A newborn infant is being evaluated by the pediatrician in the hospital. On physical exam, the infant is noted to have blue sclerae and deformities in the legs (Figure 225-1). X-rays of the long bones of the legs reveal multiple fractures (Figure 225-2). Prenatal ultrasound screening in the second trimester showed bowing of long bones, fractures, and shortened limbs, suspicious for osteogenesis imperfecta (OI). The infant is treated with supportive care and a referral to genetics and orthopedics is made. The diagnosis of OI is formally established by identifying mutations in type 1 collagen.

Osteogenesis imperfecta (OI) is a genetic disorder characterized by fragility of the skeletal system, and resulting in frequent fractures. The four major types of OI are caused by structural or quantitative defects in type 1 collagen, which is the primary component of the extracellular matrix of bone and skin protein.

Brittle bone disease (type 1 OI), Osteogenesis imperfecta congenita (type 3 OI).

• Overall incidence of OI is 1 in 20,000 births. The number of individuals affected by OI in the US is estimated to be between 20,000 and 50,000.¹

• Eight types of OI have been described and are classified according to clinical presentation, radiographic findings, mode of inheritance, and molecular findings.

• Types 1 through 4 of OI are the most common; types 5 to 8 are very rare.²

• Type 1 is the most common form and is inherited in an autosomal dominant pattern. Type 4 is also inherited in an autosomal dominant pattern. Type 2 and Type 3 are usually the result of new mutations.

• Type 2 is the most severe form; 50 percent of cases are stillborn.

• The autosomal dominant forms of OI (types 1 and 4) occur equally in all racial and ethnic groups, and recessive forms (types 2 and 3) occur predominantly in ethnic groups with consanguineous marriages.

• OI types 1 through 4 are the result of mutations of genes that code for type I collagen, while types 5 to 8 are caused by mutations of other less-well characterized genes.

• Types 1 and 4 are inherited in an autosomal dominant pattern and are caused by mutations in COL1A1 and COL1A2 genes that code for the alpha-1 and alpha-2 chains of type 1 collagen.

• Collagen structural defects are predominantly of two types:

  1. Eighty percent are point mutations causing substitutions of helical glycine residues or crucial residues in the C-propeptide by other amino acids.

  2. Twenty percent are single exon splicing defects.

• The clinically mild OI type 1 has a quantitative defect, with null mutations in one α1(I) allele leading to a reduced amount of normal collagen.³

• Types 2 and 3 may be inherited in a recessive pattern and most cases are related to new point mutations of COL1A1 or COL1A2.

• The collagen structural mutations cause OI bone to be globally abnormal. The bone matrix contains abnormal type I collagen fibrils and relatively increased levels of types III and V collagen.

• Affected parent for OI types 1 and 4.

• Consanguineous marriage for OI types 2 and 3.

• The diagnosis is made based on clinical grounds in most cases.

• Collagen and genetic testing are available to help to make the diagnosis in difficult cases.

Clinical Features

• Fragile bones, blue sclerae, and early deafness are the hallmark features of OI (Figure 225-1).

• Common presenting features include bone fragility, repeated fractures with minimal trauma, and easy bruisability.

• Deafness may be a presenting feature of children with type 1 OI.

• Prenatal ultrasound screening in the second trimester may show bowing of long bones, fractures, shortened limbs, and other bone abnormalities.

• The majority of fractures occur during childhood.

• The blue sclerae is due to thinning of the sclera.

• Some patients have short stature and develop hearing loss later in life.

• Specific features are specific to the types of OI:

  • Osteogenesis Imperfecta Type 1 (Mild).

    • Major features include blue sclerae, recurrent fractures in childhood, easy bruising, joint laxity, and hearing loss (30 to 60%), which often develops in the 2^nd or 3^rd decade.

    • Fractures result from mild to moderate trauma, are uncommon at birth, and decrease after puberty.

    • Deformities of bones are uncommon.

    • Short stature, compared with family members, may or may not be present.

    • Differentiation from nonaccidental trauma can be challenging.

  • Osteogenesis Imperfecta Type 2 (Perinatal Lethal).

    • Most severe form of OI.

    • Lethal in utero or in the majority of newborns because of respiratory insufficiency.

    • Extreme fragility of the skeleton and other connective tissues.

    • Multiple intrauterine fractures of long bones are evident, which have a crumpled appearance on radiographs.

    • Limbs are short and bowed, and legs are held abducted at right angles to the body creating a frog-leg position.

    • Multiple rib fractures create a beaded appearance and the small thorax contributes to respiratory insufficiency.

    • A large, soft skull and open fontanelles are common.

  • Osteogenesis Imperfecta Type 3 (Severe, Progressive Deforming).

    • Nonlethal form but patients have severe physical disability.

    • Usually presents in the newborn period with multiple fractures.

    • Infants have low birth weight and in utero fractures are common.

    • There is relative macrocephaly, triangular facies and blue sclera (Figure 225-3).

    • Postnatally, fractures occur from inconsequential trauma and heal with deformity.

    • Disorganization of the bone matrix results in a “popcorn” appearance at the metaphyses.

    • The rib cage has flaring at the base and pectal deformity is frequent.

    • Almost all patients have scoliosis and vertebral compression.

    • Pulmonary function can be affected due to associated scoliosis.

    • Extreme short stature is common (Figure 225-4).

  • Osteogenesis Imperfecta Type 4 (Mild to Moderately Severe).

  • Marked variability in clinical findings.

  • In utero fractures can occur.

  • Bowing of the tibia is the hallmark of this type of OI and can occur even without fractures.

  • Children require orthopedic and rehabilitation intervention, but they are usually able to attain community ambulation skills.

  • Fracture rates decrease after puberty. X-ray findings show osteoporotic and have metaphyseal flaring and vertebral compressions.

  • Short stature is common, like in other types of OI.

• Osteogenesis Imperfecta Type 5 (Hyperplastic Callus) and Type 6 (Mineralization Defect).

  • These types of OI are similar clinically to type 4, but they have distinct findings on bone histology.

  • Type 5 patients also have hyperplastic callus, calcification of the interosseous membrane of the forearm, and a radiodense metaphyseal band.

  • The absence of a collagen defect supports the distinct grouping; the genetic etiology is unknown.

• Osteogenesis Imperfecta Types 7 and 8 (Recessive Forms).

  • Caused by null mutations in proteins involved in posttranslational modifications of type I procollagen.

  • Clinically overlap types 2 and 3, but have distinct features including white sclerae, rhizomelia, and small to normal head circumference. Rhizomelia is a disproportion in the length of the most proximal segment of the limbs (upper arms and thighs).

  • Surviving children have severe osteochondrodysplasia with extreme short stature.