Chronic nonbacterial osteomyelitis/Chronic recurrent multifocal osteomyelitis (ORPHA:324964)
Chronic nonbacterial osteomyelitis (CNO), also known as chronic recurrent multifocal osteomyelitis (CRMO), is a chronic autoinflammatory syndrome that is characterized by multiple foci of painful swelling of bones, mainly in the metaphyses of the long bones, in addition to the pelvis, the shoulder girdle and the spine.
Epidemiology
Depending on the studies, prevalence of CNO/CRMO has been grossly estimated at between 1/ 160,000 to 1/ 2,000,000 and incidence at between 1/ 250,000 to 1/ 1,000,000. The disease affects predominantly females.
Clinical description
CNO/CRMO occurs mainly in children and adolescents with an average age of onset of 10 years old. It is characterized by the insidious onset of recurrent episodes of local pain, tenderness, or swelling at the areas of bone inflammation. Inflammation can occur at any site of the skeleton. Metaphyses and epiphyses of the long bones are most frequently affected, in addition to the pelvis, the shoulder girdle and the spine. The neurocranium is almost never affected. Pain occurs predominantly during day hours, but may also be present at night time. The symptoms may induce a limited range of motion, since joints may be affected by arthritis. The severity and time course may vary widely among patients, oscillating between acute exacerbations and spontaneous remission. Systemic manifestations like fever, malaise, weight loss are frequent and the disease may be associated with inflammatory disorders of the skin such as psoriasis vulgaris, palmoplantar pustulosis, acne, pyoderma gangrenosum and rarely Sweet's syndrome, and /or of the intestine, like Crohn's disease, or ulcerative colitis. Adult-onset forms are reported that resemble SAPHO syndrome. It is not clear whether SAPHO syndrome and CNO/CRMO are two separate entities or if they are part of the same disease spectrum with CNO/CRMO being the pediatric equivalent of SAPHO syndrome.
Etiology
The exact pathogenetic mechanism is unknown. An infectious origin is excluded as no apparent infectious agents are detectable at the site of the bone lesion. A genetic component is suspected for CNO/CRMO susceptibility. Immune dysregulation, particularly of the IL-10 and also the IL-1 pathway function, may play a role in the etiology of the disease.
Diagnostic methods
Diagnosis is based on a combination of clinical, radiological and histological exams. The classic findings on magnetic resonance imaging (MRI) are initial bone edema, generally followed by osteolytic or sclerotic, then hyperostotic bone lesions, as well as periosteal and soft tissue reaction. Bone lesion biopsies are typically sterile, and along with blood tests and an extensive microbial workup, show nonspecific inflammatory changes.
Differential diagnosis
Differential diagnosis includes mainly acute or subacute bacterial osteomyelitis, juvenile idiopathic arthritis, hypophosphatasia, Langerhans cell histiocytosis, and malignancies like osteosarcoma, Ewing sarcoma, neuroblastoma, rhabdomyosarcoma, leukemia, and lymphoma. Rare monogenetic syndromes with CNO/CRMO as a component must also be excluded, such as Majeed syndrome, PAPA syndrome and DIRA syndrome (sterile multifocal osteomyelitis with periostitis and pustulosis).
Genetic counseling
Most cases are sporadic.
Management and treatment
Non steroid anti-inflammatory drugs (NSAIDs) are the treatment of choice. Oral steroids, bisphosphonates and TNFα blockers can be used as an alternative treatment in cases unresponsive to NSAIDs, or during flares and in order to prevent relapses. The anti-inflammatory action of azithromycin may also contribute to a positive clinical therapeutic effect.
Prognosis
The disease is characterized by alternating periods of remission and relapse, but generally has a ''benign'' course and can eventually resolve. In some cases, bone deformities may occur that can induce long-term disabilities (e.g. vertebra plana, hyperostosis, pain syndrome). Long term evolution towards spondyloarthropathy has been described.

                            Last update: 
                            November 2013


                            - Expert reviewer(s): 
                            Pr Hermann GIRSCHICK