Fetal therapy with mTOR inhibitors in cardiac rhabdomyoma and lymphatic malformations.

IntroductionSirolimus is a mammalian target of rapamycin (mTOR) inhibitor and well-known for its anti-tumour effect increasing the tumour disappearance rate of rhabdomyoma. Cardiac rhabdomyomas are a rare condition associated with...

IntroductionMechanistic target of rapamycin (mTOR) inhibitors sirolimus and everolimus are an effective therapy for subependymal giant cell astrocytomas, cardiac rhabdomyomas, renal angiomyolipomas, and lymphangioleiomyomatosis associated with tuberous sclerosis complex (TSC). Everolimus was recently approved in the EU and the USA for the treatment of refractory focal-onset seizures. Despite frequent use of mTOR inhibitors, there are only a few studies on their effect on epilepsy control in children under 2 years of age. This study aims to assess the effect of adjunctive mTOR inhibitor treatment on seizure frequency in this age group.MethodsWe performed retrospective data analysis of medical records of patients with TSC who initiated sirolimus or everolimus under the age of 2 years. Participants’ antiseizure medication was adjusted according to their epilepsy control independently from mTOR inhibitor administration. The data was assessed separately for patients treated with mTOR inhibitors before and after the onset of seizures. We also compared the treatment group with a matched control group. The follow-up duration was up to 24 months.ResultsTwenty-one patients with TSC from two clinical centers were included in the study. Nine participants had no history of seizures before mTOR inhibitor initiation. Twelve reported active epilepsy in the month prior to treatment initiation. Most patients treated preventively with mTOR inhibitors did not report active epilepsy at the end of their follow-up. In the second group, the mean frequency of seizures decreased with time. According to the comparative analysis, seizure control was better in the groups treated with mTOR inhibitors.ConclusionPatients with TSC treated with mTOR inhibitors demonstrated better seizure control than individuals without this treatment. Adjunctive pharmacotherapy with mTOR inhibitors appears to have a beneficial effect on epilepsy outcome in young children. Further prospective clinical trials should be conducted to determine the efficacy of mTOR inhibitors on epilepsy in patients with TSC under the age of 2 years.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40120-023-00476-7.

We report the first known successful pediatric cardiac transplant from a donor with tuberous sclerosis. During the transplant, an intraoperative transesophageal echocardiogram (TEE) revealed a left ventricle outflow tract (LVOT) mass—cardiac rhabdomyoma by histopathology. CASE REPORT A 6-year-old boy presented with congestive heart failure. Transthoracic echocardiogram (TTE) revealed severe biventricular dysfunction with an ejection fraction of 10%. Ventricular function did not improve despite aggressive medical therapy, and the patient was listed for a heart transplant. The donor was a 7-year-old girl, with a medical history of tuberous sclerosis. She developed irreversible acute intracranial hypertension after a craniotomy, and the diagnosis of brain death was confirmed by angiography. TTE was technically difficult because of poor acoustic windows but showed normal right and left atrial size; intact atrial and ventricular septums; moderate left ventricular hypertrophy with cavity obliteration during systole; mild right ventricular enlargement; and normal tricuspid, mitral, and aortic valve function. Because of the severity of the recipient patient's status, the heart was accepted without further anatomic assessment, and an orthotopic heart transplant was performed. After weaning off cardiopulmonary bypass (CPB), a TEE revealed a 7-×8-mm outgrowth beneath the aortic valve in the LVOT with no obstruction; normal biventricular function; and trivial aortic regurgitation (Fig. 1). The decision was made to return to CPB, and the portion of mass protruding into the subaortic region was excised. Histopathology revealed a cardiac rhabdomyoma. After the second CPB run, TEE revealed no LVOT mass or obstruction, no other cardiac masses, normal biventricular function, and no aortic valve dysfunction.FIGURE 1.: Intraoperative transesophageal echocardiogram. Midesophageal aortic long-axis view demonstrating a 7.1-mm mass in the LVOT. LVOT, left ventricular outflow tract; LA, left atrium; ASC AO, ascending aorta; MV, mitral valve; LV, left ventricle; RV, right ventricle.Several monthly follow-up TTEs have demonstrated well-preserved allograft function with normal biventricular size and systolic function and an ejection fraction of 70%. There is no evidence of LVOT obstruction, valvular dysfunction, or mass growth. Thirty months after heart transplant, the patient is active and healthy with no signs or symptoms of cardiovascular compromise. Tuberous sclerosis is a neurocutaneous syndrome with an incidence of 1:10000. Approximately 80% of children with cardiac rhabdomyoma have a diagnosis of tuberous sclerosis (1). Large tumors may present with arrhythmias, dysfunction of cardiac valves, congestive heart failure, embolization, and inflow/outflow obstruction, (2) with LVOT obstruction being one of the rarer presentations of cardiac rhabdomyomas (3). Rhabdomyomas have a natural history of spontaneous regression; however, symptomatic impairment from outflow tract obstruction or recurrent arrhythmias is an indication for surgical resection (1). TTE of the donor had not revealed any cardiac tumors but showed moderate left ventricular hypertrophy with cavity obliteration during systole. Despite the simplicity and noninvasive technique of TTE for imaging cardiac structures, low-quality images are obtained by TTE examinations in approximately 50% of patients on mechanical ventilation such as the organ donor population (4). TEE has been widely used to assess left ventricular function and could also be a useful tool to assess cardiac anatomy during procurement of organ donors (5). TEE provides images of better resolution than TTE, providing unexpected diagnoses that are missed by TTE in up to 50% of the cases (6). This case highlights the role of TEE in the workup of the donor heart especially when the medical history is suggestive of a potential intracardiac tumor. This information could be helpful in the surgical preparation of the donor heart before transplantation. This case brings to question the practice of using only TTE to rule out cardiac pathology in heart transplant donor candidates, specifically in patients with increase risk for cardiac pathology such as tuberous sclerosis. However, this case also illustrates that donors with heart tumors should not necessarily be rejected without assessing the possibility of treatment before transplant especially in the pediatric population where donor organs are less readily available. Gracie M. Almeida-Chen1 Silvia E. Perez-Protto2 Julie Niezgoda2 Pablo Motta3 1Division of Pediatric Anesthesia Department of Anesthesiology Columbia University New York, NY 2Department of Pediatric and Congenital Heart Anesthesiology Anesthesiology Institute Cleveland Clinic Cleveland, OH 3Department of Pediatric Cardiovascular Anesthesiology Texas Children's Hospital Baylor College of Medicine Houston, TX

Topical Use of Mammalian Target of Rapamycin (mTOR) Inhibitors in Tuberous Sclerosis Complex—A Comprehensive Review of the Literature

<h3></h3> Although rare, cardiac rhabdomyomas (CRs) are the most common fetal cardiac tumors. They may be the earliest manifestation of tuberous sclerosis complex (TSC). TSC is diagnosed in 75-80% cases of multiple fetal CRs and in 30% of single cases. We retrospectively reviewed the clinical outcome of fetal CR cases. All cases of prenatally diagnosed rhabdomyoma in a single tertiary centre from 2009 to 2019 were ascertained from medical records. We identified 14 fetuses with prenatally diagnosed CRs. Mean period of follow-up was 4 years (range 4m-9y). Two fetuses were twins (BC/BA), both affected by CR with family history of TSC, and one fetus of the dichorionic pair was not affected by rhabdomyoma. The mean GA at diagnosis was 29 weeks (range 21-35). There were eleven fetuses with multiple, and three with a solitary tumor. The right and left ventricle as well as the intraventricular septum were equally affected with a slight predominance of the left ventricle. The cardiac atrium was affected in two cases. The size ranged from small tumors of several mm in diameter up to dimensions of 20x20 mm. Sixty percent were &lt;20 mm in diameter. Two of fetuses were affected by hemodynamically relevant cardiac obstruction (LVOT), and in four arrhythmias (SVES, VES, WPW syndrome, and AV block) were observed. No hydrops fetalis or fetal perinatal demise were observed. In 11 (79%) TSC was confirmed clinically or by mutational analysis. After birth, most rhabdomyomas demonstrated a stable (14%, n=2) or spontaneous regressive growth pattern (57%, n=8). In four children (29%) tumors entirely disappeared. No progression of tumor size or number was observed. After birth in five (36%) children the conduction abnormalities were confirmed by ECG and responded well to the anti-arrhythmic medication and two children were affected by LVOT obstruction. Cerebral manifestations (tubers and/or nodules) were detected by brain MRI in 9 patients (3 prenatally). Subependymal giant cell astrocytoma was diagnosed in 3 cases, 2 received treatment with mTOR inhibitor, and one child underwent VP shunt due to enlarging SEGA causing obstructive hydrocephalus. Six (55%) of the children with TSC suffered from epilepsy and psychomotoric development delay. Although CRs are benign from the cardiovascular standpoint, and have a natural history of spontaneous regression, their close association with TSC prompt for early prenatal diagnosis and family counselling regarding the dismal long-term prognosis. Recent literature suggests that early therapy with mTOR inhibitors may prevent the development of TS manifestations.

BackgroundFacial angiofibroma is the most predominant cutaneous manifestation of tuberous sclerosis complex (TSC), a rare autosomal dominant genetic disorder impacting the mechanistic target of rapamycin (mTOR). Facial angiofibroma can bleed spontaneously, impair eyesight, and cause aesthetic disfiguration causing psychological and social stress. To date, there is little or no evidence on the demographics, and other TSC features associated with facial angiofibroma or the use of mTOR inhibitor for the management of facial angiofibroma. This is a retrospective study of TSC Alliance’s Natural History Database aimed to characterize facial angiofibroma and to evaluate features associated with a higher risk of facial angiofibroma or the use of topical mTOR inhibitors for the management of facial angiofibroma. Data in the NHD was obtained from 18 clinical sites in the US since 2006.ResultsOf the 2240 patients, 2088 patients were enrolled in the US and data from 2057 patients were included in this analysis. The mean (median) age of overall TSC patients was 22.4 (19.0) years. A total of 69 patients were ≤ 5 years of age. Facial angiofibroma was noted in 1329 (64.6%) patients with TSC. Patients with facial angiofibroma were older on average (Mean: 25.9 [median, 23.0] vs. 16.0 [12.4 years] years, p < 0.0001). In patients with vs. without facial angiofibroma, TSC2 mutation (38.9% vs. 34.8%) was more common than TSC1 mutation (12.3% vs. 18.1%), and the incidence rate of most of the other TSC-related manifestations was significantly higher in patients with facial angiofibroma. Majority of patients had focal seizures (72.8% vs. 60.7%), followed by angiomyolipoma (63.7% vs. 21.8%) and renal cysts (59.4% vs. 33.5%). The age groups, 11–17 (odds ratio [OR], 2.53) and 18–45 years (5.98), TSC2 mutation (1.31), focal seizures (1.50), ADHD (1.47) angiomyolipoma (2.79), and renal cysts (2.63) were significantly associated with a higher risk of facial angiofibroma based on multivariate logistic regression. Abrasive or laser therapy was used by 17.1% and 2.6% patients, respectively. Topical mTOR inhibitor use was noted for 329 (24.8%) patients with facial angiofibroma. Overall systemic mTOR inhibitor use was observed in 399 (30.0%) patients for management of one or more TSC manifestations. Use of systemic mTOR inhibitor for facial angiofibroma was noted for 163 (12.3%) patients, among whom only 9 (0.7%) patients used exclusively for the management of facial angiofibroma. Of the patients with facial angiofibroma, 44.6% did not receive any treatment. Significantly higher use of topical mTOR inhibitor was associated with the 11–17 years age group (OR, 1.67), anxiety (1.57), angiomyolipoma (1.51), and renal cysts (1.33).ConclusionsThe presence of TSC2 mutations and most other TSC-related manifestations was significantly higher in patients with facial angiofibroma. About one-fourth of patients with facial angiofibroma used a topical mTOR inhibitor and use of systemic mTOR inhibitor for the management of facial angiofibroma or for the other manifestations was noted for 30.0%. About 44.6% of patients did not receive any treatment for the management of facial angiofibroma.

ObjectiveMechanistic/mammalian target of rapamycin (mTOR) inhibitors have been used successfully to reduce the size of cardiac rhabdomyomas. However, the number of published cases is small and thus there is no consensus about therapeutic approaches, especially regarding dosing regimens and safety profiles of mTOR inhibitors. Based on a systematic literature review and one new case report, we discuss in detail the indication and adverse effects of fetal and neonatal mTOR-inhibitor therapy.MethodsA comprehensive search was conducted on PubMed/MEDLINE and Web of Science for studies using combinations of the relevant medical subject heading (MeSH) terms and keyword (rhabdomyoma AND fetal OR fetus OR prenatal AND cardiac AND sirolimus) from the first report in 2018 until July 2025. Studies were included if they reported on pregnancies with fetal cardiac tumor and rhabdomyoma entity suspicion treated with mTOR inhibitors.Results of literature review and new case descriptionIn total, 67 results were found. After excluding non-eligible publications, a total of 20 documented cases were identified from 15 reports, all presenting lifesaving effects of mTOR inhibitors in fetuses and neonates with cardiac rhabdomyomas. We report on a patient with a prenatally suspected cardiac rhabdomyoma, which, due to imminent bilateral outflow tract obstruction, was prenatally treated with sirolimus. Tumor regression could be achieved. For maternal medical reasons, prenatal sirolimus had to be stopped after 5 weeks. Postnatal incessant atrioventricular re-entrant tachycardia occurred, which was unresponsive to electric or medical cardioversion (amiodarone) and unresponsive to everolimus. The patient developed massive capillary leak syndrome within hours. In combination with restrictive ventricular filling properties, the tachycardia resulted in death on the seventh day of life.ConclusionCardiac rhabdomyomas have the potential to become a life-threatening condition, not only by impairing myocardial function and cardiac outflow, but also by causing arrhythmia due to tumor muscle bundles as substrate for a pre-excitation syndrome resulting in intrauterine or postnatal atrioventricular re-entrant tachycardia, as observed in our patient. The pharmacological therapeutic approach is fetal and neonatal treatment with mTOR inhibitors. All previous reported cases present lifesaving effects of mTOR inhibitors in fetuses and neonates with cardiac rhabdomyomas; however, adverse effects cannot be disregarded.

COVID-19 and lymphangioleiomyomatosis: Experience at a reference center and the potential impact of the use of mTOR inhibitors.

Accelerated regression of cardiac rhabdomyoma by mTOR inhibitors in a neonate with heart failure: A case report

Background: Tuberous sclerosis complex (TSC) can present prenatally, often with cardiac rhabdomyomas, which, if large, may cause complications such as hydrops fetalis and reduced cardiac output. Prenatal treatment of these lesions with mTOR inhibitors, approved for other TSC manifestations, is under investigation. We hypothesize that mTOR inhibitors could help manage or prevent other TSC-related conditions, particularly neurological issues like epilepsy and CNS lesions, potentially improving neurodevelopmental outcomes. However, the safety of prenatal mTOR treatment remains a concern, especially for foetal development, and limited data are available on neurological outcomes. Methods: We conducted a literature review using PubMed, EMBASE, and Cochrane CENTRAL, focusing on studies involving mTOR inhibitors for prenatal TSC management. The search included case reports and series involving pregnant women diagnosed with TSC or early manifestations like cardiac rhabdomyomas. Keywords included "mTOR Inhibitor", "Rapamycin", "tuberous sclerosis complex", "prenatal", and "rhabdomyoma". Results: Three prenatal mouse studies and eight papers reporting on ten pregnant women treated with mTOR inhibitors were identified. Conclusions: The literature confirms that prenatal mTOR inhibitors may reduce cardiac rhabdomyomas. However, further studies are needed to explore their broader potential, particularly in preventing neurological complications, while carefully considering their impact on intrauterine growth and neurodevelopment.

Background: Cardiac rhabdomyomas (CRs) are the earliest sign of tuberous sclerosis complex (TSC). Most of them spontaneously regress after birth. However, multiple and/or large tumors may result in heart failure or cardiac arrhythmia. Recently, the attempts to treat CRs with mTOR inhibitors (mTORi) have been undertaken. We reviewed the current data regarding the effectiveness and safety of mTORi in the treatment of CRs in children with TSC. Methods: The review was conducted according to the PRISMA guidelines. Medline, Embase, Cochrane library, and ClinicalTrial.gov databases were searched for original, full-text articles reporting the use of mTORi (everolimus or sirolimus) in the treatment of CRs in children with TSC. Results: Thirty articles describing 41 patients were identified (mostly case reports, no randomized or large cohort studies). Thirty-three children (80.5%) had symptomatic CRs and mTORi therapy resulted in clinical improvement in 30 of them (90.9%). CRs size reduction was reported in 95.1%. Some CRs regrew after mTORi withdrawal but usually without clinical symptoms recurrence. The observed side effects were mostly mild. Conclusions: mTORi may be considered as a temporary and safe treatment for symptomatic CRs in children with TSC, especially in high-risk or inoperable tumors. However, high-quality, randomized trials are still lacking.

Tuberous sclerosis complex (TSC) is an autosomal dominant and multi-system genetic disorder in humans. TSC affects around 25,000 to 40,000 individuals in the United States and about 1 to 2 million individuals worldwide, with an estimated prevalence of one in 6,000 newborns. TSC occurs in all races and ethnic groups, and in both genders. TSC is caused by defects or mutations in two genes, TSC1 and TSC2. Loss of TSC1/TSC2 leads to dysregulation of mTOR, resulting in aberrant cell differentiation and development, and abnormal enlargement of cells. TSC is characterized by the development of benign and/or malignant tumors in several organs including renal/liver angiomyolipomas, facial angiofibroma, lymphangiomyomatosis, cardiac rhabdomyomas, retinal astrocytic, renal cell carcinoma, and brain subependymal giant cell astrocytomas (SEGA). In addition, TSC disease causes disabling neurologic disorders, including epilepsy, mental retardation and autism. Particularly problematic are the development of renal angiomyolipomas, which tend to be larger, bilateral, multifocal and present at a younger age compared with sporadic forms. In addition, SEGA block the flow of fluid within the brain, causing a buildup of fluid and pressure that leads to blurred vision and seizures. In the current review, we describe the pathology of TSC disease in key organs and summarize the use of mTOR inhibitors to treat tumors in TSC patients.

The mammalian/mechanistic target of rapamycin (mTOR) is a protein kinase that plays a crucial role in regulating cellular growth, metabolism, and survival. Although there is no absolute contraindication for the use of mTOR inhibitors during pregnancy, the specific fetal effects remain unknown. Available data from the past 2decades have examined the use of mTOR inhibitors during pregnancy in patients with solid organ transplantation, showing no clear link to fetal complications or structural abnormalities. Recently, a handful of case reports and series have described transplacental therapy of mTOR inhibitors to control symptomatic and complicated pathologies in the fetus. The effect of these agents includes a significant reduction in lesion size in the fetus and a reduced need for mechanical ventilation in neonates. In this context, we delve into the potential of mTOR inhibitors as in-utero therapy for fetal abnormalities, with a primary focus on lymphatic malformation (LM) and cardiac rhabdomyoma (CR). While preliminary reports underscore the efficacy of mTOR inhibitors for the treatment of fetal CR and fetal brain lesions associated with tuberous sclerosis complex, chylothorax, and LMs, additional investigation and clinical trials are essential to comprehensively assess the safety and efficacy of these medications.

Hypertrophic cardiomyopathy (HCM) has evoked both fascination and controversy since its first modern description >50 years ago.1 Originally described as “functional aortic subvalvar stenosis” by Brock, the majority of articles about HCM in the ensuing first decade emanated from observations made in the operating room or in the cardiac catheterization laboratory.1 The actual cause of left ventricular outflow tract (LVOT) obstruction in patients with this condition had not yet been clarified. Ironically, the mechanisms of LVOT obstruction in HCM were only elucidated several years after surgery was first performed in these patients. In fact, an early report by Morrow described the septal myotomy procedure as surgical treatment for HCM and proposed that the myotomy interfered with the sphincter-like muscular contraction ring in the LVOT.1 Article see p 40 Noninvasive cardiovascular imaging studies have greatly advanced our knowledge about HCM.2 Hypertrophic cardiomyopathy is now felt to have tremendous genetic,3 clinical, morphological, and hemodynamic heterogeneity.1 Nevertheless, the presence of LVOT obstruction in patients with HCM has continued to inspire interest. The often contentious debates surrounding LVOT obstruction have centered on its very existence, its causes, its clinical impact and prognosis, and its optimal management.1 These issues have inextricably included the mitral valve, which has long been felt to play a pivotal role in the pathophysiology of LVOT obstruction in patients with HCM. In the present issue of Circulation , Maron et al use cardiovascular magnetic resonance (CMR) imaging to characterize mitral valve leaflets in patients with HCM.4 This study assessed the lengths of the anterior mitral leaflet (AML) and posterior mitral leaflet in 172 consecutive patients with HCM. Their findings were compared with 172 normal control subjects matched for age, sex, and body surface area. In addition, the study included a small cohort of …

Background: Cardiac rhabdomyomas in tuberous sclerosis regress spontaneously, large masses can cause hemodynamic compromise. Fetal sirolimus therapy cause regression. We report a case of successful fetal therapy in mother with fetally diagnosed tuberous sclerosis (TS). Case: A 22 year old female with uncomplicated pregnancy and negative cardiac history presented for fetal echocardiogram at 21 weeks due to cardiac masses. Fetal echocardiogram: levocardia, normal segmental cardiac anatomy, d-looped ventricles, normally related great arteries. Multiple masses seen in both ventricles, largest in LV free wall from base to apex and another involving mitral papillary muscle, no initial obstruction, patent ductal and aortic arches. Amniocentesis confirmed diagnosis of TS. Fetus was followed with serial monitoring of cardiac outputs and size of masses. At 30 weeks, LV mass had doubled from 1.7 to 4 cm with LV diastolic dysfunction and reduced cavity size, large pericardial effusion, left ventricular outflow tract obstruction (LVOTO). IVC was mildly dilated with liver enlargement. Fetal MRI confirmed diagnosis of rhabdomyoma with small subependymal nodules. Given LVOTO and large effusion, mother was started on sirolimus therapy with loading dose of 5 mg and subsequent dose adjustments for target trough sirolimus of 10 to 15 ng/ml. Serial mother monitored with labs, weekly ultrasounds and echocardiograms. Mass decreased in size with resolution of effusion and LVOTO. At 37 weeks, due to oligohydramnios, baby was delivered without hemodynamic compromise. Postnatally no LVOTO and normal systolic function with mass measuring ~ 2.0 cm. Baby has been followed off sirolimus therapy. Role of Imaging: Serial echocardiograms enabled optimal decision making to treat mother with sirolimus therapy. Conclusions: Maternal sirolimus therapy can help regress cardiac rhabdomyomas with hemodynamic implications with serial close outpatient monitoring.