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1
Department of Diagnostic Radiology and Organ Imaging, Prince of Wales
Hospital, The Chinese University of Hong Kong, Shatin, N. T., Hong Kong.
2
Department of Paediatrics, Prince of Wales Hospital, The Chinese University of
Hong Kong, Hong Kong.
3
Department of Orthopaedics and Traumatology, Prince of Wales Hospital, The
Chinese University of Hong Kong, Hong Kong.
Received November 22, 1999;
accepted after revision May 8, 2000.
Address correspondence to Y.-I. Chan.
Abstract
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MATERIALS AND METHODS. Thirty-five patients with homozygous ß-thalassemia major who were undergoing regular transfusions and chelation therapy underwent coronal T1-weighted MR imaging of the femur, including the femoral head and the distal femoral epiphysis. Additional coronal fat-saturated dual-echo and sagittal T1-weighted images of the distal femur and patella were obtained in 11 patients who were suspected of having distal femoral lesions on the basis of the coronal T1-weighted images of the entire femur.
RESULTS. No dysplastic change was detected in the proximal femur on coronal T1-weighted images. In 22 distal femurs of 11 patients, the following abnormalities were detected on MR imaging: blurred physeal-metaphyseal junction (n = 22), distal metaphyseal areas of hyperintensity (n = 21), physeal widening (n = 18), metadiaphyseal lesions (n = 11), epiphyseal lesions (n = 10), and patellar lesions (n = 2). Physeal widening and distal metaphyseal hyperintense areas were all more pronounced peripherally. Of the 21 distal metaphyseal hyperintensities, lateral abnormalities were larger than medial abnormalities in 16. Of the 18 distal femurs in which physeal widening was detected, the lateral widening was more marked than the medial widening in 12. Patients with MR imaging evidence of bone dysplasia have a significantly (p = 0.003) greater height reduction than patients without such evidence of bone dysplasia.
CONCLUSION. Deferoxamine-induced bone dysplasia in the distal femur and patella is represented by a spectrum of morphologic changes in the epiphysis, physis, metaphysis, and metadiaphysis on MR imaging.
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The degree of iron overload can be assessed at liver biopsy or noninvasively with MR imaging [6]. Deferoxamine-induced bone dysplasia can be diagnosed when characteristic metaphyseal sclerotic and radiolucent foci are present on conventional radiography [1,2,3,4, 7]. Radiographic abnormality lags behind pronounced growth failure by 2-3 years [5]. MR imaging, with its unique ability to image cartilage, is a valuable technique in the evaluation of physeal and metaphyseal lesions [8,9,10]. Nonetheless, we are aware of only one previous case report in the English literature on the MR imaging appearance of deferoxamine-induced bone dysplasia [11]. Our objective was to investigate the MR imaging appearance of deferoxamine-induced bone dysplasia of the femur and patella, and its relationship to growth retardation. The femur was selected for investigation for the following reasons: the distal femoral metaphysis is a frequent site of involvement in deferoxamine-induced bone dysplasia [4]; the distal femoral growth contributes to 40% of the overall length of the lower limb [12]; and genu valgum is a well-documented secondary complication [5, 6] that frequently requires surgery for correction [7].
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The study population comprised 35 patients (19 males, 16 females with an age range of 6-20 years [mean, 12 years]) who had homozygous ß-thalassemia major and were receiving regular blood transfusions and chelation therapy with deferoxamine. The deferoxamine dose did not exceed 50 mg/kg of body weight per day (average chelation dose, 32.3 ± 8.04 mg/kg per day). The duration of deferoxamine therapy ranged from 3 years 11 months to 16 years 8 months (mean, 8.1 years). All patients were examined using a 1.5-T MR imager (Gyroscan ACS NT; Philips Medical System, Best, The Netherlands). Coronal spin-echo T1-weighted MR imaging of both femurs, including the femoral heads and the distal femoral epiphyses, was performed using a body coil with the following parameters: field of view, 450 mm; TR/TE, 450/15 msec; section thickness, 10 mm with a 20% gap; and number of excitations, two. In 11 patients with physeal or metaphyseal abnormalities suspected on these coronal images, the distal femur and patella were further studied with a knee coil using coronal turbo spin-echo selective fat-saturation (spectral inversion recovery) dual-echo sequences (TR/first-echo TE, second-echo TE, 2000/20, 60; turbo factor, 6), and sagittal spin-echo T1-weighted sequences (TR/TE, 475/15). Both sequences used a 230-mm field of view, a section thickness of 4 mm with a 10% gap, and two excitations.
The analysis of MR imaging findings was based on the 11 patients (5 females, 6 males; age range, 10-17 years; mean, 13.5 years) with evidence of abnormalities of the distal femur. All MR images were interpreted without knowledge of the growth status of the patients.
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On the sagittal T1-weighted and coronal fat-suppressed proton density-weighted images, abnormalities were detected in the distal femoral epiphysis, physis, metaphysis, metadiaphyseal region, and patella. Bilateral abnormalities were seen in the physes (11/11 patients, 100%), metaphyses (10/11 patients, 90.9%), and metadiaphyses (5/6 patients, 83.3%). The distribution of the abnormalities is listed in Table 1. The regional morphologic characteristics are summarized in the following text.
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Epiphysis
Abnormalities seen within the epiphyses (n = 6, 60%) included
irregular foci of hypointensity on T1-weighted images and hyperintensity on
fat-saturated proton density-weighted images, located in the central or
subchondral zone of the bony epiphysis or at the epiphyseal-physeal junction
(Fig.
3A,3B,3C,3D).
Hypointense circumscribed components on both T1-weighted and fat-saturated
proton density-weighted images were also noted in the central bony epiphysis
in two of these patients. Irregularity in the bony epiphyseal outline facing
the physis was detected in five distal femurs (50%)
(Fig. 2B).
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Physis and Physeal-Metaphyseal Junction
Blurring of the physeal-metaphyseal junction was detected in all 22 distal
femurs (100%) on fat-saturated proton density-weighted images. This was shown
as a loss of definition of the hypointense zone of provisional calcification
and osteoid formation of the metaphysis by the increase in signal intensity in
the juxtaphyseal metaphysis (Fig.
2B), or as a tonguelike extension of the physeal hyperintensity
into the distal metaphysis (Fig.
1B). In the latter, the physis, intermediate in signal intensity
on T1-weighted images and hyperintense on fat-saturated proton
density-weighted images, also appeared widened. Physeal widening was detected
in 18 distal femurs (81.8%). The widening was located at the periphery of the
physis in 14 (77.8%) of the 18 femurs (Figs.
2B and
3D) and centrally in four
(22.2%). Of the 14 cases of peripheral physeal widening, the lateral widening
was more marked than the medial widening in 12 cases (85.7%). The physeal
widening was confined to the lateral aspect in two (14.3%).
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Distal Metaphysis
Distal metaphyseal changes near the physis were hyperintense on
fat-saturated proton density-weighted images, and they more frequently
involved the peripheral and lateral portions
(Fig. 3D). Of the 21 involved
distal metaphyses, the lateral hyperintensities were larger than the medial
ones in 16 (76.2%). Markedly hyperintense foci consistent with pseudocystic
change were detected in 15 distal metaphyses (71.4%)
(Fig. 1B).
Metadiaphysis
Abnormalities in the metadiaphyseal region were commonly heterogeneous in
signal intensity, consisting of irregular foci that were hypointense on
T1-weighted images and hyperintense on fat-saturated proton density-weighted
images, and markedly hypointense linear or irregular foci on both T1-weighted
and fat-saturated proton density-weighted images (n = 6, 54.5%) (Fig.
1A,1B,1C,1D).
Predominantly linear or irregular hypointense changes were seen in five femurs
(45.5%).
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Patella
Two patients (18.2%) had abnormal signal changes in their patellae. An
intrapatellar circumscribed lesion was detected in one patient
(Fig. 3B), and an irregular
subchondral outline was seen in the other.
The mean height standard deviation (SD) scores at the time of examination of the 11 patients with MR imaging evidence of deferoxamine-induced changes in the distal femur was -2.96 (2.96 SDs below the 50th percentile value), whereas that of the other 24 patients was -1.33. The difference in height SD scores between the two groups is statistically significant (p = 0.003, Mann-Whitney test). Although the mean duration of deferoxamine therapy was slightly longer in the 11 patients with dysplasia (range, 7 years 6 months to 14 years 2 months; mean, 8.9 years) than in the 24 healthy patients (range, 3 years 2 months to 16 years 8 months; mean, 7.7 years), the difference was not statistically significant (p = 0.09, Mann-Whitney test). The mean age at the beginning of chelation therapy was 4.6 years (range, 1 year 1 month to 7 years 4 months) and that of the 24 healthy patients was 3.5 years (range, 1 year 11 months to 7 years 6 months). The difference between the two groups was not statistically significant (p = 0.06, Mann-Whitney test).
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Epiphyseal involvement was detected in 10 (45.5%) of 22 femurs with MR imaging evidence of dysplasia, which is more frequent than noted in a previous radiographic study [1]. This greater frequency is probably because of the high sensitivity of MR imaging in detecting bone and cartilage lesions. The subchondral and chondral locations of these abnormalities and their extent can be clearly delineated on MR imaging. The continuity of the chondral lesions with the physeal lesion can also be accurately assessed.
Physeal widening, a documented feature on radiography [2, 4, 11], is a frequent finding on MR imaging in deferoxamine-induced bone dysplasia in our study. Physeal widening may be seen in metaphyseal chondrodysplasia, spondylometaphyseal dysplasia, and myelodysplasia [13], but none of our patients had clinical evidence of these conditions. Furthermore, the more marked lateral peripheral physeal widening in our patients is not typical in these dysplasias. Although irregular foci of physeal widening may be seen in several metaphyseal chondrodysplasias, the widening is more frequently uniform across the width of the bone [14]. Traumatic insults may result in central or peripheral focal physeal widening [10, 15], but none of our patients had a history of trauma or vigorous exercise. Chronic physeal fractures or stress-related physeal widening are also unaccompanied by loss of the distinct hypointense line of provisional calcification [13]. Symmetric physeal widening in patients with rickets [16] is unlike that seen in our patients.
The normal physeal-metaphyseal junction is hypointense and is well defined on MR imaging because it corresponds to the zone of osteoid formation and provisional calcification [17, 18]. In deferoxamine-induced bone dysplasia in the distal femur, the definition of the physeal-metaphyseal junction on MR imaging is blurred. This blurring may be a result of abnormal endochondral ossification from interference of the zone of provisional calcification or osteoid formation [19]. Loss of the hypointense line of provisional calcification on MR imaging is documented in rickets [16], which is also characterized by derangement of endochondral ossification.
Distal metaphyseal lesions are shown as areas of juxtaphyseal hyperintensity or as tonguelike extensions from the hyperintense physis on fatsaturated proton density-weighted images. These lesions predominate at the periphery, particularly laterally. The signal intensity may be slightly lower than, equal to, or higher than that of the hyaline physeal cartilage. In more severe cases, marked hyperintensity consistent with pseudocystic change is observed. These changes are probably caused by defective mineralization or osteoid formation. A tonguelike extension of physeal cartilage into the metaphysis has been described after a Salter Harris type II epiphyseal injury, in chronic physeal injury in gymnasts [15], and in radiation therapy and chemotherapy-induced physeal changes [10].
The predominantly peripheral involvement of both physeal and metaphyseal lesions in this study is quite characteristic and is consistent with the radiographic finding of a circumferential deficiency of bone at the periphery of the metaphysis [2]. Although we did not obtain sagittal fat-saturated proton density-weighted images to evaluate directly the anterior and posterior margins of the distal femur, metaphyseal hyperintensity and physeal widening could be detected at the most anterior section of the coronal fat-saturated proton density-weighted images. This finding would suggest that the disease process might be circumferential. Metaphyseal changes that are hypointense on T1-weighted images and hyperintense on T2-weighted images have also been shown to correspond to the metaphyseal radiolucencies characteristic of deferoxamine-induced dysplastic changes on radiography [11]. The larger lateral physeal and metaphyseal lesions shown in our study, with their anticipated accentuated interference with bone growth on the lateral side, may help to explain the association of deferoxamine toxicity with genu valgum deformity [3,4,5].
Metadiaphyseal lesions were heterogeneous in signal with serpiginous or linear hypointensities in our MR imaging study. These lesions correspond to the thin sclerotic lines observed radiographically. The lesions may represent changes that have migrated from the metaphysis to the more proximal locations as growth at the physis continues. Migration of a lesion into the metaphyseal region has been observed in growth plate injury [20], and deferoxamine-induced metaphyseal changes have been observed to extend to the diaphyses on longitudinal follow-up [5].
The linear or irregular low-signal-intensity metaphyseal foci on MR imaging bear some similarity to immature bone infarcts, but the low-signal-intensity margins of infarcts tend to be more serpiginous [21]. In infarction, the high-signal-intensity areas on T2-weighted images are found in the center of the infarct surrounded by the low-signal-intensity margin, whereas the hyperintensities in deferoxamine-induced metaphyseal dysplasia are more scattered and randomly arranged with respect to the hypointense lines. The oblique and random orientation of these hypointense lines is different from the transverse orientation of growth arrest lines.
The mechanism by which deferoxamine affects bone growth is not entirely understood. Chelation of zinc [1, 2] and the antiproliferative effect of deferoxamine may be the underlying pathophysiologic mechanisms [22, 23]. Radiation therapy and chemotherapy have been shown by MR imaging and histology to cause tonguelike extensions of the physeal cartilage into the metaphysis [10]. This seems to suggest that the defective endochondral ossification is caused by interference with proliferation. Patients with childhood leukemia who receive cytostatic chemotherapy with or without steroids have been shown to develop circumscribed lesions in the metaphysis and epiphysis on MR imaging [24]. Impaired chondrocyte turnover at the chondroosseous junction is seen in rickets [25], which shares some common imaging features [16] with severe deferoxamine-induced bone dysplasia. Whether chondrocyte turnover is affected by deferoxamine, as it is in rickets, is unknown. It is not likely that deferoxamine affects only chondrocyte proliferation because the subsequently decreased chondrocyte turnover leads to early physeal closure [25]. Early physeal closure was not a feature in our patients or in those of Brill et al. [2]. The inhibition of proliferation of osteoblasts by deferoxamine [26] may be a factor because osteoid formation and subsequent ossification will be affected.
No dysplastic change was detected in the proximal femur on T1-weighted coronal images of the entire femur in any of our patients. The lack of dysplastic change may be due to the slower growth rate of the proximal femur compared with that of the distal femur. The distal femoral physis contributes to 70% of the overall length of the femur, whereas the contribution from the proximal femoral physis is 30% [12]. The toxic effect of deferoxamine may be less marked on the proximal femur, which has a lower proliferative activity, or the effect may be mild and undetectable.
Deferoxamine-induced changes in the distal femur on MR imaging are associated with growth retardation. This finding is consistent with findings of a previous study showing that marked radiographic abnormalities of the unossified metaphyseal matrix in deferoxamine-treated thalassemic patients is associated with a decline in height percentile [4]. Therefore, the physeal and metaphyseal changes on MR imaging may be considered indicators of interference of height growth from the toxic side effect of deferoxamine.
In conclusion, deferoxamine-induced bone dysplasia in the distal femur and patella is represented by a spectrum of changes on MR imaging, comprising characteristic morphologic lesions in the epiphysis, physis, metaphysis, and metadiaphysis. Familiarity with these features would facilitate the diagnosis of deferoxamine-induced long bone dysplasia. Its sensitivity, noninvasive nature, and absence of ionizing radiation are important factors in choosing MR imaging as the modality of choice for longitudinal monitoring of the side effects of deferoxamine chelation therapy in thalassemic children.
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