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the disease is clinically heterogeneous and is classified into three types based on the presence and severity of neurological symptoms .
type 1 is non - neuronopathic , while types 2 and 3 are acute and chronic neuronopathic , respectively .
type 3 is typified by slowing and looping of the horizontal saccadic eye movements , organomegaly and bony involvement .
bone deformities of the distal femurs , pathologic fractures , osteopenia and painful bone crises .
osteolytic lesions are rare and often characterized by large progressive intermedullary lesions with cortical thinning that may become necrotic , , .
previously , two adolescent patients with gd were reported to have bilateral symmetrical osteolytic lesions of the humerii and tibias , with cortical scalloping and indolent growth . here
we present a third patient with gd who has similar symmetrical bilateral osteolytic lesions , this time of the femurs .
all three patients are young adults diagnosed with type 3 gd at an early age , with the same genotype , l444p / l444p , and each had a favorable response to enzyme replacement therapy ( ert ) administered since childhood .
these atypical skeletal findings in unrelated type 3 gd probands sharing the same genotype further illuminate our understanding of the phenotypic spectrum in this single gene disorder in the post - treatment era .
the patient is a 23  year old female followed at the national institutes of health under an institutional review board approved clinical protocol since her diagnosis of type 3 gd at age 7  months .
two years prior to her birth , her brother , also diagnosed with gd , died from a ruptured spleen at age 2  years .
her perinatal course was unremarkable , but an enlarged liver and spleen were noted at age 6  months , prompting dna testing for gd .
the patient was started on ert with recombinant glucocerebrosidase at age 7  months at a dose of 60 iu / kg every two weeks .
the dose was subsequently doubled to 120 iu / kg every two weeks when she reported hip pain at age 10  years . while she is currently asymptomatic , diffuse moderate reticular lung densities scattered
bilaterally are noted on radiographs and computed tomographs of her chest , and pulmonary function tests show a mild restrictive ventilatory defect and a moderate diffusion abnormality .
years , the patient reported two episodes of bone pain that were sudden and severe occurring several months apart .
the first , occurring in her left anterior thigh , resolved within a few days after self - treatment with acetaminophen .
this was followed by a much more painful episode 7 months later in her right anterior thigh that lasted several weeks , was treated with tramadol , and ultimately resolved .
on evaluation at age 23  years , radiographs of her femurs showed bilateral symmetrical lucent cortical lesions , centered in the medial cortices of the mid - diaphysis ( fig .
1a ) . these had a benign appearance , resembling non - ossifying fibromas . on magnetic resonance imaging ( mri ) ,
the femoral lesions had t2 signal hyperintensity , with marginal enhancement within the cortex of the midshaft diaphysis ( fig .
the diameters of the right femur lesion were measured at 1.9  cm - craniocaudad , 1  cm - transverse and 1  cm - anterior - posterior , while the left femur lesion was 3.6  cm - craniocaudad , 1.3  cm - transverse and 1.8  cm - anterior - posterior .
the patient had normal bone densitometry for her age and no erlenmeyer flask deformities were noted on her radiographs .
the patient is a 23  year old female followed at the national institutes of health under an institutional review board approved clinical protocol since her diagnosis of type 3 gd at age 7  months .
two years prior to her birth , her brother , also diagnosed with gd , died from a ruptured spleen at age 2  years .
her perinatal course was unremarkable , but an enlarged liver and spleen were noted at age 6  months , prompting dna testing for gd .
the patient was started on ert with recombinant glucocerebrosidase at age 7  months at a dose of 60 iu / kg every two weeks .
the dose was subsequently doubled to 120 iu / kg every two weeks when she reported hip pain at age 10  years . while she is currently asymptomatic , diffuse moderate reticular lung densities scattered
bilaterally are noted on radiographs and computed tomographs of her chest , and pulmonary function tests show a mild restrictive ventilatory defect and a moderate diffusion abnormality .
years , the patient reported two episodes of bone pain that were sudden and severe occurring several months apart .
the first , occurring in her left anterior thigh , resolved within a few days after self - treatment with acetaminophen .
this was followed by a much more painful episode 7 months later in her right anterior thigh that lasted several weeks , was treated with tramadol , and ultimately resolved .
on evaluation at age 23  years , radiographs of her femurs showed bilateral symmetrical lucent cortical lesions , centered in the medial cortices of the mid - diaphysis ( fig .
1a ) . these had a benign appearance , resembling non - ossifying fibromas . on magnetic resonance imaging ( mri ) ,
the femoral lesions had t2 signal hyperintensity , with marginal enhancement within the cortex of the midshaft diaphysis ( fig .
the diameters of the right femur lesion were measured at 1.9  cm - craniocaudad , 1  cm - transverse and 1  cm - anterior - posterior , while the left femur lesion was 3.6  cm - craniocaudad , 1.3  cm - transverse and 1.8  cm - anterior - posterior .
the patient had normal bone densitometry for her age and no erlenmeyer flask deformities were noted on her radiographs .
this is the third patient with type 3 gd with the unique features of symmetrical bilateral cortical bone lesions . aside from the bone involvement
, this patient shares other similarities with the previously reported cases including abnormal saccadic eye movements , gender , approximate age of disease onset and genotype .
all three patients were free from the more common bony symptoms of gd that manifest as larger , progressively expanding lesions occupying corticomedullary regions of bone . additionally , each patient was started on ert at an early age and responded favorably , with reduced organomegaly and improved hematologic parameters including hematocrit , hemoglobin and platelet counts .
ert with recombinant glucocerebrosidase , first introduced in the early 1990s , is the standard of care for patients with types 1 and 3 gd and has remarkably altered the extent of visceral , hematologic and bony manifestations , especially in children , , .
her future treatment plan includes conservative monitoring . the symmetric appearance , and similarity to the other two patients who did have pathologic confirmation of a gd - related process , aided in this decision .
bone disease is common in patients with type 1 and 3 gd , but the pathophysiology is still not well understood .
it is believed that one cause of gd - associated bone pathology in marrow tissue is glucocerebroside accumulation which alters marrow vascularity and may lead to bone infarction , necrosis and fractures .
additionally , in gd , activation of macrophages may induce bone pathology by promoting inflammatory processes , arising from altered expression of cytokines and inflammatory mediators such as il-1 , il-6 and tumor necrosis factor - alpha .
an overall decrease in t - lymphocyte levels has also been reported in patients with gd who have bone involvement .
focal osteolytic lesions resembling those presented here have been associated with increased cathepsin k by activated osteoclasts , .
more reliable , candidate biomarkers involved in the dynamic bone processes of osteo - immunology and remodeling are needed to better understand the gd - associated bone metabolism changes .
the bilateral symmetrical osteolytic lesions seen in these three cases are atypical findings in patients with type 3 gd .
a unique feature shared by the three patients was early diagnosis and treatment with ert , associated with a relatively benign clinical course .
in previous generations , children with type 3 gd often did not survive to their second or third decade and thus , such findings may not had time to manifest and be recognized . alternately , the findings might be related to the chronic , long - term treatment .
such cases not only serve to catalog the phenotypic diversity of gd - associated bone disease , but also expand our understanding of the evolving natural history of treated gd .
type 3 gaucher disease ( gd ) manifests with hematologic , neurological and skeletal involvement including erlenmeyer flask bone deformities , osteopenia , painful bone crises and fractures . 
 we describe bilateral symmetric osteolytic lesions in a 23  year old with type 3 gd , chronically treated with enzyme replacement therapy . 
 these atypical bone findings , previously reported in two similar patients with type 3 gd , expand our understanding of the evolving natural history of gd in the post - treatment era .