BACKGROUND Tuberous sclerosis complex is highly variable in clinical presentation and findings. Disease manifestations continue to develop over the lifetime of an affected individual. Accurate diagnosis is fundamental to implementation of appropriate medical surveillance and treatment. Although significant advances have been made in the past 15 years in the understanding and treatment of tuberous sclerosis complex, current clinical diagnostic criteria have not been critically evaluated or updated since the last clinical consensus conference in 1998. METHODS The 2012 International Tuberous Sclerosis Complex Consensus Group, comprising 79 specialists from 14 countries, was organized into 12 subcommittees, each led by a clinician with advanced expertise in tuberous sclerosis complex and the relevant medical subspecialty. Each subcommittee focused on a specific disease area with important diagnostic implications and was charged with reviewing prevalence and specificity of disease-associated clinical findings and their impact on suspecting and confirming the diagnosis of tuberous sclerosis complex. RESULTS Clinical features of tuberous sclerosis complex continue to be a principal means of diagnosis. Key changes compared with 1998 criteria are the new inclusion of genetic testing results and reducing diagnostic classes from three (possible, probable, and definite) to two (possible, definite). Additional minor changes to specific criterion were made for additional clarification and simplification. CONCLUSIONS The 2012 International Tuberous Sclerosis Complex Diagnostic Criteria provide current, updated means using best available evidence to establish diagnosis of tuberous sclerosis complex in affected individuals.
Everolimus therapy was associated with marked reduction in the volume of subependymal giant-cell astrocytomas and seizure frequency and may be a potential alternative to neurosurgical resection in some cases, though long-term studies are needed. (Funded by Novartis; ClinicalTrials.gov number, NCT00411619.).
BACKGROUND Tuberous sclerosis complex is a genetic disorder affecting every organ system, but disease manifestations vary significantly among affected individuals. The diverse and varied presentations and progression can be life-threatening with significant impact on cost and quality of life. Current surveillance and management practices are highly variable among region and country, reflective of the fact that last consensus recommendations occurred in 1998 and an updated, comprehensive standard is lacking that incorporates the latest scientific evidence and current best clinical practices. METHODS The 2012 International Tuberous Sclerosis Complex Consensus Group, comprising 79 specialists from 14 countries, was organized into 12 separate subcommittees, each led by a clinician with advanced expertise in tuberous sclerosis complex and the relevant medical subspecialty. Each subcommittee focused on a specific disease area with important clinical management implications and was charged with formulating key clinical questions to address within its focus area, reviewing relevant literature, evaluating the strength of data, and providing a recommendation accordingly. RESULTS The updated consensus recommendations for clinical surveillance and management in tuberous sclerosis complex are summarized here. The recommendations are relevant to the entire lifespan of the patient, from infancy to adulthood, including both individuals where the diagnosis is newly made as well as individuals where the diagnosis already is established. CONCLUSIONS The 2012 International Tuberous Sclerosis Complex Consensus Recommendations provide an evidence-based, standardized approach for optimal clinical care provided for individuals with tuberous sclerosis complex.
Objective: Epilepsy is a major manifestation of tuberous sclerosis complex (TSC). Everolimus is an mammalian target of rapamycin complex 1 inhibitor with demonstrated benefit in several aspects of TSC. We report the first prospective human clinical trial to directly assess whether everolimus will also benefit epilepsy in TSC patients. Methods: The effect of everolimus on seizure control was assessed using a prospective, multicenter, open-label, phase I/II clinical trial. Patients 2 years of age with confirmed diagnosis of TSC and medically refractory epilepsy were treated for a total of 12 weeks. The primary endpoint was percentage of patients with a 50% reduction in seizure frequency over a 4-week period before and after treatment. Secondary endpoints assessed impact on electroencephalography (EEG), behavior, and quality of life. Results: Twenty-three patients were enrolled, and 20 patients were treated with everolimus. Seizure frequency was reduced by 50% in 12 of 20 subjects. Overall, seizures were reduced in 17 of the 20 by a median reduction of 73% (p < 0.001). Seizure frequency was also reduced during 23-hour EEG monitoring (p 5 0.007). Significant reductions in seizure duration and improvement in parent-reported behavior and quality of life were also observed. There were 83 reported adverse events that were thought to be treatment-related, all of which were mild or moderate in severity. Interpretation: Seizure control improved in the majority of TSC patients with medically refractory epilepsy following treatment with everolimus. Everolimus demonstrated additional benefits on behavior and quality of life. Treatment was safe and well tolerated. Everolimus may be a therapeutic option for refractory epilepsy in this population.
Tuberous sclerosis complex (TSC) is an autosomal dominant tumor suppressor gene syndrome due to germline mutations in either TSC1 or TSC2. 10–15% of TSC individuals have no mutation identified (NMI) after thorough conventional molecular diagnostic assessment. 53 TSC subjects who were NMI were studied using next generation sequencing to search for mutations in these genes. Blood/saliva DNA including parental samples were available from all subjects, and skin tumor biopsy DNA was available from six subjects. We identified mutations in 45 of 53 subjects (85%). Mosaicism was observed in the majority (26 of 45, 58%), and intronic mutations were also unusually common, seen in 18 of 45 subjects (40%). Seventeen (38%) mutations were seen at an allele frequency < 5%, five at an allele frequency < 1%, and two were identified in skin tumor biopsies only, and were not seen at appreciable frequency in blood or saliva DNA. These findings illuminate the extent of mosaicism in TSC, indicate the importance of full gene coverage and next generation sequencing for mutation detection, show that analysis of TSC-related tumors can increase the mutation detection rate, indicate that it is not likely that a third TSC gene exists, and enable provision of genetic counseling to the substantial population of TSC individuals who are currently NMI.
Tuberous sclerosis complex (TSC) is a rare genetic disease causing multisystem growth of benign tumours and other hamartomatous lesions, which leads to diverse and debilitating clinical symptoms. Patients are born with TSC1 or TSC2 mutations, and somatic inactivation of wild-type alleles drives MTOR activation; however, second hits to TSC1/TSC2 are not always observed. Here, we present the genomic landscape of TSC hamartomas. We determine that TSC lesions contain a low somatic mutational burden relative to carcinomas, a subset feature large-scale chromosomal aberrations, and highly conserved molecular signatures for each type exist. Analysis of the molecular signatures coupled with computational approaches reveals unique aspects of cellular heterogeneity and cell origin. Using immune data sets, we identify significant neuroinflammation in TSC-associated brain tumours. Taken together, this molecular catalogue of TSC serves as a resource into the origin of these hamartomas and provides a framework that unifies genomic and transcriptomic dimensions for complex tumours.
Background: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease affecting multiple body systems with wide variability in presentation. In 2013, Pediatric Neurology published articles outlining updated diagnostic criteria and recommendations for surveillance and management of disease manifestations. Advances in knowledge and approvals of new therapies necessitated a revision of those criteria and recommendations. Methods: Chairs and working group cochairs from the 2012 International TSC Consensus Group were invited to meet face-to-face over two days at the 2018 World TSC Conference on July 25 and 26 in Dallas, TX, USA. Before the meeting, working group cochairs worked with group members via e-mail and telephone to (1) review TSC literature since the 2013 publication, (2) confirm or amend prior recommendations, and (3) provide new recommendations as required. Results: Only two changes were made to clinical diagnostic criteria reported in 2013: "multiple cortical tubers and/or radial migration lines" replaced the more general term "cortical dysplasias," and sclerotic bone lesions were reinstated as a minor criterion. Genetic diagnostic criteria were reaffirmed, including highlighting recent findings that some individuals with TSC are genetically mosaic for variants in TSC1 or TSC2. Changes to surveillance and management criteria largely reflected increased emphasis on early screening for electroencephalographic abnormalities, enhanced surveillance and management of TSCassociated neuropsychiatric disorders, and new medication approvals. Conclusions: Updated TSC diagnostic criteria and surveillance and management recommendations presented here should provide an improved framework for optimal care of those living with TSC and their families.
BackgroundTuberous sclerosis (TSC) related tumors are characterized by constitutively activated mTOR signaling due to mutations in TSC1 or TSC2.MethodsWe completed a phase 2 multicenter trial to evaluate the efficacy and tolerability of the mTOR inhibitor, sirolimus, for the treatment of kidney angiomyolipomas.Results36 adults with TSC or TSC/LAM were enrolled and started on daily sirolimus. The overall response rate was 44.4% (95% confidence intervals [CI] 28 to 61); 16/36 had a partial response. The remainder had stable disease (47.2%, 17/36), or were unevaluable (8.3%, 3/36). The mean decrease in kidney tumor size (sum of the longest diameters [sum LD]) was 29.9% (95% CI, 22 to 37; n = 28 at week 52). Drug related grade 1–2 toxicities that occurred with a frequency of >20% included: stomatitis, hypertriglyceridemia, hypercholesterolemia, bone marrow suppression (anemia, mild neutropenia, leucopenia), proteinuria, and joint pain. There were three drug related grade 3 events: lymphopenia, headache, weight gain. Kidney angiomyolipomas regrew when sirolimus was discontinued but responses tended to persist if treatment was continued after week 52. We observed regression of brain tumors (SEGAs) in 7/11 cases (26% mean decrease in diameter), regression of liver angiomyolipomas in 4/5 cases (32.1% mean decrease in longest diameter), subjective improvement in facial angiofibromas in 57%, and stable lung function in women with TSC/LAM (n = 15). A correlative biomarker study showed that serum VEGF-D levels are elevated at baseline, decrease with sirolimus treatment, and correlate with kidney angiomyolipoma size (Spearman correlation coefficient 0.54, p = 0.001, at baseline).ConclusionsSirolimus treatment for 52 weeks induced regression of kidney angiomyolipomas, SEGAs, and liver angiomyolipomas. Serum VEGF-D may be a useful biomarker for monitoring kidney angiomyolipoma size. Future studies are needed to determine benefits and risks of longer duration treatment in adults and children with TSC.Trial RegistrationClinicaltrials.gov NCT00126672
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