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Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders of connective tissue characterised by bone fragility and other evidence of connective tissue malfunction.

https://doi.org/10.2165/00128072-200002060-00005

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Introduction:

https://www.youtube.com/watch?v=uxm7aa89Ajk

OI Clinical nomenclature:

OI clinical type Description of severity
OI 1 Non-deforming mild OI with blue sclera
OI 2 Perinatal lethal form of OI
OI 3 Severe, progressively deforming OI
OI 4 Common variable OI with normal sclera
OI 5 OI with progressive calcification abnormalities

Etiopathophysiology

Heterogenous genotype and phenotypes:

![OI clinical and genetic heterogeneity. OI clinical variability ranges from mild non-deforming OI to severe and lethal OI forms. Genetic diversity of the disorder is characterised by OI pathogenic variants in more than 22 different genes. Autosomal dominant (AD), autosomal recessive (AR) and X-linked recessive (XLR) inheritance patterns were observed among OI families. A – Autosomal chromosome; OI – Osteogenesis Imperfecta; X – X chromosome; Y – Y chromosome

Zhytnik, L., Simm, K., Salumets, A. et al. Reproductive options for families at risk of Osteogenesis Imperfecta: a review. Orphanet J Rare Dis 15, 128 (2020). https://doi.org/10.1186/s13023-020-01404-w](attachment:7baa8111-74ad-4b75-89f2-eb154efd9793:13023_2020_1404_Fig1_HTML.webp)

OI clinical and genetic heterogeneity. OI clinical variability ranges from mild non-deforming OI to severe and lethal OI forms. Genetic diversity of the disorder is characterised by OI pathogenic variants in more than 22 different genes. Autosomal dominant (AD), autosomal recessive (AR) and X-linked recessive (XLR) inheritance patterns were observed among OI families. A – Autosomal chromosome; OI – Osteogenesis Imperfecta; X – X chromosome; Y – Y chromosome

Zhytnik, L., Simm, K., Salumets, A. et al. Reproductive options for families at risk of Osteogenesis Imperfecta: a review. Orphanet J Rare Dis 15, 128 (2020). https://doi.org/10.1186/s13023-020-01404-w

Biochemistry: Collagen synthesis

![Pathogenic changes resulting in osteogenesis imperfecta can occur at any point of collagen synthesis. Beginning with transcription, followed by translation and subsequent posttranslational modification and transport. This figure outlines the basic processes involved in the molecular synthesis of collagen. 1, transcription (most common cause of OI is DNA mutation); 2, translation; 3, CRTAP-P3H1-CycB (CRTAP and P3H1 have recently been identified as causative mechanisms in OI. CRTAP, P3H1, and Cyclophylin B form a complex, which is responsible for the 3-OH of specific COL1 residues) other: prolyl-4-OH; 4, gal transferase/glc transferase; 5, assembly of procollagen chains; 6, disulfide bonds at N terminus; 7, triple helix assembly; 8, protein suicide (after spontaneous triple helix formation, the newly formed microfibril could undergo protein suicide and result in a milder clinical form of OI or the aberrant protein could be included in collagen fibril assembly, where the dominant negative effect results in more severe disease phenotype); 9, secretion; 10, N and C proteinase cleavage of propeptide; 11, collagen fibril assembly.

Basel, D., Steiner, R. Osteogenesis imperfecta: Recent findings shed new light on this once well-understood condition. Genet Med 11, 375–385 (2009). https://doi.org/10.1097/GIM.0b013e3181a1ff7b](attachment:0e3c0dc3-8118-4a64-aff2-efd5a8785eb4:41436_2009_Article_BFgim200954_Fig1_HTML.webp)

Pathogenic changes resulting in osteogenesis imperfecta can occur at any point of collagen synthesis. Beginning with transcription, followed by translation and subsequent posttranslational modification and transport. This figure outlines the basic processes involved in the molecular synthesis of collagen. 1, transcription (most common cause of OI is DNA mutation); 2, translation; 3, CRTAP-P3H1-CycB (CRTAP and P3H1 have recently been identified as causative mechanisms in OI. CRTAP, P3H1, and Cyclophylin B form a complex, which is responsible for the 3-OH of specific COL1 residues) other: prolyl-4-OH; 4, gal transferase/glc transferase; 5, assembly of procollagen chains; 6, disulfide bonds at N terminus; 7, triple helix assembly; 8, protein suicide (after spontaneous triple helix formation, the newly formed microfibril could undergo protein suicide and result in a milder clinical form of OI or the aberrant protein could be included in collagen fibril assembly, where the dominant negative effect results in more severe disease phenotype); 9, secretion; 10, N and C proteinase cleavage of propeptide; 11, collagen fibril assembly.

Basel, D., Steiner, R. Osteogenesis imperfecta: Recent findings shed new light on this once well-understood condition. Genet Med 11, 375–385 (2009). https://doi.org/10.1097/GIM.0b013e3181a1ff7b

Presentation

Three main clinical hallmarks:

  1. Bone fragility ("brittle bone disease")
  2. Skeletal deformities
  3. Growth deficiency

Secondary complications: