The Ehlers-Danlos syndromes : expanding, redefining and reviewing the spectrum

Heritable connective tissue disorders are an important group of rare genetic diseases and include the Ehlers-Danlos syndromes, cutis laxa syndromes, Marfan syndrome and other heritable thoracic aortic aneurysms and dissections, pseudoxanthoma elasticum, osteogenesis imperfecta, and skeletal dysplasias. The study of these entities has greatly improved our knowledge on connective tissue biology and more common health problems, including osteoarthritis, osteoporosis, fibrosis, joint hypermobility, aortic aneurysms and aging. This dissertation focuses on the Ehlers-Danlos syndromes (EDS) and clinically related disorders such as the cutis laxa syndromes. EDS is a clinically and genetically diverse group of connective tissue disorders hallmarked by joint hypermobility, a hyperextensible skin and varying degrees of more generalized connective tissue fragility. For the first part of this project, we aimed to harness the power of next generation techniques to uncover new disease genes in EDS and related disorders. Using different approaches, we uncovered three disease genes in two novel autosomal recessive connective tissue disorders with features of EDS and cutis laxa. This further expanded the molecular spectrum of heritable connective tissue disorders beyond structural extracellular matrix molecules, and implicated such processes as protein glycosylation and trafficking, lysosomal dysfunction, and glycosaminoglycan synthesis in the pathogenesis of EDS and cutis laxa. For our second objective, we aimed to expand the knowledge on the clinical and genetic spectrum of EDS. To this end, we brought together the hitherto largest case series for the dermatosparaxis EDS and the B3GALT6-associated spondylodysplastic EDS. This allowed us to redefine the phenotype of both conditions and unveiled genotype-phenotype correlations. In addition, we systematically reviewed the prevalence and nature of vascular complications in non-vascular types of EDS to help clinicians with counseling of patients and to guide appropriate follow-up. Finally, we contributed to an up-to-date classification of the Ehlers-Danlos syndromes. The ‘2017 International Classification of the Ehlers-Danlos syndromes’ adequately captures the clinical, molecular and pathogenetic diversity of these syndromes, and provides a guideline for clinical diagnosis and a solid foundation for future research.

Jaar van publicatie:2019

Toegankelijkheid:Closed