Diagnostic Case Study

The June 26, 2003, issue of the New England Journal of Medicine published a clinical case study that walks through the full differential diagnosis of a nine-year-old girl presenting with hepatosplenomegaly and pain in the thigh.[1] The outcome was a diagnosis of Gaucher disease, confirmed by clinical tests. This case study underscores the importance of rigorously analyzing the common signs and symptoms both individually and collectively in considering and ruling out all the differential diagnosis possibilities.

You can read the case study summary below as well as download a PDF of it in its entirety.

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Patient history and symptoms

A nine-year-old girl, US-born and of Haitian origin, was admitted to the hospital with chronic hepatosplenomegaly and acute thigh pain. The patient had generally been in good health during childhood, with no previous hospitalizations and no history of serious illness or disease in her or her family, although about three years prior to this hospital admission she began having frequent episodes of epistaxis.

Mild abdominal distention began developing about two years before admission, progressing gradually but unaccompanied by pain. Physical examination and abdominal ultrasonographic study two months before admission confirmed hepatosplenomegaly. Three days before admission the patient developed severe pain in her right thigh, rendering her unable to walk. She had had a similar episode of bone pain about a year earlier, but it had resolved on its own.

Preliminary tests

Upon admission, the patient looked thin but not ill; she had a low-grade fever, mild systolic hypertension, some enlarged lymph nodes, and slight anemia. However, liver function, lungs, and white cell count were normal; blood and urine cultures were negative; and there were no signs of ocular motor problems or other neurological abnormalities. Radiographs and MRI offered more insights into the bone issues: patchy sclerosis in the left femoral head suggesting a previous episode of avascular necrosis, as well as abnormalities in bone marrow density suggesting replacement of marrow fat by an infiltrate.

Narrowing down and ruling out explanations

The differential diagnosis process began by considering the broad categories of disease that present with hepatosplenomegaly: anatomical abnormalities, congestion, infection, hematologic disorders, and infiltrative processes. Within these, the diagnosing physicians focused on the specific disorders that could also account for the bone findings.

Anatomical abnormalities such as cysts, malformations, and development anomalies can cause organomegaly as well as bone pain; however, these options were ruled out because their symptoms are generally more regional than in this case, and they often show other signs not appearing in this patient's radiographic imaging. Passive venous congestion was eliminated as an option because it could explain the hepatosplenomegaly but not the bone pain, and there were no other indications of congestion. Infection was deemed unlikely to cause both of the patient's major symptoms; moreover, the patient's visceral involvement was chronic and thus uncharacteristic of infection, and her bone scan was "cold" rather than the "hot" typically associated with infection.

Although hematologic disorders could explain the organomegaly, several of these (including chronic hemolytic anemia, disorders associated with extramedullary hematopoiesis, myeloproliferative disorders, and sickle-cell disease) were ruled out because of the absence of other key signs. Sickle-cell disease also couldn't explain the chronic bone pain as it is generally associated with rapid liver enlargement and liver failure (in contrast to this patient's chronic enlargement and normal liver functioning).

Examining the likeliest disease category

Within the remaining category of infiltrative processes, the physicians considered two areas: malignant neoplasms and histiocytic disorders. Among the former, several childhood cancers could explain hepatosplenomegaly and bone pain, including leukemia, lymphoma, neuroblastoma, and primary hepatic tumors. However, most of these cancers present acute, rapidly developing symptoms, unlike the patient's slow progression. In addition, the patient lacked other characteristic symptoms of such cancers, including appearance of illness, fever, chills, weight loss, and cytopenia. Other types of cancer were deemed unlikely for the patient's age and gender.

Some histiocytic disorders could explain the patient's symptoms, but these were ruled out as unlikely for the patient's age and because she lacked other associated symptoms, such as rapid clinical deterioration, fever, wasting, skin rash, irritability, and central nervous system issues. Among other histiocytic disorders, several metabolic storage disorders commonly present with hepatosplenomegaly, while a few are also associated with bone pain, or bone crisis; Gaucher disease is unique in its association with both of these symptoms.

Confirming the Gaucher diagnosis

The patient's pattern of bone pain--two separate incidents a year apart--was fairly typical of Gaucher, especially as it was accompanied by fever, leukocytosis, increased erythrocyte sedimentation rate, and "cold" bone scans. The "cold" scan also indicated Gaucher-associated osteonecrosis rather than osteomyelitis, which would have a "hot" scan. The patient's three-year history of epistaxis also indicated Gaucher, which often causes bleeding because of thrombocytopenia resulting from hypersplenism.

To confirm the diagnosis, the physicians ordered a bilateral bone marrow biopsy, which showed clusters of large cells displacing most of the hematopoietic elements; their size and fibrillar cytoplasm were characteristic of Gaucher cells. (See Testing for additional information.) To rule out other diseases, such as Niemann-Pick and myelogenous leukemia, that can show similar-looking "pseudo-Gaucher" cells, an enzyme assay was performed. The results showed the patient's level of glucocerebrosidase to be 2.0 nmol per hour per milligram of protein--as compared with a normal range of 12.5 to 16.9 nmol. This enzyme deficiency conclusively confirmed the Gaucher diagnosis.


1. Larsen, EC, Connolly, SA, Rosenberg, AE. Case 20-2003: A Nine-Year-Old Girl with Hepatosplenomegaly and Pain in the Thigh. The New England Journal of Medicine. 2003; 348: 2669-2677.

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