Osteogenesis Imperfecta: New Insights into Extraskeletal Complications

This thesis aims at expanding our understanding of Osteogenesis Imperfecta (OI), a genetic disorder causing bone fragility and a range of extraskeletal symptoms. The work examines in particular the epidemiology and the extraskeletal comorbidities of the Dutch OI population. Additionally, the thesis sheds light on the genotype-phenotype correlation and the pathophysiology of the respiratory complications associated with OI. The first part of the thesis discusses the prevalence and hospital admission rates of the Dutch OI population, the genotype-phenotype relation of OI, and the health care characteristics of patients with LRP5, PLS3, or WNT1 pathogenic variants. The second part of the thesis focuses on the pulmonary complications of OI patients. A literature review provides an overview of the current knowledge and knowledge gaps surrounding the pathophysiology of respiratory complications in OI. To gain further insight into the cause of pulmonary complications, the lung pathology in patients with OI type II was analyzed, suggesting intrinsic alterations in the OI lung parenchyma. The second part of this thesis concludes by proposing a more patient-friendly lung function assessment and a pulmonary follow-up plan for OI patients for the prevention of serious respiratory complications. Finally, the third part of the thesis provides an overview of collagen regulation in the context of recent gene discoveries and describes two OI patient with new SPARC pathogenic variants.