تشخیص

بیماری گوشه     Gaucher Disease

Answer:

This nine-year-old girl, who had a long history of epistaxis and hepatosplenomegaly, presented with acute leg pain. Interestingly, a year earlier she had had similar leg pain, but it had resolved without intervention. An important observation is that the hepatosplenomegaly was chronic and probably progressive. Pertinent features of the history include the absence of fevers, trauma, scleral icterus, jaundice, weight loss, visual disturbances, medications, and previous health problems. The results of the physical examination are notable for the presence of low-grade fever, mild systolic hypertension, marked hepatosplenomegaly, and tenderness in the right thigh. The results of the neurologic examination were normal, with no ocular motor abnormalities. Laboratory screening revealed slight anemia, leukocytosis, low iron saturation, and a high erythrocyte sedimentation rate, with minor elevations in the levels of lactate dehydrogenase and aminotransferases. Cultures of blood and urine were negative.

Abdominal ultrasonographic studies confirm the presence of hepatosplenomegaly.  A pelvic CT scan showed an effusion in the right hip and patchy sclerosis in the left femoral epiphysis, which suggested a previous episode of avascular necrosis.

MRI of the pelvis and femurs was performed before and after the administration of gadolinium. On T₁-weighted images, the normal fatty marrow of the pelvis and femurs is diffusely replaced by abnormal marrow. The fatty marrow should have the same signal intensity as subcutaneous fat, which appears as a bright stripe on this image. Instead, it has the same signal intensity as muscle, indicating that the bone marrow is affected by an infiltrative process. On a T₂-weighted image, there is edema in the marrow of the proximal right femur and in the surrounding soft tissues; the scan obtained after the administration of gadolinium shows diminished enhancement of this region. These findings are characteristic of an acute bone infarct. The distal femoral metaphyses are flared, an effect that is probably due to the diffuse marrow infiltrate.

The two central features of this case are chronic hepatosplenomegaly and acute bone pain, which appears to be intermittent in nature. The imaging studies suggest the presence of an infiltrative process in the liver and the bone. I will consider the broad differential diagnosis of hepatosplenomegaly and focus on disorders that can also account for the bone findings, assuming that the hepatosplenomegaly and the bone pain are the result of a single disease process. The causes of hepatosplenomegaly can be sorted into broad categories that include anatomical abnormalities, congestion, infection, hematologic disorders, and infiltrative processes.

Several specific anatomical entities, such as cysts, malformations, and developmental anomalies, may result in hepatomegaly, splenomegaly, or bone pain. However, these entities are usually regional and are not likely to result in the constellation of findings that are present in this case. Furthermore, most anatomical anomalies have characteristic features on imaging studies, and such features are not apparent on this patient's radiographic studies.

Passive venous congestion can certainly cause long-standing hepatosplenomegaly, which can be progressive. Congestion cannot account for this child's bone pain, however, and furthermore there are no additional signs of congestion, such as venous engorgement, edema, stasis of the legs, or evidence of esophageal varices.

Infection seems unlikely in this case for three reasons. First, although several infections are known to cause either hepatosplenomegaly or bone pain, it would be distinctly unusual for infection to cause both of these clinical findings. Second, many infections tend to occur over a relatively short period, whereas this child's organomegaly was chronic. Third, most infections are associated with increased blood flow, which would typically cause increased uptake rather than decreased uptake on bone scanning.

Chronic hepatosplenomegaly is a feature of several hematologic diseases, including chronic hemolytic anemia, disorders associated with extramedullary hematopoiesis, and myeloproliferative disorders. Chronic hemolytic anemia usually causes hyperbilirubinemia, anemia, and reticulocytosis, none of which were present in this case. In addition, splenomegaly is usually more prominent than hepatomegaly in chronic hemolytic anemia.

Sickle cell disease deserves consideration, since this child's acute bone pain is suggestive of a vaso-occlusive crisis. However, her medical history includes no other manifestations of sickle cell disease, and this disorder would not account for the progressive organomegaly. Splenomegaly is a common finding in early childhood, but as children approach their teenage years, it is very uncommon. Although intrahepatic sickling may lead to some degree of liver enlargement, it usually develops rapidly and typically is associated with evidence of liver dysfunction.

Disorders associated with extramedullary hematopoiesis, such as osteopetrosis and myelofibrosis, may be associated with chronic hepatosplenomegaly, but in patients with such disorders one would expect characteristic findings in the peripheral blood and on the radiographs. Finally, myeloproliferative disorders often lead to organomegaly, but they too are associated with additional findings, such as marked abnormalities in the peripheral-blood counts.

Infiltrative processes that cause hepatosplenomegaly and bone pain include both malignant and nonmalignant conditions. Childhood cancers associated with hepatosplenomegaly and bone pain include leukemia, lymphoma, neuroblastoma, and primary hepatic tumors. Cancer seems highly unlikely in this case simply because of the time course of the patient's symptoms. Neoplasia in children usually takes the form of a relatively acute process, with escalating symptoms over the course of weeks or months rather than years. Despite this general observation, it is important to consider briefly the specific malignant conditions that could be relevant to this case.

Hepatosplenomegaly and bone pain are common findings in children with leukemia; however, there are usually additional findings, such as fever, an appearance of illness, and cytopenia.¹ Lymphomas in children may cause hepatosplenomegaly, but they have additional clinical features as well, such as fever, chills, weight loss, and marked lymphadenopathy. Hepatosplenic T-cell lymphoma is a unique form of non-Hodgkin's lymphoma that may cause marked hepatosplenomegaly without lymphadenopathy. However, this disease typically affects young men, who present with prominent fever, weight loss, and cytopenia.

Metastatic neuroblastoma often involves both the liver and bones. This degree of hepatomegaly in neuroblastoma is most commonly associated with stage IV-S disease, which occurs exclusively in infants. In older children, stage IV neuroblastoma may include both bone pain and hepatomegaly; however, these children appear very ill, the bone involvement is typically multifocal, and there is avid uptake of labeled technetium on bone scanning. Hepatoblastoma may cause liver enlargement and may metastasize to the bones, but this disease occurs almost exclusively in children less than two years of age, and the vertebrae are the usual metastatic targets.

 Histiocytic disorders that can occur in children include Langerhans'-cell histiocytosis, non-neoplastic histiocytic disorders, including familial hemophagocytic lymphohistiocytosis and the infection-associated hemophagocytic syndrome, and metabolic storage diseases. Langerhans'-cell histiocytosis is a neoplasm of the Langerhans' cells that has protean clinical manifestations. Common clinical findings include lytic bone lesions, dermatitis, organomegaly, lymphadenopathy, fever, weight loss, chronic otitis media, and diabetes insipidus. Disseminated disease is seen in young children but is unusual at this patient's age. The absence of these typical clinical findings, along with evidence of a bone infarct, makes Langerhans'-cell histiocytosis very unlikely. Patients with familial hemophagocytic lymphohistiocytosis may present with infiltrative hepatosplenomegaly, but most often they present (earlier in life than the child in this case) with rapid clinical deterioration, including fever, wasting, and skin rash, irritability, and central nervous system findings. Likewise, the infection-associated hemophagocytic syndrome usually follows a viral process, involves fever and pancytopenia, and usually occurs in the setting of immunodeficiency, which does not seem to be present in this case.

Hepatosplenomegaly is a common feature in many metabolic storage diseases, ranging from sphingolipidosis to mucopolysaccharidosis. A smaller number of metabolic disorders are associated with bone pain or, as it is often called, bone crisis. The combination of hepatosplenomegaly and bone pain is unique and is a feature of Gaucher's disease. Gaucher's disease is a lysosomal glycolipid-storage disease characterized by the accumulation of glucocerebroside in various tissues as a result of a deficiency in the enzyme beta-glucosidase. There are three forms of Gaucher's disease. The most common form, non-neuronopathic (or type I) disease, involves the progressive engorgement of macrophages over time, a process that results in organomegaly, bone marrow infiltration, and damage to the bones, which may lead to infarction or fracture. Children with this form of Gaucher's disease are healthy in the first few years of life; hepatosplenomegaly then gradually develops over the course of several years. Splenomegaly is usually more prominent than hepatomegaly, but there is notable heterogeneity in the clinical manifestations of Gaucher's disease.

Bone involvement is present in nearly all patients and typically occurs after visceral disease. The classic Erlenmeyer-flask deformity, a common radiographic finding, is caused by medullary expansion and remodeling of the distal femur due to the accumulation of histiocytes. Patients usually have episodic, painful bone crises, which have a predilection for the femoral head and sometimes are misdiagnosed as Legg–Calvé–Perthes disease.

Erlenmeyer flask deformity of the distal

These bone crises result from ischemia and infarction due to progressive marrow infiltration with enlarging storage cells. This patient's current episode of leg pain, as well as the episode one year earlier, represents a bone crisis that is fairly typical of Gaucher's disease. Classic features of bone crisis in Gaucher's disease include fever, leukocytosis, an increased erythrocyte sedimentation rate, and absence of tracer uptake on bone scans (i.e., "cold" bone scans). Patients with Gaucher's disease are at increased risk for malignant hematologic tumors that may cause bone pain, but such tumors tend to occur much later in life and typically show increased tracer uptake on bone scans.

In addition to hepatosplenomegaly and bone pain, this patient had a three-year history of epistaxis. Bleeding, particularly epistaxis, is common in patients with Gaucher's disease and is usually the result of thrombocytopenia due to hypersplenism. Qualitative defects in platelet function and decreased levels of several coagulation factors have also been described in patients with this disease.

This patient probably has type I, or non-neuronopathic, Gaucher's disease, since the rarer form — type II, or neuronopathic, Gaucher's disease — is severe, involves the central nervous system, and occurs in young children, who usually die by the age of two years. Type III, or subacute neuronopathic, Gaucher's disease cannot be definitively ruled out because neurologic signs may develop after symptomatic bone disease. Ocular motor manifestations, which are typically the first evidence of neurologic involvement, were not present in this case.

Gaucher's disease can be diagnosed on the basis of a low level of beta-glucosidase in peripheral-blood leukocytes. An alternative and more expeditious diagnostic approach is bone marrow aspiration to search for classic Gaucher's cells, which are very large macrophages with characteristic morphologic features. With regard to clinical management, bony crises typically resolve over the course of a few days with adequate hydration and analgesia. Corticosteroids may also be beneficial. Overall, this patient has an excellent prognosis and should be a candidate for long-term enzyme replacement, which effectively reverses the manifestations of Gaucher's disease and prevents long-term complications.

Clinical Diagnosis: Gaucher's disease.

The diagnostic procedure was bilateral bone marrow biopsy and aspiration of the iliac crest. The tissue specimens retrieved from the two sites had similar histologic features. The marrow contained solid sheets or clusters of large cells or single large cells that displaced most of the hematopoietic elements. These cells, with a diameter that was about two to six times that of normal macrophages, contained round or oval vesicular nuclei and abundant eosinophilic cytoplasm with a fibrillar or striated appearance. Wright–Giemsa staining of a smear of aspirate also showed numerous large cells with striated cytoplasm. These cells are histiocytes, and their large size and fibrillar cytoplasm are characteristic of Gaucher's cells. The differential diagnosis includes other metabolic storage diseases and secondary accumulation of Gaucher's cells. The other major storage disease to consider is Niemann–Pick disease. In that disorder, the large histiocytes that accumulate have foamy cytoplasm with round vacuoles, rather than a fibrillar or striated appearance. Gaucher's cells — or pseudo-Gaucher's cells, as they are sometimes called — may be found in persons without beta-glucosidase deficiency when there is a very high rate of cell turnover. The classic setting for this is chronic myelogenous leukemia, in which the presence of increased numbers of hematopoietic-cell precursors in the marrow can overwhelm the normal cellular machinery and result in the accumulation of Gaucher's cells.

The combination of the clinical findings and the morphologic features of the bone marrow specimens from the iliac crest confirm that this patient's diagnosis is type I Gaucher's disease. Gaucher's disease is the most common of the genetic lysosomal storage diseases, affecting 1 in 50,000 to 100,000 live births; it can be inherited in an autosomal recessive fashion or acquired through a spontaneous mutation. Glucocerebroside, a normal component of the cell membrane, is generated in macrophages as they degrade effete cells during routine cell turnover. In the absence of beta-glucosidase, glucocerebroside accumulates in the lysosomes of macrophages, where it is stored in a specific architectural arrangement, resulting in elongation of the lysosomes. These elongated and distended lysosomes fill the cytoplasm of the macrophages, giving it the characteristic fibrillar or striated appearance, which has been likened to wrinkled cigarette paper.

Gaucher's cells