FOCAL GIANT CELL CARDIOMYOPATHY WITH BECKWITH-WIEDEMANN SYNDROME

Sudesh Kapur. MD, Karen S. Kuehl, MD, Frank M. Midgely, MD, and Roma S. Chandra, MD Children’s Hospital National Medical Center and George Washington University School of Medicine, Washington, D.C.

Departments of Pathology, Cardiology, and Surgery,

Cardiac involvement in Beckwith- Wiedemann syndrome is mostly limited to mild cardiomegaly. Although these patients have visceromefaij, macroglossia, gigantism, and adrenal ytomegaij, no signifi- cant myocardial changes have been described. An infant with dysmorphic features o f this syndrome had supraventricular tachycardia since birth. Nodular lesions were present in the right atrium. Morphologi- cally these lesions were composed of hypertrophic myocardial fibers admixed with multinucleated giant cells of myogenic origin. The exact nature o f these lesions remains undetermined. It is postulated th3t hypertrophic myocardial cells may represent cardiac ytomegaly as a manifestation of the accelerated growth potential of cells seen with this syndrome.

KEY WORDS: Beckwith- Wiedemann syndrome, cardiomyopathy, giant cell.

INTRODUCTION

Beckwith-Wiedemann syndrome (BWS) is characterized by omphalocele, macroglossia, adrenal cortical cytomegaly, hyperplasia of gonadal interstitial cells, and hypoglycemia in the neonatal period. Other abnormalities include visceromegaly, renal medullary dysplasia, and postnatal gigantism. ’ Cardiac involvement is mostly limited to cardiomegaly or congenital anomalies such as ventricular septal defect, atrial septal defect, anomalous retroesophageal right subclavian artery, and Chiari’s net Cardiac enlargement is usually transitory and is attributed to hypoglycemia or as a component of the viscero- megaly seen in this syndrome. No significant histological changes have been described previously. We report the morphologic findings of multiple nodular lesions resected from the right atrial wall of an infant with supraventricular tachycardia and Beckwith-Wiedemann syndrome.

MATERIALS AND METHODS

The patient is a 1-year-old male with dysmorphic features consistent with Beckwith-Wiedemann syndrome. Tachycardia noted at 1 week of age was

Pediatric PatholoD, 3:261-269, 1985 Copyright 0 1985 by Hemisphere Publishing Corporation

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treated with digoxin and subsequently with quinidine and Inderal. Hemody- namic assessment at 7 months was within normal limits. Electrocardiogram from birth onward showed chaotic atrial rhythm. Electrophysiological studies at the time of cardiac catheterization showed ectopic atrial tachycardia with cycle length of 170 ms. A 2:l block was present at the atrioventricular node. At 9 months of age echocardiography demonstrated an intrinsic thickening within the anterior wall of the right atrium near the sinoatrial node. With intraopera- tive electrode mapping, four ectopic foci were demonstrated in the anterior wall of the right atrium. Three of the foci were resected, and the fourth was inacces- sible to surgery. Postoperatively the infant continued to have arrhythmia and is being controlled medically.

Atrial tissue for routine histology was examined using hematoxylin and eosin, PAS, Masson trichrome, elastic Van Geison, and phosphotungustic acid hematoxylin stains. In addition, tissue from the area of the sinoatrial node was fixed in 2 7’0 glutaraldehyde for electron microscopy. After osmication and dehy- dration, sections were stained with uranyl acetate and lead citrate.

RESULTS

The resected atrial tissue demonstrated a vaguely nodular thickening of the atrial wall measuring up to 6 mm. Sections from the right atrial wall, especially in the vicinity of the sinoatrial node, showed clusters of hypertrophic myocar- dial cells with interspersed atrophic fibers associated with fibrosis. Myocardial fibers measured up to 29 pm in diameter. The cells contained predominantly central enlarged vesicular nuclei. Occasionally nuclei were seen in chains (Fig. 1). In some cells the nuclei were peripherally located. Cross striations were easily seen in the cytoplasm of most hypertrophic cells. Some cells showed cytoplasmic basophilia with focal loss of cross striations. The nuclei of these cells were multilobated; however, in some cells 5-8 distinct nuclei were seen (Fig. 2). The multinucleated cells retained their elongated shape and only occasionally appeared to be rounded. None of the cells demonstrated characteristic features of specialized nodal tissue. The other areas of the atrial wall showed smaller foci of similar changes in the myocardial cells. No inflammatory cells were seen in any of the sections. Atrial appendage was unremarkable.

Ultrastructurally, hypertrophic myocardial fibers showed well-developed sarcomeres, irregular thickening of Z bands, clusters of mitochondria, and con- voluted central or even subsarcolemmal nuclei. Intercalated disks were discern- ible in these cells. Several cells showed focal to widespread loss of myofibrils with streams of actin filaments and irregularly dispersed Z band material (Fig. 3). Loss of myofibrils was rather severe in some cells and was accompanied by proliferation of smooth endoplasmic reticulum, clusters of mitochondria, and myelin bodies (Fig. 4). Mitochondria had normal structure. Most of these cells

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GIANT CELL CARDIOMYOPATHY 263

FIGURE 1. Hypertrophic myocardial fibers interrupted by fibrosis. Cross striations are prominent in some cells. Some fibers contain multiple nuclei in chains. Toluidene Blue, x525.

were interrupted by collagen fibers. Some cells contained thick knots of Z band material arranged circumferentially around disorganized myofilaments (Fig. 5). Some elongated cells had 3-5 distinct nuclei. Nuclei had dispersed euchroma- tin, convoluted nuclear membranes, and prominent nucleoli (Fig. 6). The cyto- plasm contained disorganized myofibrils with focal dissolution of myofibrils and dilatation of smooth endoplasmic reticulum.

DISCUSSION

Supraventricular tachycardia, although rare in infancy, can be seen with a variety of cardiomyopathies. By electrophysiological studies it has been possible to localize ectopic foci of preexcitation, and surgical resection or ablation by cryosurgery has been successful in some reports. Microscopic examination of the resected focus described by Josephson et al.4 demonstrated degenerated

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FIGURE 2. Disorganized myocardial fibers with somewhat elongated rnultinucleated giant cells. Cyto- plasm showed basophilia with loss of cross striation. H&E, x.525.

myocytes and proliferation of mesenchymal cells. In our case multiple nodular lesions were demonstrated to be the site of earliest depolarization. Because of their location, all of the lesions could not be resected. Microscopically these lesions were composed of hypertrophic myocardial fibers, multinucleated giant cells, and atrophic fibers accompanied by fibrosis. Hypertrophic myocardial cells showed a variable degree of basophilic degeneration of the cytoplasm. The multinucleated giant cells were clearly of myogenic origin. Paroxysmal tachy- cardia has been described with nodular lesions in the myocardium as histiocy- toid or lipid cardiomyopathy of infan~y.~.’ These nodules are formed of clusters of cells with xanthomatous or granular eosinophilic cytoplasm. Ultrastructurally these are demonstrated to be myocardial cells showing severe loss of sarcomeres and clusters of mitochondria containing crystalline inclusions. Although severe

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GIANT CELL CARDIOMYOPATHY 265

loss of myofibrils was seen in the present case, clustering of mitochondria was not significant, and no inclusions could be seen in the mitochondria.

Giant cells have been described in a variety of disorders and are most pronounced in giant cell myocarditis, also known as Fiedler’s myocarditis. Two types of giant cells are described-one of clearly histiocytic nature and the other of myogenic origin. Myocardium, in these cases, shows a polymorphous interstitial infiltrate composed of mononuclear cells, plasma cells, and eosino- phils. Most of these patients have a rapidly progressive course. In our case cells with central multiple vesicular nuclei are akin to degenerative and regenerative fibers seen in skeletal muscle in myositis and muscular dystrophy. The presence of fibrosis and multinucleated myocytes certainly suggests a reparative phenom-

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FIGURE 3. Hypertrophic myocardial fiber. Sarcomeres are focally replaced by streams of actin filaments and Z-band-like material. x 3100.

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FIGURE 4. Hypertrophic myocardial fiber showing severe lysis of myofibrils with a sarcoplasm contain- ing- few mitochondria and clusters of myelin bodies. x 3100.

enon to a previous insult such as myocarditis. However, in the absence of inflammatory infiltrates, myocarditis is an unlikely possibility.

The patient had dysmorphic features of visceromegaly and gigantism syn- drome. Hypertrophy and hyperplasia of viscera and soft tissues is a hallmark of this syndrome.' These patients are at a higher risk to develop neoplasia. Adrenal cytomegaly and the propensity to develop neoplasia may be a manifes- tation of accelerated growth potential of cells in BWS, as suggested by Sotelo- A d a and Goode. The only cardiac tumor described with this syndrome has been a fibrous hamartoma of the interventricular septum. In our case multifo- cal areas of hypertrophic myocardial fibers with giant cells and fibrosis do not appear to be neoplastic. The presence of extremely hypertropic myocardial fibers may represent myocardial cytomegaly. Ultrastructurally, most of the hy- pertrophic cells showed a mild to severe degree of degenerative change. These changes are similar to what has been described in hypertrophic ventricular

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GIANT CELL CARDIOMYOPATHY 267

tissue with asymmetrical ventricular septal hypertrophy or with aortic valvular disease’’ or in ventricular tissue with right ventricular outflow obstruction. Widespread loss of myofibrils and proliferation of smooth endoplasmic reticu- lum and myelin bodies probably represent myocardial fibers with basophilic cytoplasm and denote the stage of exhaustion. Subsarcolemmal accumulation of Z band material and irregular thickening of Z bands in hypertrophic myocar- dial cells with well-preserved sarcomeres probably represent the true hyperpla- sia. It has been well established that Z bands are the site of sarcomerogenesis. In tissue culture studies of myocardial tissue from rats and newborn puppies, it has been demonstrated that neosarcomerogenesis begins by proliferation of Z bands.” Z band functions as a template for contractile units to be laid down. Presence of irregular knots of Z band material separated by disorganized actin and myosin filaments in some cells in the present case may represent neosarco- merogenesis. The disarray of actin filaments with knots of Z band material may

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FIGURE 5 . Myocardial fiber showing irregular knots of Z band material clustered around streams of myofilaments. Z band material is also accumulated in subsarcolemmal location. (arrow) x 5800.

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268 S. KAPUR ET AL.

FIGURE 6. hfultinucleated cell with primitive nuclei. Note convoluted nuclear membranes, dispersed eurhroniatin. and proniinent nucleoli. Cytoplasm contains stacks of actin and myosin filaments. Some iilainenrs demonstrate irregular dense knots. x 3100.

he due to disproportionate proliferation of myofilaments and/or incomplete or- ganization of these contractile elements. Similar observations in hypertrophic myocardium with obstructive valvular lesions have been interpreted as early degenerative change secondary to myofibril lysis. Proliferation of nuclei is an important stage in regeneration of myocardial cells. The presence of convoluted nuclei with euchromatin and prominent nucleoli in the giant cells suggests ami- totic division of the nuclei without cytoplasmic division as the source of the giant cells rather than nuclear fusion.

In Beckwith-Wiedemann syndrome cytomegaly of adrenal cortical cells is frequently seen. Ultrastructurally, cytomegalic adrenal cortical cells demon- strate an increased number of interchromatin granules and stacks of granular endoplasmic reticulum suggestive of increased cellular activity.I8 Landing'' sug-

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GIANT CELL CARDIOMYOPATHY 269

gested that the constellation of anomalies in BWS occurs as a result of a defect in growth and maturation. In our case the presence of supraventricular tachy- cardia since birth suggests an intrinsic myocardial disorder. Multifocal areas of hypertrophic myocardial fibers may be a manifestation of an abnormal cellular growth seen in BWS. Ultrastructurally, the myocardial cells demonstrated hypertrophy, mild to severe degenerative changes, and evidence of regenera- tion. Giant-cell transformation may represent a regenerative process and/or an inherent defect of growth and maturation.

REFERENCES

1. Beckwith BJ: Macroglossia, omphalocele, adrenal cytomegaly, gigantism, and hyperplastic viscerome- galy. Birth Defects 5(2): 188-196, 1969.

2. Sotelo-Avila C , Singer D: Syndrome of hyperplastic fetal visceromegaly, neonatal hypoglycemia (Beck- with syndrome). Pediatrics 46:240-251, 1970.

3 . Greenwood RD, Sommer A, Rosenthal A, Craenen J, Nadas A: Cardiovascular abnormalities in Beckwith-Wiedemann syndrome. Am J Dis Child 131:293-294, 1977.

4. Josephson ME, Spear JE, Harken A, Horowitz L, Dario RL: Surgical excision of automatic atrial tachycardia. Anatomic and electrophysiologic correlates. Am Heart J 104: 1076-1085, 1982.

5. Bove K, Schwartz D: Focal lipid cardiomyopathy in an infant. Arch Pathol 5:26-36, 1973. 6. Ferrans VJ, McAllister HA, Wolfgang H H : Infantile cardiomyopathy with histiocytoid change in

7. Kauffman S, Chandra N, Peress S, Rodriguez-Torres R : Idiopathic infantile cardiomyopathy with

8. Witzleben C , Pinto M : Foamy myocardial transformation of infancy, liquid or histiocytoid, myocar-

9 . Burke J , Medline N, Katz A: Giant cell myocarditis and myositis. Arch Pathol 8:359-366, 1969.

cardiac muscle cells. Circulation 53:708-719, 1976.

involvement of the conduction system. Am J Cardiol 30:648-652, 1972.

diopathy. Arch Pathol Lab Med 1027306-311, 1978.

10. Davies MJ, Pomeranz A, Teare RD: Idiopathic giant cell myocarditis-a distinctive clinicopathological

11. Gillie I, Fox H : Mitral stenosis with giant cell myocarditis limited to the left atrium. J Clin Pathol

12. Roberts WC, Ferrans VJ: Morphologic observations in the cardiomyopathies. In: Myocardial Dis- eases, pp. 59-1 16, edited by N O Fowler, New York: Grune and Stratton, 1973.

13. Sotelo-Avila C, Goode W: Neoplasms associated with Beckwith-Wiedemann syndrome. In: Perspec- tives in Pediatric Pathology, edited by H Rosenberg and P Bolande, Vol. 3 , pp. 255-273, Chicago: Year Book, 1976.

14. Reddy TK, Schmike RN, Chang C H , Syoboda DJ, Slaven J , Therou L: Beckwith-Wiedemann syn- drome, Wilm’s tumor, cardiac hamartoma, persistent visceromegaly and glomeruloneogenesis in a two year old. Arch Pathol 94:523-532, 1972.

15. Marron BJ, Ferrans VJ, Roberts WC: Ultrastructural features of degenerated cardiac muscle in pa- tients with cardiac hypertrophy. Am J Pathol 79:387-414, 1975.

16. Jones M , Ferrans V, Morrow A, Roberts WC: Ultrastructure of crista supraventricularis muscle in patients with congenital heart disease associated with right ventricular outflow obstruction. Circulation

entity. Br Heart J 37:192-195, 1975.

21:750-752, 1968.

51:39-67, 1975. 17. Legato M: Sarcomerogenesis in human myocardium. J Mol Cell Cardiol 1:425-437, 1970. 18. Borit A, Kosek J: Cytomegaly of adrenal cortex. Arch Pathol 88?58-64, 1969. 19. Landing BH: Malformation syndromes. In: Pathobiology of Development, edited by EV Perrin and

MJ Finegold, p 135, Baltimore: Williams & Wilkins, 1975.

Received September 20, 1983 Accepted December 18, 1983

Request reprints jrom Sudesh Kapur.

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