Symptom-Based Diagnosis in Pediatrics (CHOP Morning Report) 1st Ed.

CASE 9-5

Sixteen-Year-Old Girl



A 16-year-old Caucasian girl presented to the emergency department with acute onset of epistaxis lasting 3-4 hours. Her parents estimated her blood loss to be several cups with no slowing of bleeding noted with compression. She reported a history of intermittent epistaxis since she was 8 years of age. She noted at least one nosebleed per year lasting 20-30 minutes each time. Her most recent episode was 1 year prior lasting approximately 4 hours. Her review of symptoms was notable for “easy bruising” without prolonged bleeding at sites of prior lacerations/abrasions. She reported an 18-month history of lower extremity pain, primarily in the ankles and knees. This pain would usually last for minutes and occurred twice weekly. She had no history of fractures. She endorsed worsening fatigue over recent months. Her menstrual periods were monthly with heavy flow during the first 2 days of her cycle. She denied fever, weight loss, or night sweats.


She was born at term and pregnancy was uncomplicated. There was no significant travel or exposures. Family history was remarkable for a brother with deletion of the short arm of chromosome 7, also with a history of epistaxis. Systemic lupus erythematosus was present in maternal aunt.


T 37.4°C; RR 36/min; HR 110 bpm; BP 151/83 mmHg

Height 50th percentile; Weight 50th percentile

Physical examination was remarkable for nonicteric sclera, a small amount of bleeding from the left nostril and dried blood in the oropharynx. Lung examination was normal. Cardiac exam revealed no murmurs, rubs, or gallops. Abdomen was soft and nondistended; however, the liver was noted to be 4 cm below the right costal margin, and the spleen was palpable 4 cm below the left costal margin. Rectal examination revealed normal rectal tone with soft heme-positive stool in the vault. There was no prominent adenopathy. An erythematous rash was noted across her cheeks. There were no petechiae noted, but there was mild bruising found on the lower extremities. Neurologic examination was normal.


Laboratory analysis revealed 5400 WBCs/mm3 with 4% band forms, 54% segmented neutrophils, and 37% lymphocytes. The hemoglobin was 10.0 g/dL and there were 46 000 platelets/mm3. Reticulocyte count was 2.7%. Prothrombin and partial prothrombin times were 12.6 seconds and 34.7 seconds, respectively. Serum electrolytes, blood urea nitrogen, and creatinine were normal. Lactate dehydrogenase was normal and uric acid was 6.3 mg/dL. The erythrocyte sedimentation rate was 35 mm/h. Antinuclear antibodies, antidouble stranded DNA, rapid plasma reagin test, and monospot were negative.


Hemostasis was achieved without immediate intervention other than pressure applied to her nares. The patient was admitted to the hospital where she underwent further evaluation for the bleeding and associated symptoms. Bone marrow biopsy (Figure 9-5) suggested a diagnosis that was confirmed by a blood test.


FIGURE 9-5. Bone marrow biopsy. (Photo courtesy of Marybeth Helfrich, MT, ASCP.)



Bruising and easy bleeding in this older child suggests a hematologic condition. The differential includes malignancy such as leukemia, lymphoma, or immune thrombocytopenia purpura. Idiopathic thrombocytopenia purpura (ITP) would be unlikely due to the prolonged duration of the symptoms, as ITP is an acute, often self-limited condition. Chronic forms of ITP can occur; however, it would be atypical for the acute phase of the illness to have resolved undetected. The enlargement of the liver and spleen caused consideration of an oncologic, autoimmune, or metabolic conditions. The differential diagnosis was somewhat narrowed due to the relatively low sedimentation rate and negative autoimmune serologies. Infectious causes of thrombocytopenia and enlarged liver and spleen including Epstein-Barr virus or cytomegalovirus-associated infectious mononucleosis were considered less likely in setting of laboratory results.


The bone marrow biopsy revealed macrophages with the characteristic “wrinkled tissue paper” appearance of Gaucher cells (Figure 9-5). The leukocyte glucocerebrosidase activity was 0.85 nmol/h/mg/protein (<10% of normal values), consistent with the diagnosis of Gaucher disease. Radiographs of the right femur revealed undertabulation of the distal femoral metaphysis with marked cortical thinning and sclerosis. Additionally, an elevated tartrate-resistant acid phosphatase level of 6.1 U/L (reference range, 2.0-4.2 U/L) was noted. MRI revealed diffuse infiltration of her liver, spleen, and bone marrow. All of these findings were consistent with Gaucher disease, Type I.


Gaucher disease, the most common lysosomal storage disease, is an autosomal recessive disorder associated with deficient activity of the catabolic enzyme beta-glucocerebrosidase with resultant accumulation of glucocerebroside. In Gaucher disease, macrophages, the major site of catabolism of glycolipids, accumulate glucocerebroside. There are three forms of the disorder, with varying severity. This child had Type I Gaucher disease, the most common sphingolipid storage disorder. The highest incidence is found in people of Eastern European Jewish ancestry.


Macrophages are most numerous in the liver, spleen, bone, and lung and, therefore, it is not surprising that manifestations of Gaucher disease are often related to these organs. Patients with Gaucher disease Type I can present at any age, though more severely affected present during childhood with splenomegaly and pancytopenia. Patients may complain of easy bruising and chronic fatigue. They may also have hepatomegaly and mild elevation of hepatic transaminases. Cirrhosis and liver failure may develop. As seen in this case, infiltration of the bone marrow interferes with bone mineralization and growth and compounds the pancytopenia. Skeletal complications include osteopenia, osteonecrosis, and recurrent bone pain. Pulmonary glycolipid accumulation may lead to respiratory dysfunction.

In general, the disease is slowly progressive with many individuals living well into adulthood. The disease may achieve a steady state between lipid accumulation and lipid degradation or loss. Individuals with the mildest disease may be identified incidentally as adults during routine evaluation. The central nervous system is spared in Type I Gaucher disease, and affected children have normal intelligence. Neurologic symptoms develop early in life for infants with Type II disease with death occurring by 2 years of age. In Type III disease, children develop visceromegaly early in life and late-onset neurologic complications.


The diagnosis of Gaucher disease can now be made by measurement of enzyme levels or by gene mutation analysis. In some states, Gaucher disease will be screened for as part of routine newborn testing programs.

Glucocerebrosidase levels. Since the glucocerebrosidase gene has been mapped to chromosome 1q21, identification of the underlying enzymatic defect in Gaucher disease is possible from peripheral blood. Decreased level of glucocerebrosidase activity in peripheral blood leukocytes (usually 10%-30% of normal levels) is diagnostic of Gaucher disease.

Gene analysis. DNA-based diagnosis can be used if findings from enzymatic testing are equivocal, as is occasionally the case in heterozygotes. The detection of mutations is, however, limited to the previously defined mutations. DNA analysis will detect most mutations (95%) in Ashkenazi Jews but only a few mutations in other populations who have a greater diversity of mutations.

Bone marrow biopsy. Once considered the diagnostic method of choice, bone marrow biopsy has fallen out of favor as a diagnostic tool in Gaucher disease since less invasive and more reliable diagnostic modalities have become available. Bone marrow biopsy findings include the detection of large, lipid-laden, fusiform macrophages with dense eccentric nuclei that resemble wrinkled tissue paper or crumpled silk (Gaucher cells). These cells are not pathognomonic of Gaucher disease, since the same type of cell can be found in various leukemias and some infectious disorders. This test is often performed to exclude malignancy in the child presenting with pancytopenia.

Complete blood count. Patients with untreated disease may have anemia, thrombocytopenia, and leukopenia.

Radiologic imaging. Radiographs, CT, or MRI of the femur will show the Erlenmeyer-flask deformity, due to expansion of the cortex, as well as cyst-like changes of varying sizes. MRI of various bones will show infiltration of bone marrow.

Other studies. A number of plasma enzyme activities are greatly increased in patients with Gaucher disease. Serum acid phosphatase levels, beta-hexosaminidase, and angiotensin-converting enzyme have all been found to be elevated in these patients. Acid phosphatase levels are used to monitor response to therapy. These levels become normal with adequate exogenous enzyme replacement.


Management includes symptomatic treatment, exogenous administration of the missing enzyme, and allogeneic bone marrow transplantation. Gene transfer is being explored for future therapy.

Symptomatic measures are used to improve quality of life. Surgical splenectomy can correct the thrombocytopenia, and complete or partial splenectomy is used when the splenomegaly has become symptomatic. Patients are advised to avoid activities that put stress on the skeleton that can result in fractures. In some cases joint replacement may be necessary.

Type I Gaucher disease is particularly responsive to exogenous replacement of the defective enzyme because the central nervous system is not involved. This enzyme is a macrophage-targeted modified glucocerebrosidase. Patients require enzyme replacement (alglucerase) every 2 weeks. Enzyme replacement therapy has been effective in regression of the visceral and hematologic manifestations, and to a lesser extent the skeletal manifestations of Gaucher disease. Recently, the enzyme inhibitor Miglustat has also become available for the treatment of Type 1 disease.

Bone marrow stem cell transplantation may be considered in some patients. Since macrophages are derived from the hematopoietic stem cells, the stem cell transplantation can be expected to cure Gaucher disease. Indeed, allogeneic bone marrow transplantation has led to the correction of the clinical manifestations of the disease. However, marrow transplantation carries substantial risks, and is currently reserved for a small subset of patients.


1. Balicki D, Beutler E. Gaucher disease. Medicine. 1995;74:305-323.

2. Beutler E, Grabowski GA. Gaucher disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Basis of Inherited Disease. 8th ed. New York: McGraw Hill; 2001:3635-3668.

3. Charrow J, Esplin JA, Gribble TJ, et al. Gaucher disease: recommendations on diagnosis, evaluation, and monitoring. Arch Intern Med. 1998;158:1754-1760.

4. Rosenthal DI, Doppelt SH, Mankin HJ, et al. Enzyme replacement therapy for Gaucher disease: skeletal responses to macrophage-targeted glucocerebrosidase. Pediatrics. 1995;96:629-637.

5. Chen M, Wang J. Gaucher disease: review of the literature. Arch Pathol Lab Med. 2008 May;132(5):851-853.

6. Hughes DA, Pastores GM. Haematological manifestations and complications of Gaucher disease. Curr Opin Hematol. 2012 Oct 25. [Epub ahead of print]

7. Somaraju UR, Tadepalli K. Hematopoietic stem cell transplantation for Gaucher disease. Cochrane Database Syst Rev. 2012 Jul 11;7:CD006974.

8. Venier RE, Igdoura SA. Miglustat as a therapeutic agent: prospects and caveats. J Med Genet. 2012 Sep;49(9): 591-597. doi: 10.1136/jmedgenet-2012-101070. Epub 2012 Aug 14.