British Journal of Radiology 75 (2002),A37-A44 © 2002 The British Institute of Radiology
Bone complications in children with Gaucher disease
B Bembi, MD
1
G Ciana, MD
1
E Mengel, MD
2
M R Terk, MD
3
C Martini
1 and
R J Wenstrup, MD
4
1 Burlo Garofolo Institute, Trieste, Italy, 2 Children's Hospital of the Johannes-Gutenberg University, Mainz, Germany, 3 Keck School of Medicine, University of Southern California, USA and 4 Children's Foundation Research Hospital, Cincinnati, Ohio, USA
Correspondence: Dr Bruno Bembi, Burlo Garofolo Institute, Via dell'Istria 65/1, 34137 Trieste, Italy. Tel. +39 40 3785500; Fax +39 40 3785210; email bembi{at}burlo.trieste.it
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Abstract
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For paediatric patients with Gaucher disease, enzyme replacement therapy (ERT) has the potential to prevent the development of serious, irreversible skeletal complications. Analysis of skeletal data for paediatric patients receiving ERT must take into account the pubertal growth spurt and developmental changes in bone marrow composition. In a study conducted at the Burlo Garofolo Institute in Trieste, Italy, 10 paediatric patients have received ERT, and data are available for 3–9 years of follow-up. ERT was associated with a significant increase in the mean lumbar bone mineral density (BMD) Z score after 2 years of treatment (p=0.003). Skeletal growth rates increased among patients exhibiting growth delays. At the Gaucher Disease Treatment Center in Cincinnati, OH, USA, a total of 11 paediatric patients have been followed for 2 years or more of ERT. Of these 11 patients, 6 have demonstrated significant increases in lumbar BMD after 2 years of ERT; these patients tended to have lower BMD Z scores at the start of ERT. At the Children's Hospital of the Johannes-Gutenberg University in Mainz, Germany, 7 children with type 1 Gaucher disease presented with reduced BMD in the distal ulna, and after 18–24 months of ERT, these patients demonstrated increases in BMD at this site. The patients exhibiting growth retardation experienced growth acceleration during treatment. These studies suggest that ERT improves BMD and growth rates in paediatric patients with Gaucher disease. ERT in paediatric patients may have the potential to prevent serious skeletal complications such as fractures and vertebral compression later in life.
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Introduction
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Enzyme replacement therapy (ERT) with alglucerase and imiglucerase is efficacious for treating the visceral and haematological aspects of Gaucher disease, and treatment responses are seen within months [1]. Although studies have shown that ERT is also effective for halting or reversing the skeletal pathology of Gaucher disease, less is known regarding the duration of ERT needed to observe a response to ERT and the optimal dosing regimen for treating the skeleton, particularly for paediatric patients [1]. Children have comprised only about one third of the patients enrolled in studies of ERT for Gaucher disease, so there is less data on the benefits of ERT in children than in adults. Effective treatment needs to be established in paediatric patients with Gaucher disease because the disease tends to progress more rapidly in children than in adults [2], and in approximately 50% of children growth is retarded (from 3 to 5 years of age) and puberty is delayed [3–5]. Early treatment may permit normal growth and prevent skeletal complications [1], which are the most chronic and debilitating aspects of the disease [2, 6].
The interpretation of the effects of ERT on skeletal manifestations of Gaucher disease in paediatric patients is complicated by developmental changes in bone and bone marrow and by practical considerations in dealing with younger patients. Nevertheless, a small body of clinical data suggests that ERT reverses bone marrow involvement, normalizes skeletal growth and increases bone mineral density (BMD) in paediatric patients [1, 7]. This paper will review unique problems associated with the radiological imaging of paediatric patients with Gaucher disease and some recent data on the effects of ERT on lumbar BMD, growth rates and bone marrow involvement.
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Radiological imaging in paediatric patients
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For both paediatric and adult patients with Gaucher disease, the goals of radiological imaging are to measure disease burden and progression, to characterize the skeletal complications, and to assess the response to therapy. Paediatric patients present unique problems with regard to radiological imaging methods and interpretation of data because of psychological, anatomical and developmental differences.
Paediatric patients may not be able to co-operate fully with examinations, particularly with methods such as MRI that require the patient to lie completely still for extended periods of time. Sedation of paediatric patients during radiological imaging is often required. For patients under the age of 2 years, chloral hydrate 75–100 mg/kg of body weight and a maximum total dose of 2 g are recommended. This agent is well tolerated at a wide range of dosages, but repeated fractional doses are to be avoided. Choices of sedation for patients aged 2 years and older include chloral hydrate, thiopental (rectal administration), pentobarbital 2–3 mg/kg (intravenous (IV)), pentobarbital with fentanyl citrate (IV), midazolam and ketamine. Dosages may follow Young's rule
or Clark's rule
Gaucher disease is commonly associated with hepatosplenomegaly and occasionally other organs, including the kidneys or lungs, are affected. When interpreting visceral organ images of paediatric patients obtained using CT, the ratio of visceral volume to body mass in normal paediatric patients and adults must be taken into account. For normal infants, ratios of normal visceral volume to body mass are 34.1 ml/kg for the liver and 4.5 ml/kg for the spleen, and for normal adolescents the ratios are 20.2 ml/kg for the liver and 2.4 ml/kg for the spleen.
Osteopenia is observed in virtually all patients with Gaucher disease. Assessment of the efficacy of ERT for treating osteopenia is more complicated in children than in adults. The size of the bone, pubertal status, stage of skeletal maturation, body composition and race/ethnicity all affect the BMD [8].
Bone marrow infiltration is a common finding among patients with Gaucher disease, including children. The infiltration of fatty or yellow bone marrow by Gaucher cells reduces marrow fat concentration to an extent that can be detected by MRI using spin echo sequences, with affected bone marrow exhibiting decreased T1- and T2-weighted signal intensities [9, 10]. Interpretation of MRI of the bone marrow in children with Gaucher disease may differ from that of adults because of developmental differences in composition. Bone marrow in the spinal column and appendicular skeleton of young children is mainly composed of red bone marrow with a higher content of water in comparison to fat marrow, which is replaced by yellow bone marrow during childhood, adolescence and early adulthood [11, 12]. Figure 1 shows the normal developmental pattern of change from red marrow to yellow marrow in the femur. The normal expression of red marrow in these bones in children makes it more difficult to gauge the extent of marrow infiltration by Gaucher cells, and the developmental shift to yellow marrow can be misinterpreted as response to treatment. Quantitative chemical shift imaging (QCSI) may be an accurate method of measuring increases of the fat fraction in the lumbar spine in children receiving ERT [13].
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Figure 1. Developmental conversion of red to yellow marrow in the femur (ages are in years) [12]. Reproduced, with permission of theRadiological Society of North America, from: Moore SG, Dawson KL. Red and yellow marrow in thefemur: age-related changes in appearance at MR imaging. Radiology 1990;175:219–23.
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Normal growth and skeletal maturation may be delayed in paediatric patients with Gaucher disease [3, 5], and radiological evaluation of paediatric patients should include assessment of skeletal age. Standard references for skeletal age include that by Greulich and Pyle [14]. One retrospective study of 57 children with type 1 Gaucher disease with growth delays found that both untreated patients and those receiving ERT had a late growth spurt that enabled them to achieve full height as predicted on the basis of parental height [5]. Another retrospective study of 99 children with type 1 Gaucher disease observed acceleration of previously delayed growth only in patients receiving higher doses of ERT (60–120 U/kg per 4 week period) [4]. More research is required to understand the effects of ERT on growth rate and attainment of full height.
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Italian data
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Data on the effect of ERT on BMD and other skeletal pathologies in paediatric patients with type 1 Gaucher disease were obtained from the Burlo Garofolo Institute in Trieste, Italy. 10 patients received ERT (starting with alglucerase and then switching to imiglucerase) for a period ranging from 3 to 9 years. The dose ranged from 20 to 45.5 U/kg (given every 2 weeks), with a mean dose of 26.75 U/kg. Lumbar spine BMD was assessed using dual-energy X-ray absorptiometry (DXA) during the first year of therapy, except for one patient for whom DXA was performed before the start of ERT, and after 2 years and after 3–9 years of treatment. Osteonecrosis was monitored by plain radiography. Skeletal growth was also assessed by radiography of the left wrist, using standards of Gruelich and Pyle.
These patients had a history of hepatosplenomegaly, anaemia, thrombocytopenia, failure to thrive and bone pain (Table 1). Eight of the 10 patients had altered bone density and half had Erlenmeyer flask deformity. The skeletal manifestations of Gaucher disease in these patients are summarized in Table 2.
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Table 1. Baseline general clinical assessment of paediatric patients with type 1 Gaucher disease for the study at the Burlo Garofolo Institute
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Table 2. Baseline history of skeletal involvement among paediatric patients with type 1 Gaucher disease at the Burlo Garofolo Institute
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None of these patients experienced bone crisis during the follow-up period. ERT in these patients was associated with a significant increase in mean lumbar BMD Z score after 2 years of treatment (from -2.17±1.25 at baseline to -1.57±0.97; p=0.003). At follow-up visits ranging from year 3 to year 9, ERT was associated with increases from baseline in the BMD Z score for 9 of the 10 patients (Table 3). In the 2 patients with osteonecrosis, the pre-existing sites did not exhibit improvement discernible with plain radiography, but no new sites of osteonecrosis were detected during treatment. These two patients experienced initial relief of pain associated with osteonecrosis. However, both patients experienced pain recurrence, probably owing to the progression of joint collapse secondary to osteonecrosis, during low dose therapy (20 U/kg/month). One of these patients had osteonecrosis of the left femoral head, and the pain recurred during year 8 of treatment; the other patient had osteonecrosis of the right femoral head, and the pain recurred during year 9 of treatment. Patients with growth delays achieved normal growth rates within 1–3 years after starting treatment (data not shown).
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Table 3. Changes in bone mineral density Z scores with enzyme replacement therapy in paediatric patients with type 1 Gaucher disease at the Burlo Garofolo Institute
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American data
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The Gaucher Disease Treatment Center at the Children's Hospital in Cincinnati, USA, is a mostly quaternary care centre that treats children and adults with Gaucher disease. Most of the patients receiving treatment at the Gaucher Disease Treatment Center were referred there after failing to respond to treatment at other centres.
Currently, 24 paediatric patients with Gaucher disease are receiving ERT at the Gaucher Disease Treatment Center, with a mean treatment duration of 1 year, and the effects of ERT on lumbar BMD are being assessed. The mean age of these patients at the start of ERT at this centre was 10.5 years (range 1.8–17.8 years), and the mean height and weight for these patients was not significantly different to that for age- and sex-matched controls. However, the mean lumbar BMD Z score, determined using DXA, at the start of ERT was significantly lower in paediatric patients with Gaucher disease than in normal children (p=0.006; Table 4). The individual lumbar BMD Z scores were plotted according to paediatric patients' ages, and regression analysis showed a trend for an age-related decrease in lumbar BMD (Figure 2).
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Table 4. Demographic characteristics of patients receiving enzyme replacement therapy at the Gaucher Disease Treatment Center, Cincinnati, OH, USA
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Figure 2. Lumbar vertebra bone mineral density (BMD) Z scores for paediatric patients at the Gaucher Disease Treatment Center in Cincinnati according to age.
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11 paediatric patients have been assessed for 2 years or more of ERT at the Gaucher Disease Treatment Center. 6 of these patients demonstrated increases in lumbar BMD after at least 2 years of ERT. The patients who did not show increases tended to have higher baseline lumbar BMD Z scores than those who did show improvement in lumbar BMD (Figure 3).
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Figure 3. Lumbar vertebra bone mineral density (BMD) Z scores for paediatric patients at the Gaucher Disease Treatment Center in Cincinnati according to year of treatment. ERT, enzyme replacement therapy.
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German data
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The efficacy of ERT for treating skeletal complications in Gaucher disease was assessed at the Children's Hospital of the Johannes-Gutenberg University in Mainz, Germany, in 16 children with type 1 Gaucher disease. None had a history of bone pain or avascular necrosis before starting ERT. All 16 patients received ERT for at least 12 months, with a mean of 62 months (range 24–114 months). Therapy was started using a high dose ranging 98 to 130 U/kg/month. Maintenance doses, based on stabilization of visceral disease, were established for these patients; the mean maintenance dose was 73.5 U/kg/month (range 28–100 U/kg/month).
Data on BMD in the distal ulna obtained using DXA at baseline and after 18–24 months of treatment were available for 11 patients (Figure 4). A clinically relevant reduction in distal ulna BMD Z score, defined as ![{els]](/math/els.gif)
-1.5, was observed in 7 of the children and all of these patients showed increasing bone density at this site after treatment. Growth retardation was exhibited by 8 of the children before treatment. Growth acceleration occurred during ERT among these patients, and 6 of the 8 children achieved a normal height for their age (data not shown).
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Figure 4. Bone mineral density Z scores for the distal ulna before and after 18–24 months of treatment at the Children's Hospital of the Johannes-Gutenberg University.
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Discussion
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Data from the Gaucher Registry (an international, observational, longitudinal registry established by The Genzyme Corporation in 1991) demonstrate that osteopenia, which is associated with an increased risk of pathological fractures, is prevalent among patients with Gaucher disease[15, 20]. Consistent with those data is the finding presented here of an apparent age-related decrease in BMD among paediatric patients with Gaucher disease. The three studies described here found that ERT was associated with significantly increased BMD as measured with DXA, in more than half the paediatric patients. In two of the studies, patients who exhibited BMD treatment response tended to have lower BMD scores at the start of treatment. These results suggest that ERT for paediatric patients may reduce the risk of pathological fracture and may be an effective treatment for osteopenia in these patients. ERT may maintain BMD and lessen the risk of developing osteopenia in patients with near-normal BMD Z scores.
The extent of osteopenia and the response to ERT by both paediatric and adult patients with Gaucher disease have been studied at the Burlo Garofolo Institute [21]. The paediatric patients at the Burlo Garofolo Institute presented a more diffuse form of osteopenia, whereas the adult patients had more focal involvement. Increases in lumbar vertebra BMD were observed by year 2 of ERT for both patient groups. Investigators at the Gaucher Disease Treatment Center at the Children's Hospital in Cincinnati and the Children's Hospital of the Johannes-Gutenberg University observed significant increases in BMD in the lumbar vertebra and distal ulna by year 2 of ERT.These responses were more rapid than thoseobserved by adult patients in a study by Rosenthal et al [13], in which significant increases in trabecular bone density of the lumbar vertebra, as measured using dual-energy quantitative CT, were not seen until patients had received 42 months of ERT. Although the data presented here suggest that increases in BMD may be attained with 2 years of ERT, more research is needed to determine treatment response time for improving osteopenia in patients with Gaucher disease.
Data from Rosenthal et al suggest that there may be an interaction between skeletal growth and increases in BMD in response to ERT in paediatric patients [13]. In that study, 7 of 8 paediatric patients exhibited increases in the mass of cortical bone in the midfemoral and midtibial diaphyses as measured from radiographs, and 4 of these patients achieved normalization or near-normalization of cortical bone mass at these sites. The 7 patients achieving increases in cortical bone mass were the only patients in the study to demonstrate skeletal growth during ERT.
Interpretation of the effects of ERT on skeletal response in children must take into account the influence of the pubertal growth spurt. In the study conducted at the Burlo Garofolo Institute and at the Children's Hospital of the Johannes- Gutenberg University, ERT was associated with an accelerated growth rate in children who exhibited a growth delay. Other investigators have suggested that ERT may help prevent or offset pubertal delay [5]. However, Gaucher disease patients who did not receive ERT during childhood have also been observed to achieve a normal height, although this growth was often delayed [1, 5]. The precise relationship between the onset of puberty, skeletal growth and response to ERT in paediatric patients with Gaucher disease is not yet understood.
None of the children included in the three studies experienced a bone crisis during treatment. This result is consistent with the findings of some previously reported small studies that showed that there were no bone crises or there was a greatly reduced frequency of bone crises among patients receiving ERT [16–19].
In conclusion, these studies indicate that treatment with ERT improves BMD in paediatric patients with Gaucher disease, and that this response to ERT may be seen after 2 years of treatment for some patients. Because it can increase BMD, ERT for paediatric patients may have the potential to prevent serious skeletal complications such as fractures and vertebral compression later in life.
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Acknowledgments
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We would like to thank and acknowledge the invaluable input from Pierpaolo Guastalla, MD (Instituto per l'Infanzia Burlo Garofolo, Trieste, Italy), Floriana Zennaro, MD (Instituto per l'Infanzia Burlo Garofolo, Trieste, Italy), Gregory A Grabowski, MD (Children's Foundation Research Hospital, Cincinnati, OH, USA) and Laurie Bailey, MS (Children's Foundation Research Hospital, Cincinnati, OH, USA).
Received for publication November 2, 2001.
Revision received January 3, 2002.
Accepted for publication January 14, 2002.
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Abstract
Introduction
