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Objectives: To investigate the efficacy and safety of sirolimus in the treatment of cardiac rhabdomyomas associated with tuberous sclerosis complex and the specific benefits in different subgroups., Study Design: The study was a prospective cohort and self-controlled case series study. Based on the prevalence of cardiac rhabdomyoma at different ages, we estimated the natural tumor disappearance rate. The subgroup analysis was done by Cox regression. Self-controlled case series method was used to assess the magnitude and duration of the drug effect. Adverse events were described., Results: A total of 217 patients were included in the cohort study. Tumor disappearance rate was higher in younger age groups (hazard ratio = 0.99, P = .027) and female patients (hazard ratio = 2.08, P = .015). The age-adjusted incidence ratio showed that the disappearance of rhabdomyomas between 3 and 6 months was more related to sirolimus. Adverse events were observed 60 times in 42 of 217 children, mainly stomatitis., Conclusions: Sirolimus can increase the disappearance rate of cardiac rhabdomyoma in the tuberous sclerosis complex population. Efficacy varies by sex and age: female and younger patients have higher tumor disappearance rate. Sirolimus is well-tolerated., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Although fetal cardiac rhabdomyoma can be the initial finding in patients with tuberous sclerosis complex (TSC), the challenges of precise genetic diagnosis of TSC can now be potentially overcome by new whole or targeted genomic sequencing. The goals of this study were to investigate the correlation between suspected cardiac rhabdomyoma and TSC to provide the information for a prenatal diagnosis of TSC and to validate the TSC genotype in this cohort of fetuses with suspected prenatal cardiac rhabdomyoma.We retrospectively analyzed 10,728 fetal echocardiograms from January 2013 to March 2016 in our institution. A total of 32 fetuses were suspected of having cardiac rhabdomyomas. Among them, 15 subjects met the inclusion criteria and provided written consent. Samples from fetuses (n = 13 after terminations) and newborns (n = 2) were available for targeted genomic sequencing of the exons and introns of the TSC1 and TSC2 genes and the adjacent 10 base pairs and for validated studies using Sanger sequencing.Among the 15 subjects with suspected cardiac rhabdomyoma and TSC genomic sequencing data, 7 subjects were familial and 8 subjects were sporadic cases. Fetal echocardiography showed a single tumor in 2 fetuses and multiple tumors in 13 fetuses. Gene sequencing analysis showed no mutation of the TSC1 or TSC2 gene in 2 subjects with a single tumor but positive mutations in all 13 subjects with multiple tumors. Among the latter, 5 mutations were "pathogenic" and have been previously reported (4 familial and 1 sporadic). Six new mutations were "likely pathogenic" and had not been previously reported (3 familial and 3 sporadic); 1 was of "uncertain significance" (sporadic), and 1 was suspected of being "likely benign" (sporadic).Prenatal suspected cardiac rhabdomyoma detected by fetal echocardiography should raise the suspicion of TSC. In fetuses with multiple tumors, especially the familial cases, genomic sequencing has a high yield of detecting TSC-causing genes. Patient history, prenatal fetal echocardiography, and targeted genomic sequencing may facilitate screening for, diagnosis of, and counseling for TSC.

Tuberous sclerosis complex (TSC) is a multisystem autosomal dominant disease caused by mutations in the tumor suppressor genes TSC1 or TSC2., Objective: To characterize clinically and genetically patients diagnosed with TSC., Patients and Method: Descriptive study of clinical records of 42 patients from a pediatric neuropsychiatry department diagnosed with TSC and genetic study in 21 of them. The exon 15 of TSC1 gene and exons 33, 36 and 37 of TSC2 gene were amplified by polymerase chain reaction and sequenced. The relationship between the mutations found with the severity and clinical course were analyzed., Results: In 61.9% of the patients the symptoms began before 6 months of age. The initial most frequent manifestations of TSC were new onset of seizures (73.8%) and the detection of cardiac rhabdomyomas (16.6%). During the evolution of the disease all patients had neurological involvement; 92.9% had epilepsy. All patients presented hypomelanotic spots, 47.6% facial angiofibromas, 23.8% Shagreen patch, 47.6 heart rhabdomyomas and 35.7% retinal hamartomas. In the genetic study of 21 patients two heterozygous pathogenic mutations in TSC1 and one in TSC2 genes were identified. The latter had a more severe clinical phenotype., Conclusions: Neurological and dermatological manifestations were the most frequent ones in patients with TSC. Two pathogenic mutations in TSC1 and one in TSC2 genes were identified. The patient with TSC2 mutation manifested a more severe clinical phenotype.

Background: Tuberous sclerosis complex (TSC) is a neurocutaneous disorder with a wide spectrum of manifestations. Recent consensus recommendations stress the importance of multidisciplinary management of children with TSC. The objective of this study was to examine the manifestations of TSC at a large referral centre to determine the care needs of this population., Methods: A retrospective, systematic chart review was performed of children with TSC managed at British Columbia Children's Hospital. Patients were identified through epilepsy and clinical neurophysiology databases., Results: The study population comprised 81 patients, born between 1987 and 2014, who were a median of 10 years (range, 0.2-23.2) at most recent follow-up. Epilepsy occurred in 91% of patients, including 32% with a history of infantile spasms. Nineteen patients underwent epilepsy surgery, nine (47%) of whom were seizure-free at most recent follow-up. Overall, 61% of epilepsy patients had been seizure-free for at least 1 year at the time of last follow-up. Neuropsychiatric disorders were diagnosed in 49% of children, with autism (25%), attention deficit hyperactivity order (19%) and anxiety (16%) being the most common. Cardiac rhabdomyomata occurred in 35% of children and renal angiomyolipomas were seen in 43%. A total of 91% had skin manifestations., Conclusion: This study outlines the multisystem manifestations of TSC, observed through a large pediatric referral center. Epilepsy and neuropsychiatric disorders are the major source of morbidity in this age group and provide many challenges to the treating clinician. Because a subset of the study population is still quite young, the prevalence of neuropsychiatric disorders is likely underestimated.

Objective: Epilepsy is one of the most disabling symptoms of tuberous sclerosis complex (TSC) and is a leading cause of morbidity and mortality in affected individuals. The relationship between systemic disease manifestations and the presence of epilepsy has not been thoroughly investigated. This study utilizes a multicenter TSC Natural History Database including 1,816 individuals to test the hypothesis that systemic disease manifestations of TSC are associated with epilepsy., Methods: Univariate analysis was used to identify patient characteristics (e.g., age, gender, race, and TSC mutation status) associated with the presence of epilepsy. Individual logistic regression models were built to examine the association between epilepsy and each candidate systemic or neurologic disease variable, controlling for the patient characteristics found to be significant on univariate analysis. Finally, a multivariable logistic regression model was constructed, using the variables found to be significant on the individual analyses as well as the patient characteristics that were significant on univariate analysis., Results: Nearly 88% of our cohort had a history of epilepsy. After adjusting for age, gender, and TSC mutation status, multiple systemic disease manifestations including cardiac rhabdomyomas (odds ratio [OR] 2.3, 95% confidence interval [CI] 1.3-3.9, p = 0.002), retinal hamartomas (OR 2.1, CI 1.0-4.3, p = 0.04), renal cysts (OR 2.1, CI 1.3-3.4, p = 0.002), renal angiomyolipomas (OR 3.0, CI 1.8-5.1, p < 0.001), shagreen patches (OR 1.7, CI 1.0-2.7, p = 0.04), and facial angiofibromas (OR 1.7, CI 1.1-2.9, p = 0.03) were associated with a higher likelihood of epilepsy. In the multivariable logistic regression model, cardiac rhabdomyomas (OR 1.9, CI 1.0-3.5, p = 0.04) remained significantly associated with the presence of epilepsy., Significance: The identification of systemic disease manifestations such as cardiac rhabdomyomas that confer a higher risk of epilepsy development in TSC could contribute to disease prognostication and assist in the identification of individuals who may receive maximal benefit from potentially novel, targeted, preventative therapies., (Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.)

While sparsely reported in the literature, Wilms tumor may differentiate into more mature mesenchymal tissue types, such as skeletal muscle, following chemotherapy. The frequency of this event is unknown. Chemotherapy and radiation may induce cytodifferentiation of Wilms tumor cells or select for the survival of less mitotically active cells. In follow-up biopsies, the presence of rhabdomyomatous differentiation can confound the histologic diagnosis. Furthermore, these differentiated tumors appear to be more resistant to chemotherapy, thus biopsy and positron emission tomography scans following chemotherapy and radiation may prevent unnecessary treatment. We report an unusual case of Wilms tumor in a 21- year-old man with rhabdomyomatous differentiation of pulmonary metastases after chemotherapy, which presented a challenge during frozen section diagnosis.

Cardiac rhabdomyoma (CR) is the most common heart tumor in children and is usually associated with tuberous sclerosis complex (TSC). Tuberous sclerosis complex is a genetic disorder caused by a mutation in either of 2 genes (TSC1 or TSC2) and characterized by the formation of hamartomas in multiple organs. The 2 TSC proteins, hamartin and tuberin, antagonize the mammalian target of rapamycin (mTOR) signaling pathway, thus regulating cell growth and proliferation. Recently, some trials treating TSC with the mTOR inhibitor rapamycin have been published; however, the impact of such treatment on heart tumors is not known. The aim of the present paper was to study the molecular pathobiology of CRs. Six CR samples were studied. The expression of S6K1, pErk, Erk, Akt, pAkt, 4E-BP1, hamartin, tuberin, mTOR, bcl-2, Bax, and Ki-67 was examined using immunohistochemistry and Western blot methods. Increased expression of Bax, mTOR, pS6K, pErk, and 4E-BP1 was found in all CR samples. Hamartin and tuberin expression was decreased in tumors versus normal heart tissues. This is the first study showing mTOR pathway dysregulation and an increased expression of proapoptotic Bax protein in CRs associated with TSC.

Tuberous sclerosis (TS) is a relatively rare, autosomal dominant syndrome that displays high genetic penetrance in affected families. It is identified by a classic triad of symptoms including epilepsy, skin lesions, and mental retardation. Tuberous sclerosis causes hamartomas in multiple organ systems, including the brain, skin, heart, kidneys, lungs, and liver. Awareness of the signs and symptoms and the organs involved is critical to provide safe and effective anesthesia care. We describe a 10-year-old girl with TS scheduled to receive a general anesthetic for laser treatment of facial angiofibromas. The patient had several coexisting maladies from TS, including hypertension, autism, seizure disorder, cardiac rhabdomyomas, developmental delay, and bilateral polycystic renal disease. The laser procedure was performed, and there were no surgical or anesthetic complications. However, the potential for complications due to TS remained high throughout the provision of anesthesia care. Increased knowledge of TS and diligence in anesthesia practice can greatly reduce these risks.

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem neurocutaneous disorder. TSC results in hamartomatous lesions primarily involving the skin, central nervous system, kidneys, eyes, heart, and lungs. The clinical findings and severity of TSC are highly variable. Recent advances in our understanding of the complexities of the TSC1 and TSC2 genes are making genotype-phenotype correlations possible. While managing seizures, cognitive dysfunction, and behavioral abnormalities are the primary responsibility of the neurologist, familiarity with all aspects of this disease helps provide better comprehensive care for affected individuals.

We report a child in whom multiple cardiac rhabdomyomas were identified on routine fetal ultrasonography. Molecular genetic studies identified the TSC2 gene missense mutation (E36; 4672 G>A, 1558 E>K TSC2). Both general and neurodevelopment of the patient have been normal. When last examined at age 6 years, he had no skin manifestations of tuberous sclerosis complex. Computed tomography of the brain revealed two periventricular calcifications consistent with the molecular diagnosis. This is the first report of molecularly confirmed tuberous sclerosis complex in a child with multiple cardiac rhabdomyomas and no other clinical manifestations of the disease. We propose that all cases of multiple cardiac rhabdomyomas in an infant be given a tentative diagnosis of tuberous sclerosis complex.

Rhabdomyomata are the most common cardiac tumors in childhood and are associated with tuberous sclerosis. These tumors tend to regress in the first years of life. Little is known about their intrauterine growth pattern. We describe three fetuses with cardiac rhabdomyomata and illustrate the tumor growth by serial echocardiographic views during the second half of gestation. Tumor growth is proportional to cardiac growth and tends to be somewhat slower toward the end of pregnancy.

Two dimensional echocardiography seems to be the best diagnostic tool for diagnosis of cardiac tumors. In our practice using 2 dimensional echocardiography in pediatric patients from 1984 11 cardiac tumors were diagnosed and followed-up. Four of them the cardiac rhabdomyomata (one of them diagnosed in utero) was the first manifestation of tuberous sclerosis. We summarized the follow-up data from our patients with cardiac rhabdomyomata. The detection of cardiac tumor in the fetal or infant period is of outmost importance in the early diagnosis of tuberous sclerosis and suggest careful follow-up and management. To the best of our knowledge no report of tuberous sclerosis based on echocardiographic diagnosis of cardiac rhabdomyomata has been described in our country.

Cardiac rhabdomyoma is a rare tumor. Because of its rate of regression, mainly in the first year of life, conservative therapy is generally suggested when diagnosis occurs in infancy. We report surgical ablation of a rhabdomyoma in a 2-month-old boy in whom the tumor extended into the subaortic outflow tract. The tumor, which had a dual attachment to the aortic and mitral valves, was safely removed without any valvar damage. We suggest immediate surgical intervention for those rhabdomyomas which are life-threatening because of their size, location, or arrhythmogenicity.

We report an extraordinary case of tumorous type of rhabdomyomatous dysplasia without any other malformation in a fetus of 23 weeks gestation. Histologically, autopsy showed distinctive striated muscle tissue in the upper and middle lobes of the right lung. Unusual in this case, compared with previously published reports, is the absence of further malformations, the occurrence in the apical parts of the lung and the marked degree of rhabdomyomatous dysplasia. The case report is followed by a differential diagnosis, review of the literature and discussion of the pathogenesis.

A retrospective study on twenty two cases with tuberous sclerosis, from 1972 to 1994, is done. It is also reviewed national and international literature, emphasizing epidemiologic, clinical, radiological, genetic and therapeutic aspects, as well as diagnosis and prognosis.

Objective: To investigate the influence of corticotropin therapy on cardiac rhabdomyoma., Design: Analysis of data from echocardiography performed on in-patients., Patients: Six patients with rhabdomyoma who were admitted to the authors' medical centre with either convulsion (five cases) or prematurity (one case) between 1985 and 1995. Five had tuberous sclerosis., Intervention: Size of cardiac tumours of each patient was measured by echocardiography, and volume index was calculated as the ratio of the tumour volume to its initial volume., Main Result: Increase in size of some of the tumours was found during corticotropin therapy on follow-up echocardiography. Maximum volume indexes of tumours in the case of patients (n = 4) who did not receive corticotropin therapy was 1.2 to 3.7, whereas those of patients (n = 2) who received therapy was 9.1 to 12; one of the latter patients died., Conclusion: Corticotropin may contribute to the enlargement of cardiac rhabdomyoma. The size of cardiac rhabdomyomas must be carefully followed when patients are treated with corticotropin.

To determine whether cardiac rhabdomyoma (CR) is a hamartoma of fetal cardiac myocyte, we investigated five cases of CRs that spontaneously developed in five 6-month-old hybrid swine with histological, immunohistochemical, and ultrastructural techniques. The cases were four multiple and one solitary neoplasms, which appeared as intraventricular nodules of various sizes without any congenital malformations. Histologically, the large ovoid CR cells with an occasional spiderweb appearance showed a transition from normal-looking cardiac myocytes or rarely from Purkinje cells, but no mitotic figures. Besides large amounts of glycogen, the CR cells contained many PAS-negative, large cytoplasmic vacuoles filled with eosinophilic or fibrillar substance. Immunohistochemically, the CR cells showed intense positivity for desmin and variable positivities for vimentin, alpha-atrial naturiuretic peptide, and proliferating cell nuclear antigen. These positivities were not seen in adjacent cardiac myocytes. Cytokeratin was negative in the CR cells but was positive in fetal cardiac myocytes of early gestation. Rod-like or granular positivity for alpha-actinin in the CR cells was similar to that in nemaline myopathy. Ultrastructurally, the CR cells contained myofibrils that frequently showed myofibrillar degeneration and produced large intracytoplasmic vacuoles. These myofibrils often mingled with nemaline bodies and leptofibrils that continued to the Z bands. T-systems, sarcoplasmic reticulum, and intercalated discs, which are specific features of postnatal cardiac myocytes, were sometimes observed in the CR cells. Increase of glycogen and mitochondria and appearance of atrial-specific granules associated with the Golgi apparatus were other features noted. The present findings have not been reported, even in human CR. From these new observations with the recent report on the occurrence of CR in neonatal piglets, swine CR does not belong to the entity of hamartoma but may be a congenital dysplasia of the perinatal cardiac tissues with myofibrillar degeneration, affecting mainly cardiac myocytes and rarely Purkinje cells. The various immunophenotypic changes including proliferating cell nuclear antigen and the increase and appearance of cytoplasmic elements compared with mature cardiac myocytes can be interpreted as reactive or regenerative changes due to myofibrillar degeneration.

A mesenchymal tumor with the macroscopic and microscopic features of a fetal rhabdomyoma arose in the liver of a 14-year-old boy. Thirteen years previously this boy had been treated for a fetal rhabdomyomatous nephroblastoma with nephrectomy and--for subsequent peritoneal disseminations--with surgical excision, radiotherapy, and chemotherapy. The unusual hepatic location of the rhabdomyomatous tumor in this patient supports the view that this mature tumor developed from a metastasis of the original nephroblastoma. As such, this case may represent an example of irreversible change of a malignant process into a benign tumor probably caused by the action of systemic chemotherapy.

Neonatal cardiac rhabdomyoma is the most frequent cardiac tumour in the newborn, and a classical way to diagnose tuberous sclerosis (Bourneville's disease). The authors report 4 cases, including 2 antenatal diagnosis: 2 of them had arrhythmia, one with asystolic cardiac failure and the other with cyanosis due to a right-left shunt; the tumour was asymptomatic in the 2 others. The 4 babies had clinical and radiological neurologic signs of tuberous sclerosis, initially or during the course of the disease. The authors discuss the polymorphism of the clinical presentation of tuberous sclerosis in the newborn. Although tuberous sclerosis is transmitted through a dominant gene, the expressivity and the penetrance are very variable. The authors discuss the examination and investigation of at risk family members. The genetic counsel is difficult but very important because of the poor neurologic prognosis of the disease.

An autopsy case of cardiac rhabdomyoma in a male infant is reported. Many nodules of rhabdomyoma were present in all four cardiac chambers and were microscopically composed of ovoid, glycogen-laden cells and typical "spider cells". Atrial natriuretic peptide (ANP) was immunohistochemically demonstrated in both normal myocytes and rhabdomyoma cells of both atria, but not in normal myocytes and rhabdomyoma cells of both ventricles. Ultrastructurally, atrial specific granules were present in atrial rhabdomyoma cells and normal atrial cardiocytes, and these showed ANP immunoreactivity with protein A-gold technique. It could be said that the localization and intracellular distribution of ANP in this cardiac rhabdomyoma were closely similar to those of normal human heart. With regard to the presence of ANP, cardiac rhabdomyoma cells arising in atria seemed to differ from those in ventricles, although many tumor nodules occurred in both atria and ventricles. Furthermore, it seemed that cardiac rhabdomyomas could also be divided into two parts: 1) an atrial part with ANP, and 2) a ventricular part without ANP. Therefore, this study confirms the hypothesis that cardiac rhabdomyoma is a hamartoma rather than a true neoplasm.

A malignant rhabdoid tumour of the bladder is reported from a girl aged 6. Detailed immunohistochemical and ultrastructural investigations provide evidence which suggests a histiocytic origin for this controversial neoplasm.

The electron microscopic features of three primary cardiac rhabdomyomas were studied for the first time. Distinct striated muscle cells arranged in a disorderly fashion are described. The cases demonstrated a spectrum of possible myobibril differentiation with one case having only Z-bands and myosin filaments present while the other two had well formed thick and thin filaments with all of the bands present including Z, I, A, H, and M. Glycogen bodies, numerous mitochondria with tubular cristae, lipid deposits, and peculiar striated structures resembling zebra bodies were also seen. Desmonsomal attachments suggestive of Purkinje-type fibers were seen in all of the cases and were the only types seen in cases 2 and 3. In addition, intercalated discs characteristic of myocardial fibers were noted in case 1. This finding still leaves the exact histogenesis of the lesion uncertain although origin from two types of fibers is possible.