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Pediatric Chronic Nonbacterial Osteomyelitis of the Jaw: Clinical, Radiographic, and Histopathologic Features
Accepted Manuscript Pediatric Chronic Nonbacterial Osteomyelitis of the Jaw: Clinical, Radiographic, and Histopathologic Features Bonnie L. Padwa, DMD, MD, Kelley Dentino, DMD, Caroline D. Robson, MB, ChB, Sook Bin Woo, DMD, Kyle Kurek, MD, Cory M. Resnick, DMD, MD PII:
S0278-2391(16)30230-0
DOI:
10.1016/j.joms.2016.05.021
Reference:
YJOMS 57280
To appear in:
Journal of Oral and Maxillofacial Surgery
Received Date: 12 April 2016 Revised Date:
14 May 2016
Accepted Date: 17 May 2016
Please cite this article as: Padwa BL, Dentino K, Robson CD, Woo SB, Kurek K, Resnick CM, Pediatric Chronic Nonbacterial Osteomyelitis of the Jaw: Clinical, Radiographic, and Histopathologic Features, Journal of Oral and Maxillofacial Surgery (2016), doi: 10.1016/j.joms.2016.05.021. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Pediatric Chronic Nonbacterial Osteomyelitis of the Jaw: Clinical, Radiographic, and Histopathologic Features
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Bonnie L. Padwa, DMD, MDa, Kelley Dentino, DMDb, Caroline D. Robson, MB,ChBc, Sook Bin Woo, DMDd, Kyle Kurek, MDe, Cory M. Resnick, DMD, MDa
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Department of Plastic and Oral Surgery, Boston Children’s Hospital, Boston, MA and Harvard School of Dental Medicine b Clinical Research Fellow, Department of Plastic and Oral Surgery, Boston Children’s Hospital, Boston, MA c Department of Radiology, Boston Children’s Hospital, Boston, MA and Harvard Medical School d Department of Oral Medicine, Brigham and Women’s Hospital, Boston, MA and Harvard School of Dental Medicine e Department of Pathology, Boston Children’s Hospital, Boston, MA and Harvard Medical School
Address correspondence to: Dr. Bonnie L. Padwa Boston Children’s Hospital Department of Plastic and Oral Surgery 300 Longwood Avenue Boston, MA 02115 Telephone: 617-355-6359 Fax: 617-738-1657 E-mail: [email protected].
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Pediatric Chronic Nonbacterial Osteomyelitis of the Jaw: Clinical, Radiographic, and Histopathologic Features
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ABSTRACT
Purpose: Chronic nonbacterial osteomyelitis (CNO) is a focal sterile inflammatory osteitis in children that most commonly develops in the long bones but can occur in any bone. The disease
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course is variable, ranging from acute and self-resolving isolated lesions to chronic recurrent multifocal osteomyelitis (CRMO), which is frequently associated with extraosseous
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inflammatory disease. The purpose of this study was to present our clinical experience with CNO of the mandible in children. The specific aims were to (1) document the clinical characteristics, radiographic findings and histological features of CNO and (2) determine the percentage of our
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sample with multifocal disease (CRMO).
Materials and Methods: This is retrospective case series of patients with mandibular CNO. To be included, patients had to have a mandibular lesion radiographically consistent with osteomyelitis
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without infection, onset before 18 years-of-age and complete records. Medical records were reviewed for history, clinical features, imaging, and pathology. Descriptive data were
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summarized.
Results: The sample included 22 subjects (13 females and 9 males) with disease onset at a mean age of 9.05 + 2.4 years. On presentation, all subjects reported mandibular pain and swelling, and 45% had trismus. All had clinical and/or radiographic findings of multifocal intraosseous disease and/or extraosseous inflammatory lesions. Twelve (54%) had a documented family history of
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auto-immune or auto-inflammatory disease and 15 (68%) had elevated erythrocyte sedimentation rates during a flare. CT scans typically revealed expansion of the affected mandible with sclerosis of the medullary space, small foci of poorly-defined lytic destruction with a lamellated
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periosteal reaction, and swollen muscles of mastication. Four distinct histological features were noted including parallel and interconnected osteoid seams, atypical osteoid, areas of woven bone
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and hypocellular fibroblastic stroma resembling fibrous dysplasia, and patchy nodular fibrosis.
Conclusion: Pediatric CNO of the mandible has characteristic radiographic and pathologic
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features and is usually found as one of multiple disease foci in chronic recurrent multifocal osteomyelitis (CRMO) rather than as an isolated lesion.
Keywords: Pediatric chronic nonbacterial osteomyelitis, chronic recurrent multifocal
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osteomyelitis, SAPHO syndrome
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INTRODUCTION
Chronic nonbacterial osteomyelitis (CNO) is a sterile inflammatory bone disorder of
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unkown etiology that occurs in children.1 The aseptic bone lesions of CNO typically present at a mean age of 10 years as localized pain and swelling,2,3 and are histologically characterized by nonspecific osseous inflammation in the absence of infection.4 Females are more commonly
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affected than males and the disease course is highly variable. CNO lesions can be acute or
chronic (persisting > 6 months), solitary or multifocal, and may resolve, persist or recur.4,5
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CNO can occur as an isolated lesion or can be multifocal. The term chronic recurrent multifocal osteomyelitis (CRMO) is used to describe the multifocal form of CNO.2 CRMO may be associated with extraosseous manifestations involving the skin, gastrointestinal tract, eyes, or lungs.4,6 CRMO has been linked to a number of chronic auto-inflammatory disorders including
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Crohn’s disease and seronegative spondyloarthropathies.7 It may be the pediatric equivalent of SAPHO (Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis) syndrome,7 a diagnosis in adults encompassing a variable pattern of chronic inflammatory disease affecting multiple organ
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systems and characterized by recurrent aseptic osteomyelitis.8 CNO most commonly develops in the metaphyseal plates of long bones, vertebrae, and
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clavicles; however any bone can be affected.1,9 Mandibular lesions are found in 1.5-3% of disease foci in patients with CRMO10 and the most commonly affected bone with unifocal disease is the mandible.1 CNO is poorly characterized in the oral and maxillofacial surgery literature due to inconsistent terminology (e.g., Garre’s osteomyelitis, diffuse sclerosing osteomyelitis, primary chronic osteomyelitis, juvenile mandibular chronic osteomyelitis) and
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lack of information about whether these patients have other bony foci and/or extraosseous lesions. The purpose of this study was to present our experience with CNO of the mandible in
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children. The specific aims were to (1) document the clinical characteristics, radiographic
findings and histological features of CNO and (2) determine the percentage of our sample with
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multifocal disease (CRMO).
MATERIALS AND METHODS
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To address the study question, we implemented a retrospective case series of children with CNO of the mandible. This study was approved by the Institutional Review Board of the
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Center for Applied Clinical Investigation at Boston Children’s Hospital.
The study population included patients with CNO of the mandible who presented to the Department of Plastic and Oral Surgery at Boston Children’s Hospital between 1991 and 2012.
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To be included in the study patients had to have a mandibular lesion radiographically consistent
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with osteomyelitis in the absence of infection (e.g., negative microbial cultures, no response to antibiotic treatment), onset before 18 years-of-age, and radiographs, pathologic specimens, and a rheumatologic work-up for review.
Study Variables Medical records were reviewed for age at onset of symptoms, age at diagnosis, sex, clinical presentation, findings on physical examination, clinical course, and length of follow-up.
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Other features were recorded including presence of fever and family history of associated diseases such as psoriasis, inflammatory bowel disease (IBD), severe acne, palmoplantar pustulosis, and spondyloarthritis. Laboratory reports were reviewed for microbial cultures and
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inflammatory markers including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels. Pathology specimens were examined by two pathologists (SBW, KK).
Radiographic images were evaluated by a single pediatric neuroradiologist (CR) and
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included computerized tomography (CT) exams, magnetic resonance imaging (MRI), and
nuclear medicine studies. CT exams included axial 3 – 5 mm images of the mandible and maxilla
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without contrast. Mandibular MRI consisted of 3 – 5 mm thick axial and coronal fast spin echo inversion recovery (FSEIR) images, axial T1 weighted images and gadolinium-enhanced axial and coronal fat-suppressed (FS) T1 weighted images. Nuclear medicine studies were performed as triple phase 99mTc MDP isotope planar bone scans of the whole body with SPECT images of
RESULTS
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the head and neck.
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Twenty-two patients (13 females (62%) and 9 males (38%)) met the inclusion criteria. The mean age at disease onset was 9.05 + 2.4 years (range: 3-17 years) and the mean duration of
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symptoms prior to diagnosis was 17 + 5.2 months (range: 1 month to 10 years). On average, patients had been seen by 4.2 + 1.3 providers before a correct diagnosis was made. The most common misdiagnoses included fibrous dysplasia, parotitis, fibrosarcoma, and infectious osteomyelitis (if an intraoral biopsy had been performed showing actinomycoses, streptococci, or gram positive rods). The mean follow-up was 5.6 years (range: 2-19 years) after initial presentation to Boston Children’s Hospital.
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Pain and swelling over the affected area were presenting features in all patients (Fig 1). All patients had a resolving and relapsing disease course (flares); no patients had only a single episode. Warmth and erythema were sometimes present. Other findings included trismus (45%),
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headache (18%), otalgia (18%), and fever (9%). Some patients noted a correlation between their symptoms and stress (27%) or exacerbation at night (23%). Many of these characteristics were inconsistent and varied from episode to episode. ESR and/or CRP markers were elevated in 15
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patients (68%) during flares.
All patients in this study had lesions in the mandible. Eleven had bilateral mandibular
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lesions: 1 of these also had bilateral maxillary lesions. The remaining 11 patients had unilateral involvement and 2 of these patients had a maxillary lesion on the same side. All patients had multiple recurrent CNO lesions and/or extraosseous inflammatory lesions (met criteria for CRMO). In 16 patients (73%), the jaw lesion was the first manifestation
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of the inflammatory disease; the other 6 patients had a prior symptomatic lesion elsewhere (knee (n=2), back (n=1), rib (n=1), skin (n=2)) before the development of mandibular disease. Fifteen patients (68%) had an additional osseous lesion outside the mandible, most commonly in the
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back, knees, or ankles. Twelve patients (55%) had inflammatory skin manifestations including psoriasis and pustular acne. Five patients (23%) had a diagnosis of spondyloarthritis. Twelve
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patients (55%) had a family history of auto-immune or inflammatory disease including rheumatoid arthritis, Crohn’s disease, and psoriasis.
Radiographic Findings
There were 43 images including CT (n=20), MRI (n=7) and 99mTc MDP isotope bone scans (n=16). Initial CT examinations typically revealed expansion of the affected mandible with
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sclerosis of the medullary space, and small foci of poorly defined lytic destruction with a lamellated periosteal reaction (Figs. 2-4). The lytic foci involved the medullary space and/or cortex, sometimes breaching the buccal or lingual cortices (Fig. 2). All cases involved the
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posterior body of the mandible, with 20 (90%) also affecting the ramus. Bilateral mandibular lesions were continuous across the anterior mandible (Fig. 3). Follow-up CT examinations demonstrated progression of mandibular disease, with increased sclerosis and mandibular
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expansion in all but 3 patients, in whom disease remained stable, improved, or was treated with hemimandibulectomy (n=1). One patient presented initially with a maxillary lesion that resolved,
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followed 3 years later by the development of mandibular disease that progressed over time (Fig. 4). Ipsilateral widening of the mandibular foramen was seen in 15 (75%) CT exams (Fig. 4B). This may be a reactive phenomenon related to hyperemia, as suggested by enlargement of the retromandibular vein in 1 patient.
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MRI of the mandible demonstrated contour alteration, high signal intensity on FSEIR images, and periosteal elevation/reaction with diffuse enhancement following the administration of contrast (Fig. 3). Sclerosis appeared as low signal intensity on all pulse sequences. The
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muscles of mastication appeared swollen and demonstrated high signal intensity on FSEIR MRI in 4 of 7 subjects. Two patients had prior MRI exams of the knee that showed unilateral arthritis
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several years preceding the development of the mandibular lesions. Bone scans demonstrated increased isotope uptake in the affected mandible (Fig. 4B).
Additional sites of increased uptake considered concerning or equivocal for multifocal disease were seen in 6 patients. One patient with increased uptake in a rib on bone scan had confirmation by chest CT of an additional lesion consistent with CNO.
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Histopathology Seventeen patients had at least one pathological specimen (range 1-10 specimens per patient; average 1.7). A total of 30 specimens were available for evaluation. Most were
in maximum dimension, often with clotted blood.
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submitted as multiple fragments of white-tan, irregular pieces of bone ranging from 0.3 to 2.0 cm
Histopathological evaluation revealed four distinctive features (Fig. 5): (1) parallel and
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interconnecting thin trabeculae of woven bone with thin and thick seams (n=13 patients, 76%) (Fig. 5A); (2) atypical osteoid (n=15 patients, 88%) (Fig. 5B); (3) delicate, curvilinear trabeculae
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of woven bone in a hypocellular fibroblastic stroma resembling fibrous dysplasia (n=6 patients, 35%) (Fig. 5C); (4) medullary spaces showing patchy and sometimes nodular fibrosis (n=10 patients, 58%) (Fig. 5D).
Specimens also revealed a heterogeneous pattern of additional histopathologic findings.
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Osteoblastic rimming of the bone with pockets of chronic inflammation was seen in all patients, and osteoclastic activity was observed in 12 (70%). There was neither osteoblastic proliferation within the stroma nor multi-layering of osteoblasts on the osteoid seams. Fragments of
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devitalized bone were present in 5 patients (29%). Most cases exhibited minor lymphocytic infiltrate. Distinctive areas of increased vascularity with variable caliber vessels (some grossly
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dilated) were noted focally in 16 patients (94%). Sclerotic bone was found in 6 patients (35%). In 9 patients (53%) there was atypical reactive osteoid with hyperchromatic and atypical osteocytes that, if seen on high power alone, would raise the suspicion for osteosarcoma. However, these areas were almost always in continuity with benign-appearing lamellar or woven bone consistent with reactive osteoid. The presence of patchy fibrosis, seen in 11 specimens (36%), distinguishes CNO from fibrous dysplasia, which usually has uniform fibrosis without inflammation.
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DISCUSSION
The purpose of this study was to present our clinical experience with CNO of the
mandible in children. The specific aims were to (1) document the clinical characteristics,
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radiographic findings and histological features of CNO and (2) determine the percentage of our sample with multifocal disease (CRMO).
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All subjects in our series presented with pain and swelling of the mandible and had clinical and/or radiographic findings of multiple osseous lesions and/or extraosseous inflammatory disease (CRMO). The majority had elevated ESR during a flare and a family history of auto-immune disease. The imaging findings of mandibular CNO revealed characteristic features. In spite of aggressive-appearing lytic destruction of bone that could be
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mistaken for a permeative neoplastic process, the smooth, lamellated appearance of the associated periosteal new bone formation on CT was helpful in distinguishing CNO from
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neoplasms such as Ewing sarcoma or osteosarcoma. CT can help discriminate between fibrous dysplasia and CNO: CNO has a ground glass opacification with a periosteal reaction that is not
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seen in fibrous dysplasia. There were four distinct histological features including striking parallel and interconnected osteoid seams, atypical osteoid, areas of woven bone and hypocellular fibroblastic stroma resembling fibrous dysplasia, and patchy nodular fibrosis. The differential diagnoses in any one high-power field may suggest a neoplasm or fibrous dysplasia; clinical and radiological correlation is essential for accurate diagnosis. Controversies surrounding the diagnosis and management of this disease stem largely from the inconsistent terminology that has been assigned to chronic osteomyelitis of the
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mandible.11 For decades this lesion was reported as chronic diffuse sclerosing osteomyelitis (DSO), a vague radiographic diagnosis that was broadly applied to several distinct disease processes with similar radiographic appearances. In addition, case series and clinical reports
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typically made no distinction between adult and pediatric patients when reporting group data. Chronic nonbacterial osteomyelitis (CNO) is an orphan disease (OMIM ID #259680) characterized by recurrent flares of inflammatory bone pain related to aseptic osteomyelitis.12
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CNO lesions can be unifocal or multifocal (CRMO).7 Rates of unifocal disease vary from 1056%1,7,13; it is unknown whether mandibular CNO occurs more commonly as unifocal disease or
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as one of the lesions of CRMO. In a multi-center US study of CNO, Borzutzy and colleagues found that the most commonly affected bone with unifocal disease was the mandible.1 Mandibular CNO lesions are estimated to account for 1.5 - 3% of disease foci in children with multifocal disease (CRMO).10,13 In a large cohort of 178 patients with 456 lesions, 8 of 9 patients
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with mandibular lesions had multifocal disease.10 Borzutzky found that CNO patients with comorbid autoimmune disease (arthritis, psoriasis, IBD) had a more aggressive phenotype with higher rates of multifocality.1 Wipff showed that the majority of patients with unifocal disease
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eventually have progression to the multifocal type (CRMO); only 7% of patients had a persistent unifocal pattern after 4 years.10
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The differential diagnosis of mandibular CNO includes infectious osteomyelitis,
malignancy (osteosarcoma and Ewing’s sarcoma), and Langerhans cell histiocytosis. The pathogenesis of CNO remains unknown although infection has long been suspected.14 Recent microbial studies in large CNO cohorts, including universal 16S ribosomal DNA polymerase chain reaction in bone samples have been consistently negative.7 CNO is currently thought to be in the spectrum of autoimmune and autoinflammatory disorders. This is supported by the high
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rates of inflammatory conditions, particularly psoriasis and inflammatory bowel disease (IBD), in patients and family members.1 Extra-osseous manifestations including palmoplantar pustulosis, psoriasis, Crohn’s disease, and acne have led some authors to classify CRMO as the
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juvenile form of SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome.12
Because only small case series have described the clinical course and outcomes of
pediatric mandibular CNO, the defining features of this lesion are poorly characterized.15,16,17,18,19
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In addition, many of these case series did not have long-term follow-up and did not include
documentation of whether the patient had other osseous lesions, extra-osseous involvement, or a
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family history of auto-immune disesase. In our study and others published in the pediatric rheumatologic literature,10 the inflammatory bone lesions in children are often multifocal and can be associated with inflammatory skin lesions, synotivits, and/or family history of autoimmune or inflammatory disease. Therefore, nonbacterial osteomyelitis of the mandible is usually not
(CRMO). 20,21,22,23
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unifocal, but rather one of the multiple lesions in chronic recurrent multifocal osteomyelitis
In summary, chronic nonbacterial osteomyelitis in children is an aseptic
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autoinflammatory condition of the musculoskeletal system typified by recurrent pain and swelling with characteristic pathologic and radiographic features. The diagnosis can generally be
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made based on history, clinical and radiographic examination.24 It is important to obtain a detailed history with specific inquiry regarding other areas of bone pain or swelling and the presence of extra-osseous inflammatory lesions, as well as a family history of inflammatory and auto-immune conditions. CT, which can be performed using a low dosage technique, or CBCT are the best diagnostic imaging tests as these provide adequate bone detail and visualization of soft tissues is not necessary. CT, CBCT or MRI can be used for follow-up. If the diagnosis
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remains in question, a biopsy that includes cortical and cancellous bone can be obtained. This biopsy should be obtained from an extraoral approach to avoid oral contamination and an erroneous diagnosis of an infectious etiology. We recommend referral to a rheumatologist for
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evaluation and management as this is a rheumatic disesase. Treatment is directed at reducing pain and inflammation, with the intent of halting bone destruction and disease progression.1 Although no randomized controlled trials have been carried out a variety of anti-inflammatory
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medications (NSAID, steroids), methotrexate, bisophosphonates and disease modifying agents (TNF-alpha inhibitors) have been used in the treatment of this condition.2,5,10 Surgical
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intervention is reserved for contour reduction.
Establishing a common terminology and better understanding of this condition may
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improve the clinical management and treatment outcomes of patients with this disorder.
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Pediatric chronic nonbacterial osteomyelitis. Pediatrics 130:1190, 2012
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7. Girschick H, Raab P, Surbaum S, et al. Chronic non-bacterial osteomyelitis in children. Ann Rheum Dis 64:279, 2005
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14. Renapurkar S, Pasternack MS, Nielsen GP, Kaban LB. Juvenile Mandibular Chronic Osteomyelitis: Role of surgical debridement and antibiotics. J Oral Maxillofac Surg (in
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19. Khanna G, Sato T, Ferguson P. Imaging of chronic recurrent multifocal osteomyelitis. Radiographics 29:1159, 2009
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20. Eyrich GK, Langenegger T, Bruder E, Sailer HF, Michel BA. Diffuse chronic sclerosing osteomyelitis and the synovitis, acne, pustolosis, hyperostosis, osteitis (SAPHO) syndrome in
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23. Suei Y, Taguchi A, Tanimoto K. Diffuse sclerosing osteomyelitis of the mandible: its
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characteristics and possible relationship to synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome. J Oral Maxillofac Surg 1996;54:1194, 1996
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LEGENDS
also had elevated ESR, eczema and a father with Crohn’s disease.
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Figure 1. Nine-year-old girl with left mandibular swelling and pain associated with CNO. She
Figure 2. Nine-year-old girl with (A) CT demonstrating prominent, poorly marginated lytic
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destruction of left mandibular body and cortical perforation (arrowhead). There is a smooth periosteal reaction (long arrow). (B) Axial fast spin echo inversion recovery MRI showing high
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signal intensity in left mandibular body (short arrow) and edema of masseter muscle (long arrow). (C) Gadolinium-enhanced, fat-suppressed T1-weighted MRI with enhancement of mandible and masseter.
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Figure 3. Five-year-old boy with (A) Axial CT showing diffuse sclerosis across midline with expansion of the mandible. (B) Bone scan and (C) Gallium scan demonstrating increased uptake
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throughout mandible.
Figure 4. CT scans of the same female patient over a 6-year period demonstrating progression of
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CNO. (A) Coronal reformat at age 12-years showing sclerosis and expansion of left maxilla and zygoma (asterisk). (B) Axial image at age 15 years with interval development of expansion, sclerosis, poorly-defined lucency, and periosteal reaction (long arrow) involving posterior body and angle of left mandible. Note enlarged left mandibular foramen (short arrow). (C) Image from the same level at age 18-years shows increased sclerosis of left mandible (arrow).
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Figure 5. Four distinct histological features of CNO. (A) Striking parallel osteoid seams, (B) atypical osteoid, (C) delicate, curvilinear trabeculae of woven bone in a hypocellular fibroblastic
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stroma resembling fibrous dysplasia, and (D) patchy, nodular fibrosis.
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S0278-2391(16)30230-0
DOI:
10.1016/j.joms.2016.05.021
Reference:
YJOMS 57280
To appear in:
Journal of Oral and Maxillofacial Surgery
Received Date: 12 April 2016 Revised Date:
14 May 2016
Accepted Date: 17 May 2016
Please cite this article as: Padwa BL, Dentino K, Robson CD, Woo SB, Kurek K, Resnick CM, Pediatric Chronic Nonbacterial Osteomyelitis of the Jaw: Clinical, Radiographic, and Histopathologic Features, Journal of Oral and Maxillofacial Surgery (2016), doi: 10.1016/j.joms.2016.05.021. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Pediatric Chronic Nonbacterial Osteomyelitis of the Jaw: Clinical, Radiographic, and Histopathologic Features
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Bonnie L. Padwa, DMD, MDa, Kelley Dentino, DMDb, Caroline D. Robson, MB,ChBc, Sook Bin Woo, DMDd, Kyle Kurek, MDe, Cory M. Resnick, DMD, MDa
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Department of Plastic and Oral Surgery, Boston Children’s Hospital, Boston, MA and Harvard School of Dental Medicine b Clinical Research Fellow, Department of Plastic and Oral Surgery, Boston Children’s Hospital, Boston, MA c Department of Radiology, Boston Children’s Hospital, Boston, MA and Harvard Medical School d Department of Oral Medicine, Brigham and Women’s Hospital, Boston, MA and Harvard School of Dental Medicine e Department of Pathology, Boston Children’s Hospital, Boston, MA and Harvard Medical School
Address correspondence to: Dr. Bonnie L. Padwa Boston Children’s Hospital Department of Plastic and Oral Surgery 300 Longwood Avenue Boston, MA 02115 Telephone: 617-355-6359 Fax: 617-738-1657 E-mail: [email protected].
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Pediatric Chronic Nonbacterial Osteomyelitis of the Jaw: Clinical, Radiographic, and Histopathologic Features
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ABSTRACT
Purpose: Chronic nonbacterial osteomyelitis (CNO) is a focal sterile inflammatory osteitis in children that most commonly develops in the long bones but can occur in any bone. The disease
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course is variable, ranging from acute and self-resolving isolated lesions to chronic recurrent multifocal osteomyelitis (CRMO), which is frequently associated with extraosseous
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inflammatory disease. The purpose of this study was to present our clinical experience with CNO of the mandible in children. The specific aims were to (1) document the clinical characteristics, radiographic findings and histological features of CNO and (2) determine the percentage of our
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sample with multifocal disease (CRMO).
Materials and Methods: This is retrospective case series of patients with mandibular CNO. To be included, patients had to have a mandibular lesion radiographically consistent with osteomyelitis
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without infection, onset before 18 years-of-age and complete records. Medical records were reviewed for history, clinical features, imaging, and pathology. Descriptive data were
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summarized.
Results: The sample included 22 subjects (13 females and 9 males) with disease onset at a mean age of 9.05 + 2.4 years. On presentation, all subjects reported mandibular pain and swelling, and 45% had trismus. All had clinical and/or radiographic findings of multifocal intraosseous disease and/or extraosseous inflammatory lesions. Twelve (54%) had a documented family history of
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auto-immune or auto-inflammatory disease and 15 (68%) had elevated erythrocyte sedimentation rates during a flare. CT scans typically revealed expansion of the affected mandible with sclerosis of the medullary space, small foci of poorly-defined lytic destruction with a lamellated
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periosteal reaction, and swollen muscles of mastication. Four distinct histological features were noted including parallel and interconnected osteoid seams, atypical osteoid, areas of woven bone
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and hypocellular fibroblastic stroma resembling fibrous dysplasia, and patchy nodular fibrosis.
Conclusion: Pediatric CNO of the mandible has characteristic radiographic and pathologic
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features and is usually found as one of multiple disease foci in chronic recurrent multifocal osteomyelitis (CRMO) rather than as an isolated lesion.
Keywords: Pediatric chronic nonbacterial osteomyelitis, chronic recurrent multifocal
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osteomyelitis, SAPHO syndrome
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INTRODUCTION
Chronic nonbacterial osteomyelitis (CNO) is a sterile inflammatory bone disorder of
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unkown etiology that occurs in children.1 The aseptic bone lesions of CNO typically present at a mean age of 10 years as localized pain and swelling,2,3 and are histologically characterized by nonspecific osseous inflammation in the absence of infection.4 Females are more commonly
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affected than males and the disease course is highly variable. CNO lesions can be acute or
chronic (persisting > 6 months), solitary or multifocal, and may resolve, persist or recur.4,5
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CNO can occur as an isolated lesion or can be multifocal. The term chronic recurrent multifocal osteomyelitis (CRMO) is used to describe the multifocal form of CNO.2 CRMO may be associated with extraosseous manifestations involving the skin, gastrointestinal tract, eyes, or lungs.4,6 CRMO has been linked to a number of chronic auto-inflammatory disorders including
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Crohn’s disease and seronegative spondyloarthropathies.7 It may be the pediatric equivalent of SAPHO (Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis) syndrome,7 a diagnosis in adults encompassing a variable pattern of chronic inflammatory disease affecting multiple organ
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systems and characterized by recurrent aseptic osteomyelitis.8 CNO most commonly develops in the metaphyseal plates of long bones, vertebrae, and
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clavicles; however any bone can be affected.1,9 Mandibular lesions are found in 1.5-3% of disease foci in patients with CRMO10 and the most commonly affected bone with unifocal disease is the mandible.1 CNO is poorly characterized in the oral and maxillofacial surgery literature due to inconsistent terminology (e.g., Garre’s osteomyelitis, diffuse sclerosing osteomyelitis, primary chronic osteomyelitis, juvenile mandibular chronic osteomyelitis) and
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lack of information about whether these patients have other bony foci and/or extraosseous lesions. The purpose of this study was to present our experience with CNO of the mandible in
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children. The specific aims were to (1) document the clinical characteristics, radiographic
findings and histological features of CNO and (2) determine the percentage of our sample with
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multifocal disease (CRMO).
MATERIALS AND METHODS
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To address the study question, we implemented a retrospective case series of children with CNO of the mandible. This study was approved by the Institutional Review Board of the
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Center for Applied Clinical Investigation at Boston Children’s Hospital.
The study population included patients with CNO of the mandible who presented to the Department of Plastic and Oral Surgery at Boston Children’s Hospital between 1991 and 2012.
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To be included in the study patients had to have a mandibular lesion radiographically consistent
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with osteomyelitis in the absence of infection (e.g., negative microbial cultures, no response to antibiotic treatment), onset before 18 years-of-age, and radiographs, pathologic specimens, and a rheumatologic work-up for review.
Study Variables Medical records were reviewed for age at onset of symptoms, age at diagnosis, sex, clinical presentation, findings on physical examination, clinical course, and length of follow-up.
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Other features were recorded including presence of fever and family history of associated diseases such as psoriasis, inflammatory bowel disease (IBD), severe acne, palmoplantar pustulosis, and spondyloarthritis. Laboratory reports were reviewed for microbial cultures and
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inflammatory markers including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels. Pathology specimens were examined by two pathologists (SBW, KK).
Radiographic images were evaluated by a single pediatric neuroradiologist (CR) and
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included computerized tomography (CT) exams, magnetic resonance imaging (MRI), and
nuclear medicine studies. CT exams included axial 3 – 5 mm images of the mandible and maxilla
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without contrast. Mandibular MRI consisted of 3 – 5 mm thick axial and coronal fast spin echo inversion recovery (FSEIR) images, axial T1 weighted images and gadolinium-enhanced axial and coronal fat-suppressed (FS) T1 weighted images. Nuclear medicine studies were performed as triple phase 99mTc MDP isotope planar bone scans of the whole body with SPECT images of
RESULTS
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the head and neck.
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Twenty-two patients (13 females (62%) and 9 males (38%)) met the inclusion criteria. The mean age at disease onset was 9.05 + 2.4 years (range: 3-17 years) and the mean duration of
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symptoms prior to diagnosis was 17 + 5.2 months (range: 1 month to 10 years). On average, patients had been seen by 4.2 + 1.3 providers before a correct diagnosis was made. The most common misdiagnoses included fibrous dysplasia, parotitis, fibrosarcoma, and infectious osteomyelitis (if an intraoral biopsy had been performed showing actinomycoses, streptococci, or gram positive rods). The mean follow-up was 5.6 years (range: 2-19 years) after initial presentation to Boston Children’s Hospital.
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Pain and swelling over the affected area were presenting features in all patients (Fig 1). All patients had a resolving and relapsing disease course (flares); no patients had only a single episode. Warmth and erythema were sometimes present. Other findings included trismus (45%),
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headache (18%), otalgia (18%), and fever (9%). Some patients noted a correlation between their symptoms and stress (27%) or exacerbation at night (23%). Many of these characteristics were inconsistent and varied from episode to episode. ESR and/or CRP markers were elevated in 15
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patients (68%) during flares.
All patients in this study had lesions in the mandible. Eleven had bilateral mandibular
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lesions: 1 of these also had bilateral maxillary lesions. The remaining 11 patients had unilateral involvement and 2 of these patients had a maxillary lesion on the same side. All patients had multiple recurrent CNO lesions and/or extraosseous inflammatory lesions (met criteria for CRMO). In 16 patients (73%), the jaw lesion was the first manifestation
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of the inflammatory disease; the other 6 patients had a prior symptomatic lesion elsewhere (knee (n=2), back (n=1), rib (n=1), skin (n=2)) before the development of mandibular disease. Fifteen patients (68%) had an additional osseous lesion outside the mandible, most commonly in the
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back, knees, or ankles. Twelve patients (55%) had inflammatory skin manifestations including psoriasis and pustular acne. Five patients (23%) had a diagnosis of spondyloarthritis. Twelve
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patients (55%) had a family history of auto-immune or inflammatory disease including rheumatoid arthritis, Crohn’s disease, and psoriasis.
Radiographic Findings
There were 43 images including CT (n=20), MRI (n=7) and 99mTc MDP isotope bone scans (n=16). Initial CT examinations typically revealed expansion of the affected mandible with
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sclerosis of the medullary space, and small foci of poorly defined lytic destruction with a lamellated periosteal reaction (Figs. 2-4). The lytic foci involved the medullary space and/or cortex, sometimes breaching the buccal or lingual cortices (Fig. 2). All cases involved the
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posterior body of the mandible, with 20 (90%) also affecting the ramus. Bilateral mandibular lesions were continuous across the anterior mandible (Fig. 3). Follow-up CT examinations demonstrated progression of mandibular disease, with increased sclerosis and mandibular
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expansion in all but 3 patients, in whom disease remained stable, improved, or was treated with hemimandibulectomy (n=1). One patient presented initially with a maxillary lesion that resolved,
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followed 3 years later by the development of mandibular disease that progressed over time (Fig. 4). Ipsilateral widening of the mandibular foramen was seen in 15 (75%) CT exams (Fig. 4B). This may be a reactive phenomenon related to hyperemia, as suggested by enlargement of the retromandibular vein in 1 patient.
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MRI of the mandible demonstrated contour alteration, high signal intensity on FSEIR images, and periosteal elevation/reaction with diffuse enhancement following the administration of contrast (Fig. 3). Sclerosis appeared as low signal intensity on all pulse sequences. The
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muscles of mastication appeared swollen and demonstrated high signal intensity on FSEIR MRI in 4 of 7 subjects. Two patients had prior MRI exams of the knee that showed unilateral arthritis
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several years preceding the development of the mandibular lesions. Bone scans demonstrated increased isotope uptake in the affected mandible (Fig. 4B).
Additional sites of increased uptake considered concerning or equivocal for multifocal disease were seen in 6 patients. One patient with increased uptake in a rib on bone scan had confirmation by chest CT of an additional lesion consistent with CNO.
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Histopathology Seventeen patients had at least one pathological specimen (range 1-10 specimens per patient; average 1.7). A total of 30 specimens were available for evaluation. Most were
in maximum dimension, often with clotted blood.
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submitted as multiple fragments of white-tan, irregular pieces of bone ranging from 0.3 to 2.0 cm
Histopathological evaluation revealed four distinctive features (Fig. 5): (1) parallel and
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interconnecting thin trabeculae of woven bone with thin and thick seams (n=13 patients, 76%) (Fig. 5A); (2) atypical osteoid (n=15 patients, 88%) (Fig. 5B); (3) delicate, curvilinear trabeculae
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of woven bone in a hypocellular fibroblastic stroma resembling fibrous dysplasia (n=6 patients, 35%) (Fig. 5C); (4) medullary spaces showing patchy and sometimes nodular fibrosis (n=10 patients, 58%) (Fig. 5D).
Specimens also revealed a heterogeneous pattern of additional histopathologic findings.
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Osteoblastic rimming of the bone with pockets of chronic inflammation was seen in all patients, and osteoclastic activity was observed in 12 (70%). There was neither osteoblastic proliferation within the stroma nor multi-layering of osteoblasts on the osteoid seams. Fragments of
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devitalized bone were present in 5 patients (29%). Most cases exhibited minor lymphocytic infiltrate. Distinctive areas of increased vascularity with variable caliber vessels (some grossly
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dilated) were noted focally in 16 patients (94%). Sclerotic bone was found in 6 patients (35%). In 9 patients (53%) there was atypical reactive osteoid with hyperchromatic and atypical osteocytes that, if seen on high power alone, would raise the suspicion for osteosarcoma. However, these areas were almost always in continuity with benign-appearing lamellar or woven bone consistent with reactive osteoid. The presence of patchy fibrosis, seen in 11 specimens (36%), distinguishes CNO from fibrous dysplasia, which usually has uniform fibrosis without inflammation.
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DISCUSSION
The purpose of this study was to present our clinical experience with CNO of the
mandible in children. The specific aims were to (1) document the clinical characteristics,
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radiographic findings and histological features of CNO and (2) determine the percentage of our sample with multifocal disease (CRMO).
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All subjects in our series presented with pain and swelling of the mandible and had clinical and/or radiographic findings of multiple osseous lesions and/or extraosseous inflammatory disease (CRMO). The majority had elevated ESR during a flare and a family history of auto-immune disease. The imaging findings of mandibular CNO revealed characteristic features. In spite of aggressive-appearing lytic destruction of bone that could be
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mistaken for a permeative neoplastic process, the smooth, lamellated appearance of the associated periosteal new bone formation on CT was helpful in distinguishing CNO from
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neoplasms such as Ewing sarcoma or osteosarcoma. CT can help discriminate between fibrous dysplasia and CNO: CNO has a ground glass opacification with a periosteal reaction that is not
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seen in fibrous dysplasia. There were four distinct histological features including striking parallel and interconnected osteoid seams, atypical osteoid, areas of woven bone and hypocellular fibroblastic stroma resembling fibrous dysplasia, and patchy nodular fibrosis. The differential diagnoses in any one high-power field may suggest a neoplasm or fibrous dysplasia; clinical and radiological correlation is essential for accurate diagnosis. Controversies surrounding the diagnosis and management of this disease stem largely from the inconsistent terminology that has been assigned to chronic osteomyelitis of the
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mandible.11 For decades this lesion was reported as chronic diffuse sclerosing osteomyelitis (DSO), a vague radiographic diagnosis that was broadly applied to several distinct disease processes with similar radiographic appearances. In addition, case series and clinical reports
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typically made no distinction between adult and pediatric patients when reporting group data. Chronic nonbacterial osteomyelitis (CNO) is an orphan disease (OMIM ID #259680) characterized by recurrent flares of inflammatory bone pain related to aseptic osteomyelitis.12
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CNO lesions can be unifocal or multifocal (CRMO).7 Rates of unifocal disease vary from 1056%1,7,13; it is unknown whether mandibular CNO occurs more commonly as unifocal disease or
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as one of the lesions of CRMO. In a multi-center US study of CNO, Borzutzy and colleagues found that the most commonly affected bone with unifocal disease was the mandible.1 Mandibular CNO lesions are estimated to account for 1.5 - 3% of disease foci in children with multifocal disease (CRMO).10,13 In a large cohort of 178 patients with 456 lesions, 8 of 9 patients
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with mandibular lesions had multifocal disease.10 Borzutzky found that CNO patients with comorbid autoimmune disease (arthritis, psoriasis, IBD) had a more aggressive phenotype with higher rates of multifocality.1 Wipff showed that the majority of patients with unifocal disease
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eventually have progression to the multifocal type (CRMO); only 7% of patients had a persistent unifocal pattern after 4 years.10
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The differential diagnosis of mandibular CNO includes infectious osteomyelitis,
malignancy (osteosarcoma and Ewing’s sarcoma), and Langerhans cell histiocytosis. The pathogenesis of CNO remains unknown although infection has long been suspected.14 Recent microbial studies in large CNO cohorts, including universal 16S ribosomal DNA polymerase chain reaction in bone samples have been consistently negative.7 CNO is currently thought to be in the spectrum of autoimmune and autoinflammatory disorders. This is supported by the high
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rates of inflammatory conditions, particularly psoriasis and inflammatory bowel disease (IBD), in patients and family members.1 Extra-osseous manifestations including palmoplantar pustulosis, psoriasis, Crohn’s disease, and acne have led some authors to classify CRMO as the
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juvenile form of SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome.12
Because only small case series have described the clinical course and outcomes of
pediatric mandibular CNO, the defining features of this lesion are poorly characterized.15,16,17,18,19
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In addition, many of these case series did not have long-term follow-up and did not include
documentation of whether the patient had other osseous lesions, extra-osseous involvement, or a
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family history of auto-immune disesase. In our study and others published in the pediatric rheumatologic literature,10 the inflammatory bone lesions in children are often multifocal and can be associated with inflammatory skin lesions, synotivits, and/or family history of autoimmune or inflammatory disease. Therefore, nonbacterial osteomyelitis of the mandible is usually not
(CRMO). 20,21,22,23
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unifocal, but rather one of the multiple lesions in chronic recurrent multifocal osteomyelitis
In summary, chronic nonbacterial osteomyelitis in children is an aseptic
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autoinflammatory condition of the musculoskeletal system typified by recurrent pain and swelling with characteristic pathologic and radiographic features. The diagnosis can generally be
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made based on history, clinical and radiographic examination.24 It is important to obtain a detailed history with specific inquiry regarding other areas of bone pain or swelling and the presence of extra-osseous inflammatory lesions, as well as a family history of inflammatory and auto-immune conditions. CT, which can be performed using a low dosage technique, or CBCT are the best diagnostic imaging tests as these provide adequate bone detail and visualization of soft tissues is not necessary. CT, CBCT or MRI can be used for follow-up. If the diagnosis
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remains in question, a biopsy that includes cortical and cancellous bone can be obtained. This biopsy should be obtained from an extraoral approach to avoid oral contamination and an erroneous diagnosis of an infectious etiology. We recommend referral to a rheumatologist for
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evaluation and management as this is a rheumatic disesase. Treatment is directed at reducing pain and inflammation, with the intent of halting bone destruction and disease progression.1 Although no randomized controlled trials have been carried out a variety of anti-inflammatory
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medications (NSAID, steroids), methotrexate, bisophosphonates and disease modifying agents (TNF-alpha inhibitors) have been used in the treatment of this condition.2,5,10 Surgical
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intervention is reserved for contour reduction.
Establishing a common terminology and better understanding of this condition may
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improve the clinical management and treatment outcomes of patients with this disorder.
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20. Eyrich GK, Langenegger T, Bruder E, Sailer HF, Michel BA. Diffuse chronic sclerosing osteomyelitis and the synovitis, acne, pustolosis, hyperostosis, osteitis (SAPHO) syndrome in
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LEGENDS
also had elevated ESR, eczema and a father with Crohn’s disease.
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Figure 1. Nine-year-old girl with left mandibular swelling and pain associated with CNO. She
Figure 2. Nine-year-old girl with (A) CT demonstrating prominent, poorly marginated lytic
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destruction of left mandibular body and cortical perforation (arrowhead). There is a smooth periosteal reaction (long arrow). (B) Axial fast spin echo inversion recovery MRI showing high
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signal intensity in left mandibular body (short arrow) and edema of masseter muscle (long arrow). (C) Gadolinium-enhanced, fat-suppressed T1-weighted MRI with enhancement of mandible and masseter.
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Figure 3. Five-year-old boy with (A) Axial CT showing diffuse sclerosis across midline with expansion of the mandible. (B) Bone scan and (C) Gallium scan demonstrating increased uptake
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throughout mandible.
Figure 4. CT scans of the same female patient over a 6-year period demonstrating progression of
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CNO. (A) Coronal reformat at age 12-years showing sclerosis and expansion of left maxilla and zygoma (asterisk). (B) Axial image at age 15 years with interval development of expansion, sclerosis, poorly-defined lucency, and periosteal reaction (long arrow) involving posterior body and angle of left mandible. Note enlarged left mandibular foramen (short arrow). (C) Image from the same level at age 18-years shows increased sclerosis of left mandible (arrow).
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Figure 5. Four distinct histological features of CNO. (A) Striking parallel osteoid seams, (B) atypical osteoid, (C) delicate, curvilinear trabeculae of woven bone in a hypocellular fibroblastic
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stroma resembling fibrous dysplasia, and (D) patchy, nodular fibrosis.
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