Sclerosing bone dysplasias--a target-site approach.

Skeletal Radiol (1991) 20:561-583

Skeletal Radiology

Review

Sclerosing bone dysplasias- a target-site approach Adam Greenspan, M.D. Department of Radiology and Orthopedic Surgery, University of California Davis School of Medicine, and Section of Orthopaedic Radiology, University of California Davis Medical Center, 2516 Stockton Blvd., TICON II, Sacramento, California 95817, USA

Abstract. Sclerosing bone dysplasias are a poorly understood group of developmental anomalies, much of whose etiology is still obscure. The list of conditions constituting this group is relatively short: osteopetrosis (Albers-Sch6nberg disease), pycnodysostosis (Maroteaux-Lamy disease), enostosis (bone island), osteopoikilosis, osteopathia striata (Voorhoeve disease), progressive diaphyseal dysplasia (Camurati-Engelmann disease), hereditary multiple diaphyseal sclerosis (Ribbing disease), four types of endosteal hyperostosis (van Buchem disease, Worth disease, Nakamura disease, and Truswell-Hansen disease), dysosteosclerosis, metaphyseal dysplasia (Pyle's disease), craniometaphyseal dysplasia, melorheostosis (Left disease), and craniodiaphyseal dysplasia. There are instances in which two or more of the above disorders coexist. These are termed "overlap syndromes", most commonly involving osteopathia striata, osteopoikilosis, and melorheostosis. A classification of these dysplasias is elaborated based on a targetsite approach that views them as disturbances in development associated with the processes of either endochondral or intramembranous bone formation, or both. Accumulated evidence suggests that many of these disorders stem from common defects in bone resorption and/or formation during the processes of skeletal maturation and modeling. Finally, the subgroup of overlap syndromes is emphasized as indicating a strong interrelationship between the sclerosing dysplasias of bone, with perhaps a common pathogenesis for many. Key words: Developmental anomalies - Sclerosing bone dysplasias - Bone, sclerosis

Sclerosing dysplasias of bone are a poorly understood group of developmental anomalies that reflect disturbances in the formation and modeling of bone, most commonly as a result of inborn errors of metabolism This article is one in a series of review articles which represent expansions of papers presented at the annual meeting of the International Skeletal Societyand were solicited by the editors

[118, 135]. The list of these conditions is relatively short, and some entities are better known by their eponyms: osteopetrosis (Albers-Sch6nberg disease), pycnodysostosis (Maroteaux-Lamy disease), enostosis (bone island), osteopoikilosis, osteopathia striata (Voorhoeve disease), progressive diaphyseal dysplasia (Camurati-Engelmann disease), hereditary multiple diaphyseal sclerosis (Ribbing disease), four types of endosteal hyperostosis (van Buchem disease, Worth disease, Nakamura disease, and Truswell-Hansen disease), dysosteosclerosis, metaphyseal dysplasia (Pyle disease), craniometaphyseal dysplasia, melorheostosis (Leri disease), and craniodiaphyseal dysplasia. In rare cases two or more disorders coexist [62, 129]. As a group these conditions, many of which are hereditary, exhibit a variability in their clinical, radiologic, and histopathologic manifestations and genetic background, as well as in their clinical course and prognosis. Moreover, in many instances their etiology and pathogenesis are still unknown and are the subject of speculation and hypothesis. Thus, it may be understandable that this group of developmental anomalies is one of the least clearly defined groups of skeletal dysplasias. This state of affairs is naturally reflected in efforts to classify the sclerosing dysplasias of bone. The problem with classification has become particularly apparent in recent years with reports of the identification of several new types of these anomalies [64, 74, 93], which may or may not represent legitimate additions to the group (the evidence is unclear). Coupled with this has been a proliferation of names for the same disorder(s),'which has created chaos and confusion. Several general classifications of skeletal dysplasias have been proposed in the past 30 years. One of the earliest is Rubin's, which viewed these disorders as growth disturbances affecting one of the four areas involved in bone growth: epiphysis, physis (growth plate), metaphysis, and diaphysis; each group was further subdivided into hypoplastic and hyperplastic types [105]. Later attempts at classification emphasized the hereditary nature of many of these dysplasias and categorized them on the basis of biochemical factors and metabolic disturbances [87] or morbid cell physiology [2]. Some order in classification was restored in 1983 at the Paris 9 1991 International Skeletal Society

562 meeting of world experts on bone dysplasias which produced the International Nomenclature of Constitutional Diseases of Bone [64]. Their efforts yielded a classification that included many of the more commonly recognized sclerosing dysplasias of bone under the category of osteochondrodysplasias (disorders of cartilage and/or bone growth and development) in the roentgenographic subgroup, "abnormalities of density of cortical diaphyseal structure and/or metaphyseal modeling." This emphasis on roentgenographic appearance was helpful, but since this classification was proposed, new investigations have shed light on important elements in the biochemistry, pathology, and etiology of some sclerosing bone dysplasias. These new findings have underlined the need for a reexamination of these anomalies and their relationships and a more precise and clinically useful classification. In the majority of cases of sclerosing dysplasia of bone, the diagnosis is made on the basis of characteristic roentgenographic manifestations rather than the histopathology of the lesion. Consequently, the radiologist plays a key role in the diagnosis and management of these conditions. What is interesting about these dysplasias from the perspective of roentgenographic morphology is that some reflect a process predominantly affecting cortical bone, whereas others involve predominantly trabecular (spongy) bone and the medullary cavity. In rare instances, both types of bone are affected. Identification of these apparent target sites prompted a new look at sclerosing dysplasias of bone, which Dr. Alex Norman and I published in 1986 [97]. We proposed a target-site approach (Table 1) based not only on our own observations on pathomechanics in osteopetrosis, enostosis, osteopoikilosis, and mixed sclerosing bone dystrophy, but also on the histologic confirmation of pathomechanism in several cases of osteopetrosis reported by Coccia [25], a review of the work of Fallon et al. on progressive diaphyseal dysplasia [38], and a search of the literature on various sclerosing dysplasias [1, 8, 15, 16, 22, 24, 25, 32, 67, 108, 109]. Evidence accumulated from these investigations points to common defects in many of these disorders, reflected in a failure of cartilage and/or bone to resorb during the processes of skeletal maturation and remodeling. One defect in many cases involves the resorption capabilities of osteoclasts [25, 109] or, possibly, another bone-resorbing cell [15, 16] in the presence of normal osteoblastic activity. In other instances, the defect lies in excessive bone formation by osteoblasts, which may occur in the presence of normal or diminished osteoclastic activity [22, 71, 104, 132]. These basic errors in metabolism most commonly arise during the processes of endochondral or intramembranous ossification. In rare instances, they occur to varying degrees in both processes of bone formation, yielding a subgroup of mixed sclerosing dysplasias (see Table 1). These disorders exhibit features indicating either disturbances in both types of ossification, but with a predominance of one type over the other, or the coexistence of two or more types of dysplasia (also termed "mixed sclerosing bone dystrophy"), that constitute an "overlap syndrome" [97]. The

A. Greenspan: Sclerosingbone dysplasias Table 1. Classification of sclerosing dysplasias of bone I.

Dysplasiasof endochondral bone formation ~ primary spongiosa (immature bone) Osteopetrosis (Albers-Sch6nberg disease) Autosomal-recessivetype (lethal) Autosomal-dominant type Intermediate-recessive type Autosomal-recessivetype with tubular acidosis (Sly disease) Pycnodysostosis (Maroteaux-Lamy disease) eAffecting secondary spongiosa (mature bone) Enostosis (bone island) Osteopoikilosis (spotted bone disease) Osteopathia striata (Voorhoeve disease) II. Dysplasias ofintramembranous bone formation Progressive diaphyseal dysplasia (Camurati-Engelmann disease) Hereditary multiple diaphyseal sclerosis (Ribbing disease) Endosteal hyperostosis (hyperostosis corticalis generalisata) Autosomal-recessiveform Van Buchem disease Sclerosteosis (Truswell-Hansendisease) Autosomal-dominant form Worth disease Nakamura disease III. Mixed sclerosing dysplasias (affecting both endochondral and intramembranous ossification) ~ predominantly endochondral ossification Dysosteosclerosis Metaphyseal dysplasia (Pyle disease) Craniometaphyseal dysplasia eAffectingpredominantly intramembranous ossification Melorheostosis Progressive diaphyseal dysplasia with skull base involvement (Neuhauser variant) Craniodiaphyseal dysplasia ~ of two or more sclerosing bone dysplasias (overlap syndrome) Melorheostosis with osteopoikilosis and osteopathia striata Osteopathia striata with cranial sclerosis (Horan-Beighton syndrome) Osteopathia striata with osteopoikilosisand cranial sclerosis Osteopathia striata with generalized cortical hyperostosis Osteopathia striata with osteopetrosis Osteopoikilosis with progressive diaphyseal dysplasia Modified from [97] latter subgroup suggests a common pathogenesis for most sclerosing dysplasias [131]. This review is an extension and modification of my earlier work with Dr. Norman, including the classification we proposed [96, 98]. The approach reflected in the classification is focused on target sites of involvement and pathomechanism. It provides a more systematic means of recognizing a given disorder than other approaches suggested to date, and also creates some meaningful order among these conditions [74]. To understand the target-site approach and the new classification better, it is important to review briefly some basic processes of bone formation. Endochondral and intramembranous ossification

Normal bone is formed through a combination of two processes: endochondral ossification and intramembran-

A. Greenspan: Sclerosingbone dysplasias

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Fig. 1. Normal endochondral ossification at the junction of the growth plate and metaphysis. PC, zone of provisional calcification; PS, primary spongiosa is being formed in the zone of chondroosseous transformation (H & E, x 120) Fig. 2. Normal intramembranous ossification at the junction of periosteum and cortex. Subperiosteal bone formation progresses from immature (woven) to more mature bone. P, periosteum; C, cortex(H&E, x15) ous ossification. In general, the spongiosa of bone develops by means of endochondral ossification, while the cortex of bone forms by means of intramembranous ossification. Once formed, living bone is never metabolically at rest; it constantly remodels and reappropriates its mineral along lines of mechanical stress, beginning in the fetal period, accelerating during infancy and adolescence, and continuing throughout life [113]. The factors controlling bone formation and resorption are still not well understood, but one fact is clear: Bone formation and bone resorption are related, exquisitely balanced processes that cause net bone formation to equal net bone resorption. Most of the skeleton is formed by endochondral ossification, a highly organized process that transforms cartilage to bone and contributes primarily to increasing bone length (Fig. 1). Endochondral ossification is responsible for the formation of all tubular and flat bones, the vertebrae, base of the skull, ethmoids, and medial and lateral ends of the clavicle. From the condensed mesenchymal aggregate, cartilage cells (chondroblasts and chondrocytes) produce a hyaline cartilage model of the long tubular bones, usually at about 7 weeks of embryonic life [67]. At about the 9th week, as peripheral capillaries penetrate the model, inducing the formation of osteoblasts, osseous tissue is deposited on the spicules of calcified cartilage matrix remaining after osteoclastic resorption, thereby transforming the primary spongiosa into the secondary spongiosa [18]. As this process advances rapidly toward the epiphyseal ends of the cartilage model, leaving behind a loose network of bony trabeculae with cores of calcified cartilage, a well-defined line of advance becomes apparent. This line represents the growth plate (physis) and the adjacent metaphysis to which the secondary spongiosa moves as it is formed, away from the line of growth [67, 105]. Many of the trabeculae of the secondary spongiosa are resorbed soon

after being formed, thereby establishing the marrow cavity. Other trabeculae persist. Some enlarge and thicken through the apposition of new bone, but these too eventually undergo resorption and remodeling. Others extend toward the shaft, becoming incorporated into the developing cortex of the bone, which forms by the process of intramembranous ossification. Endochondral bone formation is not normally observed after closure of the growth plate. In intramembranous ossification, bone is formed directly, without an intervening cartilaginous stage [18]. Initially, condensed mesenchymal cells differentiate into osteoprogenitor cells. These in turn differentiate into fibroblasts, which produce collagen and fibrous connective tissues, and osteoblasts, which produce osteoid. Beginning at approximately 9 weeks of fetal life, the fibrous membrane produced by the fibroblasts forms a periosteal collar and is then replaced with osteoid by the action of osteoblasts. Bones formed by this process include the frontal, parietal, and temporal bones and their squamae, the bones of the upper face, as well as the tympanic parts of the temporal bone, the vomer, and the medial pterygoid [18, 20]. Intramembranous ossification also contributes to the appositional formation of periosteal bone around the shafts of the tubular bones, thus forming the cortex of the long and flat bones. This type of bone formation is responsible for increasing bone width (Fig. 2). In addition to the periosteal envelope on the outer surface of bones, intramembranous ossification is active in the endosteal envelope which covers the inner surface of the cortex and in the haversian envelope at the internal surface of all intracortical canals [6, 40]. These three envelopes are sites of potent cellular activity involving both resorption and formation of bone through the growth period and in the mature adult [105]. It is interesting to note that the mandible and middle portions of the clavicle are formed by a process that

564 shares features of both endochondral and intramembranous ossification. These bones are preformed in cartilage in embryonic life, but they do not undergo endochondral ossification in the conventional manner [20]. Instead, the cartilage model simply serves as a surface for the deposition of bone by connective tissues. Eventually, the cartilage is resorbed, and the bones become fully ossified [105]. Errors in development can occur at the sites of both endochondral and intramembranous ossification, giving rise to the various sclerosing dysplasias of bone.

Sclerosing dysplasias of bone

Dysptasias of endochondral ossification 1. Dysplasias of primary spongiosa (immature bone) Under normal conditions, the primary (immature) spongiosa is resorbed by osteoclasts in the process of endochondral bone formation [5, 41]. Failure to resorb and remodel this matrix causes an accumulation of primary spongiosa in the medullary cavity and will eventually form masses of calcified cartilage packing the cavity. Osteopetrosis and pycnodysostosis are dysplasias that reflect this failure of resorption of primary spongiosa [25, 32, 67].

a) Osteopetrosis (Albers-Sch6nberg disease). Until recently, osteopetrosis, first described by AlbersSch6nberg [3], was regarded as manifesting itself in two forms: an autosomal-recessive form in which the manifestations are precocious, known as congenital or malignant osteopetrosis, and an autosomal-dominant form in which the manifestations are delayed [69]. The latter is referred to variously as benign or adult osteopetrosis or osteopetrosis tarda (or simply as osteopetrosis because of the rarity of the congenital variant) [26]. These two forms of the disease have starkly differing prognoses. In many instances, congenital osteopetrosis results in stillbirth. With a live birth, the disease is usually recognized by severe anemia at birth or in early childhood and progresses rapidly. Infants fail to thrive and usually die in early infancy, although in less severe cases children may survive the first decade of life. By contrast, adult osteopetrosis is compatible with a long lifespan. Only about 30% of patients are anemic, and the disease is often asymptomatic [12]. It is usually detected incidentally on radiographic examination or as a result of a pathologic fracture. More recent reports describe what appear to be additional variants of this developmental anomaly, which illustrate the heterogeneity of inheritance in this disorder [5, 13, 15, 60]. Several reports delineate an autosomalrecessive form of osteopetrosis marked by the presence of renal tubular acidosis and cerebral calcifications ("marble brain disease") [17, 114, 131]. In addition, infants showed failure to thrive, muscle weakness, hypotonia, mental retardation, and pathologic fractures; all

A. Greenspan: Sclerosingbone dysplasias bones were affected by osteosclerosis but tended to improve with age. Another genetic variant, which falls between the autosomal-recessive and the autosomal-dominant types in terms of the severity of its manifestations, has been termed an intermediate-recessive type of osteopetrosis [55, 68, 72]. Patients usually had short stature, anemia, and hepatomegaly; osteosclerosis was diffuse, particularly at the base of the skull. The roentgenographic hallmark of all types of osteopetrosis is a generalized radiopacity of the medullary portion of bone, indicating sclerosis. The cortex of bone, the site of intramembranous ossification, is characteristically unaffected, although in the long bones diffuse sclerosis may obliterate the distinction between the cortex and the medulla (Fig. 3 A). In the skull, sclerosis is more prominent at the base; in the spine, sclerosis of the vertebral end-plates gives the vertebrae a characteristic "sandwiched" or broad-striped ("rugger [rugby] jersey") appearance (Fig. 3 B). The sclerotic foci may also give the typical impression of "bone in bone," a feature noted in young patients and especially well demonstrated in the spine (Fig. 3 C) and iliac wings. Peripheral modeling defects in osteopetrosis are particularly evident in the metaphyseal areas of bones. These undergo widening and blunting, often appearing like a club or an Erlenmeyer flask, with splaying of the ends of the bone. The appearance of metaphyseal flaring may also be enhanced by a reduction in the diameter of the diaphysis [21]. The metaphyses are also the site of characteristic horizontal striations of sclerotic and normal radiolucent bone, a frequently observed feature of osteopetrosis that represents alternating periods of normal and aberrant activity (Fig. 3 D). Similar alternating bands, in this instance forming convex arcs, have been observed in the iliac wings. The major clinical and skeletal manifestations of osteopetrosis can be explained by the fact that the resorption of endochondral cartilage is markedly diminished, while bone formation continues at a normal rate [109]. The disequilibrium in these processes in the primary spongiosa allows the persistence of large amounts of calcified cartilage and bone in the metaphysis and, eventually, in the diaphysis and medullary canal. In the most severe cases, unresorbed tissue extends the length and width of the bone, completely obliterating the marrow spaces and compromising the hematopoietic marrow cells. This process in turn causes severe anemia and thrombocytopenia and progressive hepatosptenomegaty. Various hypotheses as to the pathomechanism at work in osteopetrosis have been proposed [19, 84, 109]. A great deal of recent research and investigation support the concept that the basic defect is cellular and that the osteoclasts are dysfunctional [109]. Evidence for this assertion comes from histologic, ultrastructural, and biochemical studies, as welt as from reports of successful treatment of congenital osteopetrosis with bone marrow transplantation [25]. Histologic studies have revealed that osteopetrotic bone frequently contains an overabundance, not a deficit, of osteoclasts, a factor that appears to rule out simple failure of progenitor cells to differentiate to osteoclasts as the underlying mecha-

A. Greenspan: Sclerosing bone dysplasias

Fig. 3A-E. Osteopetrosis. A Accumulation of primary spongiosa

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(calcified cartilage and immature bone) in the epiphysis, metaphysis, and diaphysis of the long tubular bones results in a general radiopacity of the bones. There is lack of differentiation between the cortex and the medulla. Note the failure of bone remodeling (arrows). B Characteristic "rugger-jersey" appearance of the spine secondary to increased accumulation of osteopetrotic bone at the sites of vertebral end-plates. C "Bone-in-bone" appearance (arrows) in the cervical spine (courtesy of Harold G. Jacobson, M.D.,

Bronx, NY). D Horizontal striations of radiolucent (normal) and sclerotic (abnormal) bone in the proximal and distal metaphyses of the tibia and fibula represent alternating periods of normal and aberrant activity. E Metaphyseal spongiosa reveals irregularly modeled trabeculae with haphazard interconnections surrounded by lighter areas of cartilaginous matrix replacing bone marrow. Some of the cancellous bone is arranged in globular structures resembling lamellar bone (H & E, x 50). (Courtesy of Michael J. Klein, M.D., New York)

nism. These ostensibly n o r m a l cells, which are appropriately positioned to the b o n e and cartilage for perform a n c e o f their resorptive function, exhibit one remarkable feature indicating i m p a i r m e n t o f that function, the absence o f H o w s h i p ' s lacunae, whose presence is a hallm a r k o f actively resorbing cells. Moreover, the osteoclasts do n o t a p p e a r to r e s p o n d to p a r a t h y r o i d h o r m o n e in a completely n o r m a l way.

Ultrastructural evidence o f the cause o f impaired functioning in the process o f e n d o c h o n d r a l b o n e f o r m a tion points even m o r e convincingly to a b n o r m a l i t i e s in the osteoclast. Osteoclasts in osteopetrosis lack the ruffled borders and clear zones characteristic o f an actively resorbing cell [58, 109]. Even osteoclasts adjacent to the surface o f b o n e or cartilage show no evidence o f a change in their surface membranes. The cells often con-

566 rain more nuclei than osteoclasts in normal bone, but the nuclei appear normal in shape and position. The endoplasmic reticulum, however, is oddly out of position, being situated in the portion of the cell most distant from the surface of the bone and cartilage. Finally, electron microscopic study of osteopetrotic bone has documented the persistence and thickening of the lamina limitans, an electron-dense osmiophilic layer present on the surface of both bone and cartilage. Under normal conditions in bone and cartilage resorption, this layer is the first organic structure to disappear [103]. Further microscopic evidence of the inability of osteoclasts to resorb the primary spongiosa in osteopetrosis can be seen in the morphologic changes induced by this dysfunction. The most striking changes are observed in the metaphyses where the tissue is organized as thickened primary trabeculae consisting of a central core of calcified cartilage surrounded by new bone, which is principally woven but is sometimes lamellar (Fig. 3 E). The cement lines are thicker and more prominent than usual [127]. The trabeculae, which are normally delicate bony spicules, appear as large cartilaginous bars that become densely packed toward the diaphyses. Virtually no marrow tissue is present. Secondary ossification centers, where the tissue is structurally similar to that of the metaphyses, undergo similar changes. In osteopetrosis, these microscopic morphologic changes underlie the increased mass of cancellous bone as well as the modeling defects commonly observed at the metaphyseal-diaphyseal junction [107-109]. Confirmation of a cellular mechanism in the pathogenesis was obtained by successful bone marrow transplantation in patients with the malignant form of the disease. In one report, bone marrow transplantation completely reversed the pretransplantation histologic picture revealed by bone biopsy: The medullary cavities contained normal bone marrow where before there had been small marrow spaces with scant hematopoietic tissue, and osteoclasts were actively resorbing bone where before an overabundance of such cells showed no evidence of activity [25]. Bone marrow transplantation has produced improvement in both experimental animals and humans with osteopetrosis [127]. The ultimate cause of osteoclast dysfunction is still unknown, but it is clear that a cellular defect lies at the root of the skeletal lesions of osteopetrosis.

b) Pycnodysostosis (Maroteaux-Lamy disease). Prior to the introduction of the term "pycnodysostosis" by Maroteaux and Lamy [85], this condition had been confused with osteopetrosis, because of a similarity in roentgenographic presentation, and with cleidocranial dysplasia, because of the presence of clavicular hypoplasia. Pycnodysostosis is a rare genetic disorder inherited as an autosomal-recessive trait (unlike the autosomal-dominant inheritance of cleidocranial dysplasia). It is twice as common in men as in women [32], and there are no racial differences. Maroteaux and Lamy suggested that the French impressionist painter Henri de Toulouse-Lautrec was afflicted with this condition [86]. Its characteristic complex of features includes dwarf-

A. Greenspan: Sclerosing bone dysplasias ism and a generalized increase in the roentgenographic density of the skeleton which reflects an osteopetroticlike process. Both features distinguish it from cleidocranial dysplasia (Fig. 4A). As in osteopetrosis, bone in pycnodysostosis has a susceptibility to pathologic fracture, even as a result of mild trauma, and modeling defects may be prominent, particularly in the distal portions of the femora (Erlenmeyer-flask deformity). One crucial feature distinguishing bone in pycnodysostosis is preservation of the medullary canal of the long bones, which clinically is responsible for the reported absence of anemia and hepatosplenomegaly as manifestations. The skull exhibits typical features of this dysplasia, including sclerosis at its base, persistence of the anterior and posterior fontanelles (Fig. 4 B), delay in closure of the sutures, and frequently the presence of wormian (sutural) bones, usually in the region of the parietal bone. Moreover, there is often a lack of pneumatization as well as hypoplasia of the paranasal sinuses. Hypoplasia of the mandible gives it an obtuse (fetal) angle (Fig. 4 C). Spinal abnormalities may also occur; failures in segmentation resulting in block vertebrae are occasionally seen, especially in the upper cervical and lumbosacral regions [32]. Aplasia or hypoplasia of the lateral ends of the clavicles.is a consistent finding, as is aplasia or hypoplasia of the terminal tufts of the fingers and toes, which may represent a true acro-osteolysis (Fig. 4D) [100]. Although histologically similar to one another, pycnodysostosis and osteopetrosis exhibit some differences on the microscopic and ultrastructural levels. Most significant among these is evidence of hematopoiesis in pycnodysostosis, because the medullary canal, though narrowed in diameter, is still patent. In addition, the endocortex may show thickening, and the volume of cancellous bone may be increased (Fig. 4E) [30]. As in osteopetrosis, the structure of cortical bone is normal. Both osteoblastic and osteoclastic activity may be diminished [116]. Electron microscopy of pycnodysostotic bone has identified large cytoplasmic vacuoles filled with bone collagen fibrils in osteoclasts. This finding suggests defective intracellular or extracellular degradation of skeletal collagen, perhaps due to an abnormality in the bone matrix or in the function of osteoclasts [34]. Ultrastructural study of cartilage has revealed abnormal inclusions in chondrocytes [119]. It has been speculated that decreased bone resorption by osteoclasts may account for the osteosclerotic changes in this dysplasia [130]. In general, however, there is a scarcity of histopathologic information [34], perhaps reflecting the rarity of this condition. 2. Dysplasias of secondary spongiosa (mature bone) Three developmental anomalies - enostosis (bone island), osteopoikilosis, and osteopathia striata can be identified as dysplasias occurring after endochondral ossification has proceeded in a normal fashion through the stage of transformation of the primary spongiosa into the secondary spongiosa. Thus, these entities are marked by a failure in bone remodeling, resulting in

A. Greenspan : Sclerosing bone dysplasias

Fig. 4A-E. Pycnodysostosis. A The overall increase in radiopacity of the bones is similar to that seen in osteopetrosis. B The skull demonstrates distinctive features of this dysplasia: Sclerosis is limited to the base, and there is persistence of the anterior and posterior fontanelles. C An obtuse (fetal) angle of the mandible is a characteristic feature of this dysplasia. D Acro-osteolysis is a frequent

the persistence of mature bony trabeculae, which appear as focal densities and/or striations.

a) Enostosis (bone &land). Enostosis represents the mildest expression of a failure in resorption of the secondary spongiosa in the process of endochondral ossification. The lesion is usually solitary and completely asymptomatic and is diagnosed largely on the basis of its roentgenographic features. It probably does not represent an inherited disorder.

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finding in pycnodysostosis. (A-C Courtesy of Walter E. Berdon, M.D., New York, D Courtesy of John Dorst, M.D., Baltimore). E Biopsy specimen from the iliac crest reveals thickened bony trabeculae and somewhat contracted spongiosa with increased cancellous bone volume (H & E, • 16). (Courtesy of Michael J. Klein, M.D., New York)

Any bone in the skeleton may be affected, and the lesion appears as a homogeneously dense and sclerotic focus of compact bone within the cancellous bone or occasionally on the internal surface of the cortex [75]. It may be ovoid, round, or oblong and is usually oriented with the long axis of the bone parallel to the cortex (Fig. 5A, B). In the majority of cases, bone islands measure 1 m m to 2 cm in greatest diameter, although " g i a n t " bone islands (over 2 cm) have been observed, usually exhibiting the same roentgenographic features

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Fig. 5A-E. Enostosis (bone island). A Dense sclerotic focus of compact bone within the cancellous bone of the proximal tibia. B CT section demonstrates its typical thornlike projections. C Slab radiograph shows the thickened trabeculae of the upper portion of the lesion blending with the trabeculae of the spongiosa (arrows). D


Low-power photomicrograph demonstrates "pseudopodia" of the lesion. Note the haversian system of nutrient canals in the center (H & E, x 16). E High-power photomicrograph shows compact bone with wide bands of parallel lamellae at the periphery of the lesion (H & E, x 90). (Reprinted with permission from [49])

A. Greenspan: Sclerosing bone dysplasias as their smaller counterparts [45, 110, 115]. A highly characteristic feature of the lesion is a pattern that has been likened to ~ thorny radiation" or "pseudopodia." Thickened mature bony trabeculae radiate in streaks through the lesion, aligned with the axes of surrounding uninvolved trabeculae and blending with them in a feathered or brushlike fashion [90]. The histopathology underlying these roentgenographic features mirrors those changes microscopically, with thornlike projections of thickened trabeculae blending intimately with the surrounding trabeculae of the spongiosa (Fig. 5C, D). This compact focus of bone, resembling cortical bone, exhibits a mature lamellar configuration and a haversian system of nutrient canals (Fig. 5 E). If present, bone turnover activity is minimal, with only rare foci of osteoblastic and osteoclastic activity observed. Occasionally, the lesion is connected to the endocortex of the host bone [78]. Most bone islands represent completed episodes of~ bone remodeling and thus are not metabolically active [99]. They usually do not grow or demonstrate activity on skeletal scintigraphy [52], although there has been a report of instability in a bone island in a patient with hyperparathyroidism whose lesion disappeared and reappeared over a period of 6 years [56]. However, there have been a few instances in which positive bone scan findings in histologically proven bone islands were linked to growth of the lesions [27, 110]. Increased activity of osteoblasts in the lesions apparently underlay these findings, because histologic examination revealed a higher degree of bone remodeling in the scintigraphically active lesions than in those showing normal isotope uptake [49].

b) Osteopoikilosis (spotted bone disease). Osteopoikilosis has a close kinship with enostosis both roentgenographically and histologically. Some investigators have suggested that a bone island may represent a minor form of osteopoikilosis, perhaps related to the degree of genetic penetration and variability of expression. Unlike enostosis, however, osteopoikilosis manifests itself as multiple bone islands clustered at the ends of bones and adjacent to the metaphyses [88]. More than 300 cases have been reported [8, 9, 79]. Inherited as an autosomal-dominant trait, osteopoikilosis is frequently seen in association with the hereditary dermatologic condition, dermatofibrosis lenticularis disseminata (Buschke-Ollendorff syndrome), which is marked by the presence of papular fibromas over the back, arms, and thighs. These fibromas appear to reflect a disorder of connective tissue inherited as an autosomal-dominant trait [125]. This association between osteopoikilosis and disseminated dermatofibrosis, as well as the common mode of inheritance, suggests that osteopoikilosis may be a manifestation of a metabolic disorder of connective tissue reflected in a failure in remodeling of mature bony trabeculae. The etiology of osteopoikilosis is, however, still unclear. Some investigators have postulated that the lesions represent remodeling of cancellous bone related to mechanical stress [79]. Like enostoses, these focal condensations of compact lamellar bone in the spongiosa have charac-

569 teristic roentgenographic features. They appear as small, symmetrically scattered radiopacities whose appearance at the articular ends of the long bones and in the small carpal and tarsal bones is pathognomic (Fig. 6A, B). The lesions may also be found in other areas of articulation, for example, around the acetabulum and the glenold fossa; the skull, spine, and ribs are rarely sites of osteopoikilosis. In general, the lesions may exhibit one of three configurations: (1)lenticular-round, oval, or nodular, (2) linear-striated or oblong, and (3) a mixture of the two. The last two configurations may not, however, represent the pure entity but rather the coexistence of osteopoikilosis, osteopathia striata, and melorheostosis, a combined condition classed among the mixed sclerosing bone dysplasias (see Table 1 and below). Like some bone islands, osteopoikilotic foci may demonstrate activity on bone scintigraphy indicating a metabolically active state, but this is rare. Some reports indicate that the lesions may also behave like bone islands by changing in size and also by disappearing and reappearing, features observed more frequently in children than in adults [571. There is a close histologic relationship between the osteosclerotic foci of osteopoikilosis and enostosis, which is reflected in their roentgenographic appearance. Both are condensing lesions associated with errors in remodeling at the intersections of trabeculae in spongy bone; these trabecular junctions often have a nodular or starlike form. The foci form nodules, representing trabecular segments of old and inactive remodeling of the spongiosa. The nodules may be circumscribed or attached to the subchondral cortex of the bone but are integrated into the otherwise normal spongiosa; their numerous thickened bony trabeculae merge gradually into the surrounding uninvolved structures (Fig. 6C). The thickened trabeculae in these areas consist of compact lamellar bone in parallel layers, which exhibits prominent cement lines and haversian systems (Fig. 6 D) [47, 67]. Histologic study of the bone marrow demonstrates no evidence of fibrosis [79].

c) Osteopathia striata ( Voorhoeve disease). Osteopathia striata is an autosomal-dominant disorder that may affect all bones except the skull and clavicles but has a particular predilection for the long bones (distal femur, proximal tibia, proximal humerus) at sites of rapid growth [36]. Patients with the pure form of the disorder exhibit no known associated physical abnormalities or characteristic laboratory findings; the diagnosis is based entirely on incidental radiographic findings. As in enostosis and osteopoikilosis, the roentgenographic featues of osteopathia striata are characteristic and consistent [42]. The hallmark of the disorder is the appearance of delicate (or sometimes coarse) dense linear striations, representing a failure in remodeling of the persistent mature (lamellar) bone. In the long and other tubular bones, the striations are seen primarily in the metaphyses and diaphyses, sites of rapid growth. They form nearly uniform lines of sclerosis running parallel to the long axis of the shaft of the bones and occasionally crossing into the epiphysis (Fig. 7). The striations, which may

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Fig. 6. A-D. Osteopoikilosis. A Multiple sclerotic foci are clustered at the proximal ends of the femora, both acetabula, and pubic and ischial bones. B Small, symmetrically scattered radiopacities at the articular ends of the radius and ulna as well as at the articular ends of the small tubular bones of both hands are the hallmark of this dysplasia. Note the involvement of the carpal bones (sites of endochondral bone formation). C Specimen radiograph of the humeral head affected by osteopoikilosis shows the same pattern of thornlike projections of thickened trabeculae as seen in enostosis, although here there are multiple lesions. D Low-power photomicrograph of one focus of osteopoikilosis shows a morphology identical to that of a bone island (compare with Fig. 5 D) (H & E, x16) Fig. 7. Osteopathia striata. Fine striations of dense bone in the metaphysis of the distal femur are characteristic of this dysplasia

A. Greenspan: Sclerosing bone dysplasias appear more prominent around the joints, vary in length in direct proportion to the rate of growth of the affected bone; therefore, the longest striations are found in the femora, the fastest growing bones. In the iliac wings, a fan-shaped pattern of striations may be seen, reflecting the growth pattern in those bones. Since this condition appears to reflect old bone remodeling, the lesions are not associated with increased scintigraphic activity [24, 131]. There are no reports of the histopathologic findings in osteopathia striata. Several investigators have hypothesized relationships between osteopathia striata and other diseases. Voorhoeve, who first described the disorder, considered it a congenital variant of osteopoikilosis marked by a different roentgenographic pattern [126], a position largely supported in a study by Lagier et al. [79]. In an interesting report of a patient presenting with features of osteopathia striata and osteopetrosis, Hurt raised the question of a relationship between these two disorders. He considered osteopathia striata an atypical example of osteopetrosis and attributed both entities to the same developmental abnormality [62]. His speculations also led him to examine the possibility of a relationship between osteopathia striata and osteopoikilosis. Suggesting, as Voorhoeve did, that the primary distinction between the two lay in the form that the lesions take, Hurt conjectured that the difference in form between the nodular lesions of osteopoikilosis and the striations of osteopathia striata could be explained by the effects of mechanical forces applied to the long bones affected by the underlying developmental error; thus, accentuation of the stimulus leading to the formation of nodular areas could yield striated areas instead [62]. The association of osteopathia striata with cranial sclerosis has also been described [59, 106] (see discussion of this combination in the section on overlap syndrome). Finally, a limited study of individuals with focal dermal hypoplasia (Goltz-Gorlin syndrome) [44] has revealed a high incidence of concomitant osteopathia striata, an association that may be more than coincidental [77, 80].

Dysplasias of intramembranous ossification Intramembranous ossification is primarily responsible for the formation of the cortex of bones, the bones of the vault of the skull, the mandible and facial bones, and the midsegment of the clavicle. A disequilibrium at these sites between endosteal bone resorption and periosteal new bone formation, due either to a slowing of the rate of bone resorption without any change in the rate of bone formation or to an increase in osteoblastic activity that results in excessive bone formation, leads to such anomalies as progressive diaphyseal dysplasia (Camurati-Engelmann disease) [61, 89], hereditary multiple diaphyseal sclerosis (Ribbing disease) [101, 104], and the group of disorders representing endosteal hyperostosis: van Buchem, Worth, Nakamura, and TruswellHansen diseases.

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a) Progressive diaphyseal dysplasia (Camurati-Engelmann disease). Neuhauser and associates, who first proposed the term "progressive diaphyseal dysplasia" in preference to Camurati-Engelmann disease [23, 33], wished to emphasize that the important feature of this disorder is a progressive hyperostosis affecting the shafts of long bones [94]. It is marked by symmetric thickening of the cortical bone of the diaphyses, with a symmetric distribution in the skeleton. The metaphyses and epiphyses of bones, sites of endochondral ossification, are characteristically spared. The disorder usually manifests itself in the first decade of life, males being more frequently affected than females [66]. Bone pain, muscle pain and weakness, and muscle wasting, particularly in the legs, are common presenting signs. Often the extremities are elongated relative to the size of the child, and there are disturbances of gait (waddling) and posture, retardation of growth in height and weight, and other signs indicating a more generalized involvement of multiple systems. The level of urinary hydroxyproline is normal, indicating normal bone turnover, and blood chemistry and marrow and peripheral blood elements are normal as well. The condition is self-limiting and generally resolves by 30 years of age. Both sporadic and familial cases of progressive diaphyseal dysplasia have been described [117]. It is not certain that these types represent the same disorder, although the clinical, roentgenographic, and laboratory evidence indicating that they are different is insufficient. The few familial cases of progressive diaphyseal dysplasia that have been described are most suggestive of an autosomal-dominant mode of inheritance, but it is not clear whether all the familial cases represented the same basic disorder or genocopies. The lack of family studies in the sporadic cases leaves open the possibility of their representing new mutations. The roentgenographic characteristics of progressive diaphyseal dysplasia are consistent. The lesions appear as fusiform thickening of the cortex in the diaphyseal portions of the long bones, specifically, in decreasing order of frequency, the tibia, femur, fibula, humerus, ulna, and radius. Distribution of the lesions in the skeleton is symmetric [51]. The thickening of the cortex, which represents both endosteal and periosteal accretion, progresses along the long axis of the bone both proximally and distally; the external contour of the bone is usually regular. Affected bone is sharply demarcated from normal bone (Fig. 8 A). The medullary canals may be narrowed. Occasionally, the skull shows hyperostosis of the calvaria and, in two patients described by Neuhauser [94], there were sclerotic changes at the base of the skull. This latter finding is curious, because such changes at the skull base are typical of an error in endochondral ossification. Such a finding invites speculation that perhaps there are two forms of progressive diaphyseal dysplasia, one in which intramembranous ossification is principally affected and a second showing an endochondral component as well (see later section on coexistence of two or more dysplasias and Table 1).

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Fig. 8A, B. Progressive diaphyseal dysplasia. A Symmetrical, fusiform thickening of the cortex (a site of intramembranous ossification) of both femora is the hallmark of this dysplasia. Note that the epiphyses and metaphyses (sites of endochondral bone formation) are not affected. B Beneath the formation of periosteal immature new bone (/) the remodeled cortical bone is arranged in mature, circumferential lamellae (m) separated by prominent cement lines (H & E, x 100). (Courtesy of Walter E. Berdon, M.D., New York)

Fig. 9A-D. Hereditary multiple diaphyseal sclerosis. A, B AP and lateral views of the right lower leg demonstrate segmental sclerosis of the midportion of the tibia. Note the slightly irregular circumferential thickening of the cortex. C Fusiform segmental thickening of the cortex of the left tibia in an asymptomatic brother of the patient illustrated in A, B. D Tomography demonstrates significant obliteration of the medullary cavity due to endosteat cortical thickening

The h i s t o p a t h o l o g y underlying these roentgenographic changes, whether they involve the m e m b r a n o u s bone o f the shafts o f the long bones or o f the skull, is characterized by thickening o f the cortex on b o t h the periosteal a n d endosteal surfaces as well as a thickening o f and an increase in the fibrous c o m p o n e n t o f the per-

iosteum (Fig. 8 B) [94]. M a r k e d osteoblastic and osteoclastic activity in the cases reported by N e u h a u s e r indicates the progressive, active processes o f b o n e resorption and new b o n e deposition. The periosteum was especially thickened in the cambial layer where, in some regions, layers o f osteoblasts three or four cells deep were applied

A. Greenspan: Sclerosing bone dysplasias to the external surface of bone. The haversian systems were well formed, but the canals, sometimes lined at the periphery by osteoclasts, often appeared larger than usual. No abnormal cells were found, and the marrow was normal, although occasionally it had a somewhat fibrotic appearance. According to Neuhauser, these findings are nonspecific as to their cause but probably reflect an error in bone resorption leading to an excess of bone formation, with subsequent remodeling defects. Later reports largely support the histopathologic findings described by Neuhauser [50, 112]. In one report of the corticosteroid treatment of progressive diaphyseal dysplasia, the investigators were particularly impressed by the apparent absence of osteoclasts and the clear evidence of decreased bone resorption [4], which appears to suggest that this disorder, like osteopetrosis, is marked by diminished activity of osteoclasts rather than excessive activity of osteoblasts. Although previously published studies of progressive diaphyseal dysplasia have noted the deposition of variable quantities of woven, cancellous, and cortical bone, a report by Fallon et al. of a sporadic case of a mild form of the disease has yielded insights into the potential pathologic processes at work in the progressive thickening of the cortex [38]. The thickened cortex exhibited three continuous zones of periosteal new bone formation. The peripheral (outer periosteal) zone consisted of spicules of immature woven bone. A layer of trabeculae containing primary osteon constituted the middle zone, in which the collagen pattern was largely woven, but focal areas of more mature lamellar bone were apparent with polarized light. Resorption bays, many containing osteoclasts, were abundant. The inner zone represented the junction between the maturing periosteal trabeculae and the subjacent cortical bone. The superficial cortex contained multiple layers of mature lamellar bone, which were demarcated by prominent cement lines reflecting previous episodes of new bone apposition. The deeper cortical bone, exhibiting haversian canals with evenly spaced circumferential lamellae, appeared normal. According to Fallon et al., these findings appeared to point to the synthesis of immature periosteal bone, marked by an abnormal woven collagen pattern, as an early pathologic process in progressive diaphyseal dysplasia. As additional periosteal new bone formed at the periphery, deeper woven bone was resorbed and replaced by lamellar bone, which in turn was incorporated into the cortex as a successive apposition of longitudinal lamellae, thus progressively thickening the cortex. The stimulus for periosteal new bone formation is unknown. Some have suggested that a deficient vascular supply to the region of involvement [112] or thick-walled blood vessels in the periosteum and endosteum [117] may act as a stimulus for the production of periosteal new bone by inducing local hypoxia. However, as poor oxygenation favors cartilaginous differentiation in newly forming osseous tissue, the histologic findings in patients with progressive diaphyseal dysplasia do not support this hypothesis [38]. What is of interest, as Fallon et al.

573 noted in the patient they described, was the relatively low level of serum calcium a finding reported in patients with other osteosclerotic disorders [67], which may reflect increased mineral deposition or decreased bone resorption, or both [28, 38].

b) Hereditary multiple diaphyseal sclerosis (Ribbing disease). Hereditary multiple diaphyseal sclerosis is a rare condition characterized by dense diaphyseal sclerosis in one or more of the long bones. Ribbing first described (and named) the disorder in a report of six cases of siblings, four of whom had a peculiar type of diaphyseal osteosclerosis and hyperostosis of the long bones, specifically the femur, tibia, proximal fibula, and distal radius. The skeletal distribution was symmetric in two and asymmetric in the other two [104]. Later, Paul noted the similarities between the fusiform thickening of the diaphyses characteristic of progressive diaphyseal dysplasia and Ribbing disease, acknowledging in addition the definite differences distinguishing the two conditions [101]. More recent investigators have come to view Ribbing disease as part of a spectrum of progressive diaphyseal dysplasias [38, J17], demonstrating the variability in clinical expression of the basic underlying disorder [61, 82, 117]. Unlike the severe symptoms and early age of onset of progressive diaphyseal dysplasia, the lesions in Ribbing disease are only occasionally symptomatic. The only clinical sign that may be present is aching pain in the involved extremity. Moreover, skeletal involvement in Ribbing disease is much less widespread, and characteristically the lesions are asymmetrically distributed. Radiographic examination reveals lesions frequently indistinguishable from those of progressive diaphyseal dysplasia. There is thickening of the cortex, with slight expansion of the shafts of affected long tubular bones, most commonly the tibiae or femora (Fig. 9A, B). The medullary portions of the bones are constricted to varying degrees (Fig. 9 C, D). Serial studies have shown that lesions may slowly progress over the years, eventually becoming stationary [38, 117]. The histopathologic findings show cortical osteosclerosis [104], reflected in the formation of dense periosteal new bone, predominantly affecting the superficial (subperiosteal) layer of the cortex. The haversian canals are narrowed. In contrast to the histologic evidence of progressive, active bone resorption and new bone deposition in progressive diaphyseal dysplasia, Ribbing disease shows evidence only of new bone formation [104].

c) Hyperostosis corticalis generalisata (endosteal hyperostosis). Among the disorders of intramembranous ossification, those exhibiting a generalized cortical hyperostosis can be classified on the basis of mode of inheritance into two groups comprising four types. Van Buchem disease [111] and Truswell-Hansen disease (sclerosteosis) [14, 64, 130] are autosomal-recessive forms of endosteal hyperostosis, and Worth disease [65, 134] and Nakamura disease [93] are autosomal-dominant forms. In

574 fact, a number of recent investigators have proposed viewing the autosomal-dominant and autosomal-recessive forms of endosteal hyperostosis as separate entities [43, 46]. The principal radiologic feature of these rare conditions is a generalized and symmetric endosteal thickening (osteosclerosis) of the diaphyseal cortex of the long bones, as well as thickening of the skull, facial bones, and mandible, all sites of intramembranous ossification. The thickening of the diaphyseal cortex is not associated with any apparent increase in the diameter of the affected bones, as in progressive diaphyseal dysplasia; rather, thickening results in narrowing of the medullary canal. Involvement of the mandible is a frequent but poorly described feature of this group of very different disorders. Bone biopsy has no value in differentiating these disorders because, other than endosteal thickening, the pathologic findings are nonspecific [43, 124]. However, in view of the fact that the formation of the medullary cavity is the result of endosteal resorption by osteoclasts, diminished activity of these cells may be responsible for the thickening of endosteal bone. Van Buchem disease and Worth disease. Van Buchem disease and Worth disease [122, 123, 134] have similar roentgenographic features, a fact that led to their being confused with one another until Beals discovered their different modes of inheritance [7]. As in the first case of a twin brother and sister described by van Buchem [123], both diseases demonstrate diffuse, symmetric endosteal hyperostosis affecting the diaphyseal cortex of the long and short tubular bones and mandible (Fig. 10A, B) and sclerosis of the skull, shoulder girdle, pelvic girdle, and thoracic cage. However, two features of van Buchem disease help distinguish it from Worth disease: (1) more severe involvement of the mandible, which may greatly enlarge (Fig. 10C) and (2) small periosteal excrescences arising from affected long bones [43]. Clinical features differentiating the two have also been observed. Unlike Worth disease, van Buchem disease is marked by progressive cranial nerve deficit, particularly of the facial nerves, and elevated levels of alkaline phosphatase [7, 29, 43, 122-124]. Consistent with their view that the autosomal-dominant and autosomalrecessive forms of endosteal hyperostosis represent distinct entities, Gelman, Gorlin, and Glass preferred the term "autosomal-dominant osteosclerosis" to Worth disease [43, 46]. Nakamura disease. Three cases of an autosomal-dominant type of endosteal hyperostosis apparently different from the Worth type have recently been reported in a Japanese family [93]. What apparently distinguishes these cases from Worth disease are unusual manifestations of sclerosis of the jaw bones for, as in Worth disease, Nakamura's patients showed no periosteal excrescences, elevated alkaline phosphatase levels, or neurologic deficits. Although involvement of the jaw bones is a frequent, but not consistent, feature of endosteal hyperostosis in general, swelling and sclerosis of the

A. Greenspan: Sclerosing bone dysplasias mandible tend to be much less severe in the autosomaldominant form (Worth disease) than in the autosomalrecessive form (van Buchem disease). In Nakamura's patients, the maxilla and mandible were enlarged, and the sclerotic changes had a mottled appearance, but the rami of the mandible were spared. As is typical of this group of disorders, the long bones exhibited symmetric thickening of the diaphyseal cortices, with only minimal widening; the epiphyses and metaphyses were unaffected. The neurocranium showed endosteal sclerosis, as well as loss of the diplo~. The report by Nakamura et al. contains no discussion of histopathology. Sclerosteosis (Truswell-Hansen disease). Sclerosteosis is an unusual autosomal-recessive disorder [54, 121] which, according to recent evidence, exhibits homozygosity for the same genetic defect as van Buchem disease [8], although the latter lacks the syndactyly and extreme stature commonly seen in the former. Cremin (personal communication) believes that sclerosteosis and van Buchem disease are the same conditions, reflecting merely a variation in the alleles. Some 30 cases of sclerosteosis have been reported to date, the majority among the Afrikaner community of South Africa [11]. Individuals with this disorder show signs of overgrowth and sclerosis of the skeleton, particularly the skull, in early childhood. The condition is progressive, and complications arise due to cranial nerve involvement. Height and weight often become excessive; adult males reach uncommonly tall stature, generally exceeding 198 cm in height, while females may attain 183 cm [9, 10]. Overgrowth of the cranium, together with hypertrophy of the mandible and frontal regions, leads to relative midfacial hypoplasia and distortion of the facies. Syndactyly of the second and third fingers is a frequent feature. Sclerosteosis is potentially a lethal disorder; death often occurrs in early adulthood as a result of raised intracranial pressure. The distinguishing roentgenographic features of sclerosteosis are a massive increase in size and density of affected parts of the skeleton, predominantly the cranium and the tubular bones, and deformities throughout the skeleton, reflecting errors in bone modeling. In sclerosteosis, defects of overgrowth are more prominent features than the increased roentgenographic density of affected bones, which appears less marked than in other endosteal hyperostoses. Gross widening and sclerotic changes are often seen in the calvaria, which appears dense and thickened, with obliteration of the diploic space (Fig. 11 A). The body of the mandible may enlarge massively in adults, resulting in prognathism. General enlargement, with thickening of the cortex and an increase in density, can be observed in the clavicles, ribs, and bones of the pelvic girdle (iliac bones, ischial and pubic rami). Vertebral changes are confined to the posterior elements, notably the pedicles and laminae of the lumbar and sacral vertebrae. The cortices of the long and short tubular bones show sclerosis and hyperostosis, with marked periosteal and endosteal thickening and evidence of disturbances in too-


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Fig. 10A-C. Van Buchem disease. A Prominent endosteal thickening of the cortex is present along the entire shaft of the humerus. The articular ends of bone (sites of endochondral bone formation) are not affected. B The cortices of the short tubular bones demonstrate endosteal thickening with almost complete obliteration of the medullary canal. Note that the articular ends of the bones and the carpal bones (sites of endochondral ossification) are not involved. C Oblique view of the mandible shows sclerotic changes and marked expansion. (Reprinted with permission from [8] Fig. 12.1 C, E and Fig. 12.2D) Fig. llA-C. Sclerosteosis. A Thickening of the vault of the skull (a site of intramembranous ossification) with obliteration of the diploic space is a constant feature of this dysplasia. B Marked thickening of the cortices of the distal humeri, ulnae, and radii is present. The medullary cavities are only slightly constricted. C The hands show evidence of periosteal and endosteal hyperostosis and disturbance in modeling. (Courtesy of Professors P. Beighton and B.J. Cremin, University of Cape Town, Rondebosch, South Africa)

deling (Fig. 11 B, C). In addition to some degree o f syndactyly, the tubular bones o f the h a n d s are enlarged, dense, and distorted, with occasional radial deviation o f the terminal phalanges. A recent neurogenetic and p a t h o p h y s i o l o g i c study o f sclerosteosis, which included h i s t o m o r p h o m e t r i c analy-

sis o f calvarial tissue following in vivo tetracycline labeling, showed that dense, thickened trabeculae were associated with active-appearing osteoblasts, increased total b o n e volume, and increased linear extent o f b o n e f o r m a tion and appositional rate [120]; osteoclastic b o n e resorption a p p e a r e d depressed. Thus, the changes o f scler-

576 osteosis appear to represent both osteoblastic hyperactivity and diminished activity of osteoclasts, resulting in a failure of bone resorption.

Mixed sclerosing dysplasias of bone Mixed sclerosing dysplasias of bone are conditions reflecting developmental errors in both endochondral and intramembranous ossification (see Table 1). In some of these disorders, dysplastic changes in endochondral bone predominate; in others, changes reflect predominance of an error in intramembranous bone formation. A third subgrouping of these conditions, formerly termed "mixed sclerosing bone dystrophy" [128], is marked by the coexistence of two or more osteosclerotic dysplasias and thus constitutes an "overlap syndrome" [97]. 1. Mixed dysplasias predominantly affecting endochondral ossification

a) Dysosteosclerosis. First described by Spranger et al. [ll8], dysosteosclerosis is marked by short stature and bone fragility; limb length is short relative to the trunk, the mandible is small, and the forehead and parietal regions are bulky [8, 81]. Bony encroachment narrows the optic foramina, and compression on the optic nerves causes blindness. Expansion of the metaphyses of the long bones may result in bowing. Inheritance is probably autosomal recessive. In general, dysplastic changes predominate at sites of endochondral bone formation. As in osteopetrosis, roentgenograms in dysosteosclerosis reveal a generalized sclerosis of the skeleton, disturbed diaphyseal and metaphyseal modeling of the long bones, and thickening of the base of the skull. In addition, there is sclerosis of the mastoids and paranasal sinuses, with narrowing of the optic nerve canals (Fig. 12A, B). Patients with dysosteosclerosis, however, typically exhibit platyspondylisis (vertebral flattening) and hypoplasia of the pelvis, as well as thickening of the calvaria. Dysosteosclerosis also differs from osteopetrosis because of the radiolucent appearance of the widened metaphyseal portions of the tubular bones (Fig. 12 C). Microscopic examination of biopsy specimens of metaphyseal bone reveals unresorbed spicules of calcified cartilage irregularly covered with a thin rim of immature osteoid, both of which appear to be heavily mineralized (hence the roentgenographic appearance) [73]. In some areas, the matrix is poorly organized, suggesting woven bone. Cartilage, on the other hand, appears normal. These findings in the metaphysis resemble those seen in osteopetrosis and suggest an error in endochondral bone formation due to diminished osteoclastic resorption, together with a subsequent disturbance in bone formation. In a study of histologic heterogeneity in hyperostotic bone dysplasias, investigators noted the similarity between the metaphyseal histopathology of dysosteosclerosis and lead intoxication, which suggested a deficiency of a lead-sensitive enzyme as the basic defect

A. Greenspan: Sclerosing bone dysplasias in this dysplasia [73]. However, involvement of the membranous bone of the skull, which appears immature and woven rather than compact and lamellar on histologic examination, points to an additional defect, one in intramembranous ossification, in the pathogenesis of dysosteosclerosis.

b) Metaphyseal dysplasia (Pyle's disease). Edwin Pyle first described metaphyseal dysplasia in a 5-year-old boy who showed genu valgum, mild limitation of extension in the elbow joints, and palpable widening of the clavicles, manifestations representing deficient modeling of the metaphyses of the tubular bones [102]. The condition is benign, general health is unimpaired, and lifespan is normal. Roentgenographic manifestations are most striking in the metaphyses of the tubular bones and the cranium, where mild sclerosis may be present, particularly at the skull base (Fig. 13A); moreover, the medial portions of the clavicles (sites of endochondral ossification) are widened. The metaphyses of the long bones (e.g., distal femur) show massive "expansions," representing the effects of undermodeling and may assume an Erlenmeyerflask configuration. The pubic and ischial bones may also be expanded. Platyspondylisis is occasionally observed in the spine. The calvaria (a site ofintramembranous bone formation) may be sclerotic, and the nasal sinuses and mastoids may be poorly developed.

c) Craniometaphyseal dysplasia. Except for the more pronounced involvement of the skull and facial bones, craniometaphyseal dysplasia is very similar to metaphyseal dysplasia. In most instances, it is inherited as an autosomal-dominant trait, although a few cases of autosomal-recessive inheritance have been reported [8]. Overgrowth of the skull may lead to prognathism and prominence of the forehead. Sclerosis and mild hyperostosis of both the vault and the base of the skull are associated with these gross changes on roentgenograms. Frequently, the mastoid and paranasal sinuses are obliterated. As in Pyle's disease, abnormalities of modeling in the long tubular bones lead to metaphyseal widening; the bones often assume a clublike shape, and the cortex of the metaphyses is thinned. Microscopic examination of biopsy specimens obtained at the costochondral junction and tibial metaphysis shows somewhat abrupt replacement of the calcified cartilage matrix with well-developed lamellar bone which, under polarized light, appears bright, with wellformed haversian systems [73]. The resorption and bone formation are normal in this dysplasia, as is evidenced by normal transition of proliferative to hypertrophic chondrocytes [73]. 2. Mixed dysplasias predominantly affecting intramembranous ossification

a) Melorheostosis. Melorheostosis is a rare condition marked by a "flowing" hyperostosis of the cortex, often


Fig. 12A-C. Dysosteosclerosis. A Lateral view of the thoracolum-

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its appearance in osteopetrosis. (Reprinted with permission from [8])

bar spine demonstrates increased radiopacity of the vertebrae and platyspondylisis. B Lateral view of the skull shows sclerosis of the base, obliteration of the frontal sinuses and mastoids, and mild thickening of the calvaria. C Lower limb of a patient with dysosteosclerosis at 20 months of age (left), 5 years (middle), and 15 years (right). Note the progression of metaphyseal widening, which has assumed an Erlenmeyer-flask configuration by 15 years of age. The radiolucent appearance of the metapbysis is in contrast to

Fig. 13A, B. Metaphyseal dysplasia. A Lateral film of the skull demonstrates sclerotic changes localized predominantly at the base (a site of endochondral ossification). Patchy sclerosis is seen in the vault (a site of intramembranous ossification). B The metaphysis and proximal diaphysis show striking expansion representing the effects of undermodeling. The cortices are thinned. (Reprinted by permission from [8])

resembling wax dripping d o w n one side o f a candle [83]. O f u n k n o w n etiology, it shows no evidence o f being a genetic disorder [35, 37]. A l t h o u g h m o s t investigators view melorheostosis as a congenital entity, s y m p t o m s o f the disorder do n o t manifest until late c h i l d h o o d or early adolescence. Its onset is insidious. The hyperostosis tends to progress t h r o u g h c h i l d h o o d and into adult life, and the disease exhibits a slow, chronic course with periods o f exacerbation and arrest [22]. The condition m a y affect only one b o n e (monostotic), representing a forme

fruste o f the disorder, one limb (monomelic), or multiple bones (polyostotic) [3/]. In rare instances the disease has been reported to involve m o r e than one limb and the trunk, as well as the spine, skull, and facial bones [22]. N e a r b y joints and soft tissues are also involved in this process. Thus, joints often show a restricted range o f m o t i o n as a result o f contracture and fibrosis, and other deformities are n o t u n c o m m o n , including flexion contractures o f the hips and knees, genu valgum, contractures o f the Achilles tendon, varus or valgus deformi-

578 ty of the feet, and overlapping toes. Joint ankylosis may also be encountered as a result of heterotopic bone formations and soft-tissue calcification. Laboratory findings for serum calcium, phosphorus, and alkaline phosphatase levels have been reported to be within normal limits [22, 47]. A number of other disorders have been found in association with melorheostosis, including scleroderma, osteopoikilosis, osteopathia striata, neurofibromatosis, tuberous sclerosis, and hemangioma [1, 129, 133]. Roentgenographic findings in melorheostosis appear to reflect developmental errors at the sites of intramembranous and endochondral bone formation, predominantly the former. Most prominent among these findings is irregular thickening of the cortex of a bone, generally on one side (Fig. 14A). This hyperostosis extends to the articular surface (a site of endochondral development) (Fig. 14 B) and, in its most severe manifestation, appears as lobules of cortical bone flowing toward the joint. There is usually a distinct border between pathologic and normal bone. The bones of the lower limbs are by far the most frequent sites of involvement, but any of the short bones of the hand and foot can also be affected [91]. The epiphyses and the carpal and tarsal bones (sites of endochondral ossification) often exhibit hyperostosis in the form of spots or patches. This produces an appearance similar to that of osteopoikilosis. Bony streaks and focal densities, as in osteopathia striata and osteopoikilosis, may be seen in the metaphyses as well. On occasion, hyperostotic bone crosses the growth plate, causing premature closure and disturbance in limb growth [22]. Such a mixed roentgenographic picture, which suggests that melorheostosis, osteopoikilosis, and osteopathia striata may represent the variable expression of a single basic abnormality, is more commonly seen in children and young adults and may reflect an early stage in the lesions' progression to confluent linear hyperostoses [47]. Bone scintigraphy is positive in melorheostosis [131]. Although the factors responsible for this are unknown, they may be partly due to the cortical location of the lesion or to the large size of individual lesions [131], or to osteoblastic activity along the margins of the hyperostotic bone. The histologic features of melorheostosis have been reported by a number of investigators [22, 53, 76, 129]. Microscopic examination of cortical specimens reveals nonspecific, hyperostotic, periosteal bone exhibiting thickened trabeculae and fibrotic changes in the marrow spaces. The bone appears primitive and consists largely of primary haversian systems, particularly on the periosteal surface, that are almost obliterated by the deposition of sclerotic, thickened, and somewhat irregular lamellae (Fig. 14D, E). Its is interesting to note that deposition begins at the proximal end of a bone and proceeds distally, somewhat like a massive periosteal reaction [71]. Osteoclastic activity is noted in microscopic examinations but is never prominent. On the other hand, Campbell et al. documented clear activity of osteoblasts along the margins of the osteons as well as thickened trabeculae and concluded that increased osteoblastic activity and persistence of intramembranous ossification accounts

A. Greenspan: Sclerosing bone dysplasias for the hyperostosis [22]. In addition, evidence of a disturbance in endochondral ossification can be observed at the centers of ossification of small bones and in the epiphyses of long bones. On the question of etiology, Murray and McCredie have proposed an intriguing hypothesis [92]. The lesions of melorheostosis, they noted, follow sclerotomes and myotomes, zones of the skeleton innervated from single spinal sensory nerves [63]. These authors observed that in 19 of the 30 patients included in their study, skeletal abnormalities corresponded to a single sclerotome or a part thereof, while in the remaining 11 cases, which were more severe, multiple sclerotomes appeared to be involved. A pattern of distribution based on segmental sensory innervation of bone and muscle could also explain the peculiar involvement of only one side of a bone or of a longitudinal column of bones, a feature foreign to osseous pathology. A longitudinal division in bones is inherent in their segmental spinal innervation. Murray and McCredie speculated that melorheostosis may represent a form of postnatal peripheral neuropathy affecting segmental spinal sensory nerves in a fashion similar to herpes zoster, with scarring of bone rather than skin. Nerve root irritation may be the stimulus for hyperostosis in corresponding sclerotomes and for the formation of ectopic bone in the soft tissues.

b) Progressive diaphyseal dysplasia with skull base involvement. The reader is referred to the earlier section on progressive diaphyseal dysplasia, where this variant is discussed among the roentgenographic features [94].

c) Craniodiaphyseal dysplasia. Craniodiaphyseal dysplasia is a progressive disorder in which the distortion of the face becomes apparent in early childhood [8]. Compression of the second and eighth cranial nerves may lead to blindness and deafness. Craniodiaphyseal dysplasia is a rare autosomal-recessive hyperostosis marked by sclerosis and dysplasia chiefly involving the skull, spine, and ribs [8]. These changes are accompanied by defective remodeling in the diaphyses and metaphyses of the long bones, which appear widened in diameter, although their cortices are sometimes thinned. The pelvis may be somewhat elongated but is not especially sclerotic. The histopathologic findings in craniodiaphyseal dysplasia, unlike those in craniometaphyseal dysplasia, suggest an increased turnover of lamellar bone in addition to hyperactive resorption, which had earlier been postulated as the single defect in this disorder [73]. A specimen obtained at the iliac crest showed normal evolution of chondrocyte columns at the growth plate. Under polarized light, bony spicules arising from the apophysis appeared very bright, suggesting a high degree of alignment of the organic fibrins and a more mature type of lamellar bone than is usually seen [73]. Examination of a tibial specimen from a patient in early childhood revealed welldeveloped, complex haversian systems, also appearing very bright under polarized light. These findings suggest a defect in both intramembranous and endochondral ossification.


Fig. 14 A-E. Melorheostosis. A, B Irregular thickening of the lateral femoral and anterior humeral cortices resembling "wax dripping down one side of a candle." C Severe involvement of the middle ray and mild involvement of the fourth ray and second metacarpal in the right hand. Note that the melorheostotic process involves not only the cortex (a site of intramembranous ossification) but also the articular ends of the metacarpals and phalanges, as well as the carpal bones (all sites of endochondral bone formation).

579

D Low-power photomicrograph reveals extensive asymmetric sclerosis of the one cortex (arrows), with encroachment on the endosteal surface representing periosteal and endosteal bone formation. Arrowheads point to normal, uninvolved cortex (H & E, x 9). E Higher magnification of the abnormal cortex reveals that the new bone is largely lamellar in architecture, reflecting stow modeling (H & E, polarized light, x 50). (D, E Courtesy of Michael J. Klein, M.D., New York)

580

A. Greenspan: Sclerosingbone dysplasias

Fig. 15A-D. Overlap syndrome. A The proximal femur shows wavy hyperostosis typical of melorheostosis. B, C The distal femur and proximal tibia exhibit coarse linear striations characteristic of osteopathia striata, as well as the focal densities that are the identifying feature of osteopoikilosis. D Lateral view of the foot again demonstrates the features of melorheostosis. A giant bone island is present in the calcaneus

3. Coexistence of two or more sclerosing bone dysplasias (overlap syndrome) Six general types of overlap syndrome - the coexistence of two or more osteosclerotic dysplasias - can be identified in the literature on the basis of their roentgenographic patterns (see Table 1). Type I [1,129, 133] combines osteopoikilosis, osteopathia striata, and melorheostosis; type II [59, 106], osteopathia striata with cranial sclerosis; type III [106], osteopathia striata with osteopoikilosis and cranial sclerosis; type IV [37], osteopathia striata with generalized cortical hyperostosis and metadiaphyseal deformity; type V [39, 62, 70], osteopathia striata with osteopetrosis; and type VI [1, 95], osteopoikilosis with progressive diaphyseal dysplasia. The most common of these overlap syndromes, which as a group are very rare, combines features of osteopoikilosis, osteopathia striata, and melorheostosis (Fig. 15) [1, 129, 132]. The appearance of the lesions may not exactly match the classic descriptions of the individual entities, but the changes are sufficiently representative to designate them as a mixture of sclerosing bone dysplasias [129]. Other combinations of dysplasias within this grouping have been reported. In addition to Hurt's description of a case of osteopathia striata in association with osteopetrosis [62] (see discussion in section on

Osteopathia striata), several reports have described the combination of osteosclerotic disorders in type I exhibiting, in addition, a widespread osteosclerosis of the axial skeleton [1, 129, 133]. This latter phenomenon usually represents an osteopetrotic-like process, except in one case reported by Whyte et al. [133]. In that instance, the histopathologic findings excluded osteopetrosis and demonstrated instead a focal cortical sclerosis, with lamellar and well-mineralized bone. Osteoblasts and osteoclasts were unremarkable in number and appearance, but electron microscopy, which might have been revealing, was not performed. The lesions also showed increased activity on bone scintigraphy [133]. These findings suggested that a different mechanism from that in osteopetrosis, perhaps increased osteoblastic activity, lay at the root of this combined dysplasia. The association of osteopathia striata with cranial sclerosis (Horan-Beighton syndrome) is a rare combination that has been the subject of two reports. Horan and Beighton are credited for recognizing the association between dense striations in the long bones and pelvis typical of osteopathia striata and thickening and sclerosis of the skull, particularly at the base but also minimally affecting the vault, as an autosomal-dominant entity in 11 members of four kindred [59]. In a similar case reported by Schnyder, a patient exhibiting the typical


lesions of osteopathia striata in the long bones also showed marked thickening and sclerosis of both the base and the vault of the skull, an association that proved to be inherited as an autosomal-dominant trait [106]. These cases have since been regarded as the variable expression of a single disorder, as their roentgenographic similarities and common mode of inheritance would indicate. Sclerotic changes in the vault of the skull, a site of intramembranous ossification, in association with other sclerotic lesions of endochondral origin clearly raise the possibility of an interrelationship between the two broad groupings of dysplasias represented in this combined osteosclerotic disorder. There can be little doubt, as Abrahamson observed, that not all sclerosing dysplasias are distinct entities and that common factors exist in their development [1]. These overlap syndromes are proof of that. Nearly every investigator in this field of osteosclerotic dysplasias has postulated a relationship between melorheostosis, osteopathia striata, and osteopoikilosis or some other reported dysplasias [1, 48, 62, 129, 133]. Osteopoikilosis, osteopathia striata, and osteopetrosis clearly are heritable disorders, whereas melorheostosis has been reported only in sporadic cases. In a recent report, however, osteosclerotic changes consistent with melorheostosis, osteopathia striata, and dysplasia epiphysealis hemimelica were reported in a patient with no family history of bone abnormality [48]. In the general approach to sclerosing bone dysplasias outlined in this review, this combination of dysplasias represents not only the coexistence of two or more entities but, in addition, the overlap of dysplasias showing individually evidence of a disturbance in endochondral or intramembranous bone formation, or both. If there is a common factor at some stage in the development of osteopathia striata, osteopoikilosis, and melorheostosis, that factor also points to a common mechanism affecting both endochondral and intramembranous ossification and thus suggests a common pathogenesis for most sclerosing dysplasias of bone. As additional associations such as these are recorded, our understanding of the pathogenesis and inheritance will improve (as will our skill in treatment and judging prognosis where required), and a more precise classification will become possible.

Acknowledgements. I would like to express my thanks to Prof. Peter Beighton, M.D., Ph.D., F.R.C.P., D.C.H., from the Department of Human Genetics, Medical School and Groote Schurr Hospital, University of Cape Town, South Africa, and Prof. Bryan J. Cremin, F.R.A.C.R., F.R.C.R., from the Department of Pediatric Radiology, University of Cape Town, Rondebosch, South Africa, for their kind permission to use some of their published and unpublished material. Special thanks to Michael J. Klein, M.D., from the Department of Pathology, Mount Sinai Medical Center, New York, for his help with the microphotographs; to Bill Gabello for his editing; and to Valerie Anderson for invaluable secretarial assistance. References 1. Abrahamson MN (1968) Disseminated asymptomatic osteosclerosis with features resembling melorheostosis, osteopoikilosis and osteopathia striata. J Bone Joint Surg [Am] 50:991

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