AJR 2001; 177:421-425
© American Roentgen Ray Society
MR Imaging of Bone Marrow in Glycogen Storage Disease Type IB in Children and Young Adults
Axel Scherer1,
Volkher Engelbrecht1,
Gudrun Neises2,
Philip May1,
Alexander Balsam2,
Ute Spiekerkötter3,
Udo Wendel3 and
Ulrich Mödder1
1
Institute of Diagnostic Radiology, Heinrich-Heine University, Moorenstr. 5,
D-40225 Düsseldorf, Germany.
2
Department of Metabolic Diseases and Nutrition, Heinrich-Heine University,
D-40225 Düsseldorf, Germany.
3
Department of Pediatrics, Heinrich-Heine University, D-40225
Düsseldorf, Germany.
Received December 19, 2000;
accepted after revision February 7, 2001.
Address correspondence to A. Scherer.
Abstract
OBJECTIVE. Patients with glycogen storage disease type IB have
neutropenia and neutrophil dysfunction that predispose them to frequent
infections, for which they are given granulocyte colony—stimulating
factor. Because neutropenia is a consequence of defects in myeloid maturation,
the bone marrow aspirations show hypercellularity due to myeloid hyperplasia.
This study evaluated MR imaging of bone marrow in glycogen storage disease
type IB with and without granulocyte colony—stimulating factor.
CONCLUSION. As confirmed by the histologic results in bone marrow
aspirations, abnormal findings on MR images of bone marrow in patients with
glycogen storage disease type IB indicate an increased myelopoietic activity,
which is augmented by treatment with granulocyte colony—stimulating
factor.
Introduction
In type I glycogen storage diseases, the microsomal glucose-6-phosphatase
enzyme system is deficient [1,
2]. Because of the deficient
enzyme system, the production of free glucose in the liver and kidney from
glycogenolysis and gluconeogenesis is blocked and causes severe postprandial
and fasting hypoglycemia and increased production of lactic acid, uric acid,
and triglycerides. Untreated patients show severe growth failure, delayed bone
maturation and puberty, and may develop liver adenomas and renal failure from
the second decade of life [3].
Patients with glycogen storage disease type IB are clinically and
metabolically indistinguishable from those with glycogen storage disease type
IA, except for an additional propensity to develop recurrent or chronic
bacterial infections in type IB. These infections are related to chronic
neutropenia, as a consequence of abnormalities in myeloid maturation and of
functional defects in the circulating phagocytic cells, in particular
neutrophils and monocytes [4,
5].
In patients with glycogen storage disease type IB, bone marrow examinations
showed hypercellularity, which results from defects in myeloid maturation,
although the initial stages of myeloid development are normal. Therefore, the
bone marrow responds to the lack of neutrophils and monocytes by myeloid
hyperplasia. Treatment with granulocyte colony—stimulating factor may
decrease the number and severity of infections, most probably through
increasing the neutrophil cell counts to low-normal values
[6,
7].
Although hypercellularity and myeloid hyperplasia, as shown in bone marrow
aspirates, are known to occur in patients with glycogen storage disease type
IB, to our knowledge, visualization of that phenomenon by MR imaging has not
been reported. Therefore, our study aimed at MR imaging of bone marrow in
patients with glycogen storage disease type IB, both with and without
treatment with granulocyte colony—stimulating factor. The results were
compared with MR imaging findings of bone marrow in patients with glycogen
storage disease type IA.
Subjects and Methods
Five patients with glycogen storage disease type IB (mean age, 18.2 years)
and two patients with glycogen storage disease type IA underwent MR imaging of
the middle and distal femoral and tibial bones. In each patient, the diagnosis
of glycogen storage disease type IA or glycogen storage disease type IB had
been confirmed by enzymatic analysis of liver tissue samples obtained at
biopsy or at mutational analysis in the genes of glucose-6-phosphatase or the
microsomal—glucose-6-phosphate transporter. Three patients with glycogen
storage disease type IB were treated with granulocyte colony—stimulating
factor for an average of 6.9 yr and received an average dose of 2.8 µg/kg
body weight per day. Data of individual patients are summarized in
Table 1. Two patients with
glycogen storage disease type IB did not receive granulocyte
colony—stimulating factor because they had an adequate response to
treatment of infection with antibiotic therapy. All patients treated with
granulocyte colony—stimulating factor had bone marrow aspirations from
the iliac or tibial bones; in two patients, bone marrow aspirations were
performed at the time of MR imaging. In one patient, the aspiration was 2
months later. Except for one patient with glycogen storage disease type IB who
had pain in the right ankle joint, all other subjects were without symptoms in
the skeletal regions examined.
MR imaging of the lower extremity was performed on Gyroscan NT 1.0-T
(Philips Medical Systems, The Netherlands) and Magnetom Vision 1.5-T (Siemens
Medical Systems, Erlangen, Germany) scanners. We chose the lower extremity for
two reasons: first, for valid comparison to prior studies dealing with the
effect of granulocyte colony—stimulating factor. Second, a total
conversion of fatty bone marrow in the lower extremity allowed us better
detection of marrow changes, especially considering the age of the patient.
Phased-array body or circular polarized knee coils were used. The examination
protocol included the following sequences: coronal short-tau inversion
recovery (STIR) sequence (TR/TE, 3975/30; slice thickness, 4.0 mm), coronal
T1-weighted spin-echo sequence (450/14; slice thickness, 4.0). MR images were
reviewed (in random order) independently by two experienced radiologists who
were blinded to the subtypes of disease, granulocyte colony—stimulating
factor therapy, and results obtained at bone marrow aspirates.
For each examination reviewed, the various appearances of signal
intensities, their distributions in bone marrow, and bone morphology were
evaluated. The signal intensity of the bone marrow was classified as fatty
(signal isointense to subcutaneous fat on T1-weighted and STIR images) or
nonfatty (hypointense on T1-weighted and hyperintense on STIR sequences). The
pattern of signal changes was classified as homogeneous or inhomogeneous
according to its distribution. In case of inhomogeneous changes, nonfatty bone
marrow signals an additional classification into small-spotted disseminated
(areas with a size range, 1-10 mm) or patchy-coalescing (areas with a size
range, >1 cm). Bone marrow appearances at identical sites in T1-weighted
and STIR studies were compared for each patient. The MR images were evaluated
and compared with bone marrow aspirations and the clinical data of each
patient according to these guidelines.
Results
The signal changes in the two patients with glycogen storage disease type
IA were uniformly classified as homogeneous-fatty. In contrast, the signal of
bone marrow in all patients with glycogen storage disease type IB was
evaluated as nonfatty. MR imaging signal properties are summarized in
Table 1. Two different types of
signal distribution and intensities were noted in patients with glycogen
storage disease type IB. Areas of homogeneous signal changes were visible in
the three patients who received treatment with granulocyte
colony—stimulating factor. Almost the entire marrow of the long bones of
the lower extremity was affected (Figs.
1A and
1B). An inhomogeneous pattern
of distribution was seen in the two patients without treatment with
granulocyte colony—stimulating factor. The most marked changes were seen
in the metaphyseal regions of the knee and ankle joints. Here, the signal
changes were large and partially coalescing (Figs.
2A and
2B). In the epiphyseal and
diaphyseal regions, the pattern of signal changes was spotty and disseminated.
The epiphyseal, diaphyseal, and tarsal bones of the patients treated with
granulocyte colony—stimulating factor showed signal changes that were
not seen in the patients without treatment.
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Fig. 1A. —20-year-old-man with glycogen storage disease type IB treated
with granulocyte colony—stimulating factor. Unenhanced coronal
T1-weighted spin-echo image of thigh and knee joint (TR/TE, 450/14; slice
thickness, 4.0 mm) reveals homogeneous hypointense signal (compared with
subcutaneous fat) of diaphyseal and metaphyseal bone marrow and spotty
inhomogeneous signal of epiphyseal bone marrow.
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Fig. 1B. —20-year-old-man with glycogen storage disease type IB treated
with granulocyte colony—stimulating factor. Unenhanced coronal
fat-suppressed short-tau inversion-recovery sequence (3975/30; slice
thickness, 4.0 mm) at same level as A shows homogeneous hyperintense
bone marrow signal of epiphyseal, metaphyseal, and diaphyseal region.
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Fig. 2A. —14-year-old boy with glycogen storage disease type IB without
treatment with granulocyte colony—stimulating factor. Unenhanced coronal
T1-weighted spin-echo sequence (TR/TE, 450/14; slice thickness, 4.0 mm) of
thigh and knee joint reveals spotty inhomogeneous hypointense signal in
epiphysis and metaphysis of bone marrow cavity.
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Fig. 2B. —14-year-old boy with glycogen storage disease type IB without
treatment with granulocyte colony—stimulating factor. Unenhanced coronal
fat-suppressed short-tau inversion-recovery sequence (3975/30; slice
thickness, 4.0) at same level as A reveals spotty inhomogeneous
hyperintense signal in epiphysis and metaphysis of bone marrow cavity with
metaphyseal coalescing bands of signal changes.
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Bone marrow aspirations taken from either the tibial metaphyses or areas
undocumented on MR imaging (iliac bone) showed abnormal myeloid maturation
with a mixture of hyperplastic cells (Fig.
1C). In every aspirate, extensive hypercellularity with a leftward
shift and hyperplasia of the myelopoietic cells were present.
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Fig. 1C. —20-year-old-man with glycogen storage disease type IB treated
with granulocyte colony—stimulating factor. Photomicrograph of
histopathologic specimen of bone marrow aspiration of iliac bone shows marked
hypercellularity of marrow cavity with clusters and reduction of total fatty
marrow and normal width of trabecular bone. (H and E, x 16)
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In all patients with glycogen storage disease type IB, the signal changes
were limited to bone marrow. Periosteal reactions or signal abnormalities of
the surrounding tissues were not seen. The patients without treatment with
granulocyte colony—stimulating factor had normally shaped bones. In
contrast, one patient treated with granulocyte colony—stimulating factor
had an undertubulation of the distal femoral metaphysis
(Fig. 3). The STIR sequence
appeared more sensitive than the T1-weighted sequence in identifying bone
marrow changes by showing signal alterations that were seen as an
inhomogeneous pattern or that were within the limits of normal on T1-weighted
imaging.
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Fig. 3. —14-year-old girl with glycogen storage disease type IB
treated with granulocyte colony—stimulating factor. Unenhanced coronal
fat-suppressed short-tau inversion-recovery sequence of thigh and knee joint
(TR/TE, 1500/15; slice thickness, 4.0 mm) shows undertubulation of distal
thigh metaphysis (Erlenmeyer flask deformity) and homogeneous hyperintense
marrow signal.
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The patient with a painful right ankle joint showed, in addition to the
previously mentioned coalescing areas of signal change, a unilateral lesion
localized in the talus (diameter, 1.6 cm) with a hyperintense signal on STIR
and a hypointense signal on T1-weighted sequences indicating avascular
osteonecrosis (Figs. 4A and
4B). The presumptive diagnosis
of an avascular necrosis was confirmed by histologic workup.
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Fig. 4A. —23-year-old woman with glycogen storage disease type IB and
pain in ankle joint. Unenhanced coronal T1-weighted spin-echo sequence (TR/TE,
500/14; slice thickness, 4.0 mm) shows hypointense and diffusely delineated
avascular necrosis (diameter, 1.6 cm) in talus and accompanying effusion in
ankle joint. Tibial marrow shows hypointense signal.
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Fig. 4B. —23-year-old woman with glycogen storage disease type IB and
pain in ankle joint. Unenhanced coronal fat-suppressed short-tau
inversion-recovery sequence (3975/30; slice thickness, 4.0) at same level as
A reveals strongly hyperintense signal of lesion and increased signal
of tibial marrow.
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Discussion
A rather characteristic feature in glycogen storage disease type IB is
neutropenia accompanied by bone marrow hypercellularity, resulting from an
arrest of myeloid maturation, with normal development in the initial stages.
The cause of these features is unknown. Abnormal findings have been described
in bone marrow aspirations of patients with glycogen storage disease type IB
[8,
9]. As reviewed by Gitzelmann
and Bossshard [4],
approximately half of the bone marrow examinations performed in patients with
glycogen storage disease type IB before 1990 showed myeloid hyperplasia. None
of these patients were treated with granulocyte colony—stimulating
factor, which was not initiated in this specific disorder until 1991
[6]. To our knowledge, a
comparable report on bone marrow aspirations from patients undergoing
granulocyte colony—stimulating factor therapy is not available, nor does
any publication exist on MR imaging changes that occur in bone marrow in
glycogen storage disease type IB independent of treatment with granulocyte
colony—stimulating factor.
In our study, MR imaging was used as a non-invasive means to depict changes
in bone marrow, with superior soft-tissue contrast
[10]. Evaluation of marrow
abnormalities on MR imaging in children and juveniles is complicated by
age-dependent alteration in the distribution of hematopoietic and fatty marrow
[11,
12]. In patients 10-20 years
old, fatty (yellow) marrow predominates in the limbs with residual
hematopoietic (red) marrow in the femur and humerus metaphyses
[13]. The short-T1 and long-T2
relaxation times of fatty bone marrow yield a hyperintense signal in both
sequences. Because of the suppression of fat signal in the STIR sequence,
yellow bone marrow has low signal intensity
[14,
15]. These normal MR imaging
findings of bone marrow were observed in our patients with glycogen storage
disease type IA.
The previously described signal changes in patients with glycogen storage
disease type IB with spotty areas of low signal in T1-weighted and a
corresponding hyperintense partially coalescing signal in STIR sequences are
markedly different from the appearance of bone marrow in healthy subjects. In
our patients with glycogen storage disease type IB who were 12-23 years old,
on MR imaging, we found hematopoietic marrow in regions in which normally
fatty conversion is expected. This finding most probably reflects myeloid
hyperplasia. The imaging findings suggest that the stimulation of
hematopoietic cells in glycogen storage disease type IB increases their number
and function enough to result in a change in marrow appearance that can be
detected by MR imaging.
To reduce the number of infections, patients with glycogen storage disease
type IB have been treated with granulocyte colony—stimulating factor, a
glycoprotein that stimulates proliferation and differentiation of
hematopoietic cells [16]. By
this measure, a sustained elevation in circulating neutrophils from low counts
to low-normal values can be achieved
[6]. Because treatment with
granulocyte colony—stimulating factor was shown to be associated with an
increase in bone marrow cellularity, we speculate that an almost complete
conversion of the fatty to the hematopoietic bone marrow, at least of the
limbs as indicated by MR imaging, is necessary to generate a relatively small
increase in circulating neutrophils. This assumption is supported by an
already increased myelopoietic activity, as indicated by the patchy MR imaging
changes in the bone marrow, with basal conditions in glycogen storage disease
type IB without treatment with granulocyte colony—stimulating
factor.
There are a few reports on MR imaging changes occurring in the bone marrow
treated with granulocyte colony—stimulating factor that concern patients
with musculoskeletal malignancies
[17,18,19,20].
In these patients, length of treatment with granulocyte
colony—stimulating factor and dosage differed significantly from that in
our patients with glycogen storage disease type IB. In patients with tumor,
granulocyte colony—stimulating factor was used to temporarily weaken the
myelosuppressive effect of chemotherapy over a course of 10-16 days, whereas
our patients received long-term treatment with granulocyte
colony—stimulating factor over a period of years (mean, 6.9 yr).
Evaluation of serial MR imaging examinations of patients with tumor treated
with granulocyte colony—stimulating factor revealed small spotty signal
changes in the bone marrow. These changes were compatible with histologically
proven partial reconversion of fatty marrow into active myelopoietic marrow
[17,
19,
20]. To what extent the broad
areas of homogeneous signal changes occupying almost the entire marrow cavity
in patients with glycogen storage disease type IB are a result of higher doses
of granulocyte colony—stimulating factor remains uncertain at this
point. A correlation between granulocyte colony—stimulating factor
dosage and signal changes in MR imaging in tumor patients has not been
established [17]. Despite
various doses of granulocyte colony—stimulating factor in our patients,
the signal changes in MR imaging seen in this study were rather uniform.
Because the patients had already been treated with granulocyte
colony—stimulating factor for several years at the time of this study,
it remains unclear whether significant changes in signal may have existed at
an earlier time or are to be expected at a later follow-up date. Because of
widespread signal changes seen in the areas examined in this study, further
and similar changes in other skeletal regions can also be expected. This
hypothesis, a correlation among absolute neutrophil counts, the frequency of
infections, and the presence of changes shown in MR imaging, needs further
clarification. In the meantime, it is important to recognize the possibility
of signal-intensity changes in the bone marrow of patients with glycogen
storage disease type IB, which can be iatrogenically accelerated in those
patients receiving growth factor support.
Because of the unilateral appearance, accompanying joint effusion and the
localization avascular necrosis in one patient were distinguishable from the
previously described signal changes in glycogen storage disease type IB.
Because no reports exist on avascular necrosis in conjunction with glycogen
storage disease, it remains unclear whether these changes were coincidental or
related entities caused by hypercellularity. Avascular necrosis as a result of
hypercellular infiltration of the bone marrow, for example in leukemia, has
been previously observed [21].
In our patient, the avascular necrosis was located in the talus and, thus, in
a comparatively unchanged skeletal region for patients with glycogen storage
disease type IB.
Besides the evidence of avascular necrosis in patients with glycogen
storage disease type IB, the question of morphologically detectable
myelodysplastic changes on MR images based on preceding myeloid hyperplasia
remains clinically significant. Although none of our patients showed signs of
malignant transformation, the signal characteristics seen in our imaging are
the basis for detecting other abnormal changes compared with expected changes
in patients with glycogen storage disease type IB.
In conclusion, on the basis of a small series of patients, we suggest that
in patients with glycogen storage disease type IB, an increased myelopoietic
activity of bone marrow caused by functionally impaired leukocytes can be
shown by MR imaging. Treatment with granulocyte colony—stimulating
factor further accentuates the bone marrow changes and may represent the
clinical increase in neutrophil number seen in these patients. Histologic
correlation supports the hypothesis that these signal changes in MR imaging
are attributable to conversion from fatty to hematopoietic marrow.
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Abstract
Introduction
