Shwachman syndrome

A 14-year-old white boy presented with a 1-month history suggestive of viral respiratory tract infection with fatigue, cough, and urticaria. The results of physical examination were remarkable for a low-grade fever and otitis. The results of examination of other systems were within normal limits. A diagnosis of a viral illness was made, and antibiotics were prescribed for the otitis.

His medical history was remarkable for Staphylococcus osteomyelitis of the right hip at the age of 2 years, for which he received a prolonged course of antibiotics.

Complete blood cell count included the following values: white blood cells, 2.5 x 10^sup 9^ / L; hemoglobin, 119 g / L; and platelets, 93 000 / mm^sup 3^. Absolute neutrophil count was 1.4 x 10^sup 9^/L. His respiratory symptoms improved during the following weeks, but he remained fatigued and complained of mild joint pain. There were no neurologic symptoms. Physical examination revealed splenomegaly at 4 to 5 cm below the costal margin. Parvovirus titers were elevated. A bone marrow biopsy was performed to investigate possible causes for his cytopenias. A view of his Wright-Giemsa-stained bone marrow aspirate at (A) 100x oil and (B) 50x demonstrated cells with blue cytoplasm with a characteristic striated appearance that resembled crinkled tissue paper (Figure 1). A hematoxylineosin-stained bone marrow biopsy specimen at (A) 20x and (B) 40x showed large histiocytes (Figure 2).

What is your diagnosis?

Pathologic Diagnosis: Gaucher Disease

Gaucher disease is an autosomal recessive sphingolipid storage disorder that results from a deficiency of lysosomal beta-glucocerebrosidase. All subtypes are autosomal recessive, and symptoms result from the accumulation of glucosylceramide-laden macrophages and monocytes in the bone marrow, spleen, liver, kidneys, lungs, and lymph nodes. Certain subtypes are also marked by significant neurologic impairment.

Monolineage, bilineage or trilineage cytopenias (reflecting bone marrow involvement) or painless splenomegaly are often the initial findings in milder forms of the disease. Hepatomegaly can result in hepatic dysfunction. Bone involvement may also lead to bone pain and pathologic fractures, bone infarcts, and osteonecrosis. Although patients may have severe anemia and thrombocytopenia, it is usually the bone disease that causes long-term disability.1 Pulmonary disease and glomerulonephritis are less common. Types 2 and 3 of the disease have neurologic symptoms, secondary to accumulation of neurotoxic glucosphingosine in neurons.

The characteristic histologic feature is the Gaucher cell, which may be seen in the bone marrow, lymph nodes, spleen, liver, lungs, kidneys, or central nervous system. Gaucher cells are histiocytes, often in clusters, measuring 20 to 100 (mu)m in diameter. By May-Grunwald-Giemsa staining of bone marrow aspirate smears, they have abundant blue cytoplasm with a characteristic striated appearance that resembles crinkled tissue paper (Figure 1). The characteristic cytoplasm may also be appreciated in routine hematoxylin-eosin-sections. The nuclei are small and inconspicuous, and periodic acid-Schiff staining will highlight the cytoplasm.

Type 1, the nonneuropathic form, is the most prevalent genetic disorder among Ashkenazi Jews? The severity of symptoms is variable and depends on the amount of enzyme activity present in the patient. Age of presentation is most commonly adolescence but ranges from early childhood to late adulthood. Most importantly, this subtype is not characterized by neurologic impairment.

Type 2, the infantile or acute neuropathic form, is associated with a rapidly progressive neurodegenerative course and death within the first 2 years of life.

Type 3, the juvenile form, presents in infancy or early childhood and is characterized by splenomegaly, bone marrow involvement, and neurologic symptoms.

To make a definitive diagnosis of Gaucher disease, assays for acid beta-glucosidase activity in white blood cells or fibroblasts must be performed, because Gaucher-like cells may be found in patients with other conditions, such as chronic myeloproliferative disorders, chronic dyserythropoietic anemias, thalassemia, Shwachman syndrome (overloading of normal enzymatic capacity to process normal cell breakdown), or other malignant conditions 3 Enzyme assays performed on our patient confirmed the diagnosis of Gaucher disease.

Treatment options include symptomatic and palliative measures (transfusions, splenectomy, analgesics, and joint replacement) and bone marrow transplantation. Enzyme replacement with modified placental human glucocerebrosidase (alglucerase) is an effective means of treating patients with type 1 disease.4

References

1. Charrow 1. Gaucher disease, recommendations on diagnosis evaulation and monitoring. Arch Intern Med. 1998;158:1754-1760.

2. Horowitz M. Prevalence of glucocerebroside mutations in the Israeli Ashkenazi Jewish population. Hum Mutat. 1998;12:240-244.

3. Schaefer H. Gammopathy-related crystal-storing histocytosis, pseudo- and pseudo-Gaucher cells. Pathol Res Pract. 1996;192:1152-1162.

4. Beutler E. Enzyme replacement therapy for Gaucher's disease. Baillieres Clin Haematol. 1997;10:751-763.

Accepted for publication September 21, 1999.

From the Department of Pathology, Loyola University Medical Center, Maywood, Ill.

Reprints not available from the author.

Copyright College of American Pathologists Aug 2000
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