The paediatric metaphysis is afflicted by a wide range of pathological processes as it is the most metabolically active and well-vascularised part of the developing skeleton. This review focuses on metaphyseal marrow signal change detected with magnetic resonance imaging, which is most often occult on radiographs. When bilateral, these imaging appearances frequently present a diagnostic quandary. This review assists the radiologist to confidently dismiss physiological signal change and confidently work through the differential diagnosis. This is achieved by illustrating a practical method of classifying signal change into four categories: physiological red marrow, red marrow reconversion, marrow infiltration, and oedema-like marrow signal intensity. In doing so, various pathological entities are reviewed along with imaging pearls and next-step investigations.

Chronic recurrent multifocal osteomyelitis (CRMO) is a non-infectious, inflammatory disorder of the bones. CRMO typically affects children, with a predisposition to females. Bone-related pain is often felt in the metaphysis of long bones, particularly of the lower extremities, but it can also target other sites at varied time intervals. Patients are likely to complain of tenderness and swelling that may cause considerable disability and adversely impact quality of life. There are three main pathophysiological mechanisms that have been hypothesized to drive CRMO including imbalanced cytokine expression, increased inflammasome activation, and enhanced osteoclast differentiation. Therapies have been based on targeting and suppressing these key players in CRMO patients. The first step in management involves pain control. Non-steroidal anti-inflammatory drugs should provide initial relief, albeit temporarily. It is imperative to initiate immunosuppressive medication that will help limit bone involvement and thereby prevent the development of fractures or leg-length discrepancies, for example. The purpose of this literature review is to study the pathophysiology of CRMO and carefully dissect the agents that have been previously employed in the management of CRMO patients. This could allow for the purposeful formulation of individualized care plans and improving the overall well-being of patients. The authors included a multitude of PubMed-indexed articles published from 2000 onwards in this review.

Autoinflammatory bone disorders are a group of diseases characterized by sterile osteomyelitis. This includes chronic nonbacterial osteomyelitis and the monogenic forms, Majeed syndrome and deficiency of the interleukin-1 receptor antagonist. These disorders result from innate immune system dysregulation and cytokine imbalance that triggers inflammasome activation causing downstream osteoclastogenesis and excessive bone remodeling. In this review, we will summarize the immunopathogenesis of pediatric autoinflammatory bone diseases with a special focus on the genetics and inborn errors of immunity, while briefly touching on the clinical manifestations and management of each disease as well as areas for future research.

Chronic recurrent multifocal osteomyelitis (CRMO) is a rare autoinflammatory disease, clinically characterized by chronic and recurrent episodes of osteoarticular inflammation, that generally presents in children and adolescents. From a dermatological point-of-view, CMRO can be associated with skin rashes mainly including psoriasis, palmoplantar pustulosis and acne. Pyoderma gangrenosum (PG) is a rare immune-mediated inflammatory skin disease classified within the spectrum of neutrophilic dermatoses that, in some cases, has been reported as cutaneous manifestation in CMRO patients. This paper presents a 16-year female patient diagnosed with CMRO, who presented PG lesions located on the lower leg, that arose after the administration of the tumour necrosis factor (TNF)-α inhibitor adalimumab. Cases of PG have been reported in patients being treated with certain medications, including TNF-α antagonists, leading to classified them in a setting aptly termed \"drug-induced PG.\" In this paper, we discuss the co-occurrence of PG and CRMO, in the light of recent evidence on the pathogenesis of both diseases and giving ample space to a literature review on drug induced PG. In our case, it is plausible that PG could be considered a cutaneous manifestation of CRMO, although the mechanisms underlying this intriguingly relationship remain to be fully unraveled.

Chronic non-bacterial osteomyelitis (CNO) is an autoinflammatory bone disorder mostly affecting children and adolescents. Although it is considered a rare disease, CNO is likely to be the single most common autoinflammatory bone disease in childhood, underdiagnosed and underreported due to a lack of awareness of the condition in both medics and patients and the absence of validated diagnostic criteria. The exact underlying pathogenesis of CNO remains unknown, making targeted treatment difficult. This issue is exacerbated by the lack of any randomised control trials, meaning that treatment strategies are based solely on retrospective reviews and case series. This review summarises the current concepts in pathophysiology, the clinical features that help differentiate important differential diagnoses, and an approach to investigating and managing children with CNO. Ultimately, the timely and thorough investigation of children and young people with CNO is vitally important to exclude important mimics and initiate appropriate management that can prevent the complications of persistent inflammatory bone disease.

We present a 9-year-old girl with persistent pain and swelling of the left wrist. X-ray, magnetic resonance imaging (MRI) and bone biopsy led to the diagnosis of chronic recurrent multifocal osteomyelitis (CRMO), affecting phalangeal and metacarpal bases and distal carpal bones on the ulnar side of the wrist. She was treated with non-steroidal anti-inflammatory drugs and complete remission with no long-term sequelae was achieved. CRMO is a rare auto-inflammatory condition with infrequent involvement of the hand. The current literature is discussed. The aim of this report is to raise awareness of the condition to reduce the time to diagnosis and unnecessary antibiotic treatment and to prevent permanent disability due to the progression of the disease. Level of Evidence: Level V (Therapeutic).

Chronic nonbacterial osteomyelitis (CNO) is a chronic, sterile, inflammatory disease. It primarily presents with nonspecific bone pain and swelling but ultimately can cause bone destruction and deformities, if left untreated. The involvement of the cranial bones (apart from the mandible) is rare in CNO. In this report, we present a rare case of CNO affecting facial and cranial bones presenting as facial palsy with a review of the literature about similar affection. A 10-year-old, previously healthy female was initially evaluated for swelling of the left side of her face with slight tenderness on palpation, but no fever. Her complete blood count was unremarkable, her inflammatory markers were elevated (C-reactive protein 7.5 mg/dl and erythrocyte sedimentation rate 104 mm/h), and CT of facial and skull bones and MRI of brain showed a destructive osseous process involving the left maxillary, zygomatic, sphenoid bones and the clivus. Bone biopsy of the left maxilla showed fibrous dysplasia with abscess formation, most consistent with an infectious aetiology (acute osteomyelitis). She was started on oral clindamycin for a 3-month course. The facial swelling improved after starting clindamycin, but on her sixth week of treatment, she developed right-sided Bell\'s palsy. An MRI of the brain showed hyperenhancement of the right seventh cranial nerve. A month later, she was evaluated for right wrist and knee swelling, pain, and limitation of movement. Skeletal survey and MRI showed multifocal lesions with mixed sclerosis and lucency. Her inflammatory markers continued to be elevated. Another bone biopsy of the right radius showed similar findings of destruction with no evidence of malignancy. She was ultimately diagnosed with CNO. She was started on nonsteroidal anti-inflammatory drugs with gastric protection and regular follow-up. Over more than a year of follow-up, the patient\'s inflammatory markers remain normal, and joint swelling/limitation has remained in remission. We found five additional cases in the literature that presented with a similar presentation. To our knowledge, our patient is the first reported case in the USA involving the cranial/facial bones apart from the mandible presenting with facial palsy. The affection of the facial bones (apart from the mandible) in CNO is very rare, but the awareness of such a presentation by the clinician is an important aspect of reaching the diagnosis.

Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory disorder primarily affecting children. It is characterized by a peripheral involvement of the metaphysis of long bones rather than axial involvement. Due to the scarcity of the disease, there are no guidelines regarding its management.
This review aims to provide an overview of the different therapeutic alternatives and recent protocols. For this reason, first-line and second-line treatment, as well as the impact of new therapies, are discussed in depth. We conducted a search through PubMed on the different aspects of CRMO. Outcomes were categorized as first and second-line treatments.
Non-steroidal anti-inflammatory drugs remain the keystone of CRMO management and are proposed as the first-line treatment. In the case of vertebral involvement, bisphosphonate should be considered, even as a first-line treatment. Several case series and retrospective studies highlight the efficacy of anti-TNF agents. Their use could be an optimal treatment choice for CRMO with comorbid immune-mediated diseases. The potentially favorable effect of interleukin-1 antagonists remains to be determined.

UNASSIGNED: Chronic recurrent multifocal osteomyelitis (CRMO) is a rare autoimmune disorder of childhood and adolescence which often manifests as recurring episodes of inflammatory bone pains. Spinal involvement is rare; however, recent studies advocate full body magnetic resonance imaging in all suspected cases to pick up asymptomatic lesions early to prevent complications. Spinal involvement may manifest as fractures, scoliosis, or kyphotic deformity.
UNASSIGNED: We present a case of a 12-year-old boy who had three-level involvement of thoracic spine, T6-T8, and was worked up and managed for pathological fracture of spine. He underwent biopsy for the same and was later diagnosed as CRMO. Here, we discuss the diagnostic challenges involved in CRMO, need for biopsy, and the management options available.
UNASSIGNED: Identifying CRMO is challenging and remains a diagnosis of exclusion. Nonsteroidal anti-inflammatory drugs often constitute the first line of treatment and other drugs such as bisphosphonates and biologics such as TNF-alpha antagonists are reserved for more severe cases. Although CRMO is considered a benign disease, recent data suggest up to 50% rate of residual impairments despite optimal management.

Majeed syndrome is a multi-system inflammatory disorder affecting humans that presents with chronic multifocal osteomyelitis, congenital dyserythropoietic anemia, with or without a neutrophilic dermatosis. The disease is an autosomal recessive disorder caused by mutations in LPIN2, the gene encoding the phosphatidic acid phosphatase LIPIN2. It is exceedingly rare. There are only 24 individuals from 10 families with genetically confirmed Majeed syndrome reported in the literature. The early descriptions of Majeed syndrome reported severely affected children with recurrent fevers, severe multifocal osteomyelitis, failure to thrive, and marked elevations of blood inflammatory markers. As more affected families have been identified, it has become clear that there is significant phenotypic variability. Data supports that disruption of the phosphatidic acid phosphatase activity in LIPIN2 results in immune dysregulation due to aberrant activation of the NLRP3 inflammasome and overproduction of proinflammatory cytokines including IL-1β, however, these findings did not explain the bone phenotype. Recent studies demonstrate that LPIN2 deficiency drives pro-inflammatory M2-macrophages and enhances osteoclastogenesis which suggest a critical role of lipin-2 in controlling homeostasis at the growth plate in an inflammasome-independent manner. While there are no approved medications for Majeed syndrome, pharmacologic blockade of the interleukin-1 pathway has been associated with rapid clinical improvement.