Case Reports @ 1992 The Japanese Society of Pathology
An Autopsy Case of Farbers Lipogranulomatosis in a Japanese Boy with Gastrointestinal involvement
Mayumi Koga, Tokuhiro lshihara2, Fumiya Uchino2, and Takehisa Fujiwaki3
A boy with Farbers lipogranulomatosis is reported. Exces- sive ceramide was revealed by thin-layer chromatography of the extracts from the liver. Acid ceramidase activity of the liver was 31.5% of control with exogenous substrate and 33.3% without exogenous substrate. The histological appearance showed granulomatous lesions, composed of spindle or oval-shaped storage cells and proliferation of the connective tissues, in the subcutaneous tissue of the lower lip, periarticular regions and the pericardium. Histo- chemically the storage cells were revealed to contain lipid and polysaccharide. The foreign body granuloma formed by the surgical suture in the liver was surrounded by a large number of foamy cells. In gastrointestinal mucosa widespread erosion, disappearance of glands and abundant collagen fibers were noted. On electron microscopy, the spindle or oval-shaped cells i n the subcutis of the lip had intracytoplasmic inclusions containing granular or fibrillar materials and a smaller number of curvilinear structures, so called Farber bodies. Our case was a typical clinical and histopathological presentation of Farbers lipogranu- lomatosis. However, ceramidase activity was higher than in previous descriptions, and severe gastrointestinal lesions and the appearance of a large number of foamy cells around the foreign body granuloma have not been described previously. Acta Pathol Jpn 42 : 42-48, 1992.
Key words : Farbers disease, Ceramidase deficiency, Cur- vilinea r struct ure, Gastrointestinal lesion, Ceramidase activity
Farbers lipogranulomatosis is a disorder of lipid metabolism due to deficiency of lysosomal acid cer-
amidase. Its clinical manifestations include growth and developmental retardation, hoarse voice, multiple subcu- taneous nodules and progressive arthropathies with periarticular swelling. I ts histological findings include granuloma formation with infiltrated lipid-laden macro- phages in the skin, periarticular regions and the larynx.
Since Farber described the first case in 1952 (l), at least 30 cases have been reported (2), including four cases(3-5) from Japan. We describe the autopsy findings of a Japanese boy with liver and gastrointestinal involvement.
A Japanese boy, the second product of healthy non- consanguineous marriage, was born at term after an uneventful pregnancy. His elder sister was healthy. A t birth he weighed 3,060 g and his length was 5 1 cm. He showed slowly progressing pes calcaneovalgus, joint contracture with painful swelling and hoarseness. At age 10 months he developed high fever and watery diarrhea. Cholecystectomy was performed at age 2 0 months to remove the gallstones. He died of broncho- pneumonia at age 2 years and 1 month. Detailed clini- cal findings will be described elsewhere (6).
His skin was sclerotic. Severe contractures with mild swell- ing were noted in the elbows, wrists, fingers, knees, ankles and toes (Fig. la) . A subcutaneous nodule with a diameter of 1 5 X 1 5 m m was noted on the lower lip, as
Autopsy was carried out three hours after death.
was a 20 m m x 2 0 m m nodule on the skin close to the anus (Fig. lb). A yellowish 10 m m x l O m m tumor was Received June 4, 1991. Accepted for publication September 30, 1991.
Department of Pediatrics and 2First Department of Patho\- seen in the right lobe of the liver under the operation scar ogy, Yamaguchi University School of Medicine, Ube. of cholecystectomy. The gastrointestinal mucOSa was 3Department of Pediatrics, Kokura Memorial Hospital, Kita- hypertrophic, and the inner surface was irregular due to kyusyu. the wide-spread erosion. Other abnormal findings were Mailing address : Mayumi Koga, Department of Pediatrics, pneumonia, hydrocephalus and stones in the bile duct. Yamaguchi University School of Medicine, Ube 755, Japan. This case was presented at the 30th Annual Meeting of the Neither liver nor Spleen was enlarged. Japanese Society of Reticuloendothelial System.
Acta Pathologica Japonica 4 2 (1): 1992 43
MATERIALS AND METHODS
Tissues were fixed in 10% buffered formalin for his- tological and histochemical studies. For transmission electron microscopy, tissues of the skin, liver, spleen and intestine were fixed in 2.1% glutaraldehyde, postfixed in 1% osmium tetroxide and embedded in Epon 812. The ultrathin sections were stained with uranyl acetate and lead citrate and examined in a Hitachi H-800 electron microscope.
Lipid analysis of the liver was performed as follows: Crude lipid was extracted from the patient and a control liver fixed in 10% formalin and developed by thin-layer chromatography. The developing fluid was a mixture of chloroform and methanol (95/5, V/V). Commercial ceramide with non-hydroxy fatty acids and with hydroxy fatty acids (Sigma, St. Louis, Mo, USA) were used as standards. Acid ceramidase activity was measured by the method described by Mitsuo et a/. (7) with slight modifications. Liver homogenates in the sodium phos- phate buffer, pH 4.5, were incubated with and without an exogenous substrate: ceramide with non-hydroxy fatty acid. Then the amounts of sphingosine produced in this
Figure 1. A patient at autopsy. a : General appearance. Joints of extremities show severe contracture with mild swell- ing. b : A subcutaneous nodule on perianal region.
reaction were measured with the high-performance liquid chromatographic method after being labeled by o- phthalaldehyde, a fluorescent probe. In addition arylsul- fatase A, B and C and other lysosomal enzyme activity was measured using 4- met h y I um bell if ery I substrate, with the exception of arylsulfatase A, which was done using p-nitrocatechol sulfate. Substrate and liver homogenate were incubated at 37'C and after that O.D. was measured at 515 nm against water using a Hitachi spectrophotometer.
Subcutaneous nodules on the lip and perianal region both had a similar histological appearance including elongation of the rete ridges, proliferation of the collagen fibers and capillaries, and scattered spindle or oval- shaped cells (Fig. 2). These cells had an enlarged cyto- plasm positive for colloidal iron, alcian blue and PAS, were resistant to diastase digestion, and showed occa- sional metachromasia with toluidine blue staining. Vari-
44 Farbet's Ltpogranulornatosis (Koga et a/.)
Figure 2. Histology of subcutaneous nodule on perianal region. There are proliferation of the collagen fibers and scattered spindle (arrows) or oval-shaped (arrowheads) storage cells.
Figure3. A large number of foamy cells around the foreign body granuloma in the liver. HE.
ous lipid stainings were as follows; orange red in Sudan 111, orange in Sudan IV, black in Sudan black B and blue in Nile blue sulfate. These results indicate that these cells contain acid or neutral plysaccharides and lipid. Typi- cal foamy cells were rarely seen, and the histochemical findings were similar to those of spindle or oval-shaped cells except that foamy cells were stained more weakly for lipid stainings compared to spindle or oval-shaped ones. Such granulomas were present in the periarticular region, larynx and pericardium.
A small tumor in the right lobe of the liver showed the
foreign body granuloma formed by a surgical suture to be composed of lymphocytes and giant cells, surrounded by a large number of foamy cells (Fig. 3). The cyto- plasm of foamy cells was stained in the same way as the cytoplasm of foamy cells in the subcutis. Most Kupffer cells had enlarged eosinophilic cytoplasm stained in the same way as the spindle-shaped cells in the subcutis. Hepatocytes had clear intracytoplasmic vacuoles which tested positive for lipid staining, but negative for polysaccharide staining. Morphological and histo- chemical findings of histiocytes in the spleen were similar
Figure 4. Wide-spread erosion in the small intestine. HE.
Acta Pathologica Japonica 42 (1): 1992 45
Figure 5. On electron microscopy storage cells in the subcutaneous nodule has intracytoplasmic inclusion bodies contain- ing granular ( a ) or fibrillar (a, b) materials, or a few Farber bodies (c: arrows).
46 Farber's Lipogranulomatosis (Koga et a/.)
to those for Kupffer cells. Endothelial cells and blood cells showed no changes. Alveolar macrophages in the lungs and ganglion cells in the central and peripheral nerve system had intracytoplasmic materials which test- ed positive for lipid and polysaccharide stainings.
The gastrointestinal mucosa showed wide-spread ero- sion with disappearance of glands and proliferation of collagen fibers (Fig. 4). Lipid droplets accumulated sparsely in the lamina propria.
In subcutaneous and periarticular fat ty tissue the cytoplasm of lipocytes was atrophic, and intercellular space contained abundant polysacc ha ride. Collagen fibers and capillaries proliferated among lipocytes.
Kidney, heart and other organs showed no particular changes.
U It ra s t ruct u ra I findings
The spindle or oval-shaped storage cells in the subcu- taneous nodule, which we consider to be fibroblasts and macrophages respectively, had an enlarged cytoplasm and membrane-bound intracytoplasmic inclusions containing flocculent, granular (Fig. 5a) or fibrillar (Figs. 5a, b) materials, with a few curvilinear tubular structures, so called "Farber bodies", which consist of two electron- dense lines separated by clear space. The diameter of tubules was 1 5 nm on the average (Fig. 5c