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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 (

Deferoxamine-induced bone dysplasia in patients with thalassemia major.

Metaphyseal irregularity and abnormal vertebral bodies resembling a bone dysplasia were seen in two of five children with thalassemia major who were b...
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