zy zy 0033-8389/01 $15.00 PEDIATRIC MUSCULOSKELETAL RADIOLOGY + .OO IMAGING OF METABOLIC BONE DISEASE AND MARROW DISORDERS IN CHILDREN Lisa J. States, MD The skeleton is the one of the largest organ systems in the body. Although they may seem static, the bones are dynamic structures and sites of physiologic activity. The bones are major repositories for calcium and phosphorus, reservoirs for hematopoietic marrow, and play key roles in calcium metabolism and the maintenance of blood cell homeostasis. In addition, the skeleton has a rich and extensive vascular network that makes it a frequent site for deposition of abnormal cells. This article reviews the pathophysiology, clinical presentation, and imaging findings of selected disorders of metabolic bone disease and bone marrow infiltration. Vitamin D, however, exists in a variety forms. Synthetic vitamin D (ergocalciferol) is used to a major extent in vitamin D therapy. Natural vitamin D (cholecalciferol) is added as a dietary supplement to milk and is also synthesized by the body. This synthesis occurs in the epidermis, where ultraviolet B radiation transforms 7-dehydrocholesterol into cholecalciferol. The formation of active vitamin D, 1,25-dihydroxycholecalciferol, however, requires additional synthesis, which includes hydroxylation in the liver at carbon 25 followed by hydroxylation in the proximal tubule of the kidney at carbon 1.’O Deficiency of vitamin D can result from inadequate exposure to the sun and disorders affecting the liver or kidney and has a profound effect on bone mineralization. Similarly, the lack of adequate calcium intake and diseases of the gastrointestinal tract and kidneys, which affect calcium metabolism, also cause abnormalities in bone mineralization. Bone mineralization occurs by both intramembranous and enchondral ossification. In intramembranous ossification, bone is formed directly from bone cells. In enchondral ossification, a calcified cartilage matrix is remodeled into bone. Enchondral ossification results in longitudinal growth of the bones and occurs at the cartilagenous growth plate (physis). zyx zyxwvu METABOLIC BONE DISEASE Normal bone development requires appropriate amounts of a variety of vitamins, minerals, and hormones, in particular, calcium, phosphorus, and vitamin D. Calcium and phosphorus are needed for the formation of crystals of hydroxyapatite, which are the mineral building blocks of bone. Vitamin D is crucial because it stimulates the active absorption of calcium from the intestines and resorption in the proximal tubules of the kidney and helps to maintain adequate levels of both calcium and phosphorus in the body. From the Department of Radiology, The Children’s Hospital of Philadelphia; and Department of Radiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania zyxwvutsrqpon ~ RADIOLOGIC CLINICS OF NORTH AMERICA VOLUME 39 * NUMBER 4 JULY 2001 749 750 zyxwvutsrq zyxwvu zyxwvutsr zyx STATES The physis is composed of columns of cartilage cells that are organized in four parallel zones: (1)resting, (2) proliferating, (3) hypertrophic, and (4) calcifying. The resting zone is a site of little activity and is closest to the epiphysis. The proliferating and hypertrophic zones are sites of active cartilage cell division and maturation, respectively. Adjacent to the metaphysis is the calcifying zone, also known as the zone of provisional calcification. This is where osteoid matrix is formed and mineralized. Bone remodeling with absorption of osteoid and calcium by osteoclasts occurs in the adjacent metaphyseal region called the ease or a unilateral process, such as infection or trauma. Accelerated or delayed bone age are also common manifestations of metabolic bone disease. The radiograph of the left hand provides not only a view of the metaphysealphyseal region of the distal radius and ulna, but also can be used to determine the patient’s skeletal age. Similarly, in children less than 1year of age the knee radiograph allows evaluation of the distal femoral and proximal tibia1 and fibular physes, and can also be used to determine skeletal age. primary spongiosa. Rickets On radiographs, the first three zones of the physis are lucent and the zone of provisional calcification is similar in density to the mature mineralized bone. Abnormalities of mineralization affect the appearance of the zone of provisional calcification. As a result, imaging of the skeleton and specifically the physis of the growing child plays a crucial role in the diagnosis and management of abnormalities of calcium-phosphorus metabolism. Mineralization and bone growth are also affected by endocrine abnormalities, such as hypothyroidism and hyperparathyroidism; enzyme deficiencies, such as hypophosphatasia; and mineral excess, such as lead poisoning, which can manifest as abnormalities of the physis and bone formation. The plain radiograph is the primary imaging tool for the evaluation of suspected metabolic bone disease. When assessing radiographs, general bone mineralization should be noted, as should specific abnormalities of the physeal region and the morphology of the bone. Additionally, in children, there are variable rates of growth and physiologic activity in different bones. The evaluation of a child with suspected metabolic bone disease begins with radiographs of the areas with the most rapidly growing bones, which varies depending on the age of the child. A chest radiograph is very useful for detecting abnormal mineralization in the infant and young child. Abnormalities of the metaphyseal-physeal region can be seen in the proximal humeri and anterior rib ends. In most children, the wrists and knees are regions of rapid growth and show the most change. A typical metabolic bone series includes views of the hands and the knees. Bilateral views of these regions are recommended to help determine if abnormal findings are caused by generalized metabolic dis- Rickets is characterized by inadequate mineralization of growing bones caused by diseases that alter vitamin D metabolism. Nutritional deficiency, renal disease, liver disease, and genetic enzyme defects can all lead to the development rickets. Causes of rickets are as follows: Younger than 6 months Hypophosphatasia Prematurity Primary hyperparathyroidism Prenatal factors Maternal hyperparathyroidism (poorly controlled) Maternal vitamin D deficiency Maternal renal insufficiency (poorly controlled) Older than 6 months Nutritional rickets: hypocalcemia and vitamin D deficiency Liver disease: impaired 25-vitamin D formation Chronic liver disease Extrahepatic biliary atresia Total parenteral nutrition Tyrosinemia Anticonvulsant therapy Malabsorption Celiac disease Inflammatory bowel disease Pancreatic insufficiency Renal tubular insufficiency: hypophosphatemia Vitamin D-resistant (familial rickets, x-linked) Vitamin D-dependent Fanconi’s syndrome Lowe syndrome Cystine storage disease Chronic renal disease: renal osteodystroPhY zy zyx IMAGING OF METABOLIC BONE DISEASE AND MARROW DISORDERS IN CHILDREN Pyelonephritis Polycystic kidney disease Chronic glomerulonephritis Renal tubular acidosis Most cases of rickets respond to vitamin D therapy and, if necessary, calcium supplementation. Rickets was initially recognized as a clinical entity during the mid-seventeenth century in Northern Europe when families were migrating to industrial centers, where sunlight was limited.1°On physical examination, infants with rickets may have enlargement of the wrists; knees; and rib ends (rachitic rosary). Bowing of the lower extremities is typically seen in the newly ambulating child and can be the first clinical finding alerting the physician to the possibility of rickets. The primary metabolic abnormality in rickets occurs at the zone of provisional calcification. Diminished calcification of cartilage cell columns, continued osteoid production by osteoblasts, and diminished resorption of osteoid and calcium because of impaired osteoclast function result in a widened, irregularly calcified physis. The contiguous metaphysis is also affected with metaphyseal broadening or "cupping" likely caused by stress at sites of ligament attachment, splaying of cartilage cells peripherally, and microfracturing of the primary spongiosa by herniation of cartilage into this a ~ e a . 4 ~ Radiographs of the long bones reveal widening and irregularity of all the physes, and fraying and broadening of the metaphyses. In addition, the bones are demineralized and the cortical outlines of the epiphyseal ossification centers become blurred or nonapparent (Fig. 1A and B). A chest radiograph may show physeal abnormalities of the rib ends and proximal humeri (Fig. 1C). In cases of ongoing, untreated rickets, deformities caused by softening of bone occur in the face of normal stress on the skeleton. Femoral and tibia1 bowing is most common. In children with poor muscle tone, genu valgum (knock knees) may develop. Findings in the pelvis include coxa vara and protrusio acetabuli. The thorax develops an hourglass shape. In the skull, postural molding and frontal bossing 0ccur.4~ Radiographs are extremely useful in detecting response to therapy. With vitamin D therapy, calcium is laid down in the zone of provisional calcification. On radiographs, the zone of provisional calcification appears as a 751 dense metaphyseal band (Fig. 2). This can be seen as early as 2 to 3 weeks after the initiation of therapy in children with nutritional rickets and after 2 to 3 months in children with renal Deformities caused by bone softening, however, may persist after successful treatment (Fig. 3). Nutritional rickets develops in children with inadequate levels of vitamin D. This deficiency may result from inadequate oral intake or insufficient exposure to sunlight. Consequently, it is not surprising that nutritional rickets occurs more frequently in conditions of limited sunlight, such as in the far northern latitudes and during the winter months. Cultural traditions limiting exposure to sunlight also play a key role in the development of nutritional rickets in the normal child.1° African American children in particular are at risk for rickets because of suboptimal vitamin D production from sunlight. Because the melanin pigment present in dark skin absorbs ultraviolet radiation, less is available for vitamin D production. As a result, dark-skinned individuals need more sunlight exposure to achieve adequate vitamin D production.'O Sunscreen also interferes with the production of vitamin D.l0 Nutritional rickets in a normal infant does not usually become clinically apparent before 6 months of age because of prenatal stores of vitamin D imparted by the mother. Breast-fed infants with marginal calcium stores are at greatest risk for developing rickets because of the low levels of vitamin D in breast milk. These infants require other sources of vitamin D through supplementation or sunlight exposure. When rickets does occur in children less than 6 months of age it may be caused by maternal problems, such as vitamin D deficiency,', 28 poorly controlled hyperparathyroidism, or renal insufficiency during pregnancy.26Alternatively, early presentation of rickets can be seen in premature infants'* or those with proximal renal tubular acidosis, primary hyperparathyroidism,22or hypophosphatasia.12 Vitamin D-resistant rickets, also known as familial hypophosphatemic rickets or x-linked hypophosphatemic rickets, is characterized by phosphate wasting by the proximal tubule and normal levels of active vitamin D. Insufficient phosphate levels impair mineralization. Progressive bowing of the lower extremities in a child over 18 months of age is the most common reason these children are z zyxwvutsr 752 zyxwvuts zyxwvutsrq STATES zyx zyx zyxw zyxw Figure 1. Nutritional rickets in a 19-month-old infant. A, Posteroanterior (PA) radiograph of the wrist shows diffuse, severe osteopenia, broadened metaphyses, and poorly defined widened physes. The radial epiphysis is barely visible because of severe osteopenia. B, Anteroposterior (AP) radiograph of the knee shows a similar degree of metaphyseal broadening with a hazy, irregular border and widened physis involving the distal femur and proximal tibia and fibula. The epiphyseal outlines are poorly defined. C, AP chest radiograph reveals ill-defined, flared anterior rib ends (cowed arrows). Note the marked demineralization of the scapulae. IMAGING OF METABOLIC BONE DISEASE AND MARROW DISORDERS IN CHILDREN zy z 753 zyxwvut zyxwvuts Figure 2. Partially healed rickets. A, AP radiograph of the knee shows broadening and cupping of the metaphyses including the fibula. Note the two dense bands (straight arrows) related to intermittent treatment. Irregularity is still seen in the distal, medial femoral metaphysis (curved arrow). B, AP radiograph of the knee after 6 weeks of treatment shows further healing and remodeling. The dense bands have migrated away from the growth plate. Note the persistent femoral bowing. brought to medical attention. Intravenous calcium therapy and high doses of vitamin D are required for treatment.6,33 According to Swischuk and Hayden,5I two different radiographic patterns (type A and type B) can be seen in this disorder. In type A, rachitic changes in the knees out of proportion to the wrists are common, a finding not described in any other type of rickets. In type B, a modeling defect with short, squat long bones and coarse bone trabeculation of the axial skeleton was found. This finding was seen predominantly in,males, thought to be a reflection of the x-linked inheritance. Vitamin D-dependent rickets, also known as pseudodeficiency rickets, is a hereditary form of rickets caused by impaired la - hydroxylation in the renal proximal tubule. These children have elevated or normal 25-hydroxyvitamin D and low levels of 1,25-hydroxyvitamin D. Symptoms of hypocalcemia develop before 2 years of age, often in infancy. Radiographic findings are indistinguishable from other forms of rickets.14 A n additional form of vitamin D-dependent rickets (type 11) is characterized by end-organ resistance to active vitamin D. These children have elevated levels of lr25-hydroxyvitamin D and hypophosphatemia. Symptoms of hypocalcemia manifest during the first few months of life.14 Another cause of rickets is renal tubular insufficiency, which impairs both tubular resorption of phosphate and la-hydroxylation of 25-hydroxyvitamin D. This is characteristic of Fanconi's syndrome with its various subtypes of hypophosphatemic vitamin Drefractory rickets. These children typically have a metabolic acidosis and other findings, such as aminoaciduria, glucosuria, or galactosemia. Hypophosphatemic rickets may also occur as a result of nephrotoxicity caused by ifosfamide therapy.49Rickets may also develop as a paraneoplastic syndrome with phosphate loss in the urine and is referred to as oncogenic rickets. In children, benign lesions, such as nonossifying fibroma, and he- zyxwvutsrq zyxwvu zyxwv 754 zyxwvuts zyxwvutsr STATES zyxwvutsrqp zyxw Figure 3. AP radiograph of the knees in a patient with a history of nutritional rickets after 1 year of treatment. The zone of provisional calcification is dense and the physes are normal in width. Note the femurs are still bowed, and there is tenting of the metaphysis. mangiopericytoma have been associated with this phenomenon.= The development of osteoporosis and rickets in children with gastrointestinal disorders is usually multifactorial. Malabsorption caused by celiac disease or Crohn's disease results in impaired absorption of calcium and vitamin D because of binding with malabsorbed fatty acids.=, 52 Chronic liver disease caused by biliary atresia or severe cholestasis may impair enterohepatic circulation of the precursor 25-hydroxyvitamin D. Direct interference with osteoblast function by unconjugated bilirubin has been described.*Anticonvulsant medications, such as phenytoin and phenobarbital, activate P-450 cytochrome oxidase causing accelerated conversion of 25hydroxyvitamin D to inactive metabolites contributing to the development of rickets in some children.33 Renal Osteodystrophy Renal osteodystrophy is a combination of osteomalacia, rickets (osteomalacia of growing bone), and secondary hyperparathyroidism that develops in children with chronic renal disease. Both glomerular and tubular dysfunction contribute to the development of this metabolic bone disease. Impaired glomerular function causes phosphorus retention, which results in hypocalcemia. Tubular dysfunction also causes hypocalcemia because of the impaired synthesis of 1,25-hydroxyvitamin D. Hyperparathyroidism then develops as the body's response to diminished serum calcium levels and causes a variety of manifestations, including demineralization of the bones. This results in osteomalacia, the development of which may be exacerbated by the presence of chronic acidosis, aluminum toxicity because of dialysis, or total parenteral nut r i t i ~ n .33~ , Bone changes caused by secondary hyperparathyroidism are well described. The classic features are subperiosteal resorption, endosteal resorption, and osteopenia. Subperiosteal resorption is best seen in the middle phalanges of the hands, upper medial proximal tibia, medial femoral neck, distal clavicle, distal radius and ulna (Fig. 4), and lamina dura of teeth.50The outer cortex has a hazy, ill-defined appearance. Endosteal resorption results in a lacy pattern of the inner cortex, referred to as cortical tunneling. Osteomalacia can appear as zy IMAGING OF METABOLIC BONE DISEASE AND MARROW DISORDERS IN CHILDREN zy z 755 provide adequate supplementation. Furthermore, diuretics used to treat bronchopulmonary dysplasia may contribute to calcium loss and liver and renal disease can also affect calcium and vitamin D stores.'* Radiographs of neonates with osteopenia of prematurity demonstrate a hypomineralized skeleton (Fig. 6). Rickets manifest as acute and healing fractures. The typical metaphyseal findings are not present because neonates are non-weight bearing and do not grow at a normal rate. After 2 months of age the knees and wrists may show signs of rickets.'* Primary Hyperparathyroidism Primary hyperparathyroidism is a rare disorder and is usually diagnosed within the first 3 months of life. It has been associated with maternal hypoparathyroidism.22Infants have severe hypercalcemia because of hyperplasia of all four parathyroid glands. Radiographs demonstrate osteopenia, subperiosteal bone resorption, and pathologic fractures (Fig. 7).45Removal of all parathyroid glands followed by autotransplantation of a small amount of glandular tissue is a promising therapy.45 zyxwvutsrqp Figure 4. PA radiograph of hand in a 3-year-old patient with renal osteodystrophy with secondary hyperparathyroidism and renal failure caused by polycystic kidney disease. There is subperiosteal resorption of the ulna, radius, and phalanges (arrows).Cortical tunneling is best seen in the metacarpals. zyxw z zyxwv Hypophosphatasia diminished density, or coarsening of the reThis is an uncommon inherited disorder sidual mineralized matrix and t r a b e ~ u l aIn .~~ characterized by deficiency of the enzyme aladdition, these children are at increased risk for slipped capital femoral epiphysis (Fig. 5).15 kaline phosphatase and accumulation of inorganic pyrophosphate. Excess inorganic pyrophosphate results in undermineralized bone with incomplete ossification of cartilage and Osteopenia of Prematurity metaphyseal regions. Large amounts of unPremature infants younger than 32 weeks' mineralized osteoid are present in all bones, gestational age and weighing less than 1500 especially in the metaphyseal regions.'* Soft tissue calcifications and nephrocalcinosis may g are at risk for the development of both osteopenia and rickets. These infants are undevelop because of hypercalcemia. Increased urinary excretion of phosphoethanolamine is able to achieve the skeletal retention of calcium and phosphorus that normally occurs also a classic feature of this disorder. during the third trimester, when 80% percent Because of a wide range of disease severity, of the skeletal mineralization takes place.l* four subtypes have been described based on The cause of these mineralization problems age of onset: (1) neonatal, (2) infantile, (3) childhood, and (4) adult. The neonatal form, is multifactorial. First of all, neonatal stores typically diagnosed during the first week of of calcium and phosphorus are limited and life, is uniformly fatal, although some infants intestinal absorption of minerals is poor. In have lived up to 6 months. The less severe addition, none of the customary sources of infant form manifests by 6 months but surnutrition (preterm milk, mature human milk, vival is variable.12In cases diagnosed during parenteral nutrition, or fortified formulas) childhood and adulthood, long-term outcome contain enough calcium and phosphorus to 756 zyxwvutsrq zyxwvutsrq STATES zyxwvu Figure 5. Renal osteodystrophy in a 3-year-old patient with prune belly syndrome and hip pain. A, AP radiographof hips shows coarse trabeculation of the bones. There is displacement of the right metaphysis superiorly caused by slipped capital femoral epiphysis (SCFE). The growth plate is vertical rather than horizontal. Coxa vara is present on the left. 6,A coronal gradient echo MR image shows the cartilaginous growth plate and epiphyses as increased signal. Coxa vara is well-demonstrated on the left, and SCFE is seen on the right. The right metaphysis is irregular and tongues of cartilage extend into the metaphysis. A medial bone fragment (arrow) is present. IMAGING OF METABOLIC BONE DISEASE AND MARROW DISORDERS IN CHILDREN zy z 757 zyxwvutsrq Figure 6. Osteopenia of prematurity. AP radiograph of chest in this 3-monthold ex-premature infant with bronchopulmonary dysplasia shows diffuse osteopenia; there is periosteal new bone along the humerus caused by a fracture. Figure 7. Primary hyperparathyroidism in a newborn. AP radiograph of chest shows diffuse osteopenia, handlebar clavicles, wavy deformed ribs, and scattered healing rib fractures (arrows). 758 STATES zyxwvutsrqp is unpredictable. Currently, therapy is supportive because there is no known treatment. Affected neonates may be born with hypotonia, bowed long bones, and short limbs. Radiographs reveal short, irregular long bones with poor ossification. Bowed long bones and fractures are often present. Focal rarefaction in the metaphyses (Fig. 8) because of clusters of unmineralized osteoid can be seen at any age. This classic, fairly specific radiographic finding can be used to distinguish this disorder from other causes of severe undermineralization and bowing, such as osteogenesis imperfecta and florid rickets.", l2 Lead Intoxication to the bony matrix and impairs function of the osteoclast. Continued osteoblastic activity and failure of bone resorption at the zone of provisional calcification results in a dense metaphyseal band (Fig. 9).25These lead lines can be seen at serum lead levels greater than 50 kg/dL.2 The presence or absence of a lead line in the fibula is a useful adjunct to establish the presence or absence of lead poisoning.46With prolonged exposure, bony modeling is impaired and underconstriction leads to an Erlenmeyer flask deformity (Fig. 10). Other heavy metals, such as bismuth, mercury, and phosphorus, and cytotoxic medications during pregnancy produce identical findings.17 zyxw Prostaglandin Periostitis Children aged 1 to 3 years are at greatest risk for lead poisoning, usually from inhaled lead dust. A less common, but still important, cause of significant poisoning is ingestion of lead paint ~hips.2~ Symptoms typically occur at serum lead levels greater than 50 pg/dL, well above the clinically acceptable level of 10 p,g/dL. Radiographic evaluation of these children may include an abdominal radiograph to detect the presence of paint chips or knee radiographs to detect lead lines. Excess lead binds Long-term prostaglandin El infusion used to maintain the patency of the ductus arteriosus in infants with ductal-dependent congenital heart disease has an unclear effect on bone metabolism. Because prostaglandins are usually inactivated during first pass through the lungs, children with right to left shunts have high levels of circulating prostaglandins. With long-term therapy radiographs show mild (Fig. 11A) to exuberant (Fig. 11B) periosteal new bone formation. Sites most involved are Figure 8. Hypophosphatasia in a newborn. AP radiograph of chest shows diffuse osteopenia and wavy deformed ribs. Note the bowed proximal left humerus and the focal, ovoid area of osteopenia (arrows), which is characteristic of hypophosphatasia. z IMAGING OF METABOLIC BONE DISEASE AND MARROW DISORDERS IN CHILDREN zy z 759 zyxwvu Figure 9. Lead intoxication. AP radiograph of both legs shows dense metaphyseal bands in all of the long bones. 760 zyxwvutsrqp STATES zyxwvuts Figure 10. Severe prolonged lead intoxication. AP radiograph of both knees shows at least four dense bands of varied width in the femur (arrows). An An Erlenmeyer flask deformity of undertubulation is present in all bones. Figure 11. Prostaglandin periostitis. A, AP radiograph of the leg shows moderately thick periosteal new bone formation along the diaphysis of both the tibia and fibula. B, AP radiograph of thigh and upper leg in another patient shows a cloak of severe periosteal new bone formation that engulfs the femur, tibia, and fibula. IMAGING OF METABOLIC BONE DISEASE AND MARROW DISORDERS IN CHILDREN the femur, humerus, ribs, scapula, tibia, and fibula. Widening of the cranial sutures may also develop.41Findings resolve after cessation of therapy. The radiographic finding of periostitis, however, is nonspecific and the differential diagnosis includes congenital syphilis, nonaccidental trauma with subperiosteal bleeding, vitamin C deficiency, congenital leukemia, metastatic disease, and Caffey's disease.20,41 zy 761 Juvenile Idiopathic Osteoporosis An interesting metabolic bone disorder of unknown cause is juvenile idiopathic osteoporosis. This is a diagnosis of exclusion in the prepubertal child with severe osteopenia and recurrent fractures. Muscle weakness, pain in limbs and joints, and refusal to walk are common symptoms. The most common presentation is kyphoscoliosis because of compression fractures (Fig. 14). Pathologic fractures of the metaphyses of the long bones are also common. Bone softening may result in acetabular protrusio (see Fig. 14). The clinical course is self-limited with remission occurring during or after puberty. With remission, bone mineralization returns to norma1.16 The differential diagnosis includes juvenile rheumatoid arthritis, leukemia, and osteogenesis imperfecta. zyxwvut Hypothyroidism Congenital hypothyroidism causes severe retardation of bone maturation and disturbed endochondral bone formation resulting in unique morphologic changes.55 Skeletal changes of a lesser degree can also be seen in acquired hypothyroidism. The mechanism by which this occurs is unclear but because both growth hormone and somatomedin levels are also decreased these hormone deficiencies also likely play a role.31Fortunately, because of the institution of neonatal screening, delayed diagnosis of hypothyroidism is now uncommon. Although radiographic findings of delayed maturation may be seen at birth, they are more severe when the diagnosis is delayed. Radiographs of the skull, pelvis, and hands show the most striking abnormalities. Skull radiographs may reveal an enlarged sella because of pituitary enlargement, widening of the sutures (Fig. 12A), and wormian bones. Tubular bones of the hands (Fig. 12B) may develop a diminished and narrow medullary cavity with a thickened overlying cortex or short, broad metacarpals with hypoplastic middle, and terminal phalanges. In the pelvis, epiphyseal dysgenesis, a cardinal feature of hypothyroidism, is well seen in the femoral heads. Impaired growth and delayed maturation of the epiphyses results in a spotty, fragmented appearance with irregular margins and uneven density (Fig. 13).55As children age, coxa vara and a flattened, irregular femoral head can be seen. Secondary changes in the acetabular roof may develop giving an appearance of the acetabulum that is similar to that seen in developmental dysplasia of the hip. Older untreated children, with either congenital or acquired hypothyroidism, are at increased risk for slipped capital femoral epiphy~is.~~ MARROW DISORDERS The marrow can be altered by infiltration of invading cells or proliferation of its own elements. Proliferation of abnormal leukocytes in the marrow is characteristic of acute lymphoblastic leukemia, the most common cause of malignant marrow infiltration in children. Neuroblastoma is the most common form of metastatic, malignant bone marrow disease in children. Inherited anemias, such as sickle cell disease, sideroblastic anemia, and thalassemia, all lead to hyperplasia of normal marrow elements. Gaucher 's disease also results in marrow packing because of enlargement of macrophages containing excess cellular substrates. Although radiographs remain the initial imaging study in these patients, MR imaging has become a useful tool because it provides superior tissue contrast and microscopic information. An understanding of normal marrow signal and age-related changes in distribution is necessary for accurate interpretation. zyxw Normal Marrow on Magnetic Resonance Imaging On MR imaging, hematopoietic red marrow is generally equal to muscle on T1- and T2-weighted images. On T1-weighted images, slight hypointensity or hyperintensity is normal. Fatty marrow is high in signal intensity on T1-weighted images even with a percent- 762 STATES zyxwvutsrqp zy zyxwvutsr Figure 12. Congenital hypothyroidism in a 3-month-old patient. A, Lateral radiograph of the skull shows widened coronal (solid arrows) and lambdoid sutures (open arrows) and significant osteopenia. B, AP radiograph of the hand shows broad proximal and middle phalanges and an irregular, illdefined radial epiphysis. age of fat as low as 20%.13,21 During childhood conversion of red to yellow marrow occurs in a predictable patternz9 In general, conversion begins in the hands and feet of the very young, followed by the distal long bones, proximal long bones, flat bones, and the vertebral bodies. In a single long bone, the pattern of conversion is diaphyseal, then distal metaphyseal. Proximal metaphyseal conversion occurs later, during young adulthood. The ossified epiphyses and trochanters virtually always contain fatty marrow signal. The pattern of marrow conversion in the femur has been well described by Moore and D a w s ~ n In . ~ the ~ diaphysis, conversion from hematopoietic to fatty marrow begins after l year of age and is complete by 10 years of age. During conversion, the marrow can have patchy slightly increased signal on T1-weighted images. In the very young child, low or intermediate T1 signal can be seen in the diaphysis. Often, by 5 years of age homogeneous fatty marrow is seen in the diaphysis. When conversion is complete, the marrow has a homogeneous increased signal on T1-weighted images. After 10 years of age, low or intermediate signal in the diaphysis is abnormal and may be the result of either cellular infiltration or marrow reconversion. The distal metaphysis undergoes conversion next, between 11 and 15 years of age. By 16 years of age, homogeneous increased signal on T1-weighted images is seen in the epiphyses, diaphysis, and distal metaphysis. Low T1 signal in the distal metaphysis beyond 15 years of age should be considered abnormal. Low T1 signal in the proximal metaphyses is normal throughout childhood. z zyxwv Gaucher's Disease Gaucher's disease is a rare, heritable metabolic disorder characterized by deficient activity of the lysosomal hydrolase p-glucosidase. Accumulation of the lipid substrate, glucosylceramide, occurs predominantly in the lysosomes of the monocyte-macrophage system. These lipid-laden cells are referred to as Gaucker's cells.44 IMAGING OF METABOLIC BONE DISEASE AND MARROW DISORDERS IN CHILDREN zy z 763 zyxwvu Figure 13. Congenital hypothyroidism in a 3-year-old patient with epiphyseal dysgenesis. AP radiograph of the pelvis shows lucency mixed with sclerosis involving both femoral heads. Note the small size of the ossification centers. Figure 14. Juvenile osteoporosis in a 15-year-old patient. AP radiograph of the pelvis shows severe osteopenia. There are concave end plate compression fractures characteristic of osteoporosis. Significant acetabular protrusio is present caused by bone softening. Bowing of the femur is seen at the site of an old fracture. 764 zyxwvutsrq STATES Three forms of Gaucher’s disease have been described. The skeletal system is involved only in type 1, the most common type. In this type, Gaucher’s cell accumulation also occurs in the liver and spleen resulting in hepatosplenomegaly and hypersplenism. Bone marrow infiltration, however, is a major source of complications and significant morbidity in these patients.44 Therapy is usually supportive and may include blood transfusion, splenectomy, and bone marrow transplant. A promising therapy with enzyme replacement (glucosylceramidase) has been shown to reverse hepatosplenomegaly and prevent or slow additional marrow infiltration. The hope is the prevention of irreversible skeletal damagej3 Skeletal changes are the result of progressive medullary infiltration of the marrow with Gaucher’s cells. This marrow packing leads to modeling defects and vascular compromise resulting in marrow infarction. Avascular necrosis occurs in the femoral and humeral epiphyses but the cause is unclear.36 In patients with Gaucher’s cell infiltration, plain radiographs may reveal osteopenia; medullary expansion; and remodeling defects (Erlenmeyer flask deformity). Osteopenia results from diffuse cortical and trabecular bone loss because of marrow packing and trabecular resorption. A coarsened trabecular pattern can be seen. The vertebral bodies and diaphyses of long bones are most affected. In moder- ate involvement, focal lytic or sclerotic lesions caused by marrow infarction are seen. Severe cases have pathologic fractures in the long bones and vertebral bodies and osteonecrosis of femoral or humeral heads. Osteoarthritis and cord compression from vertebral body collapse can occur, but are uncommon complications in children. MR imaging has proved useful in evaluating the degree of marrow infiltration and its complications. Infiltration with Gaucher ’s cells is detected best on T1-weighted images. Gaucher’s cell infiltration is intermediate signal, similar to that of hematopoietic marrow. Using T1-weighted images, the presence of fatty marrow increases the conspicuity of the lesion. Early infiltration of the marrow with Gaucher’s cells often appears patchy and irregular, and may be difficult to differentiate from normal marrow in the young child. In the femur, infiltration begins in the proximal femoral metaphysis and progresses distally to the diaphysis and distal femur. In more severe cases, cellular infiltration of the epiphyses occurs, first in the proximal femoral epiphysis, then the greater trochanter, and last the distal femoral epiphysis (Fig. 15). Spine involvement also has a patchy distribution. MR imaging techniques using chemical shift imaging can be used to quantify the amount of fatty marrow repla~ement.~~ Quantitative CT can also provide information regarding diminished trabecular bone mass and z zyxwvutsrq zyxwvutsr Figure 15. Gaucher disease in a 16-year-old patient with hepatosplenomegaly and lower extremity pain. A, Coronal T1-weighted MR image reveals marrow replacement in the epiphyses, trochanters, and diaphyses of the femurs. Note the heterogeneous marrow signal. Within the diaphyseal marrow are arcs and rings of low signal. 6, Coronal T1-weighted image of the distal femurs and knees shows that the distal femoral and proximal tibia1 epiphyses are replaced, and there is early Erlenmeyer flask deformity. IMAGING OF METABOLIC BONE DISEASE AND MARROW DISORDERS IN CHILDREN fat content.44These fat fraction analysis techniques serve an important role in evaluating the progress of patients on enzyme replacement therapy. Avascular necrosis and bone infarcts, common complications of Gaucher's disease, are easily seen on MR imaging. Ischemic necrosis of the humeral and femoral heads is low signal intensity on T1-weighted images and mixed signal intensity on TZweighted images with a dark rim surrounded by a high signal intensity rim. Marrow infarcts in the acute phase are indistinguishable from osteomyelitis and have increased signal on T2-weighted images because of edema. Periosteal new bone formation is also seen at 10 to 14 days. Nonacute marrow infarcts are easily recognized as dark rings of signal void on all sequences with regions of increased signal on T2-weighted sequences. zy 765 although young children can repopulate their marrow and lay down new bone. Plain radiographs during an acute bone crisis are normal except for soft tissue swelling. Radiographic findings become apparent 10 to 14 days after the insult and include osteopenia, periosteal new bone formation, and a permeative pattern (Fig. 16), which are indistinguishable from infection. Chronic changes include cortical thickening and areas of sclerosis. Avascular necrosis in the epiphyses of the humeral and femoral heads occurs most commonly in the sickle C hemoglobinopathy. The radiographic findings are indistinguishable from other causes of avascular necrosis (Fig. 17). Patchy sclerosis and epiphyseal collapse develop commonly. Complications of zyxwvu Sickle Cell Disease Sickle cell disease, the most common hemoglobinopathy, comprises all conditions in which the abnormal hemoglobin S is combined with itself or other hemoglobin types, such as C, D, and E, or thalassemia. Each combination has differing degrees of anemia, marrow hyperplasia, and bone involvement. The complications of sickling most commonly affect children with hemoglobin SS, hemoglobin SC, and hemoglobin S-thalassemia. The skeletal changes in sickle cell disease reflect two pathologic processes: (1) replacement of the marrow and trabecular bone with marrow hyperplasia and (2) infarction of bone and bone marrow. Extensive expansion of bone marrow into the diaphyses of the long bones and axial skeleton results in radiographic changes seen predominantly in the skull, spine, and long bones. Proliferation of marrow cells, predominantly the erythrocytic line, results in widening of haversian canals and intertrabecular spaces, thinning both cortical and trabecular bone. In young' children, nonspecific coarse trabeculation is often the only radiographic abnormality. In the setting of anoxia, sickling develops in the sinusoids of the congested cellular marrow. Even if infarcts are small, recurrent episodes are cumulative. Most affected are the lower extremities, followed by the upper extremities and the axial skeleton. The end result of infarction is usually fibrosis, zyxwv Figure 16. Acute marrow infarction in a 5-year-old patient with sickle cell disease. AP radiograph of the humerus 10 days after onset of acute arm pain shows osteopenia, periosteal newborn formation, and a permeative pattern. A technetium white blood cell scan was normal. Also note sclerosis mixed with lucency in the humeral head caused by prior avascular necrosis. 766 zyxwvutsrq zyxwvutsrq STATES zyxwvu Figure 17. Bilateral avascular necrosis in a 15-year-old patient with sickle cell disease. A, Coronal T1-weighted image demonstrates very low signal in both femoral heads caused by trabecular fractures. In the subchondral region, intermediate signal is seen in the left femoral head, and high signal is seen in the right femoral head, possibly representing hemorrhage. B, Coronal T2-weighted coronal image demonstrates heterogeneous signal with small areas of focal increased signal. These high signal areas likely represent areas of necrosis. IMAGING OF METABOLIC BONE DISEASE AND MARROW DISORDERS IN CHILDREN bone infarction are secondary osteomyelitis, growth disturbance, and rarely, neoplasm.39 Ischemic dactylitis (hand-foot syndrome) is the earliest manifestation of sickling. Dactylitis is typically encountered between 6 and 18 months of age, at a time when active hematopoiesis occurs in the hands and feet and sickle hemoglobin replaces fetal h e m ~ g l o b i nWith .~~ the onset of dactylitis, radiographs reveal soft tissue swelling. By 10 days, periosteal new bone forms aIong the diaphysis. Inflammation and edema elevate the loose periosteum of young children. This elevation may impair cortical blood flow leading to medullary ischemia and infarction. When this occurs, radiographs reveal bone destruction and patchy new bone formation (Fig. 18). In the spine, recurrent ischemia and microinfarction in combination with erythroid hyperplasia result in unique morphologic changes of the vertebral body end plate. It has been proposed that recurrent. ischemia impairs endochondral bone formation in the central portion of the growth plate leading to the development of this unique finding.39 zy 767 zyxwv zyxw Figure 19. Lateral radiograph of chest shows classic vertebral end plate abnormalities in an 18-year-old patient with sickle cell disease. Note the flat central end plate depressions in the mid- and lower thoracic spine. There is gradual development of a flat, central end plate depression of both the superior and inferior end plates. The shape has been described as fat capital H, lincoln log, and fish vertebrae.40Lateral radiographs of the spine show these findings best in the mid and lower thoracic vertebrae (Fig. 19). Common during childhood, these abnormalities have been reported in children as young as 9 months of age39but are usually encountered after 10 years of age. Findings progress until growth ceases. This appearance has also been reported in Gaucher 's disease,19,48 homocystin ~ r i a , 5and ~ thalassemia major.7 Additional radiographic findings are seen in the skull, where islands of hyperplastic marrow appear radiographically as scattered focal lucencies in a granular or patchy pattern. In addition, there is diploic widening and thickening of the outer table, which are most pronounced in the frontal and parietal regions and can be seen toward the end of the first year of life.4O zyxwvutsr Figure 18. Ischemic dactylitis in a 10-month-old patient with sickle cell disease. This infant had pain in both feet and both hands. AP radiograph of the hand reveals a moth-eaten pattern in the fourth metacarpal caused by marrow and cortical infarction. A thick layer of periosteal new bone is seen (arrowheads). A growth recovery line is seen in the distal radius. Beta-Thalassemia Beta-thalassemia, an inheritable disonkr seen predominantly in people of Mediterra- 768 zyxwvutsrqp STATES Figure 21. A 17-year-old patient requiring frequent transfusions for P-thalassemia. Frontal chest radiograph reveals a lacy trabecular pattern throughout the bones and widening of the ribs. A pleural-based left apical soft tissue mass in the left thorax is caused by extramedullary hematopoiesis. zyxwvutsrqp Figure 20. Beta-thalassemia in a 12-year-old patient. PA radiograph of hand shows widening of the medullary cavities and thinning of the cortices caused by marrow expansion, which is most prominent in the metacarpals. nean descent, was initially described by Cooley et al.'O It is characterized by deficient synthesis of the beta chains of hemoglobin. In addition, excess alpha chains precipitate in erythrocytes and erythroblasts leading to hemolysis and ineffective hematopoiesis. p-Thalassemia is subdivided into minor (heterozygous), major (homozygous),and intermediate (heterozygous) types. The most severe skeletal changes occur in thalassemia major. Severely diminished hemoglobin production results in a chronic microcytic hemolytic anemia and estimated 5- to 30-fold increases in marrow activityz4,37 more severe than in homozygous sickle cell disease. This results in distinctive radiographic findings. The characteristic radiographic abnormalities manifest as early as the second year of life and become more distinct with age. Diffuse marrow hyperplasia involves the entire skeleton. The tubular and long bones become expanded, the cortex thinned, and the trabeculae coarsened (Fig. 20). With conversion of red to yellow marrow, resolution of long bone changes O C C UPremature ~S.~ fusion of the epiphyseal ossification centers at the humerus has been described. Widened nutrient foramina are seen in the phalanges and metacar- pals. This is thought to be caused by the increased blood supply to hyperplastic marrow. These changes have also been reported in sickle cell disease, hemophilia, and Gaucher's disease.23 In the skull, the diploic space widens, the zyxwvu Figure 22. Beta-thalassemia with vertebra plana. Lateral radiograph of chest shows increased anterior posterior dimension and flattening of the vertebral bodies. IMAGING OF METABOLIC BONE DISEASE AND MARROW DISORDERS IN CHILDREN zy zy 769 of the vertebral body caused by loss of vertical trabecula, which may result in vertebra plana (Fig. 22) throughout the spine.5 Leukemia Acute lymphoblastic leukemia, most common in children aged 2 to 5 years, is associated with several radiographic abnormalities. Most bone lesions in leukemia result from proliferation of leukemia cells. Diffuse osteopenia is the most common radiographic finding. On the lateral chest radiograph vertebral body wedging may be seen (Fig. 23). In the long bones, demineralization commonly occurs in the metaphysis and may be focal or diffuse and with severe infiltration destruction of the cortex occurs (Fig. 24). Proliferation of cells beneath the periosteum causes elevation of the periosteum and a thin shell of periosteal new bone forms creating an appearance similar to hemorrhage, which often coexists. In addition, radiolucent metaphyseal zyxwvutsrqp Figure 23. Leukemia in a 6-year-old patient with anemia and failure to thrive. Lateral chest radiograph taken at presentation reveals severe diffuse osteopenia. Anterior wedging is seen in several vertebral bodies. outer table thins, and the trabecula resorb. Occipital sparing occurs because of lack of marrow. In late stages, the trabecula may appear as vertical striations described as a hairon-end appearance. Overgrowth of the maxilla impairs pneumatization of the maxillary sinuses. These findings are fairly specific for thala~semia.~ The ribs become widened and osteopenic (Fig. 21). Focal lucencies, cortical erosions, and subcortical lucencies may occur. A ribwithin-rib appearance has been described. During adolescence the rib lesions may regress spontaneously. Transfusion therapy has also been shown to be associated with regression of rib abnormalitie~.~~ Vertebral body abnormalities differ from those seen in sickle cell disease. Because of the more significant marrow packing, widening of the bone develops in the anteroposterior dimension*There is a coarsened bony texture caused by selective diminution of non-weight bearing trabeculae and flattening Figure 24. Leukemic infiltration of the radius. AP radiograph of the distal radius and ulna reveals a moth-eaten pattern and scattered lytic lesions throughout both bones. A lucent band is seen in the distal radius. Note the normal zone of provisional calcification. 770 zyxwvutsrq STATES zyxwv zyxw zyxwvutsr Figure 25. Lymphoma in a 15-year-old patient with spine pain. A, Sagittal T1-weighted image demonstrates slightly decreased signal in the third and fourth lumbar vertebra (arrows). Low signal hematopoietic marrow is seen throughout. B, Sagittal TP-weighted image demonstrates increased signal in the same vertebral bodies. zyxwv bands with a normal zone of provisional calcification (see Fig. 24) are a common finding in children with acute leukemia and are usually related to the stress of the disease rather 35, 42 than leukemic infiltrati~n.~~, Leukemic infiltration of the bone marrow may be detected on MR imaging and is indistinguishable from other types of metastatic disease. Lesions are decreased signal on T1weighted images and increased signal on T2weighted images (Fig. 25). Using fat-suppressed fast T2-weighted imaging, the lesion is higher signal than hematopoietic marrow. T2-weighted inversion recovery images can be particularly helpful because normal marrow appears relatively hypointense to muscle, whereas abnormal infiltrated marrow has significantly higher signal intensity (see Fig. 25). Contrast-enhanced T1-weighted imaging is occasionally helpful but can be misleading if used to evaluate the spine of young children. During development, contrast enhancement of the normal spine can occur in children less than 7 years of age.53 Imaging children after therapy can be chal- lenging because of the similarity between regeneration of red marrow and residual disease. This can occur after chemotherapy or bone marrow transplantation and in regions of radiation therapy, although fibrosis is more common. Reconversion to red marrow may also occur with resolution of stress from systemic illness. Symmetry is typically caused by marrow regeneration. If findings are asymmetric, however, a biopsy may be necessary to exclude residual or recurrent disease.a,32 SUMMARY There are a wide variety of metabolic and infiltrative diseases that involve the bones. Conventional radiography is the primary imaging examination for the initial evaluation of most of these disorders. MR imaging, however, provides detailed information about the bone marrow and is gaining an increasingly important role in the management of disorders of bone marrow infiltration. zyxwvu zy IMAGING OF METABOLIC BONE DISEASE AND MARROW DISORDERS IN CHILDREN References 1. Begum R, Continho ML, Dormandy TL: Maternal malabsorption presenting congenital rickets. Lancet 1:1048-1052, 1968 2. Blickman JG, Wilkinson RH, Graef J W The radiologic ”lead band” revisited. AJR Am J Roentgenol 146245247, 1986 3. 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AJR Am J Roentgenol 91:955-972, 1964 51. Swischuk LE, Hayden CK Jr: Rickets: A roentgenographic scheme for diagnosis. Pediatr Radiol 8:203208,1970 52. Sylvester FA: Bone abnormalities in gastrointestinal and hepatic disease. Curr Opin Pediatr 11:402-407, 1999 53. Sze G, Bravo S, Baierl P, et al: Developing spinal column: Gadolinium-enhanced MR imaging. RadiolOW 180497-502, 1991 54. Westerman WP, Greenfield GB, Wong PWK ”Fish vertebrae,” homocystinuria, and sickle cell anemia. JAMA 230~261-262,1974 55. Wietersen FK, Balow RM: The radiological aspects of thyroid disease. Radiol Clin North Am 5:255-266, 1967 56. Wilkins L: Epiphyseal dysgenesis associated with hypothyroidism. Am J Dis Child 61:13-34, 1941 zyxwv zyx Address reprint requests to Lisa J. States, MD Department of Radiology The Children’s Hospital of Philadelphia 34th and Civic Center Boulevard Philadelphia, PA 19104-4399 e-mail: statesQemail.chop.edu