Bone Marrow Infiltration

The bone marrow may be infiltrated by nonneoplastic disease (storage disease) or neoplastic disease. In storage disease, a diagnosis is established on the basis of the clinical picture, enzyme assays of white cells or cultured fibroblasts, and bone marrow aspiration revealing the characteristic cells of the disorder. Neoplastic disease may arise de novo in the marrow (leukemias) or invade the marrow as metastases from solid tumors (neuroblastoma or rhabdomyosarcoma). Table 5-5 lists the diseases that may infiltrate the marrow.

Gaucher Disease

Gaucher disease is the most common lysosomal storage disease, resulting from deficient activity of P-glucocerebrosidase. It is inherited in an autosomal recessive manner. More than 100 mutations are now known to cause Gaucher disease in the glucocerebrosidase gene. The degree of clinical involvement differs greatly in individual patients, even those with the same genotype and those affected within the same family.

Pathogenesis

Glucocerebrosidase is necessary for the catabolism of glucocerebroside. Deficiency of glucocerebrosidase leads to accumulation of glucocerebroside in the lyso-somes of macrophages in tissues of the reticuloendothelial system. Figure 5-1 shows a diagram of the cellular pathophysiology of Gaucher disease. Accumulation in splenic macrophages and in the Kupffer cells of the liver produces hepatosplenomegaly.

Table 5-5. Diseases Invading Bone Marrow

I. Nonneoplastic

A. Storage diseases

1. Gaucher disease

2. Niemann-Pick disease

3. Cystine storage disease

B. Marble bone disease (osteopetrosis)

C. Langerhans cell histiocytosis (Chapter 22)

II. Neoplastic

A. Primary

1. Leukemia (Chapter 14)

B. Secondary

1. Neuroblastoma (Chapter 18)

2. Non-Hodgkin lymphoma (Chapter 16)

3. Hodgkin lymphoma (Chapter 15)

4. Wilms' tumor (rarely) (Chapter 19)

5. Retinoblastoma (Chapter 23)

6. Rhabdomyosarcoma (Chapter 20)

Bone Lesions Gaucher Disease

Fig. 5-1. Diagram of the cellular pathophysiology of Gaucher disease. Monocytes are produced in the bone marrow and mature to macrophages in the marrow or in specific sites of distribution as liver Kupffer cells, bone osteoclasts, and lung and tissue macrophages. Once resident, they accumulate glucosylce-ramide by phagocytosis and become end-stage Gaucher cells. (From Grabowski GA, Leslie N. Lysosomal storage diseases: Perspectives and principles. In: Hoffmann R, Benz EJ, Shattil SJ, Furie B, Cohen HJ, Silberstein LE, McGlave P, editors. Hematology Basic Principles and Practice. 3rd ed. Philadelphia: Lippincott-Raven, 2000, with permission.)

Fig. 5-1. Diagram of the cellular pathophysiology of Gaucher disease. Monocytes are produced in the bone marrow and mature to macrophages in the marrow or in specific sites of distribution as liver Kupffer cells, bone osteoclasts, and lung and tissue macrophages. Once resident, they accumulate glucosylce-ramide by phagocytosis and become end-stage Gaucher cells. (From Grabowski GA, Leslie N. Lysosomal storage diseases: Perspectives and principles. In: Hoffmann R, Benz EJ, Shattil SJ, Furie B, Cohen HJ, Silberstein LE, McGlave P, editors. Hematology Basic Principles and Practice. 3rd ed. Philadelphia: Lippincott-Raven, 2000, with permission.)

Hypersplenism produces anemia and thrombocytopenia. Glucocerebroside accumulation in the bone marrow results in osteopenia, lytic lesions, pathologic fractures, chronic bone pain, bone infarcts, osteonecrosis, and acute excruciating bone crises.

Gaucher disease is classified into three types based on the presence and degree of neuronal involvement. Table 5-6 outlines the clinical manifestations of the three types of Gaucher disease. Patients with Type 1 Gaucher disease present with:

• Hepatosplenomegaly (rarely, portal hypertension develops)

• Pancytopenia secondary to hypersplenism and rarely from infiltration of the bone marrow with Gaucher cells

• Bone pain, osteoporosis, pathologic fractures, and bone crises

• Growth delay (Fifty percent of the symptomatic children are at or below the third percentile for height, and another 25% are shorter than expected based on their midparental height.)

• Typical foamy cells in the bone marrow

• Erlenmeyer flask deformity of the distal femora on radiographs

• Decreased glucocerebrosidase activity of white cells

• Characteristic mutations of the glucocerebrosidase gene on chromosome 1 on DNA analysis.

Diagnosis

Glucocerebrosidase assay on leukocytes or cultured skin fibroblasts is the most efficient method of diagnosis. The typical child with type 1 Gaucher's disease will have enzyme activity that is 10-30% of normal.

Further Evaluation

• DNA evaluation for glucocerebrosidase gene abnormalities in patient, parents, and siblings

• Complete blood count

Table 5-6. Clinical Classification of Gaucher Disease

Clinical features

Type 1

Type 2

Type 3a

Type 3b

Type 3c

Onset

Childhood/

Infancy

Childhood

Childhood

Childhood

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