Archives ofDisease in Childhood 1990; 65: 746-749

Echocardiographic abnormalities in type IVmucopolysaccharidosis

R M John, D Hunter, R H Swanton

AbstractCardiac involvement is well recognised inmost forms of the mucopolysaccharidoses butthere is poor documentation of abnormalitiesspecific to Morquio's syndrome (type IVmucopolysaccharidosis). Ten patients withthe classic form or type A Morquio'ssyndrome with a median age of 12-5 yearsunderwent echocardiographic assessment.Abnormalities were detected in six (60%)cases with mitral valve involvement in fivepatients and aortic valve disease in four. Onepatient had severe mitral leaflet thickening tothe point of mitral stenosis. Two patients hadevidence for myocardial involvement by wayof echocardiographic ventricular hyper-trophy. The cardiac lesions were haemodyna-mically mild. A cardiac murmur was audiblein only three of the six cases. It is concludedthat there is a high prevalence of silent cardiacabnormalities in patients with Morquio's syn-drome with predominantly left sided valveinvolvement. Echocardiography should bepart of the assessment of these patients andbacterial endocarditis prophylaxis should beadvised for those with cardiac abnormalities.

Department ofCardiology,The Middlesex Hospital,Mortimer Street,London WIN 8AAR M JohnR H SwantonDepartment ofAnaesthesia,Brompton Hospital,LondonD HunterCorrespondence to:Dr John.

The mucopolysaccharidoses are one class oflysosomal storage disease produced by an in-herited absence or defective activity of one ofthe enzymes involved in the degradation of a

group of complex polysaccharides known asglycosaminoglycans. Intralysosomal accumula-tion of glycosaminoglycans results in progres-sive disability due to differing degrees ofinvolvement of connective tissue and groundsubstance with predominant involvement of theskeletal system. Mucopolysacchariduria is acharacteristic feature and detection of the speci-fic glycosaminoglycan in the urine aidsdiagnosis. To date, eight separate types ofmucopolysaccharidoses have been identifiedbased on the specific lysosomal enzyme defi-ciency and each type has distinct clinical fea-tures leading to eponymous syndromes. TypeIV mucopolysaccharidosis was described in1929 by Morquio in Uruguay and Brailsford inEngland, and is due to defective catabolism ofkeratan sulphate and chondroitin sulphate. Twoforms of the disease has been described. Theclassic form (type A) is due to deficiency of N-acetylgalactosamine 6-sulphate sulphatase, andthe mild form (type B) deficiency of ,1-galactosidase.

Patients with Morquio's syndrome have atypical appearance. Severe skeletal deformitydue to spondyloepiphyseal dysplasia, appreci-

able dwarfism with thoracolumbar gibbus, andpigeon chest are the main features. Joint laxity,mid face hypoplasia with wide spacing of teeth,and thinning of dental enamel are other charac-teristics. Corneal clouding and deafness developin later life. Unusual among the mucopolysac-charidoses, intellect is normal or only minimallyreduced. An invariable feature of Morquio'ssyndrome is the absence or severe hypoplasia ofthe odontoid process of the second cervical ver-tebrae. This requires posterior spinal fusion toprevent cervical myelopathy. Before develop-ment of adequate orthopaedic management ofcervical spine subluxation, death resulted fromprogressive myelopathy by 20 to 40 years of age.

Cardiac involvement due to abnormal deposi-tion of glycosaminoglycans has been describedin most types of mucopolysaccharidoses,2 butlittle note made of abnormalities in Morquio'ssyndrome. The widely accepted associationwith Morquio's syndrome is aortic regurgita-tion.3 As there was no clinical evidence of aorticregurgitation in patients with mucopolysacchar-idosis IV undergoing posterior spinal fusion inthis centre, we decided to study a group ofpatients with the classical Morquio's syndromeechocardiographically in order to characterisetheir cardiac abnormalities.

Patients and methodsTen patients with the classic or type AMorquio's syndrome attending the orthopaedicclinic at the Royal National Orthopaedic Hos-pital, London, were included in the study. Thegroup had a median age of 12-5 years with arange of 3 to 40 years and comprised five maleand five female patients. Biochemical confirma-tion of the diagnosis had been obtained in sevenpatients. Three of the older patients in whombiochemical data were not available (patients 8,9, and 10 in the table 1 aged 30, 38, and 40 yearsrespectively) had diagnostic clinical features.

Patients were evaluated clinically and echo-cardiographically with an Advanced TechnicalLaboratories (ATL) Mark 600 imager equippedwith a mechanical sector scanner capable ofpulsed Doppler echocardiography in addition toM mode and cross sectional modes. Six monthsinto the study we acquired an ATL Ultramark 6ultrasound system with a phased array scanninghead and patients with positive findings earlierin the study had echocardiography repeatedusing the new equipment with inclusion ofcolour Doppler imaging. Severe chest deformitynecessitated unconventional echocardiographicviews and patients were imaged in whicheverposition ensured adequate visualisation of car-

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Echocardiographic abnormalities in type IV mucopolysaccharidosis

Details of patients studied

Patient Age Auscultation EchocardiographyNo (years), sex

1 3, M Normal Normal2 6, M Normal Normal3 10, M Soft ejection systolic murmur Aortic valve thickening; normal Doppler study

at left sternal edge4 11, F Soft systolic murmur at apex Elongated and thickened mitral valve with prolapse of both leaflets;

broad band mitral regurgitation on Doppler; aortic valvethickening with mild aortic regurgitation

5 12, M Normal Normal6 13, M Normal Posterior mitral leaflet prolapse with narrow band mitral

regurgitation7 14, F Soft ejection systolic murmur Normal

at left sternal edge8 30, M Normal Posterior mitral leaflet prolapse; mild mitral regurgitation; bicuspid

aortic valve with normal function9 38, F Ejection systolic murmur at left Thickened mitral leaflets with narrow band mitral regurgitation;

sternal edge; loud S2 thickened aortic valve with mild aortic regurgitation; no aorticvalve gradient; left ventricle apical hypertrophy

10 40, F Normal Pronounced thickening of mitral leaflets with mild stenosis (meangradient 4-6 mm Hg); mild mitral regurgitation and aorticregurgitation; biventricular hypertrophy

diac structures. Images were obtained using 2 5or 3 5 MHz transducers depending on thepatient's build and depth of structures to beimaged. All echocardiographic data wereviewed and interpreted initially by one of theinvestigators (RMJ) and findings corroboratedwith observations made independently by oneof the other investigators (RHS).

Echocardiographic mitral valve prolapse wasdefined as mid or late systolic posterior dis-placement of part of the mitral systolic closureline to at least 2 mm below the line joining thepoint of valve closure in systole (C) to the pointof valve opening in diastole (D) with superior

leaflet displacement confirmed on cross sectio-nal echocardiography. It was also diagnosed ifthere was a pansystolic prolapse with posteriordisplacement with at least 3 mm below a linejoining C and D.4

ResultsDuring the year 1988, 10 patients known tosuffer with the classic form of Morquio's syn-drome were studied and the findings are sum-marised in the table. Within the limitationsimposed by their skeletal deformities, none ofthe patients experienced cardiac symptoms.

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Figure I Systolicframe apicalfour chamber view ofpatient 4 showing mitral and aortic valve thickening andposterior bowing ofboth mitral leaflets in systole. LV=leftventricle; LA =left atrium; Ao=aorta.

Figure 2 Diastolicframe parasternal long axis view ofpatient 10 demonstratinggross mitral leaflet thickening.There is aortic leaflet thickening to a lesser extent. Ananeurysm ofthe membranous septum is also evident.LVPW=left ventricular posterior wall; MV=mitral valve;AV=aortic valve; IVS=interventricular septum;SA=septal aneurysm; LA=left atrium; LV=left ventricle.

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8John, Hunter, Swanton

No patient gave a history of rheumatic fever.All patients were in sinus rhythm and nor-motensive. Four patients had grade 2 systoliccardiac murmurs on auscultation three ofwhomhad echocardiographic abnormalities. Threepatients had echocardiographic valvular abnor-malities without associated auscultatory find-ings. Overall, echocardiographic abnormalitieswere found in six (60%) of those studied. Theseechocardiographic abnormalities are describedin detail below.

MITRAL VALVEFive (50%) patients had mitral valve disease.Mitral regurgitation was easily detected onpulsed Doppler echocardiography in all ofthese, and clear systolic mitral leaflet prolapsewas evident in three. The mitral regurgitationwas haemodynamically mild in all exceptpatient 4 in whom mild left ventricular andatrial dilatation was also present (fig 1). Theoldest in the group (patient 10) had severethickening of both mitral leaflets to the point ofmitral stenosis (fig 2). Her mitral valve crosssectional planimetric area was 1-4 cm2 and meangradient across the valve at rest was 4 to 6 mmHg. Colour Doppler echocardiography demon-strated a left ventricular inflow jet of mixedvelocities.

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Figure 3 Diastolic frame apical view ofpatient 10 showingmitral leaflet thickening and hypertrophy ofthe leftventricular lateral wall. There is also right ventricular apicalthickening demonstrated on thisframe. RV=-right ventricle;LA=left atrium; LV=left ventricle; Ao=aorta.

AORTIC VALVEAortic valve involvement was detected in fourpatients. In one (patient 3), this was an isolatedabnormality with no functional sequelae. Theother three patients had pulsed Doppler evi-dence of mild to moderate aortic regurgitation.Colour Doppler study showed mild turbulenceof outflow through the aortic valve in twopatients but in all the peak aortic flow velocitywas less than 1-2 m/second. No patient hadaortic stenosis.

MYOCARDIAL INVOLVEMENTThe two patients (9 and 10), who had bothmitral and aortic valve disease, also had myocar-dial abnormalities. These were biventricularconcentric hypertrophy in patient 10 (fig 3) andleft ventricular apical hypertrophy in patient 9.Pulsed Doppler trace on the left ventricularinflow in patient 10 showed a higher flow veloc-ity during atrial systole which suggests a degreeof restriction of left ventricular filling.

OTHER ANOMALIESPatient 10 also had evidence of a membranousseptal aneurysm (fig 2). Patient 8 had a bicuspidaortic valve but without valve stenosis orregurgitation.

DiscussionThe reported frequency of Morquio's syndromeis 0-33 per 100 000 live births.2 There are only44 cases of Morquio's syndrome registered withthe Society for Mucopolysaccharide Diseases inthe United Kingdom. It is therefore, a very rarecondition. Cardiovascular disease has beenreported in all the mucopolysaccharidoses.Dawson commented in 1954 that it was unusualfor a patient with mucopolysaccharidosis tohave a microscopically normal heart atnecropsy.5 There are many publications con-cerning the prevalence of cardiac disease in themore common mucopolysaccharidoses, but asurvey of the literature reveals only two papersdealing with cardiac disease in the Morquio'ssyndrome. Gross et al reported echocardio-graphic features in three patients, one of whomhad severe aortic regurgitation, another discreteseptal hypertrophy with systolic anterior motionof the anterior mitral leaflet and the thirdpatient was normal.6 Ireland and Rowlandspublished a case report of a 48 year old womenwith severe mitral stenosis leading to pulmonaryoedema in whom necropsy showed severemucopolysaccharide infiltration of all fourcardiac valves, the left sided valves considerablymore severely involved than the right.7We report here echocardiographic features of

10 patients with the classic form of Morquio'ssyndrome. We found a high prevalence of silentcardiac abnormalities and contrary to reports instandard text books, mitral involvement was ascommon as aortic valve disease. In this study,mitral valve involvement was more severe withpatient 10 being the extreme example. Mild tomoderate mitral regurgitation with or withoutprolapse of one or both leaflets was the most

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Echocardiographic abnormalities in typeIV mucopolysaccharidosis 749

frequent pattern. Aortic valve disease wascomparatively mild in all four cases with cuspalthickening and mild to moderate aortic regurgi-tation detected only on Doppler echocardio-graphy. Endocardial thickening also appears tobe a late feature of the disease. This was initiallycommented upon by Gross et al where discreetseptal hypertrophy was documented.6 In thisstudy endocardial thickening was evident in twopatients, the magnitude of which was out ofproportion to their valvular abnormalities.The pathology of cardiac involvement in the

common mucopolysaccharidoses is well docu-mented. Characteristically, swelling and vacuo-lation of cells and connective tissue of alllayers of the heart is seen. There is only onepaper documenting the cardiac pathology inMorquio's syndrome, and this described muco-polysaccharide infiltration of all four cardiacvalves.7 Although histological data is not pre-sented in this study, mucopolysaccharide accu-mulation and consequent collagen derangementis the probable cause of the valvular andendocardial abnormalities. The increasing fre-quency and severity of cardiac abnormalitieswith age found in this series is in keeping withthis progressive pathological process.Now that more of these patients are surviving

into later life, cardiac abnormalities will assumea more prominent role in their prognosis. Thesecardiac abnormalities are not always evidentclinically as exemplified by patient 10 whodespite her quite severe cardiac involvement,

demonstrated on echocardiography, had no cli-nical signs of cardiac disease. We suggest thatthese patients should have echocardiography aspart of their routine assessment and follow up.

Although most of these patients will be poorcandidates for mnajor cardiac surgery, ortho-paedic intervention will be necessary at somestage, usually in childhood. Haemodynamicallytheir cardiac abnormalities are unlikely to beimportant in the context of surgery, but thehigh prevalence of valvular abnormalities foundin this study suggests that antibiotic prophylaxisagainst infective endocarditis is indicated.

We would like to thank Mrs Mary Toole of the Society for Muco-polysaccharide disease for her most gracious assistance in recruit-ing patients for this study.

This work was in part supported by the Middlesex Hospitaland Medical School Research Fund.

1 McKusic VA, Neufeld EF. The mucopolysaccharide storagediseases. In: Stanbury JB, Wyngaarden JB, FredricksonDB, Goldstein JL, Brown MS, eds. The metabolic basis ofinherited diseases. 5th Ed. New York: McGraw Hill, 1983:751-77.

2 Lowden AJ, Pearse RG, Rowe RD. Cardiac involvement inthe mucopolysaccharidoses. In: Keith JD, Rowe RD,Vlad P, eds. Heart disease in infancy and chidhood. 3rd Ed.New York: MacMillan, 1978:995-1003.

3 McKusic VA, Kaplan D, Wise D, et al. The genetic muco-polysaccharidoses. Medicine 1%5;44:445-83.

4 Wilcken DE, Hickey AJ. Lifetime risk for patients withmitral valve prolapse of developing severe valve regurgit-ation requiring surgery. Circulation 1988;78:10-4.

5 Dawson IMP. The histology and histochemistry of gargoyl-ism. Journal of Pathology and Bacteriology 1954;67:587-604.

6 Gross DM, Williams JC, Caprolic C, Dominguez B, HowellRR. Echocardiographic abnormalities in the mucopolysac-charide storage diseases. Am J Cardiol 1988;61:170-6.

7 Ireland MA, Rowlands DB. Mucopolysaccharidoses type IVas a cause of mitral stenosis in an adult. BrHeartJ 1981;46:113-5.

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