Osteogenesis imperfecta and genetics
Osteogenesis imperfecta (OI), commonly referred to as "brittle bone disease," is a genetic disorder characterized by fragile bones that can break easily, often from minimal or no trauma. It affects an estimated 50,000 individuals in the United States. OI has at least eight recognized types, with the majority of cases linked to mutations in the COL1A1 and COL1A2 genes, which are essential for producing type I collagen—a vital protein that provides strength to bones and connective tissues. While types I, II, III, and IV are typically inherited in an autosomal dominant manner, types VII and VIII arise from autosomal recessive inheritance, meaning both parents are carriers. Symptoms vary by type but generally include frequent fractures, bone deformities, and distinctive blue sclerae (the whites of the eyes). Diagnosis often involves a combination of physical examinations, medical history review, and genetic testing. Although there is currently no cure for OI, treatments focus on managing symptoms, enhancing mobility, and preventing fractures, with options including medications, physical therapy, and surgical interventions like rodding. Genetic counseling is available to help families understand the risks and implications of OI. Adopting a healthy lifestyle can also aid in minimizing complications associated with the condition.
Osteogenesis imperfecta and genetics
ALSO KNOWN AS: OI
DEFINITION Osteogenesis imperfecta (OI) is a genetic problem that causes bones to break easily, often for little or no obvious reason. As many as fifty thousand Americans currently have OI. Individuals who suspect that they have this condition should contact their doctor immediately. The sooner OI is detected and treated, the more favorable the outcome.
Risk Factors
A family history of OI is a risk factor for the disease. Individuals should tell their doctors if they have a family history of OI.
Etiology and Genetics
Authorities now recognize at least eight forms of osteogenesis imperfecta, designated type I through type VIII, and there are four different genes known to be associated with this group of diseases. The COL1A1 gene, found on the long arm of chromosome 17(at position D17q21.3-q22.1) encodes a component of type I collagen known as collagen, type 1, alpha 1. Collagens are proteins that provide support and strength to various body tissues, such as bone, tendon, cartilage, and skin, and type 1 collagen is the most abundant form in the body. The “alpha 2” subunit of type I collagen is specified by the COL1A2 gene (at position 7q22.1), which interacts with the alpha 1 subunit to form the functional structural support in tissues. More than 90 percent of clinical cases of osteogenesis imperfecta result from mutations in one of these two genes, and depending on the exact nature of the mutations, the disease will present as type I, II, III, or IV.
Mutations in the CRTAP gene (at position 3p22.3) and the LEPRE1 gene (at position 1p34.1) cause the rare and severe forms, types VII and VIII, respectively. These genes encode proteins that work together in the same pathway to process collagen into its mature and functional form. Mutations in either gene are known that adversely affect the processes of folding, assembly, or secretion of collagen, and the result is weakened connective tissues and severely brittle bones. The rare types V and VI osteogenesis imperfecta result from unknown causes, and efforts are currently underway to identify the responsible genes.
Osteogenesis imperfecta types I, II, and IV are inherited as autosomal dominant diseases, meaning that a single copy of the mutation is sufficient to cause full expression. An affected individual has a 50 percent chance of transmitting the mutation to each of his or her children. Many cases, however, result from a spontaneous new mutation, so in these instances affected individuals will have unaffected parents. Most cases of osteogenesis imperfecta type III and all cases of type VII and type VIII disease are inherited with an autosomal recessive pattern, which means that both copies of the relevant gene must be deficient in order for the individual to be afflicted. Typically, an affected child is born to two unaffected parents, both of whom are carriers of the recessive mutant allele. The probable outcomes for children whose parents are both carriers are 75 percent unaffected and 25 percent affected. According to 2023 estimates, osteogenesis imperfecta occurred in 1 in 15,000 to 20,000 live births.
Symptoms
In the four most common types of OI, symptoms may include bone fractures, bone deformity, short height, and loose joints and muscle weakness. The sclera (whites of the eyes) may have a blue, purple, or gray tint. Additional symptoms may include a triangular face, a tendency toward spinal curvature, brittle teeth, hearing loss, and breathing problems.
Screening and Diagnosis
The doctor will ask about a patient’s symptoms and medical history and will perform a physical examination. The doctor will probably refer the patient to a doctor specializing in bone care (an orthopedist) for much of his or her care.
If patients have OI, their doctors may diagnose it based on their appearance alone. Tests will likely include collagen biochemical tests and a genetic DNA test that may require a skin biopsy.
When osteogenesis imperfecta may affect a developing fetus, a level II ultrasound can reveal the diagnosis by about sixteen weeks, in severe cases. Chorionic villus sampling (CVS) can also be used for prenatal diagnosis.
Treatment and Therapy
There is presently no cure for OI, so treatment is directed toward preventing health problems, improving independence and mobility, and developing bone and muscle strength. A surgical procedure called “rodding” is often considered for people with OI. This surgery involves inserting metal rods through the length of the long bones to strengthen them and prevent and/or correct deformities.
Prevention and Outcomes
OI is caused by a genetic defect. Through genetic counseling, OI can be prevented from being passed from one generation to another. Problems related to OI can be reduced or prevented by a healthy lifestyle with exercise and good nutrition. Individuals should avoid smoking and excessive alcohol consumption, which may weaken bone and increase fracture risk.
Bibliography
Antoniazzi, F., et al. “Osteogenesis Imperfecta: Practical Treatment Guidelines.” Paediatric Drugs 2, no. 6 (November/December, 2000): 465-488.
Chevrel, G., and P. J. Meunier. “Osteogenesis Imperfecta: Lifelong Management Is Imperative and Feasible.” Joint, Bone, Spine: Revue Du Rhumatisme 68, no. 2 (March, 2001): 125-129.
EBSCO Publishing. Health Library: Osteogenesis Imperfecta. Ipswich, Mass.: Author, 2009. Available through http://www.ebscohost.com.
Kleigman, Robert M., et al., eds. Nelson Textbook of Pediatrics. 18th ed. Philadelphia: Saunders Elsevier, 2007.
McLean, K. R. “Osteogenesis Imperfecta.” Neonatal Network 23, no. 2 (March/April, 2004): 7-14.
Niyibizi, C., et al. “Gene Therapy Approaches for Osteogenesis Imperfecta.” Gene Therapy 11, no. 4 (February, 2004): 408-416.
Silverwood, B. “Osteogenesis Imperfecta: Care and Management.” Paediatric Nursing 13, no. 3 (April, 2001): 38-42.
Subramanian, Surabhi, Catherine Anastasopoulou, and Vibhu Krishnan Viswanathan. "Osteogenesis Imperfecta." StatPearls, 6 Feb. 2023, www.ncbi.nlm.nih.gov/books/NBK536957/. Accessed 5 Sept. 2024.
Zeitlin, L., F. Fassier, and F. H. Glorieux. “Modern Approach to Children with Osteogenesis Imperfecta.” Journal of Pediatric Orthopaedics, Part B 12, no. 2 (March, 2003): 77-87.