Pediatric Orthopedic Deformities: Basic science, Diagnosis, and Treatment

Preface

Pediatric Orthopedic Deformities: Basic Science, Diagnosis, and Treatment provides a detailed understanding of major

ments used, and results of treatment, stressing relationships with the underlying pathobiology at each step of the way. Chapter 3 describes developmental dysplasia of the hip; Chapter 4, Legg-Calve-Perthes disease; Chapter 5, coxa vara in developmental and acquired abnormalities of the femur within which slipped capital femoral epiphysis, proximal femoral focal deficiency, infantile coxa vara, coxa vara with congenital short femur, and coxa vara with the skeletal dysplasias are discussed; and Chapter 6 reviews epiphyseal disorders of the knee encompassing the distal femur, proximal tibia, and proximal fibula. Care is taken throughout the book to review in detail the studies done so as to place the descriptions on as rigid a scientific basis as possible. Part III discusses entities crucial to an understanding of the more complicated growth-related deformities in pediatric orthopedics. These disorders produce deformities by affecting primarily the epiphyses and metaphyses. In Chapter 7, epiphyseal growth plate fracture-separations are reviewed, because this subset of childhood fractures has the potential to contribute in the most major way to limb deformity. Understanding of these fracture-separations as it has evolved over several decades is reviewed. The underlying cell biology and histopathology of growth plate injuries are reviewed such that the various classifications and the presence or absence of negative growth sequelae can be understood. The various pathoanatomic classifications are reviewed in detail, as is the pathophysiologic approach, which is dependent to a great extent on understanding the histopathology and assessing it by newer imaging modalities. Treatments specific for each of the fracture patterns at each epiphysis are reviewed. The importance of understanding the structure and blood supply of epiphysis and adjacent metaphyis, the specific fracture patterns that occur, the biologic rationale for the treatments now used and being developed, and the newer investigative technologies involving CT scanning and MR imaging are stressed. In Chapter 8 the entire entity of lower extremity length discrepancy is described in detail, including the natural history of the specific disorders that cause the discrepancies, the negative sequelae of length discrepancies, methods to project the eventual discrepancies at skeletal maturity, a review of the developmental patterns likely to occur in each of the

pediatric orthopedic deformities showing how normal developmental bone biology and abnormal pathobiology relate to the occurrence of these deformities, their diagnosis, and their treatments. An understanding of normal developmental bone biology as outlined by several research disciplines is vital to an understanding of abnormal bone development. Many orthopedic deformities of childhood worsen with growth, while others have the potential for correction either spontaneously or with appropriate therapeutic interventions over the years remaining until skeletal maturity. Management of pediatric orthopedic deformities encompasses the need to understand biologic and mechanical contributions to skeletal development. Part I of this book provides basic information on the developing skeleton and current imaging methods used to assess it. Chapter 1 describes developmental bone biology as outF,ned by several investigational disciplines. These include histology at the light and electron microscopic levels; molecular biology outlining the wide array of genetic and molecu!ar controls for skeletal tissue differentiation, growth, and synthesis of structural molecules; mechanical-biophysical effects on the developing skeleton; and basic radiologic parameters of growth such as appearance of secondary ossifi,:ation centers and times of physeal fusion. Chapter 2 has been written by Dr. Diego Jaramillo, a col":eague of several years, who outlines the rationale for diagnosis of normal and abnormal skeletal development by many imaging techniques including plain radiographs, ultrasonoglaphy, bone scanning, computerized tomography, and magnetic resonance imaging. Part II discusses disorders of the developing hip and knee. Each chapter begins with a clear description of the terminology used for the disorder discussed and then provides an outline of the basic biology relevant to the entity. For each entity, detailed review of the clinical findings, diagnostic techniques, associated surgical and nonsurgical treatments, and eventual results are provided. The literature for each entity has been presented both critically and in detail in relation to a wide spectrum of findings, including pathoanatomy, clinical presentation, diagnostic techniques, various treat-

xvii

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Preface

various disorders, and extensive overviews into shortening, lengthening, and transphyseal bone bridge resection treatments. In Chapter 9 the skeletal dysplasias are discussed, including clinical and radiographic descriptions of the entities, the molecular abnormalities recently identified, the specific orthopedic deformities, and the specific orthopedic treatments. The chapter is designed to address and correct the fragmentation of presentation of the skeletal dysplasias in the literature, in which the disorder tends to be discussed only from the viewpoint of each disciplinemradiology, molecular biology, or orthopedics. Chapter 10 reviews entities known to be associated with pediatric orthopedic deformities but also discussed in general in isolated fashion. The chapter presents these entities from

the point of view of the basic underlying biology, the pathoanatomy of deformation, and the principles and results of medical and orthopedic management. The entities described focus on the epiphyseal and metaphyseal effects of involvement with rickets of the various types, juvenile rheumatoid arthritis, benign and malignant neoplasms of the epiphysealmetaphyseal regions, pyogenic and tuberculous infections that affect primarily the epiphyseal-metaphyseal regions, and major hematologic disorders including the hemophilias. The book has two main premises: (1) current orthopedic treatments of growth deformities of the developing skeleton are most effective if based on understanding and relating to the pathobiology and (2) future treatments can be best developed if based on the underlying primary and secondary pathobiology.

Frederic Shapiro

Acknowledgments

and revising the manuscript, tables, and references; Emily Flynn Mclntosh of the Children's Hospital for artwork; James Koepfler of the Children's Hospital for medical photography; George Malatantis of the Children's Hospital for histology preparations and printing; and Taft Paschall, Joanna Dinsmore, Judy Meyer, and the entire Academic Press team for production of the book.

The author gratefully acknowledges the extensive efforts of several individuals who helped bring this work to publication: Dr. Diego Jaramillo of the Massachusetts General Hospital, Boston, for contributing Chapter 2 and MR imaging studies throughout; Dr. Frank Rand of the New England Baptist Hospital, Boston, for collaborative work in Chapters 7 and 8; Mary Doherty and Joanne Hutchinson for typing

Frederic Shapiro

xix

CHAPTER

1

Developmental Bone Biology I. II. III. IV.

Terminology Early Scientific Understandings of Bone Growth

Embryology of the Limbs Bone Development at the Light Microscopic Level Following Delineation of the Cell Theory and Advances in Microscopy and Histochemistry V. More Detailed Histologic Studies of Bone Formation VI. Fate of the Hypertrophic Chondrocyte as Interpreted from Light Microscopic Studies VII. Structural Development of the Epiphyseal Regions Including the Joints, the Metaphyses, and the Diaphyses

I. T E R M I N O L O G Y A. Overview During the embryonic period, limb buds filled with undifferentiated mesenchymal cells form from the lateral side walls. The earliest sites of skeletal formation are characterized by condensation or close packing of mesenchymal cells followed by early cartilage differentiation. Each of the long bones is preformed as a cartilage model. Bone tissue is then deposited beginning in the middle of the model on the calcified cartilaginous core using the endochondral ossification mechanism and directly by the surrounding periosteum using the intramembranous ossification mechanism. Bone deposition progresses toward each end with intramembranous bone formation at the periphery slightly in advance spatially of internally or centrally positioned endochondral bone formation. The proportional involvement of each of the three regions of a developing bone--diaphysis, metaphysis, and epiphysis--is established by the early fetal stage and remains more or less unchanged until skeletal maturity. The central part of the bone is the diaphysis or shaft; the furthermost bone extension of the diaphysis is the metaphysis; and the developing cartilaginous end of each bone is the epiphysis. Normal bone development occurs in conjunction with the proliferation and differentiation of cells, the synthesis and interaction of specific molecules, and the generation of intrinsic and extrinsic biophysical forces. Primary genetic blueprints and secondary epigenetic and inductive phenomena lead to the patterns characteristic of each bone through-

VIII. IX. X. XI.

Axes along Which Bones Are Patterned Gene and Molecular Controls of Limb Development Chemistry of the Extracellular Matrix Mineralization

XH. Epiphyseai Growth XIII. Responses of Developing Bones and Epiphyses to Mechanical Stresses XIV. Radiographic Characteristics in Development of Major Long Bone Epiphyses XV. Why Epiphyses Form and the Evolution of Epiphyses

out the skeleton. The epiphyses are responsible for long bone longitudinal growth, transverse growth at the ends of the bone, and the shape of the articular surfaces. In this book we will outline established, newly evolving, and theoretical information on normal bone development and abnormal development as it relates to the many skeletal growth disorders of childhood with their particular concentration at the epiphyseal regions.

B. Theories of Embryogenesis--Preformationism and Epigenesis Prior to the nineteenth century the most widely accepted theory of embryogenesis was preformationism, the doctrine that the entire adult individual was present in miniature in the egg or sperm and development simply involved an increase in size. With more detailed observation however, the concept of development by epigenesis became accepted more widely. Epigenesis refers to the sequential development of morphological complexity in the embryo by the gradual and progressive differentiation of homogenous material; each stage in development is considered to be dependent on and directed by the stage immediately preceding it. The works of Caspar Friedreich Wolff (373), Pander (303), and Karl Ernst von Baer (13) were particularly noteworthy in establishing the scientific validity of development by epigenesis. Wolff, in 1759, reported his observations on hen's egg development, which showed blood vessels appearing where none existed previously and intestine forming from a flat plate. He concluded that epigenesis was real:

CHAPTER 1 ~

Developmental Bone Bioloyy

"each part is first of all an effect of the preceding parts, and itself becomes the cause of the following part." The structural basis of embryogenesis was revealed more clearly by Pander, who defined the three germ layers in 1817, and then by von Baer (13), who is widely considered the founder of embryology. Von Baer performed elaborate descriptions of chick embryo development and its similarity to the development of several other vertebrate types and reported them in 1828 and 1837 (13). He recognized the significance of the three germ layers in development in all vertebrates and the truly epigenetic mechanism of development from the general to the specific. He recognized that the general path of differentiation proceeds in three sequential stages: the primary formation of the germ layer, histological differentiation of cell and tissue types within the germ layers, and morphological differentiation to early organ formation. The mode of development is from simple to complex and from undifferentiated cell masses to new organs9 The law of biological development is progressive differentiation of homogeneous, coarsely structured, and general to heterogeneous, finely structured, and specific. It is now recognized that much of development occurs in a self-assembly or "automatic" mode based on chemical and biophysical phenomena. Development is epigenetic in which only the early prepatterns are rigidly determined, after which each subsequent step is a combination of gene synthesis and automatic self-assembly based on the physical pressure of certain molecules9 Genes give approximate direction only. The detailed structure of multicellular organisms occurs on the basis of many intermediate levels of interaction each with its own immediate properties such that "the edifice is virtually entirely epigenetic."

C. Epiphysis The term epiphysis refers to the entire developing end of the bone (320, 321). This region initially is formed completely in cartilage and subsequently subdivides during development into three histologically distinct regions: (1) the cartilage immediately adjacent to the joint, referred to as articular cartilage; (2) the cartilage adjacent to the metaphysis, referred to variously as the growth plate, the epiphyseal growth plate, or the physis (it is the functionally and cytologically specialized region where the bulk of longitudinal growth occurs, and it encompasses the area from the reserve zone of cells to the end of the hypertrophic cell layer); and (3) the cartilage between the articular cartilage and the growth plate cartilage, referred to as the epiphyseal cartilage. Eventually this is transformed entirely into bone and marrow following the appearance and enlargement of what is variously referred to as the secondary ossification center, the bony nucleus, the ossific nucleus, or the bony epiphysis (Fig. 1). The epiphysis is sometimes referred to as the chondroepiphysis, but use of this term should be restricted to the time prior to formation of the secondary ossification center.

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FIGURE 1 The histologic structure of the epiphysis of the proximal tibia is illustrated. The entire developing end of the bone from the articular cartilage surface to the last cells of the hypertrophic zone of the growth plate is the epiphysis (E). This encompasses three regions that are initially cartilage: (1) the articular cartilage (AC), (2) the growth plate (GP), also referred to as the epiphysealgrowth plate or the physis, and (3) the epiphyseal cartilage (EC), which refers to the cartilage mass between the articular cartilage and the growthplate cartilage. It is within the epiphysealcartilagethat the secondaryossificationcenter (SOC), also referred to as the bony nucleus, the ossific nucleus, or the bony epiphysis, forms and expands. [Reprinted from Shapiro (1987), New Engl. J. Med. 317: 1702-1710, with permission. Copyright 9 1987 MassachusettsMedical Society.All rights reserved.]

D. Endochondral Ossification The cartilage models of a developing bone and ultimately the epiphyses form bone by a mechanism referred to as endochondral bone formation. The major characteristics of this mechanism of bone formation involve growth of the cartilage by interstitial expansion involving chondrocyte proliferation, matrix formation, and chondrocyte hypertrophy. At a certain stage of development, the cartilage matrix adjacent to the hypertrophic cells mineralizes, and there is vascular invasion of the lacunae in which the hypertrophic cells reside. This vascular invasion is accompanied by mesenchymal cells that shortly differentiate to osteoblasts and synthesize a bone matrix on the calcified cartilage cores. The calcified cartilage thus is serving as a scaffold on which bone is deposited initially at the center of the developing cartilage model of the bone and eventually at the lower regions of the physis merging into the metaphysis and also within the epiphyseal cartilage where the bone formed is referred to as the secondary ossification center. The epiphyseal cartilage immediately surrounding the secondary ossification center and undergoing chondrocytic hypertrophy can be considered as the physis of the secondary ossification center.

E. Intramembranous Ossification Long bone formation is also characterized by a mechanism referred to as intramembranous ossification, which occurs from the surrounding periosteum. In this mechanism, bone tissue is formed directly from mesenchymal cells without the mediation of a cartilage scaffold phase. The initial site of

SECTION II ~ Early Scientific Understandings o f Bone G r o w t h

F I G U R E 2 Photomicrograph of the developing end of a rabbit metatarsal is shown. The secondary ossification center is shown centrally at the top. EC, epiphyseal cartilage; P, physeal cartilage. The two closed white arrows mark the perichondrial ossification groove of Ranvier. The two open white arrows demonstrate the cortex, which is formed by the intramembranous ossification mechanism. The metaphyseal bone just below the physis is formed by the endochondral ossification mechanism as is the bone of the secondary ossification center. [Reprinted from Shapiro et al. (1977). J. Bone Joint Surg. 59A: 703-723, with permission.]

bone formation, referred to as the primary center of ossification, is at the periosteum surrounding the center of the diaphysis. The periosteum is composed of a specific structure. It has two layers: an outer fibrous layer and an inner osteogenic or cambial layer. The inner cambial layer also displays an organized cellular differentiation pattern, although it is not as structurally specific as the physis. The outermost part of the inner layer is composed of undifferentiated mesenchymal cells; these then begin to secrete and surround themselves with an osteoid matrix as they differentiate from preosteoblasts to osteoblasts. Further toward the cortex, osteoblasts line the surface of the bone to synthesize osteoid preferentially on the bone surface. When the osteoid matrix surrounds a cell completely and then becomes mineralized, that cell is referred to as an osteocyte.

F. Perichondrial Ossification Groove of Ranvier In all long and most flat bones both mechanisms of bone formation, endochondral and intramembranous, are present. They relate intimately and specifically to one another at the periphery of the growth plate in a region referred to as the perichondrial ossification groove of Ranvier (Fig. 2). The tissues comprising the intramembranous ossification mechanism circumferentially ensheathe and support the physeal cartilage at this area. A circumferential groove indenting the cartilage is present, whose deepest part is opposite the epiphyseal cartilage-physeal cartilage junction. It contains three tissue components: (1) an outer fibrous layer that is

5

continuous with the outer fibrous layer of the periosteum and inserts beyond the physeal region into the epiphyseal cartilage; (2) a zone of densely packed cells that is a continuation of the inner cambial layer of the periosteum and is present into the depths of the groove as far as the resting zone of physeal cartilage (this collection of dense cells synthesizes osteoid and intramembranous bone directly); and (3) a collection of loosely packed cells between the outermost reaches of the zone of dense cells and the fibrous tissue layer that adds chondrocytes to the periphery of the epiphysis just beyond the physis itself. The intramembranous bone synthesized by the tissues within the groove region is sometimes referred to as the bony bark of Lacroix. Frequently it is discontinuous with the cortical bone of the diaphysis and metaphysis in those areas where the metaphyseal cutback zone is extensive. The perichondrial ossification groove of Ranvier and its fibrous chondroprogenitor and osteoprogenitor cells are an integral part of the epiphyseal region (320).

II. E A R L Y S C I E N T I F I C U N D E R S T A N D I N G S

OF BONE GROWTH Clarification of the mechanisms of bone growth, representing early examples of the application of scientific method to biological phenomena, began to show definitive advances early in the eighteenth century (24, 74, 81, 88-92, 140, 169, 185,242) (Table I).

A. Hales and Belchier In 1727, Stephen Hales showed that the bones grew in length by the addition of new tissue at their ends rather than interstitially (140). He measured the leg bones of a young chicken 2 months after drilling two holes in the shaft to act as markers. The holes were no further apart although the bone itself had lengthened considerably. Bone growth studies were enhanced by John Belchier (24), a London surgeon who observed that the bones of growing pigs and fowl that had been fed on madder were colored red. The vital staining dye of the madder plant was subsequently recognized as alizarin (12). The alizarin red stain is still used today in whole mount embryo studies. Staining with methylene blue outlines cartilage structures whereas alizarin red stains the bone (322). Subsequent studies by Duhamel, Hunter, and Flourens further demonstrated that bones grow in length by continuous increments at the ends.

B. Nesbitt The formation of bone by the two now familiar endochondral and intramembranous mechanisms was noted early. Robert Nesbitt (1736) is recognized as being the first to describe the two methods of ossification in human fetal bone, one occurring directly in a membrane and the other occur-

CHAPTER 1 ~ Developmental Bone Bioloyy TABLE I .

1727 1731-1736

1736 1739-1743

1740 1815

1841-1847

1850 1852-1853

1858 1860

1864

.

Early O b s e r v a t i o n s on Bone G r o w t h .

.

.

Bones grow in length by the addition of new tissue at their ends (Hales). There are two mechanisms of bone formation, one occurring directly in a membrane (intramembranous ossification) and one via preexisting cartilage (endochondral ossification). Vascularization immediately precedes bone formation in cartilage (Nesbitt). Growing bone is stained red by madder (alizarin) in diet (Belchier). A long bone grows in length from its ends and in thickness by formation of new bone on its outer surface. The osteogenic function of the periosteum thickens the bone on its outer surface, based on madder feeding studies (Duhamel). Increased diameter of marrow cavity with growth is due to absorption of preexisting bone internally. Bone development includes both bone deposition and bone absorption (Hunter). Interplay of cartilage and bone formation in long bone development. Cartilage vascular canals in epiphyses. Gross and crudely magnified evidence of physeal cartilage. Vascularization of inner periosteum precedes earliest site of bone formation. Cartilage model determines the shape of the future bone and establishes ossification within it. Mechanical pressure variously modified is the principal agent in effecting progressive changes of structure in growing bone (Howship). Bone is formed in the periosteum, grows in thickness by superimposing new layers externally, grows in length by adding new layers at the growth cartilage at each end, and has the marrow cavity formed by resorption of the inner bone layers. There is formationresorption-reformation of the bone with growth accompanied by constant change in bone substance (Flourens). Resorption of bone as part of developmental sequence is mediated by osteoclasts (Kolliker). Tissue at epiphyseal-diaphyseal (metaphyseal) junction is characterized by differing layers as determined by careful gross and early lower power microscopic examination (Broca; Tomes and de Morgan). Detailed microscopic-histologic structural recognition of physeal layers and endochondral sequence (MUller). Bone description as a tissue (bone cells plus calcified matrix) and as an organ (encompassing bone tissue, marrow, periosteum, articular and epiphyseal cartilage, vessels, and nerves). Detailed cellular description of physeal sequence including hypertrophic chondrocyte fate (Virchow). Bone forming cells first referred to as osteoblasts (Gegenbaur).

fjring via preexisting cartilage (81,242). In his book Human Osteogeny, published in 1736, and based on lectures he gave in 1731 he indicated that he would "show the ancient and common notion of all bones being originally cartilaginous to be a vulgar error." He went on to indicate that there were two methods, or species in his terminology, of ossification. "The bony particles in the fetuses begin to be deposited or to shoot either between membranes or within cartilages." Nesbitt clearly noted that "the periosteum is a delicate fine and strong membrane which is spread on and covers not only all the bones in general but is also continued over the cartilages that have any connection with them; where from its situation it acquires the name of perichondrium." By formation of bone and membrane, therefore, he clearly was referring to periosteal new bone formation. He also recognized both the inner and outer layers, or strata as he referred to them, of the periosteum. Although bone formation from preexisting cartilage models had previously been appreciated, Nesbitt also showed that "some bones begin and continue to increase until they arrive at maturity without the least appearance of cartilage in or around them." The first

species of ossification, therefore, was intramembranous bone. "The texture of that species of ossification which is produced between membranes by a careful and proper examination may be seen to be of small particles so conjoined together as to form fine bony threads or fibres which are disposed differently according to the particular formation of each bone and its several parts. This is most visible in thin and broad bones, especially in some of those which form the cranium." He noted that "you may observe the bony particles to be gradually multiplied and so conjoined in contact as to produce the appearance of small fine bony threads or fibres which then appear a little like radii shooting from a centre." With time there was an increase in the number of bony fibers that became "pressed so close together to form a single lamina or plate of bone." Membrane bone was that type formed in the cranium and it was also seen in cylindrical bones. He defined well the periosteal intramembranous bone sequence by noting that "their ossifications begin while the circumference of the part is not larger than a small pin in the form of a broad flat ring which surrounds the internal periosteum and is surrounded by the external. As these tings

SECTION II 9 Early Scientific Understandings o f Bone G r o w t h

increase in breadth their fibres shoot toward both extremities of the part, not always in straight lines, but according to the particular figure the bone is designed by nature to be." He was aware that "the other species of ossification which first appears within a cartilage begins late." Bone formation occurred in close association with blood vessels. He described formation of the secondary ossification centers and noted that vascularization immediately preceded bone formation in the epiphyseal cartilage. "The first small corpuscles of bone which become visible are always in that part of the cartilage which has the greatest quantity of red fluid appearing in it and they are not always placed close together but often at small distances from each other." In a large series of accompanying diagrams Nesbitt indicated that "there are often 3 or more very considerable vessels going to and penetrating the ossifications" and commented that "near the ossification you will rarely miss feeling by the point of a knife bony particles." In a series of drawings of the formation of the secondary ossification center of the distal femur, he notes in one early section that vessels only are seen in the cartilage, and in others as ossification increases centrally various additional vessels appear. Thus, even before the development of the cell theory there were clear descriptions involving the transformation of cartilage to bone and the close relationship of vascularization to bone formation.

C. Duhamel Henri-Louis Duhamel of France demonstrated in papers published from 1739 to 1743 that madder colored only those parts of the skeleton that were being formed at the time of its administration (88-92). When madder feeding was suspended for several weeks before sacrifice, the bone at the extreme ends of the shafts of long bones was uncolored as was that of the most peripheral cortical bone surrounding the midshaft region. By varying the time of madder feeding, he inferred that a long bone grew in length from its ends and in thickness by the progressive development of new bone on its outer surface. The discovery of the osteogenic function of periosteum is credited to Duhamel on the basis of his interpretation of madder feeding and subsequent patterns of bone staining. Duhamel also found that bone grew in length at its extremities by drilling two holes at a measured distance in the shaft of a growing bone, filling them with metal plugs, and finding no difference in their position with time. He was unable to explain the increasing width of the marrow cavity with growth.

D. Hunter The biological cause of the increased diameter of the marrow cavity with growth was first understood in detail by John Hunter, who from 1740 onward recognized both the growth of bone in length at its ends and the deposition of new bone by the periosteum on the outer surface of the shaft, as well

7

as the absorption of preexisting bone that must occur within the marrow cavity and on the external surface of the expanded metaphyses (169). He referred to this phenomenon as "modeling absorption" and clearly expressed the dynamic component of bone formation. Hunter used madder staining and diaphyseal hole drilling approaches to assess subsequent growth in pigs and fowls. He also discussed the modeling of the head and neck of the femur. His work was the first to clearly recognize that absorption of bone was as essential to overall bone growth as deposition of bone.

E. Howship Howship demonstrated the interplay of cartilage formation and bone formation in human and animal embryos on the basis of studies with a solar compound microscope (165). His text and illustrations presented in 1815 defined the embryonic 8-week human hand, showing the primary ossification "rings of bone" of the metacarpals and phalanges. He identified cartilage canals in the epiphyseal ends of the bones and was able to oudine the laminar structure of cortical and trabecular bone tissue. In a remarkable tissue section of the distal femur of a newborn child, the epiphyseal-metaphyseal junction was magnified. The edge of the newly formed bone, by which he refers to the metaphyseal region, "exhibited an appearance of small short pointed villi shooting forward from the surface of the bone into the substance of the cartilage." He noted that "all sections exhibited an apparent alteration in the texture of the cartilage upon the surface connected with the bone. In many instances the cartilage seemed to be more opaque here than elsewhere, this slight opacity forming a line equal to 120th of an inch in breadth." The latter refers to the physeal cartilage, which indeed can be distinguished from the adjacent epiphyseal cartilage at low powers of magnification. Howship further studied the cartilage-bone junction in a distal femur from a 3-week-old child, preparing the tissue for examination by maceration, cleaning, and a form of decalcification. He examined the bone from the diaphyseal region toward the growth region. "It was observed that in proceeding from the middle of the cylindrical bones, where the medullary spaces are larger and the cancellated structure stronger towards the more recendy formed extremities of the bone, the ossific masses become more numerous, of a lighter substance, and a thinner texture; the same gradation being continued up to the margin of the newly ossified surface, where the structure is most curiously wrought, and so exquisitely fine as scarcely to admit a description." His description clearly relates to the changes at the lower end of the physis and the farthest reaches of the adjacent metaphysis. "It was ascertained that the first and earliest state in which the particles of ossific matter become apparent, after they have formed a mass by their cohesion, may be considered as an assemblage of the finest and thinnest fibers, molded into the form of short tubes, arranged nearly parallel to each other, and opening externally upon the surface connected

CHAPTER 1 9 Developmental Bone Biology with the cartilage. These tubes appeared to correspond in number to the villi noticed in the last examination." Similar studies were also performed in animals. Howship clearly defined cartilaginous canals within the cartilage tissue at the ends of the bone. He noted that the principle of bone formation involving the appearance of the cartilage and ossifying bones "was in every respect precisely similar" in many species and that "the same purpose of ossification is accomplished by one and the same means." Howship concluded that the first rudiments of ossification in the long bones were associated with vascularization and occurred "upon the internal surface of the periosteum, which produced a portion of a hollow cylinder; this form of bone having been found antecedent to the evolution of any cartilaginous structure." Howship mentioned the importance of circulation both for cellular growth and for providing the means of calcification. He noted the value of the cartilaginous mode of bone formation, indicating that "at a certain stage of the process the mode of operating is changed in order that it may proceed more expeditiously. A cartilage is formed, which, by the nature of its organization, and by admitting of a specific provision of cavities and canals lined with vascular membranes, which secrete an abundant store of gelatinous matter, is adapted to this particular purpose; while at the same time it serves to determine the future figure of the extremity of the bone by establishing and conducting the ossification within its own substance." He indicated that "from the period when the ossification proceeds in the mode above described by the medium of cartilage the process is continued in the same uniform manner until it has completed the growth of the bone. The growth of the epiphyses at the ends of the bone are also effected by the same means." He also noted the simultaneous formation of bone peripherally in cylindrical bones being "deposited primarily in the form of fine thin tubular plates: a mode of deposition of all others the most favorable for their being subsequently remodeled and for facilitating all the subsequent changes of structure they are destined to undergo." He commented on the mechanical aspects of bone development, noting that "the principal agent in extending the cylinder and in effecting the subsequent progressive changes of structure which in a growing bone are continually taking place appears to be simply the mechanical pressure exerted by the fluid secretions within the medullary cavities of bone, this power operating successively in different directions according to the particular determination given by the circulation." "The particular simplicity observable in the mode of production of the bones of the skull affords a strong argument in favor of the opinion that pressure variously modified constitutes one of the most efficient instruments in the hand of nature."

F. Flourens Flourens also emphasized that longitudinal growth of the long bone took place at the ends (Fig. 3A). He outlined six major principles of bone growth based on extensive refer-

ence to the work of Duhamel as well as his own experiments, which repeated and augmented Duhamel's work (106-110). His six principles of bone formation follow: (1) bone is formed in the periosteum; (2) bone grows in thickness by superimposing new layers externally; (3) bone grows in length by adding layers at each end; (4) the medullary cavity grows by resorption of the inner layers of bone; (5) the ends of the bone are first formed, then resorbed, and then reformed as the bone grows; and (6) bone development is accompanied by a constant change in the bony substance with the gaining of new molecules and loss of older molecules. Oilier also demonstrated the principle of long bone longitudinal growth from either end (Fig. 3B) (258).

III. EMBRYOLOGY OF THE LIMBS A. Timing and Staging of Human Limb Development The limb buds form as outpouchings of the embryo lateral plate mesoderm mass and are composed initially of undifferentiated mesenchymal cells uniformly packed throughout the entire extent of each bud and continuous with the undifferentiated mesenchyme of those regions that will become the shoulder and pelvis. There is a craniocaudal differential time gradient in development, with the upper limb buds appearing in the lower cervical region in the human on day 24 and the lower limb buds in the lower lumbar region on day 28. By 33 days the hand plate is seen, and by the end of week 6 all upper and lower limb segments can be seen. Digital rays appear in the upper limb during week 6 and in the lower limb during week 7. By the end of week 8 components of each of the upper and lower limb bones are formed in cartilage. The embryonic period comprises the first 8 postovulatory weeks, with limb morphogenesis in the human occurring between weeks 4 and 8. At 8 weeks ossification of the humeral diaphysis begins, a time at which embryonic development is arbitrarily considered to be over and fetal development, which involves the growth of fully established models, begins (102, 210, 261-264). Embryonic staging terminology follows. The human embryonic phase is divided into 23 stages using the Carnegie system. This system, adopted in the early 1970s, is a refinement of what were previously referred to as Streeter's horizons. Much human embryologic and fetal study is categorized on the basis of the crown-rump length expressed in millimeters. The Carnegie staging system incorporates 23 stages and relates them to crown-rump length and age in postovulatory days. It is printed in Table IIA, listing some general correlations in the human embryonic periods along with developmental features particularly related to limb development. A more detailed outline of human limb development is listed in Table liB. O'Rahilly (264) makes several points in terms of previous descriptions referable to embryonic staging in the human. These include the following: (1) The term horizon used by

SECTION III ~ Embryology o f the Limbs

9

FIGURE 3 Earlyexperimental illustrations showing that long bones grow in length from their ends. (A) This reproduction of an illustration from Flourens (109) depicts studies showing long bone growth followinginsertion of two metal pins in the diaphysealregion and one in each epiphysis of the rabbit tibia. The distance between diaphyseal pins two and three always remains the same, whereasthe distance between epiphyseal-diaphysealpins one and two (proximal) and three and four (distal) progressivelyincreases with time. The upper and lower sets initially are equidistant at slightly over 6 mm in this magnification, but in Figure 5 the distance is 20 mm above and 16 mm below, indicating not only that growth in length has occurred but also that proximal growth activity is slightly greater than distal. These studies, along with those done earlier by Hales, Duhamel, and Hunter, led to the realization that bone grows in length by the addition of tissue at either end rather than interstitially. As the bone grows in length, the distance between the two diaphyseal pins remains the same, but the distance between the diaphyseal pins and those in the epiphyses continually increases. (B) An illustration from Oilier (258) demonstratesthe same principle: the two diaphyseal pins remain the same distance apart even though extremegrowth in length of the rabbit tibia has occurred.

Streeter is no longer used and has been replaced by the term stage. (2) Roman numerals from the old Streeter classification have been replaced by Arabic numerals to denote what are now referred to as the Carnegie stages. (3) The most useful single measurement of an embryo or a fetus is the crown-rump (C-R) length, which is expressed in millimeters. (4) The c r o w n - r u m p lengths used by embryologists agree closely with those determined ultrasonically. (5) The length of an embryo is not a stage and when used in a descriptive mode should simply be reported as, for example, 15 mm. (6) Stages within the embryonic period are expressed as postovulatory weeks or days. (7) Ages previously described by Streeter are incorrect for the human. Finally, (8) the 23 stages of the Carnegie system refer to the embryonic period only, that is, the first 8 postovulatory weeks; no widely accepted staging system has been devised for the fetal period.

B. Outline of Embryonic Development of Long Bones Mesenchymal condensation has outlined the scapula and humerus of the upper limb and the pelvis and femur of the

lower limb by the end of week 5. By early in week 6 the developing models of the more distal limb bones are seen and chondrification has begun in humerus, ulna, and radius. By late in week 6 carpal and metacarpal chondrification has begun; by the middle of week 6 the femur, tibia, and fibula chondrify, with tarsals and metatarsals following by late week 6. By the end of week 7 all upper extremity bones are chondrifying as are all bones of the lower extremity except the distal phalanges, which do so in week 8. The appearance of the diaphyseal primary ossification centers also follows a regular sequence: clavicle, early week 7, followed by humerus, radius, and ulna; femur and tibia, week 8; scapula and ilium, week 9; ischium, week 15; calcaneus, week 16; and pubis, week 20. The developing model of each long bone is preformed in cartilage (102, 120, 131). The undifferentiated mesenchymal cells, which have undergone condensation and started to outline specific bone shapes, then differentiate, surround themselves with a cartilaginous matrix, and take on the conformation of round chondrocytes. Use of histochemical stains such as Safranin O-fast green shows the pinkish development of the matrix, indicating the presence

CHAPTER 1 9 Developmental Bone Biology

10

TABLE IIA Correlation of Timing Systems Used for Human Embryos (Weeks I-8)" Week

5

Day

Length (mm)

Carnegie stage

1 1.5-3 4 5-6 7-12

0.1-0.15 0.1-0.2 0.1-0.2 0.1-0.2 0.1-0.2

1 2 3 4 5

13 16 18

0.2 0.4 1-1.5

6 7 8

20

1.5-2.5

9

22

2-3.5

10

24

2.5-4.5

11

26

3-5

12

28

4-6

13

32

5-7

14

33

7-9

15

37

8-11

16

41

11-14

17

44

13-17

18

47

16-18

19

50 52

18-22 22-24

20 21

54

23-28

22

56

27-31

23

Features Fertilization First cleavage divisions (2-16 cells) Blastocyst free in uterus Blastocyst hatches, begins implanting Blastocyst fully implanted Primary stem villi appear; primitive streak develops Notochordal process forms; gastrulation commences Neural plate and neural folds appear; primitive pit forms; vasculature begins to develop in embryonic disk Caudal eminence and first somites form; neuromeres appear in presumptive brain vesicle; primitive heart tube forming Neural folds begin to fuse; cranial end of embryo undergoes rapid flexion; myocardium forms and heart begins to pump Primordial germ cells begin to migrate from wall of yolk sac; cranial neuropore closes; optic sulci form Upper limb buds appear; caudal neuropore closes; urorectal septum begins to form; pharyngeal arches 3 and 4 form Dorsal and ventral columns begin to differentiate in mantle layer of spinal cord and brain stem; lower limb buds appear; septum primum and muscular ventricular septum begin to form in heart Spinal nerves begin to sprout; semilunar valves begin to form in heart; metanephros begins to develop; lens pit invaginates into optic cup; cerebral hemispheres become visible Hand plate develops; arterioventricular valves and definitive pericardial cavity begin to form; lens vesicle forms and invagination of nasal pit creates medial and lateral nasal processes Foot plate forms on lower limb bud; major calyces of kidney begin to form and kidneys begin to ascend; genital ridges appear Finger rays are distinct; bronchopulmonary segment primordia appear; septum intermedium of heart is complete; cerebellum begins to form Skeletal ossification begins; elbows and toe rays appear; intermaxillary process and eyelids form on face Trunk elongates and straightens; pericardioperitoneal canals close; septum primum fuses with septum intermedium in heart; minor calyces of kidneys are forming Upper limbs bend at elbows Hands and feet approach each other at the midline Eyelids and auricles are more developed Definitive superior vena cava and major branches of the aortic arch established; gut tube lumen almost completely recanalized

aDerived from Larsen (210) and O'Rahilly (264).

of glycosaminoglycans (300). When the cartilage model of each of the long bones has been formed, the region in which the joint eventually will be present is still filled with cells and is referred to as the interzone area. Early shaping of the epiphyseal ends of the bone occurs prior to necrosis and

resorption of cells in the interzone area. When the latter occur, the joint cavity is formed and the complete model of the developing bone and joint has been formed. The cartilage model of the developing bone then increases in size by both interstitial and appositional growth of the chondrocytes. At

SECTION III 9 Embryology o f the Limbs

TABLE liB

11

Stages a t Which D e v e l o p m e n t a i F e a t u r e s Appear and Events O c c u r in Human Limbs a Feature

Stage for upper limb

Stage for lower limb

Limb bud Length: width = 1.1 Apical ectodermal ridge Hand plate-foot plate Mesenchymal skeleton Mesenchymal scapula-hip Mesenchymal humerus, radius, ulna-femur, tibia, fibula Chondrifying humerus-femur Chondrifying radius-tibia Chondrifying ulna-fibula Finger rays-toe rays Chondrifying metacarpus-metatarsus Chondrifying carpus (except pisiform) tarsus Chondrifying scapula-hip Chondrifying proximal phalanges Homogeneous shoulder and elbow-hip and knee Homogeneous wrist-ankle Three-layered elbow-knee Chondrifying middle phalanges Chondrifying distal phalanges Three-layered wrist-ankle Ossifying humerus and radius-femur and tibia Ossifying ulna-fibula Cavitation in shoulder and elbow-hip and knee Cavitation in wrist-ankle

12 14 14-17 15 15 16 16 16-17 17 17-18 17-18 17-18 18-19 18 18-19 19 ? ? 19-20 20-21 21 21-23 22-23 23 23

13 15 15-18 16 16 15-18 17 17-18 17-18 17-18 18 18-19 18-19 19 19-21 19 21 21 21 21-23 23 22-23 23 23 ?

aDerived from R. O'Rahilly and E. Gardner (263).

a certain stage of development, the primary center of ossification forms. There is some confusion in the literature as to the exact meaning of this term. It generally refers to the circumferential mid-diaphyseal rim of periosteum, which synthesizes the initial bone of the cortex using the intramembranous mechanism without the mediation of a cartilage phase. It can also refer to mid-diaphyseal endochondral ossification within the cartilage model. The initial site of endochondral bone formation is mid-diaphyseal although it appears to occur slightly after the initial periosteal cortical bone formation. Contemporaneous with the periosteal new bone formation is hypertrophy of cells in the mid-diaphyseal region of the cartilage model, calcification of the cartilage matrix, and vascular invasion of the hypertrophic cell lacunae accompanied by undifferentiated preosteoblast cells that then synthesize bone on the scaffold of the calcified cartilage matrix. The vascular invasion occurs in the areas of hypertrophic cells and serves to remove these and replace them

with marrow cells and newly synthesized bone. The zone of hypertrophic cells or ossification front is then extended toward either end of the long bone. The central replacement of hypertrophic chondrocytes with deposition of bone on the calcified cartilage cores encompasses what is referred as the endochondral mechanism. In the periosteal region intramembranous bone formation extends the periosteal new bone sleeve. The periosteal development always is spatially somewhat more advanced toward either end of the bone than the central endochondral development. As this developmental sequence works its way toward either end of the bone, the cartilage forms itself into a specifically structured region referred to as the epiphyseal growth plate. This is characterized by specific conformations of the chondrocytes and serves as a functionally specialized region responsible for longitudinal growth. This pattern of long bone development encompassing both endochondral and intramembranous mechanisms is illustrated in Fig. 4A-4E.

12

CHAPTER I 9

Developmental Bone Biology

F I G U R E 4 The five diagrams (A-E) illustrate the cell and tissue changes in long bone formation. [Derived from references 83, 188, 215, 234, 266, 326.] (A) The cartilage model of the developing bone is shown at left. A and B represent cross-sectional cuts of the developing bone with the tissue pattern illustrated below. In the diagram at far left, the tissue representations are the same because the

SECTION IV 9 Bone Development at the Light Microscopic Level

IV. B O N E D E V E L O P M E N T AT T H E L I G H T MICROSCOPIC LEVEL FOLLOWING DELINEATION OF THE CELL THEORY AND A D V A N C E S IN M I C R O S C O P Y AND H I S T O C H E M I S T R Y Although early studies clearly established that growth in long bones occurs by means of the cartilages at either end, progress was slower in elucidating the structure of the growth cartilage itself. With the development and widespread acceptance of the cell theory dating from 1838, combined with advances in microscopy techniques, the structure and function of the growth apparatus became clearer. Kolliker (1850) illustrated the sequential findings in growth of a long bone from embryonic to mature phases showing the upward and outward deposition of tissue and the need for both cell deposition and cell resorption during the process (193, 194). He initially identified and described the functions of the osteoclast as the cell responsible for tissue resorption. Gross examination of a neatly cut longitudinal section of a developing bone showed tissue and vascular differences between the epiphyseal cartilage area and the metaphyseal-diaphyseal regions that had been appreciated long before the era of microscopy. Broca defined these regions structurally on the basis of both gross inspection and the early use of histologic sections,

13

which enabled him to study the phenomenon down to the cellular level (37, 38). He was able to observe five layers at the physeal and periphyseal regions. The first was the "couches cartilaginous;" the second was a bluish region of the epiphyseal cartilage referred to as the "couches chondroid," which corresponded at the histological level to the columnar cell region or the "cartilage series." The third, toward the diaphysis, was called the "couches chondrospongioid" because it had gross appearing characteristics both of the chondroid layer above and the spongioid below. The fourth with a yellowish tinge was referred to as the "couches spongioid," which in histologic terminology represented the hypertrophic cell zone including the area of calcified cartilage, and the fifth was referred to as the "tissue spongieux," which represented the metaphyseal bone and was red in appearance. Tomes and deMorgan also described and illustrated the growth plate sequence (348). The earliest detailed descriptions of epiphyseal cartilage development and the growth plate mechanism that reached a coherent understanding at the light microscopic level were provided by Heinrich Mueller in 1858 (237). His illustrations of the growth plate apparatus depicted the cell structure of the epiphyseal growth plate and the epiphyseal-metaphyseal junction in great detail and in a way fully consistent with observations made today (Fig. 5). He clearly illustrated the palisading or proliferating cell zone of the growth plate and

F I G U R E 4 (continued) entire model of the bone is still in a cartilage phase. In the central illustrations, chondrocyte hypertrophy and matrix calcification are shown in the central or diaphyseal region. Chondrocyte hypertrophy starts as a central nidus both in the middle part of the shaft when considered in a longitudinal orientation and in the central part deep within the cartilage when considered in the transverse orientation. This eventually will pass from one edge of the shaft to the other as is shown in the transverse section A below. At far right, the intramembranous bone formation from the periosteum has begun surrounding the endochondral bone formation centrally. The two mechanisms of bone formation are illustrated most clearly in the transverse cut section A as seen at bottom. The initial formation of endochondral bone within and intramembranous periosteal bone at the periphery occurs at approximately the same time. This initial area of bone formation is referred to as the primary center of ossification. The periosteal site of bone formation appears to precede the endochondral by a very short time interval. In a strictly technical sense, that region that formed first would be the primary center of ossification. This would have biological significance, but in a practical sense both mechanisms can be referred to as the primary center. An accurate observation, however, and one made by most observers, is that the intramembranous or periosteal new bone formation is present spatially somewhat in advance of that occurring within the endochondral sequence centrally, as bone formation passes from the primary center of ossification toward either end of the bone. This is a relationship that is maintained even in relation to formation of the physis and the perichondrial ossification groove of Ranvier. (B) Events surrounding the primary ossification center formation are detailed. Once the cartilage within the midpart of the shaft has hypertrophied and its matrix has calcified, vascular invasion occurs from the periphery along with undifferentiated mesenchymal cells, which shortly lay down bone on the calcified cartilage cores. Endochondral bone formation is underway. Intramembranous bone formation at the periphery occurs directly without the mediation of a cartilage phase. Note also that the intramembranous bone is spatially in advance of the more central endochondral bone. There are no vessels within the developing diaphyseal cartilage prior to its hypertrophy and matrix calcification. It is only when hypertrophy has occurred that vascular invasion from the adjacent perichondrium-periosteum occurs. Thus, no cartilage canals are present in the diaphysis and metaphysis analogous to those seen later in the epiphysis. (C) Bone formation advances toward either end of the developing bone with a characteristic physeal orientation of the cartilage and endochondral sequence occurring. The physeal orientation is represented here by the slanted lines. The solid region below represents the calcified cartilage of the lower part of the hypertrophic zone and the persisting cartilage cores in the metaphysis. Note also the advance of the intramembranous bone formation and its slightly greater peripheral extent than that of the endochondral bone within. (D) Formation of the secondary ossification center above is shown. The endochondral sequence has moved the physes relatively closer to either end of the bone. The secondary ossification center has formed above, whereas at the lower end it has not begun to form. This is a characteristic feature of long bones in which one center, which can be at either end, forms before the other. Vessels passing from the periphery are present within the epiphyseal cartilage in cartilage canals for many weeks and sometimes for many months before formation of the secondary ossification center. This feature is not characteristic of the endochondral mechanism at the primary center of ossification. (E) The secondary ossification center is now seen at the lower end of the developing bone where the physis (oblique lines) is still open. At the other end, the physis has been closed completely and resorbed and there is continuity between metaphyseal and epiphyseal bone. The growth on the undersurface of the articular cartilage has also terminated and the innermost zone of articular cartilage is now calcified.

14

CHAPTER

1

~

Developmental Bone Biology

FIGURE 5 This histologic illustration of the growth plate from Mueller's 1858 article (237) shows his accurate depiction of the specific structures.

its transformation over a few cells to the hypertrophic zone. The calcified cartilage matrix of the hypertrophic cell region was identified, as was the invasion from below by vessels and bone forming cells, the deposition of new bone on the cartilage cores, the presence of osteocytes adjacent to the new region of bone formation, and the diaphyseal (metaphyseal) marrow. Mueller provided a series of illustrations of transverse cuts through the growth plate region of a human embryo 3 months of age. The first cut passed through the upper layer of small cartilage cells of the physis; the second through the region bordering the calcified cartilage where the cartilage cell cavities were somewhat larger, the third through calcified cartilage with large chondrocyte cavities (the hypertrophic zone); and the fourth through a zone characterized by central cores of cartilage trabeculae, surrounding

bone, and cellular marrow. Mueller recognized the structural changes at both the cell and matrix levels in the physeal regions. In his illustration of the outer reaches of the diaphysis, he showed both vessels and red cells. He concluded from his structural observations that elements of the marrow could be regarded as derivatives of young generations of cartilage cells that could transform themselves into bone cells. Mueller was described by Retterer (292) as showing "no doubt on this point: the elements or cells of the bone marrow and even the bone cells (osteoblasts) are derived from cartilage cells." He felt that the cell division was so rapid that it was impossible to observe. On the other hand many cartilage cells died by being included in the calcified matrix. His work stood as the standard for explaining and illustrating growth plate morphology over several decades in the latter part of the nineteenth century. Kolliker reproduced the drawings of Mueller accepting the transformation of cartilage cells into bone cells. Much later, in 1889, he utilized the same drawings but admitted the decline or decay of the cartilage cells and the budding of the perichondrial tissues, providing a source of new cells (194). u (1860) made the important distinction between bone as a tissue, which he defined as the bone corpuscles or cells plus the calcified intercellular substance, and bone as an organ, which encompassed not only the osseous tissue but also the medullary marrow tissue, the periosteum, articular cartilage, and all vessels and nerves (356). It would also encompass the epiphyseal cartilage in a growing child. Long bones grew in length from cartilage and in thickness from periosteum. He described the endochondral sequence in excellent detail. In reference to the cartilage cells he observed that "the greater the number of cells which undergo this change, the larger the cartilage will become and the height to which any one of us attains essentially depends upon the extent to which growth occurs in the individual groups of cartilage cells." Virchow felt that the enlarged cartilage cells (of the hypertrophic region) "may be converted by a direct transformation into marrow-cells and continue as such; or they may first be converted into osseous and then into medullary tissue; or lastly, they may first be converted into marrow and then into bone." He was aware of the calcification of cartilage in the endochondral mechanism, indicating that "what first takes place in the course of these processes is not the production of real osseous tissue, but only the deposition of calcareous salts . . . . There first of all takes place in the immediate vicinity of the border of the bone a calcification of the cartilage which gradually a d v a n c e s . . , so that every individual cartilage cell is surrounded by a ring of calcareous substance. This is not yet bone, it is nothing more than calcified cartilage . . . . " Bone tissue can arise out of marrow cells or directly from cartilage cells. Virchow indicated that "it is no doubt true that in the case of the normal growth in length of bone, most of the bonecorpuscles do not directly proceed from cartilage-corpuscles, but are immediately derived from marrow-cells.., but it is

SECTION IV 9 Bone Development at the Light Microscopic Level just as true that cartilage-cells can also be transformed straightway into bone-corpuscles." He felt that the isolated transformation of single cartilage cells into bone corpuscles was an accurate observation and also of great importance to the cell theory in general. This direct transformation was not associated, therefore, with death of the cartilage cell and its subsequent replacement. At that time, a cartilage corpuscle was considered to be composed of the cartilage cell and a surrounding membrane that was an integral part of it, whereas a bone corpuscle referred only to a bone cell with the lacunar or canalicular wall representing the endpoint of the adjacent matrix. He pointed out that the direct conversion of cartilage into osteoid tissue was clearly evident at points of transition from cartilage to bone where the boundaries of the different forms of tissue are "completely obliterated and all sorts of transitions between round (cartilaginous) and jagged (osteoid) cells are seen." Gegenbaur (1864) was a morphologist whose studies primarily involved comparative anatomy, but they did involve embryologic and histologic analyses. In studies on the development of primary and secondary bone he indicated that the tissue eventually formed was the same even though the site of bone formation and the tissue replaced differed. In his early works he defined the cell most closely involved in bone formation as the osteoblast (123) Oilier (1867) wrote a classic treatise on bone development and regeneration (258). This extensive experimental work defined the role of the periosteum in bone formation. He also demonstrated that bone irritation increased the rate of growth at the epiphyseal lines and that damage to the epiphyseal lines inhibited growth. He was the first to study the variable amounts of bone growth at the proximal and distal epiphyses, which we will summarize later. He also repeated the experiments of Duhamel and Flourens, showing that growth in length took place only at the epiphyseal lines (256-258). A brief review of the major landmarks in bone growth research is presented in Table I. Growth plate structure and development were further described beginning in the late nineteenth century with particularly excellent presentations by Waldeyer (362), Schafer (309), and Bidder (29). It was some time after the work Nesbitt published in 1736 before the two modes of bone formation, intramembranous and endochondral, were more widely appreciated. Kolliker wrote on the morphological significance of membrane and cartilage bone. Russell (303) noted that Reichert (1849) and Mueller (1858) (237) had pointed out that there was essentially no difference in the eventual histologic structure of bone whether it had been formed initially in cartilage or in membrane, a view still held today. Retterer (1900) described the development of bone by the endochondral mechanism in a detailed article entitled "The Development of the Transitional Cartilage" (292). His work on the histogenesis of the cartilage referred in detail to works of investigators throughout the previous century. The

15

various developmental phases from the embryonic limb bud onward were defined. Growth of the cartilage model was accomplished by both interstitial and appositional mechanisms in which the perichondrium contributed to the growth in width of the cartilage. He provided detailed descriptions and illustrations of the cells and matrix of the hyaline cartilage models long before bony ossification began. The matrix, at that time referred to as the "fundamental substance," was clearly recognized to have many components, among them connective tissue fibrils called collagens, which were very fine in nature and immersed in a matrix with acidlike chondroitin, also referred to as chondromucoid. The nature of the cells and matrix was assessed on the basis of light microscopic histologic preparations. Virchow is credited with being the first to describe the cartilage cell in hyaline cartilage, which was formed of a central nucleus, a surrounding cell body, and a capsule. Retterer concluded that the cartilage hyaline or fetal cell was composed of a large nucleus and a cell body with many organelles leading to a perinuclear granular chromophilic appearance, whereas the cell periphery had reticular fibrils. The capsule was felt to be a continuation of the peripheral protoplasm. The question of transport mechanisms for nutrition within cartilage was raised. It was evident that a diffusion process was available with evidence from many experiments showing that it occurred by diffusion from the synovial cavity (as we accept today), whereas others implied that it passed from cell to cell along cell processes. Retterer assessed the epiphyseal growth plate and the transformation of cartilage to bone with emphasis on the epiphyseal region and the diaphysis (by which we would currently understand both the metaphyseal and diaphyseal regions). A major concern at that time was what became of the cartilage cells at the lower part of the growth plate, with the question being raised as to whether they atrophied and died or whether they survived and were transformed to other cellular elements. This question has not been completely answered almost 100 years later, with more recent work on the hypertrophic cell pointing to its continuing functional role in some instances. Retterer outlined the cartilage transformation during the early stages of endochondral ossification. He demonstrated the cartilage model of the developing bone, the flattening of chondrocytes in the transverse plane at the early regions of physeal differentiation, and the swollen central cartilage cells that were much larger than other cells. He gave this region the name of hypertrophic cartilage ("cartilage hypertrophic"). It was in this zone that the calcium salts were deposited in the matrix, leading to the term calcified cartilage. A four-zone region of cartilage cell transformation was recognized. In the first zone the flattened cells of the cartilage were referred to as "cartilage series." The characteristic of cartilage cells in this region was their flattening in the transverse plane where they were 15-20 Ixm wide and only an average of 9 Ixm thick. The flattened cells were disposed in

16

CHAPTER 1 ~

Developmental Bone Biology

groups separated by a matrix whose long axis was parallel to the long axis of the developing bone. The second zone was the hypertrophic cell zone with calcified cartilage matrix. The cartilage cells enlarge in this region, being larger than in the adjacent zones and either round or polyhedral in shape. The question was raised as to whether the modifications of the hypertrophic cells represented a progressive or regressive phenomenon or, in other words, whether the cells of this zone were preparing to ultimately evolve or perish. Some of the cells histologically appeared to be undergoing atrophy, and most observers indeed were under the impression that the cells of the hypertrophic zone were undergoing a certain death. Retterer felt, however, that if one prepared the cartilage for histologic examination in a different way and did serial sections in paraffin, one was able to obtain preparations in which the hypertrophic zone showed intact cells rather than empty cell spaces. He felt he could demonstrate intact cells with cytoplasmic elements in place, revealing results "entirely different from those announced classically." The third zone, the "cartilage hyperplasie," included the medullary space created by the entrance of blood vessels and red blood cells through the transverse septae into the lower hypertrophic cell lacunae. In the fourth zone, there were trabeculae of bone representing the upper portion of the diaphyseal "spongieuse" ossification region. Retterer thus established a four-zone region of transformation: zone 1, "cartilage serie;" zone 2, the hypertrophic calcified region; zone 3, the zone of the initial medullary space (zone hyperplasie); and zone 4, the zone of ossification. The terminology current at that time was such that the physis was generally described as being diaphyseal due to its position at the extreme extent of the diaphysis and the term metaphysis was not used. Retterer was also able to distinguish clear zonal differentiations within the physis in particular with transverse sections slightly oblique to the horizontal axis, which showed adjacent regions shading into one another. He was able to show multiple and somewhat smaller cell components invading the hypertrophic cell lacunae. Some of the cells were red blood cells associated with the vascular invasion. The hyperplastic zone was characterized by multiple cell types, which merited the name of a zone of metamorphosis, though he wisely indicated that it would be too confusing to introduce yet another term to this complex region. Some cartilage cells passed through the hypertrophic zone without degenerating and then transformed in the upper regions of the medullary zone. Some of these he felt became multinucleated. Calcium was deposited in the matrix trabeculae of the hypertrophic zone, and no cell division had been noted in the hypertrophic zone. The hypertrophic zone did not consist only of an increase in the volume of preexisting cells, but rather the cells were also involved in a formative process that created both nucleus and cytoplasm different from those of the mother cell. He thus refers to an issue that is not fully understood, even today. He goes on to describe the invasion

of the lower parts of the hypertrophic zone by vascular tissue, the development of capillaries carrying blood cells, and the resorption of transverse cartilage trabeculae. He concluded that it was the metamorphosis of the cartilage cell that represented the initial phenomenon of endochondral ossification and indicated that "the transformation of the cartilage cell led to the development of a reticular and vascular tissue analogous to that of the perichondrium; these 2 tissues are capable subsequently of elaborating bone." Retterer also described the development of bone within the epiphysis, where the cartilage was transformed centrally to begin formation of the secondary ossification center at a much later stage. He observed that "the evolution of cartilage tissue of the epiphysis is in every point analogous to that which we have studied in the diaphysis in the developing skeleton of young embryos." Vascular canals were present within the epiphyseal cartilage, but he felt that the cartilage canals formed directly within the cartilage model itself rather than being derived from the perichondrial vessels.

V. M O R E D E T A I L E D H I S T O L O G I C

STUDIES OF BONE FORMATION A. Histogenesis of Bone The histogenesis of bone was studied in detail by Stump (1925), including both the endochondral and intramembranous mechanisms (337). Certain differences from current terminology must be recognized in reading earlier work on developmental bone biology; even as late as 1925, mention is rarely made of the metaphysis and indeed the growth plate is referred to by Stump as the "diaphyseal plate." His descriptions of the developmental sequences raise several points still pertinent to our understanding. The work included the concepts of bone as a tissue growing by apposition and cartilage growing by interstitial proliferation and of the perichondrium evolving into the periosteum "concurrently with changes in the sub-adjacent mesenchyme." Stump indicated in his discussion of the cartilage growth plate that the measure of its growth depended not only on the rate of division in forming the chondrocyte groups but also on "the velocity of enlargement of the cells collectively." The enlargement of cells is primarily in reference to the hypertrophic zone. Persistence of the cartilage cell after its hypertrophy was sought but not found, and he concluded that the hypertrophic chondrocytes "persistently showed the appearance of old mature cells with all the signs of structural degeneration." Calcification of the longitudinal cartilage trabeculae of the hypertropic zone was defined as was its scaffold function. The hypertrophic cell region was invaded by vessels and undifferentiated mesenchymal cells, soon to become osteoblasts. This invasion occurred into the lower regions of the hypertrophic cell mass, with evidence that the transverse, thin, noncalcified septae were readily resorbed

SECTION V 9 More Detailed Histologic Studies o f Bone Formation

but that osteoclasts or chondroclasts were not involved in this particular phase of development. Endochondral bone was transitory in nature, "serving to increase the stability of a bone at the site of its growth. It undergoes absorption, extending the area of the medullary cavity toward the diaphyseal [which we now describe as epiphyseal] cartilage." In the epiphysis itself, cartilage and bone deposition was more a feature of growth than absorption, although replacement of all minute trabeculae to meet new tension and pressure stresses was a continuous process.

B. Chondrocyte Shape and Orientation in Epiphyseal and Physeal Cartilage; Mineralization and Vascularization in the Endochondral Sequence (Dodds) Dodds was one of the earliest to focus on specific cellular orientations within the epiphyseal growth plates (82). He was particularly interested in longitudinal row formation of chondrocytes and their gradual enlargement toward the metaphyseal region. He described the early epiphyseal cartilage structure (as distinct from the physeal structure) at either end of a long bone as the endochondral sequence worked its way from the diaphysis toward its ultimate epiphyseal position. He summarized as follows. In the cartilaginous ends [the epiphyseal regions] of young bones, before the appearance of the epiphyseal centers, the condition of the cartilage is that of a primitive type of hyaline cartilage, such as would be found elsewhere in the body, with no relation to the process of ossification. The cells are small and all very much of the same size. They have a rounded form. They are undergoing mitotic divisions which take place in all planes. Following the divisions, the pairs of daughter cells slowly migrate apart and soon come to occupy separate lacunae. For this reason, the cells of this region occur singly, except for those, here and there, which, on account of recent division, occur in pairs. The growth of the cartilage in this region is not rapid, nor is it conspicuously greater in any one direction. It is simply sufficient in amount and of a suitable nature to keep the cartilaginous ends of the bones of proportionate size and of proper shape. This is the primitive type of cartilage-cell arrangement from which the (physeal) rows are derived. It might also be remarked, in passing, that in this region the cartilage also receives increments from the mesenchyme which underlies the perichondrium, as well as from the interstitial growth just described. Dodds describes the development of the epiphyseal growth plate cartilage region, the cytologically and functionally specialized area of the epiphysis. He defines differentiating features from the primitive (epiphyseal)cartilage described in the preceding paragraph: (1) a definite orientation of the mitotic figures; (2) the two cells resulting from each division remain close together; (3) instead of retaining the primitive rounded form, the two daughter cells become greatly flattened, assuming a discoid form; and (4) all of the pairs of flattened cells remain oriented in the same way with

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I FIGURE 6 Dodd's illustration of the genesis of row formation in the proliferating part of the cartilage growth plate from newborn dog metatarsal (82). At left (1), the mode of cell division is shown beginning with a single cell (A) at top left and progressing to a flattened chondrocyte at lower right (I). At right (2), the beginning of a row of cells by division is shown. Part (2): A, telophase; B, two daughter cells just after division; and C, the two daughter cells after flattening and final reorientation. [Reproduced from Dodds, G. S. (1930). Anat. Rec. 46:385-399, copyright 9 1930, WileyLiss, Inc., a subsidiary of John Wiley & Sons, Inc.]

their widest diameters perpendicular to the long axis of the bone. These pairs of flattened cells are the beginning of rows of chondrocytes. This area of the physis is referred to by most as the proliferating or columnar cell zone. The rows are built by the division of flat cells, which following division retain a relation "like coins in piles" (Fig. 6). The number of cells in a row is constant for most epiphyses, but different regions have different characteristic numbers. These cell divisions increase the length of the rows of cells and thus are an important, but not the only, factor in the elongation of the bone. The increase in physeal width comes by multiplication of the number of rows caused by more numerous row mother cells produced by the epiphyseal cartilage. Some would refer to this process as occurring in the germinal or resting cell zone of the physis. Cartilage matrix forms in a thin septum between the two daughter cells, with transverse partitions being much thinner than the longitudinal septae that intervene between adjacent rows. There is progressive hypertrophy of the cartilage cells. When the full number of cells in a row has been produced, the enlargement of the cells begins by generally affecting the cells in sequence, beginning at the diaphyseal ends of the rows. The growth in thickness by the physis along its longitudinal axis is greater than that in width, a disparity that tends to turn the transverse flattened cells into more discoid cells. During growth of the cells, they remain in rows such that "elongation of the cartilage which was begun by the division of the fiat cells in the rows, is continued with increased speed by the rapid enlargement of these same cells." Cells divide in the transverse plane and then rearrange in the longitudinal plane. The synthetic patterns of the chondrocytes during rapid growth of the cells in rows are recognized because there must be a consequent increase in the total length of the rows and also a corresponding increase in the length of the longitudinal trabeculae

18

CHAPTER 1 9 Developmental Bone Bioloyy

between them. These happenings represent the actual elongation of the growing bone. Dodds was one of the earliest to note that "when calcification of the cartilage matrix takes place, it affects only the longitudinal trabeculae, the transverse walls between the cells being unaffected by it. These thin, transverse, uncalcifled walls are seemingly easily destroyed by the invading marrow as are also the degenerate cartilage cells within the lacunae so that the long parallel cylindrical holes are easily produced as lining on which the first bone matrix is deposited." Formation of the primary center of ossification in each bone occurs by ossification in the central cartilage model following cell hypertrophy and vascular invasion. Dodds implies that central bone formation by the endochondral mechanism occurs "at about the time of the beginning of sub-perichondral ossification," by which he means the first evidence of deposition of periosteal intramembranous bone. Physeal structure is further summarized by Dodds in another article dealing primarily with cartilage removal by osteoclasts at the lower zone of the physis (83). Mineralization of the cartilage matrix occurs along the longitudinal septae with essentially no mineralization of the narrow or transverse septae. Invasion of the hypertrophic chondrocyte lacunae is characterized by both undifferentiated mesenchymal cells and loops of capillaries. When the lacunae have been opened by a defect in the transverse septum, the marrow cells and capillaries advance into it beside the cartilage cell and immediately adjacent to the mineralized longitudinal cartilage core. "The primitive connective tissue cells of the marrow are seen to gradually develop into osteoblasts which begin at once to deposit bone upon the persisting, longitudinal, calcified cartilage walls surrounding the cylindrical holes." The osteoclasts, which also form by a fusion of marrow cells, are not found in the advancing capillary front but are close behind it and are always applied to the persisting remains of the calcified longitudinal walls to resorb them. Osteoclasts can resorb both the bone spicules on the cartilage core or just the cartilage alone, at which time they can also be referred to as chondroclasts. The osteoclast is present only on calcified material, be it bone or calcified cartilage. A brief definition of the cells present in bone is provided.

C. Cellular Components 1. UNDIFFERENTIATED MESENCHYMAL CELLS The developing tissues of the skeleton form from undifferentiated mesenchymal cells. These are present initially in the limb buds prior to any histologic developmental differentiation. They are simply uniform appearing round to oval cells with a nucleus and cytoplasm not yet surrounded by any specific matrix. They have the potential for differentiation with the appropriate stimulus along various tissue producing lines, including becoming chondrocytes to produce cartilage, osteoblasts to produce bone, fibroblasts to produce

fibrous tissue, adipocytes to produce fat, or myoblasts to produce muscle. 2. OSTEOBLASTS Osteoblasts are active bone forming cells. They are characterized by an abundant cytoplasm filled with rough endoplasmic reticulum at the ultrastructural level. Some refer to the cell intermediate between the undifferentiated mesenchyreal cell and the osteoblast as a preosteoblast. The cells are responsible for synthesizing large amounts of collagen primarily of the type I variety, which accumulate to form the matrix of bone. We refer to two types of osteoblasts based on their topography. The mesenchymal osteoblast is surrounded completely by randomly oriented collagen fibrils and is thus responsible for the synthesis of woven bone. Surface osteoblasts line up along the surface of preexisting bone tissue and synthesize collagen fibrils along the preexisting surface in a parallel array. The surface osteoblast is thus involved in the direct synthesis of lamellar bone. As bone synthesis proceeds, the osteoblast becomes completely surrounded by matrix referred to as osteoid, and when that matrix becomes mineralized the encased cell is referred to as an osteocyte. Gene and molecular controls of osteoblast differentiation and the structural molecules synthesized by osteoblasts are reviewed in Sections IX and X. However, an osteoblast-specific transcription factor has been identified (86, 87, 195). The first osteoblast-specific transcription factor is Cbfal, one of three vertebrate homologues of the Drosophila runt and lozenge proteins. Cbfal appears to have features specific for early differentiation along the osteoblast line. Cbfal expression is initiated in the mesenchymal condensations of the developing skeleton, is strictly restricted to cells of the osteoblast lineage, and is regulated by BMP7 and vitamin D3. 3. OSTEOCYTES Osteocytes are mature bone cells. They reside in spaces referred to as lacunae, and their cell processes are connected to one another and are present in canals referred to as canaliculi. Each osteoblast and osteocyte has numerous cell processes passing from it that serve to relate to cell processes from adjacent osteoblasts and osteocytes. These cell processes link up via the gap junction mechanism. 4. CHONDROBLASTS AND CHONDROCYTES Chondroblasts and chondrocytes are cells responsible for the synthesis and maintenance of cartilage tissue. The cells surround themselves with a matrix composed primarily of type II collagen, although there are also considerable amounts of types IX, X, and XI collagen and a large array of proteoglycans. Cartilage has a high proportion of water, which composes approximately 80% by volume of its tissue mass. It is difficult to make a histologic differentiation between chondroblasts and chondrocytes because both cell types are surrounded by cartilage tissue, which unlike bone does not,

SECTION VI ~ Fate of the Hypertrophic Chondrocyte except in rare incidences, mineralize. The chondroblast or chondrocyte has an oval shape with the ultrastructure of the cytoplasmic wall having the appearance of mild scalloping. The collagen fibrils in cartilage are randomly arrayed and tend to be much thinner than those in bone, averaging 10-20 nm in diameter. 5. OSTEOCLASTS The cell type responsible for resorption of bone and cartilage tissue is the osteoclast. This is a large, multinucleated cell formed by the fusion of circulating monocytes. Thus, it is not part of the mesenchymal series but has its origin from the hematopoietic system. The same cell type can resorb cartilage or bone. If the cell is relating to cartilage exclusively then the term chondroclast can be used, although the tendency is to simply use the term osteoclast in relation to the resorption of either bone or cartilage. The osteoclast attaches itself to the underlying tissue by a characterized structural mechanism evident only by ultrastructural assessment. The cell surface has a circular region free of organelles, which is referred to as the clear zone. This serves to attach the cell in a donutlike fashion to the underlying bone and cartilage. The cell surface within the rim of the clear zone is then thrown into innumerable folds or outpouchings, forming what is referred to as the ruffled border. This mechanism serves to allow for increased secretion of lytic enzymes by the cell with the extreme increase in extent of the cell border being caused by the ruffling phenomenon. The circumferential clear zone seals the environment and allows the lytic enzymes to be present in high concentration. It is these enzymes that are responsible for resorption of the underlying mineral and then the matrix of cartilage and bone. Several factors affect osteoclast formation at differing stages of their development, including colony stimulating factor- 1 (CSF- 1 or M-CSF), interleukins-l, -6, and -11, transforming growth factor-[3, tumor necrosis factors (TNF-et, TNF-[3), vitamin D3, calcitonin, and parathyroid hormone (196). The two major molecules exclusively essential for osteoclast function, however, are macrophage colony stimulating factor (M-CSF) and the receptor for activation of nuclear factor K-B (RANK) ligand (RANKL), also known as osteoprotegerin ligand (OPGL) (196, 340). The latter is a tumor necrosis factor family molecule identified as an osteoclast differentiation factor. 6. GAP JUNCTIONS LINKING BONE CELLS Gap junctions serve as areas for direct cell-cell communication either by electrical coupling or as points of passage for small low-molecular-weight messenger molecules (325). They are intercellular channels formed by different membrane spanning proteins called connexins. Gap junctions are observed linking the cell bodies of surface osteoblasts, linking osteoblast processes passing through newly synthesized osteoid, linking osteocyte processes of adjacent cells, and on the surface of osteoblasts or of osteocytes within their lacu-

19

nae. Gap junctions are arranged in five basic shapes as defined by thin section transmission electron micrographs. These appear as linear, stacked linear, curvilinear, oval, and annular.

VI. FATE OF THE HYPERTROPHIC CHONDROCYTE AS INTERPRETED FROM LIGHT MICROSCOPIC STUDIES The fate of the hypertrophic chondrocyte is an important matter and many views have been presented, most of which continue to be debated. An important point should be made concerning the technical preparation of histologic sections of bone and cartilage for light microscopic examination. The techniques in use in the late 1800s and early 1900s in many instances allowed for the preparation of sections with better preservation of cell detail than the paraffin-embedded, hematoxylin- and eosin-stained sections that characterized much bone research of this past century. The drawings of cell and tissue appearance and improving photomicroscopy showed a degree of structural preservation supportive of some of the interpretations made. Trueta has made this point as well (349). Retterer provided a detailed assessment of previous descriptions of cartilage transformation into marrow bone in which he examined in particular the fate of the hypertrophic chondrocytes. He summed up the possibilities by which cartilage cells of the growth plate could subsequently be found in the medullary tissues of what we now refer to as the metaphysis. Many investigators of that era were comfortable describing the transformation of at least some of the hypertrophic cartilage cells into bone cells, whereas some felt that two distinct pathways were occurring: one involving cell death or one involving cell transformation in which the cartilage cell survived and underwent dedifferentiation and reemergence as a bone forming cell. Due to the current high level of interest in the fate of the hypertrophic chondrocyte, a review of previous morphologic findings and interpretations is of interest.

A. Chondrocyte Survival, Dedifferentiation, and Reemergence to a Bone Forming Cell Line Baur denied that there was any direct transformation or metaplasia of cartilage cells to bone, feeling that there was survival and proliferation of the freed cartilage cells, many of which subsequently formed cells that constituted the embryonic marrow (20). Ranvier also believed that there was no direct transformation of cartilage to bone, but rather that cartilage cells, in particular young cells, divided extensively, dissolved their capsules, and led to the formation of embryonic marrow by what appears to have been a dedifferentiation (285). Both observers felt that the medullary cells did derive directly from cells of cartilage after their surrounding capsules were dissolved. Ossification was not direct in the

20

CHAPTER I ~ Developmental Bone Biolo~ty

sense that cartilage cells did not lead directly to the formation of bone cells but underwent initial modification, or dedifferentiation using today's terminology, during which they lost their cartilage faculty. They then became embryonic marrow cells that eventually were able to form bone. Embryonic cells that had not yet taken a determined form could be seen in the development of bone from a cartilage model. The cells were thought to originate in the marrow of the bone under the influence of vessel presence. These vessels led the cartilage capsules to dissolve and the cartilage cells to be freed and then to proliferate, following which they took on an embryonic character referred to as the medullary vascularized tissue. Only later could these marrow cells align themselves along the walls or structures, at which time they were referred to as osteoblasts. The general feeling of many observers, therefore, was that cartilage cells did not transform themselves directly into bone cells, but rather that the bone forming cells developed from descendants of primordial cartilage cells. Mueller also stressed that bone cells were not derived directly from the cartilage cell capsules, but rather from their young progenitors.

B. Direct Transformation of Cartilage Cells to Bone Cells Virchow and Lieberkuhn (215, 292) stressed that cartilage transformed itself directly into bone. Bone cells were interpreted as cartilage cells that survived and bone substance was interpreted as modified cartilage matrix but not a new tissue. Schoney also thought that cells dedifferentiated in the cartilage-to-bone formation phase, although he was clear enough to note that, at the lower part of the growth plate, he had never seen a cartilage cell divide nor the protoplasm of a cartilage cell transform itself into an element of bony marrow (314). Some histologists such as Czermak (72) indicated that the connective tissues of bone and cartilage were similar and that they differed only slightly based on the nature of the surrounding matrices. Metaplastic changes therefore consisted only of a transformation of one matrix to another with one of the subtle changes involving the ability of cells to secrete calcium salts and transform themselves into bony tissue. Leser (212) and Retzius, Brachet, and Retterer (292) each described situations where growth plate chondrocytes survived and were transformed into either marrow medullary cells or osteoblasts.

C. Death of Cartilage Cells An additional view, commonly held through most of the twentieth century, was expressed by Loven and others as early as 1863. It favored the destruction of hypertrophic chondrocytes and the development of bone without any participation of previous cartilage cells (217, 292). He was impressed by the vesicular and swollen nature of the hyper-

trophic cartilage cells that occupy the calcified zone, leading to the interpretation that the cells were degenerating and that calcification led to destruction of the cartilage cells, which served to prepare a space where the bone tissue could invade and develop. He indicated that "it was the blood vessels coming from the perichondrium which contributed to the resorption of the cartilage tissue." He denied that there was any participation of the cartilage cells in the development of the embryonic marrow. Stieda also published similar observations, namely, that the marrow was a tissue whose origin was unique and not derivative from cartilage dedifferentiation (332). Stieda was never able to see a direct passage of the cell line from cartilage to medullary elements, and he felt that the medullary elements originated from the periosteal buds. It was the osteoblastic tissue of the embryonic state that invaded from the undersurface of the periosteum that formed the first bony deposits. Uranossow did not find continuity of cartilage cell division with that of the bone marrow and concluded that the medullary elements did not have their origin in cartilage (292, 354). The cell masses that gave birth to endochondral bone originally derived from the cambial layer of the periosteum. He concluded that cartilage had only a passive role in the development of bone. Levschin denied any relationship between cartilage cells and the marrow elements of long bones (214, 292). Retzius described the changes in cell shape and size as one proceeded toward the hypertrophic zone but felt that the cells were degenerating toward the ossification front (292). Strelzoff indicated that, for most bones, the cartilage was destroyed and bone itself occurred on the basis of osteoblasts derived from the periosteum (335). In some regions, however, in particular in facial bones, ossification occurred wherein cartilage cells were transformed directly to bone cells. An increasingly large number of observers thus defined the hypertrophic cartilage cells to be shriveled and withered, whereas the osteoblasts brought in by the capillary vessels appeared healthy. Others adhered to the view that cartilage cells continued to be derived from the physeal cells even though some were smaller at the lowest part of the hypertrophic zone. Seemingly all were in agreement that, below the palisading layer of the cartilage, there were no longer any mitoses. Brachet indicated that whereas in the hypertrophic zone the cartilage cells seem to be degenerating, it was as though in the region of the resorptive zone they again took on a more embryonic form and subsequently became free in the marrow (31). The question was how the cartilage cells that became hypertrophied and modified reached their ultimate goal. He noted that they essentially disappeared once the capsule had been opened and that osteoblasts filled the space along with vessels and chondroclasts. He indicated that he had never seen transitional forms between the modified chondrocytes and osteoblasts and at least stated in clearcut fashion that "it is impossible for me to determine exactly the ultimate fate of these elements." Retterer felt that most

SECTION VII 9 Structural Development of the Epiphyseal Regions

views inclined to support the classic theory, which attributed an extracartilaginous origin primarily from the blood vessels for the new osteoblasts.

D. Variable Responses Not surprisingly, opinions persisted that there were variable patterns of occurrence in relation to the final state of the hypertrophic chondrocytes. Tschistowitsch (353) indicated that some of the hypertrophic cells degenerated completely and that their space was invaded by vessels from the diaphyseal region, which brought in cells of separate origin, whereas other hypertrophic cells that appeared to be degenerating did not continue to final degeneration but persisted as pale transparent cells, some of which appeared to regenerate and persist in medullary tissue. He was not able to follow the final evolution of the cells within the medullary tissue. It is fascinating to note that today, almost 100 years later, many of the same questions about the ultimate fate of the hypertrophic cell remain. With the onset of the identification of type X collagen deposition within the hypertrophic zone matrix, and with definition by the ultrastructure of persisting organelles in the hypertrophic cells, the question has again been raised as to whether the swelling of the cells does or does not represent terminal degeneration. This phase is best referred to today as apoptosis, by which is meant genetically determined or programmed cell death. Whereas there appears to be little doubt that some and indeed most of the hypertrophic cells either die or are destroyed by vascular invasion from below, the question remains as to whether some of the cells survive and go on to contribute both bone and perhaps even marrow elements to the metaphyseal region. In works by Gerstenfeld and Shapiro (126) and by Roach et al. (297), the opinions of current cell biologists as to possible lines of cell fate in this region were reviewed. (See also Section VIIC for a discussion of the role of apoptosis and possible differentiation paths of hypertrophic chondrocytes.)

VII. STRUCTURAL DEVELOPMENT OF THE EPIPHYSEAL REGIONS INCLUDING THE JOINTS, THE METAPHYSES, AND THE DIAPHYSES Series of histologic sections and diagrams outlining the cell and tissue development in long bone formation have characterized descriptions of bone formation since the late nineteenth century. These include the works of Mathias Duval, Schafer (309), Prenant, Maillard, and Bouin (278), Renaut (289), Testut (341), Payton (271,272), Maximow and Bloom (227), Nonidez and Windle (246), Dubreuil and Baudrimont (85), Ham and Cormack (142), and Krstic (199), as well as many others. Figure 7A outlines an early yet accurate pres-

21

entation of the dynamic aspects of the developmental sequence derived from M. Duval, including the resorptive as well as synthetic phenomena in establishing bone shape and internal structure. The specific regional shaping mechanisms in long bone growth are outlined in Figs. 7B and 7C and Table IliA. The structural features of long bone development are illustrated by light microscopic photomicrographs in Figs. 8A-8J (limb bud and early endochondral and intramembranous bone formation), Figs. 9A-9L (epiphyseal formation), and Figs. 10A-10E (physeal and metaphyseal structure), and by electron micrographs in Figs. l l A - 1 1 I (physeal structure).

A. Epiphyses Once the primary ossification centers have formed and early endochondral and intramembranous bone formation has proceeded toward either end of the bone, it is at this stage that the entire cartilaginous region at the developing end of each long bone is referred to as the epiphysis. That part of the epiphysis adjacent to the joint is referred to as the articular cartilage. This merges in indistinguishable fashion histologically with the underlying epiphyseal cartilage and only reaches its definitive structure at skeletal maturity when the lowest zone of the articular cartilage calcifies, persisting in the adult as the zone of calcified cartilage. The epiphyseal growth plate is the cytologically and functionally specialized region of the epiphysis responsible for most of the longitudinal growth of a long bone. Descriptions of its cell and matrix composition vary slightly between differing authors due to the mixture of terms, some of which are purely descriptive and others imply function. Table IIIB outlines terminology for the layers of the physis that seems most consistent with current biological understanding and also summarizes common terminology used by others. The cell layer at the outermost extent of the physis is composed of resting or germinal cells, followed by the proliferating or columnar cell layer in which the chondrocytes line up in a longitudinal array, followed by the occurrence of the hypertrophic chondrocytes, and below that the peripheral margins of the metaphysis. The epiphyseal growth plate, which is also referred to as the physis or simply the growth plate, maintains its height during growth as there is a symmetrical occurrence of cell proliferation at the upper margin allowing for longitudinal growth, followed by resorption in the hypertrophic chondrocyte region allowing for the formation of metaphyseal bone and marrow.

B. Secondary Ossification Center Formation Cartilage canals that contain blood vessels are present within the epiphyseal cartilage from the early stages of epiphyseal development. At specific times, the chondrocytes within the central region of the epiphyseal cartilage undergo hypertrophy

22

CHAPTER 1 ~

Developmental Bone Biolo~ty

F I G U R E 7 Patterns and mechanisms underlying long bone growth are outlined. (A) These detailed representations illustrate nine stages of growth and development. Number 1 shows the cartilage model of the developing bone. Characteristic changes can then be seen progressing toward number 9. Illustrations from number 4 on show periosteal bone indicated by the vertical lines and endochondral bone by the horizontal lines. The dense black regions of the cortex in 7-9 represent compact cortical lamellar bone. In illustration number 6 the proximal secondary ossification center is shown, whereas in number 7 both are present. The dotted curved lines in illustrations 7-9 represent original cortical areas that have subsequently been resorbed to allow for marrow cavity formation. [Derived from Mathias Duval, modified from Prenant, Maillard and Bouin (278)]. (B) Regional shaping mechanisms in long bone growth. (C) Contributions of synthesis and resorption to long bone growth.

SECTION VII ~ Structural Development of the Epiphyseal Regions TABLE IlIA (i) Articular-epiphyseal cartilage complex (ii) Growth plate (iii) Diaphyseal cortex

(iv) Perichondrial groove of Ranvier

23

Interplay b e t w e e n Synthesis and Resorption in Long Bone Development Synthesis-expansion by interstitial cartilage growth; resorption of bone and cartilage in secondary ossification center (to shape epiphyseal regions and articular cartilage surfaces) Synthesis-expansion germinal to hypertrophic zones; resorption at lower hypertrophic zone-upper metaphysis (to maintain same growth plate thickness throughout most of the growth period) New bone formation by apposition on outer side by periosteum; resorption on inner side by osteoclasts (to maintain same relative extent of cortex throughout growth while allowing for progressive expansion of diameter of marrow cavity) Widening of physeal cartilage and farthest extent of periosteal new bone formation; resorption at lowermost groove region to remove boney ring (allows for metaphyseal funnelization)

TABLE IIIB

Structural Terms for the Epiphyseai G r o w t h Plate or Physis

Descriptive terms

1. 2. 3. 4.

Functional terms

1. Germinal zone 2. Columnar cell zone (a) Upper proliferating zone (b) Lower maturation zone 3. Hypertrophic cell zone (a) Upper part (4/5), nonmineralized matrix

Resting cell zone Columnar cell zone Hypertrophic cell zone Metaphyseal bone

(b) Lower part (1/5), mineralized matrix 4. Metaphysis outer reaches

] Zone of provisional calcification J

Ham and Cormack (142)

Zone of resting cartilage, zone of young proliferating cartilage, zone of maturing cartilage, zone of calcifying cartilage, developing trabeculae of metaphysis

Brighton (36)

Reserve zone, proliferative zone, zone of maturation, zone of degeneration hypertrophic zone, zone of provisional calcification

in association with mineralization of the cartilage matrix by a process felt to be entirely analogous to that occurring at the physeal-metaphyseal junction (182). This is followed shortly by vascular invasion of the hypertrophic region from the adjacent cartilage canals, lysis of the hypertrophic chondrocytes, and synthesis of new bone on the calcified cores of cartilage by osteoblasts, which accompany the vessels. The initial positioning of the hypertrophic cells is uniform, forming a 360 ~ continuous arc of cells. As development proceeds, this circumferential arc of chondrocytes assumes a hemispheric shape with the hypertrophic chondrocytes forming in relation to the more peripheral articular surfaces, whereas the cartilage closest to the epiphyseal growth plate stops growing and the cells assume the appearance of resting chondrocytes. The hypertrophic chondrocytes and the proliferating cells adjacent to them form what we refer to as the physis of the secondary ossification center. As growth continues the size of the cartilaginous epiphysis increases, but there is a relative increase in the amount of secondary ossi-

fication center bone formation at the expense of the epiphyseal cartilage. For each epiphysis a point is reached in which the only cartilage persisting during the remainder of growth is the physis, the articular cartilage, and its under surface, which is referred to by some as the miniplate. By this stage, the secondary ossification center has almost completely replaced the epiphyseal cartilage. We prefer the term physis of the secondary ossification center to miniplate; it is more awkward but can be used to describe this specific region throughout the developmental cycle. The cartilage region closest to the main physis no longer undergoes proliferation, and the secondary ossification center shows evidence of growth only adjacent to the side walls of the epiphysis and to the undersurface of the articular cartilage. This is also reflected by changes in the structure of the secondary ossification center. At those regions immediately adjacent to the hypertrophic cell areas there is continuing development of the endochondral sequence, with new bone synthesized on cartilage cores. At that part of the

24

CHAPTER

1 ~

Developmental Bone Biology

SECTION VII ~ Structural Development of the Epiphyseal Regions secondary center adjacent to the physes where cell proliferation is no longer occurring, bone is present almost exclusively with minimal to no traces of persisting cartilage cores. In association with this change in orientation of the physes of the secondary ossification center and its hypertrophic cell region there is also a change in the marrow pattern. That marrow immediately adjacent to the hypertrophic zone always remains hematopoietic, whereas the marrow in the regions closer to the epiphyseal bone plate demonstrates the area of earliest fatty change (94). Toward the end of active epiphyseal growth there is a slowing down of the function of the physes of the secondary ossification center. Bone formation begins to predominate over the central cartilage cores because bone synthesis from the marrow cells continues. At skeletal maturation, the lowest level of the articular cartilage becomes calcified and this layer persists through adult life. A subchondral bone plate is formed. Virtually all the marrow is now fatty. The epiphyseal growth plate itself stops its proliferative function, is gradually resorbed from the metaphyseal side, and eventually completely disappears allowing for continuity of the epiphyseal and metaphyseal bone marrow and circulation. The peripheral perichondrial ossification groove is an integral part of the epiphysis. The staging classification, including all structural aspects of epiphyseal development as outlined by Shapiro and Rivas (324), is listed in Table IV. A more detailed report will be published shortly (Rivas and Shapiro, Bone Joint Surgery [Am], in press).

C. Physis--Structure and Relation to Function The cells and matrices of the epiphyseal growth plate have been well-defined at the light microscopic and ultrastructural levels (Figs. 10-12). The resting or germinal cell layer chondrocytes are round to oval in shape and possess a central nucleus and a cytoplasm that is filled with abundant amounts of rough endoplasmic reticulum. The endoplasmic reticulum

25

is mildly to moderately dilated, a finding considered to be consistent with the synthesis of protein, which in this instance is primarily type II collagen. There is also a welldeveloped Golgi apparatus that is responsible for processing the proteoglycans. The chondrocytes of the columnar or proliferating zone are markedly flattened and align themselves into columns. There is a marked tendency for these chondrocytes to be wedge-shaped with the bases of the wedges alternating to allow the linear conformation to persist. The cells are also quite active in terms of mitoses in the proliferating upper part of the zone and in relation to protein synthesis, showing abundant amounts of dilated rough endoplasmic reticulum in the lower or maturation part of this zone. In the hypertrophic zone a characteristic cell appearance is seen with the cell volume larger than that in the above lying regions. The nucleus persists but there are many clear spaces within the cytoplasm. There is an apparent marked diminution of rough endoplasmic reticulum, and by the time one examines cells at the lower margins of the hypertrophic zone only scattered cisternae of endoplasmic reticulum persist. In the upper parts of the hypertrophic zone the cartilage matrix is not calcified. Calcification occurs in the matrix of the lower margins of the hypertrophic zone almost exclusively involving the longitudinal septae along the long axis of the bone, whereas the transverse septae are either not mineralized or only slightly mineralized. The vascular invasion from below progresses two or three cells deep into the lower margin of the hypertrophic zone, and in association with this vascular invasion of the hypertrophic cell regions there is deposition of bone by osteoblasts on the persisting calcified cartilage matrix. The sequence of events is illustrated in the adjacent figures and figure legends. Each level of the physis gradually merges with the level below; there are no sharp transitions. In addition, transitions of cell size, shape, and function occur sequentially even within each subregion. The terminology used by Buckwalter et al. (43) to describe the physis is the reserve (germinal) zone, upper and

FIGURE 8 The histologic features of the developmental sequence of the limb. These photomicrographs are from the developing limb of the rabbit, although the histologic appearance in the human is the same. (A) The developing limb bud is shown at right along with the spinal cord at upper left. At this stage the limb bud is composedof undifferentiated,closely packed mesenchymalcells with no histologic evidenceof any structure. The densely packed cells of the apical ectodermalridge are shown at far right (arrow). (B) A higher power view of the tip of the limb bud showing the mesenchymalcells (M) and the apical ectodermalridge (arrow). (C) A major segment of the developing lower limb is seen at a slightly later stage. The developingfemur (F) and tibia (T) are shown, as is the quadriceps (Q) muscle mass. The central region of the femur shows the early changes of chondrocyte hypertrophy. These bones initially were formed completely in cartilage. (D) A slightly higher power view of a developing long bone, a metatarsal,shows the cartilagemodel and central regions of cell hypertrophy. (E) A higher power view of the femur shown in part (C) highlights the hypertrophic region. There is also development of the intramembranousbone mechanism at the primary center of ossification (arrow). The popliteal artery is shown at lower left. Quadriceps muscle fibers are shown above (Q). (F) The central hypertrophic cells of the femur are shown. The outer fibrous (F) and inner osteogenic (O) layers of the developing periosteum are seen. (G) The interzone region of the developingjoint is seen at right. The cartilage models of the femur (F) and tibia (T) are shown. Cells completely fill the region between these two bone models, indicating the relativelylate time of formation of the joint. (H) A higher power view shows the dense cell accumulationwithin the interzone region. (I) The femoral cartilage is shown at left and the tibial at right. The beginning outline of density of the articular cartilage surface of the tibia is seen (arrow). (J) At a slightly later stage of developmentthe formation of the intramembranousbone sequence overlying the central endochondral sequence is seen. Endochondral bone formation is seen below and intramembranousbone above. Hypertrophic cells of the central endochondral sequence are seen to persist (white arrow). The outer fibrous layer and the inner osteogenic layer of the periosteumare marked. Surface osteoblasts overlyingnewly synthesizedcortical bone are seen (curved dark arrow).

F I G U R E 9 Some characteristic developmental features of epiphyseal formation are shown. Patterns in humans are similar to those seen in pig and rabbit. (A) The cartilaginous epiphysis at the developing end of a rabbit phalangeal bone is shown. At this stage, there is no formation of the secondary ossification center. The articular cartilage (black arrow), epiphyseal cartilage (EC), and physeal cartilage (P) are shown, as is the perichondrial groove of Ranvier (white arrow). (B) Cartilage canals containing vessels have long been recognized as an integral part of epiphyseal development. They are responsible initially for nutrition of the cartilage and only later, often several months later, are they involved in the formation of the secondary ossification center. They are shown here within the cartilage at either

F I G U R E 9 (continued) end of the developing end of human bone from an illustration by Koelliker (193) over 150 years ago. (C) The cartilage canals (Ci-Civ) from a developing proximal femoral capital epiphysis in the newborn pig are shown. [Parts Ci, Civ reprinted from Jaramillo, D., et al. (1996). Am. J. Roentgenol. 166: 879-887, with permission from the American Journal of Roentgenology.] They are never present in the articular cartilage but often traverse the physis in the fetal and early postnatal time periods. Vessels are present within a loosely packed connective tissue matrix. In parts (Cv) and (Cvi), Watermann depicts the vessel contents of a larger (Cv) and a smaller (Cvi) canal. The striated structures are arterioles, the dark solid structures are venules, and the smaller structures are capillaries. [Reprinted from Watermann, R. (1966). Zeit. f. Orthop. 101: 247-257, Georg Thieme Verlag, with permission.] (D)Central cartilage hypertrophy is seen in early formation of the secondary ossification center from a rabbit proximal humerus. Adjacent cartilage canals are shown. Articular cartilage is at top, whereas physeal (arrow) and metaphyseal tissues are at the bottom of the photograph. (E, F) Cartilage matrix mineralization followed by vascular invasion is seen in higher power photomicrographs from the same histologic section as part (D). The vascular invasion has extended from the cartilage canals. The matrix mineral is not seen because the specimens have been decalcified for better sectioning. (G) Endochondral bone formation is now seen centrally in the proximal humeral epiphysis with new bone synthesized on cartilage cores and early evidence of marrow cavitation. The hypertrophic cells of the secondary ossification center are oriented in a 360 ~ arc. (H) Early developing secondary ossification center showing a vessel at lower fight passing into the center of the region. (I) The secondary ossification center has increased in size in relation to the epiphyseal cartilage. At this stage the orientation of the hypertrophic chondrocytes of the physis of the secondary ossification center, miniplate in some terminologies,

F I G U R E 9 (continued) has changed from the 360 ~ orientation shown in part (G) to an approximately 180 ~ orientation here. The two arrows illustrate where the cell hypertrophy of this region ends, with the area between the arrows no longer showing such changes. (J) At a slightly later stage of development, the secondary ossification center moves progressively toward the articular cartilage surface. There is considerable cartilage, however, between the surface of the articular cartilage and the hypertrophic zone of the physis of the secondary ossification center. Well-formed bone with osteocytes is present now within the secondary ossification center (arrow) with only small persisting central cores of cartilage seen. The marrow (M) is hematopoietic. (K) Physeal closure shows the disappearance of proliferating and hypertrophic zones and beginning transphyseal vessel communication (arrows). A continuous bone plate of mature lamellar bone is seen at the top, indicating complete replacement of the epiphyseal cartilage. (L) Epiphyseal development classification of Shapiro and Rivas (324). [From Rivas and Shapiro, J. Bone Joint Surgery (Am), in press, with permission.]

SECTION VII ~ Structural Development of the Epiphyseal Regions

lower proliferating zones, and upper and lower hypertrophic zones. Their histomorphometric studies of proximal tibial physes in mice of varying ages show that, in transverse sections, cell profiles do not change within the same growth plate zones, but in longitudinal sections the cell profiles and profile orientations differ significantly among zones. Cell profiles in the upper and lower proliferative zones are eccentric and highly oriented, but they become more rounded and the degree of cell orientation decreases between the proliferative and hypertrophic zones. The degree of cell profile orientation decreases extensively in the upper and lower proliferative zones, decreases less in the reserve and upper hypertrophic zones, and remains unchanged in the lower hypertrophic zones at varying ages. Changes in cell profiles and in the degree of proliferative zone cell profile orientation correlate with the rate of longitudinal bone growth. Chondrocytes prior to the appearance of a growth plate have rounded profiles with no apparent orientation. Questions remain as to what mechanisms give the cells of the proliferative zone their eccentric shape and high degree of orientation. A correlation is noted between the degree of chondrocyte flattening and the rate of proliferation, with flatter cells proliferating more rapidly and less flattened cells decreasing their rate of proliferation. Others have suggested that the cell is flattened secondarily by the accumulation of matrix. Hypertrophic zone cells have a less eccentric shape and rarely if ever divide, although they do enlarge. Their height in particular is increased in relation to their width, which appears to be associated with the decreasing rate of DNA synthesis and proliferation. Cell swelling in the lower proliferative and upper hypertrophic zones tends to change the eccentrically shaped highly oriented proliferative cell into the rounded and randomly oriented hypertrophic cell. Their height is increased relative to their width, and it is felt that the growth plate matrix helps restrain transverse expansion. The flattest most highly oriented cells are those with the highest rate of proliferation, whereas development of a more spherical shape and loss of orientation seem to be associated with a decreasing rate of proliferation. A second assessment by Buckwalter et al. studied chondrocyte hypertrophy (44). It is evident that, in the hypertrophic zone, the chondrocytes enlarge and assume a more spherical shape. Morphometric analyses of electron micrographs show that, between the upper proliferative zone and the lower hypertrophic zone, the cells increase their mean volume by more than 500%. As the cells enlarge, the intercellular matrices change. The territorial matrix volume increases but the interterritorial matrix volume decreases. Between the upper proliferative zone and the lower hypertrophic zone, the absolute volume per cell of endoplasmic reticulum, Golgi membranes, and mitochondria increases by 126%, whereas the volume of cytoplasm and nucleoplasm increases by 779%, apparently by the accumulation of water. Chondrocyte enlargement thus involves some increase in organelle synthesis, but the primary mechanism of cell

29

enlargement is cytoplasmic and nuclear swelling. The chondrocytes enlarge primarily by accumulating water. The endoplasmic reticulum (ER) and mitochondria dilate, ribosomes dissociate from the endoplasmic reticulum, and distended fragments of ER or Golgi appear in the cytoplasm. This work, along with biochemical studies that identified type X collagen synthesis localized to the hypertrophic zone (147, 307, 313), again raised the question as to whether all hypertrophic cells were degenerating or whether some, and perhaps a significant number, survived and functioned deep into the physeal region and perhaps beyond. The work reviewed previously in Sections III and IV becomes relevant again. Throughout most of the first half of the twentieth century the hypertrophic chondrocyte was considered to be a degenerating cell at the terminal end of the endochondral sequence. It was recognized that its swelling helped provide longitudinal growth, but that its degeneration coincided with vascular invasion of the hypertrophic cell lacunae, following which bone was synthesized on the cartilage cores to form the metaphyseal trabeculae. Holtrop studied the hypertrophic chondrocyte at the ultrastructural level and concluded that "the results showed ultrastructural preservation of the cells that strongly suggest cell activity from the beginning of enlargement of the cell up to the stage where the lacunae breaks open" (158, 160). She felt that careful morphologic study did not confirm the long accepted view of degeneration or cell death but was, rather, consistent with cell activity. Not only did the hypertrophic chondrocytes appear to play a role in the calcification of the matrix, which was being suggested by others, but she felt that they had the potential to become osteoblasts and osteocytes. Once again, careful microscopy was raising the question not only of the function of the hypertrophic cell but also of its persistence, much as did the work of Retterer and the many authors he referenced in the late nineteenth century. Holtrop also reported on transplantation experiments of 4-week-old mice rib growth plates into leg muscles (159). These experiments were designed to assess the potency of the physeal tissue itself in relation to its presumed passive role at the terminal end of the endochondral sequence where it was resorbed. In the discussion she repeated her previous contention that "hypertrophic cartilage cells are able to transform into osteoblasts and osteocytes." She suggested that the development of endochondral ossification in cartilage transplants in the hypertrophic zone implied a more active role for the hypertrophic cells. A second study demonstrated that the function of the physeal transplant was independent of the host because younger transplants elongated more than older transplants using the same technique. The ultrastructure of the growth plate was described in detail in two subsequent articles (161, 162). Hunziker and Schenk further clarified the functions of the specific cell regions of the growth plate (172, 173, 311). The growth plate is characterized structurally by the resting or reserve zone, proliferation and hypertrophy of chondrocytes,

30

CHAPTER 1 ~

Developmental Bone Biology

F I G U R E 10 Physeal and physeal-metaphyseal junction tissues are detailed in this figure. All specimens except part (E) are from the rabbit. (A) The resting germinal cell layer of the physis is shown. This is not a particularly well-defined layer either by histologic or

SECTION VII ~ S t r u c t u r a l D e v e l o p m e n t o f t h e Epiphyseal R e g i o n s

31

calcification, a n d v a s c u l a r invasion. C e l l s w i t h i n the resting

b o r d e r b e t w e e n p r o l i f e r a t i n g a n d h y p e r t r o p h i c zones. Dis-

z o n e i m m e d i a t e l y a d j a c e n t to the e p i p h y s e a l b o n e o c c u r sing l y or in g r o u p s o f two, are d i s t r i b u t e d r a n d o m l y w i t h i n the matrix, a n d l a c k a c o l u m n a r a r r a n g e m e n t . K e m b e r has s h o w n these cells to h a v e s t e m cell f u n c t i o n a n d to u n d e r g o

t i n c t i o n is m a d e b e t w e e n the u p p e r h y p e r t r o p h i c zone, w h e r e cell e n l a r g e m e n t b e g i n s , a n d the l o w e r h y p e r t r o p h i c zone, w h e r e m o s t c h o n d r o c y t e s h a v e attained final size. T h e hypert r o p h i c c h o n d r o c y t e s are no l o n g e r c o n s i d e r e d to be d e g e n -

d i v i s i o n o n l y rarely. C e l l s a d j a c e n t to the tip o f the c o l u m n s

erate cells (69). O n the basis o f m o r e e x a c t i n g p r e p a r a t i o n

b e l o w are c o n s i d e r e d as stem cells, w h i c h f e e d d a u g h t e r cells

techniques, they m a i n t a i n a r o u g h e n d o p l a s m i c r e t i c u l u m and

into the p r o l i f e r a t i n g pool. T h e p r o l i f e r a t i n g z o n e itself has

are felt to f u n c t i o n e v e n to the l o w e s t m a r g i n s o f the zone.

a c l e a r - c u t c o l u m n a r a r r a n g e m e n t . P a r a l l e l to the l o n g axis

M i n e r a l i z a t i o n o f the m a t r i x in the l o w e r part o f the h y p e r -

o f the b o n e c h o n d r o c y t e s d i v i d e in a t r a n s v e r s e d i r e c t i o n

t r o p h i c z o n e is r e s t r i c t e d to the l o n g i t u d i n a l septae, w h i c h is

w i t h d a u g h t e r cells initially situated side b y side. T h e y then

s o m e t i m e s r e f e r r e d to as the " i n t e r t e r r i t o r i a l m a t r i x . " T h e

s w i t c h into a c o l u m n a r t r a n s v e r s e r e l a t i o n s h i p at w h i c h time

territorial m a t r i x i n v o l v e s c o l l a g e n fibrils that run trans-

m a t r i x s y n t h e s i s occurs. C h o n d r o c y t e e n l a r g e m e n t m a r k s the

v e r s e l y a r o u n d e a c h c h o n d r o c y t e . T h e r e g i o n b e y o n d the

F I G U R E 10 (continued) by autoradiographic criteria because it is present in the area at the tip of the arrows between the epiphyseal cartilage and the proliferating cell layers of the physis. It is considered to become or serve as the germinal layer for the well-structured and clearly evident proliferating cell layer of the physis below. (B) Parts (Bi) and (Bii) are presented. The proliferating (P) or columnar cell layer of the physis is shown above; these then merge into the hypertrophic cell layer (H) as the cells increase in size. Cartilage matrix is labeled (M). The metaphysis is shown below. It is recognized increasingly that these various layers merge into one another with changes in cell activity and cell size occurring gradually in a progressive fashion. The proliferating cell zone is recognized in its upper part to undergo proliferation characterized by the high uptake of tritiated thymidine, indicating DNA turnover. In its lower part, it is sometimes referred to as a zone of maturation in the sense that there is little cell turnover, but the synthesis of proteoglycans, collagen, and noncollagenous proteins occurs actively. The hypertrophic zone region also can be subdivided into an upper zone, which is characterized by a progressive increase in cell size that contributes extensively to longitudinal growth of the bone, and a lower hypertrophic zone in which the matrix mineralizes in preparation for eventual vascular invasion of the hypertrophic cell lacunae. This lower layer has been referred to by some as part of the zone of provisional calcification. Metaphyseal bone is formed in association with the advancing front of vascularization. (C) Morphological characteristics at the growth plate cartilage-metaphyseal bone interface are shown in parts (Ci-Cv). Diagrammatic illustration and surrounding high-power photomicrographs are shown. A diagrammatic outline of the major morphological and cellular events at the hypertrophic chondrocyte-metaphyseal interface is presented. RBC, red blood cell; OB, osteoblast; OC, osteocyte; OCL, osteoclast; V, vessel. The major morphological landmarks are depicted in the adjacent micrographs. Area I (upper fight): Photomicrograph illustrates a portion of an un-decalcified growth plate-metaphyseal junction from a 2-week-old rabbit metatarsal. The hypertrophic cells are seen above. Note the dark staining mineral in the longitudinal cartilage septae with very little or no mineral in the transverse septae. Vascular invasion of the hypertrophic cell lacunae has occurred (solid arrow) on one side of a mineralized cartilage trabeculum, whereas on the opposite side there are newly differentiating mesenchymal cells designed to become osteoblasts and synthesize osteoid on the calcified cartilage core. The dots represent tritiated proline in the autoradiograph, with sacrifice performed 20 min after injection. Area II (lower fight): High-power photomicrograph shows the lower regions of the hypertrophic zone at top and the vascular and mesenchymal cell invasion from below. This histologic section and those depicting areas III-V are all demineralized preparations. The hypertrophic cells from the lowest layers of the hypertrophic zone (white arrow) are seen. Red blood cells from the metaphysis are seen adjacent to the last persisting hypertrophic cell lacunae. A multinucleated osteoclast (curved arrow) is seen, as are undifferentiated mesenchymal cells that will shortly begin to synthesize an osteoid matrix on the persisting cores of calcified matrix (open arrow). (Proximal tibial growth plate-metaphyseal junction in 1-month-old rabbit; plastic embedded JB4 section stained with 1% toluidine blue.) Area III (upper left): Photomicrograph of metaphyseal tissue immediately adjacent to the hypertrophic zone of the growth plate from a 1-month-old rabbit proximal tibial metaphysis. The persisting cartilage cores (C) are black. Newly synthesized bone (B) can be seen adjacent to them. Osteoblasts (curved arrow) line the surface of the newly synthesized bone. Osteocytes are within. We refer to these as mixed trabeculae encompassing both bone and cartilage tissue. A vessel (V) is also seen. A multinucleated osteoclast is seen centrally where it is resorbing both cartilage and bone (black arrow). Area IV (lower left): Photomicrograph of tissue deeper within the metaphyseal region. There are areas of persisting cartilage (black) but much more newly synthesized light staining bone. Surface osteoblasts are seen (black arrows), as are osteocytes and osteoclasts (open arrow). Area V (lower middle): A high-power view of metaphyseal bone and cartilage trabeculae is seen. Osteoclasts (arrows) can be seen resorbing both bone and cartilage. (D) Mineralized sections of a rabbit metatarsal epiphysis and adjacent metaphysis are shown in parts (Di-Div) (see next page). Part (Di) shows mineralized longitudinal cartilage septae passing up into the lower reaches of the hypertrophic zone. At far fight the mineralized cortex is also seen. A higher power view of a part of the physeal-metaphyseal junction is shown in (Bii). It is the longitudinal septae that remain mineralized, with the transverse septae for the most part free of mineral. In parts (Diii) and (Div) a tritiated proline autoradiograph of the mineralized physeal-metaphyseal junction is shown. Centrally in (Diii) one can note the red blood cells passing into the hypertrophic cell lacunae following disruption of the transverse and oblique septae. Part (Div) adjacent to the region of part (Diii) shows, at the left side of the central cartilage septum, the proline-labeled osteoblasts, which are lying on the calcified cartilage core and shortly will begin synthesis of osteoid. (E) Photomicrograph from the metaphyseal region of a developing calf long bone. A central cartilage core is seen surrounded by newly formed bone. Young osteocytes are present within the bone matrix. Osteoblasts line the surface of the bone. Immediately adjacent to the osteoblasts one can see a multinucleated osteoclast resorbing bone and ultimately cartilage. The marrow contains two cell lines: one serves as a hematopoietic precursor, including monocytes that fuse to form osteoclasts, and the other cells, called stromal precursors, can differentiate into preosteoblasts and osteoblasts. [Parts Bi, Bii, C,

32

CHAPTER

1 ~

Developmental Bone Biology

F I G U R E 10 (continued) and Diii from Gerstenfeld and Shapiro, J. Cell. Biochem. 62:1-9, copyright 1996. Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.]

SECTION Vll ~ Structural Development o f the Epiphyseal Regions

F I G U R E 11 Electron micrographs of the physeal region of the developing mouse are shown. (A) Electron micrograph from the proliferating zone region of newborn mouse physis. The flattened cells are seen above. The rough endoplasmic reticulum is highly active and dilated, indicating synthesis of protein. The Golgi apparatus in each cell can also be seen. (B) Higher power photomicrographs from the proliferating zone are seen. Note the extensive endoplasmic reticulum and Golgi apparatuses. Mitosis is being completed below. Note two nuclei. (C) Two flattened chondrocytes of the proliferating zone are seen. Note the prominent organelles for synthesis. (D) Chondrocytes from the upper hypertrophic zone continue to show well-developed active organelles. (E) Cells farther down the zone of hypertrophy show areas of markedly distended rough endoplasmic reticulum, flattened ER, and increasing areas devoid of organellar definition. (F) Hypertrophic chondrocytes lower in the zone show a distended nucleus at left, a large focus of RER, and areas devoid of specific organellar structure. (G) Only small local collections of RER remain in the lower hypertrophic zone. (I-I) Electron micrograph

33

34

CHAPTER 1 ~ Developmental Bone Biology

F I G U R E 11 (continued) from the hypertrophic region shows mineralization primarily of the longitudinal septae, with little to no mineralization of the immediately adjacent transverse septae. The white arrows represent the long axis of the bone. The cell lacunae show remnants of hypertrophic cell organelles. The space is considered to be filled with water, which is responsible for the hypertrophic cell size increase and its contribution to longitudinal bone growth. (I) Mineralization of the longitudinal septum is shown, as is the distinct absence of mineral from the transverse septum. The hypertrophic chondrocyte in the lowermost region of the physis shows a remnant of the nucleus (N), a dilated fragment of the rough endoplasmic reticulum (R), and flattened segments of rough endoplasmic reticulum (arrows).

territorial matrix thus is in the longitudinal septae. The bulk of the transverse septae remain unmineralized. The fact that the growth plate maintains its same height during most of its growth phase indicates excellent synchronization between vascular invasion and resorption from below and addition by cell proliferation and matrix production in the upper part of the cartilage. Approximately one-third of the proliferating zone is occupied by cells and two-thirds by matrix, a ratio that is reversed in the hypertrophic zone by the tremendous enlargement of chondrocytes. The marked size change during hypertrophy is an almost 10-fold increase in volume. The orientation and shape of the cell also change

from the proliferative zone in which the cell is ellipsoid and transversely oriented to the hypertrophic zone in which it is cylindrical with its long axis oriented in the longitudinal direction. Cell hypertrophy primarily causes a stretching of the cell columns in their axial direction, which thus contributes substantially to longitudinal growth. The hypertrophic cells expand by the act of transport of water and electrolytes through their cell walls. The cells continue to produce matrix. The rough endoplasmic reticulum at first glance appears scanty and dispersed, but considering the 10-fold increase in cellular volume, detailed studies actually show the organelles to be increased in extent. Longitudinal growth rate thus

SECTION VII ~ Structural Development of the Epiphyseal Regions

35

TABLE IV The General Plan of Epiphyseai and Long Bone Development a Stage 1 Stage 2 Stage 3 Stage 3a Stage 3b Stage 4 Stage 4a Stage 5 Stage 5a Stage 6 Stage 6a Stage 7 Stage 8 Stage 9 Stage 10 Stage 11 Stage 12 Stage 13 Stage 13a Stage 14 Stage Stage Stage Stage Stage

15 15a 15b 16 16a

Limb bud formation; uniform mesenchymal cell distribution; apical ectodermal ridge Mesenchymal condensation Cartilage differentiation Interzone formation Chondrocyte hypertrophy in middle part of long bone cartilage model Epiphyseal shaping Primary center of ossification Resorption of joint interzone; smooth articular cartilage surface Vascular invasion of hypertrophic chondrocyte area, mid part cartilage model; endochondral bone Physeal differentiation and peripheral groove tissue formation Farthest relative extent of epiphyseal-physeal position Epiphyseal cartilage vascularization; cartilage canals Central chondrocyte hypertrophy to form spherical mass; development of growth plate completely surrounding secondary ossification center Vascular invasion of developing secondary ossification center hypertrophic chondrocytes adjacent to mineralized cartilage matrix Bone formation and marrow cavitation in secondary ossification center; hematopoeitic marrow Increase in size of secondary ossification center; decrease in epiphyseal cartilage Central chondrocyte hypertrophy-secondary ossification center growth plate change to hemispherical orientation Fat in marrow; hematopoietic marrow adjacent to secondary ossification center growth plate Epiphyseal bone plate formation Fullest relative extent of secondary ossification center involvement in epiphyseal cartilage articular cartilage miniplate formation Thinning of the physis Articular cartilage miniplate growth cessation Subchondral bone plate formation Resorption of physis linking epiphyseal and metaphyseal circulations Calcification of lowest zone of articular cartilage and tidemark formation; all marrow fatty

aFrom Shapiro and Rivas (324) and Rivas and Shapiro, J. Bone Joint Surgery (Am), in press, with permission.

is a function of modulation in cell turnover, fluctuations in cell hypertrophy, and changes in matrix production. Hunziker and Schenk sought to determine which of the many variables contributed most to longitudinal growth. They reviewed the fact that changes in cell proliferation rate, height, volume, and matrix production had each been generally implicated in the process. On the basis of detailed histologic and histomorphometric studies of the rat physis, they concluded that "growth acceleration is achieved almost exclusively by cell shape modeling, namely increase in final cell height and a decrease in lateral diameter." They felt that the cell proliferation rate in the longitudinal direction and net matrix production per cell remained unchanged, such that the cartilage matrix itself appeared to play a subordinate role in regulating longitudinal bone growth rate. Growth thus can

be regulated most acutely by factors acting on cell shape modeling. Hunziker and Schenk noted the frequent observation that the cytoskeleton of the chondrocyte was relatively minimal compared to other cells, which again indicated a diminished role for this organelle in controlling cell shape and size. Their morphologic studies of chondrocytes supported a high degree of coordination between matrix remodeling and chondrocyte shape change. Changes in the shape of the hypertrophic cell can occur much more rapidly than those that require changes in the cell turnover rate. Thus, during both acceleration and deceleration of linear growth, changes in hypertrophic cell activities appear to play an important regulatory role rather than the previously assumed fact that linear growth was modulated principally by changes in chondrocyte proliferation activity. In a careful quantitative

36

CHAPTER

1 9

Developmental Bone Biology

analysis of physeal cell features, they concluded that a proliferating chondrocyte needed approximately 54 hr to duplicate its own volume, whereas during hypertrophy a corresponding volume increase would be achieved in a period as short as 5 hr. Hypertrophy thus appeared to be a more proficient mechanism for bringing about columnar linear growth than did cell proliferation. They also concluded that it was a hypertrophic cell change in shape and volume itself that modulated growth because they could demonstrate that by the end of its life cycle the hypertrophic chondrocyte produced neither an increase nor a decrease in its associated matrix volume. Hunziker and Schenk felt that the matrix had its primary function as a space filling role between cells to compensate for the changes in height, diameter, and volume and thus helped to maintain columnar tissue organization during linear growth. The matrix was also crucial for maintenance of the biomechanical properties of growth plate cartilage (172-174). The duration of the hypertrophic phase at approximately 48 hr also remained remarkably constant irrespective of animal age or growth rate. Hunziker et al. also pointed out that individual physeal chondrocytes actually remained in a fixed location throughout their life during which their function and shape changed (172). The two most prominent stages were those of cellular proliferation and hypertrophy. By the late hypertrophic stage, 4-fold and 10-fold increases in the mean cellular height and volume, respectively, and a 3-fold increase in the mean volume of the matrix synthesized per cell had been achieved. The continuing high metabolic activity of hypertrophic cells was also demonstrated on the basis of a 2- to 5-fold increase in the mean cellular surface area of the rough endoplasmic reticulum, the Golgi membranes, and the mean cellular mitochondrial volume. They also concluded that the hypertrophic chondrocytes had increased their volume by active transportation of fluid (water and electrolytes) across the plasma membrane into the cell itself. The work of Wilsman, Farnum, and colleagues has shown the importance of structural changes in relation to growth plate cartilage function (19, 33, 100). Their work also supports the concept that hypertrophic chondrocytes are fully viable cells that play a major role in endochondral ossification. It has not been determined whether all hypertrophic chondrocytes die or whether some may survive and modulate to bone forming cells in the metaphyseal regions. It is now almost universally accepted that the large majority of hypertrophic cells are viable and functioning in terms of continuing matrix synthesis, with some molecules such as type X collagen synthesized primarily in the hypertrophic cells and involved directly or indirectly in the mineralization process. Terminal hypertrophic chondrocytes can be found in three morphologically distinct forms: (1) fully hydrated cells with direct circumferential attachments of the plasma membrane to the pericellular matrix identical to that of the more proximal hypertrophic chondrocytes; (2) fully hydrated cells with asymmetric attachment to the last transverse septum; and

(3) a condensed cell with the same asymmetrical attachment to the last transverse septum. They hypothesize that "the initial attachment of the chondrocyte plasma membrane to the last transverse septum represents the first of a series of rapid terminal morphologic changes that represent chondrocytic death." Wilsman et al. feel that it is only the terminal chondrocyte that undergoes changes in which there is withdrawal of the plasma membrane from its attachments to the pericellular matrix, cellular condensation, and cellular vacuolization. They indicate that "cellular disintegration is complete before the opening of the chondrocytic lacunae." Hunziker has also suggested that only the terminal chondrocyte in each cell column dies and that it does so in fashion consistent with programmed cell death. There has been a constant, if small, group of individuals studying growth plate function who have hypothesized "that terminal hypertrophic chondrocytes modulate in phenotype and change not only their chemical phenotypical expression but also their ultimate biological role." The terminal chondrocytes are viable and metabolically active. This group does not go so far, however, as to indicate that they then switch to a bone phenotype within the metaphyseal area. Breur et al. demonstrated that chondrocyte enlargement began immediately following cell division in the proliferative zone and that it consisted of two morphologically distinct phases (33). The transition point between the first and second phases of chondrocytic enlargement corresponds with the junction between proliferative and maturation zones. The controlling features in longitudinal growth are. the rate of new cell production in the proliferative zone and the role of chondrocyte hypertrophy. Their study suggested that "in growth plates, chondrocytic enlargement plays a major role in the determination of longitudinal bone growth." Chondrocyte enlargement is characterized by an increase in cell volume and a modulation of cell shape. In the proliferative zone, the cells are flattened ellipsoids, whereas in the hypertrophic zone they are more rounded and spheroid in a longitudinal plane. The increase in cell volume is mainly the result of cellular swelling by absorption of water, with only some increase in cell organelles. Chondrocyte proliferation is felt to take place only in the proximal ends of the proliferative zone, and the function of chondrocytes in the proliferative zone distal to the actively proliferating cells involves actual enlargement and hypertrophy. Each region thus merges with the next rather than being strictly separate as is sometimes indicated. In a study of rat growth plate structure, Breur and colleagues demonstrated that (1) cell volume increase started immediately following cell division in the proximal portion of the proliferative zone, (2) the process of chondrocytic enlargement as it relates to longitudinal bone growth consists of two morphologically distinguishable phases, (3) the rate of cell volume increase and the rate of cell shape modulation are significantly higher during the second than during the first phase, and (4) cell volume increase during the first phase results mainly in an increase in vertical chondrocyte diame-

SECTION VII ~ Structural Development of the Epiphyseal Regions ter, whereas cell volume increase during the second phase results in a large increase in the vertical chondrocyte diameter and a smaller but significant increase in horizontal chondrocytic diameters. The cell volume increase starts immediately following cell division in the proximal portion of the proliferative zone, and chondrocytic enlargement consists of a phase of slow and then rapid cellular enlargement. The complex functions of the hypertrophic chondrocyte during endochondral bone development have been stressed by Gerstenfeld and Shapiro in a work that combines consideration of molecular data with the histologic characteristics of the physeal-metaphyseal junction (126). Endochondral bone formation is one of the most extensively examined developmental sequences within vertebrates. The major cellular events of this process include the recruitment and induction of both osseous and vascular tissues. Presumptive osteoblasts are recruited and line the trabeculae of mineralized cartilage to synthesize osteoid. The term mixed trabeculum refers to the presence of mineralized cartilage cores surrounded by newly synthesized bone. Vascular elements invade and line the empty lacunae of the lowermost hypertrophic chondrocytes, which have undergone cell death. Pertinent questions relative to the osseous and vascular induction within these zones include the nature of the functional coupling among cartilage, bone, and vascular tissues. Signals elaborated by the endochondral cells are targeted to the subsequent development of the chondrocytic components of the growth plate (autocrine regulation) and toward the osteogenic and vascular elements (paracine regulators). Extracellular matrix components of the mineralized growth plate may elaborate signals or be a permissive substrate for osseous and vascular induction. The surrounding and resorption of the mixed trabeculae by osteoclastic cells is the terminal event in the remodeling process of the endochondral tissue. Signals elaborated from the mineralized cartilage-bone trabeculae, as well as the cells lining this trabeculae, are involved in this recruitment process. This process involves the coordinated temporal-spatial differentiation of three separate tissues (cartilage, bone, and the vasculature) into a variety of complex structures. The differentiation of chondrocytes during this process is characterized by a progressive morphological change associated with the eventual hypertrophy of these cells. These cellular morphological changes are coordinated with proliferation, a columnar orientation of the cells, and the expression of unique phenotypic properties, including type X collagen, high levels of bone, liver, and kidney alkaline phosphatase, and mineralization of the cartilage matrix. Several studies indicate that hypertrophic chondrocytes also express osteocalcin, osteopontin, and bone sialoprotein, three proteins that were widely believed to be restricted in their expression to osteoblasts. Other studies suggest that the hypertrophic chondrocytes are regulated by the calcitropic hormones, morphogenic steroids, and local tissue factors. The considerations are based on the regulation by 1,25-(OH)zD3 and the retinoids of the cartilage-specific

37

genes as well as osteopontin and osteocalcin expression in hypertrophic chondrocytes. Studies further suggest that specific transcription factors mediate exogenous regulatory signals in a coordinated manner with the development of bone. Whereas it has been demonstrated to the satisfaction of some that the majority of hypertrophic chondrocytes undergo apoptosis during terminal stages of the developmental sequence, their response to specific exogenous regulatory signals and their expression of bone-specific proteins give rise to questions about whether all growth chondrocytes have the same developmental fates and identical functions. Aizawa et al. demonstrated apoptosis in hypertrophic growth plate chondrocytes in the rabbit using specific antibody staining techniques for TUNEL [terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP)-biotin nick end labeling] (2). Gibson reviewed the active role of chondrocyte apoptosis in endochondral ossification (128). The physiological form of cell death appears not to be just a passive removal of unwanted cells but rather an event that plays an active role in initiating processes that follow cell death. The possible pivotal role of chondrocyte apoptosis is discussed for each calcification of the growth plate longitudinal septae, cartilage resorption, growth factor release, maintenance of growth plate height, and activation of vascular invasion and bone formation at the lower part of the endochondral sequence. Specific questions arise as to whether there are similar mechanisms or regulation for commonly expressed genes found in both cartilage and bone or whether these genes have unique regulatory mechanisms in these different tissues. These findings suggest that hypertrophic chondrocytes are functionally coupled during endochondral bone formation to the recruitment of osteoblasts, vascular cells, and osteoclasts. Over 100 years ago some observers, using light microscopy, continued to maintain that at least some hypertrophic chondrocytes survived and differentiated to bone forming cells in the metaphysis (see Section IV). The ability of hypertrophic chondrocytes to synthesize specific matrix molecules now is well-accepted, as is the fact that many or most of the hypertrophic chondrocytes subsequently undergo apoptosis. Surprisingly, perhaps the question of whether some hypertrophic chondrocytes do differentiate to an osteogenic line is still supported by some, now based on molecular studies. Roach et al. in a study in vitro of embryonic chick bones, noted asymmetric cell division in hypertrophic chondrocytes with diverging fates of two daughter cells, one undergoing death by apoptosis and the other surviving, dividing, and generating osteogenic cells. Their work also referred to differing views on the matter published over the previous three decades. The crucial event in differentiation to a bone line was the asymmetric division noted. This division resulted in one viable and one apoptotic cell, following which the viable cell reentered the cell cycle and gradually differentiated to the bone forming line.

38

C H A P T E R 1 ~ Developmental Bone Biology

F I G U R E 12 The cell and matrix characteristics of the perichondrial ossification groove of Ranvier are illustrated. (A) A light micrograph from the developing groove of the distal femur of the rabbit is shown. The physeal cartilage is shown at left. Three cell populations within the groove are the region of densely packed cells at the depth of the groove, the region of less densely packed cells just above it, and the outer layer of fibrous cells. The region of densely packed cells is the terminal extension of the inner osteogenic layer of the periosteum. It secretes an osteoid matrix, which ensheathes the physis and shortly begins to synthesize the intramembranous bone referred to as the bony ring or bony bark of the ossification groove. The fibrous layer is the continuation of the outer fibrous layer of the periosteum. [Reprinted from Shapiro et al. (1977). J. Bone Joint Surgery 59A:703-723, with permission.] (B) The most terminal extension of the region of densely packed cells within the depth of the groove is shown. Note the curvilinear orientation of the cells. There is virtually no matrix seen between them. These cells do not add cartilage to the transverse diameter of the epiphyseal or physeal cartilage, but rather serve as bone forming cells. (C) The fact that the cells densely packed have been differentiated along a bone

SECTION VII 9 Structural Development of the Epiphyseai Regions

D. Perichondrial Ossification Groove of Ranvier The endochondral and intramembranous bone formation systems always merge at the periphery of a developing bone in a specific series of tissue conformations referred to as the perichondrial groove of Ranvier (204, 205, 208, 285, 320, 321, 331). As we noted previously, the developmental sequence of the periosteal sleeve is always spatially and temporally slightly in advance of that of the contained endochondral sequence. This relationship persists even when the epiphyseal growth plate has established its definitive relative position at either end of the bone. The epiphyseal growth plate thus is surrounded by periosteal tissues, which serve as a structurally supportive mechanism. Three cell populations have been defined in the depths of the groove (320). The groove refers to the circumferential depression in the periphery of the epiphyseal growth plate, which has its deepest extent opposite the resting or germinal cell layer and the adjacent epiphyseal cartilage. The outer fibrous layer of the periosteum continues surrounding the epiphyseal growth plate and inserting above the deepest part of the groove of Ranvier into the cartilage of the epiphysis. The inner osteogenic cell layer of the periosteum is also continuous, serving to surround the epiphyseal growth plate and commencing as an accumulation of densely packed cells in the depth of the groove adjacent to the germinal and proliferating cell layers of the physis. At their deepest part, these cells are undifferentiated mesenchymal cells that quickly differentiate to preosteoblasts and synthesize a characteristic osteoid matrix, which shortly is mineralized to form actual intramembranous bone. These spicules of intramembranous bone surround the epiphyseal growth plate well into the level of the proliferating zone. Although they are not sufficiently wide to be seen radiographically, they are clearly present at a histological level. The bone ring is sometimes referred to as the perichondrial bony bark or bony ring of Lacroix. The third region of cells specific to the groove of Ranvier is undifferentiated cells that are more loosely packed and that lie between the outer fibrous layer and the region of densely packed cells

39

that are osteoblast precursors. These cells appear to add to the periphery of the epiphyseal cartilage and therefore serve as chondrocyte progenitors. The cells are considered to be responsible for the increase in width of the epiphysis. Once deposited in the epiphyseal cartilage with growth, they are encompassed within the epiphyseal growth plate and then pass through the developmental stages from germinal to proliferating to hypertrophic cells. An integral part of development of the periphyseal region is the cut-back zone, which is responsible for the shaping of the metaphysis, a process sometimes referred to as funnelization. As this region is narrower than that immediately above it, it is evident that osteoclastic resorption must have occurred to remove the excess tissue. Histologic slides reveal abundant amounts of these osteoclasts, which are responsible for the funnelization and shaping of the developing bone in the metaphyseal regions. In the large majority of instances, the bone bark is resorbed at the metaphyseal level along with adjacent metaphyseal endochondral bone, serving to leave the circumferential bone ring as a structure anatomically separate from the cortex of the metaphyseal and diaphyseal regions. The outer fibrous layer of the periosteum, however, always remains intact. Burkus and Ogden described the perichondrial ossification groove region of the human distal femur from the fetal time period to skeletal maturation at 16 years (48). The cell regional structure including the bony ring was most evident in the young fetus. They felt that appositional chondrocyte growth was most evident during the first 5 months of gestation, after which its activity diminished. The structural characteristics of the perichondrial groove region are illustrated in Figs. 12A-12H, Figs. 13A-13C, and Figs. 14A, 14B.

E. Periosteum and Its Relationship to the Epiphyses, Metaphyses, and Diaphyses The periosteum is widely recognized to play a major role in cortical bone formation by the intramembranous mechanism.

F I G U R E 12 (continued) forming line is shown by this alkaline phosphatase histochemical stain. The adjacent physis is seen at right. The region of densely packed cells is well-outlined by the dark staining alkaline phosphatase at left. (D) Tritiated thymidine autoradiography outlines the high cell turnover activity in the region of densely packed cells. Uptake initially is concentrated in the upper end and also along the outer margins, which corresponds to the presence of the rapidly dividing nondifferentiated cells. The physeal cartilage is at left. (E) Another tritiated thymidine autoradiograph shows extensive uptake in the region of densely packed cells. One also notes uptake in the proliferating layer of the physis, indicating interstitial growth there, uptake in the germinal zone of the physis that would serve to add more columns at the periphery and allow for interstitial widening of the physis, and also a cell right at the point of juncture of the epiphyseal cartilage and the region of less densely packed cells, indicating that this region contributes to transverse growth of the epiphyseal cartilage and ultimately of the physis by adding chondrocytes at the periphery. (F) Passage of the outer fibrous layer into the epiphyseal cartilage (arrows) beyond the physeal cartilage is shown. This is where the periosteum is firmly attached to the developing bone. The region of less densely packed cells (i, curved arrow) is seen between the densely packed cells below and the outer fibrous layer above. (G) The groove components closer toward the metaphysis show increasing osteoid synthesis by osteoblasts (arrow). These cells synthesize the bony ring. (H) The bony ring of the groove (arrows) is shown adjacent to the metaphysis. It is an example of direct intramembranous bone synthesis. The outer fibrous layer of the periosteum is shown at left. At the metaphyseal region, there is discontinuity between the bony ring of the ossification groove and the cortex of the metaphyseal-diaphyseal area due to resorption by multinucleated osteoclasts. [Reprinted from Shapiro et al. (1977). J. Bone Joint Surgery 59A:703-723, with permission.]

CHAPTER 1 9 Developmental Bone Biology

40

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BONE METAPHYSIS

OSTEOCLAST RESORPTION

(A) Tritiated thymidine labeling of progenitor cells in the region of densely packed cells is illustrated. The study assessed the number of labeled cells and their presence from 2 to 72 hr after injection. Four comparably sized regions of the densely packed cells were measured with area 1 being at the uppermost part and area 4 along the metaphyseal region. At 2 - 4 hr, most of the cells are concentrated in area 1, and they progressively appear in area 4 with time as a reflection of their presence within the groove, which itself is growing upward and outward. [Reprinted from Shapiro et al. (1977). J. Bone Joint Surg. 59A:703-723, with permission.] (B) The contributions of the various cell populations to growth at the peripheral regions of the physis are shown in parts (Bi) and (Bii). [Part Bi reprinted from "Skeletal Growth and Development," (J.A. Buckwalter et al., eds.), Ch. 28, Fig. 2B, copyright 1998 by the American Academy of Orthopedic Surgeons, with permission.] (C) Illustration showing the relative changes of position of the perichondrial ossification groove and in particular the bony ring bark with growth. The bony ring tends to be positioned in an outward and upward direction with growth. New bone is added at the top, and bone is resorbed from the bottom at the metaphyseal cut-back zone. The physis would be to the left.

SECTION VII 9 Structural Development of the Epiphyseal Regions It is composed of an outer fibrous layer and an inner osteogenic or cambial layer. Less widely appreciated, however, is the fact that the periosteum also has a major support role in relation to stability at the physeal-metaphyseal junction as well as a role in applying appropriate tensile forces to the physis during the growing years. The outer fibrous layer of the periosteum passes beyond the physis and attaches into the epiphyseal cartilage. It serves as a continuous layer from the epiphyseal cartilage of the proximal end of a long bone to the epiphyseal cartilage of the distal end of that bone. The periosteum is quite loosely attached to the underlying cortical bone in the developing child. The reasons for this relate to the differing growth rates within the bone itself and within the periosteum. The bone grows by apposition of tissue at either end, but the periosteum has been shown to grow uniformly throughout its length by interstitial cell mechanisms (364). In addition, one end of any long bone grows more rapidly than the opposite end. The loose attachment of the periosteum to the underlying bone enables the differential growth mechanisms to occur simultaneously without difficulty. The interstitial growth of the periosteum also serves to maintain the relationship of the muscle attachments to the periosteum, an occurrence that would be much more difficult if the periosteum itself grew only at its proximal and distal ends. The outer fibrous layer of the periosteum is continuous from epiphyseal cartilage to epiphyseal cartilage, whereas the inner osteogenic layer often is discontinuous at the region of the metaphyseal cut-back zone particularly where this zone is quite angled. The periosteum is firmly adherent to the growing bone at either epiphyseal end. Lacroix indicates that the only area between these regions in which periosteal elongation and bone elongation are the same is at the so-called "null point" of periosteal growth, which is farthest away from the most active growth plate and nearest to the least active growth plate (204). This would occur, for example, in the tibia at about 35% of the tibial length above the growth plate because only 35% of tibial growth occurs at the distal end of the bone. The extrinsic support that the periosteum provides for the growth plate at the periphery of the groove of Ranvier region is considerable. John Poland, in his classic treatise on epiphyseal growth plate fractures, reports an experiment by John Wilson in the 1820s in which weights were applied to anatomic specimens of human distal childhood femurs (273). When the circumferential periosteal tissues were removed from the growth plate region, the amount of weight required to dislodge the epiphysis from the metaphysis was only one-fifth as great as when the tissues were intact. Considerable structural support is provided by the periosteal and perichondrial tissues. Amamilo and associates also showed that a consistently higher force was needed in rats to produce epiphyseal displacement with the periosteum intact (5). Alexander (4) documented the occurrence of distal radial epiphyseal fractures at times of most rapid growth and im-

41

plicated changing mechanical features of the open physes at different ages. The muscles and tendons are attached directly to periosteum in the growing child rather than to the underlying cortical bone. There is a distinct change in adults, however, in whom the periosteum is much thinner, is firmly adherent to the underlying cortex, and demonstrates muscle and tendon fibrils that pass through it to gain direct attachment to the underlying cortex by Sharpey's fibers. It has been postulated that there is a strong fibroelastic periosteal sleeve effect on the physis that not only applies a certain degree of tension across it but may serve as a check to unconstrained longitudinal growth. It has long been recognized and continues to be shown that circumferential division of the periosteal sleeve, especially if it is performed close to the metaphyseal-epiphyseal regions, will allow for increased longitudinal growth of those bones (61, 80, 151). What is unclear, however, is whether the increased growth is due to the diminution of mechanical constraint during the time that the periosteal sleeve is discontinuous or due to an increase in vascularity in the peri-epiphyseal region that occurs consequent to injury and during the repair phase. The absence of overgrowth when longitudinal cuts were made in the periosteum though supports the mechanical effects (80). A medial hemicircumferential division of the proximal tibial periosteum leads to medial overgrowth and valgus deformation (64, 164). When periosteal removal was done circumferentially in 4-mm-wide strips, in the mid-diaphyseal region of 4-week-old rats, overgrowth was seen but it was minimal: only 1.5% greater than the opposite side (119). Haasbeek et al. have shown that, when periosteum is thickened adjacent to a physis, it serves as a tether to cause angular deformity (134). They demonstrated the phenomenon in two clinical cases and experimentally. In summary, the periosteum is shown to affect growth of the physes mechanically because it ensheathes the physes and inserts beyond them into the epiphyseal cartilage. When periosteal tension is reduced the longitudinal bone growth is increased, and when the tension is increased growth slows slightly.

F. Cortical (Diaphyseal) Bone Formation-Woven Bone and Lamellar Bone The histologic appearance underlying cortical (diaphyseal) bone formation is well-understood. In fact, the book Osteologia Nova or Some New Observations of the Bones by Clopton Havers published in London in 1691, in which he described longitudinal pores passing from one end of the bone to the other, is widely considered to represent the initial scientific description of bone (145). These longitudinal passages have come to be referred to as Haversian canals, even though Havers did not describe blood vessels within them. He also described transverse canals and clearly noted the internal structure of bone to be lamellar.

42

CHAPTER

1 ~

Developmental Bone Biology

SECTION VII ~ Structural Development of the Epiphyseal Regions Beginning with the primary center of ossification, and its increased development during the fetal time, woven bone is synthesized initially by the inner cambial layer of the periosteum. Very shortly, once an appropriate amount of scaffolding has been synthesized, new bone formation is lamellar in nature. The lamellar bone is deposited on the woven bone cores. With increasing development the lamellae become more compacted, and by the late fetal period Haversian systems have clearly formed. This development continues throughout the postnatal period to skeletal maturation. With the increasing length and diameter of the long bone, there is synthesis particularly on the outer layer of the cortex and resorption internally as the marrow cavity forms and widens. The term woven bone refers to the randomly oriented positioning of the collagen fibrils in the newly synthesized matrix. Any time there is rapid synthesis of new bone in a spatial area where bone did not previously exist, the osteoblasts secrete the collagenous fibrils in all directions and themselves become enmeshed among the fibrillar mass. The newly formed collagen prior to mineralization is referred to as osteoid. Histologic characteristics of woven bone involve relatively large and numerous cells in relation to the amount of matrix present. We refer to the osteoblasts of woven bone as mesenchymal osteoblasts because they are newly formed along the undifferentiated cell line to preosteoblasts and then to osteoblasts. The term lamellar bone refers to bone tissue in which the collagen fibrils are well-oriented in a parallel array. The sheets of fibrils form lamellae, which also relates to the term lamellar bone. Adjacent lamellae are at fight angles to one another although both are in a parallel array. This is sometimes referred to as an orthogonal arrangement. Lamellar bone is synthesized on preexisting cores of tissue, which in cortical bone formation is primarily the initially synthesized woven bone. A structural characteristic of lamellar bone formation is that the osteoblasts responsible for it are present on the surface and they basically secrete the fibrils not only in a parallel array but also in a directional sense only along the adjacent surface of the underlying bone. This is in counter distinction to the mesenchymal osteoblasts, which form woven bone in a 360 ~ spatial pattern around the cell. Lamellar bone tissue is synthesized in intimate relationship to the associated vessels. In a general sense, the vessels of bone run in parallel position along the longitudinal axis of

43

the developing cortex. The vessels are associated with mesenchymal cells of the osteoblast line, the cells referred to in lamellar bone formation as surface osteoblasts. Bone tends to form circumferentially around the individual vessels, forming circumferential lamellae and synthesizing tissue internally until only the vessel and a small number of adjacent cells are present. This leads to what is referred to as compaction of bone, which is also referred to as bone of increased density. The term Haversian system refers to the central vessel surrounded by the lamellae of bone that derives its nutrition from that vessel. This is sometimes referred to as the functional unit of bone and is also referred to as an osteon. The osteons and the central Haversian canal vessels tend to run along the long axis of the bone, although few are strictly parallel to it. Vessels that connect adjacent Haversian systems in a plane transverse to the long axis of the bone are present in Volkmann's canals. They typically are illustrated as being along the transverse axis of the cortex and at fight angles to adjacent Haversian systems, although in fact they tend to be somewhat oblique in orientation. The osteocytes are present in lacunae, and the osteocyte cell processes that link adjacent osteocytes are present in canaliculi. The lacunae and canaliculi in woven bone have no specific orientation consistent with the relationship of the various mesenchymal osteoblasts and young osteocytes. In lamellar bone the orientation of the cells and cell processes becomes more structured. The lacunae are oval structures flattened along the long axis of the lamella, and the canaliculi also tend to pass either parallel to the lamellae or at fight angles to them. Two additional terms referring to the structure of bone can best be introduced here. Bone is referred to as being either dense-compact or cancellous. Cancellous bone refers to spatial regions of the bone in which there is relatively more space filled with cells and vessels than there is mineralized bone tissue. Fine cancellous bone refers to this situation at a light microscopic level of resolution, and it is commonly seen in the developing cortices of the fetus. Gross examination does show what would appear to be uniformly structured cortex, but microscopic examination shows woven and early lamellar bone to be associated with relatively large spaces between the bone tissue filled with cells and vessels, leading to the cancellous description. Coarse cancellous bone refers to the appearance upon gross examination

FIGURE 14 Photomicrographsillustrate the cell and matrix contributions to the physis and the surrounding ossification groove. (A) A portion of the physis, including the perichondrial ossification groove from a rabbit metatarsal, is shown. Note the hypertrophic cell invasion by the red blood cells below and immediatelyto the fight of the bony ring of the ossificationgrooveextendingwell beyond the level of endochondral bone formation. (B) A series of transversecuts is shown, indicating the changingcell and matrixrelationships: (Bi) transverse cut through the epiphyseal cartilage; (Bii) transverse cut through the proliferating and hypertrophic cell region of the physis; (Biii) section through the hypertrophic zone; (Biv) section through the upper reaches of the metaphysis; (Bv) section through the metaphysis at the cut-back zone. Multinucleatedresorptiveosteoclastsare seen. The outer fibrous layer of the grooveremainsintact, but the inner osteogeniclayer and the bone bark are incomplete. (Bvi) Section through the lower regions of the metaphysis shows the outer fibrous layer intact but the bone bark completelyresorbed. Multinucleatedresorptive osteoclasts are prominent. The cortex will be reestablishedat the metaphyseal-diaphysealjunction as intramembranousbone from the periosteumis synthesized. [Parts A, Bi, Bii, Biv, Bv, Bvi reprinted from Shapiro et al. (1977). J. Bone Joint Surgery 59A:703-723, with permission.]

44

CHAPTER

1 *

Developmental Bone Biology

in which there is relatively more space than bone tissue. The term is applied to the noncortical metaphyseal regions in which the trabeculae of bone are surrounded by relatively large spaces filled with cells and vessels.

G. Development of J o i n t s - - G e n e r a l Description Development occurs by a series of cellular changes that are regional in scope. A series of undifferentiated cells forms initially, which then undergoes tissue differentiation and pattern formation from the very general to the specific. Work on joint development initially was described by von Baer (1837) (13), who observed that each element of the appendicular skeleton originally was laid down as a separate cartilage and that it was the unchondrified tissue between these more differentiated elements that eventually formed the joints. Appendicular development moves in a wavelike fashion from the proximal part of the extremity toward the distal part, and development in the upper limb precedes that in the lower limb by several hours to a few days. The various bones are formed by initial centers of chondrification at the central region of the developing bone, followed by progressive chondrification to each end in a well-patterned fashion. The joints form relatively late in development after the patterns of the two adjacent bones, including their epiphyseal regions and articular cartilages, have been established. Development of the joints in the human extends from the first appearance of the joint rudiments at 11 mm C - R length to the appearance of the cavities at 30-34 mm (120, 210, 263). The skeletal development of the shoulder and pelvic girdles and larger bones continues as centers of chondrification in the interior of the blastema, with one for each element at 11 mm. Muscle condensation slightly precedes chondrification. As chondrification expands toward the presumptive ends of each bone, the unchondrified mesenchymal tissues remaining between the cartilages gradually become thinned to form a series of cellular collections referred to as the interzones. It is these regions that form the first morphological indication of the joints. The cavities of the larger joints appear at or soon after the onset of periosteal ossification in the long bones. Joint development thus can be followed through clear stages of (i) homogeneous interzone; (ii) three-layered ihterzone, (iii) the stage of early liquefaction, and (iv) the stage of full separation (Fig. 16). The three-layered structure was described by Bernays (26), Schulin (315), and Kazzander (184) but was best illustrated by Hesser (152). Retterer (290, 291,293) described the histologic aspects of joint formation in detail. Haines believes that the intermediate layer of the interzone is always liquefied soon after the synovial mesenchyme differentiates, so that separation of two adjacent cartilage surfaces is complete by the 34-mm stage at the shoulder and radial-humeral joints, by 44 mm at the knee and probably at the hip, and by 45 mm at the metacarpophalangeal joints and ankle joints, whereas the wrist and carpal joints separate only after 50 mm (138).

It is only later that the joint cavities spread peripherally to develop the complex recesses they subsequently show. Hesser has indicated that the articular surfaces are shaped at a stage when their interzones are still homogeneous, such that little or no movement of adjacent developing cartilage surfaces could occur. The synovial cavities initially are formed partly in the tissues of the interzone and partly in the synovial mesenchyme, so that the articular surfaces are composed centrally of chondrogeneous layers of the interzones and peripherally of tissues of similar constitution that originally are part of the intracapsular perichondrium. Near the margins of the articular surfaces there is a zone of transition between those articular surfaces and the perichondrium. With full chondrification of the articular surfaces, the remains of the liquefied tissues of the interzone or synovial mesenchyme come to form a thin layer overlying the cartilage containing flattened cells, some of them necrotic. Eventually these cells disappear. It is felt that the capsules and the region adjacent to the joints are new formations. Joint development is outlined by photomicrographs of histologic sections in Figs. 15A-15D.

1. DETAILED DESCRIPTIONOF JOINT DEVELOPMENT Joints are first defined in the interzone regions at 11 mm and the synovial cavities of the larger joints appear at 34 mm. The joints first appear as interzones, which are formed from the remains of the skeletal blastema between the cartilages. The interzones form the more central parts of the articular cartilages and synovial cavities. Each interzone passes from a homogeneous stage to a three-layered stage with chondrogeneous layers, an intermediate loose layer, and the stage where the interzone layer breaks down and the chondrogeneous layers become fully chondrified. The fibrous capsule near the joints cuts the mesenchyme into two regions, one of which forms the synovial mesenchyme and the other the perichondrium, which can be intracapsular. The intracapsular perichondrium is partly transformed into the more peripheral parts of the articular cartilage, whereas the remainder persists throughout life. The synovial mesenchyme forms the more central part of the synovial cavities, synovial and subsynovial tissues, and all intracapsular structures including ligaments, tendons, and fibrous cartilages. The interzones of the larger joints appear at 11-12 mm, the fibrous capsule at 16 mm, the interzones become three-layered at 21-26 mm, liquefaction of the synovial mesenchyme begins at 30-34 mm, and the separation of the articular cartilages is complete by 40 mm. Eventually, when the synovial cavities are formed, the remnants of the liquefying tissue are totally destroyed. By 12 mm, the cartilages at the shoulder and elbow have adopted their characteristic shapes and the interzones are relatively thick but quite distinct, with each formed by a mass of undifferentiated blastemal tissue between the cartilage. At the knee the interzone at the first stage is indistinct because chondrification of the distal femur and proximal tibia have not progressed as far, relatively speaking, as those

SECTION VII ~ S t r u c t u r a l D e v e l o p m e n t o f t h e Epiphyseal R e g i o n s

F I G U R E 15 A series of photomicrographs shows the stages of joint development. (A) In stage 1 there is a homogeneous interzone with undifferentiated cells filling the space between the developing cartilage model of two adjacent long bones. (B) A three-layered interzone is formed with relatively more dense accumulations of tissue outlining the articular regions (arrows) of the adjacent epiphyses and slightly less dense but still homogeneous cell accumulations filling what will eventually become the joint space. (C) The stage of early liquefaction is shown here in the developing elbow joint. Although there are still cells in the interzone region, their density is diminished and areas of a cellularity are seen. (D) The fourth stage of joint development represents the stage of full separation with a clear synovial cavity seen.

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CHAPTER 1 ~ Developmental Bone Biology

of the upper extremity at the elbow. At the hip the pelvis is still represented by dense blastemal tissue continuous without form with the upper end of the femur with the interzone not yet in evidence. By 13 mm at the shoulder, hip, and knee, each interzone is now formed by a distinct plate of condensed tissue whose cells pass without interruption into the cartilages on either side. Peripherally the interzone is continuous with the perichondrium of the skeletal elements. At the hip the interzones, perichondrial tissues, and condensed tissues are in unbroken continuity. There is virtually no differentiation within the interzone area during the time in which considerable differentiation of periarticular tissues is occurring. The interzone shows little sign of the shape of any future articular surfaces. At the hip and knee in particular the interzones are fiat with the eventual shape not yet distinguishable. By 14 mm the ends of the cartilages have assumed their characteristic shapes. By 16 mm the interzones of the larger joints are still homogeneous and continuous with the perichondrium surrounding the cartilages. Differentiation of fibrous capsule and ligaments is beginning to be seen, and the interzone region is continuous at its periphery with the intracapsular perichondrium, which in turn is continuous with the extracapsular perichondrium. The early synovium forms between the capsule and extracapsular perichondrium in its own less condensed tissue. This eventually will differentiate into the synovial and subsynovial tissues and such intercapsular structures as are formed. The early derivatives of the blastema, including the cartilages, perichondrial tissues, and interzones, are free of blood vessels at this stage. Vessels ramify over the outer surfaces of the perichondrial tissues. Vessels do not enter the perichondrium until this layer alters in structure in preparation for the formation of periosteal bone. Some vessels, however, appear in the fibrous capsules of the joints and are seen lying in the synovial mesenchyme. By 19 mm the pattern of the interzone, synovial mesenchyme, capsule, and perichondrium is more distinct. The interzones remain fully homogeneous, dense structures composed of tightly packed cells at 18-20 mm, with the cells continuing to undergo frequent mitotic division. As development proceeds, a characteristic three-layered interzone is formed particularly in the intracapsular region. At 21 turn at the elbow both the humeral-radial and humeralulnar joints are clearly three-layered, with two dense cartilage layers that are destined to form the articular surfaces separated by an intermediate loose cell layer. At the periphery of the presumptive joint, the intermediate layer of the interzone is continuous with the synovial mesenchyme but the interzone tissue is always avascular. Embryologists refer to the cartilage layer of the developing ends of the bones as true perichondria, which are continuous with the extracapsular perichondrium. There are clear differences, however, from the perichondrial tissues, which can be removed from underlying surfaces and are well-vascularized from those within the joint itself, which never have a blood supply.

In the shoulder joint at 21 mm there is early loosening of the middle layer of the interzone, with the capsule and the adjacent tendons differentiated from the dense mesenchyme. At the knee dense interzonal tissue still intervenes between each femoral condyle and the articular surface of the tibia. By 23 mm the interzone of the shoulder has attained a typical three-layered structure and a fibrocartilaginous labrum is seen. At 24 mm at the hip and knee the interzones are still dense and homogeneous. At 26 mm the interzones of the knee are in the early three-layered stage. In the knee the interchondral interval is filled with an abundant vascular synovial mesenchyme, from which the cruciate ligaments appear as well as the menisci. At 29 mm, just before the joint cavities appear, the distinction of the layers of the interzone becomes sharper. In the intermediate layer the cells become flattened and lie with their surfaces parallel to the surfaces of the interzone. The matrix of this tissue becomes clearer in preparation for resorption. At the shoulder, Which is advanced in development from other joints, the synovial mesenchyme on either side of the joint is breaking down and small cavities are being formed. By 29 mm all of the larger joints have reached the stage in which the interzone is threelayered. The times at which this appearance is attained vary: shoulder, 23 mm; elbow, 21 mm; wrist and most of the carpal joints, 25 mm; all of the interzones of the fingers, 27 mm; hip, 30 mm; knee, 26 mm; ankle, 27 mm; smaller intertarsal joints, 32 mm; toes, 32 mm. By 30 mm the middle layer of the interzone and the inner portion of the synovial mesenchyme are softening and begin to break down to form the first joint cavities. Between the cartilage surfaces there is a loose liquefying tissue. At 34 rnrn the cavity of the humeroradial joint is well-formed but still contains a few cells in its interior. At the hip the cavity is spreading around the head of the femur and the ligamentum teres lies in this synovial mesenchyme accompanied by conspicuous blood vessels, which will later supply the cartilage canals of part of the head of the femur. At the knee the menisci are sharply differentiated and joint cavities have developed between the anterior parts of the menisci and the femoral condyles.

H. Epiphyseal Blood Supply 1. GENERAL DESCRIPTIONmDUAL PHYSEAL BLOOD SUPPLY FROM EPIPHYSEAL AND METAPHYSEAL VESSELS The blood supply of developing and mature bones has been well-described and is illustrated in Figures 16Ai,ii (39, 73, 255, 349-351). The growth plate itself is avascular but has a dual blood supply, receiving its nutrition from two separate sources: the epiphyseal vessels that supply the germinal, proliferating (columnar), and upper hypertrophic cell layers by diffusion and the metaphyseal vessels that supply the zone of calcification beginning in the lower hypertrophic

SECTION VII ~ Structural Development of the Epiphyseal Regions cell layers by passing only two to three cells deep into the hypertrophic cell lacunae. The epiphyseal vessels thus are responsible for permitting longitudinal growth to occur, whereas the metaphyseal vessels, accompanied by the osteoprogenitor cells, are responsible for laying down bone on the calcified cartilage matrix cores. The specific roles of the epiphyseal vessels and the metaphyseal vessels have been studied for some time in the works of Haas (1917) (132, 133), Trueta and Amato (1960) (351), and Brashear (1963) (32), the latter being most helpful. Each of these works has documented the fact that the proliferation of epiphyseal cartilage cells to enhance longitudinal growth depends on the epiphyseal circulation (Fig. 16B) and that damage to this blood supply causes not only necrosis of the secondary ossification center but marked changes in the epiphyseal plate and longitudinal growth. The diffusion of nutrients also encompasses the entire thickness of the plate, including nutrition into the hypertrophic zone. The extremely rich blood supply on the metaphyseal side of the physis plays essentially no role in the growth process, but has as its main role the calcification of the matrix in the lowermost part of the hypertrophic zone, the invasion of the hypertrophic cell lacunae, and the transport of associated osteoprogenitor cells that synthesize bone on the calcified cartilage cores. The experimental evidence points to the fact that blood carried by the metaphyseal side vessels is of no nutritional importance to the hypertrophic cells. Indeed, when the metaphyseal circulation is markedly ablated, the hypertrophic zone not only persists but increases in size due to the continuation of diffusion from the epiphyseal vessels above. The dual vascular supply to the physeal regions has been well-demonstrated by Trueta and Morgan using vascular perfusion studies (349). They demonstrated the epiphyseal vessels passing through the bone plate of the well-developed secondary ossification center and then ramifying over the surface of the germinal zone of cartilage of the physis without passing into the physeal cartilage itself. They noted that the epiphyseal arteries crossed through canals in the bone plate and expanded into terminal spurs before turning back as large veins, although not always through the same canal. Each terminal expansion covered the space corresponding to from 4 to 10 physeal cell columns, although the vessels themselves did not penetrate into the physeal cartilage. Transverse histologic sections immediately under the bone plate and thus on the surface of the germinal zone of physeal cartilage showed a very rich vascularity, with the whole of the vascular expansions forming a ceiling over the physeal cartilage. The second set of vessels for the dual blood supply represented those from the metaphyseal side, with approximately four-fifths of the vessels reaching the growth plate from the metaphyseal side consisting of the last ramifications of the nutrient artery distributed over the most central parts of the growth plate, with the outer fringe of the lower plate supplied from the system of large perforating metaphy-

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seal arteries from the adjacent periosteum. These two systems merged, however, such that there was no detectable distinction between the end vessels of the two sources on the metaphyseal side. Both repeatedly divided into ever finer arterioles. 2. EXTRINSIC BLOOD SUPPLY

There are two basic extrinsic patterns of blood supply to the epiphyses (73). In the large majority of epiphyses, vessels pass through the perichondrium of the side walls into the epiphyseal cartilage throughout the circumference of the epiphysis from the level of the articular cartilage to that of the physeal cartilage (Fig. 16B). In epiphyses that are covered almost entirely by articular cartilage, namely, those of the proximal femur and the proximal radius, the blood supply is more tenuous and vessels enter the epiphyseal cartilage in a small region between the articular cartilage and the growth plate cartilage. In the former instance the physeal regions are extracapsular in position and in the latter they are intracapsular (Fig. 16C). The vessels entering the hypertrophic zone are derived from and are the termination of both the nutrient and metaphyseal arteries. Arsenault and Hunter also studied the microvascular organization of the epiphyseal-metaphysealjunction in rats by light microscopy, serial section reconstructions, and scanning electron microscopy (10, 170). The metaphyseal and nutrient arteries undergo extensive arborization and anastomosis near their terminal ends. The microvascular system that projects into the hypertrophic cell region consists of saccular and bulbous terminal arteriole extensions. It is not formed of capillary loops returning arteriole blood to formed venules; venous return occurs below the hypertrophic zone of the epiphysis within anastomosing blood vessels, which drain into large blood sinuses. 3. INTRINSIC BLOOD SUPPLY OF EPIPHYSEAL CARTILAGE VIA CARTILAGE CANALS

Each of the major epiphyseal cartilages in the human is vascularized beginning from the third to the seventh fetal month, which represents a long period of time in each epiphysis prior to formation of the secondary ossification center (39, 48). The primary function of the canals is nutrition, and only later and secondarily do they participate in forming the secondary ossification centers. The vessels within the epiphyseal cartilage are present in cartilage canals in which a central artery or arteriole, capillaries, and a plexus of veins are enclosed in a connective tissue matrix (18, 29, 39, 49, 62, 63, 67, 68, 75, 76, 118, 135, 144, 146, 154, 168, 175, 178, 202, 213, 219, 292, 323, 328, 333, 363, 365-367, 370, 371) (Figs. 9B and 9C). In small canals there is only a capillary plexus. The vessels within the canals do not, therefore, directly contact the cartilage matrix nor do the arteries and veins run separately from each other. The canals and their contents appear to derive from and be continuous with the

Ai

F I G U R E 16 The blood supply of a developing bone is illustrated. (Ai) The epiphyseal vessels (E) are responsible for supplying the epiphyseal cartilage, the secondary ossification center, and also the growth plate, but only by diffusion from above. The lower part of the growth plate is supplied by the metaphyseal vessels coming in from the periphery and by the terminal ramifications of the nutrient (N) artery. The periosteal (P) vessels supply the outer one-third of cortical bone, whereas the nutrient artery supplies the inner two-thirds.

SECTION VII ~ Structural Development of the Epiphyseal Regions

perichondrium, although Delgado-Baeza et al. (76) commented that vessels, perivascular cells, or perichondrium was not necessary for canal morphogenesis and that on the basis of structural cell differences the canals were not a continuation of the perichondrium. Two mechanisms for formation of cartilage canals have been proposed, with support still expressed for both. One mode of origin of the cartilage canals is referred to as the theory of inclusion, whereby the vessels are considered to be present within the cartilage in a passive sense: as the cartilage matrix grows outward by perichondrial cells becoming chondrocytes it incorporates the perichondrial vessels, which continue to function. A more widely supported origin for the canals involves an active invasive or chondrolysis component to the cartilage canals, called the theory of invasion, as they position themselves into relatively large areas in need of nutrition not satisfied by cartilage canals assessed by tritiated thymidine autoradiography. It was concluded that active vessel invasion and proliferation occurred (221). Tritiated thymidine labeling studies to assess cell proliferation activity were done by using 2 Ixc/g body weight intraperitoneal injections into newborn and 3-, 4-, and 7-day-old New Zealand white rabbits that were killed 1 hr after the injection. Proximal humeral, distal femoral, and third metatarsal epiphyses were assessed by histology and serial section autoradiography. Cartilage canals were seen in each epiphysis. Transphyseal vessels were seen in each epiphysis continuous from the epiphysis to the metaphysis or present within the physis traversing the proliferating and hypertrophic cell zones (Fig. 16D). Histologic sections showed vessels from the perichondrium continuous from those of the epiphyseal cartilage canals at proximal humeral, distal femoral, and metatarsal epiphyses. Serial sections showed vascular buds and connective tissue cells lying in indentations at the periphery of and present within the epiphyseal cartilage (Fig. 16E). Autoradiographic studies showed extensive labeling of vessel wall cells and

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surrounding connective tissue cells of the cartilage canals (1) within the epiphyseal cartilage, (2) traversing the physis, and (3) within the epiphyseal cartilage but continuous with the perichondrial vessels (Fig. 16F). The labeling was always far more extensive than in the surrounding chondrocytes and was always present throughout the entire extent of the canals. The cell labeling activity strongly supports an active dynamic phenomenon underlying the vascularization of epiphyseal and physeal cartilage. Kugler et al. studied cartilage canals in the rat as they related to formation of the secondary ossification center, observing that cartilage canals advanced within the cartilage matrix by chondroblastic absorption (202). One autoradiograph showed thymidine labeling of cartilage canal connective tissue and blood vessel cells. Although some cells similar to chondroclasts can be seen within cartilage canals, our observations indicate that the large majority of canals are not associated with such cells. Fibroblast-like cells and uninuclear macrophages appear to be responsible for the chondrolysis (62, 63). Cole and Wezeman (67) noted chondroclasts in mouse epiphyseal cartilage canals but felt they were related to calcified matrix resorption specifically rather than to the invasive stage of canal positioning. Chondrolytic aspects of cartilage cell positioning do not appear to be mediated exclusively or even predominantly by chondroclasts. The primary function of the canals is to provide nutrition to the epiphyseal cartilage. Only weeks to months later do they provide vascularization for endochondral bone formation of the secondary ossification centers. Many have noted cartilage canal presence from the third fetal month. According to Haines and others there are no anastomoses between separate canals within the cartilage, and the vessels function as end vessels (135). Haines defines the patterns of cartilage canals as (1) simple branched or unbranched canals, which project into the cartilage and end blindly; (2) double or multiple rooted canals, which take their origin by two or

F I G U R E 16 (continued) There is, however, a rich anastomosis within the cortex. The tissues of the groove are supplied by the perichondrial groove artery (GA). (Aii) A cross-sectional illustration of blood supply to cortex and marrow from the mid-diaphyseal region. [Parts Ai, Aii reprinted from "Frazer's Anatomy," A. S. Breathnach, p. 10, 1965, by permission of the publisher Churchill Livingstone.] (B) A light power photomicrograph shows a perichondrial vessel (upper left) passing into the epiphyseal cartilage above the physis and well before the formation of the secondary ossification center. (C) In those epiphyses that are fully intracapsular (A, proximal femur), the epiphyseal region is covered almost completely by articular cartilage and the articular cartilage and the physeal cartilage are quite close (arrow). The vessels must enter in a restricted circumferential region through a narrow area between the articular and physeal cartilages. This pattern is seen at the proximal femoral and proximal radial epiphyses. The vessels are vulnerable to any shift of the epiphysis by acute trauma. This type of blood supply is referred to as type A by Dale and Harris (73). The more common type of blood supply to the epiphyseal regions is shown at right, referred to as type B by Dale and Harris. The vessels enter circumferentially through the side walls of the epiphysis in a broad region between the articular cartilage (arrow) and the physeal cartilage (arrow). These epiphyses are extracapsular in position. [Parts Ci, Cii reprinted from Shapiro, F. (1982). Orthopedics 5:720-736, with permission.] (D) A transphyseal vessel is seen from the proximal humeral epiphysis of rabbit. (E) Perichondrial vessels at the periphery of epiphyseal cartilage mass are illustrated from a 1-week-old distal femur (El) and newborn metatarsal (Eli) (rabbit). The curved arrow in (El) indicates the indentation at cartilage periphery. The perichondrium (P) and fibrous tissue are at upper left. The vessels in the indented areas generally are associated with a cellular connective tissue front (Eii). (F) Tritiated thymidine autoradiography demonstrates the high degree of cell proliferation in the vessels and connective tissue cells of the epiphyseal cartilage canals continuous with the perichondrial vessels in the distal femur at 1 week. This cartilage canal was continuous with a perichondrial vessel. [Parts D - F from Shapiro, F. (1998). Anat. Rec. 252:140-148, copyright 9 1998. Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.]

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C H A P T E R 1 9 Developmental Bone Biology

more separate roots from the perichondrium, but join within the cartilage and then act as simple canals; (3) tunnel canals, which traverse peripheral tonguelike projections of cartilage from edge to edge; (4) dividing and reuniting canals, which end as simple canals; and (5) transphyseal communicating canals, which originate from the perichondrium and end in the bone marrow of the shaft. After the ossification center has formed there are then (6) nutrient canals, which supply the bony center from the perichondrium, and (7) centrifugal canals, which arise from the bony center but behave as simple canals. Hurrell has noted that the vascular pattern of the cartilage canals is always different even in corresponding epiphyses in different fetuses (175). Cartilage canals are present in the human and in vertebrates such as pig, lamb, calf, and rabbit. They are not present in the mouse (111) and rat (23) in which vascular invasion of the epiphysis from the perichondrium occurs only at the time of secondary ossification center formation. 4. TRANSPHYSEAL COMMUNICATING CARTILAGE CANALS In the human in the fetal period epiphyseal cartilage canals occasionally occur, which originate from the perichondrium, pass through the physeal cartilage, and communicate with the metaphyseal marrow. The large majority of these are obliterated either before birth or soon after a secondary center is ossified. Such communicating canals are more prominent in other species such as the lamb in which several can often be seen in one section across the width of a physis. Histologically they are noted to contain red blood cells, indicating participation in blood flow, but the extent of their participation is not quantified. Many observers have noted transphyseal vessel communication in the human, including Hurrell (175), Hintsche (154), Haines (135), Bidder (29), Bardeen (15), Brookes (39), Trueta and Morgan (349), Watermann (365-367), Levene (213), Wang (363), Chappard et al. (62-63), Gray and Gardner (131), and Gardner and Gray (120). Brookes (39) studied human fetal lower extremity bone by barium sulfate microvascular injection techniques. Vascular cartilage canals were detected in epiphyses in rudimentary form as early as 16 cm-20 weeks, but they were well-developed in both ends of femur and tibia by 22 cm C - R length. Transphyseal connections were seen from 22 cm C - R length onward and were more numerous in older fetuses. They were seen at both upper and lower femoral ends. Transphyseal vessels are also present in other species. Levene (213) showed transphyseal vessels in lamb, cat (partial), rabbit, goat, and human, Parsons (268) found them in the young deer, and Hayashi (146) reported them in the fetal rabbit proximal femur. Lutfi (219) and Hunt et al. (168) showed vessels in the proliferating and hypertrophic layers of the chicken. Histologically they are noted to contain red blood cells, indicating participation in blood flow, but the extent of their participation is not quantified. We described transphyseal vessels in the New Zealand white rabbit in new-

bom, and 3-, 4-, and 7-day-old proximal humeral, distal femoral, and metatarsal bones (293) (Fig. 16D). Brookes (39) has shown that the lower end of the femur is vascularized by four groups of canals entering at the intercondylar notch, the suprapatellar surface, and the collateral aspects of the condyle. Multiple sections allow for demonstration of a vascular cartilage canal from the epiphyseal cartilage passing through the physeal cartilage into the metaphyseal area. The upper end of the tibia was canalized by vessels penetrating the intercondylar eminence and the whole circumference of the superior tibial perichondrial cartilage region. The vascular pattem showed a convergence toward the center of the epiphysis. The distal tibial epiphysis also showed arteries entering from all aspects circumferentially, with some entering the medial surface of the malleolus as a separate group. At the proximal femur, the vessels enter the femoral neck and head region circumferentially early on at 22 cm C - R length. Later two major groups are distinguished, a superior and an inferior group. Hurrell (175) felt, unlike others, that the transphyseal communication was passive, with epiphyseal vessels persisting with growth and being encompassed by the physeal cartilage and then metaphyseal marrow. The connection thus was felt to be "accidental and functionless." He particularly stressed that no vascular canal grew actively from the diaphyseal-metaphyseal shaft into the epiphysis. He noted vessels communicating at birth in upper humerus and upper tibia. Haines noted perforating transphyseal canals in several mammals at certain stages of their development. He also felt that the development of such canals was passive. Obliteration of the canals was a constant phenomenon at a slightly later stage of growth. Haines noted them to be "very conspicuous" in the early stages of ossification. The articular cartilage was always avascular. Smaller mammals such as the mouse and rat have no cartilage canals and develop their secondary centers by direct communication from perichondrial vessels at the time of bone formation. 5. CARTILAGE CANALS AND SECONDARY OSSIFICATION CENTER FORMATION Hurrell (175) and Retterer (292) have provided detailed reviews of the many descriptions of cartilage canals. The cartilage canals tend to become obliterated with time but many persist to supply the secondary ossification centers. Haines (135) believed from his serial reconstructions that the ossification center always appears centrally in an avascular zone between sets of cartilage canals. The canals are present in relatively large epiphyses and serve as sources of nutrition where diffusion from the periphery alone would be ineffective. Once an area that is not served by cartilage canals reaches a certain stage, the chondrocytes hypertrophy and degenerate, the cartilage matrix calcifies, and invasion by vessels from the cartilage canals follows bringing in osteoprogenitor cells to form the seconday center of ossification.

SECTION VII ~ Structural Development of the Epiphyseal Regions Bone is then synthesized on calcified cartilage cores. According to Haines: There can be no possibility of the osteoblasts of the epiphysis being derived from periosteal buds growing up from the bone marrow of the shaft, for at the time of ossification all communications between the shaft and the epiphysis have disappeared. It is highly likely that they are derived from the connective tissue of the cartilage canals . . . . The connective tissues of the cartilage canals and the perichondrium are exactly similar and are continuous with one another. The cartilage canals (1) determine by their distribution the position of a clear space or avascular lamina, which is where the ossification center forms, and (2) they give origin to the osteoblasts and marrow of the center. Hintsche (154), using serial section reconstructions, noted a uniform cartilage canal vascularity in epiphyseal cartilage and no relation of vessel pattern to site of secondary center formation or of center formation to avascular regions. Wilsman and van Sickle (371) noted a direct relation of cartilage canal glomerular ends to foci of calcified cartilage, such that the endochondral sequence of the secondary center was the same as that at the undersurface of the physis. They also found cartilage canals to be very evenly spaced.

I. Development of the Articular Cartilage 1. STAGES IN ARTICULAR CARTILAGE DEVELOPMENT The articular cartilage initially is being shaped during the times of epiphyseal and interzone formation. Once resorption of the interzone region has occurred, however, the smooth, free surface of the articular cartilage is evident. Four stages in the development of the articular cartilage can be defined (Fig. 17A). In the second stage the articular cartilage merges imperceptibly at a histologic level of resolution with the underlying epiphyseal cartilage. Other than the fact that the superficial one to two cell layers of the articular cartilage tend to be somewhat flattened parallel to the long axis of the surface, the underlying articular chondrocytes are dispersed randomly and demonstrate no different pattern or orientation from the chondrocytes of the epiphysis. Mankin has demonstrated differing cell proliferation zones, however, using tritiated thymidine autoradiography (223, 224). Thymidine localization in the cartilaginous epiphysis occurs in two distinct layers, indicative of regions of high cell proliferation. One zone was subadjacent to the articular surface so that it contributed to its growth and the other zone was just peripheral to the secondary ossification center, contributing to the epiphyseal expansion and laying the groundwork for enlargement of the ossific nucleus. The third stage of development occurs once the secondary ossification center has been formed and has reached its greatest relative extent referable to replacing the epiphyseal cartilage. At this time the undersurface of the articular cartilage merges with the physis of the secondary ossification center, which is referred to by

51

some as the miniplate. The physis of the secondary ossification center or the miniplate represents the mechanism by which the epiphyseal region of the bone continues to grow on the one hand and to transform to secondary ossification center bone on the other. Strictly speaking, the miniplate is part of the epiphyseal cartilage rather than being an integral part of the articular cartilage, although again there is no line of demarcation at a structural level between the lowermost portions of the articular cartilage and the outermost portions of the epiphyseal cartilage. The final stage in the development of the articular cartilage occurs at skeletal maturation at the same time that the physis closes. Both the physeal and miniplate sequences lose their proliferative capacity. The physeal cartilage is resorbed, allowing for bony continuity between the marrow of the secondary ossification center and that of the metaphysis. At this time, the innermost layer of the articular cartilage calcifies, forming the calcified layer of the articular cartilage, which persists throughout life. The articular cartilage has now reached its final development and is structurally composed of four layers, which cover the subchondral bone plate.

2. LAYERS WITHINARTICULAR CARTILAGE The outermost layer of the articular cartilage is the tangential zone in which two to three cell thicknesses of chondrocytes are flattened with their long axes parallel to the surface of the cartilage. This region is characterized by a relatively high concentration of type I collagen such that it will invariably stain green with Safranin O-fast green due to the relatively diminished amount of proteoglycan. The zone beneath this is called the second or transitional zone referring to the orientation of the collagen fibers as they pass from the superficial tangential zone where they are virtually parallel to the surface to the third or radial zone where they run perpendicular to the surface of the articular cartilage. Between the radial zone and the fourth or calcified zone is a thin, dense staining line referred to as the tidemark (288). The chondrocytes remaining within the calcified layer are viable based on autoradiographic studies, although their activity level is extremely low and perhaps nonexistent. Below the calcified zone of articular cartilage lies the subchondral bone plate. This is composed of lamellar bone and is much more dense than the marrow trabeculae of the mature epiphysis. Polarizing microscopy studies have helped to define the general orientation of the collagen fibrils of articular cartilage (25, 330). Benninghoff (1925) described their orientation as a series of arcades with the fibers of the radial zone perpendicular to the surface, anchored at the base, oblique in the transitional zone, and often parallel to the surface in the tangential zone (25). Subsequent high-power studies at the ultrastructural level failed to reveal this degree of collagen fibrillar orientation, but more recent studies have confirmed their general accuracy. The fibrils, however, do not form continuous sheaths such as can be seen in the outer fibrous layer of the periosteum. As shown at the ultrastructural level,

52

CHAPTER

1 9

Developmental Bone Biology

F I G U R E 17 Articular cartilage development in the rabbit along with the tissue of the epiphysis immediately adjacent to it is shown in photomicrographs at progressively older time periods. (A) At upper left (Ai) the interzone region (I) of the embryonic rabbit knee is shown with femur above and tibia below. The presumptive joint remains filled with cells. The area destined to become articular cartilage of the proximal tibia shows cells packed slightly more densely (arrow). At middle (Aii), the articular cartilage merges imperceptibly with the epiphyseal cartilage. The secondary ossification center at this stage is just beginning to form with hypertrophic cells (H) seen. In panel (Aiii), the secondary ossification center has formed but is still relatively far from the articular cartilage. The articular and epiphyseal cartilages still merge. At lower left (Aiv), most of the epiphyseal cartilage has been converted to secondary ossification center bone. Some still remains. The undersurface of the articular cartilage appears to be continuous over a short distance with the endochondral sequence at the periphery of the enlarged secondary ossification center. The latter region can be referred to as the miniplate at this stage. In panel (Av), the articular cartilage at skeletal maturity has its lowermost zone calcified, separating it from the subchondral bone (B) of the mature epiphyseal region. (The photomicrographs Ai-Av are not magnified to scale.) (B) Tritiated proline autoradiograph shows the nutritive pathway of immature articular cartilage. The proline was dropped onto the surface of the rabbit distal femur cartilage at open operation. Uptake (black dots) 2 hr postinjection is concentrated over the articular chondrocytes, but much label is seen in matrix. Note that osteoblasts of underlying bone have also taken up the label and synthesized collagen, with dense label indicative of new osteoid on subchondral bone surfaces (arrows). The proline is incorporated into newly synthesized collagen. At skeletal maturity the label does not pass the tidemark, indicating no nutrition of subchondral bone from synovial fluid after skeletal maturity.

SECTION VIII ~ Axes along Which Bones Are Patterned the fibrils are short and discontinuous but their cumulative orientation is consistent with the arcade pattern. 3. NUTRITION OF ARTICULAR CARTILAGE The articular cartilage is always avascular throughout the entire period of its development and in adult life. In the human and in the other relatively large species in which cartilage canals form, they are never present within the articular cartilage regions. They are not seen in random or serial histologic sections or by angiographic studies. Articular cartilage thus receives its nutrition by diffusion from the synovial fluid at all ages. In the time period prior to skeletal maturity, the cartilage of the lowermost part of the articular cartilage and the outermost part of the epiphyseal cartilage forms a miniplate, which undergoes the endochondral sequence. This miniplate, or physis of the secondary ossification center as we prefer to call it, allows for outward growth of the articular and epiphyseal cartilage and for enlargement of the secondary ossification center. Labeling studies in the immature animal clearly demonstrate that articular cartilage chondrocytes and chondrocytes of this endochondral sequence, including bone and marrow cells at the outermost reaches of the secondary ossification center, can receive nutrition by diffusion from the articular surface (Fig. 17B). The bone and marrow of the secondary center also receive nutrition from the epiphyseal blood supply to that region (232). McKibbin and associates have also shown that, in the immature rabbit, fluid (and by inference nutrition) from the epiphyseal secondary ossification center blood supply can pass freely into joint cartilage (155). In the skeletally mature adult, however, transfer from bone to articular cartilage could not be demonstrated across the lowermost calcified cartilage layer (155). At skeletal maturity the inner layer of the articular cartilage calcifies and remains calcified through life, as noted previously. At this stage, synovial nutrients cannot pass through the calcified zone into underlying bone, and there is no vascular flow and thus no possibility of nutrition passing from epiphyseal bone through the calcified zone of articular cartilage to the upper three zones of cartilage. In the adult, articular cartilage receives nutrition only by diffusion from the synovial fluid, and the subchondral or epiphyseal bone receives nutrition only from the blood supply to the bone.

VIII. A X E S A L O N G W H I C H B O N E S

ARE PATTERNED Once the limb bud forms (Fig. 18A) there are three axes along which patterning of differentiation in a developing limb occur. These involve (1) the proximal-distal longitudinal axis, with those regions closer to the shoulder and hip developing in advance of those more distal, (2) the anteroposterior axis, which defines first digit side to fifth digit side structures, and (3) the dorsoventral axis, which defines the differentiation of extensor compartment from flexor com-

53

partment structures. The apical ectodermal ridge (AER) directs proximodistal growth, the zone of polarizing activity (ZPA) directs anteroposterior patterning, and the dorsal nonridge ectoderm directs dorsoventral growth.

A. Signaling Regions That Affect the Patterns of Bone Development Four major signaling regions have been identified in developing limbs, which appear to control patterning and morphogenesis (347) (Fig. 18B). (1) A continuous ridge of elevated epithelial cells, called the apical ectodermal ridge (AER), soon forms running anterior to posterior along the distal outer tip and distal inner borders of each developing limb bud. At the tip of the limb bud this ridge is markedly thickened due to an increased number of closely packed epithelial cells induced by the underlying mesenchyme. This structure stimulates growth and differentiation of the immediately proximal mesenchymal limb bud cells by inductive means. It serves to outline limb development along the proximaldistal axis. Ridge formation depends on signals from the mesenchyme, but, once established, there are reciprocal ridge-mesenchyme (or epithelial-mesenchymal) interactions as development proceeds. Surgical removal of the ridge in experimental investigations leads to decreased cell proliferation in the underlying mesenchyme and proximal-distal growth alteration, such that the more proximal humeral and femoral segments appear normal (because they had already been patterned) whereas the more distal segments are missing. (2) The AER mediates growth at the distal tip of the limb bud immediately adjacent to it from a zone of undifferentiated cells called the progress zone (PZ). As development proceeds, proximal to distal, damage to or removal of the AER immediately halts development. Early removals lead to proximal truncations and later removals lead to more distal truncations. The types of structures formed, however, are governed by the mesenchymal cells themselves. (3) Development along the anteroposterior axis is mediated from an area in the posterior mesenchyme referred to as the zone of polarizing activity (ZPA), which is not distinctive histologically but is defined on the basis of chick embryo transplantation experiments in which damage to the posterior caudal area induced changes in wing digit development. (4) Development along the dorsoventral axis is mediated by dorsal nonridge ectoderm Each of the controlling regions AER, PZ, ZPA and dorsal non-ridge ectoderm appear to be interdependent. Both the AER and the ZPA initially were defined by transplant experiments, but presently molecular localization is occurring. The primary molecular signaling components of regions of the limb bud are shown in Fig. 18C.

B. Models of Tissue Patterning Johnson and Tabin have reviewed the mechanisms of threedimensional formation of organisms via the process referred

$4

CHAPTER

1 ~

Developmental Bone Biology

FIGURE 18 Earlylimb bud characteristicsare outlined. (A) Histologic section of a limb bud of a rabbit in which the mesenchymal cells are uniform in appearance and densely packed. The apical ectodermal ridge is shown at right. (B) The developing axes and signaling regions of the early limb bud are illustrated. The zone of polarizing activity and the progress zone cannot be differentiatedby light microscopy but require immunocytochemistryand in situ hybridization demonstration of specific molecules concentrated there. (C) Primary molecularsignaling components of regions of limb bud. [Part C reprinted from Cohn, M. J., and Tickle, C. (1996). Trends Genet. 12:253-257, copyright 1996, with permission from Elsevier Science.]

to as pattern formation (180). They indicated that the general features of the body initially were produced along the rostral-caudal axis and that during subsequent development more specific regional differentiation occurred in semiautonomous fashion in areas referred to as secondary fields. Pattern formation in secondary fields such as a developing limb then occurred in four basic stages: (1) cells that make up the field are defined; (2) specific signaling centers are established within the field to provide positional information;

(3) the positional information is recorded on a cell by cell basis; and (4) cells differentiate in response to additional cues according to the encoded positional information. The molecular basis for these changes is being determined rapidly, and much study currently is underway to assess how the molecules relate to each other in the developmental cascade. Extensive research continues to determine how the pattern of tissues is synthesized (211). Several theories of pattern formation have been devised. These are becoming increas-

SECTION VIII ~ Axes along Which Bones Are Patterned ingly amenable to experimental verification by molecular markers using techniques of in situ hybridization and transgenic mouse or avian models. A superb monograph by Held (149) titled "Models for Embryonic Periodicity" summarizes the many theories of pattern formation into three conceptual classes: position-dependent, rearrangement, and cell lineage. The concept of pattern formation clearly is crucial to understanding both normal skeletal development and abnormal development in a wide array of disorders, from the numerous skeletal dysplasias to mild abnormalities such as hemiatrophy. There clearly are situations where pattem formation has been imperfect. Development proceeds from the limb bud stage, in which one sees only a uniform mass of undifferentiated mesenchymal cells, to full limb development by a combination of mechanisms referred to as differentiation, wherein one cell has generated many different types of cells and pattern formation in which the spatial control of differentiation occurs. Relatively simple mathematical models can be generated to help understand patterning mechanisms. These can be reduced to the three classes referred to earlier based on commitment of embryonic cells to different pathways of development long before they show any tissue differentiation, such that the cells are described as determined for different fates and possessing distinct states of determination. This commitment has allowed them to be determined for synthesizing different tissues and programmed in regard to their position in the limb. In the words of Held, "given the notion of states, the problem of pattem formation can be reduced to simple mathematical terms." Although the "causal relationships define distinct classes of m e c h a n i s m s . . , actual developmental pathways typically employ multiple strategies." Many of these models are amenable to investigation by transplanting cells from one position to another. If a transplanted cell changes its fate by adopting a fate appropriate for its new position, then its position was causing its state. If the cell moves back to its original position following transplantation, then its state was causing its position. If the cell changes neither fate nor moves back, then the third type of mechanism would be indicated. When p is used to designate the position of a cell and s is its state of determination or differentiation, then any pattern can be represented as a set of ordered pairs (p, s). The general problem thus becomes: "what causes the correlation of particular values of p and s?" Whenever two entities are correlated in nature, either one causes the other or both are caused by a third force. For p and s, there are three possibilities: (1) p produces s or the position of a cell causes it to adopt a particular state (positiondependent class); (2) s produces p the state of a cell causes it to adopt a particular position (rearrangement class); and (3) X produces p and s or some third agent (X) causes the correlation of positions and states. An example of X is cell lineage because a mother cell can divide directionally (causing the p of each daughter) and bestow instructions (s) asymmetrically.

55

Held then further defines the three classes of pattern formation models with additional subclasses. (1) The positiondependent class (p producing s) involves (a) the positional information subclass, as determined by gradient models, polar coordinate models, or the progress zone model; (b) the prepattem subclass, for which there are physical force models, reaction-diffusion models and induction models; (c) the determination wave subclass, for which there are chemical wave models (Belousov-Zhabotinsky reaction), the sequential induction model, the clock and wave-front model, and inhibitory field and competence wave models; and (d) the Darwinian subclass, with cell death and state change models. (2) The second class is the rearrangement class (s producing p) with adhesion, repulsion, interdigitation, and chemotaxis models. (3) The final class is a cell lineage class (X produces p, s) with quantal mitosis, stem cell, and cortical inheritance models. In summary, cell differentiation to form specific structural patterns occurs because either a cell's position causes its state, its state causes its position, or both are caused by a third agent. In the position-dependent class, the position of each cell relative to field boundaries or neighboring cells dictates its state of differentiation. In the rearrangement class, each cell adopts a state, perhaps randomly; the states then cause cells to move until they reach particular locations. In the cell lineage class, the cells divide asymmetrically according to rigid pedigree rules, placing each daughter into a definite position and assigning it a particular state. The various models and categories and their distinguishing features as defined by Held are summarized in Table V.

C. Positional Information Mechanisms Positional information models postulate a position-dependent assignment of differentiated states, whereby cells are informed of their positions and this information causes them to select particular states according to determined rules. Wolpert has indicated that cells acquire a positional value with respect to boundaries and then interpret this in terms of a program determined by their genes and developmental history (375). Cell-to-cell interactions can then specify position. He feels that positioned fields are small, being less than 0.5 mm long, with the times needed to specify position on the order of hours. The various models differ only in how they specify positional information. The mechanical gradient model is most common in this regard being mediated by long-range diffusible molecular signals. Each cell records the concentration of a particular chemical, which has an origin or source and a terminal point or sink. The polar coordinate model is also one defining positional information and assumes that cells assess their position by observing coordinates of their immediate neighbors, presumably by direct cell surface contact (41). In this model, the position of limb cells is specified by one coordinate corresponding to the proximal-distal axis of the limb and another corresponding to the position on one of a concentric series of circles at

56

CHAPTER I ~

Developmental Bone Biology TABLE V

Models of Tissue Patterning Mechanisms a

Distinguishing features

Model or category I. Position-dependent (p ~ s) class A. Positional information subclass

The position of each cell (relative to field boundaries or neighboring cells) dictates its state of differentiation Cells know where they are via coordinates that they "interpret" as particular states of differentiation; the coordinate systems allow the patterns to "regulate"

Gradient model

The coordinate system is established (independent of growth) to be a scalar variable with fixed boundary values

Polar coordinate model

A "shortest route rule" or "smoothing rule" fills in missing coordinates by intercalary growth

Progress zone model

Coordinates are assigned temporally as cells exit a growth zone

B. Prepattern subclass

Cells assume particular states of determination due to mechanical or chemical signals within the cell layer or by induction from an adjacent cell layer Identical signals are used for identical elements Patterns do not regulate (unless ad hoc assumptions are added)

Physical force models

Deformations arise at periodic intervals within a tissue layer, causing cells to adopt particular states of determination about a certain threshold of stress or strain

Reaction-diffusion models

Chemicals that have different diffusion rates react, causing an initially uniform chemical distribution to peak at "wavelength" intervals Above a certain threshold concentratin, cells adopt a particular state of determination

Induction model C. Determination wave subclass

Periodically arranged cells in one layer induce states of determination in the cells of an apposed layer States of determination are specified within a zone that traverses an array of cells

Chemical wave models

Traveling (or standing) waves in the concentration of a diffusible molecule (or precipitate) arise through chemical reactions

Sequential induction model

Each cell induces a neighboring cell to adopt a particular state

Clock and wave front model

Cells oscillate between two states and cease oscillating when a wave front reaches them

Inhibitory field and competence wave model

Cells are not "competent" to differentiate before a wave front reaches them Cells that can adopt a "preferred" state do so and inhibit neighboring cells from doing so

D. Darwinian subclass

Each cells adopts a state (perhaps randomly) and then examines the states of its neighbors; if it matches a neighbor, then it takes action to correct this "error"

Cell death models

Homotypic matches are eliminated by having one of the matched cells die

State change models

Homotypic matches are eliminated by having one of the matched cells change its state Each cell adopts a state (perhaps randomly); the states then cause cells to move until they reach particular locations

II. Rearrangement (s ~ p) class Adhesion models

The final location of a cell is determined by its ability to adhere to a target cell(s)

Repulsion models

Each cell moves as far away as possible from cells of its own kind

Interdigitation models

Stripes of unlike cells interdigitate

Chemotaxis models

Dispersed cells aggregate by mutual attraction

III. Cell lineage (X ~ p, s) class

Cells divide asymmetrically (according to rigid pedigree rules), placing each daughter in a definite position and assigning it a particular state

Quantal mitosis model

All cells undergo an asymmetric and polarized "quanta" mitosis, which assigns left daughters one state and fight daughters another

Stem cell model

A cell cyclically changes its state as it divides, causing the states of its daughters to alternate in space as it oscillates in time

Cortical inheritance model

A periodic pattern of molecules is created in the cortical layer of a cell, and each daughter differentiates according to the molecules it inherits

aDerived from Held (149), with permission.

SECTION VIII 9 Axes along Which Bones Are Patterned

different proximal-distal levels. The molecular basis of this system is beginning to be outlined because genes that specify the circumferential coordinate have been found in Drosophila embryo, with different genes expressed in varying local segments (41). Other genes are expressed at varying proximal-distal regions. The final mechanism in this class is the progress zone model, in which the cells at a particular region of the limb bud acquire positional information via temporal information in which they can measure time and switch off their specific function when they exit a zone.

D. Prepattern Mechanisms Prepattern mechanisms define cell differentiation patterns on the basis of mechanical or chemical signals within cell layers. Identical signals thus will induce identical structures. Several models have also been defined within this subclass of developmental mechanisms. Physical force models postulate that the physical properties of cells and matrices can produce local deformations in response to internal or external forces, and these distortions could promote the development of structure. Perhaps a more accepted model today is the reaction-diffusion model defined by Alan Turing based on pattern differentiation between chemicals. Chemically reactive molecules that diffuse at different rates cause the concentration of their product to peak at wavelength intervals, which induce periodic or segmented structures. Many of these reaction-diffusion models are somewhat indeterminate in that the final configuration of the pattern cannot be predicted exactly from starting positions unlike positional information, which is strictly deterministic, by which is meant they yield identical patterns from case to case. Such patterns are defined as epigenetic in that they are not invariably the same but relate to a cascade of formative principles, by which each region is specifically dependent on that that preceded it. Even the most subtle difference, therefore, can lead the developmental pattern into slightly different areas.

E. Determination Wave Mechanisms From 1920 to 1954, the reigning paradigm in developmental biology was that of the determination wave mechanism in which a propagating signal or substance spread from an "organized center" to control the fate of cells in its domain. Subsequently, the prepattern (1954-1969) and positional information (1969-present) schools gained prominence. Many models of definition within this subclass were defined. The progress of morphogenesis sequentially and along varying axes led to the development of several wave mechanism theories. Among the theories used to support this mechanism were those of chemical waves. An example of this was the Belousov-Zhabotinsky reaction in which the concentration of a chemical oscillates in time and space and produces patterns similar to those seen in structural organisms. Intricate patterns can be defined by employing contact-mediated cel-

57

lular communication instead of diffusible chemicals. The sequential induction model is an example in which the notochord induces formation of the central nervous system. Variations on this theme include waves of developmental signals, which induce adjacent groups of cells to oscillate between active and inhibited states. Even Darwinian models have been defined utilizing cell death and state change models. The Darwinian concept implies that, even within individual embryos, selection among competing groups of cells leads to longevity of some and programmed cell death of others. Currently there is great interest in the phenomenon of programmed cell death or apoptosis, which plays a major role in developmental states. A clear example of cell death in normal limb development relates to joint formation in which the interzone cells die after formation of the model of each developing bone to subsequently allow for joint cavitation. Some consider the death of terminal hypertrophic zone chondrocytes to represent another example of apoptosis in skeletal development. State change models imply the ability of cells to react to changes in adjacent cells by subtle differentiation to help maintain or recreate their previous state.

F. Rearrangement Mechanisms Rearrangement mechanisms refer to the concept of cell and tissue movements that characterize many early developmental states. Cell movement is particularly well-defined in central nervous system development. A cell's state of determination or differentiation causes it to assume a specific position relative to other cells by propelling it in a particular direction. This developmental subclass makes use of the "self-assembly" concept, for example, in mediating the supracellular neuroarchitecture in which specific cell axons link only with specific neurons based on specific chemical reactions. Both adhesion and repulsion models have been used to account for cell movement within an embryonic region.

G. Cell Lineage Mechanisms Cell lineage mechanisms were postulated for some time but have been almost completely supplanted by newer mechanisms. They implied that a cell's positions and states are assigned via strict pedigree rules with no involvement of intercellular communication. Cell lineage plays a major role in later tissue differentiation but participates little in embryonic morphogenetic patterning. Much of developmental biology until recent decades was based on descriptive embryology on the one hand and experimental embryology on the other in which certain regions at certain stages were either removed from a developing embryo or transferred to atypical positions with development then followed carefully. With the explosion of information concerning the specific molecules present within the de-

58

CHAPTER 1 ~

Developmental Bone Biolo~ty

veloping systems and recognition of patterning genes or homeobox genes, developmental studies have become much more specific. Utilization of in situ hybridization techniques and the generation of transgenic animals with specific molecules subtracted at the varying stages of development have allowed for more specific analysis. The fact that development is hierarchical is self-evident. What is unclear, even today, however, is whether the pattern is totally deterministic, which would allow development to be reduced to an elucidation of which specific molecules at each stage of development perform which activities, such as synthesizing certain substances, acting as enzymes, or regulating genes. On the other hand, much of development conceivably could be epigenetic in which only the early prepatterns are rigidly determined, after which each subsequent step is a combination of gene synthesis and automatic self-assembly based on the physical presence of certain molecules. These questions thus span the entire spectrum from gene to ultrastructure, genotype to phenotype, or linear DNA to three-dimensional morphology. In the epigenetic approaches, there are no genes that directly specify the entire sequence of events. There are only those that give approximate direction. The rest of the formation is based on epigenetic or self-assembly mechanisms. Thus, it is the interactions among many genes that would determine the outcome of any dynamic process. Many have suggested that the detailed structure of multicellular organisms occurs on the basis of many intermediate levels of interaction, each with its own emergent properties such that "the edifice is virtually entirely epigenetic." This idea was expressed by Driesch over a century ago in which he indicated that development started with a few ordered reactions but that each reaction created new structures by interaction, which were enabled by acting back upon the original ones to provide new differences and so on. "With each effect, immediately a new cause is provided and the possibility of a new specific action." Opposed to this are the strictly deterministic approaches such as the homeobox gene synthesis patterns. The homeobox genes are ordered along their chromosomes and allow specific anatomic regions to appear. They have not only a spatial and regional preference but also a temporal one. At the basis of much modern biology is the feeling that there may be a finite number of elemental patterning strategies.

IX. G E N E A N D M O L E C U L A R

CONTROLS

OF LIMB DEVELOPMENT Findings have outlined the gene and molecular mechanisms associated specifically with the early stages of limb embryogenesis (65, 84, 95, 96, 104, 150, 156, 179, 198, 201,233, 236, 241,295, 299, 316, 338, 342, 347). Specific genes and molecules controlling limb development and comprising the extracellular matrix are listed in table VIA. Four specific regions of the developing limb play major directing roles in morphogenesis. [See section VillA (Figs. 18B and 18C).]

A. Apical Ectodermal Ridge The apical ectodermal ridge (AER) is the thickened rim of epithelium present at the tip of each limb bud (Fig. 18A). It consists of pseudo-stratified elongated cells that are closely packed and linked by extensive gap junctions. AER maintains cell proliferation in the underlying mesenchyme progress zone, and there are constant reciprocal interactions between ridge and mesenchymal tissues. The AER mediates proximodistal outgrowth of the limb bud and controls the deposition of undifferentiated cells just proximal to it in the progress zone. FGF-8 is expressed throughout the AER early in limb development, whereas FGF-4 later is detected concentrated in the AER posteriorly. FGF-4 is expressed most prominently in the AER and appears to play the major role in proximodistal outgrowth and patterning.

B. Progress Zone The progress zone is at the distal region of the limb bud in which undifferentiated mesenchymal cells actively divide. Cell division in the progress zone appears to be timed accurately, and it is felt by some that the length of time cells spend in the progress zone specifies the structures they will form.

C. Polarizing Region The zone of polarizing activity (ZPA) is not distinct histologically but its controlling features were identified on the basis of transplant experiments. In the limb bud, the highest polarization activity is posterior near the tip of the bud just proximal to the progress zone. The polarizing activity is confined to the mesenchyme (Fig. 18B). Sonic hedgehog (Shh) appears to be the signal from the posterior polarizing mesenchyme involved in anteroposterior patterning, but BMP-2 also is synthesized there.

D. Dorsal Nonridge Ectoderm The signal necessary from the dorsal nonridge ectoderm to trigger dorsoventral development appears to come from expression of Wnt 7a molecules. There is clearly mutual dependence between signaling systems (180, 243,266, 379). The expression of Shh in posterior mesenchyme maintains FGF-4 expression in the posterior apical ridge, and Wnt 7a expression in dorsal ectoderm together with FGF-4 maintains Shh expression in posterior mesenchyme. Current investigation is involved extensively with assessing the developmental cascades to define how the various transcriptional regulators and signaling proteins induce each other and eventually direct cell positioning and the synthesis of extracellular molecules. Each of the factors listed previously induces patterns of Hox gene expression throughout the limb bud.

SECTION IX ~ Gene and Molecular Controls of Limb Development TABLE VIA Gene

Protein

ADA

Adenosine deaminase

ALPL

Alkaline phosphatase liver, bone, kidney type

ANXA5

Annexin A5; calcium and phospholipid binding protein, endonexin 2, placental protein 4, anchorin CII Arylsulfatase E

ARSE BMP1

BMP2

BMP3

BMP4

Bone morphogenetic protein 1; also known as procollagen C-proteinase Bone morphogenetic protein 2, a member of transforming growth factor-[3 superfamily Bone morphogenetic protein 3, a member of transforming growth factor-[3 superfamily Bone morphogenetic protein 4

BMP5

Bone morphogenetic protein 5, a member of transforming growth factor-[3 superfamily

BMP6

Bone morphogenetic protein 6, a member of transforming growth factor-[3 superfamily

BMP7

Bone morphogenetic protein 7. a member of transforming growth factor-13 superfamily, osteogenic protein 1 Bone morphogenetic protein 8, osteogenic protein 2 Bone morphogenetic protein receptor, type 1A

BMP8 BMPR1A

CA2

Carbonic anhydrase II

CASR

Calcium sensing receptor

59

Skeletal Gene D a t a b a s e ~

Cellular function

Involved in T-cell and B-cell immune function Linked to the outer membrane, enzyme acts physiologically as a lipidanchored phosphoethanolamine and pyridoxal 5'-phosphate ectophosphatase Collagen receptor of chondrocytes predominantly expressed in chondrocytes of growth plate, down-regulated in adult growth cartilage Involved in bone and skeletal development Induce formation of ectopic cartilage and bone in vivo

Disease

Adenosine deaminase deficiency Hypophosphatasia, murine (Alp 1- / - ) seizures but normal skeletal development

X-linked recessive chondrodysplasia punctata (brachytelephalangic type)

Induce formation of ectopic cartilage and bone in vivo Induce formation of ectopic cartilage and bone in vivo Involved in bone induction and tooth development Induce formation of ectopic cartilage and bone in vivo

? Fibrodysplasia ossificans progressiva Murine: mutations in short-ear locus association with homozygous deletions of BMP5 coding regions result in viable and fertile short ear mice with specific skeletal defects

Induce differentiation of osteoblast and chondroblast lineage cells from uncommitted mesenchymal precursors; BMP6 produced by osteoblasts is increased in the presence of estrogen and is thought to mediate the skeletal effects of estrogen Induce formation of ectopic cartilage and bone in vivo

Induce formation of ectopic cartilage and bone in vivo Cell surface receptor with predicted serine-threonine kinase activity, may bind to ligands from the transforming growth factor-[3 supergene family Involved in osteoclast function, bone remodeling and resorption Parathyroid hormone sensitive, involved in calcium homeostasis

Osteopetrosis with renal tubular acidosis and cerebral calcification Neonatal severe hyperparathyroidism; familial hypocalciuric hypercalcemia; autosomal dominant hypocalcemia; murine (Casr+/-) familial hypocalciuric hypercalcemia; murine ( C a s r - / - ) neonatal severe hypercalcemia (continues)

6O

CHAPTER I ~ Developmental Bone Biology TABLE VIA (continued) Gene

Protein

Cellular function

Disease

CBFA1

Core binding factor et subunit 1

Osteoblast-specific transcription factor

Cleidocranial dysplasia; murine Cbfa + / cleidocranial dysplasia; murine Cbfa - / perinatal lethal with deficient ossification of skeleton

CBP1

Collagen binding protein 1; collagen 1

CBP2

Collagen binding protein 2; collagen 2

CD36

Type 1 collagen receptor, thrombospondin receptor; CD 36 antigen CD 36 antigen-like 1; type 1 collagen receptor-like 1; thrombospondin receptorlike 1; scavenger receptor class B type 1 (SRB 1) CD 36 antigen-like 2; type 2 collagen receptor-like 1; thrombospondin receptorlike 2 Cartilage-derived morphogenetic protein 1

Bind specifically to type I and type IV collagen and gelatin; may be involved in the biosynthetic pathway of collagen Bind specifically to type I and type IV collagen and gelatin; may be involved in the biosynthetic pathway of collagen Bind to collagen and thrombospondin; involved in platelet collagen adhesion High-density lipoprotein receptor

CD36L1

CD36L2

CDMP1/GDF5

CKTSF1B 1

Cysteine knot superfamily 1; BMP antagonist 1; also known as gremlin

COLIA1

Type I collagen ct 1 chain

COLIA2

Type I collagen (x2 chain

COL2A1

Type II collagen ct 1 chain

COL3A1

Type III collagen (x1 chain

Platelet glycoprotein IV deficiency

Lysosomal integral membrane protein II

Involved in skeletal morphogenesis, i.e., chondrocytic differentiation and growth of long bones Block BMP signaling by binding to BMPs, preventing them from binding to their receptors

Major collagen of skin, tendons, and bone Major collagen of skin, tendons, and bone Collagen of cartilage and vitreous

Fetal collagen, expressed throughout embryogenesis essential for normal fibrillogenesis of collagen 1 in cardiovascular system and other organs

Greb chondrodysplasia; HunterThompson dysplasia; brachydactyly type C; murine brachypodism Murine: limb deformity mutation (ld) disrupts Shh-FGf4 feedback loop; in mouse embryos mesenchymal expression of gremlin is lost in limb buds; grafting gremlin expressing cells into ld mutant limb buds rescued FGF4 expression and restored the Shh-FGF4 feedback loop Osteogenesis imperfecta; type VIIA EhlersDanlos syndrome; osteoporosis Osteogenesis imperfecta; type VIIB EhlersDanlos syndrome Achondrogenesis type II; hypochondrogenesis; Kniest dysplasia; spondyloepiphyseal dysplasia congenita; Wagner syndrome; spondyloepimetaphyseal dysplasia; Strudwick type and Namaqualand type spondyloepimetaphyseal dysplasia; osteoarthritis with mild chondrodystrophy; transgenic C o l 2 a l - / - mice perinatal lethal with absent enchondral ossification Ehlers-Danlos syndrome type III; EhlersDanlos syndrome type IV; murine Col3al-/-Ehlers-Danlos type IV; aortic aneurysm

(continues)

SECTION IX ~ Gene and Molecular Controls of Limb Development

61

TABLE VIA (continued) Gene

Protein

Cellular function

COL4A1

Type IV collagen e~1 chain

COL4A2

Type IV collagen oL2 chain

COL4A3

Type IV collagen o~3 chain

COL4A4

Type IV collagen c~4 chain

COL4A5

Type IV collagen e~5 chain

Collagen of basement membrane, associated with laminin, entactin, and heparan sulfate proteoglycans to form basement membranes that separate epithelium from connective tissue Collagen of basement membrane, associated with laminin, enacticn, and heparan sulfate proteoglycans to form basement membranes that separate epithelium from connective tissue Associated with lamin, entactin, and heparan sulfate proteoglycans to form basement membrane separating epithelium from connective tissue Associated with lamin, entactin, and heparan sulfate proteoglycans to form basement membrane separating epithelium from connective tissue Collagen of basement membrane

COL4A6

Type IV collagen c~6 chain

Collagen of basement membrane

COL5A1

Type V collagen oL1 chain

COL5A2

Type V collagen oL2 chain

Minor collagen involved in regulation of fibrillogenesis of dermis rather than bone Minor collagen involved in regulation of type I and type II collagen fibrils; collagen of fetal membrane

COL6A1

Type VI collagen c~1 chain

COL6A2 COL 7A1

Type VI collagen o~2 chain Type VI collagen c~3 chain type VII collagen oL1 chain

COL8A1

Type VIII collagen oL1 chain

COL8A2

Type VIII collagen oL2 chain

COL9A2

Type IX collagen c~2 chain

COL9A3

Type IX collagen c~3 chain

COL6A3

Anchoring structural protein involved in maintaining the integrity of muscle fiber Anchoring structural protein Act as a cell binding protein Main constituent in anchoring fibrils

Endothelial cell collagen expressed in eye, skin, and calvarium; major component of Descemet membrane Major component of Descemet membrane Cartilage-specific fibril-associated collagen Fibril-associated collagen with interrupted triple helices expressed in cartilage

Disease

Autosomal recessive Alport syndrome type I; murine knockout Co14a3 Alport syndrome; induction of Goodpasture syndrome Autosomal recessive Alport syndrome type II; autosomal dominant benign familial hematuria-q37 X-linked recessive Alport syndrome; canine X-linked hereditary nephropathy X-linked Alport syndrome with diffuse leiomyomatosis contiguous gene deletion syndrome Ehlers-Danlos syndrome type I; EhlersDanlos syndrome type II Ehlers-Danlos syndrome type I; EhlersDanlos syndrome type II; murine Co15a2-/- spinal deformities, skin, and eye abnormalities Bethlem myopathy; murine C o l 6 a l - / Bethlem myopathy Bethlem myopathy Bethlem myopathy Autosomal dominant dystrophic epidermolysis bullosa; autosomal recessive dystrophic epidermolysis bullosa; dystrophic epidermolysis bullosa Bart syndrome type: transient bullous dermolysis of newborn

Multiple epiphyseal dysplasia type II intervertebral disk disease Multiple epiphyseal dysplasia; multiple epiphyseal dysplasia with myopathy

(continues)

CHAPTER 1 ~ Developmental Bone Biology

62

TABLE VIA (continued) Gene

Protein

Cellular function

COLI OA1 COLllA1

Type X collagen ot1 chain Type XI collagen (x1 chain

Minor collagen of cartilage Minor collagen of cartilage; fibrillar collagen

COL11A2

Type XI collagen ix2 chain

Minor collagen of cartilage; fibrillar collagen

COL12A1

type XII collagen et 1 chain

COL13A1

Type XIII collagen (x1 chain

COL14A1

Type XIV collagen etl chain

COL15A1

Type XV collagen (x1 chain

COL16A1

Type XVI collagen et 1 chain

COL17A1

Type XVII collagen (x1 chain, bullous pemphigus antigen 2 (BPAG2 or BP 180) Type XVIII collagen (x1 chain, also contains endostatin

Fibril-associated collagen with interrupted triple helices (FACIT) Short chain collagen with some features found in genes for fibrillar collagen and some unique features Fibril-associated collagen with interrupted triple helices (FACIT); extracellular matrix protein confined to dense and soft connective tissues; associated with mature collagen fibrils May be involved in the adherence of basement membrane to underlying connective tissue stroma Fibril-associated collagen with interrupted triple helices (FACIT); associated with type I and type II collagen fibrils and is involved in interaction of these fibrils with other matrix components Collagen found in stratified epithelium, maintains adhesion between epidermis and dermis Extracellular matrix proteins that have multiple triple-helix domains and interruptions Fibril-associated collagen with interrupted triple helices; produce adhesion to fibrils and provide interaction with other matrix component; expressed in cartilage Bind collagen

COLI 8A1

COL19A1

Type XIX collagen oL1 chain

COLLAR COL4A3BP

Type I collage, (x1 receptor Collagen type IV, ct3 (Goodpasture antigen binding protein) Type XII collagen ct l-like Collagen-like tail subunit of end plate acetylcholinesterase

COL12A1L COLQ

COMP

Cartilage oligomeric matrix protein

Anchor acetylcholinesterase to the underlying basal lamina, acetylcholinesterase-associated collagen Involved in calcium binding

Disease

Schmid metaphyseal chondrodysplasia Stickler syndrome; Marshall syndrome; murine Col 11 al - / - perinatal lethal with abnormalities in cartilage of limbs, ribs, mandible, and trachea Otospondylomegaepiphyseal dysplasia (OSMED); Weissenbacher-Zweymuller syndrome; Stickler syndrome without ocular anomaly; nonsyndromic heating loss

Generalized atrophic benign epidermolysis bullosa; nonlethal variant of junctional epidermolysis bullosa

Congenital myasthenic syndrome with end plate acetylcholinesterase deficiency

Pseudoachondroplasia; multiple epiphyseal dysplasia (Fairbanks and Ribbing types) (continues)

SECTION IX ~ Gene and Molecular Controls of Limb Development

63

TABLE VIA (continued) Protein

Gene CTSK

Cathepsin K

DCN

Decorin

DDR2

EOMES

Discoidin domain receptor family member 2 Diastrophic dysplasia sulfate transporter Delta (8)-delta (7) sterol isomerase emopamil binding protein Eomesodermin

EXT1

Exostosin 1

EXT2

Exostosin 2

EXT3 FBN1

Gene not cloned yet Fibrillin 1

FBN2

Fibrillin 2

FCN1

Ficolin 1

FCN2

Ficolin 2

FCN3

Ficolin 3-Hakata antigen

FGFR1

Fibroblast growth factor receptor 1 Fibroblast growth factor receptor 2

DTDST/DTD EBP

FGFR2

FGFR3

Fibroblast growth factor receptor 3

Cellular function

Disease

Expressed in osteoclasts involved in bone remodeling and resorption Small collagen binding proteoglycan of the extracellular matrix, affects the rate of fibril formation, also binds to fibronectin and TGF-13; when expressed ectopically docorin suppresses tumor cell growth by activating the epidermal growth factor receptor Tyrosine kinases activated by collagen

Pycnodysostosis; knockout Ctsk mice pycnodysostosis

Undersulfation of proteoglycan in cartilage matrix Involved in cholesterol biosynthesis

Diastrophic dysplasia; achondrogenesis type IB; atelosteogenesis type II X-linked dominant Conradi-HianermannHapple chondrodysplasia punctata; murine male 'tattered' (Td) X-linked Murine-targeted disruption of Eomes results in mice deficient in Eomes and arrest at the blastocyst stage Multiple exostoses type I; Langer-Giedion microdeletion syndrome; chondrosarcoma (loss of heterozygosity) Multiple exostoses type II; chondrosarcoma (loss of heterozygosity) Multiple exostoses type III Marfan syndrome; Shprintzen-Goldberg craniosynostosis syndrome

Essential for mesoderm formation and trophoblast development Involved in alteration of synthesis and display of cell surface heparan sulfate glycosaminoglycan Involved in regulation of bone growth

Major constituent of extracellular microfibrils found in elastic and nonelastic connective tissue Direct the assembly of elastic fibers during early embryogenesis Containing collagen-fibrinogen domain Lectin containing collagenfibrinogen Containing collagen-fibrinogen domain Involved in tyrosine kinase activation and signal transduction Involved in tyrosine kinase activation and signal transduction

Involved in tyrosine kinase activation and signal transduction; inhibits osteogenesis

Congenital contractural arachnodactyly (Beal syndrome)

Pfeiffer syndrome Pfeiffer syndrome; Apert syndrome; Crouzon syndrome; Jackson-Weiss syndrome; Beare-Stevenson cutis gyrata syndrome; Saethre-Chotzen syndrome Achondroplasia; hypochondroplasia; thanatophoric dysplasia type I and type II; Crouzon syndrome with acanthosis nigricans; Muenke nonsyndromic coronal craniosynostosis; severe achondroplasia, developmental delay, acanthosis nigricans syndrome; SaethreChotzen syndrome (continues)

64

CHAPTER I ~ Developmental Bone Biology TABLE VIA (continued) Gene

Protein

FN1

Fibronectin 1

FMOD

Fibromodulin

FUCA1

ct-L-Fucosidase 1

GDFIO

Growth differentiation factor 10, BMP 3b-precursor, bone inducing protein, member of transforming growth factor[3 superfamily Member of GLI-Kruppel family, a zinc finger transcription factor [3-Galactosidase 1

GL13

GM1/GLB1

Cellular function

Bind cell surfaces and collagen, fibrin, heparin DNA, and actin; involved in chell adhesion, cell motility, opsonization, wound healing, and maintenance of cell shape Involvement in the assembly of extracellular matrix by virtue of ability to bind to interact with type I and type II collagen fibrils Enzyme degrades fucosidase, the accumulation results in lysosomal storage Induce enchondral bone formation

Ehlers-Danlos type X may be associated with fibronectin deficiency

Involved in vertebrate development of limbs and other tissues

Postaxial polydactyly type IA; Greig cephalopolysyndactyly; Pallister-Hall syndrome GM1 gangliosidosis; Morquio type B syndrome Pseudohypoparathyroidism; McCuneAlbright polyostotic fibrous dysplasia

Enzyme degrades mucopolysaccharides

Guanine nucleotide binding protein, o~ stimulating activity polypeptide 1 N-Acetylglucosamine 6-sulfate sulfatase [3-Glucuronidase

Involved in regulating activity of parathyroid hormone sensitive adenylate cyclase Enzyme degrades heparan and keratan sulfate Enzyme degrades mucopolysaccharides

Homeobox A1; member of a family of transcription factors Homeobox A2; member of a family of transcription factors

Determine embryonic cell fate

HOXA3

Homeobox A3; member of a family of transcription factors

Determine embryonic cell fate

HOXA 4

Homeobox A4; member of a family of transcription factors Homeobox A5; member of a family of transcription factors

Determine embryonic cell fate

GNAS1

GNS GUSB

HOXA1

HOXA2

HOXA5

Disease

Determine embryonic cell fate

Fucosidosis (dysostosis multiplex)

Sanfilippo syndrome D or mucopolysaccharidosis type III Sly syndrome or mucopolysaccharidosis type VII; canine G u s b - / - S l y syndrome

Murine H o x a - / - embryonic mice show defective axonal path-finding, resulting in loss of cochlear nuclei and enlargement of lateral part of cerebellum Murine homozygous null H o x a 3 - / embryos show complete absence of thymus and alteration of hyoid cartilage; complementation with hoxd3 protein restores thymus and corrects alteration of hyoid cartilage, suggesting that Hoxa3 and Hoxd3 can carry out identical biological functions

Determine embryonic cell fate

(continues)

SECTION IX ~ Gene and Molecular Controls of Limb Development

65

TABLE VIA (continued) Gene

Protein

Cellular function

Disease

HOXA6

Homeobox A6; member of a family of transcription factors

Determine embryonic cell fate

HOXA 7

Homeobox A7; member of a family of transcription factors

Determine embryonic cell fate

HOXA9

Homeobox A9; member of a family of transcription factors

Determine embryonic cell fate

HOXAI O

Homeobox A10; member of a family of transcription factors

Determine embryonic cell fate

Murine-targeted disruption of Hoxal0 results in homozygous H o x a l 0 - / male and female mice with lumbar vertebral abnormalities and severe fertility defects

HOXA11

Homeobox A11; member of a family of transcription factors

Determine embryonic cell fate; pattern the posterior region of the vertebrate embryo and the appendicular skeleton

Murine-targeted disruption of Hoxal 1 and Hoxdl 1 results in double mutants with abnormal phenotype not apparent in mice homozygous for individual mutations; these double mutants have virtual absence of radius and ulna of the forelimbs, homeotic transformation of the axial skeleton, and kidney defects; these anomalies suggest that paralogous Hox genes function together to specify limb outgrowth and patterning along the proximodistal axis

HOXA13

Homeobox A13; member of a family of transcription factors

Determine embryonic cell fate

Mutation of Hoxal3 results in the autosomal dominant hand-foot-uterus syndrome characterized by hand and foot dysplasia, partial duplication of the female genital tract; murine mutation of Hoxal3 results in hypodactyly due to arrest of digital arch formation

HOXB1

Homeobox B 1

Determine embryonic cell fate

HOXB2

Homeobox B2

Determine embryonic cell fate; have a determinant role in the body plan organization with Hoxa2; control dorsoventral patterning of neuronal development in the rostral hindbrain

HOXB3 HOXB4

Homeobox B3 Homeobox B4

Determine embryonic cell fate Determine embryonic cell fate

HOXB5

Homeobox B5

Determine embryonic cell fate; involved in the positioning of mouse upper limb bud

Transgenic mice generated to ectopically expressed Hoxa7 died shortly after birth with multiple craniofacial anomalies, such as cleft palate, open eyes at birth, nonfused pinna; phenotype seen in that of human retinoic acid embryopathy Several patients with myeloid leukemia were noted to have translocation t(7;11), resulting in genomic fusion of nucleoprotein gene NUP98 with Hoxa9 and suggesting that NUP98 and Hoxa9 may be involved in myeloid differentiation

(continues)

66

C H A P T E R 1 ~ Developmental Bone Biology

TABLE VIA (continued) Gene

Protein

Cellular function

Disease

Transgenic mice generated with a gain of function mutation of Hoxb6 result in early postnatal lethality and craniofacial skeletal perturbations at birth, including open eyes, micrognathia, microtia, skull bone deformities and structural and positional alterations in the vertebral columns; complete or partial absence of the supraoccipital bone and malformation of the exo-occipital and basioccipital bones are also found

HOXB6

Homeobox B6

Determine embryonic cell fate; specify positional identity along the anteriorposterior axis

HOXB7

Homeobox B7

Determine embryonic cell fate

HOXB8

Homeobox B8

Determine embryonic cell fate; involved in establishing of anteroposterior polarity of anterior mouse limb; controlled Shh through a negative feedback loop

HOXB9 HOXB13

Homeobox B9

Determine embryonic cell fate

Homeobox B 13

Determine embryonic cell fate; maintains collinearity

HOXC4

Homeobox C4

Determine embryonic cell fate; involved in mouse anterior and posterior limb patterning

HOXC5

Homeobox C5

Determine embryonic cell fate; involved in patterning of mouse anterior limb; a target for regulation by retinoic acid and HOX homeoproteins

HOXC6

Homeobox C6

HOXC8

Homeobox C8

HOXC9

Homeobox C9

HOXCIO

Homeobox C 10

HOXC11

Homeobox C 11

Determine embryonic cell fate; involved in mouse anterior and posterior limb patterning Determine embryonic cell fate; involved in mouse anterior and posterior limb patterning and innervation of the limb; may be involved in chondrocytic differentiation Determine embryonic cell fate; involved in mouse posterior limb patterning Determine embryonic cell fate; involved in mouse posterior limb patterning Determine embryonic cell fate; involved in mouse posterior limb patterning

HOXC12

Homeobox C 12

Determine embryonic cell fate

HOXC13

Homeobox C 13

Determine embryonic cell fate; may have a function common to hair, nail, and filiform papillae of tongue

Transgenic mice with overexpression of a Hoxc8 transgenic exhibit cartilage defects with accumulation of proliferating chondrocytes and reduced maturation

Murine-targeted disruption resulting in homozygous deficient Hoxc 1 3 - / - mice with defects in hair, nail, and tongue, the most striking effect being brittle hair resulting in alopecia

(continues)

SECTION IX ~ Gene and Molecular Controls of Limb Development

67

TABLE VIA (continued) Gene

Protein

Cellular function

Disease

HOXD1

Homeobox D 1

Determine embryonic cell fate

Heterozygous deletion of the Hoxd cluster (Hoxd3-Hoxdl 3) in two human patients results in developmental defects of A-P limb and genitalia with oligodactyly and penoscrotal hypoplasia

HOXD3

Homeobox D3

Determine embryonic cell fate; involved in the regulation of cell adhesion processes; required to set up physiological constriction along the previously un-subdivided gut mesoderm

Murine: homozygous null H o x a 3 - / embryos show complete absence of thymus and alteration of hyoid cartilage; complementation with Hoxd3 protein restores thymus and corrects alteration of hyoid cartilage, suggesting that Hoxa3 and Hoxd3 can carry out identical biological functions

HOXD4

Homeobox D4

Determine embryonic cell fate; required to set up physiological constriction along the previously un-subdivided gut mesoderm

Murine: construction of minicomplex with all Hoxd genes deleted except for Hoxdl and Hodx3, the latter of which was functionally impaired, results in mice homozygous for minicomplex with retarded development, death within 2 weeks, absence of ileocecal valve and aberrant pylorus of stomach; in the absence of Hoxd function, mice lack sphincters

HOXD8

Homeobox D8

Determine embryonic cell fate; expressed in genitourinary tract and may play a continuing role in adult genitourinary tract function; required to set up physiological constrictions along the previously un-subdivided gut mesoderm

Murine: construction of minicomplex with all Hoxd genes deleted except for Hoxdl and Hoxd3, the latter of which was functionally impaired, results in mice homozygous for the minicomplex with retarded development, death within 2 weeks, absence of ileocecal valve, and aberrant pylorus of stomach; in the absence of Hoxd function, mice lack sphincters

HOXD9

Homeobox D9

Determine embryonic cell fate; required to set up physiological constriction along the previously un-subdivided gut mesoderm

HOXD 10

Homeobox D 10

Determine embryonic cell fate, required to set up physiological constriction along the previously un-subdivided gut mesoderm

Murine: construction of minicomplex with all Hoxd genes deleted except for Hoxdl and Hoxd3, the latter of which was functionally impaired, results in mice homozygous for the minicomplex with retarded development, death within 2 weeks, absence of ileocecal valve, and aberrant pylorus of stomach; in the absence of Hoxd function, mice lack sphincters Murine: construction of minicomplex with all Hoxd genes deleted except for Hoxdl and Hoxd3, the latter of which was functionally impaired, results in mice homozygous for the minicomplex with retarded development, death within 2 weeks, absence of ileocecal valve, and aberrant pylorus of stomach; in the absence of Hoxd function, mice lack sphincters (continues)

68

CHAPTER 1 ~ Developmental Bone Biology TABLE VIA (continued) Gene

Protein

Cellular function

Disease

HOXD11

Homeobox D 11

Determine embryonic cell fate; required to set up physiological constriction along the previously un-subdivided gut mesoderm

Murine: construction of minicomplex with all Hoxd genes deleted except for Hoxdl and Hoxd3, the latter of which was functionally impaired, results in mice homozygous for the minicomplex with retarded development, death within 2 weeks, absence of ileocecal valve, and aberrant pylorus of stomach; in the absence of Hoxd function, mice lack sphincters

HOXD 12

Homeobox D 12

Determine embryonic cell fate; interacting with Hoxdl 3 during mouse limb development; required to set up physiological constriction along the previously un-subdivided gut mesoderm

HOXD13

Homeobox D 13

Involved in regulating patterning during limb development; may play a role in reproductive physiology; may be involved in sphincter formation

HOX11

Homeobox 11, orphan homeobox gene located outside the HOX clusters, encodes a DNA binding nuclear transcription factor

Photo-oncogene involved in tumorigenesis of T-cell lymphomaleukemia; required for survival of spleen by maintaining splenic precursors during organogenesis

HOX11 L1

Homeobox 1 l-like 1

HSPG2

Heparan sulfate proteoglycan 2, perlecan

Required for proper positional specification and differentation of cell fate of enteric neurons Interact with extracellular matrix proteins, growth factors, and receptors and influence cellular signaling; essential for cartilage and cephalic development

Murine: construction of minicomplex with all Hoxd, the latter of which was functionally impaired, results in mice homozygous for the minicomplex with retarded development, death within 2 weeks, absence of ileocecal valve, and aberrant pylorus of stomach; in the absence of Hoxd function, mice lack sphincter Synpolydactyly; murine: S P D H - / severe synpolydactyly with malformation of all 4 feet including polydactyly, syndactyly, and brachydactyly, also lack preputial glands In human patients with T-cell leukemia and chromosomal translocation involving 10q24 the proto-oncogene TCL3, also known as HOX11, becomes activated following the arrangement; murine: by targeted disruption, homozygous HOX11 null embryos have spleen formation commencing normally up to a certain stage of embryogenesis and then undergo complete and rapid resorption Murine: Enx (Hox l l L 1 ) - / - mice develop neuronal intestinal dysplasia and megacolon Murine: disruption of perlecan results in 40% of H S P G 2 - / - mice that died in embryonic day 10.5 with defective cephalic development; 60% died shortly after birth with skeletal dysplasia resembling thanatophoric dysplasia type I; only 6% H S P G 2 - / - mice had exencephaly and skeletal dysplasia

IDA/IDUA

oL-L-Iduronidase

Enzyme degrades mucopolysaccharides

Hurler syndrome (dysostosis multiplex); Scheie syndrome (dysostosis multiplex)

IDS

Iduronate 2-sulfatase

Enzyme degrades mucopolysaccharides

IGF1

Insulin-like growth factor 1, somatomedin C

Prenatal and postnatal growth regulation

Hunter syndrome Growth retardation with sensorineural deafness and mental retardation (homozygous intragenic deletion); parents short stature (homozygous intragenic deletion); Knockout murine I G F - / - profound embryonic and postnatal growth retardation with neurological defects (continues)

SECTION IX ~ Gene and Molecular Controls o f Limb D e v e l o p m e n t

69

TABLE VIA (continued) Protein

Gene

Cellular function

Disease

Overexpression (loss of imprinting) of IGF 2 in Wilm tumor; Beckwith-Wiedemann syndrome; targeted disruption of IGF2 gene in mice by line resulted in growthdeficient heterozygous progeny; homozygous mutants were indistinguishable from heterozygous affected

IGF2

Insulin-like growth factor 2, somatomedin A

Modulation of growth hormone action, stimulation of insulin action, and involvement of development and growth

ITGA1

Integrin oL1

Cell surface receptor; dimerizes with the [3 subunit to form a collagen and laminin receptor

ITGA2

Integrin oL2, CD49B; et2 subunit of very late activating protein receptor (VLA-2)

Cell surface adhesion receptor; dimerizes with the [3 subunit to form a collagen and laminin receptor

ITGA3

Integrin oL2, CD49C; oL3 subunit of very late activating protein receptor (VLA-3) Integrin ~t7, clustering of integrin and Hox genes implies parallel evolution of these gene families

Cell surface adhesion receptor; a receptor for fibronectin, laminin, and collagen

ITGA 10

Integrin et 10

Bind to type II collagen; expressed in chondrocytes of articular cartilage

ITGAM

Integrin oLM

Dimerize with ITGB2 in vitronectin, fibrinogen, von Willebrand factor, thrombospondin, fibronectin, osteopontin, and collagen

ITGAV

Integrin o~V,vitronectin receptor, cell surface adhesion receptor

ITGB1

Integrin [31, member of a family of cell surface receptors

Dimerize with ITGB3 in vitronectin, fibrinogen, von Willebrand factor, thrombospondin, fibronectin, osteopontin, bone sialoprotein, and collagen; therapeutic targets for inhibition of angiogenesis and osteoporosis Associate with oL1 or oL6 to form a laminin receptor, with oL2 to form a collagen receptor, with ct5 to form a fibronectin receptor

LAR1 LHX2

Gene not cloned yet LIM homeobox protein 2

LOX

Lysyl oxidase

ITGA7

Specific cellular receptor for the basement membrane proteins laminin-1, -2, and-4; provide indispensable linkage between muscle fibers and extracellular matrix; clustering of integrin and Hox genes implies parallel evolution of these gene families

Putative transcription factor with two LIM and one Hox domain; may be involved in the development of leukemia by formation of chimeric proteins resulting from chromosomal translocation Extracellular Cu-dependent enzymes involved in the cross-linking and maturation of collagen and elastin

Autosomal recessive congenital myopathy; murine: homozygous null I T A G 7 - / mice viable and fertile but develop progressive muscular dystrophy

Murine: ablation of ITGAV resulted in o~V null mice with 80% dead during embryogenesis but appeared normal and 20% alive with intracerebral and intestinal hemorrhages and cleft palates

Autosomal dominant Larsen syndrome Elevated levels of Lhx2 found in patients with T-cell leukemias

Menkes syndrome, X-linked cutis laxa, Ehlers-Danlos V syndrome associated with lysyl oxidase deficiency (continues)

70

CHAPTER

1 ~

Developmental Bone Biology TABLE VIA (continued)

Gene

Protein

LUM

Lumican; keratan sulfate proteoglycan

LMX1B

LIM homeobox transcription factor 113 Mothers against decapentaplegic; Drosophila homologue 1

MADH1

MADH4

Mothers against decapentaplegic; Drosophila homologue 4

MADH5

Mothers against decapentaplegic; Drosophila homologue 5

MADH6

Mothers against decapentaplegic; Drosophila homologue 6

MADH9

MA N2 B 1

Mothers against decapentaplegic; Drosophila homologue 9 oL-Mannosidase B

MAP3K7/ MAPKKK

Mitogen-activated protein kinase 7

MATN1

Matrillin 1, cartilage matrix protein

Cellular function

Play a role in the regulation of collagen assembly of fibrils; expressed at high levels in adult articular chondrocytes Dorsal-ventral patterning of vertebrate limb Involved in the BMP signaling pathway, interacting with the activated receptors, undergoing phosphorylation, translocating to nucleus after binding to MADH4 Critical mediator of TGF[3 and BMP signaling pathways; putative tumor suppressor gene mutated or deleted in pancreatic and colorectal carcinoma

Involved in the BMP signaling pathway, interacting with the activated receptors, undergoing phosphorylation, translocating to nucleus after binding to MADH4; involved in the signaling pathway by which TGF-[3 inhibits the proliferation of human hematopoietic progenitor cells Involved in the TGF-[3 and BMP signaling pathway, expressed in vascular endothelium

Involved in the TGF-[3 and BMP signaling pathway; expressed in vascular endothelium Enzyme degrades mannosidase; accumulation results in lysosomal storage Participate in the regulation of transcription by TGF-[3; involved in the BMP signaling through binding with AP13 Cartilage matrix protein is a major component of the extracellular matrix of nonarticular cartilage, it binds to collagen

Disease

Nail patella dysplasia; murine: L M X l b - / nail patella syndrome

Pancreatic carcinoma; colorectal carcinoma; juvenile polyposis coli; head and neck squamous carcinoma; murine: homozygous MADH4 mice died before embryonic day 7.5; mutant embryos have reduced size, failure to gastrulate or express a mesodermal marker and show abnormal visceral endoderm development, heterozygotes show no abnormality; murine: compound heterozygotes for MADH4 and APC can be generated by meiotic recombination; simple heterozygotes for APC develop intestinal polyps; compound heterozygotes for APC and MADH4 develop polyps, which then undergo malignant transformation

Murine: targeted disruption results in M A D H - / - mutant mice with multiple cardiovascular abnormalities such as hyperplasia of heart valves and outflow tract abnormalities

oL-Mannosidosis (dysostosis multiplex)

Rattus: rats immunized with cartilage matrix protein develop polychondritis with erosion of nonarticular cartilage

(continues)

SECTION IX 9 Gene and Molecular Controls of Limb Development

71

TABLE VIA (continued) Gene MMP2

MMP8

Protein

Matrix metalloproteinase 2; gelatinase A; 72 kDa, type IV collagenase; 72-kDa gelatinase Matrix metalloproteinase 8, neutrophil collagenase

MMP9

Matrix metalloproteinase 9, gelatinase B, 92 kDa, gelatinase, 92-kDa type IV collagenase

MMPIO

Matrix metalloproteinase 10, stromelysin 2 Matrix metalloproteinase 13, collagenase 3

MMP 13

Cellular function

Cleave type IV collagen, the major structural component of basement membranes; catalyzes extracellular matrix degradation Cleavage of interstitial collagen in the triple-helical domain; cleaves collagen type I more so than type III Cleave collagen in extracellular matrix; key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes

Weak cleavage action on collagen types II, IV, and V Degrade fibrillar collagen; probable involvement in the pathophysiology of human osteoarthritis cartilage Regulate early development of limbs, heart, and teeth

MSX1/HOX7

Homeobox 7

MSX2

MSH (Drosophila) homeobox homologue 2

Involved in tissue interaction and implicated in vertebrate craniofacial development

NFYA

Nuclear transcription factor Y,

Stimulate the transcription of various genes by recognizing and binding to the CCAAT motif in promoters of of collagen, albumin, and [3-actin genes Stimulate the transcription of various genes by recognizing and binding to the CCAAT motif in promoters of collagen, albumin, and [3-actin genes Basement membrane protein tightly associated with laminin; also binds to collagen Bind and inactive members of the growth factor-[3 superfamily, signaling proteins such as the BMPs, and are essential for proper skeletal development Involved in the processing of TGF-[3 precursor to the mature form, cleave propeptide of collagen type V, oL1

O~

NFYB

Nuclear transcription factor Y,

NID

Nidogen, enactin

NOG

Noggin

PACE

Paired basic amino acid cleaving enzyme, furin, membrane-associated receptor protein Gene not cloned yet Gene not cloned yet Peptidase D, prolidase, imidodipetidase

PDB1 PDB2 PEPD

Split immunodipeptides, play an important role in collagen metabolism because of the high levels of immunoacids in collagen

Disease

Murine: homozygous M m p 9 - / - mice with null mutation exhibit delay and abnormal pattern of skeletal growth plate, vascularization, and ossification; enlargement of growth plate eventually undergoes remodeling and produces an axial skeleton of normal appearance

Autosomal dominant hypodontia; WolfHirschhom syndrome (gene deleted); murine M s x l - / - cleft palate, facial and dental abnormalities Craniosynostosis, Boston type; MSX transgenic mice perinatal lethal with premature suture closure and ectopic cranial bone

Proximal symphalangism; multiple synostoses syndrome; murine N O G - / stillborn with multiple defects and bony fusion of appendicular skeleton

Paget disease of bone type I Paget disease of bone type II Autosomal recessive peptidase deficiency

(continues)

CHAPTER 1 ~ Developmental Bone Biology

72

TABLE VIA (continued) Gene

Protein

Cellular function

Disease

Zellweger syndrome; infantile Refsum disease Zellweger syndrome Zellweger syndrome; neonatal adrenoleukodystrophy; murine P x r l - / perinatal lethal with Zellweger syndrome Zellweger syndrome Rhizomelic chondrodysplasia punctata type I X-linked hypophosphatemic rickets; murine (HYP) X-linked hypophosphatemic rickets; murine (GYR) X-linked hypophosphatemic rickets and inner ear abnormalities microdeletion syndrome

PEX1

Peroxin 1

PEX2/PXMP3 PEX5/PXR1

Peroxin 2 Peroxin 5

Involved in peroxisomal matrix protein import Involved in peroxisomal assembly Encode a receptor for proteins with type 1 peroxisomal targeting signal (PTS 1) and also mediates PTS2targeted protein import

PEX6/PAF2 PEX7

Peroxin 6 Peroxin 7

Involved in peroxisomal assembly Encode a peroxisomal PTS2 receptor

PHEX

Phosphate regulating protein with homologies to endopeptidases on X chromosome

Involved in bone development

PLOD2

Procollagen lysine, 2oxoglutarate, 5-dioxygenase 2; lysine hydroxylase 2

PLOD3

Procollagen lysine, 2oxoglutarate, 5-dioxygenase 3; lysine hydroxylase 3

PRTN3

Proteinase 3, serine proteinase, Wegener granulomatosis autoantigen Parathyroid hormone receptor or parathyroid hormonerelated protein receptor

Form hydroxylysine residues in XaaLys-Gly sequences in collagen; serve as sites for attachment for carbohydrate units and are essential for stability of intermolecular collagen cross-links Form hydroxylysine residues in XaaLys-Gly sequences in collagen; serve as sites for attachment for carbohydrate units and are essential for stability of intermolecular collagen cross-links Cleave elastin, fibronectin, laminin, vitronectin, and collagen types I, III, and IV Involved in calcium homeostasis with hypercalcemia and suppression of PTH levels and exaggerated loss of cortical bone Involved in transcription expression of HOX genes Involved in transcription expression of HOX genes Expressed in fetal cartilage

PTHRP

SCML1 SCML2 SEDL

Sex comb on midleg (Drosophila-like 1) Sex comb on midleg (Drosophila-like 2) Sedlin

SMOH

Smoothed (Drosophila homologue)

SOX9

SRY box 9

A signaling component of the sonic hedgehog patched complex; function as an oncogene in basal cell carcinoma activated by somatic mutation in sporadic nevoid basal cell carcinoma syndrome and primitive neuroectodermal tumors targeting numerous genes (HOX, BMP) Regulates COL2A1 expression and implicates abnormal regulation of COL2A1 during chondrogenesis

Associated with Wegener granulomatosis hamster; tracheal insufflation of Prtn3 causes emphysema Murk Jansen metaphyseal dysplasia

Spondylopeiphyseal dysplasia tarda, X-linked Mutation of SMOH results in sporadic basal cell carcinoma; murine: transgenic mice overexpressing SMOH develop skin lesions resembling basal cell carcinoma

Campomelic dysplasia

(continues)

SECTION IX ~ Gene and Molecular Controls o f Limb D e v e l o p m e n t

73

TABLE VIA (continued) Gene

Protein

Cellular function

Disease

SPAR C

Secreted protein, acidic, cysteine-rich; osteonectin

Bone-specific phosphoprotein; binds selectively to hydroxypatite and to collagen fibrils at distinct sites; osteonectin accounts for unique property of bone collagen to undergo calcification

TBX1

T box 1, T named after the T or brachyury gene in mouse, member of a family of transcription factors

Involved in the regulation of developmental processes

TBX2

T box 2, transcription factor

Involved in the regulation of developmental processes

TBX3

Tbox 3

Involved in posterior elements of limb development

TBX4

T box 4, transcription factor

Expressed throughout developing hindlimb buds

TBX5

T box 5

Involved in heart and anterior elements of limb development

Holt-Oram syndrome

TBX6

T box 6, transcription factor

Involved in paraxial mesoderm and somite formation; in its absence, cells destined to form posterior somites differentiate along a neuronal pathway

Murine: creation of a Tbx6 mutation resulted in irregular somites being formed in the neck region but differentiated along neuronal pathway forming neural tube-like structures that flank the axial neural tube

TBX10

T box 10, transcription factor

TBX15

T box 15, transcription factor

Involved in the ~egulation of developmental processes Involved in the regulation of developmental processes in mouse; expressed in craniofacial region and developing limbs

TBX18

T box 18, transcription factor

Involved in the regulation of developmental processes

TBX19

T box 19, transcription factor

Involved in the regulation of developmental processes

THBS1

Thrombospondin 1

THBS2

Thrombospondin 2

Glycoprotein that mediates cell to cell and cell to matrix interactions; can bind to fibrinogen, fibronectin, laminin, and type V collagen Glycoprotein that mediates cell to cell and cell to matrix interactions; can bind to fibrinogen, fibronectin, laminin, and type V collagen

THBS3

Thrombospondin 3

Glycoprotein that mediates cell to cell and cell to matrix interactions; can bind to fibrinogen, fibronectin, laminin, and type V collagen

THBS4

Thrombospondin 4

Glycoprotein that mediates cell to cell and cell to matrix interactions; can bind to fibrinogen, fibronectin, laminin, and type V collagen

May be one of the human genes deleted in DiGeorge contiguous gene deletion syndrome

Ulnar-mammary syndrome

Murine: targeted disruption resulting in deficient mice with mild variable lordosis of spine at birth and lung abnormalities with pneumonia Murine: targeted disruption resulting in homozygous deficient mice with connective abnormalities such as fragile skin with reduced tensile strength, flexibility of tail, increased bone density and cortical thickness of long bones, abnormal bleeding time

(continues)

74

CHAPTER 1 ~ Developmental Bone Bioioyy

TABLE VIA (continued) Gene TRPS1 TWIST

VDR

Protein Gene not cloned yet Basic helix-loop-helix transcription factor, homologue of Drosophila TWIST Vitamin D hormone receptor

Cellular function

Disease

Involved in craniofacial and limb development; may function as an upstream regulator of FGFRs

Trichorhinophalangeal syndrome type 1 Saethre-Chotzen syndrome; murine TWIST + / - Saethre-Chotzen syndrome

Involved in the synthesis of osteocalcin the most abundant noncollagenous protein in bone

Vitamin D resistant rickets with end organ unresponsiveness to 1,25dihydroxycholecalciferol

aAdapted from Ho NC, Jia L, Driscoll CC, Gutter EM, Francomano CA (2000). A skeletal gene database. J. Bone Miner. Res. 15:2095-2122; with permission of the American Society for Bone and Mineral Research.

E. Overview of Gene Controls of Limb Development A large number of molecules are expressed in relation to the developing limbs serving as growth factors, transcriptional regulators, and signaling molecules. Detailed investigations are now beginning to reveal the temporal and spatial aspects of molecular expression indicating the role of each in the developmental cascade and showing in particular interrelationships between the various signaling regions in general and specific molecules in particular. Some of the major factors are listed in Table VIB. Many genes encoding regulatory molecules are expressed in the AER. The genes encode two types of protein: transcriptional regulators and signaling proteins. The Hox gene family represents an example of how transcription factors control development. Lmx-1 and engrailed-1 are other transcription factors. FGF-4 is particularly important, playing a role in signaling between the AER and underlying mesenchyme. The molecules involved include dlx, Msx-1 and Msx-2, engrailed-1 (en), bone proteins BMP-2 and BMP-4, retinoic acid, retinoic acid receptor- [3, fibroblast growth factors-2 and FGF-4, and FGF receptor-1. Retinoic acid is a major signaling molecule or morphogen in the zone of polarizing activity. Mesenchymal cells in the progress zone express several genes encoding regulatory proteins such as Msx-1 and Msx-2, Evx-1, Wnt-5A, and AP2. Mxs-1 and Mxs-2, originally known as Hox-7 and -8, are two related homeobox containing genes that are widely expressed in vertebrate embryos in particular where epithelialmesenchymal interactions occur. Msx-1 is highly concentrated in the distal mesenchyme in developing limbs with weak expression in the AER whereas Msx-2 is expressed weakly in mesenchyme but strongly in AER. The mesenchymal cells provide the signals that initiate limb bud development but the molecular trigger that stimulates AER formation is not yet known. There is rapid proliferation of mesenchymal cells, which induce the overlying ectodermal cells to form the AER. Early mesodermal induction pre-limb bud stage is the subject of intensive study with

members of each of the FGF, TGF-[3, and wingless/int-1 (Wnt) families implicated at varying stages and regions. The mesenchymal cells are primed to respond to morphogens by specific genes referred to as homeobox genes. These genes are responsible for initiating regional development by establishing patterns encoding positional information. They do so by producing transcriptional factors, which are small proteins that activate genes bound to them. Processes such as cell proliferation, cell differentiation, and cell death are regulated by homeobox genes, although these appear to be overlapping functions such that combinations of homeobox genes act on several groups of cells.

F. H o m e o b o x Genes Thirty-eight Hox genes with a homeobox sequence have been identified in mammals and are present in 4 clusters on 4 chromosomes (121,200, 201). The homeobox genes directing limb development are organized into 4 clusters termed Hox a, b, c, and d in current terminology (hox 1, hox 2, hox 3, and hox 4 prior to the 1990s). Each complex has 9-11 genes spaced over 100-150 kb. Sequence comparisons between the 4 clusters indicate that they evolved from a single cluster of genes. Hox genes within each cluster have direct homologues in the other 3 clusters. There are 13 sets of related homologues called paralog groups. The entire Hox gene family generally is displayed in a 4 (Hox a, b, c, d) by 13 (paralogs) array, with the horizontal axis representing physical linkage and chromosomal position and the vertical axis representing gene similarity. A gene is represented by a letter (chromosome location) and a number (relation to paralogs) (317) (Fig. 19). Each of the 38 Hox genes that are organized in 4 different chromosomal complexes are organized in the same way with the genes in each cluster all oriented in the 5' to 3' direction of transcription. There is also remarkable conservation of gene similarity between Drosophila and vertebrate species with the Drosophila complexes referred to as HOM-C complexes. It is the Hox genes that begin to explain the molecular

SECTION IX

|174 Group:

1.

9

Gene and Molecular Controls of Limb Development

Dimt:tions o( transcription ol" ANT-C and BX-C genes

2.

3.

4.

5.

6.

7.

IE IJ

ID 1.4

IC i.3

II 12

IA I.I

8.

9.

10.

11.

Ill I.?

IH IJI

U 1.9

12.

13.

Hox A (Hox I )

Human IF .~lou~ I..6

IK I.!1

IJ 1.10

Hox B IHox 21

|174174174174

Human -~1

2H

-~11

~F

.~A

211

)1~

3D 3.4

J4L" 3,1

.~

2D

:It

3A ,I,I

3,B 3.2

.111 JdJ

.1H ~k?

.Mr

.1(;

4s 4.3

4C 4.4

,liD U

4F U

4H 4.7

41 4.8

Hox C (Hox 31 Humln .~4ouse Hox D (Hox 4)

Human ~ .Mouse 4.1

4A 4.1

4B 4.2

3' ,11

S' Direction o( mmscrilxm o( Hon series

FIGURE 19 The Hox gene family is outlined. [Reprintedfrom Scott, M. P. (1992). Cell 71:551-553, copyright 1992, with permission from Elsevier Science.] basis for structural similarity throughout the vertebrate kingdom. Although some genes have been lost, it is evident that those that have persisted have a strong degree of structural necessity. There is also a strong correlation between the physical order of genes along the chromosome and their expression along the anteroposterior axis of the embryo. The Hox genes tend to be expressed in specific regions in an ordered array of spatially restricted domains such as the neural tube, neural crest, limbs, and hind brain segments. There is also a relationship based on the time of appearance of expression during embryogenesis. Retinoic acid (RA) induces Hox gene expression along with expression of other developmental molecules. The genes at the extreme 3' ends of the clusters are activated the earliest, have the most anterior boundaries of expression, and display the highest sensitivity to RA. As one progresses in a 5' direction, each subsequent gene has a later, more posterior, and reduced RA response pattern of expression. Hox genes are actively expressed in the polarizing region in which they appear to convey patterning information. Characteristic of patterning along the limb axis are the proximodistal morphogenetic progression, a temporal sequence in the activation of Hox genes, a partially overlapping pattern of Hox expression, especially posteriorly, and concentration in the polarizing region. There are relatively few naturally occurring mutations in mouse or human Hox, genes and their function has been inferred from their position in the developmental sequence. The large number of genes and the overlapping of adjacent areas have led to difficulty in assessing specific functions. The role played by Hox genes in skeletal development is complex. There is substantial overlap in expression domains among the members of a paralogous group, and the loss of a single gene can be overcome by functions of adjacent genes. The use of transgenic mutations has led to better definition

75

of specific Hox gene roles. With single gene transformations, however, the abnormal findings often are relatively minimal. This may be because there is compensation by other Hox genes. It is felt also that there is a requirement for several genes to combine in patterning a structure such that alteration of a single component may not be sufficient to generate a complete transformation. The Hox genes are expressed in specific patterns during morphogenesis of the upper and lower limbs (84). Studies in the chick limb bud show that evolving patterns of gene expression represent temporal and spatial overlap of several distinctly regulated expression domains. Hoxd gene expression is expressed sequentially, for example, in the development of the chick limb bud. In the early phases, Hoxd-9 and Hoxd-lO genes are expressed across the AP extent of the developing bud. The next phase of limb outgrowth involves activation of Hoxd-ll and Hoxd-12 genes in progressively restricted domains in the posterior half of the bud, and finally Hoxd-13 is activated later on. It is the sonic hedgehog (Shh) gene that is involved in the regulation of the Hoxd gene expression in the distal mesenchyme. Hoxd-9 and Hoxd-lO appear proximally before sonic is expressed. Abnormal expression of any of these genes can lead to structural abnormalities. When Hoxd-ll expression was altered in limb buds, many changes were noted including a first metatarsal with a deltoid bone shape, abnormal phalangeal structure, and metatarsals abnormal in length. Many of the structural limb abnormalities seen in the human thus can be secondary to abnormalities in Hox gene expression. It is also becoming evident that gene activity has a temporal sequence that can vary in the sense that the gene may be active early, quiet down, and then reactivate later. All of the Hox genes have specific domains of expression along the anterior-posterior or primary axis of the embryo. They are also expressed in more restricted domains along the secondary axes of the embryo such as the limb buds. The paralogous genes are not expressed in similar domains in the limb bud. Among areas of common expression, the Hoxd genes are centered in the ZPA at the posterior and distal tip of the developing limb bud, whereas the Hoxa genes are expressed in restricted domains along the proximal-distal axis of the limb but are not polarized along the AP axis of the late limb bud. With increasing studies of Hox expression patterns, it appears that the boundaries of the various genes are not as specific as once suspected. The product of the Shh gene, expressed in the ZPA, along with various FGFs produced in the apical ectodermal ridge are responsible for initiating and possibly regulating Hox gene expression. Signals from the AER and ZPA are coordinated to regulate Hox gene expression in the developing limb bud. Much less is known about Hoxb and Hoxc genes during limb development. Tickle and Eichele (347) have listed the genes involved in early vertebrate limb development as reproduced in Table VIB. They also note that hundreds of other genes both known and unknown are involved.

TABLE VIB

G e n e s Expressed in Early V e r t e b r a e Limb Buds a-~

(i) Genes Expressed in Limb Mesenchyme Transcription factors encoded by Hox complexes Hoxa-lO, Hoxa-11, Hoxa-13

Progressively more 5' genes restricted to more distal mesenchyme

Hoxd-9, Hoxd-lO, Hoxd-11 Hoxb-5

Progressively more 5' genes are restricted to more posterodistal Hoxd-12, Hoxd-13 mesenchyme Expressed anteriorly in forelimbs

Hoxe-6*

Expressed anteriorly in forelimbs

Other transcription factors Posterodistal mesenchyme Restricted to distal mesenchyme Msx-1 Anterior and distal mesenchyme Msx-2 Distal mesenchyme AP-2 Retinoid receptors and retinoid binding proteins RARoL[3 Expressed at low levels throughout mesenchyme Evx-1

RAR[3 RARe/

Throughout mesenchyme but proximally enriched Expressed at low levels through mesenchyme

RXRct[3 CRABP-I CRABP-II CRABP*

Ubiquitous Distal mesenchyme Dorsally enriched, higher levels proximally Anterior to posterior protein concentration gradient with anterior high point

Putative intercellular signaling molecules Wnt 5a Abundant in distal mesenchyme, low levels proximal mesenchyme Sonic hedgehog Discrete posterior domain associated with polarizing region BMP-2 Posterior mesenchyme, approximately coextensive with polarizing region BMP-4 Anterior and posterior mesenchymal domains FGF-2* Mesenchyme beneath ectoderm and apical ectodermal ridge (ii) Genes Expressed in Apical Ectodermal Ridge Transcription factors Dix Engrailed Msx-1 Msx-2 RAR[3 Putative intercellular signaling molecules FGF-2* Enriched posteriorly FGF-4 BMP-2 BMP-4 Wnt 5a (iii) Genes Expressed in Limb Ectoderm Transcription factors Engrailed

Enriched ventrally

Putative intercellular signaling molecules FGF-2* Dorsally enriched BMP-2 Wnt 5a

Enriched ventrally

Wnt 7a

Dorsal ectoderm only

aThis is a partial list of the best categorized molecules; a comprehensive list would consist of several hundred entries. bExpression data based on in situ hybridization analysis except for gene products marked by an asterisk, which indicates that expression pattern has been determined by immunohistochemistry. CDerived from Tickle and Eichele (347).

SECTION iX ~ Gene and Molecular Controls of Limb Development

G. Specific Details Concerning Gene and Molecular Controls on Limb Development and the Hox Gene Network The Hox genes appear to be involved in the establishment of pattems in coding positional information. The vertebrate homeobox containing Hox genes appear as candidates for pattem formation genes. As development proceeds, cells in the progress zone leave it as proliferation there continues and pushes the tip of the limb bud more distally and laterally. The cells are instructed as to their positional identities, however, while they are within the progress zone. The proximaldistal progression is seen with proximal structures at hip and shoulder developing before those more distally. The information given to the proximal cells thus is different from those more distal both in terms of quality and timing. In studies of the Hox gene clusters, those genes located at the 3' extremities of the complexes are expressed earlier and for more anterior positions than genes located at the 5' position, which are expressed later and in more restricted posterior areas. Genes appear from the 3' to the 5' regions. The ordering of the genes and their subsequent expression reflect the temporal sequence of their activation during limb bud outgrowth. The Hox expression domains also are related to establishment of the midline truncal structures. Hox gene expression in the limb as it develops reflects the clustered organization. In limbs the genes located at more 5' positions are expressed in successfully more posterior-distal areas at early stages. Expression also varies along the rostrocaudal axis. The area in the limb where Hoxd expression domains all seem to overlap is the zone of polarizing activity. Cells of the progress zone will also express various combinations of Hox proteins at different times or positions within the zone. The Hox genes thus are felt to provide patterning information or positional information, which is imparted to each cell as it leaves the zone and is then maintained during the next stages of limb development. Each Hox domain overlaps with the one adjacent to it such that there is not rigid direction of one part of one bone by one gene. Hox gene expression also leads to characteristic previously recognized patterning systems: (1) the patterning system operates in a craniocaudal or proximal-distal temporal progression; (2) the temporal sequence is observed in the activation of Hox genes; (3) a partially overlapping pattern of Hox expression domains is generated with an increasing overlap in the posterodistal areas; and (4) a particular area such as the polarizing region appears to control Hox gene expression. The Hox genes appear to impart information rather than respond to it. The progressive activation of more and more 5'-located Hox genes leads to the subsequent addition of segmented structures, such as the blastema for the limb bones.

H. Expression of Hoxa and Hoxd Genes during Normal Limb Development The earliest Hoxd gene expression was the uniform activation of Hoxd-9 and Hoxd-lO along the entire anterior-

77

posterior extent of the early limb bud. Subsequently, Hoxd-11, Hoxd-12, and Hoxd-13 were activated sequentially at the posterior border of the limb bud. Hoxa activation proceeded from Hoxa-9 and Hoxa-lO through Hoxa-11 and Hoxa-13. With the exception of Hoxa-13, the Hoxa genes appear to be activated uniformly along the extent of the limb bud. The study assessed 23 different Hox genes representing all 4 clusters. This included all of the members of the Hoxa and Hoxd clusters previously reported, all members of the Hoxc cluster from paralog 4 through 11, and one member of the Hoxb cluster. Hoxc expression was different from previous descriptions of other genes. Its most prominent domain is a wedge-shaped zone restricted to the AP region of the limb. It was not oriented around a known signaling center, such as the Hoxd genes around the ZPA or the Hoxa genes around the AER. This detailed study allows for assessment of the dynamic expression patterns of the Hoxa and Hoxd genes during limb development. It was felt that there were three independently regulated phases of gene expression, seen most clearly with the Hoxd genes. During phase 1, Hoxd-9 and Hoxd-lO are expressed uniformly throughout the early mesoderm without apparent anterior-posterior bias whereas Hoxd-11 through Hoxd-13 are not expressed. During phase 2, expression of Hoxd-9 through Hoxd-13 is initiated sequentially at the posterior-distal margin of the limb. With phase 3, there is a sequel initiation of transcription of Hoxd-13 through Hoxd-lO in a temporal sequence inverted from that observed during phase 2. The timing and positioning of Hox gene expression correlate well with the previously defined proximal-distal segment development from classical embryologic studies. During specification of the upper arm-leg, they observed the nonpolar expression of Hoxd-9, Hoxd-lO, Hoxa-9, and Hoxa-lO. During specification of the lower arm and leg, sequential activation and posteriorly polarized expression of Hoxd-9 through Hoxd-13 and uniform expression of Hoxa-11 occurred. Specification of the hand-foot region begins with phase 3 Hox gene expression, with Hoxa-13 transcription activated at the posterior border of the limb bud followed by Hoxd-13 and subsequently Hoxd-12, Hoxd-11, and Hoxd-lO. Shh can influence the expression of Hox genes in the limb. The initial phase of limb outgrowth and Hox gene expression occur prior to the onset of Shh expression. The onset of phase 2 expression, however, coincides with the onset of Shh expression, and Shh also appears to drive phase 3 Hox gene expression. The authors (241) conclude that "overwhelming experimental evidence demonstrates a causal link between Hox gene expression and morphology... Hox gene expression in the limb bud affects both the condensation of skeletal precursors in the limb bud and the subsequent growth and elongation of these elements." They note, however, that there is no obvious correlation between Hox gene expression and specific detailed morphology in the hand and foot.

78

CHAPTER 1 ~ Developmental Bone Biolofy

Genes located at 3' parts are expressed earlier and from more anterior positions, whereas genes at 5' positions are expressed later and in more restricted posterior areas. The Hox genes are expressed in a cascade fashion along the anteroposterior body axis. Their expression in the developing limb bud is initiated at a time when the pattern is being specified. Hox genes are felt to encode positional information. Hoxa and Hoxd genes are expressed in limb bud undifferentiated mesenchymal cells and then are restricted to precartilage areas and perichondrium. When their expression domains are superimposed they prefigure cartilage limb models. It has been suggested that the Hoxa genes are primarily responsible for subdividing the limb along the proximal-distal axis, whereas the Hoxd gene exerts influence on the anteroposterior axis. The AER directs limb outgrowth by maintaining undifferentiated proliferating mesenchyme immediately adjacent to it in the progress zone. As the cells leave the P, their fate in a proximal-distal sense has been determined. Removal of the AER early leads to proximal limb truncations whereas later removal involves more distal or digital truncations.

I. Expression of Hoxc Genes in the Chick Limb Bud Nelson et al. (241) undertook cloning of all Hox genes expressed in the chick limb budto note their relative position in development. Their findings are reviewed next. This group describes the expression patterns of Hoxc genes in limb development for the first time. The studies were based on in situ hybridization using both whole mount and sectioned embryos at varying stages. The Hoxc clusters are expressed in the anterior-proximal portion of either wing or leg or both. The most 3' members of the cluster, Hoxc-4 and Hoxc-5, are expressed only in the wing; Hoxc-6 and Hoxc-8 are in both the wing and leg. The more 5' members of the cluster, Hoxc-9, Hoxc-lO, and Hoxc-11, are expressed only in the leg. In contrast to the changing temporal and spatial patterns of expression of the Hoxa and Hoxd genes in limb development, the Hoxc group in the anterior and proximal region maintains the same relative domains as the limb grows.

J. Expression of Hoxb Genes There was only limited expression of Hoxb genes, and the only Hoxb gene expression in the chick limb was Hoxb-9, which specifically expresses in the hind limb in the anterior portion of the developing upper and lower leg. There was also some expression adjacent to the AER.

K. Signaling Molecules along Developing Limb Axes 1. RETINOIDS Retinoic acid (RA) was the first molecule identified that profoundly affected the anteroposterior body axis and also

the pattern of the developing limb (342). Retinoic acid is known to induce tlox gene expression, including Hoxd-11, Hoxd-12, and Hoxd-13 along with FGF-4, BMP-2, and Shh gene expression. The retinoids are small hydrophobic molecules that bind and activate nuclear receptors, which are ligand-dependent transcription factors that control the expression of target genes. Retinoic acid is present in chick and mouse limb buds in particular in the zone of polarizing activity. It is suspected that the concentration of retinoic acid varies in gradient fashion to provide positional information for cell deposition patterns. When RA is applied locally to the anterior margin of a limb bud, it induces extra digit formation. The chief observations implicating retinoic acid as a local chemical mediator in normal limb development are that it occurs in a limb bud, it is enriched in the ZPA, and the concentration of retinoic acid required for digit induction is in the same range as the endogenous retinoic acid concentration (150). Retinoids have been identified as molecules that can mimic the effects of ZPA grafts on limb patterning. Several RA receptors have been identified in the developing limb. The analysis of retinoid function provides molecular insights into the role of diffusible signals in the control of limb patterning. RA is distributed unevenly across the AP axis of the limb with a concentration greater in the posterior region, including the ZPA. It appears that secretion of the RA from the ZPA passes into the rest of the limb, producing a concentration gradient that can help to define cell position and specify the anteroposterior pattern. Retinoic acid is involved not only in limb bud differentiation but also later in the developmental sequence as a major regulator of chondrocyte maturation and matrix mineralization (177). Tissue culture studies with chondrocytes established that 3-week-old cultures treated with retinoic acid rapidly increased expression of the alkaline phosphatase, osteonectin, and osteopontin genes. There is also calcium accumulation in the RA-treated cultures in younger chondrocytes that were cultured. The effect of retinoic acid was different; it did not produce the previously described findings, but rather greatly promoted cell proliferation. RA thus appears to react throughout many stages of limb development with specific effects on each. Once cartilage has been formed, the RA appears both to induce expression of late maturation genes and to activate mineralization of the cartilage matrix.

2. SONICHEDGEHOGAND INDIANHEDGEHOG Sonic hedgehog (Shh), a secreted protein, was isolated by Riddle et al. (295) in 1993 in the chick and also by Kraus et al. (198) and Echelard et al. (95). Indian hedgehog (Ihh) was isolated by Lanske et al. (209) in 1996. It is expressed temporally slightly after Shh and regulates chondrogenic differentiation, but both Shh and Ihh have similar activities. The hedgehog proteins are a family of secreted signaling molecules that help initiate cell patterning in early embryogenesis and cartilage formation in skeletal development

SECTION IX ~ Gene and Molecular Controls of Limb Development (360). Shh is a vertebrate homologue of the Drosophila segment polarity gene, which localizes in the ZPA in chick wing bud, the posterior mesenchyme of mouse limb buds, as well as in Xenopus and zebra fish (104). It has been suggested that the Shh appears to pattern the anteroposterior limb axis. Like all the other signaling molecules, Shh is expressed in many regions of the early embryo long before limb bud formation is initiated (96). Its expression (in mouse, rat, and chick) coincides with formation of the embryonic floor plate dorsal to the notochord that induces differentiation of neural cells of the central nervous system, including the ventral spinal cord. When seen in developing limbs, Shh is expressed in a cluster of posterior mesenchymal cells, as noted previously. The temporal and spatial pattern of Shh expression suggests a close association between the gene and the organizing activity within the zone of polarizing activity (ZPA), thus serving as the molecular basis of the ZPA. Shh can induce extra digit formation in the anterior margin of a limb bud. Currently it is unclear whether Shh acts as a morphogen itself or exclusively induces the expression of other signaling molecules secondarily. Shh induces FGF-4 in the AER, the local expression of Hoxd-13 (needed for limb patterning), and also local expression of BMP-2. It has also been found that retinoic acid induces expression of Shh, which then activates Hox d - l l expression. Indian hedgehog (Ihh) is expressed in the prehypertrophic chondrocytes of cartilage in which it appears to regulate the rate of hypertrophic differentiation (305). It appears to work by inducing the expression of a second signal involving PTHrP (the parathyroid hormone-related protein), which then signals to its receptor in the prehypertrophic chondrocytes. Ihh has been seen to be expressed in the developing cartilage elements. Vortkamp et al. (359), using in situ hybridization in varying stages of chick embryos studied by whole mount preparation, detected Ihh in the endoderm of the developing midgut and in the lung and cartilage of the developing long bones of the limbs. It was not expressed early in development, whereas sonic hedgehog was expressed in the posterior mesenchyme suggesting that the two had different roles and that lhh acted later in the developmental sequence in forming skeletal elements. In companion studies, it was noted that type X collagen, as known previously, was expressed only in hypertrophic cells whereas Ihh was expressed in the transitional region between proliferating hypertrophic chondrocytes and was actually excluded from hypertrophic cells. Ihh expression, therefore, preceded hypertrophic state. BMP6 overlapped both the Ihh and the type X collagen expression domains at each stage. It was felt that lhh was expressed at a specific critical stage of endochondral bone formation. They proposed that the Ihh acts normally on the perichondrium to initiate a negative feedback loop that regulates the hypertrophic differentiation process. When lhh expressing cells underwent the final differentiation steps to become hypertrophic chondrocytes, they turned off the expression of lhh thereby allowing more cells

79

to commit to the differentiation pathway. Vortkamp et al. felt that the negative feedback loop initiated by lhh was mediated by the perichondrium and in particular by the parathyroid hormone-related protein expressed there. They concluded that both Ihh and PTHrP repressed hypertrophic cartilage differentiation and also that Ihh can induce PTHrP.

3. FIBROBLASTGROWTH FACTORS (FGFs) The fibroblast growth factors (FGFs) are a group of molecules that play a major role in normal developmental and physiological processes (78, 226). The FGF gene family currently comprises nine members, all of which are structurally related and generally encode proteins with a molecular mass of 20-30 kDa. FGF-1 and FGF-2 were purified more than a decade ago and have been studied extensively since. FGFs are potent mitogens with cells of mesodermal, neuroepidermal, ectodermal, and endodermal derivatives. Their normal physiological activities in vivo include embryonic and fetal development, neovascularization, and response to wounding. Some FGFs are oncogenes, and FGF-4 is one of the most frequently identified oncogenes in cell transformation. Although nine FGF genes have been identified, different isoforms can be generated among certain of these molecules, which would indeed underlie additional functions, and further diversity occurs by a multitude of posttranslational modifications. FGFs transduce signals to the cytoplasm through a family of transmembrane receptor tyrosine kinases referred to as the FGF receptors (FGFRs), and four mammalian FGFR genes are known. Of importance to limb development is the finding, by in situ hybridization studies, that FGFs are widely expressed during development. During the development of the vertebrate limb bud FGF-4 has been found to be synthesized by the apical ectodermal ridge, primarily in its posterior half, which itself has been implicated in outgrowth of the developing limb by maintaining proliferation of underlying cells in the progress zone (243, 244). FGF-4 can substitute for the AER in maintaining the polarizing region and can provide almost all of the signals necessary for the complete outgrowth and patterning of the chick limb. FGFs have been shown not only to induce limb bud formation but also to help maintain the proliferation of limb bud mesenchyme cells. It has been shown that beads soaked in FGF-l, FGF-2, or FGF-4 placed in the presumptive flank of chick embryos induce formation of ectopic limb buds, which can then develop into complete limbs. These results suggest that local production of an FGF may initiate limb development. Cohn et al. (66) interpreted Iheir experimental data to indicate that, under the influence of ~ , lateral plate mesoderm cells continue to proliferate and that the FGF led to local activation of sonic hedgehog in cells with potential polarizing activity, thus establishing a polarizing region. A progress zone was then established and further maintained by the activation of Hoxd genes. Cells in tlie progress zones produced a signal that induced formation of a formal AER

80

CHAPTER 1

9

Developmental Bone Biology

in the overlying epithelium. The FGF thus served to establish a limb bud not only with a polarizing region but also with a progress zone and an AER. Newly induced AER then produced FGF-4, which maintained the limb bud and led to the outgrowth and subsequent normal patterning seen. More recent studies have indicated that it is FGF-8 that is responsible for the induction, initiation, and maintenance of chick limb development (71). FGF-8 gene expression occurs in the ectoderm overlying the prospective limb forming territories, after which continuing FGF-8 secretion initiates limb bud formation. This is done by promoting the expression of sonic hedgehog (Shh) in the lateral plate mesoderm. Many studies have indicated that signaling molecules from the AER regulate limb development by their influence on cells at the distal tip of the limb bud mesoderm, referred to as the progress zone. The progress zone cells are influenced by signals from the zone of polarizing activity (ZPA) region of mesoderm at the posterior margin of the limb bud and also by signals from the ectoderm coming from Shh and Wnt-7a. Evidence indicates that FGF-8 functions to induce limb formation and plays a role in the initiation of limb bud outgrowth and the establishment of subsequent limb development, including maintaining the outgrowth and pattern formation in established limb buds. FGF activity is necessary for the initiation of Shh expression at the limb bud posterior margin.

4. WNT 7A The Wnt genes encode secreted proteins that associate with cell surface and extracellular matrix and have been implicated in many developmental processes, including the regulation of cell fate in pattern formation. Wnt 7a was noted to be expressed in the dorsal ectoderm and subsequent studies showed dorsal to ventral transformations of cell fate, indicating that Wnt 7a is a dorsalizing signal (266). It was also noted to act not only in the dorsal-ventral plane but also to have some role regulating patterning along the anteriorposterior axis. Subsequent studies showed that all three axes (dorsal-ventral, proximal-distal, and anteroposterior) are intimately linked by the respective signals Wnt 7a, FGF-4, and Shh during limb development (243). 5. TRANSFORMINGGROWTH FACTORS-~ (TGF-~) Another important group of secreted signaling molecules relating to development in general and that of the skeletal system in particular is the transforming growth factor-f3 (TGF-f3) family of peptide growth factors (50, 156). The transforming growth factor-f3 superfamily consists of as many as 25 genetically related polypeptide growth factors (191). They are often subdivided into four groups: (1) TGFJ3 family (TGF-i3 1-5); (2) activin-inhibin family; (3) BMP/ Dpp/Vgl family; (4) BMPs 2-8 and the Mulleran inhibiting substance. More recent studies indicate that five distinct TGF-[3 proteins (1-5) have been characterized from multiple vertebrate sources. The TGF-~ family consists of four dis-

tinct proteins: TGF-131,-2, -3, and-5, with TGF-~34 subclassifted under the TGF-131 group. TGF-f3 localization preceded a marked increase in type II collagen mRNA expression in transitional chondrocytes, suggesting a role for TGF-f3 in the induction and synthesis of extracellular matrix. TGF-13 has a role in the coupling of new bone formation to bone and cartilage resorption during skeletal development. Bone itself represents the most abundant source of TGF-f3 in the body. It is present and regulative of bone formation, chondrocyte, and osteoblast proliferation and has also been shown to be produced by growth plate chondrocytes. It also plays a role in inhibiting osteoclast formation and activity.

6. BONE MORPHOGENETICPROTEINS (BMPs) BMPs are signaling molecules known to induce cartilage and bone differentiation but also to play an important role in early limb patterning and even earlier in generalized embryogenesis (21, 18 l, 286, 287, 347). They are part of the larger transforming growth factor-13 family. High levels of BMP-4 expression are seen in the embryo in the posterior primitive streak and in ventral mesoderm around the posterior gut and umbilical blood vessels as well as in the body well. B MP-4 thus plays a role specifying posterior and ventral mesoderm (181). Expression of BMP-4 subsequently is seen in many tissues undergoing mesenchymal-epithelial interactions. In the limb itself, there is expression of B MP-4 throughout the mesenchyme with subsequent strong expression seen in the AER. The BMPs are members of the TGF-beta family and now comprise at least 8 members. BMP-2 and BMP-4 are expressed early in limb bud formation and are present both in the ZPA and the AER. BMPs initiate cartilage and bone formation in a sequential cascade. Cartilage and bone differentiation during the endochondral sequence involves a series of steps including initiation, promotion, maintenance, modeling, and termination events. The various signaling factors are defined at the molecular level with much focus on the BMPs. Regulatory signals by the several growth factors precede and control the deposition of the structural macromolecules of the extracellular matrix, such as the collagens, proteoglycans, and other glycoproteins. The BMPs belong to a large and continually expanding transforming growth factor-~3 superfamily, as noted earlier. The BMP family itself, which now includes subtypes, has three distinct subfamilies crucial for bone development; BMP-2, BMP-4, and BMP-5 through BMP-8. Defects in bone morphogenetic proteins are being shown to induce abnormalities of skeletal morphogenesis (190). Coordinate expression of TGF-f31, -f32,-133, and -134 has been demonstrated in chick embryo chondrocytes in vivo. In a more recent study, TGF-~31, -2, and -3 have been localized to transitional and hypertrophic chondrocytes and osteoblasts, cells that are all involved in the calcification of extracellular matrix (346). The appearance of TGF-~3 in growth plate chondrocytes appears to coincide with changes in the morphology of the cells as they pass from the proliferating

SECTION IX ~ Gene and Molecular Controls of Limb Development to the hypertrophic zone. In the growth plate, TGF-[3 functions as a stimulator of proteoglycan synthesis. Other studies have shown that TGF-[31 prevents terminal differentiation of epiphyseal chondrocytes into hypertrophic cells (14). In general, the TGF-[3 molecules stimulate the formation of extracellular matrix in connective tissues by increasing the transcription of genes and coding of many extracellular matrix proteins. The largest amounts of the TGF-[3 peptides have been found in bone and cartilage matrix. Studies have shown that TGF-[31 and TGF-[32 promote the chondrogenic differentiation of chick limb mesenchymal cells in culture. Chick limb mesenchymal cells express mRNA for chick and TGF-[31, -2, and -3 during cartilage differentiation in vitro (298).

7. PARATHYROIDHORMONE (PTH), PARATHYROID HORMONE RECEPTORPROTEIN (PTHRP), AND PTH/PTHRP RECEPTOR Each of parathyroid hormones, parathyroid hormone receptor protein (PTHrP), and the PTH/PTHrP receptor play a role in modulating skeletal development (209, 359). These important autocrine-paracrine factors have been identified in the growth plate chondrocytes. The PTH and PTHrP also act mitogenically on the growth plate chondrocytes acting through the PTH/PTHrP receptor. It is also felt that PTHrP inhibits type X collagen expression. It is the Indian hedgehog (Ihh) growth factor that induces secretion of the PTHrP by the growth plate chondrocytes. The PTHrP stimulates proliferation of chondrocytes and prevents their early hypertrophy in the growth plate. The effects of Ihh and PTHrP on chondrocyte differentiation are mediated by the PTH/PTHrP receptor. 8. INSULIN-LIKEGROWTHFACTOR (IGF) The insulin-like growth factors are regulatory molecules that also play important roles in skeletal development. IGF-1 stimulates longitudinal skeletal growth during the fetal period and throughout postnatal growth until skeletal maturation. It functions by mediating growth hormone actions on the growth plate and independently has the capacity to stimulate both chondrocyte proliferation and matrix synthesis. IGF-2 appears to be active in fetal life but its postnatal role is uncertain. There is a high degree of interaction between the IGFs and FGFs. The action of IGF-1 is such that it mediates completely the effects of growth hormone, which does not act directly on the cells. The activity involves effects on the IGF-1 receptor. The effects of growth hormone are mediated by their ability to produce growth factors such as the insulin-like growth factors. Receptors for both IGF-1 and IGF-2 have been found in the growth plate. The thyroid hormones also exert their effects on growth and in particular on the growth plate via mediation of the IGFs. Thyroxine (T4) and triiodothyronine (T3) act on the proliferative and upper hypertrophic zone chondrocytes by increasing DNA synthesis in cells and also increasing cell maturation, proteoglycan and collagen synthesis, and alka-

81

line phosphatase activity. This effect on cartilage, however, is mediated by the insulin-like growth factors. The effect appears to be mediated almost exclusively via IGF-1. IGF-1 is present in the growth plate in which it mediates the action of growth hormone. 9. VITAMIN D Vitamin D is a steroid made in the skin by the action of sunlight (157). It is biologically inert and must undergo two successive hydroxylations in the liver to 25-dihydroxyvitamin D and then in the kidney to the biologically active form, 1,25dihydroxyvitamin D [1,25(OH)2D]. The renal production of 1,25(OH)2D is closely regulated by serum calcium levels through the action of parathyroid hormone (PTH) and phosphorus. The major biologic function of vitamin D is to maintain circulating levels of calcium in the normal range. This is done by two mechanisms, one involving the efficiency of the small intestine to absorb dietary calcium and the other to allow for mobilization of calcium from bone when dietary calcium alone is inadequate to maintain normal levels. The 1,25(OH)2D induces monocytic stem cells in the bone marrow to differentiate into osteoclasts, which then perform the resorptive activity. Several different metabolites of vitamin D have been identified, including 24,25(OH)2D, but it is 1,25(OH)2D that is believed to be the major if not exclusive active agent for the biologic effects of vitamin D on calcium and bone metabolism. Vitamin D is important for bone mineralization although it does not appear to participate actively in the process. Instead it promotes the mineralization of osteoid and physeal cartilage by maintaining the extracellular calcium and phosphorus concentrations in the normal range, which then results in the deposition of calcium hydroxyapatite into the matrices. However, vitamin D has been found to play a more active role in growth plate cartilage development. All target tissues for vitamin D contain a vitamin D receptor (VDR) for 1,25(OH)2D. Such receptors also have been found in growth plate cartilage for both the 1,25 and 24,25 metabolites.

L. Matrix Metalloproteinases (MMPs) and Tissue Inhibitors of Matrix Metalloproteinases (TIMPs) Gross and histologic studies have clearly defined that the processes of synthesis and resorption are both involved in long bone growth and development. Over the past two decades the molecules involved in the remodeling processes of the extracellular matrix have been and are still being identified. The proteolytic enzymes involved in the extracellular matrix degradation are grouped into a family referred to as the matrix metalloproteinases (MMPs), which play a major role in the resorption of collagen and other macromolecules in normal prenatal and postnatal development and also in pathological disorders such as malignant tumor invasion, joint destruction in rheumatoid arthritis, and resorption of

82

CHAPTER 1 ~

Developmental Bone Biology TABLE VII Matrix Metalloproteinases a.b

MMP-1 MMP-2 MMP-3 MMP-7 MMP-8 MMP-9 MMP-10

Collagenase 1, fibroblast collagenase, interstitial collagenase Gelatinase A (72-kDa gelatinase) Stromelysin 1 Matrilysin Collagenase 2 (neutrophil collagenase) Gelatinase B (92-kDa gelatinase) Stromelysin 2

MMP- 11 MMP- 12 MMP- 13 MMP- 17 MMP- 18 MMP-19 MMP-20

Stromelysin3 Macrophageelastase Collagenase3 (rat osteoblast collagenase) MT4-MMP Collagenase4 Enamelysin

aMMP-4, -5, and -6 are no longer used. bDerived from Ann NY Acad Sci xix, 1999.

periodontal structures in dental disease. The MMPs are members of a subfamily of proteinases that contain zinc and show enzymatic proteolytic activity outside the cell (30, 127, 372). The initial MMP identified was collagenase, which is now referred to as MMP-1. Four major families of MMPs are the collagenases, gelatinases, stromelysins (including matrilysin), and the membrane type MMPs (Table VII). The metalloproteinases are essential for a breakdown of the extracellular matrix in normal development in which their activity is strictly regulated by an additional set of molecules referred to as tissue inhibitors of metalloproteinases (TIMPs). Imbalances in functions of the MMPs and/or their control by the TIMPs are associated with such pathological processes as tumor metastasis, rheumatoid arthritis, and osteoarthritic cartilage in which there is excessive tissue destruction. There are three major groups of the TIMP family (TIMP-1, TIMP-2, and TIMP-3). There is considerable specificity for tissue components for the various MMPs, although there is not an absolute tissue or molecule specificity. The collagenases are the only members of the MMP family that cleave fibrillar collagens, showing activity against types I, II, and III collagen. The collagenase family includes MMP-1, MMP-8, and MMP-13. The stromelysins can degrade many extracellular proteins, including the proteoglycans (MMP-3, MMP-7, MMP- 10, and MMP- 11). Gelatinases are affected in degrading type X and type XI collagen along with some of the other collagens. The more recently defined membrane type MMPs also have proteoglycan degradative activity. Gelatinase B (MMP-9) is limited to osteoclasts.

X. CHEMISTRY OF THE EXTRA CELLULAR MATRIX The three primary molecular constituents of epiphyseal cartilage are collagens, proteoglycans, and noncollagenous proteins, most of which are glycoproteins and phosphoproteins. The connective tissues such as cartilage, bone, tendon, ligament, and fascia are composites in a material sense of insoluble fibers and soluble polymers. The principal fibers are

collagen and elastin, whereas the principal polymers are proteoglycans and glycoproteins. Tissues such as tendon, which must withstand large tensional forces, are rich in collagen, whereas those like cartilage, which are subject to compressive forces, contain high levels of proteoglycans. Type II collagen and the proteoglycan aggrecan make up 90% of the organic cartilage matrix.

A. Collagen At present, 19 genetically distinct types of collagen encoded by at least 34 genes have been defined (344) (Table VIIIA). Approximately 80% of the total body collagen is types I and II. The collagen specific for cartilage, including the epiphyseal growth plate, is type II collagen (40). Several of the defined minor collagens, so named because they are present in relatively small amounts, have been localized to cartilage in particular types IX, X, and XI. Types VI, XII, and XIV also have a small cartilage presence. Type X collagen is localized in the matrix of the hypertrophic zone and has been hypothesized to play a major role in allowing for mineralization of the cartilage matrix, which occurs at that specific level. The collagen molecule is composed of three polypeptide chains, which are defined as oLchains and are assembled into a triple helix with a coiled-coil conformation (97, 259, 260, 282, 283) (Fig. 20A). In the major fibrillar collagens, including types I, II, and III, each c~ chain is composed of approximately 1055 amino acids. In type I collagen, there are two identical oL1 chains and one distinct a2 chain assembled into the triple helix. Type II collagen is composed of three oL1 (2) chains. The primary structure of the protein is a repeating sequence of Gly-X-Y triplets with glycine (Gly) present in every third position. Glycine is the smallest amino acid and its position is crucial for appropriate folding of the molecule. Glycine thus occupies a restricted space where the three helical a chains come together in the center of the triple helix. The most common amino acid in the X position is proline and the most common in the Y position is hydroxyproline. In collagen from mammals, approximately 100 of the X and

SECTION X ~ Chemistry of the Extracellular Matrix

83

TABLE VIIIA Collagen Types and the Location of Their Genes on Human Chromosomes a Type I

Gene COLIA1 COLIA2

II III IV

COL2A1 COL3A1 COL4A1 COL4A2 COL4A3 COL4A4 COL4A5 COL4A6

V

COL5A1 COL5A2

Chromosome

Expression

17q21.3-q22 7q21.3-q2 12q13-q14 2q24.3-q31 13q34 13q34 2q35-q37 2q35-q37 Xq22 Xq22 9q34.2-q34.3 2q24.3-q31

Most connective tissues, including bone, tendon, ligaments, skin (dermis) Cartilage, vitreous humor Extensible connective tissues, e.g., skin, lung, vascular system Basement membranes

Tissues containing collagen I, quantitatively minor component

COL5A3

VI

COL6A1 COL6A2 COL6A3

VII VIII

COL7A1 COL8A1 COL8A2

IX

COL9A1 COL9A2

21q22.3 21 q22.3 2q37 3p21 3q12-q13.1 lp32.3-p34.3 6q12-q14 lp32

Most connective tissues

Anchoring fibrils Many tissues, especially endothelium Cartilage (tissues containing collagen II)

COL9A3

Hypertrophic cartilage Cartilage (tissues containing collagen II)

COL12A1

6q21-q22 lp21 6p21.2 12q13-q14

COL12A1

6

COL13A1

10q22

Tissues containing collagen I Many tissues Tissues containing collagen I Many tissues Many tissues Skin hemidesmosomes Many tissues, especially liver and kidney Rhabdomyosarcoma cells

X

COLIOA1

XI

COLllA1 COL11A2

XII XIII XIV XV XVI XVII XVIII XIX

COL14A1 COL15A1 COL16A1 COL17A1 COL18A1 COL19A1

9q21-22 lp34-35 10q34-35 21q22.3 6q12-q14

aFrom Prockop and Kivirikko (281).

100 of the Y positions are proline and hydroxyproline, respectively. They are rigid amino acids that serve to limit rotation of the polypeptide backbone and thus contribute to the stability of the triple helix. The enzyme prolyl-4-hydroxylase converts approximately 100 proline residues in each polypeptide chain to 4-hydroxyproline. Ascorbic acid is a required cofactor for the reaction. Type II collagen is composed of three oL1 (2) chains. The fibril forming collagens are synthesized first as larger precursor molecules called procollagens. Each chain originally is synthesized intracellularly as a longer component

involving both C-terminal propeptides and N-terminal propeptides referred to as pro-oL chains (Fig. 20B). The pro-oL chains undergo proteolysis with severing of either propeptide following assembly, folding, and secretion of the procollagen molecule. The pro-oL chain N and C propeptides at the amino- and carboxy-terminal ends of the molecule, respectively, are connected to the central triple-helical collagen domain by short sequences, which are themselves nontriple-helical, that contain cleavage sites for the proteinases that process procollagen to collagen in the extracellular matrix. A folding into the triple helix occurs by spontaneous

84

CHAPTER I A

*

Developmental Bone Biology

N- PROPEPTIDE

SIGNAL

a - chain

C- PROPE P T IDE

-,,,1055 aa

"~, 250 aa

PEPTIDE

N-TERMINAL PROPEPTIDE

/

i

i

C-TERMINAL PROPEPTIDE

COLLAGEN MOLECULE

I•

GIc

(Mon)n

f'~ ~i,G IcNac l

i

,

.o

,

' I

To j'", t i

/

" \, Non-triple-Helical Domain Globular Domain /

Non-triple-Helical

I

,

s

s

" s

, ,, a

'I Domain

Non-triple- Helical Domain

Triple- Helical Domain

C ..= w A w ~ G a I - G I c GaI-O

w

Products of one, two or three genes

1

Gk~ 9 G~ ,,.. . uM

- X.V~A'xgH

(Man)n GIc Nac

Trimerization initiated via carboxy-terminal domains

J. t

o

amino-terminal domain

carboxy-terminal domain

FIGURE 20 Collagen formation is shown. (A) The components of a characteristic fibrillar collagen molecule are shown [reprinted from Olsen, B. R. (1991). In "Cell Biology of Extracellular Matrix," (E. D. Hay, ed.), pp. 177-220, Plenum Press, with permission; reproduced with permission from Prockop and Guzman, "Collagen Diseases and the Biosynthesis of Collagen," Hospital Practice 1977 12(12):61. 9 1977, The McGraw-Hill Companies, Inc. Illustration by Bunji Tagawa.]. (B) The intracellular (left) and extracellular (right) steps in collagen synthesis are shown. [From Prockop (1992), New Engl. J. Med. 326:540-546, with permission. Copyright 9 1992 Massachusetts Medical Society. All rights reserved.] (C) Mechanism of posttranslational assembly of fibrillar collagen is shown. [Reprinted from Francomano (1995), Nature 9:6-8, with permission.] (D) Electron micrograph of type I collagen from osteoid.

self-assembly in a specific zipperlike fashion from the carboxy (C) terminal toward the amino (N) terminal end of the molecule (Fig. 20C). As noted previously, the stability of the triple helix greatly depends on the presence of glycine resi-

dues at every third position in each of the three pro-et chains. Once the pro-or chains have been synthesized, significant posttranslational changes occur that are integral to normal collagen formation (97, 259, 283).

SECTION X ~ C h e m i s t r y o f t h e Extracellular Matrix

F I G U R E 20 (continued) The fibrils are 70-120 nm wide and show the typical cross-banding. (E) Type IX and type XI collagen are closely related in position to the much larger type II collagen molecule. [Reprinted from Olsen, B. R. (1995). Curr. Op. Cell Biol. 7:720-727, copyright 1995, with permission from Elsevier Science.] (F) Electron micrograph of cartilage shows narrower, dispersed type II fibrils of less than 20-nm diameter with no cross-banding seen.

85

86

CHAPTER 1 9 Developmental Bone Biology

TABLE VIIIB Steps in Collagen Synthesis" Intracellular

Extracellular

1. Gene selection, transcription, mRNA processing, translation 2. Posttranslational processing Hydroxylation of proline and hydroxyproline residues to 4-hydroxyproline, 3-hydroxyproline, and hydroxylysine Glycosylation of hydroxylysine residues (a) Galactosyl hydroxylysine (b) Glycosyl galactosyl hydroxylysine Assembly of pro-or chains, glycosylation of propeptides, disulfide bonding between pro-c~ chains Folding into triple helix Secretion from cell to extracellular region 3. Cleavage of procollagen extension peptides at C- and N-terminal ends of molecule to leave collage 4. Self-assembly of fibrils 5. Intermolecular cross-linking; conversion of lysine and hydroxylysine side chains to aldehydes and reactions of aldehydes to form covalent cross-links

aAdapted from Eyre (97), Olsen (259), and Prockop et al. (282, 283).

Intracellular steps in procollagen synthesis include the following: (1) hydroxylation of the proline residues to hydroxyproline and that of lysine residues to hydroxylysine; (2) glycosylation of hydroxylysine residues to form galactosylhydroxylysine and glucosylgalactosylhydroxylysine; (3) addition of a mannose-rich oligosaccharide to one or both propeptidases; (4) association of C-terminal propeptides; and (5) disulfide bonding to enhance chain association. Each of the preceding posttranslational changes occurs in the intracellular position with subsequent extracellular changes (97). In the amino-terminal propeptides of type I procollagen, cysteine is present and forms intrachain disulfide bonds, whereas in the carboxy-terminal propeptides, the cysteine is involved in both intrachain and interchain disulfide bonds. The propeptides account for one-third of the bulk of the procollagen molecule. They serve to direct assembly of the triple helix. After the C-propeptides have associated, the triple helix begins to form in zipperlike fashion toward the N-terminus. The protein, which is assembled in the rough endoplasmic reticulum, then passes through the Golgi complex before leaving the cell. The extracellular conversion of procollagen to collagen requires two enzymes, a procollagen amino protease that removes the amino propeptides and a procollagen carboxy protease that removes the carboxy propeptides. Once cleavage of the procollagen ends occurs, the collagen molecules remain free in the extracellular matrix and then spontaneously assemble into fibrils (Fig. 20B). Extracellular processing involves (1) conversion of procollagen to collagen and (2) cross-linking, which is mediated through lysine and hydroxylysine residues (3, 97, 98, 192, 282-284). Lysyl oxidase allows for conversion of small lysyl and hydroxylysyl residues of collagen to reactive aldehydes. Two major

types of cross-link then form. The first are referred to as intramolecular cross-links that join oL chains of the same molecule and are formed by aldol condensation of two of the aldehydes. Intermolecular cross-links involve condensation between an aldehyde derived from lysine, hydroxylysine, or glycosylated hydroxylysine and the amino group of a second lysine, hydroxylysine, or glycosylated hydroxylysine. They are Schiff bases. The main reducible cross-link is dihydroxylysinonorleucine. The major cross-links in skeletal tissues are the three hydroxypyridinium cross-links derived from three hydroxylysyl residues (98). They are particularly abundant in adult bone and cartilage. The dihydroxylysinonorleucine cross-links progressively decrease with tissue maturation, whereas the hydroxypyridinium molecules increase with time (Table VIIIB). After secretion from the cell, the procollagen molecules are enzymatically cleaved to collagen and the collagen then self-assembles into fibrils. The triple-helical collagen molecule is approximately 300 nm long and 1.5 nm in diameter. Fibrils are formed by the lateral and longitudinal association of the triple-helical molecules to each other. Each type I collagen molecule relates to the adjacent molecule in a quarterstagger array, such that the composite fibril appears as a striated pattern by electron microscopy (Fig. 20D). The crossstriations represent surface staining of the cylindrical fibril, which in cross section is composed of several hundred individual collagen molecules. The hole zone is roughly 67 nm wide. The longitudinal staggering of the molecules involves slightly less than one-quarter of the length of the molecule and leaves a "hole" between the end of one triple helix and the beginning of the next. It is widely felt by some that this hole zone in type I collagen of bone provides a site for the deposition of hydroxyapatite crystals in bone formation (130).

SECTION X ~ Chemistry of the Extracellular Matrix The three polypeptide chains of the collagen molecule are called et chains, with these then coiled into a left-handed helix with about three amino acids per turn. Each of the three helical chains together are then twisted around each other into a fight-handed superhelix. These actions lead some to refer to collagen as a "coiled coil." In the mammalian collagens, approximately two-thirds of the X and Y positions are occupied by a variety of amino acids, which help provide stability during the next higher level of hierarchical organization at the fibrillar level. In summary, synthesis of collagen has both intracellular and extracellular components (281-283) (Fig. 20B and Table VIIIB). The procollagen in the molecule is assembled and then secreted from the intracellular region, whereas in the extracellular environment the procollagen is converted to collagen and then incorporated into stable, cross-linked collagen fibrils. The first act of synthesis involves transcription and then translation of the collagen as the amino acids line up in the polypeptide sequence characteristic of the protein. Initially there is a signal sequence at the amino-terminal end, which for the pro-et chain is long, containing about 100 amino acid residues. Posttranslational changes are extensive, involving both the propeptide domains and the collagen itself in the pro-et chain. The signal sequences are removed as the amino-terminal ends of the pro-a chains enter the rough endoplasmic reticulum (RER). Hydroxylation then occurs within the RER, forming hydroxyproline and hydroxylysine. These actions are mediated partially by enzymes, including prolylhydroxylase and lysylhydroxylase. The hydroxylases act only on nonhelical substrates and not on collagen, which has reached the helical conformation. The next posttranslational change relates to glycosylation. Sugar residues are added to hydroxylysyl residues. Enzymes involved here are galactosyl transferase and glucosyl transferase. The first adds galactose to the hydroxylysyl residues and the second adds glucose to the galactosylhydroxylysyl residues. Cleavage from procollagen to collagen occurs with mediation by two enzymes, procollagen amino protease to remove the amino propeptides and procollagen carboxy protease to remove the carboxy propeptides. Cross-linking then occurs in the extracellular domain.

B. Collagen Groups The collagens are divided into differing groups on the basis of slightly differing molecular constituents (260, 344, 355), which lead to different types of polymeric structures or differing structural features. These include the following. (1) Collagens capable of forming linear fibrous structures are types I, II, III, V, and XI. Their main function is to resist tensile stresses on tissues. (2) FACIT collagens. Collagen molecules found on the surface of other collagens are referred to as FACIT collagens (fibril-associated collagens with interrupted triple helices) and include types IX, XII, XIV XVI, and XIX.

87

They are associated with collagens but do not form fibrils by themselves. (3) Network forming collagens. Collagen types IV, VIII, and X are involved in the formation of sheets or protein membranes having the ability to form regular hexagonal lattice structures. Type IV is seen in basement membranes, type VII in Descemet's membrane, and type X in the hypertrophic zone cartilage matrix (although there is no evidence that type X actually assumes a membrane conformation. (4) Beaded filament forming collagen. Type VI collagen forms beaded filaments that appear to be independent and are present in many extracellular matrices, including cartilage. (5) Collagen of anchoring fibrils. Type VII collagen forms anchoring fibrils present primarily in skin linking epithelial basement membranes to the underlying stroma. (6) Collagens with a transmembrane domain. Types XIII and XVII have both a cytoplasmic and an extracellular domain. Individual collagen types rarely are found in isolation in extracellular matrices and usually are grouped together. The cartilage-specific collagens are types II, IX, X, and XI, along with the more ubiquitous collagen type VI and the most likely types XII and XIV. Although the structures of the various collagens vary and many are hybrid molecules, whereas the collagen domain may only be small in comparison to the noncollagenous part of the molecule, certain characteristics are shared by all collagens. These include the triple helix in which three left-handed helices, ct chains, twist around each other to form a fight-handed suprahelix. Each et chain contains glycine at every third residue, and approximately 10%-12% of each of the remaining X and Y residues of the repeating sequence Gly-X-Y are proline and hydroxyproline, respectively. Hydroxyproline is essential for the formation of hydrogen bonds that stabilize the helix. The fibrillar collagens are synthesized as large precursor procollagen forms with noncollagenous propeptides at the N- and C-termini. The propeptides are completely removed in type I, II, and III collagens by specific proteinases before and during self-assembly and cross-linking of the triple helix. Collagen organization in cartilage fibrils shows evidence of structural intermixture of collagens involving primarily type II but also definable amounts of types IX and XI, forming what is referred to as a heterotypic fibril (34, 114, 234, 378). Type II collagen represents about 80% of the cartilage fibril with the remaining 20% distributed between types IX and XI (Fig. 20E). Type XI fibrils are buried within the type II fibrils, indicating a firm intermixture. It is felt that type XI collagen initially forms a core filament and that type II collagen is deposited around it. When the diameter reaches about 17 nm, the structure is such that the perimeter of the fibril serves as a binding site for type IX collagen, which is thus deposited on the surface. Attachment of type IX collagen prevents further growth in the diameter of the fibril and also limits adherence of adjacent fibrils. In summary, a core of quarter-staggered molecules of the fibrous collagen type XI is coated by molecules of the fibrous type II collagen. When

88

CHAPTER 1 ~ Developmental Bone Biology

a certain diameter is reached, which appears to be in the area of 17 nm, type IX collagen is attached to the fibril surface. There are hydroxylysine-derived cross-links between type IX collagen and type II collagen. In addition, the type IX molecules are attached to chondroitin sulfate chains of variable length. The or2 (IX) chain carries a covalently attached chondroitin sulfate chain, making this collagen a proteoglycan as well. The surface type IX plus the proteoglycan helps to prevent adjacent fibrils from aggregating. The collagen fibrils of cartilage therefore are much thinner than those of bone, averaging about 20 mm in width (Fig. 20F). The dispersed state of the fibrils prevents formation of a thicker fibril with quarter-stagger array, which explains why cartilage collagen by ultrastructure is not cross-banded. Many of the more recently defined collagens are in effect complex molecules in which the collagen is only one component. Type XVIII collagen is both a collagen and a proteoglycan with definition of heparan sulfate side chains. The type XVIII collagen has typical features of a collagen with sensitivity of its core protein to collagenase digestion, but it also has the characteristics of a proteoglycan particularly heparan sulfate because it has long heparitinase-sensitive carbohydrate chains and a highly negative net charge (141). Collagen XVIII is abundant in the basal laminae and after collagen type IV is the second most common collagen in the basal laminae. At the C-terminal globular domain the collagen XVIII molecule contains the angiogenesis inhibitor endostatin (308). This segment of the type XVIII collagen molecule has been shown experimentally to inhibit endothelial cell proliferation and to suppress angiogenesis. Currently it is the focus of much investigation in terms of therapeutic potential to minimize tumor growth.

C. Detailed Review of Specific Cartilage Collagens 1. COLLAGEN TYPE II This is the major fibrous collagen of cartilage and is also present in the vitreous humor of the eye and the intervertebral discs. It represents 80-90% of the collagen content of the cartilage matrix. It is a homotrimer of three type II ct chains [oL1(II)]3. It is processed by N- and C-proteinases in the same fashion as procollagen type I. It is closely associated with type XI collagen, which accounts for less than 5% of the cartilage collagen. Type II collagen has a higher hydroxylysine:lysine ratio and higher levels of glycosylated hydroxylysine than collagen types I and III. The degree of glycosylation also contributes to the thinness of the type II collagen fibril in relation to type I.

2. COLLAGEN TYPE XI Collagen type XI is also a fibrous collagen. It is a heterotrimer of three chains [oL1 (XI)oL2(XI)oL3(XI)]. Type XI collagen has been shown to form heterotypic fibrils with

type II, and their retention of the N-terminal noncollagenous domain is felt to restrict the overall diameter of these fibrils (Fig. 20E).

3. ThE FACIT COLLAGENS: TYPES IX, XII, AND XIV Collagen fibers in cartilage form a stable meshwork to counteract the swelling pressure generated by the hydrated proteoglycan aggregates. This is done by interaction of the collagen type II fibers with other matrix components such as type IX collagen (99, 203) (Fig. 20E). Type IX collagen is found along the surface of type II collagen fibrils. It is composed of three distinct polypeptide chains [OLI(IX)oL2(IX)et3(IX)] assembled in a 1:1:1 ratio. The type IX collagen molecules have a long triple-helical arm running along the fibril and a short triple-helical arm extending into the perifibrillar space where it terminates with a globular domain and four noncollagenous domains, one of which has a glycosaminoglycan side chain. Type IX is present throughout cartilage tissue and thus is secreted by all chondrocytes. Type IX is associated with a glycosaminoglycan (GAG) side chain consisting of either chondroitin sulfate or dermatan sulfate (230). The more recently described types XII and XIV collagen are similar to type IX collagen and are felt to associate on the surface with type I collagen containing fibrils (368). The presence of glycosaminoglycans has also been connected to types XII and XIV collagen. Type XII collagen has been localized to the perichondrium at the articular surface and around cartilage canals, whereas type XIV collagen is found throughout the matrix. 4. TYPE X COLLAGEN Type X collagen is a short chain collagen that is expressed exclusively by hypertrophic chondrocytes at sites of endochondral bone formation (147, 259, 260, 276, 312, 313). Its triple-helical domain is capable of forming a hexagonal latticelike structure. It is a homotrimeric molecule [ctl (X)]3. It is seen initially in the developing embryonic long bones in the central part of the diaphysis (where chondrocyte hypertrophy initially occurs), whereas type II collagen is seen earlier and throughout the cartilage model. Type X then is expressed farther toward each end of the developing bone as cartilage maturation and hypertrophy move in those directions. Eventually it is concentrated in the physes in the matrix adjacent to the hypertrophic cells. The amino acid sequence, gene structure, and molecular organization closely resemble those of type VIII. 5. TYPE VI COLLAGEN Type VI collagen forms beaded microfibrils, which occur in cartilage and also many other tissues. It is most commonly present as a heterotrimer [ct I(VI)oL2(VI)oL3(VI)]. Its function is still unknown, but its interactive properties suggest that it may have a bridging role between cells and their extracellular

SECTION X ~ Chemistry of the Extracellular Matrix

89

Protein Core

Aii Keratan Sulfate

Chondroitin : . ~ _ , , / S u l f a t e Chains

Chains \

Protein Core

Chondroitin Sulfate Chains

Keratan Sulfate Chains

L ee

".;,.Link Protein

e

Hyal Acid

Chondroitin Sulfate Rich Region

Keratan Sulfate Rich Region

_ ~

and Hyaluronic Acid Binding Region

CS

B Aggrecan

N

Ks,,,,.l!lll},))llii),)lli))}))ll),))l))li)))))},))l))))), c CS.'DS

Decorin

N

C .

CS,'DS Biglycan

N

Fibromodulin

N

c-x2(IX)

N

i

- C

~jKS

i ~

C

C I

CS/DS

~ I

100 nrn

F I G U R E 21 (Ai, Aii) The basic structure of the proteoglycan molecule is shown. [Reprinted from Buckwalter, J. (1983). Clin. Orthop. Rel. Res. 172:207-231 9 Lippincott Williams & Wilkins, with permission.] (B) The major proteoglycan molecules of cartilage are shown. [Reprinted from Roughley, P. J., and Lee, E. R. (1994). Microscopy Res. Tech. 28:385-397, copyright 9 1994. Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.]

matrix. The fibril diameters in cartilage are in the 17- to 20-nm range.

D. Proteoglycans The other major group of molecular constituents in the connective tissues and the group that plays a major role in all cartilage tissue is the proteoglycans (PG) (42, 45-47, 238, 240, 274, 275, 301,302, 326, 357). They are a diverse family of molecules made of a core protein to which is attached one or more glycosaminoglycan (GAG) side chains (Fig. 21A i, ii). The following basic molecules comprise the GAG group in cartilage: chondroitin sulfate (CS), dermatan sulfate (DS), heparan sulfate (HS), keratan sulfate (KS), and hyaluronic acid (HA) (Fig. 21B). Each of these GAGs is sulfated except for hyaluronic acid. Only the sulfated GAGs become part of a proteoglycan. Combinations of these primary molecules

form five specific proteoglycan macromolecules of hyaline cartilage: aggrecan, decorin, biglycan, fibromodulin, and type IX collagen. Aggrecan is the largest in size and most abundant by weight. The term aggregating refers to the ability of single proteoglycans to interact noncovalently with hyaluronic acid to form large proteoglycan aggregates. The aggregating proteoglycan of hyaline cartilage is aggrecan. This large aggregating CS-PG is composed of about 85% CS, 6% KS, and 7% protein and accounts for 10% of the dry weight of cartilage. The primary role of aggrecan is to provide cartilage with its osmotic properties: to swell and hydrate the collagen fibrillar framework, giving cartilage its ability to resist compressive loads. The term nonaggregating proteoglycan refers to all molecules that do not interact specifically with hyaluronic acid. This family of molecules interacts with collagen molecules. The following are in this category. Biglycan (small CS-DS

90

CHAPTER I 9

Developmental Bone Bioloyy TABLE IXA

Properties of C a r t i l a g e

Proteolycans ".b

Proteoglycan type

GAG typec

GAG no.

Protein size a

Chromosome location

Gene size (kb)

Exon no.

Aggrecan Decorin Biglycan Fibromodulin Type IX collagen

CS and KS CS-DS CS-DS LS CS-DS

> 100 1 2 4 1

2297 329 331 357 677

15 12 X

>50 >38 8

15 8 8 32

aDerived from Roughley, Eunicer, and Lee (302). bAll data refer to human proteoglycan except that for fibromodulin, which is bovine, and oL2(IX),which is chick. CAbbrevations used: CS, chondroitin sulfate; DS, dermatan sulfate; GAG, glycosaminoglycan;KS, keratan sulfate. dprotein size is represented as the number of amino acid residues present in the secreted proteoglycan.

proteoglycan) is the predominant small proteoglycan of cartilage, possessing two dermatan sulfate chains and localized in the pericellular matrix. Decorin is a small CS-DS proteoglycan with one dermatan sulfate chain. Fibromodulin (small CS-KS proteoglycan) bears many keratan sulfate chains and is present in many tissues, including cartilage where it binds to type II collagen. Type IX collagen is considered to be a proteoglycan as well because one of its chains bears a glycosaminoglycan chain. Type IX is present on the outer surface of type II collagen. Aggrecan synthesis and breakdown in the growth plate at varying depths and different stages of development have been assessed in the distal tibia of fetal calf tissue (326). The rates of aggrecan synthesis and turnover were highest in the resting-proliferative zone compared to either the upper or lower hypertrophic zones. Aggrecan gene expression in the cells of the resting-proliferative zone and the upper hypertrophic zones was similar, but the levels were reduced in the deepest cells of the lower hypertrophic zone. Approximately 90% of the newly synthesized proteoglycan and the total proteoglycan population were able to aggregate and the monomers were relatively large. Aggrecan is a complex macromolecule consisting of an extended core, which contains several distinct domains: N-terminal G-1 domain adjacent to the G-2 domain, keratan sulfate-rich region, and an extended chondroitin sulfate-rich region and a C-terminal G-3 domain. The G-1 domain binds to hyaluronate stabilized by a separate link protein such that many proteoglycans can bind to a chain of hyaluronate to mobilize themselves in a dense collagenous network. Proteoglycan synthesis, studied by [35S]-sulfate incorporation into the glycosaminoglycan chains, showed heterogeneity of synthesis through the depth of the tissue. The major proteoglycan in the growth plate is aggrecan, which is also found in high concentrations in articular cartilage. Other proteoglycans present in the growth plate in smaller amounts include biglycan, decorin, and type IX collagen (28). Assessment comparing the upper resting proliferative zones and the

lower hypertrophic zones shows that the cell volume per total tissue volume increases by 5- to 10-fold and the matrix volume per cell also increases by up to 3-fold. In the lower hypertrophic zone, the extracellular matrix may occupy only 10% of the total tissue volume compared with over 60% in the upper zones. Thus, there is an overall loss of extracellular matrix (ECM) and proteoglycan. The composition of the ECM also changes with depth. Aggrecan is distributed throughout the growth plate. Proteoglycan concentration in the ECM increases toward the lower hypertrophic zone, but the total amount of the proteoglycan per tissue volume decreases. There is little variability in the size of the proteoglycan monomer with depth. The rate of proteoglycan synthesis per cell is reduced dramatically only in the lower hypertrophic zone. The mRNA levels of type II collagen and osteonectin are also reduced in the hypertrophic zone compared to chondrocytes in the resting zone, but there are high levels of type X collagen and hypertrophic chondrocytes associated with the onset of mineralization. The proteoglycans are summarized in Tables IXA and IXB. E. G l y c o p r o t e i n s a n d N o n c o l l a g e n o u s P r o t e i n s

A large number of proteins other than collagens and the proteoglycans are present although in much smaller amounts in the extracellular matrix (11,344). These generally are referred to as noncollagenous proteins, a term that reflects their highly variable chemical nature (148). These molecules interact with cells, with other macromolecules of the extracellular matrix, and with the mineral phase of bone and calcifying cartilage. Many of these proteins are phosphorylated, leading them to be described as phosphoproteins, and many are glycosylated and thus referred to as glycoproteins. Many subsequently have been given names on the basis of their presumed function. One of the most abundant noncollagenous proteins of bone is osteonectin, a phosphorylated glycoprotein. The principal bone-associated noncollagenous proteins are anionic. Several extracellular glycoproteins have been

SECTION X ~

TABLE IXB Name

Chemistry o f the Extracellular Matrix

Proteoglycans of Extracellular M a t r i x "'b

Prior n a m e s

GAG

Decorin

PG-11, PG-S2, PG-40

DC/CS

45K (36,383)

Biglycan Fibromodulin Lumiscan Pg-Lb Aggrecan

PG-1, PG-S!

DS KS KS DS CS, KS

45K (37,983) 50K (42,200) 50K (38,640) 43K (35,854) 225-250K

Versican Neurocan Perlecan Type IX collagen

PG-400

CS CS HS CS

400K (262,744) 150K (136,000) 400K (396K) 320K

PG-H

PG-Lt

91

Core size ~

Comments

Small PG of fibrous tissue, leucine repeats Leucinerepeats Leucinerepeats KSPG of cornea, leucine repeats Leucinerepeats Large PG of cartilage, aggregates with hyaluronic acid Fibroblastlarge PG Largeaggregating PG of brain HSPG of basement membrane Three ct chains

aDerived by Vogel (357). bAbbreviations: GAG, glycosaminoglycans;DS, dermatan sulfate; CS, chondroitin sulfate; KS, keratan sulfate; HD, heparan sulfate; PG, proteoglycan. CApproximate size determined by SDS/PAGEafter enzymatic digestion of GAG chains. Figure in parentheses is MW.

isolated, and these molecules have been shown to interact both with cells and also with other macromolecules and even the inorganic phases of bone. Posttranslational modifications include phosphorylation of serine and threonine. Groups of glycoproteins in cartilage include cartilage matrix protein (CMP), cartilage oligomeric matrix protein, link protein, and matrix GLA protein. Cartilage matrix protein has been found to localize primarily at the lower part of the proliferating zone of the endochondral sequence between the cells of the upper proliferating zone and the hypertrophic zone cells. It has been suggested that CMP is a marker for postmitotic chondrocytes that will shortly progress to the hypertrophic stage (64). It is present in articular cartilage. Cartilage oligomeric matrix protein is a glycoprotein found in cartilage particularly during periods of chondrogenesis. It is localized preferentially in the pericellular territorial matrix. Other glycoproteins seen in cartilage but more prominent in bone and other noncartilage tissues include the following: "adhesive glycoproteins" interacting with cells, such as fibronectin, vitronectin, laminin, thrombospondin, von Willebrand factor, and fibrinogen; "skeletal tissue associated glycoproteins," such as bone sialoprotein, osteocalcin, osteopontin, osteonectin, osteogenin (361), and other phosphoproteins such as phosphoserine and phosphothreonine; and the "elastin associated glycoproteins," fibrillin and MAGP. Both bone sialoprotein and osteopontin have been defined in hypertrophic chondrocytes and the adjacent mineralized cartilage matrix. The fixed negative charge of many of the bone-associated molecules is due to the fact that many are rich in acidic amino acids such as aspartic and glutamic, some contain stretches of consecutive aspartic acid residues

(osteopontin), and others contain stretches of consecutive glutamic acid residues (bone sialoprotein). Other molecules contain ~/-carboxyglutamic acid residues (osteocalcin and matrix GLA protein). Other posttranslational changes include sulfation of tyrosine residues (bone sialoprotein). Many of these molecules have been implicated in calcification and calcium ion binding, although it has been difficult to specifically pinpoint function. The noncollagenous ~/-carboxyglutamic acid containing proteins (bone GLA or osteocalcin and matrix GLA protein) have been associated with the calcification process. Bone sialoprotein has a restricted tissue distribution found primarily in bone and mineralized connective tissues. It is expressed by osteoblasts at high levels. The molecule is extensively glycosylated; about one-half of its serine residues are phosphorylated and it contains extended sequences of acidic amino acids particularly glutamic acid, glycine, and aspartic acid. Matrix GLA protein is a vitamin K-dependent protein initially isolated from bone matrix but subsequently found also in cartilage. Bone GLA protein, also known as -y-carboxyglutamic acid containing protein or osteocalcin, is a low-molecular-weight protein found primarily in bones. It contains three "y-carboxy glutamic acid residues, providing the molecule with calcium binding properties. Osteocalcin binds tightly to hydroxyapatite and may play a role in regulating crystal growth. Its synthesis is also vitamin K-dependent. Osteocalcin is the most abundant noncollagenous protein in mineralized bone matrix. It is a small protein containing 49 amino acids. Three amino acids are ~/-carboxylated via mediation of vitamin K, a property that allows for its close relationship to hydroxyapatite. It is abundant in bone tis-

92

CHAPTER I ~ Developmental Bone Biology

sue making up approximately 20% of all noncollagenous protein, but its precise function is still uncertain. Bone sialoprotein 1 (BSP1) is now referred to most commonly as osteopontin (167, 171). It is expressed early in bone development at high levels at sites of bone remodeling and is also seen to bind to hydroxyapatite. Its finding in relation to bone remodeling is associated with an apparent increased attachment to osteoclasts. Bone sialoprotein (BSP) is synthesized by osteoblasts and is a glycosylated phosphoprotein rich in sialic acid.

F. Cell Surface Proteoglycans Proteoglycans have been found as abundant molecules of the cell surface where they play a major role in morphogenesis (27, 197, 319). Virtually all epithelial cells express cell surface proteoglycans. The major transmembrane proteoglycans of the cell surface are syndecans, which contain both chondroitin sulfate and heparan sulfate. Syndecan 3 is a member of the family of heparan sulfate proteoglycans, which function as extracellular matrix receptors mediating the interaction of cells with extracellular components and as signaling molecules that control cell shape, adhesion, proliferation, and differentiation. Syndecan 3 responds to AER signals, mediates cell-matrix and cell-cell interactions involved in the onset of chondrogenesis, and also plays a role in regulating epiphyseal chondrocyte proliferation during endochondral ossification.

G. Temporal and Spatial Changes in Specific Molecular Expression within the Endochondral Sequence Virtually all structural changes are or presumably will be found to be associated with changes in molecular synthesis by the participating cells. With increasing sophistication of molecular identification, the specific cascade of changes is being clarified. Indian hedgehog (Ihh) is secreted by prehypertrophic chondrocytes and also induces another factor from the perichondrium, parathyroid hormone-related protein (PTHrP). A number of changes have been identified specifically during the chondrocyte hypertrophy phase of the endochondral sequence. These include the acquisition of collagen type X synthesis capability by the hypertrophic chondrocytes, the loss of synthetic capacity for types II and IX, a decrease in some proteoglycan synthesis, and an increase in the activity of metalloproteinases as well as alkaline phosphatase. Studies on cultures of hypertrophic tibial chondrocytes helped characterize as many as 18 up-regulated genes during chondrocyte hypertrophy (247). The genes identified included translational and transcriptional regulatory factors, ribosomal proteins, the enzymes transglutaminase and glycogen phosphorylase, type X collagen, and the carbohydrate binding protein galactin. Temporal and spatial differences in expression have also been defined for the proteoglycan core protein, aggrecan, and cartilage proteoglycan

link protein (238). These were expressed in the same regions and were confined to chondrocytes of the developing skeleton and other cartilaginous structures. The highest expression was found in the lower proliferative and upper hypertrophic zones of the physeal regions, whereas the resting zones showed less expression. In addition, cartilage that was calcifying and thus close to the osteochondral junction showed no expression. The phenomenon of loss of expression in the area of calcification was found throughout the subsequent stages of skeletal development. It is felt by some that the large aggregating proteoglycan of cartilage inhibits mineralization and thus may well prevent calcification in the proliferative and upper hypertrophic zones. The final stages of endochondral ossification are associated with matrix metalloprotein expression in relation to cartilage resorption, with MMP-9 and MMP-13 seen and with angiogenic regulators such as vascular endothelial growth factor (VEGF) in relation to vascular invasion bringing in osteoprogenitor cells (103). Studies have been done to assess the synthesis of type IX collagen during skeletal formation. The type IX collagen began to accumulate at the onset of overt chondrogenesis during the early condensation phase of the process in which mesenchymal cells became closely packed prior to depositing the cartilage matrix. The type IX synthesis coincided with the production of cartilage proteoglycan core protein and type II collagen accumulation. Expression and localization of the proteoglycans biglycan and decorin were also assessed in human tissues (28). Tissue sampling involved femur, tibia, and humerus. Although both were found in developing cartilage, there was a marked difference in their location in the developing epiphyseal regions. Biglycan core protein was localized to an outer cap of prospective articular cartilage at each epiphyseal end, whereas decorin was not detected at these sites but was found within the more deeply located resting cartilage in which staining for biglycan was weak. The cartilage matrix remained unstained for both around the vascular canals, which grew in from the perichondrium to the epiphyseal cartilage regions. Within the physeal regions, there was a highly segregated staining pattern in the upper proliferative zone in which biglycan was restricted to the territorial capsules of the chondrocytes and decorin was restricted to the interterritorial matrix. Staining for both was virtually absent in the lower proliferative, hypertrophic, and mineralizing zones of the growth plates. High levels of biglycan were detected in the region in the forming growth plates and in perichondrium-derived mesenchymal inside vascular canals. Low levels of decorin were found in articular cartilage, with a very high level detected near a rim of cartilage at the peripheral subperichondral locations and in chondrocytes arranged around vascular canals. In growth plates, low levels of biglycan and lower undetectable levels of decorin were observed in proliferating cartilage and high levels in hypertrophic chondrocytes. The biglycan gene was expressed at

SECTION XI ~ M i n e r a l i z a t i o n

high levels in preosteogenic cells both in the periosteum and in morphologically undifferentiated mesenchymal cells and vascular canals thought to be recruited for development of secondary ossification. Decorin was expressed maximally at the sites of appositional growth in the subperichondrium, whereas as biglycan expression predominated at the site of formation of growth plates. Specific localization of the gene for cartilage matrix protein (CMP) has also been found within the physis. Chen et al. (64) identified that it was the postproliferative chondrocytes that make up the zone between the zones of proliferation and hypertrophy that specifically transcribe the gene for CMP. This is referred to as the zone of maturation. CMP translation products were present in the matrix surrounding the nonproliferative chondrocytes of both the zones of maturation and hypertrophy such that CMP is a marker for postmitotic chondrocytes. This provided further indication that chondrocytes in each zone reside in an extracellular matrix with a unique macromolecular composition. The results were thought to be compatible with the demonstration of distinct switches at the proliferative-maturation transition and at the maturation-hypertrophy transition during chondrocyte differentiation. The chondrocytes themselves synthesize new matrix molecules to modify their preexisting microenvironment as differentiation progresses. Type X collagen synthesis is specifically related to the hypertrophic chondrocyte, which can be shown in tissue culture to stop type X collagen synthesis, resume proliferation, and reinitiate aggrecan synthesis when they leave the hypertrophic zone. The data are consistent with "a high degree of plasticity in the chondrocyte differentiation program." The expression of collagens I, II, X, and XI along with aggrecan synthesis by bovine growth plate chondrocytes in situ and by human fetal tissue have also been defined (306, 307).

XI. M I N E R A L I Z A T I O N Mineralization is an integral part of the terminal stages of the endochondral sequence and of the formation of bone in which the newly synthesized osteoid is mineralized in both endochondral and intramembranous sequences. Calcification of the cartilage cores in the hypertrophic cell region of the endochondral sequence is an essential step in endochondral ossification at physes and secondary ossification centers. The calcification occurs in the longitudinal cartilage columns immediately adjacent to the final three or four hypertrophic cells at the lowest part of the physis. The region calcified, which is actually in the central portion of the longitudinal septae, is referred to as the interterritorial matrix. The transverse septae rarely are calcified. The calcified septae persist in the metaphysis as cartilage cores and serve as a scaffold on which the metaphyseal bone is synthesized. Vascular invasion from the metaphyseal side stops abruptly after enter-

93

ing the lowest of the hypertrophic cell lacunae, passing only two or three cells upward. The vessels bring undifferentiated mesenchymal cells with them, and these cells soon differentiate to osteoblasts and synthesize osteoid on the calcified cartilage cores. The exquisite control and patterning of mineralization in relation to the endochondral sequence in the lowermost parts of the hypertrophic zone have long been the focus of study in terms of causation. Of note is the fact that the mineralization is concentrated in the longitudinal septae of the hypertrophic zone. Studies have identified molecules specific to the physeal cartilage and even some specific to the hypertrophic zone, and these molecules have been proposed to be involved in the mineralization front. The overall cartilage matrix is composed primarily of type II collagen and proteoglycans, particularly aggrecan, but other molecules have been identified, including types IX and XI collagen, osteonectin, osteocalcin, osteopontin, and bone sialoprotein. In addition, type X collagen is localized specifically to the hypertrophic zone matrix and is not found either in cartilage, which does not calcify, or in intramembranous bone (313). The cartilage matrix in the calcifying region has matrix vesicles containing alkaline phosphatase. These are involved in the deposition of mineral although the exact mechanism is still uncertain (6, 130, 206). Release of inorganic phosphate as a result of the activity of alkaline phosphatase can lead to the displacement of proteoglycan-bound calcium and its precipitation. The C-propeptide of type II collagen becomes concentrated in the mineralizing sites. The synthesis of type II collagen and the C-propeptide together with alkaline phosphatase is regulated by vitamin D metabolites. The association of alkaline phosphatase with calcification was first reported in the 1920s (101). Studies by Poole et al. indicated that, when calcification starts in the lower hypertrophic zone, it is not initiated within the matrix vesicles and indeed most calcification occurs in focal sites in which there are no detectable vesicles (275). They are still quite important, however, because they represent the location in which alkaline phosphatase with the enzyme associated and responsible for calcification is present. Much interest has centered therefore on type X collagen and its possible relationship to mineralization. No clear answer, however, has been provided. Many have proposed a positive relationship of type X collagen to mineralization because type X collagen appears in the mineralizing region at the appropriate time and is not present elsewhere. Schmid et al. (313) point out that type X collagen has been isolated from hypertrophic cartilage before mineralization, from the mineralizing front, and from regions of calcified cartilage. Synthesis occurs by hypertrophic chondrocytes in the upper regions of the hypertrophic zone before mineral is detectable histologically. Type X collagen persists in the cartilage cores after their mineralization and after bone has been deposited upon them. Gerstenfeld and Landis (125) showed an increase

94

CHAPTER 1 ~

Developmental Bone Biolo~ty

in type X collagen by chondrocytes cultured in the presence of 13-glycerophosphate. On the other hand, Poole and Pidoux (276) have suggested that type X collagen does not enhance mineralization but rather inhibits it. Their ultrastructural studies of type X collagen could not identify its association near early mineral foci or in association with matrix vesicles. They suggested that a coating of type X collagen on the cartilage fibrils actually directed early mineral formation away from those fibills to interfibrillar sites. In close analysis type X collagen appears to be deposited preferentially in the immediate pericellular chondrocyte region in which mineralization does not occur. This finding is consistent with the observation that the initiation of calcification does not occur in the transverse septae, which are in the immediate pericellular region because of their narrowness but rather occurs in the longitudinal interterfitorial septae of the growth plate, which are relatively farther from the cell. Attention has also been directed to the proteoglycans and their relationship to mineralization primarily because they are so extensively present in the physeal areas. Buckwalter has defined the two theories of the role of aggrecans and aggregates in physeal mineralization (42, 46). The first theory is that aggrecans-aggregates bind the calcium and inhibit the formation of mineral clusters in the matrix, whereas proteoglycanases prepare the hypertrophic zone matrix for mineralization by degrading the aggrecans. The second theory also proposes that the aggrecans-aggregates bind calcium but that they act as sites of mineral formation in the hypertrophic zone by increasing the concentration of calcium. The current impression is that they inhibit mineral growth throughout the uppermost parts of the physis and that an alteration in their structure subsequently serves to enhance mineral formation in the lower hypertrophic zone. The calcium-phosphorus (CAP) mineral phase has been studied extensively in relation to the cartilage mineralization of the epiphyseal growth plate (42, 46, 294). In a study of the calcified cartilage of the epiphyseal growth plate of young calves, X-ray diffraction of the samples revealed very poorly crystalline apatite (294). Fourier transform infrared spectroscopy and 31P nuclear magnetic resonance spectroscopy revealed significant amounts of nonapatitic phosphate ions. Their concentration increased during the early stages of mineralization but then decreased as the mineral content rose. The initial studies characterized the calcium phosphate mineral phase as a very poorly crystal ion: immature calcium phosphate apatite that was rich in labile nonapatitic phosphate ions with a low concentration of carbonide ions compared with bone mineral of the same animal. These studies were performed on the very young and mostly newly deposited mineral. It is felt that the maturation process of the mineral phase of calcified cartilage appears to proceed as it does in bone mineral, but some distinctive differences were found in the concentration of ions and in the temporal changes that occurred in the mineral phase. One of the main characteristics

of the mineral phase of calcified cartilage was the relatively large concentration of nonapatitic ions. Other important characteristics involved its low carbonide content. Its difference from mature bone mineral could be based on the fact that the mineral in calcified cartilage was less mature than that in bone due to its more rapid turnover. At all stages of calcification in the cartilage, including the earliest phase, the only crystalline solid detected by X-ray diffraction was apatite, with no evidence of a nonapatitic solid phase found. There is no evidence that the very earliest solid phase of CaP was amorphous. In the final stage of mineralization the characteristics of the mineral phase in cartilage tended to more closely approximate those of bone mineral. The appropriate development of mineralization of the endochondral sequence is dependent on circulating levels of calcium and phosphorus. These in turn are uniquely determined by functions of the parathyroid hormone (PTH) and vitamin D. Disorders of vitamin D metabolism in particular are associated with major abnormalities of the endochondral sequence, comprising the disorder referred to as rickets. Vitamin D of exogenous or skin origin accumulates in the liver and is converted to the circulating form 25-dihydroxyvitamin D [25(OH)2D], which is further activated in the kidney within the renal tubular cell mitochondria to the active metabolite 1,25-dihydroxyvitamin D [1,25(OH)2D] or calcitriol. This metabolite passes from the kidney via the blood stream to the intestine, bone, elsewhere in the kidney, and other organs in which it is physiologically active. It stimulates absorption of the intestinal calcium and phosphate as well as the mobilization of calcium from bone so as to normalize the serum calcium concentration. The kidney also produces a second metabolite, 24,25-dihydroxyvitamin D [24,25(OH)zD]. The concentrations of calcium and phosphorus that form the mineralized portions of the skeleton are closely regulated by the vitamin D-PTH system, whose purpose is to maintain the concentration of these minerals in a relatively narrow range in the extracellular fluid. Mineralization of bone tissue involves the deposition of hydroxyapatite (HA) crystals of calcium phosphate in the organic matrix composed of type I collagen and a variety of noncollagenous proteins, including proteoglycans, glycoproteins, phosphoproteins, and GLA containing proteins. Although the initial mineral crystals are deposited with the collagen fibrils, there is fairly widespread acceptance that collagen itself is neither the promotor nor the inhibitor of mineralization. The primary molecular factors that appear to be involved in the mineralization process include alkaline phosphatase, proteoglycans, fibronectin, thrombospondin, and the primary noncollagenous proteins bone sialoprotein, osteopontin, osteonectin, and osteocalcin (matrix GLA protein). There are still differing schools of thought as to the initial nucleation site in relation to the collagen and to the specific molecules that trigger that nucleation. In the view of some it is the hole region within the collagen that serves as the initial focus of mineralization based on the presence of

SECTION XI 9 M i n e r a l i z a t i o n

phosphoproteins and the physical mechanical gap that allows the nucleation to occur (130). Others feel that deposition is not site-specific other than being related to the collagen fibrils and that initial nucleation is involved with the association of matrix vesicles, which are small membranous structures derived from both hypertrophic chondrocytes and osteoblasts (6). Much effort has been made over the past three decades both to identify the noncollagenous molecules of bone and to determine their temporal and spatial representation in relation to the bone formation process, specifically mineralization both in the hypertrophic chondrocyte matrix and in the early osteoid of bone. Alkaline phosphatase is a specific product of osteoblasts and is expressed at high levels during bone development (163). Osteoblasts actively synthesizing extracellular matrix are always strongly positive for alkaline phosphatase activity whereas older mature osteocytes are not. Alkaline phosphatase activity is found within the matrix vesicles in which it is felt that initial hydroxyapatite formation occurs (6). Several groups have defined the fact that fibronectin is one of the earliest and most widespread of the extracellular matrix proteins, whose expression occurs with the formation of preosteoblasts prior to calcification and which is seen in diminished amounts after mineralization has occurred. Thrombospondin is yet another glycoprotein found to bind to calcium, hydroxypatite, and osteonectin. Although studies vary from different reports, most appear to be in agreement that bone sialoprotein and alkaline phosphatase appear earliest following fibronectin in the developing mineralization cycle, with osteonectin and osteocalcin formed relatively later. Cowles et al. concluded that fibronectin is one of the earliest matrix proteins expressed, which is rapidly followed by type I collagen, bone sialoprotein, and alkaline phosphatase with osteocalcin, osteonectin, and osteopontin having synthesis coinciding with mineralization (70). Roach has also indicated that osteopontin and bone sialoprotein are localized ahead of the mineralization front, suggesting that both proteins are necessary for the initiation of bone mineralization (296). An additional study by Hultenby et al. showed that BSP was expressed to a great extent in the osteoid synthesized by invading osteoblasts during the endochondral synthesis of bone on calcified cartilage (167). Osteopontin on the other hand was most pronounced at sites different from those of BSP, with the largest amount observed in cells close to the metaphyseal-diaphyseal border in which osteoclastic bone resorption was particularly active (51, 231). Although these two proteins occur early in the synthesis of bone, they appear to have different roles with bone sialoprotein present during the initial phases of bone formation, whereas osteopontin was particularly enriched at sites of osteoclast bone resorption (296). The other phosphoproteins, osteocalcin and osteonectin, generally are not present in areas of initial crystal formation but clearly are found in areas of fully mineralized matrix. It has been postulated, therefore, that they are more

95

important for controlling the size and speed of crystal formation rather than initiating the crystals. Osteocalcin has also been found to recruit osteoclast precursors to resorption sites. The initiation of calcification begins with the formation of individual small CaP crystals within collagen fibrils and the whole zone regions. When studies were made, including the expression of osteopontin and osteocalcin in growth plate cartilage, both proteins first appeared related to calcified cartilage in the hypertrophic zone with both molecules found concentrated at the periphery of the calcified cartilage at the future bone-calcified cartilage interface (231). Both were also found throughout the mineralized bone matrix. Landis has done extensive studies of mineralization and organic matrix interaction in particular using the mineralizing leg tendons of the turkey (207). This model is analogous to the mineralization of bone but is simpler to study, and thus specific events of mineral-matrix interaction can be visualized. The final event in mineralization of vertebrate tissues is deposition of a calcium phosphate salt, hydroxyapatite, associated with the organic matrix composed primarily of collagen. The crystals are shaped as thin plates, referred to as platelets. The size of individual crystals shows that they vary from 30 to 45 nm, whereas crystal thickness is uniform at 4-6 nm. Crystals eventually fuse to form larger platelets. Extensive study has attempted to determine the initial site of crystal deposition. It has been postulated that the hole zone within the collagen fibril is the initial site of renucleation, and much of the study revolves around the size and shape of the hole region and the size and shape of the individual crystal. In a three-dimensional high-voltage electron microscopic tomography and graphic image reconstruction study by Landis et al., it was shown that the earliest mineral deposition is within or along the characteristic banding pattern of the collagen. Some crystals appear to traverse adjacent hole and overlap zones but much of the material is located principally within collagen hole zones. The three-dimensional study confirmed that the mineral is platelet or tablet-shaped. Basically all of the individual crystals lie parallel to one another. The authors concluded that the mineral consisted of irregularly shaped thin platelets rather than rod-shaped components. Width and length were variable but the crystals appeared limited in thickness. The crystals appeared preferentially in the hole zones of collagen but also in overlap zones. Eventually crystal size outgrows the dimensions of a collagen hole zone but may be accommodated by channels or grooves in collagen formed by adjacent hole zones in register. The crystal platelets have their long axes nearly parallel to one another and to the long axes of the collagen fibrils with which they are associated. As to the site of nucleation, many crystals appear preferentially in the neighborhood of the collagen hole zones, but other crystals spatially separate from those in the hole zones are present in the collagen overlap zones. Nucleation events occur at different, spatially discrete sites and regions of collagen. This observation by Landis and colleagues is interpreted to argue

96

CHAPTER 1 ~ Developmental Bone Biology

against the influence on collagen mineral interaction of other matrix components such as extracellular or matrix vesicles.

XlI. EPIPHYSEAL GROWTH A. Physeal Chondrocyte Metabolism Brighton and colleagues focused on the chondrocyte metabolism as well as structure in the physeal regions (35, 36). The zone of proliferation was characterized by high oxygen content, high glycogen storage within chondrocytes, and high levels of mitochondrial ATP production. As the physeal sequence progressed, cells in the hypertrophic zone had a low oxygen tension, progressive consumption and lowering of glycogen levels until depletion at the lowest levels, and a switching of mitochondrial metabolism with cessation of ATP formation. The matrix of the hypertrophic zone was increasingly laden with calcium.

B. Studies of Cell Proliferation in Physeal Cartilage Using Tritiated Thymidine Autoradiography The development of tritiated thymidine autoradiography and its application to the study of physeal chondrocytes allowed for the determination of individual cell contribution to physeal growth. The titrated thymidine autoradiography technique is an accurate indicator of cell proliferation patterns and serves as a way of assessing the dynamics of growth. Thymidine, a specific precursor of DNA, labels cells only in the process of DNA synthesis and allows those cells to be followed through division and early differentiation. Thymidine is taken up from the circulation quickly with labeling reaching a maximum in 1-2 hr (186, 187). Uptake during bone development previously has been demonstrated in the upper regions of the physis (187, 188, 218), in secondary ossification center and metaphyseal bone, in epiphyseal including articular chondrocytes (223,224), and in cells of the perichondrial ossification groove of Ranvier (320). Kember was one of the first to develop this technique in relation to physeal studies (186-188). His initial studies were performed in the proximal tibia of the rat. Studies were done from 1 hr to 7 days at eight time periods. Kember was able to note cell localization initially in the upper reaches of the proliferating zone of the growth plate, with subsequent labeling in progressively lower regions with concentration in the hypertrophic zone by 7 days. This study indicated not only the areas of rapid cell proliferation but also the rate of cell differentiation and passage to each of the chondrocyte cycles, including the hypertrophic region. The basic measurement with tritiated thymidine was the percentage of cells labeled in an animal sacrificed at 1 hr after injection because any of the cells in synthesis would have divided. The autoradiographic studies were a far more convenient and accu-

rate way of measuring the portion of cells in division than mitotic counting. The zone of active cell proliferation clearly was noted to be in the region of columnar or proliferating cells. He was able to identify the stem cell compartment of the germinal zone of the physis due to the fact that proliferation in this region and, thus, labeling was less than that immediately below it. The progression of the label through the various regions of the physis toward the lower hypertrophic zone with time was clearly illustrated. Whereas labeling with tritiated thymidine allowed for initial identification of proliferating cells and subsequent assessment of their passage through various sequences toward chondrocyte hypertrophy, the method did not allow for assessment of the contribution of hypertrophy itself to longitudinal growth.

C. Kinetics of Epiphyseal Growth The description of the epiphysis given so far has concentrated on molecular and supramolecular structure, but it is extremely important to document the dynamic growth phenomena because these represent the primary function of the epiphyseal region. The epiphyseal growth plate maintains its height at the same extent throughout the vast majority of the period of growth due to coordinated functions of matrix synthesis at the epiphyseal end and resorption at the metaphyseal end. The epiphysis must also increase in width, which it does by interstitial growth of the epiphyseal cartilage immediately above the growth plate and also by addition of chondrocytes from the zone of loosely packed cells within the groove of Ranvier. The narrowing by resorption in the metaphyseal region was described previously. Longitudinal growth is also partially controlled by the elastic forces exerted by the surrounding periosteum. More detailed studies have been done to outline the specific features of cell and matrix activity that underlie longitudinal growth. It has been determined that such growth is due to three specific factors that may vary from time to time during the cycle of physeal development and function. Growth, by which is meant an increase in length, is a function of (1) chondrocyte cell proliferation, (2) matrix synthesis, and (3) chondrocyte hypertrophy. In relation to changes in shape, Hunziker and Schenk (173) state that there is "a high degree of coordination between matrix remodeling and chondrocyte shape change." They feel that, during both acceleration and deceleration of linear growth, it is the changes in hypertrophic cell activities that appear to play an important regulatory role. It is not simply changes in proliferative activity alone that modulate longitudinal growth. Indeed the importance of cell hypertrophy in regulating growth rate lies in the fact that it is a much quicker mechanism than new cell production. In a careful study, they documented that a proliferating chondrocyte would need approximately 54 hr (cell cycle time) to duplicate its own volume whereas during hypertrophy the corresponding volume, increase would be achieved in a period as short as 5 hr. Hypertrophy was a far

SECTION Xll 9 Epiphyseal G r o w t h

more efficient mechanism for bringing about columnar linear growth than cell proliferation alone. Actual matrix synthesis is felt to play a role in effecting but not in regulating longitudinal growth (because it does not contribute directly to acceleration or deceleration of this process by column prolongation). Matrix increase is more related to retaining the biomechanical properties of growth plate cartilage and to integrating chondrocytes in a highly ordered fashion rather than to triggering growth itself. The duration of the hypertrophic phase at approximately 48 hr was found to remain constant irrespective of animal age or growth rate, indicating that changes in duration would not be the triggering growth factor but, rather, changes in cell shape and size. These findings were somewhat contradictory to previous assessments of longitudinal bone growth, which had been determined upon measurement of bulk parameters such as growth plate height, cell proliferation activity as determined by tritiated thymidine incorporation, or matrix production evaluated by autoradiography of matrix components. They concluded that "growth acceleration was achieved almost exclusively by cell shape modeling, namely increase in final cell height and a decrease in lateral diameter." Even during varying rates of growth, the cell proliferation rate in the longitudinal direction and net matrix production per cell remained unchanged. "Physiological increase in linear growth rate thus appears to be based principally upon a controlled structural modulation of the chondrocyte phenotype." Cell matrix production in particular "appears to play a subordinate role in regulating longitudinal bone growth rate. The duration of the hypertrophic cell activity phase remains constant at approximately 2 days under the various growth rate conditions."

D. Amount of Growth at Each Epiphyseal Plate It was recognized in the mid- 1800s that growth was not uniform at each epiphysis. Oilier undertook experimental studies to assess the contributions to growth of each end of the major long bones (256-258). He implanted a lead nail in the middle of a long bone in rabbits, chickens and lambs and then assessed their relative positions several weeks to months later. He concluded that the proximal end of the humerus grew far more extensively than the distal end but that it was the distal ends of the radius and ulna that grew far more extensively than their proximal ends. In the lower extremity, the relationships were reversed. In the femur, most of the growth was at the distal end, and in the tibia, along with the fibula, there was more growth at the proximal than at the distal end. He thus clearly understood and documented that growth was most extensive at the shoulder, wrist, and knee. He also indicated that it was the most actively growing epiphyses that fused latest. He indicated, however, that those epiphyses that provided more longitudinal growth did not do so because of the fact that they continued growing longer, but rather that they contributed more throughout the entire period of growth. He then identified the clinical importance

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of these varying growth features in terms of resections for disease, which were commonly performed in those days. The obvious conclusion was that resections in the elbow area had relatively few consequences for longitudinal growth, whereas at the knee they would lead to quite extensive limb shortness if done during the active growing years. Similar major growth limitations would occur with early resections at shoulder and wrist. The contributions to growth of each plate in each of the long bones were established by Digby (79) in a brief publication in 1916 as follows: proximal humerus, 80%; distal humerus, 20%; proximal radius, 25%; distal radius, 75%; proximal ulna, 20%; distal ulna, 80%; proximal femur, 30%; distal femur, 70%; proximal tibia, 57%; distal tibia, 43%; proximal fibula, 60%; and distal fibula, 40%. It is widely felt that these relative amounts of growth persist at a uniform level throughout growth. More recently, Pritchett (279) has reported a detailed study of upper extremity long bone growth in 100 males and 100 females between 1 and 19 years of age and lower extremity long bone growth in 123 males and 121 females from age 7 years to skeletal maturity. His data indicate that the percentage of growth plate activity at each long bone epiphysis is not constant throughout the growth period. He used the location of the nutrient artery as the fixed point for measurement. He concluded in agreement with Digby that the proximal growth plate of the humerus contributed 80% of the growth, the distal plate 20%, the proximal radius 25%, and the distal radius 75%. He differed from Digby in attributing the proximal ulna contribution at only 15% and distal ulna at 85 %. The proximal humerus (40%) and distal radiusulna (40%) accounted for 80% of upper extremity growth with the elbow region (10%- 10%) only 20%. Pritchett was able to assess growth at various ages with the very interesting finding that growth plate activity was not proportionately constant throughout growth. In the humerus before the age of 2 years, less than 75% of growth occurs proximally, increasing to 85% at age 8 years and remaining constant at 90% after age 11 years. At the distal ulna, 85% of growth occurred, but 90% by age 5 years and 95% by age 8 years. At the distal radius, growth was 80% overall but 85% after age 5 years and 90% by age 8 years. In the lower extremity the overall growth contributions were the same as those noted by Digby. As in the upper extremity, growth plate activity was not constant throughout growth (280). Although approximately 70% of growth of the femur occurs distally in both males and females, the proportion in the distal femoral growth plate in girls varies from 60% at 7 years of age to 90% at age 14, whereas in boys the contribution of the distal femoral growth plate varies from 55% at 7 years of age to 90% at age 16. The overall contribution of the proximal tibia growth plate is approximately 57%. This varies from 50% at 7 years to 80% at age 14 in girls and from 50% at 7 years of age to 80% at age 16 in boys. The amount of growth remaining in the distal femur and proximal tibia in males and

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CHAPTER I ~

Developmental Bone Biology

females has been documented in greatest detail by Green and Anderson (7, 8). Pritchett has also developed similar charts from his data. The amount of growth that can be expected to occur throughout childhood or what is currently remaining in the proximal femur and distal tibia can also be calculated from these charts by defining the distal femoral growth as 70%, leaving the proximal femoral as 30%. Similar calculations can be made for the distal tibia. Karrholm et al. (183) have calculated the longitudinal growth rate of the distal tibia and fibula in children from 9 years of age to skeletal maturity in 30 boys and 31 girls. The patients were studied with Roentgen stereophotogrammetric analysis (RSE) with examinations quite frequently at intervals of 1-12 months, with most patients observed at 3-6 month periods. In the distal tibia in boys and girls, the average growth rate decreased from a plateau of about 10 and 11 years, respectively. The decreasing growth rates were found somewhat later in the distal tibia than in the distal fibula in both boys and girls. The growth rates, however, were close to 0 at about the same time in distal tibia and fibula in both sexes. Growth charts were established to provide clinical guidelines. The group also calculated the average daily growth rate of differing skeletal maturity, measuring micrometer level values at distal fibula and distal tibia. Charts were produced for the calculated remaining growth in the distal fibula and distal tibia in girls from 8 years of age and in the distal fibula and distal tibia in boys from 9 years of age. The data were expressed in charts with mean values as well as one and two standard deviations above and below the mean. Several sets of growth data are available covering lengths of major long bones followed longitudinally in groups of normal patients (7, 8, 225,279, 280). These include the work of Maresh (225), who published length data for males and females separately for humerus, radius, ulna, femur, tibia, and fibula from 2 months to 18 years of age. Measurements were made between the epiphyseal plates up to and including 12 years of age and entire bones, including the epiphyses from 10 years of age upward. Green and Anderson published values for femur and tibia in males and females. Approximate estimates of growth per year in the distal femoral and proximal tibial growth plates have been described by other observers. (1) Pritchett (280): average 1.3 cm per year of growth from the distal femur (half that amount in the final 2 years of growth), and average 0.9 cm per year from the proximal tibia (half that amount in the final 2 years). (2) White and Stubbins (369): 3A" growth per year at distal femur and 88 per year at proximal tibia. Pritchett (280) has also summarized growth phenomena by reviewing concepts derived over decades of investigation going as far back as Oilier in the nineteenth century. (1) Growth contributions from each of the upper and lower extremity growth plates are not equal. One dominant growth plate makes the major contribution to length in any particular bone throughout growth: in the humerus the proximal

growth plate and in the forearm the distal radial and ulnar growth plates. In the lower extremity the major contributions are at the knee, involving the distal femoral and proximal tibial growth plates. (2) Growth is not constant at all ages. The activity of the growth plate varies with age, with the more active growth plate assuming greater importance with increasing age. (3) The nutrient foramen marking the entrance of the nutrient vessel into the cortex provides a fixed point in the long bone and growth of each end can be measured in relation to it. (4) The more active growth plate is thicker than the less active growth plate. (5) The more active growth plate closes later than the less active growth plate, and virtually all growth during the last 2 years before growth plate closure occurs at the more active growth plate. (6) The nutrient canal is directed away from the more active growth plate and toward the less active growth plate.

E. Growth Slowdown and Growth Arrest Lines (Harris Lines) Harris clearly demonstrated the presence of transverse radiodense lines across the metaphyses of growing children who had been subjected to either generalized illness or localized bone disorders from which a recovery had occurred. Harris was a British radiologist who clearly delineated the phenomenon although he was inaccurate in the histopathologic interpretation: he felt the disorder was due to the deposition of calcium within the physis itself. Since that time, studies of clinical material by Ogden (251) and experimental assessments by Siffert and Katz (327) have shown that the transverse metaphyseal line is bone and represents thickened, transversely interconnected, trabecular networks with the normal longitudinally oriented trabecular bone on either side. With the slowdown in physeal growth during the time of illness, the normal endochondral patterning is thrown off and bone accumulation at the outer reaches of the metaphysis is increased. The growth arrest line is parallel to the adjacent physis. With the slowdown or complete cessation of growth, the trabeculae become thickened and fuse with each other transversely. They contain central cores of cartilage but are primarily bone. When the child enters a recovery phase, physeal growth increases and the normal pattern of metaphyseal bone is resynthesized with the trabeculae oriented along the long axis of the bone. With increasing time between the period of growth slowdown and the time of reassessment, the physis grows away from the transverse metaphyseal line. Histologic studies show the bone thickening to be present throughout the transverse diameter of bone within the metaphysis and not to be concentrated as an inner thickened rim of the cortex. If there are recurrent episodes of poor health, then the patient will often demonstrate multiple growth arrest lines. These are seen most prominently at the distal femur and proximal tibia where growth is most rapid, and they are seen infrequently around the elbow where growth is extremely slow. They can also be seen at the prox-

SECTION Xlll ~ Responses to Mechanical Stresses

imal humerus and distal tibia where growth is relatively extensive. The growth arrest lines are seen with many types of childhood illness. On occasion they are seen, however, in the absence of serious disorders. Transverse lines related to one physeal area also frequently are seen following fractures of the adjacent bone. They can serve as valuable indicators of the state of physeal function because the distance between the physis and the growth arrest lines should be the same throughout the entire width of the bone. If there is partial or complete focal physeal arrest, early demonstration of this can be seen by angulation of the growth arrest line with diminished distance between physis and the line at the area of tethering. Whereas growth arrest lines are identified clearly on plain radiographs, they are seen with a much higher degree of resolution and in earlier states of formation on MR imaging.

XIIl. RESPONSES OF DEVELOPING BONES AND EPIPHYSES TO MECHANICAL STRESSES A. Normal Responses to Mechanical Factors The importance of mechanical or physical factors in stimulating bone development has been commented on since the early years of scientific investigation of growth phenomena. As early as 1815 Howship felt that "mechanical pressure" was the principal agent in bringing about progressive changes of structure in growing bone (165). King (1844) (189) observed: "that pressure and tension affect the evolution of all parts, scarcely requires proof at this time." In commenting on the replacement of the cartilage model of the developing bone by bone tissue itself, he indicated that "the precise site of this 'bony' deposit seems to be determined by a certain excessive degree of pressure or tension, as in the center of a cubicle bone or an epiphysis or in the middle of a parietal or cylindrical bone. The continual depositions which succeed seem also strictly determined by the directions of pressure or extension or of both." He felt that internal absorption would seem to depend on the removal of pressure from the center to the circumference. In terms of the structuring of the internal bone, he felt that "every bone has most to resist on its surface, and least internally. In proportion as the exterior is strained and excited, so is it nourished, so does it grow; while as the inner parts are the more removed from physical tensions, they are carried off by absorption." That much depends on tension seems corroborated by the final remark that "when tension is removed from the center, it becomes absorbed which explains the excavation of bone, the course of simple atrophy, and the modeling of definitive callous." The cause which fixes the precise spots of incipient fetal ossification are conceived specific. The event takes place in a solid nidus at a point where many convergent forces and pressures are concentrated. The continuance of ossification (being as it

99

were a columnar growth against gravity) follows a similar rule for it is a deposition where pressure is greatest; and whether we regard the order in which the nuclei of all the bones begin or the order of rapidity with which each one grows, the activity is evidence in dependence on the tension of the parts. The form of every bone and process of bone, and even the arrangement of every fiber of cancellus seems to me to be regulated by the above principle. It was the works of Hueter (166) and Volkmann (358), published separately in 1862, focusing on the effects of pressure on cartilage growth, and that of Wolff (374), focusing on bone structure in relation to extrinsic forces and functional patterns in his classic book in 1892, that firmly implanted the concept of mechanical or biophysical effects on bone and cartilage structure (Table X). In 1905 Parsons (268) defined "epiphyses which occur at the articular ends of long bones, by which the pressure is transmitted from bone to bone" as pressure epiphyses. He contrasted these with epiphyses into which tendons are inserted, which he referred to as "traction epiphyses" (267, 269). Traction epiphyses were noted by a projection from one end of a shaft of a long bone into which a tendon was inserted and that had a separate center of ossification. Haines (136) and Barnett and Lewis (17) felt that traction epiphyses were derived from preexisting sesamoids. As early as 1911, Schaffer (310) and Gebhardt (122) used photoelastic models to assess mechanical stresses and their relation to ossification in developing cartilaginous epiphyses. Similar studies subsequently were shown by Pauwels decades later in an effort to relate mechanical forces to bone development (270). These contributions have been reviewed by Carter and Wong (58, 59). Gebhardt concluded that the central region of the developing cartilaginous epiphysis contained the greatest accumulation of stress, which then led to the formation of the bony epiphyseal nucleus. Pauwel's studies were interpreted to indicate that Gebhardt was incorrect and concluded that the secondary ossification nucleus formed in areas of "pure and high hydrostatic pressure." More recent studies by Carter and co-workers also felt this conclusion to be inaccurate, primarily because of the use of incorrect assumptions for boundary and loading conditions. Their work will be reviewed later. Carey wrote a series of studies on the dynamics of musculoskeletal histogenesis in which he sought to relate the biophysical forces generated by growth phenomena to the structure of the tissues with which they were associated (5356). He indicated that "the biophysical aspect is as important as the biochemical one in the problem of bone origin." He was particularly interested in the effect of developing muscle on the developing skeleton. He was one of the first to attempt to assess growth from a dynamic viewpoint in which interaction of forces resulted in what he referred to as a transference of energy. The forces generated were major factors in histogenesis. He referred to his concept as the "growth motive force," which he defined as "any agency which tends to

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CHAPTER 1 ~

Developmental Bone Biology TABLE X

Bone structure Wolff's law (1870, 1892)

Cartilage growth tissues Hueter- Volkmann "law" (1862)

" L a w s " o f Bone a n d Cartilage D e v e l o p m e n t

Extrinsic forces on a bone modify the internal trabecular architecture and the external shape "Every change in the form and function of the bones, or of their function alone, is followed by certain definite changes in their internal architecture, and equally definite secondary alterations of their external conformation, in accordance with mathematical laws." There is an inverse relationship between compressive forces along the long axis of epiphyseal growth and the rate of epiphyseal growth. Increased pressure on the concave side interferes with normal bone growth while on the convex side less than normal pressure leads to overgrowth. Pressure beyond the normal on growth cartilage leads to growth retardation.

produce a transfer of kinetic energy from an active to a less active group of cells and of potential energy from a less active to an active group, and a cellular field of differential growth until equilibrium is established." Although the work postulated mechanical effects of tissue subsets on each other, no experimental work was done and some of the conclusions, though theoretically attractive and convincingly presented, have never been validated experimentally. His work did not specifically discuss the types of mechanical sources, although it frequently mentioned their importance; it was strongly based on histologic and radiographic studies. Carey referred to active and less active zones in reference to the rate of cell division per millimeter of cross section as determined histologically. He sought to assess how the increase of cellular components and their transformation of these led to the perfection of form out of the relatively formless antecedents (by which he means undifferentiated mesenchymal cells). These were phenomena that demanded close analysis. Along with many investigators at that time, he considered cellular differentiation to be influenced by the environment in the sense that it was partly dependent upon an interaction of the developing parts before external form and internal structure were perfected. He referred to the relationship of differing tissue groups to each other in development, and he used the term "inductive" to imply that some changes were produced without cell-cell contact and "conductive" to imply that change was produced with contact. Carey thus felt that, through conduction of the developing skeletal and muscular tissues upon each other, the factor of force inherently was involved. As the skeleton underwent its most rapid growth during early embryogenesis, a tensional elongating or stretching action was bound to be exerted upon the surrounding and less actively growing continuous syncytial mesenchyme. Carey defined his theory of the relationship

between muscle and skeletal development in simple terms: (1) there is a force manifested by rapid skeletal growth; (2) this force exerts a tensional or stretching action upon the surrounding mesenchyme, influencing the first steps of myogenesis; and (3) the first differentiated muscles react upon the primordial blastemal skeleton, resulting in a definite series of changes. These are seen in the formation of the condensed cartilaginous skeleton and later, as the muscles become more developed and vigorous, serve as a physiological foundation in the formation of the osseous skeleton. Carey thus defined a degree of equilibrium of the musculature and skeleton during any stage of development established between opposing myogenic and skeletal forces. His theory indicated that "mechanically, skeletal and the related muscular tissues are inter-dependent, one relying upon the other for its initial and continued differentiation." Stated another way, he felt that force was exerted in certain regions of the embryo by the genesis of a rapidly dividing group of cells upon a less active or relatively passive group of cells. In turn, the relatively passive group reacted upon the former. This action-reaction response was shown by alterations in the rate of growth or by changes produced in the external form or internal structure of groups of cells. He derived the term "growth motive" and defined it as any agency that tends to produce a kinetic and potential energy in a cellular field of differential growth. In attempting to relate biomechanical features to changes in shape and form, Carey provided brief definitions. He defined any definite alteration in the form or dimensions of an elastic body as a strain, with the simplest strain being the linear one. Elongation was defined as the ratio of change in length to the initial length. A negative elongation or shortening was called compression; a positive elongation or lengthening was called tension. He then related skeletal de-

SECTION XIII ~ Responses t o Mechanical Stresses

velopment from the limb bud stage on to the associated myogenesis in relation to the reciprocal forces of each. The core of his argument is that mechanical forces play a major role in cell differentiation as the limb bud progresses from mesenchymal condensation, to the cartilage model of the developing bone, to formation of the primary ossification center with hypertrophy of cells in the cartilage mass, and finally to cortical bone formation. He postulates that centrally there is more cell activity within the developing cartilage mass than there is at the periphery. As the central core of the limb pushes forth more rapidly than the mesenchymal cells at the periphery, there is a tendency for the latter to be pulled out, stretched, or elongated by the former. "The traction force of the rapidly growing appendicular core exerted upon the surrounding mesenchyme is the internal stimulus of a correlated part, resulting in the elongation of the nuclei of the premuscular mass in the direction of the long axis of skeletal growth." As differential growth continues, the growth motive force becomes more and more in evidence, and there is a drawing out or stretching of the peripheral syncytial cytoplasm in the direction of skeletal growth. The myofibril is formed roughly parallel to the long axis of the developing bone. The formation of the embryonic skeletal muscles is felt to represent a definite reaction to the growth of the skeleton, and in tum these muscles "tend to restrict the growth of the skeleton in length. This is manifested by an increasing condensation of the skeletal core." Cartilage then forms within the skeletal model to provide greater stability to counteract the formation that would occur as the primitive muscles begin to contract. He thus postulates continual interplay between muscle and skeletal development. As the growth motive force of differential growth continues, the musculature becomes too vigorous even for the cartilage base, which then leads to supplanting of the cartilage model by the osseous skeleton. Carey produced a series of drawings relating to the cell and matrix deposition patterns of the developing bone and the associated muscle in an effort to show how the various strains helped modulate cell differentiation (Fig. 22). He concluded that there was a direct transference of kinetic energy from the more rapidly growing skeleton to the less actively growing primitive musculature and then a reactive transference of potential energy from the latter to the former, tending to an equilibrium state. When muscle differentiated to the state that it began functioning, there was a direct transference of kinetic energy from this tissue back to the growing skeleton, tending to retard or alter its motion or growth. The active and passive play of the muscles led first to a stiffening of the skeletal model by cartilage formation and then to further stiffening by bone formation. In regard to bone formation, he noted in particular a sub-periosteal osteogenetic and constricting cell zone at the center of a developing long bone, which quickly encircled the shaft. Formation of the osseous skeleton was part of a feedback mechanism based on the stimulus of the functionally active thigh muscles and

101

the stimulus of the restriction to growth at the ends of the rapidly elongating cartilage model due to passive muscular resistance. The interactive forces also explained in a mechanical or biophysical sense why the bony epiphyses or secondary ossification center formed. The centrifugal expansion of central confined epiphyseal cartilage cells was resisted by the centripetal effect of the peripheral muscles, ligaments and tendons together producing the "adequate compression of differential growth." The epiphyseal bone thus represents a terminal pressure system segmented from the diaphysis. Carey indicates that muscle differentiation in the thigh shortly after the formation of the cartilage model of the bone is not a coincidence but a mechanically mediated cellular response to the traction or tension to which the continuous peripheral mesenchyme is subjected during the rapid growth of the femur in length. Carey then relates the rapid growth of the skeletal model of individual bones to what happens between them at the joint interface. Resistance during femoral growth, for example, is met at first at the proximal end in the centers of opposing growth for the triradiate cartilage (ilium, ischium, and pubis) and at the distal end in the centers of opposed growth for the tibia. The regions of cell concentrations between opposing developing bones are referred to as the interzone where joints eventually will form. The appearance of the joints, however, is felt by Carey to be the mechanical result of the opposed growth of contiguous accelerating growth segments. Early resistance to expansion of the femur in two directions, by associated growth of the hip region and knee region, combined with the constraints of the peripheral muscle leads to normal rotation of the limb plus slight bending of the bone. He feels that formation of periosteum around the cartilage model is also mediated by mechanical events. The perichondrial fibrosis becomes modified into a periosteal membrane. The osteoblasts form a matrix that is mechanically situated to serve effectively as a cellular reaction to the great strain to which the bent femoral beam is subjected. The appositional growth of bone strengthens the femoral beam at its weakest part. The mechanical result of this cellular reaction of bone differentiation is the progressive formation of a more stable base for the application of muscular forces. The proximal femoral-acetabular hip joint is formed due to different rates of growth of the femur and the acetabular cartilages. The head of the femur is seen, relatively speaking, to advance farther and farther into the acetabulum formed by the ilium, ischium, and pubis. The force of longitudinal interstitial growth of the femur per square millimeter of cross section is calculated to be 12 times greater than that of the acetabulum. This fact, associated with muscular restrictions to longitudinal femoral growth and a femur rendered more stable by primary ossification center bone, leads to the structural elaboration of the hip joint. Joints are not hereditary structures alone but rather the mechanical resultants of opposing centers of accelerated growth.

102

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3. Premature Physeal Closure Occurs in 25% +

FIGURE 26 The three possible causes of femoral shorteningin LeggPerthes disease.

prognostic sign and treatment is mandated, with the nature of the treatment being dependent on the stage of healing phase at which the hinging is detected. Reinker stresses that hinge abduction is an important indicator of a poor outcome if left untreated and that attempts to recognize and treat it are important even while the disorder is evolving and the head is in the healing phase but has not completed it (229).

T. Femoral Shortening as a Sequel to Legg-Perthes Disease Shortening of the involved femur is a frequent occurrence in Legg-Calve-Perthes disease. There are three possible causes of any shortening (Fig. 26). 1. PHYSEAL AVASCULARITY Shortening at disease termination, though not always a result, is not unexpected because the cause of the condition is an avascular event or series of events of the proximal capital femoral epiphysis. The epiphyseal blood supply is responsible not only for supplying the bone of the developing secondary ossification center but also for providing the stimulus to growth of the head-neck growth plate. Variable

320

CHAPTER 4 ~ Legg--Calve--Perthes Disease

patterns of length deformity are seen (246). In the most benign situation, complete reconstitution of the femoral head and neck region occurs with no long-term sequelae. Most patients develop a shortening in association with the Perthes disorder, although in many this will correct itself either partially or fully as part of the repair phase. 2. PREMATURE PHYSEAL CLOSURE Edgren documented a shortened femur in Legg-Perthes disease in almost all patients at the time of skeletal maturity with a mean discrepancy of 1.6 cm and a range of 0.2-3.5 cm. He also noted tibial shortening in some averaging 0.4 cm when present and ranging from 0.2 to 1.2 cm. Edgren reported an incidence of 12.8% premature physeal closure in his large series of 326 hips (68). Some interference with physeal growth was noted by Keret et al. in 90% of patients; in 25% of patients there also was premature closure of the proximal femoral growth plate as a delayed sequel, which further increased any discrepancy during the final year or two of skeletal growth (154). We also documented premature physeal closure as a delayed sequel, leading to the type IV lower extremity length discrepancy pattern (see Section VIII below) (246). Thompson and Westin noted 49 of 192 hips (25.5%) with premature physeal closure (264). The closure in their patients began laterally but proceeded to involve the entire physis, predisposing one to a short valgus femoral neck and a prominent greater trochanter. Barnes reported on 22 cases of premature physeal closure in Perthes disease (13). The shortening in 19 unilateral cases, most of whom had previous varus osteotomies, was a mean of 1.92 cm (range = 0.5-3.0 cm) and was present in all. Six had shortening of 2.5 cm or more and 13 of 2.0 cm or more. Premature physeal closure of the capital femoral physis was commented on by Bowen et al., who noted a 23% premature closure rate in 430 hips with Perthes disease (24). There were two patterns of femoral closure, the most common being central closure beginning at the center of the physis and progressing to the periphery usually in symmetric fashion. The neck shaft angle remained normal but overgrowth of the greater trochanter allowed for an overall coxa vara appearance. The second common pattern found closure concentrated laterally, which led to asymmetry as the head was tilted laterally in relation to the acetabulum as central and medial physeal growth continued. In these patients, the femoral head tilted laterally and tended to develop an ovoid shape with the adjacent lateral margin of the acetabulum deficient. In the study by Keret et al., 80 patients with unilateral coxa plana who had been treated conservatively were followed to skeletal maturity (154). Physeal involvement was inferred by the radiographic presence of premature physeal closure, overgrowth of the greater trochanter, change in physeal shape, lateral protrusion of the capital nucleus, and medial bowing of the femoral neck. They noted premature physeal closure in 25% of the affected femoral heads and noted a direct correlation between the severity of physeal involvement and the ultimate deformity of the head. They

commented on the obvious importance of following all patients with Perthes disease to skeletal maturity. Keret et al. felt, however, that much of the physeal injury was related to epiphyseal stress fractures. If major epiphyseal compression and distortion occurred, then damaging loads would fall on the germinal cells of the physis, which normally are shielded by the intact articular cartilage and bone of the capital epiphysis. The fractures would mechanically flatten the germinal layer of the physis such that full healing does not occur. The possibility of micro-transphyseal bone bridges also was raised. All patients with Legg-Perthes disease should be followed to skeletal maturity so as not to overlook the premature closure of the physis, which can occur several years after the onset of the disease and after repair appears to have been complete with growth reestablished. It is due to excess pressure on the lateral physis inhibiting growth, physeal damage due to vascular insufficiency of the primary disorder, and transphyseal bone bridge formation. The physis may continue to grow, with apparent healing of the secondary ossification center necrosis, but be unable to sustain full growth to the normal time of skeletal maturation. 3. TREATMENT-RELATED SHORTENING The treatment method chosen in Perthes can have an additional effect on length discrepancy at skeletal maturity. During the era in which unilateral abduction non-weightbearing bracing was prominent, decreased function of the affected limb increased the discrepancy because the normal growth stimuli to the distal femur and the tibia also were absent. Once brace use was discontinued, however, resumed function of the limbs allowed for an increase in the growth rate of the other normal physes and a diminution of the discrepancy (246). At present unilateral bracing is rarely used as it was found to be ineffective because patients tilted into pelvic obliquity, thus limiting the effectiveness of the planned abduction of the involved hip and increased coverage gained in that fashion. Operative intervention is used commonly at present in many centers. In those having femoral head coverage improved by innominate osteotomy, a secondary benefit of the procedure is a gain in lower extremity length of 1.0-1.5 cm as the pelvic osteotomy site is opened and stabilized by the inserted graft. Proximal femoral varus and derotation osteotomy also provides for better coverage of the femoral head in the standing position, but varus osteotomy almost invariably shortens the femur and further increases any length discrepancy. Mirovsky et al. provided a detailed comparative study of residual shortening after varus osteotomy for Perthes disease compared with a group of patients treated in weight relieving braces (193). They documented the residual shortening in 43 patients having subtrochanteric varus derotation osteotomy and 47 treated with the weight relieving brace, each of whom had reached complete or near-complete skeletal maturity. In both groups the average shortening was 0.9 cm. In a group of patients treated conservatively by Edgren, 50 patients had an average

SECTION VIII ~ Lower Extremity Length Discrepancies with Legg--Perthes Disease residual shortening of 1.5 cm, whereas a group of 30 patients treated conservatively by Gower and Johnston had a residual shortening of 1.6 cm. Due to concerns about shortening that arose during the development of the operative technique of varus derotation osteotomy, changes were instituted. In those having a closing wedge resection, 15 patients had an average shortening of 1.1 cm. In those who had a reversed half-wedge resection (in which a closing wedge was removed medially and then replaced into the lateral opening), the average shortening in 5 patients was 0.8 cm. Finally, when an open wedge was used allowing the gap to heal with new bone, the average shortening was diminished in 4 patients to 0.4 cm. Another way of looking at the data indicated that, after osteotomy, 58% of 55 patients had shortening of the affected limb, 27% had limb length equal to that of the opposite side, and 8 patients (15%) actually had some lengthening (although these patients mostly had a derotation without varus osteotomy). As in other series, those who had osteotomy up to 8 years of age had less residual shortening due to the remodeling potential than those who had osteotomy after 8 years of age. Poorer results in terms of more shortening also were seen in those with fair and poor results and in those who had less remodeling of the varus deformity. In 34 osteotomized patients under 7 years of age, at the onset of symptoms the residual shortening was 0.6 cm, and in 21 patients more than 7 years old when symptoms started, the average residual shortening was 1.1 cm. The data still indicate, however, that in some patients shortening can be considerable. In patients operated at a mean of 8.5 years (6 patients), the average residual shortening was 2.3 cm with a range from 1 to 3.75 cm. Some of this was felt to be due premature physeal closure. Leitch et al. noted a 6% incidence of leg length discrepancy greater than 2 cm after both nonoperative and operative treatment. They also quantified the articulotrochanteric distance (ATD), which was less than 5 mm in 23% of patients, 43% of whom had a positive Trendelenburg sign. They also noted a significantly lower mean ATD in patients treated by femoral varus osteotomy, which they felt should be avoided in patients over 8 years of age (173). No discrepancies were noted after innominate osteotomy. Thus, it is extremely important to follow patients with Legg-Perthes to skeletal maturity to assess shortening caused by three possible mechanisms: (1) the Perthes disorder, (2) premature cessation of growth in adolescence, and (3) femoral shortening by varus osteotomy. A detailed review of our experience with lower extremity length discrepancies in Legg-Perthes disease follows.

VIII. L O W E R E X T R E M I T Y LENGTH DISCREPANCIES WITH LEGG-PERTHES D I S E A S E A study of lower extremity length discrepancies in LeggPerthes disease from Children's Hospital, Boston, will be

321

reviewed (246). This series did not include patients having innominate or proximal femoral osteotomies.

A. Maximum Total Femoral and Tibial Discrepancy during Growth Years During the course of the condition, the average maximum total femoral and tibial discrepancy in all patients was 2.14 cm. In those requiring epiphyseal arrest (31 patients) it was 2.99 cm, and in those not requiting epiphyseal arrest (116 patients) it was 1.91 cm. The maximum average discrepancy reached during the course of assessment in 147 patients was 1.5 cm or more in 113 patients (77%) and 1.0 cm or more in 139 patients (95%).

B. Femoral and Tibial Discrepancy at Skeletal Maturity The average final total femoral and tibial discrepancy in the entire group was 1.21 cm. The final average discrepancy in the entire series with or without epiphyseal arrest was 1.5 cm or greater in 50 patients (34%). In the group that had epiphyseal arrest the final average discrepancy was 1.27 cm, and in the group that did not it was 1.21 cm.

C. Maximum Femoral Discrepancy Maximum femoral discrepancy in all cases averaged 1.38 cm. In those not having arrest the average maximum shortness was 1.18 cm, and in those having arrest it was 2.09 cm. The final femoral difference in those not having arrest, which is indicative of the extent of spontaneous correction, averaged 0.92 cm. As the maximum femoral difference was 1.18 cm and the final difference 0.92 cm, the average spontaneous correction was 0.26 cm.

D. Maximum Tibial Discrepancy The average maximum tibial difference in all cases was 0.93 cm. In those not having arrest the average was 0.84 cm, and in those having arrest it was 1.28 cm. The final tibial difference in the nonarrest cases averaged 0.30 cm, indicating average spontaneous correction of 0.54 cm. The time of maximum femoral discrepancy rarely coincided with the time of maximum tibial discrepancy.

E. Developmental Patterns of Discrepancies in Legg-Perthes Disease When the extent of the discrepancy in centimeters was charted in relation to age, it became evident that not all discrepancies had increased continually with time. A series of patterns of the developing discrepancies was identified and a classification made. These were presented initially as types A, B, C, and D, but are referred to here using Developmental Pattern Classification types 1-5 from our review of several

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CHAPTER 4 ~ Legg--Calve--Perthes Disease

disorders causing lower extremity length discrepancies. The type 1 developmental pattern group (discrepancy increasing continually with time) occurred in 21, the type 3 pattern in 60, the type 4 pattern in 10, and the type 5 pattern in 49, in which the discrepancy occurred, reached a plateau, and then partially or completely corrected without surgery. The marked slowdown of growth in the femoral head in Legg-Calve-Perthes disease associated with necrosis, subchondral fracture, and collapse leads to shortening, the occurrence of which has been recognized for decades (172). The average maximum femoral and tibial shortening in all patients was 2.14 cm. In the 21% of patients who eventually had epiphyseal arrest to correct discrepancies, the average maximum femoral and tibial discrepancy was 2.99 cm. A significant contribution to the lower extremity shortening in this series was from the ipsilateral tibia, with the average maximum tibial discrepancy being 0.93 cm due to disuse related to unilateral immobilization during treatment. The large majority of patients in this series were treated with the abduction patten bottom splint for 1.5-4 years, with good correlation noted between the tibial discrepancy and the time of immobilization. This study demonstrated that the repair process alone can lead to meaningful correction of discrepancies. When the discrepancies were plotted against age, differing developmental patterns were outlined, referred to as types 1, 3, 4, and 5, and illustrated by four case studies. The pattern types relate directly to the disease and repair phenomena rather than to skeletal age. The four patterns seen indicate that careful continuing assessment of lower extremity length discrepancies should improve long-term results. A good correlation was found between the average age at presentation and the final developmental pattern of the discrepancy that developed. In the type 1 pattern the discrepancy continues to increase with time. The average age at presentation in this type was the oldest of the four groups at 8.7 years. The older patients have a relatively larger amount of necrosis and, more importantly, less time for repair. The type 5 pattern, in which the discrepancy was corrected partially or entirely by the repair process, was associated with the youngest average age at presentation at 5.3 years. In these patients there was adequate time to allow for generally excellent repair to occur. In type 3, in which the discrepancy reached a plateau, the average patient age at presentation was intermediate between that of types 1 and 5 at 6.5 years. These numbers do not represent absolute correlations; they do, however, provide an indication of how awareness of the developmental pattern classification can help in determining the outcome of discrepancies with time. The type 4 pattern, if not appreciated, can worsen a discrepancy just before skeletal maturation due to premature closure of the proximal femoral capital epiphysis. There were 10 instances of this phenomenon documented when both femoral and tibial measurements were plotted. The femoral discrepancy alone showed this conformation in 14 (10%). Much of the type 5 pattern in which correction

occurs, or at least spontaneous correction that removes the discrepancy from the clinically significant group, appears to be due to the release of unilateral immobilization at the termination of therapy. The discrepancies in this group of patients are partially due to growth slowdown relating to the proximal femoral capital epiphysis, but some of the discrepancy also is due to growth slowdown in the distal femoral and both tibial physes in relation to prolonged unilateral immobilization. This phenomenon also was well-documented by Willner (285). He reported on 55 patients with unilateral LeggPerthes disease who were treated by crutches and slings, such that there was unilateral unloading while the opposite limb continued with full function. Subsequent growth studies from the beginning of treatment, throughout treatment, and continuing for as long as 5 years following treatment showed that shortening caused by the deformation of the femoral head remained unchanged, but shortening caused by immobilization of the femur distal to the greater trochanter and the tibia corrected with time. When treatment began, no observable difference in leg length could be found in most of the cases. As expected, however, the affected legs of all cases were shorter during the treatment and this shortening became more marked as treatment continued. The study then concentrated on growth changes in lower extremity lengths of the femur distal to the trochanter and the entire tibia with time. The shortening in the limb distal to the trochanter of the femur was at a mean of 8.0 mm and that in the tibia was 7.9 mm at the completion of treatment. At the beginning of treatment the mean discrepancy was only 1.7 mm short, but at 6-month intervals until 36 months of age the shortening continually increased from 6.3 to 10.3 to 17.8 to 18.8 to 22.0 mm at 36 months. Once the immobilization was released, there was an equally impressive diminution in leg length discrepancy with time. Six months after the end of treatment the discrepancy had decreased to a mean of 16.7 mm, and at 12-month intervals the value continued to diminish to 12.9, 9.9, 8.6, 4.6, and 4.2 mm at 60 months. Their illustrations fully confirm the existence of the type 5 pattern also noted in our study. Those 31 patients having distal femoral epiphyseal arrest had an average maximum total femoral and tibial discrepancy of 2.99 cm, with a final total discrepancy averaging 1.27 cm. The existence of a large head with lateral extrusion or subluxation was such that the physician planning arrest frequently wished the involved extremity to remain slightly shorter such that, in gait, head coverage would be greater. The sluggish skeletal age maturation appeared to have made timing prediction more difficult than in other diseases, and failure to appreciate the differing developmental patterns outlined here on occasion led to inaccuracies in timing. This was especially true with type 4 patients in which arrest occasionally was done late or not at all, with the end stage increase in discrepancy missed due to failure to appreciate the early closure of the proximal femoral plate. Change in

SECTION IX ~ Prognostic Indicators During the Active Disease Process

the femoral head-greater trochanter relationship is an early radiologic indicator of this occurrence.

IX. P R O G N O S T I C I N D I C A T O R S D U R I N G THE ACTIVE DISEASE PROCESS

A. General Considerations The prognosis in Legg-Calve-Perthes disease is extremely variable, ranging from reestablishment of a completely normal hip to development of a fiat misshapen head with a complete lack of congruency with the adjacent acetabulum. The treatments used also are quite variable, ranging from observation only in very young patients of 3 or 4 years of age, to long-term bracing, to femoral or pelvic osteotomy. Great efforts have been expended in attempting to define, during the active phase of the disease, what the ultimate prognosis will be so that observation alone will not be prolonged in those who could benefit from more active intervention, and, equally importantly, long-term bracing or surgery will not be done in those who might be expected to heal relatively uneventfully with minimal to no intervention. In spite of extensive efforts, however, to correlate various radiographic parameters with the eventual outcome, one of the most helpful predictive factors remains the age of occurrence of the disorder. There is not an absolute correlation between the age of occurrence and the end result, but this clinical feature still remains the simplest and best indicator. At the time of initial occurrence of the disorder, by which is meant the time of the vascular insult, plain radiographs would be perfectly normal. Currently it is possible to diagnose the disorder at the earliest stage on the basis of a negative bone scan in which the involved side shows no uptake in the secondary ossification center of the proximal femur. The condition only rarely is diagnosed at this stage currently because it usually is brought to medical attention by clinical hip or thigh discomfort with a several-week to -month history, by which time early plain radiographic changes have occurred. At the time of disease occurrence, however, we have no ability to project the future outcome other than the age of the patient at the time. The various radiographic classifications that have evolved have as a major weakness the fact that the disease process is well underway and usually well into the repair stage at the time that the radiographs are taken. Classification by radiographic appearance alone does not distinguish the age of the patient or the stage of the repair process. Two-dimensional radiographs are imperfect in estimating the three-dimensional geometric shapes of the femoral head-acetabular relationships. Another problem is the clinical demonstration that one does not need perfectly normal hip structure at skeletal maturity to assure several decades of normal pain-free function. Several categorizations have been developed over the past three decades, which are designed to provide prognostic

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and treatment guidelines. The simplest approach involves the age at which the initial disease occurs. Other plain radiographic categorizations have provided much useful information in assessing the evolution of a Perthes condition but still lack total specificity in terms of directing therapy as they tend to provide information in the revascularization and residual phases of the disorder. Thus, they have a tendency to define what has already occurred rather than defining, early on, what will occur.

B. Age of Occurrence of the Disease The age at which the Legg-Calve-Perthes disorder occurs remains the single best prognostic indicator of the outcome. Although there is not an absolute correlation, the best results occur in those developing the disorder at the younger end of the spectrum at ages 3, 4, and 5 years, and the worst results occur in those developing the disorder at the older end of the spectrum from ages 10 to 13 years. Ippolito et al. reported on an adolescent group developing Legg-Perthes from 13 to 15 years of age. All developed pain and restriction of motion between skeletal maturity and 39 years of age (130). Many other reports have documented that, when the disorder develops in late childhood or adolescence, the long-term resuits usually are poor. It is those who develop the condition between the ages of 6 and 9 who have the widest variation of end results and who represent the group in which more precisely defined treatment could allow for the most optimal results. Even within this relatively narrow age group, it is those acquiring the disorder at 8 or 9 years that have the poorer prognosis. Vila Verde et al. noted that, in children older than 9 years of age, the results invariably were poor irrespective of the head at risk criteria of Catterall or treatment measures (274). The observation that the younger ages of occurrence predisposed one to a better result is one of the most uniform in Legg-Perthes studies, a field in which great diversity of opinion is common. The work of Snyder points this out but also reminds us that deformed femoral heads are seen after repair even in those 5 years of age and younger (253). The explanation for the finding appears to rest on the fact that the younger the patient the greater the relative amount of cartilage epiphyseal tissue present compared to bone in the femoral head. The amount of bone to be repaired thus is smaller, and because it is the cartilage model that is responsible both for shaping the femoral head and for the subsequent growth, the fact that there is a relatively large amount of cartilage that is less affected by the disorder leads to the improved repair capability. In addition, the greater period of time from healing of the secondary ossification center to skeletal maturity allows the remodeling capability of femoral head and acetabular cartilage to assert itself. In contrast, the poorest results occur in the older age groups, at which time the proportion of secondary ossification center bone in relation to epiphyseal cartilage is much greater and the converse

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CHAPTER 4 ~

Legg--Calve--Perrhes Disease

situation applies, with far more bone to be repaired and far less cartilage available to serve either as a preventative to collapse or as a source for head shape remodeling. In those with excellent or good long-term results, the acetabulum has molded itself to the slightly irregular shape of the head allowing for a situation referred to clinically as congruency, which appears to have a major saving effect in terms of eventual osteoarthritis. The acetabulum in particular loses its capacity for shaping responses toward the end of the first decade.

C. Plain Radiographic Classifications Three major categorizations have been developed over the past two decades primarily based on the appearance of the femoral head during the revascularization phase (40, 117, 237). These are referred to widely, provide much useful information about the response of a particular femoral head to the Legg-Perthes disorder, and have been the focus of numerous studies designed to correlate the eventual outcome with the findings of the classification. The three most commonly used categorizations are those of Catterall (40) and Salter-Thompson (237) and the most recently described lateral column classification of Herring et al. (117). There are major problems, however, with these categorizations both in theory and, as clinical studies continue to show, in correlation with eventual outcomes. Each of the three categorizations uses a plain radiographic approach. There are high interobserver differences in gradings particularly with the Catterall classification. In each of the three there is clear potential for the change of classification with temporal progression of the disease. The major shortcoming of these approaches is that they focus on the bone pattern of the secondary ossification center of the femoral head, whereas the final outcome of any Legg-Perthes disorder is dependent primarily on the shape of the cartilage model of the head. During the stage of the evolution of the disorder, the cartilage model is much larger than the secondary ossification center, and frequently abnormal shaping of the secondary center is not reflected in the shape of the cartilage model, which may, and frequently does, remain spherical. Two additional plain radiographic classifications, those of O'Garra (205) and Hirohashi et al. (123), show yet other ways to assess the variable findings. 1. O'GARRA O'Garra commented on the prognostic value of lateral radiographs of the hip in particular (205). The lateral view demonstrated the disorder earlier and more accurately than the anteroposterior view. Two basic patterns of Perthes were defined: (1) an "anterior" group, in which the anterior onehalf or two-thirds of the head of the femur was affected and any metaphyseal changes if present were in the anterior onethird of the neck, and (2) involvement of the whole epiphysis, in which the whole femoral head was affected. O' Garra

indicated that Perthes disease in which only the anterior part of the head was involved had a good prognosis, although those with full head involvement had a poorer prognosis. This concept was later expanded in particular by Catterall to a more inclusive consideration. 2. CATTERALL CLASSIFICATION The Catterall classification is based on an interpretation of the extent of femoral head involvement on both anteroposterior and lateral plain radiographs (40-43). A precursor to this descriptive approach was the definition of two types of Legg-Perthes disease by O'Garra, who noted an "anterior" variant and a "whole head" variant. In the former, the anterior one-half or two-thirds of the femoral head was affected as seen best on the lateral radiograph. The healing was far better in those with less than full involvement (Fig. 27). The Catterall classification involves groups I-IV progressing from the most limited involvement to the most extensive involvement. The initial impression was that the prognosis worsened with an increasing grade of classification. There is a considerable element of accuracy to this, but the correlation is not complete and its use as a clinical tool other than for groups I and IV is problematic. Group I: Only the anterior part of the epiphysis is involved. The abnormality is seen most clearly on the frog lateral view, which highlights the anterior from the posterior regions of the head. There is no collapse of the bone or cartilage model of the proximal femur and the height of the epiphysis is maintained. There is complete absorption of the involved segment with no sequestrum formed. Group II: More of the anterior part of the epiphysis is involved than in type I. The involved segment, after a phase of absorption, undergoes collapse although reference is to the bone of the secondary ossification center rather than to any specific assessment of the epiphyseal and articular cartilage. The area of increased bone density, which Catterall refers to as a sequestrum, is central on the anteroposterior projection with medial and lateral bone structure maintained. Group III: Only a small part of the epiphysis is not sequestrated. This invariably refers to the portion that is medial and somewhat posterior. The anteroposterior radiograph demonstrates the "head within a head" phenomenon. It also shows the collapsed central sequestrum with some medial and lateral head continuity seen. Group IV." The whole epiphysis is involved and appears on the anteroposterior view with complete collapse of the epiphysis, producing a dense line. There is flattening of the head. The term epiphysis refers to the secondary ossification center. On the lateral radiograph there is no viable posterior segment. Metaphyseal changes may be extensive. A theoretical critique of the Catterall classification is easy to make, although it in no way diminishes the value of the work in providing a previously nonexistent framework for study of the disorder. If one considers the evolution of the disorder, then at the initial moment of osteonecrosis the plain

SECTION IX ~ Prognostic Indicators During the Active Disease Process

oup I ,

325

G r o u p II

9

"

%

No metaphyseal reaction No sequestrum No subchondral fracture line

Sequestrum present--junction clear Metaphyseal reaction~ antero/lateral Subchondral fracture line--anterior half

F.

!.,',

~ I

Group

~up

t

Sequestrum m large m junction sclerotic Metaphyseal reaction m diffuse antero/lateral area Subchondral fracture line ~ posterior half

Whole head involvement Metaphyseal reaction m central or diffuse Posterior remodelling

FIGURE 27 The Catterall classification involves groups I-IV. [Reprinted from Catterall, A. (1981). Clin. Orthop. Rel. Res. 158: 41-52, 9 LippincottWilliams & Wilkins, with permission.]

radiograph will show a normal appearing secondary ossification center. Thus, at the initial time of occurrence no prognostic feature is truly available, assuming an X ray is done at this stage, because all will be graded as class I or even appear to scarcely allow a diagnosis to be made. As noted in the earlier sections of this chapter, the radiographic changes of the secondary ossification center that ensue are a result not only of the osteonecrosis but also primarily of the repair response in which new bone is laid down on old bone, resorption of necrotic areas is occurring more or less simultaneously, and shaping changes of the cartilage model of the femoral head occur. If one looks at virtually any sequential series of X rays from a patient with Legg-Calve-Perthes disease, it is not infrequent to note that the classification would change depending on the time the radiograph was taken in relation to the disease stage. If one considers the initial appearance in which the secondary centers essentially are normal and then the appearance of a group IV lesion, it is evident that the head does not collapse overnight to a flattened radiodense image but rather goes through a series

of changes that essentially would move the patient through groups II and III. The Catterall classification rating given thus may well be dependent on the time the radiograph was taken during the disease process rather than the extent of involvement. The classification is helpful for those individuals who do not progress beyond group I or II. It can be difficult to determine, however, during the course of the disorder whether an individual is in a type II categorization as the final extent of involvement or simply is passing through this stage to a worsening type. Van Dam et al. used the Catterall classification to assess 50 hips with Legg-Perthes (272). The rating changed in 40% of the hips when they were classified before they had reached the fragmentation stage compared with only 6% changing when classified after fragmentation. In conjunction with this categorization, Catterall developed "head at risk" signs, which were considered indicative of a worsening prognosis. Although some of these signs may indicate a poor prognosis, their consideration in relation to the underlying pathoanatomy indicates that they may not

326

CHAPTER 4 ~ Le~tf--Calve--Perthes Disease

necessarily have such a poor prognosis. He defined four "head at risk" signs. (1) The Gage sign: This was defined by Catterall as a small osteoporotic segment, which forms a radiolucent " V " notch on the lateral side of the epiphysis. As noted earlier, Gage originally described lysis leading to convexity of the upper-outer border of the femoral neck as being an early radiologic sign of Perthes disease. This may not always be a head at risk sign, because revascularization occurs from the lateral and posterior aspect of the head and neck region from the retinacular vessels concentrated there, and because the initial response is resorption of the necrotic bone, it is not surprising that early lysis tends to predominate in this region. (2) Lateral subluxation: As noted earlier it frequently is unclear whether the radiologic appearance described as lateral subluxation represents a true subluxation in terms of displacement of the head of the femur in relation to a normal acetabulum, which presumably would occur due to the head being pushed out of the acetabular space by increased fluid or synovium, or whether it represents a lateralization appearance of the bone of the neck and secondary ossification center, with the enlarging radiolucent cartilage model of the head giving the appearance of a subluxed position. If the latter is the case, then the so-called lateral subluxation is not a true displacement but rather indicative of the development of a coxa magna. As Stulberg has shown, an isolated coxa magna is not a bad prognostic sign particularly in those situations in which the acetabulum is changing its shape to relate to the enlarged femoral head. (3) Calcification lateral to epiphysis: Catterall uses the term epiphysis to refer to the secondary ossification center. Lateral calcification is not surprising because in the vast majority of patients with Legg-Calve-Perthes disease the cartilage model of the head is larger than the normal side and early new bone repair formation tends to occur laterally because that is the earliest point of ingress of repair vessels. (4) Angle of the epiphyseal line: By this term, Catterall refers to the orientation of the epiphyseal growth plate, which normally has a slight obliquity to it. In many patients with Perthes, the line casts a horizontal radiographic shadow because of the fact that the medial one-third of the physis maintains its growth, whereas the lateral two-thirds tends to show growth diminution. An additional or fifth "head at risk" sign has come to be attributed to Catterall; this is defined as metaphyseal cysts or diffuse metaphyseal reaction by others. Studies have been performed in relation to the value of the head at risk concept in assessing prognosis. Vila Verde et al. assessed 75 hips with the Perthes disorder followed to skeletal maturity and concluded that patients with "head not at risk" had better results regardless of treatment (274). In children greater than 9 years of age, the results almost invariably were poor irrespective of head at risk designation. Within the younger age group, however, the presence of head at risk findings tended to worsen prognosis particularly with an increased number of findings. The group assessed head at risk signs involving lateral subluxation, lateral ossi-

fication, the Gage sign, and metaphyseal cysts, although the horizontal plate was not assessed in detail. They felt that lateral subluxation, present in 41 hips, and lateral ossification, present in 34 hips, were the most relevant signs of head at risk, particularly in the 31 hips in which they occurred together. The Gage sign was relatively rare, and metaphyseal cysts, though present, were not felt to relate to ultimate prognosis. They felt that within the head at risk group, in particular those under 9 years of age, results were improved significantly with varus derotation proximal femoral osteotomy. The head not at risk group was concentrated in the younger patients. Murphy and Marsh also assessed head at risk factors in relation to prognosis using each of the five criteria (200). Twenty-eight patients were assessed. The most common risk factor was lateral subluxation, with diffuse metaphyseal reaction being the least common. The most common risk factor with a poor result was lateral subluxation. No absolute correlations were noted, but in general those with 3-5 risk factors had a poorer prognosis than those with 0 - 2 risk factors. In the latter group, there were 11 good results, 3 fair results, and 1 poor result. They found classification by the Catterall degree of epiphyseal involvement approach to be difficult in particular at the time of initial diagnosis because the classification tended to change as the disease progressed. On the other hand, they found the five head at risk factors to be more accurately predictive of the course of Perthes disease. Dickens and Menelaus found the Catterall groupings to be applicable in the senses that a spectrum of group I-IV abnormalities could be defined reliably with good agreement between different observers and that groups I and II had a much better ultimate prognosis than those defined as groups III and IV (61). They did note changes with time in the group, however, and felt that the final gradation could not be determined definitely often for a period of up to 8 months from presentation. They also assessed their patients by the head at risk criteria and found, similar to others, that the factors most frequently indicating that the result would be poor were lateral calcification and lateral subluxation or displacement of the femoral head. The horizontal epiphysis was not felt to be of correlative value.

3. SALTER-THOMPSON SUBCHONDRAL FRACTURE CLASSIFICATION This classification is based on the impression that only that part of the epiphysis (secondary ossification center) underlying the subchondral fracture eventually is resorbed (237). The extent of the subchondral fracture thus is felt to represent an important early indicator of the eventual amount of femoral head bone involvement. Only two groups are defined in this categorization, with group A showing involvement of less than half of the head and group B showing involvement of more than half of the head (Fig. 28). The subchondral crescent when present can be seen on both anteroposterior and frog lateral X rays, although the frog lateral

SECTION IX ~ P r o g n o s t i c Indicators D u r i n g

ANTERIOR-POSTERIOR

LATERAL

ANTERIOR-POSTERIOR

LATERAL

MAXIMUM RESORPTION

MAXIMUM RESORPTION

~

ANTERIOR

ANTERIOR-POSTERIOR

327

SIJBCHONDRAL FRACTURE

B

SUBCHONDRAL FRACTURE

the Active Disease Process

SUPERIOR

LATERAL

ANTERIOR-POSTERIOR

R

)

SUPERIOR

LATERAL

SUBCHONDRAL FRACTURE

C

SUBCHONDRAL FRACTURE

ANTERIOR-POSTERIOR

LATERAL

ANTERIOR-POSTERIOR

LATERAL

MAXIMUM RESORPTION

\

MAXIMUM RESORPTION

~~

~iOR

ANTERIOR ANTERIOR-POSTERIOR

LATERAL

SUPERIOR

ANTERIOR-POSTERIOR

LATERAL

SUPERIOR

FIGURE 28 The Salter-Thompsonsubchondralfracture classificationis shownin parts (A-D). In each illustrationthe subchondral fracture line is shown along with the adjacent necrotic area, which is determinedon the basis of the extent and position of subchondral radiolucency. [Reprintedfrom (237), with permission.]

is somewhat more helpful in providing documentation using this approach. Limitations of this categorization also have become apparent with time. In large clinical studies, including that of the original description, only about 50% of patients have radiographs during the course of their assessments that demonstrate the subchondral crescent. This radiographic finding is not present for very long and in many patients has disappeared by the time of initial X ray. In some it may never occur. The sign also is dependent to a certain extent on the plane of the radiographic projection. In routine clinical instances only two radiographs are taken, and the subchondral sign can be missed unless the defect is relatively large. For those wishing to use this indicator it would appear mandatory to take multiple radiographic projections, perhaps even under fluoroscopic assessment, to detect any lucent crescent that is present. MR imaging has a greater likelihood of detecting subchondral fracture. Studies from other centers

show poor correlation of the sign with ultimate outcome, even though the initial paper indicated that "in all hips the extensive subchondral fracture correlated precisely with the subsequent extent of maximum resorption." 4. LATERAL PILLAR CLASSIFICATION: HERRING E T AL. This plain radiographic classification is based on the observation that fragmentation of the secondary ossification center in Legg-Calve-Perthes occurs in distinct anatomic sectors of the femoral head (117). The head is divided into three sectors or pillars: the lateral, middle, and medial regions. By fragmentation the authors are referring to what we have defined as interspersed areas of lysis. This classification divides the patients into A, B, and C categories during the fragmentation stage of the disease (Fig. 29). In group A there is no involvement of the lateral pillar, which is

CHAPTER 4 9 Le99--Calve--Perthes Disease

328

Lateral Pillar Classification of Legg-Perthes Disease

Normal Assessed

Group B

Group A

Group C

in fragmentation stage from antero-posterior hip radiograph

Group A Group B Group C

F I G U R E 29

Height of lateral pillar normal Height of lateral pillar > 50% Height of lateral pillar < 50%

The lateral pillar classification of Herring et

al.

radiographically normal. In group B more than 50% of the lateral pillar height is maintained, and in group C less than 50% of the lateral pillar height is maintained. Many of the criticisms directed against the previous two categorizations also apply here. The phenomenon being assessed is the bone of the secondary ossification center, whereas the shape of the cartilage model, which cannot be determined in plain radiographs, is not addressed. It is well-known that cartilage shape does not correspond during the developing stages of a Legg-Perthes disorder with the shape of the secondary bone center. Because the categorization is made during the fragmentation stage, which is well into the repair phase, it essentially documents what has already occurred rather than acting as an early prognostic determinant. If we again consider the example of a patient diagnosed very early just after the osteonecrotic insult, the lateral pillar classification would be grade A. As resorption occurs progressively over time,

none

epiphvsis

!

5. HIROHASHI ET AL. Hirohashi et al. developed a classification for Perthes dis-

ease based on the extent of both epiphyseal and metaphyseal involvement as indicated in lateral hip radiographs (Fig. 30) (123). They felt their results correlated well with the classification, with the greater the extent of involvement of both epiphysis and metaphysis, the more severe the end result.

2

I

taphysis

the patient would slip into the grade B and then grade C classifications. The paper indicates specifically that the classification does not change during the course of the disorder. If one accepts the accuracy of the example we gave earlier, it is hard to see how this can be true. Classification is not possible at the time of an initial film. Nevertheless, if the patient does not advance beyond stage A, then follow-up would indicate that involvement was less severe, and certainly if the patient is in group C then by definition involvement is severe. However, if a patient is diagnosed in category C at the time of the initial radiograph, then the categorization is not indicating what will happen but rather what has already happened. The Herring et al. group felt that interobserver reliability was highest for their classification system, lower for the Catterall classification, and lowest for the head at risk determinations. Farsetti et al. have assessed retrospectively radiographs of 49 patients at the stage of fragmentation and again at skeletal maturity (74). They found the classification to be relatively easy to apply and reliable if the radiograph for assessment is at the fragmentation stage of the disease. A total of 10 of 11 group A hips showed good reconstruction of the femoral head. Good results were noted in group B hips when the patients were less than 9 years of age at diagnosis, and all 11 group C patients showed hip deformity at follow-up.

or

slight

( ~ > in width)

( > ]/z in width)

mild

(< '2) !-I

!!

3

extensive

moderate

!-3

!-2

/y

moderate

(, ._,) !1-1

I! - 2

Iii - 1

ill - 2

~ 1 1 _ 3

severe

!!!

total

III - 3

F I G U R E 30 The extent of epiphyseal and metaphyseal involvement as indicated in lateral hip radiographs is the basis of the classification of Hirohasai et al. [Reprinted from Hirohasai et al. (1980). Internat. Orthop. 4:47-55, copyright notice of Springer Verlag, with permission.]

SECTION X 9 Results Based on Appearances at Skeletal Maturity

They also used their categorization to influence treatment approaches. Categorization follows the "the worse it is, the worse it will be" approach. The epiphyseal abnormality was defined as mild (I), moderate (II), and severe/total (III) types, whereas metaphyseal involvement was defined as none/ slight (1), moderate/less than one-half the width of the metaphysis involved (2), and extensive/greater than one-half the width of the metaphysis involved (3). A grouping of nine possible gradations was then formed with, for example, moderate epiphyseal and moderate metaphyseal involvement being graded a 11-2 type.

6. MINIMALPERTHESDISEASE Herring et al. noted a small subset of patients, 12% (24 of 193), with focal Perthes disease and a benign natural history (116). A total of 10 of the 24 had only anterior head involvement as described by O'Garra and by Catterall as group I. Other areas noted, however, were 7 posteromedial, 3 lateral, and 4 central. There was no sequestrum formation or collapse, and the localized density changes resolved as in more extensive patterns of involvement. Patients had either no treatment or relatively brief brace treatment.

D. Comparison of Classification Schemes Efforts have been made to compare the validity of the various plain radiographic classification schemes. It is important to recognize that, whereas the classification schemes themselves are subjective, comparisons between them are even more so. Nevertheless, because the ultimate value of any classification scheme is the ability of a wide group of individuals to use it in a clinically valuable fashion, such reports are of interest. Mukherjee and Fabry compared the assessment of 116 hips with Legg-Perthes disease using both the Salter-Thompson and the Catterall classifications in relation to their prognostic value at the end of the disease process (199). They felt that both of the classifications had a high degree of prognostic significance. They also assessed the Catterall head at risk factors, which involved the Gage sign, metaphyseal reaction, calcification lateral to the epiphysis, horizontal line of the growth plate, and lateral subluxation. Other major problems of interpretation occur because the patients were treated by three different modalities, including no treatment, plaster abduction casts, various types of braces, and proximal femoral varus osteotomy. Mukherjee and Fabry found that the Salter-Thompson classification was easier to make and valued its use to form the basis of decisions on management particularly in the early stages of the disease. In terms of prognostic importance, they felt that the Salter-Thompson group A could be considered almost equal to Catterall groups I and II and Salter-Thompson group B to Catterall groups III and IV. A high correlation coefficient thus was established between the two classifications. In spite of all findings, however, they reached the conclusion that it was the age at presentation and the lateral subluxation of the femoral head that were the most important adjuncts in decid-

329

ing between conservative or surgical containment. Mukherjee and Fabry felt that the Salter-Thompson classification could not be done on 22 hips (of 116) because early radiographs were unavailable. This would indicate that the SalterThompson classification was possible in approximately 80% of cases, which was much higher than that reported by Catterall at 25% and others at 59%. Ritterbusch et al. compared the predictive value of the lateral pillar classification with that of Catterall (232). They felt that the lateral pillar classification was a significantly better predictor of Stulberg outcome than the Catterall classification. Christensen et al. (48) and Hardcastle et al. (101) both reported low degrees of interobserver agreement when using the Catterall approach and questioned whether the classification should be used to form the basis of treatment decisions.

E. More Recent Clarifications of Poor Prognostic Signs With increasing study, early radiographic signs of poor prognosis in Perthes disease are becoming better defined. The use of the term early is relative; in a sense these findings are indicative of a fairly advanced pathological process and they reflect as much a delay in appreciation of the disorder or rapid advancement of the disorder as they do of the fact that the condition is being analyzed shortly after its development. The first finding of negative prognostic value is that of hinge abduction. Definition of this occurrence is aided greatly by the use of arthrography, which allows for examination of the range of motion of the hip under fluoroscopic control and thus demonstrates the hinge effect with the extremes of abduction. The second group of negative findings defined by Yrjonen et al. includes (1) lateral calcification extending far laterally outside the epiphysis toward the greater trochanter; (2) deformation and widening of the femoral head before the fragmentation stage; (3) deformation and widening of the femoral neck in the initial phases of the disease; (4) early sclerotic changes in the metaphysis; and (5) a sclerotic secondary center surrounded by a ring of less dense repair tissue (290). Most observers would agree that points 1-3 are indicative of a marked disorder, although the changes described in points 4 and 5 can be seen in cases that subsequently heal with minimal negative sequelae.

X. CLASSIFICATIONS DEFINING RESULTS BASED ON APPEARANCES AT SKELETAL MATURITY AT THE END OF REPAIR A. General Considerations The long-term effects of childhood Legg-Calve-Perthes disease have been determined by several excellent clinical studies. It is evident that imperfect looking hip radiographs can still be compatible with a full or virtually full normal functioning of the hip throughout the patient's early and mid-adult

330

CHAPTER 4 ~ Le~tg--Calve--Perthes Disease

life. It is essential to take these studies into consideration and expand them by additional studies. Of the residual radiographic findings in Legg-Perthes disease at skeletal maturity, there is good agreement that a widened femoral neck is of no prognostic or functional significance concerning ultimate arthritis. Coxa magna often has been presumed to be a bad prognostic sign, but long-term studies indicate that in certain conditions coxa magna itself has no long-term deleterious effects. If the coxa magna is associated with a spherical head, which relates in a congruous fashion to an also somewhat enlarged acetabulum, minimal to no long-term problems occur. The early presence, therefore, of an apparently laterally subluxed head and calcification lateral to the outer border of the acetabulum may not necessarily be longterm poor prognostic signs if the cartilage model of the head remains in an appropriate shape and relationship to the associated cartilage model of the acetabulum. If the coxa magna is associated with a coxa plana, then a poorer longterm result can be expected. If a coxa plana persists at skeletal maturity, the overlying articular cartilage will not conform to the acetabulum and future problems can be expected. A minimal coxa vara, if associated with a round femoral head in relation to an appropriately shaped acetabulum, should not produce any problem. It may produce a mild Trendelenburg gait, but this should be readily controllable with either abductor muscle strengthening, epiphysiodesis of the greater trochanter, or distal transfer of the greater trochanter at skeletal maturity.

B. Sundt Classification One of the earliest classifications of the end result of a LeggPerthes disorder is that of Sundt based on 172 hips (261). He defined the shape of the femoral head into four categories: (I) spherical, (II) oval, (III) cylindrical, with or without hypertrophy of the greater trochanter, and (IV) quadrangular. Sundt considered categories I and II to represent favorable results, III less favorable, and IV unfavorable. He reviewed the long-term results from 172 hips, providing one of the earliest and most detailed assessments of the evolution of the disorder. He recognized that it was malformation of the head and neck of the femur that was the primary determinant of a poor result, with acetabular deformity occurring secondarily. In these cases, the end result would be an osteoarthrosis "evoked by the incongruence of the articular surfaces" of the femur and acetabulum. The whole purpose of treatment was to prevent deformation of the upper end of the femur and thereby "avoid an incongruity between the articular surfaces."

C. Quantitative Indices of Femoral H e a d - Acetabular Repair Extensive efforts have been made to quantitate the outcome of a Legg-Perthes disorder.

1. MOSE CONCENTRIC CIRCLE TEMPLATE METHOD A well-accepted index of sphericity of the head is that developed by Mose (198). He used a concentric circle template, with each circle separated by 2 mm, which was placed over a radiographic image of the femoral head from anteroposterior and lateral projections. The Mose template method is designed to assess the shape of the head in its entirety to determine whether it was spherical, and if not then the relative degree of deformity. To be classified as spherical with a good result, the surface of the head must follow the same circle on the template with no variation in both frontal and lateral views. Variation up to 2 mm is considered a fair longterm result, and a head with variation greater than 2 mm is considered poor (Figs. 31A-31C). Additional indices were used particularly when nonsphericity was present. A number of ratios were established. 2. EPIPHYSEALINDEX (EYRE-BROOK) The epiphyseal index describes the proportion between the height and width of the epiphysis (secondary ossification center) x 100 (Figs. 32 and 33) (72). For children under the age of 7 years, the normal is 45-55; for those over 7, it is 35-45. The epiphyseal index of Eyre-Brook expresses the flattening of the epiphysis and registers the height of the epiphysis from the growth plate to the highest point of the epiphyseal surface contour divided by the width of the epiphysis. 3. EPIPHYSEAL QUOTIENT (SJOVALL) This value is derived by comparing the height and breadth of the involved epiphysis (epiphyseal index) with that of the uninvolved contralateral side (Fig. 33) (251). Sjovall converted the epiphyseal index to an epiphyseal quotient by dividing the epiphyseal index of the affected head by that of the uninvolved side. A good result is between 75 and 100%, fair is 50-75%, and poor is less than 50%. Mose and others interpreted an epiphyseal quotient of 60% to be the dividing point between normal sphericity (greater than 60%) and an abnormal flattened (less than 60%) state. 4. ACETABULAR-HEAD INDEX (HERNDON AND HEYMAN) The acetabula-head index is that part of the femoral head ossific nucleus covered by the bony acetabulum divided by the entire ossific nucleus • 100 (Figs. 34A and 35) (115, 122). MR imaging has been used to assess the cartilage model of the femoral head covered by the cartilaginous lateral acetabular margin divided by the entire cartilaginous width of the head x 100 by Sales de Gauzy et al., and arthrography has assessed the same parameters (Moberg et al.) (Fig. 35). 5. COMPREHENSIVE QUOTIENT (HERNDON AND HAYMAN) Herndon and Hayman developed a comprehensive quotient composed of values from the epiphyseal quotient (the height and length of the epiphysis), the head-neck quotient

SECTION X

A

~

9

Results Based on Appearances at Skeletal Maturity

331

SUBJECT-R.K.
50 ~)

treated by the same method. The Dunn procedure was more effective in those with severe slips displaced greater than 50 ~ The Kramer osteotomy provides correction of 50 ~ and the Southwick procedure correction of 60 ~ Carlioz et al. reviewed operative intervention for SCFE in 80 cases (43). They detailed their guidelines, from earlier studies which involved in situ fixation for displacement less than 30 ~ in situ fixation followed by corrective osteotomy at the intertrochanteric level for those in which there was 3060 ~ displacement; osteotomy through the femoral neck (cervical osteotomy, Dunn procedure) for displacement between 60 and 90 ~, and closed reduction and screw fixation for acute slipping. In no instances was casting used. When the open reduction and cuneiform osteotomy were used, they reported 20 good results, 3 fair, and 4 poor. There was relatively little use of the intertrochanteric osteotomy, but results in 5 cases were 4 good and 1 poor. In the open reduction cases, of the 4 poor results, 3 involved cases of chondrolysis. Carlioz et al. concluded that the open reduction with cervical osteotomy was "difficult and dangerous" and that it should be used rarely and only in those with extreme displacement. They ultimately recommended the triplanar trochanteric procedures as being much safer. They revised their earlier protocol recommending the open reduction only for slipping of 90 ~ or greater with the growth plate open. With such a degree of severe deformity with the growth plate closed, intertrochanteric osteotomy was mandatory. Carlioz et al. supported the belief that AVN never occurred spontaneously in the natural history of slipped epiphysis and that it essentially was always a complication of intervention. Chondrolysis could occur spontaneously but generally was associated with management involving such criteria as closed reduction, penetration of the screw into the joint cavity, excessive immobilization in cast, or excessive degrees of valgus or flexion during corrective osteotomy. There are two possible times of intervention for any compensatory osteotomy. One approach is to do both head-neck stabilizing and repositioning procedures at the same time. The other is to perform an in situ stabilization pinning and then wait several months before performing the corrective osteotomy. The latter approach is preferable in the view of some for two reasons. Most importantly, the complication of hip stiffness has been reported when osteotomy is done at the same time as pinning. In addition, some patients do not find the slight external rotation position of the lower extremity either cosmetically or functionally troubling and elect not to proceed with repositioning osteotomy. It will be important for clinical studies to determine the long-term sequelae of leaving moderate and even severe slips without corrective osteotomy. Examples of osteotomy to correct severe deformity are shown in Figs. 18B-18D. Conflicting Approaches to Treatment in Moderate and Severe Slipped Capital Epiphysis: No universal agreement has been reached concerning the treatment of moderate and severe slipped capital femoral epiphysis. Many still recommend pinning in situ of a slipped epiphysis regardless of its

SECTION II 9 Slipped Capital Femoral Epiphysis

extent followed by observation of the patient and performance of compensatory osteotomy at a later date and sometimes only with meaningful symptoms as an indication for intervention. Many patients handled under this approach, therefore, wouldhave the pinning alone with no osteotomy ever performed. This is particularly true in moderate slips. The tendency to need surgical realignment is greater with the severe slips, but even here some centers have allowed patients to go without correction and noted relatively minimal long-term symptoms. Postpinning remodeling: Pinning alone particularly in moderate slips relies on the fact that patients can compensate on their own for the mild to moderate deformity, often with the position somewhat improved by remodeling of the headneck region in association with repair and continued use. O'Brien and Fahey showed how femoral neck remodeling improved the radiographic appearance of the proximal femur several years after pinning in situ (201). A large number o f their patients were treated only by pinning in situ. In a subgroup of 12 patients with moderate and severe displacement assessed 2-17 years postpinning, all but 2 had satisfactory remodeling of the head and neck and were asymptomatic. Even the 2 with minimal remodeling were asymptomatic. They also noted some spontaneous correction of the external rotation deformities. In those in which failure of remodeling would become a problem, O'Brien and Fahey recommended the cervical osteoplasty of Heyman et al. to improve motion. This approach continues to be used and described even in papers published within the past few years. Bellemans et al. reviewed 59 hips in 44 children with SCFE, all treated by pinning in situ (22). The average clinical and radiologic follow-up was 11.4 years, and they noted 53 hips (90%) to be excellent or good. Their study assessed postoperative remodeling, which was accomplished by local resorption and apposition of bone and also, they felt, by correction of the disturbed anatomic axes in proportion to the severity of the slip along with global thickening of the femoral neck. Resorption of the superolateral prominent portion of the metaphysis of the femoral neck was noted in 54% of cases, and apposition of new bone at the posteroinferior aspect of the neck was seen in 59%. The average frog leg head-shaft angle of Southwick decreased an average of 13.5 ~ from 25 ~ immediately postoperatively to 12.5 ~ at latest follow-up. The AP head-shaft angle decreased an average of 7 ~ from 16~ on the first postoperative radiograph to 9 ~ at latest follow-up. The average thickness of the neck also was increased significantly with time compared with the contralateral normal side. Favorable results could be obtained with pinning in situ due to the global remodeling process because the remodeling was more extensive than had been reported previously. Due to the fact that pinning was felt to have fewer complications than redirectional osteotomies, the simpler procedure provided very satisfactory long-term results due to the remodeling processes. The Southwick lateral head-shaft angle was calculated on the frog leg lateral radio-

429

graphs by subtracting the head-shaft angle on the normal side from that on the affected side. The average slip in this study according to the Southwick criteria was 25 ~ with 56% of the slips mild (60~ Jerre et al. studied hip motion at an average of 32.7 years after SCFE in 128 hips without signs of osteoarthritis (129). They concluded that hips with no treatment or those treated with fixation in situ only showed no clinically significant loss of hip motion as compared with normal hips. The greatest loss of motion of the hips in those treated with fixation in situ was diminution of internal rotation. They concluded that the loss of hip motion after fixation of the epiphysis in situ over the long term was "very slight and hardly clinically relevant" and that there was no indication for early surgical intervention with osteotomy. Siegel et al. studied 39 patients 2 years after pinning in situ for slipped capital femoral epiphysis (238). The study was done to assess range of motion of the hip and femoral remodeling. Although there was considerable increase of motion from the preoperative state, they felt that this motion returned despite minimum bony remodeling. The greatest percentage of motion of the hip returned within 6 months after treatment. This served in particular to increase the amounts of flexion, abduction, and internal rotation. They attributed this increased motion to relief of pain, spasm, and synovitis and to subsequent soft tissue stretching. Plain radiograph and CT imaging studies assessed bone remodeling itself. In spite of smoothing of the contours of the head-neck axis with resorption of bone from the superior surface of the neck and synthesis of bone inferiorly and posteriorly, only minimal change occurred in the relationship of the femoral head to the shaft and no change occurred in the angle between the femoral neck and the shaft after fixation in situ. Remodeling and resorption thus led to a smoothing of the contours of the proximal femur without a change in the axes of the deformed bones. Complications versus long-term values of realignment procedures: Aronson and Karol strongly support the value of pinning in situ for the stable slip regardless of the severity (12). Stabilization of the slip and prevention of AVN and chondrolysis are paramount, and there is no role for early realignment procedures. They stressed that the stable slip will not reduce with intraoperative manipulation and that open reductions still are associated with too many complications. This is the case particularly if osteotomy is done at the same time that the slip is stabilized. Hall found AVN to be the most common cause of a poor result. The percentage with AVN was calculated for each of several treatment groups. The pattern of AVN worsened with the incidence of manipulation and the more proximal positioning of osteotomy in relation to the physis. When pinning was performed with the narrow Moore pin with or without manipulation there was no AVN. It increased to 5% with a Smith-Petersen nail without manipulation and was 9.1%

430

CHAPTER 5 ~ Coxa Vara in Developmental and Acquired Abnormalities o f the Femur

with nonoperative treatment, which did, however, include manipulation. Subtrochanteric osteotomy had a 10.9% incidence of AVN, nonoperative treatment without manipulation 12.5%, Smith-Petersen nail plus manipulation 37.5%, and all types of cervical osteotomies 38.1% (100). Realignment operations, though widely practiced for slipped capital femoral epiphysis, still show the possibility of short-term complications, although it is expected that the position closer to the anatomic norm should minimize osteoarthritis later. Convincing and definitive studies in this regard would be helpful. Jerre et al. assessed realignment procedures in 37 hips at an average follow-up of 33.8 years (130). They noted serious short-term complications in 7 of 22 hips treated by subcapital osteotomy, 3 of 11 hips treated by intertrochanteric osteotomy, and 3 of 4 hips treated several years previously by manipulative reduction. They concluded that the natural history of slipped epiphysis was "probably not improved by any of the treatments used in our study. We therefore discourage the use of subcapital and intertrochanteric osteotomy as well as manipulative reduction for the primary treatment of chronic slipped upper femoral epiphysis." The realignment procedures had been performed from 1946 to 1959. That results following severe slippage even with intertrochanteric osteotomy often were far from perfect was demonstrated in a long-term follow-up study of 26 patients by Maussen et al. (181). They reviewed 26 of their own cases of moderate to severe SCFE treated by the intertrochanteric approach. Where slippage was less than 40 ~ in 10 hips, subsequent arthritis was present only in 1. In 16 cases, however, in which slippage exceeded 40 ~ osteoarthrosis was present in 15 of 16 even though correction was adequate. They concluded that the intertrochanteric approach did not prevent degeneration in cases with the most severe slip and recommended only fixation in situ without realignment with correction only of the rotational component during the adolescent years. Follow-up was longer than in most studies with a mean of 9 years and a range from 3 to 26 years. The surgical approach had involved either a valgus derotation osteotomy or a formal Southwick procedure. Maussen et al. used a relatively rigorous grading system for osteoarthrosis of the hip, which was based on radiographic rather than clinical criteria. The inference is clear that many of these patients would go on to symptomatic hips, although at the time of assessment the problem was primarily radiographic. This report is somewhat disconcerting about the long-term results with 40 ~ slippage being the border below which good results could be achieved and above which osteotomy resulting in good correction did not seem to prevent some degree of degenerative change. The report also provided an excellent overview of results in other studies following in situ fixation alone without reorientation of the head and neck region using either metal pins or transphyseal bone grafting. Although a large number of papers are referenced, the gradation involves mild, moderate, and severe cases with the analysis

involving only the percentage classified as excellent or good. Because in all series those with in situ pinning tend to be extensively populated by mild to moderate slips, this analysis may not be valid for the entire spectrum of the disorder. Maussen et al. interpreted the results, however, to indicate that internal fixation by pinning or by bone graft epiphysiodesis without realignment produced long-term results that were good, even in cases with moderate to severe slippage. Review of the intertrochanteric osteotomy assessments from the literature, however, indicated that the question of subsequent arthrosis had not been assessed in detail. The cervical osteotomy did have many instances of poor results documented due to arthrosis and AVN. Maussen et al. present the case, therefore, that even moderate to severe cases of SCFE in the adolescent period should be treated without realignment using only pinning or bone graft epiphysiodesis. Subsequent correction would be performed only for symptomatic states rather than attempting realignment for all to prevent such problems. Differing views continue to be expressed. Another longterm study by Schai et al. assessed 51 patients with unilateral severe SCFE of 30-60 ~ treated by intertrochanteric osteotomy and examined an average of 24 years postsurgery (229). They concluded that 55% showed neither radiographic nor clinical signs of degenerative hip disease, with 28% having moderate disorders and 17% severe osteoarthritis. Intertrochanteric osteotomies were performed with stabilization by either AO blade plates or AO condylar plates. Stabilization of the epiphysis preosteotomy with 2-3 Steinmann pins was important. The principle of reestablishment of hip anatomy indirectly by compensatory means through the intertrochanteric region had been introduced by both Imhauser and Southwick. They concluded that the results were superior to pinning in situ alone. They felt that angles greater than 30 ~ warranted corrective osteotomy. c. Prophylactic Pinning o f Contralateral Side at Initial Presentation The relatively high incidence of bilaterality

noted in patients followed to skeletal maturity plus the fact that most patients at presentation have only a unilateral slip have led to the practice in many centers of pinning the contralateral normal hip at the same time that treatment is undertaken for the slipped epiphysis so as to eliminate immediately any chance of contralateral slipping. The advantages of the approach are the ability of the patient to resume full activity at all levels once both physes have fused with no risk of subsequent slippage. Some of the second side slips are asymptomatic, and the possibility exists that the second slip will not be recognized until late in its evolution such that a moderate or severe deformity is presented for treatment. Because the results are best in those with minimal to no slippage the value of pinning in situ is high. Disadvantages have resulted from prophylactic pinning, however, for two reasons. In some series, such as our own, although 50% of patients had bilateral involvement, 25% of them were bilateral at the time of presentation and only

SECTION I! ~ Slipped Capital Femoral Epiphysis 25% experienced the second side slip over the ensuing period prior to skeletal closure. If all patients in such a group had been pinned prophylactically, 3 of 4 operations would have proven to be unnecessary. Jerre et al. recommended that prophylactic pinning of the contralateral hip should not be standard (128). In reviewing 61 patients treated for unilateral slipped upper femoral epiphysis, there were 14 (23%) who had evidence of bilateral slipping at initial primary review, whereas 11 (18%) subsequently slipped prior to skeletal maturity. They concluded that, if all 61 contralateral hips had been pinned prophylactically at primary admission, 36 of the operations (59%) would have been unnecessary. Jerre et al. thus recommended that radiographs be done every 3-4 months until growth plate closure with only those hips where a slip occurred to be pinned. The reason for X rays was that in only 2 of 25 patients with bilateral involvement (8%) was slipping of the contralateral hip symptomatic. Of greater concern, however, was the finding in some retrospective series that the contralateral asymptomatic hip had a complicated pinning such that damage was caused even though none was present initially. With greater awareness of the dangers of inappropriate pin placement these complications have minimized. In many centers the patients and families are presented with two options. One simply involves pinning in situ at the same time that the primary slip is treated. The other is a recommendation to follow the child closely throughout the remaining years of growth and to intervene surgically only if a slip develops. Instruction is given on the importance of immediate orthopedic assessment for warning signs of early slippage with the development either of limp, however slight, or hip, thigh or knee discomfort. Some also take the further precaution of recommending radiographs every 3-4 months (because some second side slips are asymptomatic) and limiting sporting activities. Not surprisingly, those clinics showing the highest extent of bilaterality are the most supportive of the values of the prophylactic approach. Jensen et al. recommended bilateral pinning at initial treatment in all patients with a SCFE (127). Engelhardt strongly recommends prophylactic treatment and quotes many papers from the past few decades showing the incidence of bilaterality ranging from a low of 19% to a high of 80% in the Billing and Severin study (67). He prefers CT assessment when the child is approaching the age of skeletal maturity because growth plate closure is seen more clearly and thus earlier by CT than by plain radiography. Hagglund recommends prophylactic pinning of the contralateral hip in all cases of SCFE, with the proviso that the technique used should have a low complication rate (97). d. Complications of Slipped Capital Femoral Epiphy. sis Five major complications can be associated with SCFE. Avascular Necrosis: Avascular necrosis almost always is a complication of treatment rather than a complication of the disease itself; it rarely is seen in association with acute, acute on chronic, or chronic slips in continuity even if the slip has

431

proceeded to complete posterior displacement. Closed reduction of the chronic slip never is warranted because any correction gained risks excessive trauma, which tears the posterior vessels. Although a definite change in the relationship of the femoral head to the femoral neck has occurred in SCFE, it is important to realize that this process has been occurring for several weeks to several months and that spontaneous attempts at stabilization posteriorly and medially by fibrous, fibrocartilaginous, or osseus tissue have led to thickening and shortening of the posterior periosteum within which the retinacular vessels are situated. Many also will preclude the use of closed reduction in the acute on chronic case because it is not possible to know when only the acute component has been reduced (Fig. 19A). Avascular necrosis as a complication of SCFE began to gain wide recognition in the late 1920s. Axhausen recognized the entity referred to as "aseptic" necrosis initially to distinguish it from problems widely known to occur after infection. Moore described the histopathology well in a 12-year-old boy who had suffered an injury 1 year previously, which had responded reasonably well to treatment in bed for 4 weeks after which walking was resumed (189). There was vascular fibrous tissue invasion of the marrow spaces, which contained areas of necrotic marrow debris. The dead trabeculae, whose lacunae were empty, were being absorbed and replaced by living bone. Numerous osteoblasts, osteoclasts, and multinuclear giant cells were seen throughout the living connective tissue. The superficial zone of the articular cartilage was normal but the deeper zones were necrotic and being replaced by bone from below. Hall reviewed a series of 173 hips with SCFE noting 27 cases of AVN and 3 of chondrolysis (100). The complication is recognized as occurring due to damage to the blood vessels, which are concentrated on the superolateral and posterior aspects of the neck. Because displacement occurs in a posterior and medial direction, there is a tendency for the vessels to theihead to be stretched. Spontaneous episodes of AVN in the absence of therapy are virtually unknown. The vasculature, though slightly at risk, appears to stretch gradually~jn relation to the slowly evolving chronic slip. When treatment, however, is done in too harsh a fashion damage and subsequent AVN follow. The factors relevant in the consideration of AVN involved delay in diagnosis, the amount of displacement at time of diagnosis, and the type of treatment. Factors predisposing one to AVN include moderate to severe displacement requiring efforts at improving position, a relatively longer time prior to a diagnosis, and treatments that are characterized by manipulation and efforts at reduction be they closed or open. Due to the age of the patient and the relatively small time of growth remaining for remodeling, avascular necrosis in SCFE is a major problem and almost invariably leads to osteoarthritis sometimes in young adult life. AVN always is associated with deformation of the femoral head. Avascular necrosis also can occur following a pinning of the slip. The problem relates to pins that are placed in the

432

CHAPTER 5 ~ Coxa Vara in Developmental and Acquired Abnormalities of the Femur

FIGURE 19 Radiographicexamples of avascular necrosis (A) and chondrolysis (B), the two major severe complications of slipped capital femoral epiphysis, are shown.Both of these can lead to early adult osteoarthritis.

anterosuperior and posterosuperior quadrants in the area in which the lateral epiphyseal vessels enter the femoral head. Though there can be some damage with a pin remaining totally within head and neck bone, major problems could occur if the pin exits the neck and then reenters the head thus causing extensive damage to the vascular leash, which lies on the surface of the neck prior to entering the head between the physeal and articular cartilage regions. This region is very difficult to assess radiographically, and thus the recommendation stressed by Aronson and Loder is to place internal fixation strictly in the central zones of the femoral head and neck to minimize chances of injuring the blood supply (14). Damage also can occur if vessels traverse the neck in the anteroinferior quadrant in which the inferior metaphyseal vessels enter the head and neck and also supply some regions. Lowe summarized both his own experience with early AVN and chondrolysis and other previous assessments (172). In a study of 100 cases of SCFE, he noted 21 hips that developed necrosis of the bony epiphysis or chondrolysis following treatment. There were 6 cases of AVN and 15 of chondrolysis. Although the feeling was widespread that AVN was a complication of treatment, there were some instances, for example, those reports by Moore, that epiphyseal necrosis could occur naturally even in cases in which there was minimal displacement. The AVN could be variable and in some instances recovery was possible. All hips had had major displacement and had been treated. The incidence of AVN was much higher after "successful" reduction,

which implied movement of the head-neck junction with its implication of tearing of the associated vessels. The AVN was analogous to Perthes disease in which the articular cartilage survived. Chondrolysis: Chondrolysis refers to a destruction of the articular cartilage of the femoral head, which is associated radiologically with joint space narrowing and clinically with discomfort, decreased range of motion, and on occasion actual fusion of the joint (123, 173) (Fig. 19B). Waldenstrom pointed to chondrolysis as a complication of SCFE in 1931 (256). He reported on 3 cases of necrosis of the joint cartilage after a slipped epiphysis. All were chronic, having showed symptoms from 6 months to 1 year, and subsequently were treated with closed reduction under anesthesia followed by hip spica immobilization with the involved lower extremity in abduction and internal rotation. Mobilization was continued for 2 months prior to cast removal and rehabilitation. After some months, the joints became more and more stiff and finally all mobility ceased. The earliest finding radiographically after a few months was thinning of the joint cartilage. The joint continued with increased stiffness and often a formal ankylosis. Waldenstrom clearly differentiated the disorder from avascular necrosis of the bone, which involved variable parts of the femoral head bone but never the joint surface alone. He felt that cartilage necrosis was not due to avascularity of the bone especially because the cartilage on the acetabulum also was affected. He felt that the necrosis in his described cases involved only the joint cartilage. He felt that damage to the capsule and syn-

SECTION II ~ Slipped Capital Femoral Epiphysis

ovium was the cause of the joint surface necrosis because that was the source of nutrition. Because all of his cases occurred in hips that had been reduced, which meant manual reduction under anesthesia in a fairly forceful fashion by current standards, he felt it was the tearing of the capsule that induced fibrosis and subsequent poor nutrition. Therefore, he felt that it was the reduction of the epiphyseal slip by relatively vigorous treatments that caused the cartilage necrosis. He then treated 24 subsequent cases without vigorous reduction but rather by slow traction with the patient in bed. Chondrolysis can occur in patients with SCFE who have not undergone treatment. The large majority of instances, however, are associated with treatment, with most of those following internal fixation in which the fixation pin is either into or through the articular cartilage leading to mechanical destruction with movement. The chondrolysis entity, however, also has been reported after immobilization in a hip spica cast and after intertrochanteric osteotomy. Though early papers documented a higher incidence in black patients, more recent and detailed studies have not shown any predisposition in blacks to the disorder. The series of Lowe was unusual in that more cases of chondrolysis were present than of AVN (172). The result with chondrolysis almost invariably was poor due to stiffness of the hip and malposition. Diminution of the joint space on radiographs remained the primary radiologic sign, and clinically there was discomfort and usually markedly diminished ranges of motion. The highest positive associations were with immobilization in plaster spica or prolonged traction greater than 7 weeks. The prolonged immobilization also was a feature in other series, notably those of Moore (190), Jerre (131), Hall (100), and Waldenstrom (256). Although claoadrolysis and AVN can coexist on occasion, in general they ~ e separate entities. Heppenstall et al. noted a 26% incidence of ~chondrolysis in a series of 65 patients (17 involved), but oally 3 of 21 hips with chondrolysis had associated AVN (108). Ingrain et al. reviewed the literature on chondrolysis from Waldenstrom's initial report of 3 cases in 1930 to their own review of 79 cases in 329 hips with SCFE in 1981 (123). Many series were showing very high levels of chondrolysis, the greatest being a 55% incidence in 116 patients by Orofino et al. (203), with other high incidences being Boy~l et al. (16%) (32), Howorth (41%) (123), Maurer and Larsen (28%) (180), TiUema and Golding (40%) (253), Hartman and Gates (16%) (105), Heppenstall et al. (26%) (108), Gage et al. (38%) (84), and Ingram et al. (24%) (123). When all series, including their own, were averaged, the rate of chondrolysis was 19% (332 of 1746). The disorder was best prevented from occurring because treatment was nonspecific and essentially symptomatic, involving bed rest, crutches, traction, and various physical therapy modalities. Antiinflammatory drugs were helpful. The feeling was prevalent that there was a predisposition to the disorder, which involved some immunologic processes, never clearly defined, which led to a synovitis and subsequent degenerative cartilage changes. There was increasing evidence that

433

the disorder was higher with certain types of therapy in particular when the joint was penetrated by internal fixation devices (51%), after open reduction (55%), after cervical osteotomy (37%), after trochanteric osteotomy (59%), and with increased immobilization in cast posttreatment. The disorder was felt to be less frequent with mild slips and acute slips, although this may reflect the more benign treatment methods used and the lack of complications associated with them. Most chondrolysis complications are related to treatment rather than to an inherent predisposition of the patient to the disorder. Ingram et al. reported in detail on radiologic and biopsy assessments of the hip joint from 16 previous cases from the literature plus 23 of their own (123). The radiographic changes involved progressive joint space narrowing, usually superiorly, which often proceeded to entire concentric diminution. There tended to be a generalized demineralization of adjacent femoral and acetabular bone. The situation frequently resolved and stabilized, but on occasion proceeded within a few years to a formal osteoarthritis with marked joint space narrowing, osteophytes, subchondral cysts, and subchondral sclerosis. Persistence of synovitis greater than 6 weeks postsurgery should lead to concern about a developing chondrolysis (262) In one of the larger series 41 cases of chondrolysis were reported by Lance et al. (162). A wide variety of treatments had been used to treat the primary slip, including plaster casts alone (7), closed reduction and plaster (3), intertrochanteric osteotomies (10), open reduction (6), wedge osteotomies of the neck (5), transphyseal bone graft (3), extra articular epiphyseal arrest (4), and pedicle graft (1). Two patients had not been treated but still developed the disorder. One of the major principles of treatment for the chondrolysis is to diminish weight beating using either crutches or, if possible, bed rest with traction. It is important to keep the hip region extended and positioned along the neutral axis to prevent abduction, adduction, flexion, or rotation deformities. Gentle range of motion exercises and occasional use of antiinflammatory drugs usually are helpful. Repair tends to be very slow and symptoms can last several months to years before full or at least clinically useful motion is regained. Many patients, however, do recover fully or close to fully. In those cases not healing well, there is radiographically evident progressive diminution of joint space, osteophyte formation, and a triangular appearance of the head in association with adjacent bone and cartilage collapse. The authors felt that the best treatment was suspension-traction to enhance articular motion and joint lubrication. In those that went on to further joint destruction, a hip arthroplasty often was needed preceded by osteotomies in many instances. The authors felt that only 44% of those affected obtained a good or excellent result with absence of pain, a normal gait, and reasonably good motion. In summary, there are four contributing factors leading to the disorder. (1) Mechanical: Chondrolysis often is associated with pin penetration into the joint. With resumption of

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CHAPTER 5 9 Coxa Vara in Developmental and Acquired Abnormalities o f the Femur

walking the pin tip scarifies the adjacent articular cartilage. (2) Nutritional: Inability to receive synovial nutrition often is a cause particularly in those patients immobilized in cast for several months. (3) Ischemia: Ischemia of the bone does not necessarily lead to avascular necrosis alone but also to chondrolysis on occasion. (4) Intra-articular pressure: Osteotomies of the neck and intertrochanteric region often tighten the hip joint capsule in the process of the valgus and extension repositioning, which increases the intra-articular pressure and secondarily limits the ability of nutrients to diffuse into the cartilage. Stiffness: Stiffness occurs only as a complication of AVN or chondrolysis. External rotation left untreated diminishes the functional range of motion, although the actual arc of motion numerically is unchanged. Shortening on the Involved Side: Shortening on the involved side must be assessed in a patient with SCFE. If the disorder turns out to be bilateral, clinically significant limb length discrepancy rarely occurs. Even in those patients who have unilateral involvement, there is infrequent clinically significant limb length discrepancy. Any shortening is due to a combination of factors, including treatment, which induces a premature fusion of the proximal femoral capital growth plate, removal of excessive amounts of bone in association with compensatory osteotomy, and loss of length caused by the slippage in particular if this is not corrected by a compensatory osteotomy. Lower extremity length discrepancy, however, rarely is a problem because of the age at which the disorder occurs and the fact that most patients have only mild to moderate deformation. Because only 30% of the growth of the femur and 15% of the growth of the lower extremity occur at the proximal femoral capital epiphysis, and because most patients are 11 years of age or older at the time of the disorder, there rarely is sufficient growth remaining to account for a discrepancy of greater than one-half to threefourths of an inch. Howorth noted that most patients with minimal to moderate slip who had the transphyseal bone pegging procedure almost always had shortening limited to one-fourth to one-half inch and often less (116). The fact that most patients either have only mild to moderate slippage or are anatomically corrected if they have greater displacement minimizes the extent of shortening. A contralateral distal femoral epiphyseal arrest is needed on occasion. Adult Osteoarthritis: There is no question but that some patients with slipped capital femoral epiphysis will develop osteoarthritis in middle to late adult years. Those who suffer either chondrolysis or avascular necrosis may have moderate to severe arthritic symptoms, even in early to mid-adult life. The importance of minimizing and if possible completely eliminating the occurrence of these disorders thus is obvious. What is less certain is the amount of deformation of the head-neck region that contributes to eventual adult degenerative change. The longer range studies indicate that mild slippage is not causative in this regard and that even moderate slippage left untreated other than by fixation in situ has

an extremely low incidence of osteoarthritic change well into the fifth and sixth decades. Most but not all agree that with severe and complete slips corrective osteotomy or even primary open reduction and internal fixation are warranted because of gait and functional considerations. Some will stabilize any slip, regardless of degree, in situ and perform osteotomy later only for troublesome symptoms, which are the external rotation deformity of the lower extremity and sometimes the Trendelenberg gait. A matter of further importance, however, is whether correction must be done at the head-neck junction for optimal long-term results or whether the compensatory osteotomies at the basicervical, intertrochanteric, and even subtrochanteric regions provide sufficient correction to render treatment at those sites preferable. Krahn et al. reviewed 36 patients out of 264 with SCFE who had developed AVN (155). Twenty-four hips were assessed at an average follow-up of 31 years. AVN indeed was a complication with many negative long-term sequelae. Nine of 22 patients had already undergone reconstructive surgery, 4 during adolescence and 5 during adulthood. In the remaining 13 patients (15 hips), there had not yet been any operative intervention but all showed degenerative changes on radiography. This report did not give the treatment methods in the patients without the AVN complication, but certain characteristics were seen in those who had the AVN complication. In the 4 hips that had early deformation requiting reconstructive surgery, 2 had closed reduction with pinning and 2 had open reduction, 1 of whom also had cuneiform osteotomy. In the 5 patients with progressive changes requiring surgery in adulthood, 2 had closed reduction with pinning, 2 had closed reduction with casting, and 1 also had cuneiform osteotomy. In those patients with progressive degenerative changes that had not at that time required surgery, cuneiform osteotomy had been performed in 5 of the 13, closed reduction and pinning in 4, and open reduction in 1. In the series, therefore, the large majority of patients had either closed or open reduction and many with cuneiform osteotomy as well. These three techniques in particular almost always have been implicated in the patient with AVN. e. Long-Term Follow-up Studies Boyer et al. performed a detailed long-term study of 149 hips with SCFE assessed 21-47 years postdiagnosis at a mean of 31 years (33). They assessed treatment methods performed between 1915 and 1952 when many of the surgical interventions were relatively crude by current standards. They confirmed the previous belief that "the mild slip has an excellent prognosis when pinned in situ and if no realignment procedure is attempted." This report, written in 1981, appeared before the work of Waiters and Simon (259), which indicated that some cases of pinning were problematic even if not so recognized by the surgeon. In other words, the long-term results of mild slips pinned in situ without pin penetration would remain excellent, perhaps even somewhat better than the assessment in the Boyer paper. Their conclusion remains intact today, namely, that pinning in situ is safer than any type of reduc-

SECTION II ~ Slipped Capital Femoral Epiphysis

tion or realignment in that it presents fewer technical problems and also requires a minimum of immobilization. Their work also concluded that malunion of the moderate slip should be accepted and pinned in situ. Boyer et al. noted a considerable number of technical complications with the operative procedures then in use. At present, it would be anticipated that surgical correction techniques for the moderate slip would have been improved such that complications from the surgery would be fewer, but there are relatively few definitive studies in this regard. They also concluded that pinning in situ was a safe and reliable method of treating the moderately slipped capital femoral epiphysis. They recognized that severe slips would benefit from realignment procedures, although results in their series were not good, again because of technical surgical problems. They had a high incidence of chondrolysis or AVN. Boyer et al. were, however, able to study 7 patients with severe uncorrected slips and noted the long-term results to be "remarkable." Six of the 7 had good clinical results, marred by some limping and diminution of abduction and internal rotation, but overall showing good, painless hip function. The 7th patient had a poor result. They pointed again to the concern about AVN and chondrolysis in particular after a closed manipulation of chronic SCFE and also the risk of femoral neck osteotomy. In assessing their cases, they used the Southwick method of measurement in some, but where they only had radiographs of the affected hip a more general measurement was used, defining a mild slip as one with displacement of the head on the neck of less than one-third of the diameter of the femoral neck, moderate displacement of one-third to one-half the diameter, and severe displacement of more than one-half the diameter. A long-term study by Ordeberg et al. published in 1984 assessed 49 cases of SCFE without primary treatment 2060 years after diagnosis (202). Assessment was by questionnaire in all and clinical and radiographic examination in 44 of the 49. Patients originally seen between 1910 and 1960 were assessed, involving 57 hips with a mean observation time of 37 years (20-60 years). As a general conclusion, they indicated that "2 of these 49 (still living) cases have required surgery because of secondary arthrosis, far fewer than were found in a comparable group of cases treated with closed reduction and hip spica." A positive Trendelenburg test was noted in approximately one-third, and an even fewer number noted some limping after walking considerable distances. Limb length discrepancy of 2-5 cm was noted in 15. The index of pain correlated with the degree of displacement, and marked functional restrictions were noted mainly in cases with severe slip. Ordeberg et al. felt that deterioration in the later years of life was "comparatively slight and can in part be explained by age." They concluded that clinical observations regarding pain, walking capacity, and range of motion showed a much better function than expected. The cases with severe clinical problems almost invariably were among those with severe slipping, but some even in this

43~

group were doing well. Studies in the patients with a 35-year interval did not support the expected finding of deterioration with time. Ordeberg et al. concluded that "with few ex~ ceptions, coxarthrosis developed only in hips with severe displacement." Carney et al. continued a long-term follow-up study of SCFE from the Iowa group (44). In this study, 155 hips were assessed at a mean follow-up of 41 years after onset of symptoms. Of these, 42% were mild, 32% moderate, and 26% severe. With chronic slips, symptomatic treatment only was used in 25%, a spica cast in 30%, pinning in 24%, and osteotomy in 20%. The study indicated that degenerative joint disease as classified radiographically worsened with increasing severity of the slip and also when reduction or realignment had been done. AVN of 12% and chondrolysis of 16% also were common with increasing severity of the slip and when reduction or realignment had been performed. Their presence almost always indicated a poor result. Deterioration with time was noted to be most marked with increasing severity of the slip. The study of Carney et al. confirmed that the natural history of a malunited slip was mild deterioration related to the severity of the slip, and additional complications. Techniques of realignment, however, were felt to be associated with a risk o f appreciable complications and thus adversely affected the natural history of the disease. Their conclusion, out of step with much of the pediatric orthopedic world, was that "pinning in situprovided the best long-term function and delay of degenerative arthritis with low risk of complications." Their findings supported those of Boyer et al., even though this series was reviewed 12-15 years after the former. Studies reported by Hagglund et al. (98) and Hansson et al. (102) in a southern Sweden SCFE population noted that, in 57 cases with no primary treatment, no AVN (segmental collapse) or chondrolysis was seen. At long-term follow-up 12/53 had "severe arthrosis," but only 1 had hip replacement surgery and clinically "most patients had a good hip function with at least tolerable pain and a good walking capacity." Symptomatic treatment or pinning in situ resulted in high clinical ratings with only 2% of hips needing a secondary reconstruction procedure. When closed reduction and spica casting had been used, the combined rate of AVN and chondrolysis was 13% with reconstructive procedures sought in 35% of the hips. Cervical osteotomy had a combined rate of AVN and chondrolysis of 30% with reconstructive procedures needed in 15% (96). The group recommended pinning in situ for treatment because either open or closed reduction clearly increased problems. In their Series for 39 hips in which the slips had been reduced, osteonecrosis developed in 12 (31%) and chondrolysis in 11 (28%). In 116 hips that had not been reduced, AVN occurred in 7 (6%) and chondrolysis in 14 (12%). They concluded that the natural history of the malunited slip was one of mild deterioration related both to the severity of the slip and to complications of treatment. Realignment, however, risked

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CHAPTER 5 ~ Coxa Vara in Developmental and Acquired Abnormalities o f the Femur

"substantial complications and adversely affects the natural course of the disease." They supported pinning in situ regardless of the severity of the slip as providing the best longterm function associated with a low risk of complications and, thus, the most effective method of delaying the development of degenerative arthritis. Hagglund et al. studied long-term results after nailing in 204 slipped epiphyses evaluated at an average of 28 years postprocedure (98). The only early complication noted was segmental collapse of the femoral head seen in 4 of 179 hips nailed in situ and 4 of 25 hips operated after reduction. Subsequent osteoarthritis was twice as frequent after reduction approaches than after fixation in situ. They concluded that "nailing or pinning in situ is the method of choice when possible, regardless of the degree of slipping." Prophylactic pinning of the contralateral hip was indicated because!of tlaeir high incidence of bilaterality. The second longzterm study by this group of femoral neck osteotomy assessed 33 patients with a severe slipped capital femoral epiphysis treated primarily with wedge osteotomy of the femoral neck (96). The patients were assessed at an average of 28 years postsurgery. Segmental collapse and or chondrolysis developed in 10 of the 33 patients. In 9 of these available for reassessment, all had severe arthritis with poor function. The conclusion of Hagglund et al. was that the value of realignment by wedge osteotomy of the femoral neck was questionable. These long-term studies are essential to help determine which adolescent situations require compensatory osteotomy or open reduction with cuneiform osteotomy and whieh can be treated effectively by pinning in situ alone.

K. Coxa Vara Due to Other Acquired Causes These entities are discussed under their more specific sections in Chapter 3, Developmental Dysplasia of the Hip, Chapter 4, Legg-Calve-Perthes Disease, Chapter 9, Skeletal Dysplasias, and Chapter 10.

III. D E V E L O P M E N T A L OF THE FEMUR

ABNORMALITIES

\

1 FIGURE 20 Illustrationsfrom the work of Drehmann (61) show good awareness of the underlying pathoanatomy. (Compare with Figure 2 lB.) groupings within these general terms lend themselves to specific treatment approaches. Part of the confusion in terminology comes from the fact that these four categorizations can occur as isolated deformities in some, whereas in others two or even three of the descriptive abnormalities can be found in the same femur. Some authors have concentrated primarily on the proximal femoral abnormalities, some have focused on the coxa vara, which is a feature of the relatively milder proximal femoral focal deficiency cases but also exists in acquired disorders and in isolated fashion as infantile coxa vara, and some have considered congenital short femur as a specific entity, although many femurs with this abnormality also have a proximal coxa vara. Distal femoral developmental abnormalities are described infrequently but are present fairly often and can lead to deformities that are clinically symptomatic.

A. Terminology Developmental abnormalities of the femur comprise an extremely wide spectrum of disorders from complete absence of the femur to its presence with a normal structure and only a mild degree of shortening. Considerable attempts at classification have been made, but the disorders are so variable that no single universal approach has been acceptable to all. The overall pattern of categorization, however, is reasonably well-defined. One approach is to divide the abnormalities into proximal femoral focal deficiencies, coxa vara, congenital short femur, and distal femoral abnormalities because

B. Proximal Femoral Focal Deficiency Wmually all of the severe developmental abnormalities of th~ femur are concentrated at its proximal end (5, 8, 79, 83, 86, 134, 205). It took several decades before reasonably accurate classifications of the nature and type of the variable deformities were outlined. These truly congenital disorders often were discussed with and confused with infantile coxa vara, which now is recognized as an isolated disorder of postnatal onset in the large majority of cases. Drehmann (61) (Fig. 20)'and Golding (88) showed examples of coxa vara,

SECTION III ~ Developmental Abnormalities of the Femur which included but did not differentiate congenital and infantile varieties. Although the entity now is known as proximal femoral focal deficiency (PFFD), the several variants were recognized early under the term congenital coxa vara (61, 106, 182, 199). The deformities are quite variable in extent, and several classifications have been presented in an effort to better understand the entity and categorize it for treatment. Several classifications are presented here because each provides information on the types of deformity that have been observed. Some are strictly pathoanatomic, whereas others categorize disorders based on varying treatment approaches.

1. CLASSIFICATIONS a. Aitken Classification Aitken divided the entity into four classes, A-D. Class A: The head of the femur is present along with an adequate acetabulum and a very short femoral segment. Initially there is no bony connection noted between the femoral segment and the head of the femur, but at skeletal maturity bone continuity is seen although in most instances there is a subtrochanteric pseudarthrosis. Class B: The femoral head is present and the acetabulum is adequate, but the femoral shaft is short and deformed with a small bony tuft on its proximal end and no bone or cartilage continuity between the shaft and head and neck segment at any time. Class C: The acetabulum is severely dysplastic and there is neither a bone nor cartilage model of the femoral head. The shaft of the femur is short with an ossified tuft at the proximal end. Class D: Both the acetabulum and the femoral head are completely absent, there is a deformed shortened femoral shaft, and there is no proximal tufting of the shaft of the femur. This class of deformity frequently is bilateral. b. Amstutz Classification Amstutz defined proximal femoral focal deficiency as "the absence of some quality or characteristic of completeness of the proximal femur, including stunting or shortening of the entire femur" (8). In his study, and that of Aitken, a portion of the distal femur always was present, even if only represented by a misshapen ossicle. Amstutz also brought attention to the fact that a coxa vara deformity in addition to shortening was characteristic of many cases of proximal femoral focal deficiency. His classification defined five morphological groups identifiable radiographically at birth and also included developmental changes with time. Congenital bowed femur with coxa vara, which had not previously been included with PFFD entities, was represented (Figs. 21A-C). Type l: Congenital bowed femur with coxa vara. The anterolateral bowing of the femoral shaft, most apparent in the proximal half, is associated with medial femoral cortical sclerosis. The capital femoral epiphysis ossifies, and because it is well-positioned in the acetabulum, it is not associated

437

with acetabular dysplasia. There may, however, be a delay in appearance of the secondary ossification center. Type 2: There is a subtrochanteric pseudarthrosis with lack of bone continuity between the head-neck-trochanteric region and the rest of the shaft. This is characterized clinically by a progressive varus of the proximal femur and delayed development of the head in particular. Two possible patterns of development follow. In one, there is progressive varus and lack of union of the two fragments, whereas in the other, there is either complete bone repair or a rigid pseudarthrosis with close apposition of the bone fragments. Type 3: The hip region is formed in that there is a cartilaginous femoral head present and the acetabulum has no evidence of dysplasia. There is no initial radiologically defined bone continuity between the head, neck, and trochanteric region of the femur and the shaft. The shaft is shortened and has a variable degree of proximal bulbousness. Ossification of the femoral capital epiphysis often is markedly delayed. Subsequent development can be variable leading to four subgroups. In type 3A, there is union between the proximal and distal fragments with a coxa vara persisting. In type 3B, there also is union but the coxa vara is much more marked and the greater trochanteric epiphysis greatly overgrows the superior surface of the head. In type 3C, there is only a fibrocartilaginous union between the two fragments with marked proximal displacement of the distal fragment. In type 3D, no continuity is achieved. Type 4: The hip joint components are formed with an acetabulum and capital femoral epiphysis present in all such that acetabular dysplasia is not seen or is only minimal, although ossification of the capital femoral epiphysis may occur as late as 2.5 years of age. The proximal end of the distal femoral shaft tapers sharply, almost to a point, which differentiates it from type 3, which has a bulbous proximal end. The tapering represents an unfavorable prognostic sign as union of the two fragments never occurs and is followed by proximal migration of the distal fragment. The acetabulum eventually becomes dysplastic because of the failure of union. Type 5: Dysgenesis is severe such that none of the normal precursor hip components involving either the capital femoral epiphysis or the acetabulum develop. The classification of Amstutz has been widely used. Panting and Williams reviewed their cases in relation to his approach (204). They also pointed out, as had others, that radiographic evidence of an acetabulum in the first year of life indicated the presence of a well-located femoral head and neck, even if they were not seen due to delayed ossification of the secondary center. Additional classifications for proximal femoral focal deficiency: Over the course of the next several years, the PFFD syndrome became better recognized and treatment for the most part was intensive. Efforts were made to refine the classifications of Aitken and Amstutz to define disorders into a more practical and clinically oriented mode in relation to

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CHAPTER 5 ~ Coxa Vara in Developmental and Acquired Abnormalities of the Femur

A

TYPE IA

EARLY

TY

9 Q E II EARL TYPE II LATE

/

TYPE III EARLY TYPE IliA

TYPE III

TYPE I

TYPE III D LATE

C

F I G U R E 21

(A-C) The proximal femoral focal deficiency classification of Amstutz (8) is shown.

specific diagnosis, projected outcomes, and treatment approaches. These multiple approaches also reflect the findings that virtually no two cases are identical because the disorder represents a true spectrum in terms of extent and that with time the radiographic appearance changes in ways that also can differ depending on whether there is worsening or improvement, which can be spontaneous or based on treatment. c. Fixsen and Lloyd.Roberts Radiologic criteria were described by Fixsen and Lloyd-Roberts, which would allow one to determine whether a proximal femoral focal dysplasia was evolving to a stable or unstable state (79). In many children with this disorder, radiographs showed a short femur with a seemingly absent proximal one-third of the femoral shaft, head, neck, and trochanter. Clinical findings, however, often demonstrated a stable hip in association with the short-

ening and the femur flexed and externally rotated. The stability implied continuity between the femoral head and the proximal end of the shortened femoral shaft such that the intervening radiolucent area would be occupied by a cartilage model in which ossification was delayed. Two possible outcomes were seen clinically. In the favorable state, the cartilage model of the proximal femur gradually ossified with maintenance of stability, and eventually an entire femur was seen although the shaft remained short. The unfavorable outcome was associated with the development of one or more pseudarthroses at the osteocartilaginous junction or within the cartilaginous model so the continuity between the hip and femoral shaft was lost. The resulting instability led to proximal migration of the femoral shaft in relation to the head and neck because a breakdown of the pseudarthrosis pre-

SECTION III ~ Developmental Abnormalities of the Femur C

EARLY

~

~1"

(3 E V EARL

TYPE V LATE

FIGURE 21 (continued)

disposed to further upward displacement of the femoral shaft, although the proximal segment remained in the acetabulum. Fixsen and Lloyd-Roberts' criteria for distinguishing those that would proceed to spontaneous healing from those that would not were based on a study of 30 hips in 25 patients. All were observed until final definition of a stable or unstable state had been established. (1) In the stable hips, the shaft length was greater than one-half of the normal side in 5 of 6 cases, whereas the shaft length was less than one-half the normal side in 6 stable and 8 unstable cases. When the acetabulum resembled the normal, the femoral head always was present although ossification might be delayed. If there was no acetabulum, the head was absent. If there was acetabular dysplasia, then the head might well dislocate with time. In general, the shorter the ossified part of the shaft, the less the likelihood of spontaneous healing. The distance of the proximal end of the ossified shaft from the acetabulum was an important factor. When the distance was greater than the normal side, the hip was ultimately stable in 10 and unstable in 5, and when the distance was equal to or less than the normal side, the hip was stable in 1 and unstable in 4. (2) All unstable hips showed progressive migration of the femoral shaft upward, which indicated an impending dissolution of the pseudarthrosis. When the proximal end of the ossified

439

shaft was bulbous, all 12 hips were stable. When there was a tuft or cap, only 3 were stable with 10 unstable, and when there was a tapered point, none were stable and 5 were unstable. (3) The proximal end of the ossified shaft either was blunt and irregular or pointed. Sclerosis of the proximal shaft was related either to the site of angulation or to a pseudarthrosis. In those hips that became stable, the sclerosis essentially was in the mid-shaft region, well below the proximal end and associated with angulation. In the unstable defects, the sclerosis almost always was immediately distal to the site of the pseudarthrosis or angulation and had the appearance of an inverted " V " and was more proximal. In a retrospective study, several of the classifications in this section were reviewed, and it was the feeling of Sanpera et al. (228) that the radiologic parameters described by Fixsen and LloydRoberts were the most reliable factors for predicting future outcome of the femur from the time of birth onward. d. Lange, Schoenecker, and Baker Lange et al. classified their 42 patients into four categories (163). They often had difficulty assigning some patients to the specified Aitken or Amstutz group and formulated their categorization to conform to treatment approaches. In the less severely involved cases, these proximal shaft signs and stable-unstable concepts of Fixsen and Lloyd-Roberts were incorporated. Class 1: There is a coxa vara with the apex of angulation at the subtrochanteric region and a mild to moderate shortening of the femur associated with anterolateral bowing. Class 2: The acetabulum is present on the earliest films, but there is delayed (8-18 months) ossification of the femoral head. The proximal femoral shaft is displaced laterally, but the head and shaft are joined by a cartilage bridge. This bridge tissue eventually will ossify, although a pseudarthrosis might be present. The continuity is evident by stability with passive motion on clinical examination. Class 3: The acetabulum is intact but there also is late ossification (12-18 months)of the femoral head. The femoral shaft is separated from the head radiographically, but neither bone nor cartilage bridges are seen either initially or with time. There is detectable instability with independent motion between the shaft and the head. Class 4: There is severe proximal bone and cartilage deficiency with absence of the acetabulum, femoral head, and most of the shaft. At the distal end, there often is only a small segment of bone. On occasion, this bone fragment may be completely missing or the distal femoral bone is fused to the proximal tibial epiphyseal secondary ossification center, forming one tissue mass without a joint. e. Gillespie and Torode The patients were divided by Gillespie and Torode into two groups, which could be differentiated on clinical grounds and led to markedly different treatment options (86). In group 1, the congenital hypoplastic femur had sufficient development that the hip and knee could be made functional and lower extremity length equalization in many would be possible. In group 2, there was a proximal femoral focal deficiency in which the hip joint

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CHAPTER 5 ~ Coxa Vara in Developmental and Acquired Abnormalities of the Femur

never was normal and the knee joint always was useless. The lower extremity length discrepancies in group 1 rarely were as great as those in the more severely involved group 2. In addition, the flexion and abduction deformities at the hip in group 1 were less marked. In group 1, the radiographic characteristics showed the femur to be 40-60% of normal length with proximal to distal continuity, coxa vara usually in the subtrochanteric region, lateral bowing of the shaft, and a hypoplastic knee. In group 2, the femur was markedly shortened and a deficiency in bone always was noted. The head and neck often were absent, the shaft was markedly deficient, and the knee was hypoplastic. f. Kalamchi, Cowell, and Kim In the approach of Kalamchi et al., type 1 included patients with congenital shortening of the femur with a normal hip joint and no other femoral defects (134). Type 2 included those with a congenital short femur and coxa vara, generally with bowing and medial proximal femoral shaft sclerosis. The acetabulum was normal and the femoral head was well-positioned, although the secondary ossification center often formed late. In type 3, the proximal femur was deficient but the acetabulum was normal, indicating presence of the femoral head. This also tended to ossify late. There was shortening of the shaft and sclerosis of the proximal and middle one-thirds. If the proximal metaphysis of the affected femur was dysplastic, showing marked broadening and irregularity, the limb was designated type 3. Two patterns occurred with growth. In one, the defect went on to ossify in various degrees of varus, whereas in the other pattern the defect did not ossify, leading to a pseudarthrosis and lack of continuity between the two segments. Type 4 included limbs with no acetabulum and no femoral head and, thus, with an unstable distal segment. The distal segment was short and in the form of a tapered spike. Type 5 included limbs with no hip joint and no evidence of a separate femoral segment except perhaps a small distal fragment of bone, which usually was adjacent to the tibia. g. Haminishi Haminishi reviewed a large series of 70 patients with 91 congenital short femurs encompassing the entire spectrum of femoral developmental abnormalities (101). He compared the structural differences caused by the drug thalidomide with those of spontaneous occurrence and noted no essential anatomic difference between the two groups, although the whole complex of abnormalities differed in that the thalidomide group tended to show radius anomalies whereas the non-thalidomide group had femur-fibula-ulna anomalies. In relation to the spontaneous type, there were 67 affected femurs in 56 patients. His all-inclusive classification divides the entity into five types with varying subtypes. Type I. Simple hypoplasia of the femur: (a) normal shape; (b) slightly angulated shaft and cortical thickening. Type II. Short femur with angular shaft: (c) marked lateral angulation and cortical thickening resulting from transverse subtrochanteric ossification defect; (d) decreased neck-shaft angle. Type III. Short femur with coxa vara: (e) type IIIa (straight shaft), stable coxa vara with marked cortical thick-

ening at the lesser trochanter; (f) type IIIb (angulated shaft), progressive coxa vara with thickened cortex. Type IV. Absent or defective proximal femur: (g) absent or fibrous neck and trochanter; migration of the upper shaft, short shaft-head distance, and diaphyseal transverse ossification defect; (h) absent neck and trochanter and small femoral head connecting directly to the tapered shaft; (i) all the proximal femur is absent. Type V. Absent or rudimentary femur: (j) rudimentary distal femur, which is ossified later. h. Pappas A detailed study primarily based on patients followed longitudinally was published by Pappas, who developed a nine-class categorization (205). Pappas defined the percent of femoral shortening in each of the nine classes, detailed the femoral and pelvic abnormalities, assessed associated abnormalities of the tibia, fibula, patella, and feet, and defined treatment objectives. The large number of patients available for this study demonstrated a continuum of abnormalities. Class I refers to the situation in which the femur is entirely absent and the acetabular region of the pelvis is markedly hypoplastic. Class II: the proximal 75% of the femur is absent. Class III: there is no bony connection between the femoral shaft and head although the femoral head, which has delayed ossification, is present in the acetabulum. Class IV: the femur is present to approximately onehalf its length, but the proximal abnormalities show the femoral head in the acetabulum with the head and shaft joined by irregular calcification in a fibrocartilaginous matrix. It is these four disorders that are generally referred to as proximal femoral focal deficiency. In class V, the femur diaphysis and distal end are incompletely ossified and hypoplastic. In class VI, the proximal two-thirds of the femur is perfectly normal and the hypoplasia is in the distal one-third with an irregular distal femoral region and no evident distal epiphysis. Classes V and VI are examples of what could be described as distal femoral focal deficiency. Class VII is congenital coxa vara with a hypoplastic femur, which is shortened and somewhat bowed and also demonstrates lateral femoral condylar deficiency. Class VIII is seen infrequently but involves a proximal femoral coxa valga, a hypoplastic femur, and abnormality of the distal femoral condyles, with the lateral condyle being somewhat flattened. Most would include congenital short femur in this category, which perhaps most represents class VIII, although it characteristically has anterolateral bowing, which Pappas does not demonstrate. The class IX femur is essentially normal and might be defined by others as having only shortness referred to as hemiatrophy or anisomelia. Pappas also demonstrates the frequently seen underdevelopment of the lateral femoral condyle predisposing one to both a valgus deformity at the knee and a tendency toward lateral patellar subluxation. 2. CLINICAL CHARACTERISTICS The more severe abnormalities are recognizable at birth with a markedly shortened thigh, which is bulky with the hip flexed and abducted and the extremity externally rotated.

SECTION III ~ Developmental Abnormalities of the Femur From one-half to two-thirds of patients also have associated musculoskeletal abnormalities. The most common associated irregularity is ipsilateral fibular hemimelia, but a large number of variable abnormalities of either upper or lower extremities and also of the axial regions have been described (38, 101). One of the most detailed studies of associated congenital deformities was reported by Hamanishi in 70 patients with 91 affected femurs. No genetic basis, predisposing factors, or specific causal factors (other than thalidomide) have been identified. 3. PATHOANATOMICFINDINGS a. Soft Tissue Anatomy Magnetic resonance imaging studies have proven useful in assessing the soft tissue anatomy in association with PFFD. A detailed study by Pirani et al. of Aitken types A, B, C, and D in 6 patients with 7 affected hips demonstrated that all muscles appeared to be present (212). Most of the muscles were smaller than their normal counterparts, including the gluteus maximus, medius, and minimis complex, quadriceps, adductor brevis and longus, adductor magnus, pectineus, semimembranosus, semitenclinosus, and biceps femoris. The sartorius muscle, however, was hypertrophied, indicating a possible causative factor in the characteristic flexion, abduction, and external rotation deformity of the hip. The obturator externus muscle was elongated and remained muscular almost to its insertion. In type A PFFD, the short external rotators of the hip were larger than normal in terms of diameter and inserted into the posteromedial aspect of the greater trochanter. The abductors were smaller than normal. Hip musculature appeared to be positioned to contribute to both the normal and abnormal ranges of motion seen and clearly played a role in providing hip stability. b. Gross and Histopathologie Findings in Proximal Femoral Focal Deficiency One detailed study from a 21week-old fetus with unilateral PFFD has been reported by Boden et al. (29). Their examination indicated a unilateral PFFD with normal skeletal development of the contralateral limb and the rest of the skeleton. The radiographic appearance and the specimen photographs including the hip joint indicate that the abnormal side was developing as an Aitken type A deformity, sometimes referred to as congenital short femur with coxa vara. The femoral head was well-located in the acetabulum, there was complete tissue continuity between the head-neck trochanteric regions and the shaft, and a proximal metaphyseal-diaphyseal varus was seen with the tip of the greater trochanter lying higher than the most superior portion of the femoral head. Histologic sections clearly revealed structural abnormalities in the proximal part of the affected femur with failure of formation of a normal growth plate. On the normal uninvolved side, cartilage canals in the femoral epiphysis were noted as was the orderly array of cell changes in the physis progressing from the reserve to proliferating to hypertrophic zones, following which normal metaphyseal bone formation was seen. On the involved side, the patterning of the epiphyseal cartilage appeared normal as

441

did the vascular canals. There was slightly less organization of the proliferating zone of chondrocytes, although flattening of the cells was seen. The characteristic column formation did not occur. Most striking was the markedly decreased size of the hypertrophic zone, the lack of linear columnization of the hypertrophic zone, and the irregular formation of bone in the metaphysis due to the lack of an appropriate cartilage scaffold upon which the bone could be synthesized. The mineralization front of the hypertrophic zone was altered, and there was abnormal persistence of glycogen in chondrocytes deep into the growth zone. Many-of the clinical reports contain gross descriptions of the proximal femoral region, particularly in relation to those patients who have undergone surgical exploration of the proximal femoral bowing, either to place bone graft in the region to enhance bone development or to treat the pseudarthroses that frequently develop. Thus, there is good clinical correlation based on gross anatomic exam in the living in many instances. In those proximal femurs that are defined as clinically stable, the femoral head, neck, and trochanteric regions are present and continuous with the developing diaphysis, although tissue continuity often is maintained by persistence of the cartilage model in which ossification has been delayed. Another characteristic feature of the disorder, even when the femoral head is round and appropriately positioned in the acetabulum, is the fact that there is delayed vascular invasion of the cartilage model of the head, leading to a delay in formation of the secondary ossification center. This is described as appearing anywhere from 6 to 18 months, whereas in the vast majority of patients, the secondary center is present by 6 months and begins forming as early as 3-4 months. These clinical and radiographic observations correlate well with the 21-week fetal study by Boden et al. of an abnormal histologic appearance of the physeal region of the developing bone. In many instances, therefore, the cartilage model of the developing femur has formed, but in the proximal half there is inappropriate bone formation in relation to the proximal metaphysis and also to the secondary ossification center. The structural appearance of the physeal cartilage can be markedly abnormal with diminution of size and poor organization of the proliferating zone of the cartilage, which subsequently leads to a markedly shortened and disorganized hypertrophic cell zone. Even though there is some vascular invasion from the diaphyseal side, the abnormal structure of the hypertrophic zone and its poor mineralization contribute to diminished vascular invasion. The causes of these abnormalities remain unclear, but structural studies begin to show which part of the developmental sequence is interrupted. 4. TREATMENT OPTIONS Management in the proximal femoral focal deficiency group addresses six possible concerns: (1) the lower extremity length discrepancies; (2) the establishment of bony continuity of the femur by correcting any proximal pseudarthrosis;

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CHAPTER 5 ~ Coxa Vara in Developmental and Acquired Abnormalities of the Femur

(3) establishment of the most stable proximal femoral-acetabular relationship; (4) weakness of the proximal musculature; (5) correction of rotational or angular deformities of the femur; and (6) the effect on the extremity of other ipsilateral deformities primarily fibular hemimelia. Management of length discrepancies will be described in detail in Chapter 9. Treatment options have been detailed in several studies (5, 8, 10, 11, 38, 79, 86, 134, 154, 226). In the more severe variants of the PFFD deformity, such as the Aitken types C and D, there is little to no role for surgical intervention and treatment is directed to prosthetic management. In the less severe A and B types, considerations involve the presence or absence of bone continuity in the proximal femur between the head and neck segment, which generally is in good relationship to the acetabulum and the distal two-thirds of the shaft. In the newborn and in the first few years of life there may be no evident bony continuity between proximal and distal segments, although clinical testing may indicate stability. In these instances there is structural continuity mediated by cartilaginous tissue, which will eventually ossify. Prosthetic management and close observation are used initially to minimize proximal migration of the femoral shaft, which is indicative of a developing pseudarthrosis at the nonossified regions of the proximal femur. If the bone remains straight, it is indicative of cartilage continuity and stability and observation alone is sufficient. With time ossification of the cartilage fragment occurs. If a pseudarthrosis is developing, operative intervention with bone graft application is warranted. Location of the femoral head in a well-shaped acetabulum is essential to hip stability as with any hip abnormality. Attention to reduction of the femoral head deep into the acetabulum follows accepted principles of proximal femoral and acetabular management. On occasion coxa vara must be corrected with a proximal femoral valgus osteotomy, but only if there is sufficient depth of the acetabulum.

C. Congenital Short Femur Congenital short femur is a relatively common cause of limb length discrepancy and frequently is mentioned as an independent entity in relation to causes of lower extremity length discrepancy. It fits, however, into the spectrum of femoral developmental disorders. In the simplest variants of congenital short femur, the involved bone is shorter than that on the opposite side and demonstrates anterolateral bowing primarily in the proximal one-third of the shaft, although the headneck trochanter regions are normal and there is no coxa vara. This entity was clearly pointed out by Ring (226). In addition to being slightly bowed, the shaft of the femur shows both medial and lateral cortical sclerosis, and the clinical presentation is characterized by a slight hip flexion contracture and external rotation positioning of the femur with internal rotation markedly limited sometimes with no movement beyond neutral.

The second variant of congenital short femur is that associated with a congenital coxa vara in addition to the anterolateral bowing of the proximal diaphyseal region. This disorder often is mentioned as an Aitken type A variant of the PFFD syndrome. The coxa vara is relatively mild and only infrequently is it associated with the triangular fragment of the neck, which is far more characteristic of infantile coxa vara. A congenital short femur generally leads to shortness of the lower extremity greater than 5 cm, although most are manageable by femoral lengthening. The rate of increase in the discrepancy with time is the same throughout growth such that, if the femur is 84% of the length of the normal side at 1 year of age, it almost invariably will be 84% of the length of the opposite side at skeletal maturity. Planning for surgical intervention thus is straightforward in terms of timing. Contralateral distal femoral epiphyseal arrest is performed for discrepancies projected to be less than 4-5 cm, with ipsilateral femoral lengthening done for discrepancies greater than 4-5 cm. Management is detailed in Chapter 9.

D. Distal Femoral Developmental Abnormalities Although the major and far more severe developmental abnormalities of the femur occur in the proximal one-half, there is a small subset of associated distal femoral developmental abnormalities that can be troublesome clinically. Even in the most severe proximal abnormalities, there is almost always some presence of the distal femur, even though it is as small as a structureless cartilage mass and ossicle in the most severe forms of PFFD. Distal femoral developmental abnormalities can be present where there is an intact femur; the closer to normal the proximal half of the femur, the less dramatic the distal changes, but in those instances in which such changes are present, they may reach clinical significance. The distal femoral developmental abnormalities tend to affect the distal femoral epiphysis in two ways. One leads to slight underdevelopment of the lateral condylar region of the femur such that it is not as long as that on the medial side, tending to a valgus deformation, and the other leads to a less well-developed anterior-lateral segment, causing malformation of the patellar groove region and thus predisposing one to lateral patellar subluxation and full dislocation of the patella and quadriceps mechanism. The function of the quadriceps mechanism can be worsened further by a slight tendency to external rotation positioning of the distal femur, even in those situations in which abnormalities of the proximal one-half or two-thirds predominate. Abnormalities of the distal femur also are seen in more serious developmental disorders of the leg but can be associated with either fibular hemimelia or tibial hemimelia. Tsou has described a rare congenital abnormality of the distal femoral epiphysis in which the proximal part of the femur, including the shaft, otherwise was normal (254).

SECTION IV ~ Infantile Coxa Vara

FIGURE 22 An established infantile coxa vara lesion is shown. The triangular fragment on the inferior surface of the neck is characteristic. Note the vertical radiolucent defect. Hilgenreiner's epiphyseal angle is increased. [Reprinted from Weinstein et al. (1984), J. Pediatr. Orthop. 4: 70-77, 9 Lippincott Williams& Wilkins, with permission.] IV. I N F A N T I L E C O X A V A R A

A. Terminology Infantile coxa vara is a condition in which deformity is isolated to the proximal femur without abnormalities of the middle or distal femur or the rest of the skeleton. It is characterized by a pathognomonic bony discontinuity of the inner surface of the femoral neck, appearing as a triangular-shaped bone fragment with its base along the inferior surface of the neck bordered by the physis medially and superiorly and a vertical radiolucent fissure laterally. The disorder is limited almost exclusively to the physis and neck, with the femoral head epiphysis, greater trochanter, and acetabulum otherwise normal initially (Fig. 22). It is not congenital in that many patients have been described in whom the hip radiographs in the first year of life were normal but coxa vara deformity developed shortly afterward. There is relatively little shortening of the femur in infantile coxa vara, unlike the situation in truly congenital coxa vara associated with dysgenesis of the entire proximal femur. The limb shortening with infantile coxa vara is caused by the varus deformation and the decrease in length of the femoral head and neck region only.

B. Clinical and Radiographic Presentation of Infantile Coxa Vara It is well-established that, in some patients with infantile coxa vara, radiographs taken during the first year of life can be normal with the radiographic appearance changing during the second year of life and beyond. Infantile coxa vara generally presents around 2 years of age with a painless awkward gait with a waddling component, which may be unilat-

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eral or bilateral. In bilateral cases lumbar lordosis is present. The gait worsens progressively over the next few years. The Trendelenburg test is positive and hip abduction and internal rotation are limited. The disorder has an equal sex incidence and is bilateral in 33-50% of patients (66, 176, 208, 220). The children do not experience discomfort but tend to fatigue readily. On radiographs, the physis is more vertical than normal, and it appears inferiorly and medially to be branched like an inverted Y. This vertical fissure is the characteristic radiographic feature of infantile developmental coxa vara. It rarely if ever is seen in the first 2 years of life. Some of the pathological findings are felt to be consistent with trauma, but there have been only rare instances describing recognizable trauma. Genetic factors have been implicated because several cases of infantile coxa vara have been reported in siblings or in twins. Fisher and Waskowitz documented 16 reports of familial developmental coxa vara in the literature and added their own (78). The initial clear description of what we now refer to as infantile coxa vara was by Hoffa in 1905 (114). The disorder also had been described by Hofmeister under the name of coxa vara adducta (115). Elmslie described infantile coxa vara with great clarity (66). In his report the sex incidence was the same, and 8 of the 20 cases were bilateral. A waddling gait had been noted when the child first began to walk in one-half of the patients, and most of the other symptoms had become clearly evident by the ages of 6 - 8 years. The greatest limitation of hip motion was in abduction, which often was abolished completely. Lordosis was extremely marked in particular with bilateral involvement. At 5 years of age, there is "a downward displacement of the head of the femur carrying with it the adjoining portion of the base of the neck." The slippage of the head and its retention in apposition with the base of the femoral neck by the periosteal coveting occurred as a result of sudden accident or by a process of gradual slipping. With displacement of the head, the downward pressure of the body weight transmitted to the upper margin of the acetabulum becomes directly transverse to the line of the infraction which has been produced and nearly transverse to the epiphyseal line. With increasing age, the displacement of the head would increase owing to this mechanical factor. Moreover, the neck of the femur which develops from this epiphyseal line chiefly after the fifth year, will be developing in the wrong direction, owing to the line of growth now being nearly vertical instead of horizontal. Sequential X rays showed that (1) displacement of the head tends to increase with age, (2) the neck does develop pointing transversely or even downward, and (3) the infraction in the upper border of the neck frequently is visible. Elmslie felt that direct trauma could cause the lesion but that birth injury, although possible, was difficult to prove. The disorder was not tickets because depression of the femoral neck is not common as a result of infantile tickets. It is now widely considered that the disorder develops initially in the first and second years of life and that the

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CHAPTER 5 ~ Coxa Vara in Developmental and Acquired Abnormalities of the Femur

femoral neck is short and largely cartilaginous. Shortening can occur in unilateral cases with one report referring to about a 4-cm discrepancy. In virtually all series, the infantile coxa vara cases are isolated abnormalities with no other femoral or skeletal irregularities seen. In perhaps 15% of cases, this appearance is seen with skeletal dysplasias, generally cleidocranial dysostosis, or spondyloepiphyseal dysplasia congenita. Blockey clearly has recorded his impressions that infantile coxa vara is an acquired lesion (28). He notes that "half or more of the femoral neck is naked and the shaft looks laterally rotated. This appearance could be produced by the capital epiphysis with its epiphyseal plate and triangular fragment of metaphysis sliding distally until the superior aspect of the head abuts on the inferior surface of the proximal part of the neck. The line of cleavage remains visible and the displacement is with the femoral neck." Blockey thus likens infantile coxa vara to distal movement of the head as though an infantile slipped epiphysis with a triangular fragment of bone had occurred. He feels this is due either to unappreciated extrinsic trauma in the early months of life or to slipping through the metaphyseal side of the physis through bone that is somewhat softened or pathologic. He thus feels that "infantile coxa vara is likely to be due to distal movement of the head fragment relative to the shaft and neck." Infantile coxa vara usually presents clinically in the second and third years of life.

C. Pathoanatomy of Infantile Coxa Vara The earliest pathoanatomic study was that of Hoffa in 1905 in which he described the gross and histologic findings in both proximal femurs in a 4-year-old boy who had undergone resection of the femoral head-neck region (114). Gross anatomic drawings show the coxa vara deformity in his two cases. He also described other cases. He found no evidence of rickets or trauma. The growth region of the capital femoral epiphysis had abnormal signs of endochondral growth with a lack of the proliferating chondrocyte zone. In the cartilage, the typical proliferating zone was lacking, the trabeculae did not exhibit any growth by apposition, and the bone marrow did not resemble that of a normal child but showed regressive changes. This region was characterized by vascular invasion. Hoffa illustrated a femoral head and neck specimen cut in the coronal plane, which shows the coxa vara deformity, the secondary ossification center in its normal position, and early bone formation at the medial and inferior surface of the physeal and epiphyseal regions. Helbing drew a similar histologic conclusion in 1906 from a specimen from a 4-year-old child (106). The epiphyseal line was irregular and the cartilage cells were in complete disorder with no trace of a columnar arrangement. The bone trabeculae were thin and surface osteoblasts were not seen. Similar histologic irregularities were described by Delitala (57), Barr (20), and Zadek (274), who all noted irregularities in the physeal region of the most medial part of

the growth plate. Camitz ruled out any resemblance to rickets in a detailed histologic study of three cases (42). He noted deformity of the femoral head similar to others, but few would now accept his suggestion of similarity to Perthes disease. Vascular tissue often invading the vertical fissure ruled out a hypovascularization etiology. Although he felt the disorder was developmental, he recognized that it was postnatal in occurrence. Trauma was felt to play no role in causation. Camitz' work is most valuable for demonstrating the irregular junction between physeal cartilage and metaphyseal cervical bone. The physeal cartilage itself was normal in thickness as assessed macroscopically. The neck adjacent to the physis medially contained cartilage islands, which led to a fragmented appearance radiographically. Burckhardt also studied histologic specimens from the medial portion of the femoral neck, which showed substitution of a wellorganized cartilage region by connective tissue and poorly organized cartilage (39, 40). Babb et al. summarized this early work and concluded that there was "nothing characteristic in the microscopic appearance of tissue removed from the femoral neck" (17). By this they appeared to indicate that no primary pathognomonic cartilage or bone irregularity was seen because there are evident, although secondary, irregularities. Barr examined histologic specimens and noted that the cartilaginous junction with the metaphyseal bone spicules was abrupt (20). The endochondral sequence was not occurring in anywhere close to its normal fashion. Invasion of cartilage by blood cells was absent. The cartilage was hypocellular and appeared more like nonendochondral hyaline cartilage. Zadek reported examination of tissue removed from the superior border of the neck of the femur in a patient only 5 years of age, showing an epiphyseal cartilage plate similar to one that might be undergoing early closure rather than one actively involved in cartilage endochondral growth (274). On occasion, fragments of growth plate cartilage in the metaphysis were surrounded by compact bone. Zadek also provided a detailed translation of the histologic report by Delitala. The neck of the femur had considerable fatty tissue rather than hematopoietic marrow. It also contained isolated cartilaginous nodules surrounded by bone, indicating a disordered endochondral sequence. The physis was abnormal, being characterized more by an undifferentiated hyaline-type cartilage than by a characteristic stratified physeal cartilage. The cartilage tissue was invaded irregularly by vascular tissue, which normally would not be seen in this age group. In some sections he described vessels passing through the physeal cartilage completely and linking diaphyseal (metaphyseal) bone of the neck with bone of the secondary ossification center of the epiphysis. Endochondral ossification was seen irregularly along the physis, which clearly was abnormal. Due to the vertical nature of the physis the line of ossification was in an abnormal direction, leading to slowness of bone transformation and irregularity of form and arrangement of the spongy trabeculae. Johanning also

SECTION IV ~ Infantile Coxa Vara reported similar histologic findings (133). The physeal cartilage was wider than normal but showed scattered islands of bone adjacent to it. There were few areas showing normal transition from cartilage to bone. Pylkkanen reviewed the histological studies done prior to 1960 (220). Among the best investigations were those of Hoffa and Helbing, which were based on resection of the whole proximal part of the femur, a procedure done at the time because of concern about tuberculosis. Pylkkanen then summarized the interplay of three major factors in the pathogenesis of infantile coxa vara: growth phenomena, staticmechanical relationships, and circulatory relationships in the hip joint. He examined core biopsy tissue from the medialinferior region of the metaphysis of the femoral neck in 25 patients with the biopsies taken from the vertical fissure region during osteotomy. The epiphyseal plate itself was not studied. The biopsies were from patients ranging in age from 3 to 18 years but clustered between 6 and 10 years of age (18 of 25). Endochondral ossification was defective. Histologically each of the specimens showed a "striking uniformity," although the patients were at different ages and the lesions were of different degrees of severity. Common features involved (1) cartilaginous tissue, which in the majority of cases formed a uniform plate corresponding to the zone of rarefaction visible in the radiograph, (2) metaphyseal bony tissue immediately adjacent to the cartilage, and (3) connective tissue invading both bone and cartilage. The cartilage plate consisted of cartilage of the same type as in the epiphyseal plate, but it demonstrated pathological changes in all instances characterized by markedly disturbed cell arrangements. On occasion the growth plate structure was the same as in the normal epiphyseal plate, whereas in others the cartilage cell arrangements were completely irregular. Both hypocellular and hypercellular areas were seen. Connective tissue of a fibrovascular nature was commonly interspersed. Junction between cartilage and bone showed endochondral ossification but in all specimens the process was much slighter than normal. The cell columns were short and in some sites totally irregular. The metaphyseal bone was characterized by osteoporosis. Connective tissue was common throughout the cartilage region. Pylkkanen produced an extensive analysis of the changes dividing those in each study into slight, moderate, and marked and commenting on (1) structural changes and the nature of endochondral ossification in the cartilage regions, (2) structural changes and disturbances of the bone marrow and the bone segments, and (3) connective tissue as it related to both cartilage and bone. The radiolucent fissure in most instances was composed of cartilage, which on occasion appeared to be structured almost as though it were an epiphyseal growth plate. Major structural changes were noted, however, in all cases. "The process of endochondral ossification at the junction between this cartilage and the metaphyseal bone was considerably disturbed." Interference with ossification, which in some sites was partial, in others complete,

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was observed in all cases. Changes in the metaphyseal bony tissue were considerable, similar from case to case, and involved an osteoporosis. The amount of connective tissue within the areas of the bone or cartilage varied considerably from case to case although it tended to be more marked in more severe cases. Changes of rickets, bone necrosis, or inflammation were not seen. The zone of rarefaction running across the neck of the femur in the X rays consisted of cartilage resembling that of the epiphyseal plate, but mostly with a markedly disturbed cell arrangement. The process of ossification was severely disturbed, and the adjacent metaphyseal bone was atrophic and sometimes contained large islands of cartilage. Large amounts of connective tissue were seen within the areas of cartilage and bone. The bone marrow was scanty and fibrotic. Tissue from the zone of rarefaction showed a cartilage tissue plane across the metaphyseal spongiosa. Prior to 6-7 years of age, a cartilage pseudo-physis was seen. Much of the tissue was fibrocartilage, but some elements of a disorderly endochondral sequence were seen. In older patients beyond 8 years of age, cartilage islands were embedded in fibro-osseous tissue. Osteoporosis and fibrotic marrow were seen to either side of the cartilage. In patients 11-15 years of age, an essentially fibrous pseudoarthrosis was seen. Serafin and Szulc obtained 19 specimens for histologic investigation from the femoral neck during the process of valgus corrective osteotomy (235). Tissue from the vertical fissure was primarily cartilaginous in nature with some similarity to physeal tissue. Those parts of the physis itself available for review showed evidence of impairment of growth particularly of the endochondral ossification sequence. There were hypocellular regions, irregular arrangements of cartilage columns, and a tendency to a cartilage-bone interface in which spicules of calcified cartilage normally would extend more deeply into the metaphyseal bone and be surrounded by new bone formation on them. Once the infantile coxa vara deformity was well-established, the physeal and in particular vertical defect tissues were more fibrous and calluslike than truly cartilaginous. Bos et al. briefly referred to the appearance of lateral physeal cartilage obtained by core biopsy in two patients 4 and 9 years old at the time of valgus osteotomy of the proximal femur (31). The cartilage lacked any physeal characteristics of proliferating and hypertrophic chondrocytes and appeared as a relatively hypocellular cartilage mass interspersed between epiphyseal and metaphyseal bone but not contributing to growth by any evident endochondral mechanism. Chung and Riser published a case report of a 5-year-old boy with a unilateral infantile coxa vara who died of unrelated causes (49). He had had an intertrochanteric osteotomy on the involved femur 2 years previously. The authors reviewed previous studies of total head specimens in which it was felt that coxa vara had resulted from a defect in endochondral ossification with large amounts of fibrous tissue

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CHAPTER 5 ~ Coxa Vara in Developmental and Acquired Abnormalities o f the Femur

rather than cancellous bone noted in the femoral neck metaphysis. There has long been concern that coxa vara was due to impaired blood supply to the femoral head-neck region particularly due to defects in the medial ascending cervical artery. Chung and Riser were able to perform vessel perfusion studies in coxa vara with comparative studies done on the contralateral normal proximal femur. The neck-shaft angle on the affected side was 85 ~ compared to the normal 135 ~. The neck was shorter and the growth plate on the affected side was wider (0.3 versus 0.2 cm). Assessments of the vertical growth plate noted an absence of orderly columnization in the hypertrophic cartilage layer, sparse bony trabeculae in the metaphysis, and little evidence of endochondral bone formation. The cartilage of the involved growth plate was pulled apart at several points with slits appearing along the long axis. Cystlike cavities were left in a number of places. The perichondrial ring, however, appeared to be normal. The cartilage formed regions of clones on the metaphyseal side, but none resembled a normal endochondral sequence. Cartilage cells near the metaphyseal border did not hypertrophy nor form a characteristic calcified matrix as a template for bone trabeculae formation. The normal vascular invasion from the metaphyseal side also was irregular and abnormal. The growth plate appeared to have split medially into two parts and to have isolated a triangular fragment of cancellous bone. The vertical fissure contained cartilage cells similar to those in the abnormal growth plate but they were even more disordered. The cartilage regions of the trochanter also were abnormal, although not as markedly involved as the medial femoral growth plate regions. The vascular patterns of the capital femoral epiphysis on the involved side were normal. The lateral ascending cervical arteries or lateral epiphyseal arteries appeared to be normal outside the bone and also within in relation to the secondary ossification center. The medial ascending cervical arteries, however, were fewer in number and smaller than normal both extraosseously and intraosseously. Chung and Riser concluded that the major problem appeared to be a defect in endochondral ossification medially. The absence of orderly endochondral ossification columns at the metaphyseal border of the head-neck growth plate resulted in decreased production of metaphyseal bone. The vascular perfusion studies demonstrated that intraosseous arteries supplying the metaphyseal side of the growth plate and the extraosseous medial ascending cervical arteries on the surface of the femoral neck were fewer in number and smaller in diameter than normal.

D. Evolution of Radiographic Change Radiographs during the first year of life, if obtained, appear to be normal (9, 28, 66). The developmental changes are relatively slow thereafter and indeed the initial radiographs, even after development of the lesion, can appear normal because the changes are occurring in the nonossified cartilage regions of the physis. By 3 years of age, however, diagnostic changes are seen. These involve increased obliquity or more

vertical positioning of the physis and a developing varus deformity of the head and neck region relative to the shaft. The neck tends to be somewhat shortened. In virtually all studies it also is considered to be retroverted. There is a characteristic radiolucent vertical fissure giving an inverted V or inverted Y appearance to the physis. The vertical fissure is inferior to the physis, being within the upper and inner part of the femoral neck. The adjacent metaphysis shows irregular ossification rather than being a smooth, slightly curvilinear line. The width of the radiolucent vertical defect is generally greater than the physis. The greater trochanter continues to grow normally and tides progressively higher than the femoral head. It tends to develop a beaking at its tip. In those situations in which a considerable number of years have passed, the head appears to slip inferior to the trochanter. The trochanter may form a facet adjacent to the ilium. Initially, the acetabulum develops normally because the femoral head is situated within it. With increasing varus tilt and inferior displacement of the head in relation to the acetabulum, acetabular dysplasia can occur. Frequently there is a delayed appearance and delayed development in size of the secondary ossification center on the involved side, although the head itself tends to remain spherical. At later stages the secondary ossification center of the femoral head is osteopenic, presumably due to diminished effective weight bearing. In many instances, increased radiolucency appears between the head and the neck due to the delay in ossification. Eventually, this will be replaced by bone. Early in the second decade premature fusion of the head-neck physis occurs usually beginning at the inferior-posterior region. On occasion, in patients not treated and followed into adulthood, a true pseudarthrosis develops in which the neck-shaft angle is most abnormal and often as little as 40-60 ~. Presently, assessment of the underlying structure in a coxa vara can be better appreciated with MR imaging. Two radiographic indices have been used to measure the extent of the coxa vara deformity. The most common is simply the head-neck-shaft angle measured from an anteroposterior radiograph. This sometimes is referred to as the angle of inclination of'the neck. When this is less than 110 ~ many consider the coxa vara deformity to be established. In a relatively large study of 42 hips by Catonne et al. the average angle was 88 ~ with a range from 65 to 110 ~ (46). Similar ranges for the head-shaft angle are reported in other series. Desai and Johnson reported an average head-shaft angle initially of 96 ~ in 20 hips with a range from 85 to 115 ~ (60). Schmidt and Kalamchi noted an abnormal neck-shaft angle of 94 ~ in 22 hips with a range from 74 to 120 ~ (231). Weinstein et al. studied several patients with isolated congenital coxa vara (by which was meant the infantile coxa vara deformity), although these were grouped with other patients with congenital coxa vara associated with shortened or bowed femurs. In this group as well the average preoperative neck-shaft angle was 90 ~ with a range from 44 to 120 ~ (266). The older the patient and the longer the period of time before initial valgus osteotomy, the greater the diminution in

SECTION IV 9 Infantile Coxa Vara the neck-shaft angle. The clinical and radiographic progression of deformity was documented clearly by Pouzet (217). This also was well-documented in a large series of 130 affected hips in 106 patients from Poland studied by Serafin and Szulc (235). The average neck-shaft angles in groups aged 2-6, 7-11, and 12-16 years and post-skeletal maturation were 85 ~ 71 o, 67 o, and 55 ~ respectively. The second angle used to document the coxa vara deformity in the infantile variant is that described by Weinstein et al. and referred to as Hilgenreiner's epiphyseal (HE) angle (266) (Fig. 22). This uses Hilgenreiner's line as a horizontal axis and a line through the metaphyseal side of the physeal defect as the vertical axis. The average HE angle in their group of 100 normal hips was 16~ with a range from 0 to 25 ~ The average HE angle that developed in their coxa vara patients was 82 ~ with a range from 66 to 120 ~ Desai and Johnson also utilized this measurement in assessing 20 hips and noted an average HE angle of 66 ~ at initial evaluation with a range from 45 to 90 ~ (60).

E. Pathomechanics of Deformity in Infantile Coxa Vara There is a clear dissociation of growth between the greater trochanter, which is normal or relatively normal, and the head-neck regions, which clearly are affected. There is a uniform crescentic growth plate under the head-neck and greater trochanter until 4 years of age, at which time divergence of the head-neck axis leaves two separate physes. The trochanteric portion of the growth plate contributes to the length of the shaft, whereas that of the head-neck region is responsible for shaping of that area alone particularly due to its oblique position. Once there is a relative change in growth rate and, thus, in position of these two structures, the head and neck region is placed at a mechanical disadvantage. With the physis increasingly directed toward the vertical plane, the tendency to its slippage is markedly greater. When the head and neck angle is less than 100~ worsening is inevitable. With time the medial physeal cartilage fuses, thus allowing for further and more rapid worsening of the condition. The clinical and radiographic appearances remain consistent with a lateral rotation deformity of the neck and shaft with the head being positioned in a medial and relatively retroverted position. The radiographs indicate that one-half or more of the femoral head is uncovered and the shaft appears laterally rotated. This appearance could be produced by the capital epiphysis including the physis and the triangular fragment of the metaphysis sliding distally until the superior aspect of the head comes against the inferior surface of the proximal part of the neck. Presentations of the pathogenesis of the deformity along these lines would indicate that the patient essentially has suffered a type II fracture-separation. Due to the existence of a large number of bilateral and familial cases infantile coxa vara cannot be attributed simply to trauma alone, although the worsening displacement appears to have a mechanical cause on the basis of growth in

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relation to the disadvantageous early varus position. Pouzet felt that the primary site of abnormality was the physis and the femoral neck, with the femoral head and its secondary ossification center and the diaphysis remaining normal (216, 217). For the first few years the femoral head was round with good density of the secondary ossification center and positioning of the head in the acetabulum. Deformity occurred initially because of insufficient biological growth of the medial physis and adjacent femoral neck followed by secondary biomechanical changes due to the altered position of the head and orientation of the physis in relation to weight bearing. In the most advanced form, the neck is extremely shortened and the head essentially is plastered against the medial diaphysis adjacent to the lesser trochanter with extreme relative overgrowth of the greater trochanter. In a biomechanical sense, deformity in infantile coxa vara in a growing child worsens with time because the region of greatest stress in a proximal femur positioned into coxa vara is concentrated around the vertical radiolucent fissure and triangular fragment. The possibility has been raised that the etiology of the vertical fissure is traumatic, being analogous to a type II fracture-separation (28). It would appear, however, that rather than being acutely traumatic the vertical fissure represents a stress fracture or pseudo-fracture. Pauwels stresses that the varus malposition not only hinders the new formation of bone but as a consequence also serves to break down any newly formed trabeculae shortly after their synthesis (207). Pauwels indicates, therefore, that infantile coxa vara is a weight bearing deformity. The triangular fragment of bone on the medial surface of the neck is limited medially by the epiphyseal line and laterally by the fissure. The latter is truly vertical, whereas the epiphyseal line has increased obliquity from the normal. The radiographic abnormalities in the neck change fairly dramatically after subtrochanteric osteotomy, which again supports the stress and trauma causation. Walter postulated that relatively excess body weight in coxa vara was present, with the vertical fissure representing not a congenital deformity but a physiological reaction of the bone to excess shearing stresses of weight beating (258). The rapid healing of the lesion that occurred following valgus osteotomy was further confirmation of this finding. Chung and Riser feel that the vertical fissure is indeed a stress phenomenon and that the varus worsens from the increasing load on the femoral head of the growing individual, who is becoming progressively heavier (49). A vertical fissure tends to persist for several years because continued and increasing stress is concentrated in the area osteogenic activity decreases. When the stress is relieved by valgus osteotomy alone, the vertical fissure almost always disappears by healing, being replaced by bone. Both sides of the vertical fissure contain cartilage cells resembling those in the disorganized growth plate. Three separate events appear to occur in the development of an infantile coxa vara deformity. (1) The first event involves a decrease in function of the medial and inferior part

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CHAPTER 5 ~ Coxa Vara in Developmental and Acquired AbnormaBties of the Femur

of the growth plate. This appears evident from the histologic studies in which there is a lack of cartilage proliferation, the growth plate becomes disorganized, there is vascular and fibrous invasion, and bone islands form. It does not appear that the entire proximal femoral capital growth plate is involved initially. The involvement is of the inferior medial portion with both histologic and radiographic evidence seen for this in that considerable vertical obliquity of the growth plate develops. If the entire proximal femoral growth plate was involved initially, the physis would remain horizontal and that of the greater trochanter would continue to grow. In fact, however, there is a tilting of the entire head-neckgreater trochanter complex and the plate itself becomes oblique. This must indicate that the tethering or nongrowth effect is at the medial and inferior margin of the plate with the lateral two-thirds of the head-neck physis functioning well. (2) The second stage in the pathogenesis involves a slippage of the head and physeal region and the adjacent portion of the metaphyseal bone of the neck in relation to the rest of the upper end of the femur. Once the varus reaches a certain degree, the stresses on the vertical physeal region are sufficiently great that mechanical slippage occurs. This would seem to be gradual as the patient does not appear to experience any discomfort and as such is more along the lines of a stress fracture or even analogous to an in situ slipping of the proximal femoral capital epiphysis. This would appear to represent the etiology of the inverted triangular fragment at the inferior surface of the neck. Bone and degenerate cartilage remain present in the inferior region and the radiolucent line seen medially represents the epiphyseal cartilage and the remnant of the physeal cartilage, with the other line more lateral toward the femoral neck bone representing the vertical fissure or stress fracture. This region too shows cartilage histologically although it is even more disorganized than that of the physis. Others have postulated that there is a lateral rotation of the neck and shaft region, which also is analogous to the situation in slipped capital femoral epiphysis. There are some similarities to a type II epiphyseal fracture-separation, although the upper end of the femur is entirely cartilage at this age (except for the secondary ossification center of the head) with a single growth plate composing the head, intertrochanteric, and greater trochanteric cartilage areas. (3) Final resolution of the deformity occurs when a subtrochanteric valgus osteotomy is performed. This serves to reposition the head deeply into the acetabulum and to reposition the vertical growth plate close to its normal horizontal axis. Once the hip has been positioned in this way, there is almost invariable healing of the triangular fragment, which is consistent with it being a stress fracture rather than a cartilaginous embryonic maldevelopment. This viewpoint was defined first by Elmslie in his reports in 1907 and 1913 and appears to be accurate today. His views were reviewed more recently by B lockey, who supports a traumatic etiology. On occasion, episodes of trauma do lead to the appearance of infantile coxa vara as described by Blockey (28),

Elmslie (66), and Joachimsthal (132). The worsening of the disorder with time on a biomechanical basis was defined by Elmslie. As the vast majority of the cases of infantile coxa vara develop prior to 4 years of age, at which time there is still cartilage continuity from the head and neck region and the greater trochanter, the pathogenesis of the deformity cannot be defined clearly by radiographic studies. Whether the initial varus deformity is caused by trauma or by failure of growth in the medial and inferior portion of the neck, the varus itself will predispose one to further slipping. When the epiphysis of the head has been moved into the vertical plane, the neck of the femur develops in a horizontal rather than a linear and oblique direction because the line of growth now is nearly vertical instead of horizontal. When the head-neck-shaft axis is less than 90 ~ the femoral head does not rest appropriately in the acetabulum and the weight bearing is done on the most lateral aspect of the head, which has the thinnest cartilage surface. The waddling gait is worsened by the high-tiding greater trochanter, which serves to shorten the point of attachment of the gluteus medius and minimus muscles, leaving them relaxed and unable to perform at their normal level of function. The gait is worsened further by shortening of the involved femur if the condition is unilateral. The entire spectrum of growth deformities in infantile coxa vara was well-reviewed by Serafin and Szulc (235). The primary abnormality leads to a reduction in the neckshaft angle, which also can be documented as an increase in the Hilgenreiner epiphyseal angle. There is retroversion in the femoral neck in 85% of cases, upward overgrowth of the greater trochanter in virtually all cases, diminution in the size of the femoral head in virtually all cases, and some shallowness and underdevelopment of the acetabulum in most cases. The earlier the head is repositioned by valgus osteotomy into its normal relationship to the acetabulum and the less severe the growth abnormalities of the neck, then the better the acetabular contours.

F. Clinical-Radiographic Correlations Fairbank listed the specific radiographic criteria for a diagnosis of infantile coxa vara as (1) decreased neck shaft angle, (2) wide, vertically aligned physis or proximal femoral epiphyseal plate, (3) irregular metaphyseal ossification, (4) shortened femoral neck, (5) triangular osseus fragment adjacent to the inferior margin of the physis, (6) normally shaped but osteoporotic femoral head, and (7) straight femoral shaft (71). Johanning assessed several cases with long-term followup X rays (133). In patients with infantile coxa vara, the initial radiographs were characterized by the varus deformity of the head and neck axis, a short and poorly developed neck, and widening of the angle formed by the epiphyseal line in relation to the horizontal. He also noted the earliest formation of calcific deposits at the inferior surface of the neck in

SECTION IV ~ Infantile Coxa Vara relation to the widened and more vertical physeal space between the secondary ossification center and the metaphysis. He commented on the increasing inferior slippage of the head and neck fragment in relation to the rest of the proximal femur with time. Indeed, in the age group between 10 and 15 years, the slipping of the head became much more marked. This is illustrated particularly well in an untreated but well-documented case showing the typical development of infantile coxa vara at 3, 8, and 13 years. At 3 years of age, the superior surface of the head is at the level of the tip of the greater trochanter and the characteristic abnormalities can be seen. At 8 years of age, there is considerable overgrowth of the greater trochanter, which is now above the lip of the lateral acetabulum, whereas at 13 years, the greater trochanter approached the iliac spine and the lower part of the femoral head is well below the lesser trochanter. One of the problems is the part played by trauma in infantile coxa vara. As Johanning indicates, the trauma need not come from a single event but rather can be the outcome of abnormal stresses over time interfering with nutrition of the parts involved. The good results achieved by valgus osteotomy with appropriate healing of the vertical fissure clearly point to trauma and shear stresses as causative because no other generalized or systemic problem would respond that well to a simple change in position. Magnusson showed that the average age at which symptoms set in was 3.3 years and that the major mode of presentation was limping (176). There were no problems prior to the onset of the limping. He describes the gradual onset of changes in the radiographic picture, with the primary abnormality being the varus position and the vertical fissure occurring secondarily and not until the varus has reached a certain degree. He feels that the fissure is an "insufficiency fracture," which at a later stage may proceed to a real pseudarthrosis. Magnusson presents a series of 85 hips with infantile coxa vara treated in Stockholm, Sweden, between 1927 and 1941. The average age at subtrochanteric cuneiform osteotomy was 10.9 years and the average age at long-term follow-up was 27.3 years. The average age at first examination, at which time the diagnosis was made, was 6 years so that there was an average of 4.9 years between initial diagnosis and surgery. Some of the long-term changes involved shortening of the neck, which was particularly marked in those operated at a later age. On occasion, there also were changes in the shape of the head. During the course of the disease, there was obvious bone atrophy and deformation. Deformation of the head rarely was seen when the neckshaft angle was reestablished surgically. In virtually all cases, the acetabulum tended to be more shallow than normal. Magnusson thus felt that "to complete the picture of a fully developed coxa vara infantum, the following should be added to the roentgenological symptoms already k n o w n - the varus position and possibly the vertical fissure: 1) a shortened collum (neck); 2) a more or less deformed caput (head); and 3) a shallow acetabulum." He clearly indicated that the

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longer the process continued undisturbed, the more characteristic the changes. The only correctable deformity was the neck-shaft angle. He stressed that "the earlier this restitution takes place during the course of the pathological process, the less characteristic will the changes be in the parts concerned of the hip joint and the better the functional results will be in the long run." The major long-term problem in those treated late was a persisting pseudarthrosis. When present, virtually complete resorption of the neck had occurred. The head had been deformed and the acetabulum was quite shallow. His conclusion was straightforward-the subtrochanteric cuneiform osteotomy was the logical form of treatment and the earlier it was performed, the less progressive the long-term changes and the better the longterm result.

G. Management of Infantile Coxa Vara Coxa vara responds well to surgical repositioning of the proximal end of the femur by valgus osteotomy at the intertrochanteric or subtrochanteric level. The aim of treatment is 2-fold: to correct deformity and to enhance repair of the vertical defect by ossification. Since the 1890s when coxa vara was formally defined, proximal femoral valgus osteotomy has been performed to correct the deformity and remains the mainstay of therapy today. Nonoperative therapy plays no role. Observation remains important as the timing of any surgical intervention often is unclear. Although coxa vara will not correct spontaneously, the rate of progression can vary greatly. Due, however, to the fact that the growth plate is not normal, it is not unusual for any operation to require repetition during the growing years. The degree of correction frequently must be extensive, depending of course on the severity of deformity. Those operations that undercorrect the deformity are doomed to a far earlier repetition than would otherwise be the case. Weighill has pointed out the value of adductor tenotomy along with the valgus osteotomy (264). He felt that 10 of 10 patients with the combined approach did well, whereas only approximately three-fourths of 22 osteotomies without adductor release did well. Operative treatment involves a proximal femoral valgus osteotomy, which accomplishes the correction of each of the three major clinical abnormalities by (1) repositioning the head into the weight beating position in the acetabulum, (2) lengthening the lever arm, thus making the abductor muscles function more effectively, and (3) lengthening the limb to compensate for the loss of growth. Le Mesurier noted, as have many others, that the valgus osteotomy also allows the radiolucent vertical neck defect to heal (166). Healing of the defect was seen in 11 of 12 cases within 1 year of surgery. Babb et al. recommended subtrochanteric osteotomy at 6-8 years of age with "wide" abduction of the distal limb (17). In a mechanical sense, the negative shear forces on the head and neck would be converted to compression forces, healing the vertical osseous defect and stabilizing the

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CHAPTER 5 ~ Coxa Vara in Developmental and Acquired Abnormalities of the Femur

proximal femoral anatomic relationships. Although some surgeons recommended drilling across the triangular cervical defect or even bone grafting, neither of these are needed after valgus osteotomy to ensure healing of the defect by bone. Guidelines for therapy were defined as early as 1938 by Pouzet of Lyon, France (216). He recognized that the goals of treatment were to straighten the head and neck relationship to a normal range, to obtain ossification of the cartilaginous fissure of the neck, and, if possible at the same time, to obtain premature fusion of the growth plates of the proximal femur to prevent recurrence. This triple goal was best obtained by corrective subtrochanteric osteotomy. Previous treatments felt to be neither effective nor necessary involved closed reduction of the deformity, bone graft to the neck to allow the independent fragment to unite, and resection performed in the neck region to remove the pseudarthrosis. The subtrochanteric valgus osteotomy not only corrected the deformity but allowed for the rapid ossification of the neck as well as for premature transphyseal fusion such that the varus would not recur. Pouzet referred to several other reports of excellent results with osteotomy that had been described in the previous decade. Correction often was enhanced by adductor myotomy. The appropriate time for surgery varied from case to case but appeared to be best between 5 and 8 years of age. He also pointed out the frequent premature fusion of the femoral head-neck growth plate cartilage following osteotomy. This was not a complication of the surgery but rather indicated that the physeal cartilage was not normal as part of the disease state. Pylkkanen has also indicated that conservative measures were of no avail and that surgery was warranted (220). Subtrochanteric valgus osteotomy was needed, and "the earlier the surgical intervention, the larger was the ratio of good results in each age group." He concluded that "the lesion should be corrected as early as possible." This generally means intervention in the 4- to 8-year-old range. Additional procedures can involve a distal transfer of the greater trochanter to further lengthen and thus strengthen the abductor muscle group, although this should not be done if there is still meaningful trochanteric growth remaining. On the other hand, if done toward the end of skeletal growth the trochanteric transfer also will serve to obliterate the greater trochanteric growth plate and prevent recurrence of the deformity. The need to transfer the greater trochanter distally is dependent on its position after completion of the valgus osteotomy. In some, rotation of the proximal end of the femur alone is sufficient to appropriately position the head-neck and greater trochanter areas, whereas in others the greater trochanter still tides too high and must be separately and further displaced. Growth of the proximal femoral capital epiphysis in infantile coxa vara is, by definition, less than that of the greater trochanter. In addition there is a marked tendency for the physis to close prematurely, further worsening the prognosis. The closure may be evident radiographically or by MR imaging. If osteotomy is done early in the second decade

and the physis appears to be closed, in situ greater trochanteric epiphyseal arrest should be considered. There is no need to treat the nonunited fragment of the femoral neck; with correction of the coxa vara deformity this fragment almost invariably will heal itself spontaneously. Valgus osteotomy converts the vertical fissure subject to sheafing forces to a more horizontal plane where compression, favorable to healing, occurs. The positive Trendelenberg sign, which is always seen, is converted to normal with effective valgus repositioning. Pylkkanen noted this in 96 of 114 cases of widely varied severity. Lower extremity length discrepancy can be managed by contralateral distal femoral epiphyseal arrest. There is relatively little shortening of the femur in infantile coxa vara, unlike the situation in truly congenital coxa vara associated with dysgenesis of the proximal femur. The limb shortening with infantile coxa vara is caused by the varus deformation and the decrease in length of the femoral neck. Amstutz noted shortening in 10 patients with unilateral developmental coxa vara to be not more than 4 cm, which he felt was consistent with developmental irregularity at the head and neck region exclusively (10, 11). Pouzet referred to 3-5 cm of shortening at skeletal maturity in severe untreated cases (217). Even the mildest cases of proximal femoral focal deficiency lead to much more extensive shortening than could be accounted for by the varus of the hip. Virtually all studies note that the end results in patients with infantile coxa vara are dependent on the initial angle of inclination, the age at the time of surgery, and the extent of valgus correction at the time of surgery. Poor results are seen in those in whom the neck-shaft angle is less than 90 ~, the patients are operated initially after 9 years of age, and valgus correction is less than 130 ~ To a great extent, the timing for surgery is dependent on age at initial presentation of the disorder (over which the orthopedic surgeon has relatively little control), but it also is dependent on the extent of the deformity and its rate of progression. Schmidt and Kalamchi noted that coxa vara with mild deformity with neck-shaft angles greater than 110 ~ tends to heal the metaphyseal fragments early and subsequently improves the angles (231). In these hips only observation is performed. Similar observations have been made by others (266). Deformities less than 100 ~ on the other hand, tend to progress and surgery generally is recommended at that range. Hips with angles between 100 and 110 ~ are observed initiallywith the timing of intervention dependent on progression of the deformity. Catonne et al. strongly indicated that anatomical results were better if the osteotomy was made before the age of 9 years (46). Most recurrences in the study by Desai and Johnson were in those older than 5 years of age at surgery (60). Serafin and Szulc showed a clear temporal relationship in the extent of subsequent good results (235). In those operated between 2 and 9 years of age there were 80% good results with clear diminution after that, showing surgery at 10-11 years of age

SECTION IV ~ Infantile Coxa Vara

yielding 62% good results, 12-16 years 52% good results, and 17 years and older only 33% good results. Thus, there appears to be little to be gained by waiting if the angle of deformity is less than 100 ~ and certainly if the patient is older than 8 or 9 years of age. Correction appears to be held best with initial valgus repositioning greater than 130 ~ In terms of the Hilgenreiner epiphyseal angle measurement, invariable progression appeared with the angle greater than 60 ~ a tendency to spontaneous correction when the angle was less than 45 ~, and variable response when the angle was between 46 and 59 ~ such that especially close assessment was needed in the latter group (266). Several types of valgus osteotomy have been reported with little apparent difference in result. Weighill found no differences in results between subtrochanteric and intertrochanteric sites of osteotomy (264). In virtually all instances, healing of the vertical metaphyseal defect occurs. In addition, there is almost always premature closure of the proximal femoral growth plate. This must be followed closely in all patients, and if it appears to be occurring with a few years of growth remaining, it may be necessary to perform elective epiphyseal arrest of the greater trochanteric physis to maintain the appropriate alignment. In those undergoing surgery after 10 years of age, fusion of the greater trochanteric epiphysis at time of surgery generally is recommended. Serafin and Szulc recommend significant correction of the neck-shaft angle, advising that postsurgically it be 10-15 ~ greater than

451

normal (235). A postoperative HE angle of 35 ~ or less and a head-shaft angle of 130 ~ or more almost always correlated with consistently satisfactory results. With appropriate attention to surgical detail and relatively early intervention the aims of surgery generally can be achieved: (1) to create a normal neck-shaft angle, (2) to promote healing of the bony defect, and (3) to reorient the physis into a more horizontal position. Careful follow-up is essential after surgery because in some there can be recurrence and in almost all there is premature closure of the proximal femoral physis and a tendency to relative overgrowth of the greater trochanter after that. Premature physeal closure is an almost invariable component of the disorder and should not be attributed to the valgus repositioning itself. It is seen in virtually 90% of cases and is due to the primary deformity and not specifically to the treatment. Coxa vara can occur in association with many of the generalized skeletal dysplasias. It is common particularly with spondyloepiphyseal dysplasia congenita and cleidocranial dysostosis and also has been described in variants of multiple epiphyseal dysplasia and metaphyseal dysostosis. In the skeletal dysplasias it is common for the acetabulum to be abnormal as well. Some cases of coxa vara in the skeletal dysplasia group have the isolated neck fragment, but most do not. Coxa vara in the specific dysplasias will be discussed in depth in Chapter 9. Examples of cases of coxa vara with varying etiologies treated by valgus osteotomy are shown in Figs. 23 and 24.

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CHAPTER 5 ~

Coxa Vara in Developmental and Acquired Abnormalities of

the

Femur

F I G U R E 23 Examples of two cases of coxa vara are shown. Parts (A-F) represent the patient with bilateral coxa vara with spondyloepiphyseal dysplasia congenita. Parts (G-I) represent a unilateral case of coxa vara. (A) Anteroposterior radiograph of the pelvis in a 7-year-old girl with SED congenita. She presented with a distinct waddling gait. There is no ossification of the secondary ossification centers of the femoral head in spite of her age. Note also the characteristic triangular fragment of the medial neck region on the left. The acetabulae are markedly underdeveloped with no subchondral bone seen on either side. (B) Frog lateral view of pelvis also demonstrates the absence of secondary ossification centers and underdeveloped acetabulae. (C) Proximal femoral valgus osteotomy on the left served to reposition the head and neck into a more favorable weight bearing position. Healing of the triangular fragment soon followed. (D) Frog lateral view shows the central part of the neck indicated by the screw now pointing toward the triradiate cartilage in the depths of the acetabulum. (E) Localized view of the left hip preosteotomy shows the considerable degree of coxa vara with the tip of the greater trochanter (white arrow) well above the head and neck region. The characteristic triangular fragment of the inferior medial neck is seen. (Fi) Arthrogram and anteroposterior view of the left hip serves to outline the spherical contours of the femoral head and markedly shortened adjacent neck. The head is located in the acetabulum but the latter is extremely poorly developed. In addition, the head points medially and inferiorly rather than medially and upward to the weight bearing surface. (Fii) Frog lateral view of the arthrogram shows the spherical femoral head in appropriate relation to the acetabulum. The head and neck are markedly shortened and there is no secondary ossification center even at 7 years of age. (G) Unilateral coxa vara in a 6-year-old boy is seen. The head is spherical and is well-situated in the acetabulum, but the neck is markedly shortened and there is extreme relative overgrowth of the greater trochanter, whose tip rises above the level of the superior acetabulum. (I-I) The head now is positioned nicely in the acetabulum and the tip of the greater trochanter is displaced inferiorly following proximal femoral valgus osteotomy. (I) Frog lateral view postosteotomy shows good position of the femoral head in relation to the acetabulum.

SECTION IV ~ Infantile Coxa Vara

F I G U R E 23 (continued)

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F I G U R E 24 The patient with undefined skeletal dysplasia and bilateral coxa vara. (A) Anteroposterior radiograph of the pelvis shows bilateral proximal femoral coxa vara. The tip of the greater trochanter bilaterally is at the same level as the most superior part of the femoral head. Both femoral heads are well-located and the acetabulae are well-developed. The necks are shortened, however, even though the physeal regions appear widened. Proximal femoral valgus osteotomy was performed with Wagner blade plate fixation. There was excellent correction of the varus deformation at the time of healing. (C) High-power view of the right hip shows intraoperative positioning after osteotomy. Note that the proximal femoral head-neck physis is now almost horizontal, the tip of the greater trochanter is well below the most superior surface of the femoral head, and there has been excessive valgus angulation at the osteotomy site. Three years later at age 8 there had been recurrence of the varus deformation (not shown). (D) Proximal femoral valgus osteotomy again was repeated with even more extensive valgusization performed. Anteroposterior radiograph shows the position at healing after the second series of osteotomies. (E) Frog lateral view shows the excellent position of the femoral heads postosteotomy. (F) Anteroposterior X ray 3 years after the second osteotomy at 11 years of age shows retained position of the correction. Both femoral heads are well-located in the acetabulae. The trochanters remain normally positioned and the proximal femoral growth plates appear in their normal position with continued growth. (G) Frog lateral view shows persisting physeal function and excellent structural development of the acetabulae, femoral heads, femoral necks, and shafts. The child continues to walk without waddling and has as full range of hip motion at 14 years of age.

References

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192. Morrissy RT (1990) Slipped capital femoral epiphysis. Technique of percutaneous in situ fixation. J Pediatr Orthop 10: 347-350. 193. Morscher E (1960) Die operativ therapie der epiphyseolysis capitis femoris. Z Orthop 92:153-174. 194. Muller E (1888) Ueber die verbiegung des schenkelhalses im wachstumsalter. Ein neues krankheitsbild. Beitr Klinische Chir 4:137-148. 195. Muller E (1966) On the deflection of the femoral neck in childhood. A new syndrome. Clin Orthop Rel Res 48:7-10 (in English, partial article). 196. Newman PH (1960) The surgical treatment of slipping of the upper femoral epiphysis. J Bone Joint Surg 42B:280-288. 197. Nguyen D, Morrissy RT (1990) Slipped capital femoral epiphysis: Rationale for the technique of percutaneous in situ fixation. J Pediatr Orthop 10:341-346. 198. Nixon JR, Douglas JF (1980) Bilateral slipping of the upper femoral epiphysis in end-stage renal failure: A report of two cases. J Bone Joint Surg 62B: 18-21. 199. Noble TP, Hauser ED (1926) Coxa vara. Arch Surg 12: 501-538. 200. Nonweiler B, Hoffer M, Weinert C, Rosenfeld (1996) Percutaneous in situ fixation of slipped capital femoral epiphysis using two threaded Steinmann pins. J Pediatr Orthop 16: 56-60. 201. O'Brien ET, Fahey JJ (1977) Remodeling of the femoral neck after in situ pinning for slipped capital femoral epiphysis. J Bone Joint Surg 59A:62-68. 202. Ordeberg G, Hansson LI, Sandstrom S (1984) Slipped capital femoral epiphysis in southern Sweden: Long-term result with no treatment or symptomatic primary treatment. Clin Orthop Rel Res 191:95-104. 203. Orofino C, Innis JJ, Lowrey CW (1960) Slipped capital femoral epiphysis in Negros. J Bone Joint Surg 42A: 1079-1083. 204. Panting AL, Williams PF (1978) Proximal femoral focal deficiency. J Bone Joint Surg 60B:46-52. 205. Pappas AM (1983) Congenital abnormalities of the femur and related lower extremity malformations: Classification and treatment. J Pediatr Orthop 3:45-60. 206. Pare A (1572) Fractures of the neck of the femur. In: Cinq Livres de Chirurgie, Paris, and (1840) In: Oeuvres Completes, volume 2, book 13, chapter 21. Paris. 207. Pauwels F (1936) Zur therapie der kindlichen coxa vara. Ver Deut Orthop Ges 30:372. 208. Pavlov H, Goldman AB, Freiberger RH (1980) Infantile coxa vara. Pediatr Radiol 135:631-640. 209. Perkins G (1932) Treatment of adolescent coxa vara. Brit Med J i:55-56. 210. Peterson MD, Weiner DS, Green NE, Terry CL (1997) Acute slipped capital femoral epiphysis: The value and safety of urgent manipulative reduction. J Pediatr Orthop 17:648-654. 211. Petit JL (1709) In: Maladies des Os, p 354, Leyden, and (1837) In: Traite des Maladies des Os, Oeuvres Completes. p. 169. Paris. 212. Pirani S, Beauchamp RD, Li D, Sawatzky B (1991) Soft tissue anatomy of proximal femoral focal deficiency. J Pediatr Orthop 11:563-570. 213. Pomeranz MM, Sloane MF (1935) Slipping of the proximal femoral epiphysis. Arch Surg 30:607-624.

460

CHAPTER 5 ~ Coxa Vara in Developmental and Acquired Abnormalities of the Femur

214. Ponseti IV, McClintock R (1956) The pathology of slipping of the upper femoral epiphysis. J Bone Joint Surg 38A:71-83. 215. Ponseti I, Barta CK (1948) Evaluation of treatment of slipping of the capital femoral epiphysis. Surg Gyn Obstet 86: 87-97. 216. Pouzet F (1938) Le traitement de la coxa vara congenitale. La Presse Med 46:1095-1096. 217. Pouzet F (1934) L'evolution anatomique des aplasies du col femoral (coxa vara congenitales, a fissure verticale). Lyon Chir 31:712-724. 218. Pritchett JW, Perdue KD (1988) Mechanical factors in slipped capital femoral epiphysis. J Pediatr Orthop 8:385-388. 219. Purl R, Smith CS, Malhotra D, Williams AJ, Owen R, Harris F (1985) Slipped upper femoral epiphysis and primary juvenile hypothyroidism. J Bone Joint Surg 67B: 14-20. 220. Pylkkanen PV (1960) Coxa vara infantum. Acta Orthop Scand Supp 48:7-120. 221. Rammstedt C (1900) Uber die traumatische losung der femur kopfepiphyse und ihre folgeerscheinungen. Arch Klin Chir 61:559-583. 222. Rao SB, Crawford AH, Burger RR, Roy DR (1996) Open bone peg epiphysiodesis for slipped capital femoral epiphysis. J Pediatr Orthop 16:37-48. 223. Reikeras O, Bjerkreim I, Kolbenstvedt A (1982) Anteversion of the acetabulum in patients with idiopathic increased anteversion of the femoral neck. Acta Orthop Scand 53:847-852. 224. Rennie AM (1960) The pathology of slipped upper femoral epiphysis: A new concept. J Bone Joint Surg 42B:273-279. 225. Rey JC, Carlioz H (1975) Epiphysiolyses a grand deplacement. Reduction sanglante par la technique de Dunn. Rev Chir Orthop 61:261-273. 226. Ring PA (1961) Congenital abnormalities of the femur. Arch Dis Child 36:410-417. 227. Samuelson T, Olney B (1996) Percutaneous pin fixation of chronic slipped capital femoral epiphysis. Clin Orthop Rel Res 326:225-228. 228. Sanpera I, Sparks LT (1994) Proximal femoral focal deficiency: Does a radiologic classification exist? J Pediatr Orthop 14:34-38. 229. Schai PA, Exner GU, Hansch O (1996) Prevention of secondary coxarthrosis in slipped capital femoral epiphysis: A long-term follow-up study after corrective intertrochanteric osteotomy. J Pediatr Orthop 5:135-143. 230. Schlesinger A (1905) Zur aetiologie und pathologischen anatornie der coxa vara. Arch Klin Chir 75:629-642. 231. Schmidt TL, Kalamchi A (1982) The fate of the capital femoral physis and acetabular development in developmental coxa vara. J Pediatr Orthop 2:534-538. 232. Schreiber A (1963) Epiphyseolysis capitis femoris: Beitrag zur frage der beidseitigkeit-gleichzeitiges vorkommen von Wirbelsaulenveranderungen. Z Orthop 97:4-11. 233. Segal LS, Weitzel PP, Davidson RS (1996) Valgus slipped capital femoral epiphysis. Clin Orthop Rel Res 322:91-98. 234. Segal LS, Davidson RS, Robertson WW, Drummond DS (1991) Growth disturbances of the proximal femur after pinning of juvenile slipped capital femoral epiphysis. J Pediatr Orthop 11:631-637. 235. Serafin J, Szulc W (1991) Coxa vara infantum, hip growth disturbances, etiopathogenesis, and long-term results of treatment. Clin Orthop Rel Res 272:103-113.

236. Shapiro F, Simon S (1984) Slipped capital femoral epiphysis: Patient profile and treatment results. Orthop Trans 8:373. 237. Shea D, Mankin HJ (1966) Slipped capital femoral epiphysis in renal tickets. J Bone Joint Surg 48A:349-355. 238. Siegel DB, Kasser JR, Sponseller P, Gelberman RH (1991) Slipped capital femoral epiphysis. A quantitative analysis of motion, gait, and femoral remodeling after in situ fixation. J Bone Joint Surg 73A:659-666. 239. Skinner SR, Berkheimer GA (1978) Valgus slip of the capital femoral epiphysis. Clin Orthop Rel Res 135:90-92. 240. Sorensen KH (1968) Slipped upper femoral epiphysis: Clinical study on etiology. Acta Orthop Scand 39:499-517. 241. Southwick WO (1967) Osteotomy through the lesser trochanter for slipped capital femoral epiphysis. J Bone Joint Surg 49A:807-835. 242. Southwick WO (1984) Editorial: Slipped capital femoral epiphysis. J Bone Joint Surg 66A:1151-1152. 243. Speer DP (1982) Experimental epiphysiolysis: etiologic models of slipped capital femoral epiphysis. In: The Hip Society: The Hip. Proceedings of the 10th Open Scientific Meeting of the Hip Society. pp. 68-88, St. Louis: CV Mosby. 244. Sprengel (1898) Ueber die traumatische losung der kopfepiphyse des femur und ihr verhaltniss zur coxa vara. Arch Klin Chir 57:805-840. 245. Stambough JL, Davidson RS, Ellis RD, Gregg JR (1986) Slipped capital femoral epiphysis: An analysis of 80 patients as to pin placement and number. J Pediatr Orthop 6:265-273. 246. Stanitski CL (1994) Acute slipped capital femoral epiphysis: Treatment alternatives. J Am Acad Orthop Surg 2:96-106. 247. Sturrock CA (1894) The after results of simple separation of epiphyses. Edinburgh Hosp Rep 2:598-608. 248. Sutro CJ (1935) Slipping of the capital epiphysis of the femur in adolescence. Arch Surg 31:345-360. 249. Swiontkowski MF (1983) Slipped capital femoral epiphysis: Complications related to intemal fixation. Orthopaedics 6: 705-712. 250. Szypryt EP, Clement DA, Colton CL (1987) Open reduction of epiphysiodesis for slipped upper femoral epiphysis. J Bone Joint Surg 69B:737-742. 251. Teinturier P, Dechambre H (1968) Etude d'anteversion de la hanche de l'enfant. Rev Chir Orthop 54:545-551. 252. Terjesen T (1992) Ultrasonography for diagnosis of slipped capital femoral epiphysis. Acta Orthop Scand 62:653-657. 253. Tillema DA, Golding JSR (1971) Chondrolysis following slipped capital femoral epiphysis in Jamaica. J Bone Joint Surg 52A:1528-1540. 254. Tsou PM (1982) Congenital distal femoral focal deficiency: Report of a unique case. Clin Orthop Rel Res 162:99-102. 255. Velasco R, Schai PA, Exner GU (1998) Slipped capital femoral epiphysis: A long-term follow-up study after open reduction of the femoral head combined with subcapital wedge resection. J Pediatr Orthop Part B 7:43-52. 256. Waldenstrom H (1930) On necrosis of the joint cartilage by epiphysiolysis capitis femoris. Acta Chir Scand 67: 936-946. 257. Walker SJ, Whiteside LA, McAlister WH, Silverman CL, Thomas PRM (1981) Slipped capital femoral epiphysis following radiation and chemotherapy. Clin Orthop Rel Res 159: 186-193.

References 258. Walter H (1931) Zur genese der coxa vara. Med Klin 27: 1071-1073. 259. Waiters R, Simon R(1980) Joint destruction: A sequel of unrecognized pin penetration in patients with slipped capital femoral epiphyses. In: The Hip: Proceedings of the Eighth Annual Open Scientific Meeting of the Hip Society. pp. 145-164, St. Louis: CV Mosby. 260. Ward WT, Wood K (1990) Open bone graft epiphyseodesis for slipped capital femoral epiphysis. J Pediatr Orthop 10:14-20. 261. Ward WT, Stefko J, Wood KB, Stanitski CL (1992) Fixation with a single screw for slipped capital femoral epiphysis. J Bone Joint Surg 74A:799-809. 262. Warner WC, Beaty JH, Canale ST (1996) Chondrolysis after slipped capital femoral epiphysis. J Pediatr Orthop Part B 5: 168-172. 263. Weber BG (1965) Die Imhauser-osteotomie bei floridem gleitprozess. Z Orthop 100:312-320. 264. Weighill FJ (1976) The treatment of developmental coxa vara by abduction subtrochanteric and intertrochanteric femoral osteotomy with special reference to the role of adductor tenotomy. Clin Orthop Rel Res 116:116-124. 265. Weiner DS, Weiner S, Melby A, Hoyt WA, Jr (1984) A 30year experience with bone graft epiphysiodesis in the treatment of slipped capital femoral epiphysis. J Pediatr Orthop 4: 145-152. 266. Weinstein JN, Kuo KN, Millar EA (1984) Congenital coxa vara. A retrospective review. J Pediatr Orthop 4:70-77.

461

267. Wells D, King JD, Roe TF, Kaufman FR (1993) Review of slipped capital femoral epiphysis associated with endocrine disease. J Pediatr Orthop 13:610-614. 268. Whitman R (1894) Observations on bending of the neck of the femur in adolescence. NY Med J 59:769-774. 269. Whitman R (1909) Further observations on injuries of the neck of the femur in early life; with reference to the distinction between fracture of the neck and epiphyseal disjunction as influencing positive treatment. Med Rec 75:1-8. 270. Wiberg G (1959) Considerations on the surgical treatment of slipped epiphysis with special reference to nail fixation. J Bone Joint Surg 41A:253-261. 271. Wilson PD (1938) The treatment of slipping of the upper femoral epiphysis with minimal displacement. J Bone Joint Surg 20:379-399. 272. Wilson PD, Jacobs B, Schecter L (1965) Slipped capital femoral epiphysis: An end-result study. J Bone Joint Surg 47A: 1128-1145. 273. Wolf EL, Berdon WE, Cassady JR, Baker DH, Freiberger R, Pavlov H (1977) Slipped capital femoral epiphysis as a sequela to childhood irradiation for malignant tumors. Radiology 125:781-784. 274. Zadek I (1935) Congenital coxa vara. Arch Surg 30:62-102. 275. Zahrawi FB, Stephens TL, Spencer GE, Clough JM (1983) Comparative study of pinning in situ and open epiphysiodesis in 105 patients with slipped capital femoral epiphyses. Clin Orthop Rel Res 177:160-167.

CHAPTER

6

Epiphyseal Disorders of the Knee Distal Femur, Proximal Tibia, and Proximal Fibula

I. II.

Normal Developmental Variability

VI.

Osteochondritis Dissecans of Distal Femur

VII.

III. Infantile Tibia Vara (Biount's Disease) IV. Adolescent Tibia Vara V. Osgood-Schlatter Disease (Tibiai Tubercle Chronic Traumatic Apophysitis)

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I. N O R M A L D E V E L O P M E N T A L VARIABILITY

Congenital Dislocation of the Knee

ValgusAngulation Following Proximal Tibial Metaphyseal Fractures in Childhood Disorders of the Proximal Fibular Epiphysis

both femurs and tibias can be done, preferably in the standing position if the patient is old enough, to measure the degree of bowing and to rule out any underlying disorder. Radiographic findings in those with more marked but still physiologic genu varum include medial beaking of the distal femoral and proximal tibial metaphyses, thickening of the medial tibial cortex, and a slightly underdeveloped wedgeshaped medial secondary ossification center of both distal femur and proximal tibia (Figs. 2A and 2B). The two most common pathological causes of childhood bowing are tickets and the skeletal dysplasias. Even in severe cases of physiologic bowing improvement should be seen between 2 and 3 years of age; if this is not occurring, concern is raised about a pathologic disorder or a developing tibia vara (Blount's disease).

A. Physiologic Genu Varum and Genu Valgum in Childhood Bow legs are a normal feature of early childhood development and are commonly referred to as physiologic genu varum. Salenius and Vankka (143), in a study involving 1480 radiographic examinations in growing children, documented diminution of the femoral-tibial diaphyseal angle from a mean of 15~ varus at birth, to neutral at 24 months, to 10~ valgus at 36 months, and to an eventual 5 - 6 ~ valgus by 6 years (Fig. 1). The varus can be as high as 30-40 ~ before age 2 years and still undergo spontaneous correction. The clinical appearance is worsened by internal tibial torsion in many. Heath and Staheli (69) established the normal limits of knee angulation in 196 white children from 6 months to 11 years of age. Varus and valgus were measured from clinical photographs taken in a standardized position with markers over the anterior superior iliac spines and the centers of the patellae. The children were maximally bowlegged at age 6 months, progressed toward neutral knee angles by 18 months, showed maximal knock-knees of 8~ around 4 years, and then decreased gradually over the next few years to less than 6 ~ at 11 years. They considered bowlegs after age 2 years to be abnormal and knock-knees of more than 12~ abnormal. This developmental sequence of genu varum at birth, its disappearance during the 1st or 2nd year of life, a change to genu valgum during the 3rd or 4th year, and establishment of the final alignment of slight valgus at about 6 years of age has been well-recognized by many for some time. Due to the high likelihood of spontaneous correction, no specific treatment is needed. Anteroposterior radiographs of

B. Normal Radiographic Developmental Variants of the Distal Femoral and Proximal Tibial Epiphyses There are many developmental irregularities in the radiologic appearance of the distal femoral epiphysis, particularly of the secondary ossification center, which are well within a normal range and must not be mistaken for pathological processes. (Figs. 3A-3C) The irregularities include (1) rough or serrated margins of the secondary ossification center, (2) thin bony protuberances from the margins of the secondary center, and (3) small accessory ossification centers (30, 114, 145, 157, 230). At 1-2 years of age, there often is a serrated border of the secondary ossification center particularly at its medial, lateral, or distal margins. This border on occasion is present circumferentially and may be concentrated and particularly irregular at the medial aspect. In the older child, in whom the secondary ossification center is 462

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developed more extensively, there often are X-ray changes at the distal margins of the secondary center suggestive of an osteochondritis dissecans lesion (Fig. 3C). These irregularities are asymptomatic, disappear with time, and should not be considered as pathologic lesions. Caffey and associates defined three variants of these developmental irregularities in the older child (23). Group 1 femurs show varying degrees of roughening of the margins of the secondary ossification centers, occasionally with separate small foci of calcification within the cartilage just beyond the roughened edge. These often are present medially and laterally and are particularly well-demonstrated on the tunnel views. Group 2 lesions are larger localized marginal irregularities in the form of concave indentations. These generally tend to be on the inferior surface of the bone adjacent to the condyles or at their more lateral aspects and are not seen in the characteristic medial regions, as is the classical osteochondritis dissecans lesion. Group 3 changes feature irregularities similar to type 2 but with an independent island of bone in the marginal crater. Caffey et al. concluded that "uneven marginal ossification of the femoral condyles is a feature of healthy chondral bone formation." These essentially are transitory and the incidence of marginal irregularities falls progressively with age from 85% at age 4 years to 10% at age 12 years. Roughly 30% of all males and 17% of all females had defects sufficiently marked to place them in the group 2 and 3 categories. Many of these irregularities are

present on the posterior aspect of the bone adjacent to the femoral condyles and are detected only with tunnel views. Irregularities of the type 1 group also have been described by Sontag and Pyle and were almost invariable in a study of 220 children from 1 to 72 months of age in the sense that some irregularity of outline or texture of the distal femoral epiphysis was seen at some time (157). In the more marked groups 2 and 3, the X-ray changes were similar to the changes observed in symptomatic osteochondritis dissecans. Irregularities in marginal smoothness were detected quite early by some but were not recognized by all. Both Ludloff (114) and Christ (30) demonstrated that there was a period, generally extending from age 2 to 6 years, in the development of the femoral epiphysis when its margins normally had considerable unevenness, described as roughness in general with occasional spiny projections or protuberances in particular. These initially appeared on the medial side, which almost invariably was rough during the early years, and in the 5th year there often were irregularities although not as pronounced on the lateral margin. The protuberances occurred infrequently on the articular margins of the secondary ossification center, and after the 6th year such roughness generally had disappeared. Ludloff, as early as 1903, pointed out the existence of irregular condylar margins up to the age of 4 years, noting a serrated outline during the 1st and 2nd years of life and the more prominent protuberances from age 2 to 4 years, both medially and laterally.

464

CHAPTER 6 " Epiphyseal Disorders of the Knee

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TYPE

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F I G U R E 31

Types of fracture-separation at the distal tibia and their relation to age. [Reprinted from (299), with permission.]

type III), and separation with both epiphyseal and diaphyseal fractures 14.2% (S-H type IV). Of particular interest are the line drawings of radiographs from dozens of cases in both projections showing the variable patterns of fracture with the pathoanatomic gradings. Distal tibial fracture-separations lead to the second highest frequency of bone bridge formation after the distal femur (250). Chadwick and Bentley reported growth retardation in 8 of 28 (26.8%) distal tibial epiphyseal injuries. Dotter and McHolick reported an 18% incidence of negative growth sequelae (89). One of the reasons for this occurrence is the medial physeal irregularity jutting into the metaphysis, which frequently is damaged allowing for transphyseal vessel communication and bone formation. This local anatomic feature has been called Kump's bump or Poland's bump by some in reference to its previous descriptions (180) (Fig. 32). Growth arrests can be seen with each of type II, III, and IV injuries, with especially high complication rates in types III and IV [Cass and Peterson (58); Cooperman et al. (69); Karrholm et al. (167-173); Kling et al. (178); Landin et al. (185, 186); Nolan et al. (226); Spiegel et al. (299, 300)]. Growth plate convexity as seen in the lateral radiograph, and the proximal deviation of a localized segment of the plate in its medial one-third as seen in the anteroposterior radiograph, can result in B2 injuries by predisposition to crushing of the plate with type I and II displacements. In radiologic type III lesions, transverse fractures that histologically are at the metaphyseal level and

type IV injuries with considerable crushing can lead to epiphyseal-metaphyseal bone union of the B2 pathophysiologic type, especially if anatomic reduction is not achieved. Reports on distal tibial fracture-separations have noted the growth arrest problems and the evidence of diminished problems with accurate open reduction and internal fixation. A detailed study of 55 distal tibial and fibular epiphyseal fractures indicated that important prognostic features regarding subsequent growth arrest were the type of treatment, degree of displacement, and age at injury, whereas the Salter-Harris classification system alone "could not significantly predict the growth pattern" [Karrholm et al. (172, 173)]. Both tomography (Fig. 32B) and CT scanning have been extremely helpful in defining more clearly the actual pattern of fracture within epiphyseal and metaphyseal bone [Feldman et al. (103); Spiegel et al. (299); Von Laer (320)]. The MR imaging studies are beginning to demonstrate early transphyseal vessel communication between epiphysis and metaphysis (159, 286, 292) (Figs. 19E-19I and 36H). Hynes and O'Brien have shown that careful examination of plain radiographs following fracture repair to assess growth arrest or disturbance lines can help define the likelihood of future problems (153). 2. P A T T E R N OF C L O S U R E OF D I S T A L T I B I A L PHYSIS Many of the unique fracture patterns of the distal tibial epiphysis relate to the fact that there is not uniform closure of the physis toward the end of skeletal growth but rather medial plate closure occurring prior to lateral closure. The normal fusion pattern in the distal tibial epiphysis has been documented well by MacNealy et al. (Fig. 33) (201). Closure occurs initially at the medial-central portion adjacent to the area of the proximal medial deviation of the physis and then involves the entire medial segment. The earliest closure thus occurs throughout the entire medial segment and is a little more prominent anteriorly than posteriorly. The pattern of closure then moves in a lateral direction, but the entire time for full fusion can take up to 18 months. For a considerable period of time, therefore, the medial physis is closed while the lateral physis is open. Ogden and McCarthy also studied the pattern of growth plate maturation at the distal tibia (234). They too noted closure from medial to lateral sides over an extended several-month period of time; the physiological epiphyseal arrest began medially over the malleolus and then extended laterally. As a general finding, central and medial closure is seen beginning at 12.5 years, completion of medial closure is noted at 13 years, closure moving to the lateral segments occurs at 13.5 years, and complete closure is seen at 14 years. 3. TRANSITIONAL FRACTURES Von Laer has discussed the transitional fractures, the biplane fracture or the juvenile fracture of Tillaux and the triplane fracture, and feels that the injuries are caused by external rotation and eversion (320). The occurrence of a particular type depends on the maturity of the physis and not

SECTION Vl ~ Clinical Features o f Acute Epiphyseal Fracture-Separations

587

F I G U R E 32 (A) Anteroposterior ankle radiographs demonstrate a type III fracture-separation of the distal medial tibial epiphysis in an 11-year-old male. The degree of displacement is difficult to determine. (B) A tomogram of the distal tibial epiphysis shown in A shows the clear-cut separation of the epiphyseal fragment from the adjacent epiphysis. The question is raised as to whether the transverse fracture line passes through the hypertrophic zone, which is less worrisome, or is present within the outer reaches of the metaphysis, which is a more worrisome situation as illustrated in Fig. 15. The normal medial physeal irregularity (arrow) referred to by some as Kump's bump is seen clearly by tomography. (C) Treatment of a similar fracture by intra-epiphyseal AO compression screw to restore articular continuity.

on the m e c h a n i s m of trauma. In his study of the two groups, the average age of females was 13.3 years (range = 11-15 years) and that of the m a l e s was 14.7 years ( 1 2 - 1 6 years). In both types, the m o r e lateral the e p i p h y s e a l fracture line, the m o r e frequently the medial physis was closed. Dias and Giegerich also felt that, in both types of transitional fracture, the pattern of distal tibial physeal closure strongly influenced the type of fracture in the adolescent with external rotation injuries of the foot in relation to the leg (87).

F I G U R E 33 Pattem of closure of distal tibial physis is shown. The dotted areas represent closure on the upper or transverse sections. Closure progresses from medial to lateral sides. [Reprinted from MacNealy et al. (1982). Am. J. Roentgenol. 138:683-689, with permission from the American Roentgen Ray Society.]

a. J u v e n i l e Fracture o f Tillaux. T h e j u v e n i l e or adolescent fracture of Tillaux is a type III epiphyseal f r a c t u r e separation occurring at the distal tibia during the time f r a m e in w h i c h the distal medial tibial physis has closed while the lateral s e g m e n t r e m a i n s open (Fig. 34). Von L a e r refers to

F I G U R E 34 A Tillaux juvenile distal tibial fracture-separation is seen. This pattern occurs when the medial physis has closed while the lateral remains open.

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9

Epiphyseal Growth Plate Fracture-Separations

this injury as a biplane fracture. CT scans confirm an epiphyseal component only with no metaphyseal involvement. Tillaux performed adult cadaveric experiments in which he found that the tibial fragment of bone was produced by an avulsion force from the pull of the intact anterior inferior tibial-fibular ligament (312). This fracture is referred to by some as the juvenile or adolescent fracture of Tillaux. Kleiger and Mankin reported a large series of patients with this injury, and many subsequent reports have appeared (177). In the large majority of instances, closed reduction is successful but open reduction and AO screw fixation of the displaced fragment lead to anatomic positioning and excellent results. Growth arrest is not a problem because fusion of the physis is already occurring, and indeed the medial half has already fused. These injuries are relatively rare because of the limited time frame during which they can occur. Stefanich and Lozman (302) described 5 cases, Dias and Tachdjian (86) described 3 in a series of 71 ankle fractures, Karrholm et al. (173) reported 17 in 361 cases of distal tibial injury, and Molster et al. reported on 6 fractures as well (218). This fracture represents one of the few that is more common in gifts. The juvenile fracture of Tillaux is an avulsion fracture of the anterolateral portion of the distal tibial epiphysis caused by the pull of the intact anterior inferior tibial fibula or anterior syndesmotic ligament sustained during an external rotation injury to the foot. The displacement of the fragment is either lateral or anterolateral. Rang has indicated that the majority of these fractures are displaced so minimally that no reduction is required and short leg casting is appropriate (263). Long-term studies, however, do show some instances of articular incongruity such that open reduction and internal fixation readily are used. Internal fixation using a compression screw certainly is warranted wherever the degree of displacement is 2 mm or greater on any radiographic projection. CT or tomography is most helpful in providing clearer resolution than plain X rays. b. Distal Tibial Triplane Epiphyseal Fracture-Separation. The triplane fracture also owes its pattern to the unusual configuration of the distal tibial growth plate and, more importantly, the variability of its closure across the transverse diameter. It is essentially a type IV fracture-separation and, as such, almost invariably requires open reduction and internal fixation for optimal results. In its simplest description, it appears like a type III fracture on the anteroposterior ankle radiograph and like a type II fracture on the lateral (Figs. 35A and 35B). Von Laer has shown that the epiphyseal fracture line in biplane or triplane fractures can be intramalleolar, medial, central, or lateral as far as the anterior syndesmosis (320). The wandering fracture line has sagittal, transverse (horizontal), and coronal (frontal) components. Marmor defined the components of this fracture in 1970 (205), although Bartl had alluded to it in 1957 (17). Lynn described two cases and was the earliest to coin the term "triplanar fracture" (200). The triplane fracture is characteristically composed of two, three, and occasionally four frag-

A ~

fracture through epiphysis

po

fracture through metaphysis

~ A

fracture through

growth plate

t

med

B

ant int

med

F I G U R E 35 The triplane fracture appears as a type III fracture on the anteroposterior radiograph and a type II fracture on the lateral radiograph. Because it passes from articular cartilage through epiphysis, physis, and metaphysis it is, in three-dimensional considerations, a type IV fracture. (A) A two-part triplane injury; (B) a three-part injury. (C) The value of CT imaging in defining fracture pattern for the triplane injury is shown. At left, the type IV and type III patterns are seen, in middle, a type IV configuration, and at right, a type II pattern [three sagittal plane images from same ankle injury]. [Reprinted from Karrholm et al. (1981), J. Pediatr. Orthop. 1:181-187, 9 Lippincott Williams & Wilkins, with permission.]

ments with or without fibular fractures. The first large series was reported by Cooperman et al. (69). According to Cooperman, the two-fragment triplane fracture has the tibial shaft, medial malleolus, and anteromedial portion of the epiphysis as one fragment, with the second fragment consisting of the remainder of the metaphysis, lateral epiphysis, and attached

SECTION Vl ~ Clinical Features o f Acute Epiphyseal Fracture-Separations

fibula (Fig. 35A). In the three-fragment triplane fracture, the pattern is similar, but the anterolateral epiphyseal segment is free rather than lying attached to the distal tibial regions. Fragment 1 is rectangular and represents the anterolateral quadrant of the distal tibial epiphysis, fragment 2 consists of the medial and posterior portions of the epiphysis in addition to a posterior metaphyseal spike, and fragment 3 is the tibial metaphysis (Fig. 35B). A four-fragment distal triplane fracture has also been described on occasion. The fourth fragment is the medial tibial epiphyseal segment separated along the physis as well as by the intra-articular component (246, 300). Clement and Worlock showed that the triplane fracture can occur when the distal tibial physis is still completely open (66). Tomograms and CT scanning are the most important for clear delineation of these injuries. Ertl et al. diagnosed 11 three-fragment and only 4 two-fragment fractures using CT, tomography, and observation at open reduction, whereas a group of examiners having no knowledge of these findings and viewing only the plain radiographs diagnosed 11 twofragment and 4 three-fragment patterns (100). Due to the occurrence of this fracture near the end of skeletal growth, angular deformity and limb length discrepancy are not clinical problems (58). Of 13 patients with a triplane fracture studied by Cass and Peterson, none had growth arrest problems. The open reduction and internal fixation are done to restore joint surface anatomy. Karrholm et al. described ankle fractures of the distal tibial epiphysis as comprising four stages: juvenile Tillaux fracture comprising stages 1 and 2; stage 3 is a triplane fracture without a fibula fracture; and stage 4 is a triplane fracture with either two, three, or four fragments along with a fibula fracture (167). Dias and Tachdjian felt that the mechanism of injury was pure external rotation of the foot without either pronation or supination (86). Most observers feel that the juvenile Tillaux fracture is produced by the same mechanism of injury as the triplane form, with the mechanism being supination eversion. Studies of increasing numbers of patients from 1970 on have clarified treatment approaches. The results in general with this fracture are now very good to excellent. Growthrelated problems are extremely rare because of the relatively late age of occurrence in relation to the time of skeletal maturity. The prognosis thus is dependent on the accuracy of the reduction. Both closed and open methods have been used widely, and in each series excellent results in general are reported. In an extensive review of the literature by Rapariz et al., in which they studied several series, the distributions of closed and surgical treatment were noted (264). If one adds their series to that of Landin et al. (186), in a total of 217 cases reported 133 had either no need for reduction or closed reduction only, and 84 had operative intervention with open reduction and internal fixation. A consensus clearly is building for an approach that can be stated as fol-

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lows: CT imaging is most helpful for defining not only the pattern of fracture and the degree of displacement but the number of fragments. Plain films can be misleading in this regard. If there is no displacement, a long leg cast is appropriate. Closed reduction can be attempted in those situations with displacement. It is important to obtain anatomic or nearanatomic reduction, however, with long-term studies showing that displacement of 2 mm or more in any projection can predispose one to late arthritic changes. If closed reduction does not meet these criteria or if displacement occurs in the first few weeks of immobilization, then open reduction and internal fixation using epiphyseal and metaphyseal compression screws are warranted. Because the long-term results with anatomic reduction appear long-standing, there should be little to no reluctance to resort to open reduction and internal fixation with these injuries. Initial studies showed excellent results with both closed and open reduction. When studies progress, however, beyond 5 years, those ankles with greater than 2 mm of displacement begin to show early degenerative changes. Because this is an intra-articular fracture with the intra-articular component in the central regions well within the major weight bearing areas, the importance of anatomic reduction is evident. In a long-term follow-up of 35 patients with a triplane fracture in which the mean followup was 5 years 2 months (range = 24-162 months), there was no pain in 35, normal walking in 35, full job performance in 35, anatomically perfect radiographs in 33 of 35 (94%), and full ankle joint function in 31 of 35 (88%). There was no varus or valgus deformity, no limb length discrepancy, and only an external rotation deformity greater than 10% in 3 of 35 (8%) (186). 4. CASE ILLUSTRATIONS OF TWO TYPE III MEDIAL FRACTURE-SEPARATIONS A case of growth arrest following a type III distal tibial medial epiphyseal fracture-separation and its management are illustrated in Fig. 36. Figure 32C illustrates a fracture treated by open reduction and AO compression screw fixation, which healed uneventfully. 5. TYPE IIl FRACTURE OF MEDIAL MALLEOLUS WITH INTRA-ARTICULAR OSTEOCHONDRAL FRAGMENT Beaty and Linton presented an interesting case in which a medial malleolar type III distal tibial epiphyseal fracture in a 9-year-old girl was found associated with an intra-articular osteochondral fragment (20). This was seen on an oblique plain radiograph and by tomography. Open reduction served not only to realign the physis and articular surface but to excise the osteochondral fragment. 6. TYPE IV FRACTURES OF THE CLASSIC PATTERN Type IV fracture-separations of the distal tibial epiphysis of the classic or uniplanar pattern can occur. Virtually all of these will involve the medial malleolus. There is a tendency for these injuries to be difficult to diagnose on plain

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Epiphttseal Growth Plate Fracture-Separations

F I G U R E 36 A sequence of radiographs shows growth arrest following a type III fracture-separation of the distal tibial medial epiphysis. (A) An anteroposterior radiograph with no evidence of injury, but (B) an oblique view clearly shows the minimally displaced type III fracture-separation. (C, D) Treatment was by long leg cast with no reduction. (E) At 3 months postinjury the physis is irregular but no definitive bone bridge is seen. (F) By 6 months mild varus tilt of the distal tibia is seen along with medial tibial physeal closure. Note the distal tibial growth arrest line angling toward the medial bone bridge (arrow). (G) By 9 months the varus tilt is more marked. (I-I) MR imaging defines the medial bone bridge (arrow) with marrow signal continuity across the physis between epiphyseal and metaphyseal bone. (I-L) Distal tibial-fibular valgus osteotomy with completion of physeal closure led to restoration of normal alignment at skeletal maturity.

SECTION VI ~ Clinical Features o f Acute Epiphyseal Fracture-Separations

radiographs. Cass and Peterson noted that, in 18 ankles with a fracture involving the medial malleolus, extension of the fracture into the metaphysis could often be appreciated only on oblique radiographs or with tomography and CT scanning (58). In 9 of 18 tibias with a fracture of the medial malleolus, premature partial closure of the distal physis occurred. This led to angular deformity or limb length discrepancy sufficient to require epiphyseal arrest, osteotomy, or bone bridge excision. There was a marked tendency for the classic type IV fracture separations to occur in a younger and often much younger age group than the triplane fractures. They are also due to inversion and crush injuries and, thus, damage the physeal cartilage to a greater extent. Because of the tendency toward displacement and the high incidence of growth-related problems, the recommendation is for a perfect anatomic reduction, which generally implies open reduction and internal fixation. 7. LATE RESULTS IN DISTAL TIBIAL PHYSEAL FRACTURE-SEPARATIONSWITH AN INTRA-ARTICULAR COMPONENT Landin et al. studied a subset of patients with childhood distal tibial physeal fractures to assess patients with physeal injuries and an intra-articular component (186). They thus separated out 78 patients from 373 who had Salter-Harris lesions types III and IV of the medial malleolus, Tillaux fractures (Salter-Harris type III of the anterolateral part of the distal tibial epiphysis), and triplane fractures. The patients had all been treated during a time frame in which there was an awareness of the fact that these injuries were in a relatively high-risk category and, thus, either accurate closed reduction or open reduction and internal fixation were carefully utilized. The results in general were quite favorable. Part of this was due to the accurate repositioning and part was due to the fact that most fractures occurred at an age when the remaining growth potential of the physis was small, such that premature growth arrest was not clinically significant. In addition, most of the injuries were caused by low-energy trauma. They concluded that the intra-articular component of the fracture should be reduced exactly, preferably with open reduction and internal fixation if needed. The majority of symptomatic ankles had had a Tillaux or triplane fracture. The distribution of fractures numerically showed 14 type III lesions of the medial malleolus, 6 type IV lesions of the medial malleolus, 17 Tillaux fractures, and 28 triplane fractures.

M. Proximal and Distal Fibula Proximal fibula growth plate fractures are rare and unless associated with massive open trauma do not lead to growth problems. Havranek reported on six fractures all caused by automobiles injuring pedestrians (142). There were four girls and two boys involved at an average age of 11.9 years (range = 9.5-15.3 years). Fracture types were three type II,

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one type III, and two type IV, but all healed uneventfully. One of the six had open reduction and wire fixation; the rest were treated in cylinder casts. The distal fibula frequently is the site of undisplaced type I fractures, with types II-V virtually never seen. Isolated type I lesions, type A by the pathophysiologic classification, all appear to heal uneventfully without growth arrest. Distal fibula fractures associated with fracture-separations of the distal tibia occasionally develop premature fusion. Isolated distal fibula physeal fractureseparations are more common than statistical studies indicate. Due to the generally benign nature of the injury virtually all are treated on an outpatient basis, often symptomatically only, without specific delineation of whether the distal fibular discomfort is a sprain, an epiphyseal type I fracture, or an adjacent metaphyseal injury.

N. Growth Patterns Following Distal Tibial and Fibular Growth Plate Fracture-Separations Using Roentgen Stereophotogrammetry Karrholm and associates performed a series of detailed studies involving the mechanism of injury and growth pattern after epiphyseal growth plate ankle injuries in children (167173). They utilized the Roentgen stereophotogrammetric technique to assess growth. This method, originally developed by Selvik, involved the placement of spherical tantalum balls within the bones, and subsequently the positional relationships between each were followed radiographically with time. At operation or after fracture healing, spherical tantalum balls 0.5 mm in diameter were inserted either at the time of open surgery or percutaneously under local anesthesia. On the fractured side, 3-5 balls were inserted at each side of the growth plate in the distal tibia with 1 ball inserted on each side of the growth plate in the distal fibula as well as in the distal tibia on the intact side. Patients were followed with radiographic examination 1-3 weeks after implantation of markers and then 1 month later. Subsequent exams were performed at intervals of 3-6 months during the first year and 6-12 months in the second and later years if follow-up was indicated. Standardized radiographic technique was used, following which the films were evaluated in a precision instrument for aerial photogrammetry. This method thus allowed for detailed studies of the relative extent of growth of the distal tibial and fibular epiphyses in relation to the normal side. The second aspect of the work by Karrholm and associates involved the assessment of growth pattern in relation to the mechanism of injury. They utilized schemes for interpreting adult ankle fracture mechanisms and applied them in detail to childhood fractures for the first time. They thus related the growth pattern to supination-eversion injuries and supination-adduction injuries, as well as to pronationabduction and pronation-eversion. They were able to define five types of growth pattern following injury. These involved normal growth, initial growth stimulation of varying time length, initial and temporary growth retardation, initial

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CHAPTER 7 ~ Epiphyseal Growth Plate Fracture-Separations

and permanent growth retardation, and initial and permanent growth arrest. They felt that the Roentgen stereophotogrammetric method in conjunction with the anatomictraumatological classification permitted early determination of the growth pattern with high accuracy and demonstrated growth disturbances months before they would be evident from plain radiographs. Their summary showed that prediction of a specific growth pattern could be made only with low accuracy but separation of the growth patterns into two groups--one with symmetrical growth, initial and temporary growth retardation and growth stimulation, and the other with progressive growth retardation and growth arrestm could be made. They felt that in 67% of cases, when they compared the predicted outcome with the actual result, the correct classification was made. They felt that the SalterHarris classification alone could not significantly predict the growth pattern.

O. Ligament Damage Following Distal Femoral and Proximal Tibial Physeal Fractures Bertin and Goble performed a retrospective study of 29 cases of physeal fracture about the knee to assess the degree of ligament stability. The average age at injury for the distal femoral fractures was 12 years 5 months, and the average age at injury in the proximal tibial fractures was 14 years 4 months. Follow-up was at a mean of 66 months postfracture. They found that 6 of 16 patients with distal femoral fractures and 8 of 13 patients with proximal tibial fractures had associated ligamentous laxity to static testing at followup evaluation. This represented an incidence of 48%. They concluded that physeal fracture does not preclude ligament damage and that ligamentous assessments, though difficult, should be part of initial assessments as well as posthealing assessments and rehabilitation programs (24).

VII. T R A U M A T I C D A M A G E T O G R O W T H P L A T E S BY P A T H O L O G I C , C H R O N I C REPETITIVE, AND INDIRECT EFFECTS

A. Pathologic Epiphyseal Growth Plate Fracture-Separations 1. MYELOMENINGOCELE Pathologic epiphyseal growth plate fracture-separations are seen in patients with myelomeningocele. These have been likened to a Charcot neuroarthropathy disorder in which repeated damage to a physeal region is allowed to continue because the patient has insufficient ability to appreciate pain and continues to use the affected limb. There have been several studies documenting the occurrence of epiphyseal growth plate fracture-separation in patients with myelomeningocele, stressing in particular the often negative

sequelae. One of the earliest descriptions in the English literature is the paper by Gillies and Hartung in 1938 (122). Gyepes et al. drew clear attention to the entity of marked skeletal changes at the metaphyseal-physeal junctions of the lower extremities in meningomyelocele patients who remained ambulatory (131). The characteristic radiographic changes involved (1) widened cartilaginous epiphyseal plates, (2) irregular, dense, slightly widened metaphyses, and (3) sub-periosteal metaphyseal-diaphyseal new bone formation. To this list can be added (4) minimal to absent epiphyseal displacement, (5) prolonged healing time, and (6) a high incidence of premature growth plate fusion. Repetitive trauma with continuing mobility and limited immobilization were felt to be the keys to the pathogenesis of the clinical and radiological findings. It is evident that muscular paralysis alone does not lead to these changes because they are never seen in such disorders as poliomyelitis or other muscular disorders in which the sensation remains intact. It is the insensitivity to pain that leads to a Charcot-type neuroarthropathy or neurochondrosteopathy. The radiologic changes described will regress once appropriate and relatively prolonged immobilization is instituted. Not infrequently, biopsy of the metaphyseal region has been undertaken with the suspicion that the disorder represented either an osteomyelitis or a sarcomatous process. In the paper by Soutter, a bone marrow metaphyseal biopsy was performed immediately adjacent to the physis, and the marrow space was found to be occupied by callus and evidence of healing fractures (297). Wenger et al. reviewed the records of 244 patients with spina bifida and documented a 23% incidence of at least 1 fracture of a lower limb, including 8 epiphyseal fractures (2.8%) (326). The pattern outlined in their study was similar to that in previous and subsequent papers. The majority of epiphyseal fractures were of either the type I or type II variety. The characteristic findings involved a widening of the radiolucent area of the involved physis, irregularity of the metaphyseal layer of bone, absent to only minimal displacement of the epiphysis, and a prominent metaphyseal periosteal reaction that often led to the concern about an osteomyelitis or neoplastic condition such as osteosarcoma, Ewing's sarcoma, or leukemia. The fractures described all involve the lower extremities because of the nature of the meningomyelocele lesion sparing the upper extremities. Each of the four major lower extremity physes can be affected, involving the proximal and distal femur and proximal and distal tibia. The clinical signs involve swelling and redness about the joint region, although discomfort is minimal. Premature closure of the involved physis occurred in 5 of 9 patients. Because the fractures occur generally in those less than 12 years of age and often early in the first decade, such injuries often lead to significant lower extremity length discrepancies, which complicate an already problematic situation. The fractures generally are late in being diagnosed and tend to take much longer to heal than their counterparts in an otherwise normal child. Because of the delay in union and

SECTION VII 9 Traumatic Damage to Growth Plates the high degree of complication, immobilization in a solid cast for a 2-month period is almost always the recommendation of the various studies. Kumar et al. described 5 physeal fracture-separations in 16 patients with myelomeningocele (181). Four of these involved a distal tibial physis and one the proximal tibial physis. There was no clear-cut history of trauma. X rays revealed an increase in the width of the physis and an irregularity at the physeal-metaphyseal bone junction. The physeal fractures were most common in the lower lumbar level ambulatory group. Healing was much slower in the physeal injuries than in diaphyseal or metaphyseal fractures. The injury should be well-protected in a cast for a period of 8-12 weeks, and weight bearing should not be allowed until early signs of union are clear. Lock and Aronson described seven epiphyseal growth plate fractures in a large group of myelomeningocele patients (197). All metaphyseal and diaphyseal fractures healed satisfactorily whereas the seven fractures that involved the physeal plate were a major problem with three showing delayed union and two premature growth arrest. Four of the fractures were type I and three were type II. Roberts et al. reported five examples of physeal growth plate fracture-separation in four children with myelomeningocele and also noted physeal widening as a prime radiologic indicator of the disorder (272). Each of the injuries was un-displaced and there was no periosteal new bone formation, indicating early diagnosis. Protection from further trauma resulted in rapid clinical resolution. They felt, however, that with early diagnosis the period of immobilization could be shorter than previous studies had indicated, and usually a 4-week period was sufficient. Fromm et al. studied a large number of patients with myelomeningocele, assessing 82 children out of a group of 947 who had sustained a total of 224 fractures (118). Among these were 3 distal femoral epiphyseal separations (1.4%), 3 proximal tibial epiphyseal separations (1.4%), and 6 distal tibial epiphyseal separations (2.7%). In 1 of the 3 cases at the distal femoral epiphysis, there was premature closure of the epiphyseal growth plate, with premature closure also occurring in 1 of 3 proximal tibial and 2 of 6 distal tibial fracture-separations. Edvardsen pointed out the frequency of physeal damage in patients with myelomeningocele (94). He noted the broadening and loosening of the physis due to repetitive trauma. He observed 6 physeal disorders in 50 children from 2 to 7 years of age. Because the observations frequently were made by chance without history of either trauma or discomfort, the number seen probably underrepresented those that occurred. Physeal regions of patients with myelomeningocele could be traumatized during daily walking activities and in association with therapy such as passive joint movements. Quilis reported three cases of fracture-separation of the epiphysis, one of which suffered premature closure of the growth plate (261). The radiographic appearance of these

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fractures in the epiphyseal and metaphyseal regions can be confused with many disorders, including osteomyelitis, bone sarcoma, bone syphilis, scurvy, neurotropic joints, and battered child syndrome. Multiple case reports of the occurrence of the lesion with its characteristic finding of widening of the epiphyseal line and abundant periosteal reaction with new bone formation were made by Soutter (297) and Golding (125). Golding in particular commented on the similarity of the findings to a Charcot joint. The epiphyseal line was much wider than normal, irregularity of bone appearance occurred in the metaphysis adjacent to the widened physis, and periosteal elevation led to considerable new bone formation in the metaphyseal region. Physeal slippage was almost always minimal in extent. Rodgers et al. reviewed 19 chronic physeal fractures in 13 patients with myelodysplasia. In only 3 cases could the injury be ascribed to a traumatic event (273). Indeed, many of the patients had extreme delay in diagnosis. The most common site was the distal tibia in 10, followed by chronic epiphyseal injury in the distal femur in 4, the proximal femur in 3, and the proximal tibia in 2. All patients were treated with prolonged immobilization averaging 5.8 months (range = 3-18 months) using either braces or casts. Four of the fractures required operative fixation. All injuries had healed at 4.8 years follow-up, but in 4 of the fractures premature growth plate fusion was noted. In each of the many studies reported, fractures are seen most commonly in the distal femur, proximal tibia, and distal tibia, with some also occurring in the proximal femur in higher lesions. In occasional instances, several growth plate fracture-separations occur in the same patient. Thus, it is important to follow patients with myelomeningocele carefully, especially when excessive walking or physical therapy treatments lead to swelling in the joint regions. If an epiphyseal fracture-separation is noted, it would be wise to radiograph each of the physeal areas of the lower extremities to make certain that other injury disorders had not occurred. 2. OTHER PATHOLOGIC DISORDERS Epiphyseal growth plate fracture-separations of a pathologic nature are rare except in myelomeningocele or neurological disorders similar to it in which continuing motor function occurs in the presence of absent or markedly diminished sensation. In most reports of epiphyseal slipping in the literature, there is no clear history of trauma and the disorder generally is attributed to repetitive low-grade trauma with either walking or therapy in which slippage occurs, but with normal pain sensation not being present continuing activity leads to worsening injury. Epiphyseal slipping in relation to other disorders is seen most frequently with slipped capital femoral epiphysis, and the large number of disorders with which proximal femoral slipping can be associated is discussed in detail in Chapter 5. There are two other pathologic entities that can be associated

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CHAPTER 7 ~ Epiphyseal Growth Plate Fracture-Separations

with slipped epiphyses in areas other than the proximal femur. When such disorders occur, they are associated almost exclusively with renal osteodystrophy (see Chapter 10), although rare instances of slipping with scurvy have been reported.

B. Premature Physeal Closure Following Seemingly Unrelated Fractures of the Ipsilateral Diaphysis and Metaphysis There is increasing recognition of the occurrence of premature physeal fusion following seemingly unrelated diaphyseal or metaphyseal fractures on the same side. Whereas reports generally have been small with 1-3 patients reported, Hresko and Kasser were able to describe 7 children with this occurrence over a 3-year period from 2 children's orthopedic services (147). The large majority of patients are 11-14 years of age. The limb length discrepancy is often significant because follow-up generally was discontinued with repair and rehabilitation of the shaft fracture because there was no awareness by the treating physician of any physeal injury. In the patients to be reported later from several series, a total of 19 patients with premature physeal closure are described of whom 8 were males and 11 females. The mean age at occurrence in the males was 11 years 10 months (range = 10-14 years) and the mean age in the gifts was 11 years (9-12 years of age). In the entire series, therefore, the mean age at occurrence was 11 years 5 months (range = 9-14 years). Morton and Starr described asymmetrical closure of the upper tibial epiphysis following fracture of the distal onethird of the tibial shaft without apparent injury to the epiphysis (221). The affected epiphyses closed prematurely, resulting in progressive hyperextension deformity of the knee. One patient was an 11-year-old girl and the other a 13year-old boy. As part of their treatment, both had proximal tibial K-wires placed but the wires were not near the tibial tubercle being described as 1 and 1.5 in. or greater distal to the tubercle. The deformity became evident in the second year following injury and in both instances was major in relation to shortening and angular deformity. The authors describe the fractures of the lower one-third of the tibia as being severe although the course of treatment had seemed unremarkable. They also referred to a case of Smillie in a young girl who suffered an open fracture of the tibial shaft complicated in a late stage of recovery by a supracondylar fracture of the femur and then the discovery sometime later of a genu recurvatum caused by closure of the anterior portion of the upper tibial epiphysis. Hunter and Hensinger described multiple premature growth arrests on the ipsilateral side in an 11-year-old girl who, following major trauma, suffered a comminuted spiral fracture of the proximal one-third of the shaft of the fight femur (149). She was treated in a hip spica for 5.5 months. During the year following the injury, she was noted to have early closure of almost all epiphyseal plates of the fight lower extremity (proximal and distal femur, proximal and distal tibia, and proximal fibula) except for the distal fibula.

The growth arrest lines indicated that the closure had occurred shortly after the original injury. The closure phenomenon was so marked that premature fusion of the epiphysis of the greater trochanter and the iliac crest also occurred. Eighteen months following injury, the fight lower extremity was 5 cm shorter than the left. Abram and Thompson noted marked wrist deformity after premature closure of the distal radial physis following what appears to have been an uncomplicated torus fracture of the distal radial metaphysis in a 10-year-old girl (3). Hresko and Kasser described seven patients with long bone diaphyseal fractures who subsequently developed premature physeal closure around the knee (147). In each instance, the growth deformity was marked. There were two femoral neck fractures, two femoral subtrochanteric region fractures, a femoral diaphyseal fracture, and two tibiofibular diaphyseal fractures. Skeletal traction (which can cause premature epiphyseal arrest if the pin is placed directly into a physeal area) was used for only three patients, two of whom had physeal arrests in the bone other than the one in which the traction pin was placed, whereas in the other the traction pin was shown clearly by X ray to be well distal to the proximal tibial physis in which eventual fusion occurred. Beals described three patients who experienced the premature complete physeal closure of the ipsilateral limb following diaphyseal fracture (21). In each instance, a clinically significant length discrepancy occurred. A 14-year-old boy suffered a subtrochanteric fracture of the left femur with subsequent premature closure of the ipsilateral distal femoral and proximal tibial physes. A scanogram at age 20 documented 4.5 cm of lower extremity length discrepancy. A girl 11 years 10 months of age suffered a fracture of the distal fight femur followed by ipsilateral proximal tibial physeal closure with the fight tibia 1.6 cm short 6 months postfracture. A boy 11 years 3 months of age suffered fractures of the distal fight femur and middle fight tibia and experienced premature closure of the proximal femoral physis and the proximal distal tibial physes. Closure of the distal femoral physis was due to direct trauma. Twenty-one months after the fracture, scanograms demonstrated 8.8-cm shortening of the fight limb. Bowler et al. described two cases of premature closure of the anterior portion of the proximal tibial physis with associated genu recurvatum in a 12-year-old boy and an 11-yearold boy, both of whom suffered fight femoral shaft fractures (31). Proximal tibial osteotomies were required in both. Paul et al. reported a 9-year-old girl with a displaced fracture of the distal one-third of the radius and ulna (245). Treatment by closed reduction under general anesthesia appeared unremarkable and healing was uneventful. Three years later, she presented with 5-cm shortening of the ulna and evidence of complete arrest of the distal ulna epiphysis. Aminian and Schoenecker described two fractures of the distal radius apparently with lack of involvement of the distal radial physis, which led to subsequent complete arrest of the adjacent growth plate (14). One injury occurred in a 12-

SECTION VII ~ Traumatic Damage to G r o w t h Plates

year-old girl and the other in an 11-year-old girl who were treated with closed reduction in the first instance and casting without reduction for a torus fracture of the distal radius and a fracture of the ulnar styloid process in the second. The 12year-old girl presented 2 years later with a markedly prominent distal ulna due to premature partial closure of the distal radial physis. The 11-year-old girl presented 2 years later with progressive prominence of the distal left ulna and radiographic evidence of a premature growth arrest of the distal radius. Both eventually required corrective surgery. Although the phenomenon increasingly is well-documented, it still remains relatively rare and unfortunately no definitive understanding of the pathophysiology is available. The possibility exists that the physis is injured in an undetectable way at the time of diaphyseal or metaphyseal fracture, but this alone would appear to be insufficient cause. The age at occurrence of the phenomenon is quite narrow, however, with a mean occurrence at 11 years and virtually all patients between 10 and 13 years of age. It is known that long bone fractures speed up the overall development of the entire bone, presumably in relation to the increased vascularity of the entire bone associated with the reparative response, and the fact that this is occurring during the growth spurt at a time when relatively little growth is remaining might well make the physeal regions vulnerable to premature closure.

C. Physeal Separation Due to the Stress Injury Caused by Chronic Repetitive Activity Over the past few decades, the widespread participation of children and adolescents with open growth plates in intensive athletic training programs, especially where chronic repetitive exercises are done, has led to the recognition of a syndrome that appears compatible with an un-displaced stress separation of the overused physeal area. These appear to be most common at the distal radial physis, but convincing reports have also been presented of occurrences at the proximal humerus and distal femur. An early report by Adams defined the abnormality in the proximal humeral epiphysis of five boys involved in baseball pitching with extensive activity (4). He considered the disorder to be an osteochondrosis, but the symptoms and radiographic descriptions appear compatible with what appears to be a physeal separation. Of the five boys described, two were 13 years old, one 14 years old, and two 15 years old. The principal clinical finding was pain in the shoulder at the end of a hard throwing motion. X rays showed a characteristic widening of the proximal humeral physis and demineralization and fragmentation adjacent to the physis without evidence of avascular bone necrosis. The discomfort quietened almost immediately with rest and avoidance of activity and the X ray shortly regained normal structure. Comparative X ray studies of both shoulders showed demineralization and marked widening of the epiphyseal line in the pitching arm. The symptoms were relieved and the X ray became normal over the few months following discontinuation of the activity.

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Dotter reported a similar case in a 12-year-old pitcher with similar shoulder symptoms and X-ray changes, and he diagnosed the lesion as a fracture through the epiphyseal cartilage plate (88). Cahill et al. reported six cases of stress fracture of the proximal humeral epiphyseal plate in 11- and 12-year-old male baseball pitchers (50). Symptoms were as described previously with pain and inability to perform. Xray changes showed widening of the epiphyseal line with metaphyseal bone fragmentation and irregularity. Stress fracture through the distal femoral epiphysis in athletes also was reported by Godshall et al. with two cases (124). Chronic, strenuous, and repetitive exercise in relation to sports led to the disorder in two males 14 and 15 years of age. The 14-year-old had pain in his knee for several months on an intermittent basis with acute worsening immediately prior to his assessment. The physis in particular of the distal lateral femur was widened and a diagnosis of stress fracture of the physis was made. This healed uneventfully with rest using crutches for 3 weeks and decreased physical activity for 3 months. Follow up X rays showed complete healing of the stress fracture through the epiphyseal line. In the second case, pain developed over a 4-week period in the knee region. X rays also showed widening of the distal femoral epiphyseal line. Crutch use and diminution of activity for 12 weeks led to complete healing of the physis radiographically. In neither case did premature physeal fusion occur with resumption of more controlled activity. Most reported cases have involved the distal radial physis in gymnasts. Roy et al. reported 21 cases involving stress changes of the distal radial epiphysis in young gymnasts (277). The X ray changes appear consistent with un-displaced stress fractures of the distal radial physis. In this series, no residual growth-related problems were observed. Treatment involved wrist immobilization until the symptoms disappeared followed by increased rest and gradual reinstitution of activity at a less intensive level. In their series, 11 had radiographic changes and in these recovery took at least 3 months; in a second group, 10 had similar symptoms but no radiographic changes and they recovered within an average of 4 weeks. The mean age at time of diagnosis was 12 years with a range from 10 to 17 years. Nineteen of the 21 were female. The amount of activity was extensive, and in the 21 patients 17 worked out at least 6 hr per day, 6 days per week. The characteristic radiographic findings of nondisplaced physeal separation in relation to repetitive stress are widening of the growth plate of the distal radial epiphysis, particularly on the radial and volar aspects, cystic changes usually of the metaphyseal aspect of the epiphyseal plate associated with an increase in irregularity in the physeal-metaphyseal bone margin, and occasional haziness within the usually radiolucent area of the epiphyseal plate. Fliegel reported three cases of stress-induced widening of the distal radial growth plate in adolescent athletes (105). Characteristic radiographic features again were seen involving irregular widening of the growth plate, irregular metaphyseal borders along with flaring of the metaphysis, and,

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CHAPTER 7 ~ Epiphyseal Growth Plate Fracture-Separations

on occasion, sub-periosteal new bone formation. Symptoms resolved with diminished activity, although radiographic changes took anywhere from 9 to 24 months to fully resolve. In relatively advanced cases, there is also a tendency to sclerosis of the adjacent metaphysis. Fliegel's cases were in a 14-year-old girl, 14-year-old boy, and 14.5-year-old boy. In two of the instances, X rays returned to normal with rest, but in one, some changes in residual deformity of the metaphyseal area and relative shortening of the radius occurred. Similar stress injury findings of the distal radial growth plate were found in 21 cases by Carter and Aldrich (57). In their group, there were 17 boys (average age 13.5 years) and 4 girls (average age 14 years). Characteristic radiographic findings again involved widening of the distal radial growth plate, particularly on its volar aspect, haziness of the growth plate due to irregularity of the border between the cartilage and the metaphyseal zone, and an increase in the transverse diameter of the metaphysis. The ulnar growth plate can also be irregular. With rest, the haziness and widening of the growth plate resolve, although some irregular metaphyseal scalloping may persist. Physeal injury due to repetitive stress occurs in areas of most rapid growth in which the hypertrophic zone is felt to be most vulnerable. When increased activity is superadded, the physeal separation without displacement occurs. The physis is widened as there is interruption of the normal mineralization process in the metaphysis.

D. Genu Recurvatum after Skeletal Traction Involving Inadvertent Placement of the Proximal Tibial K-Wire through the Tibial Tubercle Physeal Area In using skeletal traction, great attention must be taken not to impinge upon the physeal regions. Skeletal wires through or immediately adjacent to physes can be shown to induce premature bone fusion. The most common area for this complication to occur is the proximal tibia, in which the K-wire usually is placed well distant to the transverse proximal tibial physis but on occasion somewhat anteriorly and thus in the region of the distal extension of the tibial tubercle physis (26, 318).

VIII. M A N A G E M E N T O F N E G A T I V E SEQUELAE OF GROWTH PLATE FRACTURE-SEPARATIONS

A. General Considerations Even with improved diagnosis and treatment of growth plate fracture-separations, some injuries will proceed to growth plate damage and negative growth sequelae. Among the measures to be taken to minimize damage are (1) recognition of non-displaced type I fractures and treatment by cast

immobilization for a minimum of 3 weeks, (2) gentle closed or open reduction of type II distal femoral fractures with metaphyseal fragment-metaphysis wire-pin fixation to minimize postreduction instability, and (3) open anatomic reduction and internal fixation for types III and IV intra-articular injuries with physeal displacement. Once growth plate damage has occurred, transphyseal bone bridge formation serves as a tether that causes either complete or partial cessation of growth. There are three possible major sequelae to a growth plate fracture-separation: shortening, angular deformity, and possible joint surface incongruity (Fig. 11). If there is complete cessation of growth, shortening without angular deformity occurs. If there is only partial or focal bone bridge formation, some shortening usually occurs but the major problem relates to angular deformity as the rest of the growth plate continues to function. Shortening alone is a characteristic of either massive complete bone bridge formation or central bone bridge formation greater than 50% of the diameter of the physis. Angular deformity is characterized by bone bridge formation adjacent to the periphery of the plate. Management of the bone bridge and the sequelae is divided into two time periods, early and late. By late we refer to the situation in which a bone bridge has formed and negative growth sequelae have occurred involving shortening, angular deformity, or joint surface incongruity. The use of the term early refers to the demonstration of a transphyseal bone bridge within the first several months after fracture but prior to the onset of any clinically detectable shortening or angulation. Articular surface irregularity is a problem from the moment it occurs. Management techniques will be described in great detail in Chapter 8 but will be outlined here. Detailed approaches have also been outlined in the literature (236, 250, 284).

B. Management of Early Bone Bridge Formation MR imaging techniques increasingly are able to show the formation of bone bridges early in their evolution within a few months of growth plate fracture. Not all bone bridges are sufficiently large to cause tethering, however. It is wellknown by both clinical and experimental investigations that not all bone bridges are sufficiently extensive to lead to growth plate arrest. The growth force generated by the physis is extremely great, and with many small bridges, such as those with 10% involvement or less, the affected physis can grow away from or stretch out the bone bridge such that no clinical sequelae follow (61,236, 250). Due to the sensitivity of the MR imaging technique it is extremely important to beware this phenomenon and to not operate prematurely for a small physeal bridge that might not cause an arrest. At present it is advisable to follow the patient sufficiently closely that some documentation of actual growth arrest involving slight shortening or early angular deformity is present before transphyseal resection is performed.

References

Once a bone bridge has been defined as clinically problematic, even in the early phase, two possible treatment approaches can be taken. Transphyseal chondrodiatasis even without formal excision of the bridge may be sufficiently effective to allow for this approach. If not, one can perform early transphyseal bone bridge resection and interposition of either fat or other tissues.

C. Management of Late Sequelae of Bone Bridges" Bone Bridge Excision, Physeal Interposition Materials, and Transphyseal Chondrodiatasis The management of the late sequelae includes management of the bone bridge, the angular deformity and any shortening. Management of the bone bridge is dependent on several considerations: the position of the bone bridge, the amount of physeal cartilage replaced by the bone bridge, and the amount of growth remaining in the affected physis. If it is felt that growth is worth preserving, then bone bridge resection can be considered. The general rule for resection of a bone bridge is that it involves only one-third of the affected growth plate or less. Tomography can be used to determine the extent of the bone bridge, although CT scans and MR imaging are used increasingly for more accurate definition. If angular deformity has occurred, osteotomy to correct that deformity as well as bone bridge resection is needed. Bone bridge resection and interposition tissues are discussed in Chapter 8. If it is determined that insufficient growth is remaining to warrant physeal excision, or if the growth plate involvement is too extensive to expect growth to continue following excision, then complete physeal closure is performed surgically to eliminate the chance of worsening angular deformity. Osteotomy is performed to correct angular deformity. One can then either accept the degree of shortening that will occur or elect to perform a physeal arrest on the contralateral side to prevent worsening limb length discrepancy. If there is already a significant limb length discrepancy, then the contralateral physis might have to be fused to prevent worsening of the deformity as well as an additional physis to allow for correction of the discrepancy that has already occurred. If physeal closure will lead to length discrepancies greater than 5 cm, the option of limb lengthening can be considered. On occasion the bone bridge can be excised followed by interposition of a material designed to prevent recurrence or a procedure to regain length using transphyseal chondrodiatasis. Experimental investigations into bone bridge resections, interposition materials, and transphyseal lengthening are discussed in detail in Chapter 8. Langenskiold created defects in rabbit growth plates and demonstrated that fat placed in the defect prevented bone bridge formation because it kept the epiphyseal and metaphyseal vessels separate (187). This procedure has been used

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clinically with many excellent results [Langenskiold (187); Peterson (250); Williamson and Staheli (329)]. Mallet (202) and Peterson (250) have used methyl methacrylate to bridge the physeal defect, but the method has not gained wide clinical applicability. Many other investigators have confirmed the occurrence of bone bridges with epiphyseal-metaphyseal circulatory communication, generally in the process of describing the effects of various interposition materials in preventing vascular mingling and bone formation. These works include those of Osterman (242) using fat, deep-frozen hyaline rib cartilage, and bone wax, Bright (35) using silastic, Eulert (101) and Lennox et al. (192) using cartilage plugs, and Olin et al. (239) using oriented iliac crest apophyseal cartilage transplants. Some laboratory investigations show possible future clinical promise for vascularized growth plate transplants [Teot et al. (307); Zaleske et al. (335)] and tissue culture growth of chondrocytes prior to their placement into focal defects [Lalanandham et al. (183)]. Another response to a developing growth plate bone bridge involves the use of chondrodiatasis in which pins are placed on either side of the growth plate and gentle distraction is applied with an extemal fixator to pull apart the bone bridge tissue and allow an interposition tissue to reform [A1degheri et al. (13); Canadell and De Pablos (52)]. Caution is warranted, however, at least based on large animal studies because Fjeld and Steen showed growth retardation after lengthening by epiphyseal distraction of 40-70% (104). At the present time this approach is not refined sufficiently to allow for widespread use, but it is beginning to be used clinically in selected instances.

References 1. Abbott LC, Gill GG (1942) Valgus deformity of the knee resulting from injury to the lower femoral epiphysis. J Bone Joint Surg 24:97-113. 2. Abe M, Ishizu T, Nagaoka T, Onomura T (1995) Epiphyseal separation of the distal end of the humeral epiphysis: A follow-up note. J Pediatr Orthop 15:426-434. 3. Abram LJ, Thompson GH (1987) Deformity after premature closure of the distal radial physis following a torus fracture with a physeal compression injury. J Bone Joint Surg 69A: 1450-1453. 4. Adams JE (1966) Little league shoulder: Osteochondrosis of the proximal humeral epiphysis in boy baseball pitchers. Cal Med 105:22-25. 5. Aitken AP (1935) The end results of the fractured distal radial epiphysis. J Bone Joint Surg 17:302-308. 6. Aitken AP (1935) Further observations on the fractured distal radial epiphysis. J Bone Joint Surg 17: 922-927. 7. Aitken AP (1936) The end results of the fractured distal tibial epiphysis. J Bone Joint Surg 18:685-691. 8. Aitken AP (1936) End results of fractures of the proximal humeral epiphysis. J Bone Joint Surg 18:1036-1041. 9. Aitken, AP (1965) Fractures of the proximal tibial epiphyseal cartilage. Clin Orthop Rel Res 41:92-97.

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604

CHAPTER 7 ~ Epiphyseal Growth Plate Fracture-Separations

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CHAPTER 8

Lower Extremity Length Discrepancies I. II. III. IV. V.

Terminology Clinically Significant Length Discrepancies Limb Length Determination Causes of Lower Extremity Length Discrepancies Developmental Patterns in Lower Extremity Length Discrepancies VI. Lower Extremity Length Discrepancies in Specific Disease Entities: Pathoanatomy, Pathophysiology, Developmental Patterns, and Ranges of Discrepancies

VII. Projection of Limb Length Discrepancies by the Time Skeletal Maturity Is Reached VIII. Use of the Developmental Pattern Classification in Projecting Limb Length Discrepancies IX. Management of Lower Extremity Length Discrepancies X. Direct Operation on Epiphyses to Enhance Growth Potential by Removing Focal Transphyseal Tethers

I. T E R M I N O L O G Y

tal maturity greater than 2.0-2.5 cm warrants treatment, whereas anything under that cannot be expected definitively to have serious negative long-term sequelae. For those wishing to "fine-tune" discrepancy management, there is some evidence that discrepancies as little as 1.25 cm or 0.5 in. predispose one to negative sequelae, but discrepancies less than that are rarely treated surgically by even the most ardent practitioners. The negative sequelae of a lower extremity length discrepancy involve (1) an asymmetric appearance, (2) an awkward gait, (3) the possibility of osteoarthritis of the hip on the longer side due to the associated pelvic obliquity and the uncovering of the femoral head associated with this, and (4) low back pain in association with the compensatory lumbar scoliosis (Fig. 1). It is the general experience, however, that those with discrepancies greater than 2.5 cm show sufficient imbalance to warrant treatment. In those with projected discrepancies of less than 2.0 cm, there is no definitive evidence that leaving these discrepancies untreated will lead to long-term degenerative problems. The gray zone conceming the need for limb equalization is between 2.0 and 2.5 cm difference. The extent of any discrepancy must also be considered in relation to the individual's total height because the effect of the same discrepancy is relatively more marked in someone 5 ft tall than in another greater than 6 ft tall.

Lower extremity length discrepancies refer to differences in length between the two extremities, which can be due to some or all of pelvic, femoral, tibial, and foot height differences. The total length differential in the standing position is not dependent solely on the height of the involved bones but can be altered further by unilateral joint dislocation or subluxation, particularly at the hip but also at the sacroiliac or knee joint; by asymmetric femoral-tibial angular deformity; by asymmetric hip, knee, or ankle contracture, and by fixed pelvic obliquity. The term leg length discrepancy is still used commonly to refer to this broad entity but is imprecise. In strict anatomic terminology, leg refers to the segment between the knee and the ankle rather than to the entire extremity. The terms lower limb or lower extremity length discrepancy are more accurate (69, 192). Lower extremity length discrepancies accompany many epiphyseal disorders. Knowledge of epiphyseal structure and function plays a major role in assessing the effects of abnormalities on growth and in projecting the need for surgical intervention at appropriate times to either minimize or eliminate such discrepancies at skeletal maturity.

II. C L I N I C A L L Y S I G N I F I C A N T LENGTH DISCREPANCIES

B. Percentage of Individuals with Equal Limb Lengths

A. General Guidelines Concerning Extent of Clinically Significant Length Discrepancies

1. CLINICAL-RADIOLOGICAL DATA It has long been recognized that only 25-50% of people have equal lower extremity lengths. Hasse and Dehner (222) over 100 years ago (1893) reported leg length differences in

There are no absolute numbers conceming the extent of length differences that requires treatment. It is the feeling of most practitioners in this field that any discrepancy at skele606

SECTION II 9 Clinically Significant Length Discrepancies

607

Clinical Consequences of a Lower Extremity Length Discrepancy

C3 Lumbar Scoliosis 9 Low back pain 9 Sciatica

Osteoarthritis of Hip 9 Long-side 9 Supero-lateral

Awkward Gait Asymmetric Appearance 9 Flexed knee (long side) 9 T o e walking (sho~ side) 9 Trunk-pelvic tilt

F I G U R E 1 The clinical consequences of a lower extremity length discrepancy are illustrated. Lower extremity length discrepancy with shortness on the left is associated with a compensatory lumbar scoliosis, pelvic obliquity, and a relative adduction positioning of the hip on the longer right side. Note the diminution of the CE angle on the longer right side, which can predispose one to superolateral osteoarthritis.

68% of 5141 soldiers with the left longer than the fight in a proportion of 3.3:1. Lower extremity lengths thus were equal in only 32%. Edinger and Bietermann (148) documented lower extremity lengths in 351 individuals radiologically. Both extremities were of equal length in 178 (51%), had less than 5 mm difference in 27 (8%), and had discrepancies between 5 and 50 mm in 146 (42%). The left was longer than the fight in a proportion of 3.6:1. In one of the few large radiographic studies of limb asymmetry, Rush and Steiner (416) documented the presence or absence of discrepancies in 1000 healthy army recruits referred to the radiology department because of a low back complaint and in 100 general duty soldiers without complaint. An anteroposterior radiograph of the lumbosacral spine, pelvis, and proximal femurs in the standing position was made in standardized fashion. The lower edge of the film was parallel to the standing platform such that any differences in the level of the femoral heads indicated a difference in lower extremity length. Length differences were measured in millimeters. The limbs were equal in length in 23% of the larger mildly symptomatic group and in 29% of the smaller fully asymptomatic group. On the basis of this study only 25% of individuals had equal lower extremity lengths. 2. A N T H R O P O L O G I C A L DATA Anthropological data involving actual skeletal measurements of paired long bones in humans also demonstrate a

tendency to increased length of the left femur compared to the right with a left:right predominance also present but less marked in the tibia. Schultz (427) reported on skeletal measurements from 753 human skeletons involving 232 white, 233 American black, 118 North American Indian, 122 Alaskan Eskimo, 41 Chinese, and 7 Australian aboriginal skeletons. On average the humerus and femur were approximately 8% shorter in females than in males. The measurements were made to the nearest millimeter. In virtually all studies reported, the right upper extremity is longer than the left, usually in the range of 75% of cases. This is felt to reflect the fight-handed dominance in the human species. Virtually all studies, however, also show the length of the femur and tibia to be longer on the left in those in which equal limb lengths are not present. When measurements in 744 individuals were averaged in all races, the left femur was longer than the fight in 50%, the fight was longer than the left in 33%, and both were equal in only 17%. The left:fight predominance therefore was 1.5:1. Differences were less marked in the tibia. In 734 individuals the left was greater than the fight in 45%, the fight was greater than the left in 40%, and the fight equaled the left in only 15%. When both femur and tibia were combined, only 5% had equal lengths in 727 individuals. The left was longer in 54% and the fight was longer in 41%, with a left:fight predominance of 1.3:1. These studies were similar to those clinical measurements made by Haase and

608

CHAPTER 8 ~ Lower Extremity Length Discrepancies

Dehner. Garson (174) measured 70 skeletons noting that the combined femur and tibia lengths were longer on the left in 54.3% and longer on the fight in 35.8%, with equal lengths being present in 10%. The combined femoral-tibial differences when the left was longer averaged 4.8 mm, and when the fight was longer they averaged 3.3 mm. In 124 skeletons from Switzerland, Schwerz (428) found the left femur longer in 52%, the right femur longer in 31%, and both equal in 17%. Almost all studies show smaller discrepancies with the tibia. In all racial groups and in both sexes, asymmetries favoring the left bone of the lower extremity, particularly in relation to the femur, are much more frequent than those favoring the right. The absolute amounts of discrepancy, however, are small with the series in the adult man showing a general average of only 2.5 mm difference in the femurs. The humeral differences were greater, however, averaging 4.1 mm longer on the right. Munter (345) compiled a detailed analysis of 326 (233 male and 93 female) adult Anglo-Saxon skeletons, although all bones were not available from each skeleton. The mean values for femoral and tibial lengths in his series also were greater on the left side for both males and females. The mean femoral lengths in the male were 2.4 mm greater on the left side for the femur and 4.5 mm longer on the left side for the tibia. In females the left side was longer for the femur by 4.8 mm and for the tibia the left side was longer by a mean of 1.5 mm. Munter noted from several other series that there was little to no racial variation in side differences or in proportional differences, such that data could be pooled for more statistical significance. There is little presentation of absolute data in the Munter study because most of the assessments related to correlative values. All of the basic numerical data, however, are presented in the paper's appendix such that the bilateral differences for each individual could be calculated.

C. Clinical Effects of Lower Extremity Length Discrepancies Possible negative sequelae of lower extremity length discrepancies have been studied in efforts to relate symptoms to particular amounts of discrepancy (Fig. 1).

1. OSTEOARTHRITISOF THE HIP Primary osteoarthritis (OA) of the hip is quite common, as is osteoarthritis secondary to the major childhood hip abnormalities of developmental dysplasia, Legg-Calve-Perthes disease, and slipped capital femoral epiphysis. It thus is very difficult to document with statistical certainty whether a length discrepancy alone is the primary determinant of a hip arthritic condition. Morscher (337) has clearly discussed the changes in hip joint mechanics due to leg length discrepancies. He pointed out that studies by Pauwels (375) had shown that a lesser amount of pressure is actually transmitted to the hip joint of the shorter leg due to the pelvic tilt, which serves to increase the area of contact between the femoral head and

the acetabulum. There also is truncal shift over the short side, further minimizing the effort needed for hip abduction. Conversely, the weight bearing characteristics of the longer side hip are worsened because there is both a decrease in coverage of the femoral head by the acetabulum on the longer side due to the nature of the pelvic tilt and an increased load at the joint on the longer side due both to diminution of the area of contact between the femoral head and the acetabulum and also to the increase in tone necessitated for the hip abductor muscles. Morscher likened the action of a lower extremity length discrepancy on the longer leg to a coxa valga deformity. The extent of increased coverage of the femoral head on the short side and decreased coverage on the long side has been documented by Krakovits (278) by a trigonometric series of calculations. When the leg is shortened by 1 cm, the diminution of the CE angle of Wiberg on the longer side is 2.3 ~ 2 cm shortening = diminution of 4.6 ~ 3 cm = 6.8 ~, 4 c m = 9.1 ~, 5 c m = 11.3 ~, 6 c m = 13.5 ~, 7 c m = 15.6 ~ 8 cm = 17.7 ~ 9 cm = 19.8 ~ and 10 cm = 21.8 ~ Gofton (187) also supported the contention that stresses imposed on the longer side hip are greater than normal, with those on the shorter side reduced. Acetabular pressure on the longer side was concentrated laterally due to the adducted position of the proximal femur, leading to superolateral femoral head OA. Goflon and Trueman (188) detected a clear association between idiopathic superolateral osteoarthritis of the hip and lower extremity length discrepancy, with the hip on the longer side involved in 33 of 36 instances. There were 31 of the 36 cases showing OA on the longer side with discrepancies from 5 m m (3~6 in.) and greater with 16 of the 36 having a discrepancy greater than 1.25 cm (0.5 in.). The differences in lower extremity lengths were determined radiographically with strict application of a standardized standing orthoroentgenographic technique. It was the superolateral variant of osteoarthritis that was particularly related to the length discrepancy. The more global or medial forms of OA were not assessed, and none of the patients were determined to have clear predisposing causes of OA such as hip subluxation or dislocation or residual evidence of any of the other childhood hip disorders. When measurements alone were considered, 4 patients had OA on the shorter side, 3 had OA but were level, and 29 had OA on the longer side. When a correction was made to allow for an estimation of the original prearthritic leg length discrepancy by adding 5 mm or 3~6 in. to the side with the OA to represent the amount of articular surface collapse, even more patients were shifted to the group showing length discrepancy with the longer side affected. They concluded that length discrepancy was present in at least 33 of the 36 cases with the longer side developing the OA. 2. L o w BACK PAIN AND SCIATICA The correlation of compensatory lumbar scoliosis with lower extremity length discrepancies also has been studied, as have attempts to equate the shortness with increases in lumbar discomfort. The relationship between shortening,

SECTION II ~ Clinically Significant Length Discrepancies

compensatory scoliosis, and discomfort, however, has been difficult to document. Morscher (337) describes the attempts at correlations well. He noted that Hult (241) found that almost 54% of patients with lower extremity length discrepancies complained of lumbar pain but that 60% of patients without such discrepancies had similar complaints. Electromyographic studies by Taillard and Morscher (469) showed that relatively small leg length discrepancies between 1 and 2 cm could lead to a remarkable increase in muscle activity in several muscle groups. The possibility remains, therefore, that even small discrepancies make it difficult to maintain a complete resting position due to secondary muscle activations. The relationship between lumbar scoliosis and lower extremity length discrepancies is not invariably the same. In the large majority of cases the convexity of the lumbar scoliosis is directed toward the shorter side, but in perhaps 1015% of cases the scoliosis is contralateral to that expected on a purely mechanical basis. Morscher (337) indicates that the development of a lumbar scoliosis may be due more to dynamic forces in association with walking than to static forces as demonstrated in the standing position. Difficulties are associated with attempting to determine whether length discrepancies cause degenerative disk disease. Low back pain in itself is quite common and relatively large numbers of patients very carefully studied would be needed to determine whether there was an increased prevalence in those with lower extremity length discrepancies alone. Many efforts have been made in this regard. In the study by Rush and Steiner (416) involving a larger group of army recruits of 1000 with low back pain and a smaller group of 100 without pain, the percentages of lower extremity length differences in the larger/smaller groups were as follows: 1-5 mm, 39.5%/38%; 6-10 mm, 22.5%/29%; 11-20 mm, 13.3%/4%; and i>21 mm, 1.7%/0%. The combined patients with length discrepancies 5 mm or less were 62.5%/67% and with length discrepancies 10 mm (1 cm) or less were 85%/ 96%. It is evident, therefore, that it was only beyond the 11-mm discrepancy level that the percentage incidence of back symptoms increased beyond the control range. The length discrepancies were then correlated with the detailed quantification of the pathological conditions of the spine seen on both anteroposterior and lateral radiographs. The radiographic abnormalities were present in the same percentage of patients with equal limb lengths and in those with length discrepancies, with 25% of each group showing changes. The authors concluded that in the symptomatic group it could have been length discrepancy itself with the associated compensatory scoliosis rather than the radiographic abnormalities that was responsible for the symptoms. Nichols (348) used clinical tape measurements from the anterior superior iliac spine to the tip of the medial malleolus to document that 7% of 1007 patients without back pain had a length discrepancy of 1.25 cm (0.5 in.) or more, whereas a limb length discrepancy of 1.25 cm or more was seen in 22% of 180 airmen complaining of low back pain. In his review of the Rush-Steiner data, Nichols also concluded that a signif-

609

icant difference in the incidence of back pain and a shortened lower extremity could only be seen when the discrepancy was 11 mm or more. It is these studies that provide some objective information of the effects of lower extremity length discrepancies. Giles and Taylor (178) studied the relationship of lower extremity length inequality and low back pain in 1309 patients and a small control group of 50. The prevalence of a length discrepancy of 1 cm or more was more common in patients suffering from low back pain (18.3% of 1309) than in the normal population (8% of 50 controls). Friberg (170) studied the correlation between lower extremity length discrepancy, low back pain, and chronic unilateral hip discomfort. He used a low-dose radiologic method with the patients in a standard posture with the single radiograph showing the lower spine, pelvis, and hips. The study comprised 1157 subjects: 653 patients with chronic low back pain with or without sciatica, 254 with chronic unilateral hip pain, and 359 symptom-free army conscripts. In the total series the lower extremities were of equal length in only 8% of patients. The left lower extremity was longer than the fight by a ratio of 1.4:1. There was excellent correlation between an increase in the amount of lower extremity length discrepancy and both back pain and hip discomfort. When all patients were assessed, those within lengths from 0.0 to 4.0 mm difference comprised 36% of the population; those 5.0-9.0 mm a further 39%, 10.0-14.0 mm, 17%, and 15.0 mm or more, 8%. Stated another way, those with lower extremity lengths less than 10.0 mm (1.0 cm) comprised 75% of the study, leaving 25% with a discrepancy of 1.0 cm or greater. The incidence of low back pain in the lower extremity length groupings 5.0-9.0, 10.0-14.0, and 15.0 mm or more was 45.3%, 18.4%, and 11.7%, respectively, with the numbers for the symptom-free group at the same length discrepancies much less at 27.9%, 13.4%, and 2.2%. Stated a different way, the ratio of symptomatic to nonsymptomatic back pain patients with limb length differences of 5.0 mm or more was 1.73:1, 10.0 mm or more, 1.93:1, and 15.0 mm or more, 5.32:1. A discrepancy of 1.5 cm or more, therefore, clearly appeared to predispose the individual to a relatively high likelihood of back discomfort; the presence of leg length inequality of 1.5 cm or more was 5.32 times more likely in 653 patients with chronic low back pain than in 359 symptomfree soldiers. Similar findings were found in relation to chronic hip discomfort. In the 254 patients with hip discomfort, the pain was located on the side of the longer extremity in 88.9% with symptoms and in the hip of the shorter extremity in only 11.1% of cases. Sciatica predisposed to the longer side by a ratio of 3.7:1, similar to findings in the small series of Redler (399) in which, in 15 cases of sciatica, it was present on the longer side by a 2:1 ratio. Rossvoll et al. (415) have assessed back pain in young adult patients before and after subtrochanteric shortening osteotomies of the femur performed after skeletal maturity. There were 22 patients followed for an average of 5 years. The mean preoperative length discrepancy was 3.2 cm with

610

CHAPTER 8 ~ Lower Extremity Len~tth Discrepancies

follow-up discrepancy diminished to 0.43 cm. Approximately half of the patients had relatively serious low back pain prior to surgery with the other half having minimal to no low back pain. The mean ages at operation in the two groups were 25.9 and 20.2 years. The degree of low back pain was felt to be significantly reduced after the operation. Other studies with small numbers of patients reflect how well some patients with length discrepancies do. Gibson et al. (176) found that otherwise healthy young adults with an average of 3 cm of limb length discrepancy perceived no functional effect, whereas Gross (202) evaluated 35 marathon runners and found 7 with limb length discrepancies greater than or equal to 1 cm who reported no effects upon their performance. 3. GAIT ASYMMETRY Additional studies have begun to define the nature of gait asymmetry in patients with limb length inequality. Kaufman et al. (264) performed detailed gait studies on 20 subjects to determine the magnitude of discrepancies that resulted in gait abnormalities. A limb length inequality greater than 2 cm (3.7% difference) resulted in gait asymmetry that was greater than that observed in the normal population. This number correlates well with the generally accepted clinical guideline beyond which length discrepancy correction is warranted. Goel et al. (184) performed gait analysis for discrepancies less than 2 cm to determine the maximum moments at the hip, knee, and ankle joints. They concluded that a minor length discrepancy of 1.2 cm did not produce meaningful biomechanical changes and that the body was well able to compensate for minor lower extremity length discrepancies up to 2 cm. Goel et al. studied 10 healthy subjects with equal limb lengths, simulated minor limb length discrepancies using a shoe lift of 1.25 cm, and an additional 10 asymptomatic patients with limb length discrepancies ranging from 1 to 2 cm. Their study "did not find an association between minor limb length discrepancies and predictable changes in lower extremity joint kinetics that might potentially lead to joint abnormalities."

III. LIMB LENGTH DETERMINATION A. Clinical Measurements Clinical examination of a patient with a lower extremity length discrepancy remains the basic form of assessment. When viewed from the back in the standing position, one looks for a compensatory scoliosis, palpates the levels of the iliac crests, and examines for the levels of the buttock and popliteal creases, the presence of a plantigrade foot, and the thigh and calf circumferences. Children with lower extremity length discrepancies use compensatory mechanisms to maintain an uptight alignment. In the standing position with the feet fiat and the knees fully extended, a compensatory

lumbar scoliosis is seen with the curve convex on the shortened side. With forward bend or in the sitting position, the scoliosis disappears as there is no longer need for any compensation. A rotatory thoracic or lumbar component is absent with forward bend in a compensatory scoliosis, whereas in a structural curve it persists. When the child is standing or walking, the discrepancy can be hidden either by flexing the knee on the longer side or by walking with the foot in an equinus position on the shorter side. Assessment of a patient with a lower extremity length discrepancy should check for the range of motion of the ankle as in some of the larger longstanding discrepancies this equinus posturing can become fixed. To measure the extent of discrepancy, rectangular blocks of known height are placed under the foot on the shortened side with the patient standing. The blocks are positioned until the compensatory scoliosis disappears and the iliac crests can be palpated at the same level. This clinical assessment is essential as it accurately denotes the entire extent of any discrepancy, including pelvic, thigh, leg, and foot components. Another characteristic clinical measurement of lower extremity length discrepancy done with a tape measure and the patient lying supine measures the distance from the inferior tip of the anterior superior iliac spine to the inferior tip of the medial malleolus. It is important to check that there is no pelvic obliquity, hip or knee contractures, or femoral-tibial angular deformities in the patients being assessed in this way. If these conditions are present, measurement from the umbilicus to the medial malleolus also can be performed to register what is referred to as the apparent limb length discrepancy. Smith (449) has reported a clinical method for determining lower extremity length discrepancy, which is particularly valuable in those with hip or knee flexion contractures. The method, referred to as the thigh-leg inspection test, is performed by placing the patient in the supine position with the hips and knees flexed 90 ~. Determination of the difference in height of the thighs is made by using a flat protractor on the most superior aspect of the knee joint on the longer side and measuring the difference between the protractor and the shortened thigh at the knee. The shortened leg then is measured as the thighs are held parallel. The difference in length of the longer side heel and the shortened heel is measured by placing the protractor on the plantar surface of the longer heel and measuring the distance between it and the shorter heel. This measurement eliminates flexion contractures at the hips, knees, and ankles as a source of error. It also measures the soft tissue component of the lower extremity as well as the bones. This measurement was found to be more reproducible than tape measurements or block measurements in a comparative study of several practitioners in 96 patients with a mean of 5.2 cm length discrepancy. The technique is yet another way of estimating lower extremity length discrepancies in a quite reasonably accurate fashion clinically and particularly bypasses concerns with hip, knee, or ankle flexion contractures. Morscher and Figner

SECTION IV ~ Causes of Lower Extremity Length Discrepancies (338) have described clinical and radiographic methods of measurement in detail.

B. Segments to Be Considered in Assessing Lower Extremity Length Discrepancies Lower extremity length discrepancies can involve any or all of four segments: pelvic height, femoral length, tibial length, and foot height. The clinical assessment measuring the length discrepancy with the patient standing on blocks takes each of these four segments into consideration, whereas most of the other length determination modalities do not. The clinical measurement from the anterior superior iliac spine to the medial malleolus eliminates consideration of the foot and only partially addresses the pelvic height; the characteristic radiographic determinations of femoral and tibial length obviously do not consider either the pelvic or the foot region, and virtually all of the limb length determinations and surgical corrections relate to the femur and tibia alone without considering the other two segments. Although the femur and tibia are responsible for the vast majority of the limb height, there can be situations in which foot and pelvic abnormalities contribute meaningfully to the length discrepancy. In these situations specific radiographic determination of their height is important.

C. Radiographic and Other Imaging Documentation of Lower Extremity Length Discrepancies Five imaging techniques have been used to document both the length of the respective lower extremity bones and the extent of lower extremity length discrepancies. Many of the screening surveys referred to in Section II documented length discrepancies using standardized standing positions but radiographs of only the lower spine, pelvis, and hips. The relative femoral head positions allowed for length discrepancy measurements but not for absolute femoral-tibialfoot height measurements. The many technical considerations in making accurate radiologic measurements have been detailed particularly well. (161,188, 197, 338) 1. TELEOROENTGENOGRAMS Teleoroentgenograms are limited to use during the first year of life. They refer to a plain X ray of the entire lower extremity centered over the knee. If taken at a 72-in.,height, they are quite accurate in terms of length due to the minimal magnification with the small limb. After this age their accuracy decreases in documenting limb length discrepancies due to angular distortion (Fig. 2A). 2. ORTHORoENTGENoGRAMS This technique was developed by Green and associates (197) in the late 1940s to document accurately lower extremity length discrepancies. Both femurs and tibias are radio-

611

graphed in their entirety. A single long X-ray cassette with a single long X-ray sheet is used. Three X-ray machines are built onto the ceiling of a specifically defined chamber 72 in. from the X-ray film. There is one machine to be centered over the hip, one to be centered over the knee, and one to be centered over the ankle. Three radiographs are taken in rapid succession. Studies have documented that the magnification factor is under 1% with this technique. In addition to providing extremely accurate length determinations, the film allows for radiographic visualization of the entire bone for an indication of structural or angular deformities. This technique is infrequently used today because of concerns about the total amount of radiation exposure with sequential studies (Fig. 2B). 3. SCANOGRAMS This is the technique used most commonly today for lower extremity length discrepancy documentation. It can be accurate if details of performance are rigidly adhered to, although in practice many inaccuracies are seen. Three radiographs are taken similar to the orthoroentgenogram centered over hip, knee, and ankle, but spot films only are taken with the intervening femur and tibia diaphyseal segments spared any radiation. A ruler is placed beside the limb and the radiographic projection of the ends of the femurs and tibias over the ruler allows for a measurement at that level. The ruler should be calibrated in millimeters. A major problem with this technique is patient movement during the repositioning of the single machine. This can lead to inaccuracies that if slight cannot be detected. Very high levels of quality control thus are needed to allow for accurate measurement.

4. COMPUTERIZED TOMOGRAPHY SCANS The CT scan can provide accurate length measurements due to the high resolution calibration of the technique. 5. ULTRASONOGRAPHY Ultrasound can be used as well to document bone length (474). It is quite helpful in the first year or two of life when cartilage elements compose the bulk of the epiphyses.

IV. C A U S E S O F L O W E R E X T R E M I T Y LENGTH DISCREPANCIES A large number of disorders during the growing years can either stimulate or retard the growth of epiphyses unilaterally or asymmetrically such that a lower extremity length discrepancy occurs. Virtually any childhood disorder that affects an epiphysis can lead either to stimulation or retardation of growth, depending on the clinical context, and a possible limb length discrepancy must be considered in relation to overall management. Even disorders that are present throughout the skeleton, such as hereditary multiple exostosis, can affect the two sides unequally. The causes, effects, and extent of lower

612

CHAPTER 8 9 Lower Extremity Len~trh Discrepancies

A A

A'

A"

iP

b T

.

.

..

c

Length of X-ray Shadow

,

.

d'" -~

F I G U R E 2 Radiographic measurements to determine lower extremity lengths. (A) Teleoroentgenogram. A single exposure of the entire lower extremity centered over the knee provides a radiographic image of both the entire femur and the entire tibia and fibula. The longer each bone, the greater the magnification error due to the increased divergence of the rays. (B) Orthoroentgenogram. In performing an orthoroentgenogram, a single long X-ray cassette is used. Three cameras that can be moved along a track are mounted at a standardized 72-in. distance from the cassette holder. Three radiographs are taken in rapid succession with one camera centered over the hip joint, one over the knee joint, and one over the ankle joint. The perpendicular rays intersect the ends of the bones recording the true length. Each long bone is imaged completely, allowing for structural and angular deformity assessments as well. [Reprinted from (197), with permission.]

extremity length discrepancies throughout the spectrum of disorders affecting the growing skeleton are listed in Table I.

V. D E V E L O P M E N T A L P A T T E R N S IN L O W E R E X T R E M I T Y LENGTH DISCREPANCIES The discrepancies that develop in children are susceptible to considerable change with time, as the involved physes have the potential for increasing the discrepancy, maintaining it at a stable level, or correcting it spontaneously. Not all length discrepancies increase continually with time during the growing years. In a review of lower extremity length discrepancies in 803 children who were followed by at least annual orthoroentgenograms for 5 or more years to skeletal maturity or to the time of corrective surgery, it was demonstrated that several patterns of developmental discrepancy can occur (433). These are dependent on the nature of the conditions causing the discrepancies and on the place and time of their occurrence. They do not refer to changes following bone surgery. Table I gives a broad categorization of disorders that can be associated with lower extremity length discrepancies, an indication of whether they cause growth retardation or stimulation, and a range of length discrepancies with which they are associated. Details relating to each specific disorder are described in Section VI.

A. Patient Population The longitudinal data on lower extremity length discrepancies from patients who had been followed in the Growth Study Unit at the Children's Hospital, Boston, over a 40-year period (1940-1980) were studied carefully. The patterns of developmental discrepancy that developed were demonstrated by charting the extent of a discrepancy directly against time as represented by the patient's chronological age (433). The patterns also were related to skeletal age to show their independence from that parameter. Lower extremity length discrepancies were documented by standard techniques using teleoradiographs for patients who were younger than 5 years of age. Orthoroentgenograms, from which femoral and tibial measurements were made, were used for all of the older patients. Skeletal age was determined from posteroanterior radiographs of the left wrist and hand. These radiographs were correlated with the Todd atlas (477) until 1950 and with the Greulich and Pyle atlas (199) thereafter. For inclusion in the review, an individual had to have been followed by radiographic means at the Growth Study Unit for a minimum of 5 years (or from the onset of disease) either to the time of skeletal maturity or to the time of bone surgery. Due to the deep interest of Dr. William T. Green and his staff, virtually all of the patients in the series were assessed annually, and often semiannually, from the time of onset or detection of the disease to maturity. It must be emphasized that these patients were followed prospectively

SECTION V ~ Developmental Patterns in Lower Extremity Length Discrepancies

TABLE I

C a u s e s , Effects, a n d Extent o f Lower Extremity Length D i s c r e p a n c i e s a Stimulation

A 1. Femoral disorders

2. Tibial and fibular disorders

B

5. Infection

C

Retardation

B

C

D

A

Coxa vara

~/

v/

Congenital short femur Developmental dysplasia of the hip

v/

~/

Proximal femoral focal deficiency

D

v/

Subluxated hip Dislocated hip Avascular necrosis Legg-Calve-Perthes disease Slipped capital femoral epiphysis

v/

Status post varus osteotomy

v/

~/

Congenital short tibia (fibular hemimelia) Tibial agenesis (tibial hemimelia)

v/

Pseudoarthrosis of tibia (anterolateral bowing) ___neurofibromatosis Posteromedial tibial bowing 3. Foot disorders 4. Trauma

613

v/

~/

Blount's disease (tibia vara) Clubfoot

~/

v/

Epiphyseal growth plate fracture-separations Diaphyseal fractures Healing with shortening or overgrowth Loss of bone mass Septic arthritis Hip or knee Meningococcal septicemia

v/

,/

Femoral-tibial osteomyelitis (metaphyseal-diaphyseal)

~/

v/

v/

~/

v/

v/

v/

Femoral-tibial osteomyelitis (infantile) Tuberculosis

6. Prolonged unilateral immobilization (9-12+ months) 7. Neuromuscular disorders

8. Vascular disorders

Hip or knee Femoral-tibial shaft Tuberculosis CDH, etc. Poliomyelitis Cerebral palsy-hemiparesis Peripheral nerve injury (unilateral); sciatic nerve paralysis Myelomeningocele Arthrogryposis Diastematomyelia Vascular malformations Klippel-Trenaunay Parkes Weber Proteus

v/

~/

Beckwith-Wiedemann Hemangioma (newer terminology)

~/

v/

Cutis marmorata telangiectatica congenita

~'

v/

Following use of neonatal umbilical or femoral catheters

(continues)

614

CHAPTER 8 9 Lower Extremity Length Discrepancies TABLE I (continued) Retardation

Stimulation

9. Hemihypertrophy, with connective tissue abnormalities

A

B

C

D

A

B

v/

v/

C

Synovial hemangioma (knee)

v/

,i/

Arteriovenous aneurysms (traumatic)

v/

v/

Cerebrovascular malformations

v/

,/'

Lipomatosis

,/

4'

Lymphedema

v/

~/

Lymphangioma Neurofibromatosis (bone structurally normal)

v/ v/

v/ v/

Silver-Russell syndrome

v/

v/

Malignant tumors: Wilm's, adrenal, carcinoma, hepatic carcinoma

v/

v/ v/

v/

4'

4'

v/

v/

v/

4'

v/

V

V

v/

Resection with growth plate damage

v/

v/

Resection with loss of bone mass

v/

v/

v/

Radiation-induced physeal arrest

v/

v/

v/

v/

v/

V

v/

v/

v/

V

v/

,/

v/

v/

v/

v/

v/

10. Hemiatrophy

Otherwise normal appearing limb

11. Inflammatory disorders

Juvenile rheumatoid arthritis

D

Scleroderma 12. Hematologic disorders

Hemophilia Thalassemia

13. Tumors-focal bone lesions

Benign lesions Fibrous dysplasia Unicameral bone cyst Aneurysmal bone cyst Osteoid osteoma

v/

,/

Caffey's disease

,/

~/

Malignant tumors

14. Skeletal dysplasia (asymmetric lengths)

Hereditary multiple exostoses

Bone diseases with high incidence of asymmetric deformities

v/

Ollier's enchondromatosis Stippled epiphyses (chondrodysplasia punctata) Dysplasia epiphysealis hemimelica Melorheostosis Camptomelic dwarfism Congenital banding (Streeter syndrome)

15.

v/

,/

v/

V

v/

v/

~/

V

Osteogenesis imperfecta

v/

v/

v/

Rickets Renal osteodystrophy Vitamin A intoxication of infancy

V

v/

v/

v/

v/

v/

V

~/

Scurvy (lack of vitamin C) 16. External causes

Bums

v/

Frostbite aCode: A = 0-2 cm; B = 2-5 cm; C = 5-15 cm; D = 15 cm+. The A-D groups also provide management guidelines-see Fig. 18. A check (v/) indicates the possible extent of the final discrepancy.

because they had an affection in which lower extremity length discrepancy was known to occur rather than being seen only after a clinically apparent discrepancy had developed. With the exception of the group of patients with a fractured femoral diaphysis, the patients included in this re-

view had to have had a discrepancy of 1.5 cm or more at some time during the period of assessment. The classification does not refer to any change in discrepancy that followed surgical physeal arrest, diaphyseal lengthening, or osteotomy.

SECTION VI ~ Lower Extremity Length Discrepancies in Specific Disease Entities

The disease entities that were studied and the number of patients in each group were as follows. There were 18 patients with proximal femoral focal deficiency, 102 with congenital coxa vara and a congenitally short femur (some with associated anomalies of the leg and foot), 17 with Ollier's disease (enchondromatosis), 21 with physeal destruction, 115 with poliomyelitis, 33 with septic arthritis of the hip, 116 with a fractured femoral diaphysis, 29 with a hemangioma, 17 with neurofibromatosis, 46 with hemiparetic cerebral palsy, 113 with hemiatrophy or hemihypertrophy (anisomelia), 36 with juvenile rheumatoid arthritis, and 140 with Legg-Perthes disease. The distribution of pattern types, the average discrepancy in centimeters, and the range of discrepancies before surgery were assessed for each group.

B. Classification of Developmental Patterns in Lower Extremity Length Discrepancies Type I, upward slope pattern: The lower extremity length discrepancy develops and increases continually with time at the same proportionate rate. Type II, upward slope-deceleration pattern: The lower extremity length discrepancy increases at a constant rate for a variable period of time and then shows a diminishing rate of increase independent of skeletal maturation. Type III, upward slope-plateau pattern: The discrepancy first increases with time but then stabilizes and remains unchanged throughout the remaining period of growth. Type IliA, downward slope-plateau pattern: The discrepancy decreases with time but then stabilizes and remains unchanged throughout the period of growth. Type IIIB, plateau pattern: The discrepancy, detected initially after it has developed, remains unchanged throughout the remaining period of growth. Type IV, upward slope-plateau-upward slope pattern: The discrepancy first increases then stabilizes for a variable but considerable period of time, and then it increases again toward the end of the growth period. Type V, upward slope-plateau-downward slope pattern: The discrepancy increases with time, stabilizes, and then decreases in the absence of surgery. The classification is illustrated in Fig. 3A, and an indication of the various patterns in various disorders is outlined in Fig. 3B.

VI. L O W E R E X T R E M I T Y L E N G T H D I S C R E P A N C I E S IN S P E C I F I C D I S E A S E ENTITIES: PATHoANATOMY, PATHOPHYSIOLOGY, DEVELOPMENTAL PATTERNS, AND RANGES OF DISCREPANCIES In this section we incorporate information from our study reported in the article "Developmental Patterns in Lower

615

Extremity Length Discrepancies," (433) as well as information from the extensive literature on the entire range of disorders that can lead to length differences. The focus is on the pathoanatomy and pathophysiology of the disorders themselves and particularly on the pattern of discrepancy development and the extent of the discrepancies in the specific diseases. In most instances the ranges of length discrepancy values are provided. Some studies refer to percentage shortening in relation to the normal side. Reference to the GreenAnderson tables then can indicate the range of values in absolute terms.

A. Congenital Limb Deficiencies Congenital limb deficiencies are among the most common causes of lower extremity length discrepancies. In the next few subsections we will refer to the most common and most severe types, but in reality they represent part of a spectrum of disorders affecting appendicular development in both upper and lower extremities. Extensive efforts have been made over the past few decades to develop encompassing classifications for these disorders, but they are so variable and the terminology used has been so awkward that there has been no universal agreement on any way of referring to them. As a result, individual terms from differing classifications have come to be used commonly and on occasion different terms are used to refer to the same disorder. 1. FRANTZ AND O'RAHILLY

The classification of Frantz and O'Rahilly (168) is an all encompassing approach that divides congenital skeletal limb deficiencies into terminal, in which no unaffected parts are distal to and in line with the deficient portion, and intercalary, in which the middle portion of a proximodistal series of limb components is deficient but the proximal and distal portions are present. Each of these two main groups then may be either transverse, in which the defect extends transversely across the entire width of the limb, or longitudinal, in which only the preaxial or postaxial portion is absent (hence, the deficiency is longitudinal). Among the terms used in the classification are the following: amelia, absence of the limb; hemimelia, absence of a large part of a limb; phocomelia, a flipperlike limb with a hand or foot attached more or less directly to the trunk; acheiria, absence of a hand; apodia, absence of a foot; adactylia, absence of a digit including the associated metacarpal or metatarsal; and aphalangia, absence of one or more phalanges. Hemimelia may be complete or partial. The term paraxial hemimelia indicates that either the preaxial or the postaxial portion of the distal half of the limb is involved. The anatomical term preaxial refers to the border of a limb on which either the thumb or the big toe is situated and the term postaxial refers to the opposite border. The preaxial paraxial hemimelias therefore are either radial or tibial and the postaxial paraxial hemimelias are ulnar or fibular. The various subtypes of paraxial hemimelia are named

616

CHAPTER 8 9

Lower Extremity Length Discrepancies A J

Type 1 Upward Slope Pattern

J,

g b (/) t5 Age

Type 2 Upward SlopeDeceleration Pattern

Type 3 Upward Slope- Plateau Pattern

I\ '1 Type 3a

Type 3b

D o w n w a r d Slope Plateau Pattern

Plateau Pattern

Type 4 Upward Slope- Plateau Upward Slope Pattern

/ J

f

Type 5 Upward Slope- Plateau Downward Slope Pattern

DISTRIBUTION OF DEVELOPMENTALPATTERNS IN THE VARIOUSDISEASES IN EIGHT HUNDRED AND THREE PATIENTS Condition Proximal femoral focal deficiency Congenitally short femur, including congenital coxa vara (with some associated leg and foot anomalies) Ollier's disease Destroyed epiphyseal growth plates Poliomyelitis Septic arthritis (hip) Fractured femoral shaft Cerebral palsy (hemiparetic) Anisomelia Hemihypertrophy Hemiatrophy Hemangiomas Neurofibromatosis Juvenile rheumatoid arthritis Legg-Perthes disease

No. of Patients

I

II

Pattern Type III

IV

V

18 102

18 65

0 29

0 8

0 0

0 0

17 21 115 33 116 46

17 21 64 14 0 15

0 0 25 4 8 5

0 0 17 12 108" 24t

0 0 9 3 0 0

0 0 0 0 0 2

86 27 29 17 36 140

48 17 9 11 7 21

20 4 8 2 0 8

18 6 10 3 16 52

0 0 1 0 0 10

0 0 1 1 13 49

* Both type-III and type-IIIA discrepancies. I" Many of these discrepancies were detected in the plateau phase (type IIIB). F I G U R E 3 (A) The developmental pattern classification showing types I-V. (B) The distribution of patterns in several of the more frequent length discrepancy categories is shown. [Reprinted from (432), with permission.]

SECTION VI ~ Lower Extremity Length Discrepancies in Specific Disease Entities

617

A TERMINAL

INTERCALARY

EMIMELIA i,',~, ,::t ;: : :~.tlt:] :.~,! i ! i i

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RAXlAL FIBULAR

HOCOMELIA / INCOMPLETE ;' : ~'/~ I DISTAL I j l I (Radiusand Ulna absent) i i ~i :I /I

HEMIMELIA

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PARAXIAL FIBULR HEMIMELIA Fibula absent All toe rays present

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TRANSVERSE TRANSVERSE

LONGITUDINAL

LONGITUDINAL

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Biii

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Biv

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o

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F I G U R E 4 Classifications of congenital skeletal limb deficiencies are illustrated. (A) The classification of Frantz and O'Rahilly is shown. The terms terminal, intercalary, transverse, and longitudinal are illustrated. (B) The classification of Henkel and Willert is shown in parts i-iv. (Bi) The teratological sequence of dysmelia of the lower extremities is shown. (Bii) Sequential changes of the tibia are shown in a series of cases. The femur is relatively normal throughout. (Biii) Sequential changes of the femur are shown with relative normalcy of the tibia, fibula, and foot regions. (Biv) Sequential changes of the femur are shown along with progressive tibial hemimelia. [Part A reprinted from (168), with permission. Parts Bi-Biv reprinted from (7), with permission.]

after the absent portion; radial hemimelia refers to a deficiency of the radius. The terminology of congenital skeletal limb deficiencies is shown Fig. 4A.

2. DYSMELIA

Henkel and Willert (231) proposed a differing approach to classification of the congenital malformations, which they

618

CHAPTER 8 ~ Lower Extremity Length Discrepancies

felt outlined more accurately the teratological sequence. The term dysmelia is used to refer to limb malformations varying from mild hypoplasia to partial and total aplasia of the tubular bones of the extremities and even to complete nonformation of the extremity. They arrange the abnormalities according to their degree of severity to form a teratological sequence linked by a common morphological pattern, enabling subtle variations to be included and to represent the abnormalities throughout an entire limb. The approach addresses three questions: (1) Which region of the limb and which skeletal elements are affected? (2) In what manner are they affected--by hypoplasia, partial aplasia, or total aplasia? (3) Have the affected skeletal elements also undergone fusion or synostosis? There are five main types of any teratological sequence of dysmelia: (1) distal form of ectromelia (ectromelia refers to involvement of the radius or tibia with its peripheral rays); (2) axial form of ectromelia; (3) proximal form of ectromelia; (4) phocomelia (abnormalities in which no remnants of long bones are seen between the limb girdle and the hand or foot); and (5) amelia (total loss of an extremity). The classification of malformations was derived from a survey of 693 deformed limbs (Figs. 4Bi-4Biv). This approach would seem to offer the best correlation with gene and molecular abnormalities as they are increasingly defined in relation to limb development. 3. INTERNATIONAL TERMINOLOGY FOR THE CLASSIFICATION OF CONGENITAL LIMB DEFICIENCIES

In 1973 the International Society for Prosthetics and Orthotics organized a working group to propose a terminology for limb deficiencies that would be acceptable internationally (267). They utilized both the system of Frantz and O'Rahilly and that of Henkel and Willert along with other terminologies in an effort to reach agreement among a wide number of practitioners. There still is little unanimity of opinion concerning descriptive terms for this wide array of disorders, although with an appropriate clinical and radiologic description rarely is there any doubt as to which entity is being discussed. Even after the adoption of any uniform terminology it would take several years before the studies and literature all conformed to a standard. It remains essential for those involved with these disorders to have a general understanding of the differing classifications used. In the following sections the most common terms will be used. Congenital abnormalities of the femur encompass a spectrum of disorders from those in which the femur is completely absent to those in which it is present, structurally normal, and only somewhat smaller than that on the opposite side. These can be classified into four broad groups including proximal femoral focal deficiency, coxa vara with congenital short femur, congenital short femur with diaphyseal bowing, and anisomelia in which the femur is essentially normally shaped but is smaller than that on the opposite side.

The pathoanatomy and overall management approaches were presented separately in Chapter 5. 4. PROXIMAL FEMORAL FOCAL DEFICIENCY In each of the 18 patients with proximal femoral focal deficiency in our study, severe progressive shortening of the type-I pattern occurred (433). In types A and B proximal femoral focal deficiency as defined by Aitken (11), the proximal part of the femur is intrinsically maldeveloped with no effective capability for normal reconstitution even though the acetabulum and femoral head are present. In types C and D the proximal structures are even more markedly abnormal, with no visible ossified head and the tapered diaphysis displaced proximal to the shallow, often unrecognizable acetabulum (Fig. 5A). Severe growth sequelae in this class of femoral developmental abnormalities are well-known (20). Proximal femoral focal deficiency in our series resulted in an average of 27 cm of shortening, with some lower limbs having as much as a 45-cm discrepancy. The range of femoral shortening averaged 60% (range = 40-80%) compared with the normal side. In patients classified as having type A, B, or C deficiency the shortening averaged 57%, and in type D it averaged 80%. Tibial shortening averaged 7.6% (range = 0-37%) and fibular shortening averaged 28% (range = 0-100%) in all types. This condition caused the most severe discrepancies seen in the series and presents an extremely difficult management problem. Accurate prediction of the final discrepancy is possible from the early years of life in patients with this condition, however, due to the invariable type I pattern. 5. CONGENITAL SHORT FEMUR INCLUDING CONGENITAL COXA VARA

This group in our study was composed of patients with congenital femoral anomalies, including congenital coxa vara, a congenitally short femur with coxa vara, and a congenitally short femur with lateral bowing and sclerosis but without coxa vara. Many of these patients also had associated mild or moderate anomalies of the pelvis, tibia, fibula, and foot. Excluded from this group were the patients with proximal femoral focal deficiency and those with a normally shaped and only mildly shortened femur, who were categorized as having hemiatrophy (anisomelia). The average preoperative limb length discrepancy in this group was 5.92 cm (range = 2.2-15.6 cm). It is important to note that 37 of these patients showed a type II or type III developmental pattern. If a discrepancy reached 6 cm, it generally persisted with a type I pattern. Those patients, however, in whom the discrepancy was less great often had a type II or type III pattern. Ring (408) has noted that patients with a congenital short femur alone--one with lateral bowing, cortical sclerosis, increased hip external rotation, and minimal to absent internal rotation, but without coxa varamwill continue to have an increase in the discrepancy at a regular rate with time (type I pattern). The relatively marked length discrep-

SECTION VI 9 Lower Extremity Length Discrepancies in Specific Disease Entities

619

Bi Class I

Class II

Class III

Class IV

Class

V

Bii Class VI

Class VII

Class VII!

Class IX

C 7-

6-

5-

4-

..j 2-

CHRONOLOGIC AGE SKELETAL

AGE

Orl

2

3

6

8

9

I0 ~

0~

-

2e 3e 4e 6

4

5

8

9

I0 6

FIGURE 5 (A) The classification of proximal femoral focal deficiency of Aitken is shown. Drawings are from Clinical Pediatric Orthopedics by M. O. Tachdjian, copyright 1997 by Appleton and Lange. (Bi, ii) The classification of congenital abnormalitiesof the femur into nine types as defined by Pappas. (C) A type I developmentaldiscrepancypattern in congenital short femur is shown. [Parts Bi and Bii reprintedfrom Ogden, J. (1982). J. Pediatr. Orthop. 2:331-377, 9 LippincottWilliams& Wilkins, with permission.]

ancies in femoral developmental disorders are well-known (20, 46, 277, 283, 517). Two studies on length discrepancies in congenital femoral anomalies have been published in which both proximal femoral focal deficiency and congenital short femur with and without coxa vara have been assessed together. A separate detailed study also primarily based on patients followed longitudinally in the Growth Study unit of Children's Hospital, Boston, was published by Pappas (366), in which the large number of patients assessed allowed a more detailed subclassification into nine types of deformity. Pappas defined the

percent of femoral shortening in each of the nine classes, detailed the femoral and pelvic abnormalities, assessed associated abnormalities of the tibia, fibula, patella, and feet, and defined treatment objectives (Fig. 5B). The large number of patients available for this study demonstrated a continuum of abnormalities. Class I refers to the situation in which the femur is entirely absent and the acetabular region of the pelvis markedly is hypoplastic. In class II, the proximal 75% of the femur is absent. In class III, there is no bony connection between the femoral shaft and head although the femoral head, which has delayed ossification, is present in the acetabulum.

620

CHAPTER 8 ~ Lower Extremity Length Discrepancies

In class IV, the femur is present to approximately one-half its length but the proximal abnormalities show the femoral head in the acetabulum with the head and shaft joined by irregular calcification in a fibrocartilaginous matrix. It is these four disorders that generally are referred to as proximal femoral focal deficiency. In class V, the femur diaphysis and distal end are incompletely ossified and hypoplastic. In class VI, the proximal two-thirds of the femur is perfectly normal and the hypoplasia is in the distal one-third with an irregular distal femoral region and no evident distal epiphysis. Classes V and VI are essentially examples of distal femoral focal deficiency. Class VII is congenital coxa vara with a hypoplastic femur that is shortened and somewhat bowed and also demonstrates lateral femoral condylar deficiency. Class VIII is infrequently seen but involves a proximal femur coxa valga, a hypoplastic femur, and abnormality of the distal femoral condyles with the lateral condyle being somewhat flattened. Most would include congenital short femur in this category, which perhaps most represents class VIII, although it characteristically has anterolateral bowing, which Pappas does not demonstrate. The class IX femur is essentially normal and might be defined by others as having only shortness referred to as hemiatrophy or anisomelia. Pappas also demonstrates the frequently seen underdevelopment of the lateral femoral condyle predisposing one to both a valgus deformity at the knee referable to the femoral deformity and a tendency toward lateral patellar subluxation. The ranges of femoral and tibial discrepancies found in each of the varying categories were listed. In class I the femur was completely absent. In class II the femur was shortened by 70-90% of that on the opposite normal side. The tibia also was shortened. In class III femoral shortening was 45-80% of the opposite side and tibial shortening ranged from 0 to 40%. In class IV femoral shortening was 40-67% of the opposite side and tibial shortening ranged from 0 to 20%. Class V: femoral shortening, 48-85%; tibial shortening, 4-27%. Class VI: femoral shortening, 30-60%. Class VII: femoral shortening, 10-50%; tibial shortening, minimal to 24%. Class VIII: femoral shortening, 10-41%; tibial shortening, 0-36%. Class IX: femoral shortening, 6-20%; tibial shortening, 0-15%. Vlachos and Carlioz (489) studied bone growth in 40 cases of congenital anomalies of the femur. They categorized their patients into five groups, with type I being congenital short femur without coxa vara but with shortening and curvature of the shaft; type II, with congenital short femur and coxa vara; type III, severe coxa vara with a dystrophic or pseudo-arthrotic junction between the proximal femur, which was in coxa vara, and the diaphysis; type IV, coxa vara, coxa vara with severe angular deformity proximally, and discontinuity with the shaft of the femur; and type V, almost complete absence of the proximal femur and no hip joint articulation. Relatively few patients were followed to skeletal maturity, with many being seen only to the ages of 3-10 years, such that definitive pattern progression could not be determined. They felt, however, that all patients regard-

less of diagnostic category increased at a constant rate with time, although this is somewhat distinct from our findings. Assessment of some of their charts also would indicate a type II pattern in some patients. They clearly documented both the percentage shortness and the absolute amount of shortness in centimeters in each group. In the mildest form, type I, the average shortening was 10% of the normal side, ranging between 88 and 97%, with the mean amount of shortening at 13 years of age being approximately 2.8 cm. In type II shortening averaged 30% of the normal side, with a range between 64 and 80% of normal length and the mean amount of shortening around 10 years of age already 9 cm. In type III shortening was in the range of 45% of the normal side, indicating 55% length compared to the opposite side, and associated with a mean discrepancy at age 12 years of 19 cm. In type IV the overall length was only 24-44% that of the normal side, indicating in many cases a 75% shortness that translated into a mean discrepancy of 11 cm, although patients in this group had only been followed to a little more than 2 years of age. In the most severe category, proximal femoral focal deficiency, shortness was 90% of the involved side translating into a length approximately 10% of normal and leading to discrepancies at age 5 years that were already 25 cm. A type I developmental discrepancy pattern in congenital short femur is illustrated in Fig. 5C. 6. CONGENITAL DEVELOPMENTAL ABNORMALITIES OF THE FIBULA: FIBULAR HEMIMELIA Congenital abnormalities of the fibula are the most common of the congenital deficiency syndromes of the lower extremity. Coventry and Johnson (126) noted the fibula to be the most common bone congenitally absent with congenital absence of the tibia, ulna, radius, and femur following in that order of frequency. Farmer and Laurin (159) reviewed congenital absence or severe maldevelopment of the long bones at the Hospital for Sick Children, Toronto, from 1931 to 1957 and noted 32 limbs with congenital absence of the fibula, whereas during that same period complete or incomplete absence of the following long bones also was noted: femur, 16; radius, 13; tibia, 5; and ulna, 2. The fibular abnormalities are referred to as fibular hemimelia or lateral (external) hemimelia. They are always accompanied by tibial shortening and frequently accompanied by same side femoral shortening, and it is this tibial and femoral shortening to which length discrepancy treatment relates. Because the primary bone undergoing treatment is the tibia, the disorder sometimes is referred to as congenital short tibia. In those with a hypoplastic fibula (fibular hemimelia) the major treatment considerations are the limb length discrepancies, although on occasion measures are needed to stabilize the ankle usually by varus osteotomy of the distal tibia and fibula and occasionally by orthotic support (151). Those with complete absence of the fibula present greater management problems because of the more significant length

SECTION VI ~ Lower Extremity Length Discrepancies in Specific Disease Entities

discrepancy and the equinovalgus foot deformity along with a subluxed or dislocated ankle (279). There also can be anterior bowing of the distal one-third of the tibia, absence of one or more rays of the foot on the lateral sidel a tarsal coalition, and a ball-and-socket ankle joint (234). Coventry and Johnson (126) developed a classification with three types. In type I the patients have partial unilateral absence of the fibula with little or no bowing of the tibia. There is little or no deformity of the foot. The extremity always is shortened but the shortening can be quite minimal and usually is handled with an epiphyseal arrest. In type II the fibula is completely or almost completely absent and involvement is unilateral. There is anterior bowing of the tibia, dimpling of the skin, equinovalgus of the foot, and absence or deformity of the lateral rays and tarsal bones. There also is marked shortening of the extremity, and amputation was frequently needed in this group. Coventry and Johnson also defined a type III in which either the type I or type II deformity was associated with other congenital deformities, which were usually either severe deformities of the ipsilateral femur or contralateral deformities of the other leg. At present a slightly different three-part classification is favored by some. Type I is characterized by a slight to moderate shortening of the fibula, proportionately lesser shortening of the tibia, and minimal femoral shortening on some occasions. Catagni et al. (100) report tibial shortening of 3-5 cm at the end of growth with little angular deformity. On occasion, the associated outer fourth or fifth ray of the foot also is abnormal but rarely is this of clinical significance. Type II has major shortening of the fibula with particular underdevelopment or lack of development of the distal one-half to one-third. The lateral malleolus usually is absent and the ankle is unstable with the foot moving into a position of valgus deformation. The tibia is shorter than in type I disorders and tends to a valgus deformation and slight distal recurvatum with posterior bowing and anterior concavity. Type III, the most severe form, is characterized by an absent fibula, showing in addition severe deformation and shortening of the tibia and a deformed foot held in a position of equinus and valgus and often associated with dislocation or severe subluxation of the ankle. Due to the shortness of the extremity, the angulation of the distal tibia, and the deformed foot, much extended orthopedic treatment is needed often including Syme or Boyd amputation for prosthetic fitting. In a large series from Children's Hospital, Boston, presented by Pappas et al. (368), 129 of 291 patients with congenital unilateral shortening of an extremity (44%) showed shortening of the fibula greater than 10%. The extent of fibular shortening in 58% was between 10 and 30%, in 9% it was between 31 and 50%, and in 33% it was more than 50%. Although absolute length discrepancy numbers were not presented, the associated tibial shortening often was in the range of 10% or more with fibular shortening greater than 30%. There was a clear correlation between the fibula shortening and foot deformities. Among the associated limb deformities

621

(.J FIGURE 6 Achtermanand Kalamchi define a classification of fibular hemimelia type Ia (left) with fibular hypoplasia, which is relatively mild, type Ib (middle) with fibular hypoplasia, which is more with a length deficiency distally leading to a tilt of the distal tibia and its epiphysis, and a type II fibular deficiency (right) in which the fibula is completely absent. [Reprinted from (7), with permission.]

was genu valgum and instability, absence of the fourth and fifth rays of the foot, anteromedial shortening and curvature of the tibia, tarsal coalitions involving the talonavicular or talocalcaneal joints, and a domed-shaped talus. Often the fibula was absent in its proximal one-third. Achterman and Kalamchi (7) studied 97 limbs with the diagnosis of congenital deficiency of the fibula. They produced a slightly modified classification, defining type I deformities as those with hypoplasia of the fibula and type II deformities as those with complete absence of the fibula (Fig. 6). They noted that congenital anomalies of the femur were present in 76% of patients with type I deficiency and in 59% with type II. The femoral abnormalities were invariably underdevelopment of the femur, leading to worsening of the limb length discrepancy. Congenital shortening of the femur was present in 46 of the 66 limbs in which femoral abnormality was detected. Approximately 20% of the patients had some bilateral involvement. Measurements were difficult in patients with a proximal femoral focal defect, and leg length inequality was assessed when data were available in 51 cases. In those in which there was complete absence of the fibula (the type III categorization listed earlier), the amount of tibial shortening in the affected limb was 25% of normal with femoral shortening 13% of normal. In those cases in which there was hypoplasia of the fibula, the type I deformity group showed fibular shortening 7% of normal, tibial shortening 6% of normal, and femoral shortening 12% of normal, and in the type II group in which there was major shortening of the fibula, particularly with underdevelopment at the ankle, the fibular shortening was 38% of normal, tibial shortening 17% of normal, and femoral shortening (although on a small number of patients ) 23% of normal. Although detailed growth data were not presented, Achterman and Kalamchi felt that growth of the abnormal limb was proportional to that of the normal limb and that the degree of tibial shortening

622

CHAPTER 8

~

Lower Extremity Length Discrepancies

increased as the fibular deficiency became more marked. Treatment of length discrepancy was by either epiphyseal arrest or tibial lengthening depending on the clinical situation. If percentage shortening numbers are converted to length measurements for a male patient whose height is at the 50th percentile at skeletal maturity, 6% tibial shortening would represent 2.2 cm, 17% shortening 6.3 cm, and 25% shortening 9.3 cm. Lefort et al. (295) reviewed 62 cases of fibular hemimelia, concentrating in particular on the pathoanatomy of the leg and the associated femoral and tibial malformations. They stressed in particular the anterior curvature of the tibia in those cases in which the fibula was either completely absent or absent to a great extent. Absolute values for long bone shortening were not presented although percentage values were. Charts demonstrated a type I pattern of discrepancy development for developmental abnormalities of both the femur and the tibia. Hootnick et al. (237) studied 43 patients with partial or complete absence of the fibula and a congenital short tibia. They also determined that the relative difference in growth between the two limbs remained remarkably constant and thus adhered to the type I pattern of length discrepancy development. The patients studied had a strictly unilateral variant, and all measurements were determined radiographically by scanograms or from films showing both tibias on the same X-ray plate in the youngest children. The serial radiographic measurements of leg length were available in 14 patients coveting an average observation period of 9.3 years. Those with sequential radiographs were in the more severe end of the spectrum with the fibula absent from 11 patients and present but abnormal in 3. The amount of limb shortening was greater as the number of metatarsal bones diminished. There were 36 patients for whom assessments could be made in terms of the number of metatarsal bones and the amount of lower extremity shortening. In 12 patients with 5 metatarsal bones the average shortening was 8.7 cm (range = 3.6-12.7 cm), in 11 patients with 4 metatarsals the average shortening was greater at 9.5 cm (range = 3.8-13.5 c~), in 11 patients with 3 metatarsals the average shortening was 11.8 cm (range = 4.8-16.5 cm), and in 2 patients with only 2 metatarsals the average shortening was 14.6 cm (range = 11.9-17.3 cm). The average age reached in the first three groups was 11 years and in the final group 9.5 years of age. The femur was only minimally affected in these patients. In the 14 followed radiographically there is excellent documentation that the percent inhibition of growth in the affected limb compared to the normal remained unchanged from the earliest documentation to skeletal maturity. Femoral involvement at skeletal maturity was relatively small, ranging from 86 to 96% length compared to the normal side, whereas tibial involvement was somewhat greater, ranging from 73 to 82% length of the normal side. In patients followed for several years, although not quite to skeletal maturity, the same pattern persisted with femoral shortening

in all patients except one being only 92-99% of normal with associated tibial shortening of 61-90% of the normal side. Hootnick et al. felt that, if the predicted shortening was less than 8.7 cm, efforts at limb equalization were warranted, whereas if projected discrepancies were between 8.7 and 15.0 cm, amputation of the modified Syme's type was in order. In those discrepancies projected to be greater than 15.0 cm, retention of the foot and its adaptation to a prosthesis were warranted. The extent of growth discrepancy as well as management considerations was well-assessed by Choi et al. (112). They evaluated 48 extremities in 43 patients with the disorders skewed to the more severe types in their series. There were 7 fibulas of the type IA categorization, 2 type IB, and 39 type liB (complete absence of the fibula or presence of only a distal vestigial fragment according to the classification of Achterman and Kalamchi). Treatment of groups varied between those having amputation and those having lengthening procedures. Choi et al. subclassified their patients according to the amount of inequality projected for the lower limbs. In group I the percentage of shortening was 15% or less with the foot of the shorter extremity at the distal onethird of the contralateral normal limb; group II, between 16 and 25% of shortening with the foot of the shorter extremity at the level of the middle one-third of the contralateral normal limb; and group III, greater than 26% shortening with the foot of the shorter extremity at the level of the proximal one-third of the contralateral normal limb. Choi et al. concluded that lengthening was best suited only for patients in group I who had stable hips, knees, and ankles and a plantigrade foot, whereas patients in groups II and III were best served by ablation of the foot and a prosthetic fitting. Either the Syme or Boyd amputation was used, with the latter increasingly favored. The data provided indicated the extent of shortening in these disorders. The group projected the limb length discrepancy at maturity, which is highly accurate due to the invariably type I pattern in these deformities. In 15 patients in the group I category the mean discrepancy projected to skeletal maturity was 8.85 cm with a range from 5.0 to 12.07 cm. In group II, 20 involved limbs had a mean projected discrepancy of 16.29 cm with a range between 12.5 and 22.5 cm. Deformities were so great, both in terms of extent and bony deformity, in group III that numbers were not provided. Farmer and Laurin (159) recommended early Syme amputation when the length discrepancy was projected to be more than 7.6 cm (3 in.) at maturity, especially when severe foot deformity was present. A similar recommendation was made by Westin et al. (497) in their review of 32 patients with 37 fibular deficiencies. Many of their patients underwent Syme amputation, the two indications of which were a foot deformity so severe that any surgery to make the foot plantigrade and functional was likely to fail and a lower extremity length discrepancy of 7.5 cm or more that would be present at skeletal maturity in the absence of any man-

SECTION VI ~ Lower Extremity Length Discrepancies in Specific Disease Entities

agement. In this group amputation was performed in 29 of 37 cases. Farmer and Laurin considered the results of the Syme amputations to be uniformly good. They noted the growth inhibition to be constant with time. The growth inhibition in those treated without amputation ranged from 7 to 12% in the tibia and from 0 to 14% in the femur. In the amputee group the inhibition was 22-42% in the tibia and 0-22% in the femur. In a listing of nine patients with unilateral Syme amputations, who were followed to skeletal maturity and who had growth data to skeletal maturity, the final femoral and tibial discrepancies ranged between 7.8 and 24.1 cm with a mean of 14.4 cm with the tibial discrepancies themselves ranging from 6.7 to 14.8 cm with a mean of 11.0 cm.

'1

9 Tibia not seen

/

a

9 Hypoplastic lower femoral epiphysis

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7. CONGENITAL DEVELOPMENTAL ABNORMALITIES OF THE TIBIA: TIBIAL HEMIMELIA

Partial or complete absence of the tibia often is referred to as tibial hemimelia. These disorders are rare and markedly less frequent than the fibular variant. There is marked shortening and bowing of the involved leg, a flexion contracture of the knee, and a rigid varus foot. Four basic patterns have been defined (258). In type IA, the tibia is completely absent and there is a markedly hypoplastic lower femoral epiphysis. In type 1B, the tibia also is completely absent, but there is a normal lower femoral epiphysis. In both instances, the fibula rides high laterally in relation to its normal position had the proximal tibia been present. In type II, the upper proximal tibial epiphysis is present as is a small portion of the metaphysis, but the rest of the tibia distally does not form. In type III, the proximal tibia is absent but the distal one-third is present. In type IV, there is a marked diastasis between the proximal tibia and the fibula and the distal one-third of the tibia is absent. The most distal tibial segment tends to be curved medially (Fig. 7). In the type II deficiency, the knee is well-preserved. In types I, II, and III the foot is in an equinovarus position. In the type IV deformity, the knee tends to be well-formed, but the talus has subluxated proximally between the now separated tibia and fibula. Treatment is directed toward early disarticulation of the knee and prosthetic fitting for type I lesions, tibiofibular fusions and prostheses for types II-IV, fibulocalcaneal fusions for types III and IV, and the frequent need for foot ablation for prosthetic fitting. Schoenecker et al. (425) studied 57 patients with congenital tibial hemimelia from the Shriners Hospital system. There were 33 type IA, 6 type IB, 15 type II, 7 type III, and 10 type IV patients. In the 54 limbs with the type I or II deficiency, there were 22 who had knee disarticulation, 25 a Syme amputation, and 1 a Chopart amputation. The foot was retained in only 6 with these two variants. There were 17 extremities with a type III or IV deficiency, and a Syme amputation was done in 9 and a Chopart in 4. In 4 the foot was retained. Schoenecker et al. report that 56 of 57 patients walked independently. Kalamchi and Dawe (261) simplified the classification, defining three types: in type I there was total absence of the

623

9 Tibia not seen 9 Normal lower femoral epiphysis

9 Distal tibia not seen

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9

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FIGURE 7 Classificationof tibial hemimelia(congenitalabsence of the tibia) by Jones et al. is shown. Severalclassificationsare in use, but this one defines the abnormalitiesclearly. [Reprintedfrom (258), with permission.]

tibia; type II, distal absence of the tibia; and type III, distal deficiency with tibiofibular diastasis. The fibula always was present but in type I it was subluxed proximal and lateral to the distal femur, with a similar position also sometimes being shown in the type II variant. In type I the disorder was also invariably associated with a marked flexion contracture of the knee, variable rotation of the leg, and marked inversion and adduction deformities of the foot. The distal femur usually was hypoplastic with marked retardation of the ossification center of the distal epiphysis. The functional status of the quadriceps muscle, the severity of the flexion contracture of the knee, and the position and function of the foot all had to be considered in planning surgical straightening or ablation. Jones et al. stressed that in all three the fibula is relatively normal in form and development, although in types I and II it often is situated proximal to the normal relationship at the knee. In some the tibial segment is greater than it appears at birth because it is present in cartilage manifesting delayed ossification. Careful clinical exam and other forms of imaging are important to clearly define the anatomic structure in the newborn. 8. POSTERoMEDIAL TIBIAL AND FIBULAR BOWING Posteromedial bowing of the tibia, which almost always is associated with bowing of the fibula, must be appreciated as an entity different from those described previously.

624

CHAPTER 8 ~ Lower Extremity Len~lth Discrepancies

FIGURE 8 Radiographsillustrate anteroposterior (A) and lateral (B) views of lower extremityof 20-month-oldfemale with posteromedialbowing. The lateral view shows full correction of posterior deformity. There had also been some correction of medial bowing on AP view. Note cortical thickening of tibia.

There is a considerable tendency for the posteromedial bow to correct during the first several years of growth, although considerable shortening often persists (Fig. 8). The condition is unilateral. The deformity is exclusively in the distal onethird of the leg and is associated at birth with foot deformities of the calcaneovalgus type. The foot and leg deformity responds well to conservative treatment with repeated application of casts or splints. On occasion, osteotomy is resorted to but only after conservative management has reached a plateau. Shortening of the affected leg, however, is progressive, increases with age, and must be followed until skeletal maturity. Sequential studies have demonstrated well the spontaneous correction of the bowing, which in both anteroposterior and lateral projections becomes either perfectly straight or sufficiently straight that osteotomy is rarely needed by the time of skeletal maturity. The most rapid straightening occurs between 6 and 18 months of age. Pappas (367) has indicated that the bowing was reduced by roughly 50% in the first 2 years, but after the age of 3 years the reduction in angulation continued at a much slower rate. Little further correction should be expected after 10 years of age. The posterior bowing almost completely resolves with the medial bowing somewhat less likely to correct fully. The fibular bowing was equal to or slightly greater than the tibial bowing and corrected more slowly, and some posterior bowing persisted in most even at maturity when tibial posterior bowing had fully corrected. The proportionate difference in lengths between the normal and bowed tibiae remains markedly stable throughout childhood, showing a type I discrepancy pattern. In the study of 33 patients by Pappas (367) the female: male incidence was 20:13 (1.5:1) and left:fight involvement

was 19:13 (1.5:1). In those patients whose limb lengths were determined radiographically within the first 2 months of life, the average initial discrepancy was 1.25 cm. Subsequent studies showed a constant increase with time. When all patients had discrepancies calculated to skeletal maturity, thus bypassing valves obscured by epiphyseal arrest surgery, tibial shortening averaged 4.1 cm with a range from 3.3 to 6.9 cm. Femoral lengths were unaffected and foot lengths little affected. Due to the extent of the length discrepancy, some form of limb equalization surgery was done or recommended for each patient, but results were not reported. The abnormality is focused in the entire distal one-half of the tibia and fibula and soft tissues of the leg. The growth discrepancy occurred exclusively at the distal end of the tibia and fibula based on radiologic appearances of proximal and distal tibial and fibular epiphyses. In 4 of the 33 patients, osteotomies were performed at an early age to correct residual bowing; all healed uneventfully. Hofmann and Wenger (235) also noted a marked tendency to spontaneous correction of the posteromedial bowing, with continuing progression, however, of the discrepancy in limb length. In 13 patients studied there was a direct relationship between the degree of initial tibial bowing and the severity of the subsequent discrepancy, which, stated slightly differently, indicates that slightly greater discrepancies in the earlier years of life would lead to greater discrepancies toward skeletal maturity. The mean posterior bowing at diagnosis was 30 ~ (range = 4 - 6 0 ~ and the mean medial bowing was 27 ~ (range = 10-45~ Hofmann and Wenger noted the relatively slow improvement in the posteromedial angulation over a few years compared with the rapid and complete correction of the calcaneovalgus deformity over a few months. The limb length discrepancy was progressive and present in each of the 13 patients. The mean discrepancy was 3.1 cm (range = 1.9-5.4 cm), but none had been followed to skeletal maturity and 10 patients were still between only 1 and 7 years of age. In the oldest 3 patients (10 years 4 months to 15 years 5 months of age) the mean discrepancy was 4.7 cm, a value similar to the 4.1-cm projection of Pappas. There were no femoral length discrepancies. A remarkably similar picture of the effects of a posteromedial angulation was reported by Carlioz and Langlais (95). They reported on 18 cases of congenital posteromedial bowing of the tibia and fibula, all of which also were associated with shortening. Both the valgus (medial bowing) and posterior bowing components corrected over the first few years of life. The valgus or medial bowing ranged between 10 and 56 ~ initially and the posterior bowing or recurvatum ranged between 10 and 65 ~ Although not all of the patients were followed to skeletal maturity, 5 had shown evidence of complete correction of both deformities during growth. The spontaneous correction occurred in 3 - 4 years. The posterior bowing or recurvatum tended to correct more completely than the medial or valgus deformation. Osteotomy was resorted to in 3 patients and in each instance healing was un-

SECTION VI ~ Lower Extremity Length Discrepancies in Specific Disease Entities

eventful. Length differences were invariably seen and ranged between 10 and 20% of the length of the normal tibia. In most the discrepancy increased at a steady rate with time, but on occasion with increased growth the rate of inhibition on the involved side lessened. Five tibial lengthening procedures were performed with the preoperative average discrepancy of 4.42 cm, whereas 3 epiphyseal arrests were performed with a presurgery discrepancy of 3.7 cm. Other patients were still being followed such that additional surgery might well have been needed. The authors projected that untreated discrepancies would have reached between 1.5 and 7 cm at skeletal maturity with the majority being in the 3- to 5-cm range.

B. Skeletal Dysplasias with Asymmetric Involvement In several of the skeletal dysplasias, asymmetric involvement is strongly associated with length discrepancies. The following variants are particularly likely to show such findings. 1. HEREDITARYMULTIPLE EXOSTOSES Femoral-tibial limb length discrepancy measurements in 32 patients from Children's Hospital, Boston, indicated a range from 0.1 to 4.0 cm (437). In 2 patients, femoral and tibial shortening was equal, in 20 femoral shortening was greater than tibial, and in 10 tibial shortening was greater than femoral shortening. On occasion, the shortening was limited to either the femur or the tibia. Of 22 patients who reached skeletal maturity, 11 (50%) had limb length discrepancies in the range for which limb length equalization would normally be recommended. Of these, however, only 5 (23%) actually had the procedure. The limb length discrepancies at the termination of growth in those who did not undergo growth arrest procedures measured 2.1, 2.4, 2.3, 2.6, 3.1, and 3.5 cm. Many of the charts were not clear as to why surgery was not performed, but the following reasons were listed: subsequent planned correction of discrepancies with associated opening wedge osteotomy for deformity on the short side or closing wedge osteotomy on the long side, difficulty of performing epiphyseal arrests in regions in which large exostoses are present, clinical impression of an acceptable situation despite the roentgenographic measurements, and reluctance of patients and their families to undergo yet more procedures. When we take into consideration all 22 patients who had reached skeletal maturity and also the 7 who were close enough that it was possible to say whether they would require an arrest, there were 29 patients, 12 (41.2%) of whom had discrepancies within the recommended range for operative epiphyseal arrest. All 5 patients who were operated on had distal femoral epiphyseal arrests, and 1 had a proximal tibiofibular epiphyseal arrest as well. The limb length discrepancies at the time that the arrest was performed and the eventual limb length

625

discrepancy at the termination of growth were as follows: 2.9 cm corrected to a 1.9-cm discrepancy; 2.8 corrected to 1.2 cm; 2.4 to 1.3 cm; 2.3 to 0.5 cm; and 4.0 to 4.0 cm. There were no overcorrections, and although 4 of the 5 limbs were corrected into an acceptable range, all were short of equalization. The last patient was operated on too late by all criteria. In the other 4, however, the question arose as to whether growth anomalies in hereditary multiple exostoses might make prediction from the normal charts slightly unreliable. We therefore plotted femur-tibia length ratios along the appropriate percentile distribution in all the patients with hereditary multiple exostoses and compared them with the standard charts. The mean value for this length ratio in the patients with hereditary multiple exostoses was 1.27, which was exactly the same as the value from the charts for normal subjects with the same size distribution. Reference to the records of each patient who underwent epiphyseal arrest indicated that there had been considerable difficulty in assessing the skeletal age from the roentgenograms of the wrists. The pattern of limb length discrepancy that can occur in this condition is variable. The discrepancy can remain unchanged for several years, it can increase at slow or moderate rates, which is the usual pattern, or it can, on occasion, decrease spontaneously. The growth study data did not support the belief that there is an increase in longitudinal growth in an affected bone following removal of an exostosis. In addition, no correlation was seen between the degree of shortening in a particular bone and the number or size of the exostoses present. Limb length discrepancies in hereditary multiple exostoses were frequent, and in approximately one-half of the patients they were great enough to warrant epiphyseal arrest. These discrepancies point to the asymmetrical growth pattern in patients with hereditary multiple exostoses. The discrepancies in our series were mild to moderate and were readily managed by appropriately timed epiphyseal arrests. Extremely careful observation is required, however, as the discrepancies can remain stable, increase at varying rates, or even, on occasion, spontaneously decrease. Osteotomies also can alter limb length relationships. Some difficulties were encountered in determining skeletal age accurately due to the associated wrist and knee anomalies, but the GreenAnderson charts were appropriate for predicted corrections in this condition. The limbs were more affected than the spine, both the femur and the tibia were involved, and limb involvement was not invariably rhizomelic.

2. OLLIER'S DISEASE (ENCHONDROMATOSIS) The 17 patients with this intrinsic bone disease demonstrated a type I pattern of discrepancy development (432, 433). As varus or valgus femoral and tibial deformities often were associated with the shortening, corrective osteotomy was performed frequently and length discrepancy data that were unsullied by any bone surgery intervention throughout the growth period were rare. Relentless shortening was

626

CHAPTER 8 ~ Lower Extremity Length Discrepancies

demonstrated, however. One patient with severe involvement who was followed to skeletal maturity, with no surgical intervention, had a type I profile with a 35.7-cm discrepancy and no decline in the rate of increase. In all patients the extent of shortening paralleled the extent of radiographic involvement. The average shortening prior to physeal arrest or diaphyseal lengthening was 9.79 cm. Enchondromatosis was the second most serious condition causing extensive discrepancies, exceeded only by proximal femoral focal deficiency. 3. MAFFUCCI SYNDROME The Maffucci syndrome refers to patients with enchondromatosis, usually but not always unilateral, and hemangiomata. The enchondromas are present primarily in the hands, feet, and tubular long bones. The hemangiomas are either dermal or subcutaneous and adjacent to areas of enchondromatosis in most instances. Thrombosis of the dilated blood vessels with phlebolith formation occurs in almost half of the cases. The hemangiomas usually are absent at birth but appear within the first 4 years of life, with 25% occurring during the first year. Intracranial tumors of cartilaginous origin are seen in approximately 15% of patients. The incidence of chondrosarcomatous change is high, similar to the finding in Ollier's disease, with the reported incidence being as high as 25-50%. The matter is difficult to determine because some authors consider virtually all enchondromatosis tissue after skeletal maturity to be presarcomatous at least. The limb length discrepancy findings are similar to those with Ollier's disease, particularly when unilateral lesions predominate. 4. DYSPLASIA EPIPHYSEALIS HEMIMELICA This rare disorder often is accompanied by a lower extremity length discrepancy particularly if the epiphyseal irregularity is at the distal femur or proximal tibia. It is generally referred to as dysplasia epiphysealis hemimelica, but other suggested terms for the disorder are tarso-epiphyseal aclasis and epiphyseal osteochondroma. Many of the disorders, however, occur at the ankle joint involving either the distal tibia or on occasion the talus. The discrepancies generally tend to be mild to moderate, and more clinical difficulty is encountered with the asymmetric joint surface rather than with the discrepancy itself. Trevor (479) was the first to delineate the disorder formally, describing 8 patients initially. He noted that the initial description of such a disorder was a case described by Mouchet and Bellot (342) in 1926 involving the talus. There was no true shortening in the 8 patients assessed, although specific limb measurements were not taken. Sixteen patients with the disorder were reviewed by Connor et al. (124). Each had only one leg involved but 12 multiple epiphyses were affected. The most common sites were the distal femur, distal tibia, and talus. Treatment of the lesion was generally by local excision and was generally effective around the knee,

although some at the ankle required arthrodesis. The disorder is characterized by asymmetrical overgrowth of one or more epiphyses in a limb or of a tarsal or carpal bone during childhood. In the 16 patients, most of whom were followed to skeletal maturity, inequalities of limb length were apparent in 5, 1 with lengthening and 4 with shortening. Discrepancies generally were of a minor degree and caused few problems. In those with shortness on the involved side, the amounts were 2, 1, 1, and 6 cm. In the one instance in which there was overgrowth on the involved side, it was only 1 cm and there was multifocal involvement of the distal femur, distal tibia, and talus. In the one patient with an extensive 6 cm of shortening, there was major involvement of the lateral half of the right distal femoral epiphysis. Approximately three-fourths of the lesions are concentrated in five regions, which, starting with the most common, involve the talus, distal femoral epiphysis, distal tibial epiphysis, proximal tibial epiphysis, and the tarsal navicular bone. When deformities are present, they tend to involve either genu valgum or genu varum, valgus deformation of the ankle, and equinus deformity of the ankle. Kettelkamp et al. (273) reported 15 new cases and also reviewed the literature; they noted that inequality of limb length was found occasionally and that the affected extremity could be either shorter or longer. The distal fibular epiphysis and the medial cuneiform also were affected in some instances. When the 7 most common sites of involvement were included they accounted for 84% of all lesions. Lower extremity length discrepancies were described in only 3 of their cases, although no specific comments about measurement were made otherwise. In those 3 instances the involvement was marked, with 1 patient having 3.5 in. short and 2 with overgrowth discrepancies of 1 and 2.5 in. Fairbank (157) reported on 14 additional cases. The length of the limb was usually unaffected but on occasion discrepancies did occur. He reported 3 instances of length discrepancy in 14 patients: 0.25 in. of shortening, 1 in. of lengthening, and 0.5 in. of lengthening. If we summarize the length discrepancy descriptions from the papers of Connor et al., Kettelkamp et al., and Fairbank, the number of instances of clinically significant length discrepancy is relatively small with 11 out of 45 involved or about one-fourth (25%) of the patients. Of those with involvement, 6 had shortness on the involved side and 5 were longer on the involved side. The range of discrepancy in those with shortening was from 0.6 to almost 9 cm (0.6, 1, 1, 2, 6, and approximately 9 cm), whereas in those with lengthening the values ranged from 1 to 5.7 cm (1, 1.2, 2.5, 2.5, and 5.7 cm). In summary, therefore, whereas clinically significant lower extremity length discrepancy occurs in only approximately 25% of patients and appears to be equally divided between shortening and lengthening, on occasion it can be marked such that examination through the growing years is essential in regard to length discrepancy as well as angular deformity and range of motion.

SECTION V! 9 Lower Extremity Length Discrepancies in Specific Disease Entities

5. MELORHEOSTOSIS The rare skeletal dysplasia melorheostosis is characterized by linear radiodensity or sclerosis primarily in the metaphyseal and diaphyseal regions and can be associated with length discrepancy due to asymmetric involvement. Daoud et aL (132) reported one case in which the predicted final discrepancy was 2.5 cm of shortness on the involved side. Campbell et al. (86) reported 14 patients with the disorder, which was characterized by the radiographic long bone abnormalities with a primary clinical finding of contractures or limitation of joint motion. The tendency of the disorder is to be either exclusively monomelic or at least concentrated in one or two of the major long bones. Any bone of the body can be involved, however. The clinical findings at birth or in early childhood involve contractures, fibrosis, and abnormal skin with the bone changes occurring over a several-year period afterward. Campbell et al. noted that the affected extremity was usually shorter, although occasionally longer, but that the affected limb usually appeared larger in circumference and often had angular bone deformities. In the epiphyses and carpal and tarsal bones, there is often a spotty or patchy collection of increased radiodensity. An inequality in limb length ranging from 0.5 to 4.5 in. was found in 9 patients; the involved or more severely involved extremity almost always was shorter, except in one instance in which it was longer. Younge et aL (516) performed a study of 14 children with the disorder. The principal presenting clinical features were unilateral soft tissue contractures and inequality of limb length. The initial bony changes involved endosteal thickening or hyperostosis marked by streakiness of the long bones and spotting of the small. As in the Campbell et al. series, there was equal involvement of males and females. Eleven of the 14 were followed to at least 16 years of age. Soft tissue contractures causing severe and rigid joint deformities occurred in all and were the presenting complaint in 11. In 8 patients only one limb was involved, in 3 two limbs, in 2 three limbs, and 1 had all four limbs affected. Contractures were most commonly seen at the hip, knee, ankle (clubfoot), fingers, and iliotibial band. Each of the 14 patients had a lower extremity length discrepancy. In 13 the affected limb was shorter, ranging from 1.2 to 10.0 cm with an average shortening of 4.1 cm. In the one patient whose limb was longer the discrepancy was 2.5 cm. Firm thickening of the skin with tethering of the underlying fascia was seen in 5 patients. The problems of joint deformity, bone deformity, and contracture were marked and poorly responsive to nonoperative and even operative attempts at correction. Indeed amputation was required on four occasions, almost always after failed surgical procedures. Epiphyseal arrest was effective in treating the length discrepancies. More recently, Marshall and Bradish (317) reported successful tibial and fibular lengthening with the callotasis technique. The discrepancy at maturity was 4 cm equally divided between femur and tibia. The regenerated bone in the distraction gap had the radiologic appearance of the original bone.

627

C. Destroyed Physes If destruction and premature fusion of a physis occur, a type I pattern of discrepancy development invariably follows except at the hip (as will be described), with no tendency to compensation by the other physes in the involved bone. Such destruction occurs most commonly today with certain physeal fracture-separations. Significant lower extremity length discrepancies are seen with distal femoral growth plate fracture-separations, especially if there are several years of growth remaining because 70% of femoral growth occurs distally. Successful focal transphyseal bone bridge resection will allow growth to resume in some instances. Other causative factors are physeal ablation during tumor resection and severe osteomyelitis, particularly in the pre-antibiotic era. Wilson and McKeever (507) documented shortening in 18 (21.1%) of 85 infected bones whose physes were damaged from an adjacent focus of osteomyelitis.

D. Abnormal Growth Following Use of Neonatal Umbilical or Femoral Catheters On occasion, prolonged use of neonatal umbilical or femoral catheters for newborn illness has been associated with mild growth stimulation on the involved side. More serious sequelae were reported by McCarthy et al. (321) in four patients in whom significant lower limb length shortening occurred subsequent to neonatal catheter use. This involved either umbilical or femoral arterial catheters or both. The projected length discrepancies were massive, varying from 10 to 20 cm at maturity. Autopsies on other patients with indwelling catheters demonstrated varying degrees of thrombosis of the major associated vessels along with many embolic phenomena, so that the complication of length discrepancy problems surfacing after a prolonged or difficult neonatal hospitalization should be considered.

E. Poliomyelitis In patients with poliomyelitis involving the lower extremity, the type I pattern was seen commonly. There was, however, a distinct tendency for the discrepancy to increase most rapidly in the first 4 or 5 years following infection, with the rate of increase diminishing after that (types II and III) (Fig. 9) (433). This fact has been pointed out previously by Green and Anderson (193), Ratliff (398), and White (500). Assessment of the 115 patients in our series who were followed for 10 years or more, either to skeletal maturity or to the time of surgical physeal arrest, indicated that almost one-third of the patients demonstrated a type II or type III pattern. It has been theorized that improved function due to tendon transfers and bracing is responsible for the lessening rate of discrepancy with time. Detailed studies during the poliomyelitis era described a good but variable correlation between the extent of shortening and the severity of involvement. No correlation

CHAPTER 8 9 Lower Extremity Len~trh Discrepancies

628

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F I G U R E 9 Type I pattern of a developmental discrepancy in a patient with poliomyelitis is shown.

between the age at onset and amount of shortening was found in one major study, although this finding was challenged (Fig. 9). During an era in which polio was common, Ratliff (398) noted that lower extremity shortening was seen in 219 of 225 affected patients. Barr (34) had stated that any child developing poliomyelitis before the age of 10 years with considerable difference in paralysis of the legs was almost certain to develop inequality of leg length. Barr had indicated in an earlier study that the incidence of leg shortening in poliomyelitis was as high as 78% of cases, but more detailed studies revealed an even greater increase in the likelihood of shortening. To a certain extent the shortening was related to the age at onset of the poliomyelitis and to the extent of the musculature weakened but there were not absolute correlations. Barr (34) found that 35% of patients developed a discrepancy of 1.5 in. (3.8 cm) or more, and Green noted that 8% developed a shortening greater than 2 in. (5 cm). Ratliff (398) analyzed several factors relating to limb shortening and poliomyelitis in 225 children in whom paralysis was confined to one leg. Patients were assessed between 5 and 17 years after infection. The study assessed length discrepancy prior to any limb equalization procedures. Measurements were clinical from anterior superior iliac spine to medial malleolus. Shortening had occurred in 219 of 225 children (97%) of whom 190 had some radiographic studies, which led to effective measurement to within 1~6in. The greatest incidence of onset of poliomyelitis was within the first 3 years of life, with relatively few developing the disease after the age of 8 years. The involved leg was always shorter. There were 65 patients followed into adult life, with no surgery having been performed, in which the shortening varied between 0.25 and 5 in. There was only

1 patient with the 5-in. shortening, such that the natural history would best be defined as leading to discrepancies between 0.25 and 3.5 in. because each 0.25-in. gradation between those two numbers had patients involved. The discrepancy was 2 in. or greater in 25 of the 65 patients. The discrepancy was almost always greater in the tibia than in the femur. In 184 patients assessed in this regard, 12 had tibial shortening only, 94 had tibial shortening greater than femoral shortening, 47 had equal tibial and femoral shortening, 30 had tibial shortening less than femoral shortening, and only 1 had femoral shortening only. Ratliff felt, after careful analysis, that it was impossible to predict accurately the distribution of shortening from a study of the distribution of muscles paralyzed. In another subset of patients followed for at least 9 years after disease onset (130 patients), three patterns of progressive shortening were noted. One involved a rapidly progressive discrepancy pattern in which 2.5 in. or more discrepancy occurred within 9 years or less of the onset of the disease, a slowly progressive pattern in which the discrepancy increased at a constant rate amounting to 2-3 in. by adult life, and a nonprogressive variant in which a discrepancy of up to 1.5 in. was present 5 years after onset of the disease and then remained constant until growth ceased (the type III pattern by our criteria). There was no evidence that reduction of shortening ever occurred (absence, therefore, of the type V pattern). Ratliff noted that almost 62% of patients fell into the nonprogressive group III pattern. Once again the classification of paralysis as mild, moderate, or severe could not reflect the pattern of length discrepancy progression. Although there was considerable overlap between groups, in general those with mild paralysis had lesser amounts of shortening than those with severe paralysis, with moderate in between. For example, each of the 5 patients without any shortening had mild involvement. In 102 of the patients assessed 9 years after poliomyelitis, those with mild paralysis had shortening from 0 to 2 in., those with moderate paralysis from 0.5 to 2.25 in., and those with severe paralysis from 1 to 3.5 in. There was no significant difference in the range of shortening that occurred in patients suffering disease onset between 0 and 2 years of age and those between 3 and 7 years of age. The range of shortening also was similar whether the paralysis involved only one muscle or all of the muscles below the knee. No child with paralysis only below the knee, however, showed a discrepancy greater than 1.75 in. On occasion, some transient lengthening of the involved paralyzed leg was noted during the first 2 years after the onset of paralysis, but this was always temporary and no patient was found in the series with lengthening of the paralyzed leg 5 years or more after onset. It is possible that inequality of leg length was present before the onset of the poliomyelitis, which of course would not have been observed. Premature physeal fusion was not a feature of the poliomyelitis disorder.

SECTION VI ~ Lower Extremity Length Discrepancies in Specific Disease Entities

Ring (406) also studied limb shortening and its relationship to paralysis in poliomyelitis. His study did not provide absolute numbers for the amount of shortening but rather assumed (somewhat incorrectly) that it would occur at a constant rate with time. The degree of shortening was basically the same in limbs with muscle power graded as 2, 1, or 0. The amount of shortening progressively increased, however, as the grade of strength diminished from 5 to 4 to 3. Shortening was least in the strongest patients. The important feature, therefore, was not the degree of weakness but whether the muscles could function against gravity; within this group the stronger the muscle the less the shortening. The cause of shortening in poliomyelitis was not felt to be weakness per se but rather the diminished vascularity that accompanied the decreased muscle mass. Absolute correlations, however, were never possible in relation to the age at onset of the disorder or the extent or type of muscle weakness. Gullickson et al. (207) determined that the average percent shortening of unilaterally affected limbs with poliomyelitis did not appear to be different between the 0-5 year age group or the 6-10 year age group in terms of age at onset of the disorder. They also noted no correlation between muscle strength of the leg and shortening of the tibia. There was, however, definite correlation between atrophy of the thigh or leg and shortening of the femur or tibia. They provided no measurements of limb shortening although percentages were provided. In those with age at onset between 0 and 5 years of age, the percentage shortening of the tibia was 2.44% and that of the femur was 2.52% in 47 cases, and in those from 6 to 10 years of age, the percentage shortening of the tibia was 2.37% and that of the femur was 1.96% in 29 cases. Green, in a discussion published in the Journal o f Bone and Joint Surgery after an article published by Stinchfield et al. (464), reviewed the fact that, in 257 cases of poliomyelitis studied in his unit in which one lower extremity was affected and the other was normal, the average maximum growth inhibition occurred from the second to the fifth year after the onset of the disease. There was less inhibition prior to the second year and less inhibition each year after the fifth year following onset. Thus, it was recognized that not all patients with poliomyelitis increased their discrepancy at a constant rate with time. Green and Anderson showed that the final result of epiphyseal arrest treatment for poliomyelitis was within 1.2 cm (0.5 in.) of the predicted amount in 88.5% of 61 cases (193). Barr (34) provided an excellent review of leg length inequality in poliomyelitis. Based on the assessment of 371 cases during an active era of poliomyelitis, with the onset before the age of 16 years, shortening was 0.5 in. (1.3 cm) or less in 41%, over 0.5 in. but less than 1.5 in. (1.3-3.8 cm) in 24%, and 1.5 in. or more (i>3.8 cm) in 35%. Numbers from his clinic indicated that approximately 80% of patients with unilateral poliomyelitis developed shortening on the involved side. Subsequent studies showed the incidence to be

629

higher, with virtually all patients with unilateral poliomyelitis having some degree of shortening. Stinchfield et al. (464) attempted to project how much the growth discrepancy would be based on the muscle power in the affected extremity compared to the muscle power in the normal extremity. A chart was constructed based on data from 64 cases who had reached adulthood such that the final discrepancy was known. The hope for a clear correlation between muscle strength and limb length discrepancy was shortly disproven, however.

F. Hemiparetic Cerebral Palsy Most of these patients have a lower and upper extremity length discrepancy, with the shortening on the more distal parts of the involved side. In our series, type I and type III developmental patterns in the lower extremity predominated (433). Lower extremity shortening in hemiplegic children occurred almost exclusively in the tibia, a correlation also noted by Staheli et al. (456). Growth alterations in the hemiplegic child were studied in 50 children with spastic hemiplegia by Staheli et al. The hemiparetic side was always somewhat shorter than the contralateral normal side. Discrepancies in the affected upper extremities were actually larger than those in the lower extremities. The mean difference in the radius in terms of percent growth inhibition in 25 cases was greatest at 6%, whereas the inhibition in the humerus was approximately 4.2% and in the tibia approximately 3%. There was essentially no difference in the femoral lengths. The limb length inequality was far more significant in terms of functional disability in the lower than in the upper limb, but lower limb discrepancies were not particularly great because femoral shortening was not a factor. A discrepancy of 2 cm or greater occurred in only 2 of 16 patients in the older age group and epiphyseal arrest was rarely used. Of the 16 patients 11 years of age or older, the lower limb discrepancy was 1 cm or more in 10 children and greater than 2 cm in only 2. We have found, however, that lower extremity length discrepancy represents a more important consideration in many hemiparetic patients. Of the 46 patients who were followed in the Growth Study Unit for 5 years or more and who had a discrepancy of more than 1.5 cm, the average discrepancy just prior to physeal arrest or at maturity was 2.0 cm (range = 1.5-3.2 cm). Physician referral strongly influenced our study of this disease entity, unlike other diseases for which the condition itself was the reason for referral. The majority of patients with cerebral palsy in our hospital were not assessed for discrepancies. Femoral-tibial shortening alone does not give a true measurement of the functional discrepancy that may be present in the limb, as subtle dynamic or static hip and knee flexion contractures and an expected, but rarely documented, shortness in the height of the foot may further decrease the functioning length of the hemiparetic limb. If

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CHAPTER 8 ~ Lower Extremity Length Discrepancies

an Achilles tendon lengthening is done and the lower extremity length discrepancy is not appreciated, there may be a tendency for equinus deformity to recur on a mechanical compensatory basis.

G. Septic Arthritis of the Hip Damage to the femoral capital epiphysis in septic arthritis can produce serious growth discrepancies especially if they occur in infancy (155,335). In our series such discrepancies tended to increase with time, but a type I pattern was seen in only 42% of the patients and most commonly when the infection had occurred relatively late after the age of 7 or 8 years (433). An assessment of pattern development in this group was obscured somewhat more often than in other groups because of the necessity for early and often frequent surgical intervention, although femoral osteotomy per se was done only infrequently in growing children. The patterns in this assessment were based on femoral and tibial lengths. In following such patients, however, it is important to be aware that, if dislocation occurs, the practical consideration in discrepancy relates to the distance between the iliac crest and the floor. This can be documented accurately by orthoradiographs, but a combination of measured blocks under the shortened extremity in association with a standing anteroposterior radiograph of the pelvis also is important, especially if only scanograms have been used to document the discrepancy. Even with complete destruction of the epiphysis, however, femoral shortening did not invariably become worse with time, particularly in the younger patients and those in whom femoral head dislocation did not occur. When the greater trochanter overtakes the involved femoral head in height, the femur resumes a somewhat more regular growth pattern as the greater trochanter and distal femoral physes are normal, thus accounting for the type II and III patterns that were seen. The relatively rare type IV pattern (Fig. 10A) also was seen with septic arthritis (Figs. 10Bi-10Biv). There are instances in which treatment effectively eradicates infection, allowing physeal growth to continue for several years in a seemingly normal fashion. On occasion, however, premature femoral head-neck growth plate closure occurs with no reactivation of infection, leading to a worsening of the discrepancy several years after the infectious insult (Fig. 10). The growth of the proximal end of the femur, particularly the relationship between the capital femoral and the greater trochanteric epiphyses, has been discussed in relation to normal, diseased, and experimental situations. The complexities of this particular growth area must be understood in order to plan the proper time for surgical intervention. Both Betz et al. (45) and Hallel and Salvati (215) found the subsequent length discrepancies after neonatal septic arthritis of the hip to range between 3.0 and 3.5 cm if the femoral head remained located and between 5.5 and 6.0 cm if dislocation occurred.

Hallel and Salvati (215) reported on the end result of 24 cases of infantile septic arthritis of the hip in 21 patients, 3 of whom were involved bilaterally. The disorders occurred in the first 7 months of life. A clear difference in length discrepancy was noted between those hips that had dislocated and those that remained located, with the far more serious length discrepancies occurring in the former group. Fifteen of the 21 patients had reached skeletal maturity and the others ranged between 11 and 14 years of age. Shortening of more than 2.0 cm was noted in 16 cases. In 8 instances it was due to arrested or delayed growth of the physis of the femoral head, and in 8 other cases the epiphyseal damage was worsened by proximal migration of the head in either subluxated or dislocated hips. In those cases in which the head remained located the mean discrepancy was 3.4 cm (range = 2.0-5.0 cm), and in the dislocated and subluxated cases the mean discrepancy was 6.0 cm (range = 3.0-9.0 cm). The growth of the femoral shaft measured from the proximal tip of the greater trochanter to the lateral femoral condyle was not affected by the septic process, and the growth rate of the trochanteric epiphysis remained equal to the opposite side even when the trochanter was placed into the acetabulum in the form of a trochanteric arthroplasty. A long-term multicenter follow-up of the late sequelae of septic arthritis of the hip in infancy and childhood was published by Betz et al. (45). They defined infantile cases as occurring from birth to 3 months of age and the childhood form in those whose onset occurred after age 3 months. All patients had reached skeletal maturity, and the study involved 28 patients with 32 affected hips. The lower extremity lengths were assessed at skeletal maturity in those for whom no epiphyseal arrest had been performed or those who were determined to have the predicted length discrepancy had epiphyseal arrest or lengthening not been performed. In the infantile group, the projected lower extremity length discrepancy was a mean of 3.93 cm with a range from 0 to 7.0 cm. In the childhood group, the mean discrepancy was 4.2 cm with a range from 0 to 8.0 cm. The discrepancy was 2.5 cm or greater in 7 of the 10. Wopperer et al. (512) studied 9 hips in 8 patients at a mean follow-up of 31.5 years after infantile hip sepsis. The authors had defined that group as having the sepsis between birth and 3 months of age. Six of the hips had dislocated and 3 had remained located. The leg lengths were equal in the case with bilateral sepsis and dislocation, leaving 7 patients in whom length discrepancy due to the disorder itself could be determined. In these 7 the discrepancy ranged from 0 (in 2 patients) to a maximum of 6.0 cm. The mean discrepancy was 2.86 cm. Cottalorda et al. (125) reported on the growth sequelae of 72 hips in 60 children with septic arthritis of the hip in early childhood. Treatment was variable. In 28 there was no lower extremity length discrepancy and in 16 the discrepancy was 2.0 cm or less, but in 16 with poor results discrepancies greater than 2.0 cm were present, with an average of 3.5 cm

SECTION VI ~ Lower Extremity Length Discrepancies in Specific Disease Entities

631

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(A) Type IV pattern in a patient with septic arthritis of the right hip in infancy is shown. The hip was treated early such that there was continuing growth of the physis for several years followed by premature cessation of growth, which added an additional centimeter to the discrepancy at the time of skeletal maturation. (Bi-Bvi) Radiographs of the proximal femurs and hips at 1, 2, 4, 8, 13, and 15 years of age are shown. Note the excellent structural recovery by 8 years of age, mild coxa vara at age 13 years with early evidence of premature physeal closure, and clear trochanteric overgrowth with a shortened femoral neck at age 15 years due to premature physeal closure years after the initial infectious insult. [Part A reprinted from (432), with permission.]

and a range of 2.0-7.5 cm. The type IV developmental growth pattern is limited almost exclusively to abnormalities of the proximal end of the femur such as occur with septic arthritis of the hip, osteomyelitis of the femoral neck, LeggPerthes disease, and avascular necrosis of the femoral head complicating treatment of congenital or developmental dislocation of the hip. In septic arthritis patients in whom damage was relatively mild, premature fusion of the proximal femoral capital physis was sometimes noted years after the infectious insult. The premature fusion can be detected 2 or 3 years prior to skeletal maturation by the progressive change in the relationship of the level of the greater trochanteric physis to that of the proximal femoral capital physis. Therefore, it is extremely important to continue periodic assessments of these children by monitoring carefully the relationship of the head and neck to the greater trochanter until

skeletal maturity, even if the discrepancy has been in a plateau phase for several years. Although the average increase in the late phase was only approximately 1 cm, this amount could convert a clinically insignificant discrepancy to one of 2.4 cm or more and thus warrants special consideration. Gage and Cary (172) have shown the value of trochanteric epiphysiodesis in patients with severe growth damage to the femoral head-neck physis.

H. Tuberculosis Tuberculosis was frequently associated with lower extremity length discrepancy especially prior to the advent of antibiotics (250). The hip was a common site of infection with the knee involved as well fairly often. The serious nature of the disease overall and the major sequela of joint destruction

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CHAPTER 8 ~ Lower Extremity Lenyth Discrepancies

limited the study of length discrepancy alone. There was early awareness, however, that tuberculous infection of the bones in childhood could affect growth. Langenbeck (284) described decreases in growth with tuberculous involvement of the joints in the lower extremities. Dollinger (144) described 41 cases of tuberculosis of the knee joint and found that, in the active phase, the diseased leg grew either at the same rate or on occasion more quickly. Because tuberculous infection was relatively indolent there was a chronic synovitis associated with it, and this stimulation of growth was similar to what one sees today in childhood rheumatoid arthritis. Dollinger also noted that retardation of growth occurred only when the disease became quiescent, by which time in that era sufficient damage had occurred to destroy the physis and also further decrease height by associated articular cartilage destruction. An increase in the length of the long bones after tuberculous infection also was noted by Reschke (400) and Pels-Leusden (378). In spite of the fact that tuberculosis of the hip had been a common disorder, very little has been written on the extent of length discrepancies resulting, although one would expect values similar to those with septic arthritis. Although the joint affected most commonly in tuberculosis was the hip and some of the femoral shortening was due to damage at the proximal end of the femur, it was frequently noted that there was premature distal femoral growth plate closure, which sometimes led to marked length discrepancies. Gill (179) demonstrated that, contrary to the previous feeling that it was disuse that led to the length discrepancy, there was often premature central closure of the epiphyseal cartilage plate of the distal femur and occasionally the upper tibia that caused most of the discrepancy. He described 15 cases of childhood tuberculosis of the hip in which the complication occurred. In each case the limb had been immobilized for an extremely long period of time. In each instance the age of the patient at the onset of tuberculosis was less than 7 years. The distal femoral arrests were almost invariably central epiphyseal-metaphyseal bone bridges, which, with continuing growth peripherally, caused the formation of an inverted V shape to the distal femoral epiphysis with a deeper bicondylar notch than on the normal side. In the tibia, central fusion also tended to occur, leading to continuing peripheral overgrowth and a saucer shape for the proximal end. With any degree of eccentricity of the central fusion angular deformity also occurred. In each instance the premature closure of the distal femoral or proximal tibial growth plate occurred on the side of the diseased hip. There was no evidence of tuberculosis of the knee joint to serve as a direct cause of the physeal fusion. Gill noted marked osteopenia of the entire affected femur, which he felt was due to a long period of immobilization, leaving the cartilage plate more susceptible to traumatic damage even if slight. Parke et al. (370) also noted a relatively high frequency of premature epiphyseal fusion at both the distal femur and the proximal tibia in tuberculous disease of the hip. They

also felt that it was due to the associated severe osteopenia of prolonged immobilization, leading to rupture of the physis and transphyseal bone bridge formation. Much of the osteopenia also was due to the generalized suppression of new bone formation by the tuberculous disease. These severe sequelae were described in the pre-antibiotic era. The physeal fusion was primarily central initially. The occurrence was with prolonged disease, which had to have been present for at least 2 years and frequently for much longer. They assessed 91 diseased hips with disease duration varying from 4 months to 22 years. It was not trauma per se but rather severe osteoporosis that was the precursor to premature fusion. They noted 29 cases of premature fusion at the ipsilateral knee in the 91 tuberculous hips. The tibial epiphysis was involved in 26 patients and the femoral in 17. Both bones were affected in 14 cases, the tibia alone in 12, and the femur alone in 3. A central bulging defect was seen most commonly in the proximal tibia, whereas in the femur a more fragmentary type of central physeal lesion was seen. Physeal growth of the normal limb was invariably unaffected. There was virtually no growth plate problem when the disease was less than 2 years in duration. The longer period of time the disease had been present the greater the incidence of fusion, such that each of the 7 patients with a 10-year history of the disorder or longer showed premature fusion. Sissons (447) confirmed the histopathology of extreme osteoporosis in the knee joint region in eight cases of joint tuberculosis from amputation or postmortem specimens, three of which were studied in detail. The osteoporosis appeared quite marked due to removal of the transverse trabeculae, making the longitudinal ones more prominent radiographically and also involving the subcortical bone adjacent to the articular surfaces and the bone in the neighborhood of the epiphyseal plates. Sissons could not directly address the physeal cartilage because his studies were performed in young adults. The central tibial arrest led to a saucer-shaped conformation of the proximal tibial epiphysis and articular surface. Wilson and Thompson also commented on the negative effects on growth with tuberculosis of the hip. They did note, however, that in relatively mild tuberculosis of the knee itself growth stimulation sometimes occurred.

I. Premature Epiphyseal Fusion at the Knee Complicating Prolonged Lower Extremity Immobilization Although premature epiphyseal arrest at the knee complicating prolonged immobilization of the hip for tuberculosis became a well-recognized clinical entity, in reality it was as much the prolonged immobilization as the tuberculosis itself that caused the disorder in the knee region. Subsequent studies showed that prolonged immobilization for many other hip disorders led to the same negative sequelae, including such conditions as septic arthritis, chronic osteomyelitis, and slipped capital femoral epiphysis treated with casting. Simi-

SECTION VI ~ Lower Extremity Length Discrepancies in Specific Disease Entities

lar negative sequelae have been described with prolonged immobilization for congenital dislocation of the hip in works by Kestler (272) and Botting and Scrase (63). These negative sequelae occur with treatments in abduction splints in recumbency and then in hip spicas for 12 months or longer. With prolonged immobilization the disorder appears to be related to severe osteopenia such that even minor trauma can lead to transphyseal injury followed by linkage of the epiphyseal and metaphyseal circulations, leading to bone bridge formation. Ross (414) also pointed out the occurrence of distal femoral and proximal tibial premature growth plate closure in association with prolonged disability of an extremity in which the site of pathology was well away from the epiphyseal areas that subsequently fused. He studied 13 patients, 9 of whom had tuberculosis of the hip, with the others suffering from septic arthritis of the hip, slipped capital femoral epiphysis, polio, and osteomyelitis of the femoral shaft. Both of the epiphyses at the knee can be involved or there can be involvement of either the distal femoral or proximal tibial region alone. When the distal femur was involved there was a high tendency for closure to occur centrally in almost all instances, leading to the inverted V appearance of the physis and increased angulation of the intercondylar notch area. In the proximal tibia, peripheral fusions occurred more frequently than central fusions. The proximal fibula was not affected in any instance. Post-immobilization epiphyseal fusion occurred after extremely long periods of cast or splint protection of the limb, especially in comparison to current treatment protocols. In general, the immobilization was greater than 1.5 years. Examples from the case reports indicate the following periods of immobilization: 2 years and 10 months; 16 months (plaster cast); intermittent immobilization of the lower extremity for 3 years between 3.5 and 7.5 years of age; immobilization in plaster dressings between the ages of 6 and 9.5 years; 4.5 years (plaster cast) of immobilization during the period of rapid growth with weight bearing not allowed until the age of 13.5 years; a long leg brace between the ages of 6 and 8 years; 1 year and 11 months (plaster cast); 7.5 months (plaster cast); and plaster immobilization between the ages of 4 and 7 years. In those patients for whom radiographs of the knee region were available during the course of the disorder, one of the early changes of a developing growth disturbance was thinness of the physis and a transverse zone of dense bone on its metaphyseal aspect, which would indicate a Harris arrest line. The growth retardation scars were numerous and osteoporosis of the regional bone was pronounced. The contour of the epiphyseal cartilage was irregular. Bony bridges were then noted to cross the physis. At the distal end of the femur the point of arrest was commonly posterior to the central portion of the disk leading to a flexion deformity as well as shortening. At the proximal tibia the arrest was often in the postero-medial quadrant, leading to a tibia vara deformity. The tibial tubercle was sometimes the site of premature un-

633

ion, leading to genu recurvatum. Histologic examples of transphyseal bone bridge formation were found. Cartilage from the physis showed fibrillation, disorganization, and shortening of the cartilage cell columns and diminution of endochondral growth. Histologic studies from the fibula showed normal physeal cartilage. The osteoporosis led to inappropriate support of the physis, and with any weight bearing transphyseal injury was prone to occur. The interpretation that weight beating played a major role in causing further damage is supported by the fact that the proximal fibular physis almost invariably remained intact and continued to grow. This physis clearly would have been subject to the same immobilization osteopenia, but because it is a nonweight-beating structure no negative sequelae occurred.

J. Osteomyelitis Both overgrowth and growth retardation can occur in long bones that are the site of osteomyelitis. Growth changes in osteomyelitis vary depending on whether the infection is controlled in the acute phase or whether it persists as a subacute or chronic osteomyelitis (439, 440). In addition, the precise site of the infection dictates the growth sequelae. If it traverses the physis, then premature growth retardation occurs leading to a shortening, whereas if it remains in the diaphysis and metaphysis juxtaposed only to the physis, then the hyperemia leads to growth stimulation with the maintenance of physeal function. Pandey et al. (365) have pointed out the change over several decades in growth phenomena related to osteomyelitis. In the pre-antibiotic era physeal damage with growth retardation was more common, whereas afterward the disorder was better controlled although often not eradicated quickly, such that periphyseal hyperemia persisted and overgrowth predominated. Hentschel (232) pointed out as early as 1908 that osteomyelitis of the proximal tibia in the growing child could interfere with growth. In a series of growing bones affected by osteomyelitis, he was able to note instances of both shortening and lengthening of the affected bone (452). McWhorter also noted a case in which osteomyelitis in a growing child led to 1.5 in. overgrowth (452). Speed (452) pointed out that acute inflammation either arising directly in the epiphyseal area or spreading by continuity from the diaphysis could damage and destroy physeal cells, leading to growth arrest problems. The associated thrombosis served to damage further the blood supply to the growth regions. Depending on the extent of the physeal damage, there would be either complete stoppage of growth or uneven growth resulting from focal physeal destruction. If it became clear that the damaged epiphysis had ceased all growth and was no longer functional, Speed referred to the possibility of excising the contralateral epiphysis to stop its growth and thus limit any further worsening of the discrepancy. In a subsequent work Speed (453) commented on specific instances of overgrowth of a long bone due to stimulation of

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CHAPTER 8 ~ Lower Extremity Lenyrh Discrepancies

the epiphyseal cartilage by inflammatory processes. He recognized that there was an actual stimulation of growth and that the increased length was not due to a delay in closure of the involved physis. He presented one case with chronic osteomyelitis that began at 6 years of age and persisted throughout the growing period. In adulthood the involved side was 2.25 in. longer with 1.75 in. increased length in the infected tibia. One inch of overgrowth was noted in a chronic instance of osteomyelitis of the tibia in a 5-year-old child. Speed was one of the earliest to note that overgrowth of long bones could follow infections of those bones, particularly when the infection did not directly involve the epiphyseal region. He pointed out that patients should be warned that after infectious disorders of a long bone either shortening or lengthening could occur. Wilson and McKeever (507) studied bone growth disturbances in 85 cases of osteomyelitis, also in the pre-antibiotic era. They also noted that both lengthening and shortening could occur after such infections in a growing bone. The onset of infection in all of their cases was prior to 12 years of age. Shortening of the bones was noted in 18 of 85 infections (21.2%). The focus of osteomyelitis, which caused an interruption of growth, was always located in the metaphysealdiaphyseal region adjacent to the physeal cartilage. Serial radiographs showed the epiphyseal line to be interrupted, narrowed, and eventually prematurely closed in many. The amount of shortening ranged from 1.0 to 4.0 cm although there was one case in which 6.0 cm of shortening occurred in a distal femur, which was complicated by a pathologic fracture. The amount of shortening would be dependent on the extent of the growth arrest and the age of its occurrence. Fifteen of the 18 episodes of shortening occurred in the femur, tibia, and humerus, and the mean amount of shortening in these 3 bones was 2.6 cm. Lengthening of the involved bones, however, occurred to the same extent, with 18 of 85 infected bones (21.2%) showing an increase in length of the involved bone. Infection in all patients with bone lengthening was located in the metaphysis and diaphysis but not necessarily immediately adjacent to the physis. Lengthening occurred in the 18 instances in osteomyelitis of the femur, tibia, and humerus. The range of lengthening was between 1.0 and 3.0 cm except for one instance of a 5.0-cm lengthening, which appeared to be somewhat usual. When that single case was eliminated, the 17 instances of overgrowth had a mean of 1.74 cm per bone. Trueta and Morgan (482) performed a long-term assessment of the late results in the treatment of 100 cases of acute hematogenous osteomyelitis shortly after the introduction of penicillin. The earliest studies of the antibiotic era soon began to show that shortening was becoming much less common than previously observed. They noted 7 instances in their series, and in each it was due to primary epiphyseal damage usually in infants. Increased growth in length of the affected bones, however, was common and 32 cases demonstrated lengthening, although in no case was the increase

more than 2.0 cm. Trueta and Morgan felt that the increase was due to the increased vascularization of the periphyseal area following damage of the nutrient vessels by the infectious process. Overgrowth following osteomyelitis lasted until medullary recanalization had occurred, a type III pattern in our classification, by which time the sequestra would have been resorbed and more normal vascular patterns would have been established (481,482). In chronic recurrent osteomyelitis of childhood, however, overgrowth will persist until the inflammatory focus is totally eradicated. With the increasingly widespread use of chemotherapy, such as sulfathiazole after 1941 and penicillin after 1946, the mortality from osteomyelitis dramatically diminished as did many of the bone deforming complications in those who survived. Patients with infantile osteomyelitis, within the first 3 months of life, continue to have serious bone sequelae. These were well-illustrated by Roberts (409), who documented the long-term disturbed epiphyseal growth at the knee after osteomyelitis of the distal femur or proximal tibia in infancy. The distal left femur was involved in 13 and the proximal tibia in 2. In many instances in the distal femur, the physis and epiphysis were not affected equally across the diameter of the bone such that severe varus or valgus malformation occurred. Multiple osteotomies may become needed along with attention to the length discrepancy. The lower extremity length discrepancies are of great magnitude due to the early stage at damage and due to the fact that the majority of lower extremity growth occurs at the knee region. In the 15 patients followed either to skeletal maturity or into the second decade of life, the maximum discrepancy reached a mean of 8.1 cm with a range from 1.0 to 14.0 cm.

K. Meningococcemia Meningococcal septicemia associated with necrotic purpura, cardioshock, and neurologic signs is a relatively rare infectious disorder that usually requires intensive resuscitation. The patient usually can be stabilized medically, but a serious complication of disseminated intravascular coagulopathy (DIC) can lead to ischemic lesions often with necrosis and on occasion full gangrene of the extremities. Once the initial and intermediate symptoms are stabilized, there is frequently evidence that a growth disturbance of the physes of several lower extremity bones has occurred secondary to emboli of the epiphyseal vessels directly linked to the DIC state. Formal recognition of the late sequelae of meningococcemia on physeal growth has occurred only within the past 20 years, with two early papers documenting the phenomenon. Fernandez et al. (160) reported on three patients developing epiphyseal-metaphyseal abnormalities limited to the lower extremities in multiple joints, whereas Patriquin et al. (374) described growth-related physeal changes in four children in whom the development of such lesions had been clinically unsuspected at the time of disease occurrence. Several years after the septicemic event, premature fusion of part

SECTION V! ~ Lower Extremity Length Discrepancies in Specific Disease Entities

F I G U R E 11 Radiograph of bone bridge formation following meningococcemia of infancy. X ray at 7 years of age shows the central bone bridge clearly (arrow).

of several physes with subsequent shortening and angular deformity was noted. Patriquin et al. commented on the frequency of central physeal fusions resulting in a cone-shaped epiphysis. Robinow et al. (411) also reported partial destruction of the right humeral and right femoral head and physeal regions in a 30-month-old girl 2 years after recovery from meningococcal septicemia and DIC. There also were symmetrical epiphyseal-metaphyseal lesions of the lower femoral and upper and lower tibial physes. The disorder was characterized radiographically by progressive narrowing of the physis, which could be either uniform across the entire extent or focal, and many of the focal deformities tended to be centrally situated (Fig. 11). A report from the University Hospital of Geneva, Switzerland, assessed 46 patients with meningococcemia with an average age of occurrence at 4.5 years (514). Twenty-six of the patients required immediate resuscitation in the intensive care unit and 15 of these subsequently died. Most of the survivors had serious complications involving cutaneous necrosis and 4 instances of gangrene of the upper and lower extremities. Two suffered serious bone growth disturbance due to partial or complete ischemic destruction of the physis with DIC. The negative growth sequelae usually do not become manifest for 1-2 years postinfection. They involve shortening of the affected limb and frequently angulation due to asymmetric involvement. Radiographs will show generalized narrowing of the physis in the more severe instances, although often a transphyseal bone bridge forms with the rest of the physis continuing its growth. O'Sullivan and Fogarty (360) reported two distal tibial physeal arrests as complications of meningococcal septicemia, which occurred initially in a boy 2 years 6 months and in an 18-month-old boy. The first patient returned at 8.5 years of age with a short leg and deformed ankle, whereas a diagnosis of growth abnormality was made 1 year postinfection in the 18-month-old boy. The fibula was unaffected.

635

Barre et al. (37) documented epiphyseal and physeal abnormalities following meningococcal sepsis and disseminated intravascular coagulation, They also reviewed papers from the literature comprising nine patients:, In each instance there was no evidence of bone or joint sepsis during the period of hospitalization and the acute phase of the disorder. The changes became evident relatively late, anywhere from 4 months to 6 years after the septic episode. In these four studies the patients were young, averaging a mean age of 14 months with a range from 2 weeks to 48 months, and had meningococcemia, with or without meningitis, complicated by septic shock and DIC. The skeletal abnormalities were of the epiphyses and physes and involved angular deformities and lower extremity length discrepancies. Involvement of the upper extremities was rare. The late radiographic changes either appeared as destructive of the secondary ossification centers reminiscent of avascular necrosis or involved epiphyseal-metaphyseal defects, by which is meant narrowing of the physis usually in an asymmetric fashion or with premature central physeal closure that produced cupping or peaking of the metaphyseal regions and often transphyseal bone bridge formation. Involvement has been reported at the proximal capital femoral growth plate epiphysis, leading to a coxa vara deformity, the distal femoral epiphysis at which central involvement often leads to the inverted V appearance, the proximal tibial physis at which central involvement again was relatively common, and the distal tibial epiphyses at which asymmetric involvement frequently led to varus or valgus deformation. In those instances in which the lesions were bilateral, the length discrepancy either was not present or was minor. Due to the age of the patients at the time of infection, major discrepancies have been reported particularly when involvement is at the knee and is associated with a bone bridge, which often can extend to involve almost the entire physis.

L. Physeal Damage Following Irradiation for Childhood Tumors Limb length inequality remains a fairly frequent occurrence following radiation therapy in childhood for malignant tumors of the lower extremities and also for those of the kidney, abdomen, and pelvis. Robertson et al. (410) documented lower extremity length discrepancy in 12 of 67 patients treated in childhood by radiation therapy in the previously mentioned regions. The use of high dosage and early age of treatment correlate with the severity of the growth complications. The more common tumors in the group of patients were Wilms' tumor, acute lymphocytic leukemia, non-Hodgkin's lymphoma, Ewing's sarcoma, Hodgkin's lymphoma, and rhabdomyosarcoma. No lower extremity length discrepancies were noted in any child who had symmetric radiation to the abdomen or pelvis. If the primary tumor was in tibia or femur, limb length inequality developed frequently. It also developed where there were asymmetric irradiation fields to

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CHAPTER 8

9

Lower Extremity Length Discrepancies

the abdomen, kidneys, or pelvis. Limbs were equal when the radiation dose was less than 2400 cGy, whereas length discrepancy was quite common in those for whom the mean level was between 4000 and 5000 cGy. The development of lower extremity length inequality was uniformly related to long bone physeal irradiation of 4500 cGy or greater. Of the 12 children who developed lower extremity length discrepancies as assessed at skeletal maturity, 5 had length discrepancies of 2 cm or less and 7 of the patients developed length discrepancies ranging from 2.5 to 9.0 cm. Katzman et al. (263) pointed to the many skeletal abnormalities in patients undergoing radiation therapy in the childhood years. They assessed material from 19 survivors of 51 patients with Wilms' tumor and 13 survivors of 46 patients with neuroblastoma treated partially or completely with radiation. Epiphyseal damage was common. Although limb length discrepancy and long bone deformity were noted, no detailed analysis of these particular parameters was performed. Lewis et al. (299) studied longer term morbidity in 55 patients with Ewing's sarcoma who survived 2 years or longer. Unfortunately, the dose level required to treat the tumor effectively with a minimal likelihood of recurrence is very close to the dose level that severely damages or destroys physeal cartilage. The length discrepancy also is dependent on the age of treatment and the region affected. In those patients who received less than 5000 rad, 18% or 64% had minimum or moderate morbidity. A dose of 5000 rad was insufficient to ablate reliably a primary tumor, with many at that level showing recurrence. The intermediate dosage level of 5000-6500 rad was most effective in terms of tumor ablation, although at the higher levels the skeletal morbidity was proportionately increased. All patients had some degree of morbidity. Those defined as having minimal problems had less than 4 cm of shortening along with joint flexion deformities and muscle atrophy and fibrosis, causing only minor limitation of activities. In the moderate group shortening was defined as from 4 to 8 cm. In the severe group, gross shortening was present that could not be compensated for by epiphyseal arrest of the opposite extremity. Dawson (135) described the orthopedic problems with skeletal radiation for various lesions in 35 children. Anisomelia or lower extremity length shortening was present in 8 of 9 receiving abdominal, 1 of 2 receiving pelvic, and 6 of 7 receiving lower extremity irradiation. There is an extremely long history of awareness of the negative effects of radiation therapy on epiphyseal function dating back to the work of Perthes (384) in 1903.

M. Fractured Femoral Diaphysis The stimulation of femoral growth after a diaphyseal fracture in children who are 2-11 years old has been well-documented. It is an obligate phenomenon and occurs regardless of whether a fracture has healed with an overlap, end to end, or in a lengthened position or whether it occurred in the proximal, middle, or distal one-third of the femur. The average

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F I G U R E 12 Type III in the developmental pattern classification is shown in this example of length discrepancy following a fractured femur and healing associated with overgrowth. [Reprinted from (432), with permission.]

femoral overgrowth from the time of fracture healing in our series was 0.92 cm (range = 0.4-1.8 cm) (431). Ipsilateral tibial overgrowth, averaging 0.3 cm, occurred in 82% of the patients. Seventy-eight percent of the overgrowth had occurred by 18 months after injury. In 85% of the patients, the overgrowth had terminated at an average of 3 years 6 months after fracture. The overgrowth phenomenon manifested itself as the type III slope-plateau pattern in 108 (93%) of the patients, with the limb length discrepancy remaining unchanged throughout the remainder of growth (Fig. 12). If a fracture heals at length or with lengthening, the overgrowth produces an upward slope-plateau pattern. If a fracture heals with shortening, the overgrowth leads to a downward slopeplateau representation. A type II pattern occurred in eight patients whose fractures had healed with excessive angulation. In these, continuing overgrowth presumably occurred due to the prolonged remodeling process. The methods of treatment and the angular deformities were reported earlier by Griffin et al. (201). Martin-Ferrero and Sanchez-Martin (319) studied femoral overgrowth in 71 patients under the age of 14 years. Each had an isolated unilateral femoral shaft fracture. Femoral overgrowth averaged 0.86 cm (range = 0.1-2.1 cm). They felt that the greatest amount of overgrowth occurred in those between 3 and 9 years of age who had had the most severely displaced fractures. Ipsilateral tibial overgrowth occurred in 60% and averaged 0.1 cm. Most of the overgrowth occurred during the first year after fracture, but it continued to a lesser extent during the second year and for as long as the fifth year postinjury in 27%. After this time the growth rate of both femurs was equal in all. These values were remarkably similar to those from the Children's Hospital, Boston, study. All patients had been treated in various forms of traction except for a hip spica cast, which was applied immediately after fracture in 7%. Reynolds (401) specifically studied growth rate changes after fractures of the shaft of the femur and tibia in children using serial radiographic measurements of length accurate to the nearest millimeter. The increased growth rate postinjury was greatest within 3 months of injury and was 38% in excess of normal with both femoral and tibial fractures. The rate then decreased but remained significantly raised for 2 years, returning to normal in the tibia approximately

SECTION VI ~ Lower Extremity Length Discrepancies in Specific Disease Entities

40 months after injury and in the femur between 50 and 60 months after injury. In unilateral femoral fractures, the uninjured tibia in the same limb also underwent an acceleration of growth but to a much lesser degree. An uninjured femur was not particularly affected by fracture of the ipsilateral tibia. Reynolds concluded that the acceleration in growth of the fractured bones reached a maximum between 3 and 6 months after injury, with subsequent acceleration decreasing and the growth rate returning to normal between 3 and 5 years after injury. Stated another way, he felt that significant measurable overgrowth ceased within 2 years after fracture of the femur and within 1.5 years after fracture of the tibia. The observations of greatest value were on 55 children with tibial fractures and 32 with femoral fractures followed for between 2 and 5 years. The average increase in femoral length was 0.7-0.8 cm (range = 0.1-1.7 cm), and every femur exhibited some increase in the growth rate. The average increase in the tibia was 0.3-0.4 cm (this for actual tibial fractures) with a maximum of 1.1 cm. Overgrowth occurred in all except 3. Stephens et al. (463) studied leg length discrepancy after femoral shaft fractures in children and assessed 30 skeletally mature patients. Only isolated closed femoral shaft fractures without other injury to the limbs were assessed. All patients were treated conservatively in skeletal traction. When the fracture occurred between the ages of 7 and 13 years, the limb overgrew by about 1 cm regardless of sex, age, fracture site, or configuration. Stephens et al. recommended that treatment aim for 1 cm of overlap at union to compensate for the postfracture overgrowth phenomenon. Treatment was by either skeletal or skin traction for an average of 6 weeks followed by a spica plaster or cast brace. The average tibia overgrowth was 0.18 cm. After fracture at 7-13 years of age, limb overgrowth averaged 1.1 cm (range = 0-2.4 cm). Because tibial overgrowth accounted for only 20% of the total, the average femoral overgrowth was 0.92 cm. A more detailed review of the Children's Hospital, Boston, study is presented (431) next. Level of Fracture: In the entire group of 116 patients, 63% of the fractures occurred in the middle one-third of the femur, 28% in the proximal one-third, and 9% in the distal one-third. In the 74 patients studied in greater detail, a similar distribution was seen with 66% in the middle one-third, 27% in the proximal one-third, and 7% in the distal onethird. The site of fracture was similar regardless of age or sex. Extent of Femoral Overgrowth: In the 74 patients with initial radiographs within 3 months of fracture, overgrowth of the fractured femur occurred universally. The average femoral overgrowth in all cases from the time of healing onward was 0.92 cm. The extent of overgrowth was not dependent on sex, age at the time of fracture, the position of healing, or the level of fracture. Temporal Aspects of the Overgrowth Phenomenon: Two patterns of overgrowth were seen. In the more common pattern, overgrowth continued after fracture healing for a limited time period and then ceased with no change in dis-

637

crepancy throughout the remainder of skeletal growth. This is referred to as the plateau pattern or plateau phenomenon. Much less frequently, overgrowth continued until skeletal maturity although at a much slower rate after the first 18 months following fracture. In the group of 74 patients with early and continuing documentation of lengths, 92% (67/74) showed temporally limited overgrowth (plateau pattern) whereas 9% (7/74) continued overgrowth with time. In the entire group of 116 patients, 93% (108/116) demonstrated the plateau phenomenon whereas 7% (8/116) persisted in overgrowth. In the 74 completely studied patients, 64% of the documented femoral overgrowth occurred within 9 months of healing (1 year postfracture). By 1 year 6 months postfracture overgrowth was complete in only 12%, by 2 years it was complete in 45%, by 2 years 6 months it was complete in 45%, by 3 years in 77%, by 3 years 6 months in 85%, and by 5 years 9 months in 91%. Premature epiphyseal closure on the fractured side with a late change in discrepancy did not occur. Tibial Overgrowth: The tibia on the side of the fractured femur increased in length from the time of femoral fracture healing, such that at skeletal maturity 82% of patients had slightly longer ipsilateral tibias. In 13% tibial length was equal, and in only 5% was the tibia longer on the contralateral, nonfractured side. The average tibial discrepancy was 0.29 cm longer on the ipsilateral side (range = 0.1-0.5 cm). Epiphyseal Arrest: In the group of 116 patients, 28 underwent epiphyseal arrest. The average preoperative discrepancy was 2.39 cm (range = 1.7-3.4 cm). The discrepancies occurred as a combined result of overgrowth and healing in an anatomical or slightly distracted position. The average discrepancy post-epiphyseal arrest at skeletal maturation was 0.66 cm (range = 0-1.5 cm), with 86% of those operated showing a discrepancy of less than 1.0 cm. Five of the 28 patients requiting epiphyseal arrest had continued to increase their discrepancy with time due to continuing stimulation on the fractured side. The 74 completely documented patients with fractured femurs were studied prospectively solely on the basis of femoral shaft fracture rather than on the basis of other clinical criteria. Overgrowth was a universal phenomenon occurring in each of the 74 patients. This finding is similar to those who studied large numbers of patients by radiologic measurements: Hedberg (224), who demonstrated overgrowth in 86% (38/44); Aitken (10), who documented overgrowth in all fractured femur patients but one (64/65); and Viljanto et al. (487), who documented overgrowth in 50 out of 51 patients over 2 years of age. The average documented femoral overgrowth in our series was 0.92 cm, which compares well with others: Viljanto et al. (487), 1.07 cm; Aitken (10), 1 cm from position on discharge; Hedberg (224), 0.9 cm; MartinFerrero and Sanchez-Martin (319), 0.86 cm; Reynolds (401), 0.7-0.8 cm; and Stephens et al. (463), 0.92 cm. The same average amount of overgrowth occurred regardless of the age at fracture when the patient group was divided into the age brackets 2-4, 5-7, and 8-12 years. Hedberg (224) and

638

CHAPTER 8 9 Lower Extremity Len9th Discrepancies

Staheli (455) noted slightly greater overgrowth in those 4-8 years of age and 2-8 years of age, respectively, but Viljanto et al. (487) found no statistically significant difference in average overgrowth in those less than 3 years old, 3-9 years old, and more than 9 years old. Overgrowth also occurred regardless of whether the fracture had been allowed to heal in a shortened position, at length, or in a lengthened distracted position. This is an important finding regarding the cause of overgrowth and is in agreement with Staheli (455) and Viljanto et al. (487). Overgrowth did not appear to be influenced by whether the fracture was in the proximal, middle, or distal one-third. Because of the large size of this series and the accurate method of assessment using frequent orthoroentgenograms, these data appear to reflect the actual situation more closely than studies that rely on clinical measurements or less accurate radiologic measurements. Truesdell (480), in one of the earliest documentations of the overgrowth phenomenon, noted that overgrowth occurred whether the fracture was in the upper, middle, or lower one-third of the femur. Similar overgrowth regardless of level disagrees somewhat with the opinion of Staheli (455), who felt that proximal fractures demonstrated more overgrowth, but is consistent with the work of Viljanto et al. (487). The overgrowth phenomenon was appreciated well over a century ago by Oilier (354) and received ample documentation early in this century (78, 117, 134). Increased blood supply to the healing bone was felt by Oilier (354), Levander (298), and Bisgard (49) to be the primary cause of the overgrowth. Although there was early disagreement as to the cause of the phenomenon, with some attributing it either to "young bone yielding to pull" as the shortening corrected itself (117) or to a law of compensatory overgrowth (134), most investigators now feel that the overgrowth is a physiologic process (55) associated with the increased vascularity of the involved bone due to healing and remodeling. The increased vascularity extends to the epiphyseal plate regions where the overgrowth stimulus occurs. This now appears to be amply confirmed especially with the demonstration that overgrowth occurs regardless of the position of fracture healing and that it occurs in all patients, thus indicating that it is an obligatory phenomenon rather than one called into play only to compensate for shortening. In addition, it has been demonstrated to occur with humeral (225) and tibial (198) fractures. Kellernova et al. (268) demonstrated increased vascularity to the entire limb following experimental tibial fracture. The tibial overgrowth documented here also provides evidence for a total limb response. Increased length of the ipsilateral tibia averaging 3 mm in 82% of the patients with only 5% showing a longer contralateral tibia is taken as presumptive evidence of overgrowth in association with femoral fracture. Such tibial overgrowth also was documented by Stephens et al. (463) at 0.18 cm and by MartinFerrero and Sanchez-Martin (319) at 0.1 cm. The frequent length assessments and the accuracy of the orthoroentgenographic method have allowed for more de-

tailed study of the temporal aspect of overgrowth than has previously been reported. The impression that most of the overgrowth occurs within the first year of fracture and that it is virtually complete by 18 months (78, 134, 55) is valid, but it is demonstrated that the overgrowth phenomenon can persist for 3 or 4 years and, more importantly, that in from 7 to 9% of patients it continues for the remaining period of skeletal growth. Prolongation of overgrowth beyond 18 months or 2 years has been alluded to by Hedstrom (225) and Viljanto et al. (487) on the basis of remodeling, which can continue for that period of time. These two findings are important in following children with femoral fractures especially if they have been allowed to heal at length or with some distraction. In the eight patients whose overgrowth continued, assessment following fracture demonstrated overgrowth averaging 1.98 cm in contrast to the entire group, which averaged 0.92 cm. The overgrowth 18 months following fracture was only 39%, in comparison to the overall group where 78% of overgrowth had occurred by that time. Overgrowth was continuing 8 years postfracture in these patients. Five of the eight had a discrepancy sufficiently large to require epiphyseal arrest. In four of the eight patients no unusual factor could be identified that might have contributed to the continuing overgrowth, but in four of the patients hyperemic stimuli may well have persisted due to excessive angulation, which prolonged the remodeling phase, and to myositis ossificans, which also is associated with an increased blood supply. During the early weeks of fracture healing there is slight motion at the fracture site, and it is neither feasible nor necessary to perform accurate orthoroentgenographic length measurements. One virtually never has accurate radiographic documentation of the lengths prior to fracture: Barford and Christensen (33) in a clinical study of 431 normal children found 8% with unequal length of the lower limbs, although only 0.7% had a 1 cm or more difference. These limitations in all clinical studies have been discussed in detail (225). Both Hedstrom (225) and Bisgard (49) attempted to assess overgrowth from the time of fracture in experimental animals. It is unknown, however, whether the vascular response begins simultaneously throughout the whole extent of the femur or whether it spreads from the fracture site toward the epiphyses. If the former mechanism occurs, then overgrowth probably would be somewhat greater as it would begin earlier; if the latter, overgrowth may well represent primarily a postconsolidation repair and remodeling phenomenon. It is our feeling that the latter is the case and that radiologic measurements begun at the time of healing reflect the total overgrowth accurately. It has been suggested that overgrowth either will not be noted or will be markedly diminished in those with childhood femoral shaft fractures who are treated with external fixation devices. The matter is of some importance because it will define the mode of reduction. If the increased stability leads to more rapid healing and anatomic reduction favors less need for remodeling, then stabilization at full length

SECTION VI 9 Lower ExtremiW Length Discrepancies in Specific Disease Entities

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(A) Developmental pattern type I in patient with hematrophy. (B) Type V discrepancy pattern in juvenile rheumatoid arthritis. The initial stimulation led to a discrepancy with ipsilateral overgrowth, which then reached a plateau, and eventually selfcorrection with premature fusion due to the continuation of the synovitis. [Reprinted from (432), with permission.]

with anatomic reduction would be needed. If overgrowth occurs because of the fracture itself, then anatomic reduction and either internal or external fixation would still lead to overgrowth. Until such a time as detailed study of a large number of cases is complete, external fixation with the 1-cm overlap should still allow healing, and remodeling of the bayonet opposition should favor the overgrowth phenomenon. Viljanto et aL (488) reported on growth responses following operative treatment of femoral shaft fractures in children. During a 10-year period from 1957 to 1966, they treated 35 femoral shaft fractures (18% of their patient population) by operative means and assessed 19 of these patients at skeletal maturity. The average age of the group at the time of fracture was 9.8 years compared with 7.2 years in the group treated conservatively. The age range at fracture in the 19 patients undergoing assessment was from 2.6 to 16 years. Sixteen of the 19 patients demonstrated femoral overgrowth. One patient with a comminuted fracture lost 7 mm of length. The overgrowth phenomenon was demonstrated, however, even in those having surgical correction. The mean longitudinal overgrowth of the fractured femur treated by operation was 9.8 mm, with a wide range from 0 to 30 mm. The corresponding group of 52 patients treated by traction and casting had an overgrowth of 10.7 mm. Slightly less overgrowth was seen in those treated with intramedullary nailing with the overgrowth value registering 7.2 mm, whereas those treated with other means of osteosynthesis had a 13.5-mm overgrowth. In the 19 patients assessed, intramedullary nailing with the Kuntscher nail was done in 7, intramedullary Rush pins in 4, cerclage wiring in 3, screw fixation in 2, plate fixation in 2, and open reduction in 1.

N. Fractured Tibial Diaphysis Tibial overgrowth following tibial fracture has been reported to be most marked in patients who are less than 9 years old. In an isolated tibial fracture, overgrowth rarely is severe enough to require continuing long-term length assessment, but it can be troublesome when there is an ipsilateral femoral fracture.

O. Hemihypertrophy and Hemiatrophy (Anisomelia) This group of patients was discussed together in our study even though two different diagnoses, hemihypertrophy and hemiatrophy, were made (433). As the study reviewed the cases of patients who were assessed over a 40-year period, it was frequently not clear what criteria were used to include a patient under each particular designation, but the diagnosis of hemihypertrophy does not include patients who were noted to have hemangiomas, lymphangiomas, lipomatosis, or neurofibromatosis (who were assessed separately). At present the term hemiatrophy is applied to patients in whom both limbs individually appear to be normal, with the short limb diagnosed as being hemiatrophic. The developmental patterns in both groups were similar, however, and for the purposes of this classification the entity is referred to as anisomelia (Fig. 13A). The term anisomelia, which means a condition of inequality between two paired limbs, is quite obviously nonspecific and is infrequently used today as a diagnostic term. Most of these patients (57%) demonstrated a type I pattern, with the remainder equally divided between types II and III. The average maximum discrepancy in these

640

CHAPTER 8 ~ Lower Extremity Length Discrepancies

113 patients was 3.16 cm (range = 1.5-6.90 cm). Beals (40) mentions 2 patients with hemihypertrophy who experienced spontaneous correction of limb length inequality in early childhood, with the maximum discrepancies radiographically documented at 1.4 and 1.0 cm prior to 4 years of age with no discrepancy at 6 years of age. We did not note this pattem in our patient group in which inclusion required at least a 1.5-cm discrepancy at some time. Pappas and Nehme (369) also reported on lower extremity length discrepancies associated with hypertrophy in a separate study of patients from the Children's Hospital, Boston, Growth Study Unit. Many of these patients would have been included in the developmental pattern paper (433), so it is not surprising that the results were similar. Pappas and Nehme divided their assessments into patients with idiopathic hypertrophy and those with vascular disease, neurofibroma, and lymphangioma. Graphs showing the progression of length discrepancies with age showed a distribution with what we referred to subsequently as type I, type II, and type III patterns. In 35 patients with idiopathic hypertrophy, the lower extremity length discrepancy immediately prior to epiphyseal arrest averaged 3.6 cm. In those with vascular disease the mean discrepancy in 18 patients preoperatively was 3.3 cm. The mean discrepancies in the neurofibromatosis group were somewhat larger, reaching a mean of 5.3 cm preoperatively. Many patients with the neurofibromatosis disorder, however, had either no hypertrophy or clinically insignificant hypertrophy. In 90 patients followed to the time of epiphyseal arrest, the average preoperative discrepancy was 3.4 cm. In each of the four groups mean values indicated that there almost always was both femoral and tibial lengthening but that tibial lengthening was greater than femoral in each of the subgroups, usually by a 2:1 margin. Hemihypertrophy is rarely a simple increase in the lengths of the femur and tibia on the involved side. Some or many mesodermal abnormalities almost always are associated, many in particular with vascular anomalies, and there also is a high incidence of neuroectodermal abnormalities. Bryan et al. (77) studied the orthopedic aspects of congenital hypertrophy, documenting 27 cases of congenital hemihypertrophy in which the entire side of the body was affected or there was segmental hypertrophy in which only one particular extremity was markedly affected compared to the contralateral side. The maximal lower extremity length discrepancies were measured. The ranges of length discrepancy involvement seemed to be comparable in the hemihypertrophy and segmental hypertrophy cases. In 22 patients in whom discrepancy data were listed the range varied from 0.9 to 6.4 cm. Although the large majority of the patients had reached skeletal maturity, a few still had several years of growth remaining. The mean discrepancy in patients 12 years of age or older (13 patients) as measured prior to surgical correction was 3.92 cm. In a brief review of hemihypertrophy, MacEwen and Case (306) reviewed 32 cases, noting a limb length discrepancy in

26. Of these they felt that 65% had, or would develop, a discrepancy great enough to require epiphyseal arrest. In 6 patients who had already been treated with epiphyseal arrest, the mean discrepancy was 3.3 cm. In reality there is a very large subset of patients with hemihypertrophy, primarily associated with a wide range of vascular and other connective tissue abnormalities. An effort is made to delineate these in the next few sections. 1. INITIAL DELINEATION OF THE HEMIHYPERTROPHY SYNDROMEmTRELAT AND MONOD

Initial delineation of the hemihypertrophy syndrome occurred in an 1869 monograph by Trelat and Monod (478). Their work reviewed the clinical findings of the entity in which they considered previous case reports, including one of their own, in great detail. Their work was titled, "On Unilateral Partial or Total Hypertrophy of the Body," and included use of the term hemihypertrophy to describe the entity. Trelat and Monod indicated that Geoffroy SaintHilaire, in his earlier book on developmental anomalies in humans, had commented on asymmetric development, which often involved only a region or small part of one side in relation to the other. They reviewed in detail case reports beginning from 1836, which led to their presentation of "a general history of this defect of conformation." They delineated it specifically as being a hypertrophy of one side and not an atrophy of the other because atrophic conditions appeared almost always to be associated with neuromuscular abnormalities and a weakened state. The initial clinical reports were accompanied by extremely detailed measurements, and Trelat and Monod were able to indicate that the average discrepancy in hemihypertrophy was between 3 and 5 cm at maturation but that the range was great, extending from 1.5 to 19.0 cm. These numbers are still good approximations. The disorder not only involved increased length but also a proportionate increase in soft tissue size in those areas affected. Trelat and Monod also clearly pointed out the large number of vascular abnormalities present on the hypertrophic side. In virtually all instances the limb itself was the site of abnormality, which in the standing position caused an elevation of the pelvis most obvious as an elevation of the iliac crest on the hypertrophic side; it was not the pelvis or trunk itself that was abnormal, but rather these changes of position were due to the increase in lower extremity length. The truncal abnormalities and pelvic obliquity were not fixed deformations but rather were due to positional effects based on limb length discrepancy in the uptight and walking position. In 11 of the 12 cases the skeleton of the trunk was normal. Almost invariable skin changes occurred on the involved side including discoloration and changes in thickness. In many instances the skin was thickened and elevated by numerous swollen venules. In one of the cases with the largest discrepancy, enormous hypertrophy of the lower extremity (19 cm), congenital lipomas, and true elephantiasis were observed. By review of these many case studies, Trelat

SECTION VI ~ Lower Extremity Length Discrepancies in Specific Disease Entities

and Monod came to define hemihypertrophy as a true congenital malformation. They noted that "vascular dilatations were frequent and encountered in varying degrees in the large majority of instances." There were two types involving skin capillaries in some and presenting with birthmarks (nevi) in others involving lesions of the subcutaneous veins, which often were true varices. The cutaneous and vascular abnormalities were always present on the hypertrophic side, and they themselves were unilateral, exactly limited to the hypertrophic regions. The cutaneous nevi were present from birth. These lesions rarely, if ever, crossed the midline, and the spots, veritable nevi of reddish discoloration, had a variable series of configurations but were always limited to the particular region of the hypertrophy. Varicose veins were often present although somewhat less frequently than the cutaneous vascular changes. These too were limited to the regions of hypertrophy, and it was felt that they were specifically connected with the general hypertrophy. Many observers also noted superficial arteries to be more dilated on the hypertrophic side. In summary, the large number of early observations made did not note any particular changes of the deep arterial circulation but rather frequent modifications of the veins and capillaries of the involved side of a general character of "angiectasies." Trelat and Monod felt that the condition was not hereditary, although they considered that the unilateral hypertrophy or hemihypertrophy was congenital. It progressed after birth and during the entire period of development, leading to the increasing limb length discrepancies. The disorder produced hypertrophy of several tissues, but some of the findings such as the varices were variable. 2. ASSOCIATION OF HEMIHYPERTROPHY WITH NEOPLASIA

There is a small, but well-documented incidence of neoplasia in association with hemihypertrophy. In many instances the hemihypertrophy had been documented well before development of the tumors. The neoplasms tend to be visceral, with involvement of liver, adrenals, and kidneys. An incidence of 2.75% hemihypertrophy was documented in a large series of Wilms' patients. Other associated tumors include adrenal carcinoma, carcinoma of the liver, pheochromocytoma, retroperitoneal sarcoma, testicular carcinoma, and cerebellar hemangioblastoma. Thus, it is evident that any patient being followed with hemihypertrophy must be assessed periodically for visceral neoplasms. No specific standard of evaluation has evolved, but renal ultrasound is an easy and relatively effective way of screening for renal Wilms' tumor and other abdominal and retroperitoneal lesions. 3. ASSOCIATION OF HEMIHYPERTROPHY WITH SILVER-RUSsELL SYNDROME

Both Silver (444, 445) and Russell (417) described a syndrome, which subsequently became well-defined and is currently most often referred to as the Silver-Russell syndrome. It was described by Silver as congenital hemihypertrophy,

641

shortness of stature, and elevated urinary gonadotropins. Russell commented on the syndrome as involving intrauterine dwarfism recognizable at birth, with craniofacial dysostosis, disproportionately short arms, and other abnormalities. With further study, manifestations of the syndrome came to involve the following: significant asymmetry; shortness of stature present at birth even though the child was born at term; variations in the pattems of sexual development, which involved elevated urinary gonadotropins, early sexual development, or markedly retarded skeletal age in relation to sexual development; unusually short fifth fingers often with increased curvature; a triangular shape to the face; and occasional cafe au lait areas of the skin. A detailed natural history study of the Silver-Russell syndrome by Tanner et al. (470) showed height at referral (4.6 years mean) averaging 3.6 standard deviations (SD) below the mean, with that level persisting throughout growth. The height at a mean age of 13 years was 3.4 SD below the mean. The predicted adult height in males was 153.5 cm and in girls was 147.0 cm. Tanner et al. felt that the limb asymmetry was a hemihypertrophy of the longer side rather than an atrophy of the shorter. The asymmetry was relatively mild, being less than 1.0 cm, which they felt was a normal variation, in 31 of 36 patients. When hemihypertrophy was present, the discrepancies in children with some growth remaining were 1.0, 1.17, 1.25, 3.33, and 6.12 cm. Specht and Hazelrig (451) reviewed the lower extremity length discrepancies in Silver syndrome in detail including 4 of their own cases and 47 from the world literature. The 51 cases gave a good overview of the length discrepancy involvement. The asymmetry was noted either at birth or during the first year of life in 29 of 40 instances where data were available. Specht and Hazelrig felt that the length difference increased in proportion to the child's skeletal growth. The length discrepancy varied from 0.5 to 6 cm, although the length data included relatively few who had reached the age of skeletal maturity. There was no sex preference for the disorder. In 4 patients who had reached skeletal maturity, each had a significant discrepancy from 4 to 6 cm. There were 7 instances in younger children in whom the discrepancy was already in excess of 3 cm. There were 40 patients for whom the length discrepancy was discussed. There appeared to be a continuing increase in the discrepancy with time. If the numbers provided are studied by age groupings, 13 values of lower extremity length discrepancy were listed from birth to 5 years of age, 15 measurements from >5 to 10 years of age, and 12 measurements from > 10 years of age to skeletal maturity. In the youngest group of 13, the mean discrepancy was 1.75 cm with a range from 0 to 5.0 cm. In the next age group the 15 measurements indicated a mean discrepancy of 2.44 cm, with a range from 0 to 4.0 cm. In the oldest age group, the 12 values listed had a mean discrepancy of 3.44 cm with a range from 1.0 to 6.0 cm. The impression is that of a type I pattern with perhaps some showing type II in the later years of growth.

642

CHAPTER 8 9 Lower Extremity Lenfth Discrepancies

Beals (40) describes a patient with Silver-Russell syndrome with a leg length discrepancy of 3.0 cm at 11 years of age. 4. ASSOCIATION OF HEMIHYPERTROPHY WITH ABNORMALITIES OF THE CEREBRAL VASCULATURE

Fischer et al. (162) described two patients with congenital hemihypertrophy and associated vascular abnormalities of the brain on the side of the hypertrophy and in the posterior fossa. The abnormalities included giant aneurysm, capillary hemangioma, and arteriovenous malformation. Literature review indicated only one previous similar patient, a girl who died at the age of 6.5 years with a vascular malformation of the thalamus. The hemihypertrophy in one patient reached 5.0 cm at 11 years of age, at which time an epiphyseal arrest was performed, whereas in the other patient the maximum length discrepancy reached was 1.6 cm at 2.5 years of age, after which the discrepancy diminished by a few millimeters over the next 15 years and surgical correction was not required. The vascular abnormalities were assessed by CT scans, arteriograms, and examination at open neurosurgical intervention in one case. The extent of the hemihypertrophy did not correlate with the presence or extent of associated cerebrovascular malformations. Other neurological abnormalities reported with hemihypertrophy include mental retardation in as many as 20% of patients, ipsilateral loss of sweating, ipsilateral indifference to pain, neurofibromatosis, metachromatic leukodystrophy, ipsilateral ventricular enlargement, and bilateral and ipsilateral enlargement of the cerebral hemispheres. Only one of the previous reports described abnormalities of the cerebral vasculature. 5. ANGIODYSPLASTIC DISORDERS ASSOCIATED WITH LOWER EXTREMITY LENGTH DISCREPANCIES

Many lower extremity length discrepancies are associated with vascular anomalies of the affected limb. This correlation has been known for some time, but in reality there is a vast array of involved vascular disorders with many patterns of irregularity noted at histopathologic examination. In addition, most patients with these disorders do not undergo surgical exploration such that clinical and some imaging criteria alone are used for diagnosis. Many of these disorders are grouped under the term "hemangiomas" in the orthopedic literature, even though, in a histopathological sense, the lesions associated with major length discrepancies are not true hemangiomas. Two patterns of nomenclature have evolved for this group of disorders with only partial correlation between them. The more specific terminology has been utilized by pathologists, cardiovascular surgeons, and plastic surgeons in their dealings with these disorders, whereas orthopedic surgeons and geneticists tend to use broader syndromal descriptions based on the clinical appearance of the limbs and particularly the nature of overgrowth (hemihypertrophy) or less frequently diminished growth (hemiatrophy)

features. Some have used the general term "angiodysplastic disorders" to refer to this broad array of conditions. The two-part article by Malan and Puglionisis (310, 311) in 1964 remains one of the clearest and most detailed correlations of the clinical symptoms, anatomic findings, and histopathologic descriptions of the wide array of congenital angiodysplasias. Mulliken and associates (343, 344) have attempted clarification by introducing a biological classification of cutaneous vascular anomalies incorporating cellular features, physical findings, and the natural history of the various disorders. The two major categories of cutaneous vascular anomalies are hemangioma, a lesion demonstrating endothelial hyperplasia, and malformation, a lesion with normal endothelial turnover. The use of the term hemangioma should be restricted to a lesion of vascular origin that grows by cellular proliferation. It is the most common tumor of infancy and demonstrates spontaneous regression. Malformations result from errors of vascular morphogenesis and are subdivided into slow-flow and fast-flow lesions. The slowflow lesions encompass capillary malformations, lymphatic malformations, and venous malformations, while fast-flow lesions involve arterial malformations, arteriovenous fistulae, and arteriovenous malformations. Combined vascular malformations are seen frequently involving capillary-lymphatic, capillary-venous, lymphatic-venous, and arteriovenous lesions. By using this classification approach, it became apparent that the vast majority of skeletal changes were associated with vascular malformations. The term hemangioma was restricted to common childhood tumors distinguished by rapid postnatal growth but followed by slow involution. When skeletal abnormalities were assessed in relation to the hemangioma-malformation categorization, it was noted that of 356 hemangiomas only 3 (1%) had bone changes, whereas 224 vascular malformations demonstrated bone changes in 77 (34%) (67). Of the 77 patients with vascular malformations, 27 were in the head and neck region and 50 were in the extremities. In the extremity group, lymphatic malformations were frequently associated with hypertrophy and on occasion with distortion of the shape of the bone. The extremity venous malformations, however, were frequently associated with hypoplasia and demineralization. When the vessel malformations were of the combined type, then both shape distortion and hypertrophy as well as hypoplasia and demineralization were found. High-flow malformations tended to produce hypertrophy and shape distortion of the bones in the terminology used by Mulliken and Glowacki. Parkes Weber syndrome is an extremity arterial malformation with arteriovenous fistulae and skeletal hypertrophy, and KlippelTrenaunay syndrome is a combined lymphatic-venous malformation with cutaneous portwine stain, with or without associated bone hypertrophy or hypoplasia. This group indicated that skeletal alterations commonly were associated with vascular malformations and rarely seen with heman-

SECTION VI ~ Lower Extremity Length Discrepancies in Specific Disease Entities

giomas. For each type of vascular malformation there might be characteristic skeletal changes, although further study would be needed in that regard. Hypoplasia, for example, was characteristic of venous or combined extremity malformations and demineralization was another common finding in venous malformations, whereas intraosseous and lytic changes were characteristically seen with high-flow lesions. Many of the complex vascular abnormalities are associated with a spectrum of disordered neuroectodermal and mesodermal elements, often with skeletal overgrowth. 6. HEMANGIOMAS" OLDER GENERALIZED "ORTHOPEDIC" TERMINOLOGY As used for a diagnostic category in our paper on developmental patterns, "hemangioma" encompassed a wide histopathological variety of vascular anomalies, including capillary hemangioma (portwine stain), cavernous hemangioma, arteriovenous aneurysms and fistulae, congenital varicosities, and mixed lymphangioma-hemangioma lesions. The term "hemangioma" has been used by the orthopedic surgeons over a period of several decades in a genetic sense, that is, to refer to any type of vascular anomaly. Ipsilateral overgrowth occurred in 29 (83%) of 35 patients, whereas in the remainder the limb was shorter on the ipsilateral side (433). Nine (31%) of the 29 patients who showed overgrowth had the type I pattern, the remainder being type II or type III. Involution is a well-known occurrence in some types of hemangiomas and may account for slowing of growth stimulation. Although there were some well-documented instances in our series when partial resection of the soft tissue lesions also diminished the growth stimulation, most patients demonstrated a type II or type III pattern in the absence of any surgery. The average discrepancy prior to bone surgery in this group of patients was 3.09 cm (range = 1.8-5.60 cm). The developmental pattern in this group must be observed carefully in the middle years of the first decade of life, as considerable discrepancy may develop and projections that are based on the expectation of the same rate of growth stimulation can be misleading. In a study of hemangioma of the extremities in 35 cases in which a broad array of histopathologic diagnoses were included, McNeill and Ray (323) noted 16 limbs with equal lengths, 8 with overgrowth on the involved side, and 11 with shortening or atrophy on the involved side. It appears from the work that overgrowth, when present, was far more extensive than shortening because no indication of the amount of shortening, other than its presence, was made. In those with overgrowth, when amounts were listed, the extent ranged from 1 to 8.75 cm. A generalized overview was provided by Maroteaux (316). a. Newer Terminology. If the more specific terminology of Mulliken and Glowacki (344) is used, a different pattern of length discrepancy involvement occurs. Due to the fact that the vast majority of hemangiomas undergo spontaneous

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regression, axial skeletal overgrowth is almost never seen in conjunction with these lesions. Most hemangiomas first appear in the early neonatal period and 80% grow as a single lesion with the rest as multiple lesions. They are far more common in females with a 3-5:1 female:male ratio. Once established, there is rapid neonatal growth during the first 6 - 8 months of life with a plateau in size being reached at 1 year, following which the lesions grow proportionately with the child with regression then beginning around 5 years and continuing until approximately 10 years of age. As the tumor proliferates in the superficial dermis, the skin becomes raised and develops a vivid crimson color. If it is deeper in the dermis and into the subcutaneous layer, the overlying lends a bluish color to it. Its contained blood cannot be evacuated completely by manual pressure. Hemangiomas can be divided into a proliferating phase, during which they enlarge, and the subsequent involuting phase. Histologically there is endothelial cell proliferation. Active pericytes are often seen as well. As the tumor regresses endothelial cell activity also diminishes. Mast cells make their appearance during the involuting phase. 7. HEMANGIOMAS OF BONE Hemangiomas of bone do occur but are extremely rare. In addition, when present they almost invariably affect either the vertebral bodies or the skull. In those infrequent instances when they affect the long bones, they tend to be innocuous in terms of clinical significance. Cohen and Cashman (115), however, have reported one instance in which hemihypertrophy of a lower extremity was associated with multifocal intraosseus hemangioma. In one patient the described involvement of both the right femur and right tibia led to overgrowth on the right side, but this was due to a combination of the right tibia being 2.9 cm longer at 12 years of age while the femur was 1.1 cm shorter. The hemangioma was present in both epiphyseal and metaphyseal bone, but the intervening growth plate was structurally normal. The authors noted that, in the few previous cases of long bone hemangioma described, no growth changes were reported. 8. VASCULAR MALFORMATIONS Vascular malformations are all present at birth but on occasion may not be obvious. Venous malformations in particular may manifest later during childhood. Males and females are affected equally. Vascular malformations tend to grow proportionately with the child. Each structural category of vascular malformation has a typical cutaneous appearance. Each of the four major categories of vascular malformation has its particular histopathological appearance, but combined forms (CVM, CLM, LVM) can be difficult to distinguish even histologically. The characteristic histopathologic finding is a lining of endothelial cells without high activity, similar to what is seen in normal vessels. Vessel walls particularly with venous and lymphatic anomalies are of variable

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thickness, and mast cell distribution in vascular malformations is normal. Treatment of the vascular malformations is beyond the scope of this work but has been well-discussed. The malformations are either arterial, venous, capillary, lymphatic, fistulae, or combinations of these. Two characteristic hematologic findings are associated with these disorders. In hemangiomas, platelet trapping, referred to as the Kassabach-Merritt phenomenon, is a rare complication of large hemangiomas and usually occurs in the neonate showing thrombocytopenia, usually less than 10,000 per mm 3. In vascular malformations, a coagulopathy can occur but is usually associated with larger extensive venous anomalies and is a true intravascular coagulative defect. It is the vascular malformations that are associated with the various syndromes leading usually to hemihypertrophy and appendicular skeletal overgrowth. The reasonably well-defined syndromes associated with hemihypertrophy, or infrequently hemiatrophy, are described in the following sections. It is important to recognize that terminology used between different institutions and in different papers, particularly in papers written several decades apart, can vary significantly. Those disorders or syndromes seen frequently with lower extremity length discrepancies include the Klippel-Trenaunay syndrome (KTS), Parkes Weber syndrome, Proteus syndrome, Beckwith-Wiedemann syndrome, congenital arteriovenous fistula, cutis marmorata telangiectatica congenita, and Maffucci disease. Some link the first two syndromes, referring to the Klippel-TrenaunayWeber syndrome. Maffucci disease was discussed earlier in conjunction with Ollier's disease. a. Klippel-Trenaunay Syndrome. This named syndrome derives from an initial description in 1900 by Klippel and Trenaunay (275). It refers to a congenital abnormality consisting of a cutaneous nevus (portwine hemangioma), varicose veins, and bone and soft tissue hypertrophy. It is usually unilateral and affects the lower limb, but occasionally more than one limb is involved. In their initial description, Klippel and Trenaunay stressed that the bones on the hypertrophic side, though larger, maintained a normal anatomic shape and proportion. They called the syndrome and their article, "le noevus variqueaux osteo-hypertrophique." Klippel and Trenaunay noted that there was considerable awareness of the existence of hemihypertrophy, often including skull and facial asymmetry, asymmetric soft tissue development of the extremities, and particularly asymmetric vascular anomalies of the skin and subcutaneous tissues. In describing the syndrome, which subsequently came to bear their names, Klippel and Trenaunay commented on the unique triad of abnormalities involving the nevus, varices, and osteohypertrophic changes. They pointed out that Trelat and Monod (478) as early as 1869 had described a syndrome in which the characteristics were unilateral bony hypertrophy generally involving the lower extremities and frequently accompanied by a vascular dilation, which could be of two types: capillary involving the nevi and subcutaneous venous

involving the varices. In the words of Klippel and Trenaunay, however, "they did not observe the remarkably frequent coexistence of the nevus, the hypertrophy of the skeleton and the venous dilations," feeling that they were secondary occurrences to the primary symptom, which was the hemihypertrophy. Klippel and Trenaunay, on the other hand, insisted "on the simultaneous presence of these three principal signs." They pointed out several examples from the literature of their era of the soft tissue abnormalities associated with hemihypertrophy and referred to previous cases to support their contention that the triad of abnormalities was a unique congenital lesion apparent since birth. They stressed that the nevus and the hypertrophy had existed since birth and that the varices became evident around 8 or 10 years of age. The length discrepancies described in their own cases and in examples of the triad from the literature were extensive; they listed discrepancies in the lower extremities of 4.5, 4, 2, 4, and 9 cm. The triad of disorders present in the same subject were not lesions grouped by accident or coincidence but rather resulted from a single disorder. The hemihypertrophy sometimes involved an entire side, including the face and skull, but was often segmental and occasionally just involved either the hand or the foot and sometimes individual digits. The bone was uniformly increased in size in terms of length, width, and thickness. In spite of this, however, the anatomic shape was normal and there were no angular or other deformations. The hypertrophy was present at birth but progressed and thus worsened with growth. On occasion, the discrepancy increased to 10 cm as noted by Oilier. Due to the limb length discrepancy, secondary deformations of the pelvis and lower spine occurred. The disorder was not particularly rare. Generally it is accepted today that the affected tissues do not contain hemodynamically significant arteriovenous communications, but often there are other soft tissue, lymphatic, and bony abnormalities. It is similar to the Parkes Weber syndrome and many studies link the two therefore describing the Klippel-Trenaunay-Weber syndrome. Baskerville et al. (39) note that the presence of arteriovenous fistulae excludes the diagnosis of Klippel-Trenaunay syndrome and is characteristic of the Parkes Weber syndrome. In their detailed study of 49 KTS patients with 56 abnormal limbs (53 lower extremity and 3 upper extremity) the male:female ratio was 1.3:1 (39). All 49 had visible varicosities, 47 had a nevus, and 47 had limb hypertrophy. In 43 of the patients the abnormality was noted at birth. There was no clinical evidence of an arteriovenous fistula in any of the 49 patients, including 22 who had formal arteriography. In 36 patients the affected limb was longer (greater than 2 cm) and in only 2 was it shorter. The feet were also usually hypertrophic. Varicose veins were visible in all 49 patients. Sixty-eight percent had a large, incompetent vein on the lateral aspect of the limb, which arose on the dorsum of the foot or ankle and extended a variable distance up the leg. Phlebography showed that approximately 50% of the abnormal lateral veins drained

SECTION VI 9 Lower Extremity Length Discrepancies in Specific Disease Entities

into the main stem leg veins, with 33% extending to the buttocks and draining via the gluteal veins into the internal iliac vein. More than one-fourth of the patients had intrapelvic venous abnormalities as well. Other abnormalities included 15% with lymphedema and 22% with cutaneous lymphatic vesicles. Five patients demonstrated gigantism of the toes. A convincing argument is made to separate the Klippel-Trenaunay syndrome in which arteriovenous fistulae are absent and the Parkes Weber syndrome, which is characterized by arteriovenous fistulae (38). It is also evident that appreciable overgrowth of the limb may occur in the absence of arteriovenous fistulae. The difference in lower extremity length discrepancies rarely increased after the age of 12 years, which would imply a type II or type III discrepancy pattern. Absolute numbers for the extent of the discrepancy were not provided, but epiphyseal stapling was performed in only 4 patients (4.5 %). It should be noted, however, that problems with vascularity render length discrepancy management potentially dangerous. Baskerville et al. suggested that KTS was caused by a mesodermal abnormality during fetal development (38). There appears to be no true atresia of the deep veins with abnormalities concentrated in the superficial system. Histologic studies, similar in all patients, showed an increase in the number and diameter of the venules in a cross section of the deeper layers of the dermis and subdermal fat. There was also widespread hypertrophy of the smooth muscle in the walls of the subcutaneous veins due to response to chronically increased flow. There were normal deep veins and normal calf pump function in 60% and 84% of patients, respectively. Both Bourde (64) and Baskerville et al. (38, 39) suggest that KTS is due to persistence of part of the embryological vascular system and that a mesodermal defect acting primarily on angiogenesis could explain the condition. The findings were felt to be consistent with a later regression than normal of the embryonic vascular reticular network in the developing limb bud. This itself would lead to increased capillary and venular blood flow during intrauterine development and to the superficial varicosities. A mesodermal abnormality would also explain the other venous abnormalities with the syndrome involving developmental abnormalities, such as the absence of valves in the deep veins or reduplication of axial veins and a large, often valveless, lateral venous channel. Management was suggested to concentrate on the correction of bony overgrowth, excision of soft tissue hypertrophy, and removal of varicose veins but only in those veins causing pain or discomfort (38, 39, 388). The widespread removal of varicose veins had not proved to be particularly successful. b. Parkes Weber Syndrome. Parkes Weber pointed out the combination of vascularization abnormalities with hemihypertrophy of the limbs. A particular syndrome has come to be associated with his name; it involves the KTS triad of cutaneous nevus (portwine hemangioma), varicose veins, and soft tissue and bone hypertrophy with arteriovenous

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malformations. In his initial presentation in 1907, he drew attention "to a group of cases in which hypertrophy of one limb, or else hemi-hypertrophy, is found to be associated with tumor-like overgrowth in the corresponding portion of the vascular system" (371). Weber felt that the disorder was congenital in most instances. In differentiating a particular syndrome from previously known developmental abnormalities of the vascular and lymphatic systems, he pointed out that the condition under consideration was distinguished by the associated vascular abnormalities and the actual increase in length of the bones of the affected limb. He pointed out that even in the late 1800s there were many cases of hemihypertrophy reported with some form or other of angiomatous formation. It was, however, in Weber's second communication in 1918 that he linked the congenital limb hypertrophy specifically to dilatation of arterial and venous trunks with a specific arteriovenous communication (372). He did this by specifically indicating that "the communication between the arterial channels and the venous channels may be so free that in it a definite kind of thrill or pulsation, rhythmical with the heart's contractions, is transmitted to the veins as in cases of arterio-venous anastomosis of traumatic origin." Weber referred to the condition as "congenital or developmental phlebarteriectasis" or hemangiectatic hypertrophy of limbs. Both of his papers were accompanied by abundant descriptions of vascular anomalies and limb overgrowth from the late eighteenth and early nineteenth centuries from English, French, and German reports. c. Proteus Syndrome. The Proteus syndrome is similar to the Klippel-Trenaunay and Parkes Weber syndromes but is characterized by more frequent progression of hamartomatous growth. It is truly a syndrome in the sense that there are an extremely large number of associated abnormalities. The disorder was first recognized by Cohen and Hayden (116), who differentiated the various symptoms from other overgrowth syndromes. The name Proteus, however, was suggested a few years later in an article by Wiedemann et al. (504), who described 4 patients documenting partial gigantism of the hands or feet, nevi, hemihypertrophy, subcutaneous tumors, macrocephaly or other skull anomalies, accelerated growth, and possible visceral affections. In a later note, yet further developmental abnormalities were described including, but not limited to, progressive kyphoscoliosis, subcutaneous abdominal lipomas, dilated veins and/or hemangiomas, facial anomalies, possible mental retardation, and occasional seizures (79). One of the characteristics of this disorder is the changing phenotype with time. Many of the patients are normal at birth to clinical assessment and develop the characteristic findings over the first year of life. Once established, the abnormalities tend to be progressive throughout childhood with growth of the hamartomata and generalized hypertrophy increasing. The disorder is stable, however, after puberty. Morbidity is considerably greater than with the KT or PW syndromes. Of 11 patients evaluated by Clark et al. (113), 2 required amputation of the leg, 6 had fingers or toes

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removed, and 2 women had breast implants and reconstruction. Spinal stenosis and neurological sequelae can develop due to vertebral anomalies or tumor infiltration. There is concern about neoplastic disorders of many types with this syndrome. Because it was described only in 1979 and clearly defined in 1983 careful assessment is needed. An extremely large number of developmental abnormalities can be associated with this syndrome. The characteristic findings involve hemihypertrophy, generalized thickening and soft connective tissue swellings of the skin and subcutaneous tissue, and macrodactyly. The overgrowth may involve the whole body, it may be unilateral involving one limb, or occasionally it is localized even to a digit. The skin and subcutaneous thickening is associated with lipomata, lymphangiomata, or hemangiomata. There is a relatively high proportion of skeletal abnormalities other than the hemihypertrophy, including bony prominences over the skull, angular deformities of the knees, scoliosis or kyphosis along with the dysplastic vertebrae, hip dislocation, and hallux valgus. There is disproportionate involvement of the hands and feet with macrodactyly and often soft tissue hypertrophy particularly over the plantar surfaces of the feet. d. Beckwith-Wiedemann Syndrome. Anothersyndrome occasionally associated with hemihypertrophy leading to lower extremity length discrepancy is the Beckwith-Wiedemann syndrome (41,503). This clinical entity is characterized by macroglossia, omphalocele or other umbilical anomalies such as umbilical hernias, macrosomia with large muscle mass and thick subcutaneous tissues, linear creases in the lobule of the external ear, and large kidneys. Other developmental anomalies are seen in differing patients. Hypoglycemia is present in early infancy in approximately one-half of the cases. e. Congenital Arteriovenous Fistula. Horton (239)drew attention to the overgrowth phenomenon with congenital arteriovenous fistula involving the extremities in an early report. He detailed findings in 23 upper and lower extremity disorders in which actual documentation of the length discrepancy was made. In the group of 23 patients described, the limb circumference was from 2 to 8 cm greater than the corresponding normal side, and in 18 of the cases there was an increase from 0.5 to 7.0 cm in the length of the bones on the abnormal side. With lower extremity involvement, tilting of the pelvis and lateral curvature of the spine invariably were seen. The involved extremity was hypertrophied and showed marked evidence of engorgement, swelling of superficial veins, and skin ulcers in most. There was a marked increase in the pulsations of the arteries and a definite increase in the surface temperature of the extremity involved. Horton used the term arteriovenous fistula to designate any abnormal communication or communications between arteries and veins by means of which arterial blood passes from an artery to a vein without passing through a capillary bed. There were 15 patients with lower extremity length discrepancies described, all of whom had reached

skeletal maturity except for 3 at 4, 5, and 9 years of age. Two of the patients had no increase in length on the involved side, but the others all showed an increase in length. The discrepancies varied from 0.5 to 7.0 cm. In the 13 patients with lower extremity length overgrowth, the mean discrepancy was 3.2 cm with 9 of the 13 showing a discrepancy of 2.5 cm or more. McKibbin and Ray (322) implicated abnormalities of venous return in experimental arteriovenous fistulae with bone overgrowth. The direction of blood flow in the vein distal to the fistula was reversed for a considerable difference. As the venous collateral channels, including those in the bone, developed the periphyseal blood supply was also altered. f. Cutis Marmorata Telangiectatica Congenita. Cutis marmorata telangiectatica congenita is characterized by a persistent vascular mottling of the skin usually involving the limbs and usually in an asymmetric pattern. The disorder was described initially by Van Lohuyzen (484) in 1922, and a detailed review by Gelmetti et al. (175) in 1987 listed approximately 150 cases described in the literature. Spontaneous regression has been observed in the majority of patients in the first few years of life, but many lesions do persist to adulthood. The disorder is referred to as congenital phlebectasia by many. Lower extremity length discrepancies occur on occasion in the disorder. As with many congenital vascular abnormalities, there is a high frequency of multiple associated congenital abnormalities such that it is a syndrome including other neuroectodermal and mesodermal defects. Gelmetti et al. pointed out that abnormalities of the central nervous system, musculoskeletal system, and vascular system were involved. Several instances of hemiatrophy or hemihypertrophy on the involved side have been described. In the detailed review referred to earlier there were 11 cases of shortness or hemiatrophy of the involved side and 7 cases of hemihypertrophy of the involved side, as well as other categorizations involving retardation of growth and asymmetric growth in which specific limb length determinations were not clear. Dutkowsky et al. (146) described a 15-year-old male with 2.9 cm of shortness on the involved side and 2 other patients 2-3 years old with 1-1.6 cm of shortness on the involved side. These studies indicate that some discrepancy in limb length could be present in as high as 25% of cases, that both hemiatrophy and hemihypertrophy on the involved side could be seen, and that evidence of growth retardation perhaps is somewhat greater than that of growth stimulation. 9. GENERAL CLASSIFICATION OF ANGIOMATOUS LESIONS BASED ON THEIR SIZE AND POSITION (GOIDANICH AND CAMPANACCI) Goidanich and Campanacci (189) derived a classification of the congenital and developmental vascular disorders based on their position and size in the extremities. Their approach was based on the dissatisfaction with confusing and variable descriptive terms used for this group of disorders.

SECTION VI ~ Lower Extremity Length Discrepancies in Specific Disease Entities

They felt that the clinical management could best be guided by consideration of the size and position of the vascular anomalies. Their six groups included (1) localized cutaneous and subcutaneous vascular hamartomata; (2) localized deep vascular hamartomata; (3) extensive deep vascular hamartomata; (4) multiple deep vascular hamartomata; (5) diffuse deep vascular hamartomata; and 6) infantile angioectatic osteohyperplasia. Goidanich and Campanacci felt that each group had distinctive clinical and pathological characteristics but agreed that there were cases that showed transitional features. For each group, they documented whether there was hemihypertrophy or hemiatrophy and also assessed bone changes radiographically, varicose veins, skin temperature, skin angiomata, pain, functional impairment, and swelling. The classification was derived from a study of 94 cases with the largest group, deep localized vascular hamartoma, comprising 45 cases and the smallest, infantile angioectatic osteohyperplasia, comprising 7 cases. Goidanich and Campanacci considered all of the angiomata of the soft tissues of the extremities to be hamartomatous, with the lesion being present from birth and growth ceasing after skeletal maturity. In terms of extremity length, examples of both overgrowth and retardation were noted. In patients with cutaneous and subcutaneous vascular hamartoma, limb length was essentially equal in each of 11 cases. In all 7 cases with infantile angioectatic osteohyperplasia overgrowth occurred on the involved side. In the other four groups, however, were examples of both overgrowth and retardation in association with the vascular lesions. In the four groups were 16 patients with overgrowth and 17 with decreased growth. In terms of length discrepancy, therefore, even site and extent of the lesion with the two exceptions noted earlier offer little prognosis as to either the extent of any discrepancy or whether there will be overgrowth or retardation. 10. LOWER EXTREMITY LENGTH DISCREPANCIES IN VASCULAR MALFORMATION SYNDROMES Most studies of Klippel-Trenaunay syndrome in the orthopedic literature link it with Parkes Weber syndrome, referring to the entire entity as Klippel-Trenaunay-Weber (KTW). In addition, relatively few reports exist on lower extremity length discrepancies with the Proteus syndrome because it was described only recently. Peixinho et al. (377) described 8 patients with KTW syndrome treated for lower extremity length discrepancy. There were 7 patients who had growth remaining at the time of treatment, ranging between 10 and 15 years of age, and 1 patient treated at skeletal maturity at 19 years of age. This report concentrates on the more severe variants but does show the extent of the length discrepancies that can develop. The range of disorders treated was between 1.5 and 10.0 cm, with those undergoing epiphyseal arrest between 2.9 and 10.0 cm. In these 6 patients the average discrepancy was 6.35 cm. In the 5 patients with epiphyseal arrest followed to skeletal maturity, the mean discrepancy initially was 6.82 cm and at skeletal ma-

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turity it had decreased to a mean of 2.1 cm. An additional patient had shortening of the femur at skeletal maturity, diminishing the discrepancy from 4.8 to 0.8 cm. Guidera et al. (205) described 28 patients with limb overgrowth and a diagnosis of either KTW (18 patients) or Proteus (10 patients) syndrome. The results were pooled. Most patients had a huge array of mesodermal abnormalities, indicating the need for extremely careful and detailed total body assessment and careful follow-up with growth. All patients but 1 had extremity involvement. Twenty-seven of 28 had lower extremity involvement, consisting of overall limb hemihypertrophy in 15, localized gigantism in 6, and macrodactyly in 10. Nine patients had lower extremity length discrepancies varying from 1 to 12.8 cm. Two patients exhibited clinodactyly. Other deformities similar to those mentioned earlier were present. No specific analysis of the discrepancies was made. The authors warned along with others of using extreme caution concerning the use of surgical intervention. Soft tissue debulking operations and vascular operations in particular often appeared to be of dubious benefit especially with the danger of heavy bleeding. Guidera et al. felt that the timing of epiphyseal arrests was not predictable in equalizing limb length discrepancies, although that does not appear to be the experience of others. Amputation was frequently required for the more massive limb deformities generally described as "grotesque." Rogalski et al. (413) utilized the term angiodysplastic lesions of the extremities to review 41 patients. They used this terminology rather than the syndromal terms referred to earlier, indicating that "identification of a specific syndrome appeared to depend on the speciality and training of the treating physician and was not predictive of initial symptoms or outcome." Rogalski et al. felt they could not categorize the vascular malformations according to either histologic or angiographic descriptions. They preferred to describe the malformations utilizing the system of Goidanich and Campanacci based on the size and location of the malformations. Eleven patients had limb length discrepancies with hemihypertrophy and 4 of these had epiphyseal arrest. No specific details concerning the extent of the discrepancies were given. The shape and size of the extremities and the associated vascular problems as well as the large number of additional malformations throughout the body made the length discrepancy itself relatively less important than in other individuals. The authors felt that anatomic location and overall size were predictive of symptomatology and thus were the more important factors at our current level of knowledge in relation to patient assessment. Rogalski et al. determined that the majority of the lesions (59%) were subcutaneous, whereas 20% were specifically identified as intramuscular. No bony lesions were identified. All limb length discrepancies were associated with overgrowth of the involved limb. The authors also commented on the limitations of surgical interventions particularly when cosmetic improvement was being sought. Paley and Evans (363) also felt that it was the depth and

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CHAPTER 8 ~ Lower Extremity Length Discrepancies

extent of the lesions that were the most significant prognostic characteristics. A review of 40 patients with KT syndrome from the Mayo Clinic documented an equal male:female distribution of 1:1 (183). Thirty patients had findings noted immediately at birth, with 3 being diagnosed before the age of 1 year and 4 between 1 and 6 years of age. A strict distinction was made between Parkes Weber syndrome and KTS with patients with arteriovenous fistulae not included in the KTS grouping. The lower extremity was involved in 38 patients (95%) and the upper extremity in 6 patients (15%), with 4 patients (10%) bilateral. The disorder was unilateral in 34 patients (85%), bilateral in 5 (12.5%), and crossed bilateral in 1 case (2.5%). The affected extremity was longer in every case. In 29 patients documented by scanogram the average difference in documented length was 2.39 cm, with the largest at 12 cm. Hemangioma was present in 39 cases (97.5%), whereas lymphangioma was the histologic diagnosis in 1 case (2.5%). The two were found together in 5 additional cases. The typical portwine fiat cutaneous hemangioma was present in 30 cases (75%). Varicosities were marked and significant with incompetent perforators in 25 cases (62.5%). Seven of the 25 had persistent large embryonic veins on the lateral aspect of the thigh. Arteriography was performed in 9 cases with no arteriovenous fistulae diagnosed. All except 2 of the patients were still under 10 years of age in terms of their assessment for length discrepancy. It again was stressed that the KTS diagnosis required three main symptoms: varicosity, hemangioma, and extremity hypertrophy. The most common form of hemangioma was the capillary type or portwine nevus, which had a pink to purplish color and represented diffuse telangiectasias of the superficial vessels of the dermis. P. N e u r o f i b r o m a t o s i s

Neurofibromatosis is associated with length discrepancies in two types of clinical situations (8, 320, 336, 485). 1. BONES APPEAR STRUCTURALLY NORMAL The bones may be structurally intact, but the soft tissues of the affected limb are characterized by care au lait spots of the skin and/or actual subcutaneous neurofibromas. Growth stimulation was documented in our series on the involved side in 17 patients who did not have a tibial pseudarthrosis (433). Prior to physeal arrest, the average discrepancy was 4.40 cm (range = 2.0-8.8 cm). Shortening was also associated with neurofibromatosis in the 6 patients in whom a pseudarthrosis occurred. The type I pattern was common, although type II, type III, and type V patterns were seen also. 2. CONGENITAL PSEUDARTHROSIS OF THE TIBIA There may be a congenital pseudarthrosis of the tibia, which is often seen with neurofibromatosis, although cutaneous abnormalities or neurofibromas of the involved segment may not be present. Because surgical intervention in an

attempt to establish union was so frequent in the patients with pseudarthrosis, the natural length discrepancy patterns in our series were infrequently available for assessment. Some information is available, however, on the maximum lower extremity length discrepancies reached from large series of pseudarthrosis of the tibia described previously. Virtually all of these patients will have had surgical interventions, often multiple times, on the affected tibia in efforts to obtain straightening and union. The discrepancies were at times worsened by angular deformity, the need to resect scarred sclerotic diaphyseal tissue, and intramedullary rod passage through the tibial epiphyses in efforts to enhance stabilization. Van Nes (485) pointed out, as many had previously, that a considerable amount of the shortening in congenital pseudarthrosis of the tibia was due to associated developmental abnormalities of the distal tibial epiphysis, which often led not only to diminished growth but also to premature fusion. The distal tibial physis was often delayed in appearance, indicative of early problems with normal development. Throughout the growing years the physis can often be noted to be misshapen and thin. Van Nes stated that the retardation of growth in the distal tibial epiphysis indicated involvement with the same segmental dysplasia as the distal part of the diaphysis that caused the pseudarthrosis originally. Both the pseudarthrosis and the retardation of growth were to be considered symptoms of the same developmental defect of the distal tibia. The closer the pseudoarthrosis to the epiphyseal region, the greater the epiphyseal involvement and the less the associated growth. Van Nes clearly pointed out that spontaneous physeal fusion could occur as early as 10-12 years of age. He presented case reports on 22 individuals. Length discrepancy measurements were listed in 18 patients, virtually all after 10 years of age and prior to any epiphyseal arrest for the length discrepancy. Though not a natural history study, the data showed the extent of the discrepancies in the more severe variants of the disorder. One patient had no discrepancy and the others ranged from 1.25 to 11.0 cm. The mean discrepancy in the 18 listed patients was 5.4 cm. The discrepancies were due to a combination of factors, including angular deformity, multiple surgical procedures some of which involved resection of bone in efforts to obtain union, diminished function of the distal tibial epiphysis due to its involvement in the dysplastic process, and premature fusion of the distal tibial epiphysis. On occasion, the physis was damaged by intramedullary nails passed through it, although many instances of continued growth following this procedure also were noted. In a long-term study from the Mayo Clinic, Masserman et al. (320) reviewed 52 cases. Of these, 20 (38%) had a known diagnosis or the clinical manifestations of neurofibromatosis. Lower extremity length discrepancies were documented in 32 of the 52 patients. Of these, 5 had no specifc number mentioned but appeared to be insignificant. In all instances except 1 the involved leg was shorter. There were 2 patients whose limbs were equal, 8 in whom the difference

SECTION VI ~ Lower Extremity Length Discrepancies in Specific Disease Entities

was between 0 and 1 in., 5 between 1 and 2 in., 3 between 2 and 3 in., 4 between 3 and 4 in., 1 between 4 and 5 in., and 3 with 6 in. of discrepancy. The 1 patient with tibial overgrowth had a 2.0-cm discrepancy. Morrissy et al. (336) analyzed 40 cases of congenital pseudarthrosis of the tibia in detail. Half of the patients in the series had neurofibromatosis. As in the study by Masserman et al., the diagnosis of associated neurofibromatosis does not affect the overall result in comparison with the group without that diagnosis. The amount of shortening in congenital pseudarthrosis of the tibia correlated extremely well with the eventual result achieved. This serves as a biological reflection of the extent of the bone abnormality, which affects not only the diaphyseal regions but also the entire bone. In those with good results the average amount of shortening was 1.4 cm (range = 0-4.0 cm), with fair results the average amount of shortening was 3.4 cm, with 1 patient having a 6.0-cm shortening and another a deficit at one time of 8.1 cm, and with poor results the average shortening was 5.5 cm (range = 2-8 cm), with all but 1 patient having at least 4.0 cm of shortness. Amputation was required eventually in 14 patients. As the results indicate, a significantly greater amount of shortening existed in patients with a tenuous union or nonunion. Much of the growth discrepancy was secondary to failure of growth in the distal physis, whereas relatively normal growth proximally continued.

Q. Juvenile Rheumatoid Arthritis Lower extremity length discrepancies occur commonly in patients with juvenile rheumatoid arthritis in which joint inflammation is prolonged and asymmetric. There had been recognition for some time that asymmetric bone growth occurred in many instances of moderate to severe juvenile rheumatoid arthritis and that this was characterized by overgrowth on the involved side early in childhood and by a tendency to premature physeal closure, leading to shortening in those affected toward the end of skeletal growth (24, 25, 70, 81, 99, 280, 290, 468). Griffin et al. (200) noted overgrowth as great as 2.6 cm in 1 patient with knee involvement and shortening as great as 3.8 and 5.1 cm in others. A retrospective study at Children's Hospital, Boston, determined the course of limb length discrepancies occurring in patients with monoarticular and pauciarticular juvenile rheumatoid arthritis (446). Data were assessed on 36 patients followed to skeletal maturity, (group I), 15 patients who had not reached skeletal maturity but who had been followed for 4 years or more, (group II), and 49 patients followed for 3 years or less (group III). In 72 of the 100 patients the onset of the disease occurred before they were 5 years old, and 90 patients had involvement of the knee. All patients in whom the disease developed before the age of 9 years had overgrowth of the involved extremity, but that overgrowth never exceeded 3.0 cm. The major discrepancy developed within the first 3 - 4 years and either in-

649

creased very slowly thereafter, remained level, or decreased. Of the 36 patients who were followed to skeletal maturity, in 29 a discrepancy of 1.5 cm or more developed at some time during the period of assessment. Twelve of the 36 patients had diminution of the discrepancy to the extent that epiphyseal arrest was not required. Fifteen eventually had an epiphyseal arrest. Rapid premature closure of the epiphyseal growth plate occurred only in those patients in whom the disease developed after the age of 9 years. This led to immediate shortening of the involved side and on occasion to marked limb length discrepancies of as much as 5.1 and 5.9 cm. Of the 51 patients included in groups I and II, although all had some length discrepancy, in 35 (70%) a length discrepancy of 1.5 cm or more developed during the study period. Twenty-one patients had a discrepancy of between 2.0 and 2.9 cm, and in 3 it was 3.0 cm or more. In the patients with unilateral disease whose disease onset was before the age of 9 years, the involved side was almost invariably the longer one (39 of 40 cases). Those whose disease onset occurred within the first 3 years of life tended to have a discrepancy greater than 1.5 cm (24 of 34 patients) relatively more often than children 3-8 years old, but overgrowth in the younger children never amounted to more than 3.0 cm. When the disease occurred initially after the patient was 9 years old (5 patients), the involved side usually became shorter (with one exception). Regardless of age at onset, the major discrepancy that developed did so within the first 4 years after disease onset. Thereafter, in the group I patients the discrepancy either increased very slowly (6 patients), remained unchanged (14 patients), or decreased spontaneously (12 patients). The other 4 patients, whose discrepancies continued to increase, were patients with late onset of the disease whose epiphyses fused prematurely on the involved side. Continuing involvement of the knee for several years in 1 patient resulted in a continuing increase with time until a prearrest discrepancy of 2.4 cm was reached, but such an occurrence was unusual. In the 12 patients whose discrepancies decreased, there was a gradual inhibition of growth in the involved limb over several years. In 7 of the 12, the discrepancy became clinically insignificant. The changes in discrepancy with time were 2.8 to 0.3, 2.5 to 1.2, 2.3 to 1.3, 2.2 to 0.4, 2.0 to 0.2, 1.8 to 1.4, and 1.5 to 0.9 cm. Evidence for rapid premature epiphyseal growth plate closure was noted in only 4 patients who had discrepancies because of shortness on the involved side. In patients with the monoarticular or pauciarticular form of juvenile rheumatoid arthritis, who have predominant involvement of the major joints of one lower extremity, the length discrepancy occurs as a result of two factors: (1) stimulation of the epiphyseal growth plates, predominantly about the knee joint, during the time the disease is active and for some time afterward and (2) inhibition of the growth potential of the involved extremity.

650

CHAPTER 8 9 Lower Extremity Length Discrepancies

The epiphyseal growth plates at the knee account for 70% of the growth potential of the lower extremity. They are sufficiently close to the synovial capsule to be affected by the hyperemia that occurs during the inflammatory process, but are not adversely affected by the concomitant destructive process. Thus, because the knee is commonly involved in the type of arthritis under discussion and so often is involved unilaterally early in the course of the disease, a great potential exists for growth stimulation of the involved lower limb. However, the severity of the disease often causes a decrease in the use of the involved extremity, either because of the patient's symptoms or because of the treatment. Such decreased use can explain the gradual reduction in epiphyseal stimulation and inhibition of growth. When the patient has activity of the disease in early adolescence, consequent hyperemia about the knee could cause rapid and premature fusion of one or both of the growth plates, with a sudden decrease in growth of the involved lower limb. In this study, the most common and well-defined pattern of development and progression of length discrepancy was ipsilateral lengthening in patients who had onset of the disease before the age of 5 years. The major part of the discrepancy then occurred within the first few years of the disease. Thirty-nine of the 40 patients with unilateral involvement whose disease began before the age of 9 years showed this pattern. We suggest that early in the course of the disease the predominant factor is stimulation of the epiphyses about the involved knee joint. The pattern of development of a limb length discrepancy described most often is followed by lack of a significant continuing increase in the discrepancy. Although occasionally (in two patients in this series) the discrepancy will increase over the ensuing years, in most patients it will decrease or remain unchanged with time. It is important to note the rapid premature closure of the epiphyseal growth plates about the involved joint that occurred at the end of growth in four children in this series. All of them had onset of the disease after the age of 9 years, and all showed shortening of the involved side. Their length discrepancies ranged from 1.9 to 5.9 cm, with the two patients who were 9-10 years old at onset of the disease showing larger discrepancies at skeletal maturity than the other two, who were 11-12 years old at onset. Early epiphyseal growth plate fusion has been recognized as a complication of juvenile rheumatoid arthritis for many years. In patients with monoarticular or pauciarticular juvenile rheumatoid arthritis, variable developmental patterns occurred. Types I, II, III, and V were all seen (Fig. 13B). The knee is the most common area of involvement in juvenile rheumatoid arthritis and involvement there is most likely to result in clinically significant discrepancies. The type I pattern was seen most frequently in patients whose initial attack of rheumatoid arthritis occurred after the age of 9 years. In these patients, a type I pattern with shortening on the involved side developed due to the relatively rapid, prema-

ture physeal fusion of the bones comprising the involved joint. The type II and type III patterns were seen most often in patients whose initial synovitis occurred in the first few years of life and resulted in physeal stimulation and overgrowth. In our series, once the synovitis had resolved, physeal growth altered toward a more normal rate and the discrepancy either persisted unchanged or increased at a much slower rate. The type V pattern resulted from a slowing of physeal stimulation over a few years prior to plate closure (Fig. 13B). Whether the type V pattern was due to decreased use or due to an alteration in the timing mechanism for closure due to disease, or to both, is uncertain, but the phenomenon itself was well-documented. It was not possible to predict which patients would have a type II, III, or V pattern. Similar overgrowth can occur following inflammatory conditions about the knee in childhood such as tuberculosis, septic arthritis, and hemophilia. Indeed, in what appears to represent a description of a type V pattern, Phemister (387) quoted Bergmann as observing "equalization of length years after overgrowth produced by tuberculosis of the knee beginning in early childhood."

R. Thalassemia Premature fusion of the epiphyses has been recognized as a fairly common occurrence in thalassemia of the homozygous or major type. In a series of 79 patients surveyed with the disorder, 14% showed premature physeal fusion almost always most marked in one growth plate (129). All instances, however, were noted in those greater than 10 years of age. When that age group alone was assessed, fully 23% of 48 patients demonstrated the physeal arrest phenomenon. The most common growth plate involved was that of the proximal humerus, with frequent occurrence in the distal femur and examples also in the proximal and distal tibia and fibula. The study by Currarino and Erlandson also noted that the premature fusion was almost always focal and generally was peripheral, such that any shortening present was usually complicated by angular deformity. The growth plate arrest in the proximal humerus was almost always seen medially, leading to varus tilt of the head in relation to the glenoid. The abnormality was not demonstrated in any of the 31 patients under 10 years of age. The incidence in males and females was approximately equal. Very little documentation exists concerning the extent of the discrepancy or the nature of the angular deformity and also little indication that surgical intervention was performed. No definitive cause of the disorder has been described.

S. Hemophilia Lower extremity length discrepancies can occur in hemophilia (412). The mechanism appears to be similar to that in juvenile rheumatoid arthritis in that a recurrent synovitis in a single joint, commonly the knee, leads to growth stimula-

SECTION VI ~ Lower ExtremiW Length Discrepancies in Specific Disease Entities

tion in the early years up to approximately 8 years of age, following which continuing synovitis tends to premature closure of the distal femoral and to a lesser extent proximal tibial physes. It is common for hemophilia to occur in a recurrent fashion in one joint, which is referred to as a target joint, with the three most common affected regions being the ankle, knee, and elbow. Caffey and Schlesinger (84) described overgrowth of the epiphyses themselves in all dimensions in joints with hemophilic arthropathy, but they did not study overall bone length. Kingma (274) described overgrowth of an extremity affected with recurrent hemarthrosis in one joint. Three patients, all less than 10 years of age, suffered repeat knee hemarthrosis and after straightening of flexion contractures were noted to be longer on the involved side. Each was still growing and report of the final discrepancy was not made. The overgrowth in an 11-year-old boy was 2.5 cm, in a 5-year-old boy it was 2 cm, and in a 7-year-old boy it was 2.5 cm. Overgrowth in hemophilia was also described by Harris (220), who reported on a 1-in. overgrowth on the involved side at 11 years of age, and by Heim et al. (227), who reported a 2.2-cm overgrowth on the side of the involved knee at 5 years of age. Length discrepancy is seen less frequently now because of improved medical control limiting hemarthrosis and synovitis. Overgrowth discrepancies were often hidden and minimized by flexion contractures and articular cartilage degeneration of involved joints.

T. Synovial Hemangioma of the Knee Joint Synovial hemangioma, a rare disorder, can occur with the most frequent site of involvement being the knee joint. Moon (333) performed a careful review of the literature in 1973 and documented 137 patients with synovial hemangioma of the knee. There was equal occurrence in males and females, with the initial occurrence of symptoms concentrated in the childhood years from birth to late adolescence. Approximately 75% of patients were symptomatic prior to age 16 years. In those reports that mentioned limb length, only 14 cases were described as having increased limb length on the involved side, with many showing only about 1 cm difference. In 8 cases the limbs were of equal length, and in 4 the involved limb was somewhat shorter. Limb length discrepancies thus were variable, although a slight majority of patients had slight overgrowth.

U. Legg-Calve-Perthes Disease Data for the extent of lower extremity length discrepancy in Legg-Perthes disease were reported in our study of a large group of patients treated with a unilateral abduction brace. The data show how both the disease and the mode of treatment used impact length differentials. In the 147 patients with a lower extremity length discrepancy associated with unilateral Legg-Calve-Perthes disease, the involved side

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abnormal extremity with time, its pattern of change in relation to the normal side could be viewed and projections made. Hechard and Carlioz considered the method for projecting the inequality in length to be easily used as well as providing a document that could follow growth evolution. Before 4 or 5 years of age the rate of growth per year increased from year to year; between 4 and 13 years for girls and 5 and 14 years for boys the rate of growth annually was constant, whereas toward the approach of skeletal maturity the rate of growth diminished in a regular fashion. The majority of children examined for a lower extremity length discrepancy were seen during the period of linear increase in growth. By eliminating the extremes of age at either end, a linear depiction of growth was felt to be accurate. The values for bone ages and femoral-tibial lengths were listed for girls from 5 to 14 years of age and for boys from 6 to 16 years of age. 9. E A S T W O O D AND C O L E Eastwood and Cole (147) described a clinical method for

the graphic recording, analysis, and planning of lower extremity length discrepancies. Their chart lists length discrep-

659

ancy in centimeters along one axis and chronological age in years along the other (Fig. 17). The average maturity lines were marked for girls at 14 years and for boys at 16 years. Superimposed on the graphs are epiphysiodesis reference slopes (slopes 1-3), which converge to the skeletal maturity lines at zero leg length discrepancy. The slopes of these lines are based on the average annual growth of 0.6 cm from the proximal tibial growth plate and 1.0 cm from the distal femoral growth plate after the age of 8 years in girls and 10 years in boys. The graphs depict the estimated mature discrepancy and timing of surgery. The pattern of differential growth of the legs is determined from the graph such that the patterns defined by Shapiro are documented and then used to predict the pattern of further differential growth and eventual leg length discrepancy projected for skeletal maturity. The observed discrepancy line (line 2) is projected to the skeletal maturity line (line 3). The point of intersection (Y) gives the estimated mature discrepancy. The mature discrepancy line (line 4) is drawn horizontally from point Y and may intersect one or more of the epiphysiodesis reference slopes. The slopes are for proximal tibial arrest alone, distal femoral arrest alone, or a combination of the two. Vertical lines are dropped from these points of intersection to give the chronological ages for epiphysiodesis of the appropriate growth plates (X and X1) (Fig. 17). This method incorporates the different patterns of discrepancy into the plotting of the appropriate time for surgery without the need for specific calculation of the growth inhibition rate as is done in the Green-Anderson method.

C. Discussion of Methods The previous subsections 1-9 have shown the evolution of approaches to determining the expected discrepancy at skeletal maturity and the appropriate time for epiphyseal arrest. Additional charts are still being created. Pritchett and Bortel (Clin. Orthop. Rel. Res. 342:132-140, 1997) incorporated information on the late increased proportion of distal femoral and proximal tibial growth into straight line graphs. Paley et al. (J. Bone Joint Surg. 82A:1432-1446, 2000) developed a multiplier method for predicting limb-length discrepancy (in the type I developmental pattern) from 1-2 measurements. Femoral/tibial lengths (from existing databases) at skeletal maturity were divided by femoral/tibial lengths at each age for each percentile to obtain the multiplier. Limb length discrepancy and growth remaining values could be calculated. Femoral/tibial male/female multiplier charts were made from birth to 18/16 years for the mean and 1, 2 standard deviations above/below the mean. Gill and Abbott basically developed the concepts needed for accurate growth determination while Green and Anderson and colleagues provided the data needed to construct the appropriate growth charts for femoral and tibial lengths and for growth remaining. Both Green and Anderson and Menelaus derived relatively simple formulae to aid in determination of the

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Chronological age (years) F I G U R E 17 The clinical leg length discrepancy graph for boys derived by Eastwood and Cole is shown. Line 1 shows the skeletal maturity line, which for boys is 16 years of age and for girls is 14 years of age. Line 2 documents the observed discrepancy in chronological years. Line 3 is the projected discrepancy. Line 4 is the mature discrepancy line. It is drawn horizontally from point Y. Slope 1 is the femoral and tibial epiphyseal arrest reference slope, slope 2 is the femoral epiphyseal arrest reference slope, and slope 3 is the tibial epiphyseal arrest reference slope. Y is the estimated mature discrepancy, with X and X' representing the chronological ages for femoral or femoral and tibial epiphyseal arrests, respectively. [Reprinted from (147), with permission.]

appropriate time for epiphyseal arrest. Green and Anderson based their determinations on skeletal age, whereas Menelaus used chronological age for most patients. Green and Anderson were able to derive a method utilizing their growth charts. They incorporated the concept of a growth inhibition formula to aid in the ultimate timing for epiphyseal arrest. Growth inhibition was calculated as a formula: (growth of the long leg - growth of the short leg)/growth of the long leg. This formula enabled them to determine a rate of growth inhibition, which then served to indicate how much the discrepancy would increase over the remaining years of growth. For example, from any time period reference to the normal growth charts would indicate how much growth of the longer or normal leg was expected prior to skeletal maturity. Growth inhibition was then calculated from a time period of sufficient length to provide accurate data in that regard. The assumption was then made that the growth inhibition would be constant throughout the period of growth. It is evident that this is not true for all discrepancies. In practice, however, the Boston Children's Hospital Growth Study Unit frequently took a slowing of growth inhibition into account, although there was no specific formulaic method for this. If the growth inhibition was calculated as 0.4 and the future projected growth of the normal leg was 10 cm, then the

future increase in discrepancy was considered to be 10 • 0.4 or 4 cm. This would be added to the discrepancy at the time that the projection was made to yield the final discrepancy at skeletal maturity. The appropriate timing for epiphyseal arrest would then be determined from the growth remaining charts. Because the correction would be made by the shortened leg, the percentile along which the shortened leg was growing was determined from the normal femoral and tibial length charts. If this was one standard deviation below the mean, then that particular line was referred to on the growth remaining chart and the appropriate skeletal age to make up the specific discrepancy was decided upon. The conceptual changes introduced by the subsequent Moseley, Hechard and Carlioz, and Eastwood and Cole graphs primarily involved depiction of the growth data graphically such that growth inhibition would not have to be specifically calculated but was simply taken into account by plotting the growth of the normal and affected limbs on the chart, which allowed the discrepancy to be read directly. These methods, each of which has its advocates, are indeed simpler than calculation of the growth inhibition itself and are now widely in use. It has been recognized for some time that the length parameter of normal growth can be represented accurately by logarithmic plotting (242, 402). It is incorrect, however, to

SECTION VIII ~ Use of the Developmental Pattern Classification in Projecting Limb Length Discrepancies assume that pathological processes are as readily predictable by logarithmic plotting or any other formula. The straight line graph of Moseley (340, 341) or the growth inhibition method of Green-Anderson (195, 196) might well lead to inaccurate projections, particularly if the assessments are done too early in patients with conditions in which type II, late plateau type III, type IV, or type V patterns may be evolving. The types of pattern that occur in each disease category have been delineated. Knowledge of the developmental pattern classification, the natural and specific history of the condition causing a particular discrepancy, and the pattern type or types that occur in the condition allow the physician to project the ultimate extent of the discrepancy with clinically acceptable accuracy. The frequency with which clinical and radiographic evaluations of the discrepancy should be done must strike a balance. The evaluations should not be terminated too early or done too frequently on the expectation that straight line graph or growth inhibition projections always will suffice, and on the other hand they should not be done unnecessarily often as though the eventual outcome were totally in doubt. The developmental patterns themselves cannot be used to make accurate mathematical projections because growth, particularly during growth spurt periods and immediately prior to skeletal maturity, is not linear with time. The patterns do, however, permit accurate projections of discrepancy to be made using the femoral and tibial length charts and the femoral and tibial growth remaining, charts, which do take the nonlinearity of growth into consideration. The method of Eastwood and Cole (147) incorporates both the discrepancy pattern classification and the Menelaus method and appears attractive in that regard. The length and growth remaining charts were developed from information obtained by making yearly orthoradiographs of 67 boys and 67 girls between the ages of 1 and 18 years; they give the most accurate indication of individual bone lengths currently available. Their value lies in indicating the lengths of the femur and tibia and the growth remaining in those bones in relation to the standard deviation position. Smooth curves of growth are shown, with the individual growth spurt that occurs between the ages of 10 and 14 years blurred by averaged data. When an individual child's growth is plotted, the growth spurt will often change the standard deviation position of the limb lengths. If maturation is relatively early, the limb length will be on a higher percentile; if maturation is late, the limb length will be on a relatively lower percentile. Awareness of this factor is important in determining the amount of growth remaining in a bone and in projecting its final normal length. Growth is generally linear between the ages of 4 and 10 years, and if a child is on the first standard deviation above the mean at the age of 7, it is very likely that at skeletal maturity limb length will also rest along that percentile. Thus, length data obtained before the adolescent growth spurt are of great value in indicating what the child's projected mature level will be. If information is available only from the period between

661

10 and 14 years, however, awareness of the relationship of skeletal age to chronological age is important. If the skeletal age is retarded or advanced by 6 months or more in relation to chronological age, the correct growth percentile can best be determined by plotting the femoral and tibial lengths in relation to skeletal age, not chronological age. The Green-Anderson growth charts are derived from studies of white North American and northern European children during the time frame 1930-1956. Thus, they reflect the growth characteristics and height variations of that group, which would differ slightly from other racial groups and even from similar racial groups at differing time periods under altered socioeconomic climates. Even if the absolute height values between groups are slightly different, however, the pattern and percentile distribution would be unlikely to change at least in any meaningful clinical way. Because the values are read from the appropriate percentile and not simply determined as means or averages, placement of any individual on his or her percentile, even if this were somewhat higher than the percentile placements for other groups of relatively smaller stature, would still lead to the appropriate projections with time. Although it is unlikely that long-term, serial, longitudinal radiographic studies will be repeated, the ability to perform accurate imaging assessments without radiographic means, for example, by use of ultrasonography, should enable newer charts of differing racial groups and in differing socioeconomic settings to be established. The assessment of skeletal age is important in using the Green-Anderson method. Although a wide variation in skeletal age reading can be demonstrated among readers who do it infrequently, the assessments become highly reproducible when done by readers who do many. Although the Greulich and Pyle atlas (199) has certain limitations, it still serves as a clinically reliable guide to the rate of skeletal maturation. Management of the growing patient with a limb length discrepancy can be improved by knowledge of the classification of developmental patterns, the type or types of patterns that can occur with the particular disease process, radiographic documentation of the lengths of the lower extremities, a chart of the relationship between discrepancy and age to outline the developmental pattern that is evolving, the percentile standing of the normal limb and the abnormal limb, and the patient's skeletal age.

VIII. U S E O F T H E D E V E L O P M E N T A L PATTERN CLASSIFICATION IN P R O J E C T I N G L I M B LENGTH DISCREPANCIES A. Type I The type I discrepancy increases at a constant rate with time, as the rate of inhibition or stimulation remains uniform throughout the growth period (433). If one is certain that a

662

CHAPTER 8 9 Lower Extremity Length Discrepancies

type I pattern will evolve, one radiographic assessment of length, especially after the age of 2 years, will suffice for an accurate determination of the final discrepancy, although more determinations are always performed. In the first 2 years of life there can be considerable shifting of length between various percentiles, whereas afterward the distinct tendency is for normal growth to persist along the same percentile. For example, if at the age of 4 years the involved femur in a child with proximal femoral focal deficiency is 63% as long as the normal femur, one can project the final discrepancy by determining the length percentile on which the normal femur lies from the femoral and tibial length charts and noting the femoral length at maturity for that percentile. Sixty-three percent of the value represents the projected final length of the involved femur, and the difference between the two lengths represents the projected femoral length discrepancy. When the type I pattern is due to physeal destruction, the femoral and tibial growth remaining data can be localized accurately to the involved physis, and the values for the distal end of the femur and proximal end of the tibia can be read directly from the chart. If the proximal femoral physis has closed, the projected growth loss is determined on the basis that 30% of the remaining growth of the normal femur would occur at the proximal physis (and 70% at the distal physis). Similarly, if the distal tibial plate has fused, projected growth loss is determined on the basis that 43% of the remaining growth would occur at the distal tibia and 57% proximally. The amount of growth remaining in the entire femur or tibia is determined from the line that corresponds to the standard deviation position of the normal bone on the femoral and tibial length charts. Thirty percent of the difference between the present normal femoral length and the projected final length along the patient's percentile is the growth remaining in the normal proximal femoral physis. B. Type II This can be a difficult pattern to project because the discrepancy shows a decremental rate of increase, which varies from patient to patient and from condition to condition. The information available from the period of constant increase has no predictive value, as the discrepancy values themselves cannot "be aware" that a change in discrepancy pattern is about to occur. This group, therefore, requires especially careful monitoring. For example, at the age of 11 years, a child's femoral discrepancy measures 5.0 cm. Length on the short side is a cumulative 87% of normal. The growth percentile on which the normal femur lies allows one to project its final length. The growth rate in the most recent 6-month period, however, indicates that the short femur has shown 93% growth in relation to the normal side, thus demonstrating a deceleration in the development of discrepancy. The growth remaining in the normal femur is 8.6 cm, as indicated by the femoral and tibial length chart. A projection of the change in discrepancy with time indicates that growth on the

shorter side, based o.n the recent 6-month deceleration, would be at least 93% of 8.6 cm, such that the discrepancy would increase by only 7% of 8.6 cm or 0.6 cm, yielding a final maximum projection of 5.6 cm of discrepancy. If there is more time before surgical intervention, a further 6-month growth assessment might allow for an additional calculation. By this time, projections that allow for a clinically acceptable result (discrepancy of less than 1.0 cm) can be made. C. Type I I I Once a plateau has been reached, the lower extremity length discrepancy will not change throughout the remaining period of growth. The prototypical type III pattern is seen with overgrowth following fracture of a femoral diaphysis. The timing for the corrective physeal arrest is determined by using the femoral and tibial length charts and the femoral and tibial growth remaining charts. The final discrepancy is known once the plateau phenomenon has been documented to have occurred, as neither further stimulation nor inhibition will occur. D. Type IV Type IV discrepancies characteristically are seen after hip diseases in childhood that affect the proximal femoral capital epiphysis, such as septic arthritis of the hip with mild-tomoderate damage, Legg-Perthes disease, and avascular necrosis of the femoral head in association with treatment of congenital or developmental dysplasia of the hip. Premature closure of the proximal femoral capital epiphysis can occur after the discrepancy has remained in a plateau phase for as long as a decade. Radiographic indication of premature fusion of the proximal femoral capital epiphysis is demonstrated by a change in the relationship of the femoral head to the greater trochanter due to relative overgrowth of the latter. The growth discrepancy to be expected from premature fusion, once it has occurred, is obtained by determining the growth remaining in the entire normal femur, multiplying that value by 30% to give the amount of overgrowth expected from the proximal end of a normal femur, and, because growth is not occurring, adding this value to the preexisting discrepancy to give the projected final discrepancy. E. Type V If a discrepancy is beginning to correct itself, the growth charts are used to determine how much growth remains. A determination can then be made as to whether the spontaneous correction will be insufficient, result in equal limb lengths, or result in overcorrection. The type V pattern is seen characteristically with chronic inflammatory disorders not fully responsive to therapy, which stimulate growth under 10 years of age but lead to premature growth cessation toward the end of skeletal growth. The type V pattern is well-documented in juvenile rheumatoid arthritis and ap-

SECTION IX ~ Management o f Lower Extremity Length Discrepancies

pears to occur in many cases of hemophilia and tuberculosis for which therapy is less than fully effective. The developmental pattern classification provides a visual representation of the varying directional changes that can occur with time in lower extremity length discrepancies (Figure 3A). The dependence of the patterns on the causes of the discrepancies and on the time and anatomical locations of their occurrence is stressed. The demonstrated relationships between the pattern type and the particular disease entity (Fig. 3B) should aid in planning the nature and frequency of discrepancy assessments. In those conditions in which several pattern types occur, the classification serves mainly to point out that variability. Some of the factors contributing to the various patterns within each disease entity have been assessed further. The patterns alone do not provide for an accurate projection of a final discrepancy (except in type III) as growth, particularly during the adolescent growth spurt and immediately prior to skeletal maturity, is not linear with time. The patterns do, however, permit accurate projections of discrepancy to be made using the femoral-tibial length and growth remaining charts of Green and colleagues or the Eastwood-Cole chart.

IX. M A N A G M E N T O F L O W E R EXTREMITY LENGTH DISCREPANCIES

A. General Considerations As a general guideline, any discrepancy projected to be less than 2.0 cm at skeletal maturity should not require limb equalization; those discrepancies between 2.0 and 5.0 cm are usually treated with contralateral epiphyseal arrests to shorten the longer side. Discrepancies greater than 5.0 cm warrant consideration for ipsilateral lengthening, those beyond 8 cm often benefit from a combination of ipsilateral lengthening and contralateral shortening, and massive discrepancies in the 15-cm range or beyond might require prostheses with or without partial amputation. The aim of management is to ensure a discrepancy of less than 1.2 cm at skeletal maturity. This goal can be achieved in four basic ways: (1) by epiphyseal growth plate arrest in the longer limb at the appropriate time before skeletal maturity; (2) by metaphyseal or diaphyseal shortening, removing a segment of bone at skeletal maturity; (3) by lengthening the shorter extremity using metaphyseal or diaphyseal osteotomy and gradual distraction, transphyseal distraction, or transiliac osteotomy; and (4) by combinations of shortening and lengthening approaches in particularly difficult cases. For relatively massive discrepancies that leave the foot on the shortened side in the region of the midleg or knee of the longer side, prosthetic fitting and some or all of correction of angular deformity, joint stabilization, limb lengthening, distal limb rotationplasty, or amputation to maximize prosthetic fit may be required (Fig. 18).

663

Several excellent reviews of the lower extremity length discrepancy entity have been published and continue to warrant study for their insights (44, 120, 256, 260, 441).

B. Procedures to Shorten the Longer Limb 1. THERAPEUTIC ARREST OF GROWTH PLATE Therapeutic arrest of the growth plate requires knowledge of the amount of further growth to be expected in each of the growth plates at a particular age and an accurate projection of the expected discrepancy at skeletal maturity. The lengths of the femur and tibia have been documented radiographically and plotted in percentile charts showing standard deviations, and charts of the amount of growth remaining in these bones have been developed. The approximate contributions of each of the major long bone epiphyses to growth have been known for some time. In patients with a discrepancy in the length of the lower extremities, Green and colleagues (22, 193-196) have used an index of the rate of growth inhibition to project the final discrepancy. Moseley has developed a straight line graph for projecting length discrepancies by using logarithmic methods to convert the normal growth curve (340, 341). Both the growth inhibition and the straight line graph methods can lead to inaccurate projections in patients in whom the rate of change varies over time, if the assessments stop too early. The five patterns of discrepancy and their prevalence in each of the major conditions causing discrepancies in length have been delineated. Not all discrepancies increase at a constant rate, but the discrepancy at skeletal maturity can still be projected if the disease and the pattern of development are assessed carefully. The growth of the distal femoral, proximal tibial, and proximal fibular growth plates may be arrested when discrepancies are projected to be less than 5 cm at skeletal maturity. The function of the growth plate can be arrested surgically by inducing premature fusion between the epiphyseal bone of the secondary ossification center and the metaphysis; the length discrepancy is then corrected by continuing growth of the shorter side. Complete growth plate arrest of a normal physis can be performed if the contralateral affected epiphysis is still functioning. The procedure allows the shorter side to catch up in terms of growth. If the affected contralateral epiphysis no longer has any growth, the epiphyseal arrest prevents any discrepancy from worsening. Complete epiphyseal arrest is most commonly used in treatment of lower extremity length discrepancies. The timing of the procedure is crucial to its success but can be determined effectively using any of several prediction systems. The most common areas of performance of elective growth plate epiphysiodesis are at the distal femur and proximal tibia and fibula. In limb segments with two long bones (the leg and forearm), complete arrest of one growth plate often mandates arrest of the adjacent growth plate to prevent worsening of the deformity and to maintain articular alignment.

664

CHAPTER 8 ~ Lower Extremity Length Discrepancies

Management Guidelines for Lower Extremity Length Discrepancies A. 0-2 cm

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nearlongside knee) rotationplasty re prosthetic fit F I G U R E 18 Management approaches to discrepancies of increasing magnitude are shown. The management profiles A - D in each of the defined disorders leading to either stimulation or retardation of growth are shown in Table I.

Four technically effective ways of inducing premature epiphyseal arrest have been used. a. Phemister Technique. At open operation, a periphyseal rectangle of bone and cartilage is removed, rotated 180~ and replaced at both the medial and lateral sides of the involved bone end (387) (Fig. 19A). The rectangle of tissue removed involves metaphyseal bone, epiphyseal bone, and the intervening growth plate with two-thirds of the rectangle length being on the metaphyseal side and one-third on the epiphyseal side. The size of the segment removed and then repositioned varies depending on the size of the bone. Phemister defined a 3 cm • 1.5 cm • 1 cm block of tissue with curettage of the physis anterior and posterior to the block of tissue removed to a depth of 1 cm. Once removed it is rotated 180 ~ such that the larger metaphyseal fragment bone completely bridges the remaining epiphyseal growth plate. The medial and lateral transphyseal bone bridges stop growth as soon as bone repair occurs and their tethering effect enhances central physeal fusion. The White modification has been popular with many (Fig. 19B). b. Green-Phemister Technique. Green, in his modification of the Phemister approach, removed a larger and deeper block of bone and cartilage medially and laterally, obliterated the remaining growth plate with drills and a curette, and packed adjacent metaphyseal bone into the physeal defect (195, 196). The rectangle of bone removed was approximately 1.5 in. long (1 in. diaphyseal, 0.5 in. epiphyseal), 1 in. wide, and 0.75 in. deep. At the end of the procedure it was reversed 180~ as in the Phemister approach and replaced

into the defect, and the periosteum was resutured in place. Metaphyseal-epiphyseal bone fusions lead to immediate growth cessation. c. Blount Stapling Technique. B lount used three large metallic staples placed medially and laterally at the anterior, middle, and posterior aspects of the physes to halt growth (56-59). The principle involved is different from in the two techniques described previously; growth cessation is gradual because the physis must continue to grow until the prongs of the staple mechanically prevent further expansion. The original reason for this approach was to allow for subsequent removal of the staples and the resumption of growth if the timing of epiphyseal arrest proved to be too early, such that the discrepancy not only was eliminated but continuing growth from the shorter side was about to reverse the discrepancy. Unfortunately, this rationale was not always realized because after the staples had led to cessation of growth there was often no continuing growth of the physis once the staples were removed. Blount and Clarke (58) made their initial report on the control of bone growth by epiphyseal stapling and clearly laid out the principles of the approach. They pointed out the work of Haas (211,212), who had both proposed and demonstrated retardation of physeal growth by a circumferential wire loop, a discovery of "the principle of temporary arrest of epiphyseal growth." This approach utilized the principle of mechanical diminution of growth and was attractive to B lount because when Haas either removed the wire or the wire broke growth continued. Pressure inhibition of growth

SECTION IX ~ Management of Lower Extremity Length Discrepancies

665

Ci

curette

1

F I G U R E 19 Technical approaches to epiphyseal arrest are illustrated. (A) Drawing from Phemister's original work shows his outline of the reversed bone block technique. (B) The White modification of the Phemister technique is illustrated. At left the medial and lateral distal femoral and proximal tibial blocks to be removed are outlined. Once removed, the 0.5-in. square plugs containing epiphyseal bone, the epiphyseal growth plate cartilage, and metaphyseal bone are rotated 90 ~ and reinserted. Bone tissue now completely covers the physis and the bone bridge formed bilaterally tethers growth and leads to its cessation. The fibular block soon was recognized as being unnecessarily large, and for fibular arrest most now simply curette the physis, which also minimizes the chance of damage to the peroneal nerve. (C) Surgical approaches for the Blount stapling technique are shown in part (Ci). The medial approach is shown at left and the lateral approach at right. (Cii) The correct insertion for the distal femoral and proximal tibial medial staples is shown. Each prong is equidistant from the physis, and the alignment of the staple is parallel to that of the epiphyseal growth plate with the cross bar at right angles to the physeal cartilage and parallel to the bone surface. Three staples were placed medially and three laterally in each bone requiring arrest. [Part A reprinted from (387), Part B from (56), Part Ci from (58), and Part Cii from (56), with permission.]

had also been demonstrated experimentally by Arkin and Katz (26). Haas (211) had utilized a mechanical principle of limiting physeal growth by passing a wire around the epiphyseal plate with one transverse path across the metaphysis and the other across the secondary ossification center with the ends twisted together to provide a continuous loop. Several experiments in the dog were performed, each of which showed a definite loss in length growth of the bone. In some instances

the wire either broke or came loose at which time growth continued, indicating that physeal growth while restrained by the intact wire did not lose its full potential, which could be realized once the restraint was released. A few similar procedures were performed on patients with some definite evidence of growth retardation noted. In the human growth also continued after breakage of the wire. Haas (212) performed additional investigations in an effort to make the technique of clinical value. In a second series of studies

666

CHAPTER 8 9 Lower Extremity Length Discrepancies

staples were used instead of wire loops. The staples applied unilaterally across the physis arrested growth on the side of insertion and also restricted it on the opposite side to a lesser degree. In many instances there was evidence of complete cessation of physeal growth. Enormous forces generated by the growing physis were readily apparent because either a single staple or the wire loop of Haas often broke, allowing growth to continue. Even when two staples were placed there was often separation of the tips or widening of the staples, again indicating the powerful forces of growth not fully controlled by the staple. Blount and Zeier (59) pointed to the work of Strobino and Colonna showing that a force greater than 120 lb was needed to halt proximal tibial growth in a calf. The routine use of three staples on the medial and lateral sides of the physis was then adopted for clinical cases and the procedure was proposed for distal femoral and proximal tibial growth arrests, which during that era generally were for poliomyelitis. The procedure, which appeared technically quite simple, was adopted widely with relatively less consideration for timing because it then was accepted that any imperfect timing could be remedied simply by removing the staples, at which time growth would resume. In a second report, Blount and Zeier (59) reviewed 117 staplings noting few complications. They concluded that staples could be left in place for at least 2 years and still removed with the expectation that growth would be resumed. After the removal of staples there was usually a local growth spurt lasting a few months. Frantz (166) reviewed 10 clinical papers summarizing the first two decades of work within the orthopedic community with this technique. Benefits and drawbacks became more clearly defined. One of the problems, which was basically present in any epiphyseal arrest operation, was that of timing. Green and Anderson reported on both formal epiphyseal arrest and stapling and felt that both procedures were satisfactory with the incidence of complications being relatively insignificant, although they used the stapling for definitive growth cessation. The complications reported, which tended to appear early in any series, included buffed staples, metal reaction, overcorrection, premature physeal closure, peroneal palsy, knee joint laxity, misplaced staples, fractured staples, extrusion of staples, angular deformity, infection, genu valgum, and false aneurysm. It was widely agreed that stapling was not warranted under the age of 8 and preferably 9 years. In an experimental series of studies, Heikel (226) demonstrated that epiphyseodesis of the proximal tibial plate had no effect on subsequent longitudinal growth distally. Siffert (438) performed asymmetric stapling of the distal femoral epiphysis in rabbits and noted production of the varus deformity with gradual histologic thinning of the physis and eventual transphyseal bone arrest. Goff (186) studied 120 biopsies of children at various stages of growth deceleration and arrest following stapling. He observed that the direct compression by staples served to inhibit the proliferation stage of the physis. The thinness of the disk increased

with time. The most sensitive signs of diminished growth were increased degeneration and shortening of the hypertrophic region. Eventually all of the hypertrophic cells disappeared and new bone formation crossed from metaphysis to epiphysis. Bone bridge formation was present invariably after 4 years or 48 months, although the markedly abnormal structure prior to that time would appear to have had little potential for regrowth. Bylander et aL (80) studied growth of the physeal regions following stapling using their highly accurate radiographic stereophotogrammetric analysis. There was a uniform pattern of growth retardation following stapling, which lasted over a period of several months to years. This pattern indeed was evidence of the applicability of the original theory of stapling because it indicated slowing of physeal growth to basal levels rather than complete cessation of growth. Bylander et al. calculated that growth at the distal femur and proximal tibia in human patients continued at a low basal level of about 5-10 Ixm per day, particularly when stapling was performed at younger skeletal ages. Blount (57) later pointed out the need for precise placement of the staples, feeling that many of the imperfect results reported were due to improper timing or less than ideal technique. The upper and lower prongs of the staple were to be equidistant from the physis and the cross member was to be perpendicular to the growth plate and parallel to the surface of the bone into which it was being driven (Figs. 19Ci and 19Cii). The staples were to be angled such that the tips of the prongs pointed toward the central axis of the distal femur or proximal tibia. Stapling was best performed after the patient had reached the skeletal age of 8 years. It was inappropriate to perform the stapling procedure according to a schedule set up for epiphyseal arrest because the stapling procedure was based on a different principle, namely, allowing for correction with growth but not being designed to cause complete cessation of growth. Staplings were thus performed earlier than epiphyseal arrests. It was important not to bury the staples under the periosteum because they would be difficult to find at the time of removal and more likely to cause periosteal new bone formation and growth plate bridging. Blount indicated that "stapling of an epiphysis retards growth 80-90% for the next few years. It causes a temporary growth spurt at the other end of the bone. At the stapled epiphysis elongation is decelerated only 50% during the first six months. Some growth continues until a year or less before the normal time for epiphyseal closure." Many continue to use this technique because it is an effective, accurate, and relatively simple way of causing the cessation of growth if the staples are not removed prior to skeletal maturity. Sengupta and Gupta (429) reported on the value of epiphyseal stapling. They used two staples on each side of the distal femur effectively in the large majority of cases, rarely resorting to three per side. The two staples on each side were equidistant from each other with their tips pointing toward the center of the physis. Seventy-one percent

SECTION IX ~ Management of Lower Extremity Length Discrepancies

of the 503 procedures led to a discrepancy of 0.5-1.0 cm of shortening at the end of growth with only 3% showing more than 2 cm of shortening. The staples should be removed at skeletal maturity. Stapling increasingly is used in situations in which only a medial or lateral growth arrest is desired to allow for the correction of angular deformity without performing an osteotomy. d. Percutaneous Technique. In this procedure, growth plate obliteration is performed through a small incision with physeal visualization by fluoroscopic image intensification (65, 92). Lateral and medial incisions are made immediately over the physis to be ablated, but for some surgeons the approach is only from one side. The soft tissues are dissected down to the physeal region at which time a guide wire and cannulated 4 - 6 mm wide drill bit is inserted. Under radiographic control, drilling is performed across the physeal region anteriorly, at the midline, and posteriorly. This serves both to destroy the cartilage and to allow for communication between epiphyseal and metaphyseal vessels, thus leading to transphyseal bone bridge formation. The postoperative scars are smaller and rehabilitation is quicker than in the previous physeal ablation techniques. The procedure was reported by Bowen and Johnson (65) in 1984 and by Canale, Russell, and Holcomb (92) in 1986. Ogilvie (351) provided an experimental report in 1986 and a clinical assessment (352) in 1990. Each group reports some differences in technique, although the principles of small incision, percutaneous surgery, and growth plate obliteration under fluoroscopic control are common to all. The physis has been damaged with the use of a drill, drill and curette, drill and burr, or osteotome and curette. Ogilvie (351) has demonstrated well the importance of several passes through the physeal plate in a fanlike pattern to assure complete obliteration. Excellent long-term results have been reported both by the original authors and by others subsequently adopting the technique. In the original report of Bowen and Johnson (65), the resuits of 12 percutaneous epiphyseal arrests noted no complications. In their later series, complications were uncommon. There were no fractures, no neural or vascular complications, and no angular deformity. Canale et al. (92), in their initial report on 13 percutaneous epiphysiodesis operations, reported that all growth plates appeared to be fused with no major complications and no clinical evidence of subsequent angular deformity. A later report by Canale and Christian (93) on 22 children with percutaneous epiphyseal arrest noted that arrest was achieved in all with no patient developing angular deformity. Ogilvie and King (352) in 7 epiphyseal arrests reported no failures of fusion, postoperative infections, restricted joint motion, or angular deformities. Horton and Olney (240) reported 42 percutaneous epiphyseal arrest procedures in which all patients achieved physeal arrest radiographically and clinically and no patient developed angular deformity from an incomplete arrest. There were no neurovascular complications or fractures. Timperlake et al.

667

(476), in a detailed study from the DuPont Institute, reported on 53 consecutive percutaneous epiphysiodeses. In their procedure, the medial and lateral two-thirds of the growth plate are ablated, but the central one-third is preserved for stability. They approach the physis from both sides, use a 3-mmwide osteotome driven 1 cm into the growth plate and rotated 180~ to create a hole in the cortex, and then use a 3-mm-wide oval curette that is swept across the growth plate to ablate it. A report by Gabriel et al. (171) recorded the results of percutaneous epiphyseal arrest in 56 physes using a cannulated 10-mm drill bit over a guide pin followed by curettage. There were no severe complications of angular deformity, deep infections, or neurovascular problems. 2. RESULTS OF TIMING DECISIONS FOR EPIPHYSIODESIS

The timing of epiphyseal arrest is still an imperfect science, and studies continue to appear indicating a range of discrepancies at skeletal maturity from fully acceptable to amounts still leaving lower extremity length discrepancy out of the desired therapeutic range. It is not essential in a clinical sense for limb lengths to be equalized because a fully acceptable result by all the criteria is to move the discrepancy to a value under 0.5 in., which is generally reported in papers as ranging between 1.0 and 1.2 cm. Even those patients with a discrepancy moved to within 0.75 in. or less than 2.0 cm would appear to have few long-term problems because of the slight difference. Because many factors go into an accurate projection of the timing for epiphyseal arrest, the better results appear to be produced by those centers at which large numbers of procedures are performed and at which a small group of individuals or a specific unit is responsible for timing the procedures. Relatively few problems are reported with the various surgical techniques used to cause the epiphyseal arrest. Two problems characterize the studies reporting less than perfect results. One is the widespread recognition of the relative inaccuracy of the skeletal maturation tables used as a key indicator of timing in most systems. The Greulich and Pyle atlas using posteroanterior radiographs of the left wrist and hand remains the most widely used indicator. There is still considerable subjectivity, however, with this system and, in addition, the radiographs used are spaced at either 6-month or 1-year intervals, which represents a considerable margin of difference between age gradings. The other problem appears to be referable to the nature of the predominant disorders being studied in any particular series. Very few studies take into account the differing developmental patterns of the lower extremity length discrepancies that have been described. In those series in which type I and type II patterns predominate, there is relatively little problem with utilizing the more straightforward projections of the Green-Anderson, Moseley, or Menelaus methods. Where, however, there are relatively large numbers of type III, IV, and V discrepancies, the failure to recognize these patterns can further worsen the

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CHAPTER 8 ~

Lower Extremity Length Discrepancies

accuracy of timing. Studies reporting on timing in epiphyseal arrest procedures should be read with these considerations in mind. A study by Blair et al. (54) reviewed retrospectively 67 distal femoral and proximal tibial epiphyseal arrests performed over a 14-year period. Only 22 patients had a final discrepancy of less than 1 cm. Setting aside 10 of 45 failures due to inadequate surgical technique, the remaining 35 failures were secondary to errors in timing. This report utilized the Green-Anderson growth predication tables. Porat et al. (389), on the other hand, reported good results in 90% of their patients, although the series was small involving only 20 children. In 5 children with anisomelia whose expected discrepancy was 4.5 cm, results at maturity show an average discrepancy of 0.7 cm. In 10 girls with lower extremity length discrepancies caused by ischemic necrosis with congenital dislocation of the hip, the average discrepancy at maturity was 0.6 cm with the expected nontreated value 4.0 cm. In 5 children with the discrepancy caused by infection, the average discrepancy was 3.8 cm at the time of epiphyseal arrest, whereas at maturity it had diminished to 0.5 cm. This group utilized the Moseley straight line graph, CT scanograms for length determination and the percutaneous epiphyseal arrest procedure. Lampe et al. (282) performed a prospective study in 30 children who underwent 33 epiphyseal arrest procedures using the Moseley straight line graph method. The mean predicted length discrepancy was 5.2 cm and the mean discrepancy at the end of growth was 1.4 cm with a range from 0 to 4.3 cm. In 9 patients out of the 30 (30%) the final length discrepancy exceeded 1.5 cm. They felt that the altered skeletal maturation was most problematic in those cases in which the projection was inaccurate. Variation in radiographic determination of skeletal age was also a source of error as noted by Cundy et al. (128). Little et al. (301) reviewed 71 epiphyseal arrest procedures in effort to compare the Green-Anderson, Moseley, and Menelaus methods of projection. They felt that each of the different methods did not have a meaningful superiority in projecting the end result and that all had somewhat limited accuracy. They thus advocated the Menelaus method due to its simplicity. The mean preoperative discrepancy in their series was 3.12 cm (range = 1.4-7.4 cm) and the mean discrepancy at follow-up was 1.05 cm (range - - 2 to 4.4 cm). Little et al. determined that 34% of the patients (24) had discrepancies greater than 1.5 cm at skeletal maturity and 27% (19 patients) had discrepancies greater than 2.0 cm. This study was quite detailed in that eight different methods were assessed involving four variations of the Anderson and Green technique and two each of the Menelaus and Moseley techniques. They concluded that it was the inherent variability of the individuals requiring epiphyseal arrest that prevented the methods from predicting the outcome more satisfactorily. Little et al. (301) also felt that it was the inability to project the date of skeletal maturity that played the major role in the imperfect results. The group also felt that

CT documentation of the length discrepancies provided the most accurate determination with the least amount of radiation. In reality there should be relatively little difference between the Green-Anderson and Moseley approaches, and even that of Menelaus, because each of these approaches uses the same source of growth data, this being the GreenAnderson femoral and tibial length charts and growth remaining charts. The Hechard-Carlioz (223) chart is also a differing method of expression of the Green-Anderson data. 3. PARTIAL THERAPEUTIC GROWTH PLATE ARREST There are two treatment situations that can lead to a recommendation for the performance of an asymmetric or partial growth plate arrest. a. To Complete an Already Existing Focal Arrest to Prevent Further Angular Deformity. Partial arrest of an affected epiphysis can be performed to terminate all growth in a growth plate that has suffered a focal or partial arrest that is considered to be too extensive for bone bridge resection. By completing the arrest across the entire width of the growth plate, development or worsening of the angular deformity is prevented. Projection of the amount of growth remaining in the opposite physis should be made. If the patient is near skeletal maturation, no additional measures are needed. If further growth is in the 2- to 5-cm range, contralateral epiphyseal arrest is warranted to prevent an invariable discrepancy from developing. If the growth remaining is greater than 5 cm, the need for ipsilateral lengthening should be discussed. b. To Treat Angular Deformity without the Need f o r Osteotomy. The second reason for the performance of an asymmetric or partial growth plate arrest relates more to treatment of the angular deformity than it does to treatment of shortening. It was recognized early in this century that the creation of an asymmetric growth plate arrest would still allow the remaining physis to continue to function such that it could be used to correct the angular deformity without the need for complete osteotomy. The earliest proponents of widespread use of this treatment were Blount (57-59) and colleagues, who utilized stapling on one side of an epiphysis to correct angular deformity. The technique has its major application at the distal femur or proximal tibia for angular deformities centered at the knee. Blount and colleagues (520) reported on 82 knees treated with epiphyseal stapling over a 20-year period and followed to skeletal maturity. The deformities were allowed to overcorrect before the staples were removed and an effective rebound phenomenon occurred in 22 patients with 35 deformities. In older children the staples were removed when the legs looked straight. Blount felt that exaggerated physiological deformities may correct spontaneously and should not be stapled before the skeletal age of 11 years in girls and 12 years in boys. Deformities secondary to specific disease processes could be corrected earlier although rarely below 8 years of age. B lount et al. concluded that results were satisfactory or improved 87% of the deformities corrected. Two staples were used

SECTION IX

9

Management of Lower Extremity Length Discrepancies

in most patients. There were 64 valgus deformities and 18 varus deformities. The two largest groups of patients were idiopathic-physiologic or secondary to poliomyelitis, with other scattered disorders involving hemihypertrophy, rickets, and occasional skeletal dysplasias. Two features are associated with removal of the staples when growth is still active. The group generally allowed for some overcorrection, counting on the rebound growth phenomenon to occur in which the stapled side of the bone elongated more rapidly than the other for a few months after staple removal. Following that the rate of growth tended to remain equal and then the physis closed 4 - 6 months prematurely on the stapled side. It is evident that a considerable amount of personal experience and judgment go into the timing of such procedures. Bowen e t al. (66) established a chart in an effort to project the appropriate time for the correction of any particular degree of angular deformity (Fig. 20). Rather than relying on stapling with removal of the staple after a certain degree of overcorrection, they performed a bony epiphysiodesis asymmetrically based on a timing chart. Their operation was performed for idiopathic or physiologic genu valgum or varum in the adolescent patient. With an asymmetric stapling, for example, on the medial side of the distal femur, continued growth from the lateral physis would be expected. The growth, however, would not be linear but would represent an arc of a circle with the radius equal to the width of the bone measured at the physis. The arc of continued growth relates to the angle of deformity as the circumference of the circle relates to the total number of degrees in the circle. With the use of a specific formula a chart was constructed to relate the amount of growth remaining to the angular change for varying physeal distances. This information was then combined with the Green-Anderson growth remaining chart, which allowed the angular deformity to be related to the linear growth remaining for the patient's skeletal age. An early study of 13 extremities treated surgically indicated that, as a general rule, following partial tibial epiphyseal arrest 5 ~ of angular correction could be expected for each year of remaining growth and following partial distal femoral epiphyseal arrest 7 ~ of correction could be expected for each year of remaining growth. The mean ages at surgery were quite similar to those recommended by B lount and his group. In the 7 patients having procedures on 13 extremities, the average chronological age was 12 years 8 months with the girls averaging approximately 12.5 years of age and the boys slightly more than 13 years. The average preoperative deformity was 11.6 ~ of femoral-tibial valgus and the average deformity at follow-up was 6.6 ~.

4. METAPHYsEAL SHORTENING OSTEOTOMIES Wagner (492) has pointed out the value of correcting a longer femur or tibia, which also has angular or rotational deformity, by performing a metaphyseal shortening osteotomy. The most common site is the proximal femoral metaphysis followed by the distal femoral metaphysis. He stressed main-

GIRLS

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DISTAL FEMUR

Greul,ch-Pykl A l l .

Skeletal A p t From

669

BOYS DISTAL FEMUR

CM 8 7 6 5

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FIGURE 20 Asymmetricstapling is performedto allow for the correction of angular deformity without need for osteotomy. A chart developed by Bowen et al. estimates the correct time of asymmetricepiphyseal arrest in relation to the patient's skeletal age and the degree of angular deformity correction sought. [ReprintedfromDePalmaand Cotler(1956),Clin. Orthop. Rel. Res. 8:163-190, 9 LippincottWilliams& Wilkins, with permission.]

tenance of a medial cortical strut in continuity with the lesser trochanter to allow for stabilization and a greater area of bone repair at the osteotomy site. An AO large fragment blade plate is used for stabilization. Shortening osteotomies of the distal femoral metaphysis are carried out in a similar fashion. A strut of medial cortical bone in the metaphyseal region is also left intact. The distal femoral metaphyseal shortening osteotomy is often complicated by relatively slow rehabilitation due to periarticular scarring and knee joint stiffness and due to disruption of the quadriceps mechanism. That site is chosen, therefore, only if the angular bone deformity necessitates correction there. Bianco (47) has reviewed shortening and angular correction procedures in the femur. Metaphyseal shortening osteotomy of the tibia and fibula is recommended only if angular deformity necessitates such a procedure. The tibia should rarely be shortened by more than 4 cm. The advantage of the metaphyseal site for shortening is the rapid bony consolidation. If metallic fixation is used, closure can be difficult and complications can occur in relation to the peroneal nerve with a relatively marked shift in length and alignment. If possible diaphyseal procedures are recommended when tibial shortening appears mandatory.

5. DIAPHYSEAL SHORTENING (RESECTION) The diaphysis can be shortened at skeletal maturity to make the final length of the limbs the same. The exact

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CHAPTER 8 9 Lower Extremity Length Discrepancies

amount of bone required is removed and the bone is stabilized with a metal plate, screws, or an intramedullary rod. When performed at skeletal maturity there is no concern about overgrowth following surgery and no need to project the final discrepancy. This approach is recommended primarily for discrepancies between 2.5 and 5 cm that were not detected by or persist at maturity. Shortening of the bones of the longer leg to achieve length equality is a much older and simpler procedure than elongation of the shorter leg. Blount and Zeier (59) have credited Rizzoli of Italy with the earliest descriptions of this procedure. White (499) and Wilson and Thompson (508) reported early attempts from the late nineteenth and early twentieth centuries, which generally involved fracturing of the shaft of the femur or open oblique osteotomy, allowing the fragments to overlap the necessary amount, and then treating the limb until healing occurred. The first formal shortening of the tibia and fibula was reported by Brooke (75) in 1927 in which segments of bone, 1 and 2 in. long, respectively, were removed and then applied as grafts to enhance healing. The femur could also be shortened by a stepcut method followed by internal fixation. The first large series of cases was reported by Camera (85), who resected a portion of the femoral shaft and then used the resected bone as an intramedullary graft. He reported on 32 cases with the average period of external fixation being 50 days. Moore (334) reported on 13 femoral shortenings with bone resection with the average amount of shortening obtained 2.5 in. and the average period for complete union being 2.5 months. White (499) reported on 45 cases of femoral shortening with a transverse osteotomy of the shaft, overlapping of the two fragments by the necessary amount, and fixation by long metal pins, which were then incorporated into a hip spica cast. Treatment then followed with casting and eventual bracing. Many patients were under age 14 years; in younger children he shortened 0.5 in. more than necessary to compensate for the overgrowth phenomenon. The quadriceps muscle always maintained its ability to fully extend the knee with no loss of strength detected. The average amount of shortening obtained was 2.5 in. with a range between 2 and 3.12 in. Wilson and Thompson (508) reported 5 femoral shortening operations using the White technique with an average shortening of 2.12 in. obtained. They reviewed the major series of lower extremity shortening procedures. In the works reported previously plus their own there were 98 femoral and 2 tibial shortening procedures for the 100 cases. The only 2 tibial procedures were those reported by Brooke. The average shortening obtained was 2 in. and the complications reported were relatively small, involving separation of fragments necessitating reoperation in 2 cases, infections in 7, delayed union in 2, and no instances of nonunion or angular deformity. In comparison to the results reported during that era for limb lengthening the relative simplicity of the procedure was clearly shown.

The large majority of lower extremity diaphyseal shortening procedures are still performed in the mid-diaphyseal or proximal subtrochanteric region of the femur where negative postoperative sequelae are less marked. There have been reports of the inadvisability of performing shortening of the tibia and fibula due to increased problems with nerve or vessel kinking or muscle control at the foot and ankle region afterward. The muscle compartments are much tighter than those of the thigh and they have more structures passing through them in a smaller area. As a result, the lag effect and the compressive effect of vascular disruption are greater in the leg. Some reports of leg shortening with good results are described next, however. An effective approach is to shorten the femoral diaphysis by resection, following which an intramedullary rod is placed to allow for rigid stabilization and immediate weight bearing (Fig. 2). Our preference is to perform open shortening of the diaphysis to remove the diaphyseal segment of the bone. There are also reports of closed shortening in which the osteotomy site is not opened so as to limit the incidence of infection and perhaps hasten the rate of healing. The operative success rate is improved with the use of an AO universal intramedullary nail locked statically at both proximal and distal sites (269). Excellent results can be achieved if the complications of malrotation and distraction at the osteotomy site are prevented (Fig. 21). As with any femoral fracture or osteotomy in the nonchildhood years, fat embolism can be encountered. Shortening of up to 2 in. or 5 cm can be performed readily in the femur in one stage. There is concern about performing more shortening than this due to the lag effect of the shortening on the quadriceps muscle. In the large majority of studies performed, any quadriceps lag can be overcome usually within 1 year of surgery with intensive physical therapy. It is, however, difficult to guarantee this effect if more than 5 cm of bone is removed. Two complications of the shortening technique that must be guarded against carefully are stabilization of the femoral fragments with inappropriate rotation and subsequent loss of close apposition of the fragments, which not only increases the likelihood of delayed or nonunion but also leads to a failure to gain a complete correction of the discrepancy. Both the rotational and distraction possibilities with intramedullary rodding can be minimized with the application of a small four-holed AO side plate with a unicortical grip or with the use of a universal AO nail with static locking proximal and distal screws. Liedberg and Persson (300) reported on 11 midshaft femoral shortening procedures in which stability was provided with a reamed Kuntscher intramedullary rod and a step osteotomy for rotational control. D'Aubigne and Dubousset (133) described excellent results with a step cut or Z shortening followed by intramedullary stabilization and fixation with screws to control rotation. Femoral shortening can also be done with the correction of proximal and distal angular deformity by removing appropriately shaped trapezoidal wedges.

SECTION IX ~ Management o f Lower Extremity Length Discrepancies

671

F I G U R E 21 Radiographs of a case of femoral shortening stabilized by an intramedullary rod are shown. Five centimeters were removed from the longer femur at skeletal maturity at open operation. (A) An anteroposterior film of the proximal two-thirds of the femur approximately 10 weeks postsurgery shows the healing osteotomy site. There are two transfixation screws proximally and two distally to serve as controls, preventing rotation or lengthening at the osteotomy site. (B) A lateral radiograph at the same time shows the maintained position of the IM rod and healing progressing well. Anteroposterior (C) and lateral (D) radiographs show the fixation device distally. (E) Anteroposterior radiograph of entire femur at healing is shown.

Wagner (492) has commented on some of the important principles underlying diaphyseal femoral and tibial shortening osteotomies. Wherever possible he has recommended the use of an intramedullary nail as distinct from a side plate and cortical screws because the intramedullary nail allows for early weight bearing. With femoral shortening he recommends removing no more than 6 cm of bone to avoid muscular insufficiency, and he supports the use of open osteotomy to remove the bony segment from the diaphysis. Attention to rotation is important. Even with a tibial and fibular shortening osteotomy an intramedullary tibial nail is favored. Reaming of the medullary cavity is essential to ensure a tight fit and minimize the likelihood of rotational abnormalities. The tibia is resected in its narrowest portion at the middle one-third. The stable mechanical fit by an intramedullary rod makes the diaphyseal site for shortening preferable to metaphyseal except for those disorders in which axial correction is needed. a. F e m o r a l S h o r t e n i n g . In a review of 46 limb shortening operations, 37 in the femur and 9 in the tibia, Kenwright and Albinana (270) felt that shortening of as much as 7.5 cm could be done in the femur and 5 cm in the tibia in adults of normal height without any loss of function. Major problems with the technique were technical in nature and involved inadequate stabilization at the osteotomy site. Attention to detail, however, should minimize or eliminate these problems. They concluded that the optimal site for femoral shortening was at the subtrochanteric region using an open approach and stabilization with an intramedullary rod with

ml mlproximal locking. Extreme importance was attached to preventing separation at the osteotomy site postoperatively and in achieving appropriate rotation. After tibial shortening, one problem, cosmetic in nature, was complaint by the patient of a localized increase in the bulk of the leg. For that reason Kenwright and Albinana recommended that tibial shortenings be limited to 4 cm or less. Closed nailing had been shown to be reliable by Winquist (509) and by Blair et al. (54), who also expressed concern about controlling rotation, possible instrumentation breakage, and the mass of bone that persisted and was occasionally troublesome. They also felt that healing in the tibial shortening procedure would be most enhanced with excision at the level of the flare in the lower diaphysis. They used either a standard AO intramedullary nail or an AO plate but felt that, with intramedullary nailing, locking mechanisms should be incorporated. Sasso et al. (423) also demonstrated results after closed femoral shortening. Shortening averaged 4.4 cm with a range from 3 to 5 cm in 18 cases. Complications included 1 episode of fat embolism and 3 cases of loss of fixation. They limited shortening to 5 cm because of concern about quadriceps lag, and in no instance at this amount of resection were any negative sequelae noted with a full knee range of motion and excellent strength regained. One possible but rare complication of closed intramedullary nailing of the femur in association with shortening is avascular necrosis (AVN) of the femoral head. Mileski et al. (326) have reported such a problem in an adolescent female who at age 11 years underwent a closed intramedullary

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CHAPTER 8 ~

Lower Extremity Lenyth Discrepancies

femoral shortening. The rod subsequently was removed after healing. AVN was not diagnosed after rod placement but was noted 15 months after rod removal. The authors feltthat the vascular insult may have been caused by using a rod entry point that was placed slightly medially, although it was also possible that rod removal had contributed to the vascular insult. This represents the first report of this complication with femoral shortening, although Herzog et al. (233) reported 4 cases of femoral head necrosis following intramedullary Kuntscher nailing of femoral fractures in 26 children and O'Malley et al. (355) reported AVN in a 13-year-old boy with a closed intramedullary nailing of a femoral diaphyseal fracture. b. Tibial-Fibular Shortening. Broughton et al. (76) reported on 12 patients who underwent tibial and fibular shortening by diaphyseal resection to correct limb length discrepancies over a 25-year period. Each of the 12 patients did well with no major complications. A step-cut technique or Z-type shortening was employed for the tibia accompanied by a midfibular resection of the required amount. The tibial fragments were then stabilized by two screws. All operations except 2 were performed either at or just beyond skeletal maturity. The shortening achieved ranged from 2.5 to 5.1 cm. Normal function and appearance were documented in all following uneventful healing.

C. Procedures to Lengthen the Shorter Limb 1. STIMULATION OF EPIPHYSEAL GROWTH PLATE OF THE SHORTER LIMB

The earliest approaches to the treatment of lower extremity length discrepancy beginning in the late nineteenth century and continuing well into the first half of the twentieth century involved efforts to stimulate growth of the shorter side prior to skeletal maturity. There was early recognition of the fact that periosteal irritation frequently led to long bone overgrowth, and the therapeutic method that evolved from this observation was an attempt to stimulate and irritate the periosteum to allow for increased growth of the adjacent physis. Ollier (354) was the first to develop this technique. He performed periosteal elevation in the rabbit tibia causing overgrowth of 2-5 mm within 3 months. Over the subsequent few decades many methods were used to stimulate the periosteum, including cutting the periosteum, circumferential stripping or elevation of the diaphyseal periosteum, and placing objects underneath the periosteum to allow for chronic irritation (these objects included ivory pegs). Several differing techniques were used, however, both experimentally and clinically to enhance physeal growth. a. Sympathectomy In 1930 Harris (219) reported on lumbar sympathectomy performed on the short side of a patient with poliomyelitis to take advantage of the observation that those having sympathectomy for vascular disease frequently developed vascular dilatation and increased warmth of the affected side. It was postulated that this increased vascular

response would enhance physeal growth. In many instances overgrowth was indeed caused by the sympathectomies, but its occurrence was unpredictable and rarely exceeded 1 cm. These techniques are not used today. In a more detatiled presentation Harris and McDonald (220) in 1936 reported on the response to 46 lumbar ganglionectomies. Use of the procedure was based on the observation that in certain pathological conditions in growing children characterized by prolonged hyperemia in the neighborhood of the epiphyseal growth plates there was overgrowth of the involved extremity. They attempted to reproduce the earlier clinical finding by performing lumbar sympathectomy in several kittens, puppies, and lambs, but in no instance were they able to reproduce growth stimulation on the ipsilateral side. They performed 70 lumbar sympathectomies in patients with poliomyelitis and assessed the clinical response. Forty-six were available for review. Harris and McDonald showed many instances in which lumbar sympathectomy enhanced the growth of the extremity. In 21 of 46 patients (46%) the shortness had decreased by amounts varying from 0.12 to 1 in. The average age at time of surgery in this favorable group was 8.5 years. In 8 cases (17%) the amount of shortness present at operation remained unchanged, which still represented a positive response because the progressive shortening had ceased. Beneficial results were demonstrated in 63% of the cases. In 17 cases (37%) the shortness progressed in spite of operation. In many of this latter group the authors felt that effective sympathectomy had not been either obtained or maintained. When they subdivided their assessment to include only those with very clear sympathectomy, 20 of 29 cases showed diminution of shortness, 4 showed no increase in shortness, and in only 5 did the shortness increase. Beneficial effects on growth were thus increased to 82%. Barret al. (35) in 1950 assessed the results of 23 unilateral lumbar gangliomectomy procedures in patients with poliomyelitis. Ipsilateral lumbar ganglionectomy had, in some instances, a stimulating effect upon the growth of the shorter extremity. The most favorable interpretation of their results showed that the patients had an average decrease in discrepancy of 1.5 cm, based upon projections of the expected discrepancy. In the control group of 23 cases, 21 increased and 2 decreased with an average increase of 1.8 cm; in the ganglionectomy group of 23 cases, 13 increased, 9 decreased, and 1 was unchanged with an overall average increase in discrepancy of 0.3 cm. It was calculated that the average decrease in discrepancy with ganglionectomy was 1.5 cm. b. Surgically Induced Arteriovenous Fistula. Observations made in the late 1800s and early 1900s reported overgrowth of childhood limbs in patients who had sustained an arteriovenous (AV) fistula. Horton (239) reported 23 cases of congenital arteriovenous fistula with overgrowth of the involved extremity almost always seen. In midcentury efforts were made to incorporate this observation into clinical practice by surgically inducing arteriovenous fistulas in the mid-thigh region on the short side to treat developing limb

SECTION IX ~ Management of Lower Extremity Length Discrepancies

length discrepancies. James and Musgrove (252) showed the growth stimulation effect of an experimentally created arteriovenous fistula. Janes created the first AV fistula in a child with a short limb due to polio and 10 years later reported his results (251). Mears et al. (324) induced 55 fistulas and studied their results in detail. The fistula was placed between the superficial femoral artery and vein. There were no major cardiopulmonary complications. Thirty-nine patients were available for long-term review. All patients but 3 had a short limb due to polio. In 28 there was either a decrease or at least no increase in the amount of discrepancy. In 11 the limb length inequality continued to increase after the fistula was established. Thus, 72% of the group had a discrepancy that was diminished or stabilized by the fistula. Lengthening of the shorter leg after establishment of the AV fistula was 0-0.5 cm in 11, 0.5-2.5 cm in 13, and 2.5-5 cm in 4. When continued shortening occurred after the AV fistula, the amounts were still much less than would have been anticipated, with 5 patients having 0-0.5 cm of additional shortening and 6 having 0.5-2.5 cm of additional shortening. The growth pattern following establishment of the fistula was unpredictable and the response was quite variable in terms of extent. Petty et al. (386) assessed their results following surgical creation of a femoral arteriovenous fistula to treat limb length discrepancy in 28 patients. Of the fistulae made, 21 of 28 were performed when the patient was felt to be the optimal 8 or 9 years of age. The fistula was created between the femoral artery and vein in the mid-thigh region. Considerable complications occurred secondary to fistula creation although none was limb threatening. Closure of the fistula was eventually performed in all by 16 years of age. Of the 28 patients operated, 17 subsequently had an epiphyseal arrest on the opposite side. The average length discrepancy in this group was 4.6 cm at the time of fistula creation and the average increased to 5.9 cm at the time of epiphyseal arrest. Eleven patients did not have an epiphyseal arrest, and in this group the average discrepancy at fistula creation was 4.1 cm and at fistula closure it had decreased to 2.4 cm. Only 9 of 28 patients (32%) showed a decrease in length discrepancy of more than 1 cm as a result of an AV fistula alone. Twentyone of 28 patients (75%) showed no further increase in discrepancy, however. The authors concluded that "artificially created arterio-venous fistulae can accelerate growth in the lower extremity, but the results vary greatly and are unpredictable." By 1970 both Janes and Sweeting (253) and Petty et al. (386) no longer performed or recommended the procedure for treatment of length inequality. c. Elevation and Stripping o f the Metaphyseal and Diaphyseal Periosteum. Increased growth in length long had been noted after stripping of the periosteum of the metaphysis and diaphysis in several experimental animal procedures. An experimental study of stimulation of longitudinal growth of long bones by periosteal stripping in dogs and monkeys was reported by Sola et al. (450). They assessed

673

not only an initial periosteal stripping but also the effects following a second stripping 1 or 2 months after the first procedure. Once again there was a tendency to show increased growth, although it was not particularly marked nor was it invariably seen. In operations on dogs involving a single stripping of the femur and tibia, the mean increase in length was only 0.16 cm with 63% showing an increase of growth on the operated side. When two stripping procedures were done the mean increase was greater at 0.35 cm, but still only 69% of the animals showed an increase on the operated side. When two procedures were done on monkeys the increase was only 0.17 cm, although 87.5% showed an increase. The stripping procedure was extensive going from growth plate to growth plate in both femur and tibia. A detailed study of the effects of stripping of the periosteum in rabbits was performed by Wu and Miltner (513). Periosteal stripping was performed in variable parts of the fight tibia and fight femur. In all instances there was overgrowth on the operated side. Twenty-two rabbits were used. The fight tibia alone was operated upon in 18 animals and both the right femur and tibia were operated upon in 4. Definite longitudinal overgrowth of the operated bone was observed in all instances except 3. The amount was small and primarily limited to the first 3 months postsurgery, with the overgrowth varying from 0.5 to 6 mm. Chan and Hodgson (109) applied this procedure to 45 patients suffering from poliomyelitis, with the operations performed between 1961 and 1968. The age at surgery ranged from 5 to 13 years and all patients had a short limb at the time of surgery, averaging 3.4 cm (1.1-9.5 cm). The periosteum was completely stripped with an elevator in both the femur and tibia. A definite overgrowth greater than 4 mm was noted in 31 patients (69%), there was no significant increase or decrease in growth over the normal side in 9 (20%), and there was continuing shortness in 5 (11%). In the favorable group the average overgrowth was 1.3 cm during the mean time period of 9 months with a range from 0.6 to 4.4 cm. In many patients the overgrowth effect was noted to persist for as long as 1, 2, and even 4 years postsurgery. The average period of stimulation, however, could not be determined accurately. The authors concluded that it was best to perform the stimulation operation when the child was 8 years of age. No meaningful or long-term complications were seen. Jenkins et al. (257) studied 13 of these patients at a later time from 3 to 5 years postsurgery. They continued to note some degree of stimulation but again a variable response. In 28 femurs assessed 3-5 years following periosteal stripping, there was a mean increase in growth of 0.5 cm in 17, a decrease in growth of 0.81 cm in 8, and no change in 3. In the 26 tibias, 18 had an increase of 0.75 cm, 5 a decrease of 0.5 cm, and 3 were the same. d. Shortwave Diathermy. Doyle and Smart (145) reported that shortwave diathermy enhanced epiphyseal growth in rats. Preliminary experiments indicated that a temperature of 40~ would be effective to induce increased growth without

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CHAPTER 8 9 Lower Extremity Len~tth Discrepancies

tissue damage. The right lower extremity was maintained at this temperature throughout the treatment. Twenty female rabbits were used in which insulated copper plates, 2 • 8 in., permitted the administration of diathermy to 4 - 6 animals via a shortwave medical diathermy apparatus. Treatment was directed to the epiphysis of the right knee. The animals were treated for 0.5-1 hr each day or on altemating days from the 21st to the 70th day of life. The average total duration of diathermy was 25 hr. Of those animals appropriate for assessment, the treated right hind limb was longer than the untreated left in all instances. The increase in the combined length of the treated tibias and femurs varied from 0.4 to 2.8 mm, averaging 1.4 mm. The advantage of the procedure was that it would increase the temperature in tissues at deeper levels without causing bodily damage. Diathermy acted by producing deep tissue heating and increased blood flow. Shortly thereafter, Granberry and Janes (191) repeated the experiment on dogs without showing beneficial effects. They used microwave diathermy to increase the temperatures 3-5~ in the tibia. In their experiment, one knee each of 7 young dogs was heated by microwave diathermy at 100 W for a total of 100 hr, but they noted no significant growth alteration.

e. Efforts to Stimulate Epiphyseal Growth by Insertion of Multiple Implants and Creation of Bone Damage in the Metaphyseal Regions. Wilson and Thompson (508) noted that the many attempts to stimulate epiphyseal growth had not been successful enough to warrant clinical use, a feeling still prevalent after additional attempts since then. Compere and Adams (122) addressed the effects of trauma to the diaphysis on subsequent longitudinal growth. They performed two series of experiments in rabbits with limited trauma. Three drill holes were placed through both lateral and medial cortices near the upper and lower metaphysis and in the middle one-third of the shaft. This served to disrupt the medullary blood supply. When animals without fracture during the postoperative phase were assessed, there were no differences in the length of either the tibia or femur. This led to the conclusion that trauma sufficient to interrupt the medullary blood supply but not great enough to cause regional hyperemia did not consistently cause growth stimulation. Fractures were then made in the femur and tibia between metal markers to assess the overgrowth phenomenon. Compere and Adams demonstrated, in agreement with Bisgard, that overgrowth of a long bone may occur following fracture even without shortening and that the longitudinal overgrowth occurred entirely from stimulation of the epiphyseal growth cartilage. They then assessed patients in relation to the growth of tibias from which bone grafts had been taken. Growth arrest lines were used for the assessment. Small amounts of increased growth ranging from 0.1 to 0.8 cm occurred following tibial bone gratis. Evidence was clear that the growth stimulus lasted only as long as healing of the defect site was occurring. Compere and Adams concluded that minimal trauma to the shaft or to the metaphysis of the long bone with or without interruption of the medul-

lary blood supply did not produce any definite increase in longitudinal bone growth. Gross trauma such as that caused by a fracture or removal of a large segment of bone for grafting, both of which necessitated extensive bone repair, did reproduce epiphyseal stimulation and increased longitudinal overgrowth. The increased rate of growth continued during the period of healing but not much beyond. The growth stimulation appeared secondary to the hyperemia, which included the epiphyseal region. Wu and Miltner (513) reviewed clinical situations in which overgrowth occurred. Metaphyseal and diaphyseal fractures were known to cause overgrowth in long bones in children. Infection could clearly damage growth if it involved the physeal cartilage, but in instances in which the physeal cartilage persisted the increased hyperemia led to overgrowth. They performed several experiments on rabbits aged 5-8 weeks to assess growth phenomena. Group 1: Insertion of foreign material into a drill hole placed immediately distal to the proximal epiphyseal cartilage of the tibia. The foreign materials included cotton, gauze, paper, wood, brass, and iron shot. There was no difference in the length of the bones operated. Group 2: Indirect interference of circulation of bone. The epiphyseal circulation was left intact but the nutrient arteries and periosteal vessels were damaged extensively. There was no appreciable change in longitudinal growth of the bone after the experiments. Destruction of the nutrient artery and the extra-periosteal blood supply in particular caused no changes in the longitudinal growth of the bone, agreeing with the extensive studies of Oilier and Haas. Group 3: Curettage of bone marrow. The tibial bone marrow was curetted through a metaphyseal drill hole. There was no significant change in the length of the operated bones. Group 4: Stripping of the periosteum. Many variable patterns were used, and in virtually all instances definite longitudinal overgrowth of the operated bone was seen from 0.5 to 6.0 mm. Chapchal and Zaldenrust (111) assessed the effect of various metals, metal alloys, and ivory placed in the metaphyses and also in the epiphyses of the bones comprising the knee joints of several animals. They concluded that some lengthening of the bones was obtained but that the amount was minimal and uncertain. Pease (376) attempted to assess overgrowth using foreign bodies in the metaphyseal regions. His work also involved clinical investigation of the phenomenon. He placed transverse screws across the entire metaphyseal diameter of the distal femur and/or proximal tibia using vitallium, stainless steel, vanadium, and ivory screws. Two screws per region were used. In all cases stimulation of growth followed the operation to a variable degree, and there were no deformities indicative of asymmetric stimulation. The screws were placed parallel to each other and to the adjacent growth plate and extended to or slightly through the opposite cortex. Seven patients were operated with two screws placed in the tibia and femur in most with 1 patient having the procedure only in the femur. The operation was

SECTION IX 9 Management of Lower Extremity Length Discrepancies

repeated occasionally. Seventeen segments were stimulated. In two instances there was no overgrowth, whereas in the others overgrowth stimulation varied from 0.1 to 2.2 cm. The mean length increase for 17 cases with growth stimulation was 0.7 cm. Carpenter and Dalton (97) repeated the clinical work in 30 cases in which epiphyseal stimulation was attempted by the use of intramedullary implants in a distal femur and proximal tibia. The periosteum was elevated and a cortical window was made to the metaphyseal side of the distal femoral and proximal tibial growth plates. The medullary canal was curetted and the cavity then tightly packed with small chips of ivory. Each patient was followed for a minimum of 2 years with radiographic and clinical measurements made at 3-month intervals. Some increase in growth was obtained in 26 of the 30 patients. The gain was 0.12 in. in 10, 0.25 in. in 11, 0.5 in. in 3, 0.75 in. in 1, and 1 in. in 1. In 70% of the cases the maximum gain was only 0.12-0.25 in., and it was concluded that the degree of stimulation was neither great enough or predictable enough to warrant clinical use. Tupman (483) reported a detailed study to stimulate bone growth by inserting beef bone pegs into the epiphyseal and metaphyseal regions in children. The first clinical attempt to stimulate growth in dogs by introducing ivory pegs into the femur and tibia was in 1869 by vonLangenbeck, who claimed 1 cm of overgrowth in 3.5 months. Tupman reviewed 28 patients who had a total of 51 operative procedures. Insertions of material were in the distal femoral and proximal tibial metaphyses. Three tunnels were made with a drill in the metaphysis close to but not involving the physis. Into each of these tunnels in the femur and tibia, a beef bone peg was inserted across the bone diameter. In some, ivory pegs were inserted for comparison. In one part of the series performed at one hospital, no leg subjected to a single operation showed any evidence of acceleration of growth. It was felt, however, that documentation might have been somewhat inadequate. In a second series at another hospital, there were groups in which effective stimulation took place, some in which the operation had no effect on progression, and some in which the operation was fully ineffective. Only limited conclusions could be made. The operation appeared to be more effective in younger children than in those close to puberty. The best that could be said was that the growth was stimulated somewhat in 12 of 28 patients, with the best resuits seen when the operation was performed between 6 and 12 years of age. Once again some stimulation was noted, but it tended to be of a small amount and unpredictable. 2. LENGTHENING OF THE DIAPHYSIS

a. Clinical Approaches from 1900 to the 1960s. Much interest in, and occasional efforts at, lengthening lower extremity long bones was reported in the nineteenth century. No acceptable techniques evolved, but valuable biological and mechanical principles gradually became evident with continued work over the next several decades.

675

Codivilla: Well-documented attempts at long bone lengthening date from accounts by Codivilla of Bologna, Italy, in 1903 and 1905 (114). He began one of his articles with the following, still relevant sentence: "The difficulties to be encountered in lengthening a shortened limb are found in operation to be greater as regards the fleshy parts than as regards the bones." Following osteotomy or fracture of the bone, skin traction had been applied characteristically with limited effect due to pressure necrosis of the skin, pain, and the fact that much of the force applied "did not reach the skeleton." Codivilla went on to describe the evolution of his technique, which eventually involved osteotomy of the bone, application of a hip spica cast, removal of the foot portion of the cast, application of a force directly to the skeleton with transverse placement of a calcaneal wire of 5 - 6 mm diameter, incorporation of the transverse pin and two side bars into the plaster cast, cutting of the cast at the level of the osteotomy, and application of counterbalanced traction to gain length immediately followed by completion of the cast at the desired length until healing. Codivilla reported on 26 patients who gained between 3 and 8 cm. Freiberg (169) supported the validity of the approach, using it following a femoral fracture in a 9-year-old boy to reduce a 2.25-in. shortening to 0.5 in. 5 weeks after injury. A double skeletal transfixator method, after the length had been achieved, then evolved. Ombredanne: Ombredanne (356) began utilizing principles subsequently incorporated in more formal apparatuses at later times. In 1913 he described an oblique osteotomy and lengthening of the femur slowly and gradually with an apparatus fitted to the side of the thigh and working against one pin inserted above the osteotomy site and one below. He achieved up to 4.0 cm of lengthening, but no detailed followup of the procedure was performed. Putti: The next technical advance in limb lengthening was described by Putti (396), also of Bologna, in 1921. He described a need for lengthening of the femur when the discrepancy was greater than 2 in. and questioned early on whether lengthening of such a magnitude was "possible without damaging the muscles, nerves and vessels." His own work and that of Magnusson then showed the possibility of lengthening safely by 2-3 in. Putti defined the need for continuous traction. He developed a unilateral distraction apparatus for lengthening the femur, which used two large transcortical metal pins on either side of the osteotomy held apart by a telescoping tube that contained a strong spring press moved by a screw. The apparatus was designed to be sufficiently strong to overcome resistance, to stabilize the osteotomy site and the alignment, and to provide traction. Gradual traction was applied to separate the bone fragments, but the time taken for lengthening was not reported. Putti (397) elaborated on operative lengthening of the femur in 1934, with an altered technique. He stressed that operative bone lengthening was particularly valuable during the period of "childhood when the reparative power of the

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CHAPTER 8 ~ Lower Extremity Length Discrepancies

long bones is most vigorous thereby minimizing the danger of non-union." Skeletal traction mandated the use of skeletal countertraction. The Z osteotomy was replaced with an oblique osteotomy. The patient then was put in bed with traction placed on the upper wire. Increasing traction was applied to the lower Kirschner wire until the desired length, usually from 2.5 to 4 in., was attained. This gradual skeletal traction usually required 18-21 days. A hip spica cast was then applied with the transfixion wires included, at which time the traction was discontinued. Results were reported in 11 patients. Putti added that "in the eleven cases I have treated by this method no complications whatever arose other than a single case of temporary 'toe drop' caused by overstretching of the external popliteal nerve presumably due to faulty position of the knee. The paralysis promptly cleared up with rest." The concept of gradual traction was introduced, and Putti indicated that the time required to obtain the desired lengthening was approximately 20 days. The period of immobilization in the corrected position was 4 months in a plaster cast with an additional period of limited support for several months, during which physical therapy continued. No indication was made of the amount of lengthening achieved. Magnuson (308) described femoral lengthening of 2.5-4 in. in 14 patients using double transfixion wires and plaster with lengthening at one sitting by skeletal traction over 20-30 min. The osteotomy was a Z-type to allow for bone contact to enhance healing. The apparatus was left on for 30 days, following which a cast was applied. In 10 cases of femoral shortening, which were operated, the lengthening varied from 3 to 4 in. Abbott: Abbott (1) directed his attention to lengthening the tibia and fibula in patients with poliomyelitis and reported a method of lengthening in 1927 that gained wide acceptance. He used Putti's concepts of skeletal traction and countertraction but developed a lengthening apparatus, which was the true precursor of apparatuses used even now. His method employed a preliminary Z lengthening of the Achilles tendon, oblique osteotomy of the distal one-third of the fibula, insertion of single proximal and distal 0.19-in.-wide traction pins, which passed completely through the limb to enable fixation to a biplanar distraction apparatus to control angulation, circumferential division of the periosteum at the osteotomy site, a Z-type tibial osteotomy, and a delay in lengthening from 7 to 10 days postsurgery. The two distraction devices consisted of telescoping brass tubes and a strong coil spring with lengthening performed by turning of a thumb screw. The limb was immobilized on a Thomas splint to which were also attached two metal stabilizers to prevent anterior angulation. Lengthening was done once daily and ranged from 0.06 to 0.12 in. In his initial report, the maximum amount of length that Abbott felt could be achieved safely was 2 in. (5 cm). The entire time in traction was between 3 and 4 weeks. Overall the apparatus remained in place for 8-10 weeks, at which time the limb was immobi-

lized in a cast. The external apparatus and the wires were removed from 4 to 5 months after surgery when there was sufficient callus to permit the patient to walk with a splint. Abbott indicated that "in every case treated by this method callus filled in this space lying between the fragments in a comparatively short time." The operation was performed in those cases with 1.5 in. or more of shortening. Abbott warned of the extreme care needed in the postoperative phase and suggested "the surgeon who has not the time to give for daily adjustment of the apparatus should leave it entirely alone." Abbott then provided a very detailed account of his first six patients, one of whom was regarded as a failure. In the other five the gains in length varied from 1.75 in. to 1.88 in., with all of these increased lengths secured from 21 to 28 days. Union of the fragments sufficient to allow for weight beating in a splint was present in all cases from 4 to 5 months after surgery, and in all of the completed cases consolidation of the callus had taken place in 6 months. The amount of lengthening was initially kept relatively small because of concerns about negative sequelae with larger lengthenings. The recommendation and determination of the initial paper, however, allowed for increasing lengthening to 2 in. The next year Abbott and Crego (2) reported on a similar procedure for operative lengthening of the femur. Eight cases were reported with the gain in length ranging between 1.5 and 3.5 in. The authors felt that with experience in an average case a gain of 2.5 in. could be secured without producing injury to the blood vessels or nerves. The principles again involved osteotomy of the bone, direct bone traction that was gradual and continuous, and maintenance of alignment and contact of the fragments obtained by transverse wires entirely through the limb above and below the osteotomy and attached to the screw extension pieces. The osteotomy was accompanied by sectioning of deep fascial structures, the iliotibial band, and the biceps tendon to diminish the resistance of the soft parts. The authors emphasized that "by far the most important and difficult part of the entire procedure is the post-operative care of the patient during the lengthening process." The lengthening began approximately 5 - 6 days after operation. Lengthening was performed once daily with average daily gains of 0.12 in. and the entire time of traction extending over a period 4 - 5 weeks. The apparatus was removed and a cast applied in 10-12 weeks, protected weight bearing was allowed at 5 months, and full weight bearing occurred in 7-8 months. Abbott (3, 4) next presented a review of 48 tibial and fibular lengthenings in which he again stressed his three principles: (1) to lengthen a bone, traction and countertraction must be taken directly on that bone; (2) to overcome the elastic resistance of the soft parts, the traction must be slow and continuous; and (3) after osteotomy and the application of traction, complete control of the fragments including their appropriate alignment must be maintained during the lengthening process. The apparatus evolved to the use of two pins above and two below the osteotomy site. The lengthening

SECTION IX ~ Management of Lower Extremity Length Discrepancies

began only when all swelling had disappeared, which usually was at 7-10 days. In the 48 patients the gain in length ranged from 1.5 to 3.25 in. The average time of union to permit weight bearing with a splint was 4-5 months, and consolidation of callus generally occurred in 6-7 months with restoration of the medullary canal in 10-12 months. The complications listed by Abbott were surprisingly infrequent, involving two fractures, one worsening of paralysis of the dorsiflexor of the foot, and one infection, which involved an osteomyelitis of the bone, and occasional overlengthening of the tibia allowed for valgus deformation at the ankle. In a later paper, Abbott (4) reviewed his results in 73 procedures, 48 of which were in the tibia and fibula and 25 in the femur. In the femur the maximum gain was 3.5 in. and the minimum was 1 in. This paper describes the technique of the apparatus and the intraoperative and postoperative approaches in great detail. Abbott noted that the tibia and fibula provided much more dependable results than the femoral lengthenings, which had more complications (5). There were only two incomplete fractures following the tibial lengthenings, but seven fractures occurred through femoral callus during the early weight bearing phase. There were three cases of nerve paralysis. One involved paralysis of the sciatic nerve associated with subluxation of the knee. Infection of the pin sites was commonly seen but only one deep osteomyelitis occurred. Other Reviews of Abbott Technique: Following Abbott's development and subsequent refinement of his technique, limb lengthening enjoyed a surge of popularity. Three major reviews of relatively large series of the Abbott procedure appeared in the 1930s. These series served to define both the benefits and negative aspects of these interventions, although the detailed descriptions of the complications considerably diminished enthusiasm for lengthenings. Haboush and Finkelstein (213) reported on 17 tibial-fibular lengthenings, 16 of which were done for poliomyelitis. They used Abbott's technique although they did modify his apparatus somewhat. Their major problems involved (1) anterior-medial angulation during the bone lengthening process, (2) more tibial elongation than fibular, (3) valgus of the foot, (4) equinus of the foot, (5) osteomyelitis both at the site of the tibial osteotomy and at the site of pin insertions, (6) delayed union, leading in some instances to nonunion. The modifications to their apparatus were designed to address these problems. One of their major conclusions was that the fascia in particular yielded poorly to lengthening, which led to both the angular problems and the severe pain that they described as being "a rather constant feature in this series of cases." One of the major changes in their operative technique was a more thorough division of the fascia in the limb along with the interosseous membrane and complete circumferential division of the periosteum of both tibia and fibula. A more positive review was published in 1935 by Brockway (74), who provided a clinical resume of 46 leg lengthening operations using the Abbott technique and apparatus.

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He provided average values for the key criteria in his longrange assessment, although ranges of numbers and case by case details were not given. His report is most instructive to note in comparison with current approaches using the distraction osteogenesis principles. The average age of the patient was 14 years. The number of days following surgery before the lengthening process was started averaged 7.5. The average length obtained was 1.9 in. The number of days required to obtain this length was 35, making the average daily increase in length 1.3 mm. The average time before the pins were removed (at which time the long leg cast was applied) was 11.4 weeks. The average time that plaster was worn following the removal of the pins was 13 weeks, and the average time before full weight beating was allowed postsurgery was 9.5 months. Brockway did note complications with the procedure, but his overall impression was positive and he indicated that "on the whole, very gratifying results have been obtained by this operation and it is now a routine procedure." Poor results involved fracture of the tibia, some cases of skin slough, delayed bone healing, and anterior bowing of the tibia. The most critical of the early reviews was published in 1936 by Compere (121), although his paper is somewhat unique by current standards. The large list of complications that he referred to led him to indicate his belief that shortening was by far the more preferable approach to limb equalization. The paper describes five patients in detail, each of whom had a large number of complications listed. There is no indication, however, as to how many patients were operated. The discussion also focuses on the negative aspects of the procedure, which is important, but almost totally neglects any positive indications in either his own work or the work of others. Compere then listed 14 complications, which, in the absence of any indication that he had any good results at all, clearly led to a major dampening of enthusiasm for this intervention particularly in North America. The complications he listed follow: (1) stretch paralysis of the sciatic or the external popliteal nerve; (2) increased weakness of lengthened muscles in old cases of poliomyelitis; (3) fracture of the osteotomy; (4) malunion; (5) delayed union or nonunion; (6) osteomyelitis from wound infection; (7) traumatic arthritis and limitation of motion in the knee; (8) late fracture; (9) pressure or stretch necrosis of the skin in the zone of lengthening; (10) necrosis of bone due to excessive subperiosteal stripping, which also might increase the likelihood of infection; (11) malposition of the foot due to rotation following lengthening; (12) circulatory disturbance with prolonged edema in the lengthened limb; (13) displacement of the head or of the distal end of the fibula when this bone is not lengthened as much as the tibia; and (14) protrusion of the osteotomy fragment of the tibia through the skin. Complications have characterized lengthening procedures from the beginning. Table II lists the large group of possible disorders. Many of these are seemingly inherent with the procedures, but awareness should help to minimize them.

TABLE II Bone

Skin

Muscle

Nerve

Vessel

Joint

Physeal cartilage

Possible Complications in Limb Lengthening Procedures Premature union Incomplete osteotomy Long latency period prior to beginning lengthening Interruption of lengthening due to other causes Malunion Angular deformity/axial deviation Unstable apparatus Imperfect pin placement or initial malalignment postosteotomy Altered muscle pull with increased extent of lengthening Proximal femur, varus Distal femur, valgus Proximal tibia, valgus Distal tibia, varus Tibial lengthening greater than fibular ~ valgus ankle Angular deformation post fixator removal (softened bone at distraction site) Scanty union Delayed union Nonunion Osteomyelitis Lengthening site Pin tract site Osteoporosis Late fracture Shortening Angular deformity Pin-wire pull-out Pin site irritation-infection Skin slough secondary to malaligned fragment pressure Fragment protrusion Fibrosis Contracture Weakness Myopathic Neurogenic Intraoperative phase Pin skewers nerve Distraction phase Excessive stretching; sciatic, peroneal, posterior tibial, radial nerve Sensory: paresthesia, hyperesthesia, anesthesia, transitory, permanent Motor: partial paralysis; paralysis Intraoperative phase Pin skewers vessel Vessel damaged during osteotomy Distraction phase Excess vessel stretching Compartment syndrome Hypertension Excessive arterial stretching Thrombophlebitis Stiffness: ankle equinus, knee extension, hip adduction-flexion contractures Cartilage degeneration Subluxation Knee Hip Dislocation Hip Septic arthritis (pin placed into joint cavity) Increased growth of femur following completion of lengthening a Diminished growth of tibia following completion of lengthening a

aln relation to prelengthening growth rates.

SECTION IX ~ Management of Lower Extremity Length Discrepancies

The major English language orthopedic journals did not publish any subsequent large limb lengthening review for 12 years until the report of Allan (48). He used a tibial distraction apparatus, which incorporated the principles of Abbott and some modifications of Haboush and Finkelstein as well as his own. An oblique osteotomy of the bone was performed to enhance repair after the sliding lengthening. Allan applied a plaster of Paris long leg cast and incorporated it into the distraction apparatus with the cast cut at the osteotomy site. This was designed to minimize angulation. The periosteum was left intact and careful surgery sought to minimize damage to the soft tissues. Distraction began immediately and proceeded at a rate of 0.06 in. per day. Allan reported that "little pain should be experienced." When sufficient callus had formed as indicated on X rays but prior to firm union, the plaster cast and wires were removed, any malalignment was adjusted, and the limb was stabilized in plaster until union was complete. Femoral lengthening produced greater difficulty than tibial. In 47 cases of tibial-fibular lengthening, the average time before weight bearing was 6.5 months and the average lengthening obtained was 2.33 in. In 40 femoral lengthenings, the average time for weight bearing was 5 months and the average lengthening obtained was 1.62 in. The technique was evolving during the course of the series. Allan felt that bone was laid down in parallel lines between the fragments with the osteogenic material strung out across the gap and that most of the repair came from periosteum. He noted that all bones returned to normal radiographic appearance within a year or so of consolidation. Union eventually occurred in every case but there was a marked delay in 12 cases, with union taking from 9 to 16 months. Although Allan recognized that the most resistant structures to stretching were the periosteum, the interosseous membrane, and the deep fascia, he specifically mentioned that these were to be left intact as much as possible. The blood vessel response distal to the lengthening site was benign. He felt that the external popliteal nerve and the compartment part of the great sciatic nerve could be stretched to 2 in. in the thigh without losing function and that they could be stretched to 3 in. with only temporary impairment. Indeed, he felt that certain vascular complications experienced by other surgeons were attributable to sub-periosteal bone exposure and to dividing the periosteum and fascial structures transversely. Anderson: The next technical advance in limb lengthening accompanied by a burst of renewed popularity came from adoption of the technique described by W. V. Anderson (21) of Edinburgh, Scotland, in the mid-1960s. This technique evolved from an operation in 1954, but he did not report the technique in detail in writing until 1967 and even then apologized for including no numerical data. His paper described the evolution of his technique from that of Abbott, which was practiced with some modifications in his institution for approximately 20 years prior to 1954 with "satisfactory results obtained, with increases of length up to 389 inches in the tibia, with no complications of any sever-

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ity." We quote from Anderson's paper, which eloquently reviews the subsequent reactions to the Abbott procedure after its seemingly excellent early results. Unfortunately, this procedure appeared to be so simple and satisfactory that its rapid and deserving popularity almost brought about its eclipse. It was performed widely by many surgeons who failed to realize the fundamental importance of suiting the operation to the patient; by this failure they were directly responsible for the numerous and terrifying complications which followed this tragic misuse. These ranged from gross sepsis to amputation, following vascular failure. The procedure was condemned loudly and bitterly because it produced too much pain and was technically difficult and destructive by those who had, in fact, made it so themselves. For many years, it was practically given up in the land where it originated. In the years following, the alternative methods of equalization were more fully developed with the perfection of epiphysiodesis and stapling, whereas shortening was much more in favor than lengthening. Eventually the Edinburgh group in which Anderson worked modified the apparatus and the procedure and began distraction on the operating room table. They noted that "contrary to the findings in America, we had none of the complications which ended in the condemnations of the operation. The pain was minimal, even from the day of the operation. There were no vascular or neurologic changes of any importance and no major sepsis occurred. The operation was accepted by operating and nursing staff, and the patient, as a simple routine procedure." One complication that was reported by others and indeed appeared in the Edinburgh series was the slowness of the lengthening of the fibula, which led to valgus deformation of the ankle. This was greatly minimized by a distal tibial-fibular synostosis obtained prior to the lengthening procedure. The Anderson technique as subsequently practiced evolved in a patient who suffered a transverse fracture of the mid-tibia as he was waiting for a more formal Abbott-type lengthening. This opportunity presented itself such that the apparatus was applied for stability and lengthening was performed. There was surprisingly good maintenance of alignment and it was noted that the lengthened site healed readily. The advantage of this approach was that only a very small linear incision was required, there was very little disruption of the periosteum, and the transverse osteotomy was made following positioning of several transcortical drill holes and manual osteoclasis. There was a 0.12-in. lengthening on the operating room table with subsequent lengthenings starting on the third or fourth day of one turn daily equaling 0.06 in. Anderson indicated that "in the average case the length of 2 to 3 inches may be obtained without difficulty" and "up to 1 and 89 inches can be expected before any tendency to foot deformity (tendoAchilles tightness) becomes evident." The patient remained in bed with the limb suspended in a traction frame. When new bone was seen radiographically, external fixation was removed and the limb was immobilized in plaster. Anderson

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CHAPTER 8 9 Lower Extremity Lenyth Discrepancies

noted empirically that 0.06 in. increase per day remained the most satisfactory rate of lengthening. Anything less may predispose one to early bone union with callus formation overcoming the rate of lengthening, thus preventing the full length desired from being obtained, and a faster rate may cause a delay in union, considerable pain, and possible nerve and vascular complications. Anderson specifically remarked that "pain is so exceptional (in their lengthening unit) that apart from the immediate post-operative pain (in itself minimal) it is regarded as indicative of something abnormal and subsequently of importance." Following new bone formation deemed sufficient to prevent collapse, the apparatus was removed and the limb was placed in a long leg cast followed by eventual transfer to a walking brace. Femoral lengthening was performed in a similar fashion. A major review of the Anderson approach was published by Coleman and Noonan (118) from the Salt Lake City Shriners Unit in 1967 and by Coleman alone later on (119). Thirty-one tibial lengthenings using the Anderson technique with limited surgical exposure were reported. They performed the Anderson technique as he had described it, emphasizing "the advantage of osteotomy of the tibia by a limited surgical exposure, in which the hematoma remains localized, periosteal stripping is avoided, there is relatively little soft tissue damage, and the periosteal tube is preserved." A distal tibial-fibular synostosis was performed initially prior to lengthening to prevent valgus deformity at the ankle, but eventually stabilization was performed using a transfixion screw at the same time as the lengthening procedure. A cast was applied at the same time as the distraction apparatus and osteotomy to help minimize the development of equinus at the ankle. Distraction was at the rate of 0.06 in. per day. In the 31 patients, satisfactory union was obtained in all with an average gain in length of 5.0 cm (range = 2.0-6.0 cm). Nonunion occurred in 4 patients but satisfactory union was subsequently obtained with bone grafting. The authors modified their technique to perform a bone grafting procedure in all patients who at 4 months after surgery "show lack of complete bone bridging." There were no wound infections and only pin tract infection. There was no permanent detectable injury to the neurovascular structures. Manning (314) reported on a large series of femoral and tibial lengthenings using the Anderson apparatus and technique. The patient remained in bed for the lengthening procedures with the distraction apparatus supported in traction. Distraction took place once daily with a gain of 0.06 in. (1.6 mm). Once length had been achieved and early healing was underway, the patient was transferred to a cast and ultimately to a brace. Lengthenings were done with 211 procedures performed, 161 on the tibia and 50 on the femur. The average gain was 3.06 cm, with 122 of the tibias lengthened by 5.0 cm or more and 21 femurs by 5.0 cm or more. Major complications related to fracture after lengthening had been completed and delayed union or nonunion. Fractures occurred in 30 limbs (14%). These all subsequently united relatively quickly but shortening occurred in many, lessening

the advantage of the original lengthening procedure. Bone grafting was resorted to for slow union or nonunion present 6 months after the lengthening had been completed. Such grafts were used in 23 tibial lengthenings (14%) and 2 femoral lengthenings (4%). Each then healed uneventfully. Chacha and Chong (108) reported on overall favorable results with 35 tibial lengthenings (31 Anderson-type) with an average gain of 5.2 cm and a range of 2.8-6.5 cm. Malhis and Bowen (312) reported on 12 tibial lengthenings using the Anderson method. The mean amount of lengthening achieved was 6 cm (range = 3-10 cm) and the mean percent lengthening was 24.5% (range = 13-42%). Bosworth (61) used the Abbott technique but recommended not beginning lengthening until 10 days after the osteotomy. One-Stage Lengthening ProceduresmLe Coeur: Le Coeur (291) of Paris described a one-stage lengthening procedure with immediate stabilization and applied the technique 169 times between 1952 and 1962. The amount of length gained varied between 3.0 and 4.7 mm, and due to the immediate fixation used the amount gained was maintained with certainty. The period of immobilization was similar to what occurred with a fracture. The tibia was the most favorable site for lengthening, but femoral procedures were also performed. The operation was accompanied by multiple transverse muscle and fascial releases, which allowed for lengthening of the soft tissues readily in conjunction with the bone elongation. A lengthy oblique incision of the tibia was made, following which a bipolar traction apparatus was applied to upper and lower regions of the tibia. Once the soft tissue releases had been performed, the oblique osteotomy made, and the traction apparatus positioned, lengthening began with the knee in partial flexion. The knee remained in flexion during the lengthening procedure and during the time in cast following stabilization. Once the desired length had been reached and the surrounding muscle and fascial tissues were released, osteosynthesis was performed with four or more transverse screws. No cast was used. The patient remained in bed with the knee flexed for approximately 45 days to allow healing to occur. The patient then began walking with crutches. Le Coeur indicated that femoral lengthening could also be performed with the same technique, although it was more difficult and laborious to perform. He briefly reviewed his results in 125 cases involving 88 tibial and 37 femoral lengthenings. The amount gained ranged between 3.0 and 4.7 mm on a regular basis. In younger children with open growth plates, there was often an added effect of overgrowth providing an additional 1-2 cm of lengthening. There were no vascular complications. There were 11 neurological complications in the 125 procedures, the large majority of which resolved fully. Two full paralyses of the sciatic nerve occurred, which lasted for a year, two partial sciatic lesions, which cleared in 1 or 2 months, three paralytic lesions, and four partial neuralgias with the tibial lengthenings. Bone repair was uneventful, occurring in most in 45 days with no pseudarthroses created. Fractures did compli-

SECTION IX ~ Management of Lower Extremity Length Discrepancies

cate the procedure and occurred both during the early repair phase and also following repair anywhere from 3 months to 4 years postprocedure. There were 14 fractures reported in the 125 lengthenings (11%), with 7 in the femur and 7 in the tibia. The vast majority of lengthenings were performed for shortening secondary to poliomyelitis. Cauchoix and Morel et al.: A one-stage femoral lengthening was also described by Cauchoix, Morel, and colleagues in 1963 (105), with results from the 100 initial patients reported in 1972 (106) and a total of 180 cases reviewed in 1978 (107). The operation involved a lengthy middiaphyseal Z osteotomy of the femur in the frontal plane with the length of the longitudinal cut being 8 cm in the adult and 6 cm in the growing child. Distraction was performed against two transverse 5-mm Steinmann pins placed in the transverse axis through the proximal and distal femoral fragments. The knee remained flexed during the lengthening procedure and care was taken to keep the bone fragments in contact using a bone holder, which was alternately opened and closed during the lengthening procedure. Considerable releases of the fascia were completed along with decortication of the middle one-third of the femur and formal exposure of the sciatic nerve to check that it was not excessively stretched during the lengthening procedure. Once lengthening had been achieved internal fixation was secured by a posteriorly placed vitallium plate. The bone gaps left by the Z lengthening were then filled with iliac crest autogenous cancellous bone graft. The average gain in 180 cases was 3.7 cm, with 169 of 175 one-stage one-time lengthenings ranging between 2.6 and 4.5 cm. In 5 instances greater lengthening was achieved by performing the procedure twice. The operation was performed with relatively strict limits in terms of the maximum amount of lengthening that could be achieved primarily due to limitations involving stretching of the sciatic nerve. A total of 111 of the 175 cases was concentrated in the lengthening range of 3.1-4.0 cm. The usual limit in the child was 3.5 cm, and the maximum lengthening to be aimed for in the adult was considered 4.5 cm. The extent of lengthening was in the range of 10-15% of the length of the femoral shaft. Only one case of nonunion was observed in the children, with 11 cases in adolescents and adults (15%). In the latter group the average time for bony union was over 6 months. During the evolution of the procedure, the subperiosteal approach to the femur was gradually replaced with the musculo-periosteal decortication approach. Knee motion was either not affected or only minimally affected by onestage lengthening of the amounts described. Of 180 patients, 157 experienced no change in knee motion. There were no vascular complications in the series. Nerve complications were evident, however; there was 1 case of sciatic nerve palsy with a 4-cm lengthening and 2 cases of quadriceps palsy, both with femoral nerve involvement with partial improvement. Additional complications involved infection, early breakage of internal fixation, nonunion, and late fractures of the lengthened femur, which occurred on 8 occasions. The authors stressed that sustained flexion of the

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knee during the procedure prevented vascular and nervous complications. They felt the procedure was warranted for moderate discrepancies, although strict observance of the maximum lengthening guidelines was essential to minimize complications. D'Aubigne and Dubousset: D'Aubigne and Dubousset (133) described a one-stage lengthening of the femur using a transverse osteotomy with lengthening performed immediately over an intramedullary rod and the lengthening stabilized by insertion of a cortical bone block. They described 16 patients in whom transient peroneal palsy occurred 3 times, delayed union or nonunion 3 times, and knee flexion contractures requiring surgical release twice. Wagner (492) has stressed that one-stage lengthenings should be restricted to the femur and that a maximum of 4-cm increase can be obtained safely. Kawamura: Kawamura and associates (265) began lengthening immediately after osteotomy, feeling that "since operative damage to soft tissues is minimized it is not necessary to delay the start of bone lengthening for a few days." Further lengthening was accomplished intermittently in 3-5 sessions under anesthesia. Their method emphasized leaving the periosteum intact. In their technique the periosteum was elevated circumferentially, following which osteotomy was performed. When the periosteum was elevated along the line of osteotomy in experimental dog models with 10% lengthening, the periosteum tore almost completely. In the second group the periosteum was incised longitudinally and detached for about 5 cm above and below the line of osteotomy. With distraction the periosteum persisted as a tube localizing the fracture hematoma, and rupture did not occur until 20% lengthening. Histologic study of 130 dog procedures was done. After tibial osteotomy, lengthening was performed gradually up to 10% over 2 - 4 weeks. At 3 weeks new bone formation from the inner surface of the periosteum was seen. Kawamura et al. felt that preservation of the periosteal tube was helpful in enhancing early bone repair. The repair response was mediated by both periosteal and nutrient vessels. Kawamura also felt that injury to the nutrient artery should be prevented if at all possible. Oblique osteotomy was used to lessen slightly the length in the gap needing repair. The nutrient artery was intact at this time frame also. In the center of the lengthened area hematoma was seen. At 3 weeks there was excellent vascular supply to the repair callus, and at 5-7 weeks there was vigorous proliferation of arterial supply from nutrient branches, although a slight avascular zone was still seen centrally. By 8 weeks most of the avascular zone had disappeared, indicating that the lengthened area had reunited. At 12 weeks there was a wellreconstituted medullary and cortical blood supply. The study showed that, after a 10% gradual lengthening following cortical osteotomy, the bone union progressed similar to that seen after a fracture. Kawamura also noted the effect of diaphyseal lengthening on the physis in dogs at either end. The effect of tibial lengthening on the longitudinal growth of the bone was

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CHAPTER 8 ~ Lower Extremity Length Discrepancies

assessed in young dogs between 1 and 3 months of age. Osteotomy was performed and lengthening was carried out to 0, 10, 15, and 20% in 4 - 6 stages over 2 weeks. Subsequent longitudinal bone growth was then studied between 2 and 18 weeks postoperation. In lengthenings of 15 and 20%, the growth plate showed marked narrowing by both radiographic and histologic study. There was marked growth plate deformity by 3 weeks in bones lengthened between 15 and 20% with disturbance of endochondral ossification. Early closure of the epiphyseal growth plate was seen in one-third of the dogs with 10% lengthening and in all dogs lengthened 15 and 20%. In those animals lengthened 15 and 20%, the ultimate gain compared to those lengthened only 10% was negated "since the normal bone growth was lost in the larger mechanical lengthenings." Kawamura et al. concluded that lengthening should be carried out gradually and limited to about 10% of the original bone length. Technique: The distal metaphysis of the fibula was resected sub-periosteally for a distance of 2-3 cm, and when lengthenings were projected to be more than 11%, it was felt to be advisable to fix the distal fibular fragment to the tibia with a screw. Four Steinmann pins were then introduced into the tibia, two above and two below the proposed osteotomy site, and the leg was placed in the distraction apparatus cradle. A small 1-cm incision was made over the mid-tibial region with the periosteum incised longitudinally and elevated from the tibial surface. The periosteum was free circumferentially. The oblique osteotomy was outlined by several drill holes penetrating the cortices with the osteotome subsequently cutting only the cortex in an effort to spare the nutrient intramedullary vessels. The initial lengthening was carried out to a distance not exceeding 3% of the tibial length immediately. Kawamura did not find it necessary to divide the deep fascia, interosseous membrane, or intermuscular septum. Lengthening of the Achilles tendon was performed if it was tight or if tightness was anticipated. Because operative damage to soft tissues was minimal, it was not considered necessary to delay the start of lengthening to allow for soft tissue repair. Further lengthening was achieved by a small amount each day or in 3-6 sessions a few days apart with more lengthening done. It was felt that 3-6 weeks might be required to gain the desired length. When the required gain was achieved and the consolidation of callus had occurred, the limb was placed in a plaster cast incorporating the pins. A similar procedure was performed for femoral lengthening. Over a 17-year period this group performed 252 tibial and 58 femoral lengthenings in children (266). The tibial technique was standardized and 223 of 252 cases were reported as obtaining "highly satisfactory results." The 58 femoral lengthenings were also considered to be satisfactory. The vast majority of patients had good or excellent results with tibial lengthening up to 15%, with similar findings in the femur with lengthenings up to 11%. Their observations in young dog experimental lengthenings done before the age of

closure of the epiphyseal growth plates showed that gains in length were preserved in lengthenings of 10%, but in lengthenings of more than 15% subsequent growth was often markedly decreased. Fifty-seven patients were studied in terms of subsequent longitudinal growth following tibial lengthening. Of the total of 57 patients, 35 showed a decrease in expected growth. Kawamura stressed that complications in this regard could be avoided with lengthenings kept to within 10-15% of overall length. The lengthening was to be carried out gradually in 3-6 stages over 3-6 weeks, and the initial lengthening performed immediately should not be more than 3% of the bone length. Complications: Kawamura listed in detail the possible complications with limb lengthening. (1) Complications due to overstretching. These included angular deformity, arthritis, stiff joints, loss of muscle power, stretch paralysis, and neuralgia. (2) Complications due to interference of blood supply. These included delayed union and nonunion, bone necrosis, and circulatory disturbances distal to the operative site. (3) Complications due to inadequate fixation of fragments. These involved overlying skin slough, fragment protrusion, anterior bone angulation, late fracture, and pin site infection, which could lead to osteomyelitis. (4) Direct operative complications included fracture of the osteotomized shaft, pin pull-out, hypertension and shock. b. Improved Results Due to More Rigid Fixators. Judet Technique: The Judet technique (259), developed in France in 1969, provided much more rigid stabilization, thus enhancing comfort in association with lengthening. It involved a lengthening by gradual distraction in association with an oblique osteotomy and decortication to hasten bone repair, but use of neither graft nor internal metallic stabilization. The external fixator used 5-mm-diameter pins with three or four placed in the proximal fragment and an equal number distally. A unilateral distractor was attached. The procedure was designed for use in the tibia. The distal fibula was stabilized by a transfixion screw to the distal tibia to allow for lengthening of both bones simultaneously and maintenance of the orientation of the ankle mortice. The oblique osteotomy of the tibia was made in the frontal plane and was of the greatest length possible, with the average amount being 10.5 cm. A plaster splint then immobilized the knee in extension and the foot at a fight angle at the termination of the operative phase. The limb was maintained in the cast during the period of the lengthening, which was performed at a rate of 1.5 mm per day. Each day hip, knee, and ankle range of motion exercises were done. When the lengthening was completed, the lower extremity was placed in a long leg cast, which was then replaced at varying times with a lighter plastic brace. At 6 months the distractor and fibular-tibial pins were removed with the tibia continuing to be protected in a brace for an additional 6 months. Pouliquen et al. (391) reviewed 108 tibial lengthenings performed by the Judet method. Of these, the large majority, 79, were due to poliomyelitis. The average lengthening ob-

SECTION IX ~ Management o f Lower Extremity Length Discrepancies

tained was 4.37 cm with a range from 2.6 to 6.0 cm. The average gain was in the range of 16%. Bone union in the most favorable cases was obtained at an average of 4 months and a secondary bone graft was needed in only 5 instances. There were 17 instances of neurological impairment, although only 2 showed persistent anesthesia and 1 permanent paralysis of the extensor hallucis longus muscle. Postlengthening fractures occurred in 9 patients, 5 of which were non-displaced and treated only with a simple cast with 4 requiring additional surgical intervention. Overall, 10 secondary bone grafts were required, 5 for a delay in primary healing and 5 for pseudarthrosis or fractures. The paper also performed a detailed comparison with tibial lengthening studies from 7 other series. Excellent reviews of the more recent limb lengthening techniques have been provided by Caton (101) and Paley (361). Some of the less well-known European precursor techniques have been reviewed by Wiedemann (505). Wagner Technique: In 1978 Wagner (493) reported his technique, which had major improvements from previous approaches and restimulated widespread interest yet again in lengthening procedures. His unilateral fixator was structurally very stable and allowed patients to be ambulatory with crutches immediately after the surgery and throughout the lengthening procedure. This alone was a major advance because virtually all previous lengthenings required prolonged bed rest, at least during the lengthening and early consolidation phases. Diaphyseal lengthening began immediately with approximately 1 cm of distraction performed in the operating room at the time of instrumentation (described by Wagner as lengthening "until stabilization is achieved by soft tissue tension"). Once daily lengthening of 1.6 mm was performed. Once the desired length was reached, a second operative procedure was performed in all patients involving the application of a long side plate, autogenous iliac crest bone grafting, and removal of the external fixator (Fig. 22). The advantage of the second operative approach was that rigid internal stabilization was achieved immediately and rehabilitation was enhanced because range of motion exercises could be performed more easily once transfixing pins were removed. The Wagner technique represented a significant advance over the Anderson and previous methods due to the fact that the patient could remain ambulatory and pain was considerably diminished due to the increased stability of the external fixator. By the time Wagner developed his approach, the etiology of limb length discrepancy had changed with fewer children suffering from poliomyelitis. Of the 58 patients in his initial paper only 10 had poliomyelitis, with the largest group involving congenital short femur and the next largest epiphyseal fracture. As a result of these differing etiologies, Wagner found that preoperative consideration of the entire limb was of increasing importance. Of particular importance prior to lengthening procedures were the correction of joint contractures and surgery to correct acetabular dysplasia and angular

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FIGURE 22 Illustrations of the Wagner lengthening technique are shown. The end result followinglengthening of a femur is shown. Following attainmentof the desired length, operationis performedat which time a Wagner plate and bone graft are applied. The plate designed by Wagnerfor this procedure has no holes spanning the lengthenedgap as these are prone to breakage if a regular AO plate is used. Althoughadditional surgeries are required with this technique, there is one major advantage to it in that rehabilitation in terms of range of motion of the adjacentjoints is markedly quickened and improved compared with subsequent techniques in which the distraction device is left on until there is full healing. Anteroposterior (A) and lateral (B) projectionsat healing.

bone deformities. He detailed the advantages and disadvantages of operative limb lengthening and the various shortening procedures. Carlioz et al. (94) reported on their first 30 cases of the Wagner lengthening involving 15 femoral lengthenings, 7 tibial lengthenings, and 8 cases associated with the correction of angular deformities or pseudarthrosis. In the straightforward femoral lengthenings the gain ranged between 4.0

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8

~

Lower Extremity Length Discrepancies

and 7.0 cm. Among the complications were 3 subsequent fractures. The percentage of lengthening was in the range of 15% with no cases beyond 20%. In the straightforward tibial lengthenings, the range of correction was between 4.0 and 5.8 mm with an average percent increase of 15% with one case being 26%. Early experience of this group was quite favorable. A few years later their group reported on 48 femoral lengthenings using the Wagner technique (Blachier et al.) (53). The mean lengthening obtained was 5.2 cm with the most extensive at 11.2 cm. In terms of percent gained, lengthening values were 15.6% of initial bone length. On 6 occasions the lengthening was greater than 20% with a maximum of 24%. Many complications were noted varying from minor to much more serious in importance. Superficial infection was frequent but easily managed. In 22 of the 48 cases, varus deformation occurred during lengthening but was easily corrected in most at the time of plate application and grafting. In some instances, however, the varus was not corrected even at the time of plate application. Subluxation at the hip and knee was seen on occasion as were contractures without subluxation at these two joints. Five patients had neurological complications; in 4 there was full and rapid recovery of the anterior foot dorsiflexors, but in 1 paralysis of the peroneal and tibialis posterior nerves was complete and recovering only slowly at the time of publication. There were 12 deep infections, which on occasion compromised the long-term result. On occasion fracture or pseudoarthrosis at the site of infection further complicated treatment. Caton et al. (102) also reported early favorable results with the Wagner technique in 33 lengthenings, 20 of which were in the femur and 13 in the tibia. The mean lengthening obtained was 5.35 cm, and although many complications were seen 70% of cases had none. The mean percent lengthening was in the range of 16.2% with a mean lengthening of 4.8 cm for the tibias and 5.7 cm for the femurs. The use of more rigid fixators such as those of Wagner or Judet became popular in the 1970s. Some series are reported in which the fixators were used, although differing techniques from those initially described by the developers were appropriated. A study by Rigault et al. (403) assessed 36 femoral lengthenings in which 21 used the Judet distractor and 15 the Wagner. In most instances, an oblique femoral osteotomy was used, there was an initial 5-10 mm of lengthening at the time of surgery, and progressive lengthening was then performed at a rate of 1-2 mm per day. The bone was then allowed to heal without application of the graft and side plate as recommended by Wagner. The mean lengthening gained in the 36 cases was 5.2 cm, which was an 18.3% increase in length. The series was complicated by a high rate of fracture with 9 of 36 or 25%. Those having the oblique osteotomy had a mean gain of 5.6 cm, whereas those having more transverse osteotomies had a mean gain of 4.7 cm. Bone graft was performed in 6 of the 36 cases because of delayed healing. Rigault et al. (404) also described 48 tibial lengthenings using either the Judet or Wagner apparatus along with a long oblique osteotomy, decortication, and mul-

tiple soft tissue releases to stabilize the knee and minimize equinus deformities at the ankle. In general, the distractor was left in place until radiographic bone consolidation was evident, following which a brace or walking cast was applied to protect the limb during the return to full weight bearing. The mean lengthening was 4.2 cm or 17.5% of preoperative bone length. Fractures were seen in 10%. In the 10 more complicated cases the mean lengthening was 5.5 cm or 16.5%. Many groups reported their results with the Wagner technique. Wagner (493) reported on 58 femoral lengthenings in patients below the age of 17 years in which the average gain in length was 6.8 cm. Bjerkreim and Helium (52) reported an average lengthening of 5.8 cm in the femur, Aldeghiri et al. (14) reported 4.9 cm in the femur and 4.0 cm in the tibia, and Paterson et al. (373) reported 5.8 cm in the femur and 5.2 cm in the tibia. Stephens (462) reported an average femoral lengthening of 5.7 cm in 18 Wagner procedures and an average tibial lengthening of 5.6 cm in 7 Wagner procedures. Osterman and Merikanto (360) reported on a mean increase with 26 tibial lengthenings of 4.1 cm and with 9 femoral lengthenings of 4.9 cm. Mahlis and Bowen (312) reported 27 femoral lengthening with a mean increase of 6 cm (range = 3-9.5 cm) (mean percent increase 17.6%, range = 7-36%) and 11 tibial lengthenings with a mean increase of 6.1 cm (range = 4.5-9 cm) (mean percent increase 20%, range = 10-32%). Ahmadi et al. (9) compared results with 50 Anderson, 40 Rezaian, and 51 Wagner lengthenings all performed for poliomyelitis. The mean gain was 4.8 cm and complications showed 6 refractures (4%) as well as others commonly seen, but in relatively low rates. Results in the three techniques were similar; the Wagner was favored for relative ease of use. Complications with the Wagner Procedure: The study of and literature on the complications of limb lengthening surgery are somewhat unique in relation to the rest of the orthopedic literature, primarily because of the intrinsic nature of the difficulties with this procedure. A characteristic approach is to divide what would generally be considered complications into (1) problems, which are felt to be intrinsic, cannot be avoided, and include such disorders as delayed union and nonunion, pin track infections, and transient restriction and motion of adjacent joints, and (2) complications, which are extrinsic and should be avoided, including infection, nerve damage, fractures, and subluxations. Others use the terms minor and major complications, an approach that is preferred in this chapter. DeBastiani et al. (137) reported a 26% complication rate with the Wagner method. Hood and Riseborough (236) noted 37 complications in 40 procedures, whereas Wagner himself noted a complication rate of 45% in 58 patients. Luke et al. (305) specifically described fractures after the Wagner limb lengthening procedure. In a series of 27 cases, there were 10 fractures following lengthening in 8 patients, 6 of whom were spontaneous and 4 traumatic. The fracture occurred through the lengthened area after plate and screw removal in 8 patients, through a proximal screw hole and

SECTION IX 9 Management of Lower Extremity Length Discrepancies

plate in 1 patient, and through an external fixator pin hole with hardware intact in another. Seven fatigue fractures occurred after plate removal in Wagner's series. Hood and Riseborough (236) reported 4 fractures after 40 Wagner lengthenings; Mosca and Mosely (339) reported 63 Wagner lengthenings with 16 subsequent fractures; and Chandler et al. (110) reported 21 lengthenings with 2 subsequent fractures. The preceding 4 studies thus reported a total of 182 Wagner lengthenings with 29 subsequent fractures (16%), whereas the most recent report of Luke noted a 37% rate (10 of 27). The amounts lengthened in both tibia and femur were not remarkable in those suffering either spontaneous or traumatic fractures with the tibial percent lengthening at approximately 16% and the femoral 20%. Some attempted to minimize the fracture sequelae by a four-stage procedure involving the osteotomy, plating and bone grafting of the lengthened area, and then, instead of removing the hardware at one stage, doing a two-stage procedure with the removal of alternate screws and partial loosening of the plate followed several months later by removal of all remaining hardware. Osterman and Merikanto (359) noted that a major complication was late femoral fracture, which occurred in 6 of the 26 instances although there were no tibial fractures. There was 1 hip dislocation, 1 talar deformation, 1 peroneal nerve entrapment, and 1 infection, which delayed bone union. The authors cautioned about early removal of the stabilizing plates and also indicated the need for bone lengthening to be performed by well-trained teams with great experience. Karger et al. (262) reported primarily on Wagner lengthenings involving 51 femurs and 18 tibias. Complications were more marked when the lengthening exceeded 25% of initial bone length. They were also much higher in the femur than in the tibia. Some modifications to the Wagner procedure were incorporated; whereas 44 patients had the entire sequence described by Wagner himself, 18 had only the stage one procedure but did not have grafting and plating because the authors felt initially that healing would be appropriate. In 51 femurs lengthened by the Wagner technique, the mean lengthening achieved was 7.57 cm, which represented a 25% increase, whereas in 18 tibias, the mean length achieved was 6.07 cm, accounting for a 23% increase in length. The complications were divided into groups referred to as problems, obstacles, minor sequelae, and major sequelae. They were commonly seen in the femoral lengthenings but somewhat less frequently in the tibial. Fractures were common, occurring in 18 of 51 femoral procedures and 3 of 18 tibial. Angulation was noted in 25 in the femoral group, all of which were varus with a mean deformity of 25 ~ Some had flexion deformities as well. There were 10 of 18 angular deformities in group 2, all of which were valgus with a mean of 16~ Pin tract infections and deep infections were noted as were joint restrictions of motion, including 12 transient knee subluxations. Salai et al. (418) described three hip subluxations during femoral lengthening with the Wagner technique. Each of

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the patients had some predisposing hip and acetabular abnormality, indicating again the importance of assessing the hip prior to and during the course of lengthening and fully correcting malposition surgically prior to the lengthening procedure. c. Distraction Osteogenesis. Although many good and excellent outcomes were obtained with the Anderson and Wagner techniques, many problems and complications occurred. The Anderson technique frequently required supplementary bone grafting, whereas the Wagner approach required at least three surgical interventions. Patient reviews reported numerous additional problems. Work continued with different techniques to improve results. Clinical Techniques: Techniques developed by Ilizarov (243-247) in Russia, Monticelli and Spinelli in Italy (332), DeBastiani, Aldegheri, and associates in Italy (137), and Canadell and associates (88-90) in Spain have allowed for lengthening and bone repair such that bone grafting and plating were infrequently required. These techniques, described collectively under the term distraction osteogenesis or callotasis, are dependent on four principles, the first two of which are truly integral to the effectiveness: (1) delay prior to the initiation of bone lengthening for 7-10 days to allow early repair, or callus formation, to occur, (2) gradual lengthening of 1 mm per day performed at four separate times to minimize damage to newly formed vessels and repair tissue, (3) corticotomy leaving the medullary vasculature intact or at least minimally disturbed, and (4) maintenance of an intact periosteum. There has been somewhat of a polarization between schools performing the distraction osteogenesis technique based on the type of external fixator used. The Ilizarov technique uses circular and hemispheric external fixators stabilized by multiple narrow wires, the Monticelli-Spinelli method uses a single circular fixator to hold epiphyseal wires and two diaphyseal level tings held together by longitudinal rods between which the metaphyseal corticotomy was performed, and the Orthofix and Monotube methods use a unilateral fixator with two upper and two lower 5-mm-wide pins (Fig. 23A). The early results are promising, but even with these techniques problems similar to those reported with earlier methods are being encountered. Healing time still remains prolonged and associated with osteopenia, muscle atrophy, and joint stiffness. Canadell has summarized the extensive experience of his group from Pamplona, Spain. A detailed assessment of 93 lengthenings performed over a 3-year period using the principles of distraction osteogenesis and a unilateral fixator has been reported along with conclusions realized over a 25year period involving more than 800 lengthenings (88-90). The 93 lengthenings involved 27 with unilateral discrepancy due to pathologic conditions and 34 patients having bilateral lengthenings due to symmetrical shortening with skeletal dysplasia disorders. The average lengthening obtained was 8.37 cm with a complication rate of 2.1 per lengthening. The repair index was the same for both femur and tibia, but humeral lengthenings healed in a much quicker fashion. There

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F I G U R E 23 (A) Examples of the distraction osteogenesis technique are shown. (Ai) Anteroposterior film of tibia and fibula shows distraction gap with early repair at 6 weeks using the Orthofix apparatus. Lengthening was begun 1 week postsurgery. Note that early bone regenerated is more dense adjacent to the upper and lower persisting bone, with the central part of the gap region showing lesser ossification and radiodensity. (Aii) Results of a femoral lengthening are shown using the distraction osteogenesis principle and the Orthofix apparatus. Anteroposterior films of the femur are shown from the time of initial osteotomy and insertion of apparatus to complete healing at 9 months. Note the close apposition of the cortices at the time of the initial procedure. Lengthening was begun at 1 week. At 12 days, there is just the beginning trace of new bone formation lateral to the cortical regions. At 1 and 2 months, new bone clearly is forming in the gap and slightly lateral and medial to it along with increasing length noted. A central gap region is seen, in particular at 2 months, with more bone formed adjacent to the cortices above and below. Progressive new bone formation is seen at

SECTION IX ~ Management o f Lower Extremity Length Discrepancies

FIGURE 23 (continued)

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F I G U R E 23 (continued) 4, 5, and 6 months. Note the marrow cavity reconstitution at 6 months particularly in comparison with the appearance at 5 months when bone across the gap was relatively uniform. Final cortical and marrow reconstitution at 9 months of age is seen. The patient has continued with normal function and increased bone density with a full range of motion at the hip and knee. (B) Classification of the shape and structure of the distraction callus by Hamanishi et al. [from (217), with permission.] The external and straight variants are ideal. (C) Radiographs of rabbit tibia undergoing distraction. The films are from 7 days (Ci), 13 days (Cii), and 22 days (Ciii) following surgery. (D) Specimen radiographs allow for better demonstration of bone repair at varying times following surgery and distraction. Distraction began at the time of surgery. The specimen radiographs in (Di) were performed 7 days after surgery and initiation of distraction (AP and lateral); (Dii) 14 days (AP and lateral); (Diii) 19 days (AP and lateral); (Div) 32 days (AP and lateral); and (Dv) 44 days postsurgery. Note the excellent cortical reconstitution and marrow reformation in the final lateral radiograph. (E) Specimen photographs obtained after decalcification and hemisectioning the bone repair gap and the adjacent cortices prior to histologic sectioning. Photograph from a rabbit sacrificed at 46 days shows the excellent reconstitution of the cortex as well as marrow continuity. The lengthened region, which totaled 9 mm or 9% of the initial bone length, is indicated by the darker stained more vascular marrow centrally. (F) The lengthened tibia is shown at sacrifice after the fixator had been removed and all surrounding soft tissues had been dissected free. This had been lengthened by 11 mm, an amount that corresponded to 10.7% of its initial length. Lengthening proceeded for 14 days and the fixator was left on for an additional 30 days, with sacrifice 44 days postsurgery.

was only a slight overall difference in repair between metaphyseal and diaphyseal osteotomies and those involving distraction epiphyseolysis. The diaphyseal and metaphyseal lengthenings provided slightly greater increases in length.

The rate of distraction was somewhat slower in the epiphyseal distraction procedures, although the rate of healing was somewhat quicker once length had been obtained. Canadell also noted that repeat lengthenings could be performed read-

SECTION IX ~ Management of Lower Extremity Length Discrepancies

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range 4-15 cm. More recent results from the European and ily on the same bone generally with an interval of 2 years North American literature have been reported as the Ilizarov between each procedure. In fact, the number of complications technique became widely adopted. Paley has reviewed the was greater during the course of the first lengthening than complications with the technique in detail (362). with the second. Two femurs had been lengthened 5 times Stanitski et al. (460) reported on 62 tibial lengthenings and 2 others had been lengthened 3 times. In his patients, using the Ilizarov technique with the average lengthening of lengthening was resorted to much more readily than is the 7.5 cm (range = 3.5-12 cm) representing the equivalent of practice in North America with discrepancies of 3 cm or a 32% average overall increase. Stanitski et al. (458) also more being candidates for lengthening procedures. In terms reported the results in 36 femoral lengthenings using the of surgical technique, it was difficult to prevent traumatic Ilizarov technique, with the average lengthening being 8.3 cm rupture of the medullary cavity and in only 30% of cases (range 3.5-12 cm) and a lengthening index of 0.74, months were the contents intact. Protection of the periosteum was of treatment/cm of lengthening. considered essential. The ideal rate of distraction appeared Franke et al. (165) reported good results with the Ilizarov to be 1 mm per day at four evenly spaced time periods with technique whether they used distraction epiphysiolysis or 0.25 mm lengthened at each time slot. Lengthening was conmetaphyseal corticotomy. In the distraction epiphysiolysis traindicated after the age of 30 years, and the ideal age to procedure, they lengthened 22 tibias with an average lengthconduct the lengthening was between 8 and 12 years at which ening of 8.25 cm (range = 4-18 cm) and 30 tibias using time the osteogenic capacity was greatest. In those younger the metaphyseal-diaphyseal corticotomy with an average of than 8 years of age, repair was often so rapid that appropriate lengthening could not be achieved. Considering all of length7.9 cm of lengthening (range = 4-15 cm). Their report repenings done the index of maturation was 1.16 months per cm. resents one of the most detailed in terms of assessing the Distraction was begun at different times after percutaneous average time of distraction, the average time to removal of metaphyseal or diaphyseal osteotomy with application of a the apparatus, and the average time to full weight bearing. monolateral fixator dependent on the age of the patient using They also subdivided results into the amount of lengthena rough guideline of 1 day of delay per year of age. Thus, a ing from 4 to 5 cm in one group, 5.5-9.5 cm in another, and child of 8 years of age had lengthening started 8 days after ml 10 cm or greater in the next. initial surgery, and for someone 15 years of age Canadell Monticelli and Spinelli (332) reported 43 cases of metaet al. waited 15 days. The quickest healing rate was most physeal lengthening using the distraction osteogenesis techfavorable in those with short stature conditions, averaging nique with their own fixator, with a mean gain of 7 cm and a 0.8 months per cm, and it was much longer in those with range from 4 to 10 cm. DeBastiani and colleagues (137), length discrepancies in the range of 1.5 months per cm. The using open corticotomy and callus distraction with their greatest lengthenings were also obtained in those with short monolateral fixator (Orthofix), performed limb lengthenings stature with an average of 11.2 cm per segment lengthened. on 100 segments with a lengthening index of 1.2 months for In 8 patients with a chondrodysplasia, Canadell reported exthe femur, 1.4 months for the tibia, and 0.8 months for the tensive lower extremity lengthenings gaining 23.2 cm dihumerus. The average amount of lengthening obtained in the vided between 12.35 cm in the femur and 10.85 cm in the femur in patients with achondroplasia was 7.8 cm (range = tibia. The ideal site for osteotomy was the metaphysis. More 5.5-12 cm), representing a mean 26% increase, whereas in sensitive angiographic studies indicated that in 90% of diathe tibia the average amount of lengthening obtained was physeal osteotomies the medullary vessels were damaged, 7.8 cm (range = 6-10.5 cm), representing a 36% increase. which was one of the reasons the metaphyseal site was faIn patients with limb length discrepancy from congenital and vored because the vascularity was more diffuse and richer acquired disorders, the average amount of lengthening in in that region. On both a clinical and experimental basis, it the femur was 4.7 cm (range = 3-9 cm, 11%), in the tibia was vastly more important to respect the continuity of the 4.7 cm (range = 3-9 cm, 17%), and in the humerus 7.5 cm periosteum than the medullary circulation. The group also (range = 7-8 cm, 34%). Aldegheri et al. (14) reported on strongly supported the importance of dynamization in en270 femoral and tibial lengthenings using the Orthofix callohancing repair. tasis method. Ninety-five patients had limb length inequality Paley (361) summarized the work of Ilizarov and the and 45 had achondroplasia-hypochondroplasia. The average Kurgan school, who worked extensively on distraction length increase was 6.6 cm or 24.6% of initial length. The osteogenesis from 1950 on. He indicated that more than mean healing index was 39 and the complication rate 13.3%. 1000 publications from their institute alone had described With the passage of time following the introduction of the various approaches to the technique, with most published in callotasis technique, long-term studies of relatively large Russian. Major studies were reported by Ilizarov of 237 femnumbers of patients have begun to accumulate and, perhaps oral lengthenings with an average lengthening of 7.4 cm, not surprisingly, show a pattern of findings similar to other range 3-15 cm, and complications listed in 12 patients lengthening techniques. Glorion et al. (181, 182) reviewed (5.6%). Ilizarov also published results of 217 tibial lengthen79 cases of femoral lengthening by the callotasis technique, ings in both children and adults with the mean gain of 7 cm, with 9 patients having the Judet apparatus and 70 the Orthofix.

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They concluded that the incidence of complications did not seem to be less than that encountered with previous methods of lengthening. The complications were the same in terms of nature and extent whether the callotasis technique had been performed using the Ilizarov or the Orthofix technique. The averaging lengthening achieved was 5.2 cm (range = 3.58.5 cm), which represented a mean increase in femoral length of 17.7%. In the 79 cases, however, there were 87 complications, a rate of 110%, although in general several complications were often encountered during one procedure. Glorion et al. noted that 30% of the lengthenings were performed without any complication and 62% with relatively mild complications such that additional surgery or anesthetic procedures were not needed. The healing index was 39.6 days per cm, which was comparable to other callotasis studies. Dynamization was considered to be an important adjunct to the healing process. Fractures continue to be seen fairly often even after distraction osteogenesis lengthenings. Danziger et al. (131) reported 9 femoral fractures after 18 Ilizarov femoral lengthenings but no tibial fractures with 8 tibial lengthenings. Glorion et al. (182), using primarily the Orthofix technique, in 61 lengthenings had fractures in 6 instances. Their technique involved percutaneous osteotomy, referred to as compactotomy when at the level of the metaphysis or corticotomy when done within diaphyseal bone. The cortex alone was cut with a small 5-mm osteotome with care taken not to enter the medullary cavity in an effort to spare the nutrient artery and medullary circulation. The periosteum remained intact. The remainder of the cortex was then broken either by rotating the osteotome to distract the bone ends or by rotating the fixator pins. Distraction did not begin for 7 days postsurgery and was at a slow rate of 0.25 mm of elongation four times daily. The average time to healing is still extensive, and the lengthening index that has been established is months per centimeter of lengthening, with most studies showing an index around 1 (if 5 cm are lengthened, the time to healing is 5 months). Suzuki et al. (467) studied 26 femoral lengthenings using the Orthofix callotasis technique. Lengthening began 1 week postsurgery with the rate of distraction 0.25 mm every 6 hr. The mean amount of lengthening obtained was 5.0 cm with a range from 2.0 to 7.5 cm. The study particularly assessed dislocation and subluxation of the femoral head during the lengthening procedure. One group of 14 hips with a CE angle of greater than 20 ~ at the start of lengthening showed no deterioration in position with the lengthening, whereas the other group of 12 hips with an angle of 20 ~ or less showed deterioration of femoral head position in 5 of the 12 hips. One developed a complete dislocation and the other 4 subluxed, showing a decrease in the CE angle. Four of the 5 had a history of congenital dislocation of the hip and the other had multiple epiphyseal dysplasia. The authors recommended that, in cases in which the CE angle was 20 ~ or less preoperatively, bone procedures such as innominate osteotomy should precede the femoral lengthening.

Limb lengthenings were performed increasingly with the callotasis technique for those with symmetrical limb shortening due to skeletal dysplasias (17, 394, 457); these will be discussed in greater detail in Chapter 9. Comparison of Techniques within the Same Centers: Many studies from centers in which large numbers of lengthening procedures were performed began to present data comparing differing techniques. An excellent review by Pouliquen et al. (393) compared femoral lengthenings in 82 cases divided between six techniques, five of which were used relatively frequently. These involved the one-stage lengthening (14 cases), Judet technique (20), Wagner (13), a transverse osteotomy and graft technique (11), and callotasis (20). The authors concluded that the callotasis technique was the best because there were no serious complications out of 20 cases. The amounts lengthened, however, were similar with the several techniques with the exception of the one-stage lengthening, which was reserved for relatively smaller discrepancies. In that group the average lengthening was 3.6 cm or 7.8% of bone length. The other four techniques had lengthenings on average ranging from 4.6 to 5.5 cm or 12.7 to 15.5%. In the one-stage lengthening, a Judet distractor was applied followed by performance of an oblique osteotomy, the application of temporary cerclage wires, lengthening by the distraction technique intraoperatively with the knee flexed, and osteosynthesis with a side plate once the desired amount of lengthening had been achieved. The Judet technique involved a unilateral distractor similar to the Wagner but with four heavy pins below and four above the osteotomy site. The lengthening was at a rate of 1.5 mm per day. Once lengthening had been achieved, the distractor was left in place while healing was allowed to occur. Walking began again under protection of a brace, which incorporated both the pelvis and the external fixator, and was generally maintained until 12 months after initial surgery. The complication rate in the callotasis technique was extremely low at 5%, whereas it ranged from 27 to 35% in the four other major approaches. The study also reviewed the literature from the 1970s and 1980s in relation to each of the major approaches then used involving the one-stage lengthening, the Judet lengthening, the transverse plus graft lengthening, Wagner lengthening, Ilizarov lengthening, and callotasis lengthening. The one-stage lengthenings assessed involved 229 cases with the lengthenings achieved ranging between 3.2 and 3.7 cm and a complication rate between 10.5 and 35%. Two series of Judet lengthenings with an oblique osteotomy were reviewed involving 56 cases with a mean lengthening of 5.2 cm and a complication rate between 25 and 41%. There were 11 cases of the transverse osteotomy plus bone graft group also with a 5.5-cm mean lengthening and a 27% complication rate, 120 cases of the Wagner lengthening with a range of 5.2-6.8 cm increase and a complication rate of 12.5-31%, Ilizarov lengthenings in 21 cases with a mean lengthening of 5.06.1 cm and a complication rate of 6-25%, and the most favorable group was the callotasis technique involving 78 cases

SECTION IX ~ Management of Lower Extremity Length Discrepancies

with a mean lengthening of 4.7 cm and only a 6% complication rate. This report remains one of the best detailing the techniques of the various procedures and providing a de, tailed review of results both from the literature and within the 82 cases of varying techniques from one unit. Faber et al. (156) reviewed several limb lengthening procedures divided between the Wagner approach, the MonticelliSpinelli metaphyseal corticotomy and distraction, and the Monticelli-Spinelli distraction physiolysis. Complications with each of the three procedures were reviewed in detail and were frequent. They concluded that the Wagner diaphyseal osteotomy involved more cases of delayed union, late fracture, and axial deviation. The list of complications in 17 femoral lengthenings included 3 with delayed union, 8 axial deviations, 3 late fractures, 2 losses of length, and 1 premature consolidation. As far as the joints were concerned, there was restriction of motion at the hip in 2, knee in 14, and ankle in 2, with 1 hip subluxation, 2 proximal tibial subluxations, and 1 patellar subluxation. There was 1 deep wound infection and 10 pin track infections. One patient had loss of muscle power, and complications leading to discontinuation of the lengthening procedure occurred in 1 with serious restriction of hip motion and in another with hip dislocation. Only 6 tibial procedures were performed with complications involving 1 nonunion, 3 axial deviations, 4 late fractures, and 2 premature consolidations. As far as the joints were concerned, there was restriction of motion at the knee in 1 and at the ankle in 3 and also 1 pin tract infection. A review of 100 lower limb lengthenings from Brazil assessed 25 tibial lengthenings by the Anderson technique, 45 femoral lengthenings by the Wagner technique, and 16 femoral and 14 tibial lengthenings by the Ilizarov technique. Once again, an assessment of the amount of lengthening achieved and the average healing time showed very little difference between the techniques. The complications seen widely in limb lengthening were present in each, although certain types of complication tended to occur with certain types of lengthenings. As with previous studies, good results could be achieved with each and considerations such as comfort and relative ease of the procedure for both the patient and the surgical team would play a primary role in choice. In the Anderson group the average lengthening achieved was 4.2 cm, range = 3-6 cm, and the average healing time was 197 days with a lengthening index of 1.72 months. In the Wagner group the femoral lengthenings had an average of 4.6 cm, range = 1-12.5 cm, with an average healing time of 185 days with a lengthening index of 1.32 months in a subsection having percutaneous osteotomy and a healing time of 166 days with a lengthening index of 1.23 months in a subgroup having corticotomy. In the Ilizarov group the average femoral lengthening was 4.7 cm, range = 1-7.5 cm, with an average healing time of 186 days and a lengthening index of 1.31 months. For the Ilizarov tibial lengthenings the average was 4.5 cm, range = 1-7.5 cm, with a healing time of 184 days and a lengthening index of 1.35 months. With the Anderson method the most common complication was

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delayed union, with the Wagner technique the most common complications related to bone healing and subsequent fracture, and with the Ilizarov method the most common complication was incomplete corticotomy. Effect of Lengthening on Muscle Strength, Articular Cartilage Structure, and Nerve Function: Three other areas of concern with lower extremity lengthening have been subject to more refined analyses than those available by clinical assessment alone. These involve the effects of lengthening on (1) muscle strength, (2) articular cartilage structure, and (3) nerve function. (1) Muscle strength before and after femoral and tibial lengthening. Maffulli and Fixsen (307) studied quadriceps strength in those with congenital short femur before and at the termination of femoral lengthening. The Orthofix technique was used. Seven patients had an average lengthening of 7.1 cm, a 23.5% lengthening of the congenital short femur. The normal side was stronger initially than the shortened side. The differences in strength, however, between the two sides did not meaningfully change with a difference of 15.7% at the beginning of the procedure and 13.1% at the end of the study. When the relationship of the knee extensor strength to the muscle and bone area of the mid-thigh was calculated, there was no change postoperatively in the normal side but a slight increase in the extensor strength in the operated side. That report is similar to the clinical impression that, once lengthening has been completed effectively and range of joint motion regained, the muscle strength is maintained. Lee et al. (292) studied changes in the gastrocnemius muscle in relation to the percentage of lengthening in the rabbit tibia using the callotasis technique. Lengthenings of 10, 20, and 30% were performed assessing 25 rabbits in each group or 75 overall. The study was based on histopathologic and morphometric assessments of the muscle. Biopsies were obtained from the medial gastrocnemius of both hind legs immediately prior to sacrifice at termination of the lengthening procedure. As compared with the control side, the lengthened side had substantial differences with fiber size variation noted in all three lengthening groups. Significant differences, however, in internalization of muscle nuclei and endomysial fibrosis, which represent more definitive changes, were observed only after 20 and 30% lengthenings. There were no differences in degeneration or regeneration among any of the lengthening groups. The fiber size variation was thought to be due to an increased number of atrophic fibers rather than due to the presence of hypertrophied fibers. As the lengthening percentage increased, the histopathologic scores of each parameter of the lengthened side showed a linearly increasing trend reflecting an increasing severity of the histopathologic changes. Because the rabbits were sacrificed at the termination of lengthening, no information was available as to whether some of these changes might have regressed. Kawamura et al. (265) also noted no significant histochemical or electromyographic changes in those lengthened up to 10% of their initial bone length. Carroll et al.

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(98), using a relatively rapid distraction model in sheep, noted that tibial lengthening greater than 11% of initial length consistently produced irreversible changes in the gastrocnemius and flexor digitorum profundus muscles, including loss of myofibrils, central migration of nuclei, and irregular shapes and sizes of myofibrils. Other observers have reported that up until approximately 20% lengthening the muscle actually lengthens throughout its entire extent, after which lengthening appears to be localized at the osteotomy site and is more associated with fibrosis, which itself would tend to weaken the muscle. Lee et al. showed, therefore, that lengthenings up to 10% have little histopathologic change in muscle and that progressively greater lengthenings to 20% and then 30% led to more conspicuous changes. They also felt that, once lengthening extended beyond 20%, irreversible changes were more likely to occur in the muscle itself. Carroll et al. felt that the changes in the muscle were primary rather than being secondary to nerve stretch phenomena. They also noted histologic changes in the articular cartilage of the tibiotarsal joint at both gross and histologic levels, with tibial lengthenings including fibrillation, empty lacunae, and matrix degeneration. The tibia had been rendered short initially by a proximal tibial epiphyseal arrest using the Phemister technique, after which a lengthening was performed in 16. Carroll et al. concluded that lengthening of the tibia by more than 11% consistently produced muscle changes in the leg and cartilage damage in the ankle joint. (2) Effects of lengthening on articular cartilage of adjacent joints. Stanitski et al. (459) also documented the effect of femoral lengthening on the articular cartilage. They felt that 30% femoral lengthening causes reproducible knee cartilage injury, which was evident by actual loss of cartilage substance and fibrillation. Application of a modified Ilizarov apparatus to the femur and tibia with coaxial hinges at the knee followed by 30% lengthening resulted in less severe damage than when the femur was lengthened independently, suggesting that there was a protective effect of the femoraltibial apparatus on joint compression. Nakamura et al. (346) studied knee articular cartilage changes in association with limb lengthening by the callotasis technique in 18 rabbits with a distraction rate of 1 mm per day. Distraction began the day after operation. On the fight side the frequency was 0.5-mm increments every 12 hr, whereas on the left it was controlled automatically leading to 120 smaller incremental increases, which averaged 0.0083 mm every 12 min. Histologic changes were much less in the multistep autodistractor technique side than in the side undergoing twice daily 0.5-mm increments. This study was also divided into assessments with length increases of 10, 20, and 30%. The incidence of cartilage degeneration on the 2-step side was 2/5, 5/6, and 6/7 at the 10, 20, and 30% length increases, respectively, whereas on the 120-step side it was much less at 0/5, 1/5, and 1/7 at the corresponding length increases. The numbers 5, 6, and 7 refer to the number of animals in each group.

(3) Nerve changes due to the lengthening procedure have been assessed. It has been recognized for several decades that nerve stretching in association with limb lengthening can lead to sensory and motor nerve deficits. In most patients, however, even with significant lengthening motor and sensory function is maintained. The more sensitive neurological testing is beginning to show that the margin between maintained function and diminished function is narrow. In those patients who develop weakness in association with significant lengthening, there has also been the question as to whether it was myopathic or neuropathic in nature. Young et al. (515) studied six consecutive patients completing tibial lengthening by the Ilizarov method by electrodiagnostic techniques. Nerve conduction studies and electromyography (EMG) were performed. At the termination of lengthening there were no complaints of sensory or motor abnormalities in the group, and all patients were normal to clinical examination. All six subjects demonstrated significant sensory and motor nerve response abnormalities. Electrodiagnostic testing showed abnormalities in six of six deep peroneal nerves and five of the six demonstrated abnormalities in superficial peroneal sensory responses. Two of six demonstrated abnormalities related to the posterior tibial nerve. Five of six patients demonstrated needle EMG abnormalities. Although the study was limited, there was clear evidence for an axonal neuropathy based on the nerve conduction and EMG results. A purely muscle etiology would not be expected to demonstrate sensory nerve abnormalities. The authors performed additional studies in an effort to implicate slightly increased compartment pressure as part or all of the causation of the neuropathic findings. In the study by Young et al., the mean lengthening was 5.6 cm with a range from 4.0 to 7.0 cm; the lengthenings, therefore, were well within the normal range in terms of extent. Galardi et al. (173) assessed peripheral nerve damage during limb lengthening. Electrophysiologic studies on limbs having five bilateral tibial lengthenings showed reduced motor conduction velocity in two tibial and three common peroneal nerves after a mean lengthening of 27%. Makarov et al. (309) reviewed much of the literature concerning neurological problems in relation to limb lengthening and published the data in chart form in terms of both intraoperative and total neurologic complications. A study of 8 reports encompassing 946 cases reported 51 intraoperative nerve injuries (5.4%), whereas total neurologic complications from 12 reports described 215 complications in 1214 patients (17.7%). A study of the Ilizarov technique by Erohin and Makarov (309), originally published in Russian, accounted for 703 of the patients, and results from this large series were parallel to the overall reports with 17% total complications and 5% intraoperative complications. Makarov et al. used intraoperative somatosensory evoked potentials (SSEP) to detect acute peripheral nerve injury during external fixation application. There were 42 Ilizarov surgical procedures of the lower extremities reported in 40 children. Significant deterioration or total loss of SSEP response dur-

SECTION IX ~ Management of Lower Extremity Length Discrepancies

ing surgery occurred in 4. They proposed the use of monitoring to detect early abnormalities and possibly to minimize or eliminate their long-term effects by changes in surgery pattern. Distraction Osteogenesis Research: Unlike previous lengthening methods, the distraction osteogenesis-callostasis technique has a considerable body of animal research data associated with it. The extensive work of Ilizarov and associates has been presented in English by Paley (361) and more recently in translation by Ilizarov (243-247) himself. Ilizarov showed that the proper biomechanical environment was extremely important for bone regeneration, which involved not only the interfragment stability but also the timing of the beginning of lengthening and the rate of lengthening. His early work demonstrated that preservation of the intramedullary circulation, particularly the nutrient artery, was important, but subsequent assessments have shown that even when cut the nutrient artery will repair quickly over a period of a couple of weeks as long as stability is present. Ilizarov also showed that the rate of osteogenesis was closely related to the distraction rate and that the optimal rate was 1 mm per day, with quicker rates of 1.5 and 2 mm per day slowing osteogenesis and a slower rate of 0.5 mm leading to premature consolidation. Repair was improved with four separate lengthenings of 0.25 mm each 6 hr apart distinct from one lengthening per day for the entire distance. The smaller, more frequent lengthenings minimize damage to the repair microvasculature and to the early repair cells and matrices. Ilizarov showed that bone formed during the course of distraction osteogenesis is well-organized and longitudinally oriented in the direction of the distraction forces. New bone forms initially in the medullary canal adjacent to the cut cortices and then passes progressively toward the center of the distraction gap. The central region between either cut cortical zone is referred to as the interzone and is the region in which bone forms latest and distraction occurs longest. The region tends to be filled with immature fibroblastic cells, which transform relatively late into osteoblasts. In most instances bone formation is via the intramembranous route with no cartilage forming in the gap region. The new bone is oriented along the longitudinal microvasculature and quickly forms a lamellar orientation. The interzone region ossifies quickly after distraction has stopped. New bone formation is seen as early as the second or third week after beginning distraction, and the interzone region then usually is seen as a central transverse radiolucency. During the several months of the remodeling phase, the cortex thickens and eventually the medullary cavity is reformed. The original work of DeBastiani and associates is almost totally clinical in nature, although use of the apparatus in experiments distracting the epiphyseal plate has been reported. Specific reports on distraction osteogenesis in the rabbit have been published by White and Kenwright (498), who noted that delayed distraction in the skeletally mature rabbit tibia led to more vigorous osteogenesis compared with immediate distraction. Kojimoto and associates (276) also

693

performed callus distraction in the rabbit and demonstrated excellent bone healing, even following medullary vessel destruction as long as the periosteum was carefully preserved. Experimental studies in the dog have been reported by Aronson and associates (27), quantifying mineralization by CT methods, and by Delloye and associates (140), documenting regenerate bone formation using microradiography and histology. DePablos and Canadell (138, 139) studied lengthening in a sheep model using a unilateral fixator with long-term assessments by radiographic and biomechanical techniques. Aronson et al. (28) studied the histology of distraction osteogenesis using Ilizarov and Wagner external fixators for tibial lengthenings with 8 dogs in each group. The distraction osteogenesis procedure was performed after a 7-day latency period and distraction at 0.25 mm every 6 hr until an osteotomy gap of 2.8 cm (about 15% of initial tibia length) was achieved. Correlative histologic and radiographic studies were then made at varying time periods. Both groups healed equally well. Radiodense columns of bone appeared regularly between days 21 and 28 of the distraction osteogenesis procedure. These took their origin from either bone end with the most central part of the gap persisting as a radiolucent band. Areas of bone repair were aligned in linear fashion parallel to the long axis of the gap and of the entire bone. The next phase of healing encompassed continuous bone tissue traversing the gap from end to end. The radiolucent band corresponded histologically to parallel bundles of collagen intermixed with cells also oriented in the direction of the distraction force. The vascular channels also were noted to be longitudinally oriented and there was no mention of cartilage formation. At higher power magnification there was direct transformation of fibrous matrix into bone strikingly similar to the intramembranous ossification characteristic of the embryonic phase. In a subsequent histologic analysis of the repair gap in tibial distraction osteogenesis by the Ilizarov method in dogs it was shown again that intramembranous ossification proceeded from each cortical end toward the central fibrous interzone. Good correlation between histologic repair and mineralization as shown by CT scanning (27). Delloye et al. (140) studied bone repair during distraction lengthening on the forearms of mature dogs using the Ilizarov system. With distraction both periosteal and medullary callus on either side of the gap gave rise to new bone trabeculae. These were oriented along the direction of distraction and progressively approached one another. The characteristic central transverse region of gap radiolucency was also reproduced. Bone in longitudinal alignment traversed the entire gap region, linking proximal and distal bone fragments 4 weeks after the end of the lengthening period. Most of the new bone formed by intramembranous ossification with some foci of cartilage seen. Specific delineation of the cortex began to be noted at 3 months but was still not fully achieved at 5 months. Procedures were performed on 13 adult female dogs, some unilateral and some bilateral, totaling 20 operative procedures. Slight variations in technique were used to

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CHAPTER 8 9 Lower Extremity Length Discrepancies

assess their influence on repair. In general, initiation of periosteal and endosteal callus at the bone ends became apparent at 3 weeks, and with progressive distraction bone repair along the long axis of the gap and adjacent to either cut end was noted. Bone regeneration occurred equally at proximal and distal ends with the central radiolucent region seen. Bone bridging of the gap was usually achieved in a month after the end of distraction, but full cortical definition was not noted circumferentially even at 20 weeks. Microangiography revealed that the integrity of the medullary artery could be preserved after careful corticotomy. Callus was vascularized by both periosteal and medullary systems. The microradiographic study showed the first signs of osteogenesis at both ends of the distracted bone segments from intramedullary and sub-periosteal sources at 2-3 weeks. Striated longitudinally oriented callus was noted at 4-6 weeks. No evident difference was observed between lengthening after corticotomy or full transverse osteotomy with respect to the amount of callus. Histologic evidence of bone repair was, as expected, slightly in advance of radiologic manifestations. Medullary and periosteal osteogenesis was particularly active at 2 weeks. Woven bone was synthesized initially and there was abundant vascularity associated with this. With progressive distraction and time the longitudinal orientation of the new bone trabeculae was seen. Bone formed from a membranous ossification sequence with the advancing fronts of osteogenesis approaching each other from either side and fusing approximately 4 weeks after distraction was ended. The healing sequence was the same regardless of whether the bone had been broken by corticotomy or by transverse osteotomy. Some areas of highly cellular cartilage and fiber cartilage were noticed during the first 2 months, but these were invaded soon by vessels followed by endochondral ossification. Bone marrow appeared to be the larger contributor to the amount of interfragmentary callus, but periosteal callus also constantly supplied the peripheral part of the regenerating bone. Similar findings were reported by Lascombes et al. (289) and Saleh (420) in studies of bone biopsies in human lengthenings. Lascombes et al. (289) were able to harvest 11 biopsies of repair bone during bone lengthening following the Ilizarov technique. The mean age of the patients was 13.5 years and the delay after the initial procedure ranged from 23 to 502 days. Bone was noted histologically along a long axis of the gap as early as the third week. There was a distinct linear alignment to the bone trabeculae along the long axis of the bone. New bone formation was of the intramembranous type without evidence of a cartilage stage. Osteoblastic and osteoclastic activities were prominent, and remodeling was continuing even 1 year after initial intervention. Mature lamellar bone was noted, however, by the fourth month postsurgery. Saleh et al. (420) analyzed bone from 8 patients undergoing distraction osteogenesis using the Orthofix technique. The specimens were obtained from 102 days to 4 years postsurgery. The earliest bone synthesized was

woven with high cellular activity. This was soon covered by lamellar bone, which with time developed a characteristic Haversian architecture. The results of each of several experimental reports on the histology of repair in distraction osteogenesis have been similar. Many have been correlated with clinical studies, primarily radiologic but on occasion utilizing biopsy material. Among the characteristic features are the orientation of newly synthesized collagen and then bone trabeculae along the long axis of the repair gap parallel to the distraction forces. In the vast majority of instances, there is direct intramembranous bone formation present initially adjacent to either cut end, with the central region or interzone healing last. There is a contribution from the inner layer of the reconstituting periosteum, which also tends to be along the longitudinal axis and to represent new bone formation. On occasion, cartilage can be seen within the distraction gap and this subsequently turns to bone by the endochondral mechanism. The presence of cartilage, however, is best interpreted as a sign of less than optimal stability and does not represent true endochondral growth, but rather the formation of cartilage on the basis of increased interfragmentary movement and then conversion of that cartilage to bone once better stabilization occurs. Callotasis means stretching of the bony callus. It is evident that not all instances of bone lengthening heal with a uniform distribution of bone surrounding a central interzone region. Hamanishi et al. (217) classified the radiologic pattern of callus formation seen with the Orthofix procedure in 35 limbs (Fig. 23B). One of the continuing problems with bone lengthening procedures is this variable state and pattern of bone formation, even when the surgeons involved appear comfortable that a relatively uniform technique is being used. The categorization defined by Hamanishi et al. involved (1) the external pattern with lateral bulging of the bone, (2) a straight pattern in which the gap filled uniformly, (3) an attenuated pattern in which the diameter of bone formed centrally was less than at either end and the opposite pattern in which, usually with angular deformity, more bone was formed on the concave than on the convex side, (4) the pillar category in which a thin linear bone collection formed centrally, and (5) the agenetic form in which there were only isolated spicules of bone within the gap. The healing index correlated nicely with the pattern, as would be expected. The index (correlating the number of months per 1 cm of lengthening) was 1.1, 1.3, 1.5, 2.1, 3.7, and 4 in the respective types, with an overall mean of 1.7 because most patients were in the external or straight healing pattern category. One of the main principles articulated by Ilizarov (243, 246, 247) and DeBastiani (137) was the need for a delay in beginning the lengthening to allow for early revascularization and early bone formation, which subsequently would enhance the repair process. Aside from the excellent clinical evidence, experimental studies also confirmed the value of delay in distraction. Gil-Albarova et al. (177) used the Or-

SECTION IX ~ Management o f Lower Extremity Length Discrepancies

thofix fixator to compare results in femoral diaphyseal osteotomy on 24 3-month-old lambs, beginning distraction in half on the first postoperative day and delaying until the tenth postoperative day in the other half. The femur was lengthened by 2 cm at a rate of 1 mm per day. Both radiographic and densitometric studies of the lengthened callus at 1, 2, and 3 months showed that delayed distraction, when compared with immediate distraction, improved the quality of the callus with quicker, denser, and more homogeneous bone formation. The value of delay prior to distraction was also shown clinically by Lokietek et al. (303), comparing clinical results with the Wagner technique with immediate intraoperative lengthening of 1 cm and postoperative distraction of 1 mm per day and the Ilizarov technique, which did not begin lengthening until 5-7 days after osteotomy. They concluded that autogenous new bone formation in limb lengthening related primarily to the management protocol and was distinct from the external device used or even the location of the osteotomy. Their best results were reached when the surgical technique involved circumferential decortication, partial corticotomy with osteoclasis or cracking of the posterior element, a postoperative period of fixation without lengthening of 5-7 days, and an eventual distraction rate of 1 mm per day. Cell and Matrix Deposition Patterns in Distraction Osteogenesis-Rabbit Model: Studies have been performed in our laboratory on the histologic responses of tibial bone lengthening procedures using 4- to 5-month-old rabbits (436). The Synthes Mini Lengthening apparatus (Synthes, USA, Inc., Paoli, PA) was found to be placed easily and well-tolerated by the animals. Figs. 23C-23Ciii show radiographs of the mini-lengthening apparatus attached to the rabbit tibia at 7, 13, and 22 days, respectively. The initial work with this apparatus involved the use of skeletally immature 4- to 5-month-old rabbits with distraction begun on the first day postsurgery. Tibial lengthenings were then performed on 20 skeletally immature rabbits using the Synthes apparatus. A complete 360 ~ turn of the spindle knob gives 0.7-mm distraction. This represents the amount of daily lengthening and was performed in two stages, one in the morning and the other in the late afternoon. Subsequent studies assessing variable age and distraction parameters increased the total number of procedures to 60. Animals were sacrificed at varying intervals from 6 to 46 days postsurgery. Nine animals were allowed to heal for additional periods after lengthening was completed. The lengthening achieved in those lengthened to the time of consolidation of the regenerate bone, which was generally 21 days, ranged from 11.8 to 13.9% of total preoperative tibial length. Periodic X rays of the leg were obtained at 1- to 2-week intervals. At sacrifice the entire tibia was removed and specimen X rays were obtained in two planes (Figs. 23Di-23Dv). The specimens were then processed for light microscopic histologic study. Tissue preparation involved removal of the distracted segment and adjacent bone with a saw, decalcification, sec-

695

tioning in sagittal or coronal planes, and slide preparation using the JB4 plastic embedding technique. This allowed excellent visualization of the histologic detail, which was then correlated with the radiographic appearance. Specimen photographs were also taken after decalcification and halving of the specimen (Fig. 23E). The specimen X rays of the entire bone were taken using a standard technique with a magnification factor of less than 0.01. This allowed accurate measurements to be made of the length of the entire bone and of the distraction gap. A lengthened tibia at sacrifice after fixator removal is shown in Fig. 23E Histologic sections were processed from all animals. At 6 days following lengthening, the gap was filled with blood clot and fibrinous tissue with no geometric pattern of organization noted. Mesenchymal cells were accumulating adjacent to each of the bone ends with early intramembranous bone formation seen. The histologic studies from intervening time periods demonstrated the pattern of new bone formation. Animals that had undergone lengthening for 16 and 20 days showed the entire spectrum of repair cells and matrices within the gap. The repair was not uniform across the lengthening gap. Immediately adjacent to the cut cortical bone ends the repair bone was being transformed to a lamellar configuration, although evidence of initial woven bone persisted. Closer toward the center of the distraction gap the bone repair matrix was aligned longitudinally, as were the accompanying blood vessels. Further toward the center of the distraction gap the repair tissue was increasingly more woven in configuration with progressively less lamellar bone deposited. In the center of the distraction gap, mesenchymal cells persisted and in some sections areas of organizing clot persisted. This histologic picture correlated extremely well with the specimen photographs, specimen X rays, and the clinical finding of an inability to further distract the bone after 3 weeks. The model reproduces the clinical and radiographic findings being described in human distraction osteogenesis. Examples of repair sequences shown by histologic processing are illustrated in Figs. 24A-24E d. Lengthening along an Intramedullary Rod. Lengthening along an intramedullary rod has two attractive features. First, the rod helps to maintain alignment and generally eliminates translational and angular deformation. Second, external fixation can either be removed earlier or in some apparatus not be used, which hastens rehabilitation. Intramedullary Rod with External Fixator Distraction: For several decades some surgeons have performed lengthening along an intramedullary rod, which serves to enhance stability and to help maintain alignment at the lengthening site. The earliest formal paper with this approach was by Bertrand (43), who used one or two narrow intramedullary rods during distraction of the femur. Bost and Larsen (61) used an intramedullary rod to assist femoral lengthening in 23 procedures. The intramedullary rod, generally a large Rush rod, was narrow enough to allow distraction to occur and wide enough to allow for stabilization. The oblique, step

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Lower Extremity Length Discrepancies

F I G U R E 24 Histologic study of the gap region correlates well with the radiographic studies showing advancing fronts of repair adjacent to each sectioned end rather than a uniform repair process throughout the entire gap simultaneously. (A) The varying regions from which the histologic studies in this figure were taken. (B) Early new bone formation adjacent to cortex. Below is undifferentiated mesenchymal tissue at the center of the gap. (C) Histologic section from the persisting cortex (PC) and gap interface at 10 days following surgery and initiation of distraction. The initial bone synthesized is woven (W), which is more darkly stained here. Shortly thereafter, better oriented lamellar (L) bone is synthesized on the woven scaffold. Osteoblasts (arrows) line up nicely on the lamellar surfaces. (D) A higher power view in another rabbit in this same general region 2 weeks following surgery now shows a predominance of lamellar (L) bone with only small remnants of woven (W) bone persisting. Note the orderly array of osteoblasts (arrows) on the lamellar trabecular surfaces. (E) A region closer toward the center of the gap at 3 weeks. Note the predominantly longitudinal orientation of the new bone formation. This is related primarily to the associated longitudinal orientation of the vasculature. At the fight, a primarily lamellar trabeculum of bone is seen lined with osteoblasts. At the left, some initially deposited woven bone persists. (F) Tissue from the center of the gap region at 2 weeks. This is the most radiolucent appearing region on the radiographs as it is the newest site of bone formation. The mesenchymal cells have formed a primarily woven bone matrix. Note, however, the longitudinal orientation, the early formation of lamellar (L) bone, the lining up of osteoblasts on these lamellar surfaces, and in particular the marked osteoclastic resorption (arrows) occurring even as synthesis proceeds.

cut, and t r a n s v e r s e o s t e o t o m i e s e a c h w e r e used, b u t ulti-

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m a t e l y t h e y f a v o r e d the t r a n s v e r s e p r o c e d u r e b e c a u s e it w a s

p i n s into the p r o x i m a l a n d distal f e m o r a l f r a g m e n t s f o l l o w e d

simpler, led to b e t t e r c o n t r o l o f a n g u l a t i o n , and s h o w e d no

b y either the a p p l i c a t i o n o f t r a c t i o n u p o n the l i m b s u s p e n d e d

d i f f e r e n c e in h e a l i n g t i m e f r o m the o t h e r t w o patterns. T r a c -

in a T h o m a s splint or the u s e o f a t r a c t i o n - c o u n t e r t r a c t i o n

SECTION IX ~ Management of Lower Extremity Length Discrepancies

apparatus designed by themselves, which had an upper femoral ring and a frame on both the inner and outer aspects of the thigh and leg. Traction was started immediately after the operation and continued at a low rate until the desired length was obtained or no further length'~was obtainable. The patient remained in bed during the lengthening procedure. The amount of lengthening of the femur varied from 0.38 to 4.25 in. In the entire series of 23 lengthening operations, the average gain was 2.18 in. or slightly less than 2.25 in. or 5.5 cm. In 20 of the straightforward patients, the average time required for the lengthening was about 11 weeks. In 13 of the 23 procedures union of the bone occurred in an average of 32 weeks and did not vary between the various types of osteotomy. After 10 of the osteotomies, one or more bone grafting procedures were necessary to obtain bony union. All of the bone grafting procedures were performed as secondary interventions because of delayed union because no primary bone grafts were used at the time of lengthening. Both of the authors, as well as Abbott and Saunders (5) in 1939, specifically noted that lengthening of the callus was occurring. Bost and Larsen indicated that "during its growth the bone callus may be stretched out in length." They pointed out that major discrepancies could be markedly improved by a combination of lengthening on one side and shortening on the other. There was one late disturbance in circulation during the process of lengthening but this resolved with reduction of the traction weight. A palsy of the peroneal nerve occurred in 7 patients but in 5 it was transient. There were 5 patients with a posterior subluxation of the tibia on the femur, but after management no major problems resulted. Fractures of the lengthened femurs occurred in 4 of the 23 cases. The primary aim of the procedure, however, the control of alignment during lengthening, was successfully obtained thus eliminating many of the difficulties associated with lengthening procedures. Transverse osteotomy led to healing as quick and as sound as the more commonly used step cut or oblique osteotomies. Once reasonable healing had occurred, the patients were protected with either a cast or a brace during the transition phase to full unprotected weight bearing. Wasserstein (494) used an unreamed, flexible intramedullary rod in association with distraction through an external fixator of the Ilizarov type, followed by a cortical allograft of the distraction gap using a tubular bone segment once the lengthening had been achieved. Wasserstein transplanted cylindrical allografts into the distraction gap both to decrease the treatment time as well as to increase the stability of the fixation and insure proper alignment of the limb. The technique was used in patients between 5 and 25 years old, although in selected cases those up to 35 years of age were operated. He felt that the technique was best used for discrepancies greater than 6 cm because lengthenings under 6 cm appeared to heal adequately with distraction osteogenesis techniques alone. The technique was used in 300 patients over a 15-year period for both femoral and tibial lengthenings.

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FIGURE 25 Femoral lengthening around an intramedullary rod is shown. [Reprintedfrom (364), with permission.]

More recently, Paley et al. (364) have performed femoral lengthening with the Ilizarov or Orthofix distractors over an intramedullary nail and compared it with a matched group of patients having lengthening with the standard Ilizarov technique (Fig. 25). The Ilizarov external fixator was used in 11 lengthenings and the Orthofix fixator in 21 with a 10-mm intramedullary femoral rod. The mean amount of lengthening in 32 procedures was 5.8 cm (range = 2-13 cm) and the mean age of the patients was 26 years (range = 1053 years). Results in several categories were compared with the standard Ilizarov femoral lengthening that had been performed in 32 matched patients. The authors noted that lengthening over an intramedullary nail reduced the average time of external fixation by almost one-half. The range of motion of the knee returned to normal an average of 2.2 times faster in the group that had lengthening over the intramedullary nail. There were 6 refractures of the distracted bone in the standard Ilizarov group but none in those protected with the intramedullary nail. Paley et al. concluded that the advantages of lengthening over an intramedullary nail included a decrease in the duration of external fixation, protection against refracture, and earlier rehabilitation.

lntramedullary Telescoping Rod for Lengthening without the Need for External Fixators: The most recent technological innovation in limb lengthening has been the use of an intramedullary rod that contains an internal telescoping mechanism, such that the lengthening can be performed in the complete absence of any external fixators. Distraction is performed following osteotomy and fixation of the upper and lower portions of the intramedullary rod to the bone by

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CHAPTER 8 ~ Lower Ex~cremity Length Discrepancies

use of a rotation maneuver of the limb, which serves to distract the two segments of the rod at the internal telescoping mechanism using a ratchet effect. Guichet and colleagues (205) in France developed a model for this form of lengthening. A precursor of this technique had been described by Gotz and Schellmann (190) in which a hydraulic distractor was placed in a modified interlocking intramedullary nail to provide for continuous distraction. The system developed by Guichet and collaborators has the two telescoping fragments relating to each other internally such that, with external rotation of the limb, a clicking and locking mechanism allows for elongation with no movement possible in the reverse direction. Fifteen external rotation maneuvers of the lower extremity, which serve to rotate the distal femoral fragment to which the intramedullary rod is attached, allow for a lengthening of 1 mm per day. The device was developed for femoral lengthening. An osteotomy is performed such as would be done for a closed femoral shortening procedure. The principles of distraction osteogenesis are used with lengthening beginning on the eighth postoperative day. The 1 mm per day lengthening is achieved in four separate time periods 6 hr apart, much as is used in the Orthofix and Ilizarov approaches. Once the appropriate length has been achieved, rotation is no longer performed and the rod serves as a regular intramedullary rod until healing occurs. Guichet et al. refer to the mechanical intramedullary system, System for Progressive Intramedullary Lengthening (SAPI), as one destined to be used as an internal dynamic fixator for the progressive lengthening of segments of the lower extremity. The apparatus also has a dynamization capability built in once lengthening has been reached. The rod is fixed to the femur both proximally and distally, allowing for stabilization at the same time that lengthening is occurring. The external rotation movement allowing for the lengthening to occur is one of 20 ~ following which the limb then returns to its normal position. Each rotation corresponds to a lengthening of 0.067 (1/15) mm such that 15 movements correspond to 1 mm of lengthening. Each movement provides an audible clicking sensation. Caton et al. (103) have presented a brief report with the elongating intramedullary nail based on a series of experiments in sheep. They inserted the nail in the femurs of four sheep bilaterally. In their report, each operation applied to the limb allowed 0.1 mm of lengthening with elongation of 1.25 mm per day. In the first group of animals the mean lengthening obtained was 3.2 cm over 24 days with a percentage elongation of 14.2%. Regenerated bone was noted radiographically at 15 days and consolidation took place at 5 months. In a second series the internal device was compared with lengthening using external fixation. In the second series the mean lengthening up to 90 days was 3.9 cm, which was actually somewhat more than with the external fixator. Caton et al. felt that bone regeneration in the intramedullary group was completely satisfactory. Although the technique has not yet achieved wide usage, its advantages are attractive

in the sense that there is no external apparatus and the skin is virtually intact. There are no structures to impede the muscles such that joint motion should be more readily obtained. Stability is maintained and angulation is either prevented or markedly minimized. e. Longitudinal Growth after Diaphyseal Lengthening Done prior to Skeletal Maturity. Clinical Studies: Although an increased rate of femoral growth has been reported after one-stage procedures for lengthening of the femur and a variable rate of growth has been noted after Judet-type procedures for lengthening of the femur and tibia, there have been few detailed radiographically documented studies of growth of bone after lengthening of the diaphysis. Authors of earlier papers that have included the results of lengthening of the diaphysis have commented on somewhatvariable, but generally good growth after the procedure. However, these studies were not directed toward the specific assessment of growth after lengthening, nor did they report data from radiographic measurements; thus, the exact rate of growth after lengthening cannot be determined from them. We noted from the data on growth in patients at Children's Hospital, Boston, that when lengthening was performed on a bone that had several years of growth remaining the lengthened bone continued to grow at a slightly increased rate in some patients, whereas in others growth became more inhibited than it was before the operation (435). In our study, data on growth were assessed from 18 patients who underwent lengthening of the femur or tibia by mid-diaphyseal osteotomy and the gradual distraction techniques of Anderson and Wagner. The goal was to define the growth responses to these lengthening procedures. Femoral Lengthening: In each of seven patients, the rate of postoperative growth of the lengthened femur, in relation to that of the normal bone, was increased compared with the preoperative rate. The average rate of preoperative growth of the short femur was 82% that of the normal side, whereas the average postoperative rate of growth was 90% of normal. In one patient the rate of postoperative growth was 21% greater than the preoperative rate, but in all of the others the increase was from 5-8%. The amount of surgical lengthening of the femur averaged 18% of the preoperative length of the bone, with a range of 6-35%. Tibial Lengthening: In all 11 patients, the rate of growth diminished from the preoperative levels, ranging from a 46% diminution to a 3% diminution. The average preoperative rate of growth of the shortened tibiae was 88% that of the normal side, whereas the average postoperative rate diminished to 64% of the normal side. The amount of lengthening of the tibiae averaged 20% of the preoperative length of the bone, with a range of 14-30%. Long bones have differing growth responses after lengthening of their diaphyses. However, when growth is assessed according to the specific bone that was lengthened (that is, according to whether the femur or tibia was operated on), more uniform patterns of response are seen. A slight increase

SECTION IX ~ Management of Lower Extremity Length Discrepancies

in the rate of growth was noted in each of 7 patients who had lengthening for congenital short femur, and the increased rate was maintained for several years after the procedure. There are insufficient data to determine whether this stimulation of growth is maintained until growth ceases. Suva et al. (466) documented an almost invariable tendency for increased growth in the femur after a one-stage lengthening. They noted stimulation of growth in 33 of 36 patients who had poliomyelitis, 8 of 13 who had a congenital short femur (including some who had proximal femoral focal deficiency), and 4 of 5 in whom the shortening had another etiology. Overgrowth after fracture of the femoral diaphysis has been recognized for several decades. Assessment of 74 patients using serial orthoroentgenograms documented overgrowth as a universal phenomenon in patients who are less than 13 years old, regardless of whether the fracture healed with anatomical reduction, shortening, or distraction. Increased vascularity to the entire bone brought about by the repair process has been thought to stimulate growth at the proximal and distal growth plates. Because the repair response that is engendered by lengthening of the diaphysis is much more extensive and prolonged than that after fracture of the diaphysis, overgrowth is expected. The primary pathological condition that causes the discrepancy and resistance of soft tissue to distraction, which can exert compressive forces on the growth plates to restrain their growth, can minimize the effects of stimulation. However, in the series reported here the patients who had lengthening of the femur all had an increased rate of growth. The decreased rate of growth that was seen in all patients after tibial lengthening in the present series does not appear to occur universally. Variable growth responses to Judet-type lengthening have been documented radiographically by Pouliquen and Etienne (392) and by Pouliquen et al. (390). In the more detailed of the two articles, the authors reviewed the results after 39 lengthening procedures; 6 were performed on the femur and 33 on the tibia although the report did not deal with the femoral and tibial procedures separately. Their report and the present series are not entirely comparable as the criteria for inclusion of patients and documentation were much stricter in the present series. Still, comparisons can be made. In the series of Pouliquen et al., of the patients who had poliomyelitis, the growth was normal after lengthening in 18, slowed in 7, and arrested in 2. Of their patients who had congenital agenesis, growth was normal in 1 and slowed in 5. The findings in the latter group were similar to those in the patients who had lengthening of a congenital short tibia in the present series. Pouliquen et al. noted almost no retardation of growth after lengthening of 5.0 cm or less and a progressively greater slowdown of growth when the lengthening, expressed as a percentage of the preoperative length of the bone, increased beyond 15%. The crucial determinant appears to be the percent of lengthening rather than the absolute amount of the lengthening. Of their patients who had lengthening of 10-15%,

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only 1 (11%) of 9 had a slowing of growth, whereas 9 (45%) of 20 who had lengthening of 15-20% and 8 (80%) of 10 who had lengthening of 20-25% had a slowdown or cessation of growth. Hope et al. (238) noted no change in growth following 10 femoral and 10 tibial lengthenings using the Wagner technique for congenital shortening of the lower limb. It is unclear why their data differ from the Children's Hospital, Boston, and the Pouliquen group data or the experimental data of Lee et al. reported later. The absolute amounts of lengthening were not given by Hope et al., only growth ratios, and it is known for the tibia that the greater the amount of lengthening the greater the growth slowdown. No patient in the present series who had lengthening of the femur had a slowdown of growth, even though the increases in length were often greater than 15% of the preoperative length. Reports made before 1978 on lengthening of the tibia raised the matter of postoperative growth, but none included rigorous radiographic documentation of this specific phenomenon. The absence of detailed data allows for only general, qualitative impressions concerning growth after lengthening. Moore (334) noted that, of 19 skeletally immature patients with poliomyelitis who had lengthening of the tibia using the Abbott method, the correction was maintained in 15, growth actually increased beyond the normal side in 3, and only 1 showed increased retardation. In another report on Abbot-type lengthening, many patients who were operated on before the age of 12 years showed an increased discrepancy between the lengths of the extremities at skeletal maturity compared with the amount of lengthening achieved. In these reports, it is unclear how much of the final discrepancy was due to the condition itself, postoperative complications, or postoperative retardation Of growth. A review of the results after 31 Anderson procedures for lengthening of the tibia revealed a variable degree of postoperative recurrence of limb length discrepancy in patients who had undergone the procedure between the ages of 8 and 19 years, especially in those who had a congenital short tibia (118). Gross (203) indicated that in some patients growth was stimulated after Anderson lengthening of the tibia, whereas in others the opposite occurred. The majority of patients referred to in these four reports had poliomyelitis. The present series included only 1 patient who had poliomyelitis. It has been proposed that extensive resistance by soft tissues in the leg is responsible for increased inhibition of growth with lengthening of the tibia. The interosseous membrane and the Achilles tendon appear to be more resistant to stretching than the tissues surrounding the femur. The negative effects of increased pressure on epiphyseal growth have been well-outlined. Shortening was noted in this series even after extensive releases of soft tissue, including lengthening of the heel cord. Attempts have been made to document the impression that retardation of the growth plate can be due to increased pressure in the limb generated by the distractive forces during lengthening of the tibia. A pressure

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CHAPTER 8 ~ Lower Extremity Length Discrepancies

gauge was developed by Pennecot et al. (383) to measure the forces generated during distraction, and the measurements were then correlated with the rate of subsequent growth. It was concluded that for the tibia there was good correlation between retardation of growth, lengthening of greater than 15% of the preoperative length of the bone, and the increased forces that were registered. In the present series, the growth response after lengthening of the tibia was different from that after lengthening of the femur. In each of 11 patients who had lengthening of the tibia, growth was retarded in comparison with the preoperative rate. The patients who had a congenital short tibia and those who had Ollier's disease had marked retardation of growth of the tibia, whereas the 1 patient who had poliomyelitis had only a 3% decrease. Greiff and Bergmann (198) demonstrated overgrowth in the tibia after tibial fracture. As the process of repair after lengthening of the tibia is more extensive than that after fracture, it is likely that the factors that cause stimulation after fracture are present after lengthening. In the patients in the present series, however, it appears that the factors limiting growth were more influential than those stimulating it. Growth responses do not appear to be dependent on the techniques that are employed to lengthen the bones. In this study, femoral growth was stimulated with the use of the Wagner apparatus, and in another it was stimulated with the use of a one-stage lengthening. Growth was maintained in some patients who had poliomyelitis after the use of the Abbott, Anderson, and Judet methods, whereas retardation of tibial growth increased in patients who had a congenital short tibia, Ollier's disease, or another nonparalytic condition using the Anderson, Wagner, and Judet methods. In the human, variable growth responses are demonstrated after lengthening of the diaphysis in bones that have several years of skeletal growth remaining. In our series, the 7 lengthening procedures that were performed for congenital short femur all led to an increased rate of growth. It is anticipated that lengthening can be performed on femurs that have several years of growth remaining with the expectation of continuation of growth at a slightly increased rate. The tibial lengthening procedures that were done for patients who had a congenital short tibia or Ollier's disease all led to retardation of growth that was more extensive than the preoperative retardation. Hadlow and Nicol (214) have incorporated this growth information into a formula used to aid in timing for femoral and tibial lengthenings, incorporating altered growth expectations as well as projections of the preoperative growth rate. Lengthening of the tibia should include a slight overcorrection to compensate for an expected retardation of growth if it is performed on a bone that has several years of growth remaining. Preferably, the tibia should be lengthened at or near skeletal maturity to avoid a loss of correction secondary to retardation of growth. The timing of surgical intervention for discrepancies in the lengths of the lower extremities before skeletal maturity should be improved by considering both the developmental

patterns that have been described previously and the patterns of growth after lengthening that have been described here. Experimental Studies: A detailed experiment assessing longitudinal growth of the rabbit tibia after distraction osteogenesis was reported by Lee et al. (293). They divided 99 5-week-old immature rabbits into five groups according to the percentage of lengthening done with group I at 10%, group II 20%, group III 30%, group IV 40%, and group V a sham operation with osteotomy without lengthening. They clearly demonstrated that tibial lengthening did not cause retardation of growth when the bone was lengthened by 1020%, but in those instances in which it was lengthened by 30-40% growth retardation was evident. These data correlate well with our clinical studies and those of Pouliquen reported earlier. In groups I, II, and V, no statistically significant growth differences were noted between the operated and control tibias. There were significant differences in the growth ratio in groups III and IV with relative growth ratios of left to fight decreased significantly in group III (average = 4.2%) and in group IV (average = 7.0%). Histomorphometric studies were also performed on the physes in each of the groups. These studies correlated well with the gross measurements of length. In groups I, II, and V there were no statistically significant differences, but in groups III and IV there were significant decreases in the total thickness of the operated tibial growth plates, both proximally and distally, compared with controls. There was thinning of both the proliferative and the hypertrophic zones. The overall heights of the growth plate were measured such that the average decrease in the proximal growth plate was 10.4% in group III and 23.9% in group IV. Distally it was 11.9% in group III and 12.4% in group IV. Similar ratios were found with diminution of the thickness of both the proliferative and hypertrophic zones studied separately. f Increased Awareness of the Need for Joint Stabilization and Axial Correction as Well as Limb Length Equalization in Complex Abnormalities. As the profile of lower extremity length discrepancies changed over the past few decades from one in which the major discrepancies in most series were due to the sequelae of poliomyelitis, the deformities became more complex such that shortness of the limb was often combined with subluxation and dislocation of associated joints and axial malalignment. Wagner (493)clearly pointed out the need to stabilize the joints and correct any axial malalignment prior to initiation of any lengthening procedure and also the need to watch carefully for joint and alignment changes during the course of any lengthening procedure. A report by Saleh and Goonatillake (419) strongly reiterated the need for adherence to these principles of treatment particularly with congenital lower extremity length discrepancies. The disorders they discussed fell into the range of femoral, tibial, and fibular congenital abnormalities in 92 patients, with the three most common groups encompassing 77 patients involving proximal femoral focal deficiency, proximal femoral focal deficiency and fibular hemimelia, and hemihypertrophy. Saleh and Goonatillake indicated that

SECTION IX ~ Management of Lower Extremity Length Discrepancies

joint stabilization was mandatory for good function and was an absolute prerequisite prior to beginning limb lengthening. In efforts to prevent or minimize the likelihood of hip subluxation or dislocation, therefore, femoral head-acetabular congruity would have to be established, such that pelvic or shelf osteotomy along with proximal femoral osteotomy would be needed. The greatest challenge is in cases of proximal femoral focal deficiency in which there often is a need for the previously mentioned procedures and on occasion, in the more severe variants, femoral-pelvic fusion or at least definitive placement of the proximal femoral shaft into the acetabulum. Knee instability due to anterior cruciate ligament and/or posterior cruciate ligament deficiency is common in dysplastic limbs. Although no specific treatment is needed for this, the occurrence of subluxation of the knee during the lengthening procedure must be observed for carefully and managed as well as possible during the procedure itself. Areas of concern at the ankle involve Achilles tendon tightness leading to an equinus deformity and varus-valgus instability, with abnormal relationships of the lateral malleolus to the medial malleolus or with changes in the rate of distal tibial versus distal fibular lengthening. In some instances the Achilles tendon lengthening, posterior ankle capsulotomy, and distal tibial-fibular stabilization are performed prior to the lengthening procedure. In other instances orthotic devices are used along with physical therapy to maintain looseness and anatomic integrity at the ankle region, with intervention occurring only with changes that develop. Abnormalities in femoral or tibial alignment of more than a few degrees should be corrected prelengthening with appropriate osteotomies. Soft tissue contractures at hip, knee, and ankle must also be released. The final area of stabilization needed prior to lengthening relates to a pseudoarthrosis either of the proximal region of the femur, such as can be seen in a proximal femoral focal deficiency, or a formal congenital pseudarthrosis of the tibia. In general, however, lengthening of a congenital pseudarthrotic tibia is rarely performed, although on occasion it has been attempted in that part of the tibia well away from the pseudarthrosis in which the bone structure appears normal. g. Humeral Lengthening. Attention has been directed to humeral lengthening for relatively extensive length discrepancy problems (104, 130, 141,385, 426). Because 80% of the growth of the humerus occurs from the proximal growth plate, injury to this region particularly in the early childhood years can lead to major limb length discrepancy. Dick and Tietjen (141) reported on a humeral lengthening following neonatal growth arrest in 1978 using the Wagner technique. The most common causes of humeral lengthening involve negative sequelae following a proximal humeral unicameral bone cyst, neonatal sepsis, humeral trauma, humerus varus, Ollier's disease and a severe skeletal dysplasia. Peterson (385) reviewed 12 cases from the literature in 1989 and added 1 of his own. The operations proceeded quite nicely with surprisingly few complications reported. This has been our observation as well. Humeral lengthenings

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are considered to be the least problematic of the major limb bone lengthenings. Many of the problems characterizing lower extremity lengthenings are infrequently seen, such as delayed union or nonunion and angular deformity. The Wagner technique is readily applicable to the humerus, as is distraction osteogenesis using the Orthofix apparatus. We have performed 4 of the latter, each with a 5.5-cm gain in length and no problems referable to delayed union or nonunion, angular deformity, joint stiffness, or neurovascular issues. In a review of several reports, the amount of lengthening achieved varied from 20 to 125 mm with a mean of 66 mm (6.6 cm). In 7 of the 12 patients reported by DalMonte et al. (130), the mean lengthening was 5.0 cm and the mean percent lengthening was 25.2%. Cattaneo et al. (104) performed 43 humeral lengthenings with the Ilizarov technique on 29 patients, 14 with achondroplasia, with an average lengthening of 9 cm achieved (range = 5-16 cm). There were 7 fractures in 6 patients following removal of the apparatus, all of which were treated successfully. There were no permanent neurovascular problems. 3. TRANSPHYSEAL LENGTHENING: DISTRACTION EPIPHYSEOLYSIS OR CHONDRODIATASIS

a. Early Experimental Findings. Transphyseal lengthening procedures were conceived initially and performed experimentally by Ring (407). He achieved lengthening of between 11 and 32 mm in 20 puppies between 4 and 6 months of age using an external distraction apparatus, which elongated both distal radius and ulna. He recognized that when sufficient traction was applied there was a physical transphyseal separation, after which continued distraction opened up a space allowing lengthening to occur with subsequent repair with a cylinder of new bone from the periosteum. The physis continued to function, and both it and the metaphysis filled the distraction gap with repair bone centrally. Some animals suffered premature growth plate fusion to limit somewhat the length gain achieved, but some continued with growth postlengthening. Continuous transphyseal traction was applied by Fishbane and Riley (163) across the proximal tibial growth plate in 10 puppies. Histologic examination revealed fracture to have occurred in all cases through the metaphyseal zone of primary trabeculae just distal to the hypertrophic zone of the cartilaginous growth plate. The physis itself appeared undamaged. Growth was felt to continue, but complete follow-up to skeletal maturity revealed early fusion preceding the normal limb by several weeks in 5 puppies. Rapid bony healing was noted in the distraction gap. The authors felt that the technique could be applied to the human as an effective and reasonably safe way of obtaining increases in limb length. Sledge and Noble (448) performed transphyseal lengthening experiments in the distal femur of the rabbit. They also varied the forces across the physis and compared histologic findings in an effort to determine the precise site of lengthening. A Salter-Harris type I transverse fracture occurred in

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CHAPTER 8 ~ Lower Extremity Length Discrepancies

13 of the 16 animals to which 5 kg or more of force had been applied. The fractures occurred at the lower part of the hypertrophic zone. At lesser levels of force, however, there were markedly fewer or no fractures and lengthening appeared to have occurred in relation to increased thickness of both the proliferative and hypertrophic zones of the physis. Thirteen of 21 animals to which 2 kg were applied and 18 of 19 animals to whom 1 kg was applied showed only a partial microscopic fracture or no fracture. In 17 of 56 animals distracted there was no fracture of any type, and overall there were 34 rabbits in which gross disruption at the plate did not occur. The response of the physis to transphyseal force, therefore, clearly was dependent on the amount of force applied. The combined force in excess of 2 kg almost always caused fracturing. There was, however, a consistent increase in length on the involved side whether or not fractures in the plate were produced. In the absence of fracturing, Sledge and Noble felt that hyperplasia and hypertrophy of the plate were representative of an increased physeal stimulation, which in turn led to the length increase. Jani (254, 255) also noted fracture in the hypertrophic zone and subsequent healing by endochondral ossification in 42 puppies in whom distraction epiphyseolysis had been performed. Further insight into the effect of chondrodiatasis on the physis itself was provided by Elmer et al. (149). They performed a study in the rabbit to assess cell activity in the physeal region and noted that the procedure did not produce any significant changes in the percentage of cells labeled with tritiated thymidine, the intensity of radioactive sulfate labeling the matrix, or the blood supply of the physis. Thus, Elmer et al. felt that lengthening was not the result of stimulating cell division or increased synthetic function of the plate, but rather the result of stretching of the matrix passively. Transphyseal lengthening is referred to as distraction epiphysiolysis when the distraction force is sufficiently great that a physeal fracture-separation occurs, or chondrodiatasis in which lesser distraction forces leave the physis intact with hyperplasia occurring in the proliferating and hypertrophic zones. In the former repair occurs by an intramembranous bone mechanism, whereas in the latter the endochondral mechanism continues. The distraction device spans the growth plate with pins anchored in the secondary ossification center of the epiphysis and in the metaphysis, and the distraction forces lengthen the limb by causing a separation at the plate. DeBastiani (136) slowed the rate of lengthening to 0.25 mm every 12 hr and advanced the concept that, in so doing, a transphyseal fracture did not occur but that a stretching of the hypertrophic zone only was the lengthening phenomenon. The term chondrodiatasis was used to refer to this occurrence. b. Clinical Use The usual sites of limb lengthening in the human have been within the diaphyseal or metaphyseal regions of bone but work by Zavyalov and Plaksin (519), Ilizarov and Soybelman (248), and Monticelli and Spinelli

(329-331) showed that transphyseal lengthening was both clinically feasible and advantageous in some regards. These advantages involved the fact that healing was much quicker than in diaphyseal lengthenings because dense cortical bone did not have to be repaired but rather only metaphyseal bone, much as would occur in a physeal fracture. Early experiments showed that actual physical separation occurred in the hypertrophic zone of the physis, leaving the major growth part of the physis intact, a phenomenon referred to as distraction epiphyseolysis. The transphyseal lengthening then occurs mechanically and subsequent growth continues once the physeal defect within the hypertrophic zone of the metaphysis has been repaired. Although this experimental technique can lead to superb results both clinically and experimentally, currently it is not widely used when there are a few years of growth remaining. There have been reports of premature growth plate cessation following this procedure. In patients, however, who have virtually no growth remaining, the procedure is attractive. It can be performed using either the circular distraction devices of Monticelli and Spinelli and Ilizarov or unilateral lengtheners such as the Orthofix device. Eydelshtyn et al. (154) reported extensively on the distraction epiphyseolysis in a clinical setting in association with meaningful limb lengthening. They noted epiphyseal separation radiologically within 7-10 days and the ability to obtain length increments of 4-7 cm. They suggested that in most instances there was no negative influence on further growth. The cleavage fractures appeared radiologically to have occurred in the metaphysis in 26 of 33 patients, with the remaining 7 occurring at the lowest levels of the growth cartilage but preserving the growth mechanism more proximally. DeBastiani and associates (136) performed chondrodiatasis using the unilateral Orthofix apparatus in 40 segments of patients with limb length discrepancies, gaining a mean of 3.3 cm in length (range = 1.5-7.0 cm), and in 60 segments in 25 achondroplastic patients, gaining a mean of 7.1 cm (range = 3-10.5 cm). In 16 distraction epiphyseolysis procedures reported by Monticelli and Spinelli (331) the tibia was lengthened by an average of 6 cm (range = 3 10 cm). The patients were all between 13 and 16 years of age with little to no growth potential persisting. Aldegheri et al. (15, 17) reported on chondrodiatasis used for elongation of 170 bone segments in 75 children, 41 with limb length discrepancies and 34 with achondroplasia. All were operated on with the growth plate open. The Orthofix apparatus was used to lengthen either the distal femoral or the distal tibial epiphyseal plates. Distraction began the day after operation at a maximum rate of 0.5 mm per day in several stages. There were 92 femoral and 78 tibial lengthenings. The average age was 11.9-12.1 years. In those treated for limb length inequalities the mean lengthening obtained was 3.4 cm (10.9% of average initial length). The mean lengthening of the femur was 3.0 cm and that of the tibia was 3.7 cm. In achondroplastic patients, the mean lengthening

SECTION IX ~ Management of Lower Extremity Length Discrepancies

obtained was 7.4 cm with virtually equal amounts in the femur and tibia. Most of the complications recorded were in the achondroplastic patients, and most of these were in the tibias primarily because of the abnormal shape of the distal tibial epiphyses. The procedure is generally performed at the distal femur or distal tibia just before skeletal maturity. It does not require the use of plates or grafts, because metaphyseal bone heals readily in the gap produced. Franke et al. (165) performed distraction epiphyseolysis using the Ilizarov apparatus in 22 lower limb segments with an average lengthening of 8.25 cm (range = 4-18 cm). Some of the patients had achondroplasia, and it was these patients in whom some of the larger lengthenings occurred. The healing was considerably quicker in the distraction epiphyseolysis group compared with the partial metaphyseal corticotomy group summarized previously. In a group of 9 patients lengthened between 6 and 9.5 cm, the average time to full weight bearing was 9.5 months with the repair index 43.6 days per cm. c. Growth Consequences Related to the Force o f Distraction and Mechanism o f Lengthening. Although initial reports from the European literature indicated that growth can continue following healing, there have been more recent reports of premature growth cessation such that the procedure is best performed within 1 year of expected growth plate closure or in situations in which metaphyseal or diaphyseal lengthening is not possible. Clinical papers reporting early physeal closure after chondrodiatasis are increasingly common. Hamanishi et al. (216) reported femoral chondrodiatasis in 5 patients, but in 4 of the 5 the physis closed shortly after lengthening and loss of gained length or further shortening occurred in each. They used the Orthofix apparatus and the lengthening rate was 0.25 mm every 12 hr. The 5 femurs were lengthened by a mean of 32 mm (range = 2543 mm) after 70 days of distraction. Subsequent growth, however, was markedly diminished in 4 and moderately diminished in the other. Hamanishi et al. felt that the 0.5 mm per day distraction caused physeal separation rather than hyperplasia of the growth plate alone. Bjerkreim (51) evaluated 10 consecutive proximal tibial physeal distraction cases with a mean lengthening of 6.7 cm. In 6 cases lengthened at 1 mm per day under 13 years of age, subsequent growth was only 6 mm compared with the normal side of 32 mm. Growth retardation has been seen in several experimental animals after epiphyseal distraction. Letts and Meadows (297) performed distraction epiphysiolysis of the proximal tibia in 18 rabbits. The average distraction gained was 0.54 cm, which was 6% of the length of the tibia at the time of intervention. Union invariably occurred. In each of 12 younger rabbits operated, once the distracted area united it was shortly followed by premature fusion of the growth plate. In 6 older rabbits operated close to the time of skeletal maturity no negative growth sequelae occurred. Subsequent histology showed no normal epiphyseal growth plates after repair of the gap. In the study by Fjeld and Stein (164), subsequent

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growth retardation was consistently experienced in all animals with an average reduction in growth ranging from 40 to 70%. The experimental groups involved 10 distal femoral epiphyseal distractions in the goat, 14 in the proximal tibia of the goat, and 18 in the distal femur of the dog. They felt that the reduction in gained length with time after the end of distraction must have been due to a retardation of endochondral growth after the elongation procedure. Jani (254, 255) also reported negative growth sequelae after distraction epiphyseolysis experiments in the rabbit. Alberty (12) performed a vascular study of the growth region following physeal distraction in the rabbit. The microangiography assessments were performed in relation to 45 distal femoral transphyseal lengthenings. Most of these were performed at a rate of 1.0 or 1.5 mm once daily increases. Both marked enlargement of the epiphyseal arteries and defective metaphyseal capillary filling were noted after 3 days of distraction, changes that persisted in specimens distracted as long as 21 days. New capillaries were observed in the hyperplastic physes and in separation gaps at 21 days. Of note, however, was the fact that vascular anastomoses were noted across the physes at 6 weeks of follow-up. The latter phenomenon was noted in those distracted from 9 to 21 days who then were assessed after an interval of 6 weeks between discontinuation of the distraction and microangiography. A premature closure or impaired function of the physis was common in association with the transphyseal vascularity. In spite of the comments of DeBastiani concerning the absence of transphyseal fracture with slower rates of distraction, dePablos et al. (138, 139) found that, in each of three models used, production of a fracture between the metaphysis and the epiphysis always occurred but that the lower the distraction rate employed the greater the viability of the growth cartilage. The optimal rate for distraction was 0.5 mm per day. The Orthofix distractor was used in 45 lambs divided into three groups each, with the rates of distraction being 2, 1, and 0.5 mm per day. Histologic studies showed that at the slowest rate the growth cartilage remained essentially normal, whereas in femurs lengthened at a rate of 1 or 2 mm per day obvious lesions of physeal cartilage were observed, particularly in those studied 45 days following the conclusion of lengthening and at 6 months of age. Spriggins et al. (454) assessed the response of the growth plate to increasing force of distraction. They studied the upper tibia in 24 rabbits close to skeletal maturity with distraction rates of 0.13, 0.26, and 0.53 mm every 24 hr. They noted two distinct patterns of response. In the group in which forces increased to maximum values of 20-22 N and then suddenly decreased subsequent distraction fracture of the growth plate had occurred, whereas in the other group lower forces of 16-18 N produced and continued to the end of the distraction period were associated only with physeal hyperplasia without fracture. These results were consistent with those of Sledge and Noble and DeBasiani et al. that a slowed rate of distraction could allow for lengthening without

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CHAPTER 8 9 Lower Extremity Length Discrepancies

fracture. It was in the two lower distraction rates that histologic evidence of fracture was not seen. d. Histologic Findings in Physeal Distraction. With the application of physeal distraction, therefore, the mode of lengthening is of two types. If distraction pressures are comparatively low, there is apparent continuity of the physis with hyperplasia of cells in the lower proliferating and hypertrophic zones. In most instances, however, there is a transphyseal fracture with the break occurring in linear fashion within the hypertrophic zone. Peltonen: Repair phenomena were studied by Peltonen (380, 381) in the distal radius of 40 growing sheep. The distraction was at a rate of 0.5-1 mm per day. In this model the first signs of ossification in the distraction gap were seen radiographically about 3 - 4 weeks after distraction began. Collagen fiber bundles were oriented parallel to the long axis of the bone in the gap region and served as the focal point for new bone formation. Abundant osteoid was demonstrated in the calcified sections. Thin trabeculae from both the epiphyseal and metaphyseal sides grew toward the center of the distraction gap. At the periphery there was active bone formation from the inner layer of the periosteum. Clinical and radiologic consolidation of the distraction area occurred within 10 weeks of the surgery. The consolidated bone area was composed of partly woven bone and lamellar trabecular bone, with most of the lamelli organized in the direction of distraction. In those instances in which the physis remained intact there was an apparent stretching of the endochondral growth mechanism due to the distractive force. In many instances, however, there was actual transphyseal rupture through the hypertrophic zone. At 12 weeks postoperation the repair bone resembled normal metaphyseal bone. Once the hematoma of the stretch injury had been removed, the gap was filled with a collagenous matrix and collagen bundles could be seen organized in the direction of the distraction. Shortly thereafter, trabecular bone had been formed from the inner layer of the periosteum and from epiphyseal and metaphyseal sides. Peltonen et al. studied gradual physeal distraction of the distal radius in 2- to 5-month-old sheep (379, 382). The bone formation occurred from the inner layer of the periosteum, from the metaphysis, and from the epiphyseal side toward the center of the distraction area. Prior to bone formation, collagen bundles were organized in the direction of distraction. Bone formation occurred from the epiphyseal and metaphyseal sides. Under polarized light microscopy lamellar trabecular bone was seen forming along the collagen bundles. Woven bone was frequently seen. In the distraction area at 11 weeks in the study by Peltonen both lamellar and woven bone were present within individual trabeculae, but it was clear that the lamellar bone predominated. Alberty and Peltonen (13) showed that all physes in 12 growing rabbits undergoing distal femoral distraction showed widening of the proliferative and hypertrophic zones, as well as a fracture-separation at the hypertrophic

zone or at the junction of the hypertrophic zone and the metaphysis in 11 of 12. Proliferation of the hypertrophic cells with 5-bromo-2-deoxyuridine (Brd Urd) labeling was noted even though normally not seen. The labeling of the physeal regions above, however, was normal in both control and distracted physes, being positive in germinal and proliferating cell zones with no labeling in the hypertrophic zone. DePablos et al: In the histologic study of dePablos et al. (138, 139), local fracture was noted in each instance. The physis tended to be poorly organized in some instances and otherwise normal in some. The lengthened zone was first wholly occupied by a hematoma, which quickly underwent fibrous organization. This then was replaced by a rich granulation tissue composed of numerous fibroblasts and collagen fibers, which aligned themselves parallel to the long axis and the traction axis of the bone. Ossification of the lengthened zone was first observed on the 20th day of lengthening. This was referred to as desmal ossification, although there was some endochondral ossification taking place in the growth cartilage at its lowest regions. The ossification progressively replaced the fibrous granulation tissue. Four months after the lengthening process had begun all of the tissue in the lengthened zone showed complete ossification. Monticelli and Spinelli: Monticelli and Spinelli (329, 330) showed that the gap invariably healed with bone, provided that the surrounding perichondrium and periosteum were not excised. The resumption of endochondral ossification was infrequently seen and was incomplete when present. The new bone consistently formed along the fibrils as well as along the undersurface of the peripheral periosteum. The bone was noted to be well-oriented in most instances. Polarization microscopy showed the fibrils to be parallel to the long axis of the bone and to the axis of the distraction. Monticelli and Spinelli carried out proximal tibial lengthening experiments on 41 sheep between 3 and 5 months of age. The duration of the distraction varied from 1 to 16 weeks. The lengthening rate varied between 0.5 and 1.5 mm per day with most either 0.5 or 1.0 mm/day. Separation of the epiphysis from the metaphysis was felt to occur after 3-5 days, and the force needed to induce fracture was approximately 18 _+ 4 kg. Separation was always noted within the hypertrophic zone. During the first and second weeks, the region between the epiphysis and the metaphysis referred to as the interzone was transparent on radiographs. At the beginning of the third week, when the interzone was 10-20 mm wide, faint irregular shadows became visible suggesting early osteogenesis. New bone formation was seen next to the epiphysis and the metaphysis with the central region initially showing little bone formation. After 1 month of distraction, the interzone was 25-30 mm wide and the new bone formation sites began to link longitudinally. Longitudinal bundles were continuous now between the epiphyseal and the metaphyseal ends. The bone formation from the metaphysis generally was more advanced than that from the epiphysis. After 2 months of distraction the interzone had increased to 42-60 mm and

SECTION IX ~ Management of Lower Extremity Length Discrepancies

the radiographic shadows were more clearly striated in a longitudinal direction. Ossification proceeded upward and downward toward the center of the interzone where bone repair was ultimately slowest. Only when distraction ceased did the central region begin to show uniform radiodensity. After lengthening of 30-40 mm it took about 2 months for the bone cortex to reform. In a few animals premature epiphyseal fusion occurred, which led to the recommendation that transphyseal lengthening be performed only when the subject's bone growth was nearly complete. The repair bone from the sheep was then subjected to a more detailed morphologic study at 1-4 weeks and 2, 4, 6, and 12 months (330). One week. An epiphyseal fracture (epiphyseolysis) occurred in all specimens. The fracture gap was filled with hematoma. There was no calcification or bone at this stage. The fracture line occurred within the growth plate around the level at which matrix calcification was beginning to occur in the hypertrophic zone. Two weeks. The hematoma occupied a wider space but persisted. Most of the chondrocytes in the physis itself were unchanged, although cell columns of the upper cartilage segment were sometimes distorted. The cartilage on the metaphyseal side was penetrated by many capillary vessels and in general looked more irregular than in the normal control. Three weeks. The distance between the upper and lower cartilage cell segments had widened due to the continuing distraction. Hematoma was becoming organized with fibrous material. No bone was yet formed. Four weeks. The gap was now filled with a compact, translucent, grayish tissue and the lower cartilage segment was less evident than previously. There now was a thin shell of bone under the periosteum surrounding the distraction space. This was also seen radiographically. The hematoma had almost been completely resorbed and replaced with connective tissue consisting mainly of elongated cells surrounded by thin fibrils. Many of these were irregularly oriented but the beginning tendency to longitudinal orientation was seen with fibrils being aligned in the same direction of the distraction force. A thin layer of circumferential periosteal bone composed of thin trabeculae of primary bone was seen. Two months. A compact gray tissue zone was evident grossly below the epiphyseal cartilage. Sub-periosteal bone formation was seen along with metaphyseal ossification. No traces of hematoma were recognizable, it having been replaced completely by connective tissue consisting of elongated fibroblasts and thick bundles of collagen fibrils, both of which were preferentially oriented parallel to the tensile force of the distraction. This was particularly evident in the middle portion of the elongated segment. Some of the collagenous material was calcified and there were small spicules of osteoblasts seen. Four and six months. A thin surrounding shell of cortical bone was seen at the distraction area. Ossification was continuing in the sub-periosteal area. New bone was also seen near both the epiphyseal and metaphyseal zones. Long thin bundles of collagen fibrils were

705

present in the elongated area. Most of these bundles were now calcified, forming thin parallel oriented trabeculae whose longitudinal orientation was the same as that of the distraction force. Together with these calcified collagen bundles true bone trabeculae were found, part of which developed from the epiphyseal cartilage and part from the dislocated metaphyseal trabeculae and the periosteum. The tips of these trabeculae were surrounded by osteoblasts. They also appeared osteoblastic by electron microscopy. The persisting physeal cartilage in some instances retained its normal structure, but in others it was irregular. Of note, however, was the fact that no bone trabeculae were present near the epiphyseal cartilage, indicating disruption of the normal endochondral sequence. Twelve months. Ossification had progressed in the elongated segment and the fibrous tissue had been replaced almost completely by bone trabeculae. The sub-periosteal bone had a compact appearance. On the whole, the elongated tibias were almost indistinguishable from the contralateral side. The process of distraction epiphyseolysis was divided structurally into three stages: (1) epiphyseolysis with formation of the hematoma; (2) resorption of the hematoma and the formation of fibrous tissue, which increases in length as long as the distraction force is applied; and (3) ossification of the fibrous tissue and reconstitution of the periosteal bone. As the fibrous tissue develops in the second phase, the cartilage on the metaphyseal side is resorbed and replaced by fibroosseous and osseous tissues, which are well-vascularized. In the third stage there is first calcification and then true ossification of fibrous tissue with the formation of longitudinal trabeculae lying almost parallel to each other. Ossification takes place directly from the periosteum and from the cellular elements of the fibrous tissue undergoing osteoblastic differentiation in connection with the displaced metaphyseal segment. Ossification also takes place from the epiphyseal cartilage but is less regular and less impressive than from the other two sites. On occasion, the endochondral ossification sequence of the physis persisted, but in others it was damaged. Cessation of endochondral ossification was not of clinical significance if the distraction epiphyseolysis was carried out at an age approaching skeletal maturity. Varying reports in the literature could easily be due to the differing types of distraction apparatuses used and the different degrees of stabilization provided. 4. TRANSILIAC LENGTHENING Millis and Hall (327) showed that, in patients with a discrepancy in lower extremity length associated with acetabular dysplasia, primary intrapelvic asymmetry, or a decompensated scoliosis, 2.5 cm of length can be gained through transiliac lengthening by means of a modified innominate osteotomy. This approach both increases lower extremity length and corrects structural pelvic abnormalities associated with the discrepancy. Three possible complications involve delayed union, sciatic nerve palsy, and sacroiliac joint

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CHAPTER 8 9 Lower Extremity Length Discrepancies

disruption. The procedure is most strongly indicated for primary correction of pelvic deformity in which slight limb lengthening is also desired.

X. DIRECT OPERATION ON EPIPHYSES TO ENHANCE GROWTH POTENTIAL

BY REMOVING FOCAL TRANSPHYSEAL TETHERS A. Bone Bridge Resection Partial destruction of the function of the growth plate is associated with the formation of localized transphyseal bone bridges (287, 313). These develop most commonly after certain growth plate fracture-separations (6, 60, 73, 304, 350, 421,434, 461,495), in severe cases of Blount's disease (infantile tibia vara), and after infection (409). The bone bridges retard growth in a localized part of the physis and predispose one to angular deformity as well as shortening because the remaining physeal tissue continues to function. The possibility of removing focal bone bridges was raised over 100 years ago by Ollier (354). He was able to demonstrate the formation of transphyseal bone bridges in experimental animals. Experimental work in rabbits by others at this time also demonstrated partial bone bridging of the physis (434). There was good clinical awareness in the latter stages of the nineteenth century of bone bridge formation following epiphyseal trauma with its subsequent effect on growth. Ollier himself made efforts to remove bone bridges surgically, but recurrence was common due to the failure to use an appropriate interpositional tissue to prevent recurrent bridge formation. The mechanism of bone bridge formation was described extensively in Chapter 7. The position of the bone bridge defines not only the type of deformity but also the surgical approach to removing the bridge and the type of material interposed to prevent reformation (Fig. 26A). Central bone bridges lead to shortening without angular deformation, whereas peripheral bone bridges lead to angular deformity as well as shortening. Bright (72) classified partial growth arrest lesions into three types: type I, peripheral lesion; type II, central lesion; and type III, combined central-peripheral lesion. The exact position and extent of bone bridges can be shown by tomography, CT scanning, and magnetic resonance imaging (Fig. 26B). Examples of bone bridges are shown in Fig. 26A. Langenskiold (285-287) refocused attention on focal bone bridge formation and developed bridge resection and the implantation of fat for use as a clinical tool. In a series of experiments in his laboratory many types of interpositional materials were used, but fat was both the easiest and the most effective in preventing the reformation of bone bridges and thus maintaining physeal function. Fat is a minimally vascularized tissue and generally persists as fat when interposed in growth plate defects, thus keeping the epiphyseal and me-

taphyseal circulations separate and allowing the remainder of the physis to continue growth. Another interpositional material used was cartilage, which in experimental studies had just as effective a result as the fat (357). In commentary on Langenskiold's first 43 clinical procedures excising local bone bridges and interposing autologous fat grafts, the results in general were good to very good; only 7 showed questionable benefit "mainly because the procedure was carfled out too close to the end of the growth period" (287). The large majority of procedures involved the distal femur, proximal tibia, and distal tibia. The etiology of partial closure in 38 growth plates was fracture in 28, osteomyelitis in 8, and tuberculosis and Blount's disease in 1 each. Following interposition of the fat graft the radiolucent area of the fat transplant usually has a rounded or oval shape, whereas following subsequent growth the radiolucent area becomes elongated. The fate of the fat implants was studied experimentally by making round cavities in the proximal end of the tibial growth plates in pigs and filling them with autologous fat. Studies indicated that the volume of fat tissue implanted in the cavities continuously increased in parallel with the growth in length of the bone. It appeared that the fat was augmented by fat cells in the metaphysis. Langenskiold et al. (288) recalled 3 patients several years after surgery for CT scan assessment of the epiphyseal-metaphyseal region. They concluded that the former resection cavities were filled primarily by fatty tissue and that the portion of implanted fat had grown in size corresponding with the growth in length of the bones in the affected ends. Some strands of fibrous tissue were intermingled with the fat. A layer of dense bone remained interposed at the periphery of the fat graft. Langenskiold concluded that the free fat grafts implanted at the time of resection continued to grow and thus had filled out the elongated cavities. The fat persisted well beyond the period of growth termination, and the cavities were not filled with fluid or bone. Examples of central bone bridge resection are shown in Fig. 26C. Other clinical studies have assessed the treatment of partial physeal growth arrest by bridge resection and fat interposition. Vickers (486) reported on 15 patients with good early results. Williamson and Staheli (506) assessed 29 physeal resections, 22 of which were followed for more than 2 years. They interpreted their results in the longer term group as 11 excellent, 5 good, 2 fair, and 4 poor. Twenty of the 29 bridges were caused by fracture, 3 by tumors, 3 by tibial traction pins, and 1 by infection. Twenty of the bridges were peripheral, 6 were central, and 3 were combined. The results correlated inversely with bridge size. They were uniformly excellent for bridges less than 25% of the physeal volume, bridges between 25 and 50% yielded good to excellent results in 9 of 12 cases, and results were generally poor in bridges greater than 50% with only 1 of 4 yielding a good result. Bright (72) reported briefly on 100 patients followed for more than 2 years with silastic interposition material, with 81% of the patients demonstrating some growth after

F I G U R E 26 (A) Mature transphyseal bone bridges can be seen on plain radiographs. (Ai) A central transphyseal bone bridge (arrow) is shown at left in a 7-year-old girl who suffered a distal tibial growth plate arrest subsequent to meningococcemia of infancy. (Aii) A peripheral bone bridge (arrow) of the proximal media tibia following Blount's disease is seen (right). Varus deformation of the tibia has developed. (B) Magnetic resonance imaging defines the extent of the bone bridge (white arrow; bone bridge is black, persisting physis is white). Image is from A, left. MRI is from the coronal (lateral) plane. (C) A series of radiographs shows the operative approach for removal of a central bone bridge (Ci, Cii), filling of the defect by fat followed by reinsertion of the bone window (Ciii, Civ), and results following growth resumption several months later (Cv).

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CHAPTER 8 ~

Lower Extremity Len~tth Discrepancies

bridge resection and 70% with good to excellent results. Aufaure et al. (29) studied 18 cases of bone bridge resection in childhood and concluded that there were 9 good results and 9 failures. The best results were obtained in cases in which the bridge was peripheral, because it was approached more easily, and following a traumatic injury in young children. The larger the bone bridge, the greater the likelihood of failure. Extensive bridges particularly those located centrally, therefore, had a poor prognosis and all bone bridges due to osteomyelitis were failures. Most of the bone bridges were resected at the distal femoral and distal tibial growth plates. Resection has proved to be clinically feasible in many instances if one-fourth or less of the growth plate is involved and there is sufficient growth remaining to warrant removing the focal tether. Interposition of fat, cartilage, silastic, or methyl methacrylate can keep the epiphyseal and metaphyseal circulations separate, thus preventing the formation of further bone bridges and allowing the unaffected growth plate cartilage to continue to grow normally. Each of these methods has advocates; the interposition of fat is the easiest and most commonly used approach clinically. Examples of a bone bridge resection procedure are shown in Fig. 26C. The extent of the bone bridge must be determined prior to making a decision to resect the bridge. Plain biplanar radiographs are inadequate. Tomography has been shown to provide a good percentage estimate of physeal area replaced by the bone bridge, but CT or MR scanning with threedimensional reconstruction is used currently (96).

B. Varieties of Interpositional Materials Several interpositional substances have been used following resection of a transphyseal bone bridge to keep the epiphyseal and metaphyseal circulations and bone apart so as to allow physeal growth to continue. Cady et al. (82) performed fat implants into 14 New Zealand white rabbit physes in an effort to determine whether physeal regeneration occurred. They found no instance in which the physis regenerated transversely across the gap in either the fat-implanted or the control femurs. The fat remained viable and was gradually replaced with fibrous tissue. Three inert materials have also been used as interpositional substances with good effects described. These have included silastic (71, 72), methyl methacrylate (313), and bone wax. Among biological substances cartilage itself was shown to be excellent in preventing transphyseal revascularization. Lennox et al. (296) performed a comparative experiment in 5- to 6-week-old New Zealand white rabbits in which two adjacent 4-mm-diameter defects were drilled in the distal lateral femoral epiphysis. In the control group, valgus angulation had a mean of 43 ~ with 2.4 cm of shortening compared to the opposite side. The group with fat interposition showed a diminution of the valgus angle, although it was still 28 ~ with shortening of 1.9 cm. Better results were achieved with the interposition of femoral head cartilage using punch bi-

opsy plugs of fresh bovine cartilage in one group and frozen bovine cartilage in another. In both the fresh and frozen groups, distal femoral growth continued with the difference being only 0.6 cm from the opposite side. The fresh and frozen cartilage also led to the least extent of valgus angulation, showing 11 ~ Eulert (152), also working on the distal femur of the developing rabbit, eliminated or greatly minimized partial premature distal physeal closure by transplantation of iliac crest growth cartilage. The best results were obtained when the growth cartilage was transplanted alone or with a thin layer of bone. The results were poor when the layer of bone transplanted with the cartilage was too thick. Eulert concluded that iliac crest cartilage could be used as a graft following bone bridge resection. When a region had been resected and no interpositional tissue placed, the mean valgus at 24 weeks postsurgery was 60 ~ When the cartilage graft was inserted with a thick lamella of bone attached, angular deformity was less but still approximately 45 ~. The best results were achieved when the cartilage graft had only an extremely thin rim of bone attached, which led to angular deformity of only 10~ As an extension of this work, early efforts at chondrocyte implantation have been presented, but the results at present are insufficient to be recommended for clinical use. Although some evidence of cartilage survival is seen, no columnation reproductive of a true physis has been identified. (These will be reviewed later.) Bright (71) showed the value of silicone rubber implants in dogs in which they were effective in preventing bone bridge reformation in a distal femoral epiphyseal growth plate model. Wirth et al. (510) even tried implanting periosteum to determine whether it would modulate into a cartilage phase; this did not occur and direct bone formation resulted. Studies have also been performed attempting to define the use of fat grafts in relatively large central defects. Osterman (358) removed approximately 65% of the central part of the plate of the distal femur in a 3-week-old rabbit and interposed autologous fat. This work attempted to show that even large defects involving more than half of the epiphyseal plate can be successfully treated. He subsequently removed the lateral third of the distal femoral growth plate in rabbits and replaced the cartilage with free fat tissue transplants which minimized angular deformity and growth loss compared with controls where the defect was left empty (358).

C. Treatment of Premature Physeal Closure by Means of Growth Plate Transplantation 1. FREE AUTOGENOUS ILIAC CREST PHYSEAL GRAFTSmFOCAL DEFECTS Efforts have been made in our laboratory to reestablish growth by the transplantation of a free partial growth plate after resection (353) (Fig. 27). This procedure is designed to keep the epiphyseal and metaphyseal circulations apart; the partial growth plate also actively contributes to growth rather than serving as a passive spacer, as does fat, silastic, or

F I G U R E 27 A series of illustrations shows the use of focal iliac crest physeal transplants in a rabbit model. (A) Photograph demonstrating the defect in the lateral aspect of the distal femoral physis. (B) Photomicrograph showing bone bridge formation following creation of a physeal defect. The lateral femoral physis had been removed, but no graft inserted, 4 weeks before the animal was sacrificed. The persisting physis (P) is on the left. There is no evidence of an attempt by the physeal cartilage to grow laterally to reform cartilage tissue at the site of the defect. Bone fills the defect site (right) and an extensive bone bridge unites epiphyseal bone (EB) with metaphyseal bone (MB). (C) Photomicrograph illustrating the iliac apophysis and the metaphyseal bone. Fibrocartilaginous layer (FC);

F I G U R E 27 (continued) cartilage of the apophysis (C): cytologically specialized region of the cartilage referred to as the physis (P); and metaphyseal bone (M). The arrow represents the line of demarcation between the green-staining fibrocartilaginous tissue and the red-staining cartilaginous tissue, as demonstrated on a Safranin O-fast green preparation. (D) Photomicrograph of the iliac apophysis after its separation from the metaphysis. Separation has occurred through the zone of hypertrophic cells, with a few spicules of metaphyseal bone persisting on the transplant specimen. (E) Photomicrograph showing an iliac physeal graft in position in the defect immediately after transplantation. The cartilage graft is below and the femoral metaphysis is above. A narrow space is present between the graft and the femoral metaphysis, which ensures a firm fit. (F) Photograph showing an iliac physeal graft in position in the lateral

F I G U R E 27 (continued) femoral physeal defect. (G-N) This series of photomicrographs demonstrates the histological appearance of the physeal graft in relation to the persisting physis and associated epiphyseal and metaphyseal bone following transplantation. Except (G), the photomicrographs are positioned with the epiphyseal areas at the top and the metaphyses below. (G) Low-power photomicrograph illustrating the distal femoral physeal graft at the right 3 months after insertion. Normal growth has occurred and no distal femoral valgus deformity is present. The graft is approximately two times as thick as the persisting nonoperated physeal tissue. Cartilage union has occurred at the graft-physis junction, and there is no continuity between the epiphyseal and metaphyseal bone and no angular deformity. (I-I) Photomicrograph of the medial aspect of the nonoperated distal femoral physis, demonstrating the normal architecture. (I) Photomicrograph from the same specimen as in (I-I), showing physeal and metaphyseal tissue from the lateral physeal transplant. Cartilage and physeal tissue are at the top and metaphyseal tissue at the bottom. Note the excellent orientation of the proliferating and hypertrophic cell layers of the transplanted physis and the smooth junction with the metaphyseal tissues. (J) Lowpower photomicrograph made 3 months after physeal transplantation. The transplanted physis (TP) is at the left and the persisting physis (PP) is at the fight. There is firm coaptation between the two physes. Persisting epiphyseal bone is at the top and metaphyseal bone at the bottom. (K) Higher power photomicrograph from the same specimen illustrated in (J) demonstrating the junction of the epiphyseal bone above and the transplanted cartilage below. Vascular invasion of the transplanted cartilage has not occurred. (L) Photomicrograph illustrating the physeal graft (fight) and the persisting physis (left). Cartilage continuity between the two has been established. At the upper fight, note the bone that has invaded the cartilage part of the transplant as distinct from the physeal part. The metaphyseal bone adjacent to the persisting physis merges imperceptibly with the metaphyseal bone adjacent to the graft. (M) Higher power photomicrograph showing, from top to bottom, epiphyseal bone, bone in the cartilaginous part of the graft, cartilage and physeal cartilage from the graft, and metaphyseal bone produced by the graft. (N) Higher power photomicrograph showing the junction between the persisting physeal cartilage (PP) and the physeal transplant (TP). There is persistence of the proliferating and hypertrophic cell zones in the graft tissue and continuity between metaphyseal bone from both segments. At the upper left, epiphyseal bone remains separate from metaphyseal bone. (O) Photograph demonstrating a poor result 4 months after transplantation (Oi). When the animal was sacrificed, the graft was found to have displaced from the defect site, allowing a bone bridge to form with significant shortening and valgus deformity. The nonoperated control femur is on the left. (Oii) Radiographs of the two bones (image reversed). (P) Photograph illustrating an excellent result 4 months after growth plate transplantation (Pi). The control femur is on the left. (Pii) Radiographs of the two bones illustrated in (Pi) demonstrating an excellent result following transplantation. (The radiograph has been reversed and the transplanted bone is on the left.) [Reprinted from (353), with permission.]

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CHAPTER 8 9 Lower Extremity Len~trh Discrepancies

methyl methacrylate. This approach takes advantage of the fact that the physeal cartilage itself has no direct blood supply but, rather, a dual supply from epiphyseal vessels on one side and metaphyseal vessels on the other. If the defect in the growth plate is at the periphery, its removal leaves the epiphyseal cartilage and bone, the metaphyseal bone, and, therefore, the dual blood supply intact. In rabbits, oriented cartilage from the iliac crest, transferred after the outer fibrocartilaginous portion has been carefully removed, has been shown to survive and function because the transplanted tissue is nourished by the intact blood supply of the host bone. Focal lesions of the physis continue to cause considerable morbidity in terms of angular deformity and shortening. Osteotomy can correct deformity, although it must be repeated frequently if the growth problem has occurred several years prior to maturity. A variety of procedures have evolved to treat the length discrepancies. In an effort to restore normal growth, well-localized focal bone bridges have been resected and a biological or prosthetic material has been inserted to prevent reformation. Free physeal and epiphyseal transplantation is attractive, but previous experimental and clinical attempts have not been successful consistently. Vascularized epiphyseal transplantation has been used with promising results in experimental animals. The cartilaginous physis has a dual epiphyseal and metaphyseal blood supply. From the epiphyseal vessels, nutrients are carried by diffusion through the cartilaginous extracellular matrix to chondrocytes; the metaphyseal vasculature serves as a source of osteoprogenitor cells that lay down bone on the calcified cartilage matrix to complete the endochondral sequence. Basic requirements for the survival and normal function of free physeal transplants are that this dual blood supply be preserved at the graft site and that the free physeal graft not be covered by tissues that impede the diffusion of nutrients from blood vessels into the extracellular matrix of the physis. We have reported our studies on the transplantation of free autogenous iliac crest physeal grafts into defects in the lateral aspect of the distal femoral physis in rabbits. The graft site in the lateral aspect of the distal end of the femur was carefully fashioned to expose the epiphyseal and metaphyseal bone and its vessels. Fibrocartilaginous and perichondrial tissues were removed from the surfaces of the free physeal graft to facilitate the diffusion of nutrients into the physeal cartilage. The physeal grafts were readily incorporated into the graft site, the morphology of the physis was retained, and the physeal transplant prevented bone bridge formation, growth arrest, and valgus deformity. Focal physeal bone bridges develop most commonly following certain fracture-separations or as medial bridging of the proximal tibial physis in association with severe Blount's disease. In such situations, the epiphyseal and metaphyseal blood supply to the bone adjacent to the physis is generally normal. The results of this study indicate that free physeal transplants might be used to prevent or decrease the bone bridge formation, growth arrest, or angular deformity that can occur in these conditions.

A procedure was first developed for creating a standard focal defect in the lateral aspect of the distal femoral physis of 3- to 4-month-old rabbits, which consistently led to the formation of a bone bridge between the distal femoral epiphysis and metaphysis. By using a dissecting microscope, the defect was created by removing the outer one-half of the lateral half of the physis. The gross appearance of the defect in a midcoronal section of the distal end of the femur is shown in Figure 27A. In creating the defect, care was taken to remove all of the cartilage from the surfaces of the epiphyseal and metaphyseal bone to leave the bone intact and, thus, to preserve the host's dual epiphyseal-metaphyseal blood supply to the physis. In the early stage following creation of the defect, undifferentiated mesenchymal cells migrated into and filled the defect, but did not differentiate into cartilage. Woven bone formed, which then transformed to the lamellar conformation. By 4 weeks after surgery, a bone bridge had formed between the epiphysis and the metaphysis (Fig. 27B). There was no tendency for the remaining physeal cartilage to grow laterally into the defect. At the periphery of the defect a fibrocartilaginous mass was sometimes identified, but this never developed into a growth plate. Seven of the 8 defects that were created resulted in bone bridge formation, growth arrest, and marked valgus deformity. In the 1 rabbit, operated on early, in which normal growth occurred, the dissecting microscope had not been used, and we assumed that the physis had not been removed completely. A procedure was then developed to remove and transplant a free autogenous iliac crest physeal graft into the focal defect created in the lateral part of the femoral physis. The graft was taken from the posterior part of the iliac crest apophysis. The overlying muscle was freed from the crest, and two parallel incisions approximately 2 cm apart were made through the fibrocartilage and physis to the underlying bone. These incisions were carried through the periosteum onto the inner and outer iliac bone surfaces and then were joined by transverse incisions. By elevating the periosteal sleeve, the iliac crest apophysis was gently separated from the metaphysis at the junction of the hypertrophic chondrocytes and the metaphysis and was pulled free of the underlying bone. On occasion, a few spicules of metaphyseal bone came free with the cartilage fragment, but specific attempts to include bone were not made. Histological studies confirmed the separation between the hypertrophic chondrocytes and the metaphysis. The graft was trimmed under the dissecting microscope to remove the periosteal-perichondrial sleeve and much of the overlying fibrocartilage. The graft was then placed in the femoral defect with the correction orientation, and the femoral periosteal sleeve was sutured to the intact femoral periosteum with 4-0 Dermalon to hold the graft in place. The animals were not immobilized postoperatively. The iliac apophysis is composed of a physis, epiphyseal cartilage, and a fibrocartilaginous layer (Fig. 27C). The apophysis was separated gently from the metaphysis of the iliac crest at the junction between the lowermost hypertrophic

SECTION X 9 Direct Operation on Epiphyses to Enhance G r o w t h Potential

chondrocytes and the metaphysis (Fig. 27D). Most of the fibrocartilaginous layer and all of the perichondrium and periosteum were removed by using the dissecting microscope. The physeal graft was then placed in the femoral defect and the overlying femoral periosteal sleeve was sutured into place (Figs. 27E and 27F). In the transplant specimens assessed as early as 1 week postoperatively, the physeal graft appeared to be intact and viable. The morphology and organization of the physis were retained. Union of the graft by cartilage at the graft-host junction was seen as early as 2 weeks. Viability of the growth plate was evident histologically by the production of metaphyseal bone, the maintenance of physeal height and cytological organization, and the absence of vascular invasion or bone formation in the germinal, proliferating, and columnar cell layers. The physis maintained its bright red stain with Safranin O. The residual overlying fibrocartilaginous tissue of the graft underwent vascular invasion and ossification with time, but the growth plate itself appeared immune. A detailed description of the histological characteristics of the transplanted physis is presented in Figs. 27G-27P. In the definitive study of the capacity of the physeal transplant to prevent bone bridge formation, shortening, and valgus deformity, 33 rabbits received transplants. Twenty-seven of the rabbits were sacrificed 21 days or more after surgery. The capacity of the graft to prevent growth arrest or valgus deformity was then assessed by its gross and radiographic appearance and by measurements of the distances between the femoral head and the medial and lateral condyles of the distal end of the femur. The results were classed as excellent, good, fair, or poor, as already defined. Photographs of the gross appearance and radiographs of the femurs demonstrate an obvious, striking difference between an excellent (Figure 27P) and a poor (Figure 270) result. Following transplantation, 16 results were rated as excellent, 3 were good, 4 were fair, and 4 were poor. In the definitive group, therefore, a good or excellent result was seen in 70% of the animals. The type of growth plate defect created in this study led to bone bridge formation and valgus deformity in experiments in which no cartilage was interposed. Similar defects created by other investigators have also led repeatedly to bone bridge formation and angular deformity. There have been reports of defects that involved only a narrow, peripheral portion of the plate in which a bone bridge formed but the bone subsequently yielded to growth, with angular deformity not occurring as the intact physis overcame the small bridge. There also have been reports of small central bone bridges forming but not restricting growth. Thus, there appears to be a relationship between the size of a physeal defect and bone bridge formation and the effect of the bridge on subsequent growth. Because in this study normal growth did not continue in the sham experiments after creation of the growth plate defect alone, the large number of good and excellent results following physeal transplantation is attributable to insertion

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of the graft. The graft may have functioned simply as a passive barrier to vascularizafion, keeping the epiphyseal compartment separate from the metaphyseal compartment, without actually contributing actively to growth. If so, the absence of deformity might have been due to the persistence of growth of the remaining growth plate alone. Separation of the two circulations is the prime function of any interpositional material, be it biological or prosthetic. Intimate communication between the epiphyseal circulation with its associated osteoprogenitor cells and the metaphyseal circulation with its osteoprogenitor cells allows a bone bridge to form. Examples of passive barriers include heterogeneous deep-frozen hyaline cartilage, fat, silastic, methyl methacrylate, and bone wax. Physeal cartilage is avascular and also possesses an anti-angiogenesis factor, which inhibits vessel ingrowth. The histological studies of the transplants reported here indicate that the morphology, viability, and normal function of the transplanted physis were retained. The proliferating chondrocytes remained organized in orderly rows and contributed to longitudinal growth. The persisting epiphyseal blood supply adjacent to the defect provides nourishment for the resting, germinal, and proliferating cell layers of the transplanted iliac physis; as long as the graft is sufficiently thin, handled gently, and well-positioned, it appears that it will survive. Cartilage union at the persisting physis-graft junction was demonstrated histologically in the several specimens from animals that were sacrificed at early time periods. Endochondral bone formation occurred beneath the physeal transplant in a fashion almost indistinguishable from that of the persisting physis. The importance of a narrow graft must be stressed. As the cells of the growth plate are supplied by diffusion, removal of most of the overlying fibrous and fibrocartilaginous tissue from the iliac crest cartilage graft allowed vascular diffusion from the epiphyseal side to supply the transplant almost immediately. With time, the fibrocartilage remaining on the graft underwent vascular invasion, followed shortly by endochondral bone formation such as occurs in iliac apophyseal ossification prior to skeletal maturation. This bone soon merged with that of the secondary ossification center of the epiphysis. The physeal portion of the graft, however, remained intact without suffering vascular invasion until the time that the entire distal femoral physis reached maturity. A bed of well-vascularized epiphyseal and metaphyseal bone is essential because the nutrition of the free graft is derived exclusively from its surrounding tissue. Lalanandham et al. (281) transplanted scapular cartilage in the rabbit into the distal ulna following curettage of the ulnar physis in animals 5-6 weeks old. They then assessed the viability and biochemical function of the transplanted chondrocytes and their histologic appearance at varying time periods. They concluded that the cartilage transplanted in an avascular fashion could remain viable, synthesize proteoglycan, and also be associated with active growth (although less than normal). Histologic sections at 2 weeks showed the

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transplanted block of cartilage to be intact, and by 8 weeks the transplanted cartilage appeared to be participating in endochondral ossification on the metaphyseal side. Histochemical studies from the graft cartilage were consistent at 2, 7, and 14 days and showed lactic dehydrogenase to be strongly present in both transplanted and unoperated control cartilage. Radiosulfate administered intravenously was clearly present throughout the transplanted tissue also at 2, 7, and 14 days. This incorporation was indicative of chondrocyte synthesis of proteoglycan. Thymidine incorporation was seen but was diminished relative to controls. This experimental approach is for well-localized, focal lesions, in this instance involving approximately one-fourth of the physis in the coronal plane and one-half of that segment in the sagittal plane. The shape of the iliac physis must also be considered in relation to the shape of the defective physis, as few long bone physes are as level as diagrammatic and radiographic projections often imply. It appears that full physeal and certainly epiphyseal grafts can be most successful only if they are transplanted with an associated vascular supply. The possibility of using vascularized iliac crest apophyseal transplants is being investigated. In focal physeal lesions, however, when the host epiphyseal and metaphyseal bone is present and well-vascularized, free autogenous iliac crest might be effective clinically as demonstrated in our study. Although not all of the transplants were successful, the dramatic differences demonstrated between the excellent, good, and even fair results in comparison with the poor and sham results clearly indicate that free physeal transplants in the appropriate environment can function well. The graft must be freed from much of the overlying fibrocartilage and surrounding periosteum and perichondrium and must be fitted gently but firmly into narrow defects so that coaptation is intimate. In addition, the host periosteum at the region of the groove of Ranvier should be sutured over the graft to provide both mechanical and physiological support. Because the majority of lesions due to trauma and Blount's disease leave the epiphyseal and metaphyseal bone intact and well-vascularized, free iliac crest physis transplants may be useful in the treatment of focal physeal arrest in patients with such conditions. 2. VASCULARIZEDAUTOGENOUS EPIPHYSEAL ILIAC CREST GRAFTS Because studies of nonvascularized transplants over several decades stressed poor or imperfect results due to failure of rapid revascularization, the use of vascularized transplants held great attraction, and once vascularized bone transplants became feasible investigation was extended to this area. Nettelblad et al. (347) transplanted successfully the proximal one-third of the fibula including the entire epiphysis, adjacent metaphysis, and diaphysis in 22 puppies, showing the feasibility of the technique. In the experimental groups the fibula switch was performed, selecting one fibula as a vascularized graft and the other as a nonvascularized graft. Con-

tinuous growth was observed in the vascularized epiphyseal transplants and in the controls with no statistical difference noted, whereas the nonvascularized transplants exhibited considerably less or no growth. Varying techniques subsequently confirmed the continued viability of the vascularized epiphyseal transplants in contrast to the nonvascularized procedures. Teot and associates (471-473) have reported on their investigations concerning vascularized partial iliac crest growth cartilage transplants. An initial study performed in 50 childhood cadavers and 25 immature dogs assessed more precisely the vascularization of the lower end of the femur and the iliac crest (473). They were able to identify regions of cartilage from the epiphyses that could be transplanted with anastomosis of appropriate pedicles. In a second brief presentation, the value of iliac crest cartilage as a graft source again was reviewed (471). Teot et al. utilized iliac crest vascularized transfers in an experimental sense in 38 puppies replacing approximately 80% of the distal femoral growth plate region. Initial indications were of growth in the range of 85% of that on the opposite normal side. An early report was also made of 1 case in a 2-year-old patient with a total epiphyseal arrest of the distal femur, who had a vascularized iliac crest transplantation after bone bridge resection. The patient was doing well 16 months later but no further follow-up was reported. The second proposed utilization was in reestablishing acetabular growth for the dysplastic hip. Allieu also provided a brief report on the feasibility of iliac crest cartilage and bone pedicle transplants into the acetabular and proximal femur regions (19). The vascular pedicle had its origin from the deep circumflex iliac artery. A more formal presentation of iliac crest pedicle graft transplantation was reported from 48 immature dogs in relation to repairing distal femoral growth plate abnormalities (472). In one group the graft was pedicled on the superficial circumflex iliac vessels and reimplanted in situ. In group 2 the pedicle graft was transferred to the groin area as an island graft. These two control groups demonstrated conservation of growth activity when the graft was pedicled on its epiphyseal vessels. In group 3 the graft was transferred to the distal epiphyseal area of the femur after resection of the portion of the growth plate (approximately two-thirds) located inside the perichondrial ring of Ranvier, with conservation of 80% of the outer cylinder. Microsurgical revascularization was achieved by using the saphenous vessels. In group 4 the latter technique was used without revascularization. Results were far more favorable in terms of growth restoration in the pedicled than in the nonvascularized transplant. In the vascularized distal transplant the possibility remained that some regeneration of cartilage was from the surrounding epiphyseal plate, which had been left intact. Teot et al. concluded that the pedicle graft "appears to act as a catalyst in the formation of a new growth plate, preventing the formation of bony bridges between the epiphysis and metaphysis." Vascularized iliac crest transplantation has been used exper-

SECTION X ~ Direct Operation on Epiphyses to Enhance Growth Potential imentally to augment acetabular growth in dogs with severely deformed hips and damaged femoral growth as a result of epiphyseal lesions. 3. PHYSEAL RECONSTRUCTION USING TISSUE FROM FETAL AND EARLYPOSTNATALEPIPHYSES Zaleske and colleagues have worked extensively on attempting physeal reconstruction with extremely young fetalneonatal tissue in an effort to take advantage of its greater growth potential (36, 127, 424, 511). A series of experiments have been done involving full and partial physeal reconstruction in mice, with most work involving 4-day-old postnatal distal femoral tissue. Whereas growth in length over brief periods of time has tended to be limited to the 25% range, autoradiographic studies using tritiated thymidine show the persistence of cell proliferation after avascular transplantation. Isolated physeal regions appear to maintain their kinetic activity at least in short-term implantations. In the 4-day-old distal mouse femur, which serves both as the source of tissue and as the area into which tissue is implanted, the epiphysis is completely cartilaginous and avascular. The work, summarized by Barr and Zaleske (36), showed that as a group the transplanted physeal blocks resulted in femurs of significantly shorter overall length. Metabolic and kinetic analyses, however, showed both tritiated thymidine and radioactive sulfate incorporation, indicating that cell viability continued even though normal function was not reconstituted. They concluded that blocks of cartilage containing important cell populations can be transplanted in a nonvascularized fashion with at least partial maintenance of viability. The bulk of this transplantation investigation was done with highly inbred strains allowing for syngeneic transplantation. The work was expanded by using complete epiphyseal replacement via knee transplantation in the murine model but utilizing tissue of different developmental times in neonatal mice in an effort to determine whether a specific stage of epiphyseal chondrogenesis led to improved results. Studies were done in 4-day-old postnatal mice, but the distal femoral and proximal tibial chondroepiphyses were transplanted in their entirety from a 4-day-old postnatal mouse, a 1-day-old postnatal mouse, and a 17-day-old fetal mouse. Histologic, metabolic, and kinetic analyses were performed similar to those that had been used previously. The animals were followed for a period of 2 months postsurgery. There was clear variability in morphology and growth from the transplanted syngeneic knee in all experimental groups, but the important observation was felt to be the presence of an unequivocal joint with distal femoral and proximal tibial secondary centers of ossification in adjacent physeal regions, implying some continuing function of the chondroepiphyseal transplant. No differences could be noted, however, between the three groups of slightly differing ages. Becausee the chondroepiphyses were transplanted prior to their vascularization, the fact that they survived and subsequently were vascularized to form secondary ossification centers demonstrated the ability to utilize

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developmentally immature tissue, which could progress to increased development in its new position.

D. Comparative Studies in Experimental Animal Models of Differing Focal Physeal Implants Several groups have used animal models to compare the effects of interpositional tissues. Martiana et al. (318) used many interpositional tissues in physeal regions of the distal left femur of a 3-month-old rabbit, including muscle, fat, physeal allograft, and iliac apophyseal autograft. A standard defect was created in the lateral distal physis of the left femur in all rabbits. A control group had no interpositional material. At 12 weeks following surgery assessments involved limb length discrepancy and angular deformity. Muscle, fat, and iliac apophyseal autograft had less severe limb length discrepancies and angular deformities than did the control group and the physeal allograft group. In terms of limb length discrepancy and angular deformity, the best results were seen with the iliac crest autograft. The second best tissue in each regard was the interposed muscle, with fat third best. Lee et al. (294) used a model excising the medial half of the proximal tibial epiphyseal growth plate in the rabbit to create a partial growth arrest and then excising the bone bridge and inserting either iliac crest physis, fat, or silastic, into the gap. Their study showed the iliac crest physeal transfer to be superior to silastic, which in turn was superior to fat. The tibias that received free fat as interpositional material developed severe varus angulation and failed to grow in length. The bony bridge redeveloped in all cases in the transferred adipose tissue, contrary to the findings of Langenskiold and his group. In the experimental group with iliac physeal grafts, varus angulation was much less and the amount of longitudinal growth much greater than those of the other groups with fat and silastic. In many of the animals, "the transferred physis remained viable and therefore could have contributed to growth and also could have prevented reformation of the bony bridge through its spacer effect." E. Transplantation of Entire Physes

and Epiphyses 1. EARLYTRANSPLANTATIONEXPERIMENTS1899-1914 Epiphyseal transplantation has intrigued investigators for over 100 years. The results of the initial experimental transplantations of entire growth plates in dogs were almost all poor in allografts, but there were some favorable reports of reimplantation and autograft viability and growth. Haas (208, 209) reviewed in great detail the studies on growth plate transplantation that had been reported in the German literature between 1899 and 1914. Although an optimistic report had been presented concerning the effectiveness of allograft (homoplastic) transplantation of the upper end of

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the radius, including the epiphyseal cartilage allowing for growth in rabbits, he felt that the interpretation of that work by the authors was inaccurate and remained unconvinced that actual growth had occurred because very little growth occurred normally in the proximal radius. In assessing all of the reports, virtually no growth was noted in any of the allograft transplantations, although on occasion there was some growth in the autotransplantations and often considerable growth in reimplantations. The term reimplantation refers to removing a segment of bone or cartilage and then replacing it in its same site. In none of these approaches were any vascular repairs performed. Among the earliest detailed epiphyseal transplantation studies were those of Helferich (228) and Enderlen (150), who provided separate reports in 1899. The investigators, who worked together, reimplanted the epiphysis in rabbits using the lower epiphyseal cartilage of the ulna with an adjoining piece of epiphysis and diaphysis. Helferich (228) reported on the macroscopic findings that the epiphyseal cartilage, under favorable conditions, need not lose its property of producing length growth. A lessening of this ability was noted, but generally there was not a complete loss of growth. Enderlen (150) reported on the microscopic findings and indicated that some of the reimplanted epiphyseal cartilage remained viable to a large extent, particularly those parts adjacent to the perichondrium. Von Tappeiner (490, 491) performed reimplantations and allograft transplantations on dogs 6 and 12 weeks of age using the distal half of the metatarsal. In the reimplantations he found no disturbance in length growth even after 6 months, whereas in the allograft transplantations growth was markedly diminished. Obata (349) performed reimplantations, autografts, and allografts of the entire metatarsal-phalangeal joint with either a partial or an entire metatarsal and phalanx. He felt that shortening occurred in all cases but that it was most marked in the allograft transplantations. An extensive study was performed by Heller (229, 230), who carried out reimplantations of the distal epiphysis of the radius and ulna as well as homotransplantations (allografts). The epiphysis did not keep its normal length growth in any of the 45 experiments, in which the epiphyseal cartilage was transplanted in the form of half joints. The best results occurred in the reimplantation group, whereas the worst, by which is meant the greatest degree of shortening, occurred in the allograft between nonrelated animals. In the allograft transplantation group there was complete cessation of epiphyseal function. Heller concluded that in autografts there was active regeneration of the epiphyseal cartilage from the perichondrium but that bone growth did not remain at a normal amount. The most favorable conditions for epiphyseal cartilage transplantation would be in the form of a thin sheet of physeal cartilage without adhering bone particles, so that the cartilage could come directly into contact with nourishment from the host. Heller reported almost normal growth in instances in which autograft transplantation had been performed transferring physeal cartilage only. Minoura (328)

transplanted metatarsal-phalangeal joints of 2-month-old rabbits into soft tissue. Varying models were used, but he too concluded that autografts were much superior to allografts and that even with autografts there was not regular growth of the epiphyseal cartilage, even though some of the tissue survived and in no case was there lengthening of the transplanted joint. Axhausen (31) had also transplanted the lower one-fourth of the femur from a growing rat into the subcutaneous tissue of another rat. The physeal cartilage was noted to degenerate such that at 20 days only the peripheral parts remained alive. With further time the entire physis was replaced by fibrous tissue. Similar findings were noted when the same experiment was repeated in the rabbit. Von Tappeiner (490, 491) performed 3 reimplantations and 8 allografts in dogs. In the reimplantations there were practically no changes in the epiphyseal cartilage line, even after 6 months as assessed microscopically. Even in the allograft group some histologic evidence of continuing function was noted. The findings of Von Tappeiner were not confirmed by Haas. Obata (349) described a progressive degeneration of the epiphyseal cartilage line in the reimplantation group until the 50th day, at which time there was some repair of function. He also ascribed almost normal functional properties to this regenerated epiphyseal cartilage. By 70 days, however, degeneration again had occurred, leading Haas to interpret the fact that under some favorable circumstances some of the physes continued to function. Otherwise the changes described by Obata were similar to those by Haas. In Obata's allograft work the epiphyseal cartilage underwent progressive degeneration with practically no regeneration. Heller noted some favorable results in reimplantations. There was some regeneration of the epiphyseal cartilage line and some new growth, but overall the bone growth was retarded. In allograft transplants the results were invariably poor. Haas felt that use of the distal ends of the radius and ulna made the interpretation of one bone transplantation more difficult than in the simpler and more straightforward metacarpal or metatarsal model. The findings of Minoura agreed closely with those of Haas. In none of the experiments was there any increase in the length of the bone after transplantation. 2. HAAS Haas reported on his 75 experimental procedures performed on dogs in relation to the effectiveness of epiphyseal transplantation in maintaining growth (208). The majority of the animals were from 1.5 to 4 months of age at the time of surgery. The metacarpals and metatarsals were selected for transplantation because they had only one epiphysis, making it easy to determine whether growth from the transplanted region had occurred. The bones were also quite stable after repositioning because of the nonoperated adjacent bones. Review of the literature indicated the failure of allograft transplantation to be effective in virtually all studies, and thus Haas concentrated on reimplantation and autograft transplantation. Following reimplantation of an entire metacarpal or metatarsal, which had been removed from its posi-

SECTION X 9 Direct Operation on Epiphyses to Enhance G r o w t h Potential

tion with the articular surface and periosteum intact and then immediately replaced, there was complete cessation of growth of the epiphysis. Autograft transplantation of the entire metacarpal or metatarsal, in which an entire bone was transplanted from one foot to another foot of the same animal, also showed no evidence of growth. No effective growth was seen with split metacarpal reimplantation or autograft transplantation. In the group most likely to succeed, namely, those having reimplantation of the epiphyseal cartilage, the cartilage was transplanted with a piece of adjoining epiphysis and diaphysis, and even here there was no effective growth. A similar approach with autograft transplantation from one foot to the other showed no definite evidence of growth, with the conclusion that after autograft transplantation of the epiphyseal cartilage its function for linear growth was entirely lost or present to only a minimal degree. There was also uniform failure of growth with reimplantation of varying lengths of the epiphyseal end of the metacarpal and metatarsal bones and uniform failure of growth after autotransplantation of varying lengths. Haas' conclusions were quite straightforward; the epiphyseal cartilage lost its power to function after transplantation of either the reimplantation or autograft transplantation type and with the physis transplanted either alone or with an accompanying piece of epiphysis and diaphysis. When Haas used the term epiphyseal cartilage "alone," he still obtained a piece with small adjacent regions of epiphyseal and metaphyseal bone. He concluded that the epiphyseal cartilage was very vulnerable and that its viability was directly dependent upon its blood supply. In no instance was any vascular repair performed with his transplants, and the physeal cartilage rarely had direct access to the persisting vascularity of the host bone because it was always transplanted with a thin rim of bone on the epiphyseal and metaphyseal sides. Haas himself addressed this question in an abstract of the discussion printed immediately following the article. He noted that "in all the excisions of the epiphyseal cartilage a piece of adjoining epiphyseal and diaphyseal bone was removed so as not to injure that particular region." Heller had commented on this matter and felt that in his work he had succeeded in transplanting the epiphyseal cartilage in the form of very thin sheets of cartilage, which subsequently resulted in almost normal growth. Haas felt that Heller's conclusions were incorrect in the sense that he could not truly effectively transplant just cartilage alone, leaving open the possibility that it was the persisting cartilage not removed for transplantation that enabled growth to occur. In a subsequent article Haas reported on the macroscopic, microscopic, and in some cases radiologic details from 58 of the 75 procedures (209). The microscopic description involved not only the epiphyseal growth plate cartilage but also the articular cartilage, the marrow and bone of the secondary ossification center, the marrow and bone of the metaphysis, and cortical bone. With epiphyseal cartilage reimplantation, the first evidence of degeneration of the epiphyseal cartilage was seen at 23 days and appeared as a

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cleavage line extending through the cartilage columns dividing the physis into a proximal two-thirds and distal one-third. With time progressive degeneration of the epiphyseal cartilage line occurred, and by 85 days there was almost complete disappearance of the physeal cartilage. With autotransplantation the epiphyseal cartilage also showed early degeneration, and at 23 days a line of cleavage was noted through what appeared to be the hypertrophic zone. By 135 days only a slight remnant of physeal cartilage persisted. Following reimplantation with varying lengths of the epiphyseal and of the metacarpal and metatarsal bones, degeneration of the cells at the junction of the proximal two-thirds and distal one-third of the physis was noted followed by fissuring and eventual degeneration of the entire cartilage. With autotransplantation, the epiphyseal cartilage line underwent progressive and complete degeneration. The epiphyseal cartilage line also underwent progressive and complete degeneration with either reimplantation or autograft transplantation of the entire metacarpal or metatarsal bone. Haas reconfirmed his observations that the epiphyseal cartilage ceased to function after either reimplantation or autograft transplantation in each of several approaches. The longitudinal growth ceased in each case. The cartilage degenerated and frequently there were transverse and vertical fissures followed by disappearance of the cells, fibrous substitution, and eventually bone transformation. The only evidence for regeneration was near the periphery beneath the perichondrium, although the new cartilage possessed none of the length performing functions of the normal physeal pattern. Haas concluded that the epiphyseal cartilage was the least transplantable of any of the components of bone due to damage to the vascular supply to the epiphyseal region. Haas later performed another series of transplantation procedures because others continued to describe some effective results with epiphyseal transplantation (210). He concluded again, however, following 20 additional procedures, that "the epiphyseal cartilage plate loses its power of causing length growth after transplantation." Haas defined the potential clinical value of epiphyseal transplantation, but he concluded after extensive and repeated experimentation that longitudinal growth ceased after reimplantation, autograft, or allograft transplantation of the epiphyseal cartilage, whether by itself or with a neighboring piece of epiphyseal or diaphyseal bone. Entire widths of physis in dogs were transplanted, and most of the many variations used were unsuccessful, as Haas recognized, due to failure to provide nutrition to the resting, germinal, and proliferating chondrocytes of the physis. Even transplants of what Haas referred to as the epiphyseal cartilage line, however, included a thin rim of adjoining epiphyseal and metaphyseal bone. 3. PHYSIOLOGIC CONCERNS IN PHYSEAL TRANSPLANTATION Subsequent studies on physeal transplants continued to use entire ulnar, radial, metacarpal, and metatarsal physes, most of which had some epiphyseal bone attached both to

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Lower Extremity Length Discrepancies

protect the physis from mechanical damage during removal and to ensure its complete transplantation. The results were variable. It is probable that even thin layers of bone attached to physeal transplants on the epiphyseal side inhibit rapid diffusion of nutrients to the physeal cartilage, result in chondrocyte death, and lead to growth plate resorption and replacement by bone. In support of this contention is the report by Heller (229) of good results in physeal transplants when a thin layer of cartilage was transplanted without a sliver of epiphyseal bone attached to the graft, although Haas has pointed out that growth might have been due in such situations to parts of physeal cartilage left behind that continued to function. Similarly good results have been reported with focal cartilage transplants performed using iliac crest cartilage without overlying epiphyseal bone. Additional problems with previously reported experimental methods can be considered. Some grafts appear to have led to poor results after transplantation with the surrounding perichondrium intact. This tissue layer would inhibit nutrition by diffusion from the host tissues, which is essential in free transplants. In addition, most of the studies on free epiphyseal transplantation have involved total physes, which undoubtedly represent too extensive an amount of tissue for consistently good results, especially if epiphyseal bone, perichondrium, and periosteum are left attached and a firm fit in the defect is not achieved. The previously mentioned technical factors, pertaining ultimately to physeal nutrition, have been discussed and appear to be essential considerations for successful free physeal transplants.

Ring then performed comparative experiments involving autograft transplantation within the same animal from right to left and vice versa and allograft transplantations from separate rabbits. Detailed and accurate length determinations of normal rabbit ulnar growth and that of the transplanted animals then were made over a several-week period well beyond skeletal maturation. Histological and radiographic studies were made. Ring concluded that only 5 of the autograft transposition group could be assessed as completely successful out of 18 procedures. The ulnar growth had to exceed 75% of that predicted and stringent radiographic criteria had to prevail to give the successful grading. In the allograft group 26 procedures were performed. By using the criteria for successful transplantation developed for the other two groups, 21 of the 24 were clear failures, and whereas 3 looked to have acceptable radiographic appearances, in each of these the epiphyseal cartilage was narrow and in none of the 3 was the growth in the experimental limb within 75% of the control. Ring thus concluded that allograft transplantation was unsuccessful in all of the animals studied, a conclusion invariably reached by investigators throughout the century. In the autograft transposition group normal growth occurred in only 5 of 18 procedures. Some of the failures were due to technical difficulties in the sense that it was difficult to obtain a snug fit of the transplanted physis into its new host bone. Even when this was present, however, growth failure occurred because of the inability to restore full revascularization in an appropriate period of time.

ETAL. Harris et al. (220) achieved a 50% success rate in autogenous transplants of immature rabbit whole distal ulnar physes by leaving the host perichondrium intact and transplanting only physeal cartilage without a sliver of epiphyseal bone, thus substantiating Heller's results at least partially, as well as the importance of allowing nutrition from the host to support the graft. An extremely careful technique was utilized to obtain the graft. Following sub-periosteal dissection of the distal ulnar metaphysis and adjacent epiphysis for about one-third of its circumference, the epiphysis was broken from the shaft with ease by manual pressure. Because the physis was quite straight there was a constant line of separation through the hypertrophied cells of the zone of provisional calcification, leaving the bulk of the epiphyseal plate attached to the epiphysis. Harris et al. then inserted a small scalpel blade as close to the bone plate of the epiphysis as possible, excising only the cartilaginous physis. Because the germinal layer was relatively thick during early development it was easier to obtain an adequate transplant in the very young animals. They performed reimplantation in 65 rabbits, autogenous transplantation (fight to left) in 65 rabbits, and allograft transplantation using animals paired as closely as possible by weight in 65 animals. A stainless steel wire was then placed through the ulnar shaft approximately 0.5 cm proximal to the plate to serve as a radiographic guide 5. HARRIS

4. RING Interest in physeal transplantation has continued due to the high potential value of such a technique, but daunting difficulties persist. Ring performed reimplantation, autograft, and allograft transplantations of the entire distal ulnar epiphysis in 3- to 6-week-old rabbits (405). He had calculated that approximately 85% of the growth of the ulna occurred distally. He also recognized that, due to the tight bond between the distal radius and the distal ulna, there could be some lengthening of the distal ulnar region after transplantation, which need not represent physeal growth but undoubtedly was due to a mechanical pulling apart of the distal ulna by the continuing growth of the radius. After a period of time, however, failure of ulnar growth would be reflected by tethering of the adjacent radius and its growth in a curved pattern. The ulnar physeal cartilage was removed following knife cuts made transversely through the bony epiphysis and metaphysis, such that the isolated cartilage was transplanted "with its thin attached slivers of bone," following which it was gently freed from the radius and removed together with its surrounding perichondrium. In a series of reimplantation experiments of 9 animals followed for 5 weeks or more, 6 showed little or no shortening and 3 were failures. The reimplantation procedure represents the most favorable in terms of prognosis.

SECTION X ~ Direct Operation on Epiphyses to Enhance Growth Potential for length measurements. Sacrifice ranged from 1 to 84 days with nine time periods in the first 2 weeks and studies then at 21, 28, 56, and 84 days. Studies were histologic. In the allograft transplantations 7 of 13 long-term (56 and 84 days) animals were successful. Normal growth was virtually never noted in comparison to controls regardless of the type of procedure. In the reimplantation group, 11 of 25 available long-term specimens showed normal histological appearance of the plate and 80% or more of anticipated growth. In the allograft transplantations there was a remarkably uniform success rate up to 28 days. All physes subsequently degenerated, however, and were destroyed between the 56th and 84th days. Harris et al. thus concluded that satisfactory survival with up to 80% of normal growth for the 12 weeks of the experiment was achieved in half of the autografts, with homografts fairing quite poorly particularly after the first 4 weeks. Technical features for a good result involved the necessity of including the germinal cells of the physis within the transplant, an adequate supply of tissue fluid (i.e., vascularization) reaching the transplant from the epiphyseal side, and a snug fit of the transplant in the recipient bed. Their interpretation, which appears to be highly accurate, suggested that the transplants had to survive an avascular stage, obtaining nutrition from the surrounding tissues before healing and stabilization occurred such that true longitudinal growth could continue. Care had to be taken to ensure that the recipient bed particularly on the epiphyseal side had been curetted to bleeding bone because it is the vascularity of the host that provides nutrition to the transplanted or re-implanted physeal graft tissue.

6. SILFVERSKIOLD;FARINE Silfverskiold (443) performed ulnar epiphyseal cartilage transfers in the rabbit and found that allografi transplantation produced a complete cessation of growth, whereas autograft exchange produced cessation of growth in 6 of 11 animals and considerable retardation in the rest. Farine (158) also performed distal ulnar transplantation procedures in the young rabbit. Sacrifice in most was from the 1st to the 90th day after surgery with occasional animals followed to 180 days. Operations were performed in 16 rabbits at 5 weeks of age. The transplant included the entire distal ulnar physis with two thin epiphyseal and metaphyseal lamellae of bone. Autograft transposition from fight to left was done in 16, and in a second group an additional 16 had reimplantation procedures performed. The results in the two groups were similar. The subsequent study was histologic and microangiographic. A major part of the cartilage transplant survived in each of the rabbits, and on one occasion there was total survival. Any imperfect result was due to the production of a hematoma, which limited passage of host vessels to the graft and thus limited revascularization. Measurements in terms of physeal function were not made, however. Experimental work in immature rabbits by Zaleske et al. (518) has shown that reimplantation of vascularized whole

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knee joints, including the epiphyses, can survive and continue growth. At present, however, such procedures have no clinical applicability, primarily because the epiphyses that can be sacrificed for transplantation do not fit the anatomical and mechanical needs of the area to which they would be transferred.

F. Implantation of Chondrocyte Suspensions The ability to grow chondrocytes, which synthesize a cartilage matrix in vitro, has led to the hope that chondrocyte suspensions grown in tissue culture subsequently might be placed within focal physeal defects to reconstitute a functioning physeal region. A few experimental reports of this possible approach have appeared. Hansen et al. (218) reported on the growth of chondrocytes into cartilage disks after culturing isolated epiphyseal chondrocytes from fetal lambs. The best results are achieved in experimental animals using fetal cartilage as the source of chondrocytes. Whereas there is some evidence that a cartilage tissue subsequently forms in the physeal defect and proliferates, there is no evidence that the cytologically specialized physis has been reconstituted. Regardless, this avenue of approach is promising as expertise is improving in cell culture and in providing a mechanical substrate on which the chondrocytes can proliferate.

G. Treatment of Premature Physeal Closure by Means of Physeal Distraction Transphyseal distraction has been used in both experimental and clinical situations to disrupt focal transphyseal bridges. DePablos et al. (32, 138, 139) used the procedure in 30 lambs at 1.5 months old after partial epiphyseal arrest in the distal femur had been induced. Physeal distraction was then performed followed by no subsequent intervention in some animals and the interposition of fat in others. They demonstrated the ability to disrupt the focal physeal bridge by the distraction technique but recommended that fat be interposed because the bridge reformed in all instances in which distraction alone had been used. DePablos et al. recommended physeal distraction to pull apart the bone bridge, and if clinically meaningful amounts of growth were still left, there was value in performing fat interposition to prevent bridge reformation. The need to resect the bridge, however, was bypassed. Connolly et al. (123) applied transphyseal traction to correct acquired growth deformities in the immature dog. Bone bridges were created across the medial distal femoral physis to produce a varus deformity. They were able to bring about correction by transphyseal lengthening both after removal of the bone bridge directly and by not intervening on the bone bridge but stretching and breaking it with the traction procedure. Many of the animals suffered premature growth plate closure. They showed, however, that mechanical epiphyseolysis after a bone bridge had formed offered

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the possibility of treating large areas of epiphyseal arrest in order to restore length and correct angulation. Correction of alignment was also performed in two patients with shortening and angular deformity due to enchondromas but without bone bridges. Correction and lengthening were obtained, but premature fusion limited effectiveness. Kershaw and Kenwright (271) were able to pull apart bone bridges by transphyseal distraction, but rabbits sacrificed 3-6 weeks after the distraction showed complete physeal closure, suggesting that distraction epiphyseolysis along with bone bridge disruption would have a high potential for producing premature physeal fusion. Bollini et al. (60) used the Ilizarov device to treat a centrally located bone bridge in the lower tibia of a 10-year-old gift caused by an epiphyseal fracture-separation. The epiphyseolysis occurred on the 4th postoperative day following lengthening or distraction of 0.25 mm per day. The bone bridge, which remained attached to the metaphysis, was surgically removed following distraction and was prevented from recurring following interposition of methyl methacrylate. Follow-up at 2 years showed no recurrence and normal growth. Canadell and DePablos (91) presented four clinical examples of breaking bone bridges by physeal distraction, thus eliminating the need for the complex and relatively inaccurate open resection of such transphyseal tissue. They used an angulated monolateral fixator, which served with distraction both to pull apart the bone bridge and then to allow for angular correction with time. The procedures were performed three times in the distal femur and once in the distal tibia. The physeal bridge broke in each instance a few days after distraction began. In those patients close to growth maturation, no effort was made to interpose tissue. If patients were treated at a younger age, then the possibility of a secondary procedure to insert an interpositional tissue would be strongly considered. Canadell and DePablos made one important technical point. It was important to fracture the bone bridge first with lengthening forces across and parallel to the angulated physis. The distraction would have to be symmetrical, and only after the bridge had broken would angular correction be performed. If angular corrective forces were applied from the beginning, they would subject the healthy part of the physis to compression pressures, which could lead to its permanent damage. Physeal distraction was also applied by Aldegheri et al. (16) to pull apart bone bridges and then allow for angular correction, utilizing the principle of epiphyseal distraction referred to as hemichondrodiatasis. The Orthofix articulated dynamic axial fixator was used to provide for the asymmetric pressures. Two cancellous screws were placed in the epiphysis and two cortical screws in the diaphysis. Earlier work by DeBastiani was quoted to show that it was possible to elongate just the lateral portion of the distal growth plate of the femur, with histologic assessment showing an increase in thickness only in the lateral part of the physis due to cellular hyperplasia and hypertrophy. The deviation was achieved without fracture of the

growth plate. Aldegheri et al. felt that the best results were achieved in posttraumatic deformities when the bone bridge occupied less than 20-30% of the epiphyseal plate. They recommended performance of the procedure with little growth remaining because the possibility of postprocedure growth arrest still existed.

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CHAPTER 8 ~ Lower Extremity Len~tth Discrepancies

412. Rodriguez-Merchan EC (1996) Effects of hemophilia on articulations of children and adults. Clin Orthop Rel Res 328: 7-13. 413. Rogalski R, Hensinger R, Loder R (1993) Vascular abnormalities of the extremities: Clinical findings and management. J Pediatr Orthop 13:9-14. 414. Ross D (1948) Disturbance of longitudinal growth associated with prolonged disability of the lower extremity. J Bone Joint Surg 30A: 103-115. 415. Rossvoll I, Junk S, Terjesen T (1992) The effect on low back pain of shortening osteotomy for leg length inequality. Internat Orthop 16:388-391. 416. Rush WA, Steiner HA (1946) A study of lower extremity length inequality. Am J Roent 56:616-623. 417. Russell A (1954) A syndrome of "intra-uterine" dwarfism recognizable at birth with cranio-facial dysostosis, disproportionately short arms, and other anomalies (5 examples). Proc Roy Soc Med 47:1040-1044. 418. Salai M, Chechick A, Ganel A, Blankstein A, Horoszowski H (1985) Subluxation of the hip joint during femoral lengthening. J Pediatr Orthop 5:642-644. 419. Saleh M, Goonatillake HD (1995) Management of congenital leg length inequality: Value of early axis correction. J Pediatr Orthop 4:150-158. 420. Saleh MB, Stubbs DA, Street RJ, Lang DM, Harris SC (1993) Histologic analysis of human lengthened bones. J Pediatr Orthop 2B: 16-21. 421. Salter RB, Harris WP (1963) Injuries involving the epiphyseal plate. J Bone Joint Surg 45A:587-622. 422. Salter RB (1973) Legg-Perthes, Part V. Treatment by innominate osteotomy. In: Instructional Course Lectures, The American Academy of Orthopedic Surgeons, volume 22. p. 309, St. Louis: CV Mosby Company. 423. Sasso RC, Urquhart BA, Cain TE (1993) Closed femoral shortening. J Pediatr Orthop 13:51-56. 424. Savarese JJ, Brinken BW, Zaleske DJ (1995) Epiphyseal replacement in a murine model. J Pediatr Orthop 15:682-690. 425. Schoenecker PL, Capelli AM, Millar EA, Sheen MR, Haher T, Aiona MD, Meyer LC (1989) Congenital longitudinal deficiency of the tibia. J Bone Joint Surg 71A:278-287. 426. Schopler SA, Lawrence JF, Johnson MK (1986) Lengthening of the humerus for upper extremity limb length discrepancy. J Pediatr Orthop 6:477-480. 427. Schultz AH (1937) Proportions, variability, and asymmetries of the long bones of the limbs and the clavicles in man and apes. Human Biol 9:281-328. 428. Schwerz F (1912) Die Alamannen in der Schweiz. Z Morph Anthrop 14:609-700. 429. Sengupta A, Gupta P (1993) Epiphyseal stapling for leg equalisation in developing countries. Internat Orthop 17:27-42. 430. Shapiro F (1982) Legg-Calve-Perthes disease. A study of lower extremity length discrepancies and skeletal maturation. Acta Orthop Scand 53:437-444. 431. Shapiro F (1981) Fractures of the femoral shaft in children. The overgrowth phenomenon. Acta Orthop Scand 52:649-655. 432. Shapiro F (1982) Ollier's disease. An assessment of angular deformity, shortening, and pathological fracture in twentyone patients. J Bone Joint Surg 64-A:95-103. 433. Shapiro F (1982) Developmental patterns in lower extremity length discrepancies. J Bone Joint Surg 64A:639-651.

434. Shapiro F (1982) Epiphyseal growth plate fracture-separations. A pathophysiologic approach. Orthopedics 5:720-736. 435. Shapiro F (1987) Longitudinal growth of the femur and tibia after diaphyseal lengthening. J Bone Joint Surg 69A:684-690. 436. Shapiro F, Rand F, Upton J, Barone L (1992) Histologic patterns of bone formation in rabbit distraction osteogenesis. Orthop Trans 16:561-562. 437. Shapiro F, Simon S, Glimcher MJ (1979) Hereditary multiple exostosis. Anthropometric, roentgenographic, and clinical aspects. J Bone Joint Surg 61A:815-824. 438. Siffert RS (1956) The effect of staples and longitudinal wires on epiphyseal growth. J Bone Joint Surg 38A:1077-1088. 439. Siffert RS (1957) The effect of juxta-epiphyseal pyogenic infection on epiphyseal growth. Clin Orthop Rel Res 10: 131-139. 440. Siffert RS (1966) The growth plate and its affections. J Bone Joint Surg 48A:546-563. 441. Siffert RS (1987) Lower limb-length discrepancy. J Bone Joint Surg 69A:1100-1106. 442. Siffert RS, Feldman DJ (1980) The growing hip. The dynamic development of the normal adult hip and the deformed hip of Legg-Calve-Perthes' disease. Acta Orthop Belg 46: 443-476. 443. Silfverskiold N (1934) Uber Langenwachstum der Knochen und transplantation von epiphysenscheiben. Acta Chir Scand 75:77-104. 444. Silver HK (1964) Asymmetry, short stature, and variations in sexual development. Am J Dis Child 107:495-515. 445. Silver HK, Kiyasu W, George J, Deamer WC (1953) Syndrome of congenital hemihypertrophy, shortness of stature, and elevated urinary gonadotropins. Pediatrics 12:368-375. 446. Simon S, Whiffen J, Shapiro F (1981) Leg-length discrepancies in monoarticular and pauciarticular juvenile rheumatoid arthritis. J Bone Joint Surg 63A:209-215. 447. Sissons HA (1952) Osteoporosis and epiphysial arrest in joint tuberculosis: An account of the histological changes in involved tissues. J Bone Joint Surg 34B:275-290. 448. Sledge CB, Noble J (1978) Experimental limb lengthening by epiphyseal distraction. Clin Orthop Rel Res 136:111-119. 449. Smith CF (1996) Instantaneous leg length discrepancy determination by "thigh-leg" technique. Orthopedics 19:955-956. 450. Sola CK, Silberman FS, Cabrini RL (1963) Stimulation of the longitudinal growth of long bones by periosteal stripping: An experimental study on dogs and monkeys. J Bone Joint Surg 45A:1679-1684. 451. Specht EE, Hazelrig PE (1973) Orthopaedic considerations of Silver's syndrome. J Bone Joint Surg 55A:1502-1510. 452. Speed K (1922) Growth problems following osteomyelitis of adolescent long bones. Surg Gyn Obstet 34:469-476. 453. Speed K (1923) Longitudinal overgrowth of long bones. Surg Gyn Obstet 36:787-794. 454. Spriggins AJ, Bader DL, Cunningham JL, Kenwright J (1989) Distraction physiolysis in the rabbit. Acta Orthop Scand 60:154-158. 455. Staheli LT (1967) Femoral and tibial growth following femoral shaft fracture in childhood. Clin Orthop Rel Res 55: 159-163. 456. Staheli LT, Duncan WR, Schaefer E (1968) Growth alterations in the hemiplegic child. A study of femoral anteversion, neck-shaft angle, hip rotation, CE angle, limb length, and

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CHAPTER

9

Skeletal Dysplasias IX. Histopathologic Changes in Specific Chondrodysplasias X. Orthopedic Deformities in Skeletal Dysplasias--Regional Abnormalities and Their Relation to Clinically Significant Deformity XI. Limb Lengthening XII. Review of Specific Skeletal Dysplasias: Pathobiology, Clinical and Radiographic Characteristics, and Orthopedic Management XIII. Anesthetic Implications in the Skeletal Dysplasias

Terminology Classification Approaches III. Prevalence of Skeletal Dysplasias IV. Diagnosis of Skeletal Dysplasias V. Chromosome Abnormality Sites in Skeletal Dysplasias VI. Genetic and Molecular Abnormalities in Skeletal Dysplasias VII. Lethal Perinatal Skeletal Dysplasias VIII. Microstructural-Morphologic Abnormalities of the Epiphyses and Metaphyses in Skeletal Dysplasias I.

II.

seal dysplasias), have come to be defined by biochemical abnormalities. Virtually all of the skeletal dysplasias are due to mutations in genes involved in skeletal development. Although the need to catalogue clinical and radiographic variations among these disorders is evident, deeper biologic understanding is being provided by elucidation of underlying gene and molecular defects in relation to collagen, glycoprotein, proteoglycan, fibroblast growth factor receptor, and other molecular components of epiphyseal cartilage, growth plate cartilage, and bone. Histology, histochemistry, and transmission electron microscopy frequently reveal structural abnormalities of physeal and epiphyseal cartilage and bone, although morphologic changes alone rarely are pathognomonic of specific diseases. The term skeletal dysplasia does not refer to all short stature syndromes but only to those in which the shape and structure of the bones are abnormal. One of the earliest distinctions made in relation to short stature syndromes was by Parrot in 1878, who used the term "achondroplasia" to distinguish disproportionately from proportionately short stature (230). It soon came to be recognized that the former syndromes were due to primary inherited skeletal abnormalities, whereas in the latter the bones were short secondary to systemic causes often acquired such as endocrine, metabolic, renal, hepatic, cardiac, or other anomalies. By the late 1920s distinctions within the disproportionate group delineated short limb dysplasias, with limb shortening greater than truncal-axial shortening, from short trunk dysplasias, with truncal-axial shortening greater than limb shortening. The prototypic short limb disproportionate dwarfism is achondroplasia and short trunk disproportionate dwarfism is Morquio's disease (mucopolysaccharidosis IV). Further

I. T E R M I N O L O G Y The skeletal dysplasias are developmental disorders of the bones and encompass a large number of conditions, most of which are genetic in origin. They can lead to such features as disproportionately short stature, angular deformities of the long bones, joint surface irregularity, joint contractures or instability, lower extremity length discrepancies, increases or decreases of bone density, and axial deformities, including cervical vertebral abnormalities, thoracolumbar scoliosis and kyphosis, spinal stenosis, and cranial bone malformations such as craniosynostosis and foramen magnum stenosis. Many terms have been used to refer to this large group of heterogeneous disorders, including chondrodysplasia, because the large majority are due to primary defects of cartilage, and osteochondrodysplasia, referring to abnormalities of both cartilage and bone, but the more general term of skeletal dysplasia is used increasingly.

II. C L A S S I F I C A T I O N A P P R O A C H E S Classification criteria for the skeletal dysplasias can be defined into three broad groups: clinical, radiographic, and molecular. Some conditions are so characteristic, such as achondroplasia or diastrophic dysplasia, that they were defined initially and accurately by clinical appearance. Some, such as the multiple epiphyseal dysplasias, spondyloepiphyseal dysplasias, or metaphyseal dysplasias, were defined, named, and categorized most clearly by characteristic radiographic findings, and others, such as the mucopolysaccharidoses (which, according to radiologic criteria, are spondyloepiphy733

734

CHAPTER 9 ~ Skeletal Dysplasias

subdivision has followed but these basic outlines remain valuable. Many of the skeletal dysplasia syndromes were initially described and referred to as dwarfisms, dysostoses, or dystrophies, but the modifying term dysplasia is used increasingly. Over 150 developmental disorders of the skeletal system have been described (17, 262) (Table I; see also Tables III and VIA in Chapter 1). The large number of disorders, the variable clinical and radiological appearance within individual disorders, the rarity of most of the defined disorders, and the fact that many patients with a skeletal dysplasia still cannot be classified definitively even with detailed and conscientious efforts have led to considerable confusion. The rapidly accumulating findings of genetic and molecular abnormalities in some mesenchymal tissue syndromes are instructive in this regard. In osteogenesis imperfecta, the wide spectrum of clinical involvement becomes understandable because virtually no two patients have the same molecular abnormality of collagen with close to 200 different mutations found (54, 156). Similar situations are being found with some of the other skeletal dysplasias. The subdivision of multiple epiphyseal dysplasia into 10-15 subtypes or spondyloepiphyseal dysplasia into even more subtypes based on clinical and radiographic variability almost certainly is reflective of varying molecular abnormalities, most as yet undefined, and of varying degrees of penetrance and expressivity (8). Relatively broad groupings at a clinical-radiographic level must suffice for now with further subdivision best based on the elucidation of genetic-molecular abnormalities. Multiple systems of classification have been described. Although all are instructive, it is essential to recognize that no universal, accurate system exists. Many of the earliest attempts at classification were hindered by the fact that many disorders currently appreciated were not even known due to their rarity and in some instances variable geographic locations. The medical discipline of those describing the disorders also plays a role in defining the format within which the patients are described. Early clinical observers defined proportionate and disproportionate syndromes, clinical geneticists elucidated autosomal dominant or recessive and sex-linked disorders, radiologists tend to favor minute descriptions often noting epiphyseal, metaphyseal, or diaphyseal localization, orthopedic surgeons distinguish between syndromes with and without spinal involvement, neurologic sequelae, angular limb deformity, and articular surface irregularity, and molecular biologists define genetic and molecular abnormalities. Though these findings interdigitate to a significant extent there is not a complete fit between groupings. On the other hand, a relatively small number of entities characterize the large majority of patients with skeletal dysplasias such that good awareness of findings in any patient is achievable. Rubin reviewed the several classification systems that had evolved for the bone dysplasias by the 1970s (271). Murk Jansen was the first to focus on description of the skeletal abnormality based on the region of the bone that was most

deformed, and his basic classification defined epiphyseal dysostosis, metaphyseal dysostosis, and diaphyseal dysostosis (138, 271). This remains a valuable way to assess radiographs initially. Brailsford wrote on developmental bone disorders, recognizing that the dysplasias are variable in degree and severity with many "transitional" forms that made classification difficult (271). He divided the disorders into three groups: (1) defective ossification of the whole skeleton, which was either osteopenic involving osteogenesis imperfecta or radiodense involving osteopetrosis; (2) abnormal metaphyseal growth in which he placed the achondroplasia disorder and chondro-osteodystrophy; and (3) proliferation of mesoblastic cells in which he defined four disorders, only one of which, melorheostosis, would be clearly recognized by most today. Fairbank in his Atlas of General Affections of the Skeleton reviewed several syndromes (74). Although seven categories of general affections of the skeleton were listed, the major value of the book rests in his description of specific entities rather than attempts to force them into specific groupings. Even in the earliest of classifications difficulties are apparent due to the mixing of clinically recognizable syndromes such as achondroplasia with those defined not by the clinical appearance of the individual but rather by the specific radiologic abnormalities. Further difficulties developed by mixing the bases of the classifications even further by defining variables such as tissue of origin, cartilage or bone, often in the absence of any convincing histopathological correlation. With each year more detailed radiographic and clinical information accumulated, and continuing studies over the past 30 years have added and continue to add additional syndromes and classification systems. The uncovering of genetic and molecular abnormalities is a welcome addition to the field, although even delineation of these abnormalities into molecular families will not totally clarify the disorders because considerable areas of overlap between seemingly disparate clinical disorders are already being found. Rubin provided an interesting approach to assessing the skeletal dysplasias based on the dynamics of bone development and the specific regions that were deformed (271). These observations made initially by Jansen and confirmed by many other studies clearly show a regional or localizing tendency for abnormal structure in many dysplasias, such that they can be defined adequately although not completely by these localizations as seen radiographically. Rubin's dynamic classification of bone dysplasias described (1) epiphyseal dysplasias (by which he meant dysplasias of the articular cartilage and secondary ossification centers), (2) physeal dysplasias, (3) metaphyseal dysplasias, and (4) diaphyseal dysplasias. The dynamic nature of his classification is accompanied by detailed reviews of bone morphogenesis and development involving synthesis and resorptive aspects. He stressed the modeling of the various regions with growth, characterizing epiphyseal enlargement as a hemispherization process, physeal function as involving growth, metaphyseal development as a funnelization process, and diaphyseal

SECTION II ~ Classification Approaches TABLE I

Classification o f O s t e o c h o n d r o d y s p l a s i a s a'b

1. Achondroplasia group Thanatophoric dysplasia, type I AD Thanatophoric dysplasia, type II AD Achondroplasia AD Hypochondroplasia AD Other FGFR3 disorders 2. Spondylodysplastic and other perinatally lethal groups Lethal platyspondylic skeletal dysplasias (San Diego, Torrance, Luton) Achondrogenesis type IA 3. Metatropic dysplasia group Fibrochondrogenesis AR Schneckenbecken dysplasia AR Metatropic dysplasia (various types) AD 4. Short rib dysplasia (SRP) (with/without polydactyly) group SRP type I Saldino-Noonan AR SRP type II Majewski AR SRP type III Verma-Naumoff AR SRP type IV Beemer-Langer AR Asphyxiating thoracic dysplasia (Jeune) AR Chondroectodermal dysplasia (Ellis-van AR Creveld dysplasia) 5. Atelosteogenesis-omodysplasia group Atelosteogenesis type 1 (includes Sp "Boomerang dysplasia") Omodysplasia I (Maroteaux) AD Omodysplasia II (Borochowitz) AR Otopalatodigital syndrome type II XLR Atelosteogenesis type III de la Chapelle dysplasia 6. Diastrophic dysplasia group Diastrophic dysplasia AR Achondrogenesis IB AR Atelosteogenesis type II AR 7. Dyssegmental dysplasia group Dyssegmental dysplasia (SilvermanAR Handmaker type) Dyssegmental dysplasia (RollandAR Desbuquois type) 8. Type II collagenopathies Achondrogenesis II (Langer-Saldino) AD Hypochondrogenesis AD Kniest dysplasia AD Spondyloepiphyseal dysplasia congenita AD (SED) Spondyloepimetaphyseal dysplasia (SEMD) Strudwick type AD SED with brachydactyly AD Mild SED with premature-onset arthrosis AD Stickler dysplasia (heterogeneous, some not AD linked to COL2A1) 9. Type XI collagenopathies Stickler dysplasia (heterogeneous) Otospondylomegaepiphyseal dysplasia (OSMED)

73S

AD

10. Other spondyloepi(meta)physeal [SE(M)D] dysplasias X-linked spondyloepiphyseal dysplasia tarda XLD Other late-onset spondyloepi(meta)physeal dysplasias (i.e., Namaqualand d., Irapa D.) Progressive pseudo-rheumatoid dysplasia AR Dyggve-Melchior-Clausen dysplasia AR Wolcott-Rallison dysplasia AR Immuno-osseous dysplasia Schimke AR Opsismodysplasia AR Chondrodystrophic myotonia (Schwartz AR Jampel), type I, type II Spondyloepiphyseal dysplasia with joint laxity AR Sponastrime dysplasia AR SEMD short limb, abnormal calcification AR 11. Multiple epiphyseal dysplasias and pseudo-achondroplasia Pseudo-achondroplasia Multiple epiphyseal dysplasia (MED) AD (Fairbanks and Ribbing types) Other MEDs 12. Chondrodysplasia punctata (stippled epiphyses group) Rhizomelic type AR Zellweger syndrome (several types) AR Conradi-Htinermann type XLD X-linked recessive type XLR Brachytelephalangic type XLR Tibial-metacarpal type AD Vitamin K-dependent coagulations defect AR Other acquired and genetic disorders including Warfarin embryopathy 13. Metaphyseal dysplasias Jansen type AD Schmid type AD McKusick type (cartilage-hair hypoplasia) AR Metaphyseal anadysplasia XLR? Metaphyseal dysplasia with pancreatic insufficiency and cyclic neutropenia (Schwachman Diamond) Adenosine deaminase deficiency AR Metaphyseal chondrodysplasia Spahr type AR Acroscyphodysplasia (various types) AR 14. Spondylometaphyseal dysplasias (SMD) Spondylometaphyseal dysplasia (Kozlowski AD type) Spondylometaphyseal dysplasia (Sutcliffe AD type) SMD with severe genu valgum (includes AD Schmidt and Algerian types) SMD Sedaghatian type AR Mild SMD (various types) 15. Brachyolmia spondylodysplasias Hobaek (includes Toledo type) AR Maroteaux type AR Autosomal dominant type AD 16. Mesomelic dysplasias Dyschondrosteosis (Leri-Weill) AD Langer type (homozygous dyschondrosteosis) AR (continues)

736

CHAPTER 9 ~ Skeletal Dysplasias TABLE I (continued)

17.

18.

19.

20.

21.

Nievergelt type AD Kozlowski-Reardon type AR Reinhardt-Pfeiffer type AD Werner type AD Robinow type, dominant AD Robinow type, recessive AR Mesomelic dysplasia with synostes AD Acromelic and acromesomelic dysplasias Acromicric dysplasia AD Geleophysic dysplasia AR Weill-Marchesani dysplasia AR Cranioectodermal dysplasia AR Trichorhinophalangeal dysplasia type I AD Trichorhinophalangeal dysplasia type II AD (Langer-Giedion) Trichorhinophalangeal dysplasia type III AD Grebe dysplasia AR Hunter-Thompson dysplasia AR Brachdactyly types A1-A4, B, C, D, and E AD Pseudo-hypoparathyroidism (Albright hereditary osteodystrophy) Acrodyostosis Saldino-Mainzer dysplasia AR Brachydactyly-hypertension dysplasia AD Craniofacial conodysplasia AD Angel shaped phalangoepiphyseal dysplasia AD (ASPED) Acromesomelic dysplasia AR Dysplasias with prominent membranous bone involvement Cleidocranial dysplasia AD Osteodysplasty, Melnick-Needles XLD Precocious osteodysplasty (terHaar dysplasia) AR Yunis-Varon dysplasia AR Bent bone dysplasia group Campomelic dysplasia AD Kyphomelic dysplasia ?AR Sttive-Wiedemann dysplasia AR Multiple dislocations with dysplasias Larsen syndrome AD Larsen-like syndromes (La Reunion Island) AR Desbuquois dysplasia AR Pseudo-diastrophic dysplasia AR Dysostosis multiplex group Mucopolysaccharidosis IH AR Mucopolysaccharidosis IS AR Mucopolysaccharidosis II XLR Mucopolysaccharidosis IliA AR IIIB AR IIIC AR IIID AR Mucopolysaccharidosis IVA AR Mucopolysaccharidosis IVB AR Mucopolysaccharidosis VI AR Mucopolysaccharidosis VII AR Fucosidosis AR oL-Mannosidosis AR

Aspartylglucoasminuria gM 1 gangliosidosis, several forms Sialidosis, several forms Sialic storage disease Galactosialidosis, several forms Multiple sulfatase deficiency Mucolipidosis II Mucolipidosis III 22. Osteodysplastic slender bone group Type 1 osteodysplastic dysplasia Type 2 osteodysplastic dysplasia Microcephalic osteodysplastic dysplasia 23. Dysplasias with decreased bone density Osteogenesis imperfecta I (without opalescent teeth) Osteogenesis imperfecta I (with opalescent teeth) Osteogenesis imperfecta II Osteogenesis imperfecta III Osteogenesis imperfecta IV (without opalescent teeth) Osteogenesis imperfecta IV (with opalescent teeth) Cole-Carpenter dysplasia Bruck syndrome Singleton-Merten syndrome Osteopenia with radiolucent lesions of mandible Osteoporosis-pseudo-glioma dysplasia Geroderma osteodysplasticum Hyper IGE syndrome with osteopenia Idiopathic juvenile osteoporosis 24. Dysplasias with defective mineralization Hypophosphatasia-perinatal lethal and infantile forms Hypophosphatasia adult form Hypophosphatemic tickets Neonatal hyperparathyroidism Transient neonatal hyperparathyroidism with hypocalciuric hypercalcemia

AR AR AR AR AR AR AR AR AR AR AR AD AD AD-AR AD-AR AD AD

AR AR AD AR AR AR Sp AR AD XLD AR AD

25. Increased bone density without modification of bone shape Osteopetrosis a. Precocious type AR b. Delayed type AD c. Intermediate type AR d. With renal tubular acidosis AR Axial osteosclerosis a. Osteomesopycnosia AD b. With Bamboo hair (Netherton AR syndrome) Pycnodysostosis AR Osteoclerosis-Stanescu type AD Osteopathia striata a. Isolated Sp b. With cranial sclerosis AD Sponastrime dysplasia AR

(continues)

737

SECTION II ~ Classification Approaches TABLE I (continued)

26.

27.

28.

29.

30.

Melorheostosis Sp Osteopoikilosis AD Mixed sclerosing bone dysplasia Sp Increased bone density with diaphyseal involvement Diaphyseal dysplasia, Camurati-Engelmann AD Craniodiaphyseal dysplasia ?AR Lenz-Majewski dysplasia Sp Endosteal hyperostosis AR a. van Buchem type AD b. Worth disease AR c. Sclerosteosis AR d. With cerebellar hypoplasia AD-AR Kenny Caffey dysplasia AR Osteoectasia with hyperphophatasia (juvenile Pagets) Diaphyseal dysplasia with anemia AR Diaphyseal medullary stenosis with bone AD malignancy (Hardcastle) Increased bone density with metaphyseal involvement Pyle dysplasia AR Craniometaphyseal dysplasia AR a. Severe type AD b. Mild type XLR Frontometaphyseal dysplasia AR-XLR Dysosteosclerosis AD-AR Oculodento-osseous dysplasia AD Trichodento-osseous dysplasia Neonatal severe osteosclerotic dysplasias Blomstrand dysplasia AR Raine dysplasia Prenatal-onset Caffey disease Lethal chondrodysplasias with fragmented bones Greenberg dysplasia AR Dappled diaphyseal dysplasia AR Astley-Kendall dysplasia AR Disorganized development of cartilaginous and fibrous components of the skeleton Dysplasia epiphysealis hemimelica Sp Multiple cartilaginous exostoses (three types) AD .

.

.

.

Enchondromatosis (Oilier) Enchondromatosis with hemangiomata (Maffucci) Spondyloendochondromatosis Spondyloendochondromatosis with basal ganglia calcification Dysspondyloenchondromatosis Metachondromatosis Osteoglophonic dysplasia Genochondromatosis Carpotarsal osteochondromatosis Fibrous dysplasia (Jaffe-Campanucci) Fibrous dysplasia (McCune-Albright) Fibrodysplasia ossificans progressiva Cherubism Cherubism with gingival fibromatosis 31. Osteolyses Multicentric predominantly carpal and tarsal a. Multicentric carpal-tarsal osteolysis with and without nephropathy b. Shinohara carpal-tarsal osteolysis Multicentric predominantly carpal, tarsal, and interphalangeal a. Francois syndrome b. Winchester syndrome c. Torg syndrome Whyte Hemingway carpal-tarsal phalangeal osteolyses Predominantly distal phalanges a. Hadju-Cheney syndrome b. Giacci familial neurogenic acro-osteolysis c. Mandibulo acral syndrome Predominantly involving diaphyses and metaphyses a. Familial expansile osteolysis b. Juvenile hyaline fibromatosis 32. Patella dysplasias Nail patella dysplasia Scyphopatellar dysplasia

Sp Sp AR AR

AD AD AD AD Sp AD AD AR

AD

AR AR AR AD

AD AR AR

AD AR AD AD

.

aModified from International Nomenclature and Classification of the Osteochondrodysplasias (1997) Am J Med Genet 79:376-382. bAR, autosomal recessive; AD, autosomal dominant; XLD, X-linked dominant; XLR, X-linked recessive; Sp, sporadic.

development as a cylindrization process. Abnormal bone modeling was a process characterized by (1) amplification, in which "the bone showing the greatest growth potential will show the greatest change, since it will magnify the same defect to a greater degree," (2) polarity, which defines the maximal direction of longitudinal growth because tubular bones grow in a differential pattern, one end predominating over the other, and (3) changes, which occur over time. The development of changes with time was delineated clinically by congenita and tarda variants. His work is valuable because of efforts to understand the complex patterning of bone formation and to explain developmental bone disease by localizing change to specific areas. Its main fault is the

rigid categorization of every disorder into a framework, which is accurate only for some. A difficulty in radiologic categorization now becoming apparent with the increase in reported syndromes is the fact that many disorders, including those defined by regional terms, affect adjacent areas radiographically and, if not apparent radiographically, must affect them nevertheless. Disorders defined as metaphyseal dysplasias must affect the physes if they are short stature syndromes. Efforts to encompass epiphyseal and metaphyseal involvement utilize terms such as spondyloeipmetaphyseal dysplasias, although the disorder pseudo-achondroplasia also involves each of the three areas. It appears that the limits of radiographic nosology

738

CHAPTER 9 9

Skeletal Dysplasias

have been reached and could benefit from simplification, although observations of extent and position of involvement in any individual case are essential for the patient involved. Bailey approached classification of short stature conditions by simplifying and concentrating on clinical anatomic features (8). Group 1 was disproportionate, absolutely short patients, group 2 was a spectrum group with a wide range of variability in stature and body proportions, and group 3 included proportionate short stature patients, the vast majority of which represent primary nonosseous problems with the bones shortened secondarily due to systemic growth failure. The current all-inclusive classification system is the International Classification of Osteochondrodysplasias defined initially by an international working group on bone dysplasias in 1972 and 1992 (17) and revised most recently in 1997 and published in 1998 (Table I) (262). The osteochondrodysplasias were divided into three groups in the 1992 classification: group A, defects of the tubular (and flat) bones and/or axial skeleton, 24 sections; group B, disorganized development of cartilaginous and fibrous components of the skeleton; and group C, idiopathic osteolyses. In the most recent version, the overall alignment of groups has been retained but the A, B, and C subdivisions have been eliminated. The classification represents an attempt to be all-inclusive, defining the disorders by using clinical and radiographic frames of reference. Over 150 disorders, not including some subtypes, are listed. This classification seeks to define disorders in which the skeletal system is involved either primarily or at least extensively. Though admirably complete it is obviously unwieldy clinically. Virtually all classifications attempted are either too brief to be definitive or so extensive that they cannot be used as clinical tools. Furthermore, any classification using solitary criteria, by which is meant clinical or radiographic or even molecular-genetic findings, invariably seems to lump diverse entities together or place similar entities in differing groups. It also is important to recognize that bone, joint, and limb malformations are present in an even larger number of developmental abnormality syndromes (95). A widely referred to compendium listing essentially all dysmorphic syndromes, Smith's Recognizable Patterns of Human Malformation, notes over 450 syndromes with a large number of disorders even beyond the intemational listing with minimal to severe skeletal involvement, such as facial bone abnormalities, hand and foot abnormalities, limb length alterations, vertebral structural defects with or without kyphoscoliosis, and joint region malformations such as hip dislocation, clubfoot, and elbow contractures (140). Elucidation of the underlying chromosomal, genetic, and molecular abnormalities is leading to more fundamental definitions of skeletal dysplasia and multiorgan dysmorphic disorders and to an evolving change in classification. Our approach considers several general criteria to be of importance in assessing a patient with a skeletal dysplasia (Table II).

lII. P R E V A L E N C E O F SKELETAL DYSPLASIAS In spite of the fact that several dysplastic syndromes have been identified, relatively few of the disorders still account for the majority of cases. These will differ in various areas throughout the world, but data from Europe, North America, and South Africa are roughly comparable. A study by Wynne-Davies and Gormley assessed individuals with skeletal dysplasias in Scotland, England, and Wales over a 30-year period (371). They were able to document 4383 patients with a skeletal dysplasia. The most common disorder, similar to a South African survey described later, was osteogenesis imperfecta involving 859 patients (19.6%). The next groups in frequency were those with a multiple epiphyseal dysplasia, 588 patients (13.4%); hereditary multiple extososis (diaphyseal aclasis), 452 (10.3%); spondyloepiphyseal dysplasia tarda, 406 (9.3%); achondroplasia, 226 (5.2%); pseudo-achondroplasia, 226 (5.2%); spondyloepiphyseal dysplasia congenita, 181 (4.1%); dyschondrosteosis, 181 (4.1%); and metaphyseal and spondylochondrodysplasias 181 (4.1%). These nine disorders represented 75.3% of the diagnosed skeletal dysplasias. In South Africa, a national skeletal dysplasia registry documented 1270 chondrodysplasias and indicated the number of patients seen in each disorder (16). The most common group, encompassing almost 27% of all disorders, was osteogenesis imperfecta with most of these type I or type III and a relatively small number of type II patients. The next most common groups involved those with achondroplasia, 8.6% of all patients (109 with achondroplasia, 21 with hypochondroplasia, and 15 with thanatophoric dysplasia), cleidocranial dysplasia 4.3%, sclerosteosis 6.4%, SED congenita 3.7%, pseudo-achondroplasia 3.6%, and multiple epiphyseal dysplasia 3.3%. In Finland, the most common skeletal dysplasia is diastrophic dysplasia (342).

IV. D I A G N O S I S O F SKELETAL DYSPLASIAS

A. Overview There are both lethal and nonlethal types of skeletal dysplasias. Many of the disorders now can be diagnosed prenatally by ultrasonography. All of the lethal disorders reach clinical awareness in the perinatal period. Some nonlethal conditions can be diagnosed clinically and radiographically at birth, whereas others do not manifest themselves for several months or years (295). Conditions that can be diagnosed at birth include achondroplasia, diastrophic dysplasia, Kniest syndrome, spondyloepiphyseal dysplasia congenita, cleidocranial dysplasia, chondrodysplasia punctata, metatropic

SECTION IV ~ Diagnosis of Skeletal Dysplasias TABLE II

Basic Considerations in Assessment o f a Skeletal Dysplasia Patient

1. Short stature

2. Disproportion a. Disproportionate short stature re extremity-trunk relationship

b. Disproportionate involvement within an extremity

3. Lethal-nonlethal

4. Classification criteria a. Clinical criteria b. Radiographic criteria

c. Genetic-molecular criteria d. Histopathologic criteria 5. Orthopedic considerations a. Spinal deformity

b. Neurological sequelae of spinal deformity

c. Upper-lower extremity deformity

d. Short stature

739

May not be fully established by reference to growth charts until 1 year of age Absolute: below 3rd percentile; Femoral Neck to Joint Cavity

___>

Femoral Head j to Joint C a v i t ~

y2 The long-termeffects of an acute neonatal-infantile osteomyelitis of the proximal and distal epiphyseal-metaphysealregions of the femur are shown.

FIGURE 9

infancy, neonatal involvement of the distal femoral epiphysis and knee joint, and sepsis of other growth regions. Definitive awareness of the problems of neonatal osteomyelitis in relation to epiphyseal damage accumulated only gradually. Prior to the development of antibiotics, neonatal osteomyelitis, by which is meant infection in the first 4 weeks of life, frequently resulted in death due to the severity of spread and frequent multibone involvement (10, 20, 79). Green and Shannon noted, however, in their series of infants with osteomyelitis under 2 years of age published in 1936, that there had been joint involvement in all but one instance in which there was eventual residual deformity (79). Weissberg et al. studied 17 infants, 1-28 days of age, with osteomyelitis and noted that joint involvement was present in 12 of the 17 and that eventually bone deformity was present in 10 patients, most with a significant functional deficit (225). In 14 of the 17 infants, the illness was not accompanied by systemic signs or symptoms and delay in diagnosis was usually seen because help was not sought until local signs became apparent. These involved swelling, discomfort, and

899

900

CHAPTER 10 ~ Metabolic, Inflammatory, Neoplastic, Infectious, and Hemaroloyic Disorders

The presence of transphyseal vessels in the human as a remnant of epiphyseal development remains somewhat poorly documented. There is considerable variability throughout vertebrates in terms of the persistence of these vessels. They are only infrequently seen in murine species and the rabbit but are commonly seen in the pig and lamb even several months after birth. Such vessels have been documented commonly in humans and other species in the late fetal and early postnatal time periods (186). The damage done to the epiphyseal apparatus of the femoral capital epiphysis by infection can be extensive and can occur rapidly over several hours to a few days in childhood septic arthritis of the hip. Diagnosis is frequently delayed for several days in those children affected in the first few months of life because they almost always are afebrile with little tendency to leukocytosis or elevated ESR values. The most common mode of presentation in this age group is listlessness and decreased use of the extremity on the involved side, referred to by some as "pseudo-paralysis." A study separated those having the disorder from 0 to 4 weeks of age from those from 1 to 3 years of age. The prognosis was clearly worse in the younger age group and also in those associated with osteomyelitis of the proximal femur. In a preantibiotic era 1936 study, Badgely reported a 12% mortality rate in septic arthritis of the hip with only 6.2% having normal hips (10). Blanche studied osteomyelitis in the first year of life in 25 patients in whom a bacteriologic diagnosis had been made between the years 1934 and 1950 (20). The age range was from 14 days to 9.5 months, but 23 of the 25 were seen within the first 2 months of life, 13 under 1 month of age, and 10 from 1 to 2 months of age. Many patients had no fever at all and the systemic temperature was rarely over 100~ Local symptoms predominated involving swelling, loss of function of an extremity, and discomfort with movement. In the 25 patients, 13 had a single focus of infection and 12 had multiple foci. The femur was the most common site by far with 22 of 50 known lesions present there. The next most common bone involved was the humerus with 7 followed by the tibia with 5 and lesser involvement of other bones. Proximal involvement of the femur was seen in 16, and of these there was an associated septic arthritis of the hip in 11 cases. Distal femoral involvement was frequently associated with growth damage to the distal physis and epiphysis. Intra-articular infection rapidly destroyed the cartilage and frequently caused disruption of the joint, pathological dislocation, and serious proximal femoral growth disturbances. The primary prognostic feature in terms of ultimate normal development and function is the quickness with which treatment is instituted. In the study, 16 neonates were affected from 0 to 4 weeks of age, of whom 11 were premature. In 14 of the 16 patients, the septic arthritis was secondary to an osteomyelitis close to the joint, with 10 patients having primary osteomyelitis of the femoral neck and

the other an osteomyelitis of the acetabulum. In the second group of 13 children affected between 1 month and 3 years of age, negative sequelae were secondary to avascular necrosis of the femoral head along with lytic damage of the articular cartilage, bone, and physeal cartilage. The greater trochanter appears to be relatively spared. Hallel and Salvatti defined results into three groups following septic arthritis of the hip in infancy (84). In group 1 there was a normal femoral head or a head only mildly deformed with a coxa magna. In group 2 there was a deformed small head-neck component with varus malposition. In group 3, there was complete absence of the head and neck due to lytic destruction. The femoral head may be in normal position, subluxed, or dislocated. Major predisposing features of neonatal septic arthritis were an indwelling umbilical catheter, prematurity, and septicemia. The earlier treatment began, the better the result. Treatment involves open arthrotomy combined with intravenous antibiotic coverage and maintenance of the hip in the reduced position using either a hip spica or Pavlik harness during the healing phase. Major negative sequelae from neonatal hip sepsis continue to be seen. Vidigal and Jacomo reported on 14 neonates with septic arthritis of the hip who had been diagnosed late, meaning that diagnosis was made and surgical drainage was carded out more than 4 days after the onset of symptoms with an average delay of 9 days (223). The age of their patients at admission averaged 17 days, with a range between 9 and 30 days. In 11 of the cases, the organism was staphylococcus aureus with one each of staphylococcus albus, enterobacter, and streptococcus hemolyticus. Radiographic features at the time of diagnosis include a normal appearance in a few, but often subluxation, dislocation, and dislocation with periosteal elevation of the proximal femur (associated osteomyelitis) or lysis of the acetabulum (osteomyelitis). Only one hip was normal at follow-up. Three patients died. The radiographic features of the femoral head seen after long-term follow-up for neonatal septic arthritis involved 7 in which the femoral head was destroyed and dislocated, 2 in which it was deformed and subluxated, 2 in which it was subluxated, 1 in which it was deformed and dislocated, 1 in which there was avascular necrosis and subluxation, and 1 that was normal.

b. Negative Growth Sequelae Following Septic Arthritis of the Hip A study by Choi et al. evaluated residual deformity and late treatment of 34 hips in 31 children who had septic arthritis when they were less than 1 year of age (36). They evolved a classification of the sequelae into four types, which incorporates well observations made over several decades including those of Hunka et al. (93). The end responses can be extremely variable due to the time that diagnosis is made, the age of the patient, and the type and effectiveness of the initial treatment used. The classification of the sequelae is illustrated in Fig. 10 and listed in Table III. An example of a damaged proximal femur is shown in Fig. 11.

SECTION IV ~ Osteomyelitis and Septic Arthritis

TABLE III

Type IA IB IIA IIB IIIA IIIB IVA IVB

FIGURE 10 The classification of the sequelae of septic arthritis of the hip in infancy developed by Choi et al. is shown. [Reprinted from (36), with permission.]

c. Treatment Approaches The long-term sequelae of septic arthritis of the hip can be extremely severe so that aggressive therapy is needed once the diagnosis is suspected. Open arthrotomy is preferable to joint aspiration for the hip. Arthrotomy releases intra-articular pressure, provides a channel through which subsequently developing pus can automatically escape, and allows for accurate bacteriological diagnosis. Maintenance of the femoral head in the fully reduced position within the acetabulum by hip spica immobilization minimizes the likelihood of a septic dislocation. Intravenous high-dose antibiotics are used to clear osseus and soft tissue infection. Treatments of the long-term sequelae have been described in several reports (10, 18, 34, 36, 59, 62, 123) and are outlined in Table IV.

901

Classification o f S e q u e l a e : Septic Arthritis o f t h e Hip in Infancy (Choi et al.) Sequelae

No residual deformity Mild coxa magna Coxa breva with deformed head Progressive coxa vara-valga Slipping of femoral neck with severe anteversion or retroversion Pseudarthrosis of femoral neck Destruction of femoral head and neck with small medial remnant of the neck Complete loss of femoral head and neck and no articulation of the hip

severe disability (197). Smith differentiated what he referred to as the "acute arthritis of infants" from any of the other recognized joint affections of childhood. The disorder occurs "in the first year of life and is characterized by the suddenness of its onset and the rapidity of its progress and termination." He concluded that "it is very dangerous to life and intensely destructive to the articular ends of the bones which of course at this period of life are largely cartilaginous." The disease "rarely produces anchylosis but leaves a child with a limb shortened by loss of part of the articular end of some bone and with a weakened flail-like joint." Smith's 21 cases all occurred within the first year of life with 8 in infants under 1 month of age and 19 of 21 under 6 months of age. The disease first attacked at the hip, shoulder, or knee and in the absence of effective treatment often involved more than one joint. At postmortem examination, he "found in all instances a considerable and rapid loss of substance in the articular end of one of the long bones entering into the joint affected." In some, the absorption or ulceration proceeded from the joint surface toward the deeper parts, whereas in others the destruction of tissue had commenced in an abscess

d. Pathoanatomy of Septic Arthritis of the Hip of Infancy Septic arthritis of the hip in infancy was referred to for many decades as Tom Smith disease after Smith's article in 1874 on acute arthritis in infants in which he described 21 patients, 13 of whom died and 8 of whom healed with

FIGURE 11 Radiographicexample of damage caused by neonatal septic arthritis of the hip. The head has been destroyed almost completely, the neck is short and wide, and greater trochanter overgrowth is marked.

CHAPTER 10 ~ Metabolic, Inflammatory, Neoplastic, Infectious, and Hematologic Disorders

902

TABLE IV Late Operative T r e a t m e n t s for Severe Sequelae o f Infantile Septic Arthritis of the Hip a ,,

1. Excision of damaged femoral head a. For necrotic, completely separated femoral head lying free in joint (septic epiphysiolysis) b. To remove projections and allow for repositioning procedures 2. Adductor-iliopsoas tenotomies a. For adduction, flexion contractures 3. Open reduction a. Femoral head into acetabulum, after septic pathologic dislocation b. Femoral neck into acetabulum, after severe head destruction c. Greater trochanter into acetabulum, trochanteric arthroplasty 4. Greater trochanteric interventions a. Trochanteric arthroplasty (see 3c) b. Distal transfer of greater trochanter c. Greater trochanteric epiphyseal arrest, all to increase hip stabilization, minimize Trendelenburg gait 5. Proximal femoral osteotomy a. Varus osteotomy, following lateral subluxation or partial premature lateral physeal closure b. Valgus osteotomy, to better position head into acetabulum following complete or medial premature physeal closure with persisting trochanteric growth, to support and align lower extremity in relation to the hip joint, disregarding shape and position of head but correcting the adduction position of femur c. Extension-derotation osteotomy, to correct additional deformities sometimes present with a or b 6. Acetabuloplasty a. Shelf, Pemberton, Salter, Chairi, other 7. Epiphyseal arrest a. For lower extremity length discrepancy b. Contralateral distal femur with or without proximal tibia 8. Ipsilateral tibial lengthening a. For lower extremity length discrepancy b. Femoral lengthening rarely done because of hip instability 9. Contralateral femoral shortening a. For severe lower extremity length discrepancy 10. Bone graft for proximal femoral pseudarthrosis a. Often accompanied by osteotomy 11. Hip arthrodesis a. For painful, unstable hip not amenable to preceding approaches ,,

,,

................................

aDerived from 10, 18, 36, 59, 62, 84, 93, and 123.

within the articular end of the bone, which then progressed outward. This often leaked into the joint by a small opening near the margin of the articular cartilage. Smith defined the term subarticular abscess referring to abscess cavities formed beneath the articular cartilage in either the cartilaginous or osseous structure of the end of the bone. He stressed that "in

many cases, the formation of a subarticular abscess in the bone must have been the first step in the joint affection since while the articular end of the bone was extensively excavated, the aperture through which the abscess had burst into the joint was a mere pinhole and though the joint contained pus, the articular cartilage was apparently healthy." Smith's description of the pathoanatomic findings remains valid today and underscores the need for rapid, accurate diagnosis and treatment. A brief summary of his descriptive findings at postmortem in several cases of septic arthritis of the hip follows. Case 3: The head and part of the neck of the fight femur were removed completely by ulceration, giving the appearance of destruction proceeding from the articular surface to the deeper part of the bone. In the opposite left hip, however, the process of destruction appeared to begin within the bone and pass toward the joint surface where the end of the bone contained a well-defined subarticular abscess opening by a small hole in the joint. The fight hip was filled with pus, the synovial membrane was thickened and vascular, the capsular ligament was perforated by abscess, there was no ligamentum teres, and the head of the femur had been completely removed. All of the acetabular cartilage had been destroyed. The left hip also contained pus, but the synovial membrane, articular cartilage, and ligaments appeared healthy. There was a small ragged hole at the margin of the articular cartilage, which led by a narrow sinus into a well-defined abscess cavity containing pus. This was situated partly in the ossifying cartilage and partly in the cancellous bone. Case 4: A huge right thigh abscess led to death 18 days after the patient presented for medical care. The fight hip joint was full of pus. The ligamentum teres had disappeared, the capsular ligament had ulcerated, the rim of the acetabulum was destroyed by ulceration, the synovial membrane was thickened and vascular, and the head and neck of the femur had disappeared completely. Case 5: There was left hip joint swelling and discomfort with an abscess found in the hip joint at postmortem. The ligamentum teres had disappeared, the capsule was opened by ulceration, the cartilage of the acetabulum totally was destroyed in places, and the head of the femur was absorbed, having lost approximately two-thirds of its structure. Case 6: The left hip was full of pus, the ligamentum teres had given way, and the cartilage, though intact, had lost its pearly appearance. Case 8: A patient, aged 7 weeks at presentation, died 6 weeks after the onset of symptoms with a fight hip abscess. Postmortem examination showed the synovium in the fight hip joint to be swollen and vascular, the ligamentum teres had disappeared, approximately one-fourth of the head of the femur had been resorbed, and the articular surface was covered with punctate ulcerations. One of the small ulcers passed through a minute sinus to a cavity in the cancellous bone just beneath the ossifying cartilage. This cavity, which was approximately 1 in. in its longest diameter was lined by

SECTION IV 9 Osteomyelitis and Septic Arthritis

a thick false membrane. The osseous nucleus and the cartilaginous head of the bone were similarly excavated and communicated by a pinhole opening in the articular cartilage with the cavity of the joint. The acetabulum was shallow, widened laterally with its sharp edge absorbed, and its cartilage gone. Case 9: There was a fight hip abscess with the hip joint full of pus. The capsule was widely opened by ulceration. The ligamentum teres had disappeared, and the acetabulum was denuded of cartilage. The head and upper part of the neck of the femur had been completely absorbed. Smith indicated, however, "that many children not only survive the attack, but recover with useful joints." His case 14 describes a 6-month-old female who developed a left hip abscess, which drained itself spontaneously. At 6 years of age, there was 1.5-2 in. of shortening, the thigh muscles were smaller, and the limb was everted in walking and somewhat flail. What remained of the head of the femur was dislocated and easily mobile. Smith described other cases with survival and reasonable function, although rarely with a normal joint. The problems were related to shortening, multiple scars where the abscesses had drained either spontaneously or by surgical intervention, tendency to a dislocated or dislocatable head of the femur, movements of the joint that were abnormally free, and considerable limping. 2. DISTURBED DISTAL FEMORAL EPIPHYSEAL GROWTH AFTER INFANTILE OSTEOMYELITIS

Although it has been recognized for a long time that infection in infancy can lead to negative growth sequelae of the bones, more recent studies of the pathoanatomy and clinical characteristics of the damage done have appeared. The vital anatomic finding underlying the possible spread of metaphyseal osteomyelitis through the physis and into the epiphysis directly in the newborn period is the persistence of transphyseal vessels during this time frame. These have been extensively documented in virtually all species with concentration in the fetal period and persistence for several months to years following birth. Neonatal osteomyelitis thus can damage epiphyses directly at the proximal femur as noted in the previous section and also in other large physes, with the two most commonly affected being the distal femur and proximal humerus. Infection at the distal femur has the next greatest tendency after the proximal femur to lead to major growth complications. Ogden and Lister performed a histopathological study of hip, shoulder, and knee from a child who died at 27 days of age in association with multifocal osteomyelitis (145). Studies of the distal femur epiphysis demonstrated severe destruction. Infectious material had led to a complete physeal separation. Metaphyseal trabecular bone was clearly affected and was being destroyed. The distal femoral growth plate had been completely destroyed and the hyaline cartilage of the epiphysis was being diffusely invaded. Serial sections demonstrated an inflammatory exudate that could be traced along the cartilage canals from the

903

metaphysis through the physis into the secondary ossification center of the epiphysis. The trabecular bone in the secondary ossification center was also being destroyed by the inflammatory process. Examples of distal femoral epiphyseal damage following neonatal infection were also reported by Banks et al. (13) and Halbstein (83). A study by Bergdahl et al. documented that neonatal osteomyelitis led to a high rate of negative long-term sequelae (17). Particular risk factors include large vessel and umbilical catheterization, a gestational age of less than 37 weeks or birth weight of less than 2500 g, and more generalized indications of systemic illness such as the respiratory distress syndrome, hyperbilirubinemia, perinatal asphyxia, and the need for an emergency Cesarean section. In the study of 40 patients with 71 sites of infection, the most commonly involved regions were the knee in 19 (27%), the hip in 17 (24%), the shoulder in 9 (13%), and the ankle in 6 (8%). Essentially any joint can be involved, but these four accounted for the highest involvement. Roberts pointed out that papers discussing osteomyelitis of the long bones in infancy in the preantibiotic era stressed high mortality, whereas information analyzed subsequent to that noted diminished mortality but increasing episodes of disturbed epiphyseal growth (167). He clarified the severity of growth problems at the knee with a study of 14 children who had bone infection present within 6 weeks of birth. One patient presented at 3 months. In 13 the distal femur was involved, whereas in only 2 was damage seen at the upper tibia. Multisite involvement of two or more sites was noted in 5 of the 15 patients. In spite of seemingly adequate treatment, growth sequelae were seen in virtually all instances. Major problems involved shortening, which was present in all, and angular deformity, which was present in most. Instability of the joint and diminution in the range of movement were seen frequently as well. Two major points are noted with neonatal infection in relation to the appearance of the epiphyses. (1) There is often considerable lysis followed by a delay in formation of the secondary ossification center particularly of the distal femoral epiphysis. Many have commented that the radiographic damage often looks greater than subsequent films at skeletal maturity indicate. The crucial factor is thus not the bony presence of the secondary ossification center but the presence, viability, and structure of the cartilage mass of the entire epiphysis. It is not infrequent after an infection that reossification occurs several years after the normal pattern if the cartilage model has managed to survive that. Often there is indication of the presence of the cartilage model based on the range of motion and function of the joint. At present this can be readily determined either by arthrography or by magnetic resonance imaging. (2) Growth may continue in a relatively normal fashion for several years after the infectious insult but then slow down well before skeletal maturation, leading to further shortening and angular deformity over the final years of growth. These patients should thus be followed to skeletal maturation. It is rare for the entire physis and

904

CHAPTER IO ~ Metabolic, Inflammatory, Neoplastic, Infectious, and Hematologic Disorders

epiphysis to be completely destroyed and corrective surgery and limb lengthening should lead to a reasonably functioning knee at skeletal maturity. Due to the fact that most of the growth of the lower extremity occurs at the knee the amount of shortening can be extensive. In Robert's series several patients had discrepancies between 10 and 14 cm, with many from 5 to 9 cm shorter on the involved side. Langenskiold reported several cases of growth disturbance of the distal femur after neonatal osteomyelitis (117). His cases also had onset of infection between 10 days and 4 weeks. The medial epiphysis was affected in 3 cases and the lateral in 4. The disorder led to partial closure of the growth plate seen in a range from 6 to 12 years of age. Growth and subsequent damage of the epiphysis were unpredictable on the basis of plain radiographic findings particularly during infancy and the early years of life. The maximum shortening documented by Langenskiold was variable depending on the nature of the involvement and ranged from 3 to as great as 19 cm. 3. SEPTIC ARTHRITIS OF JOINTS OTHER THAN THE HIP AND THEIR SEQUELAE IN RELATION TO EPIPHYSEAL DEVELOPMENT

In a large study of 102 cases of septic arthritis of childhood, the hip was most commonly affected both in the 0to 3-year-old age group and in the 3 years and older group (70). There were 42 joints involved in the 0- to 3-yearold group: hip, 18/42 or 43%; knee, 15/42 or 35%; ankle, 5/42 or 12%; wrist, 2/42 or 5%; and shoulder 1, elbow 1, 2% each. The same distribution continued in the older age group. a. Knee After the hip the next most frequently involved joint is the knee. Smith described the effects of septic arthritis of the knee in infancy as defined at postmortem examination (197). The medial condyle of the femur was involved with "a large ragged hole in the cartilage of the internal condyle, large enough to admit one's finger; this led into a deep excavated cavity in the bone and ossifying cartilage; this cavity occupied a large part of the articular part of the femur of which little remained but the shell." In another case, both knees were involved. Postmortem examination on the right showed the joint to be partially ankylosed and the synovial membrane thickened and of a pinkish color. The opposing surfaces of tibia and femur were firmly adherent by infected granulation tissue and "could not be separated by tearing." The articular surface of the femur was deeply excavated by ulceration. On hemisection, there was a small, circular cavity within the cartilaginous end of the femur, which led by a pinhole sinus through the condyle into the joint. The opposite knee was filled with pus. The synovial membrane was thickened and vascular, and the cartilage surface of the femur was irregularly absorbed to a depth of 0.5 in. or more. There was a fold on the anterior surface of the lateral condyle 0.25 in. wide and 0.5 in. deep lined by vascular tissue. Hemisection showed a cavity in the lower

end of the femur partly in the bony secondary center and partly in the ossifying cartilage. Septic arthritis of the knee continues to be described today. The distal femur suffers more growth-related sequelae than the proximal tibia. Angular deformities due to partial distal femoral physeal destruction are far more common than complete symmetric growth cessation. The most damaging growth sequelae continue to follow neonatal sepsis and to a lesser extent in those affected within the first 2 years of life. After this time, the tendency toward earlier diagnosis and more effective treatment minimize the negative sequelae. A large study of 96 septic knees in childhood demonstrated far more serious growth sequelae in patients who were 24 months of age or younger at the time of diagnosis (208). In 50 knees assessed in detail in those within 2 years of age, 26 had no deformity at follow-up and 24 did. Fifteen had a varus deformity averaging 14~ (range = 5-30~ and 9 were in valgus with an average of 22 ~ and a range from 5 to 40 ~ Seventeen of the knees had flexion contractures averaging 12~ with a range of 5-25 ~ Central growth retardation of the distal femoral physis was noted in almost every case in which metaphyseal changes were accompanied by deformity. The secondary ossification center was also delayed in appearance, or if present was partially lysed. The tibia was affected less often and less severely than the femur. b. Shoulder A shoulder septic arthritis was described by Smith with pus in the joint (197). The cartilage over the glenoid cavity had disappeared and the bone beneath was roughened. The head of the humerus was wasted, ulcerated, and deformed by absorption on hemisection. An irregular cavity was exposed between the ossifying cartilage and the shaft of the bone. Examples of septic arthritis of the shoulder with longterm sequelae continue to be described. A large series from Poland indicated that, in their referral hospital, 18% of septic joints of childhood were at the shoulder (120). In a review of 46 septic shoulders in 42 patients less than 18 months of age who were followed for an average of slightly under 7 years, only 7% of the humeral heads were entirely normal radiographically. Although length discrepancies did occur, the mean amount of shortening was only 2.4 cm after several years, but 1 patient experienced a 9-cm shortening. There were few complaints about the length either from functional or from cosmetic viewpoints. The initial appearance of the secondary ossification centers in the humeral head was slowed by infection, whereas in those patients in whom they were already present at the time of infection they usually disappeared for months to years. There was no specific pattern to the negative sequelae that occurred. There was a continuum of distortion of the shape of the humeral head from normal to knoblike, with various amounts of flattening, reorientation of the tilt of the head, and degrees of forking or saddling of the epiphysis. Schmidt et al. reviewed 9 children diagnosed with septic arthritis of the shoulder (180). Eight of the 9 were under

SECTION IV ~ Osteomyelitis and Septic Arthritis

18 months of age at the time of diagnosis. Involvement was felt to be due to transphyseal spread from metaphyseal vessels, secondary to metaphyseal perforation into an intraarticular part of the joint, and from the bicipital synovial sheath, which can be affected and which passes over the joint. Growth sequelae were relatively rare and all patients developed a satisfactory, pain-free range of motion. Even if varus of the proximal humerus and some shortening occur, these rarely present the clinical difficulties inherent with similar lower extremity damage. c. Wrist Septic arthritis of the wrist is extremely rare but can, on occasion, lead to negative growth sequelae (209). Damage can involve lysis of the secondary ossification center and destruction of all or part of the radial growth plate. d.

Long-Term Sequelae of Childhood Septic Arthritis

Involvement of major joints other than the hip with septic arthritis, particularly the knee, shoulder, and ankle, after the first year of life is due primarily to direct joint involvement rather than through spread from metaphyseal loci and transphyseal to epiphyseal spread. The physes are extracapsular, and transphyseal vessels in the human postnatal age group are infrequently documented after 1 year of age. There also is a tendency for septic arthritis in these joints to be diagnosed sooner than in the hip because they are more superficial and swelling and redness are more readily seen. After sepsis within the first 2 years of life particularly, even if it appears to have been treated effectively, it remains important to follow the growth pattern for several years and to skeletal maturity if possible. Peters et al. assessed several cases of neonatal joint sepsis other than the hip in which growth sequelae were not apparent for several years (154). It was often not clear retrospectively whether the damage resulted from a metaphyseal osteomyelitis or a primary septic arthritis. Four distal femurs suffered growth sequelae with partial growth plate arrest, leading to shortening and valgus deformation. There were four proximal humeral deformities, all varus, one distal radial shortening with ulnar prominence, and one distal humeral shortening. Growth plate arrest following sepsis often extended beyond the area of bone bridging, with the adjacent physeal tissue being fibrous rather than cartilaginous. Gillespie has analyzed cases of septic arthritis of major joints in childhood in terms of residual disability (70). In the hip, 17 of 41 cases (41%) had an unsatisfactory result, in the ankle, 2 of 13 cases (15%) were unsatisfactory, and in the knee, only 3 of 37 cases (8%) were unsatisfactory. Long-term assessment is also important because of the potential for radiographic improvement of the involved epiphyseal region several months to years after the infection. There is often lysis of the bone of the secondary ossification center and/or the adjacent metaphysis even though the cartilage model is intact. The infection can cause necrosis of bone with subsequent reabsorption but delayed new bone formation. In younger epiphyses in which the secondary center has not yet formed, vascular damage can lead to a marked delay

905

in formation of the center, but the cartilage model can continue to grow. Studies to assess the cartilaginous structure of an epiphyseal region using either arthrography or MR imaging are essential to assess growth potential when bone deficiency is seen by plain radiography.

D. Summary of Effects of Epiphyseal and Metaphyseal Infection on Epiphyseal Growth The three possible growth effects of juxtaepiphyseal pyogenic infections are stimulation of growth, retardation of growth, and angular deformity (189). The nature and extent of lower extremity length discrepancies in relation to septic arthritis of the hip and osteomyelitis of growing bones are summarized here and reviewed in greater depth in Chapter 8. 1. OSTEOMYELITIS

Overgrowth of a long bone that is the site of osteomyelitis was found in 18 of 35 patients (21%) in Wilson and McKeever's series (232). This almost always occurred when the osteomyelitis was metaphyseal and damage to the physis had not occurred. Trueta and Morgan (217) stated that overgrowth following osteomyelitis lasts until medullary recanalization occurs by which time the sequestra would have been resorbed and a normal vascular pattern would have been reestablished. The maximum overgrowth was 2.0 cm, but most patients had only a few millimeters. In chronic recurrent osteomyelitis of childhood, however, overgrowth will persist. When an infection is localized eccentrically beneath the epiphyseal plate, then growth stimulation can also be asymmetric and angular deformities may occur. The same percentage of patients had growth retardation when chronic infection damaged the physis. In the modem era, diagnosis of metaphyseal hematogenous osteomyelitis within a few days of onset followed by intravenous antibiotics and transcortical decompression drilling, if needed, has led to rapid cure, and growth sequelae are now encountered much less frequently. 2. SEPTIC ARTHRITIS OF THE HIP

Damage to the femoral capital epiphysis in septic arthritis can produce serious length discrepancies. In our series, such discrepancies tended to increase with time, but a type I pattern was seen in only 42% of the patients and most commonly when the infection had occurred relatively late, after the age of 7 or 8 years (185). An assessment of pattern development in this group was obscured somewhat more often than in other groups because of the necessity for early and often for frequent surgical intervention, although femoral osteotomy per se was performed only infrequently in growing children. Even with complete destruction of the physis, however, femoral shortening did not invariably become worse with time, particularly in the younger patients. When the greater trochanter overtakes the involved femoral head in height, the femur resumes a somewhat more regular growth pattern

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CHAPTER 10 9 Metabolic, Inflammatory, Neoplastic, Infectious, and Hematologic Disorders

because the greater trochanter and distal femoral physes are normal, thus accounting for the type II and III patterns seen. Studies of growth sequelae of septic arthritis of the hip of infancy by Betz et al. (18), Choi et al. (36), and Hallel and Salvati (84) documented mean length discrepancies of 3 3.5 cm from injury to the proximal femoral growth plate and an additional 2.5 cm if there was hip instability. The type IV growth pattern was limited almost exclusively to abnormalities of the proximal end of the femur such as occur with septic arthritis of the hip. In patients in whom damage was relatively mild, premature fusion of the proximal femoral capital physis has been noted years after the infectious insult. The premature fusion can be detected 2 or 3 years prior to skeletal maturation by the progressive change in the relationship of the level of the greater trochanteric physis to that of the proximal femoral capital physis. It is, therefore, extremely important to continue periodic assessment of these children by carefully monitoring the relationship of the head and neck to the greater trochanter until skeletal maturity, even if the discrepancy has been in a plateau phase for several years. Although the average increase in the late phase was only approximately 1 cm, this amount can convert a clinically insignificant discrepancy into one of 2.5 cm or more and thus warrants special consideration.

E. Tuberculosis 1. OVERVIEW Skeletal tuberculosis in the growing child commonly affects the spine and the epiphyseal regions of major long bones, where it presents as a combined epiphyseal osteomyelitis and septic arthritis (97). This disorder was particularly common until it became better controlled due to advances beginning early in the twentieth century, which involved the discovery of the tubercle bacillus by Koch, recognition of the spread of the disorder in association with poor living conditions involving crowded and unsanitary housing, and the discovery of effective antibiotic treatment initially involving streptomycin, isoniazid, and p-aminosalicylic acid. It is still seen in many regions of the world and even in relatively advanced industrial nations, particularly in children with other debilitating disorders. There has been a worrisome resurgence of tuberculosis over the past two decades partly due to increased drug resistance and HIVpositive and AIDS disorders. It has been estimated that there are over 1.3 million infected children globally under the age of 15 years. Approximately 1% of cases of tuberculosis have skeletal involvement. The spine is most commonly affected in childhood skeletal tuberculosis followed by the hip and knee joints (3, 97, 102, 110, 190, 218, 230, 231). In a review of 219 patients with skeletal tuberculosis in Malaysia seen between 1968 and 1976, the disorder was spread almost evenly over several age groups from the first to the sixth decade (190). From birth to age 19 years there were 67 patients (31%), and the

spine was affected in 35/67 (52%). In the entire series the spine was most commonly affected (128/219, 58%), followed by the hip (37/219, 17%), knee (17/219, 8%), ankle (13/219, 6%), and wrist (8/219, 4%). A markedly similar disease distribution was reported at varying ages in a Japanese study of 914 lesions: spinal 61%, hip 14%, knee 8%, and foot 5% (110). The onset of joint symptoms tends to be slow, with discomfort, swelling of the joint, periarticular muscle atrophy, low-grade temperature elevations, and decreased function. Involvement of the hip was particularly common, and indeed much of the early confusion involving what has come to be known as Legg-Perthes disease came because of the fact that many of the clinical symptoms were similar. Diagnosis is made by a positive tuberculin skin test and the demonstration of tubercle bacilli on either bone or synovial biopsies or following growth of the organism. Although skeletal tuberculosis is relatively common, it is still infrequent in the overall spectrum of tuberculosis. The primary tuberculous focus almost always occurs in the lung and heals in many leaving only a fibrous scar. The second stage involves a postprimary reinfection, which might then be associated with spread throughout the body. Involvement of any specific organ is referred to as the tertiary stage of tuberculosis. Primary foci of tuberculous infection are not known to appear in the skeletal system. Tuberculous infections in skeletal parts reach that area by the bloodstream from an already existing extraskeletal tuberculous disease focus. In children, the nidus of tuberculosis occurs through hematogenous spread. 2. AGE INCIDENCE Tuberculosis is rarely seen during the first year of life. Statistics presented by Jaffe indicate that "in the first half of the twentieth century.., in about 50% of all cases, the subjects were between 3 and 15 years of age" (97). The most common areas of involvement are the vertebral column, hip, and knee. The joints of the lower extremities are affected much more commonly than those of the upper extremities. The clinical characteristics of a tuberculous skeletal infection are much more indolent than those of a septic arthritis or osteomyelitis. Involvement is almost always monoarticular. 3. RADIOGRAPHIC CHANGES The radiographic characteristic of tuberculosis is a periarticular osteopenia with the presence of a lytic lesion within the secondary ossification center. Almost invariably there is an increase of joint fluid due to synovitis. Swelling of periarticular soft tissues is seen with joint involvement, which generally results in a combined epiphyseal osteomyelitis and septic tuberculous arthritis. There may be narrowing of the joint space. There is resorption of the subchondral bone and the adjacent trabeculae by granulation tissue, with minimal to absent bone reaction and no formation of sequestra. Osteoporosis can be marked. Wedge- or cone-shaped areas of destruction are often seen in epiphyseal ends of the bone.

SECTION IV 9 Osteomyelitis and Septic Arthritis

There is a tendency toward the involvement of bone on both sides of the joint. Sclerosis adjacent to the lytic lesions can be seen with prolonged, partially controlled involvement as can osteophyte formation. 4. HISTOPATHOLOGY Skeletal involvement is considered to occur following hematologic spread. Approximately 1% of tuberculosis cases show some skeletal localization (218). The tendency is for the disease to begin in the articular or epiphyseal end of a bone, break into the joint in which it becomes a septic arthritis, and then involve the synovial membrane. On occasion, the synovial membrane can become infected directly by hematogenous spread. In the long tubular bones, the tuberculous process usually originates at the epiphyseal subarticular end of the bone and spreads through the cartilage surface to involve the synovium. Tubercle formation occurs in the marrow, with the trabeculae of spongy bone affected secondarily. There are necrosis and resorption of the cancellous trabeculae with circumferential spread of the lesion. Inspection of joints often shows destruction of the articular cartilage, with the femoral head covered by a pannus of tuberculous granulation tissue. In the hip, the bone of the secondary ossification center is affected as is that of the acetabulum. Tuberculous synovitis is seen frequently, associated with inflammatory thickening of the periarticular connective tissue and fat. Synovial membranes are extremely thickened and the articular cavity will contain a large amount of necrotic material. Synovial involvement is associated with partial or complete erosion and destruction of the articular cartilage with the tuberculous granulation going both over the surface of the cartilage and along its subchondral region. Phemister has provided a detailed assessment of changes in tuberculous arthritis (157). The seat of primary infection is in the bone in some cases and in the synovial membrane in others. In the early stages, therefore, the articular cartilage is not affected and remains alive. It is attacked secondarily by tuberculous granulation tissue either along its free junctional surface with the bone and synovium or along the region of its attachment to subchondral bone. The initial destruction of cartilage is usually by granulations growing from the synovium onto the periphery of the cartilage where it is not immediately adjacent to cartilage from the opposite bone. The second region in which granulations develop is the peripheral portion of epiphyseal bone beneath the articular cartilage. A thin layer of subchondral granulation forms, which absorbs the subchondral bone and the deeper layer of cartilage, leading to detachment of overlying cartilage along with necrosis. Marginal undermining of the articular cartilage may also be seen by tuberculous granulations growing in from the synovium. The subchondral bone can be affected in two ways. In small focal areas, the bone may be broken down rapidly as the focus spreads, leaving a cavity filled with tuberculous granulations or necrotic debris. In other cases, large areas are involved and the tuberculous tissue of

907

the cancellous spaces undergoes early necrosis and caseation, leaving the dead bone trabeculae practically intact. The overlying cartilage is then affected secondarily due to subchondral bone collapse similar to what is seen in osteonecrosis where the cartilage is initially unaffected. Phemister concluded that secondary changes along the articular surfaces of the bones developed from spread of the tuberculous infection from the primary point of involvement. The most common region of tuberculous skeletal involvement after the spine and hip is the knee. Other areas of involvement are the tarsal, carpal, and elbow bones. Shoulder involvement is less frequently seen than the elbow. Involvement here, however, is in the head of the humerus, and the lesion spreads from there to the articular cavity. In joints, which go on to stabilize in the absence of full healing, fibrous ankylosis tends to develop. Cartilage is not regenerated, and in preantibiotic days there was often some degree of fibrous or bone ankylosis. In summary, in skeletal tuberculosis the tubercle is the characteristic pathological finding associated with tuberculous granulation tissue and, later on, caseation necrosis and eventual fibrosis. Except for the vertebral lesions, the majority of cases of skeletal tuberculosis involve a joint. Almost invariably there are an associated tuberculous synovitis and osteomyelitis of the epiphyseal region. Virtually all metaphyseal and epiphyseal foci sooner or later involve the adjacent joint. The epiphyseal focus extends into the adjacent joint at a margin near the synovial-cartilage junction. In association with synovial involvement, there is early invasion of the articular cortex at the joint margins. The tuberculous granulation tissue erodes through the edge of the cartilage to create a focus of advancing damage. There is subchondral granulation resulting in fibrous tissue deposition. Eventually, the zone of calcified cartilage and the noncalcified articular cartilage are slowly resorbed. Subchondral marrow fibrosis is seen. The articular cartilage is also resorbed from the surface beneath the granulation tissue creeping over it. Resorption and destruction of cartilage occur first at the margins of the joint and then move progressively onto the weight bearing surfaces. Within the bone itself, the dead trabeculae remain of normal thickness, whereas those at the periphery in the more viable regions tend to become thinner in association with decreased use and increased vascularity. The phrase "kissing" sequestra has been used for many decades to describe the pathological findings in tuberculous osteomyelitis and arthritis. These refer to secondary sequestra formed directly opposite each other in opposing epiphyses at sites of maximum pressure stress. In the preantibiotic era, there was very little, if any, tendency for tuberculous joints to heal with preservation of a useful range of motion. Healing occurred initially by a fibrous ankylosis, which in turn sometimes became a bony ankylosis. In most the healed joint became a mass of dense, fibrous adhesions with a fibrotic synovium. Figure 12 illustrates the pathophysiological changes of the joint and epiphyseal regions in the tuberculous disease.

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CHAPTER IO 9 Metabolic, Inflammatory, Neoplastic, Infectious, and Hemarolottic Disorders

Tuberculous Arthritis Epiphyseal Osteomyelitis & Septic Arthritis

~:;:/ ~ii{ ~ ~ ~

1

~ _/~ ~

~

~--~i~ PrimaryEpiphyseal /~;:~~ Osteomyelitis(1) ~i~l Primary :.,~::/~: Synovitis(2) .

~ii~ ~ ~ 2~ :/ - -

~~ y

SecondaJ/ryArticula r CartilageDamage(3)

FIGURE 12 Tuberculous involvement of the joints is a combined epiphyseal osteomyelitisand tuberculous septic arthritis. The pathophysiologic changes are illustrated here.

5. TREATMENT Treatment for skeletal tuberculosis became effective with the development of antituberculous antibiotics (isoniazid, p-aminosalicylic acid, and streptomycin). Initially this was used in combination with splinting followed by physical therapy for range of motion of the joints. It shortly became evident that repair was improved with debridement of the fibrotic, necrotic infected tissue whether this was in the joint or within the adjacent bone. For children in the acute stages of the disorder, antibiotic therapy alone was often sufficient. Because development of the infection, however, tended to be indolent and discomfort was much less than that associated with pyogenic bacteria, many patients were already in the subacute or chronic phase when diagnosis was made. The combination of joint and bone debridement with antibiotic therapy and rehabilitation, with earlier focus on range of motion activities, tended to improve results greatly. Kondo and Yamada were early proponents of focal debridement (110). In large joints, all loose cartilaginous fragments, loose devitalized bone fragments, and necrotic or devitalized infectious tissues were removed surgically. They felt that the combined therapy greatly improved results. Debridement was especially indicated during the later chronic stages of the disorder particularly when abscesses or sinuses were present, which markedly limited access by systemic antibiotics. An extensive study also from Japan by Katayama et al. strongly supported the triple-therapy antibiotics along with surgical synovectomy and joint and bone debridement to physically remove all gross tuberculous foci particularly

in those regions that communicated with the joint space (102). Synovectomy alone was commonly resorted to within the knee joint. Katayama et al. felt that these treatments improved the likelihood of retention of joint motion, even though completely normal joints were rarely achieved with chronic disorders. Wilkinson also resorted increasingly to synovectomy of the knee and hip in combination with chemotherapy to improve joint healing and function (230, 231). Care was taken to distinguish the tuberculous joint from pyogenic arthritis even when there was extensive involvement with synovial swelling and lytic areas of bone because the articular cartilage tended to survive much better in tuberculous than in the pyogenic infection. Synovectomy and even removal of the overlying pannus layer in combination with chemotherapy led to some remarkable recoveries in tuberculous arthritis. Wilkinson recognized that in tuberculous arthritis both synovium and bone were involved by the time the disease had become recognizable clinically. On the basis of extensive clinical experience, he noted the pathological involvement at hip and knee to be definable into four groups according to the tissues involved (231). The first group involved those with disease of both synovial membrane and cartilage. The cartilage involvement tended to be around the periphery of the articular surface. The next group had disease of the synovial membrane, cartilage, and bone. This involved considerably advanced disease with frequent destruction of the joint and subluxation or dislocation of the femoral head in the hip. The third group involved disease of the synovial membrane and bone with little evidence of cartilage loss. The fourth group had mainly bony changes with no change in the joint found at operation. In those with disease of the synovium and cartilage, the synovium was always more markedly involved being thickened and vascular and encroaching on the periphery of the cartilage. In some cases the synovium spread over the cartilage almost to the center of the joint. Cartilage laceration also occurred over subchondral tuberculous foci with diseased tissue attacking from bone into cartilage from below. Pannus formation was also observed, spreading from the periphery onto the cartilage surface. Even when pannus covered the cartilage, the cartilage beneath was often intact. Disease of synovium, cartilage, and bone was seen, generally, when the patient was older and destruction more severe. Chemotherapy was combined increasingly with synovectomy and joint debridement, and many joints that initially appeared to be quite damaged were restored to reasonable function for several years. Debridement and curettage of adjacent bony foci frequently were needed. In terms of bone surgery, osteotomy was required in more severe cases and, although arthrodesis was resorted to early in the series at progressively later time periods, the combination of antibiotics and more vigorous and early surgery limited the number of arthrodeses needed. Wilkinson stressed, as had others, that there was a tendency for the articular cartilage to survive even in joints that appeared to

SECTION V ~ Hematologic Disorders

be severely affected by tuberculosis. Pannus was removed if possible, and if it was of relatively recent origin the cartilage showed an excellent tendency to regenerate. Synovectomy was helpful because synovial persistence in a thickened state delayed cartilage nutrition. In addition, the presence of pannus also delayed joint recovery. More recently ethambutol has replaced PAS as one of the triple-therapeutic drug treatments. Rifampicin has also been used. Many combinations of the drugs are used by differing practitioners, and some will use only one initially holding the others in reserve. Tuli has reviewed evidence that the uptake of drug at foci of tuberculous lesions in the skeleton is surprisingly high and stresses the value of the drug over surgical intervention. He supports the primacy of antitubercular drugs, repetitive active and assisted exercises for the involved joint from the very beginning, and rest in the functional position between exercises. Surgical intervention is reserved for those with chronic synovitis not responsive to medical management. Management is predicated to a great extent on economic and social factors. When there are no specific constraints to active therapy, it appears that optimal antibiotic use, early physical therapy to stress range of motion, and surgical debridement with any evidence of slowness of repair would be the optimal approach. 6. LONG-TERM FOLLOW-UP OF CHILDHOOD TUBERCULOUS JOINT INFECTION Chow and Yau studied 30 cases of tuberculosis of the knee followed for an average of 15 years, with the majority having developed the disease during childhood (37). In 75% of the patients, the infection occurred before the age of 18 years. The peak year of incidence was 4 years, with the large majority of cases occurring from 1 to 11 years of age. Treatment varied between conservative and operative, but all had chemotherapy. In those patients treated operatively, synovectomy and debridement followed by cast immobilization and bracing were the usual approach. On occasion, the destruction was sufficiently great that immobilization was continued to the point of ankylosis. Conservative treatment involved chemotherapy with casting and bracing alone. In patients in the childhood group, deformities commonly seen involved varus deformity of the knee, flexion contractures, and lower extremity shortening. In 6 instances there was varus deformity, which was mild in 2, simply leading to loss of the normal valgus angle, 10~ in 2 cases, and 30 ~ in 2 additional cases. The flexion contractures of the knee were seen in 12 cases at 10~ in 6, 20 ~ in 5, and 30 ~ in 1. Significant clinical shortening was demonstrated in 7 cases, with the amounts being 2.5 cm in 2, 5.0 cm in 4, and 7.5 cm in 1. Most of the abnormal deformities occurred in association with each other. There were 13 knees with no deformity and an otherwise excellent result. On occasion, extensive regeneration of the bone occurred even though much of the epiphyseal subchondral bone appeared lytic at diagnosis. At review, roughly 25% of the joints were radiologically nor-

909

mal. Of those with abnormalities, the most common were described as "congruous incongruity in which the joint space was well preserved although it was irregular in outline with a matching pattern of irregularity in the two opposing surfaces of the tibia and femur." Other X-ray abnormalities were osteophytes, osteoporosis, a smaller epiphysis, chondral calcinosis, abnormal patellae, and loose bodies. Of note was the fact that "as the child grew older, the previously destroyed bone and perhaps the overlying articular cartilage showed a remarkable power of reconstitution."

V. HEMATOLOGIC DISORDERS A. Hemophilia 1. OVERVIEW Hemophilia is a sex-linked recessive bleeding disorder caused by a deficiency of blood coagulation factors VIII or IX (47, 66, 90, 170, 227). It is an inherited tendency in males to bleed. Prior to the onset of effective therapy for this disorder, damage to the joints and epiphyseal ends of the bone was extensive, and treatment methods involving surgery and physical therapy were not curative. Lethal hemorrhage was frequently seen following major trauma or after surgery performed in which the diagnosis was not recognized; Koenig (111) and Key (107) reported several documented cases in their reviews of the disorder. The natural history of the disorder has changed significantly following factor replacement therapies over the past several decades, but considerable morbidity and some mortality persist. Larsson has documented the dramatic change in life expectancy with hemophilia in Sweden where detailed statistics have been available since the eighteenth century (118). The median life expectancy of patients with severe hemophilia increased from 11.4 years from 1831 to 1920, to the mid-20s from 1921 to 1960, to 56.8 years from 1961 to 1980. The AIDS crisis then led to a significant decline in median life expectancy in the United States and western Europe from 1981 to 1990 prior to recognition of its cause and avoidance of infected blood. Hemophilia A, the most common hereditary coagulation disorder, is seen throughout the world and has an incidence of 2 per 10,000 male births. It is an X-linked recessive disorder that affects males only and is transmitted by females. The disorder is the result of a new mutation in approximately 33% of new patients, so that a family history is often not obtainable. It is due to the absence, severe deficiency, or defective functioning of the plasma coagulation factor VIII (antihemophilic factor). Several different mutations cause the disorder, which accounts for the variable clinical severity. Hemophilia B (Christmas disease) is indistinguishable clinically from hemophilia A, is also transmitted as an X-linked disorder, and is the result of factor IX deficiency. It is the result of a new mutation in approximately 20% of new patients.

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CHAPTER IO 9 Metabolic, Inflammatory, Neoplastic, Infectious, and Hematologic Disorders

Hemophilia was described as an inherited, sex-linked disorder by John Otto of New Hampshire in 1803 (149). For several decades, however, no connection was made between the bleeding disorder and the joint swelling and degeneration. According to Koenig, it was not until the 1860s that this correlation even began to be considered (111). The factor VIII deficiency (hemophilia A) occurs in approximately 85% of cases and the factor IX deficiency in 15%. Three severities of disorder are defined for both factor VIII and IX deficiencies. Those with a mild disorder have 5-25% of factor activity in the blood, moderate 1-4% factor activity, and severe 0-1% factor activity. The distinction is extremely important because mild and moderate hemophilia A rarely lead to joint bleeding. It has been estimated that in hemophilia A the severe-moderate-mild distribution is 70%15%-15% and in hemophilia B it is 50%-30%-20% (47). When unusual bleeding is encountered in a male patient, laboratory screening tests include a normal platelet count and prothrombin time but a prolonged activated partial thromboplastin time. Specific factor assays are then needed to determine the deficiency differentiating hemophilia A from hemophilia B. Patients with von Willebrand's disease also have factor VIII deficiency due not to a defect in the X chromosome but to the indirect consequence of qualitative or quantitative changes in plasma von Willebrand factor (226). Factor VIII circulates in the plasma with von Willebrand factor in a noncovalent complex, but the two factors are distinct proteins. Much of the improved treatment of hemophilia comes from the molecular understanding. Some patients, however, remain resistant to therapy because of the presence of inhibitors, which are antibodies developing against exogenous factor VIII or IX (47, 53). These inhibitors are present in 2050% of people with severe hemophilia and are suspected when good responses to therapy are not achieved with the restoration of appropriate levels of factor. The clinical hallmarks of hemophilia A are joint and muscle hemorrhages, easy bruising, and prolonged hemorrhage after trauma or surgery, although there is no excessive bleeding after minor cuts or abrasions. Hemarthroses account for 75-85% of bleeding episodes in patients with severe hemophilia. Intra-articular bleeding is highly characteristic of factor VIII and IX deficiency and is not seen in other blood clotting factor deficiencies. The joints most frequently involved are the knees, elbows, and ankles, with occasional involvement of shoulders and hips. In a small series of 44 patients hospitalized with hemarthrosis, Eyring et al. reported an incidence of knee 62%, ankle 20%, elbow 15%, hip 2%, wrist 1%, and shoulder 0.5% (61). Houghton and Duthie reported joint involvement as follows: knee 328 (44%), elbow 190 (26%), ankle 106 (14%), sternoclavicle 33 (5%), shoulder 25 (3%), wrist 20 (35%), hip 19 (3%), and hand 17 (15%) (89). The ankle is the most common joint experiencing hemarthrosis in the second decade. Gamble et al. noted intra-articular bleeding to be most common in

the knee in those under 10 years of age, but in those between 11 and 19 years of age the frequency of hemarthrosis of the ankle was 2.5 times that of the knee (67). Hemarthroses tend to be noted when the child first begins to walk and generally are spontaneous. The joint bleeding is associated with discomfort and limitation of motion and then with inflammation and synovitis. This establishes a vicious cycle, which leads to more hemarthrosis. Ultimately, hemophilic arthropathy damages and destroys the cartilage, narrowing the joint space, and is associated with small subchondral bone cysts, osteopenia, and contractures. 2. GENE ABNORMALITIES The gene that codes for factor VIII is at the tip of the long arm of the X chromosome (47, 90, 105,227). It is one of the largest human genes, comprising nearly 186 kb and constituting nearly 0.1% of the X chromosome. The initial studies of mutations were performed by screening genomic DNA digested with restricted enzymes. By 1991 more than 150 different mutations had been identified in hemophilia A. With a few exceptions, deletions in the factor VIII gene cause a severe form of hemophilia A. Nonsense mutations also cause severe hemophilia. Over 80 point mutations and 70 gene alterations have been identified in the factor VIII gene, which underscores the wide range of clinical variability. Characterization of factor VIII mutations has been slow because of the extremely large size of the gene and the variable mutations, which are reflected in the fact that the hemophilia A is a clinically heterogeneous disorder. More recently, an inversion in the factor VIII gene at intron 22 was identified and found to account for as many as 40% of all severe hemophilia A gene abnormalities. The factor IX gene is smaller, comprising 34 kb (66). More than 300 unique mutations have been found; of families with moderate to severe disease, 95% have different mutations. No link between factor VIII and IX genes has been found. With pedigree analysis and laboratory studies involving plasma levels of factor VIII and von Willebrand factor, it is now possible to determine carder or noncarder status for women with greater than 95% accuracy in roughly 80% of women who are evaluated. DNA analysis has been used to determine carrier status. Ultrasound-assisted fetoscopy has made it possible to obtain fetal blood samples in the eighteenth to twentieth weeks of pregnancy, and prenatal diagnosis of hemophilia has become feasible with the advent of factor VIII immunoassays. More recently, prenatal diagnosis during the eighth to tenth weeks of pregnancy has become possible through DNA analysis of amniocytes or chorionicvillus material. 3. ORTHOPEDIC SEQUELAE OF CHILDHOOD HEMOPHILIA

a. Musculoskeletal Damage: Arthropathy, Pseudo-tumor, Neuropathy, Contractures, Volkmann's Ischemia, Fractures, and Ectopic Ossification. The major orthopedic prob-

SECTION V ~ Hematologic Disorders

lem in hemophilia is intra-articular bleeding with subsequent hemarthropathy (8, 45, 125, 163, 170, 198, 201). This is generally associated with muscle atrophy and a tendency to joint contractures. The most commonly involved joints are the knees, ankles, and elbows. Characteristic knee deformities accompanying hemophilic arthropathy involve a flexion contracture, genu valgum, and external rotation of the tibia. In long established cases, there is posterior subluxation of the tibia. The knees tend to be "knobby" due to irregular overgrowth of the epiphyses, overgrowth of the periphery of the patella, and periarticular muscle atrophy. The ankle shows diffuse osteopenia, collapse of the superior surface of the talus, a valgus tilt of the ankle joint, and a mild equinus deformity. The elbow develops a progressive flexion contracture. Other less common disorders involve bleeding surrounding and into the bone, primarily the proximal femur and ilium, which leads to the formation of a lytic lesion referred to as a hemophilic pseudo-tumor; bleeding into muscle and soft tissues, which can lead to neuropathies, particularly of the sciatic and femoral nerves and episodes of Volkmann's ischemia of the forearm and calf; fractures, generally of the distal one-half of the femur, associated with chronic knee arthropathy, stiffness, and osteopenia; and ectopic ossification, usually in the pelvis. Arthropathy is considered in detail in the following section, followed by the other less common disorders in the subsequent section. b. Hemophilic Arthropathy. Joint involvement is rare in the first year of life and generally begins in the second year with the onset of walking. The knee is most commonly affected followed by the ankle and elbow joints. Small joints of the fingers and toes are only rarely affected. In most hemophiliacs, a single joint tends to be affected repeatedly and is referred to as a target joint. Three Stages of Hemophilic Arthropathy (Koenig): Koenig in 1892 was one of the first to recognize that the joint abnormalities of hemophilia following the hemarthrosis represented a specific pathoanatomic entity, not simply a variant of rheumatologic or arthritic disease that just happened to occur in hemophiliacs. He divided the disorder into three stages (111). The first stage due to initial bleeding was referred to as the stage of true hemarthrosis, the second stage was the inflammatory stage with a panarthritis with reactive inflammation throughout the involved joint with proliferation of the synovial membrane, and the third stage was one of regression or wasting away of the joint with destruction of the joint surfaces, contractures causing permanent deformity, and ankylosis. Koenig recognized that the initial symptoms were often vague with apparently spontaneous but rapid onset of the hemarthrosis occurring without trauma, usually without associated pain and with a surprisingly good range of motion retained. The deterioration of function occurred gradually after several bleeding episodes. Aspiration yielded bloody fluid. Koenig was able to diagnosis a "bleeders' joint" of hemophilia "due to the patient's pallor, the

911

sudden appearance of the fluid effusion, lack of pain in the joint, and the freedom of movement." Depalma and Cotler distinguished four grades of hemophilic arthropathy (45). Grade 1: Intra-articular hemorrhages that have not resulted in any functional joint impairment. There are no or only minimal radiographic changes. Grade 2: The affected joint presents a slightly reduced range of motion but the joint space is well-preserved, there is no irregularity of the subchondral bone, and the spongy trabeculae are only somewhat more prominent. Grade 3: There is fixed deformity of the joint associated with periarticular muscle atrophy, pericapsular and capsular thickening, irregular articular surfaces, and subchondral cysts with marginal spur formation. Grade 4: The deformity is pronounced and fixed with marked periarticular muscle atrophy. The articular bone ends are irregular and deformed with increased radiolucency and narrowing of the joint space. With time, the bone ends, particularly at the knee, tend to flatten and widen and subluxations are common. Fibrous ankylosis may lead to bony ankylosis. Marginal exostoses are seen. Gross Pathologic Findings: Koenig, in his initial paper from 1892, described changes observed in three cases of open arthrotomy or postmortem examination (111). Joint aspiration in the early phase yielded blood. This was still found a few weeks after the onset of bleeding, but some blood clots were free in the joint whereas others were attached to the capsule. With time the capsule was thickened and its inner lining was discolored with a blood-colored fluid. Fibrous deposits were noted to occur both on the capsule and on part of the cartilage surface of the distal femur. Even at this stage, "the cartilage starts to change, to become fibrous, and the strangely sharp-edged defects described below start to develop." In the second stage, Koenig noted that, if no new bleeding had taken place, the contents of the joint are "not purely blood but bloody serous or purely serous with a slightly brown color." At arthrotomy in these joints a "great number of brownish synovial tufts was particularly noticeable." He then described the villous appearance of the synovium plus its red-brown, brown, or gray discoloration. He also noted changes in the cartilage. "All over it has lost its white color and its shine; it is discolored a dirty red-brown or gray-brown." Koenig noted the tendency for the cartilage to become fibrous. "The truly characteristic changes consist in strangely sharp-edged defects, small and big, deep and on the joint surface with gnawing defects to the cartilage in various spots of the joint but mostly at the same places where the fibrous deposits are found." There was a characteristic central position of the defects in which "we have found no actual changes on the edge of the cartilage surface as is the case in arthritic deformity." With histologic sections, there was granular blood pigment in both the cartilage and the synovium. The third stage he referred to as "regressive metamorphosis." Scarring and shrinking of the connective tissue set in with superadded mechanical influences. The joint continued to degenerate and became stiff and deformed.

912

CHAPTER IO ~ Metabolic, Inflammatory,

Neoplastic, Infectious, and Hematologic Disorders

FIGURES 13 and 14 Exampleofjoint damagecausedby severehemophilicarthropathyis shown.At right (Fig. 14) is the humeral head of a 27-year-oldhemophilic patient; this can be compared with the opposite normal nonaffected humeral head at left (Fig. 13). [Reprinted from DePalma and Cotler (1956), Clin. Orthop. Rel. Res. 8:163-190, 9 LippincottWilliams & Wilkins, with permission.]

Koenig went on to describe the fibrous and then bony ankylosis and the fibrosis and tightening of the capsule. Flexion contractures and slight valgus deformation of the knee joint followed. Key provided the earliest and most detailed description of the hemophilic joint in English (107). At operation (for a mistaken diagnosis of traumatic arthritis), it was noted that the synovial membrane was unusually dark in color. Blood without clots escaped once the arthrotomy had been made. The synovial membrane was dark chocolate in color and the joint cavity was filled with hypertrophied synovial folds and villi. The articular cartilage on femoral, tibial, and patellar surfaces was yellowish brown in color, and there were many areas in which the cartilage either was thinned or had disappeared entirely. The underlying bone was covered by a chocolate-colored connective tissue. The areas of cartilage erosion were irregular in size and contour but were sharply demarcated as described by Koenig. Some of the synovial villi were pedunculated, whereas others were sessile. Many of the synovial folds branched extensively, giving areas of a mosslike structure. The villi were markedly friable. DePalma and Cotler provided an excellent description of the gross pathology (45). Postmortem study of two shoulders showed one side to be perfectly normal and the other with marked abnormalities (Figs. 13 and 14). The affected side was totally degenerated. There was no trace of hyaline cartilage, and the subchondral bone was eburnated and covered with numerous craterlike defects varying in size and shape. Subchondral cystic regions were seen that communicated with the joint cavity. Many of the defects in the cancellous bone had a smooth, firm, compact inner surface, indicating

that the contents of the cyst were under great pressure. There was considerable erosion of both cartilage and bone elements along the superior and posterior borders. The soft tissues of the joint were discolored. The synovial membrane was thin with only minimal villus formation noted at this stage. The ligaments were thicker and broader than normal. In the knee joint, the entire synovial lining was discolored in varying shades of reddish brown. The entire thickness of both menisci and the quadriceps tendon was permeated by blood pigments. The articular cartilage was similarly discolored, swollen, wavy, and shredded. Numerous fine villi covered its surface. The cartilage was markedly pitted and also exhibited clefting, but there were no areas of erosion to the level of the subchondral bone. There was no eburnation. The synovial membrane and subsynovial tissues were thickened markedly. Numerous fine villi extended from the synovium. The intercondylar notch was filled with thickened hyperplastic synovial tissue. The extent of joint damage in hemophilic arthropathy is shown in Fig. 14. Pathogenesis of Hemophilic Arthropathy: Clinical swelling of a joint is rarely documented before 12 months of age, and most of the bleeding episodes become prominent at 4 - 5 years of age. It is usual that the first massive hemarthrosis can be resorbed with no apparent sequelae. It is the recurrent intra-articular bleeding that becomes problematic. The three-stage progression of the disease outlined by Koenig remains accurate today: hemarthrosis, inflammatory panarthritis, and regressive stages (111). The repeated insuits of numerous and frequent hemorrhages can be either massive or small and subclinical. When the stages of chronicity begin, the synovium is involved first followed by the

SECTION V ~ Hematologic Disorders

cartilage and then the bone. The subsequent synovial hyperplasia serves as a deterrent to effective resorption of blood from the joint cavity with repeated episodes. Bleeding occurs more frequently with even minimal trauma because the thickened synovium is hypervascular. Organization of the subsynovial granulation tissue further worsens the process by producing dense scar tissue. Pannus ensues covering the periphery of the articular cartilage and leading to underlying cartilage degeneration. Occasional osteophytes are seen at the periphery. The subchondral and cancellous bone tends to atrophy. There is coalescence of small marrow spaces forming larger cystic spaces. There is proliferating vascular connective tissue in some of the cysts, whereas in other areas there is blood clot associated with intraosseous bleeding. Most cysts eventually gain communication with the joint cavity as the overlying cartilage degenerates. Articular cartilage degeneration is an invariable part of the picture, with marked fibrillation of the collagen fibers and in some areas focal full thickness defects. In some cartilage areas, cellular elements have disappeared almost completely. In areas in which the entire thickness of the cartilage has been destroyed, surface tissue is replaced by vascular granulation tissue extending from the marrow. With cartilage destruction the joint space narrows. In the final or third phase of Koenig the bleeding episodes diminish because the synovium has become so thickened and sclerotic that vessel involution has occurred. By this time joint cartilage can be nonexistent, and bone on bone crepitus is very painful, motion is limited, contracture deformity is great, and function is markedly diminished. Histopathologic Findings: The early synovial reaction to intra-articular bleeding resembles the changes occurring with rheumatoid arthritis. Initial hemarthroses are quickly resorbed with no clinical sequelae. With multiple bleeds, however, resorption is slower and persisting intra-articular blood and blood clot lead to the development of progressively severe changes. The synovial lesion is characterized by hemosiderin deposition and fibrovascular proliferation. There is inflammation, reactive proliferation, and brownish discoloration of the synovial membrane, which eventually lead to osteoarticular changes. The synovial membrane with time becomes hypertrophic and thickened with villous proliferation, increased vascularity, and round cell infiltrates. The blood products are resorbed by the synovium, but it is the overload of iron that appears to be most damaging to the synovial cells. Hemosiderin accumulates within synovial villi. Synovial cells that absorb too much iron disintegrate, releasing lysosomal enzymes that destroy articular cartilage and further irritate the synovium. Chondrocytes are also damaged directly by the iron. The synovium gradually becomes fibrotic and, in end stage disease, loses the capacity for excess bleeding and joint distention. These changes are soon followed by articular cartilage degeneration from superficial to deep. A brownish pannus covers the cartilage from the periphery. If full thickness focal regions of cartilage are lost, the subchondral bone becomes exposed and thickened. Subchondral cysts form and there

913

FIGURE 15 Outlineof early (A) and late (B) arthropathic changes in hemophilia from the work of Speer (198). c/j, synovitis; f/h, subchondral cyst; g, chondrolysis,fibrillation; i, osteochondral cyst; k, bone sclerosis; 1, widened notch. [Reprintedfrom Speer (1984), Clin. Orthop. Rel. Res. 185: 250-265, 9 LippincottWilliams& Wilkins, with permission.]

may be collapse of the articular surfaces. Subchondral cysts are often found to begin with an intraosseous hemorrhage that breaks down the atrophic bony trabeculae and can reach giant proportions. Coalescence and collapse of these defects produce marked deformities of the bone ends and flattening and incongruity of the articular surfaces. The cysts are formed by destruction of the overlying subchondral bone and cartilage by vascular connective tissue originating in the marrow spaces immediately adjacent to the subchondral bone. Cartilage surface pitting and focal erosion occur. The entire hypervascular process is associated with osteopenia of the underlying trabeculae. The capsule of the joint becomes thickened. The subchondral cystic cavities communicate at times with the joint space and contain fresh clot as well as fibrous tissue. Key defined the microscopic anatomy with findings similar to those reviewed earlier (107). The synovium was thrown into innumerable folds and villi. The subsynovial tissues were thickened by cellular proliferation and edema and filled with granules of yellowish-brown pigment. The changes were seen universally throughout the joint lining. The surface synovial cell layer was from 4 to 10 cells in thickness. Many of them had pigment granules. There were also phagocytic cells or macrophages loaded with pigment. The subsynovial layer was markedly thickened and composed of a markedly vascularized component, increased collagenous tissue, and macrophagic cells. Beyond this the capsular tissues were markedly thickened and fibrotic. The margin of the articular cartilage was invaded at its periphery by the vascular synovial and subsynovial tissue. The surface of much of the cartilage had undergone fibrosis with little evidence of hyperplasia. The underlying bone was extremely atrophic, and in many places the cartilage virtually rested upon the bone marrow and the cancellous bone of the epiphysis. Speer has delineated well the early pathogenesis of hemophilic arthropathy particularly in relation to the evolution of the subchondral cysts (198) (Fig. 15). His study was based on patients undergoing synovectomy of the knee. Six of the 9 patients were in the younger age group showing early stage changes, but all had had more than two episodes

914

CHAPTER 10 ~ Metabolic, Inflammatory, Neoplastic, Infectious, and Hematologic Disorders

of hemarthrosis in the affected knee and chronic synovitis of greater than 6 months duration that was not responding to therapy. The changes described are similar to those reviewed earlier. Speer noted osteochondral defects at central load bearing areas of the femoral condyles with the surrounding articular cartilage relatively spared. The flattened or gently curvilinear space at the bottom of each osteochondral defect was 3-7 mm below the surface of the joint and was invariably depressed below the contour of the normal subchondral bone plate. Fluid-filled osteochondral cysts were seen in several patients, the surface layer of which was continuous with superficial zones of the articular cartilage. The cysts, when unroofed, contained a dark viscous fluid with no evidence of bone or cartilage. Although a pannus was seen, it was not as vascular or as advanced as that in rheumatoid arthritis. In addition, at the osteochondral junction, the fibrovascular pannus appeared to invade the articular cartilage from the surface, but the marrow cavity itself did not show cystic or fibrous changes in contrast to early rheumatoid arthritis. Eventually the fibrous pannus extended to the margin of the osteochondral defects in the central parts of the condyles. At the bases of the osteochondral defects, there were thickened, sclerotic, laminated bone plates depressed below the plate of the normal subchondral bone. It was Speer's feeling that "a subchondral cyst evolves as an expanding hematoma that aggressively destroys the subchondral bone and the overlying articular cartilage before eventually communicating with the joint space. The subchondral cyst progressed to an osteochondral cyst and then to an osteochondral defect." Because these cysts occurred in the intercondylar notch in the central portion of the condyles, they related to the characteristic radiographic findings. Speer defined five mechanisms by which the articular cartilage was destroyed in hemophilic arthropathy: (1) enzymatic digestion of articular cartilage due to the production of proteolytic enzymes including collagenases during the chronic synovitis stage; (2) direct cellular destruction of articular chondrocytes by phagocytic and other cells; (3) direct damage to articular chondrocytes by "blood or other tissue products;" (4) mechanical factors of load pressure, abrasion, and abnormal loading secondary to contractures and osteopenia; and (5) changes resulting from the subchondral hemorrhagic cysts. Speer states that "the cyst of hemophilic arthropathy is the result of subchondral hemorrhage." An inciting event for the subchondral cyst was fracture of the subchondral bone plate with a resulting subchondral hemorrhage. The osteopenic bone would increase the likelihood of fracture. The hemophilic arthropathy begins in the center of the condyle and moves progressively outward, which is different from the progression of rheumatoid arthritis from the periphery toward the center. Due to its position, the subchondral cyst expands with its hematoma by direct bone and articular cartilage tissue destruction until rupture into the joint space occurs. The subchondral cyst thus paves the way for eventual joint destruction as the articular cartilage, which is initially

intact overlying it, subsequently collapses. In summary, the evolution of hemophilic arthropathy begins in the synovium with acute and chronic synovitis. Subchondral cysts develop following subchondral hemorrhage with osteolysis and/or collapse resulting in flattening of the condyles and widening of the intercondylar notch. Fibrillation and wear of the joint surface then occur on both a chemical and mechanical basis. The subchondral cysts expand with lysis of overlying cartilage to form an osteochondral cyst. This can be associated with full thickness articular cartilage loss. In the later stages, chronic synovial fibrovascular pannus grows to undermine the osteochondral junction of articular cartilage peripherally. Bone sclerosis occurs at the base of the osteochondral defects. There is further widening of the intercondylar notch due to further subchondral osteolysis and/or collapse with overlying articular cartilage loss. Stein and Duthie reported on chronic end stage hemophilic arthropathy, analyzing 44 tissue specimens from 39 adult patients during reconstructive joint surgery (201). The mean age of patients having hip, knee, and ankle procedures ranged from 20.5 years for knee synovectomies to 41.5 years of age for total hip replacements. Specimens were obtained from 21 knees, 15 hips, 6 ankles, 1 foot, and 1 wrist. Their assessments understandably showed extensive damage of both the hemophilic synovium and articular cartilage. The synovial lining became progressively fibrotic and the hyaline cartilage disintegrated and eventually disappeared. Both mechanical and chemical processes were considered to cause degeneration of cells, but enzymatic processes in particular appeared to be primarily responsible for degradation of the cartilage matrix. Synovial changes worsened with age. In those less than 20 years of age there was marked villous proliferation, whereas in all adult patients the synovium was progressively replaced showing marked thinness, an increasing tendency to avascularity, and eventual fibrous thickening. In the younger age groups the lining cells of the synovium were heavily filled with hemosiderin. There was inflammation around the synovial hemosiderin deposits. Subsynovial layers were almost totally free of hemosiderin. The cartilage was understandably thinned and degenerated. Fibrous tissue invaded from the synovial regions at the periphery of the joint and from the underlying subchondral bone and marrow. Pyknotic chondrocytes were frequently seen. The cellularity of the cartilage was increased in some areas with chondrocyte clones but in general was decreased with destruction and disappearance of damaged chondrocytes. Connective tissue often covered and partially replaced the superficial layer of the original articular cartilage. Histochemical stains revealed hemosiderin in both the superficial synovial membrane and the chondrocytes of the articular cartilage. Stein and Duthie concluded that the synovial membrane underwent extensive fibrosis with time, with scar tissue replacing the entire thickness including the lining layer. The architecture of articular cartilage was severely disrupted. Chondrocytes degenerated. At one stage they were irregu-

SECTION V ~ Hematologic Disorders

REPEATED HAEMARTHROSES

J/

SUBCHONDRAL HAEMORRHAGES

ACTIVATED PLASMIN

BLEEDS CHRONIC EPIPHYSEAL EASILY SYNOVITIS~ OVERGROWTH DUE TO

HYPERTROPHIC SYNOVIAL MEMBRANE

1 DESTRUCTION OF BIOLOGICAL "SHOCK ABSORBER"

ACCUMULATION OF INTRACELLULAR ~ IRON DEPOSITS / ~ SYNOVIAL FIBROSIS

LIBERATION OF LYSOSOMAL ENZYMES (CATHEPSIN~, D) FURTHER INFLAMMATORY RESPONSE

~

l

cartilage :eikdct:n

ARTICULAR "-* CARTILAGE BREAKDOWN

~ ~=

FIGURE 16 The sequel of changes in the pathogenesis of chronic hemophilic arthropathyas outlinedby Stein and Duthie is shown [reprinted from (201), with permission]. larly dispersed in the matrix and aggregated in cell clusters referred to as clones. With time many areas of matrix were acellular. Fibrous tissue then invaded the cartilage both from the subchondral bone and from the periphery of the synovial lining. Iron deposits were seen both in the synovial cells and even within chondrocytes. All cells containing iron deposits eventually showed degeneration and disintegration. Mechanical, chemical, and particular enzymatic effects of the hemophilic arthropathy led to articular cartilage breakdown. This is illustrated in Fig. 16 from their work. Radiologic Findings: The striking radiographic changes of hemophilic arthropathy were recognized early and in great detail (28, 88). Some felt that the radiographic features of hemophilia, once it entered the nonacute phases, were sufficiently characteristic to allow diagnosis to be made radiographically. These included generalized osteopenia, markedly increased density of the synovial tissues, enlargement of the epiphyseal bone in comparison to the normal side, narrow joint spaces, roughened articular surfaces, cystic lesions in the subchondral region, and widening and deepening of the intercondylar notch of the femur. Several observers had noted clinical evidence of joint involvement in hemophilia before the age of 10 years, with Thomas reporting 89% of 98 hemophilic patients so involved (215). In Thomas' early study of 98 hemophiliacs prior to the era of blood and factor replacement, 78% gave a history of joint involvement and 61% had permanent deformities. The distribution of joints affected was knees 68%, ankles 56%, el-

915

bows 53%, hips 16%, fingers 15%, wrists 5%, and toes 2%. In the earliest stages with acute hemarthrosis, soft tissue swelling could be noted but the radiograph was otherwise unremarkable. As the arthropathy worsened with recurrent bleeds, the soft tissue hypertrophy led to increased density radiographically, and this was often increased because of the high iron content of the synovial and subsynovial tissues. The joint space was often reduced because of degeneration of the articular cartilage. The articular surfaces of the bones became irregular and there were focal subchondral bone cystic defects noted. Petersson et al. based their classification on radiographic changes previously described in the literature, including intra-articular effusion, periarticular soft tissue thickening, periarticular soft tissue calcification, synovial thickening and increased density, enlargement of the secondary ossification centers of the epiphyses, periarticular osteoporosis, narrowed joint spaces, irregularity of subchondral surfaces, subchondral sclerosis, subchondral cysts, incongruence between articular surfaces, erosions of joint margins, and Harris lines (155, 156). They then formed their radiologic classification of changes by determining which of the preceding criteria could be quantified in some form radiologically, and each change was allotted 0, 1, or 2 points according to severity. The sum of points allotted to a given joint at each examination led to its score. The radiologic evaluation classification recommended by the orthopedic advisory committee of the World Federation of Hemophilia is shown in Table V. A widened intercondylar notch of the distal femur seen on the anteroposterior radiograph is a characteristic finding in hemophilia after recurrent hemarthroses. There can also be broadening of the radial head at the elbow. Other radiographic findings included soft tissue swelling, osteopenia, and overgrowth of the epiphysis. Later bone changes included subchondral cysts, marginal erosions, subchondral surface irregularity, widening of the intercondylar notch of the distal femur, squaring of the patella, enlargement of the radial head, and widening of the trochlear notch of the olecranon. The latest stages are characterized by articular cartilage joint space narrowing, flexion contractures, and angular deformity. An additional radiographic classification has been defined by Arnold and Hilgartner (8). Stage 1: There are no skeletal abnormalities visible on radiographs, but there is soft tissue swelling due to hemarthrosis or periarticular bleeding. Stage 2: Subacute hemarthropathy. There is osteoporosis particularly in the epiphyses along with overgrowth of the epiphyses, maintenance of joint integrity with no narrowing, and no bone cysts. Stage 3: Joint disorganization is evident radiologically but with no significant narrowing of the cartilage space. Subchondral cysts, squaring of the patella, denser synovium (hemosiderin deposit), widening of the intercondylar notch of the distal femur, and ulnar trochlear notch widening are characteristic findings. Stage 4: Narrowing of the joint space with articular cartilage destruction. Stage 3 changes are magnified. Stage 5: Fibrous joint contracture,

CHAPTER 10 ~ Metabolic, Inflammatory, Neoplastic, Infectious, and Hematoloyic Disorders

916

Radiologic Evaluation Recommended by the Orthopedic Advisory Committee of the WFH

TABLE V

Finding

Score (points)

Absent Present Absent Present Absent Partly involved Totally involved Absent Joint space > 1 mm Joint space < 1 mm Absent 1 cyst > 1 cyst Absent Present Absent Slight Pronounced Absent Slight Pronounced

0 1 0 1 0 1 2 0 1 2 0 1 2 0 1 0 1 2 0 1 2

Type of change Osteoporosis Enlarged epiphysis Irregular subchondral surface

Narrowing of joint space

Subchondral cyst formation

Erosions of joint margins Gross incongruence of articulating bone ends Joint deformity (angulation and/or displacement between articulating bones)

apossible point score: 0-13 points.

loss of joint space, extensive enlargement of the epiphyses, and disorganization of the joint structures are seen. Radiologic changes are illustrated in Fig. 17. The radiologic changes reflect the cumulative changes following large and smaller subclinical hemorrhages that have occurred. DePalma and Cotler noted irregular sub-periosteal ossification following sub-periosteal hemorrhages in some patients (45). In addition to the other epiphyseal changes described frequently, they commented specifically on premature closure of part or all of the epiphyseal plate, leading to shortening of the bone or angular deformities. DePalma and Cotler did not note a discrepancy in bone length that could be attributed to overstimulation at the epiphyseal plate to the extent that it led to an operable limb length discrepancy. We have noted very few hemophilia patients in the growth study series, despite the fact that a large hemophilia program has existed in the hospital for some time. One of the earliest summaries of accumulated information on the radiology of developing joints suffering from hemophilia was by Caffey and Schlesinger (28). As well as providing a review of earlier scattered observations, this review summarized an era in which no effective treatment for the bleeding was available. Radiologically there was advanced maturation of the bony epiphyses, enlargement of the epiphyses, and irregular and asymmetrical ossification particularly in the hip joint. They described five children who

also showed both advanced and abnormal epiphyseal development. Measurements indicated that all of the epiphyses in the involved joints were larger than their counterparts on the opposite nonaffected side. The sizes of the secondary ossification centers in the various axes were measured. There was early awareness of the acceleration of epiphyseal maturation in those with hemophilic hemarthrosis, and Holmes and Ruggles commented on the squaring and enlargement of the epiphyses in the disorder (88). There was also recognition of Perthes-like changes in the femoral capital epiphysis with pronounced hip bleeds.

Joint Evaluation Grading: Semiquantitative Criteria Established by World Federation of Hemophilia: The World Federation of Hemophilia has established some semiquantitative standards for joint evaluation (69). They consider four parameters involving pain, bleeding, physical examination, and the radiologic evaluation. The scoring system for pain goes from 0 to 3, bleeding from 0 to 3, physical examination from 0 to 12, and radiologic evaluation from 0 to 13. Following the score, any patient requiting aids to ambulation is subcategorized as B for the use of a brace or orthosis, C for cane, CR for crutches, and WC for wheelchair. Pain Scores: A score of 0 is registered if there is no pain, no functional deficit, and no analgesic use except for acute hemarthrosis. A score of 1 indicates mild pain that does not interfere with occupation or activities of daily living (ADL) and may require occasional nonnarcotic analgesic. Moderate pain is given a score of 2 when there is partial or occasional interference with occupation or ADL, use of nonnarcotic medications, and occasional narcotic medication use. A score of 3 for severe pain involves discomfort that interferes with occupation or ADL and requires frequent use of nonnarcotic and narcotic medications. Bleeding Scores: A score of 0 is given if there is no bleeding, a score of 1 if there are no major or 1-3 minor criteria, a score of 2 if there are 1-2 major or 4 - 6 minor criteria, and a score of 3 if there are 3 or more major or 7 or more minor criteria. The guidelines for a minor grading are mild pain, minimal swelling, minimal restriction of motion, and resolution within 24 hr of treatment. Guidelines for major criteria include pain, effusion, limitation of motion, and failure to respond within 24 hr. The number of occurrences is registered in terms of hemarthroses per year. Physical Examination Scores: Physical examination includes grading of swelling 0 - 2 or more with a subgradation for chronic persisting synovitis, muscle atrophy 0 or 1, axial deformity 0-2, crepitus on motion 0 or 1, range of motion 0-2, flexion contracture 0-2, and instability 0-2. Radiographic Scores: The specific criteria here have been listed in Table V. These four groups of criteria are listed in full in the paper by Gilbert published in Seminars in Hematology (69). c. Other Musculoskeletal Damage: Intramuscular Hemorrhage followed by Contractures, Ischemic Muscle Necrosis, and Neuropathies. Ischemia of the calf muscles

F I G U R E 17 Radiographic changes in patients with hemophilic arthropathy are shown. (A) Anteroposterior views of affected right elbow (Ai) and nonaffected left elbow (Aii) show decreased joint space (arrow) and premature fusion of proximal radial physis on the affected side. (B) Anteroposterior knee radiograph (Bi) shows widened intercondylar notch (arrows), joint space narrowing, and irregular subchondral bone. In a different patient, (Bii) changes at skeletal maturity show markedly diminished medial femoral-tibial joint space due to cartilage destruction. (C) Anteroposterior ankle radiograph (Ci) shows joint space narrowing and both distal tibial epiphyseal and talar cysts (lytic areas). Oblique radiograph (Cii) shows joint space narrowing and talar subchondral lysis (arrow).

918

CHAPTER 10 ~ Metabolic, Inflammatory, Neoplastic, Infectious, and Hematologic Disorders

can occur following intramuscular bleeding in which a Volkmann-like compartment syndrome evolves. One of the occasional sequelae of such an occurrence is tightness of the gastrosoleus muscle and associated Achilles tendon shortening. This can be effectively repaired with the Achilles tendon lengthening. The most common area of muscle bleeding in some series is within the iliopsoas muscle mass. This can be recurrent and leads to difficulty because of the problems immobilizing the muscle. In one study of muscle bleeding in hemophilia, the sites included the quadriceps muscle (44%), posterior calf muscles (35%), hip adductors (7%), and anterior leg muscles (7%) (9). In the study by Houghton and Duthie, over a 10-year period, muscle hemorrhage was noted in the iliopsoas in 53 (31%), thigh in 40 (24%), calf in 34 (20%), forearm in 32 (19%), shoulder girdle in 7 (4%), and buttock in 4 (2%) (89). The study involved 170 episodes. The complications of muscle hemorrhage involved limb contractures, which were present in 20% of severe calf and forearm bleeds. The other complication was neurological with nerve palsies. In the 170 patients with muscle bleeds, 43 (25%) had an associated peripheral nerve lesion. This was usually a neuropraxia or axonotmesis and, with the exception of the sciatic nerve, full recovery invariably occurred. There were 30 femoral nerve palsies complicating 53 iliacus muscle hemorrhages, and virtually all of these recovered although return to full function often took 6 months. Katz et al. completed a more detailed review of peripheral nerve lesions in hemophilia over a longer period of time, also from the Nuffield Orthopaedic Center in Oxford, England (103). They identified 88 lesions in 54 patients over a 24-year period. The femoral nerve was most commonly involved. There were 61 lesions in which long-term follow-up was obtained. In 30 (49%) of the lesions the nerve had full motor and sensory recovery, in 21 (34%) there was a residual sensory deficit, and in 10 (16%) both a persistent motor and sensory deficit was noted. Patients with antibodies to factor VIII were significantly less likely to recover full motor or sensory function, and the time to full recovery in these patients was significantly longer. The most common nerve involved was the femoral, which was affected in 31 of 61 instances (51%). The next most common nerves involved were the median (10, 16%), ulnar (7, 11%), sciatic (4, 7%), and radial (5%). The most common cause of nerve palsy was intramuscular hemorrhage. Full motor recovery was more likely than full sensory recovery. Fractures: Hemophiliacs are not considered to have an increased incidence of fractures, and with appropriate treatment any fractures that occur unite without complications within the anticipated time. Skeletal traction is contraindicated, but open reduction and internal fixation are often most helpful. In the series of Houghton and Duthie there were 23 fractures over a 10-year period (89). The most common were those of the femoral shaft (10) and tibial shaft (4). Hemophilic Pseudo-tumor: A hemophilic pseudo-tumor is a slowly progressive hemorrhage that increases in size in

a confined space (169). The most common site is the pelvis and proximal thigh, and the lesions may originate within bone, in the periosteal region, or occasionally in adjacent soft tissues. Because a pseudo-tumor is an expanding hematoma or hemorrhage it must not be biopsied or aspirated for diagnosis. No malignant change of a pseudo-tumor has been documented, although they can be confused with malignancy initially. Pseudo-tumors have always been infrequent in hemophilia and with improvements with medical therapy they are becoming even less common. They are dramatic lesions, however, and have the potential to lead to disastrous results with inappropriate intervention; hence, a clear understanding of them is essential. Rodriguez-Merchan reported on 17 pseudo-tumors within bone (169). Eight were in the femur, 2 in the pelvis, 2 in the radius, 2 in the hand, and 1 each in the tibia, humerus, and big toe. The pseudo-tumor is a progressive cystic swelling produced by recurrent bleeding involving muscle and accompanied by bone involvement. The most common sites are the proximal long tubular bones in which repeated and unresolved intramuscular hematomas may lead to encapsulation and calcification with a progressive enlargement of the mass and erosion of the adjacent bone. The pseudo-tumor is an encapsulated hematoma. The hemorrhage is chiefly extraosseus with extensive subperiosteal bleeding and reactive new bone formation. The mass expands both externally and internally causing extensive destruction of the adjacent bone. They are most commonly proximal particularly around the femur and pelvis where they start in the soft tissues and erode bone secondarily. They tend to develop slowly over many years. They occur in adults and do not respond to conservative treatment. Calcification within the mass is common. Biopsy is absolutely contraindicated because of the danger of severe and perhaps lethal hemorrhage. Many of these are simply observed and appear to progress slowly over several years with minimal damage. In those in whom there is discomfort, unacceptable bone and joint disruption, or associated neurological problems, treatment is mandatory. Extensive preoperative workup with multiple imaging techniques is essential. It is extremely important to outline the associated vascularity. The best approach, if possible, is to remove the entire mass en bloc with clear attention to its vascularity. Efforts to curette and pack the lesion are contraindicated. 4. CURRENT TREATMENT CONSIDERATIONS a. Medical Treatment. The treatment of hemophilia became effective in 1940 when whole blood transfusions were utilized to replace the missing factor VIII and IX components (47, 66, 90, 129, 227). Treatment shortly evolved into the use of fresh-frozen plasma. In 1964, cryoprecipitate was developed; it represents the protein that precipitates in freshfrozen plasma when it is thawed at 4~ which is rich in factor VIII and fibrinogen. In 1970, specific factor concentrate began to be used. Each of these methods, however,

SECTION V ~ Hematologic Disorders

919

FIGURE 18 Massiveextent of a hemophilicpseudo-tumoris shown. (A) Radiograph of pelvis shows extensiveinvolvementof left iliac bone (P). (B) Magnetic resonance image (cross section) shows extensive bone lysis and soft tissue mass (P) both anterior and posterior to iliac wing.

required the use of human blood, a situation that became devastating in terms of complications with transmission of the AIDS virus. At present, both factor VIII concentrates and cryoprecipitate are prepared from donors screened carefully for the human immunodeficiency virus (HIV). In addition, all factor VIII preparations are processed further to diminish the likelihood of any viral contaminants. Methods to destroy viruses are based on terminal heating of the lyophilized product at 80~ heating in solution at 60~ (pasteurization) in a suspension containing various organic solvents, or adding an organic solvent and a detergent during the manufacturing process. Heating serves to inactivate heat-sensitive viruses such as HIV-1. Other preparations involving solventdetergent-extracted factor VIII remove coated viruses including HIV-1 and hepatitis viruses. Because factor VIII concentrates are obtained from screened donors and have other antiviral steps performed, their use is recommended today over cryoprecipitate. The risk of transmission of hepatitis B and C viruses has also diminished because of the use of virucidal methods, but it has not been abolished completely. Many clinics turn increasingly to even safer factor VIII concentrates using either monoclonal factor VIII concentrates prepared using affinity chromatography or recombinant factor VIII, which is a synthetic product prepared in Chinese hamster ovary cells or baby hamster kidney cells. The monoclonal or recombinant forms of factor VIII have essentially no risk of hepatitis, AIDS, or hemolysis. Replacement therapy in hemophilia B includes the infusion of factor IX concentrate or fresh-frozen plasma. Cryoprecipitate and factor VIII concentrate play no role. The hemophilia community was hit particularly hard during the time period when AIDS began to flourish but its recognition within blood bank samples was neither appreciated nor specifically screened. In some clinics, approximately 90% of patients with hemophilia who had been

multiply transfused with untreated products became HIVpositive. One study showed 55% of patients with hemophilia infected with HIV-1 from 1979 through 1985, with even larger percentages of this population infected with hepatitis C. A study of mortality in patients with hemophilia between 1986 and 1992 showed that nearly one-third of deaths (27%) were related to HIV infection and only one-fifth were related to hemorrhage. Prior to the AIDS epidemic, excess mortality among hemophiliacs had always been due to intracranial hemorrhage. The magnitude of the problem was also illustrated by Rodriguez-Merchan in a review of statistics from Spain (171). Of the 435 hemophiliacs in his unit, 257 (59%) had HIV infection caused by therapy with human plasma. Of these HIV-positive patients, 95 (37%) had already developed full-blown AIDS. In Spain roughly 70% of hemophilic patients who received pooled, untreated factor VIII preparations became HIV-positive, with 90% of severe hemophiliacs so affected. One estimate of the occurrence of AIDS in hemophilia in North America listed 6% of the entire hemophilia population as having or having had AIDS. As of June 1992, more than 1600 patients with hemophilia A and no other risk factors had been given a diagnosis of AIDS. Greene et al. demonstrated that effective surgery could still be performed in hemophilic AIDS patients and listed preoperative evaluation criteria (80). AIDS was first identified in 1982 in a patient with hemophilia who had received transfusions. This number has diminished dramatically in new patients over the past few years. All blood has been screened for the HIV virus, and manufactured monoclonal coagulation factors increasingly are used, thus bypassing completely the need for human blood. Fresh-frozen plasma (FFP) contains all coagulation factors but is rarely used. Single donors with a low risk of hepatitis or other viruses continue to provide blood products needed for some cases. Cryoprecipitate contains factor VIII

CHAPTER 10 ~ Metabolic, Inflammatory, Neoplastic, Infectious, and Hematologic Disorders

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TABLE VI

Brief Outline o f Factor T r e a t m e n t for Musculoskeletal Bleeding in Hemophilia A a n d Ba Hemophilia A

Hemophilia B

Initial dose

Repeat dose

Initial dose

Repeat dose

Site or situation

(U/kg)

(U/kg)

(U/kg)

(U/kg)

Acute hemarthrosis Early

15-30+

Rarely needed

20

Rarely needed

25-50+ 25-50+

25 ql2h 25 ql2h, often for several days

40-80+ Mild to moderate: 20-40 Severe: 80

20-25 q24h 30 q24h, often for several days

25 q-12h or 25 followed by continuous fusion IV 3-4 UNg/hr

80

40 q24h or loading dose plus continuous IV fusion

Late Intramuscular hemorrhage

Major surgery or trauma

50

Desired range of factor levels

Early (less than 3 hr from onset): raise factor level to 25-30%, repeat if needed clinically Late: raise factor level to 50-100% Major: calf, forearm, iliopsoas, hip; raise factor level to 100%, maintain several days to several weeks, taper range to 30-50% for additional periods Minor: other areas, superficial bleeds, raise factor level to 50%, usually for 2-3 days only Initially 100%; 50% early heeling; 30% late heeling

aAbstracted from Boston Hemophilia Center guidelines, 2/98, B. Ewenstein, E. Neufeld, J. Gorlin; see also D. DiMichele, ref 47; + lower ranges represent "textbook" responses of 1 U/kg = 2% factor increase.

and fibrinogen and still can be used in hemophilia A and von Willebrand's disease. Each bag is also manufactured from one donor with a low risk of hepatitis or other viruses. The most commonly used treatment now is genetically engineered recombinant factor VIII or plasma-derived, monoclonal-antibody-purified factor VIII for hemophilia A. Desmopressin (DDAVP) increases the plasma levels of factor VIII and von Willebrand factor and can be used for nontransfusional treatment of patients with mild or moderate hemophilia and von Willebrand's disease (128,227). An outline of factor replacement in varying bleeding and operative situations is shown in Table VI. b. Early Intervention for Bleeding Episodes. The most common approach to medical management in North America has involved early intervention for bleeding episodes with increased factor given at the onset of discomfort and, if possible, even prior to the observation of joint swelling. This approach is often referred to as an on-demand treatment. This treatment involves the use of home infusion of factor VIII without the need to be seen initially at a hospital or a clinic. Most clinics and families use this approach, which is based on patient and parent awareness of the earliest symptoms of disorder and easy communication between families and comprehensive hemophilia clinic personnel. c. Prophylactic Factor VIII Coverage. Over the past several years, a treatment approach involving continual prophylactic use of factor VIII has become more popular particularly in western Europe (2, 143, 182). This approach seeks to maintain the factor VIII levels in a therapeutic range of 1-5% at all times rather than reacting to the occurrence of

joint bleeding. This level is chosen because moderate severity hemophiliacs rarely develop significant arthropathy. The prophylactic treatment converts severe patients to a moderate or even mild grading. The infusion of factor VIII is done three times weekly and factor IX twice weekly. Trials in Europe extending as far back as three decades have been positive. A major Swedish study of prophylactic treatment for hemophilia A and B in 60 severe hemophiliacs (52 A, 8 B) has been reported (143). Treatment was started when the boys were 1-2 years of age with a regimen of 24-40 IU of factor VIII kg -1 three times weekly for hemophilia A (greater than 2000 IU kg -1 annually) and 25-40 IU of factor IX kg-1 twice weekly for hemophilia B. Of those subjects aged 3-17 years, 29 out of 35 individuals had joint scores of 0 (normal). Factor VIII and IX concentrations were designed not to fall below 1% of normal. The study concluded that it appeared to be possible to prevent hemophilic arthropathy by giving effective continuous prophylaxis from an early age and preventing factor VIII and IX concentrations from falling below 1% of normal. The treatment served to convert hemophilia from a severe to a moderate form, thus preventing joint bleeds and hemophilic arthropathy. The best results were obtained when treatment began at the age of 1-2 years with factor VIII given in dosages of approximately 3000 IU kg -1 annually. Studies have also been performed in Germany, with one study analyzing 70 patients treated actively when bleeding occurred and 17 receiving factor VIII regularly on a prophylactic regimen for a mean of 4.5 years (182). Both pediatric and adult patients were included. The mean age of the pro-

SECTION V ~ Hematologic Disorders

phylactic group was 18.9 years. The prophylactic group missed fewer days of work due to joint bleeding. There was less differential in relation to joint pain, but the on-demand therapy patients experienced more pain with increasing age. The age of the patient was considered to be more important than treatment strategy in the development of joint symptoms. To be most effective, prophylactic regimens should be started in the very young prior to any occurrence of joint pathology. Because of the extremely high cost of prophylactic treatment, the German group felt that specific indications for its use should be developed rather than simply offering the treatment to all hemophilic patients with severe involvement. A longitudinal study of orthopedic outcomes for severe factor VIII deficient hemophilia was performed by Aledort et al. (2). Twenty-one international hemophilia centers were used to assess patients over a 6-year period. Physical and radiologic examinations of ankle, knee, and elbow involvement were assessed. The study population involved those with severe factor VIII deficiency (less than 1% factor) under the age of 24 years without inhibitors. Some patients were treated on a prophylactic regimen, but most had an ondemand response for any joint bleeding. The authors concluded that year-long prophylaxis significantly reduced the rate at which joints deteriorated by both physical examination and radiographic criteria. Patients on prophylaxis had significantly fewer days lost from work or school and fewer days spent in the hospital. Aledort et al. concluded that higher doses of factor in themselves did not produce improved orthopedic outcomes but that full-time prophylaxis was likely to produce the best orthopedic outcome. The most critical factor for a good orthopedic outcome was diminution in the number of joint bleeds. Full-time prophylaxis had been assessed in 66 of 477 patients with appropriate physical examination data and 53 of 323 patients with full radiographic data. These assessments led the authors to conclude that prophylaxis significantly reduced the rate at which joints deteriorated and that it did so by dramatically reducing the number of bleeds, thus minimizing joint damage. The number of days lost from work or school was significantly lower in the entire population studied for those who received > 2000 units of factor VIII/kg per patient per year. Patients treated with on-demand therapy progressed significantly more than those on prophylaxis. The obvious observation was made, however, that those on prophylaxis required significantly more factor than those on on-demand therapy. The authors felt that their findings strongly supported the previously mentioned Swedish experience that a high dose of regular prophylaxis starting at a very young age can maintain hemophilic joints in an essentially normal range for prolonged periods of time. Prophylaxis, however, could decrease the rate of deterioration of patients' joints if begun after some damage was already present. If prophylaxis was not performed, doses of factor VIII from 25 to 40 units/kg per bleeding episode were best in reducing the progression of arthropathy. This approach is currently reserved for those

921

in the severe category, partly because it is enormously expensive and the need to maintain comfortable, infection-free continuous intravenous access can be problematic. d. Inhibitors. Despite continuing improvement in the effectiveness of treatment for hemophilia A, the development of factor VIII inhibitors remains a serious problem. Factor VIII is a foreign protein for most patients with severe hemophilia. Because the antibody develops against factor VIII itself the fact that monoclonal purified concentrates are used increasingly does not change the development of the inhibitor effect. Hoyer has summarized the various strategies used for patients with inhibitors (90). Possible reasons for high numbers of inhibitor patients include the increased use of factor VIII, for example, in prophylactic regimens, and perhaps stronger antigenicity of clotting factors. A study by Ehrenforth et al. clearly delineated the severity of the problem, although they did not feel that antibody formation was greater using the monoclonal recombinant factor VIII (53). In a long-term study, they assessed 63 children with hemophilia A and 17 with hemophilia B. Only those with severe and moderate forms were analyzed because very few patients with mild hemophilia of either type ever develop inhibitors. Factor VIII inhibitors developed in 15 of 46 (33%) hemophilia A patients. The percentage was greater in severe hemophilia, with 14 of 27 (52%) developing inhibitors compared with only 1 of 19 with moderate hemophilia. If patients with mild hemophilia were also taken into account, the proportion affected was still 24% in the entire group (15 of 63). Inhibitors developed quickly with the mean number of exposure days only 11.7. Inhibitors developed by age 1 year in 33% of the affected patients, by the age of 2.5 years in 73%, and by the age of 5.2 years in all who were destined to develop them. In no patient did an inhibitor first develop after age 6 years. Virtually all patients with factor VIII deficiency who developed inhibitors were those in whom factor VIII activity was less than 3% (53). Because previous studies tended to include all patients the number of patients affected with inhibitors was relatively lower. If one limits the study to severe and some moderate patients, the number correspondingly increases. New inhibitor formation occurred in 24% of all hemophilic patients, in 33% of those with factor VIII levels of 5% or less, and in 52% of severe hemophilic patients with factor levels less than 1%. In larger studies inhibitors rarely develop after the age of 11 years, and the greatest risk of inhibitor formation is before the age of 5 years. Data in this study are higher than those reported elsewhere. The general consensus is that in moderate and severe hemophilia A inhibitors develop in 20-33% of patients. Inhibitors are much less common in factor IX deficiency. Previous reports indicated that inhibitors to factor IX developed in only about 3% of all patients with hemophilia B or 7-10% of those with severe disease. e. Pain M a n a g e m e n t . The best form of pain management in hemophilia is the use of factor VIII or IX replacement plus splinting of the involved joint. Analgesics are

922

CHAPTER IO

~

Metabolic, Inflammatory, Neoplastic, Infectious, and Hematologic Disorders

often helpful. The use of aspirin is contraindicated because of its tendency to further limit platelet adhesiveness and particularly to predispose one to gastrointestinal bleeding. Nonnarcotic analgesics such as acetaminophen are favored particularly in the childhood and adolescent age groups. On occasion, acetaminophen and codeine or propoxyphene can be added. If chronic hemophilic arthropathy causes discomfort because of the arthritic component, nonsteroidal medications can be used. Trilisate is preferred, but ibuprofen and naproxen can also be used with close observation for a change in bleeding patterns. f. Orthopedic Management. The orthopedic management of hemophilia has been modified and aided greatly by the use of factors VIII and IX. Factor VIII and IX concentrates treated to inactivate viruses or produced by recombinant technology in viral-free environments prevent or control bleeding in most patients. Whether factor VIII is used as a prophylactic or immediately upon the onset of joint symptoms, the results have markedly improved the management profile from those described two and three decades ago. The mainstay of orthopedic management for intra-articular, periarticular, or intramuscular bleeding is rest of the involved limb, factor replacement, and gentle reinstitution of motion and muscle strengthening once the bleeding symptoms are controlled. Joint aspiration plays virtually no role currently in the management of the hemophilic patient. The nature of the immobilization during the acute phase is dependent on the joint involved as well as the age and activity level of the patient. We never use solid circumferential casts in the upper extremity in which the elbow is most commonly involved, preferring either a sling in a particularly cooperative patient or a sling and bivalved long arm cast in one who is less cooperative. Increasingly, a bivalved cylinder or long arm cast is used when splinting and/or factor VIII replacement has been ineffective. Immobilization of the knee involves the use of a knee immobilizer or bivalved long leg cylinder cast and crutches, and at the ankle either a posterior splint, a bivalved short leg fiberglass cast, or a lightweight air splint is used along with crutches. Immobilization is recommended for a few days followed by active range of motion exercises and eventually by muscle strengthening as part of the rehabilitation process. The ankle has proven to be the most difficult joint to maintain at a high functioning level. Ribbans and Phillips stated that there was no evidence that the pattern of ankle function had improved despite advances in medical therapy over the previous four decades (164). g. Recalcitrant Joints. On occasion, the return of normal function with full resolution of synovial thickening and joint effusion is difficult and more intensive or prolonged mechanical treatment measures are needed. It remains extremely important to quieten the synovitis such that splints or bivalved casts must be used frequently. It is not appropriate, in our opinion, to rely completely on factor replacement to treat a hemophilic hemarthrosis. If there is a recurrence of

bleeding after seemingly quietening the disorder, then further protection particularly at the ankle area can be achieved with a solid ankle AFO followed by a hinged AFO to allow for joint motion in a controlled plane. In situations in which the synovitis and bleeding are recurrent even with seemingly excellent control of factor VIII, two possible modalities have been used to control the synovitis. h. Surgical Synovectomy. Prior to the availability of factor VIII concentrate in the late 1960s, major reconstructive surgery was simply not attempted for patients with hemophilia. Once factor replacement became feasible, however, orthopedic surgical intervention was used widely to help alleviate some of the damage to involved joints. Synovectomy has played a major role in the surgical treatment of hemophilia ever since factor VIII and IX replacement became feasible. It is resorted to when recurrent joint hemarthroses prove to be difficult or impossible to control with factor replacement and nonoperative orthopedic measures. In many instances, the synovitis reaches a degree of magnitude that appears manageable only by synovectomy. Removal of the synovium from a hemophilic joint is a major debulking procedure that removes a thickened, hypertrophic, hypervascular mass of tissue, which is releasing toxic enzymes such as cathepsin D into the joint environment, serving as a source of repeat hemorrhage due to its extreme friability, and showing ineffectiveness in resorption. The procedure is not without its complications, however, and considerable controversy continues in regard to indications for it. Some clinics resort to it after two or three episodes of poorly controlled hemarthrosis, whereas others wait for several episodes until the synovium is so hypertrophied that resolution of a spontaneous nature would appear impossible. The procedure itself can induce considerable bleeding and fibrosis such that postoperative factor and rehabilitation management must be extremely rigorous. There must be maximal hemophilic control. Rehabilitation must also be maximized. The use of the continuous passive motion apparatus has been extremely helpful particularly in relation to synovectomy at the knee. With the increasing use of arthroscopic synovectomy, a further decision must be made between open and closed procedures. Much of the choice is dependent upon the expertise of the surgeon, but we have been more impressed, both in personal experience and in reviews of the literature, with open synovectomy for the knee as well as the elbow, hip, and ankle, although the closed procedure in expert hands has much to recommend it. A lengthy midline or medial parapatellar incision is used for the knee. Depending on the extent of synovial hypertrophy, a posterior incision may also be needed. In some adolescent patients a Baker's cyst is present, which virtually mandates an additional posterior incision for removal. Use of the continuous passive motion apparatus for 10 days to 2 weeks postsurgery has been extremely helpful in minimizing postoperative stiffness and eliminating the need for manipulations with all the risks they entail.

SECTION V ~ Hematologic Disorders

Synovectomy was first used widely for hemophilic arthropathy in the mid-1960s, with early reports by Storti et al. of Italy noting positive results (206). Storti and Ascari reported that they had performed 63 synovectomies for hemophilia A and B between 1966 and 1975 (205). By removing the highly vascularized synovial tissue they sought to prevent or at least minimize further bleeding. The synovectomy was thus viewed as a "hemostatic" procedure. The operation was performed when the synovial membrane had undergone a series of hypertrophic changes after repeated hemorrhages such that it was highly prone to further bleeding with minimal to no trauma. The increased vascularization was accompanied by proliferation of the synovial lining into innumerable villi, each with a central vascular stem. A selfperpetuating cycle was established in which hemarthrosis led to synovial hypertrophy, which itself was highly vascularized and led to recurrent hemorrhages with even more minimal trauma. Review of the results following knee synovectomy showed a significant diminution of recurrence of hemarthrosis episodes. In 48 knee joints (94%) the markedly reduced recurrence of hemarthrosis was observed. In 34 (66%) the hemorrhage had been completely stopped; whereas in 14 (28%) there were occasional episodes of mild knee swelling of short duration, these being much less severe than the preoperative episodes. Storti and Ascari also noted increases in joint function with knee joint mobility improved in 28 cases (55%), unchanged in 17 cases (33%), and worsened in only 6 cases (12%). In their discussion, they reviewed results from several European clinics during the same time period also showing good to excellent results from the procedure and the associated medical control. Luck and Kasper reported on knee synovectomy and debridement, either open or arthroscopic, in 62 patients (125). Results reported in open and closed arthroscopic synovectomy for the knee have been roughly comparable. In general, there is perhaps slightly increased range of motion maintained after the arthroscopic approach, but most feel that open visualization allows for a more effective removal of synovial tissue. Rodriguez-Merchan et al. performed 18 open and 9 arthroscopic synovectomies and felt that the procedure by both methods significantly reduced bleeding episodes (172). Arthroscopic synovectomy can lead to good short-term and long-term results (229). It was recognized, however, that these were still essentially palliative procedures, which appeared to slow but did not halt deterioration of the joints. One of the problems following knee synovectomy has been stiffness. In a study by Montane et al. completed before development of the concept of postoperative continuous passive motion, knee synovectomy in 10 of 13 patients was followed by a mean loss of 41% of motion (141). De Gnore and Wilson reported on 34 synovectomies: 16 of the knee, 15 of the elbow with radial head excision, and 3 of the ankle (44). The average number of bleeding episodes preoperatively was 26 per yearin the target joint, and with an average follow-up of 4.8 years there was a marked diminution in the

923

number of bleeding episodes after surgery to 4 per year. The continuous passive motion machine was utilized in the first week postsynovectomy. The general consensus of opinion is that synovectomy relieves pain, decreases swelling, and diminishes the number of bleeding episodes per year. It is clearly not curative and one of the earlier complications was joint stiffness. Post et al. reported on a 5-year follow-up of 12 knee and 4 elbow synovectomies with the previously mentioned impressions (161). In their small group of patients, elbow motion was reduced significantly. Favorable results were also reported in open synovectomy of the elbow by Balc'h et al. (11). They reported on 23 elbow synovectomies in 18 patients 8-25 years of age. Those elbows operated after skeletal maturity frequently had associated resection of the radial head. The authors noted a significant improvement in mobility for pronationsupination in 9 elbows and for flexion-extension in 14. Episodes of bleeding were diminished markedly. They strongly recommended the open synovectomy performed through a single lateral incision in those hemophiliacs in whom the nonoperative treatment had failed. i. R a d i a t i o n S y n o v e c t o m y . Radiation synovectomy has been used in some centers but has not received governmental approval for unrestricted use in the pediatric age group in the United States. Radioactive substances are injected into the joint to damage and/or kill synovial cells once they are absorbed into them (63, 134, 194). Radiation synovectomy has been reported using radionuclides such as yttrium-90, gold-198, phosphorus-32, and Rhenium-186. Merchan et al. reported on a long-term series of results with the use of gold-198 in the treatment of hemophilic synovitis of the knee (134). They described treatments in 38 males with a minimum follow-up of 13 years and representative of treatment between 1974 and 1976. One hundred affected joints in 64 patients were injected with a single dose of gold-198. Follow-up was limited to those who had survived and had not had subsequent surgical synovectomy. The results based on the difference between the clinical joint score of the year before injection and the year of review were good in 8 (21%), fair in 23 (60%), and poor in 7 cases (19%). There were more good results, 31%, in those with a stage I (milder) grading than in those with a stage II (more advanced) grading at the time of intervention, in whom only a 14% good rating was achieved. Good and fair results were also more common in those whose symptoms were less than 1 year before injection compared with those greater than 1 year. Merchan et al. concluded that there was a degree of effectiveness that might subsequently be improved with other radioactive agents or different protocols. Fernandez-Palazzi et al. briefly reviewed the use of radiation synovectomy for hemophilic hemarthrosis (63). They reported on 50 procedures in 43 of their patients, whose ages ranged from 6 to 43 years. They concluded that there was a significant reduction of hemarthroses, immense diminution of the amount of

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CHAPTER IO ~ Metabolic, Inflammatory, Neoplastic, Infectious, and Hematologic Disorders

antihemophilic factor needed, and a markedly diminished period of treatment needed for the patient because basically only an injection was required. Fernandez-Palazzi et al. estimated that good results had been obtained in 80% of patients, which was felt to be similar to the results with the more invasive surgical synovectomy procedures. A possible problem with the technique is concern that the damaging effects of the radioactivity are not strictly limited to the synovium but could clearly also affect the articular chondrocytes that already are abnormal because of the repeated episodes of hemarthrosis. Although this has not been studied in detail, it remains a primary biologic concern. j. Soft Tissue Releases and Lengthenings. Once a joint has been effectively quietened either with medical and physical therapy alone or with the association of synovectomy, persistent tightness and rigidity can be improved with soft tissue releases and tendon lengthenings. Those areas most frequently approached by these techniques are the posterior knee and particularly the ankle area where Achilles tendon lengthening with or without posterior ankle capsulotomy can be most beneficial. k. Osteotomy. In many patients, angular deformity occurs due to the relative overgrowth of one side of a physis in relation to the other, which can cause valgus, varus, or flexion deformities particularly at the major lower extremity joints, the knee and ankle. Fibrous contractures also contribute to the malalignment. In those instances in which rehabilitation physical therapy is not effective or in which bony deformity is too great, osteotomy has been shown to improve alignment. The most common joint deformity is a flexion contracture of the knee, often associated with a valgus, external rotation deformity. Distal femoral supracondylar osteotomy may be required especially if 25 ~ of flexion persists with nonoperative management. The hyperextension osteotomy should always be accompanied by some bone shortening to prevent neurovascular bundle stretching. Good results have been reported at the distal femur (196), proximal tibia and fibula, and also distal tibia and fibula in the supramalleolar region (152). 1. Arthrodesis. Once operative therapy became feasible with appropriate factor VIII and factor IX coverage, many joints had been so damaged that arthrodesis alone appeared to offer effective relief. This allowed for the correction of angular deformity and elimination of pain. The joint fused most commonly and most effectively has been the ankle. With the increasing effectiveness of total hip and total knee arthroplasty, these two joints now rarely are considered for fusion. When bleeding occurred in the ankle in the second decade, there was a tendency for relatively rapid degeneration of the joint to occur with flattening of the talus, markedly diminished joint motion, overgrowth of the medial side of the distal tibial epiphysis, and a valgus alignment of the ankle joint. Gamble et al. protected the ankle by casts and orthoses, but they felt that compliance with treatment in this age group was poor (67). In those joints not responsive to

treatment, synovectomy was apparently not used and with degeneration of the joint there was a relatively early resort to arthrodesis. The results were good in terms of stabilizing the ankle, correcting equinus deformity, and eliminating discomfort and recurrent episodes of bleeding. The most common approach is still to perform a synovectomy, and reports of this in hemophilia have been made. m. Adult Surgical Treatments. Although treatment of the adult hemophiliac is beyond the scope of this presentation, it should be noted that total hip and total knee arthroplasty have been highly effective in adult patients with destroyed joints. The complication rate is much higher than in otherwise uncomplicated joint arthroplasties, but relief of discomfort and improvement of range of motion are most beneficial to the patients. Other procedures in the adult with severe joint destruction have involved synovectomies, excision of the radial head at the elbow, fusion of the ankle and knee, and patellectomy, meniscectomy, and debridement of the knee. An excellent review of 168 procedures over a 20-year period in end stage adult hemophilia was presented by Luck and Kasper (125).

B. Von Willebrand Disease Von Willebrand disease is a mild bleeding disorder, which must be distinguished from hemophilia (165). It is now recognized to be the most common congenital bleeding disorder, affecting as many as 1% of the population. Von Willebrand factor plays two major roles in normal hemostasis (226). It is the cofactor for platelet adhesion and the carrier protein for factor VIII. When abnormal yon Willebrand factor fails to bind to factor VIII, the clinical picture resembles hemophilia. It is very rare, however, that the clinical bleeding disorder is anything more than mild. Most of the clinical manifestations of yon Willebrand disease relate to superficial or postoperative bleeding such as epistaxis, menorrhagia, and cutaneous hemorrhage. There are three types of yon Willebrand disease (vWD). (1) Type 1 vWD. Most common type, affecting 70-80% of patients. Caused by partial shortage of vW factor protein. (2) Type 2A vWD. Affects 15-30% of people with vWD. Caused by absence of an important part of the vW factor protein, high-molecular-weight multimers (HMWM), which are needed to help form blood clots. (3) Type 2B vWD. Affects 15-30% of people with vWD. The vW factor protein does not work properly and binds to platelets in the wrong way. This can lead to both a shortage of vWD protein and a shortage of platelets. (4) Type 3 vWD. This is the rarest form of vWD, affecting only 1 person per million. The blood does not clot properly due to an almost complete shortage of vW factor protein. These patients also may have a shortage of factor VIII. Treatment for vWD in the milder variants is by desmopressin available as a highly concentrated nasal spray, although it also can be used as an injection (DDAVP-

SECTION V ~ Hematologic Disorders

desmopressin acetate). In the more severe forms or when surgery is needed, the treatment of choice is replacement therapy with a factor concentrate. The only vW factor protein concentrate approved for use in the United States today for vWD is Humate-P antihemophilic factor-von Willebrand factor complex (human) manufactured by Aventis Behring (165).

C. Hemoglobinopathies: Sickle Cell Anemia and Thalassemia 1. OVERVIEW The hemoglobinopathies can lead to bone growth problems primarily due to osteonecrosis, which is a characteristic of sickle cell anemia, and premature fusion of physes, which is a characteristic of thalassemia. In these diseases autosomal dominant mutations of the hemoglobin gene lead to disorders of hemoglobin structure and a tendency to premature breakdown and change of cell shape from a round concave disk to a pointed ellipse or sickle-shaped cell (25, 46, 116). The three most important abnormal hemoglobin genes are the sickle gene hemoglobin S, hemoglobin C, and the thalassemia gene. When an abnormal hemoglobin gene is inherited from both parents, the patient will show the clinical features of a hemoglobinopathy. When an abnormal hemoglobin gene is inherited from only one parent, there are usually no clinical manifestations and the involved patient is said to have the sickle trait. Hemoglobin C abnormalities tend to be mild. Sickle cell disease is a hemoglobinopathy that causes sickling of the red cells, leading to thromboembolic infarcts in bone. There is increased hemolytic destruction of inefficient sickle red cells, and subsequent erythroblastic activity increases the volume of the marrow cavity, leading to the appearance of increased lysis radiographically. The normal fetal hemoglobin (HbAF) is gradually replaced by sickle cell hemoglobin (HbSS) within the first year of life. The normal hemoglobin genotype is HbAA. When sickle hemoglobin (hemoglobin S) is deoxygenated, the replacement of [36glutamic acid with valine results in a hydrophobic interaction with another hemoglobin molecule, triggering an aggregation into large polymers (25). The polymerization of deoxygenated hemoglobin S is the primary event in the pathogenesis of sickle cell disease, resulting in distortion of the shape of the red cell and a marked decrease in its deformability. These rigid cells are then responsible for the vasoocclusive phenomena that characterize the disease. 2. CLINICAL CHARACTERISTICS Those with severe sickle cell disease, generally referred to as sickle cell anemia, are affected by multiple episodes of pain and by sickling crises, which lead to vaso-occlusive disorders. These in turn can lead to stroke, acute chest syndromes, impaired neuropsychological function, and premature death. Sickle cell disease is present when the abnor-

925

mal hemoglobin gene is inherited from both parents (HbSS). When the gene is inherited from only one parent, there are usually no clinical manifestations and the patient is said to carry the sickle trait only (HbAS), which has no clinical significance in relation to the skeleton. The disorder is far more problematic in homozygous HbSS than in heterozygous HbAS or HbSC. Acute osteomyelitis is common, and often the early stages cannot be distinguished clinically from the vaso-occlusive crises of bone infarcts. Chronic osteomyelitis can occur. Salmonella is the major organism involved with osteomyelitis in this disorder, accounting for 65-80% of cases. Other problems involve leg ulcers and growth retardation particularly in the early years of life in those with active crises. This rarely leads to short stature because in many skeletal maturation is delayed, allowing normal height to be reached. A large study of 3578 patients with sickle cell disease found the number of pain episodes per year to correlate well with frequency of death in patients greater than 20 years of age, with those with high rates of pain episodes tending to die earlier than those with low rates (160). High rates were associated with high hematocrit and low fetal hemoglobin levels. Mortality was greatest in sickle cell anemia and sickle [3(0)-thalassemia and lower in hemoglobin SC disease and sickle [3(+)-thalassemia. The fetal hemoglobin level had a strong influence on the pain rate without a threshold effect. Increments in the fetal hemoglobin level were beneficial even when the level was low. The presence of fetal hemoglobin in effect converted the severity of the sickle cell disorder to those with the milder hemoglobin SC disease. Thalassemia is a form of hemolytic anemia and sickle cell disease common in those of Italian and Greek descent and previously was referred to as Mediterranean anemia. The severe variant referred to as sickle [3-thalassemia (S [3thalassemia) results from inheritance of a sickle (S) gene from one parent and a [3-thalassemia gene from the other. In the " + " type some normal [3-chain is produced, and in the "0" type no normal [3-globin is produced. Even in the severe forms, bony changes are only slight during the first year of life. Bony abnormalities frequently affect the femurs and vertebral bodies. The vertebral bodies are osteopenic and may be flattened with prominent cupping due to displacement of the adjacent intervertebral disks. The cortices are thin and the trabeculae are markedly reduced in number. On occasion, there is shortening of the spine without deformity, but instances of scoliosis or kyphosis also occur. The cortex of the long bones tends to be thinned and the marrow cavities are widened and prominent. Angular bone deformities occur due to the structural weakness. Premature fusion of the epiphyses of long tubular bones has been noted in severe cases of thalassemia. When this is asymmetric in relation to left and right femurs or tibias, length discrepancies occur. When asymmetric involvement occurs within the same epiphysis, angular deformity also is seen. The head of the humerus is often found to be tilted medially into a varus position.

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CHAPTER 10 9 Metabolic, Inflammatory, Neoplastic, Infectious, and Hematologic Disorders

3. MOLECULAR AND OTHER APPROACHES TO THERAPY

It was felt that therapy with drugs such as hydroxyurea, which increased the production of fetal hemoglobin, could reduce the pain rate and by implication improve survival (159, 160). Molecular approaches to therapy currently being investigated include chemical inhibition of hemoglobin S polymerization, reduction of the intracellular hemoglobin concentration, and pharmacological induction of hemoglobin F because F is a very potent inhibitor of the polymerization of deoxyhemoglobin S (25, 57). Hemoglobin E therefore, inhibits sickling and drugs that could increase its synthesis would be expected to benefit patients with sickle cell disease. Hydroxyurea has been used widely to enhance hemoglobin F production in patients with sickle cell anemia. Bone marrow transplantation has been used effectively to cure sickle cell anemia, but the complications of this treatment can be devastating and considerable concern exists as to its advisability for this disorder, (159, 224). At a minimum, only severely symptomatic cases of sickle cell disease are considered in most centers (sickle cell anemia, HbSS; sickle cell hemoglobin C disease, HbSC; and sickle cell [3-thalassemia). 4. PATHOPHYSIOLOGY OF BONE DISEASE IN HEMOGLOBINOPATHIES

Jaffe noted that the more specific changes in the bone result from (1) hyperplasia of the erythroblastic elements of the bone marrow; (2) plugging or thrombosis of local blood vessels by masses of sickle cells; and (3) a complicating infection, usually salmonella, involving bones at the site of infarcts (97). In a patient with sickle crisis there may be an anemia, but it is the thrombotic episode with fever and leukocytosis along with pain that simulates an acute bone or joint infection. When a bone is the main site of thrombosis acute osteomyelitis is suspected, and if in a joint acute arthritis may be suspected. Two pathological processes are involved: (1) sickling of the red cells results in thrombotic infarcts in bone, which cause pain, crises, and in some cases, osteomyelitis; and (2) increased destruction of inefficient sickle red cells produces hemolysis. Pathologic occurrences in bones in sickle cell disease are due to blockage of the microcirculation, which causes infarction of the bone marrow and adjacent bony trabeculae. The marrow infarcts occur during generalized vaso-occlusive crises and are the main cause of pain. Bone marrow aspirated from areas of infarct during crises actually shows necrotic hemopoietic cells. The earliest skeletal symptoms in crises often occur in the digits and are referred to as dactylitis or the hand and foot syndrome. This occurs in approximately 60% of patients presenting between the ages of 9 months and 4 years with painful tender swelling of the hands and feet along with fever and leukocytosis. The discomfort is caused by expansion of the bone at the metaphyseal regions. Bone and joint pain then occurs between 3 years of age and skeletal maturity.

Diggs has pointed out that the bone marrow in sickle cell anemia is hypercellular and contains little fat (46). Even in infants the red marrow fills all of the marrow spaces, including the small bones of the hands and feet. In older children and adults, the marrow recedes from the tubular bones of the hands and feet but persists in the carpal and tarsal bones and the shafts of the long bones. The cellular marrow extends into the widened Haversian and Volkmann canals within the cortices. There is widening of the medullary cavities and intertrabecular spaces and thinning of both trabecular and cortical bone. Avascular necrosis is most common in the femoral head and to a lesser extent in the humeral head. It is the femoral lesion that is most disabling. Due to necrosis of the bone and the poor ability to repair, an involved femoral head almost invariably proceeds to complete degeneration with the need for early arthroplasty. Necrosis also tends to occur in the vertebral bodies, which not only causes considerable back pain but also flattening of the vertebrae due to osteoporosis. The pathoanatomy is characterized by a hypercellular marrow, superimposed on which is vascular occlusion due to sickled erythrocytes and increased viscosity of the blood, chronic stasis, and hypoxia. Focal areas of ischemia thus occur. Chung and Ralston have reviewed the stages of femoral head necrosis in sickle cell anemia (39). The bone changes, as noted by Diggs, fall into two categories: (1) those due to erythroid hyperplasia, and (2) those due to thrombosis and infarction. They have summarized the changes extremely well. Hyperplastic changes involve the following: the vertebral bodies (osteoporosis with biconcave cupping and bulging of the disks); the skull (loss of trabecular definition, thinning of the outer table, hair-on-end appearance, localized osteoporosis, lamellated new bone); the fiat bones (osteoporosis, widening of the trabecular pattern, cortical thinning); and the long bones (osteoporosis, widening of the medullary canal, thinning of the cortex, and widening of the diaphyseal trabeculae). The changes associated with thrombosis and infarction are seen in the vertebra (massive infarction with collapse); the small tubular bones (periostosis, cortical destruction); the flat bones (patchy sclerosis); the shafts of long bones (cortex thickened and sclerosed, patchy and irregular segmental necrosis); and the epiphyses (retardation of growth, acceleration of growth, and necrosis and collapse).

a. Femoral Head Osteonecrosis. The major problem referable to the epiphyses is avascular necrosis with the disorder becoming apparent clinically between the ages of 10 and 15 years (46, 76, 86, 112). The head of the femur is affected most commonly after puberty. Milner et al. studied a large group of 2590 sickle disease patients who were over 5 years of age at entry (136, 137). Hip radiographs were taken at least twice several years apart in the large group followed for an average of 5.6 years. The overall prevalence of osteonecrosis of the femoral head in sickle cell disease is about 10%. Patients with the hemoglobin SS genotype + oLthalassemia were at the greatest risk for osteonecrosis. The

References patients with hemoglobin SS genotype alone had approximately the same extent of involvement as those with the hemoglobin SC genotype. Intermediate rates of osteonecrosis were seen in those with hemoglobin S 13-thalassemia of either type. Osteonecrosis was occasionally found in patients as young as 5 years old. It was further noted that 3% of the patients under 15 years of age had osteonecrosis. Virtually none of these, however, were of the thalassemia or hemoglobin SC variants. For the entire series the prevalence of osteonecrosis of the hip was 9.7%. This was 10% in SS, 11.9% in S 13 0, 9.1% in SC, and 6.9% in S 13 +. There was progressive involvement the older the patient. In those from 5 to 9 years of age involvement was only 1.3%, and in those from 10 to 14 years of age it was 4.6%. At each decade following 15 years of age the rate of involvement increased. When disease was present it was bilateral in 54.2%. The estimated median age at diagnosis was 28 years for the most severe hemoglobin SS 13-thalassemia group, 36 years for those with hemoglobin SS alone, and 40 years for those with hemoglobin SC. In approximately half of the patients in whom osteonecrosis developed during the time of the study, no pain or limitation of motion was initially noted. A high percentage of patients went on to hip arthroplasty. The lesions appear like those of Legg-Perthes disease, although those affected are somewhat older than those with Perthes. The disorder begins with subchondral sclerosis, progressing to a Pertheslike necrosis and finally to total collapse of the femoral head with degenerative changes of osteoarthritis occurring 5 - 1 0 years later regardless of the age of the patient. Early management appears to have no beneficial effect. Avascular necrosis of the hip generally leads to a disabling disorder necessitating relatively early intervention with hip arthroplasty. When osteonecrosis occurs in the femoral capital epiphysis prior to skeletal maturity, healing can occur but distortion of the head similar to that in Legg-Perthes disorder is seen almost invariably. This is particularly true because the osteonecrosis occurs later than in patients with Perthes disease and generally is not seen until just before skeletal maturity. The patients do not tend to do well. In a study by Hernigou et al. assessing 95 affected hips in 52 patients with sickle cell disease, whose osteonecrosis of the femoral head occurred between the ages of 7 and 15 years, 80% of the hips were painful and showed permanent damage with decreased mobility, limb length discrepancy, and an abnormal gait at a mean follow-up of 19 years (86). When patients were evaluated at an average age of 31 years, 15 hips (16%) had already undergone surgery and 60 (63%) had major problems due to pain. Premature closure of the physis was seen frequently. The premature closure, however, either was across the entire physis leading to a short femoral neck with no major change in the head-neck-shaft angle or involved only the medial portion of the physis leading to broadening of the femoral neck and development of a varus deformity. Lateral physeal arrest leading to valgus angulation of the femoral neck was never noted. The closure also

927

occurred sufficiently late that it did not appear to have any effect on development of the acetabulum. b. H u m e r a l Head Osteonecrosis. The head of the humerus can also be affected by osteonecrosis (136, 138). Osteonecrosis was studied in a large group of 2524 patients in a multicenter study. The patients had HbSS (1737), HbSC (510), sickle cell 13 (+) thalassemia (139), and sickle cell 13 (0) thalassemia (138). The overall prevalence of humeral head necrosis was 5.6%. It was bilateral in two-thirds of those involved. Osteonecrosis was seen in each of the variants in approximately the same amounts. There was a gradual increase in osteonecrosis the older the patient. The prevalence was 1.2% of those between 5 and 9 years of age at initial assessment, 2.6% in those between 10 and 14 years of age, and 3.8% in those between 15 and 24 years of age. The prevalence increased with each advancing age of adult assessment. Those slowest to develop the disorder were in the sickle cell 13 (+) thalassemia group, none of whom had the disorder under the age of 25 years. The disorder, however, was much less debilitating than that that occurred in the femoral head. At the time of diagnosis, 80% of the patients were completely asymptomatic. Pain and limitation of motion developed in most at a later date, but this was mild to moderate and only one patient in the entire study had undergone shoulder arthroplasty for severe symptoms.

References 1. Albright F, Butler AM, Bloomberg E (1937) Rickets resistant to vitamin D therapy. Am J Dis Child 54:529-547. 2. Aledort LM, Haschmeyer RH, Petterson H (1994) A longitudinal study of orthopedic outcomes for severe factor-VIIIdeficient haemophiliacs. J Intern Med 236:391-399. 3. Ambekar AP, Joshipura JCN (1973) Classification and treatment of tuberculosis of the hip joint: Analysis of 104 cases. Ind J Surg 35:309-315. 4. AndrewTA, Porter K (1985) Primary subacute epiphyseal osteomyelitis: A report of three cases. J Pediatr Orthop 5:155-157. 5. Ansell BM, Bywaters EGL (1959) Prognosis in Still's disease. Bull Rheum Dis 9:189-192. 6. Ansell BM, Bywaters EGL (1962) Diagnosis of "probable" Still's disease and its outcome. Ann Rheum Dis 21:253-262. 7. Apel DM, Millar EA, Moel DI (1989) Skeletal disorders in a pediatric renal transplant population. J Pediatr Orthop 9: 505-511. 8. Arnold WB, Hilgartner MW (1977) Hemophilic arthropathy: Current concepts of pathogenesis and management. J Bone Joint Surg 59A:287-305. 9. Aronstam A, Browne RS, Wassef M, Hamad Z (1983) The clinical features of early bleeding into the muscles of the lower limb in severe hemophiliacs. J Bone Joint Surg 65B: 19-23. 10. Badgley CE, Yglesias L, Perham WS, Snyder CH, Arbor A (1936) Study of the end results in 113 cases of septic hips. J Bone Joint Surg 4:1047-1061. l l. Balc'h TL, Ebelin M, Laurian Y, Lambert T, Verroust E Larrieu M (1987) Synovectomy of the elbow in young hemophilic patients. J Bone Joint Surg 69A:264-269.

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CHAPTER IO ~ Metabolic, Inflammatory, Neoplastic, Infectious, and Hematologic Disorders

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CHAPTER 10 ~ Metabolic, ln[lammatory, Neoplastic, Infectious, and Hematoloyic Disorders

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201. Stein H, Duthie RB (1981) The pathogenesis of chronic haemophilic arthropathy. J Bone Joint Surg 63B:601-609. 202. Stern MB, Cassidy R, Mirra J (1976) Eosinophilic granuloma of the proximal tibial epiphysis. Clin Orthop Rel Res 118: 153-156. 203. Stern PJ, Watts HG (1979) Osteonecrosis after renal transplantation in children. J Bone Joint Surg 61A:851-856. 204. Stickler GB, Morgenstern BZ (1989) Hypophosphataemic tickets: Final height and clinical symptoms in adults. Lancet ii:902-905. 205. Storti E, Ascari E (1975) Surgical and chemical synovectomy. Ann NY Acad Sci 240:316-327. 206. Storti E, Traldi A, Tosatti E, Davoli PG (1969) Synovectomy, a new approach to haemophilic arthropathy. Acta Haemat 41: 193-205. 207. Strom TM, Francis F, Lorenz B, Boddrich A, Econs MJ, Lehrach H, Meitinger T (1997) Pex gene deletions in Gy and hyp mice provide mouse models for X-linked hypophosphatemia. Hum Mol Genet 6:165-171. 208. Strong M, Lejman T, Michno P, Hayman M (1994) Sequelae from septic arthritis of the knee during the first two years of life. J Pediatr Orthop 14:745-751. 209. Strong M, Lejman T, Michno P (1995) Septic arthritis of the wrist in infancy. J Pediatr Orthop 15:152-156. 210. Sundberg J, Brattstrom M (1965) Juvenile rheumatoid gona~hritis II. Disturbance of ossification and growth. Acta Rheum Scand 11:279-290. 211. Swann M (1990) The surgery of juvenile chronic arthritis: An overview. Clin Orthop Rel Res 259:70-75. 212. Swierstra BA, Diepstraten FM, Heyden BJ (1993) Distal femoral physiolysis in renal osteodystrophy: Successful nonoperative treatment of 3 cases followed for 5 years. Acta Orthop Scand 3:382-384. 213. Tapia J, Stearns G, Ponseti IV (1964) Vitamin D-resistant tickets. J Bone Joint Surg 46A:935-958. 214. Tebor GB, Ehrlich MG, Herrin J (1983) Slippage of the distal tibial epiphysis. J Pediatr Orthop 3:211-215. 215. Thomas HB (1936) Some orthopedic findings in ninety-eight cases of hemophilia. J Bone Joint Surg 18:140-147. 216. Thomson J, Lewis IC (1950) Osteomyelitis in the newborn. Arch Dis Child 25:273-279. 217. Trueta J, Morgan JD (1954) Late results in the treatment of one hundred cases of acute haematogenous osteomyelitis. Brit J Surg 41:449-457. 218. Tuli SM (1987) Judicious management of tuberculosis of bones, joints, and spine. U Penn Orthop J 3:31-40. 219. Uittenbogaart CH, Isaacson AS, Stanley P, Pennisi AJ, Malekzadeh MH, Ettenger RB, Fine RN (1978) Aseptic necrosis after renal transplantation in children. Am J Dis Child 132:765-767. 220. Usui M, Matsuno T, Kobayashi M, Yagi T, Sasaki T, Ishii S (1983) Eosinophilic granuloma of the growing epiphysis. Clin Orthop Rel Res 176:201-205. 221. VanHorn JR, Karthaus RP (1989) Epiphyseal osteoid osteoma: Two case reports. Acta Orthop Scand 5:625-627. 222. Verge CF, Lam A, Simpson JM, Cowell CT, Howard NV, Silink M (1991) Effects of therapy in X-linked hypophosphatemic tickets. New Eng J Med 325:1843-1878. 223. Vidigal EC, Jacomo AD (1994) Early diagnosis of septic arthritis of the hip in neonates. Internat Orthop 18:189-192.

References 224. Walters MC, Patience M, Leisenring W, Eckman JR, Scott JP, Mentzer WC, Davies SC, Ohene-Frempong K, Bernaudin F, Matthews DC, Storb R, Sullivan KM (1996) Bone marrow transplantation for sickle cell disease. New Eng J Med 335: 369-376. 225. Weissberg ED, Smith AL, Smith DH (1974) Clinical features of neonatal osteomyelitis. Pediatr 53:505-510. 226. Werner EJ (1996) Von Willebrand disease in children and adolescents. Ped Clin North Am 43:683-707. 227. White GC (1995) Coagulation factors V and VIII: Normal function and clinical disorders. In: Blood: Principles and Practice of Hematology, eds RJ Handin, TP Stossel, SE Lux. pp. 1151-1174, Philadelphia: JB Lippincott. 228. White PH (1990) Growth abnormalities in children with juvenile rheumatoid arthritis. Clin Orthop Rel Res 259:46-50.

933

229. Wiedel JD (1996) Arthroscopic synovectomy of the knee in hemophilia: 10-15 year follow-up. Clin Orthop Rel Res 328:46-53. 230. Wilkinson MC (1962) Partial synovectomy in the treatment of tuberculosis of the knee. J Bone Joint Surg 44B :34-41. 231. Wilkinson MC (1969) Tuberculosis of the hip and knee treated by chemotherapy, synovectomy, and debridement: A follow-up study. J Bone Joint Surg 51A:1343-1359. 232. Wilson JC, McKeever FM (1936) Bone growth disturbance following hematogenous acute osteomyelitis. J Am Med Assoc 107:1188-1193. 233. Winters RW, Graham JB, Williams TF, McFalls VW, Bumett CH (1958) A genetic study of familial hypophosphatemia and vitamin D-resistant tickets with a review of the literature. Medicine 37:97-142.

Index

A Abduction devices, LCP treatment, 344-346 Acetabula acute epiphyseal growth plate fractureseparation, 574-575 childhood hip, 167 corrective procedures, CDH, 208-212 development hip reduction treatment, 232-233 limbus removal in infancy, 233-234 stages, 159-160 dislocated hip, 180 experimental femoral head displacement, 190-192 Fairbank's studies, 176 femoral head-acetabular repair index, 330-333 femoral osteotomies, DDH, 213 growth after surgery, 234 hip development, 155 LCP disease deformation, 296 head index, 330-331 reconstruction, 362-363 responses, 316-318 shelf arthroplasty, 363 Acetabular dysplasia, 196, 789 Acetabular index, hip position radiography, 214,217 Achondrogenesis, 759, 769, 771 Achondroplasia clinical and radiographic characteristics, 795-796 craniocervical junction abnormalities, 798-799 developmental milestones, 799 histopathologic changes, 773 macrocephaly-hydrocephalus, 798 morbidity and mortality, 796-798 orthopedic aspects, 800-801 overview, 794-795 spinal abnormalities, 799-800 Acquired coxa vara, 377 Acrodysplasias, 815-816 Acromelic dysplasia, 785, 815-816

Acromesomelic dysplasia, 813-815 Acute on chronic slip, SCFE, 396 Acute epiphyseal growth plate fractureseparation distal femur, 576-582 distal fibula, 591 distal humerus, 562, 566-570 distal radius, 570-574 distal tibia, 585-591 distal ulna, 574 ligament damage, 592 management principles, 560-561 metacarpals, 574 phalanges, 574 proximal femur, 575-576 proximal fibula, 591 proximal humerus, 561-562 proximal radius, 570 proximal tibia, 582-585 Roentgen stereophotogrammetry, 591-592 triradiate acetabular cartilage, 574-575 Acute slip, SCFE, 396 Adductor muscle, congenitaldevelopmental hip abnormalities, 196 Adolescent hip dysplasia, 239 Adolescent tibia vara clinical profile, 493-495 deformity, 495 femoral varus association, 496 pathoanatomy, 496-497 physeal height details, 495-496 radiographic assessments, 496 terminology, 493 treatment, 497 AER, s e e Apical ectodermal ridge Age distal femoral fracture-separations, 580 epiphyseal growth plate fractureseparation occurrence, 558-559 infantile tibia vara deformity after osteotomy, 488-490 osteochondritis dissecans, 468, 477-478 role in LCP disease, 362 SCFE, 398, 400-402 tuberculosis incidence, 906

935

AI, s e e Acetabular index Airways, skeletal dysplasias, 861 Ambulation hip MR imaging, 259 LCP treatment, 345-346 Anesthesia, skeletal dysplasias, 860-861 Aneurysmal bone cyst, 896 Angiomatous lesions, 646-647 Angioplastic disorders, lower extremity length discrepancy, 641-642 Anisomelia, lower extremity length discrepancies, 639-640 Ankle, skeletal dysplasias, 793-794 Anterior tibial spine, growth plate fractureseparation, 582-584 Apert syndrome, 816 Apical ectodermal ridge bone patterning, 53 definition, 58 limb development control, 74 Apoptosis, hypertrophic chondrocytes, 37 ARSE, s e e Arylsulfatase Arteries, DDH, 240-243 Arteriovenous fistula, surgical induction, 672-673 Arthritis, s e e Juvenile rheumatoid arthritis; Septic arthritis Arthrodesis, hemophilia, 924 Arthrography coxa vara, 378 hip position, 218-221 index for LCP classification, 333 knee joint in infantile tibia vara, 486 proximal femur cartilage model, 311-312 Arthropathy, s e e Hemophilic arthropathy Articular cartilage development, 51-53 diaphysis lengthening effect, 692 pin penetration, in chronic SCFE treatment, 413-414 Arylsulfatase, skeletal dysplasias, 751 Ascending cervical arteries, DDH, 240-243 Asphyxiating thoracic dysplasia, 761,773 Atelosteogenesis, 759

936

Index

Atlantoaxial instability, cervical spine in skeletal dysplasia, 779-780 Authors, notable research studies achondrogenesis I, Parenti-Fracaro, 769 achondrogenesis II, Langer-Saldino, 769, 771 bone development Belchier, John, 5-7 Broca, 13 Duhamel, Henri-Louis, 7 Flourens, 8 Hales, Stephen, 5-7 Howship, 7-8 Hunter, John, 7 Kolliker, 13 Nesbitt, Robert, 5-7 Oilier, 15 Retterer, 15 bone as tissue or organ, Virchow, 14-15 congenital dislocation of hip Barlow, 204-205 Hilgenreiner, 203-204 Ortolani, 204 Putti, 204 Severin, 205-206 Von Rosen, 204-205 congenital limb deficiences, Frantz and O' Reilly, 615-617 developmental dysplasia of hip Badgley, 178-179 Bennett, 175 Brodhurst, 165-166 Bucholz, 252 Calandriello, 179-180 Clarke, 172 Cruveilhier, 164 Deutschlander, 176 Dunn, 181-183 Dupuytren, 162-163 Fairbank, 176-177 Goldsmith, 184-186 Graf, 221,223,225,229 Hirohashi, 253 Howorth, 179 Ippolito, 186 Kalamachi, 252 Keetley, 172-173 Kirmisson, 169-170 Kuhlmann, 252-253 Lance, 176 Le Damany, 173-175 Leveuf, 177-178 Loeffler, 176 Ludloff, 175-176 MacEwen, 252 Massie, 251-252 McKibbin, 183-184 Ogden, 252 Palletta, 161-162 Pavlik, 249-250

Ponseti, 186 Ralis, 183-184 Reeves, 166 Robert, 252 Roser, 164 Sainton, 166-169 Salter, 181 Scaglietti, 179-180 Sedillot, 163-164 Seringe, 252 Somerville, 186-187 Stanisavljevic, 180-181 Tonnis, 252-253 Verneuil, 164-165 Walker, 184-186 Werndorf, 176 diaphysis lengthening Abbott, 676-679 Anderson, 679-680 Cauchoix and Morel et al., 681 Codivilla, 675 D'Aubigne and Dubousset, 681 distraction osteogenesis, 688-695 Judet technique, 682-683 Kawamura, 681-682 Le Coeur, 680-681 Ombredanne, 675 Putti, 675-676 Wagner technique, 683-685 epiphyseal cartilage, Mueller, Heinrich, 13-14 epiphyseal growth plate, Dodds, 17-18 epiphyseal growth plate fractureseparations Aitken, 531-532 Aitken, Steinert, Weber, and Morscher, 536 Bergenfeldt, 531 Bidder, 526 Bret and Curtillet, 526 Broca, 523,535-536 Carothers and Crenshaw, 537 Cornil and Coudray, 526-528 Foucher, 523-525 Gueretin, 521-522 Hutchinson, 528-529 Jouon, 529 Morscher, 534 Nove-Josserand, 526 Ogden, 534-535 Oilier, 525-526 pathophysiology, Shapiro, 537-539 Peterson, 535 Poland, 529-530 Rognetta, 520-521 Salter and Harris, 532 Smith, 522 Steinert, 533 Vogt and Bruns, 525

Weber, 533-534 epiphyseal transplantation Farine, 719 Haas, 716-717 Harris et al., 718-719 Silfverskiold, 719 hemihypertrophy, Trelat and Monod, 640 hemophilic arthropathy, Koenig, 911 hip dislocation Bost, 202 Farrell, 202 Gill, 202 Howorth, 202 Leveuf, 201-202 hip position radiography, Tonnis, 214 infantile tibia vara B lount, 480-481,484 Golding and McNeil-Smith, 486 Jaffe, 485-486 Lamy and Weissman, 486 Langenskiold, 481,484-485 Sloane, Sloane, and Gold, 485-486 innominate osteotomy, Salter, 208-210 Legg-Calve-Perthes disease Axhausen, 282-283 Bell, 290 Bennett, 286-287 Birmingham splint, 345-346 Boldero, 299 Brailsford, 298-299 Brotherton and McKibbin, 345 Butel, Borgi, and Oberlin grading system, 335 Caffey, 299 Catterall, 293-295,304, 324-326 Delchef, 284 Dolman, 290 Evans, 343 Eyre-Brook, 330, 342 Ferguson, 285-286 Freeman, 292 Freund, 298 Gage, 304 Gall, 286-287 Green, Beauchamp, and Griffin, 332 Haythorn, 287 Heitzmann, 283 Herndon and Heyman, 330-331 Herring et al., 327-328 Hirohashi et al., 328-329 Hirrayama, 289-290 Hosoya, 292-293 Howorth, 285-286 Inoue, 292-293 Jansater, 333 Jensen, 292 Jonaster, 287-289 Kelly et al., 343 Kemp, 299

Index

Kendig, Evans, and Bohr, 344-345 Konjetzny, 283-284 Kotani, 289-290 Larsen, 290 Lauritzen, 292 Lippmann, 284 McKibbin, 290-292 Meyer, 331-332 Mizuno, 289-290, 292 Moiler, Fleming, 337 Mose concentric circle template method, 330 Nagassaka, 284-285 O'Garra, 324 O'Hara et al., 343 Ono, 292-293 Perpich et al., 343 Phemister, 282 Pike and Gossling, 342-343 Ponseti, 289, 295 Ralis, 290-292 Reiman, 290 Riedel, 283 Rockemer, 284 Salter-Thompson subchondral fracture, 326-327 Schwarz, 282 Shigeno and Evans, 333 Simazu, 289-290 Sjovall, 330 Stulberg, 333-335 Sundt, 330, 337-338 Takaoka, 292-293 Vernon-Roberts, 292 Walter, 283 Wiberg, 331 Yoshioka, 292-293 Zemansky, 281-282, 285 lower extremity length discrepancies Gill and Abbott, 654-655 Goidanich and Campanacci, 646-647 Green and Anderson, 655-658 Hatcher, 653 Hechard and Carlioz, 658-659 Menelaus, 658 Moseley, 658 White, 653-654 Wilson and Thompson, 654 Osgood-Schlatter disease Ehrenborg and Engfeldt, 498, 503-504 Hulting, 498 Krause et al., 507 Lazerte and Rapp, 501-502 Ogden, Hempton, and Southwick, 498-500 Uhry, 502-504 Woolfrey and Chandler, 506-507 osteochondritis dissecans Axhausen, 470

Barth and Kappis, 471 Konjetzny, 471 Paget, Teale, and Koenig, 466-467 osteogenesis imperfecta Shapiro, 848 Sillence, 848-849 pericapsular osteotomy of ilium, Pemberton, 210-211 physeal distraction DePablos et al., 704 Monitcelli and Spinelli, 704-705 Peltonen, 704 physeal transplantation Ring, 718 primary and secondary bone, Gegenbaur, 15 proximal femoral focal deficiency Aitken, 437 Amstutz, 437-438 Fixsen and Lloyd-Roberts, 438-439 Gillespie and Torode, 439-440 Haminishi, 440 Kalamchi, Cowell, and Kim, 440 Lange, Schoenecker, and Baker, 439 Pappas, 440 proximal femur Harris lines, O'Brien, 234 rickets Dodds and Cameron, 872-873 Shohl and Wolbach, 873-874 short rib-polydactyly syndromes Majewski, 772 Saldino-Noonan, 772 skeletal dysplasias Jeune, 761 Majewski, 761 Naumoff, 761 Saldino-Noonan short rib syndromes, 760-761 slipped capital femoral epiphysis Agamanolis et al., 388 Balensweig, 386 Cruess, 388 Elmslie, 385 Frangenheim, 384 Grashey, 385 Haedke, 384 Hofmeister, 384-385 Howorth, 386 Ingram, 389 Jerre, 389 Kallio et al., 397 Key, 386 Kleinberg and Buchman, 385 Kocher, 384 Lacroix and Verbrugge, 387 Lance et al., 389 Loder et al., 397 Mueller, 384 Ponseti, 387-388

937

Ponseti and Barta, 388 Rammstedt, 385-386 Schlessinger, 384 Sprengel, 385 Sutro, 386 Waldenstrom, 388 Walters and Simon, 413-414 teratological congenital dislocation of hip Cautru, 171 Grosse, 170-171 Kirmisson, 171 LePage, 170-171 Potocki, 171-172 Autoradiography, cell proliferation studies, 96 Avascular necrosis childhood CDH-DDH, 258 DDH treatment basic problem, 246-247 clinical and research studies, 247-249 closed reduction age, 249 Denis Browne splint, 254 extreme immobilization positioning, 258-262 Frejka abduction pillow, 253 milder sequelae, 251 Pavlik harness, 253-254 Pavlik's functional treatment, 249-250 prereduction traction benefits, 250-251 recent studies, 254-258 treatment principles, 247 as SCFE complication, 431-432 Avulsion fractures, proximal tibial tuberosity, 584-585 Axes, bone patterning mechanisms, 55-58 signaling regions, 53 tissue patterning models, 53-55 B Back pain, osteopetrosis, 845 Beckwith-Wiedemann syndrome, lower extremity length discrepancies, 646 Bed rest, LCP treatment, 343 Benign autosomal dominant osteopetrosis, 837, 841 Bilateral abduction brace, LCP treatment, 346-349 Bilateral abduction-internal rotation cast, LCP treatment, 346 Bilaterality, SCFE, 402-403 Biologic non-diplacement osteotomy, LCP treatment, 344-345 Biopsy, iliac crest bone, osteopetrosis, 844 Birmingham splint, LCP treatment, 345-346

938

Index

Births birth order, hip dysplasia, 194 epiphyseal growth plate fractureseparations, 528, 559-560 Bleeding hemophilia, 920 hemophilic arthropathy, 916 Blood chemistry, osteopetrosis, 843 Blood supply epiphyseal, s e e Epiphyseal blood supply epiphyseal growth plate fractureseparation, 540, 542-543, 548 proximal femur, DDH treatment, 239-245 Blount's disease, s e e Infantile tibia vara Blount stapling technique, limb shortening, 664-667 Body side SCFE predominance, 403 shortening in SCFE, 434 Body temperature, skeletal dysplasias, 861 Body weight, SCFE diagnosis, 400 Bone bridge epiphyseal growth plate fractureseparation, 596-597 lower extremity length discrepancies, 706-707 Bone cells cartilage cell transformation, 20 gap junction links, 19 Bone cysts aneurysmal cysts, 896 LCP disease, 314-316 unicameral cysts, 895-896 Bone disease, hemoglobinopathies, 926-927 Bone grafts chronic SCFE treatment, 418 LCP treatment, 360 SCFE treatment, 406-407 Bone growth early studies, 5-8 MR imaging, 135-136 Bone lesions, renal osteodystrophy, 885 Bone marrow imaging characteristics, 135 transplantation, osteopetrosis treatment, 846 Bone matrix, X-linked hypophosphatemic tickets, 879-880 Bone morphogenetic proteins, limb axes, 80-81 Bone patterning mechanisms, 55-58 signaling regions, 53 tissue patterning models, 53-55 Bones childhood renal osteodystrophy, 885-887 developing, s e e Developing bone

epiphyseal growth plate stimulation, 674-675 formation, 4-5, 16-19 hemangiomas, lower extremity length discrepancies, 643 imaging characteristics, 135 LCP disease, 278-279, 287-288 neurofibromatosis, 648 osteogenesis imperfecta, 857-858 renal osteodystrophy, 887-888 tissue vs. organ, 14-15 Bone scan, osteopetrosis, 843-844 Bone sialoproteins, 92, 95 Bowing, s e e Genu varum Breech position congenital-developmental hip abnormality effects, 193-194 young rabbit hip dislocation, 192 BSP, s e e Bone sialoproteins Burns, lower extremity length discrepancies, 652 C Caffey's disease, lower extremity length discrepancies, 652-653 Calcitriol, osteopetrosis management, 845-846 Calcium-phosphorus mineral phase, mineralization, 94 Caliper, LCP treatment, 343 Campomelic dysplasia, 760, 772 Capital epiphysis, epiphyseal growth plate fracture-separation, 575-576 Capsule dislocated hip, 180 Fairbank's studies, 177 laxity in hip abnormalities, 195-196 Caput index, LCP classification, 333 Cardiac system, skeletal dysplasias, 861 Cartilage achondrogenesis II, electron microscopy, 771 change in LCP disease, 288 MR imaging, 133-134 necrosis, SCFE, 388-389 Retterer's studies, 15-16 skeletal dysplasias, 753-754 Cartilage canals DDH treatment, 245-246 epiphyseal intrinsic blood supply, 47-50 secondary ossification center formation, 50-51 skeletal dysplasias, 767 Cartilage cells, 20-21 Cartilage collagens, epiphyseal tissue, 88-89 Cartilage-hair metaphyseal dysplasia, 812 Cartilage hyperplasie, Retterer's studies, 16 Cartilage matrix, skeletal dysplasias, 768

Cartilage matrix protein, epiphyseal tissue, 91 Cartilage models, LCP disease femoral head, 307-311 proximal femur, 311-312 Cartilage oligomeric matrix protein, skeletal dysplasia, 751 Cartilaginous epiphyses, skeletal dysplasias, 767 Catheters, abnormal lower leg growth, 627 CBFA1, skeletal dysplasias, 751-752 CDH, s e e Congenital dislocation of hip CDK, s e e Congenital dislocation of knee Cell death cartilage, 20-21 epiphyseal growth plate fractureseparation, 548-549 Cells bone forming, 19-20 bone patterning, 57-58 LCP disease, 281-295 proliferation, physeal cartilage, 96 skeletal dysplasias, 767-768 X-linked hypophosphatemic rickets, 879-880 Cell surface heparan sulfate, 751 Cell surface proteoglycans, 92 Cerebral vasculature, hemihypertrophy association, 641 Cericothoracic spinal stenosis, in achondroplasia, 799 Cervical arteries, DDH, 240-243 Cervical osteoplasty, 407-408 Cervical spina bifida occulta, 780 Cervical spinal stenosis, 781 Cheilectomy, LCP treatment, 363 Chiari osteotomy, LCP treatment, 363 Chick, limb bud, H o x c genes, 78 Childhood congenital dislocation of hip adult osteoarthritis, 198-199 avascular necrosis, 258 Childhood hip acetabulum, 167 anatomy, 166-167 congenital luxation of femur, 167-168 femoral-acetabular articulation, 167 pathoanatomy, 168-169 Childhood infantile tibia vara, 491-493 Childhood osteochondritis dissecans, 478-479 Childhood renal osteodystrophy, 885-887 Childhood septic arthritis, 905 Children's Hospital, Boston distal femoral fracture-separation studies, 579-582 SCFE epidemiologic data, 398-400 Chondroblastoma, 894-895 Chondroblasts, bone formation, 18-19 Chondrocytes bone formation, 18-19

Index

epiphyseal growth plate fractureseparation, 548-549 epiphyseal and physeal cartilage, 17-18 hypertrophic, s e e Hypertrophic chondrocytes physeal, metabolism, 96 suspensions, implantation, limb length discrepancy, 719 Chondrodysplasias characteristics, 759-760, 804 Grebe chondrodysplasia, 815 histopathological changes, 769-774, 777 lethal chondrodysplasias, 769-773 nonlethal chondrodysplasias, 773-774, 777 Chondrolysis, as SCFE complication, 432-434 Chondrosarcoma, hereditary multiple exostoses, 836 Chromosomes, skeletal dysplasias, 744-749 Chrondrolysis, SCFE, 388-389 Chronic repetitive activity knee lesions, 147 resulting physeal separation, 595-596 Chronic slipped capital femoral epiphysis treatments chronic slip, 396 femoral head-neck epiphysiodesis with bone graft, 418 femoral head position change, 419-430 growth plate fusion, 409-410, 413-419 hip spica casting, 418-419 pinning treatments, 409-410, 413-415, 417-418 Circulatory disturbances, distal femur osteochondritis dissecans, 469-470 Circumflex femoral arteries, DDH, 240 Clavicle, skeletal dysplasia, 785 Cleidocranial dysostosis, 813 Closed reduction CDH treatment, 205-206 chronic SCFE treatment, 419 DDH avascular necrosis, 249 femoral head vascularity, 261-262 early infancy hip development, 232 hip acetabular development, 232-233 CMP, s e e Cartilage matrix protein Collagen epiphyseal tissue, 82-89 mineralization, 93-94 osteogenesis imperfecta, 856-857 skeletal dysplasias, 750-754 COMP, s e e Cartilage oligomeric matrix protein Compensatory osteotomies, chronic SCFE treatment, 425-428

Compressive stress, epiphyseal plates, 103-105 Computerized tomography coxa vara, 378 DDH studies, 142 distal tibia and fibula disorders, 147 epiphyses, 132 hip structure, 230-231 LCP pathology, 303 lower extremity length discrepancies, 611 osteopetrosis, 843 upper extremities, 147-148 Concentric circle template method, LCP classification, 330 Congenital arteriovenous fistula, 646 Congenital coxa vara, 377 Congenital-developmental hip abnormalities acetabular dysplasia, 196 adductor muscle tightness, 196 capsular laxity, 195-196 ethnic considerations, 194 extrauterine postnatal environment, 194 genetic considerations, 194 idiopathic dysplasia, 197 intrauterine environment effects, 193-194 overview, 195 proximal femoral dysplasia, 196 secondary change worsening, 197-198 sex incidence, 192-193 side of instability, 193 soft tissue deformation, 196-197 stabilization without treatment, 194-195 teratologic dysplasia, 197 treatment, avascular necrosis, 250-251 Congenital dislocation of hip acetabular corrective procedures, 208-212 acetabular-proximal femoral osteotomies, 213 characteristics, 789 childhood adult osteoarthritis, 198-199 avascular necrosis, 258 Dunn's studies, 181-183 experimental reproduction, 190-192 Hilgenreiner's studies, 203-204 open reduction treatment, 206-207 Ortolani, 204 Pavlik harness, 206 proximal femoral osteotomies, 212-213 Putti, 204 radiographic classification system, 205-206 Stanisavljevic's studies, 181 Von Rosen and Barlow, 204-205 Congenital dislocation of knee classification, 507

939

clinical profile, 507 diagnostic considerations, 509 pathoanatomy, 508-509 treatment approaches, 509-510 Congenital hip subluxation, 180-181 Congenital limb deficiences classification, 615-617 dysmelia, 617-618 fibular hemimelia, 620-623 international terminology, 618 posteromedial bowing, 623-625 proximal femoral focal deficiency, 618 short femur, 618-620 tibial hemimelia, 623 Congenital lower extremity length discrepancies dysmelia, 617-618 fibular hemimelia, 620-623 Frantz and O'Reilly classification, 615-617 international terminology, 618 posteromedial bowing, 623-625 proximal femoral focal deficiency, 618 short femur, 618-620 tibial hemimelia, 623 Congenital luxation, child femur, 167-168 Congenital proximal tibial-fibular synostosis, 511 Congenital pseudoarthrosis, tibia, neurofibromatosis, 648-649 Congenital short femur, 442 Contralateral hip abnormalities, LCP disease, 279 Cord-root compression, cervical spine skeletal dysplasia, 781 Cortical bone, osteopetrosis, 842 Couches cartilaginous, 13 Couches chondroid, 13 Couches chondrospongioid, 13 Couches spongioid, 13 Coxa magna avascular necrosis in DDH treatment, 251 LCP disease, 307-309 Coxa plana, LCP disease, 309 Coxa valga, hereditary multiple exostoses, 832 Coxa vara acquired type, 377 causes, 376-378 clinical presentation, 378 congenital limb deficiences, 618-620 congenital type, 377 deformities, 376-377 imaging assessments, 378 infantile, s e e Infantile coxa vara LCP disease, 309-311 osteopetrosis, 844 skeletal dysplasias, 789 terminology, 376

940

Index

Craniocervical junction, achondroplasia, 798-799 Craniofacial dysostosis, 815-816 Craniosynostosis, campomelic dysplasia, 772 Crouzon syndrome, 816 Crown-rump length, hip development, 154 Crushing, mechanical, chondrocytes, 548-549 Crutches, LCP treatment, 343 CT, s e e Computerized tomography Cuneiform osteotomy, chronic SCFE treatment, 419-425 Cutis marmorata telangiectatica congenita, 646 Cysts, s e e Bone cysts Cytoarchitecture, growth plate, skeletal dysplasias, 766-767 D Databases, skeletal gene, 59-74 DDH, s e e Developmental dysplasia of hip Dedifferentiation, hypertrophic chondrocytes, 19-20 Deep femoral arteries, DDH, 240 Denis Browne splint, DDH treatment, 254 Determination wave mechanism, bone patterning, 57 Developing bone articular cartilage, 51-53 axes patterning mechanisms, 55-58 signaling regions, 53 tissue patterning models, 53-55 deformity, 107-109 diaphyseal bone formation, 41-44 early studies, 5-8 embryogenesis, 3-4 endochondral ossification, 4 epiphyseal tissue blood supply, 46-51 cartilage collagens, 88-89 cell surface proteoglycans, 92 collagen, 82-87 collagen groups, 87-88 endochondral sequence, 92-93 glycoproteins, 90-92 growth, 96-99 long bones, 111-118 noncollagenous proteins, 90-92 overview, 4, 21, 118-119 proteoglycans, 89-90 histological studies, 16-19 hypertrophic chondrocyte fate, 19-21 intramembranous ossification, 4-5 joint development, 44-46 light microscopic studies, 13-16 limb development apical ectodermal ridge, 58

dorsal nonridge ectoderm, 58 embryology, 8-11 gene control overview, 74 homeobox genes, 74-75, 77-78 matrix metalloproteinases, 81-82 polarizing region, 58 progress zone, 58 signaling molecules, 78-81 TIME 81-82 mechanical stresses abnormal pressure responses, 107-109 compressive and tensile stresses, 103-105 normal responses, 99-103 pressure effects, 109-111 skeletal development effects, 105-107 mineralization, 93-96 perichondrial ossification groove of Ranvier, 5, 39 periosteum relationships, 39-41 physis, structure and function, 25, 29, 31, 34-37 secondary ossification center formation, 21-25 skeletal gene database, 59-74 Developmental dysplasia of hip 3 months of age, 236-237 6 months of age, 237-238 12 months of age, 238 18 months of age, 238 18 months to 4.5 years of age, 238-239 after 5 years of age, 239 associated terminology, 153-154 avascular necrosis basic problem, 245-247 clinical studies, 247-249 closed reduction age, 249 Denis Browne splint, 254 extreme immobilization positioning, 258-262 Frejka abduction pillow, 253 milder sequelae, 251 Pavlik harness, 253-254 Pavlik's functional treatment, 249-250 prereduction traction benefits, 250-251 research studies, 247-249, 251-253 treatment principles, 247 early clinical-pathoanatomic descriptions, 161-170, 172-176 early treatment result reviews, 200-201 epiphyseal blood supply, 245-246 experimental reproduction, 190-192 extrinsic causes, 189-190 imaging, 142-143 intrinsic causes, 187-189

later clinical-pathoanatomic descriptions, 176-179 mid-twentieth century results, 201-203 newborns, 221,223,225,229-230, 235-236 overview, 187, 234-235 preadolescent-adolescent age, 239 proximal femur blood supply ascending cervical arteries, 240-243 deep and circumflex femoral arteries, 240 general pattern, 239-240 intracartilaginous-intraosseous vessels, 243-244 lateral and medial circumflex arteries, 240-243 ligamentum teres vascularity, 240 vascular pattern changes, 244-245 recent clinical-pathoanatomic descriptions, 179-187 teratological CDH, 170-172 treatment in 1800s and early 1900s, 199- 200 Diaphyseal periosteum characteristics, 39-41 elevation and stripping, 673 Diaphysis ipsilateral fracture, premature physeal closure, 594-595 lengthening, Ollier's disease, 820 lower extremity length discrepancy femoral diaphysis, 636-639 shortening, 669-672 tibial diaphysis, 639 lower extremity length discrepancy, lengthening concerns in complex abnormalities, 700-701 distraction osteogenesis, 685, 688-695 early clinical approaches, 675-682 humeral lengthening, 701 intramedullary rod lengthening, 695-698 longitudinal growth, 698-700 rigid fixator results, 682-685 woven and lamellar bone, 41-44 Diastrophic dysplasia characteristics, 805-807 histopathologic changes, 774 Diastrophic dysplasia sulfate transporter, 751,753 Digital dysplasia syndromes, 816 Diminished stature, LCP disease, 278-279 Distal femur acute epiphyseal growth plate fractureseparation, 576-582, 592 developmental abnormalities, 442 epiphyseal growth after infantile osteomyelitis, 903-904

Index

epiphyses, 362, 462-465 Ollier's disease, 818-819 osteochondritis dissecans age of occurrence, 468 causes, 468-470 childhood OD, treatments, 478-479 current understanding of disease, 474-475 disease profile, 465-466 healing factors, 477-478 original descriptions, 466-467 pathogenesis and pathoanatomy, 470-474 radiography and imaging, 475-477 site of occurrence, 468 stages, 467-468 radiographic characteristics, 116 stress analysis, 103 tilt in adolescent tibia vara, 495-496 Distal fibula acute epiphyseal growth plate fractureseparation, 591-592 disorders, imaging, 147 radiographic characteristics, 117 Distal humerus acute epiphyseal growth plate fractureseparation, 562, 566-570 radiographic characteristics, 112-115 Distal radius acute epiphyseal growth plate fractureseparation, 570-574 radiographic characteristics, 115 Distal tibia acute epiphyseal growth plate fractureseparation intra-articular component, 591 overview, 585-586 physis closure pattern, 586 Roentgen stereophotogrammetry, 591-592 transitional fractures, 586-589 type III medial fracture-separations, 589 type III medial malleolus, 589 type IV fracture, 589-591 associated disorders, 147 epiphysis, hereditary multiple exostoses, 832-833 radiographic characteristics, 116-117 Distal ulna acute epiphyseal growth plate fractureseparation, 574 radiographic characteristics, 115 Distraction osteogenesis, diaphysis lengthening articular cartilage effect, 692 associated research, 693-695 cell and matrix deposition patterns, 695 clinical techniques, 685, 688-690 muscle strength effect, 691-692

nerve function effect, 692-693 technique comparison, 690-691 Dorsal nonridge ectoderm, 58 Drilling, LCP treatment, 360 DTDST, s e e Diastrophic dysplasia sulfate transporter Dyggve-Melchior-Claussen dysplasia, 808 Dyschondrosteosis, 813 Dysmelia, congenital limb deficiences, 617-618 Dysplasia epiphysealis hemimelica characteristics, 803-804 lower extremity length discrepancies, 626 Dysplasias acetabular dysplasia, 196, 789 acrodysplasias, 815-816 acromelic dysplasia, 785, 815-816 acromesomelic dysplasia, 813-815 adolescent hip dysplasia, 239 asphyxiating thoracic dysplasia, 761, 773 campomelic dysplasia, 760, 772 cartilage-hair metaphyseal dysplasia, 812 CDH, s e e Congenital dislocation of hip chondrodysplasias, 759-760, 769-774, 777, 804, 815 DDH, s e e Developmental dysplasia of hip diastrophic dysplasia, 774, 805-807 digital dysplasia syndromes, 816 Dyggve-Melchior-Claussen dysplasia, 808 Grebe chondrodysplasia, 815 hip, natural history, 198 Hunter-Thompson acromesomelic dysplasia, 815 idiopathic dysplasia, 197 Jansen metaphyseal dysplasia, 812 Kniest dysplasia, 774, 804 lethal chondrodysplasias, 769-773 lethal thoracic dysplasia, 761 McKusick metaphyseal dysplasia, 812 mesomelic dysplasias, 813 metaphyseal dysplasia, 774, 812 metatropic dysplasia, 774, 804 multiple epiphyseal dysplasia, 774, 777, 801-803 nonlethal chondrodysplasias, 773-774, 777 proximal femoral dysplasia, 196 rhizomelic chondrodysplasia punctata, 772 Schmid metaphyseal dysplasia, 812 skeletal, s e e Skeletal dysplasias Smith-McCort dysplasia, 808 spondyloepimetaphyseal dysplasia, 8O4-8O5

941

spondyloepiphyseal dysplasia, 774, 807-808 spondyloepiphyseal dysplasia congenita, 807 spondyloepiphyseal dysplasia tarda, 807-808 spondylometaphyseal dysplasia, 774, 812-813 teratologic dysplasia, 197 thanatophoric dysplasia, 756-758, 771-772 trichorhinophalangeal dysplasia, 860 E Elbow, imaging, 148 Electron microscopy, achondrogenesis II cartilage, 771 Ellis-Van Creveld syndrome, 815 Embryonic development acetabulum, 159-160 basic theories, 3-4 femur, 158-159 limbs, 8-11 Enchondromatosis, lower extremity length discrepancies, 625-626 Endochondral ossification hypertrophic chondrocytes, 36-37 mechanism, 4 Endochondral sequence epiphyseal tissue, 92-93 mineralization, 93-96 Endocrine disorders, SCFE, 392-394 Eosinophilic granuloma, 895 Epidemiology LCP disease, 277-281 SCFE, 398-404 Epigenesis, embryogenesis theory, 3-4 Epiphyseal arrest, Ollier's disease, 820 Epiphyseal blood supply cartilage canals, 50-51 DDH treatment, 245-246 dual physeal supply, 46-47 extrinsic supply, 47 intrinsic supply, 47-50 transphyseal communicating cartilage canals, 50 Epiphyseal cartilage blood supply, DDH treatment, 245-246 chondrocyte shape, 17-18 early descriptions, 13-14 intrinsic blood supply, 47-50 skeletal dysplasias, 767 Epiphyseal extrusion index, LCP classification, 332 Epiphyseal growth plate fractureseparation acute, s e e Acute epiphyseal growth plate fracture-separation blood supply, 540, 542-543 chronic repetitive activity, 595-596

942

Index

Epiphyseal growth plate fractureseparation ( c o n t i n u e d ) clinical profile, 556-560 deformity pathogenesis, 548-549 early clinical descriptions, 519-520 genum recurvatum, 596 growth deformity pathogenesis, 548-549 incidence, 558 joint capsule position, 539-540 later studies, 528-530 MR imaging, 549-556 negative sequelae management, 596-597 other notable studies, 547-548 pathoanatomic studies, 523-528 pathologic, 592-594 pathophysiologic classification, 537-539 physeal cartilage, 543-545 premature physeal closure, 594-595 radiographic clinical approaches, 531-537 seminal studies, 520-522 shape, 541 slow research acceptance, 522-523 stability, 540-541 Epiphyseal index, LCP classification, 330 Epiphyseal-metaphyseal junction abnormalities, skeletal dysplasias, 768-769 shaping abnormalities, 762 Epiphyseal osteomyelitis acute neonatal-infantile type, 898-905 knee, 147 primary subacute-chronic type, 897 secondary to transphyseal spread, 897-898 tuberculosis, 906-909 Epiphyseal quotient, LCP classification, 330-331 Epiphyseal tissue, developing bone blood supply, 46-51 cartilage collagens, 88-89 cell surface proteoglycans, 92 collagen, 82-87 collagen groups, 87-88 endochondral sequence, 92-93 glycoproteins, 90-92 growth, 96-99 long bones, 111-118 noncollagenous proteins, 90-92 overview, 4, 21, 118-119 proteoglycans, 89-90 Epiphysiodesis, limb shortening, 667-668 Epiphysis blood supply, 46-47 cartilage collagens, 88-89 cell surface proteoglycans, 92 collagen, 82-87

collagen groups, 87-88 definition, 4 endochondral sequence, 92-93 formation and evolution, 118-119 fusion, knee, 632-633 glycoproteins, 90-92 growth cell proliferation, 96 freezing effects, 652 growth quantity, 97-98 Harris lines, 98-99 infection effect, 905-906 kinetics, 96-97 mechanical stress responses, 109-111 physeal chondrocyte metabolism, 96 slowdown, 98-99 stimulation in limb lengthening, 672-675 imaging growth and ossification, 135-137, 142 lower extremities, 142-147 technical aspects, 129-135 upper extremities, 147-148 lower extremity length discrepancies bone bridge resection, 706-707 chondrocyte suspension implantation, 719 focal physeal implant models, 715 free autogenous iliac crest physeal grafts, 708, 712-714 interpositional materials, 708 physeal reconstruction, 715 physes and epiphyses transplantation, 715-719 premature physeal closure treatment, 719-720 vascularized autogenous epiphyseal iliac crest grafts, 714-715 mechanical stress responses abnormal pressure responses, 107-109 compressive and tensile stresses, 103-105 normal responses, 99-103 skeletal development effects, 105-107 neoplastic disorders aneurysmal bone cyst, 896 chondroblastoma, 894-895 eosinophilic granuloma, 895 osteogenic sarcoma, 896-897 osteoid osteoma, 895 unicameral bone cyst, 895-896 noncollagenous proteins, 90-92 osteopetrosis, 841-842 periosteum relationship, 39-41 proteoglycans, 89-90 proximal femoral acute epiphyseal growth plate fractureseparation, 575-576

LCP disease, 304 proximal fibula disorders, 511-512 proximal tibial, radiographic developmental variants, 462-465 secondary ossification center formation, 21-25 shaping abnormalities, 762 skeletal dysplasias, 761-762, 767-768 slipped capital femoral, s e e Slipped capital femoral epiphysis Ethnicity, hip dysplasia, 194 EVC, s e e Ellis-Van Creveld syndrome Exostoses cord-root compression, 781 hereditary multiple exostoses, 831-832 skeletal dysplasias, 793 External fixator, intramedullary rod lengthening, 695-697 Extra-articular ligaments, hip development, 156 Extracellular matrix, epiphyseal tissue cartilage collagens, 88-89 cell surface proteoglycans, 92 collagen, 82-87 collagen groups, 87-88 endochondral sequence, 92-93 glycoproteins, 90-92 noncollagenous proteins, 90-92 proteoglycans, 89-90 Extrauterine postnatal environment, hip dysplasia, 194 Extremities lower, discrepancies, s e e Lower extremity length discrepancies skeletal dysplasia, 785-787 upper hereditary multiple exostoses, 833-835 Ollier's disease, 819 skeletal dysplasias, 794 F FACIT collagens, epiphyseal tissue, 88 Factor VIII, prophylactic coverage in hemophilia, 920-921 Familial hypophosphatemic rickets, s e e X-linked hypophosphatemic rickets Femoral-acetabular articulation, childhood hip, 167 Femoral arteries, DDH, 240-243 Femoral catheters, neonate abnormal lower leg growth, 627 Femoral diaphysis, lower extremity length discrepancies, 636-639 Femoral head abnormality in skeletal dysplasias, 789-790 chronic SCFE treatment, 419-430 LCP disease, 307-311, 319, 343-349, 351,353-355, 358-360

Index

osteonecrosis, hemoglobinopathies, 926-927 pathogenesis, LCP disease, 296 postreduction, MR imaging, 231-232 vascularity, after DDH treatment, 261-262 Femoral head-acetabular repair index, LCP classification, 330-333 Femoral head-neck epiphysiodesis, in chronic SCFE treatment, 418 Femoral neck, LCP disease, 313-316 Femoral-tibial diaphyseal angle, infantile tibia vara, 486-487 Femora vara, hereditary multiple exostoses, 832 Femur child, congenital luxation, 167-168 congenital limb deficiences, 618-620 developmental abnormalities, 436-442 developmental stages, 158-159 diaphyseal lengthening, 698 discrepancies in LCP disease, 321-323 dislocated hip, 180 distal, s e e Distal femur experimental head displacement, 190-192 Fairbank's studies, 176-177 LCP disease, shortening, 319-321 proximal, s e e Proximal femur shortening, lower extremity length discrepancies, 671-672 Fetus acetabulum and femur, 158-160 epiphyses, physeal reconstruction, 715 FGFR, s e e Fibroblast growth factor receptor FGFs, s e e Fibroblast growth factors Fibroblast growth factor receptor, skeletal dysplasias, 750, 753-754 Fibroblast growth factors, limb axes development, 79-80 Fibrochondrogenesis, histopathology, 772-773 Fibula bowing, posteromedial, 623-625 childhood proximal tibial metaphyseal fractures, 511 distal, s e e Distal fibula hemimelia, 620-623 hypoplasia, 511-512 lower extremity length discrepancies, 672 physes, radiographic characteristics, 117 proximal, s e e Proximal fibula Flexion contractures, skeletal dysplasias, 793 Focal physeal bone bridge resection, infantile tibia vara, 491 Focal physeal implants, animal models, 715

Foot, skeletal dysplasias, 794 Forearm, skeletal dysplasias, 785-787 Fractures avulsion, proximal tibial tuberosity, 584-585 childhood nonphyseal fractures, 557-558 physeal fractures, 557-558 proximal tibial metaphyseal fractures, 510-511 tibial metaphyseal fractures, 510-511 epiphyseal growth plate fractureseparations, 528, 545-547 hereditary multiple exostoses, 836 juvenile, Tillaux, 587-588 metaphyseal, renal osteodystrophy, 887 osteopetrosis, 844 pathological, Ollier's disease, 820 Salter-Harris type, 511,559 triplane, distal tibial epiphyseal fractureseparation, 588-589 Freezing, lower extremity length discrepancies, 652 Frejka abduction pillow, DDH treatment, 253 G Gadolinium, MR imaging, 132 Gait asymmetry, lower extremity length discrepancies, 610 Gap junctions, bone cell linking, 19 Gender epiphyseal growth plate fractureseparation incidence, 558 hip dislocations, 192-193 SCFE, 398, 400 Genes arylsulfatase, 751 hemophilia, 910 hip dysplasia, 194 H o x , 74-75, 77-78 limb development control, 58, 74-75, 77-78 osteochondritis dissecans of distal femur, 469 S H O X , 751 skeletal gene database, 59-74 S O X 9 , 751 X-linked hypophosphatemic tickets, 879 Genum recurvatum, after skeletal traction, 596 Genu valgum childhood, 462 skeletal dysplasias, 790-792 Genu varum physiologic, 462-465 posteromedial fibular and tibial, 623-625 skeletal dysplasias, 790-792 X-linked hypophosphatemic tickets, 880-881

943

GLA protein, epiphyseal tissue, 91 Glenoid labrum, hip development, 154-155 Gluteus medius, dislocated hip, 179-180 Glycoproteins, epiphyseal tissue, 90-92 Grafts, s e e Bone grafts Greater trochanter, LCP disease responses, 316 surgical intervention, 362 Grebe chondrodysplasia, 815 Green-Phemister technique, limb shortening, 664 Groove of Ranvier, skeletal dysplasias, 761-762 Growth disturbance lines, s e e Harris lines Growth plates fracture, s e e Epiphyseal growth plate fracture-separation fusion, in chronic SCFE treatment, 409-410, 413-419 lower extremity length discrepancies, 663-669 medial, childhood proximal tibial metaphyseal fractures, 511 proximal femoral growth plate, 117-118, 383 proximal tibial growth plate, 117-118, 582 radiographic characteristics, 117-118 skeletal dysplasias, 766 transplantation, 708, 712-715 H HA, s e e Hydroxyapatite Harness LCP treatment, 343 Pavlik harness, 206, 253-254 Harris lines epiphyseal growth, 98-99 proximal femur, 234 Head, deformity mechanism, 289-292 Head-neck area, SCFE, 382-383 Hemangiomas, lower extremity length discrepancies, 642-643 Hematologic disorders hemophilia, s e e Hemophilia osteopetrosis, 842-843 von Willebrand disease, 924-925 Hemiatrophy, lower extremity length discrepancies, 639-640 Hemihypertrophy, lower extremity length discrepancies Beckwith-Wiedemann syndrome, 646 cerebral vasculature abnormalities, 641 initial delineation, 6,40 Klippel~.Igri~iman~a~yndrome, 643-645 neoplasin associafi'on, 640-641 overview, 639.?--640 Parkes Weber~yndrome, 64~5 Proteus syndrome, 645-646

944

Index

Hemihypertrophy, lower extremity length discrepancies ( c o n t i n u e d ) Silver-Russell syndrome association, 641 Hemiparetic cerebral palsy, 629-630 Hemoglobinopathies bone disease pathophysiology, 926-927 clinical characteristics, 925 overview, 925 therapeutic approaches, 926 Hemophilia adult surgical treatment, 924 arthrodesis, 924 bleeding intervention, 920 childhood hemophilia, 910-918 gene abnormalities, 910 hemoglobinopathies, 925-927 inhibitors, 921 lower extremity length discrepancies, 651 medical treatment, 918-920 orthopedic management, 922 osteotomy, 924 overview, 909-910 pain management, 921-922 prophylactic factor VIII, 920-921 radiation synovectomy, 923-924 recalcitrant joints, 922 soft tissue manipulation, 924 surgical synovectomy, 922-923 Hemophilic arthropathy gross pathology, 911-912 histopathology, 913-915 joint evaluation, 916 pain and bleeding, 916 pathogenesis, 912-913 radiology, 915-916 stages, 911 Hereditary arthro-ophthalmopathy, 813 Hereditary multiple exostosis clinical problems, 831-836 deformities, 832-835 general stature, 831 histopathology, 821 overview, 512, 625,821 pathogenesis, 821,825,827-831 Hinge abduction, LCP treatment, 364 Hip childhood, s e e Childhood hip computerized tomography, 230-231 development acetabulum, 159-160, 232-234 early infancy, 232 etiologies, 160-161 femur, 158-159 general aspects, 154-158 normal and abnormal, 230 dislocations, 164-165, 198 disorders, imaging, 142-145 growth, 234 infancy, acute septic arthritis, 899-903

juvenile rheumatoid arthritis, 893 osteoarthritis, 608 position, 214, 217-221 septic arthritis, 630-631,905-906 skeletal dysplasias, 787-790 subluxation, natural history, 198 Hip spica cast, LCP treatment, 343 DDH immobilization, 261-262 SCFE treatment, 404-405 Hip subluxation congenital hip, 180-181 knee extension, 190 Histogenesis, bone formation, 16-17 Histology bone formation, 16-19 hip MR imaging, 259 physeal distraction, 704-705 skeletal, osteopetrosis, 841 transphyseal bone bridge, 549-552 Histopathology hemophilic arthropathy, 913-915 hereditary multiple exostoses, 821 LCP disease, 285,297 lethal chondrodysplasias, 769-773 nonlethal chondrodysplasias, 773-774, 777 Osgood-Schlatter disease, 503-504 osteogenesis imperfecta bone, 857-858 osteopetrosis, 841-842 proximal femoral focal deficiency, 441 skeletal dysplasias, 762, 766-769 tuberculosis, 907 Homeobox genes, limb development, 74-75, 77-78 Homozygous achondroplasia, 758-759, 772 Hormones, laxity, young rabbits, 192 H o x genes, s e e Homeobox genes Humerus acute epiphyseal growth plate fractureseparation, 561-562, 566-570 distal, s e e Distal humerus lengthening, 701 osteonecrosis in hemoglobinopathies, 927 proximal, s e e Proximal humerus radiographic characteristics, 111-115 Hunter syndrome, 810 Hunter-Thompson acromesomelic dysplasia, 815 Hurler syndrome, 810 Hyaline cartilage, imaging characteristics, 134 Hydroxyapatite, mineralization, 94 Hyperabduction, hip MR imaging, 259 Hyperparathyroidism, SCFE, 394 Hypertension, LCP disease, 280 Hypertrophic cell zone, Retterer's studies, 16

Hypertrophic chondrocytes apoptosis, 37 endochondral bone development role, 37 endochondral mechanism, 11 endochondral ossification, 36 enlargement, 36-37 light microscopic studies, 19-21 physis, 29 Hypochondrogenesis, 759, 771 Hypochondroplasia, 773,801 Hypophosphatasia, 760, 773 Hypophosphatemic rickets, pathophysiology, 878-879 Hypoplasia, fibula, 511-512 Hypothyroidism, 393 I Idiopathic dysplasia, congenitaldevelopmental hip abnormalities, 197 IGF, s e e Insulin-like growth factor Iliac crest bone biopsy, osteopetrosis, 844 free autogenous physeal grafts, 708, 712-714 vascularized autogenous epiphyseal grafts, 714-715 Iliopsoas muscle groups, dislocated hip, 179-180 Imaging, s e e Magnetic resonance imaging; Radiography Immobilization DDH treatment, 258-262 hip ischemia, 258-262 knee, 632-633 Implants epiphyseal growth plate stimulation, 674-675 focal physeal implants, 715 lower extremity length discrepancy treatment, 719 Indian hedgehog, limb axes development, 78-79 Infantile coxa vara characteristics, 377 clinical-radiographic correlations, 443-444, 448-449 deformity pathomechanics, 447-448 management, 449-451 pathoanatomy, 444-446 radiographic change, 446-447 terminology, 443 Infantile cortical hyperostosis, 652-653 Infantile malignant autosomal recessive osteopetrosis, 837 Infantile paralysis, hip dislocation, 164-165 Infantile tibia vara childhood, adult sequelae, 491-493 clinical and radiographic profile, 480-481

Index

deformities, 481-484, 488-490 femoral varus-tibia vara association, 496 imaging, 147,486-487 management, 487-488 pathoanatomy, 484-486 spontaneous correction, 490 surgical treatment, 490-491 terminology, 479-480 Infarction, LCP disease, 280-281 Infection childhood tuberculosis joints, 909 effect on epiphyseal growth, 905-906 Inflammatory disorders juvenile rheumatoid arthritis, 889-894 pigmented villonodular synovitis, 894 Inflammatory-pathologic theory, childhood hip, 167-168 Innominate osteotomy hip dislocation treatment, 208-210 LCP treatment, 355, 358-359 Insulin-like growth factor, limb axes, 81 Interferon ~/, osteopetrosis treatment, 846 Intermediate mild autosomal recessive osteopetrosis, 837 Interpedicular narrowing, achondroplasia, 799-800 Interpositional materials, epiphyses operation, 708 Interterritorial matrix, hypertrophic chondrocytes, 31, 34 Intertrochanteric compensatory osteotomies, 427-428 Intracartilaginous-intraosseous vessels, 243-244 Intramembranous ossification, 4-5 Intramedullary rod, diaphysis lengthening, 695-698 Intrauterine environment, congenitaldevelopmental hip, 193-194 Ipsilateral diaphysis, premature physeal closure, 594-595 Irradiation, childhood tumor, physeal damage, 635-636 Ischial weight bearing brace, LCP treatment, 343

J Jansen metaphyseal dysplasia, 812 Joints childhood tuberculosis infection, 909 contractures, juvenile rheumatoid arthritis, 893 development, 44-46 epiphyseal growth plate fractureseparation, 539-540 hemophilia, 922 hemophilic arthropathy, 916 hip development, 155 osteopetrosis, 842

septic arthritis, 904-905 skeletal dysplasias, 787 stabilization in limb length abnormalities, 700-701 Joint surface quotient, LCP classification, 331-332 Juvenile fracture, Tillaux, 587-588 Juvenile renal osteodystrophy, slipped epiphyses, 395 Juvenile rheumatoid arthritis lower extremity length discrepancies, 649-650 pathobiology, 889-890 profile, 889 skeletal abnormalities, 890-893 surgery, 893-894 K Klippel-Trenaunay syndrome, 643-645 Klippel-Trenaunay-Weber syndrome, 647-648 Knee disorders, imaging, 145-147 extension, hip dislocation, 190 infantile tibia vara, arthrography, 486 juvenile rheumatoid arthritis, 892-893 lower extremity immobilization, 632-633 septic arthritis, 904 skeletal dysplasias, 790-794 synovial hemangioma, 651 Kniest dysplasia, 774, 804 Knock-knee, s e e Genu valgum KTW, s e e Klippel-Trenaunay-Weber syndrome K-wire, proximal tibia placement, 596 Kyphoscoliosis, skeletal dysplasia, 782-783 Kyphosis, skeletal dysplasia, 782-783

L Lamellar bone, diaphyseal bone formation, 41-44 Langenskiold grade, infantile tibia vara deformity after osteotomy, 488 Larsen's syndrome, 816 Lateral circumflex femoral arteries, DDH, 240-243 Lateral epiphyseal lysis, Gage-Catterall sign, 304 Lateral humeral condyle, epiphyseal growth plate fracture-separation, 562, 566 Lateral-proximal neck convexity, Gage sign-Catterall sign, 304 LCP, s e e Legg-Calve-Perthes disease Legg-Calve-Perthes disease acetabular deformation, 296 acetabulum responses, 316-318 age of occurrence, 323-324

945

basic considerations, 323 Calve's study, 273-275 cartilage model, proximal femur, arthrography, 311-312 classification, skeletal maturity, 329-336 contralateral hip abnormalities, 279 definition, 272 delayed bone maturation role, 278-279 diminished stature role, 278-279 epidemiologic features, 277-278 femoral head cartilage model, 307-311 femoral head containment, 343-349, 351,353-355,358-359 femoral head non-containment, 360 femoral neck anteversion, 316 femoral shortening, 319-321 general features, 276-277 greater trochanter responses, 316 hinge abduction, 319 imaging, 143-145 imperfect healing, 319 incipient to residual stages, 297 late-stage surgical intervention, 362-364 Legg's study, 273 lower extremity length discrepancies, 321-323, 651-652 metaphysis response, 313-316 multiple infarctions, 280-281 nonhereditary disorder, 279 nonoperative, noncontainment treatment times, 361-362 non-weight-bearing treatment, 341-343 overview, 272-273 pathology, 281-295,300-303 Perthes' study, 275 physis response, 312-313 plain radiographic classifications, 297-299, 324-329 proximal femoral epiphysis nutrition, 304 radiodensity-radiolucency areas, 306-307 relation to age, 362 residual phase, remodeling, 318 sagging rope sign, 313 secondary ossification center, 304-306, 360 Sourdat's study, 276 subchondral fracture, 304-305 transient synovitis, 279-280 treatment approaches, 336-341, 360-361,364-368 venous hypertension role, 280 Waldenstrom' study, 275-276 Lesions angiomatous lesions, 646-647 bone, renal osteodystrophy, 885 childhood OD treatment, 479 knee, chronic repetitive trauma, 147

946

Index

Lethal chondrodysplasias, 769-773 Lethal thoracic dysplasia, 761 Ligamentum teres DDH, 240 dislocated hip, 180 hip development, 156 Light microscopy abnormal cell appearance, skeletal dysplasias, 767 bone development studies, 13-16 hypertrophic chondrocytes, 19-21 osteopetrosis ultrastructure, 841 Limb axes bone morphogenetic proteins, 80-81 fibroblast growth factors, 79-80 insulin-like growth factor, 81 parathyroid hormone, 81 parathyroid hormone receptor protein, 81 PTH/PTH/aR/AP receptor, 81 signaling molecules, 78-79 transforming growth factors-[3, 80 vitamin D, 81 Wnt 7A, 80 Limb bud chick, Hoxc genes, 78 hip development, 154-155 Limb development apical ectodermal ridge, 58 dorsal nonridge ectoderm, 58 gene control, 74-75, 77-78 long bones, 9-11 matrix metalloproteinases, 81-82 polarizing region, 58 progress zone, 58 timing and staging, 8-9 TIMP, 81-82 Limb lengthening lower extremity length discrepancies concerns in complex abnormalities, 700-701 distraction osteogenesis, 685, 688-695 early clinical approaches, 675-682 epiphyseal growth plate stimulation, 672-675 humeral lengthening, 701 intermedullary rod lengthening, 695-698 longitudinal growth, 698-700 rigid fixator results, 682-685 transiliac lengthening, 705-706 transphyseal lengthening, 701-705 skeletal dysplasias, 794 Limb shortening, lower extremity length discrepancies diaphyseal shortening, 669-672 epiphysiodesis, 667-668 growth plate therapeutic arrest, 663-667 metaphyseal shortening osteotomies, 669

partial therapeutic growth plate arrest, 668-669 Limbus CDH patients, infant acetabular development, 233-234 dislocated hip, 180 Long bones Broca's studies, 13 embryonic development, 9-11 epiphysis, radiographic characteristics, 112-118 formation, intramembranous ossification, 4-5 growth rate in skeletal dysplasia, 785-787 Kolliker's studies, 13 lower extremity length discrepancies, 653 osteopetrosis, 845 perichondrial ossification groove of Ranvier, 5 Salter-Harris type fracture distribution, 559 Low back pain, lower extremity length discrepancies, 608-610 Lower extremity length discrepancies angiomatous lesion classification, 646-647 associated angioplastic disorders, 641-642 Caffey's disease, 652-653 causes, 611-612 childhood tumor irradiation, 635-636 clinical effects, 608-610 clinically significant discrepancies, 606 congenital, see Congenital lower extremity length discrepancies destroyed physes, 627 developmental patterns, 612-615, 661-663 diaphysis lengthening, 675-685, 688-701 epiphyses operation, 706-708, 712-720 equal limb length, 606-608 external causes, 652 fractured femoral diaphysis, 636-639 fractured tibial diaphysis, 639 hemangiomas, 642-643 hemiatrophy, 639-640 hemihypertrophy, 639-641 hemiparetic cerebral palsy, 629-630 hemophilia, 651 hereditary multiple exostoses, 835-836 juvenile rheumatoid arthritis, 649-650, 890-892 knee joint synovial hemangioma, 651 LCP disease, 321-323, 362, 651-652 limb length determination, 610-611 limb lengthening, 672-675,701-706 limb shortening, 663-672

management considerations, 663 meningococcemia, 634-635 neonate catheter effects, 627 neurofibromatosis, 648-649 Ollier's disease, 819-820 osteomyelitis, 633-634 poliomyelitis, 627-629 premature epiphyseal fusion at knee, 632-633 SCFE, 652 septic arthritis of hip, 630-631 skeletal dysplasias, 625-627, 785 skeletal maturity, 653-661 thalassemia, 650-651 tuberculosis, 631-632 vascular malformations, 643-648 Lower limb, hereditary multiple exostoses, 832-833 Lumbar lordosis, 783 Lumbar spinal stenosis, 783 Lysosomal enzyme, 751 M Macrocephaly-hydrocephalus, 798 Maffucci syndrome, 626, 821 Magnetic resonance imaging bone and marrow, 135 cartilage, 133-134 coxa vara, 378 distal tibia and fibula disorders, 147 epiphyseal growth plate fractureseparation, 549-556 epiphyses, 130-132 femoral head postreduction, 231-232 hip disorders, 142-145 hip ischemia, extreme positioning, 258-262 infantile tibia vara, 486 knee disorders, 145-147 LCP pathology, 302-303 normal and abnormal bone growth, 135-137, 142 osteopetrosis, 843 upper extremities, 147-148 Malformations, childhood hip, 168 Malignant degeneration, hereditary multiple exostoses, 836 Malignant transformation, Ollier's disease, 820-821 Maroteaux-Lamy syndrome, 812 Matrix metalloproteinases, limb development, 81-82 McKusick metaphyseal dysplasia, 812 Mechanical stress, developing bone and epiphyses responses abnormal pressure responses, 107-109 compressive and tensile stresses, 103-105 normal responses, 99-103 pressure effects, 109-111

Index

skeletal development effects, 105-107 Medial circumflex femoral arteries, DDH, 240-243 Medial gap, hip, radiographic measurement, 214 Medial growth plate, childhood proximal tibial metaphyseal fractures, 511 Medial humeral condyle, epiphyseal growth plate fracture-separation, 569-570 Medial malleolus, type III fracture, 589 Medial physeal slope, infantile tibia vara, 487 Medial tibial articular surface, infantile tibia vara, 491 Melorheostosis, lower extremity length discrepancies, 627 Meningococcemia, lower extremity length discrepancies, 634-635 Mesomelic dysplasias, 813 Mesomelic shortening, skeletal dysplasia, 785 Metacarpals, acute epiphyseal growth plate fracture-separation, 574 Metaphyseal-diaphyseal angle, infantile tibia vara, 487 Metaphyseal dysplasia, 774 Metaphyseal fractures, renal osteodystrophy, 887 Metaphyseal periosteum, elevation and stripping, 673 Metaphyseal shortening osteotomies, 669 Metaphysis infection, effect on epiphyseal growth, 905-906 osteopetrosis, 841-842 periosteum relationship, 39-41 response in LCP disease, 313-316 skeletal dysplasias, 761-762, 766 Metatarsal growth plate, radiographic characteristics, 117-118 Metatropic dysplasia, 774, 804 Micromelic shortening, skeletal dysplasia, 785 Microscopy electron, achondrogenesis II cartilage, 771 light, s e e Light microscopy Midcervical kyphosis, cervical spine skeletal dysplasia, 780 Mineralization endochondral sequence, 17-18, 93-96 hypertrophic chondrocytes, 31, 34 MMPs, s e e Matrix metalloproteinases Models bone patterning, 55-57 cartilage, LCP disease, 307-312 focal physeal implants, 715 osteopetrosis, 841 rabbit, distraction osteogenesis, 695

rickets, 872-874 tissue patteming, 53-55 X-linked hypophosphatemic rickets, 880 Morbidity, achondroplasia, 796-798 Morphology, osteopetrosis, 841 Morquio syndrome, 810 Mortality, achondroplasia, 796-798 MPS, s e e Mucopolysaccharidoses MPSIH, s e e Hurler syndrome MPSII, s e e Hunter syndrome MPSIII, s e e Sanfilippo syndrome MPSIS, s e e Scheie syndrome MPSIV, s e e Morquio syndrome MPSVI, s e e Maroteaux-Lamy syndrome MPSVII, s e e Sly syndrome MRI, s e e Magnetic resonance imaging Mucolipidosis, 777 Mucopolysaccharidoses, 777, 808-812 Multiple epiphyseal dysplasia, 774, 777, 801-803 Muscles adductor, congenital-developmental hip abnormalities, 196 Fairbank's studies, 177 iliopsoas, dislocated hip, 179-180 strength, distraction osteogenesis, 691-692 Mutations, skeletal dysplasias, 744, 749-752 Myelomeningocele, 592-593 Myogenesis, childhood hip dislocation, 168 N Necrosis avascular, s e e Avascular necrosis osteonecrosis, s e e Osteonecrosis SCFE, 388-389 secondary ossification centers, 360 Neonates epiphyses, physeal reconstruction, 715 post-catheter abnormal lower leg growth, 627 proximal femoral physeal separation, 576 Neoplasia, hemihypertrophy association, 640-641 Neoplastic disorders, epiphyses aneurysmal bone cyst, 896 chondroblastoma, 894-895 eosinophilic granuloma, 895 osteogenic sarcoma, 896-897 osteoid osteoma, 895 unicameral bone cyst, 895-896 Neurofibromatosis, lower extremity length discrepancies, 648-649 Neurogenesis, childhood hip dislocation, 168 Neurology concerns in osteopetrosis, 845

947

diaphysis lengthening effect, 692-693 skeletal dysplasias, 861 Newborns DDH diagnosis, 235-236 fractures in distal femoral epiphysis, 579 Noncollagenous proteins, epiphyseal tissue, 90-92 Nonhereditary disorder, LCP disease, 279 Nonlethal chondrodysplasias, 773-774, 777 Nonphyseal fractures, distribution in childhood, 557-558 Nutritional rickets, deformities, 878 O OA, s e e Osteoarthritis Obesity, SCFE, 382, 403 OD, s e e Osteochondritis dissecans Odontoid process, cervical spine abnormalities, 779-780 OI, s e e Osteogenesis imperfecta Ollier's disease clinical sequelae, 818 deformities, 818-819 disease profile, 816-818 distal femoral deformities, 818-819 lower extremity length discrepancies, 625-626, 819-820 malignant transformation, 820-821 pathological fractures, 820 terminology, 816 tibial deformities, 818-819 upper extremity, 819 Open reduction CDH treatment, 206-207 chronic SCFE treatment, 419-425 hip acetabular development, 232-233 Organs, bone as, 14-15 Orthoroentgenograms, lower extremity length discrepancies, 611 Osgood-Schlatter disease adults, 506-507 clinical and radiologic features, 504 complications, 506 general treatment approach, 504-505 pathoanatomic changes, 501-504 pathophysiology, 497-498 surgical treatment, 505-506 terminology, 497 tibial tuberosity development, 498-501 Ossification endochondral ossification, 4, 36-37 intramembranous, mechanism, 4-5 MR imaging, 136 perichondrial groove of Ranvier, 5, 39 secondary centers, s e e Secondary ossification centers Osteitis fibrosa, renal osteodystrophy, 887-888

948

Index

Osteoarthritis adult, as SCFE complication, 434 hip, lower extremity length discrepancies, 608 osteopetrosis, 845 post-childhood CDH, 198-199 Osteoblasts, bone formation, 18 Osteocalcin, epiphyseal tissue, 91-92 Osteochondral fragment, medial malleolus fracture, 589 Osteochondritis dissecans age of occurrence, 468 causes, 468-470 childhood OD, treatments, 478-479 current understanding of disease, 474-475 disease profile, 465-466 healing factors, 477-478 imaging, 147 lesion in LCP disease, 319 original descriptions, 466-467 pathogenesis and pathoanatomy, 470-474 radiography and imaging, 475-477 site of occurrence, 468 stages, 467-468 Osteoclasts bone formation, 19 osteopetrosis, 842 Osteocytes bone formation, 18 diaphyseal bone formation, 43 Osteogenesis imperfecta bone, histopathology, 857-858 characteristics, 759 classification, 848-849, 855-856 clinical characteristics, 849, 852, 854 collagen defects, 856-857 diagnosis, 854-855 medical management, 860 orthopedic management, 858-860 overview, 847-848 Osteogenic sarcoma, 896-897 Osteoid osteoma, 895 Osteomyelitis epiphyseal, see Epiphyseal osteomyelitis infection effects, 905 lower extremity length discrepancies, 633-634 osteopetrosis, 845 Osteonecrosis hemoglobinopathies, 926-927 renal osteodystrophy, 885-888 Osteopetrosis blood chemistry studies, 843 diagnostic criteria, 842-843 hematologic studies, 842-843 histopathology, 841-842 iliac crest bone biopsy, 844 imaging studies, 843-844

neurologic concerns, 845 orthopedic concerns, 844-845 overview, 837 systemic management, 845-846 types, 837, 841 Osteoprogenitor cells, epiphyseal growth plate fracture-separation, 548 Osteotomy chronic SCFE treatment, 419-428 DDH, 212-213 hemophilia, 924 hip acetabular development, 232-233 hip dislocation treatment, 208-210 ilium, 210-211 infantile tibia vara, 488-490 LCP treatment, 344-345,349, 351, 353-355,358-359, 363-364 lower extremity length discrepancies, 669 proximal femoral growth, 234 P Pain hemophilia, 921-922 hemophilic arthropathy, 916 LCP treatment, 340-341 Parathyroid hormone limb axes, 81 mineralization, 94 Parathyroid hormone receptor protein, 81 Parathyroid hormone related peptide receptor, 751 Parkes Weber syndrome, lower extremity length discrepancies, 645 Parks-Harris line, MR imaging, 137, 142 Patellar dislocation, skeletal dysplasias, 793 Pathoanatomy adolescent tibia vara, 496-497 childhood hip, 168-169 congenital dislocation of knee, 508-509 epiphyseal growth plate fractureseparations, 523-528, 531-535 infantile coxa vara, 444-446 infantile tibia vara, 484-486 Osgood-Schlatter disease, 501-504 osteochondritis dissecans of distal femur, 470-474 proximal femoral focal deficiency, 441 SCFE, 383-392 septic arthritis of infant hip, 901-903 Pathobiology, rheumatoid arthritis, 889-890 Pathogenesis congenital luxation of femur, 167-168 developing bone deformity, 107-109 epiphyseal growth plate fractureseparation, 548-549 femoral head, LCP disease, 296 hemophilic arthropathy, 912-913

hereditary multiple exostoses, 821,825, 827-831 infantile tibia vara deformity, 481-484 LCP disease, venous hypertension role, 280 nutritional rickets skeletal abnormality, 877-878 osteochondritis dissecans of distal femur, 470-474 renal osteodystrophy bone deformities, 887-888 rickets, 872 SCFE, 389-392 skeletal dysplasias, 769 Pathological fractures, Ollier's disease, 820 Pathology hemophilic arthropathy, 911-912 LCP disease, 281-295 vitamin D deficiency rickets, 874-876 Pathomechanics, infantile coxa vara deformity, 447-448 Pathophysiology epiphyseal growth plate fractureseparation blood supply, 539-548 classifications, 537-539 deformity pathogenesis, 548-549 MR imaging, 549-556 familial hypophosphatemic rickets, 878-879 hemoglobinopathy bone disease, 926-927 nutritional rickets, 877 Osgood-Schlatter disease, 497-498 renal rickets, 884-885 Patterning, bone mechanisms, 55-58 signaling regions, 53 tissue patterning models, 53-55 Pavlik harness avascular necrosis in DDH treatment, 253-254 CDH treatment, 206 Percutaneous fixation, in chronic SCFE treatment, 415-417 Percutaneous technique, limb shortening, 667 Pericapsular osteotomy, ilium, 210-211 Perichondrial ossification groove of Ranvier epiphyseal growth plate, 39 mechanism, 5 Perichondrium, imaging characteristics, 134 Periosteum diaphysis, epiphysis, and metaphysis, 39-41,673 Nesbitt's studies, 6 Periphyseal tissues, groove of Ranvier, 761-762

Index

Pfeiffer syndrome, 816 PFFD, s e e Proximal femoral focal deficiency Phalangeal growth plate, radiographic characteristics, 117-118 Phalanges, acute epiphyseal growth plate fracture-separation, 574 Phemister technique, limb shortening, 664 Physeal cartilage cell proliferation, 96 chondrocyte shape, 17-18 epiphyseal growth plate fractureseparation direct damage, 543-545 fracture pathway, 545-547 skeletal dysplasias, 767 Physeal chondrocytes, metabolism, 96 Physeal distraction histology, 704-705 premature closure treatment, 719-720 Physeal fracture, distribution in childhood, 557-558 Physis closure avascular necrosis in DDH treatment, 251 distraction treatment, 719-720 growth plate transplantation treatment, 708, 712-715 premature, LCP disease, 320 radiographic characteristics, 117 damage, childhood tumor irradiation, 635-636 destroyed, lower extremity length discrepancies, 627 height, adolescent tibia vara, 495-496 response in LCP disease, 312-313 skeletal dysplasias, 768 structure and function, 25, 29, 31, 34-37 transplantation, 715-718 Pigmented villonodular synovitis, 894 Pillar, classification in LCP disease, 327-328 Pinning, chronic SCFE treatment articular cartilage penetration danger, 413-414 femoral head position change, 429 in situ studies, 417-418 stabilization pins, 414-415 transphyseal pinning, 409-410, 413 Plain radiography, coxa vara, 378 Poland syndrome, 816 Poliomyelitis, lower extremity length discrepancies, 627-629 Polydactyly syndromes, 816 Positional information models, bone patterning, 55-57 Preformationism, embryogenesis theory, 3-4

Prepattern mechanism, bone patterning, 57 Pressure epiphyseal growth effects, 109-111 phenomena in hereditary multiple exostoses, 836 physes responses, abnormal pressure, 107-109

Progress zone, 58 Prophylactic pinning, chronic SCFE treatment, 430-431 Proteoglycans cell surface heparan sulfate, 751 cell surface type, 92 epiphyseal tissue, 89-90 mineralization, 94 Proteus syndrome, lower extremity length discrepancies, 645-646 Proximal femoral dysplasia, 196 Proximal femoral epiphysis, LCP disease, 304 Proximal femoral focal deficiency classifications, 437-440 clinical characteristics, 440-441 congenital limb deficiencies, 618 imaging, 142 pathoanatomic studies, 441 treatment options, 441-442 Proximal femoral growth plate radiographic characteristics, 117-118 SCFE, 383 Proximal femoral osteotomies, DDH, 212-213 Proximal femoral valgus osteotomy, LCP treatment, 363-364 Proximal femur acute epiphyseal growth plate fractureseparation, 575-576 blood supply, DDH treatment ascending cervical arteries, 240-243 deep and circumflex femoral arteries, 240 general pattern, 239-240 intracartilaginous-intraosseous vessels, 243-244 lateral and medial circumflex arteries, 240-243 ligamentum teres vascularity, 240 vascular pattern changes, 244-245 cartilage model, LCP disease, arthrography, 311-312 growth after osteotomy, 234 Harris lines, 234 radiographic characteristics, 115-116 stress analysis, 103-105 Proximal femur varus-derotation osteotomy, LCP, 349, 351,353-355 Proximal fibula acute epiphyseal growth plate fractureseparation, 591 elongation, 511

949

epiphysis disorders, 511-512 radiographic characteristics, 117 Proximal humerus acute epiphyseal growth plate fractureseparation, 561-562 radiographic characteristics, 111-112 Proximal radius acute epiphyseal growth plate fractureseparation, 570 radiographic characteristics, 115 Proximal tibia acute epiphyseal growth, plate fractureseparation anterior tibial spine, 582-584 avulsion fractures of tibial tuberosity, 584-585 ligament damage, 592 growth plate, radiographic characteristics, 117-118 infantile tibia vara, metaphysealdiaphyseal angle, 487 K-wire, placement, 596 metaphyseal fractures, childhood deformities, 510-511 physeal arrest, infantile tibia vara treatment, 490-491 physis, secondary proximal fibular overgrowth, 512 radiographic characteristics, 116 stress analysis, 103 Proximal tibial-fibular osteotomy, infantile tibia vara treatment, 490 Proximal ulna, radiographic characteristics, 115 Pseudo-achondroplasia, 777, 808 PTH, s e e Parathyroid hormone PTH/PTHrP receptor, limb axes, 81 PTHRP, s e e Parathyroid hormone receptor protein PTHRPR, s e e Parathyroid hormone related peptide receptor Pulmonary system, skeletal dysplasias, 861 Pycnodysostosis, 846-847 R

Rabbit breech malposition, 192 distraction osteogenesis model, 695 femoral head displacement, 190-192 knee extension, 190 Radiation synovectomy, hemophilia, 923-924 Radiodensity, LCP disease, 305-307 Radiography achondroplasia, 795-796 adolescent tibia vara, 496 CDH studies, 205-206 epiphyseal growth plate fractureseparation, 531-537 hip position, 214, 217-218

950

Index

Radiography ( c o n t i n u e d ) infantile coxa vara, 443-444, 446-447, 449-451 infantile tibia vara, 480-481 LCP disease, 297-299, 324-329, 364-366 long bone epiphyses, 111-118, 462-465,475-477 lower extremity length discrepancies, 611 nutritional tickets, 878 osteopetrosis, 843-844 plain, coxa vara, 378 SCFE severity, 396 skeletal dysplasia diagnosis, 743-744 tuberculosis, 906-907 X-linked hypophosphatemic tickets, 880-882 Radiology equal lower extremity limb lengths, 607-608 hemophilic arthropathy, 915-916 Osgood-Schlatter disease, 504 Radiolucency, LCP disease, 306-307, 314-316 Radiotherapy, in predisposition to SCFE, 394-395 Radius acute epiphyseal growth plate fractureseparation, 570-574 radiographic characteristics, 115 Renal osteodystrophy bone deformity pathogenesis, 887-888 bone lesions, 885 childhood bone deformities, 885-887 orthopedic treatment, 888-889 pathophysiology, 884-885 Renal tickets, s e e Renal osteodystrophy Retinacula of Weitbrecht, hip development, 155-156 Retinoids, limb axes development, 78 Rheumatoid arthritis, s e e Juvenile rheumatoid arthritis Rhizomelic chondrodysplasia punctata, 772 Rhizomelic shortening, skeletal dysplasia, 785 Rickets experimental models, 872-874 nutritional tickets, 877-878 pathogenesis, 872 renal tickets, 884-889 terminology, 872 vitamin D deficiency, pathology, 874-876 X-linked hypophosphatemic, s e e X-linked hypophosphatemic tickets Rigid fixators, diaphysis lengthening, 682-685 Roentgen stereophotogrammetry, growth plate fracture-separations, 591-592

S Sagging rope sign, radiographic LCP disease characteristic, 313 Salter-Harris type fractures childhood proximal tibial metaphyseal fractures, 511 epiphyseal growth plate fractureseparation, 559 Sanfilippo syndrome, 810 Scanograms, lower extremity length discrepancies, 611 SCFE, s e e Slipped capital femoral epiphysis Scheie syndrome, 810 Schmid metaphyseal dysplasia, 812 Sciatica, lower extremity length discrepancies, 608-610 Scintigraphy LCP pathology, 300-302 skeleton, 132-133 Scoliosis achondroplasia, 800 skeletal dysplasia, 782-783 Screening, SCFE, 403-404 Secondary ossification centers formation, 21-25, 50-51 hip position radiography, 217-218 LCP treatment, 304-306, 360 osteopetrosis, 842 skeletal dysplasias, 767 Septic arthritis childhood, long-term sequelae, 905 hip, 630-631,905-906 infant hip negative growth sequelae, 900 overview, 899-900 pathoanatomy, 901-903 treatment approaches, 901 non-hip joints, 904-905 tuberculosis, 906-909 Short rib syndromes characteristics, 760-761 polydactyly type, 772 Short stature homeobox, skeletal dysplasias, 751 Shortwave diathermy, limb lengthening, 673-674 Shoulder imaging, 147-148 septic arthritis, 904-905 SHOX, s e e Short stature homeobox Sickle cell anemia, clinical characteristics, 925 Signaling molecules, limb axes bone morphogenetic proteins, 80-81 fibroblast growth factors, 79-80 Indian hedgehog, 78-79 insulin-like growth factor, 81 parathyroid hormone, 81 parathyroid hormone receptor protein, 81

PTH/PTHrP receptor, 81 retinoids, 78 sonic hedgehog, 78-79 transforming growth factors- [3, 80 vitamin D, 81 Wnt 7A, 80 Signaling regions, bone development patterning, 53 Silver-Russel syndrome, hemihypertrophy association, 641 Skeletal dysplasias achondroplasia, 794-801 acromelic dysplasia, 815-816 acromesomelic dysplasia, 813-815 affected developmental cycle, 754-755 anesthetic considerations, 860-861 associated coxa vara, 378 chondrodysplasia punctata, 804 chromosome abnormalities, 744-749 classification approaches, 733-734, 737-738 cleidocranial dysostosis, 813 clinical examination, 740-743 developing epiphyses and metaphyses structures, 761-762 diastrophic dysplasia, 805-807 Dyggve-Melchior-Claussen dysplasia, 808 dyschondrosteosis, 813 dysplasia epiphysealis hemimelica, 803-804 hereditary arthro-ophthalmopathy, 813 hereditary multiple exostoses, 821,825, 827-836 histopathologic classification, 762, 766-769 hypochondroplasia, 801 Kniest dysplasia, 804 laboratory studies, 743-744 Larsen's syndrome, 816 lethal chondrodysplasias, 769-773 lethal perinatal achondrogenesis, 759 asphyxiating thoracic dystrophy, 761 atelosteogenesis, 759 campomelic dysplasia, 760 chondrodysplasia punctata, 759-760 diagnostic profile, 755-756 homozygous achondroplasia, 758-759 hypochondrogenesis, 759 hypophosphatasia, 760 osteogenesis imperfecta, 759 short rib syndromes, 760-761 thanatophoric dysplasia, 756-758 limb lengthening, 794 lower extremity length discrepancies, 625-627 Maffucci syndrome, 821 mesomelic dysplasias, 813

Index

metaphyseal dysplasia, 812 metatropic dysplasia, 804 molecular function defects, 752-754 mucopolysaccharidoses, 808-812 multiple epiphyseal dysplasia, 801-803 mutation families, 744, 749-752 nonlethal chondrodysplasias, 773-774, 777 Ollier's disease, 816-821 orthopedic deformities ankle abnormalities, 793-794 cervical spine abnormalities, 779-781 clavicle abnormalities, 785 extremity abnormalities, 785-787 foot abnormalities, 794 hip abnormalities, 787-790 knee abnormalities, 790-794 lumbar lordosis, 783 lumbar spinal stenosis, 783 overview, 778-779 skull abnormalities, 785 thoracolumbar spine abnormalities, 782-783 upper extremity abnormalities, 794 osteogenesis imperfecta, 847-849, 852, 854-860 osteopetrosis, 837, 841-846 overview, 738-740 pathogenesis, 769 prenatal assessment, 740 prevalence, 738 pseudo-achondroplasia, 808 pycnodysostosis, 846-847 radiographic examinations, 743 Smith-McCort dysplasia, 808 spondyloepimetaphyseal dysplasia, 804-805 spondyloepiphyseal dysplasia, 807-808 spondylometaphyseal dysplasia, 812-813 terminology, 733 trichorhinophalangeal dysplasia, 860 Skeleton development, mechanical stress effects, 105-107 gene database, 59-74 hip development, 156 histology, osteopetrosis, 841 juvenile rheumatoid arthritis, 890-893 maturity, LCP disease adult responses to childhood disorder, 335-336 Butel, Borgi, and Oberlin grading system, 335 femoral head-acetabular repair indices, 330-333 general considerations, 329-330 Stulberg classification, 333-335 Sundt classification, 330

maturity, lower extremity length discrepancies long bone growth percentage, 653 methods of determination, 659-661 prediction systems, 653-659 maturity, prior diaphysis lengthening, 698-700 nutritional rickets, 877-878 osteopetrosis, imaging studies, 843-844 prenatal sonographic evaluation, 129-130 scintigraphy, 132-133 ultrasonography, 129 Skin traction, LCP treatment, 343 Skull, skeletal dysplasia, 785 Sling, LCP treatment, 343 Slipped capital femoral epiphysis anatomic-physiological features, 382-383 classifications, 396-398 clinical awareness and description, 379-381 complications adult osteoarthritis, 434 avascular necrosis, 431-432 chondrolysis, 432-434 involved side shortening, 434 stiffness, 434 diagnostic imaging studies, 404-408 epidemiologic characteristics Children's Hospital, Boston, 398-400 overview, 398 school screening recommendations, 403-404 study comparisons, 400-403 imaging, 145 initial theories, 381-382 juvenile renal osteodystrophy, 395 long-term follow-up studies, 434-436 lower extremity length discrepancies, 652 medical disorder predisposition, 383 obesity, 382 pathoanatomy, 383-389 pathogenesis and pathoanatomy, 389-392 predisposing medical disorders, 392-395 terminology, 378-379 therapy goals, 404 treatment, 404-409, 430-431 Slipped epiphyses, renal osteodystrophy, 885-887 Sly syndrome, 812 Smith-McCort dysplasia, 808 Smith-Peterson nail, SCFE treatment, 407 Soft tissues childhood proximal tibial metaphyseal fractures, 511 congenital-developmental hip abnormalities, 196-197

951

manipulation in hemophilia, 924 PFFD, 441 Sonic hedgehog, limb axes development, 78 Sonography indices, normal and abnormal hip development, 230 prenatal skeleton, 129-130 SOX9, skeletal dysplasias, 751,754 Spine abnormalities in achondroplasia, 799-800 skeletal dysplasias, 861 Splints Birmingham splint, LCP treatment, 345-346 Denis Browne splint, DDH treatment, 254 Spondyloepimetaphyseal dysplasia, 804-805 Spondyloepiphyseal dysplasia, 774, 807-808 Spondylometaphyseal dysplasia, 774, 812-813 Stickler syndrome, 813 Stiffness, as SCFE complication, 434 Stress compressive, epiphyseal plates, 103-105 mechanical, see Mechanical stress resulting physeal separation, 595-596 tensile, epiphyseal plates, 103-105 Structural proteins, skeletal dysplasias, 752-753 Subluxation congenital hip, 180-181 hip, knee extension, 190 LCP disease, 309 Sub-periosteal bone, osteopetrosis, 842 Superior gap, hip, radiographic measurement, 214 Superior talar articular surface, hereditary multiple exostoses, 833 Surgery acetabular growth, 234 adult hemophilia, 924 childhood OD treatment, 479 epiphyseal growth plate fractureseparation treatment, 530 induced arteriovenous fistula, 672-673 infantile tibia vara treatment, 490-491 juvenile rheumatoid arthritis, 893-894 LCP disease, 349, 351,353-355, 358-359, 362-364 Osgood-Schlatter disease treatment, 505-506 SCFE treatment, 404-405 Surgical synovectomy, hemophilia, 922-923 Survival, hypertrophic chondrocytes, 19-20

952

Index

Sympathectomy, limb lengthening, 672 Syndactyly, 816 Synovectomy, hemophilia, 922-924 Synovial hemangioma, knee joint, 651 Synovium, hip development, 155 T Teleoroentgenograms, lower extremity length discrepancies, 611 Tensile stress, epiphyseal plates, 103-105 Teratologic dysplasia, congenitaldevelopmental hip abnormalities, 197 TGF-[L s e e Transforming growth factors-[3 Thalassemia, 650-651,925 Thanatophoric dysplasia, 756-758, 771-772 Therapeutic arrest, lower extremity length discrepancies, 663-669 Thoracolumbar kyphosis, in achondroplasia, 800 Thoracolumbar spine, skeletal dysplasia, 782-783 Tibia congenital pseudoarthrosis, 648-649 diaphyseal lengthening, 698 distal, s e e Distal tibia LCP disease, 321-323 lower extremity length discrepancies, 672 metaphyseal fractures in childhood, 510-511 Ollier's disease, 818-819 Osgood-Schlatter disease, 498-501 proximal, s e e Proximal tibia Tibia-fibula relationship, hereditary multiple exostoses, 832 Tibial bowing, posteromedial, 623-625 Tibial diaphysis, lower extremity length discrepancies, 639 Tibial hemimelia, 623 Tibial metaphyseal fractures, childhood, 510-511 Tibial tubercle chronic traumatic apophysitis, s e e Osgood-Schlatter disease Tibia valga, hereditary multiple exostoses, 832 Tibia vara, imaging, 147 Tillaux, juvenile fracture, 587-588 TIMPs, s e e Tissue inhibitor of matrix metalloproteinases Tissue inhibitor of matrix metalloproteinases, limb development, 81-82 Tissues bone as, 14-15 epiphyseal, s e e Epiphyseal tissue fetal and postnatal epiphyses, 715 LCP disease, 281-295

patterning models, 53-55 periphyseal, groove of Ranvier, skeletal dysplasias, 761-762 soft, s e e Soft tissues Tissue spongieux, early description, 13 Traction avascular necrosis in DDH treatment, 250-251 genum recurvatum, 596 skin, LCP treatment, 343 Transcription factors, skeletal dysplasias, 751-752, 754 Transformation, cartilage cells to bone cells, 20 Transforming growth factors-[3, limb axes, 80 Transient synovitis, LCP disease, 279-280 Transiliac process, lengthening, 705-706 Transphyseal bone bridge, epiphyseal growth plate fracture-separation, 549-552 Transphyseal chondrodiatasis, epiphyseal growth plate fracture-separation, 597 Transphyseal communicating cartilage canals, blood supply, 50 Transphyseal drilling, SCFE treatment, 406 Transphyseal fracture, epiphyseal growth plate fracture-separations, 528 Transphysis, lengthening in lower extremity length discrepancies, 701-705 Transplantation bone marrow, osteopetrosis treatment, 846 growth plates, 708, 712-715 lower extremity length discrepancies, 715-719 Trauma chronic repetitive, knee lesions, 147 distal femur osteochondritis dissecans, 468-469 distal tibia and fibula, 147 Traumatic births, epiphyseal growth plate fracture-separations, 528 Traumatic theory of congenital dislocation of hip, 167 Trichorhinophalangeal dysplasia, 860 Triplane fracture, distal tibial epiphyseal fracture-separation, 588-589 Trochanteric height, LCP classification, 333 Trochanteric overgrowth, avascular necrosis in DDH treatment, 251 Tuberculosis age incidence, 906 childhood, joint infection, 909 histopathology, 907

lower extremity length discrepancies, 631-632 overview, 906 radiography, 906-907 treatment, 908-909 Tumors, irradiation in childhood, physeal damage, 635-636 U Ulna acute epiphyseal growth plate fractureseparation, 574 radiographic characteristics, 115 Ultrasonography coxa vara, 378 LCP pathology, 302 lower extremity length discrepancies, 611 newborn DDH, 221,223, 225, 229-230 SCFE, 397 skeleton, 129 Umbilical catheters, neonate abnormal lower leg growth, 627 Undifferentiated mesenchymal cells, bone formation, 18 Unicameral bone cyst, 895-896 Upper extremities hereditary multiple exostoses, 833-835 Ollier's disease, 819 skeletal dysplasias, 794 V Valgus deformity childhood proximal tibial metaphyseal fractures, 510-511 knee in juvenile rheumatoid arthritis, 892-893 SCFE, 397-398 Vascularity cartilaginous epiphyses, skeletal dysplasias, 767 endochondral sequence, 17-18 femoral head after DDH treatment, 261-262 postreduction, 231-232 malformations, lower extremity length discrepancies Beckwith-Wiedemann syndrome, 646 congenital arteriovenous fistula, 646 cutis marmorata telangiectatica congenita, 646 Klippel-Trenaunay syndrome, 643-645 Klippel-Trenaunay-Weber syndrome, 647-648 Parkes Weber syndrome, 645 Proteus syndrome, 645-646

Index

953

Venous hypertension, LCP disease, 280 Vitamin D limb axes, 81 mineralization, 94 Von Willebrand disease, 924-925

Woven bone, diaphyseal bone formation, 41-44 Wrist imaging, 148 septic arthritis, 905

gene abnormality, 879 hypothetical model, 880 medical treatment, 882-883 orthopedic management, 883-884 pathophysiology, 878-879

W Weight, infantile tibia vara deformity after osteotomy, 488 Weight relieving caliper, LCP treatment, 343 Wnt 7A, limb axes, 80

X XLH, s e e X-linked hypophosphatemic rickets X-linked hypophosphatemic rickets cell and matrix abnormalities, 879-880 characteristics, 880-882

Z Zone of polarizing activity definition, 58 gene control of limb development, 75 sonic hedgehog, 79 ZPA, s e e Zone of polarizing activity