Osteogenesis Imperfecta (OI) comprises a heterogeneous group of patients who share bone fragility and deformities as the main characteristics, albeit with different degrees of severity. Phenotypic variation also exists in other connective tissue aspects of the disease, complicating disease classification and disease course prediction. Although collagen type I defects are long established as the primary cause of the bone pathology, we are still far from comprehending the complete mechanism. In the last years, the advent of next generation sequencing has triggered the discovery of many new genetic causes for OI, helping to draw its molecular landscape. It has become clear that, in addition to collagen type I genes, OI can be caused by multiple proteins connected to different parts of collagen biosynthesis. The production of collagen entails a complex process, starting from the production of the collagen Iα1 and collagen Iα2 chains in the endoplasmic reticulum, during and after which procollagen is subjected to a plethora of posttranslational modifications by chaperones. After reaching the Golgi organelle, procollagen is destined to the extracellular matrix where it forms collagen fibrils. Recently discovered mutations in components of the retrograde transport of chaperones highlight its emerging role as critical contributor of OI development. This review offers an overview of collagen regulation in the context of recent gene discoveries, emphasizing the significance of transport disruptions in the OI mechanism. We aim to motivate exploration of skeletal fragility in OI from the perspective of these pathways to identify regulatory points which can hint to therapeutic targets.

Introduction Respiratory failure is a major cause of death in patients with Osteogenesis Imperfecta. Moreover, respiratory symptoms seem to have a dramatic impact on their quality of life. It has long been thought that lung function disorders in OI are mainly due to changes in the thoracic wall, caused by bone deformities. However, recent studies indicate that alterations in the lung itself can also undermine respiratory health. Objectives Is there any intrapulmonary alteration in Osteogenesis Imperfecta that can explain decreased pulmonary function? The aim of this systematic literature review is to investigate to what extent intrapulmonary or extrapulmonary thoracic changes contribute to respiratory dysfunction in Osteogenesis Imperfecta. Methods A literature search (in PubMed, Embase, Web of Science, and Cochrane), which included articles from inception to December 2020, was performed in accordance with the PRISMA guidelines. Results Pulmonary function disorders have been described in many studies as secondary to scoliosis or to thoracic skeletal deformities. The findings of this systematic review suggest that reduced pulmonary function can also be caused by a primary pulmonary problem due to intrinsic collagen alterations. Conclusions Based on the most recent studies, the review indicates that pulmonary defects may be a consequence of abnormal collagen type I distorting the intrapulmonary structure of the lung. Lung function deteriorates further when intrapulmonary defects are combined with severe thoracic abnormalities. This systematic review reveals novel findings of the underlying pathological mechanism which have clinical and diagnostic implications for the assessment and treatment of pulmonary function disorders in Osteogenesis Imperfecta. KEY MESSAGES Decreased pulmonary function in Osteogenesis Imperfecta can be attributed to primary pulmonary defects due to intrapulmonary collagen alterations and not solely to secondary problems arising from thoracic skeletal dysplasia. Type I collagen defects play a crucial role in the development of the lung parenchyma and defects, therefore, affect pulmonary function. More awareness is needed among physicians about pulmonary complications in Osteogenesis Imperfecta to develop novel concepts on clinical and diagnostic assessment of pulmonary functional disorders.

Osteogenesis Imperfecta (OI) is a complex disease caused by genetic alterations in production of collagen type I, and collagen-related proteins. Bone fragility is the most common patient issue, but extraskeletal complications also present an adverse factor in the quality of life and prognosis of patients with OI. However, still little is known about the morbidity and mortality of these patients. The objective of this paper is to determine and describe to what extent OI impacts patients’ life in terms of hospitalization and complications describing the incidence and prevalence of the Dutch cohort of OI patients and the characteristics of their hospital admissions. Information regarding OI patients and their hospital admission was extracted from the Statistics Netherlands Database and matched to the OI Genetics Database of Amsterdam UMC. Hospital admission data was available for 674 OI patients. This OI nationwide registry study shows that the life expectancy of OI patients is adversely affected by the disease. The median annual incidence risk of OI between 1992 and 2019 was 6.5 per 100,000 live births. Furthermore, patients with OI had a 2.9 times higher hospitalization rate compared to the general Dutch population. The highest hospitalization rate ratio of 8.4 was reported in the patient group between 0 and 19 years old. OI type and severity had impact on extraskeletal manifestations, which play a key role in the numerous hospital admissions. More awareness about the impact of OI on patients’ life is needed to improve and implement prevention and follow-up guidelines.

Osteogenesis imperfecta (OI) is a heritable connective tissue disorder that causes bone fragility due to pathogenic variants in genes responsible for the synthesis of type I collagen. Efforts to classify the high clinical variability in OI led to the Sillence classification. However, this classification only partially takes into account extraskeletal manifestations and the high genetic variability. Little is known about the relation between genetic variants and phenotype as of yet. The aim of the study was to create a clinically relevant genetic stratification of a cohort of 675 Dutch OI patients based on their pathogenic variant types and to provide an overview of their respective medical care demands. The clinical records of 675 OI patients were extracted from the Amsterdam UMC Genome Database and matched with the records from Statistics Netherlands (CBS). The patients were categorized based on their harbored pathogenic variant. The information on hospital admissions, outpatient clinic visits, medication, and diagnosis-treatment combinations (DTCs) was compared between the variant groups. OI patients in the Netherlands appear to have a higher number of DTCs, outpatient clinic visits, and hospital admissions when compared to the general Dutch population. Furthermore, medication usage seems higher in the OI cohort in comparison to the general population. The patients with a COL1A1 or COL1A2 dominant negative missense non-glycine substitution appear to have a lower health care need compared to the other groups, and even lower than patients with COL1A1 or COL1A2 haploinsufficiency. It would be useful to include the variant type in addition to the Sillence classification when categorizing a patient’s phenotype.