Manifestations Of Tuberous Sclerosis Complex Research Articles

Bleeding solitary SEGA in non-tuberous sclerosis complex adolescent: a case illustration and review of literature.

Subependymal giant cell astrocytoma (SEGA) represents a benign brain tumor occurring in 5-20% of individuals diagnosed with tuberous sclerosis complex (TSC), serving as a major diagnostic criterion. The presence of SEGA in a patient often prompts consideration of TSC as a probable diagnosis, given its unique association with this disorder. Typically, only one additional major criterion or two minor criteria are necessary to fulfill the diagnostic criteria for TSC. However, in rare instances, SEGA may manifest in patients without clinical features of TSC, termed solitary SEGA. The occurrence of solitary SEGA in patients lacking both clinical manifestations of TSC and genetic confirmation is extremely rare. Furthermore, the presentation of SEGA with intratumoral bleeding is exceedingly uncommon. Here, we presented a case of bleeding solitary SEGA in non-TSC adolescent who underwent surgery and has remained free of disease for a minimum of 3years. Genetic analysis of peripheral blood and tumor tissue yielded negative results for TSC-related mutations. While SEGA occurrence in non-TSC patients is uncommon, it remains one of the possible diagnoses of intraventricular tumors. However, comprehensive genetic and physical evaluations are imperative to confirm the TSC status and guide further investigations and follow-up appropriately.

The role of TSC1 and TSC2 proteins in neuronal axons.

Tuberous Sclerosis Complex 1 and 2 proteins, TSC1 and TSC2 respectively, participate in a multiprotein complex with a crucial role for the proper development and function of the nervous system. This complex primarily acts as an inhibitor of the mechanistic target of rapamycin (mTOR) kinase, and mutations in either TSC1 or TSC2 cause a neurodevelopmental disorder called Tuberous Sclerosis Complex (TSC). Neurological manifestations of TSC include brain lesions, epilepsy, autism, and intellectual disability. On the cellular level, the TSC/mTOR signaling axis regulates multiple anabolic and catabolic processes, but it is not clear how these processes contribute to specific neurologic phenotypes. Hence, several studies have aimed to elucidate the role of this signaling pathway in neurons. Of particular interest are axons, as axonal defects are associated with severe neurocognitive impairments. Here, we review findings regarding the role of the TSC1/2 protein complex in axons. Specifically, we will discuss how TSC1/2 canonical and non-canonical functions contribute to the formation and integrity of axonal structure and function.

Retrospective Analysis of Canadian Adults with Tuberous Sclerosis Complex.

Our study goal was to characterize the relative frequencies of molecular and phenotypic traits of tuberous sclerosis complex (TSC) in a Canadian adult population. Previous studies have sought to identify TSC-related genotypic and phenotypic trends in pediatric cohorts, but little is known about clinical manifestations and severity when it presents in adults. We conducted a retrospective chart review of adult patients seen at the TSC clinic at the University Health Network genetics clinics (Toronto, Ontario) to compare trends in the relative frequency of TSC manifestations with genotype. Fifty-one patients were eligible for this study. Eight patients had a pathogenic/likely pathogenic variant in the tuberous sclerosis complex 1 (TSC1) gene, 18 had a tuberous sclerosis complex 2 (TSC2) pathogenic/likely pathogenic variant, 6 patients had multiple variants identified in TSC1/TSC2 or TSC2/PKD1, 11 had no mutation identified (NMI) and 8 had no genetic testing done. Patients with a pathogenic/likely pathogenic variant in TSC2 presented with an increased involvement of multiple systems and a higher frequency of TSC-related manifestations relative to the other mutation groups. Previous studies comparing the wide phenotypic variability with TSC genotype have mainly comprised pediatric cohorts. With a focus on adults, we found trends to be similar across previous literature. An informed multidisciplinary approach should be taken to ensure proper surveillance and management of adults with TSC until a correlation between genotype and phenotype, especially past infancy, is better understood.

Cerebral vascular and blood brain-barrier abnormalities in a mouse model of epilepsy and tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a genetic disorder, characterized by tumor formation in the brain and other organs, and severe neurological symptoms, such as epilepsy. Abnormal vascular endothelial growth factor (VEGF) expression may promote angiogenesis in kidney and lung tumors in TSC and has been identified in brain specimens from TSC patients, but the role of VEGF and vascular abnormalities in neurological manifestations of TSC is poorly defined. In this study, we investigated abnormalities in brain VEGF expression, cerebral blood vessel anatomy, and blood-brain barrier (BBB) structure and function in a mouse model of TSC. Tsc1GFAP CKO mice were used to investigate VEGF expression and vascular abnormalities in the brain by Western blotting and immunohistochemical analysis of vascular and BBB markers. Invivo two-photon imaging was used to assess BBB permeability to normally impenetrable fluorescently labeled compounds. The effect of mechanistic target of rapamycin (mTOR) pathway inhibitors, VEGF receptor antagonists (apatinib), or BBB stabilizers (RepSox) was assessed in some of these assays, as well as on seizures by video-electroencephalography. VEGF expression was elevated in cortex of Tsc1GFAP CKO mice, which was reversed by the mTOR inhibitor rapamycin. Tsc1GFAP CKO mice exhibited increased cerebral angiogenesis and vascular complexity in cortex and hippocampus, which were reversed by the VEGF receptor antagonist apatinib. BBB permeability was abnormally increased and BBB-related tight junction proteins occludin and claudin-5 were decreased in Tsc1GFAP CKO mice, also in an apatinib- and RepSox-dependent manner. The BBB stabilizer (RepSox), but not the VEGF receptor antagonist (apatinib), decreased seizures and improved survival in Tsc1GFAP CKO mice. Increased brain VEGF expression is dependent on mTOR pathway activation and promotes cerebral vascular abnormalities and increased BBB permeability in a mouse model of TSC. BBB modulation may affect epileptogenesis and represent a rational treatment for epilepsy in TSC.

A rare case of subependymal giant cell astrocytoma presenting with spontaneous intratumoral hemorrhage

ABSTRACT Subependymal giant cell astrocytomas (SEGAs) are low-grade gliomas usually arising in the periventricular regions near the foramen of Monro seen exclusively with tuberous sclerosis complex. Incidence of hemorrhage in SEGA is less than 1% with only 10 cases reported in English literature. We present a similar case of SEGA with spontaneous intratumoral hemorrhage in a 35-year-old male with cutaneous manifestations of tuberous sclerosis complex and acute onset headache with convulsion.

Treatment of tuberous sclerosis complex manifestations in children with mTOR inhibitors.

Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder that affects multiple organ systems. Mutations in the TSC1 and TSC2 genes result in the constitutive hyperactivation of the mammalian target of rapamycin (mTOR) pathway, contributing to the growth of benign tumors or hamartomas in various organs. Due to the implication of mTOR pathway dysregulation in the disease pathology, increasing evidence supports the use of mTOR inhibitors for treating multiple manifestations of TSC. In this study, we conducted a retrospective analysis of clinical findings and treatment data from 38 patients diagnosed with tuberous sclerosis who were followed up in the Pediatric Oncology Clinic between 2010 and 2020. We collected information on patients' ages, genders, affected sites, familial history, imaging findings, presence of tumors, and treatments. Among the patients, nine individuals with TSC manifestations were treated with mTOR inhibitors. Specifically, everolimus was successfully administered to five patients with inborn cardiac rhabdomyoma causing hemodynamic impairment. In addition, two patients with refractory seizures received everolimus in combination with anti-epileptic drugs. A patient with renal angiomyolipomas larger than 3cm was treated with everolimus, while a patient with extensive facial angiofibroma received topical sirolimus. All patients tolerated the mTOR inhibitors well, and the side effects were deemed acceptable. The utilization of mTOR inhibition in TSC is expected to become more prevalent in clinical practice, as current research is anticipated to provide a better understanding of the therapeutic roles of these treatments in TSC.

Neurological and Dermatological Manifestations of Tuberous Sclerosis Complex: Report from a Romanian Tertiary Hospital Cohort.

Tuberous sclerosis complex is a rare multisystem genetic disorder characterized by multiorgan involvement, frequently associated with intellectual impairment and epilepsy. The aim of our study was to describe the neurological and dermatological manifestations of TSC in 32 adult patients (of whom 19 were females) who attended the Neurology and Nephrology Clinics of Fundeni Clinical Institute in Romania from 2015 to 2020. Seventeen patients were diagnosed with epilepsy, nine patients had intellectual impairment, and complete neuroimaging was available for twenty-two patients. As expected, the most frequent dermatological lesions were cutaneous angiofibromas in 20 patients, but with a lower frequency than described in the current literature. Statistical analysis was performed considering the small number of patients. Cortical tubers in neuroimaging seemed to be associated with the diagnosis of epilepsy, while subependymal nodules represented a risk factor for intellectual impairment. Males showed a larger number of dermatological types of lesions, especially café -au-lait patches. Interestingly, we found a statistically significant positive association between epilepsy and the presence of cutaneous angiofibromas, as well as total dermatological involvement. Females had significantly higher Charlson comorbidity index scores, indicating a higher burden of disease. Everolimus seemed to be a well-tolerated treatment and showed promising results in controlling epileptic seizures alone in two patients. More studies, with the inclusion of a larger number of patients, are needed to confirm these results.

Subependymal Giant Cell Astrocytoma Tumors in Patients Without Clinical Manifestation of Tuberous Sclerosis Complex: A Diagnostic Puzzle

Subependymal Giant Cell Astrocytoma Tumors in Patients Without Clinical Manifestation of Tuberous Sclerosis Complex: A Diagnostic Puzzle

Paradigm shift in the treatment of tuberous sclerosis: Effectiveness of everolimus

Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterised by abnormal cell proliferation and differentiation that affects multiple organs and can lead to the growth of hamartomas. Tuberous sclerosis complex is caused by the disinhibition of the protein mTOR (mammalian target of rapamycin). In the past, various therapeutic approaches, even if only symptomatic, have been attempted to improve the clinical effects of this disease. While all of these therapeutic strategies are useful and are still used and indicated, they are symptomatic therapies based on the individual symptoms of the disease and therefore not fully effective in modifying long-term outcomes. A new therapeutic approach is the introduction of allosteric inhibitors of mTORC1, which allow restoration of metabolic homeostasis in mutant cells, potentially eliminating most of the clinical manifestations associated with Tuberous sclerosis complex. Everolimus, a mammalian target of the rapamycin inhibitor, is able to reduce hamartomas, correcting the specific molecular defect that causes Tuberous sclerosis complex. In this review, we report the findings from the literature on the use of everolimus as an effective and safe drug in the treatment of TSC manifestations affecting various organs, from the central nervous system to the heart.

Sclerotic Bone Lesions as a Clue in the Diagnosis of Three Generations of Tuberous Sclerosis Complex: Case Report and Review of Literature

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder that can involve multiple organ systems. Diagnosis is based on independent clinical diagnostic criteria and genetic diagnostic criteria (pathogenic variants on TSC1 and TSC2 genes). To make a definitive diagnosis can be especially difficult in oligosymptomatic or asymptomatic patients and in those patients with genetic variants of uncertain significance (VUS). Early diagnosis and lifelong surveillance are paramount to avoid morbidity and potentially life-threatening complications. To increase diagnostic sensibility, less known manifestations of TSC can be helpful. Herein we show a case in which SBLs were used as a diagnostic clue to help diagnose three generations of oligosymptomatic TSC carrying a VUS in TSC1. SBLs are commonly detected in imaging studies of patients with TSC and have been recently included as a minor clinical diagnostic criterion. Clinicians and radiologists should be aware of their significance as they can be mistaken with osteoblastic metastases.

Subependymal Giant Cell Astrocytoma Tumors in Patients Without Clinical Manifestation of Tuberous Sclerosis Complex: A Diagnostic Puzzle

Subependymal Giant Cell Astrocytoma Tumors in Patients Without Clinical Manifestation of Tuberous Sclerosis Complex: A Diagnostic Puzzle

EE177 Topical Sirolimus 0.2% Gel for Treatment of Facial Angiofibroma Associated with Tuberous Sclerosis Complex in the United States: A Budget Impact Analysis

Facial angiofibroma (FA), one of the predominant dermatological manifestations of tuberous sclerosis complex (TSC) disorder, occurs in 75%-88% of patients. Managing FA with TSC adds a substantial clinical and economic burden on the healthcare system. We assessed the budget impact of including sirolimus 0.2% gel (HYFTOR™), the first and only US FDA approved topical medication for FA associated with TSC from a US third-party payer perspective (Commercial, Medicaid, and Medicare).

EE407 Healthcare Resource Utilization and Cost Burden of Facial Angiofibroma Associated with Tuberous Sclerosis Complex: A Real-World Claims Database Analysis in the United States

Tuberous sclerosis complex (TSC), a rare genetic disorder affects over 50,000 people in the United States (US). The disease burden of facial angiofibroma (FA), the most predominant cutaneous manifestation of TSC, is substantial. We aimed to document healthcare resource utilization (HCRU) and costs related with management of TSC and in a subset of TSC patients with FA.

Development and internal validation of a clinical risk score to predict incident renal and pulmonary tumors in people with tuberous sclerosis complex (P14-9.008)

<h3>Objective:</h3> Develop and internally validate a clinical risk score to predict incident renal angiomyolipoma (AML) and pulmonary lymphangioleiomyomatosis (LAM) in people with tuberous sclerosis complex (TSC). <h3>Background:</h3> TSC affects approximately 1/6000 live births. The primary sources of morbidity and mortality in children are manifestations affecting the brain and heart. Adolescents and adults, on the other hand, are at the greatest risk of developing AML and LAM. <h3>Design/Methods:</h3> We will leverage data from 2,420 participants in the TSC Alliance Natural History Database for these analyses. This is the largest international research database for TSC. We will use Cox regression models to predict AML and LAM development using 13 brain, heart, and cutaneous manifestations of TSC as potential predictors. We will use the results of these regression models to develop clinical risk scores. These will then be internally validated using bootstrap resampling, measuring discrimination and calibration. <h3>Results:</h3> We have acquired access to all required data and our analyses are underway, to be completed by the end of 2022. So far, descriptive analyses have shown that 426 out of 2,420 individuals in our data developed AML, while 77 developed LAM. Preliminary analyses have demonstrated excellent calibration for AML, and discrimination that is either good or strong for AML and LAM (c-statistics from 0.72 to 0.81). <h3>Conclusions:</h3> It is currently unknown whether the clinical TSC features during the childhood of an individual can accurately estimate the risk of developing AML or LAM during adolescence and adulthood. Our work will be an important step towards identifying individuals who would benefit from prophylactic treatments (e.g. with mTOR inhibitors) and lead to more tailored schedules for screening imaging. We expect that our work will allow for more personalized medicine in people with TSC. <b>Disclosure:</b> Mr. Loubert has nothing to disclose. Dr. House has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AstraZeneca. Dr. House has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Baxter. Dr. House has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Canadian Medical Protective Association. Dr. Larochelle has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen, Novartis, Sanofi-Genzyme, Alexion, EMD-Serono, FIND therapeutics, Actelion. The institution of Dr. Larochelle has received research support from Université de Montréal-CHUM. Dr. Major has nothing to disclose. The institution of Dr. Keezer has received research support from UCB . The institution of Dr. Keezer has received research support from Eisai. The institution of Dr. Keezer has received research support from TD Bank. The institution of Dr. Keezer has received research support from Savoy Foundation. The institution of Dr. Keezer has received research support from TSC Alliance. The institution of Dr. Keezer has received research support from Quebec Bio-imaging Network. The institution of Dr. Keezer has received research support from Canadian Institutes of Health Research. The institution of Dr. Keezer has received research support from Fonds de Recherche Québec Santé. The institution of Dr. Keezer has received research support from Canadian Institutes of Health Research.

Cutaneous manifestations of tuberous sclerosis complex: An uncommon entity

A middle aged female from Northern India, presented to the Outpatient department with cutaneous lesions typical of Tuberous Sclerosis Complex (TSC) without intellectual disability. She had multiple skin lesions which are enlisted below:

Safety of Sirolimus in Patients with Tuberous Sclerosis Complex under Two Years of Age—A Bicenter Retrospective Study

mTOR inhibitors are a novel pharmacotherapy recommended for subependymal giant astrocytomas, refractory epilepsy, and the treatment of the other clinical manifestations of tuberous sclerosis complex (TSC). Clinical trials on everolimus proved it to be effective and safe in children. Despite its common use in clinical practice, the research on sirolimus is limited. This study is the first to determine and assess the severity of the adverse effects (AEs) of sirolimus administered to children with TSC under two years of age. We performed a bicenter retrospective data analysis of medical records of individuals with TSC who initiated therapy with sirolimus under the age of two. Twenty-one patients were included in the study. At least one AE was reported in all participants. The most prevalent AEs were anemia, thrombocytosis, and hyperlipidemia. Infections and mouth ulcerations, often reported in the studies on older patients, were infrequent and of mild or moderate grade. Adverse effects associated with sirolimus use in infants and young children with TSC are frequent yet not life- or health-threatening. Further multicenter prospective clinical trials should determine the long-term safety of sirolimus.

Spine morphogenesis and synapse formation in tubular sclerosis complex models.

Tuberous sclerosis complex (TSC) is caused by mutations in the Tsc1 or Tsc2 genes, whose products form a complex and inactivate the small G-protein Rheb1. The activation of Rheb1 may cause refractory epilepsy, intellectual disability, and autism, which are the major neuropsychiatric manifestations of TSC. Abnormalities in dendritic spines and altered synaptic structure are hallmarks of epilepsy, intellectual disability, and autism. In addition, spine dysmorphology and aberrant synapse formation are observed in TSC animal models. Therefore, it is important to investigate the molecular mechanism underlying the regulation of spine morphology and synapse formation in neurons to identify therapeutic targets for TSC. In this review, we focus on the representative proteins regulated by Rheb1 activity, mTORC1 and syntenin, which are pivotal downstream factors of Rheb1 in the alteration of spine formation and synapse function in TSC neurons.

[Analysis of TSC2 gene variant in a neonate with tuberous sclerosis complex].

To explore the clinical characteristics and genetic variant in a neonate with tuberous sclerosis complex (TSC). Clinical data of the neonate was collected. Genomic DNA was extracted from peripheral blood samples of the child and his parents and subjected to next-generation sequencing (NGS). The child was noted to have yellowish hair upon birth. NGS revealed that he has harbored a heterozygous c.3914del (p.P1305Rfs*20) frameshifting variant of the TSC2 gene. The variant has probably caused premature termination of translation, resulting in a truncated protein. Yellowish hair has rarely been described as the first manifestation of TSC. The c.3914del (p.P1305Rfs*20) variant of the TSC2 gene probably underlay the TSC in this patient.

Cerebellar Tubers in Tuberous Sclerosis Complex Patients: New Imaging Characteristics and the Relationship with Cerebral Tubers

Abstract Objective The imaging characteristics, evolution, and clinical features of cerebellar tubers in tuberous sclerosis complex (TSC) patients have not been well described. The purpose of this study is to investigate the imaging characteristics of cerebellar tubers, including their dynamic changes, and to evaluate the relationship with cerebral tubers in TSC patients. Materials and Methods Two observers retrospectively reviewed 75 consecutive TSC patients to identify cerebellar tubers and to evaluate their imaging characteristics, including location, presence of retraction change, calcification, contrast enhancement, and the presence of an associated vascular anomaly, as well as dynamic changes in these characteristics. The number of cerebral tubers was compared between TSC patients with and without cerebellar tubers. Results Twenty-five TSC patients with 28 cerebellar tubers were identified. All cerebellar tubers occurred within the lateral portions of the cerebellar hemispheres. Thirteen cerebellar tubers demonstrated calcification. Ten cerebellar tubers showed contrast enhancement, half of which demonstrated a zebra-like appearance. A vascular anomaly was associated with 12 tubers, one of which subsequently developed parenchymal hemorrhage. Fifteen cerebellar tubers demonstrated complex dynamic changes in size and contrast enhancement. Patients with cerebellar tubers had more cerebral tubers (p = 0.001). Conclusion Cerebellar tubers demonstrate a specific distribution, suggesting a possible influence on higher brain function. The presence of an associated vascular anomaly may be an important imaging characteristic. Cerebellar tubers may be associated with a more severe manifestation of TSC, given their association with increased numbers of cerebral tubers. These findings may provide insights into the pathogenesis and clinical manifestations of cerebellar tubers in TSC patients.

Neurological manifestations of tuberous sclerosis complex: the importance of early diagnosis.

Neurological manifestations of tuberous sclerosis complex: the importance of early diagnosis.