► [Increased density of trabecular bone (osteosclerosis), thickening of cortical bone (hyperostosis) (Whyte 1997)]
Increased bone mass, the result of focal or widespread osteosclerosis and/or hyperostosis, can occur in association with any of a variety of conditions, including metabolic and endocrinological disorders, neoplasms, infections, trauma, skin disorders, various arthritides, sickle cell anemia, and several primary or secondary disorders of bone. In addition, there is a sizable group of sclerosing bone dysplasias characterized by variable clinical, radiologic, and histopathological manifestations and caused by different gene defects (Greenspan 1991). Of the several classification systems developed during the last decades for these disorders, many have emphasized their roentgenographic appearance (Rubin 1964; Norman and Greenspan 1986; Spranger 1992). This is because the diagnosis of many sclerosing bone disorders is based on radiograms. A valuable initial step in the roentgenographic evaluation of a sclerosing bone disorder is to identify whether sclerosis involves primarily the spongiosa or the cortex of bone. This 'target-site' approach usually narrows significantly the spectrum of diagnostic possibilities. In addition, it may provide insights into understanding of whether the endochondral or membranous bone formation is disturbed in a given disorder - indeed, the spongiosa develops by means of endochondral ossification, while the cortex is formed by way of intramembranous ossification (Greenspan 1991). Despite the several cases in which both the spongiosa and cortex are involved by the sclerosing process, and the rare situations in which two or more scle-rosing disorders coexist in the same individual (so-called overlap syndromes), differentiation between the two bone compartments retains most of its diagnostic value. The disorders manifesting with cortical hyperostosis are discussed in Chapter 5, section "Cortical Thickening." In the current section, five ra diographic patterns of spongy bone hyperdensity are recognized, and pertinent disorders are discussed.
Disorders Manifesting with Single or Multiple Spotty Lesions of Increased Density. Focal, homogenously dense lesions localized within the cancellous bone or occasionally on the internal surface of the cortex are termed enostoses, or bone islands. These are discrete, usually solitary, foci of compact bone, ovoid or round, measuring 1 mm to 2 cm in greatest diameter. 'Giant' bone islands measuring more than 2 cm occasionally occur (Smith 1973). A characteristic radiographic pattern is one of thickened bony trabeculae radiating in streaks from the lesion and blending intimately with the surrounding trabeculae of the spongiosa (Greenspan 1991). Histologically, a mature lamellar structure and haversian system of nutrient canals is observed. Bone turnover activity is absent or minimal, with only rare foci of osteoblastic and osteoclastic activity (Hall et al. 1980; Greenspan et al. 1991). Enostoses are totally asymptomatic, their clinical importance residing only in their differentiation from sclerosing bone metastases. Osteopoikilosis (OMIM 166700), an autosomal dominant disorder, is marked by the presence of multiple small, well-defined, circular or ovoid bone islands clustered in the spongiosa at the ends of bones and in the periarticular regions (Melnick 1959).
Disorders Associated with Metaphyseal Striations. The radiographic hallmark of osteopathia striata is the presence of fine linear striations of hyperdensity situated in the metaphyses and diaphyses of bones, occasionally crossing into the epiphyses and running parallel to the long axis of the bony shafts. In the iliac wings, a fan-shaped pattern of striations may be seen, whereas the hands and feet, skull and facial bones, and vertebrae are usually not involved. Osteopathia striata can occur in association with other sclerosing disorders, such as osteopoikilosis, melo-rheostosis (Fig. 9.4 a,b), and osteopetrosis (Brennan et al. 2002). Osteopathia striata with cranial sclerosis (OMIM 166500) is marked by progressive cranial sclerosis with cranial nerve palsies as a distinguishing feature in addition to the vertical striations in the long bones (Horan and Beighton 1978). A pattern of metaphyseal dense striations similar to that of osteopathia striata occurs in SPONASTRIME dysplasia (OMIM 271510) in association with vertebral and nasal defects; and in focal dermal hypoplasia (Goltz-Gorlin syndrome, OMIM 305600) in association with osteopenia and multiple bone lesions resembling giant cell tumors.
Fig. 9.4 a, b. Mixed sclerosing bone dysplasia in a 44-year-old man with melorheostosis associated with osteopathia striata, who in addition developed osteosarcoma. a Note dense sclerosis involving the proximal femur and pelvic bone in a sclerodermal distribution, which is typical of melorheostosis. b Note also vertical metaphyseal stria-tions of distal femur and proximal tibia, consistent with os-teopathia striata. There is an area of permeative bone destruction of the distal femoral diaphysis at the site of the superimposed osteosarcoma. (From Brennan et al. 2002)
Disorders Manifesting with Generalized Bone Sclerosis.
Osteopetrosis can manifest in at least four different forms: an autosomal recessive infantile type (Albers-Schönberg disease, OMIM 259700), characterized by precocious clinical manifestations (severe anemia, hepatosplenomegaly, brittle bones) resulting in stillbirth or death in early infancy; an autosomal dominant adult type (OMIM 166600) with variable expression, but often clinically asymptomatic and detected incidentally on radiograms; an autosomal recessive intermediate type (OMIM 259710), with clinical manifestations (short stature, anemia, hepatomegaly) that fall between the infantile and adult type in terms of severity; and an autosomal recessive type with renal tubular acidosis (OMIM 259730) and a clinical picture of growth retardation, muscle weakness, hypotonia, cerebral calcifications, and mental retardation. An increased susceptibility to pathologic fractures is common to all types. The roentgenographic hallmark is generalized sclerosis of the trabecular bone, with lack of differentiation between the cortex and medullary cavity in the long bones. The cortex of bone, a site of intramembranous ossification, is characteristically unaffected. Bone sclerosis is also prominent at the skull base and vertebral end-plates, giving the vertebrae a characteristic 'sandwich-like' or 'bone-within-bone' appearance. Modeling defects are particularly evident in the metaphyses, with widening and splaying. Horizontal striations of sclerotic and normal ra-
diolucent bone in the metaphyses and iliac wings are also characteristic. It seems likely that the primary defect in osteopetrosis is the inability of osteoclasts to resorb the primary spongiosa, which accumulates in the medullary cavity and eventually forms masses of calcified cartilage packing the cavity (Greenspan 1991; Bollerslev and Mosekilde 1993). A generalized increase in the roentgenographic density of the skeleton similar to that of osteopetrosis also occurs in py-knodysostosis (Maroteaux-Lamy disease, OMIM 265800), an autosomal recessive disorder. However, the medullary cavity, though narrowed, is characteristically patent in pyknodysostosis, accounting for the reported absence of anemia and hepatosplenomegaly as manifestations. Additional distinguishing features include the pattern of skull abnormalities (more severe basal sclerosis, multiple wormian bones, wide sutures and fontanels, small facial bones, hypoplastic paranasal sinuses, obtuse mandibular angle), clavicular hypoplasia, spinal segmentation defects, and progressive osteolysis of the tuftal phalanges (Elmore et al. 1966). The pattern of bone sclerosis in the autosomal recessive dysosteosclerosis (OMIM 224300) is also similar to that of osteopetrosis: generalized sclerosis of the skeleton, defective bone modeling, thickening of the skull base, and susceptibility to fractures (Spranger et al. 1968). Distinctive features in dysos-teosclerosis include sclerosis of the mastoids and paranasal sinuses, bony encroachment on cranial nerve foramina, sclerosis of the cranial vault, platyspondyly, pelvis hypoplasia, and radiolucent appearance of the widened submetaphyseal portions of the tubular bones (John et al. 1996). Generalized bone sclerosis also occurs in Blomstrand dysplasia (OMIM 215045) and Raine dysplasia (OMIM 259775), two lethal sclerosing dysplasias discussed in below in the section headed "Dwarfism with Neonatal Death."
Disorders Manifesting with Skull Sclerosis. Sclerosis and hyperostosis predominantly involving the bones of the skull occur, in order of declining severity, in the following skeletal dysplasias: craniodiaphyseal dysplasia (OMIM 218300, 122860), craniometaphyseal dysplasia (OMIM 123000, 218400), frontometaphy-seal dysplasia (OMIM 305620) and metaphyseal dysplasia (Pyle disease, OMIM 265900). The facial bones are severely affected and distorted in craniodiaphy-seal dysplasia (leontiasis ossea) and, to a lesser extent, in craniometaphyseal dysplasia, in which obliteration of paranasal sinuses and sclerosis of the mandible predominate. A characteristic facial finding in craniometaphyseal dysplasia is a thick bony wedge over the bridge of the nose and glabella, associated with ocular hypertelorism. In both craniodiaphyseal and craniometaphyseal dysplasia, symptoms related to cranial nerve encroachment (hearing loss, visual impairment, facial paralysis) are common. In Pyle disease the facial bones and mandible do not show sclerosis, whereas in frontometaphyseal dysplasia a torus-like outgrowth of the supraorbital ridge of the frontal bones is characteristic. All the above disorders also display varying degrees of defective modeling of the tubular bones, with metaphyseal expansion and cortical thinning, the most severe findings occurring in Pyle disease (Erlenmeyer flask deformity), followed by, in order of declining severity, craniometaphyseal dysplasia and frontometaphyseal dysplasia (Brueton and Winter 1990; Beighton 1995; Lievre and Fischgold 1956; Holt et al. 1972; Feld et al. 1955). Widespread sclerosis of the cranial vault, skull base, and vertebrae occurs in Lenz-Majewski dysplasia (OMIM 151050) (Gorlin and Whitley 1983). Cranial hyperostosis and mandibular overgrowth, in association with microphthalmos, abnormally small nose, hypotrichosis, dental anomalies, neurological symptoms, 5th finger camptodactyly, syndactyly of the 4th and 5th fingers (type III syndactyly), and missing toe phalanges, are features of oculo-dento-osseous dysplasia (oculo-dento-digital dysplasia, OMIM 164200), an autosomal dominant disorder caused by mutation in the connexin-43 gene mapped to 6q21-q23.2 (Gorlin et al. 1963;Gillespie 1964;
Beighton et al. 1979; Loddenkempler et al. 2002; Paznekas et al. 2003). In the recessive variety of oculo-dento-osseous dysplasia (OMIM 164200) more severe ocular manifestations occur in association with distinguishing skeletal changes (obtuse mandibular angle, widened long bones, and marked diaphyseal widening in the bones of the hands and feet) (Beighton et al. 1979; Traboulsi et al. 1986). Tricho-dento-osseous dysplasia (OMIM 190320), an autosomal dominant disorder that can be caused by mutations in the distal-less homeobox gene DLX3 that has been mapped to 17q21 (Price et al. 1998),is marked by the presence of enamel hypoplasia, strikingly curly hair,sclerosis and thickening of the calvaria and facial bones with obliterated mastoid processes, and long bones that show subtle undertubulation but no sclerosis (Robinson and Miller 1966; Lichtenstein et al. 1972; Quattromani et al. 1983). While taurodontism and enamel hypoplasia are fully penetrant features, bone and hair abnormalities are variably expressed (Hart et al.1997).
Disorders with Axial Sclerosis. In axial osteosclerosis (osteomesopyknosis, OMIM 166450), an autosomal dominant disorder, sclerosis is confined to the bones of the pelvis and spine, with sparing of the skull, tubular bones, hands, feet, ribs, and clavicles (Maro-teaux 1980; Stoll et al. 1981). Radiographic manifestations consist of patchy areas of sclerosis involving the vertebral end-plates, pelvis, and proximal femurs. Clinically, the disorder typically manifests in the 2nd decade of life with back pain and discomfort. The rare osteosclerotic disorder designated - in spite of the radiographic appearance - axial osteomalacia (OMIM 109130) may be the same disorder (Whyte et al. 1981). Central osteosclerosis with ectodermal dysplasia is characterized by ichthyosis, brittle air, mental retardation, decreased fertility, and short stature. Osteosclerosis predominantly involves the skull, spine, ribs, clavicles, pelvis, and proximal portions of the tubular bones. The remainder of the tubular bones are osteopenic, instead (Civitelli et al. 1989). Except for axial osteosclerosis, the clinical spectrum is identical to that of trichothiodystrophy (Tay syndrome, OMIM 601675), a disorder with sulfur-deficient brittle hair and nails, ichthyosiform erythroderma, sensitivity to sunlight, and physical and mental retardation, caused by mutations in the XPD and XPB gene, which encode helicases of TFIIH, a basal transcription factor involved in DNA repair (Price et al. 1980; Tay 1971). Interestingly, in an animal model of mice with ERCC2 mutation, many symptoms, including osteoporosis, osteosclerosis, and infertility,
overlapped with those of the osteosclerotic variant of trichothiodystrophy (de Boer et al. 2002). Axial osteosclerosis sometimes occurs in association with bamboo hair (Porter and Starke 1968).'Bamboo hair,' that is to say trichorrhexis nodosa (or, because of the nodes, invaginata),is the cardinal clinical finding, together with congenital ichthyosiform erythroder-ma and atopic diathesis of the Netherton syndrome (OMIM 256500), a disorder caused by mutations in the SPINK5 gene which encodes the serine protease inhibitor LEKTI located on chromosome 5q32 (Netherton 1958; Chavanas et al. 2000). Some infants may develop severe complications, such as progressive hypernatremic dehydration, failure to thrive, and enteropathy (Stoll et al. 2001). Because the diagnosis is based on the typical hair shaft anomaly, or bamboo hair,the diagnosis is often delayed (Smith et al. 1995). Axial sclerosis may be observed in patients with advanced Paget disease (OMIM 602080), a metabolic bone disorder characterized by excessive and abnormal remodeling of bone. Its active phase is associated with aggressive bone resorption and formation due to activated osteoclasts. The disease usually affects individuals over 40 years of age (Klein and Norman 1995) and is particularly common in England (Barker et al. 1980) and Australia (Gardner et al. 1978), which suggests that environmental factors are important in the etiology. There are several reports of familial aggregation of cases, with affected individuals distributed over multiple generations (McKusick 1960; Jones and Reed 1967); in these families the disease segregates as an autosomal dominant trait (Morales-Piga et al. 1995). It has been calculated that for first-degree relatives of an affected patient the risk of developing Paget disease is 7 times that in the general population (Siris 1994). The disorder is ge netically heterogeneous. Some cases are caused by mutation in the TNFRSF11A gene encoding RANK, a protein essential in osteoclast formation, which is located on chromosome 18q22.1 (Hughes et al. 2000). Mutations in the same region also cause familial expansile osteolysis (OMIM 174810), a disorder sharing features with Paget disease (see the section headed "Osteolyses" in this chapter). Some other cases of Paget disease are caused by mutation of the SQSTM1 gene on chromosome 5q35 (Laurin et al. 2001), with additional disease loci mapped to 5q31 (Laurin et al. 2001) and 18q23 (Gkood et al. 2002). In addition to the genetic etiology, a viral theory is supported by the evidence that the osteoclasts, which are primarily defective in Paget disease, contain characteristic virus-like inclusions, while osteocytes, osteoblasts, hematopoietic cells, and connective tissue cells do not (Mills and Singer 1976; Harvey et al. 1982). Paget disease can be a localized process involving one or more skeletal regions without causing any major clinical symptom or a widespread, severe, bone disorder producing significant clinical signs and symptoms such as bone pain and deformities, increased susceptibility to fractures, deafness, and neurological complications (Hamdy 1995). The active stage of the disease is marked by intense bone resorption, followed by bone sclerosis and condensation. The inactive stage is dominated by the osteosclerotic process, manifesting with patchy or diffuse areas of increased density, coarse trabeculae, cortical thickening, 'cotton-wool' appearance of the cranial vault with diploic thickening and basilar invagination, ivory vertebrae, thickened pelvic ring, and variable degrees of deformation and widening of the long bones (Fig. 9.5). The disease predominates in the axial skeleton, especially the pelvis, sacrum, and lumbar spine. In addition, the proximal portion of the femur is frequently affected, while the ribs, hands, and feet are usually spared (Paget 1877). Pathologic fractures, stress fractures, sarcomatous degeneration, superimposition of other neoplasms, osteomyelitis, and articular problems are major complications in patients with Paget disease (Resnick and Niwayama 1995).
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