Chronic Recurrent Multifocal Osteomyelitis with an uncommon presentation and disabling features: A case report

Background: Chronic recurrent multifocal osteomyelitis (CRMO) is one of the auto-inammatory bone disorders with yet to be determined etiology. Due to overlapping signs and symptoms with other bone involvements, the diagnosis of this disease might take a long period of time and the patients may develop deformities in long-term. Thus, increasing awareness about different presentations of the disease seems benecial. Case presentation: A 12-year-old boy was referred to our center with severe back pain in his thoracic vertebrae from 18 months before referral. He had previously undergone two vertebroplasty surgeries due to his kyphosis and had received several courses of antibiotics, which resulted in no improvement in his disabling pain. His physical examination was unremarkable, except for severe thoracic vertebrae tenderness and a mild dextroscoliosis. MRI showed diffuse multiple hypo-signal lesions in thoracic vertebral bodies with slight enhancement, causing compression fractures of T 8 , T 11 and T 12 bodies. Bone scan revealed increased activity in thoracic region (T 7 -T 8 -T 9 -T 12 vertebral bodies) and left clavicle. Other differentials were ruled out by bone marrow aspiration, bone biopsy and laboratory tests. His disease showed a favorable response to treatment with Pamidronate, Methotrexate and Indomethacin and he had no relapse in three years of follow-up. Conclusions: Uncommon presentations of CRMO can be misleading to the specialists and might result in prolonged diagnosis process. Increased awareness among different specialists about such presentations can potentially lead to earlier diagnosis, and timelier and more effective treatment of the CRMO patients.


Background
Chronic recurrent multifocal osteomyelitis (CRMO) is one of the auto-in ammatory bone disorders with still debated etiology. It is the most severe subgroup of chronic non-bacterial osteomyelitis (CNO), which is aseptic, mono-to multi-focal in ammation of the bones (1).
CRMO mostly affects children and adolescents, and the most common age of onset has been reported to be 7-12 years (2). Although the incidence of CNO/CRMO was considered to be low at past, a recent study has demonstrated that the incidence rate of CNO can be comparable to bacterial osteomyelitis (3).
The clinical course mainly includes having chronic recurrent episodes of bone in ammation with symptoms of mild to severe bone pain, mild fever, malaise, and fractures. The most frequent sites for bone lesions are metaphyses of long bones (Tibia and Femur), pelvis, vertebral bodies and the shoulder girdle including clavicle (2,4). The prognosis of the patients with CNO/CRMO is generally good according to previous studies, and minority of cases will show severe disease in long-term follow-ups (5).
Here we discuss a 12-year-old boy, presenting with severe and disabling back pain and kyphosis as the rst presentations of CRMO. This is an uncommon presentation of this disease, and only few cases with such severe symptoms as their rst presentation have been reported before.

Case Presentation
Our patient was a 12- year-old boy presenting with severe back pain in his thoracic vertebrae from 18   months before referral. He had developed an abnormal forward bend in his vertebral column after his   back pain started, and had problem standing straight due to his pain. The pain was constantly present  and did not radiate elsewhere. It was severe and interfered with the patient's daily tasks, such as walking, showering, and etc.
Except the current problem, his past medical history was unremarkable. He was born at term with no birth insults and no anomalies. His growth and development were normal and he had complete childhood vaccination. His current weight was 57 Kg. He did not use any medications prior to the onset of the  Three phase Technetium-99m ( 99m Tc) bone scan was also obtained ( Figure 1). The scan revealed increased activity in thoracic region (in T 7 -T 8 -T 9 -T 12 vertebral bodies) and mild increase in the left clavicle with no other remarkable abnormalities in the rest of the skeleton. At this stage, the diagnosis of CRMO became more probable regarding clavicle involvement, and according to the consults with pediatric orthopedist and pediatric oncologist, spine MRI, bone-marrow aspiration (BMA), and open bone biopsy were requested and done.
The MRI manifested diffused multiple hypo-signal lesions in upper and middle portions of thoracic vertebral bodies with slight enhancement, causing compression fractures of T 8 , T 11 and T 12 bodies.
Signi cant collapse fracture deformity was also seen in T 7 with posterior pedicle involvement.
BMA had normal cells with no signs of malignancy and ow cytometry results were normal. Biopsy of the vertebral bone showed chronic osteomyelitis with in ltrations composed of mostly neutrophils, lymphocytes, and some macrophages, with no Reed-Sternberg cells and no granuloma. The results were negative for malignancy and infections (which were ruled out through cultures, and Polymerase Chain Reaction (PCR) testing for Mycobacterium and Non-mycobacterium tuberculosis and Brucellosis).
By ruling out other probable differentials, an autoin ammatory cause for this chronic osteomyelitis was our nal diagnosis. With the impression of CRMO, we started the treatment with Non-Steroidal Antiin ammatory Drugs (NSAIDs)-Naproxen 500 mg tablet twice a day-and 30 mg Intravenous Pamidronate for three consecutive days. Regarding the favorable response to this treatment and partial improvement of the symptoms, our patient was discharged with 15 mg of oral Prednisolone (5 mg TDS), and his NSAID treatment was changed to 75 mg Indomethacin BID.
After six months of follow-up, the patient still complained about moderate back pain and was not in full remission. Therefore, 7.5 mg Methotrexate once a week was added to his medications. The symptoms resided thereafter. Nevertheless, the patient discontinued the medication after a few months, which caused another episode of relapse. Considering the complications of long-term corticosteroid use, Prednisolone was not included in the new regimen, and the treatment was restarted with 7.5 mg Methotrexate weekly, 70 mg Alendronate fortnightly, and Folic acid tablets.
We followed the patient biannually for another three years, during which no more relapses were observed.
His Methotrexate treatment was tapered and discontinued during this time. He has been on the treatment with 70 mg Alendronate (every two weeks), Folic acid, and vitamin D3, and has no complaint about any discomfort. There has been no sign of disease activity since.

Discussion
We described a case of CRMO whose nal diagnosis and treatment was delayed for over 18 months due to uncommon presentation of his disease. The patient had received several courses of different antibiotics and had two vertebroplasty surgeries prior to his CRMO diagnosis.  (7), and its classic presentation is involving the lower extremities (metaphysis of the long bones), spine, pelvis, and clavicle (8). The disease typically affects more than one site; however, at the initial workup the number of lesions might be underestimated due to some of them not having any symptoms (1).
Having described the typical from of CRMO involvement, the disease can manifest a variety of presentations (9). There have been many case reports and case series of patients with atypical involvement (4, 10, 11). For instance, patients with acute vertebral deformities (12), chronic painful scoliosis (13), and chronic mandible involvement as their only presentation (9). This variety has been considerable, to the point that some studies have proposed classi cation of CRMO cases into subgroups based on their presented phenotypes, such as spinal or axial versus peripheral form (14,15).
Spine involvement can be seen in almost 26% of CRMO patients (16). Since presenting only with chronic osteomyelitis of the vertebrae is not a common presentation of this rare disease (1), and there can be other serious conditions causing the symptoms, CRMO was not among the probable differentials for our patient at rst. However, after nding clavicle involvement alongside spine osteomyelitis through imaging, CRMO diagnosis became most likely, since the clavicle can be considered a classical involvement site in CRMO (1). Thus, it can be suggested that in similar cases, whole-body imaging can be considered beside other workups. A great example of such imaging modalities is Whole-Body MRI, which has recently been considered the gold standard for CRMO diagnosis, as it is not invasive and does not expose the patient to radiation (1,9).
According to the studies that report long-term follow-up of the patients, CRMO is generally well-prognosed (1). In a multicenter study following 131 CRMO patients, 82% of them were in remission a few years after treatment and had no relapse (7). Nonetheless, there are some concerns regarding this disease. De nite diagnosis of CRMO is only achievable by ruling out other critical diseases, namely infectious osteomyelitis and malignancies (2). This matter, in addition to its vast range of presentations (explained before) might result in delayed diagnosis of the disease. A study have reported the median time to CRMO diagnosis to be 15 months, with up to 92 months delay for one case (17). Moreover, another study reported a 6-year-old boy in whom symptoms started when he was 2, and it took 4 years to be diagnosed and properly treated (18). A delay in the diagnosis, similar to our case, can lead to the following issues: First, the patient might receive several prolonged and unnecessary courses of treatment, such as antibiotics (13). In our case, the patient had received various antibiotics, and was on the treatment with Linezolid, which is mostly used for resistant, complicated and hospital-acquired infections (19). Second, the patients might develop deformities during this long period of disease activity without proper treatment (20). In the present case, our patient had developed spinal deformities and had undergone two spine surgeries. Earlier diagnosis can prevent the future cases from experiencing multiple invasive diagnostics (such as biopsies) and treatments, that will most probably have nancial and emotional burden on the patients and their family. Another disadvantage of delayed diagnoses is that chronic pain and the impression of having a chronic disease might have psychological impact on the affected children, especially when the disease gives rise to physical deformities (21,22). This might lead to their depression, anxiety, and consequently, less favorable educational and social function in the school and in future (5,23). One study reported that even after the remission of their disease, children affected by CRMO had lower health-related quality of life than their healthy peers (24).
CRMO is considered as a rare disease, with estimated incidence of 4 per million children (1). However, as awareness about the disease increased through years, it can be stated that CRMO's incidence has not been much far behind the incidence of bacterial osteomyelitis (3,25). Thus, the low incidence rate can be due to underestimation and underdiagnosis of the disease. Nevertheless, the awareness about this disease is still suboptimal, leading to prolonged times to diagnoses (26, 27).
CRMO patients may initially approach or be referred to varying specialists. A case like ours is likely to be seen by an orthopedic surgeon at rst because of his kyphosis. Hence, having different specialists, such as orthopedic and general surgeons, radiologists (considering various radiological patterns of the disease mimicking other diagnoses (9, 28)), and rheumatologists, as well as family physicians and general practitioners (as the frontline doctors that visit and refer these patients in the rst place) in a close collaboration network is called for. Such interdisciplinary collaboration can possibly establish opportunities to discuss similar cases, and might lead to a timelier diagnosis by increasing the knowledge and awareness about the vast and varied presentations of CRMO.

Conclusions
We described a 12-year-old boy with CRMO whose disease presented with severe and debilitating pain and deformity in thoracic vertebrae, and the diagnosis was made 18 months after his initial symptoms, following two vertebroplasties and numerous workups. Increased awareness among different specialists about such cases can potentially lead to earlier diagnosis, and timelier and more effective treatment of the CRMO patients. We explained the process of participating in this research article to the patient's parents and written informed consent was obtained from them. The ethics committee of Children's Medical Center, Tehran University of Medical Sciences have approved this study.

Consent for publication
Written informed consent was obtained from the child's parents for the case to be published with all details.
Availability of the materials Not applicable. Figure 1 99m Tc bone scan showing increased uptake in thoracic vertebrae and left clavicle.