Gaucher disease, a lysosomal storage disorder common in Ashkenazi Jewish population, is characterised by autosomal recessive inheritance of a deficiency in the enzyme glucocerebrosidase, leading to its accumulation which typically presents with hepatosplenomegaly, cytopenias, and Erlenmeyer flask deformity on radiographs.
Description
Gaucher disease is the most common lysosomal storage disorder, caused by a deficiency of the enzyme glucocerebrosidase, leading to an accumulation of glucocerebroside in cells, particularly macrophages, which become engorged and are termed Gaucher cells.
Pathogenesis
The disease arises from a mutation in the GBA gene, which codes for glucocerebrosidase, an enzyme that breaks down glucocerebroside, a component of cell membranes. With the deficiency of this enzyme, glucocerebroside accumulates in macrophages transforming them into Gaucher cells, which are typically found in the liver, spleen, and bone marrow.
Subtype
- Type 1 (non-neuropathic or adult form) is the most common subtype, where central nervous system is typically not involved.
- Type 2 (acute infantile neuropathic form) involves significant central nervous system disease.
- Type 3 (subacute or juvenile neuropathic form) also involves the central nervous system but is not as severe as type 2.
Epidemiology, Risk Factors & Associations
- More prevalent in the Ashkenazi Jewish population (1 in 800)
- Autosomal recessive inheritance
Clinical Features
- Hepatosplenomegaly, anaemia, thrombocytopenia, and bone disease are commonly observed
- Neurological symptoms such as seizures, dementia, and movement disorders may be present in the neuropathic forms of the disease
Complications
- Osteonecrosis of the hip
- Splenic rupture
- Liver disease
- Bone pain and pathological fractures
- Pyogenic osteomyelitis
- Growth retardation in children
- Neurological complications in types 2 and 3
- Pulmonary infiltration by Gaucher cells (type 2) and parenchymal infiltration with fibrosis (type 3)
- Pulmonary hypertension
- Increased frequency of multiple myeloma, Parkinson disease and Lewy body dementia
- Gaucheromas: rare pseudotumors comprising a mass of Gaucher cells
Pathological Features
Histopathology
- Macroscopic: Enlarged liver and spleen
- Microscopic: Gaucher cells are typically found, characterised as large cells with striated cytoplasm
Serology
- Decreased glucocerebrosidase enzyme activity
Biochemistry
- Increased levels of chitotriosidase and glucosylsphingosine
Radiological Features
General Features
- Characteristically demonstrates hepatosplenomegaly and bone involvement such as osteopenia, lytic lesions, fractures, and bone marrow infiltration.
X-ray
- Skeleton:
- The most characteristic radiographic skeletal abnormality in Gaucher disease is the Erlenmeyer flask deformity, where the distal femur is flared due to bone marrow expansion and lacks the normal concave contour. This is generally seen in Type 1 Gaucher disease.
- Bone infarct: Classically a medullary lesion of sheet-like central lucency surrounded by shell-like sclerosis with a serpiginous border. There is a significant delay between the infarct onset and radiographic manifestation.
- Chest: In some cases, Gaucher disease may present with pulmonary infiltration or interstitial lung disease, visible as diffuse opacities or fibrosis.
- Spine: H-shaped vertebrae may be seen.
CT
- Abdomen: Massive splenomegaly with nodules and infarcts. Hepatomegaly to a lesser degree compared to spleen.
- Skeleton: Patchy or serpiginous sclerosis surrounding a central metadiaphyseal lucency.
MRI
Abdomen:
- T1: Liver and spleen are diffusely low in signal.
- T2: Liver and spleen are high in signal.
Hip:
- T1: Serpiginous peripheral low signal due to granulation tissue and sclerosis. Peripheral rim may enhance post gadolinium. Central signal usually that of marrow
- T2: Acute infarct may show ill-defined non-specific area of high signal. Double-line sign hyperintense inner ring of granulation tissue and a hypointense outer ring of sclerosis.
Diagnosis
Diagnosis is typically based on clinical findings, radiological features, and confirmed by enzyme assay showing deficient glucocerebrosidase activity. Genetic testing can confirm the diagnosis.
Differential Diagnosis
- Other causes of hepatosplenomegaly such as amyloidosis, sarcoidosis, and lymphoma
- Other lysosomal storage diseases
Management
Management typically involves enzyme replacement therapy to reduce the accumulation of glucocerebroside. Allogeneic bone marrow transplantation may be considered in severe cases.