EEX] charren | oiseases or te hemaroeoienc sistem T lymphocytes, differentiating ic pathologically from that of juve- nile rheumatoid arthritis (148). Septic arthritis must be ruled cout in both acute and chronic presentations because mycoplas- 1mal infection was the leading cause of chronic arthritis in a series of 358 patients with XLA (149). ‘The arthritis, if aseptic, usualy responds to immune globulin treatment and anti-nflammacory ‘medication (146). A knowledge of che clinical picture and conse- quences of XLA will allow the orthopaedist to appropriately refer patients for further evaluation and treatment. Initially reported by Bruton in 1953 as the first recognized primary immunodeficiency, XLA is otherwise known as Bruton ‘agammaglobulinemia (150). XLA results from one of more than 750 possible mutations in the gene for B-lymphocyte tyrosine kinase, which is necessary for B cell maturation (151). The immunologic abnormality of XLA therefore consists of very low numbers of mature B cells and profoundly decreased production of all three major immunoglobulin classes (152). ‘The number and function of T cells are usually normal. Individuals with XLA are normal at birth, but as mater- nal IgG levels begin to decline in the first few months, recur- rent infections begin to appear (153). Respiratory infections are common and are typically caused by organisms such as Streptococcus spp. and H. influenzae (144). Infections are usu- ally severe enough to require hospitalization before a diagnosis of XLA is made (154). Therefore, the orthopaedist who is eval- ating a child wich unexplained arthritis should inquire about past history of hospitalization for respiratory or other infec- tions. Infectious disease consultation should be obrained if an infection history accompanies a clinical picture of archritis in ‘young children. The diagnosis of XLA is presumed in che setting of hypogammaglobulinemia and very low numbers of circulat- ing B-lymphocytes. ‘Ireatment of XLA consists of immune globulin replacement and aggressive treatment of infections. Immune globulin, given asa regular prophylaxis, can lower the incidence of respiratory infections or other systemic infection and thereby prolong life (155). Recurrent respiratory infec- tions lead co chronic lung disease, and respiratory failure is a major cause of mortality (153). DISORDERS OF THE MONOCYTE- MACROPHAGE SYSTEM ‘The monocyte-macrophage system is a group of cell types derived from a common bone marrow precursor that provides important immune functions in various parts of che body. Macrophages ingest cellular debris, pathogens, and foreign bodies, and are particularly abundant in the spleen, liver, ymph nodes, lungs, and bone. Ostcoclasts are a specialized form of ‘macrophage, derived from the same precursor. Dendritic cells are nonphagocytic antigen-presenting cells that are chought to arise from the monocyte-macrophage stem cell. A wide variety of diseases affect the monocyte-macrophage system. Two discases with musculoskeletal manifestations discussed in this chapter are Gaucher disease, which is a lysosomal storage disease, and Langerhans cell histiocytosis (LCH), which is a dendritic cell proliferative disorder. Gaucher Disease. Lysosomal storage disorders involve deficiencies of catabolic enzymes that allow toxic accumulation of metabolic pathway products, A variety of enzyme deficien- cies lead to a variety of discases with different manifestations. ‘The most common lysosomal storage disease is Gaucher dis- case, and this example will be discussed in detail in this chap- ter. Gaucher disease has significane skeletal manifestations, and can require orthopaedic attention for bone pain, osteomyelitis, osteopenia, pathologic fractures, and ON, In his doctoral thesis in. 1882, Phillipe Charles Emest Gaucher described a disease that causes splenic enlargement (156). The cause of the disease was not identified until 1965, when Brady et al. (157) linked it to a deficiency of glucocer- ebrosidase, a membrane-bound enzyme responsible for cleav- ing glucocerebroside. ‘The lipid glucocerebroside accumulates in macrophages, and such lipid-laden macrophages are termed Gaucher cell, ‘The clinical manifestations of Gaucher disease are caused by the accumulation of these cells in organs, result- ing in organ dysfunction, Gaucher disease is the most common inherited lysosomal storage disease, with an autosomal recessive inheritance pattern and a prevalence of 1 in 40,000 in the general population and 1 in 400 to 1 in 600 among Ashkenazi Jews (158-161). Three forms of Gaucher disease are recognized: type 1 (nonneurono- pathic), type 2 (acute neuronopathic), and type 3 (subacute neuronopathic). Type 1 is by far the most common form and is characterized by hepacosplenomegaly, pancytopenia, and pre- dominant skeletal manifestations. ‘ype 2 is a rare form that involves the central nervous system and cranial nerves and usu- ally causes death by apnea or aspiration before the age of 2 years (162). Type 3 disease is characterized by neurologic symptoms, including seizures, that begin during adolescence (163). More than 100 disease-producing mutations ofthe glucocerebrosdase gene, which is located on the short arm of chromosome 1, have been identified (163), and some mutations predict the phenotype (164). ‘The detection of ghucocerebroside in blood and urine confirms the diagnosis of Gaucher disease. "The age at onset and clinical presentation depend upon the genotype and clinical type. Ina series of 53 patients, Zimran eal, (165) found that che average age at diagnosis was 25 years (range, 8 months to 70 years). Another series (164) of 34 children and adolescents with type 1 disease found that most of them pre- sented before che age of 10 years. A patient with Gaucher disease ‘ay present initially to the orthopaedise with musculoskeletal symptoms. Bone pain or fracture isthe reason for presentation in 13% co 60% of patients (165, 166). Growth retardation is also a common musculoskeletal presenting symptom, with 26% and 30% of patients presenting with les than the third percen- tile of normal values for weight and heighs, respectively (164). Skeletal abnormalities are detected radiographically in 88% to {949% of patients at presentation (164, 166) "The clinical manifestations of Gaucher disease depend on which organs are affecced by accumulated Gaucher cells. Splenicinvolvement causes splenomegaly and can cause hypersplen- ism, leading to anemia, thrombocytopenia, or pancytopenia, Liver involvement can cause mild liver dysfunction. Impaired hepatic synthesis of clotting factors may compound the throm- boeytopenia, causing clinically significant coagulopathy. Skeletal involvement is a prominent feacure in Gaucher disease and substantially impacts the quality of life (165, 167). In a review of 602 patients with type 1 Gaucher disease from the Gaucher registry, 21% were found to have some form of dis- abilcy in mobility laced to skeletal involvement (168). Skeletal ‘manifestations include pain, deformity, osteopenia, ON, ostco- ryclitis, pathologic fracture, and vertebral collapse (167). Gaucher disease is associated with a classic abnormality that shows up on radiographs as an “Erlenmeyer flask” deformity of the distal femur and proximal tibia, representing impairment of remodeling (Fig, 10-5). However, this finding is not pathogno- monic for Gaucher disease and occurs only in 56% t0 70% of patients with known Gaucher disease (165, 166). Bone crises are a common symptom of skeletal involve- ‘ment. Bone crises are thought to be related to intramedullary or subperiosteal hemorrhage (169, 170) made possible by chrom- bocytopenia and deficient clotting Factor synthesis. Bone crises are episodes of acute bone pain accompanied by fever, leuko- ytosis, and clevated erythrocyte sedimentation rate, Because of this clinical picture, bone crises are also known as pseudo- steomyelitis, Blood calcures may help differentiate between bone crisis and osteomyelitis, Further differentiation is difficult, as in SCD, and imaging studies may not be helpful. Karly in bone crises, plain radiographs are normal, but may progress to show periosteal reaction and arcas of radiolucency (171, 172). Radionuclide bone scans may show an area of decreased uprake carly in the course of the process (173) and increased uprake FIGURE 10-5. Radiographs of the knee in a child with Gaucher disease. Note the typical flaring ofthe cistal femoral mataphysis, or Erienmayer flask deformity. {Photo courtesy of Henry J. Mankin, MD.) HAPTER‘ | oISEASESOF THE EMATOPOLETC sre EEE around a photopenic rca later in the course (174). MRI shows marrow edema on T2-weighted images, with or without signs of hemorrhage (168, 170). Periosteal uid accumulation seen on MRI may indicate infection and should be aspiraced for culture under sterile conditions and radiographic guidance. ‘Treatmenc of bone crises is supportive. Severe pain early in the course usually requires opioid analgesics, which can be augmented with high-dose prednisolone (175). The symptoms gradually abate over 2 to 4 weeks. Failure of the symproms to improve should warrant further investigation into the pos- sibility of osteomyelitis. Bone aspiration in an operating room setting may be required. Osteomyelitis can follow a bone cri- sis, often with anacrobie organisms, suggesting that there has been a period of ischemia (176). Treatment of osteomyelitis in Gaucher disease parallels that in SCD as discussed earlier, although attention should be paid to the altered structural integrity of bone and increased bleeding risk when surgical debridement is considered in a patient with Gaucher disease, ON can follow a bone crisis, so routine radiographic evalua- tion of an affected area is necessary even after the crisis resolves. Chronic bone pain varies in severity and does not corre- Jace well with other signs of skeletal involvement. Back pain is common in children with spinal involvemenc (177). Chronic back pain may be severe enough to require bracing, ON occurs in 12% to 34% of patients with Gaucher dis- case (165, 166, 168). ‘The common sites are the femoral head, femoral condyles, tibial plateau, and humeral head (167, 172). Despite poor radiographic findings following ON, total joint arthroplasty is not often required (178). Of the 1476 patients in the Gaucher Registry, 79% of whom were adults, toal joint arthroplasty had been performed in only 13% (168). The possi- bility chat thrombosis plays a role in the pathogenesis of ON is supported by clevated p-dimer levels in patients with Gaucher discase and ON compared to those without ON (179) Pathologic fractures are not uncommon in patients with Gaucher disease. Fractures occurred in 23% of 1476 patients in the Gaucher Registry (168). The common sites of fracture are the distal femur, proximal tibia, and femoral neck, and (65% of the fraccures occur at the site of a prior bone crisis (180), Fraccures at the base ofthe femoral neck occur in young children and can be complicated by coxa vara, pseudoarthro- sis, and ON. Vertebral compression fractures occur with spinal involvement and can lead to severe kyphosis and spinal cont compromise on rare occasions (177, 181). Fracture healing is impaired in patients with untreated Gaucher disease, and delayed union and nonunion are common, Osteopenia is nearly universal in Gaucher disease in chil- ddren (167). Osteopenia can affect trabecular and cortical bone and present as a focal or diffuse process (168). Osteopenia in Gaucher discase can be quantified by dual-energy x-ray absorp- tiometry (DEXA) (182, 183) or broadband ultrasound artenua- ton ofthe calcaneus (182). Quantitative computed tomography (C1) can also accurately measure bone mineral density, but is not recommended in children because of the very high radia- tion doses involved (184). Chemical markers of bone turnover are also abnormal in Gaucher disease. When compared with aED) charreno | oiseases ore hetaroeoienc sistem control group, patients with Gaucher disease had clevated uri- nary excretion of pyridinoline and dcoxypyridinoline (182), as ‘well as elevated serum levels of carboxy terminal celopeptide of type I collagen (185), all of which are- markers of bone resorp- tion, Serum levels of carboxyterminal propeptide of type I col- lagen, a marker of bone formation, are significantly lower in patients with Gaucher discase chan in the controls (185). Infiltraion of bone marrow by Gaucher cells can be quan- tified. Quantitative chemical shift imaging (QCSI) is an MR spectroscopic technique that utilizes che difference in resonance beeween fat and water in bone marrow to quantify the reduc- tion in far fraction that occurs in Gaucher disease (186, 187). ‘Marrow infiltration in vertebral bodies measured by QCSI corre- lates well with disease severity (187), and the technique is repro- ducible (188). A bone marrow burden score has recently been developed to allow quantification of marrow infiltration using standard MRI (189), with high incer- and intrarater reliability and sensitivity only slightly less than that of QCSI. Several other semiquantitative techniques using standard MRI have been developed and are currently under investigation (184, 190). Because Gaucher disease is a deficiency of a specific enzyme, enzyme replacement therapy (ERT) is the comerstone of treatment. In fact, replacement of mactophage-directed glu- cocerebrosidase has become standard medical treatment for type I Gaucher disease (164, 191-193). Given incravenously at 2-week intervals, ERT reliably reverses anemia, thrombocyto- penia, and splenomegaly with a dose-dependent (194) relation- ship. Although marrow infiltration responds more variably and more slowly (195-197), bone mineral density and bone pain improve with ERY (198, 199). Children cend to respond more quickly and reliably than adults (199). Enzyme replacement, if started early in life, can prevent skeletal deformity and allow normal skeletal development and growth (200, 201)..A decrease in the incidence of fractures has also been observed (202). Bone marrow transplantation has been used in patients with a variety of lysosomal storage diseases, including Gaucher disease (203). ‘Also, because the pathogenesis of Gaucher disease involves an accumulation of glucocerebroside, efforts to decrease produc- tion of this molecule may prove effective in tating the disease (204). Gene therapy is nor yer routinely available. Langerhans Cell Histiocytosis. | LCH refersto. disease complex characterized by abnormal proliferation of a marrow- dlrived histiocytic cell intially described by Langerhans in 1868 (205). ‘The skeletal manifestations of LCH were not described in dlecail in che literature until a report by Fraser in 1935 (205). In 1940, Lichtenstein and Jaffe coined che term eosinophilic granu- Joma of bone (205). One year later, Farber argued that cosino- philic granuloma of bone belonged to the same spectrum as Hand-Schiillr-Christian disease and Letterer-Siwe disease, Later Lichtenstein grouped all three conditions under the term histio- tosis X (205), In 1961, Birbeck used electron microscopy to dlcecr the oblong granules in Langerhans cells (205), but it was not until 1973 that Nezelof identified these granules in speci- ‘mens of histiocytosis X and recognized the disease as a prolif- cration of Langerhans crlls (206). ‘Today, che term LCH is the preferred name ofthe spectrum of conditions Approximately two to five cases of LCH are diagnosed per million persons per year (207, 208). The median age at diagnosis is berween I and 3 yeats, but the diagnosis can be made at any age from infancy to over 80 years (209). ‘There is.a slight male preponderance in the occurrence of the condi- tion (210, 211). Bone involvement is found in 80% to 97% of patients with LCH (208, 210-215). ‘The skull is the most often affected bone, followed by the femus, spine, ribs, man- dlible, and pelvis (216-218). Bone involvemenc in che hands and fect is uncommon (219, 220). Widespread involvement of ‘multiple organ systems can occur and carries a worse prognosis than isolated bone involvement (221). This chapter will dis- cus in detail the evaluation and management of bone lesions only, whether solitary or multiple. ‘The most common pattern of LCH at presentation in chil- dren is a solitary bone lesion without a soft-tissue mass (108, 213-215), Polyostotic involvement is seen at presentation in 10% oF cases (22). Presentation with a solitary bone lesion carries a favorable prognosis, and no deaths have been reported in this group (208, 213, 214, 223, 224), It is uncommon for patients who present with solitary bone lesions to develop sec- ondary bone lesions. However, a series with 52 patients found thar 30% of them developed secondary bone lesions, half of which were asymptomatic; the lesions were detected «luring rou- tine skeletal surveys (215). The prognosis in patients with multi- ple bone involvement without soft-tissue lesions is still favorable, with death occurring in 1 of 22 patients in one series (208) ‘The most common symptoms of LCH of bone are pain, swelling, or limping. The pain is usually of <2 months’ dura- tion. Symptoms such as lethargy; cough, dyspnea, and failure to thrive are uncommon, and may indicate widespread involvement. Because diabetes insipidus is che most com- ‘mon extraskeletal abnormality that develops in patients pre- senting with bone involvement (225), specific questioning is required regarding polyuria and. polydipsia. Skin rash, jaun- dice, hepatosplenomegaly, tachypnea, exophthalmos, hearing difficlties, and poor growth are important signs of widespread involvement. Physical examination may reveal 2 tender mass associated with a bone lesion in the skull, jaw, or extremities. ‘Torticolis, scoliosis, kyphosis, and neurologic impairment ‘may accompany a spine lesion (26-230). Plain radiographs are the first step in evaluating LCH of bone (Lig, 10-6). ‘The radiographic appearance of LCH of bone depends upon the phase of the disease and the site of ‘occurrence. In the early phase of the disease, the lesion may appear aggressive, with a permeative pattern of osteolysis and laminated periosteal reaction mimicking Ewing sarcoma (231-233). Later in the course of the disease, che lesion appears less aggressive, with well-defined margins, a narrow zone of transition, and mature or absent periosteal reaction (220). Widening of the medullary cavity with cortical thin- ning, scalloping, or penetration are also common findings in Jong bone lesions (220). In the long bones, the lesion typically cxists in the diaphysis or metaphysis. Epiphyseal involvement is uncommon (220, 234, 235). In the skull, LCH may give rise to alesion that appears round, radiolucent, and “punched-out” when viewed on plain radiographs (Fig. 10-7).