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561
Deferoxamine-Induced Dysplasia in Patients Thalassemia Major
Susanna
Paula W. Brill1 Patricia Winchester1 Patricia J. Giardina2 Cunningham-Rundles2
Bone with
Metaphyseal irregularity and abnormal vertebral bodies resembling a bone dysplasia were seen in two of five children with thalassemia major who were begun on a regimen of hypertransfusion and chelation with deferoxamine before the age of 3 years. Similar changes were not seen in 22 other children in whom chelation was started after the age
of 3. Whether the dysplastic bone growth was related to drug dose or age of onset of chelation could not be determined, as deferoxamine dosages differed in the two groups. Findings on radiographs included flattening of the thoracic and lumbar vertebral bodies, circumferential metaphyseal osseous defects, sharp zones of provisional calcification,
and widened growth plates. Healing was noted in one of the patients after the dose of deferoxamine was decreased. Zinc levels in both affected patients did not differ from those in the 25 other chelated patients. AJR
Received July 26, 1990; October 8, 1990.
accepted
after revision
Presented at the annual meeting of the Society for Pediatric
Radiology,
Cincinnati,
April 1990.
This work was supported in part by National Institutes of Health grants NCI CA29502 and NIH 19898-01 , the General Clinical Research Centers Program Office of the Division of Research Resources Foundation (RR-47), and the Children’s Blood Foundation. I Department of Radiology, The New York Hos-
March 1991
156:561-565,
Current treatment of thalassemia major includes the use of blood transfusions to maintain hemoglobin at acceptable levels and chelation to remove excess iron stores resulting from multiple transfusions. In 1988, de Virgiliis et al. [1] reported the occurrence of a growth disturbance associated with radiologic changes in the long bone metaphyses in patients with thalassemia major treated with hypertmansfusion and chelation. They related the abnormalities to the early institution of chelation therapy with deferoxamine and postulated that a direct toxic effect of the drug on growing bone or the loss of minerals other than iron, or both factors, could be responsible. They recommended delaying chelation therapy until after the age of 3 years and until the patient had received 20 to 30 blood transfusions and had accumulated a large iron load as evidenced by a serum ferritin level of 800-1000 ng/ml. In 1 989 we instituted a retrospective radiologic study of our population of 27 patients with thalassemia major who have been treated with hypertransfusion and who began chelation therapy with deferoxamine before the age of 7 years. Our aims were to characterize the long bone abnormalities more fully, to determine whether the spine is also affected, to establish the prevalence of bony abnormalities in relation to the patient’s age and iron load at the onset of chelation therapy, and to consider the significance of zinc deficiency in the production of bone lesions.
pital-ComeIl Medical Center, 525 E. 68th St., New York, NY 10021 . Address reprint requests to P. W.
Brill. 2
Materials Department
Hematology, ical Center,
of Pediatrics, Division of Pediatric The New York Hospital-Comell Med-
New York,
NY 10021.
0361 -803x/91/1 563-0561 C American Roentgen Ray Society
In 1 989,
and Methods 27 patients
with
thalassemia
major
started before the age of 7 years were treated with
a regimen
administration
of
hypertranstusion
of ABC
transfusions
and
in whom
chelation.
to maintain
deferoxamine
treatment
had been
in the New York Hospital Thalassemia Hypertranstusion
a pretransfusion
involved
hemoglobin
the
level
Clinic regular
greater
BRILL
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562
ET AL.
AJR:156,
March
1991
than 1 1 g/dl. Deferoxamine was administered subcutaneously during an 8-hr period by using a battery-operated syringe pump. The dosage of deferoxamine in these 27 patients was maximized to 60 mg/kg
by atomic absorption on blood collected without hemolysis into tubes with zinc-free stoppers. Serum levels of zinc were obtained twice.
per day in the last 3 years of observation. Before this, the deferoxamine chelation dosage was 20-40 mg/kg per day. Six patients (cases 1-5 and 8) (Table 1) were begun at a dosage of 40-60 mgI
of deferoxamine was documented on follow-up radiographs. results of visual and auditory assessment were recorded.
kg per day, whereas the remainder were begun at 20-40 mg/kg day. These dosages are approximate because of differences
patients’
compliance
with the recommended
use of deferoxamine
per in
We retrospectively reviewed all available radiographs of each patient. Since the onset of deferoxamine therapy, all patients had yearly radiographs of the hands and wrists for bone age and yearly chest radiographs to monitor heart size. Twenty-six patients had one of the thoracic
and lateral projections. trauma. Ten patients clinical
indications;
the
and lumbosacral
Nine patients had additional had abdominal radiographs femoral
heads
and
necks
spine
in frontal
radiographs after for a variety of were
included
in
these films. The chest radiographs included the proximal humeral epiphyses and metaphyses. In cases 1-5, frontal and lateral radiographs of the knees were obtained in addition to the other radiologic studies listed above. We recorded the appearance of the metaphyses and spine as well as instances of premature epiphyseal fusion and fractures. We made a qualitative assessment of osteopenia as mild, moderate, or severe. The radiologic findings were correlated with growth patterns, age at onset and duration of therapy with deferoxamine, serum ferritin level, number of blood transfusions at the time chelation was started, dose of deferoxamine, and serum zinc levels. Zinc levels were measured
TABLE 1: Age, Ferritin Levels, and Transfusion Status in 27 Children with Thalassemia Major Who Started Deferoxamine
Chelation
Before 7 Years of Age
Case
a
Status at Onset of Chelation
Present
No.
Age (yr)
Age (yr)
Ferritin (ng/ml)
No. of RBC Units Transfused
1
7
1.7
1302
12
2 3
7 6
1.8 1.8
2006 2094
33 18
4a 5a
7 5
6 7
10 11
2.1 2.8 3.0 3.3
1969 1448 5564 4068
26 28 31 48
8 9
6
4.0
1497
9
15
4.4
10
13
4.5
11
14
4.5
4340 4340 2300
68 66 42
12
15
4.9
2400
56
13
15
2600
76
14
14
4.9 5.0
15
17
5.3
4600 2703
74 55
16 17 18
16 18 15
5.3
1250
45
5.4 5.4
2610 4000
97 92
19
19
5.4
2580
65
20 21 22 23 24
15 19 18
5.6 5.8 5.8
1800 2880 4200
65 77 96
14
5.9
2110
160
18
25
17
26 27
19
6.0 6.2 6.3
2855 5000 1620
76 77 69
17
6.8
This patient
had metaphyseal
7000 and vertebral
94 changes.
with
bone
lesions,
the
effect
of a decrease
in the
dose
The
Results
5-
7 days of each week.
or two examinations
In patients
Serum ferritin level, number of transfusions, and age at onset of chelation are listed in Table 1 . Five of the 27 thalassemic children began chelation therapy before age 3 years. Radiographs of two of the five (cases 4 and 5) showed changes in the long bones and spine, first noted at 7 and 4 years of age, respectively. At the time of initial chelation both had received over 25 transfusions and had serum ferritin levels greater than 1 400 ng/dI. Growth mate decreased within 6 months of chelation therapy in both children. In case 4, growth fell gradually during a 4-year period to below the fifth percentile. In case 5, subsequently found to be hypothyroid, the growth failure was more abrupt, with height below the fifth percentile after 2 years of chelation. Leg pain and prominent knees developed in case 4 at the age of 6 years and prompted radiologic evaluation. The case 5 patient was asymptomatic except for decreased growth mate. All 27 patients were of normal height at birth and in infancy, but most showed a gradual decrease in height percentile during childhood. Four patients who entered puberty (cases 1 1 , 1 3, 16, and 21) were growing at or above the fifth percentile, with one at the 50th percentile (case 1 1). Zinc levels were obtained once in 19 of the patients. Serum zinc levels were low (