Chronic non-bacterial osteomyelitis presenting as fever of unknown origin in a child: a diagnostic pitfall

BACKGROUND: Chronic non-bacterial osteomyelitis (CNO), also referred to as chronic recurrent multifocal osteomyelitis (CRMO), is a rare autoinflammatory bone disorder in children and adolescents. Bone pain is the most common presenting symptom, whereas prolonged recurrent fever of unknown origin is uncommon and may mimic infection or malignancy, leading to extensive diagnostic evaluations, including invasive procedures. CASE PRESENTATION: We report a 12-year-old girl who presented with recurrent fever as the predominant symptom, accompanied by delayed and intermittent musculoskeletal pain. Extensive infectious, rheumatologic, and oncologic investigations, including repeated cultures, metagenomic next-generation sequencing, and bone marrow examination, were unrevealing. Magnetic resonance imaging demonstrated multifocal bone marrow edema, and positron emission tomography-computed tomography showed multifocal FDG-avid skeletal lesions, with a maximum SUV of 6.85 among the focal skeletal lesions, raising concern for malignancy. Histopathological examination of a femoral bone biopsy revealed lymphoplasmacytic infiltration with focal fibrosis and no evidence of infection, granulomatous inflammation, necrosis, or malignancy. Based on the clinical course, imaging findings, exclusion of infection and malignancy, and histopathological findings, a diagnosis of CNO/CRMO was established. The patient improved after stepwise treatment with naproxen, methotrexate, and prednisone. CONCLUSION: This case illustrates an uncommon fever-dominant presentation of pediatric CNO/CRMO with multifocal skeletal lesions mimicking malignancy. CNO/CRMO should be considered in children with fever of unknown origin accompanied by delayed musculoskeletal symptoms or multifocal bone marrow lesions. In typical cases, biopsy may be avoided when clinical and imaging findings are characteristic; however, in atypical presentations with systemic symptoms and malignancy-like imaging findings, bone biopsy may remain necessary to exclude infection and neoplastic disease.