# Comparative study of radio-clinical parameters in pediatric forms of fibrous dysplasia and chronic recurrent multifocal osteomyelitis

Elise Le Coq, Anne-Sophie Delemazure, Emmanuelle Mourrain-Langlois,
Pierre Corre, Hélios Bertin, Soizic Tiriau

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## ► To cite this version:

Elise Le Coq, Anne-Sophie Delemazure, Emmanuelle Mourrain-Langlois, Pierre Corre, Hélios Bertin, et al.. Comparative study of radio-clinical parameters in pediatric forms of fibrous dysplasia and chronic recurrent multifocal osteomyelitis. Journal of Cranio-Maxillofacial Surgery, 2025, 53 (5), pp.596 - 603. 10.1016/j.jcms.2025.01.032. hal-05063467

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# Comparative study of radio-clinical parameters in pediatric forms of fibrous dysplasia and chronic recurrent multifocal osteomyelitis

Elise Le Coq<sup>a</sup>, Anne-Sophie Delemazure<sup>b</sup>, Emmanuelle Mourrain-Langlois<sup>b</sup>, Pierre Corre<sup>c,d</sup>, Hélios Bertin<sup>c,e,f</sup>, <sup>g</sup>Soizic Tiriau<sup>a</sup>

<figure><img src="image_4.png" /></figure>

## ARTICLE INFO

Keywords:

Chronic recurrent multifocal osteomyelitis

Fibrous dysplasia of bone

Differential diagnosis

Craniofacial

## ABSTRACT

Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory disease with clinical and radiological symptoms that overlap with fibrous dysplasia (FD), particularly in children. This study aimed to compare the clinical and radiological features of craniofacial CRMO and FD in a pediatric population. Seven children with CRMO and 14 with FD were retrospectively identified in our tertiary centre between 2012 and 2022. Their clinical, radiological, and biological (when available) data were collected. Two experienced radiologists reviewed imaging modalities following a standardized form, including characteristics of the lesions, soft-tissue involvement, and signal abnormalities (MRI). Swelling and pain were common symptoms in the CRMO group (7/7 and 5/5, respectively), compared with 11/14 and 2/14 patients in the FD group. Imaging (CT scan) comparisons revealed a predominance of erosive lesions, cortical interruption, periosteal apposition, and soft-tissue involvement in CRMO compared with FD (4/5 vs 0/6, $p_1 = 0.01$; 5/5 vs 1/6, $p_2 = 0.01$; 5/5 vs 0/6, $p_3 = 0.002$; and 4/5 vs 0/6, $p_4 = 0.02$, respectively). Hyperosteosis was mainly associated with FD lesions (6/6 vs 2/5, $p = 0.06$). Knowledge of the clinical and radiographic differences between CRMO and FD could help clinicians to differentiate between the two diseases.

## 1. Introduction

Chronic recurrent multifocal osteomyelitis (CRMO) is a rare autoinflammatory disease in adults and children, with a prevalence of one in 1 million (Giedion et al., 1972). CRMO may be associated with general autoinflammatory or autoimmune diseases, including psoriasis, palmo-plantar psoriasis, and inflammatory bowel disease (IBD). The pathophysiology of CRMO remains unclear; the disease probably results from an imbalance between pro-inflammatory and anti-inflammatory cytokines favoring bone inflammation. Analysis of the monocytes from CRMO patients have showed impairments in MAP kinase Erk1 and 2 signaling, leading to reduced expression of the immune regulatory interleukins IL-10 and IL-19 (Hofmann et al., 2011, 2012).

The expression of pro-inflammatory cytokines (IL-1β, IL-6, tumor necrosis factor (TNF)-α, and IL-20) is then increased, as well as the

interaction between membrane receptor activator of NF-κB (RANK) and its ligand RANKL, promoting the differentiation and activation of osteoclasts (Hofmann et al., 2017). The disease usually affects the metaphysis of long bones (typically femur or tibia), clavicle, vertebrae, and pelvic bones; craniofacial involvement is rare (5–18% of cases) and usually localized in the mandible (Bhat et al., 2018; Beck et al., 2023). Patients mostly suffer from unspecific symptoms associated with bone pain (Jansson et al., 2007) and local inflammation with skin redness, warmth, or swelling (Jansson et al., 2007; Zhao et al., 2021). Joint limitation, including trismus, is possible.

Data from the Eurofever international registry have shown that 42% of patients present a continuous disease, 52% suffer from recurrent forms, and 5% report both continuous and recurrent evolution (Girschick et al., 2018). Standard radiological imaging (X-rays, computed tomography (CT) scan and cone-bean CT (CBCT)) may be

<footnote><sup>a</sup> Nantes Université, CHU Nantes, Service de pédiatrie, F-44000, Nantes, France</footnote>

<footnote><sup>b</sup> Nantes Université, CHU Nantes, Service d'imagerie médicale, F-44000, Nantes, France</footnote>

<footnote><sup>c</sup> Nantes Université, CHU Nantes, Service de chirurgie maxillo-faciale et stomatologie, F-44000, Nantes, France</footnote>

<footnote><sup>d</sup> Nantes Université, Oniris, Univ Angers, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR 1229, F-44000, Nantes, France</footnote>

<footnote><sup>e</sup> Nantes Université, Univ Angers, CHU Nantes, INSERM, CNRS, CRCI2NA, F-44000, Nantes, France</footnote>

<footnote>* Corresponding author. Nantes Université, CHU Nantes, Service de chirurgie maxillo-faciale et stomatologie, F-44000, Nantes, France.
*E-mail addresses:* elise.lecoq@chu-nantes.fr (E. Le Coq), annesophie.delemazure@chu-nantes.fr (A.-S. Delemazure), emmanuelle.mourrainlanglois@chu-nantes.fr (E. Mourrain-Langlois), pierre.corre@chu-nantes.fr (P. Corre), helios.bertin@chu-nantes.fr (H. Bertin), soizic.tiriau@chu-nantes.fr (S. Tiriau).</footnote>
falsely normal in the early stages of the disease (Taddio et al., 2017), or can show osteolytic lesions, sclerosis and hyperosteosis, periosteal reaction, and inflammatory signs (Eyrich et al., 2003; Obel et al., 2013; Roderick et al., 2016).

By showing bone inflammation, MRI with STIR sequences presents good sensitivity for disease detection and monitoring. Furthermore, an aseptic biopsy showing chronic inflammation is considered as one of the main criteria for the diagnosis of CRMO (Jansson et al., 2007); however, the patterns remains unspecific and could mimic fibrous dysplasia (Jia et al., 2023). Bone biopsy is not obligatory in typical forms, and mainly serves to rule out differential diagnosis — especially bone tumors. Due to the low specificity of clinical and radiological signs, diagnosis and treatment are often delayed by a mean of 15 months after the first symptoms in CRMO (Roderick et al., 2016).

Fibrous dysplasia (FD) is a benign fibro-osseous skeletal disorder affecting 1/30 000 people (Chapurlat and Orcel, 2008). FD is secondary to a postzygotic mutation of the GNAS gene located in chromosome 20q13.3, which is of osteoblastic lineage and encodes the subunit alpha of the protein G (Weinstein et al., 1991). This results in defects in the differentiation of osteoblasts and proliferation of undifferentiated skeletal stem cells in the marrow space, resulting in the formation of fibro-osseous lesions (Boyce and Collins, 2020). FD presents various clinical forms, ranging from the monostotic disease affecting only one skeletal site to the polyostotic disease and McCune-Albright syndrome (MAS), which combines FD and extra-skeletal disorders (café-au-lait skin macules, endocrine disorders) (Boyce and Collins, 2020; Javaid et al., 2019).

FD is usually absent at birth and manifests in childhood and adolescence through bone pain, bone deformity, and fractures (Chapurlat and Orcel, 2008). The craniofacial skeleton is involved in 25% of cases, mostly affecting the maxilla (28%), the orbit (27%), and the mandible (25%) (Yang et al., 2017). FD may then cause deformations of aesthetic concern, with visual loss and hearing impairment due to cranial nerve compression (Bertin et al., 2020; Wang et al., 2019). An inflammatory process with local inflammatory lesions may occur in high-progressing disease in children, mimicking CRMO. Furthermore, FD usually presents with unspecific radiological signs, associated with sclerotic or osteolytic radiolucent lesions with a ground-glass appearance (Bertin et al., 2020). Bone biopsy is usually indicated in unusual or questionable cases, providing a definitive diagnosis of FD by showing a poorly arranged fibrous stroma with irregularly shaped bone trabeculae (woven bone) (Javaid et al., 2019; Riminucci et al., 1999). Identification of the pathogenic variant of the GNAS gene is pathognomonic for the disease; however, the mutation is found in 71.9% of the patients and its absence does not exclude the diagnosis (Lee et al., 2012).

In our tertiary center specializing in bone and metabolic disorders, we are regularly confronted with difficulties in differentiating craniofacial CRMO and FD. Therefore, the aim of this retrospective study was to collect and compare the clinical and radiological features of craniofacial CRMO and FD in a pediatric population.

## 2. Materials and methods

### 2.1. Study population

This retrospective study included patients under 18-years, with a diagnosis of craniofacial CRMO or FD in the Department of Pediatrics and Maxillofacial Surgery of Nantes University Hospital (Nantes, France), between January 2012 and September 2022. The study was approved by the institutional review board (Groupe Nantais d'Éthique dans le Domaine de la Santé, authorization number 23-22-01-305). Medical records were identified in the biomedical databases using structured information, such as the diagnosis code, or unstructured information (Table 1).

Diagnosis of CRMO was based on clinical inflammatory bone

<table><caption>**Table 1**
Keywords used to identify patient records in the Nantes University Hospital database.</caption><thead><tr><th>Structured information: CIM-10 code</th><th>Unstructured information: text search in reports</th></tr></thead><tbody><tr><td><ul><li>M863 Chronic osteomyelitis, multiple site</li><li>M869 Chronic osteomyelitis, no precision</li><li>M866 Chronic osteomyelitis, other site</li><li>K102 Inflammatory conditions of the jaws</li><li>H050 Acute inflammation of the orbit</li><li>M8638 Chronic multiple osteomyelitis, other locations</li><li>M8508 Fibrous dysplasia, other locations</li><li>M8500 Fibrous dysplasia, multiple site</li><li>M8509 Fibrous dysplasia, site not specified</li><li>K108 Other specified jaw diseases</li><li>Q781 Polyostotic fibrous dysplasia</li></ul></td><td><ul><li>Non-bacterial mandibular osteomyelitis</li><li>Facial non-bacterial osteomyelitis</li><li>Facial CRMO</li><li>Facial fibrous dysplasia</li><li>Mandibular fibrous dysplasia</li></ul></td></tr></tbody></table>

CIM: Classification Internationale des Maladies (French version of the ICD, International Classification of Diseases (10th revision)).

manifestations evolving for more than 6 months, as well as compatible imaging. CRMO is a diagnosis of exclusion, based on the convergence of positive and exclusionary criteria. These include a prolonged course interspersed with asymptomatic intercritical periods, multifocal lesions, absence of response to antibiotics, association with psoriasis, palmo-plantar pustulosis, IBD, and radiological findings. At present, there is no validated classification for the diagnosis of the disease.

FD was diagnosed based on formal radiological and/or histological evidence. Regarding the classification of patients into CRMO or FD groups, biopsy was not mandatory and constituted additional evidence.

Exclusion criteria included: diagnosis of tumoral, infectious, or autoinflammatory pathology; CRMO or FD with only extracranial manifestations.

The patient charts were reviewed and data documenting the age of the patients, their gender, the mean delay from first consultation to diagnosis, medical history, and clinical signs, including extracranial manifestations, were compiled.

### 2.2. Evaluation criteria

Two experienced radiologists (ASD, EML) specialized in craniofacial imaging reviewed the available radiographic examinations (no-contrast CT-scan, CBCT, MRI), and were blinded to patient clinical data and final diagnosis. Cases were discussed between the radiologists in a concerted way, and no interindividual variability was measured. The radiologists were asked to fill out a standardized form, which included disease location, number of lesions, and characteristics of bone lesions (local erosion, intraosseous air bubbles, osteolysis, sclerosis, ground-glass pattern, bone enlargement, cortical rupture, irregular border, periosteal apposition, and soft-tissue thickening adjacent to bone lesion). For MRI, the presence of bone marrow and soft-tissue inflammatory signs (hypointense T1, hyperintense T2 lesions) and contrast enhancement were recorded (Table 2). The two groups of patients with CRMO and FD were also compared regarding their clinical characteristics, and the results of bone biopsy.

### 2.3. Statistical analyses

Qualitative variables were presented as numbers and percentages, while quantitative variables were assessed using medians and interquartile ranges. The statistical analysis was performed using GraphPad Prism 10.2 software for Mac (GraphPad Software, La Jolla, CA, USA). Categorical variables were analyzed using a Fisher exact test, while quantitative data were compared with a Wilcoxon test. A p-value <0.05
<table><caption>**Table 2**
Standardized form for imaging evaluation.</caption><tbody><tr><td>Normal</td><td>☐ Yes</td><td>☐ No</td></tr><tr><td>Bone involvement</td><td>☐ Mandible<br>☐ Maxilla<br>☐ Zygoma<br>☐ Frontal bone<br>☐ Sphenoid<br>☐ Ethmoid<br>☐ Skull vault</td><td></td></tr><tr><td>Number of distinct bone lesions</td><td></td><td></td></tr><tr><td>Local erosion</td><td>☐ Yes</td><td>☐ No</td></tr><tr><td>Intraosseous air bubble</td><td>☐ Yes</td><td>☐ No</td></tr><tr><td>Osteolysis</td><td>☐ Yes</td><td>☐ No</td></tr><tr><td>Sclerosis</td><td>☐ Yes</td><td>☐ No</td></tr><tr><td>Ground-glass pattern</td><td>☐ Yes</td><td>☐ No</td></tr><tr><td>Bone enlargement</td><td>☐ Yes</td><td>☐ No</td></tr><tr><td>Cortical rupture</td><td>☐ Yes</td><td>☐ No</td></tr><tr><td>Irregular border</td><td>☐ Yes</td><td>☐ No</td></tr><tr><td>Periosteal apposition</td><td>☐ Yes</td><td>☐ No</td></tr><tr><td>Soft-tissue involvement measured using soft-tissue thickening (for CT) or signal abnormalities (for MRI)</td><td>☐ Yes</td><td>☐ No</td></tr><tr><td>Inflammatory signs (hypointense T1, hyperintense T2 lesions) (MRI only)</td><td>☐ Yes</td><td>☐ No</td></tr><tr><td>Diagnosis</td><td>☐ Chronic osteomyelitis<br>☐ Fibrous dysplasia<br>☐ Other</td><td></td></tr></tbody></table>

indicated statistical significance.

# 3. Results

## 3.1. Patient characteristics

From the 323 records reviewed, 21 patients were finally included, based on inclusion and exclusion criteria (seven CRMO and 14 FD) (Supplementary materials, Fig. S1). The median age of patients was 8 years in the CRMO group and 12 years in the FD group. Median duration from symptoms onset to diagnosis was 5 months (range 4.5–18.5 months) for CRMO versus 9 months (range: 6.0–33.0 months) for FD. Regarding medical history, one patient in the CRMO group suffered from a bowel disease and another from systemic inflammatory disease. In the FD group, four patients presented with McCune-Albright syndrome (MAS). Regarding clinical symptoms, most of the patients presented with local swelling (n = 7) and bone pain (n = 5) in the CRMO group,

while swelling was the most common symptom in the FD group (n = 11). The characteristics of the patients are presented in Table 3.

## 3.2. Radiological findings (main outcome)

Various imaging records were available, including CT, CBCT, and MRI for five, three, and four patients in the CRMO group, and six, six, and four patients in the FD group, respectively. Whole-body imaging was available for six patients with CRMO and eight patients with FD. Regarding the location of CRMO, four children presented with a monostotic mandibular lesion, two patients had an extended lesion involving the maxilla-zygomatic bones and the frontal bone, while one patient presented an isolated lesion of the zygoma. In the FD group, 6/14 patients presented a lesion involving one bone (two in the maxilla, two in the sphenoid bone, one in the frontal bone, and one in the mandible). Eight other patients presented with a lesion involving multiple adjacent bones (frontal and sphenoid bones in two patients, frontal and ethmoid
<table><caption>**Table 3**

Characteristics of patients with a diagnosis of CRMO or FD.</caption><thead><tr><th></th><th>CRMO n = 7</th><th>FD n = 14</th></tr></thead><tbody><tr><td>Age at diagnosis (years), median (IQR)</td><td>8.00 (6.50, 10.00)</td><td>12.00 (8.50, 15.00)</td></tr><tr><td>Sex</td><td></td><td></td></tr><tr><td>Male, n (%)</td><td>2 (29)</td><td>9 (64)</td></tr><tr><td>Female, n (%)</td><td>5 (71)</td><td>5 (36)</td></tr><tr><td>Time to consultation (months), median (IQR)</td><td>3 (2, 11.50)</td><td>1.50 (0.00, 4.50)</td></tr><tr><td>Delay to diagnosis (months), median (IQR)</td><td>5.00 (4.50, 18.50)</td><td>9.00 (6.00, 33.00)</td></tr><tr><td>Extracranial lesions, n (%)</td><td></td><td></td></tr><tr><td>McCune-Albright syndrome, n (%)</td><td>-</td><td>4 (29)</td></tr><tr><td>'Café au lait' skin macules, n (%)</td><td>-</td><td>3 (21)</td></tr><tr><td>Endocrine disorders, n (%)</td><td>-</td><td>2 (14)</td></tr><tr><td>Clinical symptoms</td><td></td><td></td></tr><tr><td>Asymptomatic, n (%)</td><td>0 (0)</td><td>3 (21)</td></tr><tr><td>Pain, n (%)</td><td>5 (71)</td><td>2 (14)</td></tr><tr><td>Swelling, n (%)</td><td>7 (100)</td><td>11 (79)</td></tr><tr><td>Clinical adenopathy, n (%)</td><td>3 (43)</td><td>0 (0)</td></tr><tr><td>Neurological involvement, n (%)</td><td>1 (14)</td><td>1 (7)</td></tr><tr><td>Ocular involvement, n (%)</td><td>0 (0)</td><td>3 (21)</td></tr></tbody></table>

n: number of patients; IQR: interquartile range; CRMO: chronic recurrent multifocal osteomyelitis; FD: fibrous dysplasia.

bones in one patient, and maxilla-zygomatic and sphenoidal bones in five cases). Mandibular localization was associated with CRMO (4/7 versus 1/14 for FD; *p* = 0.03), sphenoid involvement was associated with FD (8/14 cases versus 0/7 in CRMO; *p* = 0.02).

Whole-body imaging was available for six patients with CRMO, comprising MRI for two patients and bone scintigraphy for four patients. These imaging modalities revealed distant locations for two of them, affecting the femoral metaphysis or the contralateral mandible. In the FD group, eight patients were investigated using bone scintigraphy, with four presenting polyostotic disease (affecting upper or lower limbs, vertebrae, or ribs).

The comparative analysis of imaging records highlighted a lack of specificity for osteolysis and ground-glass pattern signs in both CRMO and FD for CT and CBCT (5/5 and 4/5 for CRMO vs 5/6 and 6/6 for FD,

<table><caption>**Table 4**

Radiological characteristics of craniofacial lesions in chronic recurrent multifocal osteomyelitis and fibrous dysplasia after radiological reviewing.</caption><thead><tr><th></th><th>CRMO n = 7</th><th>FD n = 14</th><th>p-value</th></tr></thead><tbody><tr><td>CT</td><td></td><td></td><td></td></tr><tr><td>Bone erosion, n</td><td>4/5</td><td>0/6</td><td>0.01</td></tr><tr><td>Osteolysis, n</td><td>5/5</td><td>5/6</td><td>0.99</td></tr><tr><td>Sclerosis, n</td><td>0/5</td><td>2/6</td><td>0.45</td></tr><tr><td>Ground-glass pattern, n</td><td>4/5</td><td>6/6</td><td>0.45</td></tr><tr><td>Hyperosteosis, n</td><td>2/5</td><td>6/6</td><td>0.06</td></tr><tr><td>Cortical interruption, n</td><td>5/5</td><td>1/6</td><td>0.01</td></tr><tr><td>Irregular border, n</td><td>1/5</td><td>0/6</td><td>0.45</td></tr><tr><td>Periosteal apposition, n</td><td>5/5</td><td>0/6</td><td>0.002</td></tr><tr><td>Soft-tissue thickening, n</td><td>4/5</td><td>0/6</td><td>0.02</td></tr><tr><td>Cone-beam CT</td><td></td><td></td><td></td></tr><tr><td>Bone erosion, n</td><td>3/3</td><td>1/6</td><td>0.04</td></tr><tr><td>Osteolysis, n</td><td>3/3</td><td>2/6</td><td>0.17</td></tr><tr><td>Sclerosis, n</td><td>1/3</td><td>1/6</td><td>0.99</td></tr><tr><td>Ground-glass pattern, n</td><td>2/3</td><td>6/6</td><td>0.33</td></tr><tr><td>Hyperosteosis, n</td><td>2/3</td><td>6/6</td><td>0.33</td></tr><tr><td>Cortical interruption, n</td><td>3/3</td><td>2/6</td><td>0.17</td></tr><tr><td>Irregular border, n</td><td>1/3</td><td>0/6</td><td>0.33</td></tr><tr><td>Periosteal apposition, n</td><td>3/3</td><td>1/6</td><td>0.04</td></tr><tr><td>MRI</td><td></td><td></td><td></td></tr><tr><td>Bone marrow edema, n</td><td>4/4</td><td>2/3</td><td>0.43</td></tr><tr><td>Contrast enhancement, n</td><td>3/4</td><td>1/3</td><td>0.49</td></tr><tr><td>Hyperosteosis, n</td><td>2/4</td><td>3/3</td><td>0.43</td></tr><tr><td>Irregular border, n</td><td>1/4</td><td>0/3</td><td>0.99</td></tr><tr><td>Periosteal appositions, n</td><td>1/4</td><td>0/3</td><td>0.99</td></tr><tr><td>Soft-tissue infiltration, n</td><td>3/4</td><td>0/3</td><td>0.14</td></tr></tbody></table>

respectively; *p*₁ = 0.99 and *p*₂ = 0.45) (Table 4) (Fig. 1). Similarly, on MRI, local inflammatory signs including signal abnormalities and contrast enhancement were present in both pathologies and did not allow any radiological distinction to be made (4/4 and 3/4 for CRMO vs 2/3 and 1/3 for FD, respectively; *p*₁ = 0.43 and *p*₂ = 0.49). Some of the radiological signs, such as sclerosis and irregular border, were rarely found by radiologists, and therefore did not allow a distinction to be made between CRMO and FD (0/5 and 1/5 for CRMO with CT vs 2/6 and 0/6 for FD, respectively; *p*₁ = 0.45 and *p*₂ = 0.45). Bone erosion and periosteal reaction were more specific to CRMO on both CT and CBCT than FD (4/5 and 3/3 vs 0/6 and 1/6, respectively; *p*₁ = 0.01 and *p*₂ = 0.02 for CT, *p*₃ = 0.04 and *p*₄ = 0.04 for CBCT, respectively). With CT, cortical interruption and soft-tissue infiltration were mostly found with CRMO compared with FD (5/5 vs 1/6 and 4/5 vs 0/6, respectively; *p*₁ = 0.01 and *p*₂ = 0.02) (see Fig. 2).

### 3.3. Secondary criteria

Regarding symptoms, cervical lymph nodes were clinically assessed in three patients with CRMO, and in no patients with FD. Clinical symptoms were systematically found in CRMO, while three patients with FD were asymptomatic, with lesions identified by systematic imaging.

Biological parameters were available for nine patients (six CRMO and three FD). Inflammation (defined as CRP >10 mg/L and/or leukocytes >10 G/L) was found in three patients with CRMO, and no patients with FD (*p* = 0.46). Serum alkaline phosphatase was elevated in 2/4 patients with available data in the FD group.

Bone biopsy results were available for 10 patients, including six patients in the CRMO group and four patients in the FD group). Biopsy confirmed the disease in four cases of CRMO and three cases of FD, showing inflammation with an infiltrate dominated by both neutrophils and lymphocytes in CRMO, while FD lesions exposed an arranged fibrous stroma with irregularly shaped bone trabeculae (woven bone), and with no signs of inflammation. The GNAS mutation was found in only one patient with FD.

All CRMO patients benefited from first-line treatment with non-steroidal anti-inflammatory drugs (NSAIDs): six received drugs over several months, and one only during inflammatory flares. Two children required a second line of treatment, consisting of a change in NSAID class for one case and the addition of pamidronate for another. At least three patients received antibiotics before initiation of specific effective treatment. No patient was surgically treated. During treatment, painful symptoms resolved in all patients, bone swelling improved in four patients and disappeared in three patients, while three patients relapsed after ending treatment. Eight out of the 14 FD patients received treatment involving pamidronate monotherapy (n = 7), or in association to ibuprofen (n = 1). Three patients with FD were treated surgically. Eight patients presented stable bone swelling, one improved, and one worsened.

## 4. Discussion

CRMO and FD are rare bone conditions that may present a combination of clinical and radiological parameters, and may represent a diagnostic challenge, particularly with regard to the pediatric population (Campbell et al., 2020; Johannsen, 1977; Camison et al., 2018). In our opinion, diagnosis requires a multidisciplinary assessment by experienced practitioners of a range of clinical, radiological, and even histological evidence. Through the presentation of two case series, the aim of our study was to better describe both pathologies in order to help clinicians in the differential diagnosis of these diseases.

Our study confirmed the difficulty in differentiating between both diseases, since five patients with CRMO were initially misdiagnosed as having FD. In this context, Jansson et al. proposed a diagnostic classification of CRMO based on a study of 89 pediatric patients (Jansson
<figure><img src="image_5.png" /><figcaption>**Fig. 1.** Axial (a) and coronal (b) sections of a cone-beam CT performed in a 7-year-old patient with mandibular CRMO. Axial (c) and coronal (d) sections of a CT scan obtained in a 10-year-old child with craniofacial FD. Both pathologies exhibit similar ground-glass appearance and osteolytic lesions.</figcaption></figure>

et al., 2007). The authors suggested that the diagnosis could be based on the presence of two major criteria among radiologically proven osteolytic/sclerotic bone lesions, multifocal bone lesions, palmoplantar pustulosis (PPP) or psoriasis, sterile bone biopsy with signs of inflammation and/or fibrosis, or sclerosis. Alternatively, it could be based on the presence of one of these major and three minor criteria among normal blood count, CRP and ESR mildly-to-moderately elevated, observation time longer than 6 months, hyperostosis, association with other autoimmune diseases aside from PPP or psoriasis, or Grade I or II relatives with autoimmune or autoinflammatory disease, or with non-bacterial osteomyelitis (Jansson et al., 2007). While the use of this classification in clinical practice could help to reduce misdiagnosis, it has not been validated in large cohorts of patients.

For other CRMO craniofacial locations, diagnosis could be even more difficult, since few descriptions have been published (Barrani et al., 2015; Mudri et al., 2022; Fraleigh et al., 2023). Our series confirmed that CRMO may occur not only in the mandible but also in other craniofacial bones. Regarding FD, the FD/MAS international consortium has produced best practice management guidelines for the diagnosis of, and therapeutic approaches to, the disease (Javaid et al., 2019). However, there are currently no defined clinical or radiological diagnostic criteria for FD. Bone biopsy is the cornerstone of definitive diagnosis; it is widely used in CRMO, particularly for confirming the absence of bacterial proliferation, and for showing signs of chronic bone inflammation (Wipff et al., 2015). The use of bone biopsy is more controversial in FD since it can lead to acute episodes of pain and inflammation, and is reserved for unusual or questionable cases (i.e. monostotic forms), or if a malignancy is suspected (Javaid et al., 2019). Testing for GNAS mutation has also been reserved for uncertain diagnosis, and false negatives

are not uncommon (Lee et al., 2012). A multidisciplinary approach involving surgeons, radiologists, and rheumatologists/endocrinologists is essential for carrying out diagnostic explorations and to avoid bone biopsies as far as possible.

Regarding the clinical symptoms, pain was mostly associated with CRMO and rarely found in FD – indeed, patients with FD could be asymptomatic. These results were consistent with those of Jia et al., who compared 37 patients with CRMO with 32 patients with FD in both adult and pediatric populations (Jia et al., 2021). The authors reported bone swelling to be rather specific to FD, whereas our study suggested that this symptom was present regardless of the pathology studied (Jia et al., 2021). Children with CRMO typically present with nonspecific bone pain at a single site, sometimes associated with localized inflammation signs, such as skin redness, warmth, or swelling (Zhao et al., 2021). Although trismus was not found in our series, it is possible when mandibular involvement occurs, and is due to edematous changes in masticatory muscles (Jia et al., 2021). The bone distension associated with FD is generally painless (Javaid et al., 2019), particularly in children, while pain is more frequent in adults and unrelated to the burden of the disease (Chapurlat et al., 2012; Kelly et al., 2008). Physical examination is essential when searching for secondary CRMO localizations, mainly in metaphyseal regions of long bones (typically femur or tibia), clavicle, vertebrae, and pelvic bones (Bhat et al., 2018), and to investigate any possible soft-tissue swelling, which is quite specific for the disease (Jia et al., 2021). Asthenia or altered growth could also appear during the course of CRMO.

Our study investigated the radiographic parameters of both diseases using direct comparison of imaging modalities by two experienced radiologists. CT appeared to be more powerful than CBCT and MRI in
<figure><img src="image_6.png" /><figcaption>**Fig. 2.** Axial (a) and coronal (b) sections of a CT scan in a 10-year-old girl with CRMO of the right zygomatic bone. The lesions present bone erosion, cortical interruption, and inflammation of the maxillary sinus mucosa. Axial (c) and coronal (d) sections of a CT scan performed in an 8-year-old boy with monostotic FD of the right zygomatic bone and corresponding pterygoid process, revealing hyperosteosis.</figcaption></figure>

differentiating between the two pathologies. Our results suggested that the ground-glass appearance, classically associated with FD, is relatively unspecific and could be found in CRMO, causing confounding radiological diagnosis. Erosive lesions with cortical interruption, periosteal apposition, and soft-tissue involvement were found to be more specific to CRMO than to FD. These results were in line with those obtained by Jia et al., showing cortical lysis, subperiosteal reaction, and poorly demarcated cortex to be more specific to CRMO (Jia et al., 2021). The same authors reported bone expansion to be more associated with FD (Jia et al., 2021), as in our study, which reported more cases of hyperosteosis in the FD group. With regard to the inflammatory signal in bone, MRI is probably more discriminating than we showed in this study, where very few patients benefited from this examination. Furthermore, MRI allows for a whole-body exploration, with no radiation generated, and has become the gold standard for exploring CRMO (Zhao and Ferguson, 2018; Khanna et al., 2009). Combining CT and MRI in patients should avoid diagnosis errancy; a combination of both examinations is recommended by the French national guidelines for craniofacial lesions of FD.

Assessing the diagnosis of CRMO and FD is essential because the two diseases do not share the same therapeutic management. Since CRMO is accompanied with immune dysregulation, it requires anti-inflammatory and immune modulators. NSAIDs are typically given as first-line treatment, with most patients experiencing a decrease in pain within a month (Beck et al., 2010; Zhao et al., 2017), but with heterogeneity in complete remission rates, ranging from 13% to 71% (Zhao et al., 2017). More recently, other therapies have emerged for treating CRMO children refractory to NSAIDs, including disease-modifying antirheumatic drugs (DMARDs) mostly represented by methotrexate (MTX) and

sulfasalazine, tumor necrosis factor inhibitors (TNFi), and bisphosphonates (Zhao et al., 2018). DMARDs have shown poor response rates (<40%) and poor tolerance of MTX, but more standardized studies are needed to assess their efficacy in CRMO (Zhao et al., 2017). TNFi are reserved for severe and refractory disease; despite good responses and better clinical remission than observed with MTX, reports of their efficacy have involved small cohort studies (Jansson et al., 2007; Wipff et al., 2015; Borzutzky et al., 2012). The use of pamidronate has also been reported in several studies, with good outcomes in pediatric patients refractory to first-line treatments (Miettunen et al., 2009; Gleeson et al., 2008; Simm et al., 2008). Although it has been used in the past, surgical treatment of CRMO, including decortication or tissue resection, is no longer part of the treatment strategy (Beck et al., 2023; Baltensperger et al., 2004).

Regarding FD, surgical treatment may be discussed on a case-by-case basis after the age of 16 in cases of facial deformity. Radical surgery can then be proposed in cases of removable lesion and with ease of reconstruction (Bouet et al., 2023), otherwise bone remodeling can be performed, but this is associated with a high recurrence rate (25%) (Bertin et al., 2020). However, optic decompression should be performed in cases of visual loss due to optic nerve involvement (Bertin et al., 2020; Satterwhite et al., 2015). Medical treatment of FD is reserved for severe forms with a high fracture risk, persistent moderate-to-severe bone pain as defined by a visual analog scale (VAS) score >3/10, or metabolic disorders (Javaid et al., 2019). This treatment is based on the use of antiresorptive agents, including bisphosphonates and, more recently, denosumab (Gun et al., 2024). Only one RCT has been performed, which failed to prove a significant improvement in pain in patients treated with an oral bisphosphonate (Boyce et al., 2014). Nevertheless, the overall
efficacy of intravenous bisphosphonates has been established in FD in terms of reducing bone remodeling, improving bone density, and reducing pain (Bertin et al., 2023). Recent studies have reported the use of denosumab with good outcomes, but this treatment is currently reserved for adults patients (Trojani et al., 2023; Castro et al., 2023; Van Der Bruggen et al., 2021).

Our study suffered from several limitations. The first lay in the retrospective design, which limited the clinical and therapeutic information that could be reported. Moreover, the point of entry for patients was shared between surgery and pediatrics, leading to misdiagnosis and missing investigations in the absence of clear recommendations. The small number of patients included in this study prevented any robust statistical analysis, but the two conditions remain rare diseases, whose analysis can only be descriptive. Finally, MRI examination was not available for most of the included patients, and analysis of the inflammatory signal would have been valuable. However, the analysis focused on the bone parameters on CT and CBCT, and followed a predefined framework, thus making this study valuable.

## 5. Conclusion

The results of this study improve the current knowledge on craniofacial presentation of CRMO and FD in children. The clinical and radiographic characteristics were compared between both diseases, highlighting swelling and pain as being more specific to CRMO, as well as erosive lesions, periosteal reaction, and soft-tissue infiltration in CT. FD lesions were less clinically striking and were usually associated with hyperostosis on imaging. Diagnostic and therapeutic management must be carried out by multidisciplinary teams, experienced in bone and metabolic disorders, whether to discuss the benefits of biopsy or to initiate medical treatment.

## Authors' contribution

Elise Le Coq: conceptualization, methodology, formal analysis, writing — original draft; Anne-Sophie Delemazure: formal analysis, writing — original draft; Emmanuelle Mourrain-Langlois: formal analysis, writing — original draft; Pierre Corre: writing — review and editing; Hélios Bertin: methodology, formal analysis, writing — review and editing; Soizic Tiriau: methodology, supervision, writing — review and editing.

## Declaration of generative AI and AI-assisted technologies in the writing process

None.

## Funding source

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

## Declaration of interest

None.

## Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.jcms.2025.01.032.

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