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Pediatric Chronic Nonbacterial

Osteomyelitis of the Jaw: Clinical,
Radiographic, and Histopathologic
Bonnie L. Padwa, DMD, MD,* Kelley Dentino, DMD,y Caroline D. Robson, MB, ChB,z
Sook Bin Woo, DMD,x Kyle Kurek, MD,k and Cory M. Resnick, DMD, MD{
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 course is variable,
ranging from acute and self-resolving isolated lesions to chronic recurrent multifocal osteomyelitis
(CRMO), which is frequently associated with extraosseous 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 histologic features of CNO and 2) deter-
mine the percentage of our sample with multifocal disease (CRMO).
Materials and Methods: This is a retrospective case series of patients with mandibular CNO. To be
included, patients had to have a mandibular lesion radiographically consistent with osteomyelitis without
infection, onset before aged 18 years, and complete records. Medical records were reviewed for history,
clinical features, imaging, and pathology. Descriptive data were summarized.
Results: The sample included 22 patients (13 female and 9 male patients) with disease onset at a mean
age of 9.05  2.4 years. On presentation, all patients reported mandibular pain and swelling, and 45% had
trismus. All had clinical and/or radiographic findings of multifocal intraosseous disease and/or extraoss-
eous inflammatory lesions. Of the patients, 12 (54%) had a documented family history of autoimmune
or autoinflammatory disease and 15 (68%) had elevated erythrocyte sedimentation rates during a flare.
Computed tomography scans typically showed expansion of the affected mandible with sclerosis of the
medullary space, small foci of poorly defined lytic destruction with a lamellated periosteal reaction, and
swollen muscles of mastication. Four distinct histologic features were noted including parallel and inter-
connected osteoid seams, atypical osteoid, areas of woven bone and hypocellular fibroblastic stroma
resembling fibrous dysplasia, and patchy nodular fibrosis.
Conclusion: Pediatric CNO of the mandible has characteristic radiographic and pathologic features and
is usually found as one of multiple disease foci in CRMO rather than as an isolated lesion.
2016 American Association of Oral and Maxillofacial Surgeons
J Oral Maxillofac Surg 74:2393-2402, 2016

*Associate Professor, Harvard School of Dental Medicine, Oral {Instructor, Harvard School of Dental Medicine, Department of
Surgeon-in-Chief Department of Plastic and Oral Surgery, Boston Plastic and Oral Surgery, Boston Childrens Hospital, Boston, MA.
Childrens Hospital, Boston, MA. Conflict of Interest Disclosures: None of the authors have any
yResearch Assistant, Department of Plastic and Oral Surgery, relevant financial relationship(s) with a commercial interest.
Boston Childrens Hospital, Boston, MA. Address correspondence and reprint requests to Dr Padwa:
zAssociate Professor, Harvard Medical School, Division Chief, Department of Plastic and Oral Surgery, Boston Childrens Hospital,
Neuroradiology, Department of Radiology, Boston Childrens 300 Longwood Ave, Boston, MA 02115; e-mail: bonnie.padwa@
Hospital, Boston, MA.
xAssociate Professor, Harvard School of Dental Medicine, Division Received April 12 2016
of Oral Medicine and Dentistry, Brigham and Womens Hospital, Accepted May 17 2016
Boston, MA. 2016 American Association of Oral and Maxillofacial Surgeons
kAssistant Professor, Cummings School or Medicine, University of 0278-2391/16/30230-0
Calgary, Departments of Pathology and Medical Genetics, Alberta
Childrens Hospital & Research Institute, Boston, MA.


Chronic nonbacterial osteomyelitis (CNO) is a sterile Plastic and Oral Surgery at Boston Childrens Hospital
inflammatory bone disorder of unknown etiology between 1991 and 2012. To be included in the study,
that occurs in children.1 The aseptic bone lesions of patients had to have a mandibular lesion radiographi-
CNO typically present at a mean age of 10 years as cally consistent with osteomyelitis in the absence of
localized pain and swelling2,3 and are histologically infection (eg, negative microbial cultures, no response
characterized by nonspecific osseous inflammation to antibiotic treatment); onset before age 18 years; and
in the absence of infection.4 Female patients are radiographs, pathologic specimens, and a rheumato-
more commonly affected than male patients, and the logic workup for review.
disease course is highly variable. CNO lesions can be
acute or chronic (persisting $6 months); can be soli- STUDY VARIABLES
tary or multifocal; and may resolve, persist, or recur.4,5 Medical records were reviewed for age at onset of
CNO can occur as an isolated lesion or can be multi- symptoms, age at diagnosis, gender, clinical presenta-
focal. The term chronic recurrent multifocal osteomy- tion, findings on physical examination, clinical course,
elitis (CRMO) is used to describe the multifocal form of and length of follow-up. Other features were recorded
CNO.2 CRMO may be associated with extraosseous including presence of fever and family history of associ-
manifestations involving the skin, gastrointestinal ated diseases such as psoriasis, inflammatory bowel dis-
tract, eyes, or lungs.4,6 CRMO has been linked to a ease (IBD), severe acne, palmoplantar pustulosis, and
number of chronic autoinflammatory disorders spondylarthritis. Laboratory reports were reviewed
including Crohns disease and seronegative for microbial cultures and inflammatory markers
spondyloarthropathies.7 It may be the pediatric equiv- including erythrocyte sedimentation rate (ESR) and C-
alent of SAPHO (synovitis, acne, pustulosis, hyperosto- reactive protein level (CRP). Pathology specimens
sis, osteitis) syndrome,7 a diagnosis in adults were examined by 2 pathologists (S.B.W. and K.K.).
encompassing a variable pattern of chronic inflamma- Radiographic images were evaluated by a single
tory disease affecting multiple organ systems and char- pediatric neuroradiologist (C.D.R) and included
acterized by recurrent aseptic osteomyelitis.8 computed tomography (CT) examinations, magnetic
CNO most commonly develops in the metaphyseal resonance imaging (MRI), and nuclear medicine
plates of the long bones, vertebrae, and clavicles; how- studies. CT examinations included axial 3- to 5-mm im-
ever, any bone can be affected.1,9 Mandibular lesions ages of the mandible and maxilla without contrast.
are found in 1.5 to 3% of disease foci in patients with Mandibular MRI consisted of 3- to 5-mm-thick axial
CRMO,10 and the most commonly affected bone and coronal fast spin echo inversion recovery (FSEIR)
with unifocal disease is the mandible.1 CNO is poorly images, axial T1-weighted images, and gadolinium-
characterized in the oral and maxillofacial surgery liter- enhanced axial and coronal fat-suppressed
ature because of inconsistent terminology (eg, Garre T1-weighted images. Nuclear medicine studies were
osteomyelitis, diffuse sclerosing osteomyelitis, pri- performed as triple-phase 99mTc methylene diphosph-
mary chronic osteomyelitis, juvenile mandibular onate isotope planar bone scans of the whole body
chronic osteomyelitis) and lack of information about with single photon emission computed tomography
whether these patients have other bony foci and/or (SPECT) images of the head and neck.
extraosseous lesions.
The purpose of this study was to present our expe-
rience with CNO of the mandible in children. The spe-
cific aims were to 1) document the clinical Twenty-two patients (13 females [62%] and 9 males
characteristics, radiographic findings, and histologic [38%]) met the inclusion criteria. The mean age at dis-
features of CNO and 2) determine the percentage of ease onset was 9.05  2.4 years (range, 3 to 17 years),
our sample with multifocal disease (CRMO). and the mean duration of symptoms before diagnosis
was 17  5.2 months (range, 1 month to 10 years).
Materials and Methods On average, patients had been seen by 4.2  1.3 pro-
viders before a correct diagnosis was made. The
To address the study question, we implemented a most common misdiagnoses included fibrous
retrospective case series of children with CNO of the dysplasia, parotitis, fibrosarcoma, and infectious osteo-
mandible. This study was approved by the Institu- myelitis (if an intraoral biopsy had been performed
tional Review Board of the Center for Applied Clinical showing actinomycosis, streptococci, or gram-
Investigation at Boston Childrens Hospital. positive rods). The mean follow-up period was
5.6 years (range, 2 to 19 years) after initial presentation
STUDY SAMPLE to Boston Childrens Hospital.
The study population included patients with CNO Pain and swelling over the affected area were pre-
of the mandible who presented to the Department of senting features in all patients (Fig 1). All patients

had a resolving and relapsing disease course (flares); symptomatic lesion elsewhere (knee [n = 2], back
no patients had only a single episode. Warmth and er- [n = 1], rib [n = 1], skin [n = 2]) before the develop-
ythema were sometimes present. Other findings ment of mandibular disease. An additional osseous
included trismus (45%), headache (18%), otalgia lesion was present outside the mandible, most
(18%), and fever (9%). Some patients noted a correla- commonly in the back, knees, or ankles, in 15 pa-
tion between their symptoms and stress (27%) or exac- tients (68%). Inflammatory skin manifestations
erbation at night (23%). Many of these characteristics including psoriasis and pustular acne were found
were inconsistent and varied from episode to episode. in 12 patients (55%). A diagnosis of spondylarthritis
ESR and/or CRP markers were elevated in 15 patients was made in 5 patients (23%). A family history of
(68%) during flares. autoimmune or inflammatory disease including rheu-
All patients in this study had lesions in the mandible. matoid arthritis, Crohn disease, and psoriasis was
Eleven had bilateral mandibular lesions; 1 of these also noted in 12 patients (55%).
had bilateral maxillary lesions. The remaining 11 pa-
tients had unilateral involvement, and 2 of these pa- RADIOGRAPHIC FINDINGS
tients had a maxillary lesion on the same side. There were 43 images including CT (n = 20), MRI
All patients had multiple recurrent CNO lesions (n = 7), and 99mTc methylene diphosphonate isotope
and/or extraosseous inflammatory lesions (ie, they bone scans (n = 16). Initial CT examinations typically
met the criteria for CRMO). In 16 patients (73%), showed expansion of the affected mandible with scle-
the jaw lesion was the first manifestation of the in- rosis of the medullary space, as well as small foci of
flammatory disease; the other 6 patients had a prior poorly defined lytic destruction with a lamellated peri-
osteal 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 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 showed progression of
mandibular disease, with increased sclerosis and
mandibular expansion in all but 3 patients, in whom
disease remained stable, improved, or was treated
with hemimandibulectomy (n = 1). One patient pre-
sented initially with a maxillary lesion that resolved, fol-
lowed 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
CT examinations (75%) (Fig 4B). This may be a reactive
phenomenon related to hyperemia, as suggested by
enlargement of the retromandibular vein in 1 patient.
MRI of the mandible showed contour alteration,
high signal intensity on FSEIR images, and periosteal
elevation or reaction with diffuse enhancement after
the administration of contrast (Fig 3). Sclerosis ap-
peared as low signal intensity on all pulse sequences.
The muscles of mastication appeared swollen and
showed high signal intensity on FSEIR MRI in 4 of 7
patients. Two patients had prior MRI examinations
of the knee that showed unilateral arthritis several
years preceding the development of the mandib-
ular lesions.
Bone scans showed increased isotope uptake in the
affected mandible (Fig 4B). Additional sites of
FIGURE 1. A 9-year-old girl with left mandibular swelling and pain increased uptake considered concerning or equivocal
associated with chronic nonbacterial osteomyelitis. She also had an
elevated erythrocyte sedimentation rate and eczema, and her father
for multifocal disease were seen in 6 patients. One pa-
had Crohns disease. tient with increased uptake in a rib on a bone scan had
Padwa et al. Pediatric Chronic Nonbacterial Osteomyelitis. J Oral confirmation by chest CT of an additional lesion
Maxillofac Surg 2016. consistent with CNO.

FIGURE 2. Imaging in a 9-year-old girl. A, Computed tomography scan showing prominent, poorly marginated lytic destruction of the left
mandibular body and cortical perforation (arrowhead). There is a smooth periosteal reaction (arrow). (Fig 2 continued on next page.)
Padwa et al. Pediatric Chronic Nonbacterial Osteomyelitis. J Oral Maxillofac Surg 2016.

HISTOPATHOLOGY Fragments of devitalized bone were present in 5

Seventeen patients had at least 1 pathologic specimen patients (29%). Most cases exhibited minor lympho-
(range, 1 to 10 specimens per patient; mean, 1.7). A total cytic infiltrate. Distinctive areas of increased vascu-
of 30 specimens were available for evaluation. Most larity with variable caliber vessels (some grossly
were submitted as multiple fragments of white-tan, dilated) were noted focally in 16 patients (94%). Scle-
irregular pieces of bone ranging from 0.3 to 2.0 cm in rotic bone was found in 6 patients (35%). In 9 pa-
maximum dimension, often with clotted blood. tients (53%) there was atypical reactive osteoid
Histopathologic evaluation showed 4 distinctive fea- with hyperchromatic and atypical osteocytes that, if
tures (Fig 5): 1) parallel and interconnecting thin seen on high power alone, would raise the suspicion
trabeculae of woven bone with thin and thick seams for osteosarcoma. However, these areas were almost
(13 patients, 76%) (Fig 5A); 2) atypical osteoid (15 pa- always in continuity with benign-appearing lamellar
tients, 88%) (Fig 5B); 3) delicate, curvilinear trabeculae or woven bone consistent with reactive osteoid.
of woven bone in a hypocellular fibroblastic stroma The presence of patchy fibrosis, seen in 11 speci-
resembling fibrous dysplasia (6 patients, 35%) mens (36%), distinguishes CNO from fibrous
(Fig 5C); and 4) medullary spaces showing patchy and dysplasia, which usually has uniform fibrosis without
sometimes nodular fibrosis (10 patients, 58%) (Fig 5D). inflammation.
Specimens also showed a heterogeneous pattern of
additional histopathologic findings. Osteoblastic
rimming of the bone with pockets of chronic inflam-
mation was seen in all patients, and osteoclastic activ- The purpose of this study was to present our clinical
ity was observed in 12 (70%). There was neither experience with CNO of the mandible in children. The
osteoblastic proliferation within the stroma nor mul- specific aims were to 1) document the clinical charac-
tilayering of osteoblasts on the osteoid seams. teristics, radiographic findings, and histologic features

FIGURE 2 (contd). B, Axial fast spin echo inversion recovery magnetic resonance imaging showing high signal intensity in the left mandib-
ular body (short arrow) and edema of the masseter muscle (long arrow). C, Gadolinium-enhanced, fat-suppressed T1-weighted magnetic reso-
nance imaging with enhancement of mandible and masseter.
Padwa et al. Pediatric Chronic Nonbacterial Osteomyelitis. J Oral Maxillofac Surg 2016.

FIGURE 3. Imaging in a 5-year-old boy. A, Axial computed tomography scan showing diffuse sclerosis across the midline with expansion of
the mandible. B, C, Bone scan and gallium scan showing increased uptake throughout the mandible.
Padwa et al. Pediatric Chronic Nonbacterial Osteomyelitis. J Oral Maxillofac Surg 2016.

of CNO and 2) determine the percentage of our sam- neoplastic process, the smooth, lamellated appear-
ple with multifocal disease (CRMO). ance of the associated periosteal new bone formation
All patients in our series presented with pain and on CT was helpful in distinguishing CNO from neo-
swelling of the mandible and had clinical and/or radio- plasms such as Ewing sarcoma or osteosarcoma. CT
graphic findings of multiple osseous lesions and/or can help discriminate between fibrous dysplasia and
extraosseous inflammatory disease (CRMO). The ma- CNO: CNO has a ground-glass opacification with a
jority had elevated ESR during a flare and a family his- periosteal reaction that is not seen in fibrous dysplasia.
tory of autoimmune disease. The imaging findings of There were 4 distinct histologic features including
mandibular CNO showed characteristic features. striking parallel and interconnected osteoid seams,
Despite aggressive-appearing lytic destruction of atypical osteoid, areas of woven bone and hypocellular
bone that could be mistaken for a permeative fibroblastic stroma resembling fibrous dysplasia, and

FIGURE 4. Computed tomography scans of the same female patient over a 6-year period showing progression of chronic nonbacterial oste-
omyelitis. A, Coronal reformatted image at age 12 years showing sclerosis and expansion of the 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
the posterior body and angle of the left mandible. The enlarged left mandibular foramen (short arrow) should be noted. (Fig 4 continued on
next page.)
Padwa et al. Pediatric Chronic Nonbacterial Osteomyelitis. J Oral Maxillofac Surg 2016.

FIGURE 4 (contd). C, Image from the same level at age 18 years showing increased sclerosis of the left mandible (arrow).
Padwa et al. Pediatric Chronic Nonbacterial Osteomyelitis. J Oral Maxillofac Surg 2016.

patchy nodular fibrosis. The differential diagnoses in Borzutzky et al1 found that the most commonly
any one high-power field may suggest a neoplasm or affected bone with unifocal disease was the mandible.
fibrous dysplasia; clinical and radiologic correlation Mandibular CNO lesions are estimated to account for
is essential for accurate diagnosis. 1.5 to 3% of disease foci in children with multifocal dis-
Controversies surrounding the diagnosis and man- ease (CRMO).10,13 In a large cohort of 178 patients
agement of this disease stem largely from the inconsis- with 456 lesions, 8 of 9 patients with mandibular
tent terminology that has been assigned to chronic lesions had multifocal disease.10 Borzutzky et al found
osteomyelitis of the mandible.11 For decades, this that CNO patients with comorbid autoimmune disease
lesion was reported as chronic diffuse sclerosing oste- (arthritis, psoriasis, IBD) had a more aggressive pheno-
omyelitis, a vague radiographic diagnosis that was type with higher rates of multifocality. Wipff et al10
broadly applied to several distinct disease processes showed that most patients with unifocal disease even-
with similar radiographic appearances. In addition, tually have progression to the multifocal type (CRMO);
case series and clinical reports typically made no only 7% of patients had a persistent unifocal pattern af-
distinction between adult and pediatric patients ter 4 years.
when reporting group data. The differential diagnosis of mandibular CNO in-
CNO is an orphan disease (OMIM [Online Mende- cludes infectious osteomyelitis, malignancy (osteosar-
lian Inheritance in Man] identification number coma and Ewing sarcoma), and Langerhans cell
259680) characterized by recurrent flares of inflamma- histiocytosis. The pathogenesis of CNO remains un-
tory bone pain related to aseptic osteomyelitis.12 CNO known, although infection has long been suspected.14
lesions can be unifocal or multifocal (CRMO).7 Rates of Recent microbial studies in large CNO cohorts,
unifocal disease vary from 10 to 56%1,7,13; it is including universal 16S ribosomal DNA polymerase
unknown whether mandibular CNO occurs more chain reaction in bone samples, have been consis-
commonly as unifocal disease or as one of the lesions tently negative.7 CNO is currently thought to be in
of CRMO. In a multicenter US study of CNO, the spectrum of autoimmune and autoinflammatory

FIGURE 5. Four distinct histologic features of chronic nonbacterial osteomyelitis: striking parallel osteoid seams; hematoxylin & eosin stain, orig-
inal magnification  40 (A); atypical osteoid; hematoxylin & eosin stain, original magnification  200 (B); delicate, curvilinear trabeculae of
woven bone in a hypocellular fibroblastic stroma resembling fibrous dysplasia; hematoxylin & eosin stain, original magnification  100 (C);
and patchy, nodular fibrosis; hematoxylin & eosin stain, original magnification  100 (D).
Padwa et al. Pediatric Chronic Nonbacterial Osteomyelitis. J Oral Maxillofac Surg 2016.

disorders. This is supported by the high rates of inflam- include documentation of whether the patient had
matory conditions, particularly psoriasis and IBD, in other osseous lesions, extraosseous involvement, or
patients and family members.1 Extraosseous manifes- a family history of autoimmune disease. As reported
tations including palmoplantar pustulosis, psoriasis, in our study and others published in the pediatric
Crohns disease, and acne have led some authors rheumatologic literature,10 the inflammatory bone
to classify CRMO as the juvenile form of SAPHO lesions in children are often multifocal and can be asso-
(synovitis, acne, pustulosis, hyperostosis, osteitis) ciated with inflammatory skin lesions, synovitis, and/
syndrome.12 or a family history of autoimmune or inflammatory dis-
Because only small case series have described the ease. Therefore, nonbacterial osteomyelitis of the
clinical course and outcomes of pediatric mandibular mandible is usually not unifocal, but rather one of
CNO, the defining features of this lesion are poorly the multiple lesions in CRMO.20-23
characterized.15-19 In addition, many of these case In summary, CNO in children is an aseptic autoin-
series did not have long-term follow-up and did not flammatory condition of the musculoskeletal system

typified by recurrent pain and swelling with character- 6. Costa-Reis P, Sullivan K: Chronic recurrent multifocal osteomye-
litis. J Clin Immunol 33:1043, 2013
istic pathologic and radiographic features. The diag-
7. Girschick H, Raab P, Surbaum S, et al: Chronic non-bacterial oste-
nosis can generally be made based on history and omyelitis in children. Ann Rheum Dis 64:279, 2005
clinical and radiographic examinations.24 It is impor- 8. Magrey M, Khan M: New insights into synovitis, acne, pustulosis,
hyperostosis, and osteitis (SAPHO) syndrome. Curr Rheumatol
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regarding other areas of bone pain or swelling and 9. Beck C, Morbach H, Beer M, et al: Chronic nonbacterial osteo-
the presence of extraosseous inflammatory lesions, myelitis in childhood: Prospective follow-up during the first
year of anti-inflammatory treatment. Arthritis Res Ther 2:R74,
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mune conditions. CT, which can be performed using a 10. Wipff J, Costantino F, Lemelle L, et al: A large national cohort of
low-dosage technique, and cone-beam CT are the best French patients with chronic recurrent multifocal osteitis.
Arthritis Rheum 67:1128, 2015
diagnostic imaging tests because these provide 11. Baltensperger M, Gratz K, Bruder E, et al: Is primary chronic
adequate bone detail and visualization of soft tissues osteomyelitis a uniform disease? Proposal of a classification
is not necessary. CT, cone-beam CT, or MRI can be based on a retrospective analysis of patients treated in the past
30 years. J Craniomaxillofac Surg 32:43, 2004
used for follow-up. If the diagnosis remains in ques- 12. Wipff J, Adamsbaum C, Kahan A, Job-Deslandre C: Chronic recur-
tion, a biopsy specimen that includes cortical and rent multifocal osteomyelitis. Joint Bone Spine 78:555, 2011
cancellous bone can be obtained. This biopsy spec- 13. Jansson A, Renner E, Ramser J, et al: Classification of non-
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imen should be obtained from an extraoral approach
and genetic aspects in 89 patients. Rheumatology (Oxford) 46:
to avoid oral contamination and an erroneous diag- 154, 2007
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