Autoinflammatory bone diseases: Genetic mutations, clinical manifestations, and modern therapeutic approaches

Autoinflammatory bone diseases result from dysregulation of innate immune responses, leading to systemic inflammation and sterile inflammatory bone lesions. These disorders primarily affect children and adolescents but can persist into adulthood or present later. Chronic nonbacterial osteomyelitis (CNO) and its severe form, chronic recurrent multifocal osteomyelitis (CRMO), are the main phenotypes associated with these conditions. CNO serves as an umbrella term encompassing various presentations characterized by the insidious onset of local bone pain, typically exacerbated at night, with or without fever. Affected lesions commonly involve the metaphyseal regions of long bones, clavicle, spine, and pelvis, although any bone segment can be implicated. The etiology of CNO remains unclear, although familial predisposition exists, and a notable association with other inflammatory conditions, such as psoriasis, inflammatory bowel disease, and spondyloarthropathies, has been observed among sporadic CNO patients and their first-degree relatives, suggesting a genetic basis. Monogenic disorders, including deficiency of interleukin-1 receptor antagonist (DIRA) and PAPA syndrome (Pyogenic Arthritis, Pyoderma gangrenosum, and Acne), manifest prominent CNO symptoms. Syndromic forms, such as Majeed syndrome and Cherubism, also exemplify this association. CNO is diagnosed through exclusion, with whole-body magnetic resonance imaging (WB-MRI) regarded as the gold standard. MRI findings typically reveal bone cortical thickening, lytic lesions with sclerosis, and bone edema, while differential diagnoses must consider infections and malignancies. First-line treatment typically consists of nonsteroidal anti-inflammatory drugs (NSAIDs), while bisphosphonates and tumor necrosis factor-alpha (TNF-α) inhibitors may serve as effective second-line options. Although CNO is often benign, inadequate or delayed treatment can lead to severe complications, including valgus deformity, vertebral collapse, and limb length asymmetry.