What is the pathophysiology of osteogenesis imperfecta (OI)?

Updated: Feb 24, 2020
  • Author: Manoj Ramachandran, MBBS, MRCS, FRCS; Chief Editor: Harris Gellman, MD  more...
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Answer

In OI, pathologic changes are seen in all tissues of which type 1 collagen is an important constituent (eg, bone, ligament, dentin, and sclera). The basic defect is one of a qualitative or quantitative reduction in type 1 collagen. Mutations in genes encoding type 1 collagen affect the coding of one of the two genes, accounting for approximately 80% of OI cases. [9, 10, 11, 12]

Most cases of OI, previously thought to be either autosomal dominant or autosomal recessive, are now known to arise from autosomal dominant mutations. These mutations are either genetically inherited or new. The inherited mutations have a recurrence risk in subsequent pregnancies of 50% if a parent is affected, whereas the new mutations have an unpredictable recurrence risk.

A small number of cases previously thought to be autosomal recessive have now been proved by molecular and linkage analysis to be secondary to gonadal mosaicism. The recurrence risk for these cases is also unpredictable.

In bone, the degree of histologic change correlates well with the clinical severity of the disease. The disease affects both endochondral and intramembranous ossification.

In OI due to quantitative defects of type 1 collagen, a mild form of the disease occurs. On light microscopy, osteoporotic bone is present, with thick osteoid seams and reduced intercellular matrix. The numbers of osteoclasts and osteocytes are normal. Bone trabeculae are thin and disorganized. Lamellar bone is seen in the diaphysis and metaphysis. On electron microscopy, osteoblasts show distended rough endoplasmic reticulum (possibly because of accumulation of incomplete procollagen molecules), and collagen fibers are of reduced diameter.

In OI due to qualitative defects of type 1 collagen, a severe form of the disease occurs. Light microscopy reveals hyperosteocytosis and increased vascular channels. Other findings are reduced cortical bone thickness, lack of normal cortical bone formation, and disorganization of the growth plate. Woven bone is seen, with minimal osteoid bone and no lamellar bone. Electron microscopy shows poorly preserved osteoblasts and collagen bundles of variable diameter, particularly in the more lethal forms of OI.

The epiphysis and physis tend to be broad and irregular, with disorganization of the proliferative and hypertrophic zones and loss of the typical columnar arrangement. Thinning of the zone of calcified cartilage is evident, along with deficiency of the primary spongiosa of the metaphysis and delay of the secondary centers of ossification in the epiphysis.

With respect to the axial skeleton, scoliosis and kyphosis are common. Vertebral bodies tend to be wedged, translucent, and shallow. Thinning of the skull and multiple ossification centers (wormian bones) are present, particularly in the occiput.


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