PATHOLOGY

Pediatric Chronic Nonbacterial

Osteomyelitis of the Jaw: Clinical,
Radiographic, and Histopathologic
Features
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
Surgeon-in-Chief Department of Plastic and Oral Surgery, Boston
Childrens Hospital, Boston, MA.
yResearch Assistant, Department of Plastic and Oral Surgery,
Boston Childrens Hospital, Boston, MA.
zAssociate Professor, Harvard Medical School, Division Chief,
Neuroradiology, Department of Radiology, Boston Childrens
Hospital, Boston, MA.
xAssociate Professor, Harvard School of Dental Medicine, Division
of Oral Medicine and Dentistry, Brigham and Womens Hospital,
Boston, MA.
kAssistant Professor, Cummings School or Medicine, University of
Calgary, Departments of Pathology and Medical Genetics, Alberta
Childrens Hospital & Research Institute, Boston, MA.
{Instructor, Harvard School of Dental Medicine, Department of
Plastic and Oral Surgery, Boston Childrens Hospital, Boston, MA.
Conflict of Interest Disclosures: None of the authors have any
relevant financial relationship(s) with a commercial interest.
Address correspondence and reprint requests to Dr Padwa:
Department of Plastic and Oral Surgery, Boston Childrens Hospital,
300 Longwood Ave, Boston, MA 02115; e-mail: bonnie.padwa@
childrens.harvard.edu
Received April 12 2016
Accepted May 17 2016
2016 American Association of Oral and Maxillofacial Surgeons
0278-2391/16/30230-0
http://dx.doi.org/10.1016/j.joms.2016.05.021

2393
2394
Chronic nonbacterial osteomyelitis (CNO) is a sterile
inflammatory bone disorder of unknown 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 swelling2,3 and are histologically
characterized by nonspecific osseous inflammation
in the absence of infection.4 Female patients are
more commonly affected than male patients, and the
disease course is highly variable. CNO lesions can be
acute or chronic (persisting $6 months); can be soli-
tary or multifocal; and may resolve, persist, or recur.4,5
CNO can occur as an isolated lesion or can be multi-
focal. The term chronic recurrent multifocal osteomy-
elitis (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 autoinflammatory disorders
including Crohns disease and seronegative
spondyloarthropathies.7 It may be the pediatric equiv-
alent of SAPHO (synovitis, acne, pustulosis, hyperosto-
sis, osteitis) syndrome,7 a diagnosis in adults
encompassing a variable pattern of chronic inflamma-
tory disease affecting multiple organ systems and char-
acterized by recurrent aseptic osteomyelitis.8
CNO most commonly develops in the metaphyseal
plates of the long bones, vertebrae, and clavicles; how-
ever, any bone can be affected.1,9 Mandibular lesions
are found in 1.5 to 3% of disease foci in patients with
CRMO,10 and the most commonly affected bone
with unifocal disease is the mandible.1 CNO is poorly
characterized in the oral and maxillofacial surgery liter-
ature because of inconsistent terminology (eg, Garr
e
osteomyelitis, diffuse sclerosing osteomyelitis, pri-
mary chronic osteomyelitis, juvenile mandibular
chronic osteomyelitis) and lack of information about
whether these patients have other bony foci and/or
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
characteristics, radiographic findings, and histologic
features of CNO and 2) determine the percentage of
our sample with multifocal disease (CRMO).
Materials and Methods
To address the study question, we implemented a
retrospective case series of children with CNO of the
mandible. This study was approved by the Institu-
tional Review Board of the Center for Applied Clinical
Investigation at Boston Childrens Hospital.
STUDY SAMPLE
The study population included patients with CNO
of the mandible who presented to the Department of
PEDIATRIC CHRONIC NONBACTERIAL OSTEOMYELITIS
Plastic and Oral Surgery at Boston Childrens Hospital
between 1991 and 2012. To be included in the study,
patients had to have a mandibular lesion radiographi-
cally consistent with osteomyelitis in the absence of
infection (eg, negative microbial cultures, no response
to antibiotic treatment); onset before age 18 years; and
radiographs, pathologic specimens, and a rheumato-
logic workup for review.
STUDY VARIABLES
Medical records were reviewed for age at onset of
symptoms, age at diagnosis, gender, clinical presenta-
tion, findings on physical examination, clinical course,
and length of follow-up. Other features were recorded
including presence of fever and family history of associ-
ated diseases such as psoriasis, inflammatory bowel dis-
ease (IBD), severe acne, palmoplantar pustulosis, and
spondylarthritis. Laboratory reports were reviewed
for microbial cultures and inflammatory markers
including erythrocyte sedimentation rate (ESR) and C-
reactive protein level (CRP). Pathology specimens
were examined by 2 pathologists (S.B.W. and K.K.).
Radiographic images were evaluated by a single
pediatric neuroradiologist (C.D.R) and included
computed tomography (CT) examinations, magnetic
resonance imaging (MRI), and nuclear medicine
studies. CT examinations included axial 3- to 5-mm im-
ages of the mandible and maxilla without contrast.
Mandibular MRI consisted of 3- to 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
T1-weighted images. Nuclear medicine studies were
performed as triple-phase 99mTc methylene diphosph-
onate isotope planar bone scans of the whole body
with single photon emission computed tomography
(SPECT) images of the head and neck.
Results
Twenty-two patients (13 females [62%] and 9 males
[38%]) met the inclusion criteria. The mean age at dis-
ease onset was 9.05  2.4 years (range, 3 to 17 years),
and the mean duration of symptoms before diagnosis
was 17  5.2 months (range, 1 month to 10 years).
On average, patients had been seen by 4.2  1.3 pro-
viders before a correct diagnosis was made. The
most common misdiagnoses included fibrous
dysplasia, parotitis, fibrosarcoma, and infectious osteo-
myelitis (if an intraoral biopsy had been performed
showing actinomycosis, streptococci, or gram-
positive rods). The mean follow-up period was
5.6 years (range, 2 to 19 years) after initial presentation
to Boston Childrens Hospital.
Pain and swelling over the affected area were pre-
senting features in all patients (Fig 1). All patients
PADWA ET AL
had a resolving and relapsing disease course (flares);
no patients had only a single episode. Warmth and er-
ythema were sometimes present. Other findings
included trismus (45%), headache (18%), otalgia
(18%), and fever (9%). Some patients noted a correla-
tion between their symptoms and stress (27%) or exac-
erbation at night (23%). Many of these characteristics
were inconsistent and varied from episode to episode.
ESR and/or CRP markers were elevated in 15 patients
(68%) during flares.
All patients in this study had lesions in the mandible.
Eleven had bilateral mandibular lesions; 1 of these also
had bilateral maxillary lesions. The remaining 11 pa-
tients had unilateral involvement, and 2 of these pa-
tients had a maxillary lesion on the same side.
All patients had multiple recurrent CNO lesions
and/or extraosseous inflammatory lesions (ie, they
met the criteria for CRMO). In 16 patients (73%),
the jaw lesion was the first manifestation of the in-
flammatory disease; the other 6 patients had a prior
FIGURE 1. A 9-year-old girl with left mandibular swelling and pain
associated with chronic nonbacterial osteomyelitis. She also had an
elevated erythrocyte sedimentation rate and eczema, and her father
had Crohns disease.
Padwa et al. Pediatric Chronic Nonbacterial Osteomyelitis. J Oral
Maxillofac Surg 2016.
2395
symptomatic lesion elsewhere (knee [n = 2], back
[n = 1], rib [n = 1], skin [n = 2]) before the develop-
ment of mandibular disease. An additional osseous
lesion was present outside the mandible, most
commonly in the back, knees, or ankles, in 15 pa-
tients (68%). Inflammatory skin manifestations
including psoriasis and pustular acne were found
in 12 patients (55%). A diagnosis of spondylarthritis
was made in 5 patients (23%). A family history of
autoimmune or inflammatory disease including rheu-
matoid arthritis, Crohn disease, and psoriasis was
noted in 12 patients (55%).
RADIOGRAPHIC FINDINGS
There were 43 images including CT (n = 20), MRI
(n = 7), and 99mTc methylene diphosphonate isotope
bone scans (n = 16). Initial CT examinations typically
showed expansion of the affected mandible with scle-
rosis of the medullary space, as well as small foci of
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
increased uptake considered concerning or equivocal
for multifocal disease were seen in 6 patients. One pa-
tient with increased uptake in a rib on a bone scan had
confirmation by chest CT of an additional lesion
consistent with CNO.
2396 PEDIATRIC CHRONIC NONBACTERIAL OSTEOMYELITIS

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
(range, 1 to 10 specimens per patient; mean, 1.7). A total
of 30 specimens were available for evaluation. Most
were submitted as multiple fragments of white-tan,
irregular pieces of bone ranging from 0.3 to 2.0 cm in
maximum dimension, often with clotted blood.
Histopathologic evaluation showed 4 distinctive fea-
tures (Fig 5): 1) parallel and interconnecting thin
trabeculae of woven bone with thin and thick seams
(13 patients, 76%) (Fig 5A); 2) atypical osteoid (15 pa-
tients, 88%) (Fig 5B); 3) delicate, curvilinear trabeculae
of woven bone in a hypocellular fibroblastic stroma
resembling fibrous dysplasia (6 patients, 35%)
(Fig 5C); and 4) medullary spaces showing patchy and
sometimes nodular fibrosis (10 patients, 58%) (Fig 5D).
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-
ity was observed in 12 (70%). There was neither
osteoblastic proliferation within the stroma nor mul-
tilayering of osteoblasts on the osteoid seams.
patients (29%). Most cases exhibited minor lympho-
cytic infiltrate. Distinctive areas of increased vascu-
larity with variable caliber vessels (some grossly
dilated) were noted focally in 16 patients (94%). Scle-
rotic bone was found in 6 patients (35%). In 9 pa-
tients (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 speci-
mens (36%), distinguishes CNO from fibrous
dysplasia, which usually has uniform fibrosis without
inflammation.
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 charac-
teristics, radiographic findings, and histologic features
PADWA ET AL 2397

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.
2398 PEDIATRIC CHRONIC NONBACTERIAL OSTEOMYELITIS

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-
ple with multifocal disease (CRMO).
All patients in our series presented with pain and
swelling of the mandible and had clinical and/or radio-
graphic findings of multiple osseous lesions and/or
extraosseous inflammatory disease (CRMO). The ma-
jority had elevated ESR during a flare and a family his-
tory of autoimmune disease. The imaging findings of
mandibular CNO showed characteristic features.
Despite aggressive-appearing lytic destruction of
bone that could be mistaken for a permeative
neoplastic process, the smooth, lamellated appear-
ance of the associated periosteal new bone formation
on CT was helpful in distinguishing CNO from neo-
plasms 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 seen in fibrous dysplasia.
There were 4 distinct histologic features including
striking parallel and interconnected osteoid seams,
atypical osteoid, areas of woven bone and hypocellular
fibroblastic stroma resembling fibrous dysplasia, and
PADWA ET AL 2399

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.
2400
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
any one high-power field may suggest a neoplasm or
fibrous dysplasia; clinical and radiologic correlation
is essential for accurate diagnosis.
Controversies surrounding the diagnosis and man-
agement of this disease stem largely from the inconsis-
tent terminology that has been assigned to chronic
osteomyelitis of the mandible.11 For decades, this
lesion was reported as chronic diffuse sclerosing oste-
omyelitis, a vague radiographic diagnosis that was
broadly applied to several distinct disease processes
with similar radiographic appearances. In addition,
case series and clinical reports typically made no
distinction between adult and pediatric patients
when reporting group data.
CNO is an orphan disease (OMIM [Online Mende-
lian Inheritance in Man] identification number
259680) characterized by recurrent flares of inflamma-
tory bone pain related to aseptic osteomyelitis.12 CNO
lesions can be unifocal or multifocal (CRMO).7 Rates of
unifocal disease vary from 10 to 56%1,7,13; it is
unknown whether mandibular CNO occurs more
commonly as unifocal disease or as one of the lesions
of CRMO. In a multicenter US study of CNO,
PEDIATRIC CHRONIC NONBACTERIAL OSTEOMYELITIS
Borzutzky et al1 found that the most commonly
affected bone with unifocal disease was the mandible.
Mandibular CNO lesions are estimated to account for
1.5 to 3% of disease foci in children with multifocal dis-
ease (CRMO).10,13 In a large cohort of 178 patients
with 456 lesions, 8 of 9 patients with mandibular
lesions had multifocal disease.10 Borzutzky et al found
that CNO patients with comorbid autoimmune disease
(arthritis, psoriasis, IBD) had a more aggressive pheno-
type with higher rates of multifocality. Wipff et al10
showed that most patients with unifocal disease even-
tually have progression to the multifocal type (CRMO);
only 7% of patients had a persistent unifocal pattern af-
ter 4 years.
The differential diagnosis of mandibular CNO in-
cludes infectious osteomyelitis, malignancy (osteosar-
coma and Ewing sarcoma), and Langerhans cell
histiocytosis. The pathogenesis of CNO remains un-
known, 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 consis-
tently negative.7 CNO is currently thought to be in
the spectrum of autoimmune and autoinflammatory
PADWA ET AL 2401

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-
matory conditions, particularly psoriasis and IBD, in
patients and family members.1 Extraosseous manifes-
tations including palmoplantar pustulosis, psoriasis,
Crohns disease, and acne have led some authors
to classify CRMO as the 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.15-19 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, extraosseous involvement, or
a family history of autoimmune disease. As reported
in our study and others published in the pediatric
rheumatologic literature,10 the inflammatory bone
lesions in children are often multifocal and can be asso-
ciated with inflammatory skin lesions, synovitis, and/
or a family history of autoimmune or inflammatory dis-
ease. Therefore, nonbacterial osteomyelitis of the
mandible is usually not unifocal, but rather one of
the multiple lesions in CRMO.20-23
In summary, CNO in children is an aseptic autoin-
flammatory condition of the musculoskeletal system
2402
typified by recurrent pain and swelling with character-
istic pathologic and radiographic features. The diag-
nosis can generally be made based on history and
clinical and radiographic examinations.24 It is impor-
tant to obtain a detailed history with specific inquiry
regarding other areas of bone pain or swelling and
the presence of extraosseous inflammatory lesions,
as well as a family history of inflammatory and autoim-
mune conditions. CT, which can be performed using a
low-dosage technique, and cone-beam CT are the best
diagnostic imaging tests because these provide
adequate bone detail and visualization of soft tissues
is not necessary. CT, cone-beam CT, or MRI can be
used for follow-up. If the diagnosis remains in ques-
tion, a biopsy specimen that includes cortical and
cancellous bone can be obtained. This biopsy spec-
imen should be obtained from an extraoral approach
to avoid oral contamination and an erroneous diag-
nosis of an infectious etiology. We recommend referral
to a rheumatologist for evaluation and management
because this is a rheumatic disease. Treatment is
directed at reducing pain and inflammation, with the
intent of halting bone destruction and disease progres-
sion.1 Although no randomized controlled trials have
been carried out, a variety of anti-inflammatory medi-
cations (nonsteroidal anti-inflammatory drugs,
steroids), as well as methotrexate, bisphosphonates,
and disease-modifying agents (tumor necrosis factor
a inhibitors), have been used in the treatment of this
condition.2,5,10 Surgical intervention is reserved
for contour reduction. Establishing a common
terminology and better understanding of this
condition may improve the clinical management and
treatment outcomes of patients with this disorder.
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