PETER G.

BULLOUGH Osteogenesis imperfecta (OI) comprises a number of distinct syndromes, some inherited as an autosomal dominant trait, others as a recessive trait, and still others occurring as spontaneous mutations. Sillence and associates have proposed at least four distinct groups. 1 The largest group, Type 1, has an autosomal dominant inheritance with osteoporosis and gray-blue sclera. Type 2 is found in children who died before or soon after birth and shows an autosomal recessive mode of inheritance. The long bones are said to be characteristically broad and crumpled, and contain multiple fractures. Type 3 is found in children with a severe form of the disease, resulting in progressive deformities and multiple fractures. In these patients, the scleral color is almost normal, and both autosomal dominant and recessive inheritance patterns are observed. The final group, Type 4, has an autosomal dominant pattern of inheritance of osteoporosis associated with normal scleral color. These various syndromes have in common an increased propensity for fracture and short stature (usually below the tenth percentile). Many patients also have poorly formed dentin, hearing loss, and Marfan-like features. However, it is the susceptibility to fracture that gives rise to most of their clinical problems. From a clinical standpoint, it has been found convenient to separate the patients into two main groups: the more severe (congenita) type of the disease manifests at birth with multiple fractures and deformities, a soft skull with multiple centers of ossification (wormian bones), and radiographically generalized osteoporosis; the less severe (tarda) type (which usually does not have fractures at birth) may be further separated into two groups (tarda I and tarda II), depending on functional disability. 2 In the tarda I patients, deformities of the lower limbs (the result of repeated fractures) limit ambulation. Tarda II patients are without significant deformity and therefore are functionally far less disabled. Both tarda I and tarda II patients are osteopenic when examined radiographically. The final adult size (height, weight, build) of any individual is the result of many complex factors. Among the most important are (1) the total number of connective tissue cells involved in producing the extracellular matrix, (2) the quantity of extracellular matrix produced by each of the connective tissue cells, and (3) the proper functioning of the epiphyseal growth plate during the period of development. Bone strength is determined both by genetic factors and by nongenetic factors such as diet and activity level. Thus, a person with an inherited disease that results in weak bone, such as osteogenesis imperfecta, may experience further weakening of the bone because of aging and inactivity. With these considerations in mind, the following discussion deals with the pathology of the skeleton in OI as seen in radiographic and anatomical studies. RADIOGRAPHIC ANATOMY The radiologic appearances in osteogenesis imperfecta depend on the severity of the clinical disease, but the hallmark of the disease is osteopenia associated in the majority of cases with multiple fractures, often accompanied by deformities. 3 The entire skeleton is affected (Fig. 1). 2 VOL 5 / SKELETAL RADIOLOGY Fig. 1. Radiograph of an infant with the congenita form of osteogenesis imperfecta. Healing fractures are present in most of the long bones. Note also the triangular facies typical of many of these patients. In the spine, platyspondyly and biconcavity are evidence of compression fractures in the vertebral bodies (Fig. 2), and in many cases these multiple fractures give rise to kyphoscoliosis (Fig. 3). Odontoid fractures are a rare complication, occurring mostly in children. 4 In the severely affected patient, the pelvis is often markedly deformed and sometimes referred to as being triradiate in appearance (Fig. 4). OSTEOGENESIS IMPERFECTA / CHAP 8 3 Fig. 2 . A photograph of a bisected segment of the thoracolumbar spine, obtained at necropsy from an 11-year-old girl with osteogenesis imperfect. The marked platyspondyly, wedging ballooning of the intervertebral discs, as well as scoliosis, all of which are characteristically seen in osteogenesis imperfecta, are apparent in this specimen. (Bullough et al: The morbid anatomy of the skeleton in osteogenesis imperfecta. Clin Orthop 159:43, 1981, by permission of the publisher) Fig. 3 . Radiograph of a 25-year-old female patient with osteogenesis imperfecta congenita demonstrating a moderately severe kyphoscoliosis. Fig. 4 . Radiograph of a teenage boy with osteogenesis imperfecta to demonstrate the degree of pelvic deformity that may occur. Note also the healing fractures in both femora. The skull films reveal a large vault with temporal bulging and typically a small triangular face beneath. Multiple centers of ossification may be observed in the skull, particularly in the occipital portion (wormian

bones) (Fig. 5). Occasionally, there is a "hair on end" appearance. Basil impression with deformity and encroachment upon the foramen magnum may lead to compression of the medulla oblongata. 5 Fig. 5. Radiograph of a child with osteogenesis imperfecta to demonstrate multiple ossification centers in the skull (wormian bones). Note also the fractures of the ribs and both humeri. Fairbank described three radiologic types of disease in the appendicular skeleton: the thick bone, slender bone, and cystic types. The thick bone type (which is rare) is generally seen in early infancy and in severely affected individuals, and is thought to be due to multiple fractures, with telescoping of the bones. In most cases, however, the long bones are very slender (Fig. 6). The ribs may be so attenuated that one sees a "ribbonlike" configuration suggestive of neurofibromatosis. Fig. 6 . Radiograph of a young adult patient with osteogenesis imperfecta tarda to demonstrate the slender, attenuated appearance of the long bones so typical of these patients. Multiple stress fractures apparent along the anterior border of the tibia are seen as round, radiolucent defects. We have seen one less severely affected case in which such a stress fracture was initially mistaken radiologically as an osteoid osteoma. Only when a similar lesion developed on the opposite leg did the true diagnosis become apparent. Fractures vary in number, depending on the severity of the disease, but they are commoner in the lower limbs. Usually they heal at the normal rate. The number of fractures sustained each year is maximal in the growing period and decreases after adolescence. Fractures again become a problem with aging and the onset of senile osteoporosis. Hyperplastic callus develops in a few cases, resulting in excessive swelling, heat, throbbing pain, and tenderness. 6-9 Most authors stress the difficulty and the importance of distinguishing hyperplastic callus from acute osteomyelitis and from neoplasm. Klenerman, Ockenden, and Townsend (1967) reported two cases of osteogenesis imperfecta with proven osteosarcoma, but they questioned whether osteosarcoma was more common in osteogenesis imperfecta than in the general population. 10 Many patients, particularly those with the congenita form of the disease or the severe tarda forms, will be treated with intramedullary rods, which both correct deformity and help to prevent further fracture (Fig. 7). 11 Complications associated with this procedure include breakage of the rod, cutting out of the bone at one end of the rod associated with the continuing growth of the bone, and migration of the rod. Infection around the rods is very rare. Some authors have recommended the use of extensible rods that can be lengthened with the growth of the patient. This would prevent cutting out of the rod, which is the most common complication of rodding. 12 Fig. 7 . Radiograph of the left leg of an 11-year-old boy treated with intramedullary rodding. Note the slenderness of the bones, which might on occasion make it difficult to introduce an intramedullary rod, and also the radiodense nodules in the lower femoral and upper tibial epiphyses, which are discussed in detail in Figures 8, 12, and 13. The radiographic differential diagnosis in the newborn might include congenital hypophosphatasia, although in that condition the alkaline phosphatase level is abnormally low. In a child, the differential diagnosis might include "battered baby syndrome" or the early stages of leukemia. In the preadolescent, the self-limiting condition of juvenile osteoporosis might have to be considered. 4 VOL 5 / SKELETAL RADIOLOGY Approximately 50% of the growing (epiphyseal) ends of the bones in children with osteogenesis imperfecta congenita or tarda I whose roentgenograms we have reviewed have a collection of rounded, scalloped radiolucencies with sclerotic margins. 13 In some cases this is accompanied by a ballooned-out epiphysis and metaphysis, giving a "popcorn bag" appearance similar to that described by Fairbank as cystic (Fig. 8). These lesions are seen only in the long bones, most commonly in those of the leg with equal incidence on the right and left sides of the body. The lesions are present in two thirds of the patients who were classified as having the congenita form and in fewer than half of those classified as tarda I. There were no cases among the patients classified as tarda II. In all instances where such lesions occur, the cartilaginous growth plate is irregular, partially absent, or completely absent. In six of our cases, films obtained during the neonatal period showed normal epiphyses and growth plates, indicating that the lesions are not congenital. Films taken after the adult state have been achieved were available for review in 40% of the patients, and in all of these cases the epiphyseal changes had resolved. A summary of the radiographic findings is shown in Table 1. Scroll right to see more columns. TABLE 1 Summary of Radiographic Findings in Osteogenesis Imperfecta Bone Structure Osteogenesis Imperfecta Tarda Osteogenesis Imperfecta Congenita

Texture Osteopenia with thin cortices and porous cancellous bone, proportional to the severity of the clinical disease. Fractures Generally seen during growth period. Frequency 1-4 per Fractures present at birth; many fractures each year; occur year; most frequent in lower limbs. Fractures may be in all four limbs, but always associated with severe present at birth, but not generally. Deformities usually deformities confined to the lower limb, most often the tibia and fibula. Long Bones Usually slender May be widened during infancy due to telescoping. In older patients. usually very slender Epiphyses Usually normal in appearance, although irregularities may Frequently irregular. with failure to recognize a normal be present in the lower femoral and upper tibial epiphysis growth plate, and replacement by bubbly, calcified nodules: most frequently seen in the lower femur, upper tibia, upper femur, and upper humerus Spine Osteopenia; platyspondyly; mild scoliosis Severe osteopenia with hiconcave vertebrae and frequently severe kyphoscoliosis Normal Frequent deformities with thinning. malunited fractures Pelvis Normal Triradiate Skull Wormian bones; occasional "hair on end" Fig. 8 . Radiographs of the knees of a 9-year-old boy. The growth plates are not well visualized. Within the epiphysis as well as in the region of the metaphyses, spherical lucent areas are outlined by sclerotic rims resembling a plastic bag filled with popcorn. BONE HISTOLOGY The distribution and amount of cortical and cancellous bone and its microscopic appearance depend on anatomical location. It is therefore important in the assessment of any metabolic bone disease to use a uniform biopsy site to enable comparisons with other patients and normal controls. The tissue we have studied was obtained from the lilac crest, and interpretation of the material took into account the clinical classification of the disease. 14 Bone from patients with OI congenita was characterized by large areas of osseous tissue devoid of an organized trabecular pattern. Plump osteoblasts were crowded along prominent osteoid seams. Large oval osteocytes were surrounded by small amounts of matrix that showed an irregular tangle of collagen fibers, In areas where the collagen specimens showed a lamellar pattern, the osteoblasts were numerous and the osteocytes were large, crowded, and less elliptical than those in the control bone. The lamellae of collagen were themselves abnormally thin. The osteoclasts appeared morphologically normal, although both they and the resorptive surfaces were somewhat more numerous (Figs. 9 and 10). OSTEOGENESIS IMPERFECTA / CHAP 8 5 Fig. 9 . Photomicrograph of a portion of normal lamellar bone (A) to compare with bone obtained from a patient with osteogenesis imperfecta (B). These two photographs are at the same magnification, and the line superimposed on the photograph is the equivalent of 100 m m. Note in particular the increased cellularity of the bone in osteogenesis imperfecta. (H&E, Nomarski optics) Fig. 10 . Photograph (at a higher magnification) of the samples shown in Figure 9. The superimposed line represents 50 m m. Note that the lamellae in the sample from the patient with osteogenesis imperfecta (B) are thinner and more closely packed than those seen in the normal bone sample. (H&E, Nomarski optics) Bone from OI tarda was characterized by a predominantly lameliar pattern, with only small areas of woven bone. Osteoblasts were prominent, but appeared smaller and less numerous than their counterparts in the congenita group. Osteoid seams were also prominent. The osteocytes, although more mature-looking than those in OI congenita, were crowded, larger, and less homogeneously arranged throughout the trabeculae than were the osteocytes in the normal controls. The lamellae were again abnormally thin. The osteoclasts appeared morphologically normal but increased in number. Bone specimens removed from two necropsy subjects (an 11-year-old girl with OI congenita and a 3month-old baby girl also with the congenita form of the disease are shown in Figure 11. 15

Fig. 11 . Photograph of a femur obtained at necropsy from an 11-year-old girl with osteogenesis imperfecta. Note the extreme thinness of the cortex. (Bullough et al: The morbid anatomy of the skeleton in osteogenesis imperfecta. Clin Orthop 159:48, 1981, by permission of the publisher) The epiphyseal ends of the long bones, including the articular surfaces, retained a recognizable shape, but in proportion to the rest of the bone they appeared larger and some showed irregularity of the articular surface when the bones were sectioned. The secondary centers of ossification were poorly ossified, distorted in shape (lacking the regular ovoid outline of the normal epiphysis), and contained numerous small cartilaginous nodules measuring 1 mm to 4 mm in diameter. The growth plates varied in appearance from bone to bone, from normal to total disruption of its regular outline (Fig. 12). 6 VOL 5 / SKELETAL RADIOLOGY Fig. 12. A radiograph of a bisected humeral head obtained at necropsy from an 11-year-old girl with osteogenesis imperfecta demonstrates the crumpled appearance of the cartilaginous growth plate, as well as small nodules of cartilage in the epiphysis, which are visualized by the bony rimming. The articular surface is somewhat flattened and irregular. (Bullough et al: The morbid anatomy of the skeleton in osteogenesis imperfecta. Clin Orthop 159:51, 1981, by permission of the publisher) In cases with disrupted growth plates, irregularly shaped masses of cartilage were found in the epiphyseal growth plate region. Between these cartilaginous bodies were soft hematopoietic marrow and a minimal amount of spongy bone (Fig. 13). The cartilaginous nodules within the secondary centers of ossification contained both calcified and noncalcified cartilage, surrounded in some areas by a thin rim of woven bone. Roentgenographs of these specimens showed multiple scalloped radiolucencies with radiodense borders reflecting the gross anatomical findings and corresponding to the cystic "popcorn" epiphyses seen in clinical radiographs. OSTEOGENESIS IMPERFECTA / CHAP 8 7 Fig. 13 . A. Gross photograph. B. Roentgenogram of specimen slice of the distal femur obtained at necropsy from an 1l-year-old girl with osteogenesis imperfecta, The diameter of the distal femur just above the condyles was 5.5 cm. The articular cartilage appears normal, measuring 2.0 mm in thickness. The funnelization of the metaphysis appears normal. The cortical bone is thin and fragmented easily. The femoral condyles are filled with multiple small cartilaginous nodules measuring between 1.0 mm and 4.0 mm in diameter, as well as irregularly shaped masses of cartilage 1 cm to 2 cm across. The small nodules are confined to the region of the epiphysis, although the larger masses extend proximally into the metaphysis for approximately 1.5 cm. The region between the cartilaginous bodies is filled with soft red and yellow marrow and a minimal amount of spongy bone. There is no recognizable growth plate apart from small fragments abutting the cortex. Roentgenogram of the bisected specimen shows that the cortices are well mineralized, although extremely thin. The epiphyseal end of the bone, and to some extent the metaphysis, contain numerous radiodense circles with radiolucent centers. Few trabeculae are noted in the metaphysis. (Bullough et al: The morbid anatomy of the skeleton in osteogenesis imperfecta. Clin Orthop 159:52, 1981, by permission of the publisher) DISCUSSION Osteogenesis imperfecta is not one disease; it is a collection of diseases having in common decreased stature and the propensity to fracture. From the anatomical viewpoint, three levels of organization are considered in patients with OI: cellular defects, tissue abnormalities resulting from the cellular defects, and structural or skeletal abnormalities. Although only scant information is available relating to cellular defects in OI, biochemical evidence indicates that this disease results from various disorders in collagen synthesis, quantitative and/or qualitative. 16-18 More information is available concerning tissue abnormalities. The increased number of osteoblasts and osteoclasts, the large size of the osteoblasts, and the greater amount of osteoid-covered surfaces all suggest an increase in bone turnover, and this is supported by increased tetracycline labeling. 19 One of the most characteristic histologic features in OI is the apparent abundance of osteocytes. 14 The quantity of extracellular matrix separating the cells is reduced, and as a consequence the cells are much closer together. This finding is present in both woven and lamellar bone, suggesting a decrease in the amount of collagen matrix produced by each osteoblast before it becomes an osteocyte. The diminution in the size of the skeleton in OI can partly be attributed to this absolute decrease in extracellular matrix production, particularly of collagen. The fact that the lamellae appear unusually delicate and thin is in accordance with this interpretation. 20 As has already been stated, the overall dwarfing results to some extent from decreased collagen matrix production by the connective tissue cells. Other reasons for dwarfing must be considered, chiefly dysfunction of the epiphyseal growth plate. Sillence and coworkers have reported that patients with

dominantly inherited OI develop a markedly short stature; nevertheless, at birth these same patients are of normal length. 1 This suggests that it is only as the cartilaginous skeleton is replaced by bone that shortness becomes evident. Several authors have reported that in cases of osteogenesis imperfecta, the growth plate is normal; however, in 1944 Heise noted that scattered islands of cartilage might be found in the metaphysis. 21-25 Engfeldt and colleagues reported that the epiphyseal plate may be broad and irregular, lacking the typical columnar arrangement in the hypertrophic and calcified zone. 26 In autopsy cases we have studied, two processes were found to affect the epiphyseal end of the bone. First, a failure in the normal development of the secondary center of ossification results in residual islands of cartilage in the epiphysis. (This process was present in most of the epiphyses examined.) Second, disruption of the epiphyseal growth plate often leaves only irregular islands of growth-plate cartilage. The radiographic survey showed that the most severe involvement occurred in the distal femoral growth plate. It seems likely that these epiphyseal changes are secondary to trauma rather than developmental in origin. This view is supported by the findings of progressive changes in the clinical radiographs. Since in these patients there is little or no supportive medullary cancellous bone, it seems to us that the delicate cartilaginous growth plate, rendered brittle by the zone of calcification, is extremely vulnerable to lateral compression. The resulting fragmentation of the growth plate might be expected to interfere with growth. In this regard, it is interesting to observe that in a number of patients with the tarda I form of the disease, there is considerable disproportionate shortening of the femur as compared with the humerus. In such cases that we have examined roentgenographically, fragmentation of the growth plate of the lower femoral condyles was generally apparent.