Scoliosis in β Thalassemia

Scoliosis

in

fi

Thalassemia

Skeletal abnormalities in patients with homozy-gous 3 thalassemia have been noted as early as 1927 by Cooley et al’ and have been the subject of many

reviews.25

Abnormalities have been observed in the entire skeletal system, especially the skull and the

mandible, giving the patients a characteristic ap-pearance. Bone changes cause mainly expansion of the medullary cavity, subperiosteal overgrowth of the bones of the skull, and cortical thinning with porous rarefaction ofthe long bones. Although most

of

the bone abnormalities in inadequately

trans-fused thalassemic patients result from the over-growth of the bone marrow, hypoparathyroidism

and vitamin C deficiency occasionally occur and

may cause bone deformities.6’7 Recently, skeletal abnormalities and growth retardation in fi thalas-semic patients have been associated with early

mi-tiation

of

iron-chelation therapy and the resulting zinc depletion.8

This study reports the spine abnormalities in 3 thalassemia identified by clinical and radiological evaluation of randomly selected patients.

MATERIALS AND METHODS

We studied 67 thalassemic patients, 34 males and

33 females, treated during the past 7 years in the Thalassemia Unit of the University of Patras

Med-ical School at the Regional General University Hos-pital of Patras. The patients were randomly

Se-lected among the 120 patients followed up in the Thalassemia Unit, with the only criterion being their willingness to participate in the study. Eleven (16.4%) of the 67 patients had f thalassemia inter-media, whereas the remainder 56 (83.6%) had f thalassemia major. Eight (11.9%) ofthe 67 patients,

aged 9 years or older, had had splenectomy per-formed at an earlier age.

The mean chronological age ± SD of the patients

studied was 10.4 ± 3.8 years, with a range from 3

to

20 years. Only two patients were older than 16 years.

All patients were transfused with 10 to 15 mL of

washed red blood cells per kilogram of body weight,

at intervals of 15 to 30 days depending on the

hematocrit value. Over the 7-year follow-up period

the mean hematocrit ± SD was 34.5 ± 2.3%. All

Received for publication Mar 23, 1990; accepted Sep 21, 1990 Reprint requests to (N.G.B.) Dept of Pediatrics, University of Patras Medical School, P0 Box 1045, 261 10 Patras, Greece. PEDIATRICS (ISSN 0031 4005). Copyright © 1991 by the American Academy of Pediatrics.

patients except six, who refused the treatment, were treated with subcutaneous infusions of defer-oxamine. The mean deferoxamine dose ± SD they

reported receiving was 49.2 ± 18.2 mg/kg per day,

4 to 5 days per week. The recommended daily dose

was

40 to 60 mg/kg per day, 5 days per week. The

mean

age ± SD of the 61 patients at the initiation of the deferoxamine treatment was 5.0 ± 2.2 years. The

mean

duration ± SD of the deferoxamine therapy was 5.3 ± 3.0 years. Plasma ferritin level

was

measured every 6 months. The mean ferritin value ± SD was 2914 ± 1684 ng/mL.

In all /3 thalassemic patients studied a physical

examination was performed, with particular

atten-tion

paid to signs of scoliosis and other spinal deformities. Sexual maturity was determined ac-cording to Tanner.9 Each patient had a roentgeno-gram of the left hand performed for skeletal age determination.’0 Also, all patients had a standing posteroanterior roentgenogram of the spine for

es-timation

of

the location (thoracic, thoracolumbar,

lumbar, or S-shaped), direction (right or left), ro-tation of the apical vertebra (rotation of the pedicle of the apical vertebra in relation to the position of

the lateral side ofthe vertebral body), and extention

of

the scoliosis curvature (number of vertebrae in-cluded in the scoliotic curvature). The degree of the rotation of the apical vertebra was determined ac-cording to the method of Nash and Moe.” The grading 0 to IV is made by the location of the pedicle shadow on the convex side of the scoliotic

curvature.

In grade 0 rotation the pedicle shadows are equidistant from the sides of the vertebral body.

In grade IV, that is the most severe degree of

vertebral rotation, the pedicle shadow is past the

center of the vertebral body. A lateral standing roentgenogram of the spine was also obtained for determining the sagittal profile of the spine.

Studies were performed with the informed

con-sent of the patients and in the case of children,

with the informed consent of their parents.

Regression analysis, the r coefficient, the x2 test,

and the t test were used for the statistical analysis

of

the data.

RESULTS

Of the 67 thalassemic patients studied, 44 (65.7%) were found to have a scoliosis of 5#{176}Cobb

or more. Thirteen (29.5%) of the 44 scoliotic pa-tients had a scoliosis of 10#{176}Cobb or more, whereas

the remaining 31 patients (70.5%) had a curvature

between 5#{176}and 9#{176}Cobb. The greatest curvature observed was 15#{176}Cobb. Figure 1 illustrates the distribution of the patients with scoliosis according

to the degree of the major curvature. Table 1 lists

the rotation

of

the apical vertebra of the major

curvature

according to Nash and Moe.” Sixty-one

percent of the patients with scoliosis had a left-sided curvature, whereas in 43.2% of them the pattern of the curve was left lumbar. The difference

between left- and right-sided scoliosis was statisti-cally significant (t = 2.36, P < .025). Also, the

difference between left- and right-sided lumbar

sco-liosis was statistically significant (t = 2.55, P <

.01). However, no statistically significant difference was found between left- and right-sided scoliosis located at the thoracic (t = 0.382, P > .25) and the

thoracolumbar region (t = 0.89, P > .1), but the

number of such patients was too small for

mean-ingful analysis. The greatest lumbar, thoracic, and S-shaped curvatures observed were 12#{176},15#{176},and

14#{176},respectively. It must be noted that of the 67 thalassemic patients studied, 6 (8.9%) had a

ky-phosis of 7#{176}to 24#{176}located at the thoracolumbar region of the spine.

Twenty patients with scoliosis were males,

whereas the remaining 24 were females. The ratio of females to males was 1.24:1.0. The difference in the frequency of scoliosis between males and

fe-males was not statistically significant (x2 = 0.861,

P.3).

Also, there was no significant difference in the occurrence of scoliosis between patients with the

20

6” z

If, 12

I-. z w

4

0

5-7 7-9 9-11 11-13 1315 15 Ii

;IADtS OF 5C01 ItJ;i;

Fig 1. Distribution of the scoliotic patients according to

the degree of the major curvature.

major or the intermedia form of 3 thalassemia. Of the 56 patients with the major form of the disease,

35 (62.5%) had scoliosis, whereas of the 11 patients with the intermedia form, 9 (81.8%) had scoliosis

(x2 1.522, P .2).

All eight patients who had previously undergone

splenectomy had scoliosis. The difference in the occurrence of scoliosis between patients with and

without splenectomy was statistically significant

(x2 4.749, P .05). Splenectomized and

nonsple-nectomized patients had a similar mean hematocrit

value (34.3 ± 1.3 and 34.6 ± 2.4%, respectively; t =

0.298, P > .375), deferoxamine dose (50.4 ± 3.6 and

49.0 ± 19.1 mg/kg per day, respectively; t = 0.197,

P > .4), and plasma ferritin value (3538 ± 2127 and 2828 ± 1617 ng/mL, respectively; t = 1,12, P > .1). In four patients with splenectomy and scoliosis the

curvature pattern was left lumbar, in two right

lumbar, and in two S-shaped.

The standing roentgenograms of the spine dem-onstrated certain widespread structural bone

ab-normalities, such as osteopenia, cortical thinning

of vertebral body, and increased vertebral trabecu-lation. Osteopenia was the commonest abnormality, observed on the vertebrae of 62 patients (92.5%).

In 47 patients (70.1%) there was marked cortical

thinning of the vertebral body, and in 25 (37.3%) there was increased trabeculation of the spine. In

25 patients (37.3%), all vertebral abnormalities

de-scribed above were present. However, there was no correlation between these structural vertebral bone abnormalities and scoliosis, inasmuch as scoliosis appeared with the same frequency both in patients

with

one or more of the previously described ver-tebral abnormalities and in patients without any abnormal roentgenographic findings.

Some patients with scoliosis showed localized structural deformities of the fourth and less

fre-quently of the fifth lumbar vertebral body. Of the 44 patients with scoliosis, 4 (9.1%) had flattening ofthe fourth lumbar vertebral body and 5 additional patients (11.4%) had a wedge deformation also of

the fourth vertebral body demonstrated by the pos-teroanterior roentgenogram. In these patients the

TABLE 1. Location and Direction of the Scoliotic Curvature (Convexity) and Grades of

Rotation of the Apical Vertebra of the Major Curvature According to Nash and Moe” in fi Thalassemic Patients With Scoliosis*

Location of Sco- Direction Grade of Rotation

liosis

Right Left Total 0 1 2 3

Thoracic 3 4 7 . . . 7 ...

Lumbar 8 19 27 . .. 20 7 ...

Thoracolumbar 2 4 6 .. . 4 2 ...

Total 13 27 40 .. . 31 9 ...

* Total

x2

= 1.017, P > .90.

_,15

S

13

0

S

C 11

U

07>SSS

U, 55555

9 S

w

(.5 5 - 55

5 .*.a*.. , .R* ,*. ,S

2 6 10 14 18

A6E (YEARS)

Fig 2. Correlation between the age of the scoliotic

pa-tients and the degree of the major curvature; r = .467, P

.001.

degree and the side of the wedge deformation of the L-4 corresponded well with the degree and the side

of

scoliosis. The youngest of the above patients was

4 years old. In 1 patient a first-degree spondylolis-thesis of the L-5 was detected and in another there

was spondylolysis of the L-5. A lateral rotational

sliding of the L-4 was observed in a patient with a left-sided scoliosis (L-1-L-5) of 10#{176},with a rotation

of

the apical vertebra estimated to be grade II according to Moe.

No correlation was observed between scoliosis

and the existence

of some

potential etiological fac-tors, such as low or high ferritin levels, adequate or

inadequate blood transfusions, and high or low doses of deferoxamine. Specifically, of the 6

pa-tients who were never treated with deferoxamine, 4

had scoliosis, whereas of the 61 who received iron

chelation therapy, 40 had scoliosis. Statistical analysis of the data demonstrated no difference

between the two groups of patients

(x2

0.003,

P

> .95).

Table 2 demonstrates the distribution of the

chronological and the skeletal age of the

thalas-semic patients with and without scoliosis. The

youngest patient with scoliosis was 3.5 years old.

In the group of 2- to 7-year-olds, all three patients

aged 5 years and eight of the nine patients aged 6 years had scoliosis. All these patients had

main-tamed

a

good hematocrit value up to the time of

the study because they had been cared for from early life in our Thalassemia Unit. Furthermore, there was no statistically significant difference in the occurrence of scoliosis between different age

groups (total x2 = 3.132, P .3), indicating that

the frequency of scoliosis did not increase with age.

Bone maturation was retarded in most

of

the pa-tients and, therefore, scoliosis appeared not only in

very young patients, but in young patients who also

had a retarded skeletal age. The mean skeletal age

± SD of the thalassemic patients was 9.1 ± 3.7 years, with a range from 2 to 17 years. The mean

retardation, therefore, of the skeletal age ± SD was 1.2 ± 1.2 years. Table 3 lists the number of patients

with and without scoliosis according to the stage of

sexual maturation by Tanner.9 The frequency of scoliosis was similar in all five stages of maturation.

Although the frequency of scoliosis did not in-crease with advancing age, the magnitude of the

curvatures

was

greater in the older patients than in the younger ones. Figure 2 illustrates the correla-tion between the age of the scoliotic patients and

the degree of the major curvature (r = .467, P

.01). Up to the age of 10 years there were 19 patients with a curve from 5#{176}to 9#{176}Cobb and only 3 patients with a scoliosis curve of 10#{176}Cobb or more. On the contrary, in the patients older than 10 years, 10 had a scoliosis curve of 10#{176}Cobb or more and only 12 had a curve of 9#{176}Cobb or less. The difference in

TABLE 3. Stage

Tanner9 and Pres

assemic Patients*

of enc

Sexual Maturation According to

e or Absence of Scoliosis in

Thal-Stage of Maturation

Patients With Thalasse-mia

No. (%) No. (%)

Without With

Scoliosis Scoliosis

I

II

III IV V

14 (32.6) 29 (67.4)

4 (50.0) 4 (50.0)

3 (30.0) 7 (70.0) 1 (33.3) 2 (66.7)

1 (33.3) 2 (66.7)

TABLE 2. Scoliosis in j3 Thalassemic Patients According to Chronological and Bone

Age*

Age Groups, y

Chronol ogical Age Bone Age

No. of Patients

No. (%) With

Sco-liosis

No. of Patients

No. (%) With

Sco-liosis

2-7 16 12 (75.0) 18 14 (77.8)

7-12 25 17 (68.0) 32 19 (59.4)

12-17 24 13 (54.2) 15 9 (60.0)

17-22 2 2 (100.0) 2 2 (100.0)

* Presence vs absence of scoliosis (chronological age): total x2 = 3.132, P > .3. Presence

v.1

U,

0

-S

0 U

U,

La. 0

0

4

CD

15

‘3

11

9

7

c

S

S S

55 S_

S S S#{149}SS S#{149} #{149}

0 2000 4000 6000

1[RRITIN (ng/ml)

Fig 3. Correlation between the ferritin levels of the scoliotic patients and the degree of the major curvature;

r = .375, P .05.

the magnitude of scoliosis between patients older and younger than 10 years was statistically signifi-cant (x2 5.35, P .05).

Patients with scoliosis and high ferritin levels in

the plasma developed curves of greater magnitude than patients with low ferritin levels (Fig 3). The

difference was significant (r = .375, P s .05). No

relationship was identified between the magnitude

of

scoliosis and the presence or absence of chronic anemia or the dose of deferoxamine given. Also, there was no significant difference in the prevalence

of

scoliosis between patients with early and late

initiation

of

the iron-chelation therapy.

DISCUSSION

Differences in the prevalence of idiopathic

sco-liosis in the general population have been reported

by various investigators. Shands and Eisberg’2 noted idiopathic scoliosis of 10#{176}or more in 1.9% of individuals older than 14 years, with a female-male

ratio

of

3.5:1.0. Patynski et al’3 studied children 7 to 15 years old and found scoliosis in approximately

2.6% of them, whereas Bruszewski and Kamza’4 reported a prevalence of scoliosis in the general population of 3.7%. Wynne-Davies,’5 in a survey of 10 000 schoolchildren in Edinburgh, noted scoliosis

in

1.3 per 1000 younger than the age of 8 and in 1.8

per 1000 older than the age of8. In children younger

than 8 years, the ratio of female to male was 1:1,

but in children older than the age of 8 this ratio was 23:1. The incidence of idiopathic scoliosis

greater than 5#{176}in Athens, Greece, among children aged 10 to 15 years was found to range between

3.7%

and 7 7% 16

The severity of scoliosis depends on the degree

of

the scoliotic curvature. Curvatures 5#{176}to 30#{176}are characterized as mild, 30#{176}to 60#{176}as moderate, and greater than 60#{176}as severe. In this study, 44 (65.7%)

S of the 67 /3 thalassemic patients investigated had a

scoliosis curve between 5#{176}and 15#{176}.In idiopathic

scoliosis the progression of the disorder depends on the location and direction of the scoliotic curvature and the rotation

of

the apical vertebra. The most severe forms of the disease are right thoracic with

a rotation grade III to IV. In the /3 thalassemic patients we investigated, the left lumbar curvatures were the most frequent. Also, the greatest rotation observed was grade II. Although the natural history

8000 of scoliosis in thalassemia is not well determined

at the present time, it appears that it is different from that of the idiopathic. It is of interest that scoliosis in 3 thalassemia appears very early in

childhood, between the third and the seventh year

oflife. The fact that its prevalence does not increase

with age after the seventh year suggests that no

new cases appear after this age. Although the prey-alence of the disorder does not enhance with age, there is a significant increase in the magnitude of

the scoliosis curves in older patients, indicating that

the spinal deformity is slowly progressing. The association between high plasma ferritin levels and greater degrees of scoliosis suggests that iron

ac-cumulation is an important factor leading to the

progression of scoliosis. In only a small number of

patients wedge deformation of the L-4 had led to lumbar scoliosis.

In all ages, male and female thalassemic patients

were approximately equally affected. However, only

a limited number of patients older than 16 years were investigated and the bone maturation in the

majority of the patients was retarded. Evaluation,

therefore, of older thalassemic patients and

long-term follow-up of young patients is warranted,

in-asmuch as the current treatment protocol has in-creased the life expectancy of these patients and it

is expected that they will survive even longer.

Although bone abnormalities in thalassemia

have been described since 1927’ and many subse-quent papers have been published on this

sub-ject,25”7 scoliosis in

fi

thalassemia has never been described earlier. The question, therefore, has

arisen

whether scoliosis is a manifestation of 3

thalassemia per se or whether it is a complication resulting from the application of the modern

treat-ment

regimens.

Indeed, in a recent paper De

Vir-gillis et a18 reported that initiation of iron-chelation

therapy as early as the first year of life results in

significant bone deformities and short stature, pos-sibly due to zinc depletion by the deferoxamine

treatment. However, in all patients included in the

study, the deferoxamine treatment was begun after

the second or third year of life. Furthermore, there was no correlation between the prevalence of

pa-REFERENCES

1. Cooley TB, Witwer ER, Lee P. Anemia in children with

splenomegaly and peculiar changes in the bones. AJDC. 1927;34:347-363

2. Aksoy M, Camli N, Dincol K, Erdem 5, Dincol G. On the problem of ‘rib-within-a-rib’ appearance in thalassemia in-termedia. Radiol Gun BiOL 1973;42:126-133

3. Caffey I. Cooley’s anemia: a review of the roentgenographic findings in skeleton. Am J RoentgenoL 1975;78:381-391 4. Middlemis JH, Raper AB. Skeletal changes in the

haemo-gbobinopathies. J Bone Joint Surg Br. 1966;48B:693-702 5. Moseley JE. Skeletal changes in the anemias. Semin

Roent-genoL 1974;9:169-184

6. Flynn DM, Fairney A, Jackson D, Clayton BE. Hormonal changes in thalassemia major. Arch Dis Child. 1976;51:828-836

7. Gabrielle 0. Hypoparathyroidism associated with

thalasse-mia. South Med J. 1971;64:115-116

8. De Virgillis ST, Congia M, Frau F, et al. Deferoxamine induced growth retardation in patients with thalassemia major. J Pediatr. 1988;113:661-669

9. Tanner JM. Growth atAdolescence. 2nd ed. Oxford, England: Blackwell Scientific Publications; 1962

10. Greulich WW, Pyle SI. Radiographic Atlas of Skeletal

De-velopment of the Hand and Wrist. 2nd ed. Stanford, CA:

Stanford University Press; 1959

11. Nash C, Moe J. A study of vertebral rotation. J Bone Joint Surg Am. 1969;51A:223

12. Shands AR Jr, Eisberg HB. The incidence of scoliosis in the state of Delaware: a study of 50 000 minifilms of the chest made during a survey for tuberculosis. J Bone Joint Surg Am. 1955;37A:1243-1249

13. Patynski J, Szczekot J, Szwaluk F. Boczne skrzywienie Kregoslupa w swietle statystyki. Chir Narzadow Ruchu Or-top PoL 1957;22:111-114

14. Bruszewski J, Kamza Z. Czestosc wystepowania skolioz na podstawieanalizy zdec maloobrazkowych. Chir Narzadow

Ruchu Ortop PoL 1957;22:115-116

15. Wynne-Davies R. Infantile idiopathic scoliosis. J Bone Joint Surg Br. 1975;57B:138-141

16. Smyrnis P, Valavanis J, Alexopoulos A, Siderakis G, Gi-anestras NJ. School screening for scoliosis in Athens. J

Bone Joint Surg Br. 1979;61B:215-217

17. Dines DM, Canale VC, Arnold WD. Fractures in thalasse-mia. J Bone Joint Surg Am. 1976;58A:662-666

18. Weatherall DJ, Clegg JB. The Thalassaemia Syndromes. 3rd

ed. Oxford, England: Blackwell Scientific Publications tients with low or high ferritin values, and finally

patients receiving high or low doses of

deferoxam-me.

These findings suggest that the treatment

reg-imens applied may not be responsible for the initial development of scoliosis. However, it is noteworthy that a positive correlation was identified between

high ferritin levels and the degree of the scoliosis

curvatures.

It appears that whichever are the

path-ogenetic mechanisms that lead to the development

of scoliosis, they operate early during the first few years

of

life.

It should be noted that scoliosis developed in all

splenectomized patients. This observation may in-dicate that splenectomy can be a factor contributing

to

the appearance of scoliosis. Statistical analysis

failed to demonstrate an association of scoliosis in

the splenectomized patients with the mean

hema-tocrit

value, the deferoxamine dose, and the plasma

ferritin levels.

The intermedia form of the disease differs from the

major

form

in

that the hemolytic process is

milder and, therefore, patients are subjected less

frequently to blood transfusions.’8 However,

sco-liosis appeared with a similar frequency in patients

with both forms of the disease.

In conclusion, it was found that scoliosis of 5#{176}

Cobb or more developed in more than half of the patients with fi thalassemia. Inasmuch as the degree of scoliosis increased with age, the skeletal

matu-ration was delayed, and the life span of the

thalas-semic patients is steadily increasing, it is necessary

to

observe these patients for long periods of time

to determine the magnitude of the scoliosis process and treat the patients, if it becomes necessary. In addition, long-term follow-up studies may help to

uncover

the pathogenetic mechanism(s) causing scoliosis in 3 thalassemic patients.

OURANIA PAPAGEORGIOU, MD DIMITRIS A. PAPANASTASIOU, MD

NICHOLAS G. BERATIS, MD Dept

of

Pediatrics

University of Patras Medical School

Regional General University Hospital

Patras, Greece

PANAGIOTIS KOROVESSIS, MD Dept of Orthopedics

General Hospital “St Andreas”

Patras

ALEKOS OIK0NOM0P0UL0S, MD

Dept of Radiology

1991;88;341

Pediatrics

BERATIS, PANAGIOTIS KOROVESSIS and ALEKOS OIKONOMOPOULOS

OURANIA PAPAGEORGIOU, DIMITRIS A. PAPANASTASIOU, NICHOLAS G.

Thalassemia

β

Scoliosis in

Services

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1991;88;341

Pediatrics

BERATIS, PANAGIOTIS KOROVESSIS and ALEKOS OIKONOMOPOULOS

OURANIA PAPAGEORGIOU, DIMITRIS A. PAPANASTASIOU, NICHOLAS G.

Thalassemia

β

Scoliosis in

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