyCentreforCancerBiologyUniversityofSouthAustraliaEvaSevick-Muraca,PhDProfessor,CullenChairinMolecularMedicineDirector,CenterforMolecularImagingUniversityofTexasHealthScienceCenter,HoustonCarrieShawber,PhDAssistantProfessor,ReproductiveSciencesinOB/GYN&SurgeryDepartmentofObstetrics&GynecologyColumbiaUniversityMedicalCenterMelodySwartz,PhDWilliamB.OgdenProfessor,InstituteforMolecularEngineeringUniversityofChicago

JensMarcTitze,MDAssociateProfessor,DepartmentofMedicine,MolecularPhysiologyandBiophysicsVanderbiltUniversityH.EserTolunay,PhDDeputyChief,VascularBiologyandHypertensionBranchDivisionofCardiovascularSciencesNationalHeart,Lung,andBloodInstituteNationalInstitutesofHealthHenricusGerardusJacobusVoesten,MDGeneralandEndovascularSurgeryChiefSurgeon,ExpertCentreforLymphovascularMedicineNijSmellingheHospital

PeterWangDoctoralCandidate,DepartmentofPathologyandImmunologyWashingtonUniversity,SchoolofMedicineAnnalisaZecchin,PhDPostdoctoralFellow,LaboratoryofAngiogenesisandVascularMetabolismVesaliusResearchCenter(VRC)VIB-KULeuven

LIPEDEMAFOUNDATIONREPRESENTATIVES

FelicitieDaftuar,MBAFounderandExecutiveDirectorBoardMemberandFormerPresident,FatDisordersResearchSocietyDanielleWildsteinVicePresident,OperationsShannonSeebergVicePresident,Communications

Table of Contents AUTHORS...................................................................................................................................................1

LIPEDEMASCIENTIFICADVISORYGROUP...........................................................................................1

LIPEDEMAFOUNDATIONREPRESENTATIVES.....................................................................................3

PHILANTHROPIST’SFOREWORD...........................................................................................................5

EXECUTIVESUMMARY............................................................................................................................7

OVERVIEW.................................................................................................................................................8

EpidemiologyofLipedema......................................................................................................................9

HEALTHBURDENANDQUALITYOFLIFE...........................................................................................10

DiagnosisChallenges.............................................................................................................................10

ImpactonQualityofLife.......................................................................................................................10

Pain........................................................................................................................................................11

MentalHealthandPsychosocialStress.................................................................................................12

LIPEDEMADIAGNOSIS,STAGING,ANDPROGNOSIS......................................................................13

DiagnosticCriteria.................................................................................................................................13

TypeandStageofLipedema..................................................................................................................18

PrognosisofLipedema...........................................................................................................................21

DISEASEBIOLOGY..................................................................................................................................22

AdiposeTissue.......................................................................................................................................22

LymphaticSystem..................................................................................................................................23

PainandInflammation..........................................................................................................................24

EndocrineSignaling...............................................................................................................................24

TREATMENTS..........................................................................................................................................25

CLINICALPIPELINE.................................................................................................................................27

RESEARCHCHALLENGESANDPHILANTHROPICOPPORTUNITIES................................................29

NONPROFITORGANIZATIONSINVOLVEDINLIPEDEMA................................................................32

Research-FundingFoundations.............................................................................................................32

PatientSupportandAdvocacyGroups..................................................................................................32

GLOSSARY................................................................................................................................................34

REFERENCES............................................................................................................................................38

5

PHILANTHROPIST’SFOREWORD

Iwastoldtostophavingchildrenbythefirsttherapistwhoconfirmedmysuspicionoflipedema.IwastoldtogotoGermany,getliposuctionandwait18monthsbeforecontinuingtohavechildrenbyanexpert.IwastoldbymyamazingGPthatthelumpoffatandfluidundermykneewaspostpartumdepression,eventhoughIwasn'tdepressed.Ihiredaconciergemedicinecompanytoinvestigate1)Islipedemaarealthing?2)DoIhaveit?3)WhatshouldIdoaboutit?Monthslater:Yes,Yes,Wedon'tknow.SoIdidwhatothersbeforemedid.IsearchedPubmedandGoogleScholarforresearchpapers.Ireadsomeofthem.Iputtheminaspreadsheet.IjoinedFacebookgroupsandLinkedIn-edpeopleIthoughtwouldhelp.Iwenttopatient,researcher,andtherapistconferences.Ihelpedresurrectadefunctnon-profit,theFatDisordersResearchSociety,andtheteamsetupawebsiteandhosted2patientconferences(onewith270attendees!).In2015,Inarrowedmyfocustoresearch,startedtheLipedemaFoundation(LF),andstartedfundingresearchprojects.ButIkeptcomingupshort.Howcouldadiseasethat'sseeminglyeverywherehavesolittlepublished?Suretherearesomedescriptivepapers,casereports,andstudieswithafewpatients.Thereareevenliteraturereviews.Butnopathogenesis.Nogenes.Nobloodtest.Nobiomarkers.Noreplicableimagingtest.Nadazipzero.Icouldn’tfindanswerstomyquestionsaboutlipedema.Whyarepainandswelling(whicharesubjective)recognizedcriteriaoflipedema,butthephysicalchangeinthetextureofthefatisnot?Whyarethereonly5USphysicianswillingtodiagnoselipedema,butthereare12surgeonswillingtooperate,100softherapistswillingtotreat,and2,000patientsparticipatinginFacebookgroups?Domyrelativeshaveit?Aremy3daughtersgoingtogetit?HowcoulditbethatIcarried3children,andmyabdomenlooksbetter,butmylegslookworse?Isitadisease?Acondition?Asyndrome?Idon'tfeelsick,butmybodyisdifferent.WhycanIfeelnodulesoffatinmylegs,butnoonecanimagethemwithultrasound,MRIorahighlytechnicalpieceofequipment?WhyisitthatifIcookhealthymealsandexercisetherightway,Idon'thavepain,butifIgoonvacationmylegsburnwhenIlaydownatnight?DoIreallyneedliposuctionifmyBMIisinthe20s?Willitgetworse?Willitgetbetter?Willitevergoaway?Howislipedemadifferentfromlymphedema,obesity,lipodystrophyandDercum’sdisease?Istheprevalencereally11%ofpost-adolescentwomen?Or5%?Or1%?HowwasInowoneoftheworld'sexpertsinamedicalcondition?

6

Alongcameasmallbandofheroes.Peoplewhohadseenthisbefore.PeoplewhothoughtIwasn'tcrazyforhuntingforanswers.Peoplewhoraisedthelevelofdiscoursearoundsomethingthathadbeenpredominantlypatient-leddiscussions.Peoplewhoknowtheinsandoutsofthetypicaldiseasepathfromdiagnosistotreatmenttocure.TheMilkenInstitute’sCenterforStrategicPhilanthropy(CSP)openeddoorsIcouldn't.Theyperseveredthroughsetbacksthatweretoughformetodealwith.Theyremainedobjectiveandfocused,divingdowndeepintomanyfacetsofthebiologyandthenresurfacingtoputthebigpicturetogether.CSPcouldtalktoresearchersanddoctorsontheirlevel.Theycouldassesswhichexpertiseofresearcherswereneededinordertomoveforward,andbrought20differentspecialtiesintotheconversation.TheheroesaresowellnetworkedaroundDCthattheycouldgetboththeNIDDKandNHLBIrepresentedatourfirsteverLipedemaScientificRetreat.Theyinvitedmetositattableswithotherpeoplelikeme.Theykeptmyexpectationsgroundedandatonepointtoldme:weareattheverybeginningofthecourseofthisdisease;weknownothing.Buttheyprovidedaroadmapandtoolstomoveforward,viaboththisGivingSmarterGuideandaninvaluableprivatereportidentifyingnames,tools,andprojects.Ibecamewe.Wewenttoconferencesandcalledpeoplearoundtheworld.Weworkedtogether.Wewonderedtogether.Weopinedtogether.Wehostedameetingconveningaglobalcohortofthebest-of-the-bestand,andtogetherattheScientificRetreat,wemappedoutthegapsinthefieldoflipedemaresearchsothatwecouldcollaborateandcoordinatetheresearchneededtodefinethespace.Wehavechosentostrategicallyaddresskeyresearchchallengesoflipedema.Fortheshortterm,LF'sfirstpriorityisthesciencebehindthecause(s)oflipedema.Wecannotdomeaningfulresearchintolipedematreatmentsuntilweunderstandthescientificcause(s)ofthecondition.Thereisalackofscientificconsensusonthemostbasicelementsofthisdisease,andLFhassetabouttofixthat.Wecan’tgetanywhereuntilwetacklethefundamentals.Please,readonandbecomepartofourjourney.Takenotesandjotdownideas,thencallLF.We'llbehappytotalktoyouaboutyourideastomovethisforward.Wehavealongroadaheadofusandwe'dlikeyourcompany,becauseittakesavillagetomovediseasesforward.

FelicitieDaftuarFounderandExecutiveDirectorLipedemaFoundation

7

EXECUTIVESUMMARY

Lipedemaisachronicconditionthatoccursalmostexclusivelyinwomenandmanifestsassymmetricalbuildupofpainfulfatandswellinginthelimbs,sparingthehandsandfeet.Acriticalissueisthepoorlyunderstooddiseasebiology,whichfordiagnosedpatientsresultsinlimitedtreatmentoptionsthat,atbest,amelioratethesymptomsoflipedema.Individualswhosufferfromthediseasearefurtherimpactedbytheabsenceofdiagnostictools,thelackofpublicandmedicalawarenessoflipedema,andthestigmaassociatedwithweightgain.Asaresult,thetruenumberofwomenwithlipedema,oritsepidemiology,isunknown.

Bravingthesechallengesisanactive,numerous,andengagedpatientcommunityeagertoparticipateinlipedemaresearch.Supportedbyequallydevotedcaregiversandresearchers,thelipedemafieldpresentsanimmenseopportunityforscientificandmedicaladvancements.Tocapitalizeonthispotential,theLipedemaFoundationandtheMilkenInstitute’sCenterforStrategicPhilanthropyconvenedleadingstakeholderstodiscussthecurrentstateoflipedemascienceandidentifythekeyphilanthropicresearchopportunitiestoadvancethefield.

Littleisknownabouthowandwhylipedemadevelopsinapatient.Althoughthediseaseisreportedtooccurduringpubertyandotherperiodsofhormonalchanges,whythishappensisnotunderstood.Thepainfulfatandswellinginsomepatientscanbesodebilitatingthattheirmobilityisimpaired;yetwhatdrivesthesesymptomsisunknown.Psychosocialissuesarealsoprevalentinwomenwithlipedema,contributingtohealthburdenandcomplexityofdiseasemanagement.Furthermore,manypatientsdevelopthediseasealongsideobesity;however,diet,exercise,andweightlosssurgeryhavelimitedeffectonlipedemafat.Althoughthelackofdiseasebiologyisstaggering,philanthropicinvestmentsinresearchcanleveragethedesireofpatientstoparticipateinstudiestoimprovetheirandtheentirefield’sunderstandingoflipedema.Theconvergenceofmultiplescientifictopicsaroundlipedemaindicatesthataddressingthesegapsinresearchwillalsoimprovetheunderstandingofhormone,painandedema,mentalhealth,andmetabolicbiology.

Therearenodiagnostictoolsortestsforlipedema.Diagnosisoflipedemainvolvesaclinicalassessmentanddiscussionoftheindividual’smedicalhistory,aprocessthatisdifficulttoscalewithinthecurrenthealthcaresystem.Theabsenceofdiagnostictoolstostreamlineorconfirmaclinicaldiagnosisisakeyunmetneed,whichifaddressedbyphilanthropy,hasthepotentialtodramaticallychangethetrajectoryofthedisease.Investinginresearcheffortstoadvancenovelimagingtechnologiestodiagnoselipedemaisapromisingresearchavenuethatwouldsimultaneouslybenefitindividualswhosufferfromthediseaseandhealthcareprovidersunfamiliarwiththecondition.

Thepublicandmedicalcommunityarenotawareoflipedema.Lipedemawasinitiallydescribedin1940,yetlittleknowledgeaboutthediseasehaspermeatedthegeneralpublic,withaconcomitantlackofmentionintheeducationalcurriculumofmedicaltrainees.Addressingthischallengewillrequirephilanthropiceffortstodefinethediseasefromabasic,clinical,anddiagnosticperspective.Akeyphilanthropicopportunityissupportforalipedemapatientregistrylinkedtoatissuebiorepository.Thisefforthasthepotentialtogenerateandsupporttheneededdiseaseresearch,whileengagingpatientsaspartnersinunderstandingthescienceoflipedema.

8

OVERVIEW

Firstdescribedinthe1940s,lipedemaisachronicconditionthatpresentsassymmetricalaccumulationoffatinthesubcutaneoustissuewithalmostexclusiveoccurrenceinwomen.1,2Fattissueexpandsprimarilyinthelowerlimbs,frombuttockstoankles,aswellasinthearms,withweightlossstrategiesexhibitinglimitedeffectsonlimbfat.1,3,4

Lipedemaisfurthercharacterizedbypain,tendernessuponcontact,easybruising,swelling(edema),andpsychosocialissuesthatallimpactapatient’soverallqualityoflife.Onsetoflipedemaisreportedtooccurduringpuberty.5However,itcanoccurorbeexacerbatedbyperiodsofhormonalshifts,suchaspregnancyormenopause,althoughdataastowhyarelimited.6Weightgainandobesityarealsoconsideredtoplayaroleinlipedemaonsetandexacerbationofsymptoms.7

Unmet Clinical and Research Needs

Thelackofaconsistentandscalablediagnosticprocedure,multiplenames(seebox),andlimitedawarenessofthediseaseinthemedicalfieldstymielipedemadiagnosis,culminatinginsparseepidemiologicalinformation.

Theclinicalpresentationandsymptomsoflipedemacancommonlyresultinamisdiagnosisoflymphedema,obesity,Dercum’sdisease,orchronicvenousinsufficiency,resultinginincorrecttreatment(seeDiagnosis).Thusaffectedindividualandthefieldwouldgreatlybenefitfromadiagnostictooltoserveasaninitialtestorconfirmatorytestofaclinicaldiagnosis.

Inaddition,thestaggeringlackoflipedemabasicbiologyresearchhaslimitedunderstandingofthediseaseetiology,ororiginanddriversofonset.

Consequently,patientscontendwithapoorlyunderstoodchronicconditionwiththerapeuticoptionsthat,atbest,onlyamelioratesymptoms.

Synonyms and related terms for l ipedema v Lipoedemav Lipödemv Lipoedemv Lipoedeemv Lipolymphedemav PainfulFatDisorderv Lympholipedemav Lipohypertrophyv Lipohypertrophydolorosav Lipomatosisdolorosaofthelegsv Lipalgiav Adiposalgiav Adipoalgesiav RareAdiposeDiseasev Adiposisdolorosav Dercum’sdisease

9

EPIDEMIOLOGYOFLIPEDEMA

Unfortunately,dataontheincidence(occurrence,rate,orfrequency)andprevalence(commonness)oflipedemaareunknown.Becausemanypeoplewithlipedemaaremisdiagnosedwithlymphedema,themajorityofprevalencevaluesarebasedonthepercentageofpatientsseeninlymphedemaclinics.Thefollowingarecurrentlyavailablebutlimitedlipedemaepidemiologicaldata:

• TheFöldiClinicinGermanystatedaprevalenceinwomenof11percent.However,thispercentagewasderivedbyextrapolatinganestimateofmisdiagnosedlipedemapatientsseekingmedicalattentionintheclinictothegeneralpopulation.8

• TheLymphedemaUnitofUniversityHospitalLaFe(Valencia,Spain)reportedthat18.8percentofthe843patientsseenbyitsclinicfrom2005to2011havelipedema.9

• AreviewofpatientstreatedbyalymphedemaclinicinGermanyfrom1995to1996foundthat15percenthavelipedema.10

• In2003,fourlymphedemaclinicsinGermanyreportedthat8to17percentoftheirpatientshavelipedema.4

• UsingdataaboutpeopleseenbytheregionalDermatologyDepartmentofSt.GeorgesHospital(London,UnitedKingdom),researchersestimatedthat,ataminimum,0.0014percentofwomenhavelipedema.However,theystressthatthispercentageislikelyasignificantunderestimatebecauseofproblemswithmisdiagnosisorfailurebycommunityphysicianstoreferpatients.11

Itisnotablethatmostoftheseepidemiologicaldatacomefrommisdiagnosescapturedbylymphedemaclinics.Giventhepotentialfordiseaseonsetduringperiodsofhormonalshift,thecloserelationshipwithobesity,anddisease-associatedchangesintheskin(seeDifferentialDiagnosissection),researchisneededtodeterminewhetherundiagnosedpatientscanbefoundinObstetricsandGynecological,EndocrineandObesity,andDermatologydepartments,respectively,tounderstandbetterthetruepopulationburdenoflipedema.

10

HEALTHBURDENANDQUALITYOFLIFE

Thechronicnatureoflipedemagreatlyimpactsthephysicalwell-beingandmentalhealth(psychosocialstress)ofpatients.In2012,LipoedemaUKandTheBritishLymphologySocietylaunchedasurveytoprovideobjectivedataandstatisticsonhowwomenwithlipedemawerediagnosedandtreatedbythemedicalprofession,therangeofsymptoms,theefficacyofinterventions,andtounderstandbetterthepatientexperienceoflivingwiththedisease.Thesurvey’skeyfindingsfrom250womenwithlipedemafollow.5

DIAGNOSISCHALLENGES

• Lipedemaispoorlyunderstoodbythemedicalcommunity.Only9percentofrespondentsreportedthattheirhealthprofessionaldiagnosedlipedemathefirsttimetheyreportedtheirsymptoms.Only5percentwerediagnosedbytheirgeneralpractitioner.

• 46percentofrespondentsreportedthatlipedemaonsetcoincidedwithpuberty;however,theaverageageofdiagnosiswas44yearsold.

• Themajorityofrespondentsreportedthatmedicalprofessionalsweredismissiveoftheconditionandmisdiagnosedtheirlipedemaasexcessweight/baddiet/lackofexercise.

• Themostcommonlyreportedresponsetodiagnosiswasrelief.Respondentsalsofeltangryandfrustratedthatdiagnosishadtakensolong,aswellasscaredaboutafuturewithnocureandfewoptionstoamelioratesymptoms.

IMPACTONQUALITYOFLIFE

• Lipedemaaffectsapatient’semotionalstate:87percentofrespondentsagreedthattheirlipedemahashadanegativeeffectontheirqualityoflife.

• Lipedemaalsoaffectspatients’careers:51percentreportedthatlipedemahasaffectedtheirabilitytosucceedintheirchosencareer,commonlycitingalackofmobility,discomfort,andinabilitytostand.Inaddition,39percentbelievedthattheirlipedemarestrictedtheircareerchoices.

• Whenasked“Hasyourbodyshapeleadtoanyofthefollowing?”

o 95percentreporteddifficultyinbuyingclothesandboots

o 86percentreportedlowself-esteem

o 83percentreportedavoidingbeingphotographed,orensuringthattheirbodydidnotappearintheimage

o 76percentreportedlackofenergy

o 60percentreportedrestrictedsociallife

o 60percentreportedfeelingsofhopelessness

o 55percentreportedrestrictedmobility

o 50percentreportedrestrictedsexlife

11

PAIN

Painandtendernessoflipedema-affectedareasisaconsistentlyreportedproblemandposesasignificanthealthburden.Generallyreportedaschronic,thispaincansignificantlyimpactmobilityandoverallqualityoflife.77percentofrespondentstotheLipoedemaUKsurveyexperiencelegpain.5Thefollowingresultsfromlipedemapublicationsandpatientsurveysthatfurtherdescribetheeffectofpainonpatientlives:

• InAllenandHines(1940),andanexpandeddiseasedescriptionbyWoldetal.basedon119lipedemacasereports,foundthatpainwasthedistinguishingcharacteristicfor40percentofpatients.1,3

• Acontextualbehavioralapproachassessmentofthequalityoflifeof120womenwithlipedema,whowererecruitedthroughonlineandFacebookpatientdiscussiongroups,foundthat93percentofthesewomenexperiencedlipedema-associatedpainandtenderness(sensitivitytotouch),withalmosthalfofthemratingthesymptomsasseveretoextremelysevere.12

• Amedicalchartreviewandsurveyof50lipedemapatientsseenbyanacademicmedicalcenterreportedthatnearly90percentexperienceddailypain.13

• Anapplicationofthevisualanaloguescale(VAS),whichisapsychometricresponsescaleusedinquestionnairestomeasuresubjectivecharacteristicsorattitudesthatcannotbedirectlymeasured,wasusedtoquantitativelyassesslipedema-associatedcharacteristicsin25pre-liposuctionsurgerypatients.Mostpatientsreportedpaininlipedema-affectedareas,and,sixmonthsaftersurgery,theyreportedasignificantreductioninpainfrom7.2to2.1VASpointswithaconcomitantimprovementinpsychologicalstressfrom8.7to3.6VASpoints.14

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MENTALHEALTHANDPSYCHOSOCIALSTRESS

AsdescribedbytheLipoedemaUKsurvey,patients’qualityoflifecanbeaffectedbymorethanthesymptomsandphysicalissuesassociatedwiththedisease.5,12,15,16Patientsmustalsocontendwiththementalhealthissuesthatoftenaccompanythechallengesofmanaginglipedema.Itiscurrentlyunknownwhethermentalhealthissuesprecedeoroccurwithonsetoflipedema;however,suchstressorsaffectpatientqualityoflifeintermsof:

• Psychologicalhealth(e.g.,anxiety,depression)

• Levelandqualityofsocialrelationships,includingsupportandengagementoffriendsandotherlipedemapatients(seebox)

• Perceptionoftheenvironment(e.g.,stigma)

Toaccountforpsychosocialstress,theDutchSocietyofDermatologyandVenereologydevelopedaguidelinesdocument(DutchLipedemaGuidelines)whichincludedaholisticassessmentandcaremodelthatassessesapatient’sphysicalstateandlevelsofpsychosocialdistress.7,17Thismodelwasbasedonevidence-andexpert-basedrecommendationstoinformanddefinethecriteriaforamedicaldiagnosisoflipedema.

Importantly,theguidelinesproposeaminimumdatasetofrepeatedclinicalmeasurements,orclinimetrics,tooutlineandassessachroniccaremodelforlipedemameasuringtheimpactandsuccessofconservativetreatmentprogramsforthedisease(seeTreatmentssection).17-19Thevalueofthisclinimetrics-basedcaremodelisderivedfromitsholisticapproachtoassessingapatient’sphysicalstate,dailyandindividual-driventreatmentprogram,andlevelsoflipedema-associatedpsychosocialdistress.

TheapplicationofclinimetricstoevaluatediagnosisandtreatmentisexemplifiedbythecalculationofmeanVASvaluesbeforeandafterliposuctionsurgerytoassesschangesinpainandpsychosocialstress.14

Alongwiththeactiveandconnectedlipedemapatientcommunity,theseeffortssetthestageforaholisticandquantitativelydrivenapproachthatwillhopefullycaptureandunderstandthetruehealthburdenoflipedema.

Facebook L ipedema Pat ient Groups Highlevelsofsocialconnectednesswerefoundtocorrelatewithhighlevelsofqualityoflifeandsatisfactionoflife.Listedbelowareonlinepatientgroupsfocusedonlipedema:

v FriendsofLipedemaSistersUSA(anyonecanjoin)

v FatDisordersResearchSociety(FDRS)v LipedemaSistersUSAv LipedemaEducationv LovingLifewithStage1and2Lipedemav LipedemaStage3and4v LipedemaFitnessv LiposuctionforLipedemav LipedemaUSAEspañolv LipedemaCanadianSupportGroupv LipoedemaAustraliaSupportSocietyv LipoedemaUKv LipoedemaLadiesUKv TalkLipoedema

Somegroupsareprivateandrequestthatinterestedpeopleagreetotheirrulesbeforecontactingorjoiningthegroup.

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LIPEDEMADIAGNOSIS,STAGING,ANDPROGNOSIS

DIAGNOSTICCRITERIA

Diagnosinglipedemainvolvesatakingthemedicalhistoryandperformingaphysicalexaminationofthepatient.7Asthefieldlacksadiagnostictest,cliniciansconsidermultiplecriteriatodeterminewhetheranindividualhaslipedema.Thefollowingsectionsdescribethesecriteria,aswellashowlipedemaisdifferentiallydiagnosedfromlymphedema,obesity,Dercum’sdisease,andchronicvenousinsufficiency.

Allen & Hines diagnostic criteria Lipedemawasfirstdescribedin1940byAllenandHines.In1949,Wold,Allen,andHinespublishedaseminalreportthatelaboratedontheclinicalpresentationandproposeddiagnosticcriteria,basedon119cases.1,3Becauselipedemaiscommonlymisdiagnosedaslymphedema(seebox),theproposeddiagnosticcriteriaweredesignedtodistinguishbetweenthetwodiseases.Stillusedtodaythecriteriainclude:

1. Almostexclusiveoccurrenceinwomen

2. Abilateralandsymmetricalaccumulationofadiposetissue(bodyfat)onthelegswithminimalinvolvementofthefeet,resultinginabraceleteffectorcuffattheankle(Figure1,A)

3. MinimalpittingedemaandnegativeStemmer’sTest(Figure1,B)

4. Painandtendernessofaffectedtissue

5. Persistenceofthetissueenlargementdespitecaloricrestrictionorstimulationoflymphaticflowthroughelevationoftheextremities

6. Increasedvascularfragility,andeasybruising

Figure1:VisualizationofLipedemaDiagnosticCriteria.(A)Front,side,andrearviewofalipedemapatient’sanklecuffs.Woldetal.notedthepresenceofprominentinnerankle,ormalleolarfatpads(rear).(B)Pittingedemaiscommoninlymphedema,whereinapplicationofpressure(left)leavesanindentationinthetissue(right).ImagescourtesyoftheFatDisordersResearchSociety(A)andWikimediaCommons(B).

Lymphedemaisabuildupofthefluidsurroundingtissues,orinterstitialfluid,inthemuscleandskinleadingtoincreasedfatdeposition.Thediseasecanbehereditary(primarylymphedema)orarisefromdamagetothelymphaticsystemfromdifferentinsultssuchascancer,surgery,radiationtherapy,trauma,orinfection(secondarylymphedema).Itcanoccurinbothmenandwomenandpresentsasunilateralorbilateralswelling—mostofteninthearmsorlegs.CommonpresentationsincludepittingedemaandpositiveStemmer’sTest;swellingthatrespondstoelevationchanges;afeelingofheaviness;restrictedrangeormotion;discomfort;recurringinfections;andhardeningandthickeningoftheskin.

B

14

Clinical characteristics of lipedema Treatmentprovidersusethefollowingcriteriatofacilitateadifferentialdiagnosisoflipedemafromotherdiseases.

Lipedemaischaracterizedbyaccumulationoffatonthelimbs,whichcanbepainfulandfeelnodular.Thisfatbuild-upnecessitatesadifferentialdiagnosisoflipedemafromobesityandDercum’sdisease.(Table1)

• Disproportionalfatdistributiononthelegs,withoutasimilarlyproportionalbuildupintheupperbody/trunkregion,isakeydistinguishingcharacteristicoflipedema.ThisfatdistributionisunlikethatforobesityorDercum’sdisease,inwhichfataccumulatesatthetrunkandthroughoutthebody4,20,21.Becausemanylipedemapatientsarealsoobese,considerabledebateexistsregardingwhetherobesitybegetslipedemaorviceversa.22

• Unlikethesmoothfeelofobesefat,reportsindicatethatlipedemafatcanpresentwithpalpablenodules–describedasfeelinglikefrozenpeasinabagorpearls–whichcanbemorenoticeablyfeltatlaterstagesofthedisease.4,6ThisnodularityissimilartothediffusetypeofDercum’sdisease.6,24

Table1:DifferentialDiagnosisbetweenObesity,Dercum’sDiseaseandLipedema4,6,20,23

Obesity Dercum’sDisease Lipedema

Areasofexcessfataccumulation

Trunk,throughoutbody Trunk,throughoutbody ArmsandLegs

Tendencytobruise Mild Mild-Moderate Moderate-Severe

Painassociatedwithfat Mild Severe Moderate-Severe

Presenceofnodularfat No Yes Yes,especiallyatlaterstages

Comorbidwithdiabetes Yes Yes No

Comorbidwithhypertension Yes Yes No

Dercum’sdisease,alsoknownasadiposisdolorosaandMorbudDercums,isararediseasethatoftenpresentswithgeneralobesityandpainfulfatinaffectedareas.21Unlikethesmoothfeelofobesityfat,Dercum’sdiseasefatcanfeelnodularwhenpalpated,andformmassesoffattissue(lipomasorangiolipomas).Dercum’sdiseaseisclassifiedbasedontheareasoffatthatexperiencepain:diffuse,widespreadpainfrominareaswithfattissue;nodular,intensepaininandaroundfattissuewithnodulesorlipomas;andmixed.6Thediseaseismorecommoninwomenthanmen,withtheaverageofonsetbetweentheagesof35-50,buthasbeenreportedtooccurearlier.22

15

• AlthoughthefatdistributionbetweenlipedemaandDercum’sdiseaseisdifferent,thehighprevalenceofobesityinbothpopulationsincreasesthechallengeofaccuratelydiagnosinglipedema.ThenodularityandpainassociatedwiththefatlipedemaandDercum’sdiseasefurtherincreasesthecomplexityofdifferentialdiagnosis.

Theageofonsetforlipedemahasbeenreportedtooccurprimarilyduringpuberty.5Furthermore,patientshavereporteddevelopmentorexacerbationoflipedemaduringtimeperiodssurroundingpregnancyormenopause.3,9,11

Swellingoredemaofaffectedregionsworsenswhilestandingupright(orthostasis)andduringhotweather.3,6Thepresenceofedemainlipedemacontributestoamisdiagnosisoflymphedema.4

Vascularchangeslikespiderveinsandtelangiectasiaarepresentinlipedema-affectedareas(Figure2).3,11Becausethesevascularmanifestationsalsooccurinpatientswithchronicvenousinsufficiency(CVI),withadvancedcasesdevelopinguni-orbilateraledemaandswellingofthelegsknownasphlebedema,CVIisadifferentialdiagnosisthatrequiresconsideration.4,25

Theskinelasticityisreducedinlipedema-affectedareas,suggestingimpairedconnectivetissuebeneaththeepidermis.6,26Insomecases,theskinalsofeelscoldtothetouchbutisnotfirmorhardenedasinlymphedema.6,27

Lipedemaisalsoconsideredtohaveaheritabilitycomponent,becausepatienthistoriesoftenrefertorelativeswithsimilarlegandbodystructure.3PedigreestudiesfromasingleacademicmedicalcentersuggesteitheranX-linkeddominantinheritance,orautosomaldominantinheritancewithsexlimitation.11However,morestudiesarerequiredtoaccuratelydeterminethegeneticarchitectureoflipedema.

Figure2:SpiderVeinsandVenousManifestationsonaWomanwithLipedema.(Top)Rightleg,(Bottomleft)rightfoot,and(Bottomright)leftcalf.ImagescourtesyoftheFatDisordersResearchSociety.

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Table2:DifferentialDiagnosisofLipedemavsLymphedemavsObesityvsCVI6,25,28–31

Lipedema Lymphedema(PrimaryandSecondary)

Obesity Phlebedema,ChronicVenousInsufficiency

DiseasePresentation

Symmetricalfatdepositionandswellinginlegsand/orarms,butnotthefeetorhands

Fatdepositionandswellinginaffectedlimb,includinghandsorfeet

Widespreadfatdeposition,withthepotentialforswellingduetocomorbidities

Nofat,butswellinganditchyareasnearankleswithabrownishdiscolorationoflowerlegs

Sex Almostallfemale Malesandfemales Malesandfemales Malesandfemales

DiseaseOnset Duringhormonalshifts(puberty,pregnancy,menopause)andperiodsofweightgain

Primary:Congenital,duetopresenceofgeneticmutationsSecondary:Duetodamagetothelymphaticsystem

Ageindependent Duringpregnancyoronsetofcomorbiditiessuchasobesity,diabetes,orhypertension

PresenceofPain

Yes,inaffectedtissues

Discomfortandachingcanoccurovertime

Yes,chronicpainassociatedwithcomorbidities

Yes,inaffectedareas

ImpactofCaloricRestrictionandExerciseonFat

Limited None Weight-lossstrategiescanbeeffective

Notapplicable

RiskofCellulitis

No Increased Increased Increasedriskinareasaffectedbyedema.Itchyanddiscoloredareaswitheczemacanlooklikecellulitis

Heritability Potential Primarylymphedemacanbeinherited

Potential Potential

Forfurtherdifferentialdiagnosistools,see:

• DifferentialDiagnosis:ApproachtothePatientwithSwollenLegs

• FatDisordersResearchSocietyContinuingMedicalEducation

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Hypermobility in lipedema patients Accordingtoarecentstudyof160lipedemapatientsfromasingleacademicmedicalcenter,58percentdemonstratedhypermobilityofthejoints,asdeterminedbyBeightonScore23(Figure3).Hypermobilityistheabilitytomovejointsbeyondthenormalrangeofmovement,althoughaBeightonScoreofhigherthan5isnottheonlycriterionforhypermobility,becauseothersignsandsymptomsofthesyndromearerequiredforanaccuratediagnosis.32,33

Diagnostic devices and lipedema Todate,noimagingassayisapprovedasaninitialdiagnostictoolortesttoconfirmaclinicaldiagnosisoflipedema.Althoughmultipleimagingtechniquessuchasmagneticresonanceimaging,34,35computedtomography,36lymphscintigraphy,37dual-energyX-rayabsorptiometry,38indirectlymphangiography,39andultrasound35haveallbeenappliedtoandgeneratedconsiderablelipedema-specificdata,moreresearchisneededtodeterminewhetheranindividualmodalityorcombinationofimagingtestscansuccessfullydiagnosethedisease.

Figure3:HypermobilityinWomenwithLipedema.Examplesofhypermobilityof(A)hipjoints,(B)shoulder,elbow,andwristjoints,and(C)fingerjoints.ImagescourtesyoftheFatDisordersResearchSociety.

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TYPEANDSTAGEOFLIPEDEMA

Nearly97percentand30percentofwomenwithlipedemapresentwithfatonthelegsandarms,respectively.4,10,28Differentclassificationschemesexist,andthisreportwillutilizetheType(I-V)andStage(1-4)parametersasdescribedbySchmellerandMeier-Vollrath.4,6OtherclassificationsystemsincludethoseusedbycliniciansinAustralia,UnitedKingdomandtheNetherlands.7,11

Lipedematypedescribestheareasofthebodywithfat,whilestagesindicatethelevelofthefataccumulationandrelatedcomorbidities.Itshouldbenotedthatawidevarietyofdiseasepresentationexists,anditisnotfullyunderstoodwhethereachpatientprogressesthrougheachstage.6Thefollowingimagesareofwomenwithdifferenttypesandstagesoflipedema,andareprovidedcourtesyoftheFatDisordersResearchSociety.Unfortunately,imagesofeveryiterationofType/Stage(e.g.,TypeI/Stage3,TypeIVb,TypeV)arenotavailable.Thefullphotoessaycanbefoundhere.

LipedemaType:Areasofthebodywithfataccumulation

Type I:Pelvis,buttocks,andhips

Type II:Buttockstoknees,withformationsoffoldsoffataroundtheinnersideoftheknee

Type III:Buttockstoankles

Type IV a-c:a,Upperarm;b;Lowerarm;c,Wholearm

Type V:Kneestoankles

LipedemaStages:Diseasepresentationandlevelsoffataccumulation

Stage 1:Normalskinwithenlargedsubcutaneoustissue

Stage 2:Unevenskinwithindentationsinthefat;largermoundsoffattissue(lipomas)arepresent

Stage 3:Largeextrusionsoftissuecausingdeformations;especiallyonthethingsandaroundtheknees

Stage 4:Developmentoflipolymphedemawithlargeoverhangsoftissue Figure4:LipedemaTypeIwithFatAccumulationatthe

Pelvis,Buttocks,andHips.(Top)Stage1;(Bottom)Stage2,notethepresenceofindentationsintheskin.Whitearrowsindicateendingoflipedemafatabovetheknees.ImagescourtesyoftheFatDisordersResearchSociety.

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Figure6:LipedemaTypeIIIwithFatAccumulationfromButtockstoAnkles.(Top)Stage1;(Middle)Stage2;(Bottom)Stage3,notethatthisimageisnotscalewiththeothersbecauseonlythelowertorsoisvisualized.ImagescourtesyoftheFatDisordersResearchSociety.

Figure5:LipedemaTypeIIwithFatAccumulationfromtheButtockstoKnees,andFormationsofFoldsofFataroundtheInnerSideoftheKnee.(Top)Stage1;(Middle)Stage2;(Bottom)Stage3.ImagescourtesyoftheFatDisordersResearchSociety.

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Transitionoflipedematolipolymphedema(Stage4)canoccurduringstages2or3andinvolvesdevelopmentoflymphedemaclinicalcharacteristicssuchasapositiveStemmer’sTest,increasedfibrosisandstiffeningofskin,andswellingandadiposetissuebuildupatthehands,feet,trunk,andhead.

Figure7:LipedemaTypeIVArmPresentationwithFatAccumulationattheUpperandLowerArm.(A)TypeIVa,Stage3sideandrearview.(B)TypeIVc,Stage3sideviews.ImagescourtesyoftheFatDisordersResearchSociety.

B

A

Figure8:TypeIII,Stage4Lipolymphedema.(A)Frontview.(B)Rearview.Pleasenotethatfor(A)and(B)thepatientdoesnotexhibitthecharacteristicaccumulationoffatseeninmanyStage4patients.(C)Demonstrationofhypermobility.(D)TypeIVcarmpresentation.ImagescourtesyoftheFatDisordersResearchSociety.

A B C

D

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PROGNOSISOFLIPEDEMA

Theprognosisoflipedemaisnotfullyunderstood.4,13Althoughthestageoflipedemadescribestheseverityoffataccumulation,somepatientsmayremainatonestageformanyyears,whileothersmayrapidlyprogressthroughstagesasaresultofstressfulevents(surgery)orchangesinoverallweight.28,40,41Theoccurrenceoflipedemafromlipohypertrophyortolipolymphedemaandobesityisdiscussedbelow:

• Lipohypertrophy―Thesimilarphysicalmanifestationsoflipohypertrophyandlipedemaraisethequestionofwhethertheformerisanearly-stageprecursortothelatter.Casereportsindicatethatpatientswithlipohypertrophycandeveloptolipedema;however,theexacttriggersofdiseasetransitionarenotunderstood.4,9

• Lipolymphedema―Lipedemapatientscandeveloplymphedemasuddenly,gradually,ornever.Theexactdriversofsecondarylymphedemaisnotfullyunderstood;however,developmentofthiscomorbidityresultsinstage4lipolymphedema.28Furthermore,itispoorlyunderstoodwhetherthediseaseprogressionisdrivenbyanincreaseinlocalizedfatorbuildupofedemainaffectedareasthatdrivesdegradationoflymphaticfunctionand/oranincreaseinfibrosis,andtherebyresultsinprogressiontolipolymphedema.4,42

• Obesity―Lipedemapatientsmayalsopresentwithobesity.TheFöldiClinicreportedthatthemajorityoflipedemadiagnosesoccurinobeseindividuals.22However,howdiseaseprognosischangesifobesityorlipedemaistheinitialinsultisnotknown.20

Overall,moreresearchisneededtounderstandfullyhowlipohypertrophy,lymphedema,obesity,andlipedemaaffecteachother’sprognosis.Furthermore,lipedemaisoneofseveralfatdisorders,suchasDercum’sdisease,Madelung’sdisease,andlipodystrophy,andexactlyhowthesedisordersaresimilarordifferintheirbiologyispoorlyunderstood.6Increasedresearchandawarenessofthemedicalfieldofthesharedanduniquepathwaysacrossallthelistedconditionswouldultimatelyimprovetheoutlookforallpatientsaffectedbythesediseases.

Lipohypertrophyisaconditionthatexhibitsahighlysimilarbodyshapetoearly-stagelipedema.Patientswiththisconditionpresentwithfataccumulationinthelowerlimbs,rarelyinthearms,and—criticalforadifferentialdiagnosis—donotexperiencepainorbuildupofedemaintheaffectedareas.Althoughreportsindicatethatpatientswithlipohypertrophyhavedevelopedlipedema,moreresearchisneededtodeterminewhethertheconditionservesasaveryearlystageoflipedema.4LipohypertrophyisatermismorecommonlyusedinEurope.ThetermisusedintheUnitedStates,butisunrelatedtolipedema,whereinitreferstothebuild-upoffatatsitesofinsulin-injection.

22

DISEASEBIOLOGY

Littleisknownaboutthebasicbiologyandetiologyoflipedema,withmostpublicationsfocusedonthevascularandlymphaticfindingsofsurgeonsandphysicaltherapists.Thetissuemostaffectedbylipedemaisskin,composedoftheepidermis,dermis,andhypodermis―andincludesthefatthatexpandsinpatients.Giventhedisease’spresentationofadipose,lymphatic,andinflammationissues,aswellasapotentiallinktoendocrinesignaling,itishighlypossiblethatresearchershaveonlyjustbeguntoexplorethebiologyunderlyingthedisease.43

ADIPOSETISSUE

Adipocytes(fatcells)areapartoftheendocrinesystemandarethemajorcomponentofadiposetissue(bodyfat).Thereareseveralsitesofadiposetissuestorage,ordepots,andtheycanbroadlybedividedintovisceral(locateddeepintheabdomen),subcutaneous(locateddirectlybelowtheskin),andectopic(aroundorgansliketheliver,andwithinmusclefibers)depots.44Subcutaneousdepotsarepresentthroughoutthebody,includingtheface,chest,arms,legs,abdomen,andbuttocks.Lipedemacanaffecttheseveralsubcutaneousdepotsbutpredominantlyimpactsthelegsandarms.4,13

Insubcutaneousadiposetissue,adipocytesaresurroundedbyfluidthatbathesthecells(interstitialfluid),anetworkofproteinsthatprovidestructureandstability(extracellularmatrix),aswellasothercellsimportantforadiposetissuephysiology45(Figure9).Otheradiposetissuecellsincludeadipocytestemcells(thecellsourceofadipocytes),immunecells,andtissueandbloodlymphaticcapillariescomposedofendothelialcells.46

Dependingondiseasestage,reportsindicatethatthefeeloflipedemaadiposetissuecanrangefromsmooth,granular,tonodular.1,4,6,28Furthermore,MRI,CTscans,andtissuebiopsiesindicatethat,intheearlystagesoflipedema,edema(composedofinterstitialfluid)isminimal,andthatadiposetissueexpansionislikelyduetoadiposecellenlargement(hypertrophy)and/oranincreaseinnumber(hyperplasia).42-46Researchershavehypothesizedthattheedemaassociatedwithlipedemamayinvolveimpairmentoflymphaticvesselsduetopressureexertedbyfattissue,whichsubsequentlylimitstheinwardflowofinterstitialfluid.42,43Limitedresearchhasbeenperformedtoassesswhetheradiposegrowthandsubsequentimpairmentlymphaticvesselsplaysarolecausativeroleinlipedema.

Despitethecentralroleofadipocyteexpansioninlipedema,littleisknownaboutthecharacteristicsofthesecells.Forexample,themechanismsofhyperplasiaandhypertrophyaredistinct,withtheformerdrivenbycelldivision,andthelatterbasedinthetissue’sneedforadditionalfatstorage.43,47Adipocytes,ascomponentsoftheendocrinesystem,respondtoandreleaseavarietyofmoleculesthatmayberelatedtolipedema.Theseincludethekeyplayersinhormonalresponse,levelsofinflammationandtheresultingpainandtenderness,andmetabolism.52Towhatextentthesegrowthandsignalingactivitiesareon/offorimpairedisunknownforlipedema.

Figure9:SubcutaneousAdiposeTissue.Pinkcellsareadiposecells,greenisthelymphaticvessel,andlightgreencellsarelymphaticendothelialcellsthatserveasthewallofthelymphaticcapillary.Greenarrowsindicatetheflowofinterstitialfluidintothelymphaticvessel.ImagemodifiedfromWikimediaCommons.

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LYMPHATICSYSTEM

Thelymphaticsystemiscomposedofanetworkoflymphaticvessels,thefluidinthevesselscalledlymph,andlymphnodesthatfilterlymphasitpassesthroughthem.Thesystemalsoincludesthetonsils,adenoids,spleen,andthymus.Unlikeblood,thelymphaticsystemisnotpumpedbytheheart,butinsteadreliesonthemovementofthediaphragm,musclecontraction,skintension,andthefluidpressuresinthebloodcapillaries,lymphaticcapillariesandinterstitialspacetopropellymphfluidfromacrossbodytowardsthetrunk.53Previouslyderidedas“thebody’ssewersystem,”thelymphaticsystemisnowunderstoodtobeapartofthecirculatorysystemandavitalcomponentoftheimmunesystem.

Adiposecells,likeanycellinthebody,arefedbybloodthroughbloodcapillaries,andbloodreturnstomaincirculationbysmallveins,orvenules.45Theinterstitialfluid,fluidthatleavesthecells,bathesandsurroundstheadiposetissue,beforeflowingintolymphcapillariesandeventuallyintolymphaticvessels,therebycomprisingthemajorityoflymphfluid(Figure10).

Inlipedema,theedemaexperiencedbypatientsisprimarilycomposedofinterstitialfluidanditscomponents.4,42,54Theswellingoflipedematissuehasbeenfoundtohaveanincreaseininterstitialspace,hypothesizedtoresultfromtheincreaseinfluid.20Thusthepresenceofedemainearlystagesoflipedemaindicatesaslightimpairmentofthelymphaticsystem’sabilitytotakeupfluid.48

Previousworkhasshownthatsomelipedemapatientspresentwithleakylymphaticcapillariesandvessels,referredtoasmicroaneuryms.55,56Ascomponentsofthevascularsystem,spiderveinsandvascularchangesinlipedemapatientsalsosuggestalevelofmicroangiopathy(diseaseofthesmallbloodvessels).57Acouplingoftheseresultswouldsuggestthatlipedemamaybedrivenbyvascularissuesthatmanifestinincreasedbuildupofedema,andsubsequentlimitationsoffluidremovalfromtheinterstitialspace.8

Thecomplexbidirectionalrelationshipbetweenimpairmentofthelymphaticsystemandgrowth/enlargementofadipocytesisapotentialdriveroflipedema,aslate-stagepatientsdemonstrateboth.However,toshedlightontheinitialinsultthatcauseslipedemaonset,moreresearchisneededtodeterminewhetherlymphaticdysfunctionarisesfromanintrinsicimpairedlymphaticandvascularactivityorisasecondarymanifestationofthediseasearisingfromthepressureexertedbyexpandedadipocytesonthelymphcapillariesandvessels.

Figure10:InterstitialSpaceofAdiposeTissue.Theredandtransitiontobluetubesdepictsthetransitionofbloodfromthecapillarytovenule;theyellowcellsrepresentadiposetissue;thegreentubesrepresentthelymphaticcapillariesandvessels;andtheblackarrowsshowtheflowofinterstitialfluidintothelymphaticsystem,andsubsequentrenamingtolymphfluid.ImagemodifiedfromWikimediaCommons.

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PAINANDINFLAMMATION

Thepainandtendernessexperiencedbylipedemapatientssuggestsanactivatedstateofinflammationwithinthesubcutaneousspace(Figure11).Withintheepidermis(dermisandadiposetissuethatcomposethesubcutaneousspace),multipleimmunecellsplayaroleinactivatingandmediatinganinflammatoryresponse.58Althoughnoresearchhasbeenperformedonwhetherdendriticcells,Tcells,orLangerhanscellsplayaroleinthesymptomsoflipedema,activatedmacrophageswerefoundinasinglestage4lipolymphedemapatient.59

Researchisneededtodeterminetheroleofanactivatedimmunesysteminlipedema,anditspotentialimpactonthepainassociatedwiththedisease.Furthermore,stressisknowntoplayaroleininflammation,andwhetherthelong-termmentalhealthissuesexperiencedbylipedemapatientscontributestoimmuneactivationiscompletelyunknown.

ENDOCRINESIGNALING

Theendocrinesystemisthecollectionofglandsthatproducehormonesthatregulateahostofbodilyfunctions.Giventhealmostexclusiveoccurrenceinwomenanddiseaseonsetduringpubertyandperiodsofhormonalshift,thereisapotentialroleforfemale-specifichormonesinlipedemaetiology6(Figure12).Aroleforsex-specifichormonesisalsosupportedbytherareoccurrenceoflipedemainmen.2

Giventhecentralroleofestrogen,itsnumeroustypes,receptors,andinvolvementinmanybiologicalprocesses,researchisneededtounderstandwhetherdiseaseonsetisaffectedbytheestrogenpathway.23,60,61Furthermore,estrogenanditstypescompriseonlyaportionofthesex-specifichormonesthatfluctuateduringperiodsofhormonalshift;thusmoreresearchisneededtounderstandtheoverallroleofhormonesinlipedema.

Figure11:ImmuneCellsintheSkinOccupyDistinctLocationsandFunctionalRoles.TheseimmunecellsincludeTcells,Langerhanscells,lowerlayerofskindendriticcells(dermalDC),innatelymphoidcells(ILC),andmacrophages.FigurecreatedbyRachelCotton,JustSkin.Deep–YourImmuneSystemattheSurfaceforPLOSBlogs.

Figure12:Sex-specificHormonesProducedbyReproductiveEndocrineOrgans.ImagecourtesyofWikimediaCommons.

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TREATMENTS

Lipedemaisachronicdiseasewithlimitedtherapeuticoptions.Becausethecausesordriversofdiseaseonsetremainunknown,currentlyavailabletherapiesaregearedtowardamelioratingsymptomsandpreservingpatienthealth.TheDutchLipedemaGuidelinesalsodevelopedclinimetricstoassessthehealthprofilesofpatientsundergoingtherapyforlipedema.Thesemeasurementsincludecircumferenceoflipedemaaffectedareas,mobility,strength,painviatheVAS,fatigue,weight,levelsofactivity,conditionandwalkingcapacity,andqualityoflife.7,17

CONSERVATIVETHERAPY

Thegoalofconservativetherapyistoaidindiseasemanagementandaddressthesymptomsassociatedwithlipedema.7TheFatDisordersResearchSocietyprovidesvideosthatcomprehensivelydescribetreatmentoptions.Itiscriticaltonotethatalthoughthetreatmentsbelowarewhatpatientsandcaregiversemploytoaddresslipedema,limitedresearchisavailabletounderstandwhycertaintreatmentsareeffectiveorineffectiveforpatients.

Exerciseisakeycomponentofconservativetherapyandservestoreduceorstabilizeweight,strengthenmuscles,improvebloodandlymphflow,andboostmentalhealth.5,16,17,62Commonlyusedexercisesincludelow-impactworkoutssuchaswalking,lymphaticyoga,rebounding,cycling,andPilates.Aquaticexerciseinvolvessubmersioninapooltoperformlow-impactexercises.5,63

Healthyeating,suchastheRareAdiposeDiet,PaleoDiet,andAnti-inflammatoryDiet,isastrategythathasbeenusedbythepatientcommunity.Althoughtheeffectsandsuccessofspecificdietsdifferfrompatienttopatient,regularexerciseandpropernutritionwillaffectbodyfat,therebyimprovingapatient’swell-being.16,64

Psychosocialcounselingandsupportgroupsareimportantduetothementalhealthissuesassociatedwithlipedema.Patientsareencouragedtoparticipateinsupportgroups,engagetheirfriendsandfamily,andseektheaidofmentalhealthprofessionalstosupportdiseasemanagement.5,30,62

Locomotion(orthopedic)problemsandlackofpropershoewearareverycommoninpatientswithlipedemaandleglymphedema.Thisissuenegativelyimpactsupwardtransportoffluidfromthelegs,therebycontributingtothebuildupandprogressionofedema.Flatfeetshouldbeanalyzedandtreatedwithadequateshoes.Mechanicalhindranceduetoenlargedfatdepositsontheinnerandupperthighsshouldbetreatedaspossible,asthiscandirectlyimpactpatientmobilityandhealth.65,66

Compressiontherapyinvolvesgarmentsthatcanbefittedtospecificareasaffectedbylipedema.Theseincludebandagingwithgarmentswithinelasticsystems,andwrapswithVelcroattachmentstoallowforeasywearandadjustment.Thesegarmentsworkbyapplyingpressuretotheaffectedlimbstokeeplymphmovingfromthetissuesintothevesselsandareusefulforpatientswhoexperienceedemabuildup,andhavebeenreportedtoreducepain.5,16,17

Manuallymphaticdrainage(MLD),sometimescalledmanuallymphatictherapy,isaspecifictypeofmassagedesignedtomoveexcessinterstitialfluidoutofthetissuesandintothelymphaticvessels.ThegoalofMLDistoincreasetheflowoflymph,therebygeneratingasuctioneffectanddrivinglymphfromafluid-richareatoafluid-poorarea.5,16,30,67AlthoughMLDisstandardtherapyforlymphedema,itssuccessfortreatinglipedemaisconsideredunproven.17

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Completedecongestivetherapy(CDT),alsocalledcomplexdecongestivetherapyanddecongestivelymphatictherapy,isaprogramthatcombinesmultipletreatmentapproachestoreducetheswellingandedema-relatedsymptomsoflipedema.Tailoredtotheindividual,CDTinitiallyinvolvesregularsessionswithaphysicaltherapistinvolvingMLDorintermittentpneumaticcompression,useofbandagingandcompressiongarments,andtherapeuticexercises.57Oncetheswellingisreduced,patientself-managementinvolvesapplicationtheirownbandaging,compression,andexerciseinanefforttomaintainthereductioninswelling.5,16CDTandMLDhavebeenshowntoreducecapillaryfragilityinlipedemapatients,buttowhatextentthisimpactsthediseaselong-termisnotfullyunderstood.57

Deepbreathingisbeneficialasitactivatesthediaphragmandpromoteslymphaticpumping.63

SupplementssuchasButcher’sBroomandseleniumhavebeenusedbypatientswithisolatedandanecdotalreportsofimprovementoflymphaticflowandlimbreduction.68

LIPOSUCTIONANDREDUCTIVESURGERY

Surgeryistheonlyavailabletechniquetocorrectabnormaladiposetissue.Twotypesofsurgeryhavebeenusedinlipedematreatment,liposuctionandreductivesurgery.

Liposuctionisasurgicaltreatmentthatinvolvesapplicationofgeneralorlocal(tumescentandwater-assisted)anesthesia,andsubsequentremovalofadiposetissuethroughastraw-likedevicecalledacannula.42Oneendofthecannulaisconnectedtoavacuumdevice,andtheotherendisinsertedthroughasmallincisionoftheskinandremovesfatviaaspiration.

• Tumescent l iposuction involvesintroductionoflargevolumesoftumescentsolutionintothesubcutaneousspacetotumesce(swell)thearea.Thesolutioncontainsananesthetic,whichinduceslocalnumbing;epinephrine,whichcausesconstrictionofbloodvesselstoreducebleeding;andsaline,whichcausesswellingoftheadiposetissue.Thesolutionisallowedtoinfiltratethetissue,anditshighsalinitycausestheadiposetissueandcellstoswellandseparatefromtheconnectivetissue,atwhichpointthecannulaisusedtoaspiratethefat.14,20,69,70

• Water-assisted l iposuction doesnotinvolveover-swellingoftheadiposetissue.Instead,smallamountsoftumescentsolutionandwaterareintroducedintotheadiposetissue.Oncesufficientnumbingoccurs,amodifiedcannulawithanattachedfan-shapedwaterjetisinsertedintothesubcutaneousspaceandappliedtoseparatetheadiposecellsfromthetissue,whilesimultaneouslyaspiratingthesolutionanddetachedcells.71

Althoughliposuctionhasbeenmorecommonlyusedtotreatlipedema,theDutchlipedemaguidelinesstatethat“[liposuction]isonlythetreatmentofchoiceforpatientswithasuitablehealthprofileand/orinadequateresponsetoconservativetherapy.Beforeusing[liposuction],associateddeterioratingcomponentssuchasedema,obesity,unhealthylifestyle,lackofphysicalactivity,lackofknowledgeaboutthedisease,andpsychosocialdistressshouldbeaddressed.Moreover,evenafterliposuction,womengenerallyrequireconservativetherapy,andweightnormalizationshouldremainagoal.”17

Reductivesurgery,alsocalledexcisionandresection,isamoreinvasiveprocedurethatinvolvesexcisionoflargelocalizeddepositsoflipedematoustissue,orlumps,possiblyincludingthesurroundingskin.Developmentoftheselumpscancausethekneestotwistoutward(valgusdeformity)ordrooptothesideoftheleg(ptosis)and,inseriouscases,leadtotheinabilitytowalk,therebydramaticallyimpactingthepatient’slife.

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CLINICALPIPELINE

Clinicalresearchisabranchofbiomedicalresearchthatinvolveshumansubjects.Thegoalofclinicalresearchistounderstandbetterthehealthoutcomesofparticipantsandtoevaluatethesafetyandefficacyoftherapy,drugs,medicaldevices,ordiagnosticsintendedforuseinhumans.Thesestudiescanalsobeusedtocollectspecimensfromhumansubjectsforfurtherresearch.Therearetwokeytypesofclinicalstudies:observational,andinterventional(seebox).

Importantly,informationonpotentialsideeffectsofinterventionsaregatheredduringthestudyandweighedagainstthepotentialtherapeuticbenefitofthetreatmentunderinvestigation.

L IPEDEMACLINICALSTUDIES

AsofJanuary2017,onlyfourclinicalstudieshavebeenconductedinlipedema.ObservationalStudiesInsightIntoSubcutaneousAdiposeTissueDisorders(INSIGHT)―Thisstudyaimstounderstandtheobservablephysicalcharacteristicsofapersonthatresultsfromtheinteractionofhisorhergeneticmakeupwiththeenvironment.Thistypeofinteractioniscalledaphenotype.Morespecifically,thisstudyfocusesonunderstandingthephenotypesofindividualswithsubcutaneousadiposetissuedisorderssuchaslipedemaandDercum’sdisease.Thisstudyiscurrentlyrecruitingparticipants.ImagingLymphaticFunctioninNormalSubjectsandinPersonswithLymphaticDisorders—Thisstudyaimstounderstandthepotentialapplicabilityofnear-infraredfluorescencelymphaticimagingasadiagnosticassayoflymphaticflowinparticipantswithlymphedema,lymphaticdisorders,vasculardisorders,orlipedema.Thisstudyisenrollingparticipantsbyinvitationonly.

ObservationalStudiesInthistypeofclinicalstudy,investigatorsassessthehealthoutcomesingroupsofparticipantsaccordingtoaresearchprotocolwithoutanyspecificmedicalintervention.InterventionalStudy(orClinicalTrial)Inthistypeofclinicalstudy,participantsareassignedtoreceiveanintervention/therapysothatresearcherscanevaluatetheeffectoftheinterventiononhealth-relatedoutcomesaccordingtoaresearchprotocol.Participantsmayreceivediagnostic,therapy,ordruginterventions.

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InterventionalStudiesPhysicalConditioninLipedemaandObesity—Becauselipedemaandobesityareoftenmisdiagnosedforeachother,theprimaryaimofthisstudyistounderstandwhetherthereisadifferenceinmusclestrengthbetweenwomenwithlipedemaandwomenwithobesity.ThisstudyhasbeencompletedandcontributeddatatotheDutchLipedemaGuidelines.17

QuadrivasTherapytoReduceLipedemaSubcutaneousAdiposeTissue—Quadrivasisanintensivemassagetherapyfordifferenttissues.Thisstudyaimstounderstandwhetherthetherapycanreducesubcutaneousadiposetissueinparticipantswithlipedema.Thisstudyisongoingbutisnotrecruitingparticipants.

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RESEARCHCHALLENGESANDPHILANTHROPICOPPORTUNITIES

Thelittlethatisknownabouttheetiologyoflipedemaanditsholisticeffectonpatientsisbasedonisolatedclinicalcasereportsandlimitedresearchstudies.Researcheffortsarecomplicatedbyasubjectiveclinicaldiagnosisprocessthatfacesscalabilityandstandardizationissues.Discussionsbefore,during,andafterthe2016LipedemaScientificRetreatrevealedseveralresearchchallengesandphilanthropicopportunities,which,ifaddressed,willhelptodefineanddevelopthelipedemaresearchfield.

Lipedema Basic Biology and Genetics

Todefinelipedemaanddeveloptreatmentsforpatients,researchtoolssuchascelllines,mousemodels,andanunderstandingoftheaberrantcellsandphysiologicalprocessesthatdrivethediseasearerequired.Giventhemultiplediseasesthatrequiredifferentialdiagnosisfromlipedema,itislikelythatexpansionoflipedemaresearchwillcontributetotheunderstandingoflymphedema,obesity,Dercum’sdisease,lipohypertrophy,andotherfatdisorders.Furthermore,developmentofmultidisciplinaryteamsthatspanresearchfields(adipose,lymphatic,metabolic,etc.)anddisciplines(academics,clinicians,surgeons,etc.)wouldbetheidealapproachtoaddressthekeyunmetresearchneedsofthedisease.

Developmentoflocalsurgeon-researcherteams

• ResearchChallenge:Accesstofreshresearchsamplesandtheirsharing/storageatbiobanksarecomplicatedbyprocessingchallengesforresearchersandfewincentivesforliposuctionsurgeonstoparticipateinresearchefforts.

• ResearchOpportunity:Apotentialapproachistoleveragethedesireoflipedemapatientstoreceiveliposuctionsurgerybydevelopinglocalsurgeon-researcherteams,whichwillfacilitateaccesstofreshpatientsampleswhilemaintainingandexpandingabiorepository’stissuebank.

RNAsequencingoflipedemapatientsamplessuchasblood,adiposetissue,andexosomes

• ResearchChallenge:Thetranscriptional(geneexpressionlevels)differencesinthegenestranscribedintoRNA,orbetweennormalandlipedemafat,remainunknown.

• ResearchOpportunity:Inanunbiasedmanner,thisefforthasthepotentialtodeterminethegenesthataredifferentiallyexpressedbetweenlipedematissueandnon-lipedematissuefromthesamepatient,aswellasbyaffectedandunaffectedfamilymembers.

Histology,morphology,andimmunostainingoflipedematissue

• ResearchChallenge:Todate,lipedemapublicationsoffertwotothreecasereportswiththeoccasionalhematoxylinandeosinstainingofpatientbiopsiestovisualizecellularstructures.

• ResearchOpportunity:Ifperformedinaconcertedandcollaborativemanner,thisefforthasthepotentialtovisualizeaberrantcellularstructuresandprocessesoflipedematissue.

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Molecularprofilingoflipedemaadiposestemcells

• ResearchChallenge:Itisunknownwhetheradiposestemcellsdrivetheexpansionandgrowthoflipedematissue.

• ResearchOpportunity:Thisefforthasthepotentialtodeterminethecurrentproteomic(proteinexpressionlevels),transcriptomic(geneexpressionlevels),andmetabolicstateoflipedemaadiposestemcells,andwhetherkeypathwaysarealteredinthesecells.Furthermore,theseresearcheffortscanbeappliedtootherpotentialcellsofinterestinlipedematissue,suchaslymphaticendothelialcells,differentiatedadiposecells,andskeletalmuscle.

Assessmentofcirculatingandlocalcytokineandhormonelevelsoflipedemapatients

• ResearchChallenge:Althoughstandardpanelshavebeenperformedonlipedemapatientbloodsamples,theseeffortshavebeenneithercomprehensiveintheirtestingofallknowncytokines/hormones,norindicativeofthelocallevelsofcytokines/hormonesinlipedematissue.

• ResearchOpportunity:

o Cytokine-focusedeffortsmaydeterminewhatdrivestheinflammatoryandpaincomponentoflipedema.

o Hormone-focusedeffortsmayshedlightonwhatdrivesonsetandexacerbationofthedisease.

Lipedemasymptoms-basedmousestudies

• ResearchChallenge:Intheabsenceofknowngeneticmutationsandalteredcells/signalingpathways,therelevantmousemodelsforlipedemaareunknown.

• ResearchOpportunity:Apotentialapproachistostudythesymptomsoflipedemapatientsincurrentlyavailablemousemodels.Thiseffortwouldexpandthenetworkofanimalmodelresearchers,andpotentiallytherangeofdiseasesandresearchfieldsrelatedtolipedema.

Determinethegeneticmarkersanddriversoflipedema

• ResearchChallenge:Becausethegeneticarchitectureoflipedemaiscurrentlyunknown,theheritabilitycomponentandgeneticmarkersanddriversofthediseasearepoorlyunderstood.

• ResearchOpportunity:Understandingofthegenesthatunderliedevelopmentoflipedemacouldserveasapotentialdiagnostictoolthatwouldinformbasicbiologystudies.Theseeffortswouldbenefitfrommultiple,well-phenotypedcohortstofacilitatedatacomparisonandreproducibility.

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Lipedema Diagnosis and Epidemiology

Theepidemiologyoflipedemaisunknown,andavailablestudiesarerestrictedbysmallsamplesizesandcomparisondifficulties.Toincreaseawarenessandacceptanceoflipedemaasadisease,accuratevaluesofincidence/prevalenceareneeded.Collectionofdatatodetermineincidence/prevalencewouldincreaseclinical,research,andindustryinterestinthefield.Furthermore,toolstofacilitatepatientidentificationandengagementareessentialtoperformingepidemiologicalstudies.

Developmentoflipedema-specificdiagnostictools

• ResearchChallenge:Currentlyavailableimaginganddiagnosticassaysarenotapprovedtoserveasaprimarytesttodiagnoselipedemaorasconfirmationofaclinicaldiagnosisoflipedema.

• ResearchOpportunity:Developmentofnoveldiagnostictoolsorimprovedapplicationofcurrentlyavailabletoolstobetterdiagnoselipedemawouldbeacriticaladvancementforthefield.

o Apotentialapproachistoexplorethevalueandapplicabilityofnovelimagingtechniquessuchassodium-basedMRIornear-infraredfluorescencelymphaticimaging.

o AnotherapproachistoexpandandimprovetheuseofcurrentlyavailableimagingtechniquessuchasMRI,CT,ultrasound,anddual-energyx-rayabsorptiometryscanstodeterminewhetheracombinationofimagingtestsmightgeneratelipedema-specificparametersabletodifferentiallydiagnosethedisease.

Developmentofconsensusandscalablesolutionsforlipedemadiagnosisandepidemiology

• ResearchChallenge:Anaccurateandscalablediagnosticprocedureforlipedemaisaclearunmetneed.However,theexactprocessforaddressingthisneedremainsundefined.

• ResearchOpportunity:Apotentialapproachistoformaworkinggroupfocusedondevelopingastandard,minimalsurvey/questionnairethatwouldbeapplicableforpatientregistryintakequestions;anepidemiologicalincidenceandprevalencestudy;andgeneralpractitionersandcentersthatseepotentiallyundiagnosedindividualswithlipedema.

Developmentandlaunchofapatientregistry

• ResearchChallenge:Lipedemapatientsarehighlyinterestedinparticipatinginresearch,andtheirparticipationiscentraltoleveragingthebasicbiology,genetic,andepidemiologicalopportunities.However,convertingpatientinterestintoengagementrequiresthereturnofresultstostudyparticipants,aswellasthesharingofresultswiththebroaderlipedemaresearchfield.

• ResearchOpportunity:Apotentialapproachistodevelopawell-curatedlipedemapatientregistryconnectedtoanexistingbiorepository.Suchaneffortwouldfacilitate

o Assessmentofdiagnosisandepidemiologystudies

o Patientrecruitmentintobasicbiology,genetic,anddiagnosticresearchstudies

o Developmentofalong-termnaturalhistorystudythatcapturesdiseaseprogression,symptoms,andtreatmenthistoryoflipedemapatients;followedbydisseminationofresultstoallparticipantsandpatientnetworks

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NONPROFITORGANIZATIONSINVOLVEDINLIPEDEMA

RESEARCH-FUNDINGFOUNDATIONS

LipedemaFoundation―Thisfoundationwasfoundedin2015withthemissionofdefining,diagnosing,anddevelopingtreatmentsforlipedema.Todate,theFoundationhascommittedmorethan$2.9milliontowardslipedemaresearch,includinggeneticstudies,supportforpostdoctoralfellows,mousemodelresearch,andlaunchoftheUniversityofArizonaTreatment,Research,Education,AdiposeTissue(TREAT)programandtissuebiorepository.

FatDisordersSociety(FDRS)―Asafundingorganizationandpatientsupportandadvocacygroup,thisU.S.-basedsocietywasfoundedin2009andisdedicatedtoimprovingthequalityoflifeforallpeopleaffectedbyadiposetissuedisordersthroughresearch,education,advocacy,andcollaboration.Thesocietyalsoholdsannualconferencesthatbringtogetherpatients,clinicians,therapists,caregivers,andresearcherstodiscusskeyissuesfacingthefield.

LymphaticEducationandResearchNetwork(LE&RN)―Foundedin1998astheLymphaticResearchFoundation,LE&RN’smissionistofightlymphaticdiseaseandlymphedemathrougheducation,research,andadvocacy.WithfinancialsupportfromtheFatDisordersResearchSociety,LE&RNfacilitatedtheawardingofthreelipedemapostdoctoralfellowshipsin2015.

PATIENTSUPPORTANDADVOCACYGROUPS

LipoedemaUK―ThisUnitedKingdom–basedcharitableorganizationwasfoundedin2012bywomenwithlipedemaandtheLymphoedemaServiceatSt.George’sHospitalinLondon.Itsfocusistoeducatedoctors,healthprofessionals,andthepublicaboutlipedemaanditssymptomstofacilitatediagnosisandearliertreatment.

TalkLipoedema―ThisUnitedKingdom–basedcharitableorganizationprovidessupporttopeoplewithlipedemaandtheirfamiliesandcaregivers.Theorganizationsupportseffortsthatwillimprovetheaccuracyoflipedemadiagnosis,developmentofindividualpatientcareplans,andpatientaccesstoservicesandself-supportmanagement.

LipoedemaLadies―ThemissionofthisUnitedKingdom–basednonprofitorganizationistosupportwomenwithlipedema,raiseawarenessaboutthediseaseaswellastreatmentandmanagementoptions,andcontributetotheoverallbodyofknowledgeandunderstandingforlipedema.

LipoedemaAustraliaSupportSociety(LASS)―ThisAustralia-basedsocietyaimstoraisediseaseawarenessthroughpatientsupportandadvocacy.Theassociationwasformedtoinvolveandeducatesufferers,aswellastofacilitatecoordinationofthedifferentmedicalareasnecessaryforongoingmanagementoflipedema.

LipoedemHilfe(LipoedemaHelp)―ThisGermany-basedorganizationwasfoundedin2011withthegoalofincreasinggeneralawarenessandrecognitionoflipedemaasachronicdisease.Theorganizationaimstoimprovepatientaccesstotreatmentsbyfosteringclosercooperationamongdoctors,healthinsurers,hospitals,authorities,andpoliticians.

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NederlansNetwerkvoorLymfoedeem&Lipoedeem(DutchLymphedemaandLipoedemaNetwork)―Foundedin2006,thisNetherlands-basedfoundationisfocusedonhelpingindividualsaffectedbylymphedemaandlipedema.Thenetwork’sgoalsaretodevelopanindependentplatformforscientificknowledge,throughthedevelopmentofnationalandinternationalguidelines,andtoserveasaresourceforpatients,patientorganizations,andcaregivers.

StichtingNederlandseLipoedeemdag(DutchLipoedemaFoundation)―ThisNetherlands-basedfoundationhasthegoalofraisingregional,national,andinternationalawarenessofthedisease.Thefoundationconvenesanannualsymposiumforpatients,partners,physicaltherapists,andmedicalpractitionerstosharebestpracticesandrecentdevelopmentsinlipedema.

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GLOSSARY

adenoids Alsoknownasapharyngealtonsilornasopharyngealtonsil,itisamassoflymphatictissuesituatedwherethenoseblendsintothethroat.

adipocytestemcells Thecellpopulationfromwhichmatureadipocytesarisefrom.adipocytes Alsoknownasfatcells,theyaretheprimarycomponentsofadiposetissueand

specializeinstoringenergyasfat.adiposetissue Fat;alooseconnectivetissueprimarilymadeupofadipocytes.adiposisdolorosa AlsoknownasDercum'sdiseaseorAndersdisease,itisarareconditioncharacterized

bygeneralizedobesityandfattytumorsintheadiposetissue.Thetumorsarenormallypainfulandfoundinmultiplesontheextremities.TheunderstandingofthecauseandmechanismofDercum’sdiseaseremainsunknown.

anesthetic Adruggiventoapatienttopreventpainduringsurgery.angiolipoma Abenignmassoffattissueandbloodvessels.Theyoftenappearatmultiplesitesand

occuraspainfulsubcutaneousnodules.autosomaldominantinheritancewithsexlimitation

Aninheritedgeneticconditionwhereintheonlyonecopyofthemutantgeneisneededtopresentthephenotype.Thesexlimitationcomponentindicatesthatphenotypeisonlyexpressedinonesex.Forlipedema,itmaybeanindicatorofwhythediseaseoccursalmostexclusivelyinwomen.

cellulitis Acommon,potentiallyseriousbacterialskininfection.Itappearsasaswollen,redareaofskinthatfeelshotandtender,andcanspreadrapidlytootherpartsofthebody.

chronicvenousinsufficiency

Aconditionthatoccurswhenthevenouswalland/orvalvesinthelegveinsarenotworkingeffectively,makingitdifficultforbloodtoreturntotheheartfromthelegs,therebycausingbloodto“pool”orcollectintheseveins.Thispoolingiscalledstasis.

circulatorysystem Alsocalledthecardiovascularsystemorthevascularsystem,isanorgansystemthatcirculatesblood,facilitatingthetransportationofnutrients,oxygen,carbondioxide,hormones,andbloodcellstoandfromthecells.

clinimetrics Thepracticeofassessingordescribingsymptoms,signs,andlaboratoryfindingsbymeansofscales,indices,andotherquantitativeinstruments.

computedtomography Animagingprocedurethatusesspecialx-rayequipmenttocreatedetailedpictures,orscans,ofareasinsidethebody.Itisalsocalledcomputerizedtomographyandcomputerizedaxialtomography(CAT)scans.

connectivetissue Tissuethatconnects,supports,binds,orseparatesothertissuesororgans,typicallycomposedofcollagenorotherfibers,andincludingcartilaginous,fatty,andelastictissues.

cytokines Anyofanumberofsubstances,suchasinterferon,interleukin,andgrowthfactorssecretedbycertaincellsoftheimmunesystemandhaveaneffectonothercells.

dendriticcells Antigen-presentingcells(alsoknownasaccessorycells)ofthemammalianimmunesystem.TheirmainfunctionistoprocessantigenmaterialandpresentitonthecellsurfacetotheTcellsoftheimmunesystem.Theyactasmessengersbetweentheinnateandtheadaptiveimmunesystems.

Dercum’sdisease AlsoknownasadiposisdolorosaorMorbudDercums,isarareconditioncharacterizedbygeneralizedobesityandfatmasses,orlipomasintheadiposetissue.Thelipomascanbepainfulandfoundinmultiplesontheextremities.TheunderstandingofthecauseandmechanismofDercum’sdiseaseremainsunknown.

dermis Thelayeroftissuebelowtheepidermiscontainingbloodcapillaries,nerveendings,sweatglands,hairfollicles,andotherstructures.

diabetes Adiseaseinwhichthebody’sabilitytoproduceorrespondtothehormoneinsulinisimpaired,resultinginabnormalmetabolismofcarbohydratesandelevatedlevelsofglucoseinthebloodandurine.

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diaphragm Asheetofinternalskeletalmusclethatextendsacrossthebottomofthethoraciccavity.Thediaphragmseparatesthethoraciccavity,containingtheheartandlungs,fromtheabdominalcavity.Duringrespiration,asthediaphragmcontracts,thevolumeofthethoraciccavityincreasesandairisdrawnintothelungs.

dual-energyX-rayabsorptiometry

DXA,previouslyDEXA,isameansofmeasuringbonemineraldensity(BMD).TwoX-raybeams,withdifferentenergylevels,areaimedatthepatient'sbones.Whensofttissueabsorptionissubtractedout,theBMDcanbedeterminedfromtheabsorptionofeachbeambybone.AlthoughwidelyusedtoassessBMD,DXAhasbeenusedtomeasuresofttissuemassandadiposity.

ectopicfat Ectopicmeans"notwhereit'ssupposedtobe".Ectopicfatisnon-normalaccumulationoffatinareassuchastheabdominalregion(beerbelly),liver,muscletissueincludingtheheart,pancreas,andperhapsinlipid-richdepositsinthearteries.

eczema Alsoknownasdermatitis,eczemaisagroupofdiseasesthatresultsinskininflammation.Thesediseasesarecharacterizedbyitchiness,redskin,andarash,withtheareaofskininvolvedvaryingfromsmalltotheentirebody.

edema Themedicaltermforswelling,whichmaybecausedbytrappedfluid,inflammation,andothercauses.

endocrinesystem Thecollectionofglandsthatproducehormonesthatregulatemetabolism,growthanddevelopment,tissuefunction,sexualfunction,reproduction,sleep,andmood.

endothelialcells Thesecellsmakeuptheendothelium,whichisatypeoftissuethatlinestheinteriorsurfaceofbloodvesselsandlymphaticvessels,forminganinterfacebetweencirculatingbloodorlymphinthelumenandtherestofthevesselwall.

epidemiology Thebranchofmedicinethatdealswiththeincidence,distribution,andpossiblecontrolofdiseasesandotherfactorsrelatingtohealth.

epidermis Theouterlayerofcellsthatoverlaysthedermis.epinephrine Ahormone,neurotransmitterandmedication.Duringsurgicalproceduresitusedasa

medicationthatfacilitatesconstrictionofbloodvessels.estrogen Theprimaryfemalesexhormonewhichisresponsibleforthedevelopmentand

regulationofthefemalereproductivesystemandsecondarysexcharacteristics.etiology Thecause,setofcauses,ormannerofcausationofadiseaseorcondition.exosomes Cell-derivedvesiclesthatarepresentinmanyandperhapsalleukaryoticfluids,

includingblood,urine,andculturedmediumofcellcultures.Researchhasshownthatthesesmallvesiclesplayaroleincell-to-cellsignalingandcanserveasdiseasebiomarkers.

extracellularmatrix Acollectionofmoleculesontheoutsideofcells,andwhicharesecretedbycellstoprovidestructuralandbiochemicalsupport.

fibrosis Thethickeningandscarringofconnectivetissue,usuallyasaresultofinjury.genotype Thegeneticconstitutionofanindividual.geneticarchitecture Referstotheunderlyinggeneticbasisofatraitordisease,anddescribeswhetherthe

genotypeconnectedtothephenotypeoccursrarely,oriscommon,andwhetheritseffectishighlypenetrant,moderateorminimal.

hematoxylinandeosin Oneoftheprincipalstainsinhistologyandisthemostwidelyusedstaininmedicaldiagnosis.Thehematoxylinstainnuclei,whiletheeosinstainsproteinsinsideandoutsideofthecells.

hormones Anymemberofaclassofsignalingmoleculesproducedbyglandsinmulticellularorganisms.Theyaretransportedbythecirculatorysystemtotargetdistantorganstoregulatephysiologyandbehavior.

hypermobility Jointsthataremoreflexiblethannormalorthatmoveinexcessofanormalrangeofmotionareconsideredhypermobile.Whengeneralized,hypermobilityoccurswithsymptomssuchasmuscleorjointpainwithoutsystemicdisease,andiscalled-hypermobilitysyndromeorjointhypermobilitysyndrome.

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hyperplasia Infatcells,thisprocessreferstoanincreaseintherateofcellularreproductionhypertension Abnormallyhighbloodpressure.hypertrophy Infatcells,thisprocessreferstoanincreaseinthesizeofcellshypodermis Theinnermostandthickestlayerofskin,whichisprimarilycomposedofadipocytes.immunesystem Anetworkofcells,tissues,andorgansthatworktogethertodefendthebodyagainst

attacksby“foreign”invaders.Theseareprimarilymicrobes—tinyorganismssuchasbacteria,parasites,andfungi,thatcancauseinfections.

incidence Theoccurrence,rate,orfrequencyofadisease.indirectlymphangiography

AnX-raybasedassayusedtovisualizeanddelineatelymphaticvessels.Theindirectaspectoftheassayreferstoadministrationofcontrastagentstoimage,or"lightup"vessels.

inflammation Acomponentofthecomplexbiologicalresponseofbodytissuestoharmfulstimuli,suchaspathogens,damagedcells,orirritants,andisaprotectiveresponseinvolvingimmunecells,bloodvessels,andmolecularmediators.Thefunctionofinflammationistoeliminatetheinitialcauseofcellinjury,clearoutnecroticcellsandtissuesdamagedfromtheoriginalinsultandtheinflammatoryprocess,andtoinitiatetissuerepair.Theclassicalsignsofinflammationareheat,pain,redness,swelling,andlossoffunction.

interstitialfluid Thefluidreleasedbycellsandthatbathesthesurroundingcellsandtissue.Langerhanscells Dentriticcellsthatarepresentintheskinandmucosa.lipedema Achronicdiseasethatoccursalmostexclusivelyinwomen.Itpresentsassymmetrical

accumulationoffatinthesubcutaneoustissueofthelimbs.Theaffectedareasarealsopainful,easytobruise,withthefattissuedemonstratinglimitedresponsetoweightlossstrategies.

lipodystrophy Aconditioncharacterizedbyabnormalofdegenerativeconditionsinadiposetissue.lipohypertrophy AtermmorecommonlyusedinEurope,itreferstothesymmetricalaccumulationof

fatinthelegsthatdonotpresentwithpain.lipolymphedema Thelatestageoflipedema,whereintheincreasedfataccumulationandstraininthe

lymphaticsystemresultsinlymphedemaaswell.lipomas Massesoffattissuethatexpandundertheskin.lymph Thefluidinsideoflymphvessels,whichiscomposedofimmunecells,proteins,and

lipids.lymphnode Anorganofthelymphaticsystempresentwidelythroughoutthebody.Theyactas

filtersforthelymphthatpassesthroughthem.lymphangiography AnX-raybasedassayusedtovisualizelymphnodesandlymphvessels.lymphaticcapillaries Asmallnetworkofthin-walledvesselsthatcollecttheinterstitialfluidandallows

themtoflowintothelymphaticsystem,becominglymph.lymphaticvessels Thelargernetworkofvesselsthatcollectlymphfluid,passesitthroughlymphnodes,

andtowardsthetrunk.lymphedema Adiseasethatpresentswithbuildupofthefluidsurroundingtissues,orinterstitial

fluid,inthemuscleandskinleadingtoincreasedfatdeposition.Thediseasecanbehereditary(primarylymphedema)orarisefromdamagetothelymphaticsystemfromdifferentinsultssuchascancer,surgery,radiationtherapy,trauma,orinfection(secondarylymphedema).

lymphscintigraphy Animagingprocedurethatallowsvisualizationoflymphnodesthroughtheuseofinjectedcontrastagents.

macrophages Alargecellfoundinstationaryforminthetissuesorasamobilewhitebloodcell,especiallyatsitesofinfection.Itischaracterizedbyitsphagocytic,orsampling,capacityofitsextracellularsurroundings.

Madelung’sdisease Alsoknownasbenignsymmetriclipomatosis,itisaconditioncharacterizedby

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extensivefatdepositsinthehead,neck,andshouldgirdlearea.magneticresonanceimaging

Aformofmedicalimagingthatmeasurestheresponseoftheatomicnucleiofbodytissuestohigh-frequencyradiowaveswhenplacedinastrongmagneticfield,andthatproducesimagesoftheinternalorgans.

metabolicbiologyormetabolism

Thesumofallchemicalreactionsinanorganismbywhichdigestionoffoodisturnedintoandstoredasenergy.

microaneuryms Withrespecttolipedema,thisreferstotheenlargementanddilationofavesselwall.microangiopathy Avascularconditionwhereinthevesselsappearsmallerthannormal.obesity Theconditionofhavingexcessivebodyfat,withitsrelatedcomorbiditiesthat

increasetheriskofhealthproblems.phenotype Thesetofobservablecharacteristicsofanindividualresultingfromtheinteractionof

itsgenotypewiththeenvironment.phlebedema Edemaorswellingthatistheresultofvenousinsufficiency.prevalence Thecommonnessofadiseaseortraitinapopulation.prognosis Thelikelycourseofadiseaseorailment.proteomicstudies Researchthatfocusesontheamount,types,andfunctionofgeneratedproteins.spleen Anabdominalorganinvolvedintheproductionandremovalofbloodcellsinmost

vertebratesandacomponentoftheimmunesystem.spiderveins Smallred,purple,andblueveinsthattwistandturnandareeasilyvisiblethroughthe

skin,alsocalledvenulectasia.Tcells Alymphocyteproducedorprocessedbythethymusgland,andplaysanactiveinthe

immuneresponse.telangiectasia Aconditioninwhichtherearevisiblesmalllinearredbloodvessels(broken

capillaries)ontheskin,alsocalledtelangiectases.thymus AlymphoidorgansituatedintheneckofvertebratesthatproducesTcellsforthe

immunesystem.Thehumanthymusbecomesmuchsmallerattheapproachofpuberty.

tonsils Eitheroftwosmallmassesoflymphoidtissueinthethroat,oneoneachsideoftherootofthetongue.

transcriptomicstudies Researchthatfocusesontheamount,types,andfunctionofgeneratedRNAtranscripts.

ultrasound Amedicalimagingassaythatusessoundsorvibrationsatanultrasonicfrequencytogenerateandimage.

visceralfat Depotsoffattissuelocateddeepintheabdomen.X-linkeddominantinheritance

X-linkeddominantinheritance,sometimesreferredtoasX-linkeddominance,isamodeofgeneticinheritancebywhichadominantgeneiscarriedontheXchromosome.

38

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