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Osteogenesis imperfecta (all types)
Also known as Osteogenesis imperfecta type I · Osteogenesis imperfecta type II (lethal perinatal) · Osteogenesis imperfecta type III
OI is a lifelong genetic disorder characterised by bone fragility, often called 'brittle bone disease'. It affects people of all ages, with varying severity, due to issues with the body's collagen, a key building block for bones and other tissues.
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Overview
Osteogenesis Imperfecta (OI) is a hereditary condition that primarily causes bones to be fragile and prone to fractures. It is often referred to as 'brittle bone disease'. This condition is not a single disorder but a group of related genetic disorders that vary in severity, from mild forms with few fractures to severe forms that can be life-threatening [PMID:20301331].
OI affects the body's connective tissue, specifically how it produces type I collagen. Collagen is a crucial protein that provides strength and structure to bones, tendons, ligaments, skin, and other tissues. When collagen is faulty or not produced in sufficient amounts, these tissues, especially bones, become weak. The exact prevalence of OI is estimated to be between 1 in 15,000 and 1 in 20,000 people.
Symptoms & clinical features
The main symptom of Osteogenesis Imperfecta is increased bone fragility, leading to frequent fractures from minimal trauma or sometimes even without an apparent cause. The number and severity of fractures can vary greatly among individuals, even within the same type of OI.
Beyond bone fractures, other symptoms of OI can include blue or grey sclera (the white part of the eye), which is a common finding, especially in milder types. Some individuals may experience hearing loss, which can develop in childhood or adulthood. Dental problems, such as brittle or discoloured teeth (dentinogenesis imperfecta), can also occur. Other features might include short stature, a curved spine (scoliosis), loose joints, and muscle weakness. The specific combination and severity of symptoms depend on the underlying genetic cause and the type of OI [PMID:28751551].
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Affected organs
Osteogenesis Imperfecta primarily affects the skeletal system, leading to brittle bones and an increased risk of fractures. However, its impact extends to other organs and tissues rich in type I collagen. The eyes can be affected, often presenting with blue or grey discolouration of the sclera. The ears may experience otosclerosis, a condition leading to hearing loss. Teeth can show dentinogenesis imperfecta, causing them to be fragile and discoloured.
Connective tissues throughout the body can also be affected, leading to joint laxity and sometimes contributing to issues like hernias. In more severe forms, the chest wall and lungs can be impacted, potentially leading to respiratory complications, particularly in perinatal types. The heart can also be affected, with some individuals experiencing problems such as aortic root dilatation or valvular issues, though these are less common than skeletal manifestations.
Risks & severity
The severity of Osteogenesis Imperfecta varies widely, ranging from very mild forms with only a few fractures over a lifetime to severe, lethal forms where fractures can occur before birth. The risks associated with OI include recurrent bone fractures, chronic pain, progressive deformity of bones, and short stature. Some individuals may experience severe physical limitations requiring mobility aids.
Respiratory complications are a significant concern, especially in severe OI, and can be life-threatening. Hearing loss often progresses with age, and dental issues can lead to pain and difficulty eating. The age of onset for symptoms is highly variable; severe forms may present in the womb or at birth, while milder forms might only be diagnosed in childhood or even adulthood after an unexpected fracture. There is no typical lifetime risk of fracture as it is highly dependent on the OI type and individual factors, but frequent fractures are a hallmark of the condition [PMID:33604928].
Genetic causes
Osteogenesis Imperfecta is caused by pathogenic variants in genes involved in the production or processing of type I collagen. Type I collagen is the most abundant protein in the human body, providing strength and structure to bones, tendons, ligaments, and skin. Pathogenic variants disrupt this crucial process, leading to weakened connective tissue.
Key genes associated with OI include COL1A1 and COL1A2. COL1A1 produces the pro-α1(I) chain, and COL1A2 produces the pro-α2(I) chain. These chains combine to form the triple helix of type I collagen. Pathogenic changes in either COL1A1 or COL1A2 can lead to either reduced amounts of normal collagen or the production of abnormal collagen, both resulting in fragile bones. The CRTAP gene is also associated with some forms of OI. The CRTAP gene plays a role in modifying collagen before it forms its final structure. Variants in CRTAP can lead to defects in collagen processing, thereby impairing bone quality and strength.
- COL1A1 collagen type I alpha 1 chainThe COL1A1 gene provides instructions for producing a key component of type I collagen, a protein vital for the structure and strength of bones, skin, tendons, and other connective tissues.
- COL1A2 collagen type I alpha 2 chainThe COL1A2 gene provides instructions for making the pro-α2(I) chain, a vital part of type I collagen, which is crucial for the strength and support of many connective tissues throughout the body.
- CRTAP cartilage associated proteinThe *CRTAP* gene provides instructions for making a protein crucial for bone formation and mineralisation, and variants in this gene are linked to certain forms of osteogenesis imperfecta.
Inheritance pattern
The inheritance pattern for Osteogenesis Imperfecta can be either autosomal dominant (AD) or autosomal recessive (AR), depending on the specific gene involved. Most cases of OI, particularly the more common types, follow an autosomal dominant pattern. In autosomal dominant inheritance, a person needs to inherit only one copy of a pathogenic variant in a gene (e.g., COL1A1 or COL1A2) from one parent to develop the condition. This means there is a 50% chance for each child of an affected parent to inherit the condition.
Less commonly, OI can be inherited in an autosomal recessive pattern. This occurs when a person inherits two copies of a pathogenic variant, one from each parent (e.g., in the CRTAP gene). Parents who each carry one copy of the pathogenic variant are typically unaffected and are called carriers. For each child of two carrier parents, there is a 25% chance of inheriting the condition, a 50% chance of being an unaffected carrier, and a 25% chance of being unaffected and not a carrier.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Subtypes & variants
This page covers Osteogenesis imperfecta (all types) as a single condition. Several distinct variants and clinical subtypes are recognised in the literature - they share the underlying biology and broad management approach, but differ in severity, age of onset, or causative gene:
- Type I (mild) OMIM 166200
Most common form. Blue sclerae, mild bone fragility, normal stature. Fractures decrease after puberty. Typically autosomal dominant COL1A1 variants reducing collagen quantity (haploinsufficiency).
- Type II (lethal perinatal) OMIM 166210
Severe form, usually lethal in the perinatal period from respiratory insufficiency due to severe rib fractures and underdeveloped lungs. Caused by structural COL1A1 / COL1A2 variants.
- Type III (severe progressive) OMIM 259420
Severe progressively deforming form. Multiple fractures from infancy, short stature, bone deformity, scoliosis. White sclerae in adulthood. Mobility often requires wheelchair.
Diagnosis & testing
The diagnosis of Osteogenesis Imperfecta often begins with clinical assessment based on symptoms such as frequent fractures, blue sclera, or short stature. Imaging studies, such as X-rays, can reveal characteristic bone features, including multiple fractures at different stages of healing or bone deformities. However, a definitive diagnosis typically requires genetic testing.
Genetic testing can identify pathogenic variants in genes like COL1A1, COL1A2, or CRTAP, confirming the diagnosis and helping to determine the specific type of OI. In the UK, genetic testing for OI is generally coordinated through the NHS Genomic Medicine Service (GMS). Referrals for genetic testing usually come from a specialist clinician, such as a paediatrician, orthopaedic surgeon, or clinical geneticist, particularly when OI is suspected. Relevant NHS R-codes would be used for ordering specific genomic tests.
Management & lifestyle
Management for Osteogenesis Imperfecta focuses on minimising fractures, managing pain, promoting mobility, and maximising quality of life. This involves a multidisciplinary team approach, often including orthopaedic surgeons, physiotherapists, occupational therapists, audiologists, and clinical geneticists. Treatment strategies may include medication to strengthen bones, such as bisphosphonates, which help reduce the rate of fractures.
Physiotherapy is crucial to maintain muscle strength and mobility, and occupational therapy can help adapt daily activities. Surgical intervention may be necessary for severe fractures or to correct bone deformities, including rodding procedures where metal rods are inserted into long bones to prevent fractures. Regular monitoring for complications like hearing loss or scoliosis is also important. The NHS provides care pathways for individuals with rare genetic conditions, and individuals with OI will typically be supported by regional specialist centres. Genetic counsellors can provide essential information and support regarding inheritance patterns and family planning.
UK care pathway
In the UK, individuals suspected of having Osteogenesis Imperfecta are typically referred to specialist services within the NHS. Clinical geneticists and specialist orthopaedic teams often lead the diagnostic process and ongoing care. Genetic testing is available through the NHS Genomic Medicine Service (GMS) once a specialist determines it is appropriate, utilising specific R-codes for testing panels. This ensures a standardised approach to diagnosis and helps inform personalised management plans.
Genetic counsellors play a vital role, offering support and information to individuals and families about the inheritance pattern of OI, implications for other family members, and reproductive options. Patients are typically managed through a multidisciplinary team at regional centres, ensuring access to a range of specialists for comprehensive care.
Frequently asked questions
Is Osteogenesis Imperfecta always inherited from parents?
Not always. While many cases are inherited from a parent, some people with OI have a new genetic change (called a de novo variant) that wasn't present in either parent. This means they are the first in their family to have the condition.
Can Osteogenesis Imperfecta be cured?
Currently, there is no cure for Osteogenesis Imperfecta. Management focuses on reducing symptoms, preventing fractures, and improving quality of life through various treatments like medication, physiotherapy, and sometimes surgery.
How is the severity of OI determined?
The severity of OI is determined by the specific genetic variant, the amount and quality of collagen produced, and the resulting clinical symptoms. It ranges from very mild with few fractures to severe forms with many fractures and significant complications.
What support is available for families with OI in the UK?
Families in the UK can access support through the NHS, including specialist clinical genetics services, orthopaedic teams, and rehabilitation services. There are also patient support groups and charities like the Brittle Bone Society that provide information and community support.
Will my child with OI be able to lead a normal life?
Many individuals with OI, especially those with milder forms, can lead fulfilling and independent lives. With appropriate medical management, therapy, and support, people with OI can manage their condition and pursue their goals, although they may face unique challenges.
References
- Garman CR, Graf A, Krzak J. Gait Deviations in Children With Osteogenesis Imperfecta Type I. Journal of pediatric orthopedics. 2019. PMID: 31393309
- Bardai G, Lemyre E, Moffatt P. Osteogenesis Imperfecta Type I Caused by COL1A1 Deletions. Calcified tissue international. 2016. PMID: 26478226
- Ammenti A, Nitsch M. Hypercalciuria in osteogenesis imperfecta type I. Klinische Padiatrie. 2003. PMID: 14520592
- Pouliot-Laforte A, Veilleux LN, Rauch F. Physical activity in youth with osteogenesis imperfecta type I. Journal of musculoskeletal & neuronal interactions. 2015. PMID: 26032209
- Al Kaissi A, Ryabykh S, Ben Chehida F. The Tomographic Study and the Phenotype of Wormian Bones. Diagnostics (Basel, Switzerland). 2023. PMID: 36900016
- Takken T, Terlingen HC, Helders PJ. Cardiopulmonary fitness and muscle strength in patients with osteogenesis imperfecta type I. The Journal of pediatrics. 2004. PMID: 15580207
- Jakubowska-Pietkiewicz E, Maćkowska A, Nowicki J. Anthropometrics of Polish children with osteogenesis imperfecta: a single-centre retrospective cohort study. BMC pediatrics. 2022. PMID: 36203124
- Mingazov E, Gvozdev N, Popkov A. Preliminary Results of Bone Lengthening over Telescopic Titanium Intramedullary Rod. Case reports in orthopedics. 2023. PMID: 36756206