Introduction
Tuberous sclerosis complex is an autosomal inherited genetic syndrome with a highly variable phenotype that may affect several organ systems, including heart, brain, kidney, and skin. Reference Davis, Filip-Dhima and Sideridis1 Dysfunction of the proteins hamartin and tuberin, the products of the TSC1 and TSC2 genes, results in an upregulation of the mechanistic target of the rapamycin pathway and produces dysregulated of cellular growth. Reference Crino2 Therefore, as a disease-modifying approach, mechanistic target of the rapamycin inhibitors like Everolimus became a viable and safe treatment option for angiomyolipoma associated with tuberous sclerosis complex. Reference Bissler, Kingswood and Radzikowska3
Cardiac manifestation of tuberous sclerosis complex includes rhabdomyoma, which could lead to arrhythmias or intracardiac obstruction of blood flow, especially during the first year of life. Everolimus has been used in a multitude of cases in neonates and children to regress cardiac tumours associated with tuberous sclerosis complex. Reference Nespoli, Albani and Corti4,Reference Dhulipudi, Bhakru, Rajan, Doraiswamy and Koneti5,Reference Aw, Goyer, Raboisson, Boutin, Major and Dahdah6,Reference Garg, Gorla, Kardon and Swaminathan7
Case report
We report on a female infant born at term, birth weight was 2710 g (small for date) with normal postnatal adaptation. On the fifth day of life, echocardiography was performed as a heart murmur was heard. The echocardiography revealed normal cardiac anatomy and function, but the presence of three cardiac tumours (two of which are shown in Figure 1a). One tumour was located just beneath the pulmonary valve (estimated volume 1300mm³, Figure 1a,c) and led to severe right ventricular outflow tract obstruction (dp > 70 mmHg, Figure 1b). No arrhythmias were detected on repeated 24-hour Holter electrocardiogram and during home monitoring. Genetic evaluation confirmed the diagnosis of TSC-2 (duplication of 3589 base pairs of the Exon 11–14).
Echocardiographic images documented at day 4 of life. ( a ) Parasternal short axis shows two tumours marked with a red arrow: one attached to the left atria, the second in the right ventricular outflow tract, resulting in a dynamic outflow tract obstruction with a peak gradient > 70 mmHg ( b ). ( c ) The tumour is shown simultaneously without on the left and with colour Doppler ultrasound on the right in a modified long axis.
Because of the right ventricular outflow tract obstruction, a therapy with Everolimus was initiated in the first week of life (0.02mg/kg), resulting in blood Everolimus levels of 2–3µg/l. A rapid regression of tumour volume was seen during the following weeks, and therapy was stopped at an age of two months because attending doctors were worried about possible side effects of Everolimus (Figure 2). However, consequent echocardiography at an age of 1.5 months showed regrowth of the right ventricular outflow tract tumour and Everolimus therapy was restarted. Again, very low blood levels of Everolimus (2–3µg/l) led to immediate tumour regression. Everolimus was stopped for a second time at the age of 18 months, but regrowth of the tumour occurred, requiring a second restart of the Everolimus therapy. Altogether, low-dose Everolimus therapy was started/re-started five times in this patient (after birth, at the age of 1.5, 25, 36, and 60 months, respectively (Figure 2). After the latest start of therapy at the age of 5 years, the tumour remains very small (app. 10mm³) without relevant right ventricular outflow tract obstruction. All echocardiographic images were performed in the outpatient clinic of the department by qualified investigators. No side effects of Everolimus were documented in this patient.
The size of the tumour in the first 5 years of the patient. The * marks the starting/restarting of the therapy with Everolimus.
Discussion
Mechanistic target of the rapamycin inhibitors have been shown to be beneficial for the treatment of several clinical manifestations of tuberous sclerosis complex, including epilepsy, facial angiofibromas, cardiac rhabdomyomas, and lymphangioleiomyomatosis. Reference Capal and Franz8 Based on previous case reports of regression of intracardiac tumours, Everolimus therapy was initiated in the present case. In previous reports, Everolimus was effective with serum levels of 5–15 ng/mL. Reference Dhulipudi, Bhakru, Rajan, Doraiswamy and Koneti5,Reference Aw, Goyer, Raboisson, Boutin, Major and Dahdah6 Two reports describe that a low-dose therapy with Everolimus and a level of 3–7 ng/mL Reference Nespoli, Albani and Corti4,Reference Garg, Gorla, Kardon and Swaminathan7 was sufficient to reduce tumour size. In the present case, we showed that an even lower Everolimus level of 2–3 ng/ml was enough to diminish tumour size. This effect was proven unintentionally as starting/restarting was performed five times in this patient.
Ongoing very low-level Everolimus therapy might also have beneficial effects in cardiac or other tissues, because this directly targets the constantly upregulated mechanistic target of the rapamycin pathway and might lead to a more normalised mechanistic target of the rapamycin pathway activation, while side effects like stomatitis or systemic infections might be lower than reported. Reference Hatano, Endo and Tamari9 Prospective studies are needed to address if longer very low-dose therapy might have beneficial effects for tuberous sclerosis complex patients.
Acknowledgements
None.
Financial support
This research received no specific grant from any funding agency, commercial, or not-for-profit sectors.
Competing interests
The authors declare none.
Ethical standard
The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national guidelines on human experimentation and the Helsinki Declaration of 1975, as revised in 2008, and have been approved by the institutional committees (Justus-Liebig-University).
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