Osteogenesis imperfecta is an inherited disease belonging to the group of genetic disorders, characterized by the reduced bone mass (due to the violation of osteogenesis), which leads to the increased fragility of bones and is often accompanied by a blue coloration of sclera, teeth anomalies (dentinogenesis imperfecta), progressive hearing loss.The basis of osteogenesis imperfecta are the mutations in one of the genes encoding the synthesis of collagen of type 1 (COL1A1 and COL1A2), as well as in genes CRTAP (cartilage-associated protein) and LEPRE1 (prolyl 3-hydroxylase 1) at the development of rare and often severe osteogenesis imperfect types (Byers et al., 2006). As a result of mutations, insufficient volume of collagen is synthesized or its structure is disrupted. While collagen type 1 is a significant part of bones, tendons, ligaments, skin and other connective tissues.
Presently, 8 types of the disease are distinguished; types VII and VIII have been identified and described in 2006 (Therapeutic Strategies for Osteogenesis Imperfecta, 2011). There are four main types of osteogenesis imperfecta, however, the symptoms vary from person to person. Type 1 is the most common and mildest form, followed by the types 2, 3 and 4. Types 5 and 6 share the same clinical features as the 4th, but each has a unique histological findings (Byers et al., 2006).
Type 1 has the following symptoms (Roughley et al., 2003):
- Collagen is of normal quality, but produced in insufficient quantities
- Bones break easily, especially before puberty
- Easily obtained spinal curvature
- Weak ligaments of joints
- Reduced muscle tone
- Discoloration of sclera (whites of the eyes), usually giving them a bluish-brown color
- Early hearing loss in some children
- Slightly protruding eyes
There are also the types 1A and 1B differentiated by the presence or absence of dentinogenesis imperfecta (characterized by opalescent teeth, absent in 1A, and present in 1B). Except the increased risk of fatal fracture, the life expectancy is in the normal range (Roughley et al., 2003).
Type 2 is characterized by (Roughley et al., 2003):
- Collagen is of insufficient quantity or quality
- Most patients die within the first year of life due to respiratory failure or intracranial hemorrhage
- Breathing difficulties due to underdeveloped lungs
- Severe bone deformities and short stature
Type 2 can be further divided into subclasses A, B, C, distinguished by radiographic analysis of long bone and ribs.
Type 3 characteristics are (Roughley et al., 2003):
- Collagen is in sufficient quantities, but poor quality
- Bones break easily, sometimes even at birth
- Bone deformities, often severe
- Breathing difficulty is possible
- Short stature, spinal curvature, sometimes barrel-shaped chest
- Weakness ligaments of joints
- Weak muscle tone in arms and legs,
- Discoloration of sclera
- Sometimes early hair loss
Third type is distinguished from other classifications as a type of progressive deformation, where the newborn shows slight symptoms at birth and develops the above symptoms during life. Life expectancy may be normal, although with severe physical disabilities.
Type 4 has the following features (Roughley, 2003):
- Collagen is in sufficient quantity, but not high quality
- Bones break easily, especially before puberty
- Short stature, spinal curvature and barrel-shaped chest
- Bone deformities in the range from mild to moderate
- Early hair loss
Like type 1, type 4 can be further divided into subclasses 4A and 4B, which are characterized by the absence (4A) or presence (4B) of dentinogenesis imperfect (Roughley et al., 2003).
The type of inheritance in types I-V is autosomal-dominant, and patients inherit a mutant gene from their parents, but often (in approximately 60% of cases) there are spontaneous mutations. For osteogenesis imperfecta type VI, the type of inheritance is not determined, while types VII and VIII are inherited in an autosomal-recessive manner (Byers et al., 2006).
The clinical picture is characterized by the increased bone fragility at the lowest loads; the fractures can occur spontaneously. In severe damages, multiple fractures (including rib fractures) occur antenatally. Many patients suffer from the deformation of the chest, shortened and deformed extremities, formation of false arthrons, resulting in the development of distinguished stunting (Therapeutic Strategies for OI, 2011). In the mild disease course, only separate fractures of limbs occur, the frequency of which decreases after puberty. In this case, the deformations after fractures are not typical, but there may be spinal compression fracture, scoliosis. All the types of the disease are characterized by osteopenia and the tendency to the progressive skeletal deformities. Extra-skeletal symptoms include blue sclera, teeth dentin formation disorders, slight tooth destruction (“amber teeth”), progressive hearing loss in youth age, laxity of joints, contractures, muscular hypotonia, increased frequency of umbilical and inguinal hernias, congenital heart disease, prolapses of aortic and mitral valves, aortic root dilatation, nephrolithiasis (Roughley et al., 2003).
The diagnosis of osteogenesis imperfecta is based on family history data, clinical data, results of X-ray examination, the structure of collagen type 1 synthesized by dermal fibroblasts in vitro (skin biopsy), molecular genetic analysis; there may be also conducted the histomorphometric study of iliac bone biopsy (Byers et al., 2006).
The goal of the treatment of osteogenesis imperfecta is to improve bone mineralization and prevention of fractures, the maximum possible restoration of abilities and improvement of quality of life. The typical treatments are surgical treatment of fractures, osteosynthesis, exercise therapy, physiotherapy. Drug treatment comprises administering bisphosphonates, growth hormone, calcium and vitamin D, treatment of complications. There have also been some researches on the methods of gene therapy (Therapeutic Strategies for OI, 2011).
Byers, P.H., Krakow, D., Nunes, M.E., & Pepin, M. (2006). Genetic evaluation of suspected osteogenesis imperfecta (OI). Genetics in Medicine, 8 (6), pp. 383–388. http://www.acmg.net/StaticContent/StaticPages/OI.pdf
Roughley, P.J., Rauch, F., & Glorieux, F.H. (2003). Osteogenesis imperfecta –Clinical and Molecular Diversity. European Cells and Materials, 5, pp. 41-47. http://www.ecmjournal.org/journal/papers/vol005/pdf/v005a04.pdf
Therapeutic Strategies for Osteogenesis Imperfecta. (2011). National Institutes of Health.