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Review of radiologic skeletal changes in

Thalassemia
ARTICLE in PEDIATRIC ENDOCRINOLOGY REVIEWS: PER NOVEMBER 2008
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Review of Radiologic Skeletal Changes

in Thalassemia
By
Elsaid M Aziz Bedair, Abbas N E Helmy*, Khaled
Yakout, Ashraf T Soliman@
Departments of Radiology and Pediatrics@, Hamad
Medical Center, Qatar
And University of ElMenia*, Egypt

Corresponding Author:
Elsaid M Aziz Bedair
Professor of Radiology and Senior Consultant
Department of Radiology, Hamad Medical Center,
PO box 3050, Doha Qatar
Email Address: elsaid_bedair@hotmail.com
Phone: +9746696894

The modern radiologist is unlikely to encounter the classic radiographic

thalassemic features other than in teaching files, on visits to Mediterranean
countries, or in isolated patients never managed with hyper-transfusion therapy.
This is because therapy by hyper-transfusion and chelation has improved both the
general health and the radiographic appearance of patients.

The main pathological change that leads to radiological skeletal response in

beta thalassemia major is extensive marrow proliferation. The bone marrow is 630 folds hyperactive than normal, which affects both cortical and cancellous bones
with secondary expansion of the medulla, cortical thinning and resorption of the
secondary and tertiary bone trabeculae with subsequent prominent primary
trabeculae. This results in a generalized loss of bone density. The appearance of
small areas of lucency, as a result of focal proliferation of marrow may be present
and can extend to break through the bone cortex initiating variable periosteal
reactive responses depending on the bone involved and the extent of proliferation.
(1-5) In addition, endocrinopathies including growth hormone (GH) insulin-like
growth factor-I (IGF-I) abnormalities, hypogonadism, defective calcium
homeostasis , hypoparathyroidism and reduced 25-hydroxylation of cholecalciferol
contribute variably to these bony changes. (6-11 ) The pathological consequence of
iron deposition in the bone and the toxic effect of desferal (DXF) may add to and
modify these skeletal changes .(12)

The severity of the skeletal responses is related to the type of thalassemia, the
extent and duration of the disease, the type of treatment and the amount of
transfusions given to the patient as well as the side effects of the transfusionchelation therapy.(6,8) The spectrum of radiological appearance of skeletal
manifestation also depends on the bone involved. The radiographic features of
thalassemia may occur in other hemoglobinopathies, or other reticuloendothelial
storage diseases as Gaucher disease. Although these may be diagnosed radio
logically with a high degree of confidence, additional clinical and laboratory
information may be required for the differential diagnosis of hemoglobinopathies

(13,14). These features can be divided into those affecting the skeleton ( axial and
appendicular) and those occurring extra-medullary.

1. Axial skeletal changes:

Skull and facial bones; in severely affected patients, show widening of the
diploic space with thinning of the tables, frequently with complete obliteration of the
outer table. Sub periosteal reactions in the form of bony spicules may be seen
radiographically and result in a classic "hair-on-end" appearance. The occipital
bone is exempted from these changes as there is lack of hematopoietic marrow
within it. ( 2,3,9,15) (Fig 1)

Poor pneumatization of paranasal sinuses secondary to hypertrophy of

osseous structures and a consequent prominence of the lateral margins of the malar
eminences, together with anterior and medial displacement of developing teeth can
explain the clinical findings of these patients. Characteristically, ethmoidal sinuses
are not involved because of the absence of red marrow in their walls. Prominent
vascular impressions 2ry to hypertrophy of calvarial vessels may be identified. The
size of the vascular impressions in the calvarium is related to the age of onset and
type of transfusion therapy.(2,3,9) (Fig 1).

In vertebral bodies, weight-bearing bones, only the primary bone trabeculae

are preserved, this gives a vertical striated appearance due to thickened vertical
trabeculae. While in severely affected patients, biconcavity of the superior and
inferior margins of the vertebral bodies or compression fractures may occur. (Fig
2,3) Spinal cord compression is rarely encountered secondary to bone expansion.
(5,7,13,16) Morphological deformities including decreased spinal height, increased
thoracic kyphosis, vertebral flattening and elongation anteriorly, as well as disk
calcification were found in patients on DXF therapy . These changes are believed to
be caused by interference with spinal growth-plate development and differ both

morphologically and pathologically from vertebral deformities occurring as a sequel

to compensatory marrow hyperplasia in poorly transfused patients (7,13)

2. Appendicular skeleton :

In general the manifestations are more pronounced in peripheral bones

mainly hands and feet. The phalanges show cortical thinning, osteopenia, and
coarsening of the trabeculae with possible loss of normal tubulation, which
frequently results in a squared or sausage-shaped configuration (fig 4).(9)
Increased incidence of fractures in thalassemia patients have been reported,
although less commonly than expected from the degree of osteoporosis.( 17) The
nutrient foramina are prominent and their size in the phalanges are related to onset
of transfusion therapy , but do not appear to regress with therapy and hence remain
as a permanent record of earlier marrow changes.(18) (fig 5).

In severely affected patients, well-defined erosions of the sub-periosteal

margin of the cortex of the metaphysis or diaphysis may be identified. The
expanded bone marrow destroys the medullary trabeculae with initial cortical and
trabecular thinning and subsequent trabecular coarsening, which may result in the
appearance of cob-webbing in the pelvis, medullary lucencies involving the
metaphyseal and diaphyseal regions of humeri and femori may occur (2). (Fig 6)
Irregular transverse radio-dense lines near the ends of the long bones represent
growth arrest and recovery lines are not uncommon specially in untreated
patients.(19) Patients on iron-chelation therapy may demonstrate dense
metaphyseal bands and tibial deformity secondary to premature epiphyseal fusion.
(20,21,22).
The ribs show variable spectrum of appearance depending on the severity
of the disease , from normal appearance to osteopenia, localized lucencies,
broadening (widening), thin cortices, cortical erosions and prominent vascular
impression at inferior aspect of the lower ribs.(Fig 7) A descriptive term , rib
within a rib appearance, may be encountered at middle to anterior aspect of the

ribs. Subcortical elongated lucency and to a lesser extent focal rib enlargement
involving posterior rather than anterior parts of the ribs and possibly associated
with soft tissue densities (representing hematopoietic tissue hyperplasia) are the
most striking rib changes present in patients with thalassemia intermedia who were
never transfused. Regression of these rib abnormalities after transfusion was not
uncommon. (23,24)

3. Extra medullary hematopoiesis :

May be manifested as soft tissue shadows within posterior and to lesser extent
anterior mediastinum as well as para vertebral location.(25) In some instances this
may lead to subperiosteal new bone formation and secondary osteomata like
formations in the ribs (Fig 7 c) and less likely long bones(26).

Premature fusion of epiphysis is encountered in 23% of patients with B

thalassemia older than 10 years and about 36% of patients with thalassemia
intermedia. (19,21) Either unilateral or bilateral affection of proximal humeral and
to lesser extent distal femoral and upper tibial epiphysis are involved with
subsequent secondary abnormal angulations and varus deformity of the affected
fused epiphysis . Hemosiderin deposition in bones can only be identified by MRI.
(27,28,29) Arthropathy and even arthritis resembling primary hemochromatosis has
been reported.(16)

4. Dysplastic features due to DXF therapy :

Dysplastic changes in transfused and chelated patients are more common and
severe in those who commenced iron-chelation therapy DFX at a younger age
(under 3 years) and those on higher doses (50 mg DFX/kg/day).(9) Reduction of
DFX dosage may lead to healing of these dysplastic lesions.(19) In a study of 12
patients with DFX-induced long bone changes, distal ulnar involvement was seen in

all cases.(12) Therefore an annual hand radiograph may be justified, not only to
monitor growth retardation but also to assess DFX induced dysplasia.

In summary, the use of hyper-transfusion protocols that inhibits marrow

hypertrophy, adjusting iron-chelation therapy and/or the use of less bone-toxic
chelators and early correction of the endocrinopathies associated with thalassemia
can markedly improve bone health and prevent the occurrence of the above
mentioned skeletal abnormalities.

References
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Fig 1: Plain X ray skull OF, Lateral (A and B) and spot magnified views AP and lateral
( C&D) showing marked thickening of the diploic space, well identified inner table and
hazy eroded outer table with typical hair on end appearance of the prominent trabeculae
secondary to bone marrow hyperplasia. Note the exemption of the occipital bone from
thickening.

(A)

(C)

(B)

(D)

Fig. 2: Lumbar spines AP ( A,B) lateral view (C) and spot magnified lateral view (D).
showing prominent longitudinal striations of the vertebral bodies with partial wedging of
the body LV1 secondary to diminished bone mass, with haziness of the anterior cortex of
bodies.

Fig 3: Lumbar spines Spot lateral view for two different patients showing biconcavity
and partial wedging .

Fig 4: (A). plain X ray right hand AP (B), magnified view for proximal phalanges
showing loss of normal trabeculation , thinning of the cortices, coarse lace like primary
trabeculations, and sausage shaped 1st and 5th metacarpal bones .

(A)

(B)

Fig 5: (A) Plain X ray Left hand AP view and (B) spot magnified view demonstrating
marked prominent nutrient foramina secondary to hypertrophied nutrient vessels of the
phalanges.

(A)
(B)
Fig 6: (A) Plain X ray left upper humerus and (B) mid part left femur of the same
patient demonstrating thinning of the cortices and elongated medullary lucency
secondary to bone marrow hyperplasia.

Fig 7: Plain X ray chest PA ( A-C) and spot views for the ribs ( different patients)
showing generalized broadening of the ribs, multiple elongated lucencies along the long
axis of the ribs ( secondary to bone marrow hyperplasia) , prominent inferior vascular

groove of the ribs 2ry to hypertrophied vessels, erosions of the inferior margins of the
ribs with osteopenia osteomata like formations 2y to extra medullary hematopoiesis .