ASYNDROMECHARACTERIZEDBYECTODERMALDYSPLASIAPOLYDACTYLYCHONDRODYSPLA - PDF document

ASYNDROMECHARACTERIZEDBYECTODERMALDYSPLASIA,POLYDACTYLY,CHONDRO-DYSPLASIAANDCONGENITALMORBUSCORDISREPORTOFTHREECASESBYRICHARDW.B.ELLIS,M.D.,F.R.C.P.andS.VANCREVELD,M.D.(FromtheChildren'sDepartment,Guy'sHospital,London,andthePaediatricDepartment,UniversityofAmsterdam)Theassociationofthefourfollowingcongenitalabnormalities-ectodermaldysplasiaaffectingthehair,teethandnails;polydactyly;chondro-dysplasia;andcongenitalmorbuscordis-hasbeenobservedintwochildreninwhomtheclinicalpictureissostrikinglysimilarastojustifyitsdescriptionasaseparatesyndrome.Althoughmanyatypicalcasesofachondroplasiaandchondro-osteo-dystrophyhavebeenrecordedwithassociatedabnormalities,andthereisanextensiveliteraturerelatingtocongenitalectodermaldysplasia,wehavefoundnodetaileddescriptionofthesyndromepreviouslypublished.McIntosh(1933),however,inthetentheditionof'DiseasesofInfancyandChildhood'includesillustrationsandsomeclinicalparticularsofachildwhoisclearlyanincompleteexampleofthesamesyndrome.Hehaskindlyfurnishedafullreportonthiscase,anditisincludedascase3inthepresentseries;thanksarealsoduetoDr.S.Levine,ProfessorofPediatricsattheNewYorkHospital,forpermissiontoincludesubsequentobservationsmadeonthesamepatient.InCockayne's(1933)comprehensivereviewoftheliteraturerelatingtoinheritedabnormalitiesoftheskin,therearenoexamplesshowingmorethantwofeaturesofthetetrad.OnesuchisthatdescribedbyWindle(1891).Inthisinstance,afemaleofaGermanfamilyfromEisenbach,inwhomdeficiencyofteethwithconicalincisorswasinheritedasasimpledominant,marriedamansufferingfrompolydactyly,andhadtwochildrenwithbothpolydactylyanddentalabnormalities.Thisfamilyisofparticularinterestinshowinghowapossiblelinkageofcharactersmayarise,butthiswillnecessarilybeofextremerarity,sinceitwillrequirethetwocharacterstobeincorres

pondingchromo-somes,thelinkagethenonlyoccurringbymeansofacross-over.(Inthepresentcasesneitherthedentaldefectnorthepolydactylywasinheritedasamendeliandominant.)PiresdeLima(1923)alsorecordsdominantpolydactylyandprematureeruptionofteeth(asseenincase1ofthepresentseries)occurringseparatelyinseveralmembersofafamilyandunitedinonemember.TherearenumerousexamplesofpolydactylyofrecessivetypebeingF65 ARCHIVESOFDISEASEINCHILDHOODassociatedwithabnormalitiesoftheskinanditsappendages,suchasringedhairandmelanodermiadescribedbyMeachen(Cockayne,1933),albinism(Pearsonetal.,1913),epidermolysis(Callomon,1910),anddominantichthyosis(Hofmann,1927),butnoneoftheseshowanyclosesimilaritytothepresentsyndromewiththepossibleexceptionofBetz'scase(Cockayne,1933),inwhichrecessivepolydactylywasassociatednotonlywithanectodermaldefect(aplasiacutiscongenita)butalsowithatresiaofthepulmonaryartery.AlthoughavaTrietyofcongenitalabnormalitiesincludinghypospadias,spinabifida,defectiveauricles,cleftpalate(Emerson,1909),herniae,andcongenitalcysticdiseaseofthekidneys(PorakandDurante,1905),havebeendescribedinassociationwithachondroplasia,theredoesnotappeartobeanyrecognizedtendencyforachondroplasiacstosufferfromeithercongenitalmorbuscordis,ectodermaldefect,orpolydactyly.Theonlysuggestivecaseofwhichanaccounthasbeenfoundisthatofa'polydactylousmonster'founddrownedintheriveratAmsterdamanddissectedbytheanatomistRuysch.TheskeletonwasdescribedbyKerckringinhisSpicilegiumAnatomicumin1670,anditisclearfromthedescriptionandillustrationofboththelongbonesandskullthattheconditionwasinfactachondroplasia.Theinfantboreatotalofthirty-onedigits('inauditahactenusfoecunditate'),sevenoneachhand,eightontherightfootandnineontheleft.Unfortunatelythereisnorecordofeitherthenailsortheheart,butitistemptingtospec

ulatewhetheritwasentirelycoincidencethatthischildshouldhavebeendescribedinthesamecityasthatinwhichcase2ofthepresentserieswasobservedmanygenerationslater.Thefollowingthreecasesarethereforepresentedasexamplesofahithertounclassifiedsyndrome.Thename'chondro-ectodermaldysplasia'istenta-tivelysuggested,asemphasizingtheassociationoftwooutstandingfeatures.(Theterm'chondro-dysplasia'ratherthan'achondroplasia'hasbeenusedindescribingtheosseousconditioninthesepatients,sinceitdiffersincertainrespects,whichwillbediscussedbelow,fromtheclassicalpictureofachondro-plasia.)CasereportsCase1.M.C.,agirl,aged20months,wasreferredtoGuy'sHospitalonMay17,1939,byDr.H.R.Kidner.Sheisthoughttohavebeenfourormoreweekspremature,weighing43lb.(2-200kgm.)atbirth.Pregnancyanddeliverywereuneventful.Atbirth,itwasnotedthatthenailsweredefectiveandthattwoupperincisorteethwerepresent.(Oneoftheselattersubse-quentlyfelloutspontaneouslyandtheotherwasremoved.)Theinfantsucked,breathed,andcriednormally,andhadnotappearedcyanoticordyspnoeicatanytime.Shewasfedondriedmilk,withtheadditionoforangejuiceandcod-liveroilaftertheageofthreemonths.Shehadbeenwellthroughoutinfancy,andhadgainedweightsteadily.Themotherandfatherarebothhealthy,butarefirstcousins,thefather'smotherandmother'smotherbeingsisters.Itwasonlypossibletoexaminethemother,whoisnormal,butsheiswellacquaintedwithalargeproportionofherownandherhusband'snearerrelatives,andknowsofnootherexampleofmicromeliaorectodermaldefectineitherfamily.Physicalexamination(May17,1939.)Awell-nourishedinfant,weighing24lb.(11-64kgm.).Thementalityisnormalforage.Sheisofgoodcolour,withnocyanosisorclubbing.Height745cm.ECTODERMALDEFECTS.-Thenailsofbotlhhandsandfeetshowanextreme66 CHONDRO-ECTODERMALDYSPLASIAFIG.I(aandb).-Frontandbackviewofcase1,aged20months,wit

hnormalcontrolofsameage,showingshortlimbs,longtrunkandpaucityofhair.degreeofdysplasia,andarealtogetherabsentfromthethumb,index,andsixthfingersofbothhands.Thehairisfine,fair,andsparse.(Microscopicalexaminationofahairshowednoabnormality.)Thescalpisdryandscaly,buttheskinelsewhereappearsnormal.FIG.2.-Hands(case1).Polydactylyanddystrophyofnails.REPORTONDENTALCONDITION(Mr.R.E.Rix):UPPERJAW.Theonlyteetheruptedarethefirstandseconddeciduousmolars.Theyareslightlymoreconicalinshapethanarecommonlyseen.Theusualbulboussidesoftheteethareflattenedfromthecervicalmargintotheocclusionsurface.Thecuspsandridgesareaccentuatedandthefissuresdeep,thusgivingacrenatedappearancetotheocclusalsurface.Therearelocalizedswellingsofthegumintheregionofthedeciduouscentralincisorssuggestiveoftheirimminenteruption.67 ARCHIVESOFDISEASEINCHILDHOODThereisnosulcusbetweenthegumpadandthelip.Thelabialmucousmembraneisattachedalongtheridgeinthedeciduousincisorandcanineregions.LOWERJAW.Theonlyteetheruptedarethefirstdeciduousmolars.Theypresentthesamecharacteristicsastheuppermolars.Thegenerallevelofthegumpadisinterruptedbyadepressiononeachsideofthedeciduouslateralincisorregion.Fromthecentreofthegumpadlyingbetweenthesetwodepressionsafraenumlabiiisattachedwhichbifurcatesasitpassesforwardtofusewiththelip.RADIOLOGICALEXAMINATIONOFJAWS:CAACDeciduousteethpresentbutuneruptedECCE66Permanentteethinprocessofcalcification6|6Thereisnoevidenceofanyotherteeth.Inspiteoftheabsenceofteeththejawsarenotsmall,andtheantero-posteriorrelationshipofthejawstoeachotherisnormal.TheSKULLandfaceappearclinicallyandradiologicallynormal,anddonotshowthecharacterstypicallyseeninachondroplasia.Circumferenceofhead44-7cm.Intermeatalmeasure(oververtex)307cm.Externaloccipitalprotuiberancetonasion(oververtex)29cm.LIMBSAND

TRUNK.Thelimbsareextremelyshortinrelationtothelongtrunk,andhavetheproportionsofthoseofanachondroplasiac,theproximalsegmentsbeingmorereducedthanthedistal.Owingtothegreatlengthofthetrunk,however,thereisnodwarfing.Therearesixdigitsoneachhandandfiveoneachfoot.Thesixthfinger(whichissituatedontheulnarsideofthehand)iswellformedandispartiallybutnotcompletelymobile,interferingtoaslightextentwithmanualdexterity.RADIOLOGICALEXAMINATIONofthelongbonesshowtheshort,thickbonesofachondroplasiawithatendencytoexostosisintheregionofthehips.F1G.3.-1Femora(case1),resemblingachondroplasia,withtendencytoexostosisinregionofhips.68II-1%-11II-I. FIG.4.-Leftleg(case1).._FIG.5.-Rightarm(case1). ARCHIVESOFDISEASEINCHILDHOODTheterminalphalangesofthefingersarepoorlydeveloped.Asixthmetacarpalboneispresentontheleft,andthereispartialdivisionofthefifthmetacarpalontheright.Thespineshowsnoabnormality.MEASUREMENTS:Trunklength(seventhcervicaltotipofcoccyx)37cm.(i.e.halfthetotalheight).Circumferenceofchest(nipplelevel)46-5cm.Upperextremity:Acromiontoolecranonprocess115cm.Acromiontoradialstyloid18-5cm.Lowerextremity:Anteriorsuperioriliacspinetomid-patella16-5cm.Anteriorsuperioriliacspinetointernalmalleolus28cm.Circumferenceofabdomen(umbilicallevel)48-5cm.HEART.Theareaofcardiacdullnessextendsfromonefingerbreadthtotherightofthesternum,tothenipplelineinthefifthleftintercostalspace.Therateis100to120perminute.Aloudroughsystolicmurmurisbestheardoverthethirdandfourthintercostalspacestotheleftofthesternum,butisconductedovertheprecordium.ORTHODIAGRAM:heart:M.T.D.8-2cm.Chest:12-2cm.ELECTROCARDIOGRAMnormal.FIG.6.-Skiagramofheart(case1),showingenlargement.OTHEREXAMINATIONS.Thelungs,abdomen,centralnervoussystem,specialsensesandgenitaliawerenormal.TheWassermannreactionwasnegative.Theurine

showedaslighttraceofalbumininonespecimenonlybutnootherabnormality.Case2.M.D.,aboyaged4years3months,wasadmittedtothePaediatricClinicoftheUniversityofAmsterdamonApril5,1939.Hewasbornspontane-ouslyatfullterminJanuary1935,weighing5{lb.(25kgm.).Asecondchild,alsoaboy,bornsubsequently,isquitenormal.Pregnancyanddeliverywereuneventful.-Thechildwasbreast-fedforthreemonths,butgrowthwasim-pairedfrombirth.Thefirstteethappearedaftertheageoftwoyears,andwereofpeculiarshape(seebelow).In1937asixthdigitwasremovedfromtheulnarsideofbothhands.Thechildcontractedwhoopingcoughin193770 CHONDRO-ECTODERMALDYSPLASIAandmeaslesin1938.Theappetitehadalwaysbeenpoor,andtherehadbeenfrequentabdominalcomplaints.Thereisnoconsanguinityoftheparents.Themothersuffersfrombronchialasthma.Nodeformitiesareknownoneithersidethefamily.Physicalexamination(AprilandJune1939).-Thepatientisawell-nourishedboyweighing12kgm.Thementalityisnormalforage,thechildhavingagreatcapacityforclowning.Thecolourisgoodandthereisnocyanosisorclubbing.FIG.7(aandb).-Frontandsideviewofcase2,showingshortlimbs,longtrunk,faciesandpaucityofhair.Thereisabundantperspirationonthehead.Numeroussmalllymph-glandsarepalpableintheneckandgroins.ECTODERMALDEFECTS.Thenailsofallthefingersandtoesaresmallanddystrophic,resemblingsmallscales.Thehairoftheheadisfair,fineandscanty,especiallyinthetemporalandoccipitalregions,andtheeye-browsarescanty.Microscopicalexaminationofahairshowednoabnormality.Thescalpissomewhatdry,buttheskinelsewhereisnormalwiththeexceptionofsomeeczematouspatchesontheface.REPORTONDENTALCONDITION(Mr.W.L.vanAndel):UPPERJAW.Oneitherside,twohypoplasticdeciduousmolarsarepresent.Inaddition,therearetwoconical-shapedcanines.Onecentraldeciduousincisorhaserupted,andonecentraldeciduousincisorisunerupted.Thelateralincisors

areabsent.LOWERJAW.Oneitherside,twohypoplasticdeciduousmolarshaveerupted.Thereareinadditiontwoconical-shapedcaninesandtwocentraldeciduousincisors,thelatterbeingbell-shaped.Thelateralincisorsareabsent.71 ARCHIVESOFDISEASEINCHILDHOODFIG.8.-Hands(case2).Dystrophyofnails.Theimpressionisobtainedthatthefrenulumisaswideasthefourdeciduousincisors;onliftingtheupperlip,thelabialmucousmembraneisseenpassingoverwithoutinterruptionintothemucousmembraneofthepalate,thecentralincisorperforatingthismembrane.RADIOLOGICALEXAMINATIONOFJAWS.Nopermanentincisorsarevisibleineitherjaw,butonlythefirstmolars;inthelowerjaw,onlythefirstpre-molarsandpossiblyapermanentcuspidcanbeseen.SKULL.Theskullisclinicallyandradiologicallysomewhatenlarged,andtheforeheadprominent.Clinically,thefontanelleappearsclosed.Thefaceissmallwithapointedchin,andslightlysunkennasalbridge.Radio-logically,theanteriorfontanelleisstillvisibleandthefrontalsuturepatent.Thesellaturcicaisnormal.Changestypicalofachondroplasiaareabsent.Circumferenceofhead49-2cm.;intermeatalmeasure(oververtex)32cm.;externaloccipitalprotuberancetonasion(oververtex)315cm.FIG.9.-Leftleg(case2).Shortthicktibia;linesofarrestedgrowthatlowerendoffemur.72 CHONDRO-ECTODERMALDYSPLASIALIMBSANDTRUNK.Thelimbsareshortinrelationtothelongtrunk,andtheproportionsarethoseofanachondroplasiac.Ontheulnarsidesofbothhandsascarshowsthesiteofremovalofasixthdigit.Therearefivedigitsonbothfeet.Thehandsaresmallandplump,withshortandshapelessfingers.Theindexfingersdeviatetotheradialside,andthelittlefingersareslightlycurved.Thelowerlimbsarealsoshortandplump,withshortdigits.RADIOLOGICALEXAMINATION.Thelongbonesareshortandthick,butdonototherwiseshowthetypicalstructureofachondroplasicbones.Severallinesofarrestedgrowtharevisible.Theproximaltibialepiphysis

oneithersideispoorlydeveloped.ThemetatarsalandmetacarpalbonesareFIG.10.-Feet(case2).Thickmetatarsals.Dystrophyofterminalphalanges.moretypicalofachondroplasia.Theterminalphalangesofthefingersandtoesarepoorlydeveloped.Thebonesofthewristshowpartialsynostosis;theirnumbercorrespondstotheageofthepatient.Asixthmetacarpalisvisibleontheleft.MEASUREMENTS:Height81cm.Trunklength(seventhcervicalvertebratotipofcoccyx)405cm.(i.e.halfofthetotallength).Circumferenceofchest(nipplelevel)48cm.Circumferenceofabdomen(umbilicallevel)48-2cm.Upperextremity:Acromiontoolecranonprocess(leftandright)14cm.Acromiontoradialstyloid18cm.Lowerextremity:Anteriorsuperioriliacspinetomid-patella(leftandright)19*5cm.Anteriorsuperioriliacspinetointernalmalleolus31cm.HEART.Theareaofcardiacdullnessextendsfromonefingerbreadthtotherightofthesternumtotheleftnipplelineinthefifthintercostalspace.Aloudroughsystolicmurmurisbestheardovertheapex.Theheartrateis80to110perminute.ORTHODIAGRAM.Heart:M.T.D.10cm.Chest:14-6cm.ELECTROCARDIOGRAMnormal.LIVERANDSPLEENpalpable1lfingerbreadthsbelowthecostalmargin.GENITALIA.Penissmall;testiclesundescended.73 ARCHIVESOFDISEASEINCHILDHOODOTHEREXAMINATIONS.Lungs,centralnervoussystem,andspecialsensesnormal.TheWassermannreactionwasnegative,thetuberculintestnegativeandtheurineandstoolsnormal.FIG.11.-Skiagramofheart(case2),showingenlargement.BLOOD.Noanaemia.Differentialbloodcountnormal.Inorganicphosphate4f4mgm.percent.Phosphatase6-8units.Serumcalcium11mgm.percent.Case3.BerniceP.wasadmittedtoBabiesHospital,NewYork,January19,1932,attheageof4years4months.Thecomplaintswere:retardedphysicalgrowth,supernumerarydigits,andsquint.Thefatherwas29yearsofage,livingandwell,andthemother27yearsofage,livingandwell.(Itwaslaterlearnedthatthefatherandmotherarefirstcousins.)Bo

thparentsareofJewishstock.Therehadbeentwopregnancies1,thepatient,and2,amiscarriage,induced,atthreemonths'gestation.Therewasnofamilyhistoryoftuberculosis,syphilis,orofanycongenitalmalformations.Thepatientwasbornattermbydifficultbreechdelivery;weightatbirth,7lb.2oz.(3-235kgm.).Nodifficultyinresuscitation.Shewasbreastfedforthreemonths.Cerealsandsoupwerebegunatfivemonths.Therestofherfeedinghistoryisnotremarkable.Herappetitewasneververygood,butshehadnodigestivedisturbancesandshowednofoodidiosyncrasies.Shesatupaloneatfivemonths;walkedatninemonths.Firsttootheruptedatfourteenmonths,anupperincisor.Forthefirstyearandahalfsheissaidtohavegainedweightsteadily,butatthattimeitwasnoticedthatherheightwassmallforherage.Attwoyearsofageshewas28inches(71-2cm.)tall.(Shedidnotattendschooluntilsevenyearsofage,butsincethattimeshehasalwayskeptupwellwithhercoevalsandhascon-stantlybeeninthe'honourgroup.')Noillnessesofnote.74I CHONDRO-ECTODERMALDYSPLASIA75Physicalexamination(January1932,aged4years4months).Weight,13-60kgm.Height,84cm.(33ins.).Headtoumbilicus,41cm.;umbilicustosole,45cm.Circumferenceofhead,47-5cm.Awell-nourishedbutshortFIG.12(aandb).-Frontandbackviewofcase3,aged4years4months,withnormalcontrolofsameage.Noteshortlimbs,trunkofnormallength,facies.FIG.13.-Lateralviewofcase3showingprominentfrontalregionandlordosis.andabnormallydevelopedgirl.Allfourextremitiesrelativelyshort.Sixfingersoneachhand. ARCHIVESOFDISEASEINCHILDHOODSkinnormal.Nailshypoplastic(seebelow).Nolymph-glandenlargement.Prominentfrontalandparietalbossingofskull,symmetrical.Fixationwithrighteye.Internalsquintoflefteyeofabout20degreesofarc.Spasmofleftinferiorobliquemuscle.Conjunctivae,sclerae,pupilsandeyegroundsnormal.Earsandnosenormal.REPORTBYDENTALCONSULTANT.'Thischild'steethareveryrudi-me

ntaryinform.Thesuperiorandinferiordeciduouslateralincisorsaremissing.Dentalfilmsshowcongenitallackofthedevelopingtoothbudsofthesuperiorandinferiorcentralandlateralincisors.CalcificationoftheFIG.14.-Teethofcase3(aged43years),showinglocationandconicalincisors.deciduousteethseemstobecomplete.Resorptiondoesnotappeartohavebegun.Thedevelopingbudsoftherestofthepermanentteetharepresentanddevelopmentwouldseemtobenormalforachildofthisage.Thereissomedentalcariespresent.Bothrightandleftlateralroentgenogramsshowevidenceofcalcificationinthesubmaxillaryglands.'Nootherabnormalityofbuccalcavityorpharynx.Tonsilspresent.Thyroidisthmuspalpable;enlargementquestionable.Thoraxpoorlydevelopedbutsymmetrical.Noevidenceofabnormalityinheartorlungs.Bloodpressure105/85.Abdomensoft,tympanitic,slightlydistended.Liveredgejustpalpablebelowcostalmargin.Spleennotpalpable.Conspicuousshorteningofallfourextremities.Theextradigitoneachhandisadjacenttothelittlefinger;itisincapableofindependentmotion.Thehandsandfeetarebroadandstubby.Thereismarkedlumbarlordosis.BLOOD.Haemoglobin,14-3grammesper100c.c.;redbloodcells,50millionperc.mm.;whitebloodcells,13,300;polymorphonuclears,74percent;lymphocytes,24percent.;monocytes,1percent.;eosinophils,1percent.Redcellsandplateletsappeartobenormal.URINE.Alkaline;specificgravity,1020;albumin,0;reduction0;acetone,0;occasionalsingleleukocyteandafewepithelialcells.TUBERCULINTEST(Mantoux,0.1mgm.),negative.BLOODCHEMISTRY.Bloodnon-proteinnitrogen,35mgm.per100c.c.sugar,95mgm.per100c.c.Serumcalcium,116mgm.per100c.c.;inorganicphosphate(asphosphorus),4*1mgm.per100c.c.;cholesterol,211mgm.per100c.c.Plasmaalbumin,5-1grammesper100c.c.;fibrinogen,0X26grammes76 CHONDRO-ECTODERMALDYSPLASIAper100c.c.;carbondioxidecombiningpower,36-4volumesper100c.c.Kahntestneg

ative.BASALMETABOLICRATE,416caloriespersq.m.perhour.Totalcalories,23-7perhour.Onaccountoftheabnormalproportionsinthischild'sheightmeasurements,thebasalmetabolismwascalculatedbytwodifferentstandards.UsingheightandweightaccordingtoDubois,theresultis21b7percent.belownormal.However,whenweightaloneisused(Dryer),theresultis+07percent.Inthissituation,thelatterfigureisprobablythemorereliable,sincethepatientpresumablyhasanunusualsurfaceareaasregardsherchronologicalage.RADIOLOGICALREPORT.Thereareextensivemultipleabnormalitiesinthelongbones.Themetacarpalsandphalangesareshort.Bothhandsshowsixfingers,withfusionofthefifthandsixthmetacarpalsontheleft.Thecarpalcentresaresmallonbothsidesandconsistofoneunusuallylargeboneinthecentreofthecarpus,withthreesmallcentresvisibleontheleft,andoneontheright.Theradiiandulnaeareshortandofbizarreshape.Thecorticesarenotthickened,andbearapracticallynormalrelationshiptothemedullarycavities.Bonetrabeculationdoesnotappeartobedefinitelyaltered.Thedistalendsoftheboneshavearaggedlimitingboundary,butprovisionalzonesofcalcifica-FIG.15.-Rightarmofcase3(aged4-Isyears).Shortradiusandulnaofabnormalshape;shallowbowingofhumerus.tionareintactandinnowayresemblerickets.Thehumerishowshallowbowing,withconvexitydirectedposteriorly.Inthefeettheproximalphalangesarevisibleinallfivetoesoneachside.Inthefifthtoeoneachside,onlytheproximalphalanxshowscalcification.Thesameistrueofthefourthtoeontheright,butasmallcentreofossificationcanbeseenontheleftrepresentingthemiddlephalanx.Inthethirdtoethemiddlephalanxshowssomecalcificationoneachside.Inthesecondtoethreephalangescanbeseenoneachside,thoughthedistalphalanxisrudimentary.(Theterminalphalangesofthefingersarealsosmallthroughout,andthedistalphalangesofthefifthandsixthdigitsshownocalcification.)Theme

tatarsalsareshortandthick.Centresforthesemilunar,scaphoidandcuboidbonesarevisibleineachtarsus.Thetibiaeandfibulaearebothshortandheavy.Thedistalossificationcentreofthefibulaisunusuallylargeoneachside,andthereismarkedroughen-ingandirregularcondensationofboneatthedistalendsofbothtibiaeandinthedistaltibialcentreofossification.Thereisapparentlyafusionoftheendsoftheshaftofthefibulaewiththedistalossificationcentreofbothtibiae.Attheproximalendofthelefttibia,asmallexostosisprojectsdownwardandmediallyfromthemedialaspectofthemetaphysis.Theproximalendsofthe77 ARCHIVESOFDISEASEINCHILDHOODtibiaearegreatlywidenedandshowasmall,irregularcentreofossificationsituatedmedially.Incontrasttothis,thedistalendsofthefemoraareapproxi-matelynormalintheantero-posteriorview,withverylittledeformityofthecentresofossification.Thereismoderatecoxavarawithnodislocationofthehips.Inthelateralviewoftheskulltheclinoidprocessesarelarge.Thebonesseemtobeofnormaldensity.Thereisamoderateincreaseinthedigitalmarkings,butnotenoughtowarrantaninterpretationofincreasedintra-cranialpressure.Atthesametime,thesuturelinesareunusuallysmallforachildoffouryears,thecoronalsuturebeingpracticallyclosed.Followingthehorizontalramusofthemandible,fromtheanglethroughtwo-thirdsoftheposteriorportion,thereisastripofabnormaldensityparalleltotheboneandsituatedabout1mm.awayinthesofttissues.Thisstripconsistsofmultiplesmallshadowsofcalciumdensity,clusteredinthreemaingroups.Theinter-pretationoftheseshadowsisuncertain.Thisisaninterestingcombinationofboneandcartilagedystrophy,which,whileresemblingachondroplasia,hasmanyadditionalchangeswhichhardlyFIG.16.-Legs(case3).Shortandheavytibiae,withirregularcondensationofboneatdistalends;exostosisatproximalendoflefttibia.admitsuchasimpleclassification.Thechangesallrepr

esentabnormalitiesofbonegrowth,withtendencytoshorteningofallthelongbones,andperhapsfusionofthecarpalbones,togetherwithspurformationonthelefttibiaandmarkedirregularityofthegrowingendsofthebonesthroughout.Thechangesatthedistalendsofthetibiaeareinterestinganddifficulttointerpret.Adescriptiveclassificationofthesechangeswouldincludechondrodystrophy,polydactylism,andsolitaryexostosisofthelefttibia.NOTEBYDR.A.A.WEECH(February3,1932).'Thischildpresentsacombinationoftwoformsofcongenitalanomaly,thefirstaffectingskeletalgrowthandproducingtheapproximatepictureofchondrodystrophy,theotheraffectingseveralofthetissuesofectodermalorigin.Thechild,thoughfouryearsold,measuresonly33inchesinheight,andthecentralpointofthebodyliesaboutone-halfinchabovethenavel.Thehandshangingatthesidesextendapproximatelyasfarasthegreatertrochanterofthefemur.Theshortening78 CHONDRO-ECTODERMALDYSPLASIAoftheextremitiesisespeciallynoticeableinthefingers.Inadditiontothesupernumerarydigits,whichhavealreadybeendescribed,onefindsanapparentankylosisoftheindexfingersofbothhands.Thenailsofbothfingersandtoesareextraordinarilyhypoplastic.Theyshowingeneralatendencytoconvexityinformandaremorethickenedatthetipthanatthebase.SeveralofthenailsFIG.17.-Hands(case3).PolydactylyanddystrophyQfnails.standoutatananglefromthenailbed.Thesupernumerarydigitsshownonails.Examinationoftheotherectodermaltissuesdisclosesaratherfineheadofhairwithapparentlynormaleyebrowsandeyelashes;thesepartscannotbeconsideredabnormal.Theteethdisclosecone-shapedupperandlowerFIG.18.-Feet(case3).Dystrophyofnails.centralincisorswithabsenceofthelateralincisors,butasidefromcariestheteethintherearofthemoutharenormal.Thereisnonoticeableabnormalityoftheskinitself;thatis,therearenopapularlesionsontheface,thevermilionborderofthelipsisw

elldefined,thesweatandsebaceousglandsarebothapparentlyfunctioningnormally,andbothmammaryglandsarenormally79 ARCHIVESOFDISEASEINCHILDHOODdeveloped.Thereisnothingabnormalintheconfigurationoftheears,andtheconformationoftheheadisnotunusual.Thepatientpresentsaleftinternalstrabismus.'Thepatient'sectodermalanomaliesareinterestinginthatnohereditaryfactorshavebeenuncovered,andinthenatureoftheabnormalitiesoftheteethandnails.Thetypeofteetharethosewhichoccurintheanidrotictypeofectodermaldysplasia,agroupofcasesinwhichthehereditarytransmissionissex-linkedincharacter,whereasthenailsaresimilartothosewhichoccurinso-calledcombineddystrophyofthehairandnails(Clouston,1929;Jacobsen,1928),agroupinwhichthetransmissionismendeliannon-sex-linkedintype.Thepresenceoffactorsfrombothgroupstendstoshowtheimpossibilityofasharpclinicaldifferentiationofsuchanomaliesintorigidcategories.'PROGRESS.Theparentshavesteadilyrefusedtosubmitthechildtoopera-tivecorrectionofstrabismusorresectionofthesupernumerarydigits.ThetonsilsandadenoidswereremovedinOctober1937.Apartfrommeaslesatfiveyearsofage,complicatedbyotitismedia(left),andchickenpoxatnineyearsofage,therehavebeennoimportantillnesses.InMay,1938,whenthepatientwas1Oyearsofage,shewasstudiedatNewYorkHospital.Weight,23-4kgm.Height,114cm.Circumferenceofhead,52cm.Shewasofnormalintelligence.Mostofthephysicalfindingsarecomparabletothosegivenabove,butthereareadditionaldetailsinregardtotheextremities.Botharmsandlegsaremuchshorterthannormalandhaveacontracted,truncatedappearance.Thesofttissuesappearabnormallybulkyforthelengthofthemembers.Motilityofthemusclegroupsisimpaired.Bothhandsarebroadandpudgy,withstubbyfingers.Thereisonlyonefunctioningphalangealjointineachfinger,exceptintheindexfingers,bothofwhicharestiff.Thesupernumeraryfingersap

peartofunctionaswellastheothers.Inthefeet,whicharealsostubby,thefirstandthirdtoesoneachsideoverridethesecondtoe,whichappearsshorterthantherest.Thenailsonallfingersandtoesaredistorted,tinybrownishstructureswhichprojectslightlyupward.Thelaboratorytestsreportedareessentiallynormal,exceptthatthebasalmetabolicrateiscalculatedtobe+35percent.X-rayexaminationshowssixmetacarpalsontheright,andanattempttoformsixontheleft,butthetwolateralonesarefused.Thereisalsofusionofthecapitateandhamateonbothsides.Twoofthemetacarpalsontherightshowdoubleepiphyses.Thefemoraareshortenedandthickened,withirregularepiphyseallinesandspurformation.Nopermanenttoothbudsareseeninthelowerincisorregion.Thefourthandfifthmetatarsalbonesontheleftarefusedproximally,andsimilarbutlessmarkedfusionisseenontheright.Inviewoftheoccurrenceofcongenitalmorbuscordisincases1and2,thepatientwasre-examinedattheNewYorkHospitalinNovember1939,attheageoftwelveyearsonemonth.TheHEARTshowednoenlargementtopercussion,therhythmwasregular,andthesoundsofgoodquality.Inthesupinepositiononlytherewasafaintsystolicmurmur,heardjusttotheleftofthesternum.Themurmurwasinconstantanddisappearedentirelywhenthepatientsatup.Theblood-pressurewas120/90,andthepulserate98.RADIOLOGICALREPORT.Filmandfluoroscopyofthechestshowasymmetricalthorax.Thediaphragmsaresmoothandtheanglesareclear.Theheartisnormalinsize.Thereissomefullnessofthepulmonaryconus.Therearenoabnormalitiesofthebonycage.AnalysisofthesyndromeOsseoussystem.Inallthreecases,thelongbonesareshortandthick,theradiologicalchangescorrespondingmoreorlesscloselytotheclassical80 CHONDRO-ECTODERMALDYSPLASIApictureofachondroplasia,thoughtheadditionalchangesseenincase3makesomequalificationofthediagnosisnecessary.Asisusualinthiscondition,theproximalsegmentsofthelimbstendtobemor

ereducedinlengththanthedistal.Case1showsatendencytoexostosisintheregionofthehips.Case3showsspurformationonthelefttibiaandirregularcondensationatthedistalendsofbothtibiae,withfusionoftheshaftofthefibulawiththedistalcentreofossificationofthetibiaonbothsides,whilstthedistalendsoftheradiiandulnaehavearaggedlimitingboundary.Parsons(1936)hasexpressedtheIIFIG.19.-Skiagramofhands(case1).Sixthmetacarpalpresentonright;fifthleftmeta-carpalpartiallydivided.Dystrophyofterminalphalanges.FIG.20.-Skiagramofhands(case2).Partialsynostosisofcarpalbones.Sixthmeta-carpalpresentonleft.Dystrophyofterminalphalanges.FIG.21.-Skiagramofhands(case3,aged4years4months).Singlelargecarpalboneincentreofcarpus.Sixthmetacarpalpresentinright;fusionoffifthandsixthmetacarpalsonleft.Dystrophyofterminalphalanges.viewthattypicalachondroplasiashouldberegardedasonlyonemanifestationofchondrodystrophy(ormorecorrectly,chondrodysplasia)ofwhichhereditarydeformingchondrodystrophy,Ollier'sdisease,andMorquio'sdiseasearefurtherexamples.Instancessuchascase3,whichshowfeaturesofmorethanonetypeofchondrodystrophy,wouldappeartosubstantiatethisview.Theskullincase1doesnotshowthebrachycephalyandhydrocephalicappearancecommonly(butnotinvariably)seeninachondroplasiaduetoprematurefusionofthebase,andtheradiologicalappearanceandfaciesarenormal.Cases2and3,however,doshowsomeenlargementoftheskullandG81 ARCHIVESOFDISEASEINCHILDHOODdepressionofthenasalbridge,althoughtheskiagramsarenot-altogethertypicalofachondroplasia.Thetrunkinthefirsttwocasesappearsexceptionallylong,notonlyinrelationtotheshortlegsbut(incase1)incomparisonwithanormalcontrol.Inbothcases,thereislittleornolordosisand,attheirpresentages,practicallynodwarfing.Thelengthofthetrunk(seventhcervicalvertebratotipofcoccyx)isinbothinstancesalmostexac

tlyhalfthestandingheight.Incase3,ontheotherhand,bothlordosisanddwarfingarewellmarked.Polydactyly.Thisisremarkablysimilarineachcase,asixthdigitbeingpresentontheulnarsideofeachhandandthefeetbeingunaffected.Incase2theextradigitshavebeenremoved,butincases1and3theyformfunctionalfingerswithamoderatedegreeofmovement,thoughgivingrisetosomeclumsiness;boththesecasesshowradiologicallyaseparatesixthmetacarpalontheleftandapartialdivisionofthefifthmetacarpalontheright(fig.19,20and21).Incase2thereistheremainderofaseparatesixthmetacarpalontheleftandawidefifthmetacarpalontheright.Ineachcasetheterminalphalangesarepoorlydevelopedandcalcified,andthereisatendencytofusionofthecarpalbones.Ectodermaldefects.Inallthreecasesthenailsandteethwereaffected,andincases1and2thehairwasabnormallysparse,althoughshowingnomicro-scopicabnormality.Thesweatglandsappearedtofunctionnormallyineachcase,norwastherechronicrhinitisasisfrequentlyseenintheanidrotictypeofectodermaldysplasia.Weech(above),whoexaminedcase3in1932,consideredthattheabnor-malityoftheteethcorrespondedmostnearlytothatseenintheanidrotictypeofectodermaldysplasia.Thislatterconditionoccurseitherasasex-linkedrecessive,oranincompletedominant(Cockayne,1933),'sparingthefemalesoraffectingthemas'arulelessseverely.'ThedefectofthenailscloselyresemblesthatdescribedbyClouston(1929)andothers,Weech'sobservation(above)beingborneoutbythefactthatcases1and2showinadditionhypotrichosis('hypotrichosisetdystrophiaunguium'),althoughinnonearethedefectsassociatedwithpigmentationoranyevidenceofhypothyroidism.Cockayne(1933)showsthattheexistingfiguresbearouttheassumptionthathypotrichosisetdystrophiaunguiumisadominant,whilstthegreatmajorityoftherecordedcaseshavebeenofFrenchorFrench-Canadianorigin,ifnotactuallyrelated.Innoneofthepresentseri

es,however,isthereevidenceofFrenchdescentordominance.Thethreecasesheredescribedappearthereforetobelongtoatypeofectodermaldysplasiawhichdoesnotcorrespondexactlywithanyonerecog-nizedform,eitherclinicallyorgenetically(seebelow).Congenitalmorbuscordis.Incases1and2,theorthodiagramshowsgrosscardiacenlargement,particularlytotheright,theM.T.D.being8-2cm.(chest12-2cm.)and10cm.(chest14-6cm.)respectively.Aloudsystolicmurmurwaspresentinbothcases,bestheardincase1inthethirdandfourthintercostalspacetotheleftofthesternum,andincase2attheapex.Inneithercasewascyanosisorclubbingobserved,andtherewasnodyspnoea.Apatency82 CHONDRO-ECTODERMALDYSPLASIAoftheseptumventriculorummightaccountforthesignsinbothcases,thoughitwouldbeunusualtogetsuchdegreeofcardiacenlargementwithoutanycardiacsymptoms.Thethirdcasewasinvestigatedbothclinicallyandradiologicallyandnoevidenceofcongenitalmorbuscordisfound,ifthetransientandpositionalsystolicmurmurheardtotheleftofthesternumbedisregarded.Physicaldevelopment.Twooutofthethreechildrenweresmallatbirth,case1weighing4ulb.(2-2kgm.)andcase2weighing51lb.(25kgm.).Case3wasofnormalweight(7lb.3oz.).Apartfromtheirdeformities,allthreechildrenarenowrobustandingoodgeneralhealth.Race.ThethreechildrenareofEnglish,DutchandJewishAmericanextractionrespectively.DiscussionThemostsignificantpointsinthefamilyhistoriesofthesethreecasesarethatintwooutofthreeinstancestheparentswerefirstcousins,andinnocasewereanyofthefeaturesofthesyndromeknowntohaveexistedinrelatives.Thelatterobservationisthemorelikelytobereliablesince,withtheexceptionofcongenitalmorbuscordis,anyoneofthecomponents(ectodermaldefects,chondro-dysplasia,andpolydactyly)wouldalmostcertainlyhaveexcitedcommentinthefamily.Itisthereforestronglysuggestedthatthesyndromehadbeeninheritedasarecessivegeneo

rgenesandhadappeared,apparentlydenovo,ontheunionoftwoindividualsbothcarryingtherecessivecharacter.Itisimpossibleatpresent,inviewofthesmallnumberofcasesobserved,todomorethanspeculateastothemechanismofappearanceofsuchabizarrecollectionofabnormalities.Asindicatedabove,theectodermaldysplasianmustbeconsideredasdistinctbothfromtheanidrotictypewhichoccursasasex-linkedrecessiveorincompletedominant,andfromhypotrichosisetdystrophiaunguium,whichoccursasadominant.Polydactylymayoccuraseitherdominantorrecessive,buttrueachondroplasiaisprobablyanincom-pletedominant(Cockayne,1933),afurtherreasonfordescribingtheosseousconditioninthesecasesnotasclassicalachondroplasiabutas'chondro-dysplasia.'PossiblyalinkageofrecessivegenessuchasthatpostulatedinrelationtotheLaurence-Moon-Biedlsyndrome(Cockayneetal.,1935;Sorsbyetal.,1939)wouldaccountbothforthevarietyofthestructuresinvolvedandfortheextremerarityofthesyndrome.Ifsuchwerethecase,onemightexpecttofindoneormorecomponentsofthesyndromeappearingseparatelyincollaterals.InadditiontotheLaurence-Moon-Biedlsyndrome,andthoseexamplesofectodermaldefectlinkedwithabnormalitiesofthemesodermmentionedabove,conditionswhichexcitecomparisonarearachnodactyly,inwhichthebonyabnormalitiesarefrequentlyassociatedwithcongenitalmorbuscordisanddislocationofthelens;cleido-cranialdysostosis,withassociateddefectsoftheteeth(LaChapelle,1919);andgargoylism(Ellisetal.,1936),inwhichconditionchondro-osteo-dystrophyislinkedwithanumberofmoreorless83 84ARCHIVESOFDISEASEINCHILDHOODconstantabnormalitiesincludingcongenitalopacitiesofthecorneaandhepato-splenomegaly.Eachoftheseconditionsthereforeshowsacombinationofmesodermalandectodermaldefects,anditremainstobeprovedwhethertheyareinfacttheresultofalinkageofgenes,orwhetherasinglegenemayberesponsibleforthe

wholepicture.Summary1.Asyndromeconsistingofectodermaldysplasiaaffectingthehair,nails,andteeth;polydactyly;chondro-dysplasia,andcongenitalmorbuscordis,isdescribed.Nodetailedaccountofthissyndromehasbeenfoundintheliterature.2.Thefullsyndromewasobservedintwochildren,andathirdchildshowedallthecomponentsexcepthypotrichosisandcongenitalmorbuscordis.3.Twoofthepatientswerefemalesandonemale.TheywereofEnglish,DutchandJewishAmericanracerespectively.4.Intwooutof-thethreecases,theparentswerefirstcousins.Nosimilarconditionhadbeenobservedamongstrelatives.Theconditionisheldtobeamendelianrecessive,withoutsex-linkage.ThanksareduetoDr.RustinMcIntoshandDr.S.Levine;andtoDr.E.A.Cockayneforhishelpfulcriticism.REFERENCESCallomon(1910).Arch.Derm.Syph.,Wien,104,292.Clouston,H.R.(1929).Canad.med.Ass.J.,21,18.Cockayne,E.A.(1933).InheritedAbnormalitiesoftheSkinanditsAppendages,London.,Krestin,D.,andSorsby,E.(1935).Quart.J.Med.,4,93.Ellis,R.W.B.,Sheldon,W.P.,andCapon,N.B.(1936).Ibid.,5,119.Emerson,C.P.(1909).Achondroplasia,OslerandMacrae'sModernMedicine,London,6,683.Hofmann,E.(1927).Zbl.Haut-u.GeschlKr.,23,619.Jacobsen,A.W.(1928).J.Amer.med.Ass.,90,686.Kerckring,T.(1670).SpicilegiumAnatomicum,Amsterdam.LaChapelle,E.H.(1918).Thesis,Leyden.McIntosh,R.(1933).HoltandHowland,DiseasesofInfancyandChildhood,tenthed.,NewYork,362.Parsons,L.G.(1936).Achondroplasia,Brit.EncyclopaediaofMed.Practice,1,135.London.Pearson,K.,Nettleship,E.,andUsher,C.H.(1913).DrapersCo.Res.Mem.,BiometricSer.9,AlbinisminMan,London.PiresdeLima,J.A.(1923).Bull.Soc.Anthrop.Paris,4,71.Porak,C.,andDurante,G.(1905).NouvelleIconographiedelaSalpetrie're,17,481.Sorsby,A.,Avery,H.,andCockayne,E.A.(1939).Quart.J.Med.,8,51.Weech,A.A.(1929).Amer.J.Dis.Child.,37,766.Windle,B.C.A.(1891).J.Linn.Soc.(Zool.),23,473.