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.
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:
Eighty percent are point mutations causing substitutions of helical glycine residues or crucial residues in the C-propeptide by other amino acids.
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.
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.
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 2nd or 3rd 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.
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