Rhabdomyoma Research Articles

Prenatal mTOR Inhibitors in Tuberous Sclerosis Complex: Current Insights and Future Directions.

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.

Molecular diagnosis of tuberous sclerosis complex in fetuses and infants: an institutional case series

ObjectiveWe describe the clinical and genetic characteristics of fetuses and infants diagnosed with tuberous sclerosis complex (TSC) in our centre, prenatally or neonatally, for a better understanding of the benefits...

Upper Esophageal Fetal Rhabdomyoma: A Case Series of 4 Children and Review of Literature.

Objective: The aims of the present study were to provide objective evidence for identifying fetal rhabdomyoma (RM) in the upper esophagus of children, enhance clinical understanding of the diagnosis and treatment of this condition, and optimize the treatment strategy for fetal RM. Methods: The clinical medical records of 4 children with upper esophageal fetal RM were retrospectively collected, and were admitted to the Department of Otolaryngology, Head and Neck Surgery at our hospital between July 2016 and July 2022. Their clinical, histological, and therapeutic characteristics were analyzed in combination with the literature. Results: Four children diagnosed with upper esophageal tumors were included and all of them underwent resection of the upper esophageal tumor with esophageal-pharyngeal reconstruction, and 2 of them underwent prophylactic tracheotomy due to recurrent laryngeal nerve adhesion. Preoperative biopsy was performed in 2 cases (case 2 and case 4), while intraoperative frozen section analysis was conducted in the other 2 (case 1 and case 3), with pathological results consistent with fetal RM. Patients were followed up for 25 to 96 months after the surgery. So far, only 1 patient has experienced a recurrence of fetal RM and underwent a second surgical resection to remove the tumor. Conclusion: Fetal RM is a benign tumor prone to recurrence, and complete excision is the preferred optimal treatment. Clinicians need to understand and master the management algorithm for fetal RM to standardize its diagnosis and treatment.

Third Trimester Stillbirth Associated With Hamartoma of Mature Cardiac Myocytes (HMCM).

Fetal primary cardiac tumors (FPCTs) are very rare. The majority of them correspond to cardiac rhabdomyomas, followed by other benign neoplasms or hamartomas. We describe the case of a third trimester female stillborn with an incidental autopsy finding of Hamartoma of Mature Cardiac Myocytes (HMCM), a rare benign cardiac tumor previously unreported in the fetal or neonatal period. The intrauterine demise occurred at 32 + 6 weeks gestation after an uneventful pregnancy. The fetal autopsy revealed a structurally normal heart with a small subendocardial nodule just below the membranous septum. Microscopically, the nodule was well-demarcated from the surrounding penetrating bundle of the conduction axis and the adjacent left ventricular myocardium and consisted of disorganized mature cardiac myocytes in a haphazard arrangement with patchy mild interstitial fibrosis, consistent with HMCM. Awareness that HMCM can occur in the fetus is important in order to consider it among the differential diagnosis of FPCTs.

Challenges in the Management of Giant Cardiac Rhabdomyoma in a Toddler: Unresponsive to Everolimus Therapy.

Challenges in the Management of Giant Cardiac Rhabdomyoma in a Toddler: Unresponsive to Everolimus Therapy.

Characteristics and Outcomes of Fetal Cardiac Rhabdomyoma With or Without mTOR Inhibitors, a Systematic Review and Meta-Analysis.

To investigate the characteristics and outcomes of fetal cardiac rhabdomyoma with or without prenatal use of mammalian target of rapamycin inhibitor (mTORi). We systematically searched PubMed, Scopus, and Web of Science until June 2023. Studies reporting on pregnancies with fetal cardiac rhabdomyoma were included. A meta-analysis of proportions was conducted only on studies that included three or more cases. A systematic review included 61 studies reporting on 400 fetuses with cardiac rhabdomyoma, of which 52 studies (389 fetuses) had expectant management and 9 studies (11 fetuses) were managed with mTORi. The meta-analysis included 26 studies reporting on 354 fetuses. Prenatally, 14% (95% CI 4-36) had pericardial effusion, 13% (95% CI 6-27) had arrhythmia, 16% (95% CI 7-31) had outflow tract obstruction, and 10% (95% CI 4-21) had hydrops. Fetal demise occurred in 12% (95% CI 5-30). Before delivery, tumor size reduction was noted in 13%, and after birth in 58%. Following birth, 8% (95% CI 3-14) had neonatal death and 9% (95% 4-17) required cardiac surgery. 60% (95% CI 41-79) of cases were diagnosed with tuberous sclerosis. Seizures were reported only in cases with a tuberous sclerosis diagnosis (41/71 infants). For the 9 studies reporting all together on 11 fetuses with tuberous sclerosis receiving prenatal mTORi, they showed improvement in the size of cardiac rhabdomyoma as well as outflow obstruction and none had fetal demise or neonatal death, and none required postnatal cardiac surgery. We report on the natural history of prenatal cardiac rhabdomyoma, including characteristics, progression, and survival. We report 11 fetuses with tuberous sclerosis and cardiac rhabdomyoma receiving prenatal mTORi, showing promising results.

Genotypic and phenotypic analysis of Korean patients with tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a rare autosomal dominant disorder caused by mutations in the TSC1 or TSC2 gene. The aim of this study was to analyze the genotypes and phenotypes of Korean patients diagnosed with TSC and expand our understanding of this disorder. This retrospective observational study included 331 patients clinically diagnosed with TSC between November 1990 and April 2023 at Severance Children's Hospital, Seoul, South Korea. The demographic and clinical characteristics of the patients were investigated. Thirty novel variants were identified. Of the 331 patients, 188 underwent genetic testing, and genotype-phenotype variation was analyzed according to the type of gene mutation and functional domain. Fourty-nine patients (49/188, 26%) were had TSC1 mutations, 103 (55%) had TSC2 mutations, and 36 (19%) had no mutation identified (NMI). Hotspots were identified in exons 8 of TSC1 and exons 35 and 41 of TSC2. Patients with TSC2 mutations exhibited a significantly younger age at the time of seizure onset and had refractory epilepsy. Infantile epileptic spasms syndrome (IESS) was more common in the middle mutation domain of TSC2 than in the hamartin domain. Additionally, retinal hamartoma, cardiac rhabdomyoma, and renal abnormalities were significantly associated with TSC2 compared with other gene types. This study contributes to our understanding of TSC by expanding the genotypic spectrum with novel variants and providing insights into the clinical spectrum of patients with TSC in Korea.

Clinico-histopathological correlation in cardiac rhabdomyoma.

Clinico-histopathological correlation in cardiac rhabdomyoma.

Giant cardiac rhabdomyoma: an atypical cause of ST-segment elevation in the newborn

Giant cardiac rhabdomyoma: an atypical cause of ST-segment elevation in the newborn

Cardiac rhabdomyoma: an uncommon culprit in sudden infant death

Sudden death in infants remains a common and poorly understood cause of childhood mortality in the USA. Pediatric cardiac tumors, although rare, may underlie some cases of unexplained sudden infant death. Autopsy is a crucial diagnostic step in these cases, as both gross and microscopic examination of the heart may uncover occult cardiac tumors. Rhabdomyomas are the most common cardiac tumors in childhood and may result in arrythmia and sudden death. We present a case of sudden death in a healthy 5-month-old infant which initially appeared “SIDS-like” until thorough histological analysis revealed an underlying cardiac rhabdomyoma. The case is of particular importance in that the gross examination of the heart was considered completely normal, and the tumor only involved certain portions of the heart microscopically. Had a single random section of myocardium been the only heart section examined microscopically, the diagnosis might have been missed. This case emphasizes the importance of thorough microscopic examination in infant cases, especially in cases where the heart appears grossly normal.

Neonatal Cardiac Rhabdomyoma: A Single-Center Experience.

Cardiac rhabdomyoma, known as the most common benign cardiac tumor in childhood, is strongly associated with tuberous sclerosis complex. This study aims to present our single-center experience regarding clinical observations, diagnostic approaches, and treatment modalities for cardiac rhabdomyoma identified during the neonatal period. In this clinical observational study, we retrospectively assessed the outcomes of 12 newborn patients diagnosed with cardiac rhabdomyoma who were followed up in our neonatal intensive care unit over the past 12 years. The mean gestational age of the patients was 38.2±1.6 weeks, with an average birth weight of 3193±314 grams. The mean postnatal age at initial diagnosis was 12.42±15.75 days. Tuberous sclerosis complex was clinically identified in 50% of cases (six patients). Seven infants received everolimus treatment, while three infants underwent clinical monitoring without specific interventions. A significant reduction in cardiac mass size was observed in all surviving patients, leading to their subsequent discharge from the hospital. Cardiac rhabdomyomas often undergo spontaneous regression in early childhood. However, in cases with obstructive lesions or arrhythmias, they may present life-threatening consequences. Timely diagnosis, appropriate clinical management, and monitoring are crucial in optimizing outcomes for neonates with cardiac rhabdomyoma.

Exploring Cardiovascular Involvement in Tuberous Sclerosis: Insights for Pediatric Clinicians.

Tuberous sclerosis is a rare genetic disorder involving mainly the nervous and cardiovascular systems. The early recognition of the cardiovascular manifestations by the pediatrician allows an appropriate management and therefore enhances the quality of life of the affected children. Cardiac rhabdomyomas and the associated arrhythmias are the first cardiac features and they might represent a diagnosis challenge given their wide spectrum of clinical manifestations. We aimed to provide the paediatric practitioners with current knowledge regarding the cardiovascular complications in children with tuberous sclerosis. We overviewed the antenatal and postnatal evolution of cardiovascular manifestations, the systematic screening and long-term follow-up strategy of cardiac rhabdomyomas and arrhythmias in children with tuberous sclerosis.

Diagnosis of tuberous sclerosis in the prenatal period: a retrospective study of 240 cases and review of the literature.

Tuberous sclerosis complex (TSC) is a rare multisystemic disorder caused by a pathogenic variant in the TSC1 or TSC2 gene. A great phenotypic variability characterises TSC. The condition predisposes to the formation of hamartomas in various tissues, neurologic and neurodevelopmental disorders such as epilepsy, psychiatric disorders, as well as intellectual disability in 50%. TSC may be responsible for cardiac rhabdomyomas (CRs), cortical tubers, or subependymal nodules during foetal life. Detecting multiple CRs is associated with a very high risk of TSC, but the CR could be single and isolated. Few data exist to estimate the risk of TSC in these cases. We report the largest series of prenatal genetic tests for TSC with a retrospective study of 240 foetuses presenting with suggestive antenatal signs. We also provide a review of the literature to specify the probability of clinical or genetic diagnosis of TSC in case of detection of single or multiple CRs. Indeed, an early diagnosis is crucial for the counselling of the couple and their families. In this series, a definite diagnosis was assessed in 50% (41/82) of foetuses who initially presented with a single CR and 80.3% (127/158) in cases of multiple CRs. The prevalence of parental germinal mosaicism was 2.6% (3/115).

Multiple recurrent supraventricular tachycardia in infantile tuberous sclerosis complex: management requiring triple-drug therapy.

We report the case of a female neonate admitted to the neonatal ICU with a rapid, narrow-complex tachyarrhythmia determined to be supraventricular tachycardia. Multimodality imaging and genetic testing confirmed a diagnosis of tuberous sclerosis complex with multiple cardiac rhabdomyomas. At 13 days of age, the patient was readmitted, exhibiting recurrent supraventricular tachycardia non-responsive to first-line treatment. Management required triple-drug therapy, whereafter the patient remained stable without recurrences. This is a rare report of supraventricular tachycardia in a functionally normal heart with the occurrence of supraventricular tachycardia due to structural abnormalities, with the possibility of multiple concealed accessory pathways.

Early Subclinical Status Epilepticus May Contribute to Developmental Delays in Infants With Tuberous Sclerosis Complex

We present a case of a newborn with a prenatally discovered cardiac rhabdomyoma leading to early genetic diagnosis of tuberous sclerosis complex (TSC). This early diagnosis prompted a presymptomatic electroencephalography (EEG) that revealed subclinical seizures meeting the definition for status epilepticus on day 1 of life. Antiseizure medications (ASMs), including vigabatrin, were started. The EPISTOP and PREVeNT trials demonstrated that early life initiation of vigabatrin may reduce the degree of refractory epilepsy and epileptic spasms (ES) in this population (TSC). Although neonatal seizures are a known entity in TSC, continuous neonatal EEG monitoring is not standard at birth. This case supports early consideration for neonatal EEG monitoring to identify and treat neonatal seizures, reduce risk for infantile spasms, and potentially improve neurodevelopmental outcomes.

Echocardiography-Guided Radiofrequency Ablation for Cardiac Tumors

BackgroundPatients with cardiac tumors may present challenges for surgical resection due to poor clinical condition. Echocardiography-guided transapical radiofrequency ablation for cardiac tumors (TARFACT) potentially offers a less invasive palliative therapy option. ObjectivesThis study aimed to evaluate the safety and efficacy of TARFACT. MethodsFive patients with cardiac tumors (mucinous liposarcoma, myocardial hypertrophy with inflammatory cell infiltration mass, fibrous tissue tumor hyperplasia, myocardial clear cell sarcoma, and cardiac rhabdomyoma) were included. All patients underwent TARFACT and were assessed with electrocardiogram, echocardiographic imaging, biochemical analysis, and pathological confirmation. ResultsThe median follow-up for all patients was 9 (range 4-12) months. Three surviving patients were alive at their last follow-up (9, 12, and 12 months, respectively), whereas 2 patients with late-stage tumors survived 6 months and 13 months after TARFACT, respectively. After TARFACT, all patients showed significant reductions in tumor size: the mean length decreased from 6.7 ± 2.0 cm to 4.7 ± 1.8 cm (P = 0.007); and the mean width decreased from 5.0 ± 2.1 cm to 2.5 ± 0.7 cm (P = 0.041). NYHA functional class also improved: median (IQR) decreased from 3.0 (1.5) to 2.0 (1.0) (P = 0.038), Peak E-wave on echocardiography showed a mean increase from 64.4 ± 15.7 cm/s to 76.6 ± 18.6 cm/s (P = 0.008), and NT-pro BNP levels had a median (IQR) reduction from 115.7 (252.1) pg/mL to 55.0 (121.6) pg/mL (P = 0.043). ConclusionsTARFACT is a novel palliative treatment option for cardiac tumors, reducing accessible tumors and improving clinical symptoms in a preliminary group of patients. (Cardiac Tumors Interventional [Radio Frequency/Laser Ablation] Therapy [CTIH]; NCT02815553)

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.

Patients’ and physicians’ awareness of clinical symptoms and disease severity in tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is a rare inherited disease with the potential to affect virtually every organ system. Clinical presentation is age- and partly sex-dependent and varies broadly with respect to disease manifestations including treatment-refractory epilepsy, intellectual disability and TSC-associated neuropsychiatric disorders, chronic kidney disease or progressive lung function decline. Given the complexity of this disease, multidisciplinary care in specialized TSC centres is recommended. We aimed to elucidate the state of knowledge of patients/caregivers and physicians on individual disease manifestations. We further examined whether the association to a TSC centre has an impact on the comprehensive consideration of potential disease manifestations. Therefore, a survey was performed in a cohort of German TSC patients and their physicians. Complete information was available for 94 patients with a median age of 18 years [range 1–55] and a sex distribution of 53.2% (male): 48.8% (female). Using almost identical questionnaires for patients/caregivers and their respective physician, there was a good correlation for disease assessments associated with relevant morbidity and mortality like epilepsy, renal angiomyolipoma, cardiac rhabdomyomas or intellectual disability. Correlation was moderate for several neuropsychiatric disorders and only poor for hypomelanotic macules, dental pits or retinal achromic patches. Estimation of overall disease severity using a numeric rating scale correlated highly significantly (Pearson correlation coefficient = 0.767; p < 0.001) between patients/caregivers and physicians. In general, physicians more likely quoted items as ‘unknown’ than patients (822 answers vs. 435 answers in the respective groups). Questionnaires completed by physicians who were associated with a specialized TSC centre declared a significantly lower proportion of items as unknown (mean 8.7% vs. 20.5%; p < 0.001). These findings indicate that patients treated by specialized TSC centres seem to obtain a more comprehensive surveillance. Furthermore, it shows that there were reasonable surveillance strategies in general and sufficient patient/caregiver interaction and education in the examined cohort. However, for the most prominent disease characteristics there was a good awareness within both the patients/caregivers and the physicians group.

Tuberous Sclerosis: A Case of Delayed Retrospective Diagnosis

Tuberous sclerosis is a rare genetic disorder, often diagnosed based on clinical manifestations. We report a case of a 39-year-old woman retrospectively diagnosed with tuberous sclerosis after giving birth to a child with cardiac rhabdomyomas. This case highlights the awareness of clinical manifestations of orphan diseases among physicians and the need for a broader approach to managing patients, extending beyond the limited perspective of medical professionals specializing in a particular area of health and facilitated through multidisciplinary consultations, highlighting the significance of educational initiatives among specialists and the general population for early detection and implementation of corrective measures in rare genetic disorders.

A large deletion in TSC2 causes tuberous sclerosis complex by dysregulating PI3K/AKT/mTOR signaling pathway

Background/aimTuberous sclerosis complex (TSC) is a multi-system syndrome caused by loss-of-function mutation in TSC1 or TSC2. Most TSC patients present with cardiac rhabdomyoma or cortical tubers during fetal life, and the symptoms are not uniform as their age. The gene products of TSC1/2 are components of the TSC protein complex and are important role in the PI3K/AKT/mTOR (PAM) signaling pathway. Based on three members of a family with variable expressivity, the purpose of this study was to clarify the clinical features of TSC in different age groups and to analyze the genetic characteristics of TSC2 gene. MethodsClinical exome sequencing and co-segregation were used to identify a three-generation family with four affected individuals. HEK-293T cell model was constructed for subsequent experiments. Quantitative RT-PCR, western blotting, and subcellular localization were used to analyze the expression effect of TSC2 mutation. CCK-8 assay, wound healing assay, and cell cycle analysis were used to analyze the function effect of TSC2 mutation. ResultWe identified a TSC family with heterozygous deletion of exon 4 in TSC2 by clinical exon sequencing. Sanger sequencing indicated that the affected individuals have 2541-bp deletion that encompassed exon 4 and adjacent introns. Deletion of exon 4 decreased the TSC2 mRNA and protein levels in HEK-293T cells, and activated the PI3K/AKT/mTOR pathway, thereby altering the cell cycle and promoting cell proliferation and migration. ConclusionWe confirmed the pathogenicity of the large deletion in TSC2 in a three- generations family.. Deletion of exon 4 of TSC2 affected cell proliferation, migration, and cell cycle via abnormal activation of the PAM pathway. This study evaluated the pathogenic effect of deletion of exon 4 of TSC2 and investigated the underlying mechanism.