A clinical scoring system for congenital contractural arachnodactyly

Ilse Meerschaut; Shana De Coninck; Wouter Steyaert; Angela Barnicoat; Allan Bayat; Francesco Benedicenti; Siren Berland; Edward M Blair; Jeroen Breckpot; Anna de Burca; Anne Destrée; Sixto García-Miñaúr; Andrew J Green; Bernadette C Hanna; Kathelijn Keymolen; Marije Koopmans; Damien Lederer; Melissa Lees; Cheryl Longman; Sally Ann Lynch; Alison M Male; Fiona McKenzie; Isabelle Migeotte; Ercan Mihci; Banu Nur; Florence Petit; Juliette Piard; Frank S Plasschaert; Anita Rauch; Pascale Ribaï; Iratxe Salcedo Pacheco; Franco Stanzial; Irene Stolte-Dijkstra; Irene Valenzuela; Vinod Varghese; Pradeep C Vasudevan; Emma Wakeling; Carina Wallgren-Pettersson; Paul Coucke; Anne De Paepe; Daniël De Wolf; Sofie Symoens; Bert Callewaert

doi:10.1038/s41436-019-0609-8

A clinical scoring system for congenital contractural arachnodactyly

Genet Med. 2020 Jan;22(1):124-131. doi: 10.1038/s41436-019-0609-8. Epub 2019 Jul 18.

Authors

Ilse Meerschaut^{1

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 Green^{11

12}, Bernadette C Hanna¹³, Kathelijn Keymolen¹⁴, Marije Koopmans¹⁵, Damien Lederer⁹, Melissa Lees³, Cheryl Longman¹⁶, Sally Ann Lynch¹⁷, Alison M Male³, Fiona McKenzie^{18

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

Affiliations

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. [email protected].

PMID: 31316167
DOI: 10.1038/s41436-019-0609-8

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.

Keywords: Beals syndrome; clinical score; congenital contractural arachnodactyly; diagnostic criteria; fibrillin-2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Arachnodactyly / diagnosis*
Arachnodactyly / genetics
Child
Contracture / diagnosis*
Contracture / genetics
Diagnosis, Differential
Early Diagnosis
Female
Fibrillin-2 / genetics*
Genetic Testing
Humans
Male
Marfan Syndrome / diagnosis
Marfan Syndrome / genetics
Phenotype
Retrospective Studies
Sensitivity and Specificity
Sequence Analysis, DNA / methods*

Substances

FBN2 protein, human
Fibrillin-2

Supplementary concepts

Congenital contractural arachnodactyly