Osteogenesis Imperfecta Workup

Results from routine laboratory studies in patients with osteogenesis imperfecta (OI) are usually within reference ranges, and they are useful in ruling out other metabolic bone diseases.

An analysis of type I, III, and V collagens synthesized by fibroblasts may be helpful. Collagen synthesis analysis is performed by culturing dermal fibroblasts obtained during skin biopsy. The occurrence of false-negative results is not clear, although the rate may be about 15%. Results are negative in syndromes resembling OI.

Tests include the following:

• Sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE)
• 2-Dimensional SDS-PAGE
• Cyanogen bromide (CNBr) mapping
• Thermal stability studies

An analysis of the amino acid composition of collagens may be useful.

DNA blood testing for gene defects has an accuracy of 60-94%. Prenatal DNA mutation analysis can be performed in pregnancies with risk of OI to analyze uncultured chorionic villus cells. Samples are obtained during chorionic villus sampling performed under ultrasonographic guidance when a mutation in another member of the family is already known.

Prenatal ultrasonography is most useful in evaluating OI types II and III. It is capable of detecting limb-length abnormalities at 15-18 weeks’ gestation. In its most severe form, the disease may be evident as early as 16 weeks’ gestation.

Mild forms of OI may result in normal findings on ultrasonography. Features include supervisualization of intracranial contents caused by decreased mineralization of calvaria (also calvarial compressibility), bowing of the long bones, decreased bone length (especially of the femur), and multiple rib fractures.

Obtain a radiographic skeletal survey after birth. Plain radiographs may depict the following 3 radiologic categories of OI:

• Category I – Thin and gracile bones
• Category II – Short and thick limbs
• Category III – Cystic changes

Radiologic features commonly seen include the following:

• Fractures – Commonly, transverse fractures and those affecting the lower limbs (see the first image below)
• Excessive callus formation and popcorn bones - Multiple scalloped, radiolucent areas with radiodense rims
• Skull changes - Wormian bones (see the second image below), enlargement of frontal and mastoid sinuses, and platybasia with or without basilar impression
• Deformities of the thoracic cage - Fractured and beaded ribs (see the third and fourth images below) and pectus carinatum
• Pelvic and proximal femoral changes - Narrow pelvis, compression fractures, protrusio acetabuli, and shepherd’s-crook deformities of the femurs Newborn has bilateral femoral fractures. Wormian bones are present in skull. Acute fractures are observed in radius and ulna. Multiple fractures can be seen in ribs. Old healing humeral fracture with callus formation is observed. Beaded ribs. Multiple fractures are seen in long bones of upper extremities.

In mild OI (type I), images may reveal thinning of the long bones with thin cortices. Several wormian bones may be present. No deformity of long bones is observed.

In extremely severe OI (type II), the survey may reveal beaded ribs, broad bones, and numerous fractures with deformities of the long bones. Platyspondylia may also be revealed.

In moderate and severe OI (types III and IV), imaging may reveal cystic metaphyses, or a popcorn appearance of the growth cartilage. Normal or broad bones are revealed early, with thin bones revealed later. Fractures may cause deformities of the long bones. Old rib fractures may be present. Vertebral fractures are common.

Dual x-ray absorptiometry (DEXA) may be used to assess bone mineral density in children with milder forms of OI. Bone mineral density, as measured with DEXA, is low in children and adults with OI regardless of severity. Bone mineral densities can be normal in infants with OI, even in severe cases. In pediatric patients, DEXA results are not useful for predicting the risk of fracture. No reliable published reference data regarding DEXA in infants are available.

CT densitometric bone scanning may be helpful in atypical cases of OI, though normal bone density does not exclude mild forms of the disease.

Polarized light microscopy or microradiography may be used in combination with scanning electron microscopy to assess dentinogenesis imperfecta.

With skin biopsy, collagen can be isolated from cultured fibroblasts and assessed for defects, with an accuracy of 85-87%.^[14]

Bone biopsy may show changes in the concentrations of noncollagenous bone proteins, such as osteonectin, sialoprotein, and decorin.

The width of biopsy cores, the width of the cortex, and the volume of cancellous bone are decreased in all types of OI. The number and thickness of trabeculae are reduced.

Samples may show evidence of defects in modeling of external bone in terms of the size and shape, the production of secondary trabeculae by endochondral ossification, and the thickening of secondary trabeculae by remodeling. Therefore, OI might be regarded as a disease of the osteoblast.^[15]

Bone formation is quantitatively decreased, but the quality of the bone material is probably most important in the pathogenesis of the disease.