TuberOus SClerosis registry to increase disease Awareness (TOSCA) \u2013 baseline data on 2093 patients

J Chris Kingswood ,Finbar O’Callaghan,Guillaume Beaure D’augères ,Yukitoshi Takahashi,Martha Feucht,Renaud Touraine,Mirjana P Benedik ,Sotiris Youroukos,Christoph Hertzberg,Matthias Sauter,Petrus J De Vries,Alfons Macaya,Paolo Curatolo,John A Lawson,Jiong Qin,Rima Nabbout,Carla Fladrowski,Sergiusz Jóźwiak ,Thomas Carter ,Gabriella Gislimberti,Valentin Sander,José Carlos Ferreira ,Vincent Cottin,Ramon Castellana,Elena Belousova,Maria Dahlin,Rúben Marques ,Bernard A Zonnenberg ,Anna Jansen

doi:10.1186/s13023-016-0553-5

Abstract

BackgroundTuberous 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.MethodsPatients 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.ResultsBaseline “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.ConclusionTOSCA 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.

Highlights

Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder
Recent research has helped us understand the pathophysiology of TSC, which has led to the use of mammalian target of rapamycin (mTOR) inhibitors for the treatment of certain manifestations of TSC including subependymal giant cell astrocytomas (SEGAs) and renal angiomyolipomas [7,8,9,10]
There is ongoing discussion with respect to the most accurate definition of SEGA, which may have been of influence on the number of SEGA reported in TuberOus SClerosis registry to increase disease Awareness (TOSCA)

Summary

Introduction

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. Tuberous sclerosis complex (TSC) is a rare genetic disorder characterized by the development of benign tumors in several organs of the body [1]. TSC is caused by genetic mutations in either of the TSC1 or TSC2 genes [3]. 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]. The recently revised guidelines for the surveillance and management of TSC provided updated recommendations for standard, optimal care for patients [10]

Methods

Results

Discussion

Conclusion