Periodic fever as a presenting sign of childhood acute lymphoblastic leukaemia

E. C. Koffeman, N. M. Wulffraat1, M. Bruin2, P. H. G. Hogeman3 and J. Frenkel

Departments of General Paediatrics, 1 Paediatric Immunology and 2 Paediatric Haematology, Wilhemina Children's Hospital, University Medical Center, Utrecht, and 3 Department of Paediatrics, Meander Medisch Centrum, Amersfoort, The Netherlands.

Correspondence to: J. Frenkel, Wilhelmina Children's Hospital KE.04.133.1, PO Box 85090, 3508AB Utrecht, The Netherlands. E-mail: j.frenkel{at}umcutrecht.nl

SIR, Periodic fever in childhood is usually due to genetic autoinflammatory diseases but may be the presenting sign of more serious illness. We describe a girl with acute lymphoblastic leukaemia (ALL), presenting with periodic fever.

The patient, an East-Asian girl, had been healthy until the age of 11 yr when she started to experience episodes of 6–10 days of musculoskeletal pain and fever of 39–40°C, occurring about once a month. Over time, the pain during these attacks worsened. Its localization varied from chest, shoulders and elbows to the sacro-iliacal region and hips and sometimes the abdomen. Non-steroidal anti-inflammatory drugs (NSAIDs) reduced the pain. Between episodes she was completely well. She had not recently travelled abroad. The family history was negative for periodic fever.

Physical examination between attacks was initially normal, but later revealed painful limitation of movement in hips, shoulders and elbows, without frank arthritis.

During the fever episodes the patient was anaemic (haemoglobin 6.0–8.7 mg/dl). Peripheral blood repeatedly showed normal platelet, white cell and differential counts and no blasts. The erythrocyte sedimentation rate (ESR, 53–140 mm/h) and C-reactive protein (CRP, 52–152 mg/l) were raised. Between episodes the CRP was below 5 mg/l. Analysis of the anaemia revealed a heterozygous beta-thalassemia.

There were no localizing signs of infection and the tuberculin test was negative. X-rays of chest, abdomen, lumbar spine and pelvis, ultrasound of the abdomen and hips and magnetic resonance imaging (MRI) of the lumbar spine were all normal.

The genes MEFV (familial Mediterranean fever), TNFRSF1A (TNF receptor associated periodic syndrome, TRAPS) and CIAS1 (Muckle–Wells syndrome) were analysed. All exons and intron–exon boundaries were sequenced and were found to be normal. Serum immunoglobulin D (IgD, 51 IU/ml) and urinary mevalonic acid excretion (hyper IgD periodic fever syndrome) were also normal.

Fifteen months after the first symptoms, the girl presented with extreme pallor, 39°C fever, respiratory distress and pain in the back, legs and arms. On examination she had tachycardia (150/min), low blood pressure (115/50 mmHg), a -systolic murmur over the base of the heart and crackles over the right dorso-basal lung area. Blood tests showed a raised lactic dehydrogenase (LDH, 1227 U/l) and ESR (>140 mm/h), severe anaemia (haemoglobin 2.9 mg/dl) and thrombocytopenia (29 x 109/l). The white cell count was normal (5.8 x 109/l), but now showed peripheral blast cells (3.03 x 109/l).

A bone marrow aspirate contained 89% blasts with a pre-B-cell immunophenotype, confirming a diagnosis of ALL. Cerebrospinal fluid was normal and a chest X-ray showed no widened mediastinum or lymph nodes. Liver and spleen were enlarged on ultrasound.

Induction chemotherapy according to the DCOG ALL-9 protocol was started and soon the fever and pain disappeared. Both leukaemia and fever have remained in complete remission for 12 months now.

The cause of episodic high-grade fever and musculoskeletal pain in this patient had remained elusive for over a year. A hereditary periodic fever syndrome was suspected [1], but could not be confirmed. Moreover, the episodes were unusual in that bone pain and profound anaemia were prominent. The fever pattern was not typical for Pel–Ebstein fever, which typically lasts 1–2 weeks, separated by afebrile periods of similar duration [2]. We initially ascribed the anaemia to the combination of chronic inflammation and beta-thalassemia minor.

Fever is a common sign of leukaemia [3, 4], but periodic fever as a prodrome is rare. One report describes chronic relapsing fever in an adult over a 15-month period, before leukaemia (not otherwise specified) was diagnosed [5]. Two cases of relapsing fever preceding acute myelogenous leukaemia have been reported [6]. One, a 26-yr-old male, had a 6.5 month history of bone pain, progressive anaemia, neutropenia and episodic fever before a third blood smear showed leukaemia. The other, a 28-yr-old male, had suffered intermittent fever and migratory pain around the joints for 9 months, while blood and bone marrow smears initially failed to reveal leukaemia.

Bone pain and arthralgias are common presenting symptoms of childhood [3], often accompanied by fever and raised ESR. Interestingly, children with leukaemia who present with musculoskeletal symptoms often have low peripheral leukocyte numbers and few, if any, peripheral blasts [7, 8].

In conclusion, periodic fever accompanied by skeletal pain or profound anaemia should alert the physician to the possibility of underlying leukaemia.

The authors have declared no conflicts of interest.

References

  1. Grateau G. Clinical and genetic aspects of the hereditary periodic fever syndromes. Rheumatology 2004;43:410–15.[Abstract/Free Full Text]
  2. Racchi O, Rapezzi D, Ferraris AM, Gaetani GF. Unusual bone marrow relapse of Hodgkin's disease with typical Pel-Ebstein fever. Ann Hematol 1996;73:39–40.[CrossRef][ISI][Medline]
  3. Nathan DG, Orkin SH, Ginsburg D, Thomas Look A, Oski FA (eds). Nathan and Oski's Hematology of Infancy and Childhood, 6th Edn. Philadelphia: Saunders.
  4. Vidal C, Baer MR, Bloomfield CD. Uncommon patterns of presentation of leukemia, review article. Hematol Oncol 1999;17:11–29.[CrossRef][ISI][Medline]
  5. Zanger B, Dorsey HN. Fever—a manifestation of preleukemia. J Am Med Assoc 1976;236:1266–8.[Abstract]
  6. Kumar S, Bhargava M. Pre-leukaemic acute myelogenous leukaemia. Acta Haematol 1970;43:21–30.[ISI][Medline]
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  8. Ribeiro RC, Pui CH, Schell MJ. Vertebral compression fracture as a presenting feature of acute lymphoblastic leukemia in children. Cancer 1988;61:589–92.[ISI][Medline]
  9. Caudle RJ, Crawford AH, Gelfand MJ, Gruppo RA. Childhood acute lymphoblastic leukemia presenting as ‘cold’ lesions on bone scan: a report of two cases. J Pediatr Orthop 1987;7:93–5.[ISI][Medline]
Accepted 1 August 2005





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