Ilse Meerschaut1,2, Shana De Coninck1, Wouter Steyaert1, Angela Barnicoat3, Allan Bayat4, Francesco Benedicenti5, Siren Berland6, Edward M Blair7, Jeroen Breckpot8, Anna de Burca7, Anne Destrée9, Sixto García-Miñaúr10, Andrew J Green11,12, Bernadette C Hanna13, Kathelijn Keymolen14, Marije Koopmans15, Damien Lederer9, Melissa Lees3, Cheryl Longman16, Sally Ann Lynch17, Alison M Male3, Fiona McKenzie18,19, Isabelle Migeotte20, Ercan Mihci21, Banu Nur21, Florence Petit22, Juliette Piard23, Frank S Plasschaert24, Anita Rauch25, Pascale Ribaï9, Iratxe Salcedo Pacheco26, Franco Stanzial5, Irene Stolte-Dijkstra27, Irene Valenzuela28, Vinod Varghese29, Pradeep C Vasudevan30, Emma Wakeling31, Carina Wallgren-Pettersson32, Paul Coucke1, Anne De Paepe1, Daniël De Wolf33, Sofie Symoens1, Bert Callewaert34. 1. Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium. 2. Department of Pediatrics, Ghent University Hospital, Ghent, Belgium. 3. Department of Clinical Genetics, Great Ormond Street Hospital NHS Foundation Trust, London, UK. 4. Department of Pediatrics, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark. 5. Clinical Genetics Service and South Tyrol Coordination Center for Rare Diseases, Department of Pediatrics, Regional Hospital of Bolzano, Bolzano, Italy. 6. Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway. 7. Oxford Centre for Genomic Medicine, Oxford, UK. 8. Center for Human Genetics, University Hospitals Leuven, Catholic University Leuven, Leuven, Belgium. 9. Center for Human Genetics, Institute of Pathology and Genetics (IPG), Gosselies, Belgium. 10. Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Madrid, Spain. 11. Department of Clinical Genetics, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland. 12. Department of Medicine and Medical Science, University College Dublin, Dublin, Ireland. 13. Clinical Genetics Department, Westmead Hospital, Sydney, Australia. 14. Centre for Medical Genetics, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium. 15. Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. 16. West of Scotland Regional Genetics Service, Queen Elizabeth University Hospital, Glasgow, Scotland. 17. Department of Clinical Genetics, Temple Street Children's Hospital, Dublin, Ireland. 18. Genetic Services of Western Australia, Perth, WA, Australia. 19. School of Paediatrics and Child Health, University of Western Australia, Perth, WA, Australia. 20. Centre de Génétique Humaine, Université Libre de Bruxelles, Brussels, Belgium. 21. Department of Pediatric Genetics, Akdeniz University Medical School, Akdeniz, Turkey. 22. Clinique de Génétique, CHU Lille, Lille, France. 23. Centre de Génétique Humaine, Université de Franche-Comté, CHU Besançon, Besançon, France. 24. Department of Pediatric Orthopedics and Traumatology, Ghent University Hospital, Ghent, Belgium. 25. Institut für Medizinische Genetik, Universität Zürich, Zürich, Switzerland. 26. Pediatria, Alava iniversity hospital, Alava, Spain. 27. Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 28. Department of Clinical and Molecular genetics and Rare disease Unit, University Hospital Vall d'Hebron, Barcelona, Spain. 29. Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK. 30. Medical Genetics, University of Leicester, University Hospitals of Leicester NHS Trust, Leicester, UK. 31. North West Thames Regional Genetics Service, London North West University Healthcare NHS Trust, Harrow, UK. 32. The Folkhaelsan Institute of Genetics and the Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland. 33. Department of Pediatric Cardiology, Ghent University Hospital, Ghent, Belgium. 34. Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium. Bert.Callewaert@UGent.be.
Abstract
PURPOSE: Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder manifesting joint contractures, arachnodactyly, crumpled ears, and kyphoscoliosis as main features. Due to its rarity, rather aspecific clinical presentation, and overlap with other conditions including Marfan syndrome, the diagnosis is challenging, but important for prognosis and clinical management. CCA is caused by pathogenic variants in FBN2, encoding fibrillin-2, but locus heterogeneity has been suggested. We designed a clinical scoring system and diagnostic criteria to support the diagnostic process and guide molecular genetic testing. METHODS: In this retrospective study, we assessed 167 probands referred for FBN2 analysis and classified them into a FBN2-positive (n = 44) and FBN2-negative group (n = 123) following molecular analysis. We developed a 20-point weighted clinical scoring system based on the prevalence of ten main clinical characteristics of CCA in both groups. RESULTS: The total score was significantly different between the groups (P < 0.001) and was indicative for classifying patients into unlikely CCA (total score <7) and likely CCA (total score ≥7) groups. CONCLUSIONS: Our clinical score is helpful for clinical guidance for patients suspected to have CCA, and provides a quantitative tool for phenotyping in research settings.
PURPOSE: Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder manifesting joint contractures, arachnodactyly, crumpled ears, and kyphoscoliosis as main features. Due to its rarity, rather aspecific clinical presentation, and overlap with other conditions including Marfan syndrome, the diagnosis is challenging, but important for prognosis and clinical management. CCA is caused by pathogenic variants in FBN2, encoding fibrillin-2, but locus heterogeneity has been suggested. We designed a clinical scoring system and diagnostic criteria to support the diagnostic process and guide molecular genetic testing. METHODS: In this retrospective study, we assessed 167 probands referred for FBN2 analysis and classified them into a FBN2-positive (n = 44) and FBN2-negative group (n = 123) following molecular analysis. We developed a 20-point weighted clinical scoring system based on the prevalence of ten main clinical characteristics of CCA in both groups. RESULTS: The total score was significantly different between the groups (P < 0.001) and was indicative for classifying patients into unlikely CCA (total score <7) and likely CCA (total score ≥7) groups. CONCLUSIONS: Our clinical score is helpful for clinical guidance for patients suspected to have CCA, and provides a quantitative tool for phenotyping in research settings.
Authors: Silke Peeters; Pauline De Kinderen; Josephina A N Meester; Aline Verstraeten; Bart L Loeys Journal: Hum Mutat Date: 2022-04-28 Impact factor: 4.700
Authors: Xenia Latypova; Stefan Giovanni Creadore; Noémi Dahan-Oliel; Anxhela Gjyshi Gustafson; Steven Wei-Hung Hwang; Tanya Bedard; Kamran Shazand; Harold J P van Bosse; Philip F Giampietro; Klaus Dieterich Journal: Genes (Basel) Date: 2021-07-08 Impact factor: 4.096