Cardiac Rhabdomyomas Presenting with Critical Cardiac Obstruction in Neonates and Infants: Treatment Strategies and Outcome, A Single-Center Experience.

Cardiac rhabdomyomas are the most common benign pediatric heart tumor in infancy, which are commonly associated with tuberous sclerosis complex (TSC). Most rhabdomyomas are asymptomatic and spontaneously regress over time. However, some cases especially in neonates or small infants can present with hemodynamic instability. Surgical resection of the tumor, which has been the gold standard in alleviating obstruction, is not always possible and may be associated with significant morbidity and mortality. Recently, mammalian target of rapamycin inhibitors (mTORi) have been shown to be safe and effective in the treatment of TSC. We present the outcomes of neonates and an infant who received treatment for symptomatic rhabdomyomas at a tertiary cardiology center. Medical records were reviewed to obtain clinical, demographic, and outcome data. Six patients received interventions for symptomatic rhabdomyomas, median age at presentation was 1 day old (range from 1 to 121 days old), and 67% of the patients had a pathogenic mutation in TSC gene. One patient underwent surgical resection of solitary tumor at right ventricular outflow tract (RVOT) successfully. In the four patients with left ventricular outflow tract (LVOT) obstruction, two patients received combined therapy of surgical debulking of LVOT tumor, Stage I palliation procedure, and mTORi and two patients received mTORi therapy. One patient with RVOT obstruction underwent ductal stenting and received synergistic mTORi. Four of the five patients had good response to mTORi demonstrated by the rapid regression of rhabdomyoma size. 83% of patients are still alive at their latest follow-up, at two to eight years of age. One patient died on day 17 post-LVOT tumor resection and Hybrid stage one due to failure of hemostasis, in the background of familial factor VII deficiency. Treatment of symptomatic rhabdomyoma requires individualized treatment strategy based on the underlying pathophysiology, with involvement of multidisciplinary teams. mTORi is effective and safe in inducing rapid regression of rhabdomyomas. A standardized mTORi prescription and monitoring guide will ensure medication safety in neonates and infants with symptomatic cardiac rhabdomyoma. Although the majority of tumors responded to mTORi, some prove to be resistant. Further studies are warranted, ideally involving multiple international centers with a larger number of patients.

Surgical Treatment of Pediatric Refractory Ventricular Tachycardia Originating From a Left Ventricular Rhabdomyoma.

Cardiac tumors are very rare in children, and echocardiography is very important in their detection. The clinical presentation can vary greatly depending on arrhythmia or obstruction. One of the most important factors determining the surgical approach is the clinical process. In this case report, we report the surgical treatment of a rhabdomyoma that caused refractory ventricular tachycardia.

Long-term use of everolimus for refractory arrhythmia in a child with tuberous sclerosis complex.

Tuberous sclerosis complex is associated with the occurrence of cardiac rhabdomyomas that may result in life-threatening arrhythmia unresponsive to standard antiarrhythmic therapy. We report the case of an infant with multiple cardiac rhabdomyomas who developed severe refractory supraventricular tachycardia (SVT) that was successfully treated with everolimus. Pharmacological mTOR inhibition rapidly improved arrhythmia within few weeks after treatment initiation and correlated with a reduction in tumor size. Intermediate attempts to discontinue everolimus resulted in rhabdomyoma size rebound and recurrence of arrhythmic episodes, which resolved on resumption of therapy. While everolimus treatment led to successful control of arrhythmia in the first years of life, episodes of SVT reoccurred at the age of 6 years. Electrophysiologic testing confirmed an accessory pathway that was successfully ablated, resulting in freedom of arrhythmic events. In summary we present an in-depth evaluation of the long-term use of everolimus in a child with TSC-associated SVT, including the correlation between drug use and arrhythmia outcome. This case report provides important information on the safety and efficacy of an mTOR inhibitor for the treatment of a potentially life-threatening cardiac disease manifestation in TSC for which the optimal treatment strategy is still not well established.

Solitary atrial Rhabdomyoma in an infant with tuberous sclerosis: a case report and review of the literature.

BACKGROUND: Despite its rare incidence of 1/40,000, fetal cardiac rhabdomyoma (CR) represents the prevailing type of benign cardiac fetal tumors, which commonly affects the ventricles. Fetal CRs rarely occur in the right atrium. Thus, the presentation of atrial fibrillation and premature atrial contractions (PAC) due to a solitary cardiac rhabdomyoma is an extremely rare scenario. Our literature review found that only 2% (1 out of 61) of rhabdomyoma cases were found in the right atrium. The majority of fetal cardiac rhabdomyomas are associated with tuberous sclerosis complex (TSC). CASE PRESENTATION: A 7-day-old male neonate presented with arrhythmias and an atrial mass for further evaluation. Echocardiography revealed a hyperechoic, round, uniform right atrial mass (25 mm). An abdominal and testicular ultrasound showed multiple thin-walled cortical cysts in both kidneys and a scrotal hydrocele, respectively. His laboratory workup was insignificant except for hypomagnesemia. Electrocardiography revealed junctional rhythm and PACs with wave distortions. A brain magnetic resonance imaging scan revealed multiple subependymal lesions on the frontal and occipital horns of the lateral ventricles. These findings (Fig. 1), along with a family history of TSC, confirmed the diagnosis of TSC with associated CR. The patient was treated symptomatically with an anti-convulsant and monitored with regular follow-ups. Surgical resection was not required. CONCLUSION: Despite CR's predominance in the ventricles, a diagnosis of rhabdomyoma should be kept in mind in the presence of a solitary atrial mass and PACs. Physicians should evaluate systemic findings related to TSC and provide appropriate follow-up and family screening. Surgical resection is not always required, and symptom management can be achieved through medical treatment alone.

Cardiac rhabdomyomas: clinical progression, efficacy and safety of everolimus treatment.

BACKGROUND: Primary cardiac tumors are extremely rare. Cardiac rhabdomyoma is the most common primary cardiac tumor. 50-80% of solitary rhabdomyomas and all multiple rhabdomyomas are associated with tuberous sclerosis complex. Due to spontaneous regression, surgery is necessary only in severe hemodynamic compromise and persistent arrhythmias. Everolimus, a mechanistic target of rapamycin (mTOR) inhibitor, can be used in the treatment of rhabdomyomas seen in tuberous sclerosis complex. We aimed to evaluate the clinical progression of rhabdomyomas followed-up in our center between the years 2014-2019 and evaluate the efficacy and safety of everolimus treatment on tumor regression. METHODS: Clinical features, prenatal diagnosis, clinical findings, tuberous sclerosis complex presence, treatment and follow-up results were evaluated retrospectively. RESULTS: Among 56 children with primary cardiac tumors, 47 were diagnosed as rhabdomyomas, 28/47 patients (59.6%) had prenatal diagnosis, 85.1% were diagnosed before one year of age and 42/47 patients (89.3%) were asymptomatic. Multiple rhabdomyomas were present in 51% and median diameter of tumors was 16mm (4.5 - 52 mm). In 29/47 patients (61.7%) no medical or surgical treatment were necessary while 34% of these had spontaneous regression. Surgery was necessary in 6/47 patients (12.7%). Everolimus was used in 14/47 patients (29.8%). Indications were seizures (2 patients) and cardiac dysfunction (12 patients). Regression in size of rhabdomyomas was achieved in 10/12 patients (83%). Although, in the long-term, the amount of tumor mass shrinkage was not significantly different between patients who received everolimus and untreated patients (p=0.139), the rate of mass reduction was 12.4 times higher in patients who received everolimus. Leukopenia was not detected in any of the patients, but, hyperlipidemia was noted in 3/14 patients (21.4%). CONCLUSIONS: According to our results, everolimus accelerates tumor mass reduction, but not amount of mass regression in the long term. Everolimus may be considered for treatment of rhabdomyomas which cause hemodynamic compromise or life-threatening arrhythmias before surgical intervention.

A case of massive fetal cardiac rhabdomyoma: ultrasound features and management.

We report the case of a massive fetal cardiac rhabdomyoma recently occurred at our clinic. A woman at 23 weeks of gestational age was referred to our center for a fetal cardiac echogenic mass of 26 mm detected at the second-trimester screening ultrasound. During pregnancy, though, the mass progressively increased its dimensions until reaching 48 mm in diameter at 37 weeks of gestation. Fetal echoencephalography and brain magnetic resonance did not show any further fetal anomalies, but molecular genetic testing at amniocentesis revealed a heterozygotic missense variant of gene TSC2 associated with Tuberous Sclerosis. The mass was therefore most likely preferable to a single large rhabdomyoma of gradually increasing dimensions. The baby was delivered at term with a cesarean section. Because of the rhabdomyoma remarkable size and newborn ECG electrical alterations, postnatal therapies with Flecainide and Everolimus were started. Everolimus treatment led to a significant and progressive reduction in the cardiac mass volume. This case, therefore, shows the efficacy of what seems to be a promising treatment in pediatric patients with large rhabdomyomas.Learning points:Rhabdomyomas may present with different features: most often they appear as multiple masses along the interventricular sept, but they may also appear as a single large thoracic mass.When a rhabdomyoma is suspected, genetic counseling is recommended.Both before and after birth, a multidisciplinary approach is useful to choose the appropriate therapy for the newborn.mTOR inhibitors therapies look like promising therapeutic approaches to stimulate the involution of rhabdomyomas.

Imaging of pediatric cardiac tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper.

Cardiac tumors in children are rare and the majority are benign. The most common cardiac tumor in children is rhabdomyoma, usually associated with tuberous sclerosis complex. Other benign cardiac masses include fibromas, myxomas, hemangiomas, and teratomas. Primary malignant cardiac tumors are exceedingly rare, with the most common pathology being soft tissue sarcomas. This paper provides consensus-based imaging recommendations for the evaluation of patients with cardiac tumors at diagnosis and follow-up, including during and after therapy.

[Tuberous sclerosis complex]. / Tuberöse-Sklerose-Komplex.

CLINICAL BACKGROUND: Tuberous sclerosis complex (TSC) is a phakomatosis and is a tumor predisposition syndrome. As a genetic multisystem disease, patients present with a broad range of changes in the brain, heart, skin, kidneys, and lungs. OBJECTIVES: Which imaging modalities are required to monitor TSC patients according to current international recommendations? MATERIALS AND METHODS: Common findings in TSC are cortical tubers, subependymal nodules, and giant cell astrocytomas in the central nervous system (CNS), rhabdomyomas in the heart, and cysts and angiomyolipomas in the kidneys. Magnetic resonance imaging (MRI) of the brain and kidneys and abdominal ultrasound are the imaging modalities of choice, due to the very good soft tissue contrast and lack of X­ray radiation. RESULTS: Using standard and functional MRI sequences in a multimodal approach, the type, malignancy, size, and morphology of changes in TSC can be reliably determined. Abdominal ultrasound using high-resolution transducers can be used to rapidly and reliably detect even the smallest changes in the kidneys. CONCLUSION: Regular follow-up of patients with TSC using MRI and ultrasound is necessary for early detection of complications, for planning individualized therapy, and for optimal lifelong care.

Management of neonatal cardiac rhabdomyoma obstructing the aortic valve.

Rhabdomyomas associated with tuberous sclerosis are common cardiac tumors in children, and no surgical intervention is needed in most cases. However, when the tumor causes left ventricular outlet tract obstruction (LVOTO), immediate surgical intervention is indicated. Here, we report a newborn who was diagnosed antenatally with multiple cardiac rhabdomyomas, one of which blocked the aortic valve during systole. The tumor was resected early in the postnatal period with excellent outcomes. Until surgery, we maintained ductus arteriosus patency and systemic circulation using prostaglandin E1, which helped to reduce the risk of sudden death due to LVOTO. Postoperative two-dimensional echocardiography at discharge showed that surgery was effective in resolving LVOTO.

Congenital cardiac masses: a case report.

BACKGROUND: Cardiac tumors in infants and children are rare. The most common cardiac tumor is rhabdomyoma, which may be associated with tuberous sclerosis. However, not all cardiac rhabdomyomas are pathognomonic for tuberous sclerosis, and not all congenital cardiac tumors are rhabdomyomas. During the prenatal period, early cardiac tumor detection provides important information about fetal wellbeing, delivery planning, and necessary postnatal care. CASE PRESENTATION: We report a 36-year-old African American pregnant women. At 32 weeks 5 days gestational age, the male fetus had a fetal echocardiogram due to fetal arrhythmia. The fetal echocardiogram showed two small echogenic, RV apex and septal masses, suspicious of rhabdomyomas. After a routine pregnancy and a normal spontaneous vaginal delivery (39 weeks 1 day), the male baby was admitted to the neonatal intensive care unit for further monitoring and postnatal evaluation. CONCLUSIONS: Rhabdomyomas are extremely rare and unique tumors. These tumors are very dangerous, but they usually regress after birth. During the prenatal period, early cardiac tumor detection provides important information about fetal wellbeing, delivery planning, and necessary postnatal care. We present this case to share our findings with our pediatric colleagues. Although a rarely reported case, we hope this cardiac rhabdomyoma case report and literature review can increase cardiac tumor awareness.

Neonatal rhabdomyoma with cardiac dysfunction: favourable response to sirolimus.

Cardiac rhabdomyoma is the most common cardiac tumour in childhood, with a strong genetic association to tuberous sclerosis complex. Although most of the patients remain asymptomatic, a small proportion present with cardiac complications in the early neonatal period. Timely initiation of treatment can potentially reduce disease morbidity, and mammalian target of rapamycin (M-TOR) inhibitors play an effective role in promoting regression of these tumours. A healthy term newborn was diagnosed with a giant congenital cardiac rhabdomyoma at birth. He developed clinical signs of compromised cardiac function and progressive myocardial ischaemia, with echocardiography showing significant dyskinesia. He was treated with M-TOR inhibitors and clinical response was monitored via serial echocardiography. Remarkable regression of the tumour was visibly demonstrated within 4 months of sirolimus treatment. The infant continues to be reviewed by a multidisciplinary team of physicians and monitored for features of tuberous sclerosis complex.

Fetal cardiac rhabdomyomas as a sonographic sign of tuberous sclerosis complex - a diagnosis not to be missed. A pictorial essay.

Fetal cardiac rhabdomyomas should trigger the awareness of a potential coexisting tuberous sclerosis complex that can lead to a poor neurological outcome. This condition is not only uncommon but can be easily unrecognized prenatally in the absence of a meticulous neurosonogram and MRI. We emphasize that careful consideration of all prenatal facilities is required to confirm the diagnosis of tuberous sclerosis complex as early as possible during pregnancy.

Outcomes of antenatally diagnosed fetal cardiac tumors: a 10-year experience at a single tertiary referral center.

OBJECTIVE: The purpose of this study was to analyze the clinical and perinatal outcomes along with ultrasonographic characteristics of fetuses with a cardiac tumor. METHODS: The data were obtained retrospectively between January 2010 and December 2019 in a tertiary referral center. The Cardiovascular Profile Score (CVPS) was used for the diagnosis of heart failure. Clinical outcomes of the cases identified in the postnatal period were analyzed. RESULTS: Fourteen cases were evaluated with the fetal cardiac tumor. One case made the decision to terminate the pregnancy. Perinatal death was seen in 4 (30.7 %) cases out of 13 cases. In 3/14 (21.4%) cases, a solitary cardiac tumor was found while multiple cardiac tumors were found in 11/14 (78.6%) cases. All living cases 9/9 (100%) had the diagnosis of tuberous sclerosis complex (TSC). When the cases which survived were compared with the cases which died during the prenatal period, a significant difference in tumors' biggest diameters (16.44 ± 5.12 mm vs. 32.25 ± 9.28 mm; p: .011, respectively) was found. No statistically significant difference was found in the number of the tumor(s) and heart failure. CONCLUSION: Fetal cardiac tumors can have serious perinatal mortality. The cardiac tumor size was found to be associated with perinatal mortality. The survival is not different between the cases with solitary and multiple tumors and those with and without congestive heart failure.

Everolimus as a possible prenatal treatment of in utero diagnosed subependymal lesions in tuberous sclerosis complex: a case report.

INTRODUCTION: The association between cardiac rhabdomyoma and intraventricular tumors and/or subcortical nodules is characteristic of tuberous sclerosis complex (TSC). Patients with TSC may have refractory seizures, autistic behavior, and cognitive decline. CASE REPORT: The patient received the fetal diagnosis of TSC at the age of 19 weeks of gestations, where presented at prenatal ultrasound cardiac and brain tumors. Fetal MRI showed a lesion in the right and left lateral ventricles near the foramen of Monro associated with subependymal lesions along the entire ependyma of the lateral ventricles and several subcortical tubercles, and the fetal Doppler echocardiogram revealed three cardiac lesions. The fetus underwent intrauterine treatment with everolimus and presented regression and subsequent stabilization of the cardiac and brain lesions; additionally, the patient did not develop seizures or autism and presented good neuropsychomotor development. CONCLUSION: It is the first evidence that mTOR inhibitors may help to prevent neurological complications associated with TSC.

Everolimus treatment in a 3-month-old infant with tuberous sclerosis complex cardiac rhabdomyoma, severe left ventricular outflow tract obstruction, and hearing loss.

Tuberous sclerosis complex is a rare multisystem genetic disorder characterised by the growth of numerous tumour-like malformations in many parts of the body including skin, kidneys, brain, lung, eyes, liver, and heart. Mutations in the TSC1 or TSC2 genes have been reported to cause disruption in the TSC1-TSC2 intracellular protein complex, causing over-activation of the mammalian target of rapamycin protein complex. In this study, we present a 3-month-old male infant diagnosed with tuberous sclerosis, bilateral neurosensorial hearing loss, Wolff-Parkinson-White syndrome on electrocardiography, multiple cardiac rhabdomyomas with severe stenosis in the left ventricular outflow tract, who responded well to the Everolimus therapy.

Rapid response of a cardiac rhabdomyoma causing severe right ventricular outflow obstruction to Sirolimus in an infant with negative genetics for Tuberous sclerosis.

Mammalian target of rapamycin inhibitors was found recently to be an effective treatment for manifestations of Tuberous sclerosis complex, including cardiac rhabdomyomas. Most cases with Cardiac rhabdomyoma treated with mammalian target of rapamycin inhibitors to date were diagnosed with Tuberous sclerosis. We report a case of cardiac rhabdomyoma and severe right ventricular outflow obstruction in a baby with negative genetics for Tuberous sclerosis that responded rapidly to Sirolimus.

Mitral Ebstein's Anomaly Modified with a Scarred Rhabdomyoma in Tuberous Sclerosis: An Extremely Rare Cause of Mitral Insufficiency.

We present an extremely rare case of mitral Ebstein's anomaly that resulted in severe mitral regurgitation (MR). A 41-year-old woman with a history of tuberous sclerosis underwent surgery. Preoperatively, it was assumed that MR had occurred due to leaflet tethering related to left ventricular posterior wall motion asynergy due to a scarred rhabdomyoma. However, surgical inspection revealed a dysplastic posterior leaflet adhering to the ventricular wall, which was completely covered by the endocardium. Both congenital mitral Ebstein's anomaly and acquired wall motion abnormality due to a scarred rhabdomyoma may have contributed to the development of severe MR in this case.

Everolimus for cardiac rhabdomyomas in children with tuberous sclerosis. The ORACLE study protocol (everOlimus for caRdiac rhAbdomyomas in tuberous sCLErosis): a randomised, multicentre, placebo-controlled, double-blind phase II trial.

INTRODUCTION: Tuberous sclerosis complex is a rare genetic disorder leading to the growth of hamartomas in multiple organs, including cardiac rhabdomyomas. Children with symptomatic cardiac rhabdomyoma require frequent admissions to intensive care units, have major complications, namely, arrhythmias, cardiac outflow tract obstruction and heart failure, affecting the quality of life and taking on high healthcare cost. Currently, there is no standard pharmacological treatment for this condition, and the management includes a conservative approach and supportive care. Everolimus has shown positive effects on subependymal giant cell astrocytomas, renal angiomyolipoma and refractory seizures associated with tuberous sclerosis complex. However, evidence supporting efficacy in symptomatic cardiac rhabdomyoma is limited to case reports. The ORACLE trial is the first randomised clinical trial assessing the efficacy of everolimus as a specific therapy for symptomatic cardiac rhabdomyoma. METHODS: ORACLE is a phase II, prospective, randomised, placebo-controlled, double-blind, multicentre protocol trial. A total of 40 children with symptomatic cardiac rhabdomyoma secondary to tuberous sclerosis complex will be randomised to receive oral everolimus or placebo for 3 months. The primary outcome is 50% or more reduction in the tumour size related to baseline. As secondary outcomes we include the presence of arrhythmias, pericardial effusion, intracardiac obstruction, adverse events, progression of tumour reduction and effect on heart failure. CONCLUSIONS: ORACLE protocol addresses a relevant unmet need in children with tuberous sclerosis complex and cardiac rhabdomyoma. The results of the trial will potentially support the first evidence-based therapy for this condition.