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      Tuberous sclerosis complex: review based on new diagnostic criteria*

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          Abstract

          Tuberous sclerosis complex is a multisystemic, autosomal dominant genetic disorder with complete penetrance, that can evolve with hamartomas in multiple organs, such as skin, central nervous system, kidney and lung. Due to the wide phenotypic variability, the disease is often not recognized. Tuberous sclerosis complex affects one in 10,000 newborns and most patients are diagnosed during the first 15 months of life. The diagnostic criteria for tuberous sclerosis were reviewed in 2012, at the second International Tuberous Sclerosis Complex Consensus Conference. The diagnosis is based on genetic criteria, by the identification of inactivating pathogenic mutation of tumor suppressor genes TSC1 and TSC2, and clinical criteria, including cutaneous, renal, pulmonary, cardiac and neurological manifestations. The treatment of tuberous sclerosis complex consists, mainly, in management of the symptoms caused by hamartomas and in prevention of organ failure. Multidisciplinary approach is recommended, in order to obtain better clinical outcomes.

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          Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial.

          David Franz, Elena Belousova, Steven Sparagana … (2013)
          Tuberous sclerosis complex is a genetic disorder leading to constitutive activation of mammalian target of rapamycin (mTOR) and growth of benign tumours in several organs. In the brain, growth of subependymal giant cell astrocytomas can cause life-threatening symptoms--eg, hydrocephalus, requiring surgery. In an open-label, phase 1/2 study, the mTOR inhibitor everolimus substantially and significantly reduced the volume of subependymal giant cell astrocytomas. We assessed the efficacy and safety of everolimus in patients with subependymal giant cell astrocytomas associated with tuberous sclerosis complex. In this double-blind, placebo-controlled, phase 3 trial, patients (aged 0-65 years) in 24 centres in Australia, Belgium, Canada, Germany, the UK, Italy, the Netherlands, Poland, Russian Federation, and the USA were randomly assigned, with an interactive internet-response system, in a 2:1 ratio to oral everolimus 4·5 mg/m(2) per day (titrated to achieve blood trough concentrations of 5-15 ng/mL) or placebo. Eligible patients had a definite diagnosis of tuberous sclerosis complex and at least one lesion with a diameter of 1 cm or greater, and either serial growth of a subependymal giant cell astrocytoma, a new lesion of 1 cm or greater, or new or worsening hydrocephalus. The primary endpoint was the proportion of patients with confirmed response--ie, reduction in target volume of 50% or greater relative to baseline in subependymal giant cell astrocytomas. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00789828. 117 patients were randomly assigned to everolimus (n=78) or placebo (n=39). 27 (35%) patients in the everolimus group had at least 50% reduction in the volume of subependymal giant cell astrocytomas versus none in the placebo group (difference 35%, 95% CI 15-52; one-sided exact Cochran-Mantel-Haenszel test, p<0·0001). Adverse events were mostly grade 1 or 2; no patients discontinued treatment because of adverse events. The most common adverse events were mouth ulceration (25 [32%] in the everolimus group vs two [5%] in the placebo group), stomatitis (24 [31%] vs eight [21%]), convulsion (18 [23%] vs ten [26%]), and pyrexia (17 [22%] vs six [15%]). These results support the use of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis. Additionally, everolimus might represent a disease-modifying treatment for other aspects of tuberous sclerosis. Novartis Pharmaceuticals. Copyright © 2013 Elsevier Ltd. All rights reserved.
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            Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study

            Jacqueline French, John Lawson, Zuhal Yapici … (2016)
            The Lancet, 388(10056), 2153-2163
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              TuberOus SClerosis registry to increase disease Awareness (TOSCA) – baseline data on 2093 patients

              John C Kingswood, Guillaume B. d’Augères, Elena Belousova … (2017)
              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. Electronic supplementary material The online version of this article (doi:10.1186/s13023-016-0553-5) contains supplementary material, which is available to authorized users.
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                Author and article information

                Journal
                Journal ID (nlm-ta): An Bras Dermatol
                Journal ID (iso-abbrev): An Bras Dermatol
                Journal ID (publisher-id): abd
                Title: Anais Brasileiros de Dermatologia
                Publisher: Sociedade Brasileira de Dermatologia
                ISSN (Print): 0365-0596
                ISSN (Electronic): 1806-4841
                Publication date (Print and electronic): May-Jun 2018
                Publication date (Print): May-Jun 2018
                Volume: 93
                Issue: 3
                Pages: 323-331
                Affiliations
                [1 ] Outpatient Clinic of Pediatric Dermatology, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HC-FMUSP), São Paulo (SP), Brazil.
                [2 ] Department of Dermatology, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HC-FMUSP), São Paulo (SP), Brazil.
                Author notes
                Mailing address: Larissa Karine Leite Portocarrero. E-mail: larissakleite@ 123456hotmail.com
                Author information
                http://orcid.org/0000-0003-3357-1013
                http://orcid.org/0000-0002-5920-8186
                http://orcid.org/0000-0001-7077-8553
                http://orcid.org/0000-0002-8596-1999
                http://orcid.org/0000-0003-2910-7330
                Article
                DOI: 10.1590/abd1806-4841.20186972
                PMC ID: 6001077
                PubMed ID: 29924239
                SO-VID: 2e97e73b-c14a-4a80-b75c-db782d0f8f5f
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivative License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium provided the original work is properly cited and the work is not changed in any way.

                History
                Date received : 06 February 2017
                Date accepted : 18 July 2017
                Categories
                Subject: Continuing Medical Education

                Keywords: diagnosis,hamartoma,sirolimus,tuberous sclerosis
                Data availability:
                Keywords: diagnosis, hamartoma, sirolimus, tuberous sclerosis

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