foamy myocardial transformation of infancy: inheriteddisease · morphological features of foamy...

J Clin Pathol 1987;40:329-334

Foamy myocardial transformation of infancy: an

inherited diseaseV SUAREZ,* W J FUGGLE,t A H CAMERON,t T A FRENCH,*T HOLLINGWORTHI

From the Department of *Histopathology, Central Pathology Laboratory, Stoke-on-Trent, the Department oftHistopathology, Birmingham Children's Hospital, and the tCellular Pathology Department, Russells HallHospital, Dudley, Birmingham

SUMMARY Five cases of foamy myocardial transformation of infancy, a condition which predom-inantly affects female children under 2 years of age and which causes cardiac arrhythmia or suddendeath, are reported. Of these five cases, four occurred in two sets of siblings, suggesting a possiblehereditary basis for the disease. As far as we know, no other familial cases have been reported. Theother case was of focal disease of the myocardium, as opposed to the diffuse myocardial changesseen in the four familial cases.

Voth' first recognised this rare condition in 1962 anddefined it as arachnocytosis of the heart muscle. In1965 Hudson2 referred to a child who had died inatrial tachycardia and whose heart showed an un-usual form of lipid storage disease with no otherorgan affected.The cases reported have been predominantly in fe-

males and under 24 months of age. Various arrhyth-mias, mainly tachycardias, have been detected beforedeath in several cases. Sudden death in an apparentlyhealthy infant, however, has been documented inseveral others.At necropsy the heart is enlarged. Histological ex-

amination shows myocytes with a swollen, foamy,and granular cytoplasm. Ultrastructural studies haveshown that this granularity is due to increased num-bers of enlarged mitochondria.The aetiology is unknown, but a genetic basis has

been proposed, based on the strong female prepon-derance.3 The following case reports add further evi-dence to a hypothesis of a genetic aetiology.

Case reports

CASES 1 AND 2Two children were born to caucasian non-consanguineous parents (family A), were separatedby an eight year interval. A third sibling, a 7 year oldmale, at the time of death of the second child, is aliveand well at the time of writing.

Accepted for publication 4 September 1986

Case IA 4 month old female infant was admitted to hospitalwith a history of failure to thrive and in severe heartfailure. She was pale but not cyanosed, with a systolicmurmur at the left sternal border. The pulse rate was160/minute. She died eight days after admission insevere congestive cardiac failure.

Case 2An 8 month old baby girl, sibling of case 1, wasadmitted to hospital in congestive cardiac failure. Shehad been completely well until six days previously,when she became sweaty and had diarrhoea. An elec-trocardiogram performed on admission showed a su-praventricular tachycardia with a rate of 155/minute.She died 24 hours later.

CASES 3 AND 4Cases 3 and 4 were two of five children born to cau-casian non-consanguineous parents (family B). Thereare no surviving children from this marriage. Twopregnancies resulted in spontaneous abortions at 12and 20 weeks' gestation. Another sibling died ofencephalitis aged six months and this child had noevidence of cardiac disease at necropsy.Four children from previous marriages and liaisons

are all alive and well at the time of writing.

Case 3Case 3 was a 16 month old male infant who had pre-viously been well and suddenly collapsed and died athome.

329

on March 22, 2021 by guest. P

rotected by copyright.http://jcp.bm

j.com/

J Clin P

athol: first published as 10.1136/jcp.40.3.329 on 1 March 1987. D

ownloaded from

http://jcp.bmj.com/

330Case 4Case was a 4 month old male infant who had beenunwell with a cough and loss of appetite for five daysprior to admission. He had a severe pallor but nofever. His pulse rate was 140/minute, and there wereno cardiac murmurs. There was moderate subcostalrecession, but his breath sounds were vesicular withno added noises. Respiratory infection with possiblesepticaemia was diagnosed. He died 10 hours laterafter a cardiac arrest.

CASE 5An 18 month male infant born to caucasian non-consanguineous parents had been unwell for a fewdays with a rash and one episode of vomiting. Hisgeneral practitioner found that the child was sweatyand feverish with a rash over the trunk. The chest wasclear. Measles was diagnosed. Two days later he wasfound dead in his cot by his mother. Three other sib-lings now aged 10, 3, and 2 years are all well at thetime of writing.

Methods

Random blocks from the free wall of the left ventricle(cases 1-5), right ventricle and interventricular sep-tum (cases 1-4), and both atria (cases 1, 2, and 4) wereeither fixed in formol saline (cases I and 2) or bufferedformalin (cases 3, 4, and 5). Specific blocks to showthe conducting system were not taken. Best's Carminestain (case 2) was used on frozen section and alcoholfixed sections. Two mitochondrial stains were used incase 2. The first was on formalin fixed tissue post-fixed in dichromate and stained by Altmann's acidfuchsin-picric acid technique and the second was ablock staining method.

In the latter- method blocks of formalin fixedwashed tissue were placed in 1% osmium tetroxide inthe dark for seven to 14 days, with two changes ofosmium during that time. After washing in distilledand tap water the blocks were dehydrated, cleared,and embedded in paraffin wax-cut and mounted inthe usual way. Mitochondria were shown as blackgranules. This gave the clearest light microscopic im-pression of the numbers of mitochondria.

Tissue from the free wall of the left ventricle forelectron microscopy (case 2) was fixed in 2-5% phos-phate buffered gluteraldehyde plus 5% sucrose, post-fixed in 1% osmium tetroxide, processed andembedded in TAAB resin, cut and stained in uranylacetate and lead citrate; and viewed with an AEI 801microscope. In case 4 tissue from the free wall of theleft ventricle for electron microscopy was fixed inphosphate buffered formalin, post-fixed in glu-teraldehyde, and secondarily fixed in osmium tetrox-ide. Tissue from the paraffin blocks in case 3 was

Suarez, Fuggle, Cameron, French, HollingworthTable Heart weights at necropsy

Case no Age (months) Heart weight (g) Normalfor age (g)4

1 4 100 272 8 114 373 16 120 484 4 88 27

dewaxed and secondarily fixed in osmium tetroxide.Tissue of cases 3 and 4 was then processed and em-bedded in Emix resin, stained with uranyl acetate andlead citrate, and viewed with an AEl Corinth 500 mi-croscope. Tissue was excised from the paraffin blockin case 5, dewaxed, and treated as case 2. Electronmicroscopy was not performed in case 1.

Pathology

At necropsy the hearts were hypertrophied withprominent left ventricular hypertrophy except forcase 5, in which heart weight was not recorded (table).The endocardium was slightly thickened and opaquewith pale pink pallor of the myocardium (fig 1). Therewere no cardiac malformations. The other organsshowed changes secondary to congestive cardiac fail-ure.

Light microscopic examination of the myocardiumshowed some fatty vacuolation throughout the depth

SP,;.~~~~~~~~~~~~~-

Fig I Case 2: longitudinal slice through heart showingventricular hypertrophy andpallor, especially insubendocardial zone.



j.com/

J Clin P


ownloaded from

http://jcp.bmj.com/

Foamy myocardial transformation of infancy

of the wall in most areas. These stained positivelywith oil red 0. The cytoplasm had a granular appear-ance and did not stain for glycogen, except for thenormal small amount in the subendocardial zone. Theappearances were similar in all the chambers buttended to be most obvious in the left ventricle. Thegranular cytoplasm gave a positive reaction with thetwo mitochondrial stains (fig 2).

Ultrastructurally the myocytes contained largenumbers of mitochondria in wide pools betweenscanty, morphologically normal, myofibrils (figs 3and 4). The mitochondria were concentrated centrally

IIiiiZ

331

in the myocytes and not under the plasma membrane.As well as being unusually numerous, the mito-chondria were rounder and larger than normal. Theirmaximum diameter was about 1-9 gim, but many weremore than 1 25 im. Many contained small dense bod-ies which correspond to the mainly calcified bodiesobserved in several conditions,5 including variouscaridomyopathies. A few mitochondria containedparallel arrays of microtubules 700 nm in length.Most of the mitochondria showed rounded di-latations of the cristae. Several mitochondria con-tained rounded aggregates of glycogen.

Fig 2 Case 2: myocardial mitochondria. (Modified Swank-Davenport.) x 650.

Fig 3 Case 2: myocytes filled with mitochondria andperipherally displaced myofibrils. x 2600.

Fig 4 Case 2: myocyte with round large mitochondria withdense inclusions. x 16 500.



j.com/

J Clin P


ownloaded from

http://jcp.bmj.com/

Suarez, Fuggle, Cameron, French, Hollingworth.r' .

Ic . . -I.,,

s H F _ e s ; U '{

-' .'vt i .,'' 4 .,X 9

,. f. _ s. s '- i ;..s-F . . v -#

i it

Fig 5 Case 5: subendocardial ventricular myocytes withfoamy cytoplasm on right and normal myocytes on left.(Haematoxylin and eosin.) x 125.

Lipid vacuoles, often with a double limiting mem-brane, seemed to correspond with the oil red 0 posi-tive material seen on frozen sections. They wereinterpreted as mitochondria with dissolution of thecristae.The distribution of the changes in the myocardium

in case 5 was less diffuse with numerous focal areas upto 3mm in diameter in the trabecular and sub-endocardial zones of the left ventricle where the myo-cytes were large with abundant granular eosinophilic

cytoplasm (figs 5 and 6). They showed a superficialresemblance to rhabdomyomata but were negative toperiodic acid Schiff, were more granular, and lessvacuolated.

Discussion

Foamy myocardial transformation of infancy is a rarecondition of unknown aetiology. It has been de-scribed mainly in female infants under the age of twoyears and as isolated cases. It has been referred to byvarious names, including isolated cardiac lipidosis,6infantile cardiomyopathy with histiocytoid reaction7or changes,8 histiocytoid cardiomyopathy,39 1011xanthomatous cardiomyopathy,12 -14 focal myo-cardial degeneration,'5 idiopathic infantile cardio-myopathy,'6 focal lipid cardiomyopathy,'7 foamymyocardial transformation of infancy, 18 19 and onco-cytic cardiomyopathy.Yo

These cases present either as sudden deaths, or,more commonly, with acute illnesses lasting a fewhours or days. In the latter instances electro-cardiography shows a variety of arrhythmias includ-ing runs of supraventricular and ventriculartachycardia and Wolff-Parkinson-White syn-drome.' 3 6-9 12 13 15-18 20The principal necropsy findings are in the heart,

which is usually grossly hypertrophied. Yellow nod-ules or a more diffuse yellow discolouration are foundin the myocardium, often as subendocardial lesions.These are mainly found in the left ventricule but alsocommonly affect the right ventricle and both atria. Inour four familial cases the left ventricle was diffuselyhypertrophied and had a pinkish pallor rather than a

332

.1

i'4 ,'. .0

.:

-v ;"1$

- " .II

1,

k"I . -%

I



j.com/

J Clin P


ownloaded from

http://jcp.bmj.com/

Foamy myocardial transformation of infancy 333

yellowish discolouration. In case 5 the changes werefocal and somewhat nodular but were not evident onmacroscopic examination.

Conventional light microscopic examination showslarge myocardial fibres with granular cytoplasm.Stains for mitochondria are positive, and there mayalso be a few lipid globules. It has been suggested thatthe lipid may be derived from mitochondrial mem-branes.16 This view is supported by our ultra-structural findings of membrane bound fat vesicles inthe mitochondria. Electron microscopic examinationshows swollen cells distended by large numbers ofcentrally located mitochondria. At the periphery ofthe cells there are myofibrils, leptofibrils, and occa-sional lipid vacuoles. Most workers regard these cellsas changed myocardial muscle cells. Our casesshowed a similar appearance to those previouslydescribed.Twenty one of the 26 reported cases were female

(where sex was stated), and no other affected mem-bers of the family were described. This female pre-dominance has led some authors3 to suggest apossible X-linked disorder.

Other authors89 have implicated a viral mech-anism as an aetiological factor. In some instancesthere was a prodromal illness, which, they suggested,may have been due to a viral infection; this resemblesthe presentation of case 5. These proposed ae-tiological factors do not explain the female predom-inance or the cardiac hypertrophy.

Silver et al20 described a case with oncocyticchange in several organs, including salivary gland,and have postulated an early antenatal rubella infec-tion as the cause, with subsequent arrest in devel-opment of myocytes in the myocardium. Our familialcases are unlikely to be due to this, although we can-not rule out a non-specific effect of different viruses inearly pregnancy.Our familial cases occurred in two sets of siblings,

one set male and the other female. Both showed themorphological features of foamy myocardial tran-formation of infancy on gross, light microscopic, andelectron microscopic examination. The mother -infamily B had four normal children with two differentsexual partners prior to the current marriage, whichhad resulted in three liveborn children, two of whomdied of foamy myocardial transformation of infancyand one of whom died of encephalitis with no evi-dence of cardiac disease on gross, light microscopic,or electron microscopic examination. Family A hadthree liveborn children; the surviving sibling wasseven years old at the time of writing.From the family histories of these four cases it

would seem likely that foamy myocardial trans-formation of infancy may be an inherited condition,possibly due to an autosomal recessive gene rather

than an X-linked condition, as has been previouslysuggested. A simple autosomal recessive condition,however, cannot explain the female predominance ofthe reported cases.

It is possible that the changes of foamy myocardialtransformation represent the end result of injury tothe myocardium. Different aetiological factors maybe responsible for similar appearances in the heart ofsusceptible subjects. This might account for some ofthe apparent disparities in the presentation of the re-ported cases and the differences in distribution of thefoamy change within the myocardium.The Swank-Davenport method for degenerate my-

elin fibres2` was successfully adapted to show mito-chondria in case 2. The lipid in the membranes of themitochondria is responsible for the positivity, and,although non-specific, has also proved useful inoncocytomas.

We thank Mrs C Price for typing the manuscript.

References

1 Voth D. Uber die Arachnocytose des Herzmiuskels. FrankfurterZeitschr Path 1962;71:646-8.

2 Hudson REB. Cardiovascular pathology. Baltimore: Williams andWilkins Co, 1969:1289.

3 Bruton D, Herdson PB, Becroft DMO. Histiocytoid cardio-myopathy of infancy: an unexplained myofibre degeneration.Pathology 1977;9:1 15-22.

4 Copolleta JM, Wolbach SB. Body length and organ weights ofinfants and children. Am J Pathol 1933;9:55-70.

5 Ghadially FN. Ultrastructural pathology of the cell and matrix.London: Butterworths, 1982:136-8.

6 Ross CF, Belton EM. A case of isolated cardiac lipidosis. BrHeart J 1968;30:726-8.

7 Reid JD, Hajdu SI, Attah E. Infantile cardiomyopathy: a pre-viously unrecognised type with histiocytoid reaction. J Pediatr1968;73:335-9.

8 Ferrans VJ, McAllister HA, Haese WH. Infantile cardio-myopathy with histiocytoid change in cardiac muscle cells.Circulation 1976;53:708-19.

9 Amini M, Bosman C, Marino B. Histiocytoid cardiomyopathy ininfancy: a new hypothesis? Chest 1980;77:556-8.

10 Zimmermann A, Diem P, Cottier H. Congenital "histiocytoid"cardiomyopathy: evidence suggesting a developmental dis-order of the Purkinje cell system of the heart. Virchows Arch(Pathol Anat) 1982;396:187-95.

11 Saffitz JE, Ferrans VJ, Rodriguez ER, Lewis FR, Roberts WC.Histiocytoid cardiomyopathy: a cause of sudden death inapparently healthy infants. Am J Cardiol 1983;52:215-7.

12 MacMahon HE. Infantile xanthomatous cardiomyopathy. Pedia-trics 1971;48:312-5.

13 Radford DJ, Chalk SM. Infantile xanthomatous cardio-myopathy. Aust Paediatr J 1980;16:123-5.

14 Cunningham NE, Stewart J. A rare cause of cot death-infantilexanthomatous cardiomyopathy. Med Sci Law 1985;25:149-52.

15 Haese WH, Maron BJ, Mirowski M, Row RD, Hutchins GM.Peculiar focal myocardial degeneration and fatal ventriculararrhythmias in a child. New Engl J Med 1972;287:180-1.

16 Kauffman SL, Chandra N, Paress NS, Rodriguez-Torres R. Idio-pathic infantile cardiomyopathy with involvement of theconduction system. Am J Cardiol 1972;30:648-52.

17 Bove KE, Schwartz DC. Focal lipid cardiomyopathy in an infant



j.com/

J Clin P


ownloaded from

http://jcp.bmj.com/

334 Suarez, Fuggle, Cameron, French, Hollingworthwith paroxysmal atrial tachycardia. Archives of Pathology1973;95:26-36.

18 Witzleben CL, Pinto M. Foamy myocardial transformation ofinfancy. Arch Pathol Lab Med 1978;102:306-1 1.

19 Becker AE, Anderson RH. Pathology of congenital heart disease.London: Butterworths, 1981:407-12.

20 Silver MM, Burns JE, Sethi RK, Rowe RD. Oncocytic cardio-myopathy in an infant with oncocytosis in exocrine and endo-crine glands. Hum Pathol 1980;11:598-605.

21 Culling CFA. Handbook of histopathological and histochemicaltechniques. 3rd Ed. London: Butterworths, 1974:259-60.

Requests for reprints to: Dr Valerie Suarez, Departmentof Histopathology, The General Hospital, BirminghamB4 6NH, England.



j.com/

J Clin P


ownloaded from

http://jcp.bmj.com/

foamy myocardial transformation of infancy: inheriteddisease · morphological features of foamy...

Documents