Clinical Pediatrics

http://cpj.sagepub.com A Child With Severe Joint Pain

Jyothi Mallepalli and Abraham Gedalia Clin Pediatr (Phila) 2010; 49; 605 originally published online Jul 14, 2008; DOI: 10.1177/0009922808321446 The online version of this article can be found at: http://cpj.sagepub.com

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Resident Rounds

Unique cases written by pediatric residents with a faculty member.

Clinical Pediatrics 49(6) 605-607 The Author(s) 2010 Reprints and permission: http://www. sagepub.com/journalsPermissions.nav DOI: 10.1177/0009922808321446 http://clp.sagepub.com

A Child With Severe Joint Pain

Jyothi Mallepalli, MD, MRCP,1 and Abraham Gedalia, MD, FAAP, FACR1

Patient Report
An 11-year-old white girl was referred to the pediatric rheumatology clinic with a 4-week history of joint pain and swelling. Pain had first started about 4 weeks ago in the right wrist, then moved to involve the knees. A few days later, the pain in the knee improved, and at the time of her presentation to our clinic, she had pain in the left arm as well as in both legs. Pain was episodic and severe enough to waken her up almost every night. She had no fever or chills and had no morning stiffness. There was a history of poor appetite and weight loss of 4 pounds. There was no history of trauma. The patient was taking ibuprofen 400 mg every 4 hours for pain but with no relief. She did admit to having a cough that was nonproductive as well as a runny nose for 3 to 4 days prior to her clinic visit. The patient did not have past medical problems and had had no previous surgery. She was a sixth grader who had been unable to go to school because of the pain and had been off school for 4 weeks. There was no family history of connective tissue disease. On examination, the patient appeared to be well nourished. Her blood pressure was 120/60, pulse 100, and temperature 96.6F. Examination of head and neck showed no lymphadenopathy and her mucous membranes were pink and moist. Her heart sounds were normal, and no heart murmurs were heard. Her lungs were clear to auscultation. An abdominal exam did not reveal any organomegaly. A musculoskeletal exam revealed mild swelling of both elbows with pain on extension and pain on extension and flexion of right wrist. Both knees appeared puffy without effusion but with pain on extension. She had no skin rash.

elevated at 93 mm/h, and C-reactive protein was elevated at 5.8 mg/dL. Antinuclear antibodies and rheumatoid factor were negative. The monospot test was negative, and she had normal urinalysis. Based on the history, physical examination, and laboratory evaluations, the differential diagnosis at that time included juvenile rheumatoid arthritis; viral diseases caused by Epstein-Barr virus, cytomegalovirus, and parvovirus B19; and malignancy. The next step was to test for lactate dehydrogenase (LDH), uric acid, and viral titers. The results showed elevated uric acid at 7.4 mg/dL and elevated LDH at 1522 U/L. X-rays of the right wrist, both elbows, and chest were normal. A bone scan was performed showing abnormal increase of tracer activity in both fibulas as well as in the left tibia (Figure 1). These findings could be suggestive of stress fractures or abnormal bony infiltrates. A bone marrow biopsy showed a near total replacement of the marrow by a monomorphic population of cells with a high nuclear/cytoplasm ratio as well as delicate lacy chromatin with inconspicuous nucleoli and no cytoplasmic granules, compatible with lymphoblastic leukemia (Figure 2).

Discussion Musculoskeletal Manifestations and Malignancy

Some malignancies have rheumatologic symptoms and may present with joint, muscle, and soft tissue manifestations. The malignancies that have the most frequent musculoskeletal findings are leukemias and lymphomas, but such findings may also occur with solid tumors.1
1

Laboratory Evaluation
The initial laboratory tests that were done by the primary care physician showed a white blood cell count of 10 300/mm3 with 14% segmented neutrophils, 15% bands, and 71% lymphocytes; hemoglobin was 11.5 g/ dL and hematocrit 35.8%; the platelet count was 176 000/mm3. Her creatinine and liver function tests were normal. The erythrocyte sedimentation rate was

Section of Rheumatology, Ochsner Clinic Foundation (JM); and the Division of Pediatric Rheumatology, LSU Health Sciences Center and Childrens Hospital (AG), New Orleans, Louisiana. Corresponding Author: Abraham Gedalia, Division of Rheumatology, Childrens Hospital of New Orleans, 200 Henry Clay Ave, New Orleans, LA 70118 Email: agedal@lsuhsc.edu.

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Clinical Pediatrics 49(6)

Figure 1. Total body technetium 99m bone scan showing abnormal increase of tracer activity in the proximal third of the fibular shafts bilaterally and in the distal left-tibial metaphysic.

Figure 2. Bone marrow biopsy shows near total replacement of the marrow by a monomorphic population with scant and thin rim of cytoplasm (a high nuclear/ cytoplasm ratio).

Distinguishing acute lymphoblastic leukemia (ALL) from juvenile idiopathic arthritis (JIA) can be very difficult. Children with leukemia may first present with musculoskeletal symptoms mimicking JIA and often have normal hematological variables.2 In ALL, which is the common childhood malignancy, the initial presentation may involve the musculoskeletal system in up to two thirds of cases,3 and arthritis may be the only presenting feature of leukemia.4 Robazzi5 found that in ALL, 16% of the patients presented with arthralgias as the initial manifestation of leukemia, 26% had arthritis, 26% had bone pain, 49% had limb pain, and 33% had antalgic gait. In addition, night pain has been observed frequently in children with leukemia.6 Children with JIA usually describe pain, stiffness, and a dull discomfort over the joints that are worse in the mornings. Excruciating pain that wakes the child from sleep at night is not typical for JIA.7,8 Medical literature during the past 50 years describes small numbers of children who presented to rheumatologists for arthritis who were later diagnosed with ALL. Among those cases, severe nighttime pain, mild to moderate blood smear abnormalities, and increased LDH were often reported.7,8 Both elevated LDH and uric acid are known to be a useful marker of cell turnover and are often raised in malignancy. Wallendal et al9 showed that although normal LDH concentrations do not exclude malignancy, the presence of arthritis with raised LDH and otherwise normal laboratory results is a cause for concern. However, previous reports by Ostrov et al10 and Cabral and Tucker1 revealed that high LDH showed low sensitivity in distinguishing JIA from ALL.

Serum uric acid appears to be a less useful marker to differentiate childhood leukemia from JIA. Uric acid levels were usually reported as being normal1,10-12 or mildly increased.13 In a more recent multicenter case-control study by Jones et al,14 data (including symptoms, physical signs, blood tests, and radiographs) on 71 ALL and 206 JIA patients were analyzed. They concluded that the presence of 2 low complete blood count markers (low WBC, low hemoglobin, or low-normal platelets) along with a history of nighttime pain was the most predictive set of findings for peripheral blast-negative ALL. However, high LDH, high uric acid, positive antinuclear antibodies, abnormal radiographs, arthritis, rash, and functional disability were not reliable in distinguishing JIA from ALL. Finally, abnormal radiographs with osteopenia and joint effusions were noted both in patients with ALL as well as in those with JIA. However, the presence of radiolucent bands, osteolytic lesions, and sclerotic lesions should alert the physician to consider malignancy (such as ALL) until proven otherwise.13,15 All the above results were gathered retrospectively after the diagnosis was made and may be biased. Therefore, a prospective chart study would help determine the real diagnostic value of these variables. In summary, we therefore recommend that malignancy, and in particular leukemia, must be considered in the initial differential diagnosis when a child presents with unexplained musculoskeletal symptoms, especially nighttime pain. This caveat assumes even greater importance when the clinical or laboratory findings are

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Mallepalli and Gedalia atypical for JIA. Few clinical signs and symptoms can differentiate JIA from acute leukemia. Very careful evaluation with attention to subtle historical, clinical, laboratory, and radiological details as well as close follow-up with additional evaluations may help expedite the diagnosis and treatment of malignancies, especially ALL, in the subset of children presenting with predominant musculoskeletal complaints. Declaration of Conflicting Interests
The author declared no potential conflicts of interests with respect to the authorship and/or publication of this article.

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5. Robazzi TC, Barreto JH, Silva LR, Santiago MB, Mendonca N. Osteoarticular manifestations as initial presentation of acute leukemias in children and adolescents in Bahia, Brazil. J Pediatr Hematol Oncol. 2007; 29:622-662. 6. Silverstein MN, Kelly PJ. Leukemia with osteoarticular symptoms and signs. Ann Intern Med. 1963;59:637-645. 7. Schaller J. Arthritis as a presenting manifestation of malignancy in children. J Pediatr. 1972;81:793-797. 8. Bowyer SL, Hollister JR. Limb pain in childhood. Pediatr Clin North Am. 1984;31:1053-1081. 9. Wallendal M, Stork L, Hollister JR. The discriminating value of serum lactate dehydrogenase levels in children with malignant neoplasms presenting as joint pain. Arch Pediatr Adolesc Med. 1996;150:70-73. 10. Ostrov BE, Goldsmith DP, Athreya BH. Differentiation of systemic juvenile rheumatoid arthritis from acute leukemia near the onset of disease. J Pediatr. 1993;122: 595-598. 11. Fink CW, Windmiller J, Sartain P. Arthritis as the presenting feature of childhood leukemia. Arthritis Rheum. 1972;15:347-349. 12. Spilberg I, Meyer GJ. The arthritis of leukemia. Arthritis Rheum. 1972;15:630-635. 13. Thomas LB, Forkner CE, Frei E, Besse BE, Stabenau JR. The skeletal lesions of acute leukemia. Cancer. 1961; 14:608-621. 14. Jones OY, Spencer CH, Bowyer SL, Dent PB, Gottlieb BS, Rabinovich CE. A multicenter case-control study on predictive factors distinguishing childhood leukemia from juvenile rheumatoid arthritis. Pediatrics. 2006;117: e840-e481. 15. Rogalsky RJ, Black B, Reed MH. Orthopaedic manifestations of leukemia in children. J Bone Joint Surg Am. 1986;68:494-501.

Funding
The author received no financial support for the research and/ or authorship of this article.

References
1. Cabral DA, Tucker LB. Malignancies in children who initially present with rheumatic complaints. J Pediatr. 1999;134:53-57. 2. Bradlow A, Barton C. Arthritic presentation of childhood leukaemia. Postgrad Med J. 1991;67:562-564. 3. Barbosa CM, Nakamura C, Terreri MT, Lee ML, Petrilli AS, Hilrio MO. Musculoskeletal manifestations at the onset of acute leukaemias in childhood. J Pediatr (Rio J). 2002;78:481-484. 4. Jonsson OG, Sartain P, Ducore JM, Buchanan GR. Bone pain as an initial symptom of childhood acute lymphoblastic leukaemia: association with nearly normal haematologic indexes. J Pediatr. 1990;117:233-237.

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