Sirolimus Can Increase the Disappearance Rate of Cardiac Rhabdomyomas Associated with Tuberous Sclerosis: A Prospective Cohort and Self-Controlled Case Series Study.

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.

Antenatal screening and diagnosis of tuberous sclerosis complex by fetal echocardiography and targeted genomic sequencing.

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.

[Clinical and genetic study patients with tuberous sclerosis complex]. / Estudio clínico genético en pacientes con complejo de esclerosis tuberosa.

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.

Manifestations of Tuberous Sclerosis Complex: The Experience of a Provincial Clinic.

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.

Estudio clínico genético en pacientes con complejo de esclerosis tuberosa / Clinical and genetic study patients with tuberous sclerosis complex

El complejo de esclerosis tuberosa (CET) es una enfermedad autosómica dominante multisistémica producida por mutaciones en los genes supresores de tumores TSC1 o TSC2. Objetivo: Caracterizar clínica y genéticamente pacientes pediátricos con diagnóstico de CET. Pacientes y Método: Estudio descriptivo de registros clínicos de 42 pacientes pediátricos controlados en un servicio de neuropsiquiatría infantil con diagnóstico de CET y estudio genético en 21 de ellos. Se amplificó por reacción en cadena de la polimerasa y secuenció el exón 15 del gen TSC1 y los exones 33, 36 y 37 del gen TSC2. Se analizó la relación entre las mutaciones encontradas con la severidad y evolución clínica. Resultados: En el 61,9% de los pacientes las manifestaciones comenzaron antes de los 6 meses de edad. Las manifestaciones iniciales de CET más frecuentes fueron las crisis convulsivas (73,8%) y el hallazgo de rabdomiomas cardiacos (16,6%). Durante su evolución, todos los pacientes presentaron compromiso neurológico; el 92,9% presentó epilepsia. Todos los pacientes presentaron máculas hipomelanóticas, 47,6% pangiofibromas faciales, 23,8% parches de Shagreen, 47,6% rabdomiomas cardiacos y 35,7% hamartomas retinianos. El estudio genético realizado a 21 pacientes identificó 2 mutaciones heterocigotas patogénicas en TSC1 y una en TSC2. Este último paciente presentaba un fenotipo clínico más severo. Conclusiones: Las manifestaciones neurológicas y dermatológicas fueron las más frecuentes en los pacientes con CET. Se identificaron 2 mutaciones patogénicas en el gen TSC1 y una en el gen TSC2. La mutación en TSC2 se manifestó en un fenotipo clínico más severo.

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.

Systemic disease manifestations associated with epilepsy in tuberous sclerosis complex.

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.

Rhabdomyomatous differentiation in Wilms tumor pulmonary metastases: a case report and literature review.

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 rhabdomyomas in tuberous sclerosis complex show apoptosis regulation and mTOR pathway abnormalities.

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.

Cardiac rhabdomyoma in tuberous sclerosis: hyperactive Erk signaling.

Tuberous sclerosis (TS) is a neurological disorder associated with the formation of tumors in several organs. Cardiac rhabdomyomas are possibly the earliest symptom of TS. Although rhabdomyomas are present in about half of TS patients, little is known of their molecular background since these tumors are rarely resected. Here we present a patient diagnosed with TS, in whom rhabdomyoma has been excised due to deterioration of hemodynamics. We found, that the tumor remained heterozygous for the affected TSC2 gene. To analyze molecular mechanisms implicated in rhabdomyoma growth, we determined the status of mTOR, Akt and Erk pathways. We found that Akt was not upregulated, while mTOR, Erk and its substrates were hyperactive. Classic activator of Erk, MEK, was only modestly active. We hypothesize that rhabdomyoma arising in TS may progress due to Erk potentiation.

The diverse clinical manifestations of tuberous sclerosis complex: a review.

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.

Anesthesia concerns for children with tuberous sclerosis.

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.