Osteogenesis Imperfecta 

The earliest known case of osteogenesis imperfecta is in a partially mummified infant's skeleton from ancient Egypt now housed in the British Museum in London. In 1835, Lobstein coined the term osteogenesis imperfecta and was one of the first to correctly understand the etiology of the condition. Other names for osteogenesis imperfecta are Lobstein disease, brittle-bone disease, blue-sclera syndrome, and fragile-bone disease.

Osteogenesis imperfecta is one of the most common skeletal dysplasias. It is a generalized disease of connective tissue that may manifest itself with one or more of the following findings: blue sclerae, triangular facies, macrocephaly, hearing loss, defective dentition, barrel chest, scoliosis, limb deformities, fractures, joint laxity, and growth retardation. Additional features, such as constipation and sweating, may also occur. A multidisciplinary approach is required to manage the disease.^{[1, 2]}

In osteogenesis imperfecta, pathologic changes are seen in all tissues in which type 1 collagen is an important constituent, such as 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 1 of the 2 genes, accounting for approximately 80% of cases of osteogenesis imperfecta.^{[3, 4, 5, 6]}

Most cases of osteogenesis imperfecta, 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 proven 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 is well correlated with the clinical severity of the disease. The disease affects both endochondral and intramembranous ossification. In osteogenesis imperfecta 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 osteogenesis imperfecta that results from qualitative defects of type 1 collagen, a severe form of the disease occurs. Light microscopy reveals hyperosteocytosis and increased vascular channels. Other findings are a reduction in 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 osteogenesis imperfecta.

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.

Frequency

International

The birth incidence is approximately 1 case in 20,000 births.

Mortality/Morbidity

Morbidity and mortality associated with osteogenesis imperfecta vary widely depending on the genotype. In addition, variability occurs between individuals with different mutations, and variability has also been observed between unrelated individuals with the same mutations, between members of the same family, and even between identical twins on occasion.

• At one extreme, early stillbirths occur, and virtually every bone in the body has multiple fractures. The severe perinatal form (type II) is usually fatal within hours after birth, although some babies survive for several months.
• At the other extreme is osteogenesis imperfecta in its mildest form. In this setting, adults who have never had a fracture come to medical attention only because their family members are affected.
• Between these extremes is a smooth continuum of severity.

Race

Osteogenesis imperfecta has been described in every human population in which skeletal dysplasias have been studied. The disease appears to have no predilection for a particular race.

Sex

Osteogenesis imperfecta is equally common in males and females.

Age

Osteogenesis imperfecta can present at any age, although the more severe forms tend to become evident at a younger age.