Address correspondence to: Lawrence Dolkart, MD, 600 Fitch Street, Elmira, New York, 14905-1634 Tel: 607-737-1184, Fax: 607-737-1185.

Synonyms: Myocardial hamartoma.

Definition: A benign smooth muscle tumor of the myocardium, consisting of immature myocytes.

Prevalence: Tuberous sclerosis: 0.2-1:10,000 persons^1,2; rhabdomyoma in association with tuberous sclerosis: up to 50-60% of cases^3-5.

Etiology: Tuberous sclerosis is an autosomal dominant Mendelian condition, though the majority of new cases represent new mutations. At least two gene loci have been identified (chromosomes 9 and 11) ^6-8. The cause for associated tumor generation is unknown.

Pathogenesis: Rhabdomyomas are probably not true neoplasms, but rather hamartomas, with few mitotic figures and the absence of metastases.

Associated anomalies: Tuberous sclerosis is associated with widespread hamartomatous malformations in multiple organs⁹.

Resulting cardiac anomalies: Arrhythmias,^10,11 pericardial effusions,¹² hydrops,¹³ ventricular outflow obstruction.

Differential diagnosis: Cardiac fibroma, myoma, teratoma, sarcoma⁵.

Prognosis: High mortality rate by 5 years of life in autopsy series¹⁴; the natural history of the disease diagnosed in the antenatal period remains poorly defined.

Recurrence risk: A parent with tuberous sclerosis has a 50% chance of having a child with the disease, though penetrance and expressivity are variable.

Management: Expectant observation in utero; after birth, observation for tumor regression or surgical resection when possible remain alternative options^15-19.

National support group (USA): National Tuberous Sclerosis Association: Ph: 800-225-NTSA.

MESH Heart-Neoplasms -congenital, complications, diagnosis, complications, pathology. MIM 191100 POS 3417 ICD9 212.7 (benign tumor of the heart), 746.8 (other specified anomalies of the heart) CDC 746.990 (cardiac anomaly) 759.500 (tuberous sclerosis)

Introduction

Tuberous sclerosis is a genetic disease with protean manifestations which affect almost all organ systems. The condition is passed in an autosomal dominant manner, though there are many cases of new mutations²⁰. Definitive antenatal diagnosis using DNA probes or linked markers has not yet been achieved. However, myocardial rhabdomyomata are among the classic manifestations of the disease and, not uncommonly, are discovered in the neonatal period. Prenatal diagnosis may be made with appropriate family history and visualization of characteristic tumors on ultrasonographic examination^21-32. We present a kindred with tuberous sclerosis, describe two fetuses in this family with cardiac tumors, and examine their postnatal course.

Case #1

An 18-year-old G₁P₀ with known tuberous sclerosis presented at 35 weeks of gestation with polyhydramnios. A brother and nephew also had tuberous sclerosis. Fetal echocardiography revealed a 60x45x60 mm echodense mass attached to the left ventricle and cardiac apex (fig. 1).

Figure 1: Left longitudinal view of fetal heart in case #1. A large echodense mass, outlined by a pleural effusion (PE), fills the large chest. The stomach (ST) is noted just below the diaphragm.

A smaller tumor mass was associated with the right ventricular wall (fig. 2).

Figure 2: Four-chamber view of fetal heart in case #1 (only the right atrium [RA] and right ventricle [RV] are labelled). A mass attached to the right ventricular wall and bulging into a pleural effusion (PE) is imaged.

A significant pericardial effusion was noted. A cordocentesis demonstrated a normal female karyotype. At 37 weeks" gestation, an amniocentesis confirmed pulmonary maturity. A primary cesarean section was performed so that the appropriate neonatal support personnel could be present. Birth weight was 2,936g. Intubation was required because of a decreased oxygen saturation and carbon dioxide retention. An aortogram and serial echocardiography confirmed the presence of inoperable rhabdomyomas, mitral and tricuspid regurgitation, a patent ductus arteriosus which closed with Indomethacin therapy, and a pericardial effusion which resolved after a single pericardiocentesis. Extubation was accomplished, feedings began, and there was no evidence of congestive heart failure when the infant was discharged. Tumor size remained unchanged on subsequent echocardiographic examinations, and there never was any evidence of outflow tract obstruction or hemodynamic compromise. Surgical resection was not believed to be an option. The child is now 2 years old, and remains asymptomatic despite persistance of the cardiac tumors. The facial features of the mother are shown in fig. 3.

Figure 3: Pedigree analysis of family with tuberous sclerosis. Fetus in case #1 is III-1 (red arrow); fetuses in case #2 are III-2 and III-3 (blue arrow). Dark blue/red boxes/circles represent males/females with tuberous sclerosis.

Case #2

About 4 months after the patient in case #1 presented, her brother"s spouse, a G₂P₁, was found to be carrying a fetus with two cardiac tumors. This patient"s previous child had tuberous sclerosis but no associated cardiac lesions. The brother had known tuberous sclerosis (see pedigree in fig. 4).

Figure 4: The mother of case #1. Notice the facial angiofibromas (often improperly referred as "adenoma sebaceum").

Fetal ultrasonographic study demonstrated an echodense mass filling the left ventricle. A smaller tumor near the right ventricular outflow tract was noted. An elective repeat cesarean section was performed at 38 weeks" gestation after an amniocentesis demonstrated pulmonary maturity. Birth weight was 3,799g. The infant required nasal continuous positive airway pressure and was rapidly weaned to room air. Postnatal echocardiography confirmed the presence of two cardiac tumors consistent with rhabdomyomas, and an MRI of the brain revealed parenchymal hamartomatous lesions. The infant was discharged without evidence of cardiac decompensation. However, the infant died suddenly at the age of 2 months, presumably from the onset of an arrhythmia.

Discussion

Prevalence

Cardiac tumors are rare, with an incidence among patients of all ages of about 1 in 10,000³³. In the neonate, the rhabdomyoma is the most common tumor, accounting for up to 60% of such lesions³⁴. There have been at least 13 reports of antenatal diagnosis, associated with tuberous sclerosis (reviewed in table I). Since as many as 50% of pediatric patients with tuberous sclerosis will present with rhabdomyomas^35,36, these tumors can serve as markers for this disease, especially in families previously identified as genetic carriers. Crawford et al²¹ were the first to suggest that rhabdomyomas can identify tuberous sclerosis on an antenatal basis. Subsequently, other investigators have confirmed that the prenatal diagnosis of a rhabdomyoma is preliminary evidence that the fetus will have other postnatal manifestations of tuberous sclerosis. Unfortunately, many cases of tuberous sclerosis are new mutations, and a familial history of the disease is often negative.

Etiology

Recent studies have delineated at least two genetic loci, on the long arm of chromosome 9 (9q34) and the long arm of chromosome 11 (11q23)^6-8. Additional loci are possible and are being actively investigated. The specific gene deficit itself is unknown, as is the underlying process by which the tumor is produced.

Table 1: Review of prenatal diagnosis of rhabdomyoma with tuberous sclerosis.

Pathogenesis

A cardiac rhabdomyoma associated with tuberous sclerosis is considered a benign hamartoma of muscle cells. It does not appear to represent a true neoplasm¹⁴, with unchecked cellular mitoses and metastases.

Prenatal diagnosis

Table 1 reviews those case reports which have detected cardiac rhabdomyomas in the prenatal period, in association with tuberous sclerosis. Only reports of such tumors in association with tuberous sclerosis have been included. The tumors are often multiple and present as echodense masses in the myocardium. Tumor size is variable, with some tumors being only a few millimeters in diameter. The largest rhabdomyoma noted in the prenatal literature is presented in our case report. Though the cardiac tumors may be correlated with fetal hydrops or arrhythmias, the massive tumor in this case did not appear to compromise the fetus. A careful search for extracardiac hamartomas should be performed in all cases of fetal cardiac tumors, since such lesions are common in tuberous sclerosis. The extracardiac tumors typically found in children and adults with tuberous sclerosis have thus far not been described in association with cardiac rhabdomyomas on prenatal ultrasound examinations. It is clear that a family history of tuberous sclerosis should mandate the search for cardiac lesions in the fetus of carrier parents. Similarly, any fetus discovered to have a cardiac tumor on ultrasonographic study should require a careful pedigree analysis for tuberous sclerosis in other family members.

Differential diagnosis

The differential diagnosis of any cardiac tumor discovered in the antenatal period should include a teratoma, sarcoma, myxoma, and fibroma (p 2127-5)⁵.

Prognosis and management

Most fetuses with rhabdomyomas in association with tuberous sclerosis do well in the antenatal period. Occasionally, arrhythmias may be noted on fetal heart rate monitoring¹⁰, and in at least one report a rhabdomyoma was related with fetal hydrops¹³. After birth, the natural history of cardiac rhabdomyomas remains uncertain. Some patient series have suggested a poor outcome with a high mortality rate^14,37-39. More recently, some reports have noted the spontaneous regression of these tumors^{15,16,18,19,40,41}. In earlier reports, the worse prognosis may reflect autopsy data rather than cases diagnosed early and followed prospectively using ultrasonographic or other techniques. The reports of spontaneous tumor regression may be consistent with the hamartomatous nature of these lesions.

In the fetus with a rhabdomyoma, serial ultrasound evaluation is indicated to rule out the onset of fetal cardiac decompensation and hydrops. A careful family history may reveal tuberous sclerosis, if this disease is not already obvious in the index case. Tuberous sclerosis in a parent may present with facial angiofibromas Fig. X and hypopigmented skin lesions, and a history of convulsions or mental deficits. Appropriate genetic counselling should be offered to the parturient and other family members. The absence of a family history of the disease does not rule out tuberous sclerosis in the fetus, as many cases may represent new mutations². After delivery, if the neonate is not presenting with significant hemodynamic compromise, expectant observation for tumor regression should be considered. Serial ultrasound evaluation, magnetic resonance imaging, and, in some cases, angiography may be indicated. Surgery may not be necessary, even with massive tumor sizes, especially if tumor regression can be documented. When cardiac outflow obstruction, persistent arrhythmias, cardiac failure, or cardiogenic emboli are present, surgical resection could be lifesaving^17-19. However, surgery may not be possible because of tumor size or position. Delivery at a tertiary care center, with pediatric cardiology and surgery services, is recommended.

References

1. Wiederholt WC, Gomez MR, Kurland LT: Incidence and prevalence of tuberous sclerosis in Rochester, Minnesota, 1950 through 1982. Neurology 35:600-603, 1985.

2. Hunt A, Lindenbaum RH: Tuberous sclerosis: a new estimate of prevalence within the Oxford region. J Med Genet 21:272-277, 1984.

3. Steinbiss W: Zur Kentniss der Rhabdomyome des Herzens und ihrer Beziehungen zur tuberosen Gehirnsklerose. Virchows Arch 243:22-38, 1923.

4. Durass FP: Cardiac manifestations in a case of tuberous sclerosis. Br Heart J 7:37, 1945.

5. Malisch TW, Jeanty P: Cardiac fibroma. The Fetus 2771-1-4, 1991.

6. Fryer AE, Connor JM, Povey S, et al: Evidence that the gene for tuberous sclerosis is on chromosome 9. Lancet 1:659-661, 1987.

7. Clark RD, Smith M, Pandolfo M, et al: Tuberous sclerosis in a live born infant with trisomy due to (11q23.3:22q-11.2) translocation. Am J Hum Genet 43:44 (abstr.), 1988.

8. Smith M, Smalley S, Cantor R, et al: Mapping of a gene determining tuberous sclerosis to human chromosome 11q14-11q23. Genomics 6:105-114, 1990.

9. Roach, ES: Diagnosis and management of neurocutaneous syndromes. Semin Neurol 8:83-96, 1988.

10. Hamner LH, Kaye, MF, Weingold, AB: Difficulty of fetal monitoring in a fetus with intracardiac tumors. Am J Obstet Gynecol 73:477-481, 1989.

11. Brand JM, Frieberg DZ: Spontaneous regression of a primary cardiac tumor presenting as fetal tachyarrhythmias. J Perinatol 12:48-50, 1992.

12. Shenker LI, Reed KL, Anderson CF, et al: Fetal pericardial effusion. Am J Obstet Gynecol 160:1505-1508, 1989.

13. Guereta LG, Burgueros M, Elorza MD, et al: Cardiac rhabdomyoma presenting as fetal hydrops. Pediatr Cardiol 7:171-174, 1986.

14. Fenoglio JJ, McAllister HA, Ferrans VJ: Cardiac rhabdomyoma: a clinicopathologic and electron microscopic study. Am J Cardiol 38:241-251, 1976.

15. Alkalay AL, Ferry DA, Lin B, et al: Spontaneous regression of cardiac rhabdomyoma in tuberous sclerosis. Clin Pediatr 26:532-535, 1987.

16. Smith HC, Watson GH, Patel RG, et al: Cardiac rhabdomyomata in tuberous sclerosis: their course and diagnositc value. Arch Dis Child 64:196-200, 1989.

17. Murphy MC, Sweeney MS, Putnam JB, et al: Surgical treatment of cardiac tumors: a 25-year experience. Ann Thorac Surg 49:612-618, 1990.

18. Smythe JF, Dyck JDS, Smallhorn JF, et al: Natural history of cardiac rhabdomyoma in infancy and childhood. Am J Cardiol 66:1247-1249, 1990.

19. Farooki ZQ Ross RD, Paridon SM: Spontaneous regression of cardiac rhabdomyoma. Am J Cardiol 67:897-899.

20. Emery AE, Rimoin DL: Principles and practice of medical genetics, Edinburgh, Churchill Livingstone, 1990, p 440-442.

21. Crawford DC, Garrett C, Tynan M, et al: Cardiac rhabdomyomata as a marker for the antenatal detection of tuberous sclerosis. J Med Genet 20:303-312, 1983.

22. Birnbaum SE, Mcgahan JP, Janos GG, et al: Fetal tachycardia and intramyocardial tumors. J Am Coll Cardiol 6:1358-1361, 1985.

23. Plais MH, Baril JY, Lebret M: Diagnostic antenatal d"une tumeur cardiaque evocatrice d"une sclerose tubereuse de Bourneville. J Gynecol Obstet Biol Reprod 14:759-762, 1985.

24. Muller L, De Jong G, Falck V: Antenatal ultrasonographic findings in tuberous sclerosis. S Afr Med J 69:633-638, 1986.

25. Journel H, Roussey M, Plais MH, et al: Prenatal diagnosis of familial tuberous sclerosis following detection of cardiac rhabdomyoma by ultrasound. Prenat Diagn 6:283-289, 1986.

26. Gresser CD, Shime J, Rakowski H, et al: Fetal cardiac tumor: A prenatal echocardiographic marker for tuberous sclerosis. Am J Obstet Gynecol 156:689-690, 1987.

27. Platt LD, Devore GR, Horenstein J, et al: Prenatal diagnosis of tuberous sclerosis: The use of fetal echocardiography. Prenat Diagn 7:407-411, 1987.

28. Chitayat D, McGillivray BC, Diamant S, et al: Role of prenatal detection of cardiac tumours in the diagnosis of tuberous sclerosis - report of two cases. Prenat Diagn 8:577-584, 1988.

29. Monnier JC, Tiverghien B, Vaksmann G, et al: La sclerose tubereuse de Bourneville. J Gynecol Obstet Biol Reprod 17:495-499, 1988.

30. Sadoun E, Adotti F, Dupard MC, et al: Rhabdomyome cardiaque neonatal et phacomatoses. Arch Fr Pediatr 45::349-351, 1988.

31. Gava G, Buoso G, Beltrame GL, et al: Cardiac rhabdomyoma as a marker for the prenatal detection of tuberous sclerosis. Case report. Br J Obstet Gynecol 97:1154-1157, 1990.

32. Wallace G, Smith HC, Watson GH, et al: Tuberous sclerosis presenting with fetal and neonatal cardiac tumours. Arch Dis Child 65:377-379, 1990.

33. Rowe RD, Freedom RM, Mehrizi A: The neonate with congenital heart disease. WB Saunders, Philadelphia, 1981, p 681-688.

34. Foster ED, Spooner EW, Farina MA, et al: Cardiac rhabdomyoma in the neonate: Surgical management. Ann Thorac Surg 37:249-253, 1984.

35. Bass JL, Breningstall GN, Swaiman KF: Echocardiographic incidence of cardiac rhabdomyoma in tuberous sclerosis. Am J Cardiol 55:1379-1382, 1985.

36. Keith JK, Rowe RD, Vlad P: Heart disease in infancy and childhood, 2nd ed. Macmillan, New York, 1967, p 1171.

37. Mair DD, Edwards WD, Seward JB: Tuberous sclerosis, 2^nd ed.Raven Press, Ltd, New York, 1988, p 147-158.

38. Simcha A, Wells B, Tynan M et al: Primary cardiac tumours in childhood. Arch Dis Child 46:508-514, 1971.

39. Bini R, Westaby S, Bargeron L, et al: Investigation and management of primary cardiac tumors in infants and children. J Am Coll Cardiol 2:351-357, 1983.

40. Khattar H, Guerin R, Fouron J et al: Les tumeurs cardiaques chez l"enfant. Rapport de 3 observations avec evolution spontanement favorable. Arch Mal Coeur 68:419-429, 1975.

41. Ross RE, Paridon SE, Humes RA, et al: Spontaneous regression of cardiac rhabdomyomas. Am J Cardiol 64:416, 1989.