Author: Manal Mirreh, MD - Children’s Hospital of Philadelphia
A 3-year-old child with tuberous sclerosis complex and a large cardiac rhabdomyoma develops increasing episodes of ventricular tachycardia. The cardiology team prescribes a medication specifically to reduce the size of the cardiac rhabdomyoma and improve the associated arrhythmia burden. Which of the following medications is MOST LIKELY to be prescribed, and what is its mechanism of action?
EXPLANATION
Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem neurocutaneous syndrome characterized by the development of hamartomas distributed throughout the body. Two-thirds of cases of TSC are due to sporadic mutations. The classic triad of phenotypic manifestations in patients with TSC are seizures, intellectual delay, and cutaneous angiofibromas. However, the full triad occurs in only 29% of patients, and 6% of patients lack all three aspects of the triad. Two tumor suppressor genes responsible for TSC have been identified: TSC1 gene on chromosome 9 and TSC2 on chromosome 16.1 Mutations in those genes lead to hyperactivation of mTOR, causing abnormal cell growth and manifestations of TSC.
TSC exhibits wide phenotypic variability both between and within families, with regards to the number and severity of manifestations. In a longitudinal study of 125 patients, the median age at presentation was seven months. Seizures were the most common initial manifestation in infancy or early childhood, occurring in 62 percent of cases, while prenatal ultrasound abnormalities, primarily cardiac rhabdomyomas (CR), were the second most common, seen in 14 percent of cases.2
CR are the hallmark cardiac lesion of TSC and often occur as multiple benign masses. They are among the most common pediatric cardiac tumors. Although frequently asymptomatic, symptoms are most likely to be experienced in the neonatal and early infancy period, after which these tumors generally regress spontaneously. Morbidity and mortality are primarily related to the potential for significant intracardiac obstruction if they enlarge enough to impair blood flow and can also lead to arrhythmia. Surgery is reserved for cases with severe hemodynamic compromise. Children with TSC, especially those under three years of age, should undergo baseline echocardiography to assess for rhabdomyomas and electrocardiography (ECG) to screen for arrhythmias.3
Everolimus and sirolimus are mTOR inhibitors that may alleviate TSC manifestations. They have proven effective in trials for brain and kidney tumors (SEGA, AML) and epilepsy and are increasingly used off-label for CR.4 To date, no randomized trial results or formal guidelines exist for treating CR in children with TSC, but the ongoing ORACLE trial may provide high-quality evidence on the safety and efficacy of everolimus for this indication. The study group will consist of children with TSC and symptomatic CRs that do not need immediate surgery (overall 40 children, 20 patients per arm). The primary trial’s aim is at least a 50% reduction in tumor size on everolimus therapy compared to the placebo arm. Treatment is planned for three months with follow-up until 12 months. Starting dose is set as 4.5 ng/m2 with a targeted blood level of 5–15 ng/mL.
Other answer choices are incorrect because they do not directly target the TSC1/TSC2 mutation pathway, which drives overactive mTOR cellular overgrowth, tumor regression, and reduction in arrhythmias. Propranolol is a beta-blocker that reduces sympathetic tone, slows AV nodal conduction, and can suppress arrhythmias symptomatically but does not affect tumor size. Bevacizumab is an anti-VEGF agent that inhibits angiogenesis; although it is used to treat tumors such as rhabdomyosarcoma, it is not effective for shrinking TSC-related cardiac rhabdomyomas.
REFERENCES
1. Schwartz RA, Fernández G, Kotulska K, Jóźwiak S. Tuberous sclerosis complex: advances in diagnosis, genetics, and management. J Am Acad Dermatol. 2007;57(2):189-202. doi:10.1016/j.jaad.2007.05.004.
2. Kwiatkowski DJ, Northrup H. Tuberous sclerosis complex: Clinical features. UpToDate. Updated October 31, 2024. Accessed October 22nd, 2025. https://www-uptodate-com.proxy.library.upenn.edu/contents/tuberous-sclerosis-complex-clinical-features?search=tuberous%20sclerosis&source=search_result&selectedTitle=1~105&usage_type=default&display_rank=1
3. Northrup H, Aronow ME, Bebin EM, et al. Updated International Tuberous Sclerosis Complex Diagnostic Criteria and Surveillance and Management Recommendations. Pediatr Neurol. 2021;123:50-66. doi:10.1016/j.pediatrneurol.2021.07.011
4. Sugalska M, Tomik A, Jóźwiak S, Werner B. Treatment of Cardiac Rhabdomyomas with mTOR Inhibitors in Children with Tuberous Sclerosis Complex—A Systematic Review. International Journal of Environmental Research and Public Health. 2021; 18(9):4907. https://doi.org/10.3390/ijerph18094907