Case 1: A limping child...with abdominal pain

A four-year-old healthy boy presented with a two-day history of fever, abdominal pain and left hip pain, with refusal to walk. He was admitted to hospital, and was started on intravenous ceftriaxone. Laboratory evaluation revealed a peripheral white blood cell (WBC) count of 7×10⁹/L, and an erythrocyte sedimentation rate (ESR) of 105 mm/h. His hip x-ray and abdominal computed tomography were normal. ‘Pus’ was aspirated from the left hip. Gram stain and bacterial culture from the hip, blood and urine were negative. The patient’s magnetic resonance imaging scan of the hip demonstrated tenosynovitis, without evidence of osteomyelitis. He had no rash, upper respiratory symptoms, history of trauma, sick contacts or recent travel. His fever resolved on hospital day 8, and he was discharged home with cephalexin for a presumed diagnosis of septic hip.

He was readmitted on day 22 of illness, with recurrence of symptoms. His appetite was poor, and he had lost weight in the recent weeks. Laboratory evaluation revealed a WBC count of 5×10⁹/L, absolute neutrophil count of 1×10⁹/L, lymphocyte count of 4×10⁹/L and an ESR of 95 mm/h. His hip x-ray and abdominal computed tomography were again normal. Magnetic resonance imaging scan showed a small left hip joint effusion and heterogeneous infiltrates of the iliac bones (the left side more than the right side). He was treated with broad-spectrum intravenous antibiotics for presumed partially treated osteomyelitis.

On day 39 of illness, he was readmitted again with recurrence of symptoms. On examination, his temperature was 39.2°C, heart rate was 150 beats/min, respiratory rate was 20 breaths/min and blood pressure was 100/60 mmHg. He was pale and appeared tired. There was a mild diffuse tenderness to palpation on abdominal examination and over the left hip. Pain was elicited with hip movement, but no swelling, erythema or warmth was noted. The rest of the physical examination was unremarkable. Laboratory evaluation revealed a WBC count of 3.0×10⁹/L (absolute neutrophil count of 0.5×10⁹/L), hemoglobin level of 100 g/L, platelet count of 250×10⁹/L, ESR of 97 mm/h and normal chemistry panel. On further review of his investigations, the diagnosis became clear.

CASE 1 DIAGNOSIS: ACUTE LYMPHOBLASTIC LEUKEMIA

Blasts were seen on the patient’s peripheral smear. Bone marrow biopsy confirmed the diagnosis of precursor B cell acute lymphoblastic leukemia (ALL). Symptoms resolved completely once chemotherapy was started.

ALL is the most common malignancy of childhood, with an incidence of 35 cases per million per year (1–5). Approximately 2500 children are diagnosed with ALL each year in the United States. ALL occurs most commonly in children two to five years of age, and is more common in boys and Hispanic children.

ALL is caused by dysregulated proliferation of lymphoblasts arrested in early stages of development (1–4). Chromosomal changes (rearrangements and changes in ploidy) are common. TEL-AML t(12;21) and hyperdiploidy are the two most common chromosomal changes, and also the two that portend the better prognosis. Few cases of ALL are associated with inherited genetic syndromes; the etiology in the majority remains unknown.

Proliferating lymphoblasts replace the normal bone marrow and may result in anemia, thrombocytopenia, neutropenia and bone pain (1–4). Clinical manifestations include fatigue, pallor, petechiae and ecchymoses, fever, anorexia and weight loss (6). Lymphoblasts also proliferate in the liver, spleen and lymph nodes, resulting in enlargement of these organs. One-half of children with ALL have an elevated white blood cell (WBC) count (greater than 10×10⁹/L), while the rest have normal or low WBC counts. Neutropenia (absolute neutrophil count lower than 0.5×10⁹/L) is very common, even in the presence of lymphocytosis (5). Neutropenia predisposes to various infections. Fever results either from infection or endogenous pyrogen production by malignant cells (1–4). High lactate dehydrogenase and uric acid levels (from destruction of leukemic cells) are found in over one-half of children with ALL (7).

A review of the peripheral smear may reveal circulating blasts (1–4), but definitive diagnosis of ALL is based on bone marrow aspiration or biopsy demonstrating more than 25% lymphoblasts (2). Immunophenotyping (flow cytometry) and cytogenetic studies can further classify ALL into lineage subtypes and identify translocations and changes in ploidy (3,4).

One-third of children with ALL (as in the present case) present with musculoskeletal complaints; however, the majority do not have blasts in the peripheral blood (5–7). Proliferating lymphoblasts may cause local hemorrhage and necrosis of adjacent bone, and interference with osteogenesis. Joint effusion and swelling are infrequent, while erythema and warmth are typically absent. Radiographical abnormalities may be present, are generally nonspecific, may be multifocal (as in the present case) and correlate poorly with symptoms (5). However, radiolucent bands, lytic or sclerotic lesions are suggestive for malignancy.

In addition to ALL, the differential diagnosis for fever and atraumatic limp includes systemic juvenile inflammatory arthritis (JIA), rheumatic fever, septic arthritis, osteomyelitis, transient synovitis and Lyme disease.

The child with a septic joint or osteomyelitis usually has an ill appearance, high fever, an extremely painful limb and a history of concomitant infection. Markedly elevated erythrocyte sedimentation rates (ESRs) and WBC counts are typical. Aspiration or biopsy of the joint or bone is critical in establishing the diagnosis. A negative culture examination and poor response to antibiotic therapy makes the diagnosis of infection much less likely. In addition, a septic joint or osteomyelitis may occur in the setting of an established diagnosis of ALL.

Systemic JIA shares in common with ALL the presence of fever, joint pain, hepatosplenomegaly, elevated ESRs, anemia and leukocytosis. A characteristic salmon-coloured rash with areas of central clearing supports the diagnosis of JIA. Diaphyseal bone pain that is worse at nighttime and unresponsive to salicylate therapy, in the setting of thrombocytopenia and neutropenia, supports the diagnosis of ALL instead (7). Of note, both JIA and ALL respond to steroid therapy; therefore, it is crucial to rule out ALL before initiating therapy for JIA (6). In one multicentre case-control study (7) of children who were referred to a rheumatology clinic with musculoskeletal complaints, 75% of the children who were ultimately diagnosed with ALL had no blasts in the initial peripheral blood smear. Three factors predicted ALL – low WBC counts (lower than 4×10⁹/L), low-normal platelet counts (150×10⁹/L to 250×10⁹/L) (ie, lack of expected inflammatory response) and history of nighttime pain. Other findings (positive antinuclear antibody test, rash and objective signs of arthritis) occurred at similar rates in children with ALL and JIA.

A child with transient synovitis usually has a viral prodromal illness, mild hip joint pain, and mild elevations in temperature, WBC counts and ESRs. Lyme disease should be suspected and serum Lyme titres should be examined in the case of a swollen warm joint with the characteristic ‘bull’s eye’ rash, tick bite or residence in an endemic area.

In our patient, the initial low WBC count and bilateral magnetic resonance imaging findings were potential clues to the diagnosis of malignancy.

Current treatments for ALL incorporate a combination of systemic (intravenous, intramuscular and oral) and intrathecal chemotherapy (1–4). To prevent complications of tumour lysis syndrome during the period around diagnosis and initiation of therapy, hyperhydration and allopurinol or rasburicase are used (4). In addition, frequent laboratory tests (lytes, calcium, phosphate, lactate dehydrogenase and uric acid) and strict input and output monitoring is important. Supportive care with blood products and antibiotics are often needed (3). More than 95% of children with standard risk ALL attain remission after induction chemotherapy, and approximately 80% survive free of recurrence at least five years from diagnosis (1–4). Hematopoietic stem cell transplantation is reserved for patients who fail to respond or relapse (1–4). The central nervous system and testes are considered to be sanctuary sites and potential areas for relapse.

Children younger than one year of age or older than 10 years of age, or those with a high WBC count and certain chromosomal translocations (eg, t[9;22] Philadelphia chromosome) have a poorer prognosis (1–4). Radiological abnormalities at presentation are not prognostic factors (6).

CLINICAL PEARLS

• ALL can mimic osteomyelitis, septic arthritis and systemic JIA.

• To avoid delay in appropriate treatment, physicians evaluating a child for persistent fever and atraumatic limp must maintain a high index of suspicion for underlying leukemia. The peripheral smear should always be reviewed for blasts.

• The majority of children with musculoskeletal complaints secondary to ALL may present before the appearance of blasts in the peripheral blood.

• Differentiating factors for ALL include low WBC counts, neutropenia, low-normal platelet counts, lack of response to antibiotic therapy, negative cultures, and multifocal and bilateral radiological abnormalities, especially radiolucent bands, lytic or sclerotic lesions.