Osteogenesis imperfecta (COL1A1 and COL1A2): brittle bone disease explained

The Brittle Bone Society describes OI as a genetic bone disorder characterised by fragile bones that break easily, even without trauma, and that a person is born with it and affected throughout their life. It is a disorder of collagen, the protein that forms the framework for bone. In OI the collagen may be of poor quality, or there may not be enough of it to support the mineral structure of the bones.

The NHS Genomics Education Programme lists the typical features: fractures after minimal or no trauma, short stature, bowing of the long bones, blue sclerae (the whites of the eyes), dentinogenesis imperfecta (brittle teeth), joint hypermobility and hearing loss that develops after puberty. The Brittle Bone Society adds that ligaments stretch more easily, fatigue is common, and scoliosis can occur. It stresses wide variation: some people hardly have symptoms, while others need walking aids or wheelchairs.

OI is classified into types by severity, described as mild, moderate or severe.

COL1A1 and COL1A2 carry the instructions for the two chains of type I collagen. The NHS Genomics Education Programme says over 80% of cases are due to a harmful variant in one of them, and that OI is heterogeneous, with multiple inheritance patterns. Other genes account for the rest, including some inherited recessively and a few inherited in an X-linked way.

Because of this variety, the programme notes that diagnosis has traditionally rested on clinical and X-ray features, but molecular confirmation now helps accurate genetic counselling and may in future help personalise treatment. Clinical features seen on X-ray include fractures at various stages of healing, more than ten Wormian bones in the skull, compressed spinal vertebrae and low bone mass.

In the dominant form a person with a COL1A1 or COL1A2 variant has a 50% chance, or one in two, of passing it on to each child. But most of these variants (about 60%) are new in the person and the parents are unaffected, which is why the Brittle Bone Society reports that around 25% of children with OI are born into a family with no history.

The question parents often ask is whether it will happen again. The NHS Genomics Education Programme explains that, unusually among rare dominant conditions, the chance of another affected child in a family where a child has a new change is relatively high: 3% to 8% because of gonadal mosaicism, in which some egg or sperm cells carry a variant that the blood does not, and up to 16% if somatic mosaicism is present. It points out that in most rare dominant conditions the rate of gonadal mosaicism is below 1%, and that the reason it is higher in OI is not clear.

In recessive OI, both parents are carriers and typically unaffected; each pregnancy then carries the standard 1 in 4 chance of an affected child, the usual rule for recessive conditions. A genetics service identifies which pattern applies in a family, which is why testing is recommended even where the clinical diagnosis is clear.

OI may be diagnosed before or after birth, usually from clinical and X-ray features, and confirmation requires referral to clinical genetics services, according to the NHS Genomics Education Programme. The Brittle Bone Society publishes factsheets on genetics and on diagnosis, a diagnosis flowchart, and a podcast on the genetics of OI, and signposts a Medical Genetics Centre locator.

The programme adds that OI may sometimes be identified before symptoms appear through the Generation Study, in which case management may differ from that for someone presenting with fractures.

The NHS Genomics Education Programme says management of children and adults is complex and delivered by a multidisciplinary team, using supportive, medical and surgical therapies with a focus on fracture prevention and treatment, pain control and management of dental and hearing complications. The Brittle Bone Society describes itself as the sole organisation set up to address the needs of people born with OI, supporting people in the UK and Republic of Ireland, and lists information on NHS OI services, children's and adult services, orthopaedic surgery and fracture management, pain, dental and hearing care, mental health and independent living.