Update on the diagnosis and treatment of CNO in children: a clinician's perspective

Abstract

Chronic non-bacterial osteomyelitis (CNO) is caused by aseptic inflammation of bones, primarily driven by the innate immune system. CNO may display different clinical presentations (acute vs chronic, uni- vs multifocal) and is accompanied by other inflammatory disorders in up to a third of patients. Once considered a rare disorder, it has become clear that many patients were underdiagnosed. With increasing awareness and the development of total-body MRI protocols, CNO recognition and diagnosis have greatly improved. Our knowledge of the clinical manifestations and outcomes of CNO has been refined in recent years, especially thanks to the recruitment of large international series. Similarly, new insights into the pathogenesis have been gained by the development of mice models and identification of rare monogenic diseases that resemble CNO. Unfortunately, these advances have not been paralleled in the therapeutic management. In the absence of prospective controlled trials, therapeutic strategies still rely on low-level evidence studies. About half of the patients respond to first-line therapies, but a more refractory and/or chronic disease course requires additional treatments. This narrative review aims to provide the practicing physician with an update on CNO pathogenesis, clinical presentation, associated inflammatory conditions, and diagnostic investigations, and includes a concise summary of current therapeutic recommendations.

Conclusion: While major progresses have been made in the recognition and management of CNO, significant challenges remain, in particular regarding the treatment of refractory patients, and those with associated inflammatory disorders.

What is known: • Many physicians caring for children will encounter patients suffering of (suspected) CNO. CNO diagnosis requires exclusion of numerous conditions included in the differential diagnosis, which may be challenging.

What is new: • We provide an updated review of recent findings in the field CNO, including imaging and diagnostic strategies, associated inflammatory diseases and long-term outcomes data. • We focus particularly on the challenges encountered by clinicians in the diagnosis and treatment of these patients. • We highlight knowledge gaps in the understanding and treatment of CNO, that should stimulate future research.

Keywords: Chronic non-bacterial osteomyelitis; Chronic recurrent multifocal osteomyelitis.

Fig. 1

Histological features and spatial distribution of osteitis in CNO/CRMO. A-B. Bone tissue displays mixed inflammatory infiltration A, hyperostosis and sclerosis B in CNO/CRMO (courtesy of Prof. Christine Galant). C. Distribution of bone lesions in CNO/CRMO. Adapted from [48] and [18], two studies of 37 and 75 paediatric CNO/CRMO patients with systematic total body MRI. Figure prepared with the help of https://smart.servier.com/

Fig. 2

Typical aspect of CNO/CRMO Radiographs findings in CNO/CRMO (A-C). Typical CNO/CRMO lesion on the medial clavicle portion, with osteolysis and periosteal reaction (A, arrow). CNO/CRMO lesions of the 3rd and 5th metatarsal bones showing osteolysis and hyperostosis (B, arrows). Favorable evolution of the lesions after 1.5 years of treatment (C). MRI findings in CNO/CRMO (D-F): hyper intense signal (STIR-TSE sequence) in lower limbs epiphysis/metaphysis (D), thoracic spine (E), and clavicle (F). White arrows show osteitis. Panel D also demonstrates perilesional soft-tissue edema, and E spontaneous compression fracture of T9. G. Typical clinical aspect of clavicle CNO/CRMO involvement: sensitive (spontaneous or on palpation) or painless tumefaction of medial clavicle (arrowhead). H. Aseptic pustulosis on the back of a patient with clavicle CNO/CRMO. I: palmoplantar rash associated with CNO/CRMO

Fig. 3

Iconographic illustration of the imaging appearance of several conditions included in the differential diagnosis of CNO/CRMO A. Vertebral metastasis of neuroblastoma in a 10 years old boy. MRI (coronal 2D STIR), shows abnormal signal in vertebral bodies (arrow), vertebral collapse and peri-vertebral soft tissue mass (arrowhead). B. Femoral metastasis of neuroblastoma. Radiograph (left panel) shows irregular cortical thickening and heterogenous bone density (arrow). MRI (right panel,coronal T2 sequence) shows abnormal hyper-intense signal in the diaphysis with soft tissue extension (arrow). C. Spontaneous vertebral compression fractures in a toddler with leukemia. MRI (sagittal view T2) shows collapse of multiple vertebral bodies and discrete heterogeneity of the bone marrow signal (arrows). D. Langerhans cell histiocytosis in a 10 years old girl. MRI (STIR sequence) shows vertebra plana, bone marrow edema of posterior vertebral arch and extension to prevertebral soft tissues (arrow). E. Lymphoma in a 16-year-old female patient. MRI (sagittal STIR) of the cervicothoracic spine shows multiple foci of bone marrow replacement (arrows); extraosseous spread to epidural spaces (arrowheads) is not seen in benign inflammatory disease, but suggests multifocal tumor involvement of the skeleton. A targeted bone biopsy of a bone lesion confirmed the diagnosis of lymphoma. F. Vitamin C deficiency in a six years old boy. MRI image (coronal 2D STIR) shows homogenous, symmetrical high signal intensity of the bone marrow in distal femur and proximal tibia metaphyses (arrows). G-H. Osteoid osteoma in an adolescent. Coronal (G, STIR sequence) and axial (H, T2 SPAIR sequence) MRI views show extensive left calcaneum edema, associated with presence of a typical “nidus” (arrows)