Introduction
Gaucher disease (GD), the most common of the lysosomal storage disorders, results
from mutations in the gene for acid β-glucosidase (glucocerebrosidase, GBA) leading
to insufficient enzyme activity [1]. Glucocerebroside accumulation in the lysosomes
of various cell types is responsible for the clinical manifestations of GD, which
may include hepatomegaly, splenomegaly, anemia, thrombocytopenia, and bone marrow
infiltration by lipid-engorged “Gaucher cells.” Occurring panethnically, type 1 (non-neuronopathic)
is the most prevalent form of GD, while the less frequent type 2 (acute neuronopathic)
and type 3 (chronic neuronopathic) are characterized by neurological involvement.
More than half of type 1 patients are diagnosed in childhood and an earlier age of
onset is indicative of more severe disease due to its progressive nature.
Affecting both the marrow and mineral compartments, GD-related bone disease is the
most significant cause of morbidity and long-term disability for patients. GD-related
bone disease in children is a major cause for concern as it puts them at risk of developing
irreversible and debilitating bone complications and interferes with normal growth
and achievement of optimal bone mass during a critical period of growth. Timely initiation
of appropriate disease management is necessary to avoid serious long-term complications
such as growth retardation, osteoporosis, and fractures, and includes an initial radiological
assessment and ongoing monitoring of both the bone marrow and mineral components.
General guidelines for the monitoring of skeletal disease in children with type 1
GD recommend magnetic resonance imaging (MRI) of the spine and femora; radiography
of the spine (when clinically indicated), chest, pelvis, and long bones; and dual-energy
X-ray absorptiometry (DXA) of the spine and hips at baseline and every 12–24 months
[2, 3]. However, these recommendations require further clarification in view of the
challenges associated with their use in children with GD, especially since the use
of conventional radiography is limited by a high burden of radiation and lack of sensitivity
and specificity.
The current standard of care for type 1 GD is enzyme replacement therapy (ERT) with
imiglucerase (Cerezyme®; Genzyme Corporation, Cambridge, MA, USA). Oral substrate
reduction therapy with miglustat (Zavesca®; Actelion, San Francisco, CA, USA) is also
available for the treatment of patients with mild to moderate GD for whom ERT is not
an option. The availability of therapy that may prevent or reverse GD-related bone
disease heightens the need for early diagnosis and initiation of disease management
in children.
A Working Group of international experts met in October 2006 to recommend evidence-
and consensus-based guidelines to facilitate the assessment and monitoring of bone
disease in children with type 1 or type 3 GD.
Assessment of bone marrow infiltration in pediatric Gaucher patients by MRI
Magnetic resonance imaging, the most widely used and accepted method of assessing
and evaluating changes in bone marrow, is the method of choice for monitoring marrow
displacement in adults with GD. This technique has also been used in children with
GD to qualitatively evaluate and characterize bone marrow infiltration by Gaucher
cells [4]. Advantages of MRI include widely available technology, semi-quantitative
assessments, ease of measurement, high sensitivity, and lack of associated ionizing
radiation.
The displacement of fatty marrow by Gaucher cells is best detected by T1-weighted
MRI and appears as an abnormally low-intensity signal, which is unique compared with
the triglyceride signal. Following ERT with imiglucerase in patients with GD, the
responding bone marrow shows increased triglyceride content and an increase (brightening)
in the bone marrow signal. T2-weighted fat saturation or short tau inversion recovery
(STIR) sequences are the most sensitive for the detection of additional bone marrow
complications of GD, including irreversible avascular necrosis.
Interpretation of MRI measurements with respect to the physiologic conversion of bone
marrow
Neither the chronology of pediatric GD bone marrow involvement and its variations
nor the impact of delayed skeletal maturation on the conversion of hematopoietic to
fatty marrow in children with GD are known. Knowledge of the typical conversion patterns
of bone marrow in Gaucher patients on MRI by age group as well as the availability
of normative pediatric MRI data will eventually allow a more clinically useful interpretation
of MRI-derived data. MR images of children with GD should be interpreted in comparison
with normal physiological conversion patterns, especially in very young children whose
low signal due to a high percentage of red marrow appears similar to pathologically
infiltrated bone marrow. The potential contributions of therapy to observed changes
in bone marrow infiltration must also be considered.
Clinical interpretation of MRI measurements
Numerous semi-quantitative scoring systems have been developed for the evaluation
of bone marrow infiltration in adult Gaucher patients, including the Rosenthal score,
the Düsseldorf Gaucher score, the Terk classification, the vertebra-disc-ratio, and
the bone marrow burden (BMB) score [5]. Dixon Quantitative Chemical Shift Imaging
(QCSI), a quantitative MR-based technique, reports the displacement of triglyceride-containing
marrow by Gaucher cells as a fat fraction. The BMB scoring method is preferred over
the other available scoring systems as it includes measurements of both lumbar spine
and femur, key anatomical sites of Gaucher cell infiltration, and has been validated
against other methods and applied in multiple studies [6, 7]. Although numerous studies
on age-related distribution of fat in bone marrow in children have been performed,
normal QCSI vertebral fat fractions have yet to be established for children.
Use of sedation
Children between birth and the age of 6 years usually require sedation or a general
anesthetic for successful examination by MRI. In the absence of local “best practice”
protocols, MRI examinations of children with GD should be carried out in accordance
with the guidelines established by the American Academy of Pediatrics and the American
Society of Anesthesiologists.
99mTc-Sestamibi: an alternative to MRI?
99mTc-Sestamibi accumulation in the bone marrow has been used to assess the severity
of bone marrow infiltration by Gaucher cells in adults and results correlate highly
with other indicators of systemic disease burden. Despite this technique’s independence
from the influence of bone marrow conversion, scintigraphic images are less spatially
resolved than MR images, the radiation burden to the growing child is significant,
and pediatric normal controls do not exist. Therefore, at present 99mTc-Sestamibi
is not an acceptable alternative for assessing or monitoring bone marrow infiltration.
Assessment of BMD in pediatric Gaucher patients by DXA
Widely available, relatively inexpensive, and involving low ionizing radiation exposure,
DXA is safe, noninvasive, rapid, painless, and the preferred technique for the diagnosis
of osteopenia and osteoporosis in adults. DXA is routinely used to evaluate bone mineral
density (BMD) in patients with GD and is capable of providing a quantitative assessment
of bone involvement and monitoring changes in bone density in response to therapy.
DXA is potentially useful for the evaluation of BMD in children with GD, although
specific technical and practical issues need to be considered.
Technical aspects of DXA measurements in children
Due to the two-dimensional nature of DXA technology, DXA measurements are highly influenced
by bone size as well as by bone age and pubertal stage. Therefore, small bone size
may be misinterpreted as a low BMD. Since growth retardation, pubertal delay, and
decreased body mass are common problems in pediatric GD and may distort measured BMD,
these factors must be considered when interpreting the DXA-derived data. With serial
measurements in the presence or absence of therapy, normal growth in a child with
initially small bones should not be perceived as a false increase in BMD. Additional
confounding factors for DXA scans of the hip or lumbar spine include avascular necrosis
and vertebral compression fractures respectively, both of which may occur with GD.
Awareness of these potential influences on BMD measurements obtained by DXA can prevent
misinterpretation and improve the clinical usefulness of these data.
Clinical interpretation of DXA measurements
In adults DXA measurements are reported as T-scores, which represent the number of
standard deviations from the mean BMD of a reference group of normal gender-matched
individuals in the age range (3rd decade) during which BMD peaks. T-scores are not
applicable for individuals under the age of 20 years; measurements made in children
are reported as age- and gender-matched Z-scores. Although Z-scores cannot diagnose
osteopenia or osteoporosis, a Z-score below −2.0 or above 0.0 represents a value outside
the normal range.
The clinical usefulness of DXA in children with GD depends on access to appropriate
software for data analysis, normative pediatric data, and familiarity with the correct
methods of reporting measurements. The major DXA manufacturers currently provide pediatric
reference data of BMD versus chronological age, and gender- and ethnicity-specific
reference data for healthy European and North American children have recently been
published for the assessment of BMD measured by DXA [8, 9]. However, standards for
adjusting BMD on the basis of bone size, pubertal stage, skeletal maturity, and body
composition are also needed. Furthermore, correlations between DXA-derived data and
the likelihood of developing fractures would increase the usefulness of DXA for the
evaluation of BMD in children with GD.
Quantitative computed tomography: an alternative to DXA?
Unlike DXA, quantitative computed tomography (QCT) can assess bone density independently
of bone size, allowing measurement of the actual volumetric density of a specific
compartment and eliminating the potentially confounding factors of growth retardation
and pubertal delay observed in some pediatric Gaucher patients. However, few pediatric
studies using this technique and no standard analyses are available, and QCT of the
spine results in considerable radiation exposure. Therefore, QCT currently cannot
be recommended for use in children.
Recommendations
We recommend the following guidelines as appropriate for monitoring skeletal manifestations
in children with type 1 or type 3 GD.
Performing measurements with MRI
Perform assessments at centers with MRI expertise in children.
Assess anatomical sites including a substantial part of the preferably axial bone
marrow compartment (femur, pelvis, and spine) at baseline and at least every 2 years,
ideally annually.
T1 and either T2 or STIR sequences are recommended for routine evaluation, and STIR
sequences are recommended to detect complications.
Clinical interpretation of MRI measurements
Magnetic resonance images of children with GD should be interpreted in comparison
with normal physiological conversion patterns.
The potential contributions of therapy to observed changes in bone marrow infiltration
must be considered.
Use of sedation for MRI measurements
The American Academy of Pediatrics and the American Society of Anesthesiologists provide
guidance to facilitate the administration of sedation, if needed, in the safest manner
possible.
Performing measurements with DXA
Perform assessments at centers with DXA expertise in children and where normal pediatric
data are available.
Assess lumbar spine and proximal femur and the entire body at baseline and annually
thereafter, provided that normal pediatric reference standards are available.
Perform serial scans on the same DXA machine and analyze with the appropriate pediatric
option.
Clinical interpretation of DXA measurements
Dual-energy X-ray absorptiometry measurements from children (males or females < 20 years
of age) with GD should be interpreted and reported in accordance with the recommendations
and caveats provided by the International Society for Clinical Densitometry [10]:
Z-scores must be used; T-scores should not be used in children.
Z-scores must be interpreted using the best available pediatric databases of age-,
gender-, and ethnicity-matched controls. Reports should cite the reference database
used.
Terminology such as “low bone density for chronologic age” or “below the expected
range for age” may be used if the Z-score < −2.0.
The diagnosis cannot be made on the basis of densitometric criteria alone.
The value of BMD to predict the likelihood of fractures in children has not been clearly
determined.
No agreement exists on standards for adjusting BMD for factors such as bone size,
pubertal stage, skeletal maturity, and body composition. If adjustments are made,
they should be clearly stated in the report.
Deviation from standard adult analysis protocols, such as use of low-density software
and manual adjustment of the region of interest, should be stated in the report for
the accurate comparison of DXA-derived data.
Role of conventional radiography
Although widely available and relatively inexpensive, we do not recommend the routine
or exclusive use of conventional radiography due to its high burden of radiation and
lack of sensitivity and specificity.