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|Imagerie de la maladie de Gaucher de type 1 chez l’enfant|
|La surveillance radiologique systématique joue un rôle essentiel dans l’évaluation de la progression de la maladie de Gaucher et de la réponse au traitement : chez l’enfant elle requiert une attention particulière afin de minimiser l’exposition aux rayonnements et d’interpréter l’importance de l’atteinte médullaire au regard des modifications normales liées à la croissance. Le groupe de travail sur la maladie de Gaucher recommande la pratique d’une IRM des fémurs, du bassin et du rachis (soit une bonne partie du compartiment médullaire osseux) au moment du diagnostic puis tous les 2 ans. Une absorptiométrie biphotonique est recommandée tous les ans (rachis lombaire, fémur proximal et corps entier). La radiographie n’est pas hautement spécifique ni sensible mais elle peut représenter une première technique d’évaluation osseuse quand l’accès à l’IRM est limité. Elle permet de visualiser certaines atteintes osseuses de la maladie de Gaucher et s’avère particulièrement utile dans l’identification des causes de douleurs osseuses aiguës (fractures pathologiques, ostéonécrose) et dans le suivi post-arthroplastie. Plus rarement elle permet d’évoquer le diagnostic de maladie de Gaucher devant la découverte de la déformation classique en flacon d’Erlenmeyer (élargissement de la région métaphyso-diaphysaire des os longs). La splénectomie est associée à l’apparition de lésions ostéolytiques, d’ostéonécrose et de diminution de la densité minérale osseuse. Les découvertes radiographiques incidentes constituent rarement le premier indice d’une maladie de Gaucher chez un enfant.|
Imaging Findings in Pediatric Type 1 Gaucher Disease: What the Clinician Needs to Know
Green, Brian A. MD*; Alexander, Alan A.Z. MD†; Hill, Phillip R. MD*; Lowe, Lisa H. MD‡
*Department of Radiology, University of Missouri School of Medicine, 1 Hospital Drive, Columbia
‡Department of Radiology, University of Missouri-Kansas City and Children's Mercy Hospital and Clinics, Kansas City, MO
†Department of Radiology, University of Virginia, 1 Hospital Drive, Charlottesville, VA
The authors have no financial disclosures to report.
Reprints: Alan A.Z. Alexander, MD, Department of Radiology, University of Virginia, 1 Hospital Drive, Charlottesville, VA 22908 (e-mail: email@example.com; e-mail: firstname.lastname@example.org).
This study presents visceral and skeletal imaging findings commonly observed in pediatric patients with type I Gaucher disease. Presented images show methods used for radiologic assessment of pediatric Gaucher patients, and imaging findings are discussed in the context of the underlying pathophysiology of the disease. Routine radiologic surveillance plays a central role in assessing Gaucher disease progression and response to treatment, but monitoring of pediatric patients presents specific challenges with regard to minimizing radiation exposure and interpreting extent of marrow involvement against the backdrop of normal growth-related changes in marrow composition. In addition to highlighting imaging findings in children with type I Gaucher disease, this manuscript discusses alternate modalities, which minimize radiation and may be just as accurate, if not better, than conventional methods exposing the child to radiation.
Keywords: gaucher disease; marrow; hepatosplenomegaly; imaging; enzyme replacement therapy
Table of contents
Gaucher disease is an inherited autosomal recessive metabolic disorder resulting from mutations in the gene encoding [beta]-glucocerebrosidase, an enzyme in the glycosphingolipid degradation pathway.1 Glucocerebrosidase deficiency leads to massive accumulation of the insoluble lipid glucocerebroside in lysosomes of cells of monocyte/macrophage lineage, principally macrophages. Engorgement with glucocerebroside alters macrophage morphology producing the so-called “Gaucher cells” that are a hallmark of the disease (Fig. 1). Gaucher cells may occur anywhere where macrophages are found, but they are particularly abundant in tissues of the reticuloendothelial system.
Symptoms and management
Gaucher disease is a rare disorder, but is the most commonly occurring lysosomal storage disease.1 Gaucher disease has been divided into 2 major clinical subtypes based on whether the nervous system is affected. The non-neuronopathic form, designated as type 1, accounts for 90% of all cases.2 The extremely rare neuronopathic variants have been subdivided into acute (type 2) and subacute (type 3) forms. Type 2 manifests in early infancy and is characterized by rapidly progressive nervous system and brain degeneration with patients seldom surviving past 2 years of age.3 Type 3 has a more protracted course with neurological signs appearing in late infancy or childhood. Inidividuals reaching adolescence may survive into their third or forth decade.1,3
Non-neurological manifestations of Gaucher disease are due to progressive infiltration of organs by Gaucher cells. Anemia, thrombocytopenia, and hepatosplenomegaly arise in all 3 forms of the disease. Patients with type 1 disease commonly develop skeletal complications due to bone marrow infiltration. Macrophage activation concomitant with lipid deposition can cause chronic, low-grade inflammation or acute flare-ups with severe bone pain.4 Children with type 1 Gaucher disease are frequently growth restricted and experience delayed puberty.4,5
Treatment for type 1 disease is enzyme replacement therapy (ERT) using macrophage-targeted recombinant human glucoceribrosidase (Cerezyme, Genzyme Corporation, Cambridge, MA).6 Treatment goals include alleviating symptoms, reducing hepatosplenomegaly, stabilizing or reversing skeletal disease, and for children, restoring normal growth rates.2,6 Most type 1 patients have near normal life spans, particularly if ERT is started early.1
A misconception about type 1 is that it is an “adult” form of Gaucher disease; 66% of type 1 patients are diagnosed before the age of 20 years.6 Childhood onset of type 1 disease generally predicts a more rapid, severe course.6,7 Noting an underappreciation of the prevalence and severity of pediatric type 1 disease, the International Collaborative Gaucher Group has called for increased focus on recognizing and assessing non-neuronopathic Gaucher disease in children.7
Although imaging is not generally used for diagnosis, radiology at initial presentation is useful in assessing initial severity and extent of disease in the skeleton. Furthermore, it plays an important role in monitoring disease progression and response to ERT. Careful monitoring of skeletal disease is essential for preventing irreversible complications and crippling disability.8 The following is a review of visceral and skeletal imaging findings typically encountered in children with type 1 Gaucher disease.
Spleen and liver imaging findings
Hepatosplenomegaly is one of the most common effects of Gaucher disease (Fig. 2A). In children, splenomegaly can be marked and often is accompanied by growth failure, cachexia, and hypermetabolism.5 Significant organ enlargement increases the likelihood of focal abnormalities identified with cross-sectional imaging, including Gaucher cell aggregations, vascular infarctions, and regions of fibrosis 5 (Fig. 2B).
Reductions in spleen and liver size are early, sensitive indicators of response to ERT.6 Therefore, obtaining accurate baseline measures of organ volumes is important for assessing treatment response and adjusting ERT dosage. Magnetic resonance imaging (MRI) and computed tomoghaphy (CT ) were generally considered to be superior to ultrasound (US) for making volume determinations, especially in older children, and have greater accuracy and increased sensitivity for detecting focal lesions (Fig. 3). However, recently developed 3-dimensional techniques available on contemporary US machines may offer an alternative method to assess organ volumes in younger children without need for sedation or ionizing radiation exposure. Many Gaucher specialists consider US measures to be sufficiently accurate for clinical decision making.9
International Collaborative Gaucher Group guidelines recommend volume determination for children at baseline, when ERT is begun, at time of dosage change, and every 12 to 24 months thereafter.6 Measured volumes can be compared with age-based or weight-based estimates of normal volumes to determine extent of enlargement.10,11
Skeletal imaging findings
Skeletal complications are the most painful and disabling aspect of type 1 disease, with the long bones and vertebrae being most commonly affected.6 Skeletal effects are not because of glucocerebroside deposition per se, but rather result from marrow packing and replacement by Gaucher cells. Effects related to marrow infiltration by Gaucher cells include vascular occlusion, ischemia, and cytokine-induced alterations in bone turnover rates.2,10 More than 80% of patients have some degree of skeletal involvement.12 Skeletal disease manifestations include bone pain related to inflammation and edema, trabecular resorption with fibrosis, generalized osteopenia, cortical thinning and bone remodeling, pathologic fractures, and joint deformity or collapse due to avascular necrosis. Joint replacement surgery may be necessary; however, arthroplasty failure rates are higher for Gaucher-diseased bones.13
Skeletal response to ERT is slow and may take years. Children respond more quickly than adults, possibly because of their higher bone turnover rates.14 Treatment goals in pediatric patients are to prevent pain and osteonecrosis and to restore bone mineral density by the second year of treatment.2
As substantial marrow infiltration can occur before changes become apparent on plain radiographs, MRI is the preferred modality for monitoring skeletal disease.6,13 T1-weighted sequences are most sensitive for detecting marrow infiltration (Fig. 4A). Mature, adipose-containing marrow is normally hyperintense on T1-weighted MR images, but Gaucher cell infiltration reduces marrow signal intensity to approximately that of muscle. T2-weighted imaging with fat-suppressed sequences facilitates detection of complications such as infarcts (Fig. 4B). Coronal T1 and T2-weighted scans of the femora should be performed at the same intervals and frequency as the visceral assessments described above. Sagittal echo train inversion-recovery (STIR ) images may be used as an alternative to T2-weighted images if desired.6
In very young children, growth-related changes in marrow composition complicate interpretation of marrow T1 images.6,13,14 As children mature, hypointense, hematopoietic red marrow is replaced by hyperintense fatty marrow in a centripetal pattern.13,14 Therefore, increase in signal intensity due to marrow maturation may be misread as a positive treatment response, and red marrow signal may obscure Gaucher cell infiltration in younger children. To circumvent this problem, some clinicians have suggested monitoring the distal regions of the lower extremities, that is, the tibiae and ankles.13 As marrow matures earliest in these regions, reduced T1 signal would indicate significant skeletal involvement.
Several semiquantitative scoring methods have been developed to assist in staging skeletal involvement and treatment response.12,13 A quantitative assessment of marrow involvement can be obtained using chemical shift MRI, which can directly measure absolute marrow fat content.13,14 However, this methodology has not yet been widely adopted into clinical practice in children (though it has in adults). The use of 99mTc-sestamibi scintigraphy for assessment of skeletal involvement in Gaucher disease has also been discussed. Accumulation of sestamibi in the bone marrow reflects the degree of infiltration by Gaucher cells, and is not affected by physiologic age-related changes in bone marrow composition. Despite this, radiation exposure favors the use of MRI over sestamibi scintigraphy in children.8
With each sestamibi scan, the pediatric radiation exposure is at least 500 to 600 mrem, and upward of 10 mSv. According to the Alliance for Radiation Safety in Pediatric Imaging (Image Gently), <100 to 150 mSv is the acceptable cumulative low level dose during childhood years. Unique to children with radiation exposure, there is a longer time to manifest changes from exposure thereby increasing their cancer risk. Their tissues are also more radiosensitive, and the effective dose is higher for small cross sections in children when compared with adults (with similar CT parameters). Radiation dose is also cumulative over a lifetime and the risk estimate is based on a linear model; risks have been reported as high as 1:500 in the literature when exposed to low level radiation. For these reasons, we prefer use of US or MRI when possible. If CT is necessary, it is important to image only the area of interest, avoid multiphase scanning, and limit the radiation exposure by “child sizing” the CT technique.15
Dual-energy x-ray absorptiometry may also be used to monitor bone mineral density in children with Gaucher disease, as a persistently low bone mineral density in Gaucher patients on ERT may warrant consideration for bisphosphonate therapy.13
On the basis of The Gaucher disease Working Group recommended guidelines with regards to imaging, several of these aforementioned modalities may be used. The recommendations include imaging a substantial part of the bone marrow compartment (femur, pelvis, and spine) at baseline and at least every 2 years, ideally annually; T1-weighted and either T2-weighted or STIR sequences are recommended for routine evaluation, and STIR sequences are recommended to detect complications. Dual-energy x-ray absorptiometry is recommended to assess lumbar spine, proximal femur, and the entire body at baseline and annually thereafter.8
A number of Gaucher osseous effects are visible on conventional plain radiographs (Figs. 5, 6).16 Radiography is most useful for identifying causes of acute bone pain such as pathologic fractures or osteonecrosis. It is also the modality of choice for arthroplasty follow-up.12,13 Although not highly sensitive or specific, radiographs may be the primary method of evaluating the skeleton in locations with limited access to MRI. Infrequently, the diagnosis of Gaucher disease may be initially suspected by recognition of Erlenmeyer flask deformities of the long bone metaphyses (a classic radiography sign). Splenectomy is associated with the development of osteolytic lesions, osteonecrosis, and bone mineral density deficits. In addition, asymptomatic vertebral collapse may be noted, along with medial proximal humeral notching. Incidental radiographic findings may rarely provide the initial clues that a child has Gaucher disease, therefore it is essential to consider this in the differential when observing such findings.17
The authors thank Pamela S. Cooper, PhD, for editorial assistance in preparation of the manuscript, and Lei Shao, MD, for her assistance with the pathologic figure.
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Journal of Pediatric Hematology/Oncology 2011; 33(4): 301-5