Clinical quiz. Gaucher disease.

Abstract

A previously healthy 8.5-year-old girl was incidentally found to have hepatosplenomegaly on a routine clinic visit. Previous evaluation of increased abdominal girth, noted since early infancy, included a normal esophagogastroduodenoscopy (EGD) at age 2 years. She had no history of blood transfusions, surgical procedures, fractures, or bone pain. She was small for her age (height and weight < 5th percentile). Her liver was firm and extended 3 to 4 cm below the right costal margin. The spleen was hard and palpable 5 to 7 cm below the left costal margin. She had no icterus and no stigmata of chronic liver disease. Her complete blood count included a hemoglobin concentration of 12.4 g/dL, a hematocrit value of 37%, an MCV of 75.6 fL, a white blood cell count of 4,800/cu mm, and a platelet count of 192,000/cu mm. Her liver-associated laboratory test values were as follows: aspartate transaminase: 73 IU/L (normal, < 41); alanine transaminase: 27 IU/L (normal, < 45); γ-glutamyl-transferase: 19 IU/L (norma1, 5–55 IU/L); and bilirubin: 0.7 mg/dL (normal, 0.2–1.2 mg/dL). The prothrombin/partial thromboplastin times were normal. Serology results for hepatitis B virus, hepatitis C virus, and cytomegalovirus were negative. Her antinuclear antibody was positive at 1:40 (speckled pattern), anti–smooth muscle antibody was weakly positive at 1:20, and anti-liver–kidney microsomal antibody was not detected. Serum amino acids and urine organic acids were normal. The acid phosphatase was 41 U/L (normal, 0.8–5 U/L). An abdominal sonogram revealed only hepatosplenomegaly. No esophageal varices were noted at esophagogastroduodenoscopy. A percutaneous liver biopsy was performed (Fig. 1).FIG. 1.: Liver biopsy. What is your diagnosis? A. Niemann-Pick disease B. Chronic granulocytic leukemia C. Lymphoproliferative disorder D. Gaucher disease E. Farber disease Answer The diagnosis of Gaucher disease was confirmed with a glucocerebrosidase activity of 2 nmol · h−1 · mg protein−1) (normal 12.5–16.9 nmol · h−1 · mg protein−1)). The liver biopsy demonstrated the classic “Gaucher cells” (Fig. 2). These are abnormal Kupffer cells that have accumulated glucosylceramide and related glycosphingolipids because of a deficiency of the lysosomal enzyme glucocerebrosidase. Gaucher cells have an eccentric nucleus and classic “wrinkled tissue paper” appearance caused by lightly staining eosinophilic striations of the accumulated material in the cytoplasm. Gaucher cells are typically located in hepatic sinusoids, the lymph nodes, bone marrow, the spleen, and other tissues. There is usually no accumulation of glucosylceramide in the hepatocyte. The liver-associated enzymes and bilirubin concentrations are normal or slightly elevated. Hepatic dysfunction, cirrhosis, and portal hypertension are uncommon, except in the most severe cases, although hepatic fibrosis has been reported.FIG. 2.: Arrow demonstrates typical Gaucher cell.Comment: Gaucher disease is the most common lysosomal storage disease. It is inherited in an autosomal recessive fashion and manifests as one of three types, each having a diverse phenotypic appearance. Type I is the most common and has an increased incidence in Ashkenazi Jews. It is often called “adult” onset; however, it can present at any age, including early childhood. It is not uncommon for patients with Type I Gaucher disease to present incidentally with hepatosplenomegaly or thrombocytopenia. Types 2 and 3, unlike Type 1, have central nervous system involvement. Type 2, the acute neuronopathic form, appears in infancy with severe central nervous system involvement and ends in death in early childhood. Neurologic manifestations do not develop until later childhood in Type 3. Our patient could have either Type l or Type 3 because systemic illness may present before neurologic symptoms in the latter type. The diagnosis of Gaucher disease is made by assay of β-glucocerebrosidase activity in peripheral blood leukocytes or cultured skin fibroblasts. Genotyping can identify genes that are associated with more or less severe disease. Hematologic abnormalities, with thrombocytopenia and anemia caused by hypersplenism or bone marrow failure from infiltration of Gaucher cells, are common in Gaucher disease. The children with Gaucher disease are usually small for their age. Infiltration of the bone marrow with Gaucher cells can lead to bone pain crisis, avascular necrosis of the femoral head, arthralgia, and osteopenia (1–3).