Rare manifestations and malignancies in tuberous sclerosis complex: findings from the TuberOus SClerosis registry to increAse disease awareness (TOSCA)

Orphanet Journal of Rare Diseases

Guillaume B. d’Augères¹  Carla Fladrowski²  J. Chris Kingswood³  José C. Ferreira⁴  Sergiusz Jozwiak⁵  Renaud Touraine⁶  Rima Nabbout⁷  Jiong Qin⁸  Petrus J. de Vries⁹  Alfons Macaya^1,10  Vincent Cottin^1,11  Finbar O’Callaghan^1,12  Maria Dahlin^1,13  Matthias Sauter^1,14  Yukitoshi Takahashi^1,15  Lisa D’Amato^1,16  Ruben Marques^1,17  Seema Shah^1,18  Anna Jansen^1,19  Elena Belousova^2,20  Mirjana P. Benedik^2,21  Sotiris Youroukos^2,22  Tom Carter^2,23  Valentin Sander^2,24  John A. Lawson^2,25  Paolo Curatolo^2,26  Bernard Zonnenberg^2,27  Martha Feucht^2,28  Christoph Hertzberg^2,29 

[1] Association Sclérose Tubéreuse de Bourneville, Gradignan, France;Associazione Sclerosi Tuberosa ONLUS, Milan, Italy;In Den Birken, European Tuberous Sclerosis Complex Association, Dattein, Germany;Cardiology Clinical Academic Group, Molecular and Clinical Sciences Research Centre, St Georges University of London, London, UK;Centro Hospitalar Lisboa Ocidental, Lisbon, Portugal;Department of Child Neurology, Medical University of Warsaw, Warsaw, Poland;Department of Neurology and Epileptology, The Children’s Memorial Health Institute, Warsaw, Poland;Department of Genetics, CHU-Hôpital Nord, Saint Etienne, France;Department of Pediatric Neurology, Necker Enfants Malades Hospital, Imagine Institute, Paris Descartes University, Paris, France;Department of Pediatrics, Peking University People’s Hospital, Beijing, China;Division of Child and Adolescent Psychiatry, University of Cape Town, Cape Town, South Africa;Hospital Universitari Vall D’Hebron, Barcelona, Spain;Hôpital Louis Pradel, Claude Bernard University Lyon 1, Lyon, France;Institute of Child Health, University College London, London, UK;Karolinska University Hospital, Stockholm, Sweden;Klinikum Kempten, Klinikverbund Allgäu, Robert-Weixler-Str. 50, 87439, Kempten, Germany;National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Aoi-ku, UrushiyamaShizuoka, Japan;Novartis Farma S.P.A, Origgio, Italy;Novartis Farma S.P.A, Origgio, Italy;Institute of Biomedicine (IBIOMED), University of León, León, Spain;Novartis Healthcare Pvt. Ltd, Hyderabad, India;Pediatric Neurology Unit, Department of Pediatrics, UZ Brussel VUB, Brussels, Belgium;Research and Clinical Institute of Pediatrics, Pirogov Russian National Research Medical University, Moscow, Russian Federation;SPS Pediatrična Klinika, Ljubljana, Slovenia;St. Sophia Children’s Hospital, Athens, Greece;TSA Tuberous Sclerosis Association, Nottingham, UK;Tallinn Children Hospital, Tallinn, Estonia;The Tuberous Sclerosis Multidisciplinary Management Clinic, Sydney Children’s Hospital, Randwick, NSW, Australia;Tor Vergata University Hospital, Rome, Italy;University Medical Center, Utrecht, The Netherlands;Universitätsklinik Für Kinder-Und Jugendheilkunde (Affiliated Partner of the ERN EpiCARE), Vienna, Austria;Vivantes-Klinikum Neukölln, Berlin, Germany;

关键词: Rare manifestation;    Malignancy;    TOSCA;    TSC;    Tuberous sclerosis complex;   

DOI  :  10.1186/s13023-021-01917-y

来源: Springer

【 摘 要 】

BackgroundTuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant disorder caused by pathogenic variants in either the TSC1 or TSC2 gene. Common manifestations of TSC have been grouped into major and minor clinical diagnostic criteria and assessed in clinical routine workup. However, case studies point towards the existence of rare disease manifestations and to the potential association of TSC with malignant tumors. In this study we sought to characterize rare manifestations and malignancies using a large cohort of patients.MethodsTuberOus SClerosis registry to increAse disease awareness (TOSCA) is a multicenter, international disease registry collecting clinical manifestations and characteristics of patients with TSC, both retrospectively and prospectively. We report rates and characteristics of rare manifestations and malignancies in patients with TSC who had enrolled in the TOSCA registry. We also examined these manifestations by age, sex, and genotype (TSC1 or TSC2).ResultsOverall, 2211 patients with TSC were enrolled in the study. Rare manifestations were reported in 382 (17.3%) study participants and malignancies in 65 (2.9%). Of these rare manifestations, the most frequent were bone sclerotic foci (39.5%), scoliosis (23%), thyroid adenoma (5.5%), adrenal angiomyolipoma (4.5%), hemihypertrophy and pancreatic neuroendocrine tumors (pNET; both 3.1%). These rare manifestations were more commonly observed in adults than children (66.2% vs. 22.7%), in females versus males (58.4% vs. 41.6%; except for scoliosis: 48.9% vs. 51.1%), and in those with TSC2 versus TSC1 (67.0% vs. 21.1%; except for thyroid adenoma: 42.9% vs. 57.1%). In the 65 individuals with reported malignancies, the most common were renal cell carcinoma (47.7%), followed by breast (10.8%) and thyroid cancer (9.2%). Although malignancies were more common in adult patients, 26.1% were reported in children and 63.1% in individuals < 40 years. TSC1 mutations were over-represented in individuals with malignancies compared to the overall TOSCA cohort (32.1% vs. 18.5%).ConclusionRare manifestationswere observed in a significant proportion of individuals with TSC. We recommend further examination of rare manifestations in TSC. Collectively, malignancies were infrequent findings in our cohort. However, compared to the general population, malignant tumors occurred earlier in age and some tumor types were more common.

【 授权许可】

CC BY