Pediatric Puzzler: Bone pain and fever


Puzzler for the month




Recurrent bone pain and fever in a 4-year-old:
All of a piece?

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Choose article section... Painful story No rheum at all Diagnosis is imminent (you can feel it in your bones) Discussion

By Melissa Larzo, MD, Balram Gangaram, MD, Frank Keller, MD, and Deepak Kamat, MD, PhD

You have just completed your last note for the day and are happily thinking of going home. Think again: The on-call resident hails you to describe a new admission to the floor: a 4-year-old boy with intermittent fever and bone pain of six months' duration. She also shows you a stack of papers sent with the boy. You decide to review the contents of the stack before going to see the patient.

Painful story

Six months ago, at 4 years of age, the boy was seen for intermittent abdominal and leg pain of six weeks' duration. Before this, he had no significant medical problems. Although no history of fever had been reported, his temperature in the clinic was 39.4° C. There was no history of headache, vomiting, or urinary tract symptoms. His appetite was normal and he had not lost any weight. The patient is adopted; a family history was unavailable. The chart note describes him as appearing pale and being terrified; he would not allow a physical examination and screamed if the physician tried to touch him. He was hospitalized for examination under sedation and for laboratory evaluation and abdominal computed tomography (CT).

You read on: Performed while he was under sedation, examination of the head, eyes, ENT, and cardiac and respiratory systems was normal. The abdomen was soft and nondistended without appreciable masses or organomegaly. He had no skin rash or lymphadenopathy, and joints were neither swollen nor red. The laboratory examination showed a low hemoglobin (10.2 g/dL); a normal white blood cell (WBC) count (10.1 x 103/µL) with 39% polymorphonuclear neutrophils and 59% lymphocytes; and a mildly elevated platelet count (406 x 103/µL). The erythrocyte sedimentation rate (ESR) was elevated (28 mm/hr).

Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and bilirubin values were within normal limits; the same was true for amylase, lipase, serum electrolytes, calcium, magnesium, blood urea nitrogen (BUN), creatinine, and creatine kinase.

The abdominal CT scan was likewise negative. The boy did not have a fever at any time during his brief stay, and the pain he reported seemed to have resolved somewhat by discharge. He was sent home with a presumptive diagnosis of viral syndrome and given an appointment for outpatient follow-up.

At home, the boy was asymptomatic for one week, but then the leg and abdominal pain recurred, accompanied by low-grade fever. He was given ibuprofen as needed. During that episode, he also had difficulty walking because of back and hip pain. He returned to the clinic, where his temperature was recorded at 38.1° C. Again, the note describes him as very difficult to examine: He refused to stand or walk because he said "it hurts too much." There now appeared to be slight swelling around the knees.

Because juvenile rheumatoid arthritis (JRA) appeared to be a possibility, the patient was given a presumptive diagnosis of JRA, started on scheduled acetylsalicylic acid (ASA), and referred to the ophthalmology and rheumatology services for further evaluation. His response to ASA within the first one to two weeks was striking, and his mother reported that he was a "new person."

No rheum at all

Six weeks later, however, despite treatment with ASA, the boy again developed abdominal and bone pain accompanied by low-grade fever. He was then evaluated by a pediatric rheumatologist, who performed additional testing. Levels of complement and quantitative immunoglobulins (A, G, M, and D), thyroid function, and iron studies were all normal. Tests of antinuclear antibody, rheumatoid factor, anti–DNAse B, and antistreptolysin O titer were negative. The hemoglobin level had fallen—to 9.3 g/dL—and the ESR had risen to 53 mm/hr. Taken together, these results made it unlikely that any rheumatologic process was involved, the rheumatologist concluded. During this time, the pain became worse. A nuclear bone scan was scheduled.

Diagnosis is imminent (you can feel it in your bones)

Now, on your way to see this patient, you drop by the radiology department to review previous imaging studies. The bone scan, performed earlier today using technetium-99m methyldiphosphonate, is notable for increased uptake in the left shoulder and acromion, right wrist, and right lateral ribs and along multiple areas of the thoracic spine. These findings, combined with the history of intermittent fever, bone pain, anemia, and an elevated ESR, had prompted today's admission. Could you be dealing with a malignancy?

When you arrive to see the patient in his room, you're confronted by a desperate mother who wants to know what's wrong with her son. You explain that, given the abnormalities found on the bone scan, you'd like to perform additional laboratory tests and imaging studies. She is already frustrated, but she consents.

A repeat hemoglobin test shows a further drop—to 8 g/dL—but the WBC count, differential, and platelet count are all normal. At 7.9 mg/dL, the uric acid level is elevated (normal, 2.0 to 5.5 mg/dL), and lactate dehydrogenase is 322 IU/dL (normal <170 IU/dL). It appears that you are dealing with a malignancy after all—but what kind? Neuroblastoma? Leukemia perhaps? The only abnormality on multiple complete blood counts was a low hemoglobin level; WBCs and platelets were normal. Based on that finding, leukemia seems unlikely, although you can't rule it out with certainty. Neuroblastoma might be more likely, you consider, because it is a common solid tumor in children that often causes bone pain and anemia with a relatively normal WBC count and platelet count.

The abdominal CT performed earlier was negative, so you order a chest CT. Same result. Urine levels of homovanillic acid (HVA) and vanillylmandelic acid (VMA) are normal, making neuroblastoma unlikely. Still, you have a nagging suspicion about malignancy.

On the third hospital day, the patient appears significantly pale. Repeat blood count shows a hemoglobin level of 7.7 g/dL; WBC count, 3.9 x 103/µL, with an absolute lymphocyte count of 2.5 x 103/µL; platelet count, 144 x 103/µL; and abnormal lymphocytes on the peripheral smear. You discuss these results with the boy's parents, and they consent to bone marrow biopsy.

Examination of the biopsy specimen reveals a hypercellular marrow containing 95% lymphoblasts. Cytogenetic analysis, including fluorescent in-situ hybridization (FISH), shows t(12;21) (TEL-AML 1)—a common translocation in childhood acute lymphoblastic leukemia (ALL), but also one that imparts a more favorable prognosis in a child who has this disease. Cerebrospinal fluid (CSF) is normal. The boy undergoes induction therapy with vincristine, asparaginase, and dexamethasone, along with intrathecal methotrexate. He subsequently attains remission without complications.


The index of suspicion for malignancy in children tends to be low, in large part because the incidence of newly diagnosed malignancy in children in the US is only approximately 150 in 1 million annually.1 But even when one considers malignancy in the differential diagnosis when a child has recurrent bone pain, with or without fever, trying to decide when it is appropriate to obtain a bone marrow aspirate or bone scan in the face of a normal WBC count isn't always easy.

Acute leukemia accounts for one third of all cancers in children, and 80% of cases of acute leukemia in children are ALL.1 The disease most often manifests in children between 2 and 5 years of age; it is more common in boys than in girls (1.2:1) and more common in Caucasians than in African-Americans (1.8:1).2

Typically, the initial presentation of a child who has ALL includes fever, malaise, irritability, loss of appetite, weight loss, and easy bruising. Hepatosplenomegaly is present in almost 70% of patients; lymphadenopathy, in approximately one-half. Laboratory evaluation in most reveals anemia, and the WBC count can be normal for age, elevated, or depressed. A markedly elevated WBC count—>50 x 103/µL—occurs in only about 20% of patients. Most demonstrate absolute neutropenia.

Notably, although thrombocytopenia is present in 75% of children who have ALL, isolated thrombocytopenia (i.e., with a normal hemoglobin level and neutrophil count) is extremely rare.3 In a very small number of ALL patients (and as in this patient), lymphoblasts may not be detected in the peripheral smear for a prolonged period.

The picture of ALL in children is complicated by the fact that patients may not exhibit typical symptoms and signs and laboratory evaluation isn't always helpful. Bone pain is present in fewer than one third of children who have leukemia of any type4 and, as in this boy, patients are sometimes referred to a rheumatologist with a presumptive diagnosis of JRA. In one review of this problem, 29 children referred for presumed rheumatologic illness over a 13-year period (0.4% of all referrals) were eventually given a diagnosis of malignancy—most often, ALL.4 In the past, some children who had ALL were treated with a corticosteroid after an erroneous diagnosis of JRA; ALL was recognized only when patients relapsed after a period of remission.5

It has been suggested that clinicians maintain a high index of suspicion for malignancy when a child complains of nonarticular bone or back pain.6 Patients who have ALL with bone pain often have a low WBC count and a peripheral smear free of abnormal cells,7 yet a bone scan is abnormal in 75% of patients in the presence of such unremarkable laboratory results.8

Childhood ALL is one of the great success stories of modern medicine. Considered uniformly fatal a few decades ago, the five-year relapse-free survival rate of the disease approaches 80% today. Certain clinical variables that affect prognosis have been identified: Patients younger than 1 year and older than 10 years at presentation, patients who have a high WBC count (>50 x 103/µL), and patients in whom central nervous system involvement has been confirmed by examining a specimen of CSF have a higher risk of relapse. Biologic variables that are important negative prognostic indicators include T-cell vs. B-cell lineage differentiation; hyperdiploidy (i.e., extra chromosomes within the malignant cell population); and the presence or absence of specific chromosomal translocations.

Nonspecific symptoms and signs and an atypical clinical presentation delay the diagnosis of ALL in many cases. Consider ALL in the differential diagnosis of any child who complains of bone pain of extended duration. And beware of assigning a diagnosis of JRA or other rheumatic disease to a patient who has persistent or recurrent bone pain when other characteristic features of a specific rheumatic disease are absent. That is all.


1. Robinson LL: General principles of the epidemiology of childhood cancer, in Pizzo PA, Poplack DG (eds): Principles and Practice of Pediatric Oncology, ed 3. Philadelphia, Lippincott-Raven, 1997, pp 1–10

2. Margolin JF, Poplack DG: Acute lymphoblastic leukemia, in Pizzo PA, Poplack DG (eds): Principles and Practice of Pediatric Oncology, ed 3. Philadelphia, Lippincott-Raven, 1997, pp 409–462

3. Friebert SE, Shurin SB: ALL: Diagnosis and outlook. Contemporary Pediatrics 1998;15(2):118

4. Pui CH: Childhood leukemias, in Murphy GP, Lawrence W, Lenhard RE (eds): American Cancer Society Textbook of Clinical Oncology, ed 2. Atlanta, American Cancer Society, 1995, pp 501–523

5. Chessells JM: Pitfalls in the diagnosis of childhood leukemia. Brit J Hematol 2001;114:506

6. Cabral DA, Tucker LB: Malignancies in children who initially present with rheumatic complaints. J Pediatr 1999;134:53

7. Hughes RG, Kay HE: Major bone lesions in acute lymphoblastic leukemia. Medical Pediatric Oncology 1982;10:67

8. Bernard EJ, Nicholls WD, Howman-Giles RB, et al: Patterns of abnormality on bone scans in acute childhood leukemia. J Nucl Med 1998;39:1983

THE AUTHORS work in the department of pediatrics at West Virginia University, Morgantown, where DR. LARZO is a resident, DR. GANGARAM is assistant professor in the division of general pediatrics, DR. KELLER is associate professor in the division of hematology/oncology, and DR. KAMAT is a professor in the division of general pediatrics.
DR. SIBERRY is a fellow in pediatric infectious disease at The Johns Hopkins Hospital, Baltimore, Md.


George Siberry, ed. Deepak Kamat, Melissa Larzo, Balram Gangaram, Frank Keller. Pediatric Puzzler: Bone pain and fever. Contemporary Pediatrics 2003;4:17.

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