Bilateral Symmetrical Cortical Osteolytic Lesions in Two Patients with Gaucher Disease

Abstract

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder characterized by the reduced or absent activity of glucocerebrosidase. The disease is split into three types. Type 3, or chronic neuronopathic GD, manifests with heterogeneous clinical presentations. Skeletal manifestations of GD can include abnormal bone remodeling resulting in the characteristic Erlenmeyer flask deformities, painful bone crises, osteopenia, and an increased frequency of fractures. Osteolytic lesions can also occur, but are rare, and tend to be large expanding intramedullary lesions with cortical thinning. We present two adolescent patients with type 3 GD who developed bilateral symmetrical cortical osteolytic lesions. The lesions in both cases demonstrate predominant cortical scalloping with fairly indolent growth. Neither patient manifests some of the more common bony manifestations of GD; the Erlenmeyer flask deformity, bone crises, or osteonecrosis. These atypical and unique skeletal findings in two unrelated probands with type 3 GD further expands the extent of phenotypic variation encountered in this single gene disorder.

Introduction

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder characterized by the reduced or absent activity of glucocerebrosidase. It is a disorder of the reticuloendothelial system; the deficient enzyme activity causes lipids to accumulate in macrophages, which develop the classic appearance of the Gaucher cell (1)(2). It has been traditionally divided into three phenotypic types: non-neuronopathic (type 1), acute neuronopathic (type 2), and chronic neuronopathic (type 3) (3). However, there is wide phenotypic variance within each type.

The clinical presentation of type 3 GD is heterogeneous, including symptoms affecting neurological, hematological, visceral, pulmonary, and skeletal domains. The onset of symptoms is usually during childhood. Skeletal manifestations can include abnormal bone remodeling resulting in the characteristic Erlenmeyer flask deformities, painful bone crises, osteopenia, and an increased frequency of fractures. Osteolytic lesions can also occur, but are rare, and tend to be large expanding intramedullary lesions with cortical thinning (4)(5)(6).

Patients with type 3 GD generally show marked improvement in hematological and visceral symptoms when treated appropriately with enzyme replacement therapy (ERT) using recombinant glucocerebrosidase. However, the skeletal response to ERT tends to be slower (7). ERT also does not cross the blood-brain barrier and does not alleviate neurological symptoms such as the oculomotor deficits that are commonly found in type 3 GD patients.

Case Report 1

This patient is a 15-year-old female followed at the National Institutes of Health in Bethesda, MD since her diagnosis of GD type 3 at age 21 months. Her parents are first cousins and are both from Spain. Family history is positive for Fabry disease, dementia and thalassemia. Her perinatal course was unremarkable, but she presented with massive splenomegaly at age 14 months, identified after a viral illness. Absent horizontal saccades were also noted. Further examination revealed Gaucher cells in her bone marrow and glucocerebrosidase deficiency was confirmed in fibroblasts, and her genotype was determined to be L444P/L444P. ERT was begun at age 21 months at 60 IU/kg every two weeks, with an excellent response. Spleen volume decreased from 503cc at age 21 months to 139cc at age 5. Development was normal, and currently the patient is in honors level high school classes. Increased interstitial markings were noted on radiographs and computed tomographs of the chest, and pulmonary function tests showed a moderate diffusion abnormality, but these findings have remained static. Proteinuria was noted at age 12, but this has also been asymptomatic. A mild hearing deficit was noted at age 13.

At age 9, a 3.4mm lytic lesion with cortical thinning was observed in the right mid-radial shaft, along with cortical lesions in the left and right humerus, bilateral coxa valga, and generalized osteopenia. By age 10, the radial lesion had expanded to 9.7mm and showed further cortical thinning and marrow expansion (Figure 1). The lesion was removed at the University of Virginia, and the pathology was significant for Gaucher cells (Figure 2). Subsequently, bilateral symmetrical circumscribed radiolucent lesions with cortical scalloping were found on both medial tibias and medial humeri (Figure 3). Coxa valga and osteopenia were unchanged. At age 12, it was noted that the tibial lesions had increased in size, with intramedullary extension. Bisphosphonate therapy was begun at 35 mg once a week in an attempt to treat the osteopenia and bone lesions. Tibial and humeral lesions remained stable over the next 2 years, and bisphosphonate therapy was discontinued at age 14 at the parents’ request. At age 15 the patient jumped into the shallow end of a swimming pool with knees locked and fractured her tibia through one of the tibial lesions. No complications were noted in healing.

Figure 1.

Radiographs of the right radius of patient 1 taken at age 9 (A), age 10 (B), and T2-weighted MRI taken at age 10 (C). The lytic lesion initially showed cortical scalloping, but then progressed to encompass the medullary region of the radius.

Figure 2.

Biopsy sample light micrograph from right radius of patient 1 showing Gaucher cells.

Figure 3.

Radiographs (A–C) and computed tomographs (D–E) of patient 1 showing bilateral symmetrical circumscribed radiolucent lesions with cortical scalloping on both medial tibias and medial humeri.

Case Report 2

This patient is a 13-year-old female seen at Hospital Infantil de San José in Bogotá, Colombia, who was diagnosed with GD type 1 at age 4. Her genotype was determined to be L444P/L444P.

ERT was begun at age 4 at 60 IU/kg, although therapy was often erratic. At age 10, the patient’s diagnosis was revised to GD type 3 and ERT was increased to 120 IU/kg. Regular therapy was achieved in 2006 and included supplementation of vitamin D and calcium carbonate. The therapy led to improved hematologic parameters such hematocrit, hemoglobin, and platelet counts, as well as a reduction in organomegaly.

The patient has not experienced any bone crises or bone pain and has normal bone densitometry. However, her growth curve is below the 5^th percentile. She has bilateral bone lesions in the femurs, tibias, olecranons, humeri, radii, proximal clavicles, and spine, although there is a greater predominance on her left side. The humeral and tibial lesions show a bilateral symmetrical distribution (Figure 4). A bone biopsy of the left tibia was performed, and large areas of necrosis and Gaucher cell infiltration were observed. The lesions appear to be progressive, but the patient is asymptomatic. Progressive kyphosis was also noted.

Figure 4.

Bilateral, symmetrical, lytic bone lesions displaying cortical scalloping, located in the diaphyses of the tibias from patient 2 (A). Proximal humeral lesions are similar to those in the tibias; the mid-shaft humeral lesions show more extensive medullary involvement (B–C).

Discussion

These two cases illustrate similar unique features of bone involvement in GD. Both are adolescent girls with the same genotype, L444P/L444P, and type 3 Gaucher disease with bilateral symmetrical lytic cortical bone lesions that are asymptomatic. Neither child was splenectomized. While osteolytic lesions are described in GD, most are large, expanding intramedullary lesions that grow to occupy the entire corticomedullary region of the bone(4)(5)(6). In contrast, the lesions in these two cases demonstrate predominant cortical scalloping with fairly indolent growth. Neither patient manifests some of the more common bony manifestations of GD; the Erlenmeyer flask deformity, bone crises, or osteonecrosis. Additionally, both patients have had a similar favorable response to ERT, which was begun at an early age.

Due to the history of consanguinity in the family of patient 1, co-inherited genetic causes of bone disease in addition to GD were considered. However the presence of Gaucher cells in the bone biopsies of both patients confirms a GD-related pathophysiology. Treatment for osteopenia with bisphosphonates may have stabilized the progression of the bone lesions in patient 1 but does not appear to have reduced them.

The pathophysiology of bony complications of GD is not fully explained. The accumulation of Gaucher cells in the bone marrow cavity is thought to have two consequences. First, red marrow expansion may interfere with vascularity at the cortical surface, and second, glucocerebroside may cause macrophage activation resulting in changes in cytokine expression. Both of these processes could result in the skeletal manifestations encountered in GD. Regarding osteolytic lesions, the increased production of cathepsin K by osteoclasts may be significant (5)(8).

Although the bone lesions are asymptomatic, their progressive nature may affect the patient’s future course. Vigilant orthopedic monitoring is warranted to reduce the risk of further fractures.

These atypical and unique skeletal findings in two unrelated probands with type 3 Gaucher disease further expands the extent of phenotypic variation encountered in this single gene disorder. It is likely that an enhanced awareness of this finding may lead to its recognition in further cases and help to elucidate the pathophysiology of the bony manifestations associated with glucocerebrosidase deficiency.