Osteogenesis imperfecta (OI) is caused by mutations in the genes that code for type I procollagen (ie, COL1A1 and COL1A2).
The most common classification for OI was developed by Sillence. The following types of Osteogenesis imperfecta have been reported:
- Type I – Mild forms
- Type II – Extremely severe
- Type III – Severe
- Type IV – Undefined
A few patients with many of the symptoms of OI were recently found not to have mutations in the genes for type I collagen. These patients have a characteristic lamellar patterning of bone, and distinctive clinical and radiological findings. They have been assigned the classifications of types V, VI, and VII OI.
- Type V- Moderate to Severe
- Type VI- Moderate to severe
- Type VII- Moderate
Type V and VI differ in terms of inheritance.
The classification OI is not always prognostic because of variations in the clinical course. Some patients appear normal at birth and become progressively worse; others have multiple fractures in infancy and childhood, improve after puberty, and fracture more frequently later in life. Women are particularly prone to fracture during pregnancy and after menopause. A few women from families with mild variants of OI do not develop fractures until after menopause, and their disease may be difficult to distinguish from postmenopausal osteoporosis.
- Autosomal dominant for Type I,III,IV and V
- Autosomal recessive for Type VII, rarely AR for type II and III
- Sporadic for type II
- Inheritance of Type VI is unknown
Type I OI has a frequency of about 1 in 30,000. Type II OI has a reported incidence at birth of about 1 in 60,000, but the combined incidence of the three severe forms that are recognizable at birth (types II, III, and IV) may be much higher. Only a few patients with types V, VI, and VII have been reported.
Type I collagen fibers are found in the bones, organ capsules, fascia, cornea, sclera, tendons, meninges, and dermis. Type I collagen, which constitutes approximately 30% of the human body by weight, is the defective protein in Osteogenesis imperfecta. Qualitative defects (eg, an abnormal collagen I molecule) and quantitative defects (eg, decreased production of normal collagen I molecules) are described.
i) Skeletal effects
- In type I OI, the fragility of bones may be severe enough to limit physical activity or be so mild that individuals are unaware of any disability. Radiographs of the skull in patients with mild disease may show a mottled appearance because of small islands of irregular ossification.
- In type II OI, bones and other connective tissues are so fragile that massive injuries can occur in utero or during delivery. Ossification of many bones is frequently incomplete. Continuously beaded or broken ribs (figure-1) and crumpled or bent long bones (accordina femora) may be present (figure-2). The long bones may be either thick or thin.
Figure-1- Beaded ribs in OI
Figure-2- Bent long bones in OI
- In types III and IV, multiple fractures from minor physical stress can produce severe deformities.The appearance of “popcorn-like” deposits of mineral in x-rays of the ends of long bones is an ominous sign.
In all forms of OI, bone mineral density is decreased. Surprisingly, fractures appear to heal normally.
ii) Ocular Features
The sclerae can be normal, slightly bluish, or bright blue (figure-3). The color is probably caused by a thinness of the collagen layers of the sclerae that allows the choroid layers to be seen. Blue sclerae, however, are an inherited trait in some families who do not have increased bone fragility. Blue sclera is not found in type IV, V, VI and VII.
Figure-3- Blue sclera in OI
The teeth may be normal, moderately discolored, or grossly abnormal. The enamel generally appears normal, but the teeth may have a characteristic amber, yellowish brown, or translucent bluish gray color because of improper deposition or deficiency of dentin (figure-4).The deciduous teeth are usually smaller than normal, whereas permanent teeth are frequently bell-shaped and restricted at the base. In some patients, the teeth readily fracture and need to be extracted. The defect in dentin is directly attributable to the fact that normal dentin is rich in type I collagen.
Figure-4- Dental defects in OI
IV) Hearing Loss
Hearing loss usually begins during the second decade of life and occurs in more than 50% of individuals over age 30. The middle ear usually exhibits maldevelopment, deficient ossification, persistence of cartilage in areas that are normally ossified, and abnormal calcium deposits.
V) Other Features
Changes in other connective tissues can include thin skin that scars extensively, joint laxity with permanent dislocations and, occasionally, cardiovascular manifestations such as aortic regurgitation, mitral incompetence, and fragility of large blood vessels. For unknown reasons, some patients develop a hyper metabolic state with elevated serum thyroxin levels, hyperthermia, and excessive sweating .
- OI is usually diagnosed on the basis of clinical criteria.
- The presence of fractures together with blue sclerae, dentinogenesis imperfecta, or family history of the disease is usually sufficient to make the diagnosis.
- Other causes of pathologic fractures must be excluded, including battered child syndrome, nutritional deficiencies, malignancies, and other inherited disorders such as hypophosphatasia.
- The absence of superficial bruises can be helpful in distinguishing OI from battered child syndrome.
- X-rays usually reveal a decrease in bone density that can be verified by photon or x-ray absorptiometry.
- Bone microscopy can be helpful in the diagnosis.
- A molecular defect in type I procollagen can be demonstrated in over two-thirds of patients by incubating skin fibroblasts with radioactive amino acids and then analyzing the proα chains by polyacrylamide gel electrophoresis.
- After a mutation in a type I procollagen gene is identified, a simple PCR test can be used to screen family members at risk or for prenatal diagnosis.
- Those with mild disorder may need little treatment when fractures decrease after puberty,
- Women require special attention during pregnancy and after menopause, when fractures again increase.
- More severely affected children require a comprehensive program of physical therapy, surgical management of fractures and skeletal deformities, and vocational education
- Moderately to severely affected patients should be evaluated periodically to anticipate possible neurologic problems.
- Counseling and emotional support are important for patients and their parents.