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Chronic recurrent multifocal osteomyelitis (CRMO) is a rare condition in which a child’s bones become inflamed and painful.

The important thing is that this condition is
 not caused by an infection though the symptoms are very similar to bone disease caused by the infection called osteomyelitis. CRMO has periods of remission and exacerbation which means that symptoms are sometimes present and sometimes they are not. It primarily affects the skeletal system although sometimes ‘extra-skeletal’ sites can be affected too. The most common sites are the metaphyses of long bones, spine, pelvis, and shoulder girdle. Even though this disease has been recognized as a clinical entity for almost three decades now, its origin and pathogenesis are not entirely clear.
The clinical and radiological features on the disease are variable and the diagnosing can be difficult.

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Multiple names have been used to describe this condition and they include

  • chronic multifocal osteomyelitis,
  • chronic recurrent multifocal osteomyelitis, and
  • SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis).

Incidence of the condition

This disease is rare and it mostly affects children. It is more common in girls than boys, at a ratio of five to one. However, the adults can also be affected. In children it may develop between the ages 4 and 14, with the age of 10 being the most common starting point for the development of this condition. No epidemiological data on incidence and prevalence have been published so far. However, the incidence might be estimated at 1:1,000,000.

What are the common symptoms?

Chronic recurrent multifocal osteomyelitis is a disorder that damages the affected area of the bone and creates characteristic formations also known as bone lesions. The problem is that, when these lesions flare-up they cause

  • deep aching pain,
  • limping,
  • fever,
  • possible constitutional upset,
  • swelling
  • skin redness.

The pain can be quite severe and may limit the child’s activities. Not only that it may prevent the kid from going to school, but sometimes it may even require hospitalization. It mainly affects the metaphyses of the long bones, in addition to the spine, the pelvis and the shoulder girdle. Some bones seem to be more affected by CRMO than others and this includes the shinbone, thighbone and clavicle (collarbone). Many young people with CRMO have pain in more than one area of the bone.

Possible cause of CRMO

The cause of this condition is unknown, despite the intensive investigation over a period of more than 30 years. Carefully done culture and tissue sampling on bone lesions in children with this disease, using the best available techniques, has failed to yield any apparent infectious agents.
The main suggestions for possible causes include:

  • infectious disease,
  • autoimmune reaction (where white blood cells instead of seeking out and destroying foreign invaders turn on the body and attack normal cells instead) or
  • a defect in the immune system.

Propionibacterium acnes has been postulated to be involved in the pathogenesis. However, in larger cohorts and by using state of the art microbial techniques, no apparent infectious agents have been detected at the site of the bone lesion in pediatric patients.
There are also some experts who believe it is an inherited condition and that genetics play a major role in its development. They have found a significant association of CRMO with a rare allele of marker D18S60, resulting in a haplotype relative risk (HRR) of 18.
This suggests the existence of a gene in this region contributing in a significant manner to the etiology of CRMO and concomitantly demonstrates evidence for a genetic basis of CRMO. This gene is different from RANK, which is mutated in familial expansile osteolysis (FEO), but not in CRMO.

Differential diagnosis

The differential diagnosis includes

  • bacterial osteomyelitis,
  • Ewing sarcoma,
  • leukemia,
  • lymphoma,
  • rhabdomyosarcoma,
  • neuroblastoma metastasis,
  • eosinophilic granuloma
  • Langerhans cell histiocytosis.


Some experts have named a few precise criteria for diagnosing this condition:

  • two or more bone lesions mimicking osteomyelitis,
  • radiological and bone scan findings consistent with osteomyelitis,
  • six months or more of chronic and relapsing symptoms,
  • failure of response to at least one month of appropriate antibiotic therapy,
  • A lack of other identifiable cause.

Clinical manifestations

Skeletal manifestations

  • Unifocal or multifocal, initially osteolytic, later hyperostotic and sclerotic lesions mainly in the metaphyses of the long bones and shoulder girdle, but any bone can be affected. Relapses are frequent even under therapy.
  • Arthritis of adjacent and distal joints is frequent. CRMO can be a feature of enthesitis-related arthritis at onset or during the disease course.


Other organ involvement

  • Palmoplantar pustulosis, psoriasis or acne conglobata
  • Uveitis
  • Inflammatory bowel disease

Diagnosis of chronic recurrent multifocal osteomyelitis

Clinical diagnosis in affected children can be difficult because the clinical picture and course of the disease may vary significantly. CRMO can have similar symptoms to other conditions, for example arthritis. Radiological and magnetic resonance imaging features of CRMO have been described, but differential diagnosis remains difficult, including rheumatic diseases, bacterial osteomyelitis, and malignancy. To get a diagnosis the person needs to have a series of tests and scans.

Bone biopsy
Bone biopsy is often the best way to do this. During this procedure, a small sample of the inflamed bone is removed with a needle, usually under anaesthetic, to be examined under the microscope. The gold standard for diagnosis of CRMO is histopathology of bony lesions. Lesions consist of chronic inflammatory cells and cultures are characteristically negative. In very early lesions granulocytes can be observed, and later on there are mainly lymphocytes or monocytes. All bacterial and fungal cultures from native biopsy tissues should be negative.

Plain radiographic findings
Findings made by plain radiographic imaging are variable. CRMO can present as an osteolytic, sclerotic, or a mixed lytic-sclerotic lesion.

MRI
This is a very good and effective diagnostic method. Magnetic resonance imaging scans have been used to evaluate the activity of lesions and to identify the most appropriate site for biopsy.

Treatment of chronic recurrent multifocal osteomyelitis

The effective and definite treatment is still impossible. The aim of the treatment is to try to prevent flare-ups and treat them if they occur. Long term treatment is usually required to monitor any growth disturbances in the affected bones.

Antibiotics are no good
Experience has shown that antibiotic treatment is not effective in dealing with CRMO flare-ups as there is no underlying infection to treat. This is probably because no bacteria can be found in the bone biopsy specimens.

Non-steroidal anti-inflammatory drugs (NSAIDs)
Affected bones respond well to non-steroidal anti-inflammatory drugs (NSAIDs), and they are the primary choice for the effective treatment. Azithromycin has been used in the treatment of this condition because of its anti-inflammatory and immuno-modulatory effects.

Physiotherapy
Physiotherapy has shown to be a very effective therapeutic method. It is proven that physiotherapy can also help improve movement and flexibility of the affected bones and the surrounding joints.

Steroids
Severe cases of CRMO can often be treated with regular doses of steroids, which damp down the inflammation and allow the bone to heal. Oral steroids, bisphosphonates, and sulfasalazine have been used in specific cases. Other medicines that have the same ‘damping down’ effect may also be recommended, either alone or in the conjunction with steroids.

Surgical operations
If the bone lesions are obvious and cause problems, they can be removed with an operation. Aggressive surgical treatments, and procedures that increase the risk of pathological fracture in particular, should be avoided.

Disease course and prognosis

The long term outcome of CRMO is poorly understood. However it may induce:

  • school difficulties,
  • bone deformities,
  • psoriasis,
  • inflammatory bowel disease


Most children with CRMO go into remission in late childhood, but some have relapses in late adolescency or early adulthood. However, if certain areas of bone are affected, this may cause the limb not to develop properly leaving it shorter than the other. This can be treated in various ways including surgery. Although children and young people with CRMO may need to miss some schooling due to their illness, most of them grow up to lead normal lives, working and raising a family.
Recently, evolvement of CRMO into arthritis or spondyloarthropathy has been documented in several cohort studies of children and young adults. It seems that tht inflammatory joint involvement at the time of  thediagnosis and during the course of the disease might have been underestimated until recently. Pathogenetically, CRMO is linked to juvenile arthritis and features of CRMO can overlap features of enthesitis-related arthritis or psoriatic arthritis.
The bottom line is that, generally, the outlook for children and young adults with CRMO is excellent. The majority respond well to treatment and suffer few long-term effects.