MORQUIO'S DISEASE

(1)

MORQUIO’S

DISEASE

A

Radiologic

and

Morphologic

Study

Eric A. Schenk, M.D.,

and

James Haggerty, M.D.

Departments of Pathology and Radiology, Universitq of Rochester Medical Center, and Strong ‘tIC7flOrial Hospital, Rochester, New ‘York

(Submitted NIarch 9; accepted for publication July 17, 1964.)

ADDRESS: (E.A.S.) Strong Memorial hospital, 260 Cnittenden Boulevard, Rochester 20, New York.

PEDI:ti’mucs, December 1964

839 I

N 1929 Morquio reported two siblings

afflicted witil a skeletal disorder wllich

he

termed

“a

form

of

familial

osseous

dvs-trophy.m

A

few

months

after

this

report

appeared

in

tile

literature,

Brailsford2

pub-lished a single case of the same type umider

the

name

of

“chondro-osteodystrophy.”

Similar

cases

had

apparently

been

pre-viously described tinder various names

such

as

“dwarfism”I

and

“achondro-plasia,”’ hut lack of sufficient clinical and

x-ray description prohibited more precise

classification. Since that time a relatively

large number of cases of

Morquio-Brails-ford

disease

have

beemi

reported,

and

clini-cal

amid

radiologic

features

have

been

well

defined

and

differentiated

from

other

forms

of

hereditary

chondrodysplasias.

The

disorder

is apparently

recessively

in-herited.

The

I)atient

is

usually

normal

at

birth,

but

at

approximately

age

1 to

2 years

skeletal

abnormalities

become

maui-fest. These consist of thoracolumbar

kyphosis

,

scoliosis,

sternal

deformities

,

short

neck, reduced truncal length, amid short

extremities.

There

is

swelling

and

limited

articulation

of the

joints

of long

bones,

but

hyperlaxity of fingers and wrists. Tile

af-fected child develops a dwarf-like

appear-ance with a normal head. Radiologic

examination shows flat irregular vertebral

bodies, severe dsplasia of epiphyseal

growth

cemiters,

widened

joint

spaces,

slen-der diaphyses of long bones and general

osteoporosis.

The

cramiium

is

normal.

In

contrast

to

the

nimmerotms

clinical

and

radiologic case reports of

Morquio-Brails-ford disease, pathologic material has been

extremely scare. Only one autopsy#{176} and a

few I)One biopsies’ #{176}‘#{176}‘

have

been

re-ported to date. The present report is a

din-ical, radiologic, and pathologic study of two

siblings with Morquio-Brailsford disease,

one of whom ‘as autopsied.

CASE

REPORTS

Clinical Summary

D. NI., an 1 1-year-old white male, the third

Oldlest of seven siblings, was horn on August :30,

1949, after a pregnancy characterizedi by much

nausea andi vomiting and i 20-lb maternal weight

loss. lie weighe(l 9 Ib, 13 oz, at birth and

imp-peared unremarkable except for a slightly

pro-truding sternuni. his cari’ dleve’lopnme’nt was

normal; he stoodl at 10 months and walked at 1

year.

He sas first seen at Strong Memorial

Hos-pital in Aimgust, 1950, at the age of 1 for

evalua-tion of a heart niurnitlr. This niurnitmr vas

ap-parentl’ not heard at 6 months of age. There

was fl() history of cyanosis or dvspnea.

Physical exanmination reveald’(l a high

prottlb-erant sternum and pigeon chest deformity,

tachvcardia, a blowing harsh systolic murmur

over the entire precordium, loudest at the apex.

Fluoroscopv showedi left atrial enlargement. One’

observe’r felt that the murmur had a to-and-fro

(illality. EKG sho\vedl first-de’gree atrioventricular

block and sinus tachvcardia. It svas felt that lie

had either an interatrial septal de’f#{128}’ctor a patent

diUctus arteriosus. lie \vas followed in Clinic for

approximately 4 months and then lost to

follosv-up.

From approximately age 2 on, it became

in-creasingly apparent that his lt’gs were deformed,

that his extremities were shorte’r than normal,

but r(’lativclv long in proportii to his short

trunk, and that his habittls svas that of a dwarf.

His nmcntal status vas normal, and lie attende(l

school regularly. lie had chronic otitis medli1l

until age 9.

lie was seen again at Strong Memorial

Hos-1)itdl in October, 1961, at the age of 12, with a

(2)

840 MORQUIO’S

DISEASE

Fic. 1. (DNI) The chest shows paddle-shapedl ribs.

The PrxiIm1i1l hunieral e)ipiise’s are flattened and

Iilissha1)d’(l. The aorta is prI1mi1ie11t, time )Ul1UOnary

otitfirsw tract grt’atl elmlarg(’(l, (111(1 the’re’ is increase’ei

yascularitv of time’ roots.

.botit 4 months prior to admission dh’spnea on

e’x(’rti(mlm s’as IiIst Iiot(’(l 5111(1 stmbs(’(1uentlv l)ecaIii(’

)rogre’ssivelv s(’vcrc. Tell (lays l)rir to admissiol)

he i)cgan to (‘xp(’ri(’1mc’(’ left anterior chd’st I)aiIi

:lSsOdiat(’(l svitlm exercisc’ (111(1 r(’lid’yedl 1)\ re’st. He

tirc(l easily, tnd cVililOSiS Wl5 noted after

exer-tion.

Physical (‘xaniiliat iOIl sliosvt’d a l)lOOdl prt’ssurt’

of 1 10/80. PtIls(’ 122. ltIi(1 respiration 42. There

\‘as nlarke(l ll)IdlOSIS ilOdi kvphosis, ig#{176}

c’h’st,

short Ii(ck, l)ro1mn1it (‘pi)l)is(’s of the vrists and

k;iecs, short extremities, long fingers and tm’s

svith Ir liganientous sup)ort, amid hands and

fcct 11(1(1 in tl)dlIctiOIi. A fe’sv rales ene heard

in the’ bug i)JSi’S

l)ilatt’ralh,

an(1 1 Cradle lI-TV

“rieJiing” immurniimr \vis (l(’sdril)c(l which began

in late’ 5VstOi(’, bcco;iiing loudest in early (liastole

55-i tim a foIls \‘ing (lcscr(’sc(’ndlo. The pulmonari’

sec’on(l 501111(1 \as v(’rv loud1. Flnoroscopv shoss’ed

aIm ali(’urysin :ill (I ilated niain l)tllIllOnar\’ arter’

svitli )romi;m’1 It I)ulsatioli . E KG revealedl right

entriciil ii’ im\1)rrtn)j)hy. Cardliac cathet(’rizati(’n

shOsV(’d a right l(’ntricular an(l main pimlmnar

artery pre’ss;;rt’ of 125 mni SV5t(mli(’ an(l no chamige

ifter oxygen l)rcathillg. A diagnosis of probable

l)at(’nt (llI(’tlIs arteriosus \as madle.

Iit’ \‘is slIl)s(’(1tI(’Imtl\ a(lnhittedl ill Fe’hruarv,

1962, l)t’(lllI(a’ of cmligcstiyc heart failure and \saS

(ligitalize(1.

Tsvo \5(’(’kS later lie was again adlnhitt(’(l

l)c-(‘01St’ of Ii(itIS(’)t 5111(1 vonmiting 5111(1 right lower

(Iti()(lr:iImt abdominal pain with r(’bound

tendlcr-11(55. \Vhitc 1)1(10(1 (‘OtlIst \VdS 16,700 vith 80

i)’rd,11i: 1)iy1m1rpho1)t1dl(’l1r c(’lls. i.Jrinalsis

ShO\V(’(l 1 + ltli)1lIiiiIl, 2+ sugar. 1 -4- acetone, aiii

Ocd’asiolial lialiiie 5111(1 granular casts and 1-3

svhit’ 1)100(1 dells/high posser fieldi. An

aplx’n-ilectomy \ts l)(’rfrm(’(l tlire’’ liotirs after

ad-IilissiOIl nlld(’r cvclopropane an(’sthcsia. The’

ic-s(’cte(l 1I)i)(’n(lix shosvcd iic’tlt(’ inflammation. On

tlit’ first Postl)d’r()tivc (l)L the patient had an

ap)5Ir(’Iit stld(l(’Ii l)iIt tcnhl)orarv rise in ptmlse,

teml)erature, an(l conconiitamit fall in bloodi

p’’-sure. On tiit’ s(’d’OIS(l l)5tPe’r1ti\d’ dliii. he

stl(l-(l(’nl’ l)ed’anle d’iaIiOtic, (l(’ld’lOI)e(l cardiac arrest,

,iiid (‘xpiredl.

Radiologic Changes (at age 12)

SKULl. : The nm(’ml)ranous vault andi the carti-lagiliolls l)i1S(’ \\d’re iiormal.

CHFST (Fig. 1 ) : There was de’creased height,

s(’con(larv to 1)latVS1)Ondvly, andl incr(’asedl

antero-pstt’rir (lianlet(’r. TIme ril)s \vd’r(’ 1)a(ldle’ sllapd’d,

i.e. , \vi(l(’nc(l a;mtt’riorlv iImdl tapd’redl 1)5td’riorl.

The’ PromiIi’;it aortic arch, the large piilm;imry

arte’r’, iiildl tIme’ (‘ngorge(l pulmonary roots were

f’it to lx’ secon(larv to tht’ I)iltent ductus and not

relatd’dl to \Iorqt;ios disease.

SPINE

(

Fig. 2

)

: Platvspondlvlv was presc’Iit in

thei ce’rvical, thoracic, an(l lumbar spine. The

l)Odlid’5 we’re’ “wafer-like,” i.e., normal in

antero-Posterior (111(1 transv(’rs(’ dlinlensions hut deficient

ill he’ight. There \sas anterior wedging, svith some

deformity andl anterior lip)imig of the tipper

1tiiii-1)ar and lover thoracic vertcl)I’ac. The height of

the’ intcrvvrtt’bral spact’s \Vd5 ilicre’lsedl. Lower

thoracic aIi(i upcr lt;mhar kvphosis was present.

PELVIS (Fig. 3): Undierdevelopnient andi

in-t(’rnal I)rotrtisioil of the acetahillar fossac \‘ere

I)r’s’nt. The femoral capital e1)i1)hyses were

se-v(’relv deformed and represcntd’dl only by a few

bone fragments. There was associatedi widening

of the metaphvses andl remainde’r of the femoral

neck. The femurs a)pearedl to be partially

dis-located, aIi(l ther(’ vas a vartis dleforrnity of the

femoral necks.

LONG BONES (Figs. 4 and 5): The epiphyses

w(’re niost severely affected with the femoral

cal)ital e1)i1)hVseS severe’lv dleforme(l as described.

The proxilmial hillileral epiphiscs were markedly

Hattd’nedl. The’ e’piphvs&’s else’svhere were not as

grossly affected. Thert’ ‘as metaphvseal widening

(111(1 flattening wh’re’ve’r the’ epiphvses were

se-vere’l’ affected. Tlu’ dliaphvses dis1)laved some

cortical thinmiing and bowing of the shaft in the

forearm.

SHORT BONES (Fig. 4): There was minimal

(3)

pha-FIG. 2. (DM) The tlmoraco-iunmbar P#{176}’slmovs

uni-versa! I)lltY5I)ndlYlY with immarked irre’gularitv of

vertebral Ixely contour which is umost I)ro1mmi1e1mt ill

the lower thorad’ic and uper lunmbar region.

langes st’ere sttmbbv but otherwise unremarkable.

The carpal bones were undlerdievelopeel for a

12-year-oidi male’.

Autopsy Findings

GRoss: The l)O(I\’ was that of a 12-year-oldl,

well-nourished, white male’ dwarf. TIme’ over-all

body length was 107 cm. The t11)i)e’r extrenmitit’s

nieasureel 46 cm; the lower extremities, from

the anterior iliac crest, 61 cm. The crown-rump

length was 46 cm; the manubrial xi1)iloid length

1.3.5 cm; xiphd)idl umbilical 17 cm; and unibilical

5Vm1)hcsis length 1 1.5 cm. Time circumferemice of

the heael ‘as 56 cm; that of the chest 72 cm;

and that of the abdomen 64 cm. The bridge of

the miose was flat, time tip of the’ nose broad with

wide nostrils. The ups were large, pattllous, and

dusk’. The lover jaw ‘as nmoeleratelv

I)rotu-berant, and the distance l)etween the most anterior

portion of the nmandihle audi time manelibular ranmus

was 7 cm. The facial features appeared coarse.

The neck was shortened. The antero-postenior

diameter of the chest s’as increase’(l and the

sternum markedly protuberant. There was a

Se-vene kyphoscohiosis. Time abdonmen was flat, and a

7 ciii long, right psmramidhne, recent surgical

in-FI;. 4. (DNI) The epiphses are mimisshapeel anel

tht’re is radlial bosving a;md ullmar shortenilmg. ‘I’he

immetacarpals are’ I)0iI1te’dl prxi1mm1hiy ; phalanges are

(4)

842 MORQUIO’S

DISEASE

1 #{149}l’

I’.

. ,(1

: ‘

;t .

!

‘ .

I

FI(;. 5. (DNI) I)\ve’r leg shows soimme’ cortical

thin-lung; (iiaI)imvst’ai le’Imgtim is IiOrlmiai, Iifllsch’ Iliass is

die’c’r(’ase’(i. There’ is Immarked irregtilaritv of e’oimtot;r

of the’ (‘1)ipimyst’s IIidl tarsal bone’s.

cision \ts I)r’s’Iit ill tim(’ right luse’r (111a(lrant.

Iimt’ (‘xtre’miti(’s \erc S\ Immnl(’trical. Timere \vas

niarked ilvpcrext(’nsih)ilitv of time’ wrists, filigers,

(10(1 tIikl(’5.

The lK’art w(’ighmt’dl 3:30 gm tIm(l showed Imiarkedi

right ve’imtricular a;md ri ghmt atriai e’nlargcmelmt.

Time cndocardiulm) of tlu’ right atritim slmosve’el

ilttc’im’ gras ish thickening. ‘I’ime papillar Imitlscies

iflidl trLh)e’c(Ila(’ of time right vcimtricle ere

Imiarkd’(liv imvpertrophmi(’cl . Time’ valve rilmgs of both

timt’ I)tllllio;mi’ (111(1 aortic \al\t5 ve’r’ siigimtlv etl

cifit’d. The tricttspid almd I)lIlmOImit’ \‘alvc leaflets

were somt’wimat timickelmedi alm(l lma(l grayish svlmite

stre’aks i)Ii(l focal areas of e’llosv nodul(’s along

time’ free (‘dige’. Time right velmtricuiar Imivocarelitim

In(’asur(’(l 1 (‘1mmill tlmiekncss; th(’ l(ft \(‘I)tricuiar

niyocar(litlm 0.8 cm.

.‘\)proximatt’l\ I cnn distal to tIme origilm of tIme

h’ft subclavialm art(’ry was a 1)tte’Iit (Itictus

arterio-stls 6 rum iii (liLmeter. Time adiVelmtitidl surfaces

(if the Pt1lmnilrY artery ltIm(l iortt ve’re

i;mti-match’ in (.‘Olitltct to jriti’e’ i \ViImdlO’l’ tVI)e

(hlIct(ul opemmilmg. lime niailm p11l1mm1m51ry art(’rv had1

a (iiani(’te’r of 8.5 c’mm, alm(l the 0)rta imad ,t

(iialmm-(‘ter e)fCmeni.

The’ left 1111mg sv(’ighe’(l 140 gm, the rigimt 180

gm. There se’n’ nman firimu fibrous I)1’urll

adihe-5iOII5 011 1)0th) side’s. Both lulmgs w’re

lmvpocrepi-tant and 51i(m\Vedl focal atel(’ctasis. Time’ pt1l11m11(Lry

i)arec’imY1mmit vas firom and! conge’sted, and vascular

markings wt’re pronunent.

TIme 51)11(I) w(’ighmc(l 70 gni )Lii(l ssas

UIlrd’mark-ah)le’.

Time gastroint(’stinal tract simo\vt’(i um(l(h’rat(’

(‘Ii-largenic;mt of mcscnte’ric lvniph 1)0(11’s Ii time’

ilco-ce’(.’al region (411(1 Ii iIlV(’rt(’(l, slightly

hemor-rilagic itI)I)cI)dliccai sttilm)i).

TIme liver \v(’iglm(’d 750 gili o)(1 \\as

ulirt’n)alk-ilh)le.

Time le’ft kiel;mcv w(’ighe(l (45 gni, the riglmt 80

gum. Sectiolm slmosvt’d nu’(luliarv colmgcstiolm.

All oth’r orgasms tIid tissu(’s a)pe’arcd

tinri’-markabic’.

Pe’rnlissioim for (‘xalmiinatioll of time’ brain wts

riot gramit(’dl.

NIICROScOPIc : \1oca;’dial fih)crs of tiit’ rigimt

ventricle sserc imvp(’rtropimi(’dl. ‘lim(’r(’ 55515 a focal

I)eri’tr1iltl rotlmmd cell iiifiltrate. Focal i;mtt’rstitial

acute ammel chroimic inflamnmatory cell ilmhitratiolm

and immvofibe’r (lt’ge’neratioim we’r(’ present iii thmc’

iimtervcntricular s(’pttIIim . Sttbe’Imdoca rdhial Imlvocvtes

ve’re I)rmi1i’1mt. Art(’ri(’s :111(1 art(’riol(’s shosveel

nmtimal proliferation a;md I1)eelial sclerosis. fhere

as pr1mminc’1mt right ve’Imtricular ‘Ii(locar(hial

Iil)ro-(‘lastic tissu(’ proliferation.

Time’ pt;1um;mtr artt’rv shmO\V(’dl intimal

timicken-ing (ltR’ to fibrosis aIm(l smooth iIttlscli’

1)rolif(’ra-tiomi. ‘limt’re’ \se’re focal atlmcromata \Vitim

(‘tlcilica-tioim.

Time itings showed ‘Xtclmsi\e alld severe

arte’rio-sclerosis aimd ple’xifom’ni structur(’ forlnatiolm. \Ianv

arterial Ion 011)1 \\(‘fl’ comliple’telv occitm(leel 1))’

FI(;. 6. (FNI) Time cimest slmows l)ildllle’-simiuI)e’l ribs

vitim anterior flaring. Ihe’ se’rtebral i)(m(iies are vide

LIi(l flit. ‘I’he I)el\i5 ShOVs ad’e’tahular 1)rtsi1m, iliac’

(5)

FI9.9

Fig 10

Ftc;. 8. Ileael of femur. There is collapse ammd

obliteration of time ossificatiolm center.

Choimdro-cte and matrix mmiasse’s extend laterally into time

me’ta1)hvsis and gre’ater trochianter. The epiphvse’al

line is irregular.

Fi;. 7. (FM) Thoraco-iimmhar spine. There is

uni-versa1 platVS1)Ofld\l\ with sonme anterior I)re’akumg,

alm(l lower timoracic kvpimosis.

fibrous tissue. Tlmere was ilmterstitial fibrosis and

a chronic inflammatory ce’ll infiltration. Focal

are’as of i;mtra-alveoiar im(’Immorl’imagv were Pr:’Se’Imt

as \vehl itS areas of organizing I)nennmommia. Tla’rc

was generalized congestion audi ate’lec’tasis.

Time spleen, l)iuImc’re’:ls, (111(1 gastrointestinal tract

s’ere unremarkable.

The liver shmoweel evidlelmce of slight chronic

congestion. Pare’Imclmvlmmal cells were unremarkable.

The kidne’vs slmowt’el marked! meeluliarv

con-gestion anel focal tubular calcification.

The thyroid and 1)arathvroid \ere

unremark-aI)le.

Lymph nodes from the Im)esemmtery shmoved

lvmphocytic folhicular lmvperplasia and focal

re-ticular hvperplasia.

Svnovium and skeletal mt;scle were’ unre’ma’

k-able.

BONE : Available’ for imistologic examilmatioll were

thoracic anel lumbar vertel)rae, fourtlm, fifth and

sixth ribs, afld the right up)e’r femur, iimcluding

the femoral heael, Cimalmges ilm all of these sve’re

qualitativeh’ similar. Most severely affected were

the femuoral lletdl amid lunmbar vertebrae.

There s’as a severe dlisorgalmization of time

ei-1)hvseal growth zone vith a elisorelereel pattern

of endocholmdlral ossification. The superficial

layers of articular cartilage’ c’e’lls ap)(’arc(l

Ill)-remarkable. The columlms of pr(mlife’ratiimg aimd

hpe’rtroplmic cartilage cells we’re’ marke’ellv

shorteneel, dhisorgalmize’d, and focally absent. \Ian

hvpertrophieel cartilage’ cells occurred in cltmlmmps

andi nests rathe’r than i;m r(’gular columns. The’

metapimvsis \vas svideime’el almd showc’d broach,

ir-regularly Shlilpt’dl trabecttlae’ undergoing

ossilmca-tion. Irregular caicifie’dl and noim-calcifleel

cartilag-inous masse’s pensisteel in the metapim\sis; sonic of

the’se’ masses we’re undergoing a lmvali;me’-tvpe

dc-ge’neration anel fibrosis.

The’re were large irregular masse’s of

cartilag-inous Immatrix (lIm(l c’lmolmdrocvtd’s in thu (‘)iplmV5(-’al

ilfl(l articular cartilage’ clmOlmdfl)cVte proliferating

areas. TIme ossification cc’Imte’r in time’ he’a(l of time

fenmur s’as obliterateel by these masses of

chon-elroctes amid matrix, svlmich also extt’ndl(’(l along

the outer aspe’ct of time pericimondritlm aimel

re-I)liic’e’dl niost of time greater troclma;mter (Fig. 8).

There was an exte’nsion of thmis process into

a(l-jacent skeletal musch’ ammdl colllme’ctivc tissue, anti

isolated degemm’rating skeletal muscle fmi)t’rs st’re

present within time proliferating cartilaginotis

imiisses. Some of the’ cartilagillous masse’s a)pearedl

to he iimrtiahl ossifie’d. lntt’rsl)erse’el among tue

sheets of elisorganize’d cartilage were areas of

fibrosis, vascular chaimime’ls, almd nests of

(6)

Fi;. 9. Foalmi ce’hl ;m’st \vitlmilm cartilag(’.

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844 M()RQUIO’S

DISEASE

Fi;. 10. Epiphvseal lull’ slmowing transverse voveim hone’ plates, lack of (‘imolmdrocvtc’ columns, audi nests

(7)

Cartilage Coiii poi(eflt S/alit

Lacunar (‘apsule

Normal

Matrix Lesion (f 1!orqulo8 i)isa.ve

Fibrillar ,1inorphou.s

+++ toO

++ toO

Azure A l)lI (2

almiorl)Ilous Bisniarck brown

+ to 0

0

+ td)0

I)

0

+ to ++++

++++

0

(I

ARTICLES

referred to as foam cells (Fig. 9). The cortical

bone in the mmietaphseal area of the femoral head

was very thin audi diel not extend! to the

epi-physeal plate. Metaphyseal bone presented a

variable Iatterml. Transverse woven bone plates

which mm)erged svitim the e1)i)hyseal cartilage were

common. Longitiidiimally oriented trabeculae were

only focally I)resent

(

Fig. 10). Diaphvseal

trahec-ulae were fewer in number and thinner than

usual, while the diaphvseal cortical bone

ap-Pearce! unremarkable. Osteoblasts and osteoclasts

were of normal size and distribution, except in

the areas of transverse woven bone plates where

they were decreased to absent. The penichondnium

was generally broader than normal and! focally’

infiltrated! by foam cells and chone!rocytes. This

change in the perichondrium was most prominent

at the costochondral region.

The chondrocytes varied markedly in size,

shape, and! orientation. Many appeared! swollen

and! enlarged to two to three times normal size

and had a finely vacuolateel to granular

cyto-plasm. Sonic showed wlmat we have interpretedi

aS transitions to foam cells.

The following stains s’ere utilized to study the

cartilage abnormalities : Periodic acid Schiff,

alcian blue, azure A at pH 2 and pH 4, Hale

colloidal iron, M#{252}llen-Mowry’ colloidal iron,

Bis-marck brown, Gomori tnichrome, phosphotungstic

acid

imematoxyiin, Heidenhain azan, Wilder’s

reticulum, Ahul-Haj aldehyde fuchsin,

mucicar-mine, and Van Gieson. Table I sumimianized the

histochemical staining reactions of the

com-Ponents of normal cartilage and in cartilage from

our patient with Morquio’s disease.

The cartilage nmatnix from all areas examined!

displayed two distinct changes. In one, which we

have termed “fibnillar matrix lesion,” the

granu-br interterritoial matrix showed clumping and

frank fibrillar transformation of the granules. This

fibnillar component retained the staining

character-istics of the gramlular interternitonial matix with

acid rnucopolvsacchanide stains, and in adldhition

assumed

the staining and birefringent qualities

of fibrillar connective’ tissue (collagen, reticulin,

and osteoid). The territorial matrix in these areas

was absent or non-stainable. In the second type

of change, which we have termed “amorphous

matrix lesioim,’ time interterritorial matrix was

devoid of any stainable granular component, anel

there was a marked decrease to absence of

stain-ing of the amorphous component with azure A

at pH 2. No stainable territorial nmatrix was

pres-ent. The amorphous material in which

chondro-cytes are embeelded! stained svith Bismarck brown

and in a less striking manmmer with Van Gieson

(Fig. 11).

The femoral head and vertebral bodies showed

both the fibrihlar and amorphous matrix lesions

equally well. The costochondral cartilage showed

pred!ommantly the amorphous change.

Chondrocytes in both the fibrillar and

amor-plloims matrix lesion showed swelling andl

cytoplas-mic vacuolization. The nests of foam cells had

no apparent unique relationship to either of the

two matrix lesions. The cyto)lasm of these cells,

as svell as of chondrocvtes, staine’el strommgly with

colloidal iron and Bismarck brown, less so with

alcian blue, PAS anel azure A at pH 4, and not

at all with azure A at pH 2 (Figs. 12-17).

Clinical Summary (F. M.)

F. NI., the oldest of seven sibliimgs, was born at

term, weighing approximately 10 Ib, after a

pregnancy characterized by’ mmmch nausea and

vomiting. Delivery’ followed a frank breech

pres-entation, and it ‘as noted immediately after birtlm

that “the legs did mmot fit right at the hips.”

i-low-TABLE I

(Figs. 1-17)

Colloidal iroti

Aztire A pH (2

‘l’erritorial IllmltriX Azure A p!l 4

Interterritoriai Ale’ia;i blue

itiatrix: Colloidal iron

gralmular Birefringence

++++

++++ ++++ +

(8)

846 \-IORQUIO’S

DISEASE

,

I #{149}

;.‘:

‘:-;:;

. #{149}( ‘, #{149}

- .. U(n #{149}1, b

#{149}:‘#{149}“ ,A

‘S #{149}

/:

I ‘II4 #{149},

‘d3 ‘ -‘ s #{149} #{149}. #{149}#{149}

a

‘:

‘

#{149}1

. , ‘

(

tlppe’r center), Ofld! foam cell nest (right).

lesion (left and lower cente’r), amorphous matrix le’sion

-q

4 5)

..,,

y

‘

c_ . , .

“0

a

_(‘ tjl

I_) “

‘

)

fr*-

‘.. , #{149}.

.-i. ts

c:’

‘ -

.“t

-(, - ,) ‘

,1 . f ., 4 4

. ) . -. .

‘.

(

‘-- - , ‘..- S

5

i:3

t ‘

F;;. 1 1. (.artilage simosving fibrillar niatrix

(,vcr, at :3 montims 1)0 hip ah)Imormalitv was

ill)-1)llr’Imt. Time’ 1)llti’Iit \‘ltlk(’(i Ot 9 ImmolitIms and sas felt to h)d’ (1 nornmal clmiid, Bctsveemm time’ age of 1

ltIm(l 2 ears a protrtidlilmg st’rmmum um(1 ‘ari;s

(le-formities of the’ k;mecs h)e’came’ mi)l)1re’nt. FIe’r

he’altim imas l)ce’Ii good (‘xc(’l)t for asthma. She is

curremmtlv 17 \cars old ((11(1 of normal intelligence.

Her mmemscs started at age 16.

Physical e’xamilmation simo\ve’dl time follosvimig

skeletal al)Imormaliti(’s : I Icr lialmitus was that of a

immisshap’n ehvarf svitim a hlea(l of normal adult

size resti;mg almost 00 the shoulde’rs, the neck

be’immg bare’i 1)e’rc’(’1)tihle. Time arnis reached to

time klmccs 011(1 Ii(ld’(l il) short sttli)i)V fingers. The

trulik (ti)1)e’(mr(’(l disproportiommatc’l large compared

to her imt’igiit. There’ sas a )igeon l)rt’ast

deform-it\’. Slit’ walked vitim a sligimtly \vadldling gait. She

d!e’molmstrate’d corlical opacification vhich re’ehlce’dl \‘isiOII imm time’ rigimt eye’ to 20/25 corrected and in

time’ left e”e’ to 20/80 corre’ctcd, although there

\Vit5 astigmatism as well imm thme le’ft eye probably’

accounting for mticlm of time’ rcdtlction. The

re-immaindler of time physical examination Vas

unre-markable.

Radiographic Changes (F. M.)

The’ rahiographic chalmges \s’(’re esselmtially

sim-ilar to tlmose’ of I). NI., time’ Imiajor dliffe’re’ncc being

a ;iorniai cal’(iiovas(’ular sillmotie’tte in timis l)tti#{128}’Imt

withotlt evide’imce’ of commge’mmital Imeart disease. The

prd)ximml5ml hulmmeral ej)i1)hvses sve’re less affected in

this patie’nt (Figs. 6-7).

COMMENT

The

apparent

relationship

between

Hur-ler’s

disease

and

Morquios

disease

has

been

extensively

(liscussed

in

the

medical

literattmre. Hurler’s disease in its typical

form is characterized by skeletal

abnor-malities amid also by extraskeletal changes

such

as

corneai,

opacities,

deafness,

he-patosplemioniegaly,

mental

deterioration,

neurological

disturbances,

and

cardiac

ab-normalities

due

to

valvular

and

coronary

artery

lesiomis.

The

general

body

habittms,

like tilat of

the

Morqui()

patient,

is that

of

a drawf. The pathologic picture is one of

clear cell infiltration of various organs. Thc

miature

of

the

substance

found imi these

clear

cells,

which

for

many

years

was

tilouglmt to

he

a lipid,

has

now

been

identi-fled

as

a

mucopolvsaccharide

(MPS)

and

characterized as sulfated and miomi-sulfated

yt-IPS

and

gl\’co)rIteiml.

increased

amiiounts

of ciiondroitin sulfate B and heparin

(9)

tis-2

4

5

:‘- ‘ .

.4 \s --:::‘ ;.r _ t

l c

\?

T

, I

.--- ., I (

I

‘ :

,-#{231}--, ..t. ,..,,_,Sa .,-‘. ‘. 1

. - -

:

‘. ‘-.. -i .‘(aI :: .

. : 1”’ ?

‘)4 ‘; s, ‘.

#{231},.,

, ‘ 4I’-.

-I.- .‘,

-

.

6

--.---- ‘:

‘.1_:. vTh I)

A.. - ‘4

I-S I 4.r #{149}‘.‘“

.‘. ,

-‘

1:4

. . ‘;

4---

. -‘

-13

17

I”ic. I2, Nommnal camtilage. (/OhlOi(lsml iron stain . ( i’ammtmlar immtert(rritorial lmmatri\ taii IS 1)lu(

FI(.. 13. N orlmmai cartilage. Bisn)am-ck 1)105%-I) stain. .\nmol’phmt)tms iIltc’rt(rritlIrial muitrix stains l)rII\vs).

Fit;. 14-17. (;artiiage’ frcmmm patie’imt svitlm \Ior(1uios Disease.

II(;. I 4. FiI)Iillal’ nmatl-ix lesion. Coll(midal irolm stailm shmovs Iii)Iilldl trammfllrl IlItillIm 11 till Ill Iln)lhI\

grIll-imlar interte’rritorial nmatrix.

(

Bismarck h)rO\vI1 counterstailm .

Fir;, 15. Ammmorphmous matrix lesion a(ljacent to normal cartiiag(’. Ilm(’r( i III h)SllC(’ of gramiimiar

inter-territorial niatrix :111(1 Ill l cm’case ill ammiorpimous intert(’rrit(lI’ial n:ttI-ix. (/ollilidai irl 11 am (h B is;Ilarek

brown stains.

11G. 1 (-:i. \(‘t (If foalmm cells a(ljace’lmt to afl)0I’plmoIIs Inatrix I(siolm. ‘I’hmc c\ tI)1)lllll af tlm((’ ((his. l \l Ii

(15 timat (If chondroctts, stains svith (‘Olloi(i(li iron.

(10)

848 v1ORQUIO’S

DISEASE

sues

(especially

liver

and

brain)

ill

patients

svith

Ilurier’s

disease.

“Reilly

granules”

\Vllidll also

have

the

staimling

cilaracteristics

of ‘s-IPS are foumid in

lympilocytes

and

gran-ulocytes

of

the

peripheral

blood

in

some

patien

ts

.11

The

typical

form

of

Hurler’s

disease

is

hot

difficult

to differentiate

from

the

ty)ical

form

of

slorquios

disease.

However,

there

have

been

reported

a number

of cases

with

certain

features

of

each,

and

these

have

been

referred

to

as

“mild

Hurler’s”

or

“atypical Morquios disease. The term

“Spaet-Hurler” was coined by Ullrichm2 to

characterize patients with corneal

cloud-ing

in addition

to the

skeletal

abnormalities

of Morquios disease. This disorder, now

most commonly termed Morquio-Ullrich

disease,i

manifests

itself

by

variable

de-grees of cardiac and other visceral

involve-Irlent, some mental retardation, hearing

defects,

Reilly

granulations

of

white

blood

cells, corneal opacities, and Morquio-like

skeletal deformities. Increased amounts of

MPS

have

lieen

found

in

the

urine1

I

and

identified

as

kerotosulfate

by

some

workers,m3,

11;

and

as

chondroitin

sufate

B

tIid

altered

liyaluroiiic’

acid

by

othlers.1

A

bone

biopsy

has

shown

increased

amounts

of

stainable

NIPS

in

the

cartilage

matrix.15

No

information

as

to

extraskeletal

involve-ment,

storage

cell

accumulation,

and

the

chemical

nature

of

intracellular

MPS

has

as

yet

come

to

light.

Because

of

the

presence

of

increased

amounts

of

urimiary

and

tissue

NIPS

imi

Hurler’s

and

Morquio-Ullrich

disease,

the

concept

of

genetically

determined

diseases

of iMPS metabolism, termed the

“mimcopoly-saccharidoses,”

has

beemi

roposel

and

germ-erally

accepted.

Meyer19

has

proposed

that

the

fundamental

defect

may

be

a

genetic

error in differentiation or fibroblasts

(“chemical

metaplasia”)

with

subsequent

excessive

production

,

accumulation

,

and

I)rol)al)le

storage

of

MPS

Iw

cells

in

tis-sues

in which

miormally that particular MPS

is not

found.

No

abnormiiality

of

1’s’IPS

storage

or

cx-cretion has to our knowledge been reported

ill

cases

of

\lorquios

disease.

The

bone

i)iOpsies amid one autopsy

which

have

been

reported have alluded to the presemice of

vacimolated,

foamii

or

clear

cells

in

the

hya-hue cartilage. The findings in the present

case

confirm

the

presence

of

foam

cells

in

the

iiyaline

cartilage

and

further

establish

that

these

cells

contain

MPS.

The

MPS

present

iii hyaline cartilage are

ciiondroitin,

dilondroitin

sulfates

A

and

C,

and

keratosulfate.

The

lirecise

histocliemi-cal

localizatiomi

of

these

MPS

is as

yet

not

possible.

It

is 1)osSible,

iiovever,

by

use

of

histochemically

specific

stains

to

delineate

certain ciieniical miioieties lresent imi the

MPS.

Periodic

acid

Shiff

stains

all

polysac-charides and MPS

with

adjacent hydroxyl

groups.

Azure

A at pH

2 stains

stromigly

acid

sulfated mucins such as cliondroitin and

heparin

sulfate.

\Veakly

acid

sulfomucins

stain

with

azure

A at pH

4.

21

Colloidal

iron

stains sialomucins and weakly acid

sulfo-mucins. Bismarck brown has been reported

as

staining

keratosulfate,21

although

the

specificity

of

this

reactiomi

needs

further

clarification.

Utilizing

these

vIPS

stains,

a miumber

of

zones

within

cartilage

matrix

have

been

defined

and

designated

as

the

lacunar

cap-sule,

territorial

matrix,

and

granular

amid

amorphous

interterritorial

matrices.

The

genesis

of the

hvahine

cartilage

matrix

from

chondrocytes

Ilas

been

defined

by

the

electron

microscopic

studies

of

Godman

and

22

Both

granular

and

amorphous

contents of the vesicles of ciiondrocvte

cytoplasm

are

discharged

into

the

matrix.

Whether

normal

genesis

takes

place

at

the

cell

cortex

or

within

the

matrix

remains

umicleam’.

The

hvahne

cartilage

of

the

patieuit

re-I)Ortedl

llere

show-s

atypical

features

in

all

of the matrix components as

vell

as

of

chondrocytes

and

of

the

over-all

pattern

of cartilage formation amid endochondral

bomie formiiation. Two specific chamiges of

the

cartilage

matrix

have

been

identified.

Iii

one,

the

gramiular

acid-IPS

component

of

the

interterritorial

matrix

becomes

(11)

col-lagen

and

reticulin.

In

the

other,

stainable

granular

acid-MPS

is absent,

and

increased

staining

with

Bismarck

brown

of

the

re-maining

amorphous

material

suggests

ac-cumulation

of

keratosulfate.

The

lack

of

staining

of

any

matriceal

component,

and

of

chondrocyte

or

histiocyte-type

cell

cyto-plasm,

with

azure

A at

pH

2 indicates

the

absence

of

accumulation

or

storage

of

strongly

acid

MPS

such

as

chondroitin

and

heparin

sulfate.

Histochemically

definable

atypism

in

chondrocytes

has

not

been

pos-sible,

and

the

proposal

that

these

cells

are

abnormal

is

based

primarily

on

their

shape,

size,

growth

pattern,

and

abnormal

MPS

production.

The

foam

cells

with

vac-uolated

cytoplasm

arranged

in

nests

and

sheets

contain

greater

quantities

of

stain-able

acid-MPS

and

possible

keratosulfate

than

do

adjacent

chondrocytes.

Their

nature

is

difficult

to

define,

and

it

is

not

possible

to

state

with

certainty

whether

they

represent

(a)

nests

of

true

histiocytes

phagocytizing

abnormal

matrix

compo-nents,

(b)

chondroblast

nests

differentiating

into

chondrocytes,

or

(c)

chondrocytes

undergoing

transformation

into

histiocyte-like

cells.

While

it is not

possible

to

assess

the

specific

nature

of

many

of the

changes

described,

it

seems

plausible

to

propose

that

abnormalities

of

the

cartilage

matrix

are

the

result

of

abnormal

MPS

production

by

chondrocytes.

It

also

seems

plausible

to

propose

that

the

pattern

of growth

and

de-velopment

of

abnormal

cartilage,

as

in-fluenced

by

external

stresses,

may

be

markedly

different

from

the

normal.

The

morphologic

pattern

seen

at any

one

partic-ular

time

must

be

the

composite

expres-sion

of

the

primary

biochemical

defect

as

well

as

the

secondary

changes

in

growth

influenced

by

external

stimuli.

In

the

pres-ent

case,

cartilage

from

the

costochondral

junction

shows

relatively

less

abnormality

in epiphyseal

chondrocyte

proliferation

than

does

cartilage

from

the

vertebral

bodies

and

femoral

head.

Also,

only

the

amorphous

type

matrix

lesion

is apparent

in the

costo-chondral

areas.

These

differences

between

cartilage

which

is

primarily

articular

and

weight

bearing

(vertebral

bodies

and

fem-oral

head)

and

cartilage

which

is

not

subjected

to such

a stress

suggests

a possible

contribution

of

this

factor

in

stimulating

chondrocyte

proliferation

and

matrix

fi-brillogenesis.

The

finding

of a patent

ductus

arteriosus

in

the

present

case

may

not

be

incidental

to

the

Morquio’s

disease.

Von

Thoenes

and

Holldach23

have

reported

a

case

of

Morquio’s

disease

associated

with

coarcta-tion

of

the

aorta.

Unfortunately,

neither

radiologic

nor

pathologic

material

was

available,

and

a statement

in

their

clinical

summary

to

the

effect

that

corneal

abnor-malities

were

present

suggests

that

this

case

may

have

been

of

the

Morquio-Ullrich

type.

There

is

apparently

no

increase

in

the

incidence

of

congenital

heart

disease

in

Hurler’s

disease.

The

cardiovascular

ab-normalities

of

Hurler’s

disease

are

to

the

infiltration

of

coronary

arteries

and

the

myocardium

by

MPS

containing

histio-cytes. Histologic examination of

the

aorta

and

pulmonary

artery

in

the

present

case,

especially

at

the

site

of

the

window-type

ductus arteriosus, revealed no

abnormali-ties

of

connective

tissue

or

ground

sub-stance.

There

is little

doubt,

however,

that

reversal

of flow

through

the

ductus,

severe

pulmonary

hypertension,

and

congestive

heart

failure

were

more

important

factors

in

this

patient’s

demise

than

the

Morquio’s

disease.

The

presence

of

typical

skeletal

changes

of

Morquio’s

disease

as

well

as

recently

discovered

corneal

opacities

in

a

17-year-old

sister

suggests

that

this

patient

has

or

is

developing

the

Morquio-Ullrich

variant.

Thus

far

she

shows

no

evidence

of

mental

deterioration

or

visceral

storage

disease.

Urinary

analysis

for

MPS

and

biopsy

of

bone

are

contemplated.

SUMMARY

The

radiologic

and

morphologic

changes

seen in a patient with Morquio’s disease who

came

to

autopsy

are

described

and

(12)

850 MORQUIO’S

DISEASE

cartilage

and

consisted

of

cytochemically

definable

lesions

of the

matrix

characterized

by

the

presence

of amorphous

and

fibrillar

lesions

and

the

accumulation

of foam

cells.

An

abnormal

accumulation

of

mucopoly-saccharides

in foam

cells

and

cartilage

ma-trix was present. No evidence of visceral

storage

of

mucopolysaccharides,

such

as

is

seen

in Hurler’s

disease,

was

present.

In

ad-dition

to Morquio’s

disease,

this

patient

had

a patent

ductus

arteriosus.

Clinical

features

and

radiologic

changes

in

an

older

living

sibling,

who

has

had

Morquio’s

disease

and

is

now

apparently

developing

the

Morquio-Ullrich

variant,

are

described.

REFERENCES

1. Morquio, L. : Sur une forme de dystrophie

osseuse

familiale.

Arch.

Med.

Enf.,

32:129,

1929.

2. Brailsford,

J.

F.

:

Chondro-osteo-dystrophy.

Amer.

J.

Lung, 7:404, 1929.

3. Drysdale,

J.

H. : An undescribed form of

dwarfism associated with a spatula

condi-tion

of

the

hands.

Quart.

J. Med.,

1:103, 1908.

4. Wheeldon,

T. F. : A study of achondroplasia.

Amer.

J. Dis.

Child.,

19:1,

1920.

5. Grudzinski, Z.: tYber eine neue mit

Achon-droplasie

Krankheitsform.

Fort-schr.

Rontgenstr.,

38:873,

1928.

6. Einhorn, N. H., Moore,

J.

R., and Rowntree, L. C. : Osteochondrodystrophia deformans

(Morquio’s

disease).

Amer.

J. Dis.

Child.,

72:536, 1946.

7. Einhorn, N. H., Moore,

J.

R., Ostrum, H. W.,

and

Rowntree, L. G. :

Osteochondrodys-trophia

deformans

( Morquio’s

disease).

Re-port of 3 cases. Amer.

J. Dis.

Child.,

61:776,

1941.

8. SHELLING, D. C. : Osteochondrodystrophia

deformans (Morquio’s

disease).

In Brenne-man’s Practice of Pediatrics. Chapter 29. Hagerstown, Maryland: W. F. Prior, 1959. 9. Aegerter, E. E., and Kirkpatrick,

J. A.,

Jr.:

Orthopaedic

Diseases:

Physiology,

Pathol-ogy, Radiology.

Philadelphia:

W. B.

Saunders, 1958, p. 99.

10. Anderson, C. E., Crane,

J.

T., Harper, H. A.,

and

Hunter,

J.

W. :

Morquio’s

disease

and

Dysplasia Epiphysalis Multiplex.

J.

Bone

Joint

Surg., 44-A:295, 1962.

11. McKusick, V. A.: Hereditable Disorders of Connective Tissue. 2nd edition. St. Louis:

C. V. Mosby, pp. 242-284, 1960.

12. Ulirich, 0. : Die Pfaundler-H#{252}rlersche Krank-heit. Ergebn. Inn. Med. Kinderheilk.

63:929, 1943.

13.

Wiedemann,

H. R. :

Aus

gedehnte

und

ailge-meine

erblichbedingte

Bildungs-

und

Wachs-tumsfehler des Knocheingerustes. Mschr.

Kinderheilk,

102:136, 1954.

14. Dyggve, H. V., Melchior,

J.

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Acknowledgments

We wish to acknowledge the

assistance

of Dr.

Roger

Terry

and

Dr. John Ashton of the

De-partment

of

Pathology and Dr. Lent C. Johnson

of the Armed Forces Institute of Pathology in the

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1964;34;839

Pediatrics

Eric A. Schenk and James Haggerty

MORQUIO'S DISEASE: A Radiologic and Morphologic Study

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