Phenotypic Variability and Diagnostic Characteristics of Pediatric Osteogenesis Imperfecta: A 10-Year Multicenter...

Background/Objectives: Osteogenesis imperfecta (OI) is a rare hereditary connective tissue disorder characterized by bone fragility, recurrent fractures, and variable extra-skeletal manifestations. There are scarce epidemiological and clinical data from Eastern Europe, including Romania. This study aimed to characterize the phenotypic spectrum and diagnostic features of pediatric OI in a Romanian multicenter cohort. Methods: A retrospective, multicenter observational study was conducted over a 10-year period (January 2014-December 2024) in three tertiary pediatric referral centers in Bucharest, Romania. Children with a diagnosis of OI based on clinical, radiological, and, where available, molecular criteria were included. Clinical, phenotypic, genetic, and therapeutic data were extracted from medical records. Statistical analyses included the Mann-Whitney U test, Kruskal-Wallis test with Bonferroni correction, Fisher's exact test, Kaplan-Meier survival analysis, and Spearman correlation. Results: Forty-seven patients were included (53.2% female; median age at diagnosis 36 months, IQR 5-87). OI type I was the most frequent subtype (42.6%), followed by type III (29.8%) and type IV (21.3%). Molecular genetic testing was performed in 40.4% of patients; among genetically tested patients, COL1A1 variants represented the most common finding (52.6%). The median number of documented fractures was 5 (IQR 3-9), with a significantly higher annual fracture rate in type III compared to type I (0.99 vs. 0.34 fractures/year, p = 0.019). Short stature was the most frequent skeletal manifestation (66%), with significantly more severe growth impairment in type III compared to type I (-4.38 ± 1.67 vs. -1.56 ± 1.03 SD, p < 0.001). Blue sclerae was present in 87.2% of patients and dentinogenesis imperfecta in 68.1%. Cryptorchidism was identified in 50% of male patients. Developmental motor milestones were significantly delayed in type III OI patients, with 10.6% failing to achieve independent walking by last follow-up. A strong positive correlation was observed between age at first fracture and age at diagnosis (Spearman R = 0.764, p < 0.001), with type I patients diagnosed significantly later than type III (median 71.5 vs. 6.5 months, p = 0.006). Conclusions: This study provides the most comprehensive phenotypic characterization of pediatric OI reported from Romania to date. Our findings confirm established genotype-phenotype correlations and underscore the diagnostic challenge of milder OI forms. The high prevalence of cryptorchidism in male patients represents a clinically relevant finding needing prospective validation. The data highlight the need for expanded molecular diagnostic capacity, increased disease awareness among frontline clinicians, and the development of a national OI registry to support longitudinal research and integration with European rare bone disease networks.