Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in the TSC1 or TSC2 genes, characterized by benign tumors in multiple organs, including the heart. Cardiac rhabdomyomas are the most frequent neonatal primary cardiac tumors in TSC, often resolving spontaneously but sometimes necessitating intervention due to arrhythmias or flow obstruction.
This case report describes a term male neonate with TSC alternating between baseline bradycardia and supraventricular tachycardia (SVT) episodes. Imaging revealed multiple cardiac rhabdomyomas and cortical tuberomas, confirming the TSC diagnosis with a TSC2 gene mutation. Initial anti-arrhythmic therapy titration was not possible due to baseline bradycardia and failed to control SVT. Everolimus, an mTOR inhibitor, was introduced, leading to complete regression of cardiac rhabdomyomas and stabilization of baseline heart rate, which allowed adjustment of anti-arrhythmic therapy and heart rate control. The patient, now 12 months old, is clinically stable, off anti-arrhythmic drugs, and continues preventive anti-epileptic therapy and Everolimus with no significant adverse effects.
This case underscores the potential efficacy and safety of Everolimus in treating TSC-associated cardiac rhabdomyomas, advocating for further research to refine therapeutic strategies for TSC’s cardiac manifestations.
Highlights
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Successful use of Everolimus, an mTOR inhibitor, resulted in complete regression of cardiac rhabdomyomas in a neonate with TSC.
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Initial anti-arrhythmic therapy was ineffective due to baseline bradycardia, but Everolimus stabilized the baseline heart rate, allowing for effective arrhythmia management.
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Genetic testing confirmed a TSC2 mutation, aiding in the precise diagnosis and targeted treatment approach.
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The patient remained clinically stable and free of significant adverse effects from Everolimus at 12 months of age.
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This case supports the potential efficacy and safety of Everolimus in managing TSC-associated cardiac manifestations and highlights the need for further research in this area.
1
Introduction
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects multiple organ systems. It results from loss-of-function mutations in one of two genes, TSC1 or TSC2, and is characterized by multiorgan growth of benign neoplasms. Major features of the disease include tumors of the brain, skin, heart, lungs, and kidneys, seizures, and TSC-associated neuropsychiatric disorders, which can include autism spectrum disorder and cognitive disability. Cardiac rhabdomyomas are the most frequent cardiac manifestation and, by far, the most common neonatal primary cardiac tumor. Although these masses often regress spontaneously, patients may present with significant arrhythmias or cardiac flow obstruction. Surgical resection or alternative therapies may be indicated in such rare cases [ ].
TSC1 (also known as hamartin) and TSC2 (also known as tuberin) together form the TSC protein complex, which acts as an inhibitor of the mechanistic target of rapamycin (mTOR) signaling pathway. This pathway plays a pivotal role in regulating cell growth, proliferation, autophagy, and protein and lipid synthesis. Significant advancements in research and global trials have led to the regulatory approval of mTOR inhibitors for treating brain subependymal giant cell astrocytomas, renal angiomyolipomas, and pulmonary lymphangioleiomyomatosis. However, additional research is needed to establish further indications for these therapeutic agents in TSC, particularly those with cardiac manifestations [ ].
The utilization of Everolimus, an mTOR inhibitor, for treating cardiac rhabdomyomas remains infrequent, with limited mentions in the literature. However, several reports indicate a notable benefit in specific patients, especially those at risk of hemodynamic compromise or life-threatening arrhythmias [ ].
2
Case Report
The authors present the case of a term male neonate delivered via cesarean section to a healthy woman due to fetal bradycardia. Fetal echocardiogram (performed at 33 weeks of gestation), and all obstetric ultrasounds were normal. The delivery was unremarkable, with Apgar scores of 8 and 9 at 1 and 5 minutes.
After birth, the neonate appeared clinically well but still exhibited bradycardia, rapidly progressing to supraventricular tachycardia (SVT) before spontaneously reverting to sinus bradycardia while being transferred to the Neonatal Intensive Care Unit. An electrocardiogram was performed, revealing sinus bradycardia (90 bpm) with no other significant findings.
Transthoracic echocardiography revealed multiple hyperechoic lesions highly suggestive of rhabdomyomas ( Fig. 1 ), including one on the right atrium at the superior vena cava (SVC) ostium near the sinoatrial node, potentially contributing to the bradycardia.
On the same day, a cranial ultrasound was performed, revealing the presence of multiple cortical tuberomas, subsequently confirmed by cerebral magnetic resonance imaging. Video EEG recording showed two epileptiform foci and preventive vigabatrin was started (maximum dose of 100 mg/kg/day). An ophthalmological evaluation was also conducted, revealing the presence of a retinal hamartoma. All these abnormalities led to the clinical diagnosis of TSC. A genetic study was then carried out, resulting in the identification of a pathogenic variant in the TSC2 gene [c.658C>T p.(Gln220*)].
Despite an initial period of stability, on the seventh day of life, the newborn presented onset of frequent SVT episodes with a heart rate of approximately 280 bpm ( Fig. 2 ) while maintaining hemodynamic stability. Transient reversion to sinus rhythm with adenosine suggested the likelihood of atrioventricular re-entry tachycardia via a concealed accessory pathway, the most common cause of SVT in infancy, with atrial tachycardia being a less probable mechanism. On the other hand, the presence of baseline bradycardia, likely due to the giant rhabdomyoma located on the SVC ostium , posed treatment challenges for the tachyarrhythmia.
