Osteogenesis imperfecta is a clinically and genetically heterogeneous disorder of connective tissue, manifested by bone fragility and low bone mass. Affected patients have blue sclerae, hearing abnormalities, defective dentition, hyperlaxity of the joints, and normal intelligence (Brons et al., 1988). The majority of affected individuals are heterozygous for mutations of the COL1A1 or COL1A2 gene, which alters the structure of type I procollagen (Cole and Dalgleish, 1995).

Osteogenesis imperfecta was originally classified into four clinically distinct disorders that were first delineated by Sillence et al. (1979), and modified by Rauch and Glorieux (2004) (Table 91-1). Type I is the common mild form, type II is the perinatal lethal form, type III is the severe form, and type IV is the moderately clinically severe form (Cole and Dalgleish, 1995). More recently, an additional three types (V, VI, and VII) have been described (Rauch and Glorieux, 2004). The clinical severity of OI is type II > type III > types IV = V = VI = VII > type I.

Type I is a form of dominantly inherited osteoporosis that leads to fractures. Affected patients have distinctly blue sclerae and between 35% and 50% have presenile conductive hearing loss or deafness. The earliest age of onset of hearing loss is 10 years, and 40% of affected adults eventually require hearing aids. Approximately one fifth of patients with type I osteogenesis imperfecta (OI) have kyphosis and scoliosis, although severe spinal curves are rarely seen. These patients also bruise easily. All patients with type I OI are able to walk independently. Type I is further subdivided into type IA, patients with normal teeth and type IB, patients who have dentinogenesis imperfecta. Only 10% of patients with type I OI have fractures that are identifiable at birth (Sillence, 1981). Patients affected with type I OI have a progressive loss of height due to platyspondyly and kyphosis. Birth weight and length are generally normal and short stature is of postnatal onset. These patients are also notable for a head size that appears large for height.

Patients with type II OI comprise the majority of cases detected pre- and post-natally. Type II has been further subdivided into types IIA, IIB, and IIC. In type IIA broad, crumpled femurs and continuous beading of the ribs are present. In addition, the patients are small for gestational age and have severe osteoporosis of the skull and face. In type IIB, there are minimal or no rib fractures present. Because the ribs are less severely affected, the chest configuration is more normal and the resulting respiratory distress is less severe. Type IIB is the only form with potential postnatal survival. In type IIC there are thin femurs and ribs with extensive fractures. In this form, the fetuses are very small for gestational age and severe osteopenia is present. However, many investigators state that distinction between the subgroups of type II is of limited value because all fetuses and infants with OI type II die during the perinatal period.

Type III is a rare form of OI, characterized by marked fragility and fractures of the long bones and skull, which are sometimes present at birth (Sillence et al., 1986). In utero, the defect in ossification of the skull is not as marked as it is in Type II. Posnatally, there are spine and long bone fractures, which result in progressive short stature and kyphoscoliosis. Although blue sclerae are present at birth, they fade with time. Hearing impairment is rare in type III OI. Affected patients have a triangle-shaped face with a wide bitemporal diameter. These patients are among the smallest of adults with OI. They have considerable difficulty walking. They suffer from multiple pulmonary complications.

Type IV is a dominantly inherited form of osteoporosis that leads to fractures. Variable deformity of the long bones exists, but affected patients have normal sclerae. There are no associated hearing abnormalites. Type IV has been further subdivided into IVA and IVB. In type IVA there is normal dentition and in IVB there is dentinogenesis imperfecta. To date, types V, VI and VII have not been associated with a specific prenatal presentation. All are associated with bone fragility, but none are known to be caused by mutations in COL1A1 or COL1A2. Patients with Type V OI have hypertrophic callus formation at fracture sites, calcification of the interosseous membranes between bones of the forearm, and a radio-opaque metaphyseal band adjacent to the growth plates. The distinctive feature of type VI OI is the histologic appearance of bone lamellae that resemble fish scales. Patients with type VI OI also accumulate excessive osteoid. Type VII OI is inherited in an autosomal recessive pattern, and it is characterized by proximal shortening of the humerus and femur (Roughley et al., 2003).

The incidence of type I OI is 1 in 28,500 livebirths, while type II occurs in 1 in 62,000 livebirths and type III occurs in 1 in 68,800 livebirths (Sillence et al., 1979). In Sillence et al.’s original article, they did not quote an incidence for type IV OI (Sillence et al., 1979). Rasmussen et al. (1996) identifed 16 cases of OI among 126,316 deliveries that occurred over a 15-year period in a single teaching hospital. These authors estimated a prevalence (with exclusion of high-risk patients) of 0.24 in 10,000 deliveries of type II OI and 0.4 in 10,000 of types II and III OI combined. OI has been described in all ethnic groups (Sykes et al., 1986).

The prenatal sonographic findings in OI are summarized in Table 91-2. The characteristic antenatal findings of OI include in utero fractures that occur with callus formation at the site of healing. These result in prenatally acquired long-bone deformities and significant limb shortening (Figure 91-1). Abnormalities of the fetal skull are the most striking findings in OI (Constantine et al., 1991). In addition, soft and fractured ribs contribute to a small thoracic circumference, which has been described as having a “champagne cork” appearance. The unusual clarity of intracranial structures is due to poor calvarial ossification (Figure 91-2). This has led to the term supervisualization (Andrews and Amparo, 1993). The compression of the fetal head by the ultrasound probe and the low echogenicity of the cranium should raise the suspicion of a skull dysplasia. However, this finding is not diagnostic for OI (Berge et al., 1995).

The following sonographic criteria have been proposed for type II OI: multiple fractures, demineralization of the calvarium, and a femoral length less than 3 SD below the mean for gestational age coupled with a wrinkled appearance of the long bones (Munoz et al., 1990). In a retrospective study of 459 fetuses and infants with bent femurs, 18.1% had OI (Alanay et al., 2007).

In the absence of a known family history of OI, most fetuses detected prenatally will have type II. The major diagnostic criteria for this type of OI include shortened deformed long bones, underossification of the cranial vault, which results in easily seen intracranial structures, an abnormal and varying skull shape, a small chest circumference with broad and irregular ribs (Figure 91-3), decreased fetal movements, and unusual fetal limb position (Constantine et al., 1991). In one case report, Morin et al. (1991) described a case of type IIA OI in one of dizygotic twins diagnosed at 27 weeks of gestation. In this report, the affected fetus was so translucent that only one twin could be seen on a plain radiograph. In another case report, D’Ottavio et al. (1993) described a case of type II OI in the fetus of a woman at 14 weeks of gestation who underwent routine transvaginal ultrasonography. In this fetus, both femurs were short and severely angulated because of fractures. Even at this early point in gestation, the fetal skull was noted to be hypoechogenic, and an abnormal curvature of the right radius was present.

Prenatal diagnosis of OI types I and III is more difficult to make on a sonographic basis. Most of the cases described in the literature have been diagnosed in fetuses known to be at risk because of a positive family history. For example, Robinson et al. (1987) described a fetus at risk for type III OI that was followed with serial sonography. At 15 weeks of gestation, there was a low normal fetal femur length. By 20 and 22 weeks, however, shortening of the long bones and deformity of the femurs were noted. There was not an impressive decrease in ossification of the fetal skull. Several case reports of prenatal diagnosis of type I OI have appeared in families known to be at risk. Chervenak et al. (1982) described a fetus whose mother was affected with type I OI. This fetus had a normal sonographic examination at 20 weeks, but bowed femurs developed at 24 weeks. By 32 weeks of gestation, demineralization of the fetal skull was observed. No fractures were seen in utero, but a right femur fracture developed at 9 days of age, which was postulated to be due to the effect of intrauterine curvilinear stress on weakened bones.

Brons et al. (1988) reported on the sonographic diagnosis of OI in seven fetuses collected from the experience of three major teaching hospitals in the Netherlands. The gestational age at the time of scanning was between 15 and 34 weeks. The indications for sonography included large for gestational age (two fetuses), small for gestational age (two), previous child affected with OI (two), and routine anatomy scan (one). The biparietal diameter was normal in all seven. The abdominal circumference, however, was either normal or small for gestational age. In most cases, the chest circumference was narrow as compared with the abdominal circumference. The heart was noted to completely fill the chest. The limbs were the most severely shortened in type IIA OI. The prenatal diagnoses of types IIB, IIC, and III were made later in gestation than in type IIA (Brons et al., 1988).