Altered collagen I and premature pulmonary embryonic differentiation in patients with OI type II.

Pulmonary hypoplasia and respiratory failure are primary causes of death in patients with osteogenesis imperfecta (OI) type II. OI is a genetic skeletal disorder caused by pathogenic variants in genes encoding collagen type I. It is still unknown if the collagen defect also affects lung development and structure, causing lung hypoplasia in OI type II. The aim of this study was to investigate the intrinsic characteristics of OI embryonic lung parenchyma and to determine whether altered collagen type I may compromise airway development and lung structure. Lung tissue from nine fetuses with OI type II and six control fetuses, matched by gestational age, was analyzed for TTF-1 and collagen type I expression by immunohistochemistry, to evaluate the state of lung development and amount of collagen. The differentiation of epithelium into type 2 pneumocytes during embryonic development was premature in OI type II fetuses compared to controls (p < 0.05). Collagen type I showed no significant differences between the two groups. However, the amount of alpha2(I) chains was higher in fetuses with OI and the ratio of alpha1(I) to alpha2(I) lower in OI compared to controls. Cell differentiation during lung embryonic development in patients with OI type II is premature and impaired. This may be the underlying cause of pulmonary hypoplasia. Altered cell differentiation can be secondary to mechanical chest factors or a consequence of disrupted type I collagen synthesis. Our findings suggest that collagen type I is a biochemical regulator of pulmonary cell differentiation, influencing lung development.

Medical Care Use Among Patients with Monogenic Osteoporosis Due to Rare Variants in LRP5, PLS3, or WNT1.

Pathogenic variants in the LRP5, PLS3, or WNT1 genes can significantly affect bone mineral density, causing monogenic osteoporosis. Much remains to be discovered about the phenotype and medical care needs of these patients. The purpose of this study was to examine the use of medical care among Dutch individuals identified between 2014 and 2021 with a pathogenic or suspicious rare variant in LRP5, PLS3, or WNT1. In addition, the aim was to compare their medical care utilization to both the overall Dutch population and the Dutch Osteogenesis Imperfecta (OI) population. The Amsterdam UMC Genome Database was used to match 92 patients with the Statistics Netherlands (CBS) cohort. Patients were categorized based on their harbored variants: LRP5, PLS3, or WNT1. Hospital admissions, outpatient visits, medication data, and diagnosis treatment combinations (DTCs) were compared between the variant groups and, when possible, to the total population and OI population. Compared to the total population, patients with an LRP5, PLS3, or WNT1 variant had 1.63 times more hospital admissions, 2.0 times more opened DTCs, and a greater proportion using medication. Compared to OI patients, they had 0.62 times fewer admissions. Dutch patients with an LRP5, PLS3, or WNT1 variant appear to require on average more medical care than the total population. As expected, they made higher use of care at the surgical and orthopedic departments. Additionally, they used more care at the audiological centers and the otorhinolaryngology (ENT) department, suggesting a higher risk of hearing-related problems.

Pathophysiology of respiratory failure in patients with osteogenesis imperfecta: a systematic review.

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 MESSAGESDecreased 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.