Osteogenesis Imperfecta 

The earliest known case of osteogenesis imperfecta (OI) 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 OI are Lobstein disease, brittle-bone disease, blue-sclera syndrome, and fragile-bone disease.

OI is one of the most common skeletal dysplasias. It is a generalized disease of connective tissue that may manifest itself with 1 or more of the following findings:

• Blue sclerae
• Triangular facies
• Macrocephaly
• Hearing loss
• Defective dentition
• Barrel chest
• Scoliosis
• Limb deformities
• Fractures
• Joint laxity
• Growth retardation

Additional features, such as constipation and sweating, may also occur. A multidisciplinary approach is required to manage the disease.^{[1, 2]}

In OI, pathologic changes are seen in all tissues in 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 1 of the 2 genes, accounting for approximately 80% of OI cases.^{[3, 4, 5, 6]}

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.

Type 1 collagen is a triple helix formed by 2 copies of the alpha₁ chain and 1 copy of the alpha₂ chain. The COL1A gene on chromosome 17 encodes the pro-alpha₁ chain, and the COL2A gene on chromosome 2 encodes the pro-alpha₂ chain.^[7]

The gene sequence coding for the triple-helix domain has a repeating motif of (Gly-X-Y)(n), where X is commonly hydroxyproline and Y is commonly hydroxylysine. Glycine, being the smallest of all amino acids, fits into the core of the superhelix when the chains wind around each other; therefore, glycine plays an important role in the superhelix formation.

In 85-90% of cases, the gene mutation occurs in the region where the exon and intron splice sites are sequenced. All current mutations for type 1 collagen and their associated phenotypes can be found in the Human Type 1 Collagen Mutation Database.

In OI due to quantitative defects of type 1 collagen, mutations are usually found on the COL1A gene. The mutations result in the production of a premature stop codon or a microsense frame shift, which leads to mutant messenger RNA (mRNA) in the nucleus. However, the cytoplasm contains normal alpha₁ mRNA; therefore, reduced amounts of structurally normal collagen are produced.

In OI due to qualitative defects of type 1 collagen, autosomal dominant mutations are found on either the COL1A or the COL1B gene. The mutations result in the production of a mixture of normal and mutant collagen chains. Substitution of a larger amino acid (eg, cysteine or alanine) for glycine results in abnormal helix formation, but these chains can combine with normal chains to produce type 1 collagen. The type 1 collagen thus formed is functionally impaired because of the mutant chain; this is the so-called dominant negative mechanism.

The overall incidence of OI is approximately 1 case for every 20,000 live births; however, the mild form is underdiagnosed, and the actual prevalence may be higher. [#IntroductionRace]Prevalences appear to be similar worldwide, although an increased rate has been observed in 2 major tribal groups in Zimbabwe.

OI can present at any age, although the age when symptoms (ie, fractures) begin varies widely. Patients with mild forms may not have fractures until adulthood, or they may present with fractures in infancy. Patients with severe cases present with fractures in utero.

OI is equally common in males and females. It 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.

Morbidity and mortality associated with OI vary widely, depending on the genotype. (See also the adapted Sillence classification in Presentation.) 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, though some babies survive for several months. At the other extreme is OI in its mildest form. In this setting, adults who have never sustained a fracture come to medical attention only because their family members are affected. Between these extremes is a smooth continuum of severity.

The life expectancy of subjects with nonlethal OI appears to be the same as that for the healthy population, except for those with severe OI with respiratory or neurologic complications. Although patients with lethal OI may die in the perinatal period, individuals with extremely severe OI can survive until adulthood.

Patients with OI are generally well motivated and keen to achieve as much as possible despite their physical limitations. Education is extremely important, particularly for those patients who may respond to their condition in a more negative way and therefore be prone to low self-esteem and depression.

Education of parents and families of OI patients is also important for helping them deal with the day-to-day implications and ongoing management of the disorder. For example, parents need special instructions in handling affected children. They need to know how to position the child in the crib and how to hold the child so as to minimize the risk of fractures while maintaining bonding and physical stimulation.