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Publicly Available Published by De Gruyter July 6, 2017

Everolimus treatment of a fetal intracardiac rhabdomyoma not associated with the tuberous sclerosis complex: a case report

  • Monica Schmidt-Fittschen EMAIL logo , Stephan Spahn , Ammar Al Naimi , Dietmar Schranz and Franz Bahlmann

Abstract

Introduction

Benign cardiac rhabdomyomas are the most common cardiac tumors in fetuses and children. They are most often located in the ventricles and may disturb myocardial function, the severity correlating with location and size of the tumor. Rhabdomyomas are commonly associated with the tuberous sclerosis complex (TSC) and are the first clinical manifestation in 50–80% of the cases [Isaacs H Jr. Fetal and neonatal cardiac tumors. Pediatr Cardiol. 2004;25:252–73, Colosi E, Russo C, Macaluso G, Musone R, Catalano C. Sonographic diagnosis of fetal cardiac rhabdomyomas and cerebral tubers: a case report of prenatal tuberous sclerosis. J Prenat Med. 2013;7:51–5]. Several authors have documented the sensitivity of TSC-associated rhabdomyomas to everolimus treatment [Hoshal SG, Samuel BP, Schneider JR, Mammen L, Vettukattil JJ. Regression of massive cardiac rhabdomyoma on everolimus therapy. Pediatr Int. 2016;58:397–9, Mlczoch E, Hanslik A, Luckner D, Kitzmüller E, Prayer D, Michel-Behnke I. Prenatal diagnosis of giant cardiac rhabdomyoma in tuberous sclerosis complex: a new therapeutic option with everolimus. Ultrasound Obstet Gynecol. 2015;45:618–21, Tiberio D, Franz DN, Phillips JR. Regression of a cardiac rhabdomyoma in a patient receiving everolimus. Pediatrics. 2011;127:e1335–7]. The present study provides convincing evidence of successful everolimus therapy in a newborn without the TSC complex.

Case presentation

A cardiac rhabdomyoma measuring 35 × 28 × 24 mm was seen in a fetus in pre- and postnatal echocardiography. There was no family history for TSC and amniocentesis showed no mutations in the TSC1/TSC2 genes. Off-label treatment with everolimus began when the neonate was 11 days old and was discontinued when the infant was 11 months old after echocardiography showed marked regression of tumor size and improvement of the tricuspid valve insufficiency. Echocardiography 3 months later showed an increase in size to 13.2 × 9 mm, so that everolimus therapy was re-instated. The next echocardiography, 10 weeks later, showed renewed regression of tumor size and a residual moderate tricuspid valve insufficiency under everolimus therapy.

Discussion

The present report of a rhabdomyoma in a newborn without an association with TSC is of interest because it identifies a treatment effect of everolimus. A medical approach in patients with cardiac decompensation due to intracardiac rhabdomyomas offers an attractive alternative to surgery.

Introduction

Benign cardiac rhabdomyomas are recognized as the most common cardiac tumors in fetuses and children, although fetal cardiac tumors are generally rare. They are hamartomatous tumors most often located in the ventricles, but may occur in any area of the fetal heart [1], [2]. Rhabdomyomas may disturb myocardial function by causing arrhythmias, pre-excitation, mechanical obstructions of the outflow tracts and valve regurgitations. The severity correlates with location and size of the tumor. As spontaneous regression is frequently seen during the first year of life, surgical treatment is considered only in cases of persistent cardiac instability and threatening clinical signs [1]. Rhabdomyomas are commonly associated with the tuberous sclerosis complex (TSC) and are the first clinical manifestation in 50–80% of the cases [1], [2]. TSC is a genetic disorder with autosomal dominant inheritance and variable expression caused by the mutation of one of the two TSC genes, whose gene products regulate the mammalian target of rapamycin (mTOR) signaling pathways. TSC is characterized by benign tumors such as hamartomas and angiofibromas in multiple organ systems as well as by mental retardation and epilepsy [1], [2]. Previous reports have documented the sensitivity of TSC-associated rhabdomyomas to everolimus treatment [3], [4], [5]. The basic mechanism of action of compounds such as everolimus is the inhibition of the mTOR complex, similar to the hamartin-tuberin (TSC1-TSC2) complex, which antagonizes the mTOR signaling pathway that regulates cell growth and proliferation [6]. The present study provides convincing evidence of successful everolimus therapy in a newborn free of the TSC complex.

Case presentation

A 24-year-old primipara presented at our tertiary care center at 22+2 weeks’ gestation with a cardiac mass in the right ventricle of the fetus. After fetal echocardiography, we suspected a rhabdomyoma, measuring 17.3 × 13.7 × 12.7 mm at the time. There was no tricuspid valve regurgitation or outflow tract obstruction. Fetal growth and neurological development appeared normal. There was no family history for TSC and the cytogenetic analysis of amniotic fluid showed no mutations or deletions in the TSC1/TSC2 genes. The tumor grew progressively to 34.3 × 27.7 × 19.4 mm (Figure 1), causing increased holosystolic tricuspid valve insufficiency without signs of fetal hydrops. We referred the patient to the University Clinic in Giessen, Germany, where a cesarean section was performed at 37+0 weeks’ gestation. The male newborn weighed 3280 g (95th centile) and APGAR scores were 6/7/9 at 1 min, 5 min and 10 min, respectively.

Figure 1: 
A fetal cardiac rhabdomyoma measuring 2.77 × 1.94 × 3.43 cm in a fetus in the 36th gestational week.
It was located in the right atrium and protruded into the right ventricle, thus causing severe tricuspid valve insufficiency.
Figure 1:

A fetal cardiac rhabdomyoma measuring 2.77 × 1.94 × 3.43 cm in a fetus in the 36th gestational week.

It was located in the right atrium and protruded into the right ventricle, thus causing severe tricuspid valve insufficiency.

Postnatal magnetic resonance imaging (MRI) of the brain showed no TSC-specific cortical tubers or nodules. Genetic analysis confirmed the absence of mutations and deletions in the TSC1/TSC2 genes in the neonate. Postnatal echocardiography and MRI of the heart confirmed the prenatal diagnosis of a cardiac rhabdomyoma measuring 35 × 28 × 24 mm that protruded from the right atrium into the right ventricle through the tricuspid valve, thus causing severe valve insufficiency.

Off-label treatment with everolimus began with the parents’ informed consent, at a dose of 0.1 mg/day (2 × and 1 × 0.1 mg everolimus every other day, target range 6–10 μg/L) when the neonate was 11 days old. The infant was discharged from the hospital at 4 weeks of age in stable medical condition.

Everolimus therapy was discontinued when the infant was 11 months old after echocardiography showed marked regression of tumor size to 8 × 8 mm as well as improvement of the tricuspid valve insufficiency. Repeat cerebral MRI, EEG, neuropediatric examinations and abdominal ultrasound showed no abnormalities. As the possibility of a spontaneous regression of the tumor could not be ruled out, it was not clear at this point whether or not everolimus therapy was solely responsible for tumor regression. A cardiac MRI performed only 3 weeks after discontinuation of everolimus therapy showed an increase in size to 10 × 11 mm, and 3 months later to 13.2 × 9 mm as shown by echocardiography. Everolimus therapy was re-instated at a dose of 2 × 0.4 mg/day. At the next echocardiography, only 10 weeks later, the patient presented with renewed regression of tumor size to 8 × 7 mm and a residual moderate tricuspid valve insufficiency. At the time of this report, the child is 2 years old, still on therapy with everolimus at the same dose, with stable cardiac function and no clinical signs of TSC.

Discussion

The present report of a rhabdomyoma in a newborn without the genetic abnormalities associated with TSC provides convincing evidence that the partial regression of the tumor is attributable to the everolimus treatment. Partial regression during the initial treatment period followed by renewed tumor growth in the off-treatment period and another regression during the second treatment clearly identifies a treatment effect of everolimus.

Previous publications have reported successful treatment of TSC-associated rhabdomyoma with everolimus, suggesting that this therapy could be especially useful for patients with severe cardiovascular symptoms who are not eligible for surgical intervention [3], [4], [5].

Thus, Hoshal et al. [3] reported a male fetus born in the 35th week of gestation with TSC and a massive intrapericardial rhabdomyoma severely depressing systolic function. Ten months after commencing treatment with everolimus, the tumor had almost completely regressed and the left ventricular ejection fraction was normal (63%). Tiberio et al. [5] reported the case of a 5-year-old boy born with TSC and a large left ventricular rhabdomyoma. Thirteen months after initiation of treatment with everolimus, echocardiography showed that the rhabdomyoma had almost completely regressed, suggesting a treatment effect. A possible explanation for this therapeutic effect was provided by a recent publication demonstrating increased mTOR expression (the target of everolimus) in cardiac rhabdomyomas associated with TSC [6]. In a patient without TSC, mTOR would presumably be expressed normally. This raises the interesting question whether the successful everolimus treatment of our patient’s rhabdomyoma not associated with TSC was due to the same pharmacologic mechanism active in rhabdomyoma that are associated with TSC, i.e. downregulation of mTOR. Alternatively, although perhaps less likely, everolimus could also have a yet unknown off-target effect that is responsible for tumor regression. Unfortunately, in the present case, no quantitative data are available of the levels of TSC1 and TSC2 nor of mTOR or of proteins of TSC-independent signaling pathways regulating mTOR [7], [8]. Such data would be helpful to evaluate the mechanisms responsible for tumor regression in our patient. These questions will need to be addressed in future studies.

Regardless of these mechanistic considerations, the reports discussed above [3], [5] as well as our own observations, show that everolimus therapy seems to offer an attractive alternative to surgery in newborns, infants and children with cardiac decompensation due to intracardiac rhabdomyomas. It is of particular interest that three publications described the use of everolimus for the purpose of immunosuppression in patients with kidney transplants even during pregnancy. In these reports, all infants showed normal growth and no congenital anomalies [9], [10], [11]. Taken together, all these observations suggest that everolimus may even become an encouraging therapy in utero.

Acknowledgments

We would like to thank the Dr. Senckenbergische-Stiftung Foundation in Frankfurt, Germany, for their support.

Author’s statement

  1. Conflict of interest: The authors declare no conflict of interest.

Material and Methods

  1. Informed consent: Informed consent has been obtained from all individuals included in this study.

  2. Ethical approval: The research related to human subject use has complied with all the relevant national regulations, and institutional policies, and is in accordance with the tenets of the Helsinki Declaration, and has been approved by the authors’ institutional review board or equivalent committee.

References

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Received: 2016-11-14
Accepted: 2017-03-06
Published Online: 2017-07-06

©2017 Walter de Gruyter GmbH, Berlin/Boston

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