Osteogenesis imperfecta (OI) is the most common inherited systemic connective tissue disorder. It presents with multiple fractures and progressive bone deformities due to congenital bone fragility.
The earliest known evidence of OI is found in the skeleton of a mummified infant from ancient Egypt. In 1788, Ekman described it as “brittle bone disease.” In 1833, Lobstein reported type I, and in the 1850s, Vrolik reported type II.
In most cases, mutations in the COL1A1 and COL1A2 genes, which encode type I procollagen, are responsible. Mutations in CRTAP, LEPRE1, and P3H1 genes are also associated. Clinical manifestations range from nearly asymptomatic mild cases to severe perinatal lethal forms.
The prevalence in the United States is estimated at 1 in 20,000 births. It is mainly autosomal dominant, but de novo mutations also occur. There is no gender or racial predilection. Mild cases may be underdiagnosed, so the actual prevalence may be higher.
OI is notable for skeletal symptoms, but ocular complications are also diverse. It can present with blue sclera, refractive errors, retinal detachment, decreased corneal rigidity, and glaucoma. Ocular symptoms can cause permanent vision loss, making regular ophthalmologic follow-up important.
The prevalence is estimated at 1 in 20,000 births. There is no gender or racial predilection. Mild cases may be missed, so the actual prevalence may be higher.
Subjective symptoms due to ocular manifestations of OI are as follows.
OI presents a variety of ocular findings.
Type I collagen that makes up the sclera becomes thinned due to genetic mutations, allowing the dark choroidal vasculature underneath to show through, resulting in a blue color. This is not seen in all types of OI; types III and IV may have normal color.
OI is a polygenic disorder primarily caused by mutations in type I collagen genes.
Inheritance patterns are as follows:
More than 90% of cases are autosomal dominant due to mutations in COL1A1 or COL1A2 genes. Severe types often involve new mutations. Rarely, autosomal recessive inheritance occurs due to mutations in CRTAP or P3H1. See the section on “Causes and Risk Factors” for details.
Diagnosis of OI is complex due to the diversity of clinical findings and involves a combination of medical history, family history, radiological findings, and genetic testing.
Since OI is often autosomal dominant, a thorough family history is important for diagnosis. Check for the following systemic symptoms:
| Differential diagnosis | Key differentiating features |
|---|---|
| Ehlers-Danlos syndrome | Skin hyperextensibility, joint hypermobility |
| Non-accidental trauma (abuse) | Fracture pattern, clinical context |
| Lethal skeletal dysplasia | Skeletal imaging findings |
Other conditions requiring differentiation include perinatal hypophosphatasia, achondrogenesis type 1B, campomelic dysplasia, and osteoporosis-pseudoglioma syndrome.
Treatment of OI involves both systemic management and ophthalmic management. Because the disease presents as a spectrum, treatment is individualized.
Systemic Management
Musculoskeletal system: Evaluation of fractures and deformities. Physical therapy, occupational therapy, and orthopedic surgery.
Pharmacotherapy: Bisphosphonates are the main drugs. They reduce bone resorption and increase bone mass and strength.
Surgical treatment: Intramedullary rod fixation is the main option. The fixation period should be as short as possible.
Audiology and dentistry: Regular hearing evaluation. Dental checkup by 2–3 years of age.
Ophthalmic Management
Regular check-ups: Monitor eye changes at least once a year.
Glaucoma monitoring: Intraocular pressure assessment considering corneal thinning is important.
Injury prevention: Recommend glasses with sturdy frames.
Corneal protection: Use eye drops or ointments for lagophthalmos. In severe cases, consider taping or tarsorrhaphy.
No specific ophthalmic treatment for OI has been established. Individual treatment is provided for each associated eye disease.
At least once a year is recommended for ophthalmic follow-up. The goals are to assess glaucoma risk, monitor changes in the cornea and sclera, and detect retinal detachment early. If symptoms change, earlier visits are advisable.
The pathology of OI is based on dysfunction of type I collagen.
Type I collagen is composed of two pro-α1(I) chains and one pro-α2(I) chain. These form a triple-helical procollagen, which is secreted extracellularly, then processed by enzymes and cross-linked to become mature collagen. Type I collagen is the most abundant collagen in the body and is present in bone, cartilage, tendons, skin, and the following ocular tissues.
Trabecular Meshwork
Aqueous humor outflow pathway: Reduced type I collagen increases resistance to aqueous outflow, contributing to elevated intraocular pressure.
Optic Nerve
Optic disc and lamina cribrosa: Changes in type I collagen cause structural weakening. Combined with elevated intraocular pressure, the optic nerve becomes more susceptible to damage.
Sclera
Collagen thinning: Thinning of the sclera reduces ocular rigidity. The choroidal vasculature becomes visible, resulting in blue sclera.
COL1A1 mutations form abnormal pro-α1(I) chains, and COL1A2 mutations form abnormal pro-α2(I) chains. In both cases, defective procollagen is produced, leading to fragile type I collagen throughout the body.
The CRTAP gene and P3H1/LEPRE1 genes encode cartilage-associated protein and prolyl-3-hydroxylase, respectively. Mutations in these genes impair normal folding, assembly, and secretion of procollagen, causing more severe forms of OI (types VII and VIII).
Reduced type I collagen in the uveoscleral outflow pathway may also affect aqueous humor drainage, similar to the trabecular meshwork. Thus, in OI, abnormalities of type I collagen in multiple ocular tissues form the basis for ocular complications including glaucoma.
The four main types based on the Sillence classification (1979) are shown below.
| OI type | Features | Scleral color |
|---|---|---|
| Type I | Mild, most common | Blue |
| Type II | Perinatal lethal | — |
| Type III | Severe, progressive deformity | Normal |
| Type IV | Moderate | Normal |
Currently, more than 15 types of OI have been identified, but a standard classification system has not been established. All types exist on the spectrum of these four types.
- Zoller T, Righetti M, Cont R, et al. Previously Unreported TMEM38B Variant in Osteogenesis Imperfecta Type XIV: A Case Report and Systematic Review of the Literature. Int J Mol Sci. 2025;26(24):12169.
- He D, Luo Y, Wei S, et al. A novel splice-altering frameshift variant in the COL1A1 gene underlies osteogenesis imperfecta type I: molecular characterization of a four-generation Chinese pedigree and literature review. Human Genomics. 2025;19:103.
