TuberOus SClerosis registry to increase disease Awareness (TOSCA) – baseline data on 2093 patients

Kingswood et al. Orphanet Journal of Rare Diseases TuberOus SClerosis registry to increase disease Awareness (TOSCA) - baseline data on 2093 patients John C. Kingswood Guillaume B. d'Augères Elena Belousova José C. Ferreira Tom Carter Ramon Castellana Vincent Cottin Paolo Curatolo Maria Dahlin Petrus J. de Vries Martha Feucht Carla Fladrowski Gabriella Gislimberti Christoph Hertzberg Sergiusz Jozwiak John A. Lawson Alfons Macaya Rima Nabbout Finbar O'Callaghan Mirjana P. Benedik Jiong Qin Ruben Marques Valentin Sander Matthias Sauter Yukitoshi Takahashi Renaud Touraine Sotiris Youroukos Bernard Zonnenberg Anna C. Jansen on behalf of TOSCA consortium TOSCA investigators Background: Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder. Many gaps remain in the understanding of TSC because of the complexity in clinical presentation. The TuberOus SClerosis registry to increase disease Awareness (TOSCA) is an international disease registry designed to address knowledge gaps in the natural history and management of TSC. Here, we present the baseline data of TOSCA cohort. Methods: Patients of any age diagnosed with TSC, having a documented visit for TSC within the preceding 12 months, or newly diagnosed individuals were included. The registry includes a “core” section designed to record detailed background information on each patient including disease manifestations, interventions, and outcomes collected at baseline and updated annually. “Subsections” of the registry recorded additional data related to specific features of TSC. Results: Baseline “core” data from 2093 patients enrolled from 170 sites across 31 countries were available at the cut-off date September 30, 2014. Median age of patients at enrollment was 13 years (range, 0-71) and at diagnosis of TSC was 1 year (range, 0-69). The occurrence rates of major manifestations of TSC included - cortical tubers (82.2%), subependymal nodules (78.2%), subependymal giant cell astrocytomas (24.4%), renal angiomyolipomas (47.2%), lymphangioleiomyomatosis (6.9%), cardiac rhabdomyomas (34.3%), facial angiofibromas (57.3%), forehead plaque (14.1%), ≥ 3 hypomelanotic macules (66.8%), and shagreen patches (27.4%). Epilepsy was reported in 1748 (83.5%) patients, of which 1372 were diagnosed at ≤ 2 years (78%). Intellectual disability was identified in 451 (54.9%) patients of those assessed. TSC-associated neuropsychiatric disorders (TAND) were diagnosed late, and not evaluated in 30-50% of patients. Conclusion: TOSCA is the largest clinical case series of TSC to date. It provided a detailed description of the disease trajectory with increased awareness of various TSC manifestations. The rates of different features of TSC reported here reflect the age range and referral patterns of clinics contributing patients to the cohort. Documentation of TAND and LAM was poor. A widespread adoption of the international TSC assessment and treatment guidelines, including use of the TAND Checklist, could improve surveillance. The registry provides valuable insights into the necessity for monitoring, timing, and indications for the treatment of TSC. Tuberous sclerosis; Registry; Epilepsy; Subependymal giant cell astrocytoma; Angiomyolipoma; TOSCA - Background Tuberous sclerosis complex (TSC) is a rare genetic disorder characterized by the development of benign tumors in several organs of the body [1]. The birth incidence of the disorder is approximately 1 in 5800 individuals [2]. TSC is caused by genetic mutations in either of the TSC1 or TSC2 genes [3]. Based on routine diagnostic techniques, a pathogenic mutation is detected in up to 85–90% of individuals with a clinical diagnosis of TSC [1]. In the remaining 10–15% patients with ‘no mutation identified’, next generation DNA sequencing (NGS), a high-throughput sequencing, identified mosaic or intronic mutations in TSC1 or TSC2 genes in a vast majority suggesting that it is unlikely that a third TSC gene exists [4]. Mutations of TSC1 or TSC2 gene result in overactivation of the mammalian target of rapamycin (mTOR) complex 1, a key intracellular regulator of cell growth and proliferation, resulting in the hamartomatous lesions found in multiple organs [5, 6]. Recent research has helped us understand the pathophysiology of TSC, which has led to the use of mTOR inhibitors for the treatment of certain manifestations of TSC including subependymal giant cell astrocytomas (SEGAs) and renal angiomyolipomas [7–10]. The recently revised guidelines for the surveillance and management of TSC provided updated recommendations for standard, optimal care for patients [10]. There is, however, still a lack of clarity with respect to the natural history of many of the TSC manifestations, their variability, the age-related expression pattern, and their prognostic roles. Gaps also exist in understanding the rare symptoms and comorbidities of TSC, the relationship between genotype and phenotype, and the various interventions, tr (...truncated)