Mitral Stenosis in
an
Atypical Case of Gargoylism:
A Case Report with Pathologic and Histochemical
Studies of the Cardiac Tissues
By
PETER
W.
VANACE, M.D., SIDNEY FRIED-MAN.
BERNARD M. WAAGNER, M.D.
M.D.,
A-ND
Severe alterations of cardiac tissue oci'ur
association with couuiplete mind incoamplete
formos of gargoyhisini. It is the purpose of this paper to record the clinical, pathologic,
and histochemtnical findings in the cardiovescular systei of a child with an atypical forim
of gargovlisml and m:litral stenosis.
in
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IN 1948, Linddsay emphasized the frequency
of cardiac involvenent ini gargoylismr, anid
reported the first case with m-nitral steinosis at
autopsy.1 SubsequLently, the cardiac alterations in typical as well as atypical or incomlplete fornms of this disorder have b)een ie-
imiitral stelnosis. The findinigs in this ease are
compared with similar clinieal and pathologic
observations in the literatuLre.
Case Report
The patient was a white boy knowni to have an
atypical variety of congenital chondrodystrophy.
lie was first admiiitted to The Children's Hospital
of Philadelphia at the age of 5 vears for cardiac
evaluation shortly after the discovery of a cardiac
niiurniur and cardiomeg'alv associated with dimniiinished exercise tolerance. He died 4 mwonths later
in acute congestive heart failure, a few hours after
the onset of an intercurrent respiratory tract infection.
Both parents and a 3-year-old brother were niormnal and healthy. There had been no previous
miscarriages. No history of consangnuinity could
be elicited; both maternal clnd paternal grandparcaits wer e Jewish and had immliiigrated from-l the
saine localitv in eastern Europe.
The patienit was borii following an 8-imioath
plegnanmcy which was term:linated premuaturely beause. of placenta praevia. Following the onset of
v-agrinal bleeding, during the second month of pregnancy, the muother received dailv oral "hornione"
miiedication. The birth weight was 2,210 Gin.;
there wer e no immllwediate neonatal difficulties.
Physical examiination ini the nursery revealed
small, square hands and feet, short upper extrei=nities, and a position of extension of all extremnities.
No cardiac abnormiialities were noted at this timne.
Roentgenogramns of the long bones were reported to
be noramal. Ineubator care was inainitained for 3
weeks following' which the patienit was diseharged
weighing 2',515 Gm.
The patie-nt fed poorly and gained weight slowly
(lurling the first few imiouiths of life. Beginning' at
thle ag-e of 2 m:onths, episodes of "'croup" occurred
fr equentlv. The inifanlt seemed alert and showed
nio -loss retardation in uweuroiuscular developmi=enit
ported.2-4
In 1932 Brante demnonstrated that the basic
abnormality in gargoylismi is related to the
deposition of acid mucopoly-saceharide substanees ini various tissues. This observationi has
been substanitiated bv a nrumber of chemimal
and histochemuieal studies.58)- Nevertheless,
little information is avTailable at present concerning the chemaieal amid histochemical alterations of the cardiovascular tissues in gar goylism. Although the inicidenee of typical
gargoylism is lmNo, the study of such patients
may yield infornmatioln that muay perniiit the
diagnosis in initerniediate or atypleal ca,es
anid inay give futrther insight concerning' tile
pathogenesis of other disorders of connecetive
tissue.
It is the purpose of this report to iecord
the clinical, patholofgic, anid Iiistoeheuicieal
findings in the cardiovascular svstemii of a 51,2year-old child with an inieomplete or atypical
formn of gargoylism. who demonstrated severe
Froni the I)iv-isions of Pathology and Carldiology,
The Children 's Hospital of Philadelplhia, and the
Department of Pecliatriics, Schlool of M[ed icinule, Uimv'ersity of Penarlsylvaidia, Philadelphlia, Pa.
This study was supported in part l' -r.S.
Health Service Grant H -432(C).
Pul,dic
8o
Cireulation, Volume XXI, Janutary 196"J
G1ARG
1O( Yl A SAI
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(iiii'iig tLe first yea i'. Teatintent withi ortlhopedic
A
a ppllIanCes pu1as
nimstituted beca-tiuse of a. dorsiflexion
d(1f(orinitv of the feet. At thle <age of 11 imonths,
the 1)atient -w,as llospit-lizedl for .31/2 weeks for
t
tre-vatilalet of diarrlhela'. Plhy'sical exaaination
i1cve-aledl shoit ans, vide aild short feet and hlnds,
atl d externa .l ro1ttion of the hi1) joitts. tflec extr-eiities Wuere held sonlewlhnt rigid; and ito teeth
hIad etullpted. Blodv iiieasul(llaents ere as follows
h (
7 7it
lit,
hevighlt, (il-lc7 weig.;
G 1.; hiead circunltferlence, 41.3 (111.; abdo nittial ('i(utinfterelte, 38.1
Th1 ifnilt (co1ld(1 sit alone while leallingl forrlJll.
1(1isd ) itIh lls thmllllb) alld foreward. a11nd(1 go
filln(l, lunt wais unablle to rioll over fr-omni Iii back
to hiis abdomen. Plroteti-bound iodine.> nild 111 ulptake itiastirt-ments w 'i'e normal. ioentoenog'raials
ol 'Vic
tho uppei' e(xtreliiti('s shlowved 110 ossifiention fol
thie carl)al hones. Tlhe Spine, i'il)s, ald clavicles
w\veiv noiittgenoglt phicalix ininal. Thie bones of
thle' hainds 'wereT gos'i08Sl\v albnlorml-1. '1lle ItietacaiphlIdn-ges wer-e broad nd111(
palS a1d(1 pi
sht(a.; tlhe m iddle 1)118ll-nges presented aI bi'oa d b1ase
d111(1 Were talpered at tfeIlistvlidl ens. 'I'li l)oin's of
tle forea x118 were shlort a iid soinewblat tilickenexd
thle h1Umercf-i were nlol-1 . Roetget(ograns (of tle
othfelr lower.- extlemllitie^s wNt'tei iiorital excelpt for the
IPet, xhicli siowed c1iaitgi-cs Sitinlar to thiose in th e
Il1,i1(ls. Tlwt roeit-tglno-rap)ltic diai-noses were tiehIved e}piplh\ steal olsl:sification and dyvsostosP,
ii iiltiAfter disclharge
f
pIlex involving thl lhands nindIeet.
flmil thle hlospital, phlysical '1(l lleurolllsellbar
growth1H111(d (devehlopiient contillued at a slow pace.
Tue ptatienlt (lid niot walk ahoneuiinitil the ageof 2
e.1i is. i1
epeated attaks (If' '"(ro111'!.'spcallyj1
(filill" thle winte(r m1ontlhs, w(vre tll' on1ly ittercul'ilet il1lnesses.
iXA PPlr&oximatel>t] 8 1outlihs pilot' to admnission tin
pa-Itient began to sliox ('11sv' filtigmtl)1bit , cyano,si s,
an1d (lsplleli thlat beceamle p)rl-og'ssivelxy Wlrsel. Ermolitillaltioui llis('loo-etd(l11(} card
1111111ui'ns. Upoll
r'e-exatimlintion a few weeks pri'or to admission to
The1 Ch1ildillen's I Hospittll (If Philadelphlia, a loud(1
l)i'ccoi'dili sy stolic iunllil-ilr w11s inote(l fo til(' first
tijjj(' I)N, t1j(, SX1ljl(., l:)fi\7Si 11ll
On adiniission to the hospital the patient had cn
highpl-itchled vievi, scemiaed vI>y sn11111 for Ilis chronllolog'ical age, and ws- of' loilll. inite(lligeller'. The
('vIts wee1 w7' idely' sp11cedI; thew e w\'1s an unusual
1il ount (If hI<ii (In tlOle face, particulirlyli about the
(vylb)rows (fig'. 1). Thie body weFight wa.s 14.9 Kg.;
t1he body length,i 99 ('iMi. Thi' lictiol (If thel tT'U1iuk
leig-t1l to thie telletil of ti1e( lIoNei' e(xtrenliities was
1.27, wlhhlih is withinii thew o1(110l mange. Thpe1 pltilet
wa-lked on hiis, toes with hiis hiips in external rotatioiI. Tiis `tiptoe"' gait wIs due to contr'lletur("
(If both Aclillles tendons. Th1e-re weic contallctu('s
inI flexion (I)f' I1(1(st 1111 i IjOl
a
joiitnts, with tigtitness
Circutlation, Volume XXI, January 1960
81
]Figure 1
oTbc h1(1ad 01(/ ]o ce of p)otilent (it, o(otojf,it. Note tilt
(1/ tile dfceI. c of' k1pertelosm and tite hisittism
of' the fa-ce.
o,, th1e Soft tisli(s (,'Sp)'i('1a,y)Iii the partaspinial re11
ovi(It an d bout
th,e tIltio.'cil vaige.
Eixatninationl
(If the ('-N(' t('revaled eitdophlthtliitos a1ld( limitilltionl
of ullplpr --tze, p)irob,lbly atttiibutable to the ahitOlrltial alaitomvtI\ of his otbits. No eorltical opaciti('s NwIre nolteld, but slit-lamp) 'Xallitiniiltion wals Ilst
done. The blood p)ressui'e ini tll' ulpl)er extreittities
Nva1i 110/72, and the fentntoral (11(1d balbhial pulses
\NVt111(1 tlIl0ittl. Thiere wats slighit evz)mnosis of the
iliLl('l(115 itt(iltbi'brtiles 111d nailbeds, but ill) (lubbing'.
TI'he heart wtts (n'largedl to thie left b)v percussioll.
'flIe, (c.ad-dio'i 1ute alnd ritlftliti wace norital ; the pullolnii' seecoi(l sound w.as accentuated and not redupliaeloted. A- loud high-pitched systolic tiiurnliur
Of blowing' qnutlitv, aulible over the enitire precor(dillut, was loudest at the apex and wafs transnmitted
to tlec left aixilla amid to thie blick oti the, left side.
[it adl(litiont, a soft, high-litehed, earl)' dialstolic,
blowxxilltg' itiuiiltull wus IludhiblI' to the left of the
upper' stcturiiiii. This itiuriIiuri had tlte characteristic qu;alitv of' a utOuriIIur of setitilunar insufficiency.
No tlllls were felt. The lunigs were clear; the
li-Vel w.ts palpable 2 ('iii. below the right costal
litaigili Ill tll' utidelxvicnulari il'e. The remainder
oIf tlte p)hsical examitiiation wasun;iremartlXkable.
The bloo1 stul(iies (loit admiissioti wcere normal exepIt for a wlite cell eount (If 17,900 per mni.1 mind
ai serumil albuitinii of 3.51' arid glohunin (If 4.0 Gm. pet
elit. SeIru it (it olester'ol, ol(stt'rol e'stem's, ceplia-
VANACE, FRIEDMAN, WA-GNER
82
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Figure 2
Rtoentgenograms of the chest. A moderate degree of cardiac enlar-gement of (a diffuse
natuere is aplpaurent.
Figure 3
Left. Photograph of right hanxd taiken at autopsy. The hand is short and spade-shaped,
the fingers tatper tolward the dlistal ends. The fifth finger showvs moderate incurvotion.
Rigfht. Ioentgenogramn of hands of the same patient, taken a few months prior to death,
demonstrfacting the presence of only 2 ossified carpal bonies, short aind broad metacarpals,
(and the tlistal tapering of the phalangeoil bones.
.ill flOenulation, and tlhy iiol turbidity, ery-throev i
s-diiettitton r'ate, priote'il-bounid iodine1, a 111
streptoeocac,ll antibody titers were all ait normal lexvels.
Roentgenograp1)11iC exam inn tion revelveled moder]
alte generalized enlargenment of the heart (fig. 2).
The wrists (lenlonstrated only 2 earpal bonies, w-hihi
pJaieed the pa)-tient in the tenth percentile among
4-year-old bo-s. All of thie phaulanges aind eietcairpal bones w1ere abnorimially short. There waus
tapering of the distal. ends of each phalanx of all
(igits' , anid a tendeniey towward tapering- of the proxijmi I e nids; of the metacarptals was iiotetl (fig. 3).
-fta the feet, 6 ts] (enters plus the secMonleid cunei-
were l)resent, in(licatim,g a bone age of 4
riv
years. The tatrsoncavicular cemiter wvas niot ossified.
The head of the rladius had niot ossified in either
elbow, but there was easrlv ossification of the patella, both of whlieh are 5-year-old centers. The
hips anid pelvis were normtial. The dorsolumblar
spine revealled wedging, of the anterior body of the
third lumbar xertebra, narroxwing of the interspaces
of the thoracic spine, anid slight kyphosis.
The electrocardiogram (fig. 4) revealed right
axis deviatioii and right ventricular hypertrophy.
The P wa-v-es were tall and pea-ked, indicating atrial
enlairemient. A. phoniocardio-raphie tralcing recorded ait time car(liac a pex demonstrated at short
Circulation, VoOlue XXI, January 1960
GARGOYLISM
883
41
AVR
aWL
aVr
I
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r
-J
vi vs~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~l4, .
s.i
rigure 4
rec'ord(ed tj tiooths prior to d(fleh. PIghit. Sroiad tIIiciiPY 0reco.edh
(it the so mte time from the e0 tv/die apea . Th/u aamt rts .1 0(1 '2 jodicate ftche H tt smon juts
})re.svstoli(' mUnaur-ii In addlitioii to the hiolos-ystolic
mturmiiur (fig. 4).
Be,cauise of' sign1s, oft incipient congestive heart,
failure, the patietit wa,s dlig-ita-lized. One miouith
aifter a(dmission lie wa-,s, discharged fronti the hospital oni a niatintenance tio)se of digitalis, and propihy
lactic, doses of oral penicillin. Ora-.l diuretics w-ere
later added but Providled little relief of syinptoimis.
Four months later, the l)atient developed bradycardia and the dosage of-- dig4ittalis wvas reducedl. AN
few%. days late~r, however, signs of' an upper respiratory tract iiitcctioin appeared and were followed
shortly by severe resJ),ira tory distress anld tacehvcardia. Ott r-e-enitry' to thie hiospital the pattienit wa,s
g-reatly ag-itated, severely evanuotic, anid appea-red
in acute congestive hieart fiail'.ure. Ilie died several
niinutes after adaiiissioni. The final clinical iopicssioii was ani a-typical formi of g-argovlisia anid conigrestive heart failure.
At postinortemn examination the body NN ciglied
14.15 Kgr. anld measured 99 cin. (heel to crowx a).
The mueous membranles were imoderatt'lv e'vano'tic'
anid there wasi,, slighit pitting edemia over theloe
extremities.
Thfli'heart weighied 250 Gmi. The righlt atrium
wa,,s niorimal ini sIZE w\ithaii waill thickness o)f 01.3 em.
and1( showed 110 abitorimal 'otainuniication wvith tihe
Circulation, Vol/umc XXI, January 1.960
left atriuia. The tri'ieusl)i(l xalve wans itoriti. except for. a 'atoll, firm, White nodule iiea".suring. 1
by' I iiima. omi the right atria-l aspect of the aiteio)
medial leaflet. The ri'-iht vxent-riele was moderately
dilated and by pertrophided, and was I- eta. thick.
The puhimommary' valOve xwas slightly' thickened at its
edges anid measured 7 cmi. ini circunieireiiee. Tw~o,
siiiall,1 thickened sclerotic area,(s WereI totted in the
intimna. of the left puhmiionary' artery' just j)roxiiiial1
to its enti-vx inito the lift himmig1. The1 dinitit arteriousli
wvts niot l)iiteiit. Tihie left atriinii wxas mxoder:itely
dlilatedi and hypertrophied; thev xvll -was 0.5 cii.
thicek. Th-e, eiidocardinm xvas miioderately thickened.
'[he miitr-al valdve (fig. .5) xvais ima ukedly' thickened
and was niade Up of a, pficaited, irregular imass
Ini xvhich the bounldaries of. the x'alve le"aflets could
niot be dleliiieatedl. '[it a interotiedial a.spect of this
valve presenited a, siill,-I triang11ular ompelimig inito the
left ventiricle iieasuri'iig, 5 by 5 by 2 miot. A thini
himmar
iidoardal jet lesion" iv;as noted (ii the(
l)ostelroinledi:1l wall of.thle left ventriti i beginning
ait tih. aitral orifice tind ending at the apex of thel-eft veiitricel. '[hit left ventricle, wits stoaller titani
normal in size and the tiuscular wall measured (0.9
cini. in thickntess. '[le etniocardiumi was moderately
thickened. 'Thi p)apilhiry iliuschles of. time mIiiti'1
v'aive wer-e drawvn togethier aind thit'kemied aind flit'
84
-VA.NA(.',E, FRIEDMAN, AVAONER
I
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Figure 5
f/iiq f/i Ii ft 0/rill in, mi/nil
mit/o)oy. Ieft. Section 1d1h111
tht, iifiiil in/ce. Tih
r11r0) (1n(d1 left Pritttie/c. I'tobe is seeti to /1115s throng/h orifc of 1to
iilfocmtvdiil f/i ic/eitt olt of f/toe lof t /rIomta ond loft entr It tc iiil f/it diffi.sc plic led thIicnicit if'
tof/e( iitial raio
1 ore pClj)rieitt.
n
Boight. Close up ion U f/i f in itiiif
(enIt(
markv/oil/i t/hickene d nlce leQi Is, the fnuion of tie Iofh(tsi, IlMid the
olrific e. Note t ate
specimeio
(Gloss
4 toe leien it of
t/iiu tened tolled
MV,
(
(af/i
s iidjaceutf
to tie small rvMi1ining uit vol ortficc The fifti vs 1
viii
Id LV i tdic(fte the le(ft ati iiiton, mtitrl
ic/f ci nric1cv sjJ iei,t.
c/, itnd(lI't
ho-rdace tendilleae Were shortelelil aild shi-tlvbtix
thiekened. The norftic valve, the coiroliln' ostin, the
coronary tarteries, and theirta Were normal. The
ren'lll<tainnur enldon1aildiut., epi,eardiu;n, and pericailldiutta -wer1e not abnormaml, aitld the Imyocardiu;n o1
liioth ventricles was Imlilderatelv lirm' In consistellne.
A.11 tissuie sectionls weve imminediately p)he(d1 inI
co)ldd7neutral forinalin antd fixed at 4 C. IBloeks of
tissue fron the lhecart ittlileil
1)dedboth atri ati
apppendlages, ventrieles, "j)icarudiunt, a iid coronarIx
arteries. Alultiple sections wx ere taken of all valves,
illeludilln the ann
Il1ulus, Clhoche tendiinele andp1apillarv ituslcies. P lle tissues Wer1le embeddedlit pa raffini anid cut in serial s,etions front 4 to 6 1 in
thicikness-. Rou)ltinIte sta inin-u ])pr(tcedu re(s included
elsftic'a-Vanl C ieson-, he;1atiixvin and cosilln, Ailder
silv er, and phllosphotungstie etci(l heiatoxy lin. The
histochlendcal aIndl enzymle dligestiin technlie at1 i
ploIed have been 'previousliy described.h"
MIcspei,cOst
())ix , the hleanrt showxed iioiderate livpertrophy of the ventricular. ,nvofibers. Scattered
focal clusters of pale-sta,inlingp tlnilliUelcear cells
were present in the interstitial Colillective tissSue.
These cells showed regular, oval nuclei witlh secat
tered chrontatin and failit, granular, eositlophilic
cytoplasit;. A11inlcleal':se in collIhagen fibers was obsieved in the suhbendicardiu;o, adjaceent to the ndi-
1,
tritl ani puftnant
uli
vx lves. TIe end1oc rditnitt of
thet left a1triuml, p)ndage,;t11n(i left ventricle WaIs
thickened because iiof ni incealense in col tt gen a11(a
ela,stic tibet's. The upien(fi;itim and prvvil-d1adiUMttt
shoxwed Hi) abttortttl) ities.
The mittitl vxnlve (figs. 6 to 8) w,-ais thtickened andl
(istorted as aI result of intel-er.cillac fI aIscicles of colliaen fibers irrged in dense b)1u les at the m1litral
sulcus tnd lit the peipheriaIl )olitions of the valve
leafle ts. These thickened fiheits extended to the
ittIetl Por)itio)n of the x ye s:ltstanel where they
blended witlttihn tttnl)rphullis grlituntl substanice eottlinin'-, isol't"teel, Stellate-hli)tIptl itononuelear cells.
Ttite stellite-like cells v-ee-, ustittill hIt l)erchromlaItic
w\itlh little olr nio c\-toplIl)ts soile a,Ippeared to htave
( pertlnutrletal
hfnlo. The centt;.1;1 colemiio;fttorpltous
iaterial in the vtalv-e, leaflets coifttinedl thiln wvidelv
separated t rg,'>o'philic' fnibils atidfragmented co1laget,ne fiberls. The dense collttgenizaitiont of the pe!ripheral vxaixe nia rgins, continued to involve the
chlorda.e an.d the, upper) politionts of' the papillatry
muscles. The changes nited ill the liulitolt'l),,ve wxere due to 1a
vR
t11es ill coAllaen li hers in
focafil are-as. The aortiortc al tricuspid vtlvex swee
questiortably altered.
Table I slhows the htisto,ltettcalI studies eiploxved
Ill Itll attel-l)t to cltaracterize tte al.terations ill tle
Circulation, Volume Xxi, January 1960
(1ARI(-IOYFLASM
85
Table 1
(Ir (it It d ¼-ibst(o
IJlnlf i-i rIl
rti
ifitt
f
cc
Jlliti-trl ValIr
lif copolysaclJh al itlc
Toloidine 1 1110
Periolic ;vl-Sellif
(1
n01tit-t)l
+-+-+ (oetavliroumasia
+++
Colloidal i1101) (lI'io)]ic
i ffuse stni oiog
1101i( Seliiff
Alcian blue 8G1 8++
Testielda11 !1111oitolil:is'l;1- Idigest iolI
Li/)ipd
811(1:d11 black 14I eglItiX e
sulfate
Nile 1e11w
negatiVe
Suda 1 1 V
ikegativ c
IPr0t Ui
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A,ailiie lIllue (111011))troj, 211
Ninhydri n1kS (iif
reaectiot
s11 ial 8- 8
Suopplied
liegat ae to +
grolps
by
tories, Newx. eler.sex.
1l1itn'1ll
V,-llN't'.
---+
ilega t.ix e
\Wortlinigtoll
Iti ochemiieal [nd(ll
Then1(sslim-pholl(US -1'(IIllound
wls InlllOtiIhlm11111ti
tlll
t4)lUldicllC d)1 1111( 1gv.
hlff re.1etioln. 1lthe lega1)Sitivetpeijodie acid Si
tive Selhiff control and1(1 )h1011X lh> drazille-blocking
Ireactionss, ggest thit the p)li((die a id-Sehifif positivity mava be due to po1lysa1('c11i-ide icate tial. A1c*i.ll-W-)le' dl\-t Wa.s llllaiIIII-II] I.)I (csellt ill t1'(haStil
roi tic. The ((olh)(101l iro ii ietliod
W'Il'(e iiietnt(li'
was (1liftuse ill stainn the' tiitil.e' str0)o
of the
v,alve a blue color. Testicular livalutr-onidase talled
to remiiove the substa noes resp)llsihle for the tolui)d lIlet1cIlr((11111si11 11( 1(a i'11-11 lue l)ositilvitXTe
diiie-ble
Attempts to (elmOlnstlilte lieutr-al tat .11d 1)11(sp)11lipids were inega1tive. Tile tesults (11 the inethods
1ist(d foir the demonstraftion of pr-oteins valrie(l
1111 -iaiegtive to wea1klV- positiX .
withi
-
F(0,11 1r1011s 0of eiidotllelial prloliferl'ltio(11 Nve10 o0C('ISioiitdly(.\ lI(oted ill the( vpieawli'[ditd 'o-'0mia-l',v artteries.
Scatter-ed, isolalted ilItlil-a}llvo('idiail iI-ttelies delioniof Ege 11on1on1ifle00 Ir
at1ltedl SUbilItiIllill 0(11lhti((11s Ioi
v1 ()lallted oIll-rilnhlilr ('3yt(opls181.
(cells witihlpale,
i
'1'ie evtoplasnll ill these cells WIls tililltlIy lltIetllo()lliltinf aInd pelriodic 11d1(1-Schiff neg-ative wh-lile the
cell borlders weire (c'4101'i llOtilOllrOllllnti
c 1 peJ)0(dic ibtid
Schift 1)o(sitiv\e^. The ilOltil X118 nolt 1im11180111.
1 I11and
'flie hlngs sliowell 1m1r1ked1 l)UllIl1oIUY, (1(1n
n1un11e10ts heart-flilurt' 1m1onoilluleax ce'lls ill the
aIveolal' spaces. M1any (of the p1ul11ionat-v vessels
showed mlodoaete to ima-rked degrT(sS (f medial
thickeninig aind ilIti 1011l 1i POI')1 aSi0 Colnsistenlit witi
a maiiakeol degree of puhll((llamonary hypl)tensioll.
There wXVs a striking laIck of micrioscopic allteraCirculation, Volume XXI, January 1960
a
iPhutoolcloql)'la1Jl)
Figure 6
theil(ft side of tile hietrat.
Ntoe tIlt 11odl1teen0£doealdidal thictkening of tilt
lte f t ftrin ; thetllicit 1ti! If tihe mi tra1 l'alt/
(111(1
filt( tled thiitlei?lg e(en(d shortleIiIg ol tile
hl0ordttt Itffdilette. 7/h oel?,rl.t3r
(s
r/ iv
ill this
stetioll 4)0)) no sit,lllificallt c-Illlgtes. JematoxJylil
(sil, sta(i-n; X 40.
(1d co
the spleen ndfv111rl
or. Flie costochoiidral
julIlctiol o(f thie ribls (fig. 9) sIoXwXd0 1 11a ked dis0l'glllIizntionl o1f cl(l0ll'm(idr tes with 11 loss of noriIItll
I,Iarelite('Atlll'. BoneP:O'IIlt(l
Fom.A1 1S lle8bli
(11 d inlco,llllhtt.
tioniS ill
Discussion
'T'l.e safliet eh.inealt1
n
finldinigs li this patienit
1 .tN
i1m11d
llapi hll ('11011(drodstrlo)lIV inlvoIi11g_ pIt'iniar'ily tel(-} liai(ds aittl feet, a 0ecilliai' faieies, 81(1 liven'e11 111'gellellt. rhp
p)altlIologic( ffinoiiogs ill the lilealt aitid at thte
ostoc(Ioin(liral jll tiolls ai11'0 (eoisistentt withl
tile (liagl(osis (of .11n atypical or incoinplete
for-Im of gargoyvisnm. Thiis case, we believe
is thlie se1)1( r'et'omrdedl Jproved instacee of
llitil stenosis asslso(iate(l witli gargoylisnm and
the fir'st assol(iated \w7ith ani incomnplete or
atypical form.
V6AVANA(E. FRIE D.AAN'. A GINEl4,R
86
Figure
/P
uot
i-rof
ii
t
ph'ii of
7
C oroI/tf.
not)ii.
(
i,PJiu
oituir
-
S.-illt; X1008.
f}9'01i'{(ic
t
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2n.tiE
i,e i#;,ca$\t.,W2Ug
ML%&#"
gg2''
g
i't
EE'iE
E'
-,8iEs
of v\(alxlart alterationls.
rI-gure
qi.isf'vpl sof
0lh
i
f
tin(t
uT
c1i.s)
aln l
(
tf
ad.ild Scib
il
2-
c
ilth
lt
t,
h11ave
l.
ati
'
l0ii
jci
i
uC l idtai
ti'i.
-
001
-1(
C
m
Qgo
ti
d
O
to-
tiiit,
JP
iotit
4 O.l.
I)cscriprilons,
associates,
ne r
-stiilni
tf
pafiholog,ic~changles
(eain-diovasentlar' 5s>stern
(goylisun
niiinf
l
ulo r
lhitt J(
.
kc
t ?(
nott,
lI
iF
X
i?;
/t(
the initial
ti
f/i th
fcc ls
('et
(iit
ig
lit
btarr
inn
typia.cal
Ireliorted
Stranrss
( eases
inn.
of
Lillnrdsalv
by
Jlet
(tianiw
tIre
garl-
antiu
ler-soii et
Enriantnellue1. Although A.tll tissue Ilayinav be artic led iii varyillng
tllhe changto,es that occ.ur ilr the vatlves,
(e'rs of tIre heart
degrees,
the elitloeladial liningI0 Of the
th
oonary
(cor
essels
art'
ehambers, an(d
usually
mi1ost promii-
irent. Valvlarh- involv eennt itray be, sing'le or
ilrultip)le ; thel mnitrlA ar(i aortie valves ar-e
ro(le
lly affe eted tlian- tlhct' }mlm om tnav
anI tritcspitl. C rossl
the valve leaflets. are
I
llckerrlleti
ith-ir frIet'
nrtLd contllainc
ed(Jes. The
1)e(e10o1W thiokened as well as shtort.eniei. Mi.cros;)ieal flytl)ickeniig t111nd collagenization of
thei strorIna of
t
fc(
valve leaflets oceur. witlh
varvin- numinbers of vaeuiolated mononueleart
l
(elIs scattered
within this striloma. TPhe enidot(ardial inl vol veutenrt is uisually limited to tire
left sidle of thle lheart an-id may result iii a
tiegryee. of enrdoearadial thie.kenring siimiilar to
th-alt otblseredl iii enildoeardial fibroolastosis.' 1
.l1itimiial proliferation and varving degrees of
OelsiSiOn may8iV oeenIr ill malny of the larger and
sialler coronarv\Vessels.
Thie eardiovasenilarfindinogs at autojpsy iln
atypi'al or iiitermediate forms of gargoylism
have been infrequiently repor-ted. Lindsay and(I
eowAV(o-rkersi' an(i Straluss and1e 1]latt'' reported
obse.rvat.ionl,s ill 4½/-monlth-old anid 5-nlonthlold inlfanl-ts, botll of AvlhoII demonstrated th1
tvp1ieal eardiae ehaaiges but none of the associatedl eMterlman11COallifestatiolls eonllsidere(l
tI of this disorder. Steed1'deseribed 83
as;exs, txx ills al' 81/2 years aidl a lrother age
7 years, who are apparent]> still living. Thelwse1
8- ehildre'llr wev(e'(, (elassified as, atsypical eases
;rnrd all hiad w eli doeuinrenrtedl (linieal evideltee
Sim dil nlo d(ullationlls
ehortlae
teir(tinieae
aldo n)
also
'firii alterations of car-diae tfissuie ii ouir ease
W1ere i.dentieal to those deseribed in other
tttsis (Of gargolxy0lis
I1s anid are the, most severec
elianges vet d.escribed in the eardiae valve-s
of an atx pieal 0r intermediate foi-irm of this
disord er. AltIn onugh tire path ologic alteration1s
iii thle heart arid eostoehondral juncetions of
tli(r ribs wx-ere eonrsisterrt w ith a proloitged
l)eriod of tisste reaet ivity, cl inical evidence
of heart disease was irot nioted inn our patienit
irirtil applroxinrately 6 miioniths prior to death.
'T he pat it,V of tvpi.eal large vae nol ated iono1m11i1(tar eetlIs andt asso"_) iated eonnective-tissue
ehariges in otber organs,sluceth as the liver and1
spleeni emphl)hasized the variability of organ
in\volvement inn this disorder.
'Itle hasie almormality in gargoylism, first
tIennonstrated by B3ranite,'1 is apparenitly relate( to the aeenulmatiomr of aeid mucopolysa;eehfarides iii the conneetive tissuie, retieuloenidotlelial, arid parenchymal eells of various
organs. The rieslmtant tissuLe alteration-s probCirculation, Volume XXI, January
1960
G4ARGOYLISM
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al)ly depenad upjonl the degyree of ''storage'' of
thiese, Materials anid the~sec~ondary responise of
altered tissue umetal)olism iii eac-h organ involved. TJie0 existenc.e of typical and jiiter'mediate formis of thins dlisordIei is })robalblv r-elated to the miode of inheritaniec of the basic
defeet, i.e. autosomial r-ecessi-ve or sex-linked
reIcessive.
Atthotig(h chiemical and( Iiistocheinical stmdies'
of the liver, spleen, and( central nervous svstelin tissues in var-iouis forms. of g,argoylism'I
have been previously reported,"'~relativelylittle iniformiationi of Iibis nature is availalble
withl reg,ar(1 to the c-ardliovaiscular tiSMsue.
Previous lustoclihemicat studies oni routine 1-0
p)QP cen-t ac~id formalii fixed tissues indlicated
that munch of the a,ccumulated mucopolysaccharide material was lost and( miost of the studies dlemonistrated primarily thte lark of at-cuimuilationi of glycogein and fatt. Recently Strauss
and l]latt1 demonstJrated imetatclu ouatic~
gr1anlules in the large connective-tissue 1mo01o0
nuclear c-ells andi( r-epor-ted the removal of this
LiL(tachromaiaL~ byv the action. of an- unslp-cified
tx pe of hmyalu-ronidase.,
Ouir studIies demonstrated a small amount
of inetachroinatic material iii the inonoinmelear
cells of the connective tissute -stroma in tIme
mnitral valve, leaflets. Iii add-ition, thie alter-a
tioiis ini grioiiid substance of the -valve, werel(
duie priuia-rilv to the aeccumulation of aceid
mucopoysacebride
aterial with varx-incrg7
degvrees of collagrenizatIon of thIis inatcrial.
Repeated attemtpts to remove the muetacliromuatie coinpoinents writh ('rude testicular hyalu-
ron-idase were totally ismmsuceessful. Mfetachromasi.a of amyvlo)id is,- also known to be resistant
to bivaluronidaisc' (ligestioli, pirobablly because
of the presence of a sulfated acidi mtucopolysacehari/le'4 Thie stainingf technies emi-ployedI
are niot specific anid finial clarification of thlese
histoehemuical interpretations mu-Lst await (lata
fr-omt more dIirect biochemical anal vses,,. Neverthe'less, the evidence p)reseinte(d by these stud(ies
sugtgests d1iat thie basi', tissut-e alterations iii.
thie cardiovascuilar system are simitlar- to the
findinlgs by chemnica~l analyses in othier orgyans
a s111 mpport I rant e s originial cotitentiou thtat
Circulation, Voluno XXI, January 1960
287
Figure 9
Pho/ur Icicnroaodh of1 07o5/dc huirtclc /7117cion. iThere
1
77'uoc icilt(1r,i/h 7/ccrois/c i17 chcA7cloc(// N t17iI
ol, /hc bout / 7wc/bc 7fta77 (717(I d J o 7 47OiiII0
(77d
/7 770O01/o( 17/11
)7(7/ 70. Colloida(l i)7)7)-
garg0o01li-mu1 is, a geir1alized nmucopolv saccharidosis.Tit 111 atteilpIt tO dleteruiil the sc/leq iitial
dcvelopnont of clillical. cardiacl finldingos in
(-ats/s, of g-argov lismn, 2/) (sI i/-ports that inl(-lu/lcd auilops> dese.ripiionls (If the heart wvIre
17 il
reviewed'5
.Ti
/iN
~~~~~~Tls
(li/I il/t
clili
data
for
a
prlovi/le aIdcc{iaie
ical
signuifiriaitt cliii -opathologic ev~ahlatibn of the ('.ardiac iInvolvN c177t in thle variious f/rIns
o05(f thfis
(1isorde/1. Since all lavers of the l/vart may lIe
aft/ci-ed i/I -varvillg, die"res, at Can> onle tiinc,
1lf117' /liiil-a 7-aIr/lial- fimdingosl a55s0'iatI/d/ withl
gargovl
10( I]isnII
villI lep1)e;Id onitl - (.1
/iiulul at ive
cxi lilt otf ilie paritieuliarn tissue lavers /)f the
hca it affe't cd ait the timie /)f stud>I Never-thi
less, it 1178> bc o)f /(Ii/, sigiiifimaiie, that the
i1ti/st frcqucnt ('aldiac, alt/rations in. gargoyli5111 arc those iinv/Ilviiig the val-vular structmmres amild thaict the order (If frequency (If inl
V/OINTeWllet adthe(Il re0sultant ll(hang/s (If tlhe,Se
valves Iv-/smlnhl/ closely thiose foundi( in rb/uIlatie/ lialt disease~(. Thuis, a sequIentle of clini/cal ca-diar c entils similarl to those o/'/nIriliig,
int progiressive rheulinatlic hait (lis/asel mnight
he anlti/cipatedl in patients' wiNth grargroylisni.
'Illi clinlical finlding-s ill our1 C-l//e teil/I to subsstaittiatc this /1oit/ept lint tIl /d/tail//I cflnical
ailalysis of' mau,IIivmore c aseoswill h/' required
f/a- /oilfirili.tioll.
8
88
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Cardiac involvemnent may occur with little
clinical evideiiee of other organ involvemnent
considered typical of oargoylisni, and this disorder should be eoinsidered in the differential
diagnosis of valvular heart disease ii cllil(lhood. The recenit findings of Mever et al.26 aiid
Dorfniau anid I.orincz27 of in ereased urinarv
exeretion of chonldroitinsulfuric acid B and
heparin inonosulfurie acid in patients with
gargoylisin may aid in establishing the diagimosis of in-coiplete forims of this disorder.
Summary
The clinical an-d pathologie findiings in a
'1/2-year-old wvIhite boy with fatal, atypical
gargoylisin and severe mnitral stenosis are
presented. Histoeheniieal studies of the cardiac alterations in this patient are outliined
and discussed. These alterations in the cardiac
tissue suggest that thi accumulation of acid
mnucopolysaceharides in the comnnective tissue
of the valve leaflets leads to the forniationi of
collagen fibers and sclerosis. The basic tissue
alterations iii the heart are sim-ilar to those
reported to oecur in other organ systemns in
this disorder anid support the conicept that
gargoylism is a generalized Rmucopolysaccharidosis." Because sev%ere cardiac invol-vemiienit nmay occur in this svndromiie in the abseiiee of nianv of the other (linical nianifestations of this disorder, gargoylisum should be
inc,luded iii the differenitial diagnosis of valvtilar heart disease in childhood.
Summario in Interlingua
Es presentate le constatationies cliniic e palthologiw
in un puero de r acia blalnc de 5½/, annos (le etate coii
atypic mortal chondrodystrophia e sever stenosis mitral. Studios histoehiaiic del alter atioines car diac in
iste patieiite es delineate e diseutite. Iste alter-ationes in le histos cardiae pare ilidicar qlue le accuiinulationi de mucopolysaceharidos acide in le Iuistos
conjunctive del cuspides valvular resulta in le form:lation de fibras collageinie e de selerosis. Le basic alterationes del histos cardiac es siiile a illos reportate
pro altere systemiias de orgaiios in iste disordinie e
supporta le conceptioli quie clhonidrody strophia CS liii
9alnueopolysacClhari dosi s" generalisa te. Proque SevePI
affectiones cardiac pote oecaurrer in iste synidiomiie iit
le abseiitia de multes del altere maaaifestationes eliniti
de iste disordine, choncdrodystrophiha dle erea esserincludite in le diagnose differenitial de morbo valvular
del corde in le pueritia.
ANACE, FRJ{IED)MAN, WAGNER
Acknowledgment
We are iindebted to Dr. Robert Kaye and Dr. Paul
Morris for permnissioni to study this patienit.
1.
2).
I.
4.
5.
6.
7.
8.
9.
1 0.
11.
12.
R3f:ren-- s
LINDSAY, S., REILLEY, W. A., GOTHAM, T. J., AND
SIKAHEN, R.: Gargoylisas 11. Study of the patlological lesioiis ancd eliinical review of twelve
cases. Am. j. Dis. Child. 76: 239, 1948.
: The cardiovaseullar systeias in gargoylism:l.
T,Iit. Heart J. 12: 33, 1950.
STR AI SS, L.: The patlhology of gar goylismii. Report of a case ancd review^ of the literature.
Am. J. Path. 24: 853, 1948.
CaRAIG, W. S.: Gargoylisiai in a twinl brothier aInd
sister. Arch. Dis. Childlhood 29: 293, 1954.
HENDERSON, J. L., MI ACGREGOR, A. R., TH ANNHALUSER, S. J., AND HOLDEN\, R.: The pathology
and biocheniistry of gargoylismn. A report of
three cases witlh reviews of the literature. Archl.
Dis. Childhood 27: 230, 1952.
DAWsoN, I. M. P.: The htistology and histochemiiistry of gargoylisasi. J. Path. & Bact. 67: 587,
1954.
BISHTON, R. IT., NORMNAN, R. M., AND TINGEY, A.:
The pathology and chemistry of a case of gargoylismii. J. Clin. Path. 9: 3005, 1956.
UZMAN, L. I.: Chemical inature of the storage
substanee in gargoylisms (Hurler-Pfaundler 's
disease). Arcl. Path. 60: 308, 1955.
WAGNER, B. '\.: Hypersensitivity-Role of the
Coinnective Tissue. Analytical Pathology, edited
by R. C. Mellors. New York, McTGraw-Hill Co.,
1957, p. 429.
EMA NUEL, R. W.: Gargohlismn wvith cardiovascular insvolvea-euet in twso brothers. Brit. Heart J.
16: 4:17, 1954.
STR AUSS, L., AND PLATT, R.: Endocardial sclerosis in infancy associated with abnormal storage
(gargoylisiia). Report of a case in ani inifant,
aged five months, aiid review of the literature.
J. Mt. Sinai Hosp. 24: 1258, 1957.
STEEN, R. E.: Huiiter 's polydystrophy (gargoyl-
ismll) wivth cardiac lesions antd somie foraiies
frustes. Brit. Heart J. 21: 269, 1959.
13. BRAN-TE, G.: Gargoylisai 1A iimucopolvsaebharidosis. Scanid. J. Clin. & Lab. Invest. 4: 43, 1952.
14. WAGNER, B. M.: -Nature of amyrloid. Fed. Proc.
17: 464, 1958.
15. NJA, A.: Sex-liniked tylpe of gargoylismn. Acta
Paediat. 33: 267, 1946.
16. KRESSLER, R. J., AND AEGERTER, E. E.: Hurler's
syndromiie (gargoylisim): Summary of literature ad(l report of case withn auttopsy findlings.
J. Pediat. 12: 579, 1938.
17. STRAu;S, R., MERLISS, R., AND REISER, R.: Gargoylisin. Review of the liter-ature an d report
Circulation, Volume XXI, January 2.960
GARGOYLISM8
18.
19.
20.
01.
220.
89
of the sixtlh autopsied case wiith chemical studies. Amn. J. Clin. Path. 17: 671, 1947.
ASHBY, W. R., STEWART, R. M., AND WATKIN,
J. H.: Chondlr o-osteodystroplhy of the Hurler
type (gargoylisml): A pathological study.
Brain 60: 149, 1937.
SMITH, E. B., HEMPLEMANN, T. C., MOORE, S.,
AND BARR, D. P.: Gargoylism (cdyostosis multiplex): Two adult cases wvith one autopsy.
Ann. Int. MIed. 36: 652, 1952.
JELKE, H.: Gargoylism II. Post mnortem finidings
in an earlier publislhed case. Ann. Paediat.
184: 101, 1955.
NISBET, N. W., AND CUPIT, B. P.: Gargoylismii.
Report of a case. Brit. J. Surg. 41: 404, 1954.
SCHWARZ, H., ANTD GAGNE, B.: A case of gayrgoylism. Canad. MN.A.J. 66: 375, 1952.
23. ELIVI, A. M., KATIB, H., MAZNY, A.: Gargoylism.
J. Egyptian M.A. 39: 182, 1956.
24. GILBERT, E. F., AND GUIN, G. H.: Gargoylism.
A review including two occurrences in the
Americail Negro. J. Dis. Childhood 95: 69,
1958.
25. DELANGE, C., GERLINGS, P. G., D1EKLEYN, A., AND
LETTINGA, T. WT.: Sonie renmarks on gargoylism.
Acta Paediat. 31: 398, 1944.
26. MEYER, K., GRUMBACH, M. M., LINKER, A., AND
HOFFMAN, P.: Exeretion of sulfated mueopolysaccharides in gargoylism (Hurler's syndroimie).
Proc. Soc. Exper. Biol. & Med. 97: 275, 1958.
27. DORFMAN,, A., LORINcz, A. E.: Occurrence of
urinary acid niucopolysaceharides in the Hurler syndromiie. Proc. Nat. Acad. Se. 43: 443,
1957.
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Forthcoming Articles
Hypertension and Vascular Disease. Harry Goldblatt
Familial Muscular Subaortic Stenosis: An Unrecognized Form
Disease" with Clinical and Autopsy Observations. Lawrence B.
of "Idiopathic Heart
Brent, Akio Aburano,
Don L. Fisher, Thomas J. Moran, Jack D. Myers, and Jape W. Taylor
Critical Evaluation of Electrocardiographic Diagnosis of Ventricular Hypertrophy
Based on Autopsy Comparison. Bertramn J. Allenistein and Hirovoshi Mori
Heart Disease and Filtrable Viruses. John MA. Pearce
Social Aspects of Cardiovascular Rehabilitation. M1arvin C. Becker, Wayne Vasey, and
Jeroine G. Kaufman
Circulation, Volume XXI, January 1960
Mitral Stenosis in an Atypical Case of Gargoylism: A Case Report with
Pathologic and Histochemical Studies of the Cardiac Tissues
PETER W. VANACE, SIDNEY FRIEDMAN and BERNARD M. WAGNER
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Circulation. 1960;21:80-89
doi: 10.1161/01.CIR.21.1.80
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