Osteogenesis imperfecta

Osteogenesis imperfecta caused by pathogenic variants in COL1A1 or COL1A2 is inherited in an autosomal dominant manner; rarer OI-associated genes follow autosomal recessive or X-linked inheritance. Each child of an affected individual has a 50% a-priori risk of inheriting the familial pathogenic variant. A substantial proportion of probands represent simplex cases: approximately 60% in mild OI and virtually 100% in progressively deforming or perinatally lethal OI, reflecting de novo pathogenic variants or transmission from a parent with gonosomal or gonadal mosaicism (parental mosaicism rate up to 16%).

Characteristic radiographic findings support the clinical suspicion and include fractures of varying ages and stages of healing (often of the long bones), “codfish” vertebrae from compression fractures, wormian bones (more than ten sutural bones of at least 6 × 4 mm in mosaic arrangement), protrusio acetabuli, and low bone mass or osteoporosis on dual-energy X-ray absorptiometry (DXA). The diagnosis is established by identification of a heterozygous pathogenic variant in COL1A1 or COL1A2, or by biallelic or dominant pathogenic variants in one of the more than twenty additional OI-associated genes, through molecular genetic testing.

Main differential diagnoses include:

• Non-accidental trauma: multiple or recurrent fractures and fractures at different stages of healing without an inherited bone disorder; absence of blue sclerae, dentinogenesis imperfecta, family history of fragility
• (perinatal or infantile): defective calvarial and vertebral ossification with bowing of the long bones and characteristically low serum alkaline phosphatase; ALPL.

• Establishing the molecular diagnosis confirms the clinical suspicion, identifies the underlying genetic cause, and enables accurate assessment of inheritance patterns, including predictive testing of at-risk relatives and informed reproductive counselling.
• A confirmed molecular diagnosis supports specific and individualised surveillance and clinical management, including multidisciplinary follow-up across the lifespan, which is determined by the treating physicians in consultation with the affected individual.

• Rodriguez Celin M, Steiner RD, Basel D. COL1A1- and COL1A2-Related Osteogenesis Imperfecta. 2025 May 29. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: .
• Storoni S, Treurniet S, Maugeri A, Pals G, van den Aardweg JG, van der Pas SL, et al. Prevalence and Hospital Admissions in Patients With Osteogenesis Imperfecta in The Netherlands: A Nationwide Registry Study. Frontiers in endocrinology. 2022;13:869604. doi: 10.3389/fendo.2022.869604. PMID: . PMCID: PMC9082351.
• Sagastizabal B, Calvo I, Martínez-Ferrer À, Clancy J, Pérez Á, Gil A, et al. Current situation of osteogenesis imperfecta in Spain: results from a Delphi study. Orphanet journal of rare diseases. 2024;19(1):239. doi: 10.1186/s13023-024-03248-0. PMID: . PMCID: PMC11186096.
• Mordenti M, Boarini M, Banchelli F, Antonioli D, Corsini S, Gnoli M, et al. Osteogenesis imperfecta: a cross-sectional study of skeletal and extraskeletal features in a large cohort of Italian patients. Frontiers in endocrinology. 2023;14:1299232. doi: 10.3389/fendo.2023.1299232. PMID: . PMCID: PMC10809148.
• Forlino A, Marini JC. Osteogenesis imperfecta. Lancet (London, England). 2016;387(10028):1657–1671. doi: 10.1016/S0140-6736(15)00728-X. PMID: .
• Marini JC, Forlino A, Bächinger HP, Bishop NJ, Byers PH, Paepe A, et al. Osteogenesis imperfecta. Nature reviews Disease primers. 2017;3:17052. doi: 10.1038/nrdp.2017.52. PMID: .