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Another Disease Associated with MEFV Gene Mutations P.O Paediatric rheumatology Chronic non-bacterial osteomyelitis: another disease associated with MEFV gene mutations P.O. Avar-Aydin1, Z.B. Ozcakar1, N. Cakar1, S. Fitoz2, F. Yalcinkaya1 1Department of Paediatric Rheumatology, ABSTRACT Introduction 2Department of Paediatric Radiology, Objective. Chronic non-bacterial os- Chronic non-bacterial osteomyelitis Ankara University Faculty of Medicine, teomyelitis (CNO) is an autoinflamma- (CNO) is an autoinflammatory bone Ankara, Turkey. tory bone disease of unknown aetiolo- disease primarily of children and young Pinar Ozge Avar-Aydin, MD, MBA gy. The relationship between CNO and adults and it is characterised by sterile Zeynep Birsin Ozcakar, MD familial Mediterranean fever (FMF) inflammatory bone lesions. Its multifo- Nilgun Cakar, MD Suat Fitoz, MD is not clearly documented so far. This cal form with frequent relapses is called Fatos Yalcinkaya, MD cross-sectional study aims to evaluate chronic recurrent multifocal osteomy- Please address correspondence: the clinical and laboratory character- elitis (CRMO (1)). The aetiology of the Pinar Ozge Avar-Aydin, istics of a cohort of CNO patients with- disease is still not clear; however, some Department of Paediatric Rheumatology, in the context of its relationship with susceptibility genes and dysregulation Ankara University Faculty of Medicine, FMF and MEFV gene mutations. in the innate immune system have been 06000 Ankara, Turkey. Methods. Demographic and clinical shown (2-4). Persistent or relapsing E-mail: [email protected] data were extracted from electronic and remitting focal bone pain, absence Received on September 23, 2020; accepted medical records of patients with CNO. of constitutional symptoms, multifocal in revised form on November 12, 2020. The MEFV gene analysis was per- bone lesions on imaging with typical Clin Exp Rheumatol 2020; 38 (Suppl. 127): formed for all patients. lesion characteristics on typical loca- S112-S117. Results. A total number of 18 patients tions, and a personal and/or family © Copyright CLINICAL AND with CNO with a median follow-up history of CNO-associated disorders EXPERIMENTAL RHEUMATOLOGY 2020. of 36.50 (13.00-84.00) months were suggest a diagnosis of CNO although it included in the study. Five patients remains a diagnosis of exclusion (5, 6). Key words: chronic non-bacterial (27.8%) were found to have at least Supporting its genetic and pathogenic osteomyelitis, chronic recurrent one exon 10 mutations (four with bases, CNO has been frequently asso- multifocal osteomyelitis, familial M694V and one with M680I). Four ciated with a wide spectrum of inflam- Mediterranean fever, MEFV gene of them (22.2%) had homozygous or matory disorders, including but not compound heterozygous mutations of limited to inflammatory bowel disease the MEFV gene. Two patients had a (IBD), arthritis, and skin diseases (7). previous diagnosis of FMF and devel- Familial Mediterranean fever (FMF) is oped CNO while FMF was under con- a well-defined hereditary autoinflam- trol. Patients with MEFV mutations matory disease typically presented had an earlier onset of CNO, higher with recurrent and self-resolving epi- acute phase reactants, lower haemo- sodes of fever and serositis (8). The globin concentrations, and a higher responsible gene called the MEditer- number of bone lesions at disease on- ranean FeVer (MEFV) gene is located set with a persistent course of disease on chromosome 16p and encodes a more frequently. protein known as pyrin. The mutated Conclusion. Our results demonstrated pyrin causes augmented inflammation an increased frequency of MEFV gene with excessive IL-1β and NF-κβ secre- mutations in CNO and a more severe tion that induces a pro-inflammatory disease phenotype of CNO in patients condition both in patients with FMF with MEFV gene mutations. Physi- and in asymptomatic carriers of MEFV cians practicing in regions where FMF mutations (9). This pathogenetic prin- is prevalent should be aware of this re- ciple of the disease causes persistent Funding: departmental funds were used lationship and ask about the symptoms subclinical inflammation in a substan- for MEFV gene testing in patients without of FMF in detail in patients with CNO. tial portion of FMF patients, facilitates typical FMF presentation. Moreover, FMF should be included in the coexistence of other inflammatory Competing interests: none declared. CNO-associated conditions. diseases, and further, the MEFV gene S-112 Clinical and Experimental Rheumatology 2020 CNO with MEFV mutations / P.O. Avar.Aydin et al. carriers to be associated with totally contrast sagittal spin-echo T1-weight- 232-20). Signed informed consent was different inflammatory diseases other ed (T1W), coronal gradient-echo T1W, obtained from the patients and their than FMF (9-11). Several diseases coronal short tau inversion recovery parents. such as vasculitis, juvenile idiopathic (STIR), axial plane diffusion-weighted arthritis (JIA), and IBD have been as- single-shot echo-planar imaging (b- Statistical analysis sociated with FMF but CNO is not values of 0 and 1000 s/mm2). Contrast- The IBM SPSS Statistics 21.0 software one of those (10). Moreover, although enhanced coronal and sagittal plane (IBM Corp. Released 2012. IBM SPSS bone involvement is a widening spec- T1W images with a slice thickness of Statistics for Windows, version 21.0. trum of several hereditary autoinflam- 3 to 6 mm were obtained in patients Armonk, NY: IBM Corp) was used to matory diseases, the relation of CNO with abnormal signal changes in the perform statistical analysis. Results with FMF is not clearly reported (12). pre-contrast MR series. Regional MRI were described with mean ± standard Beginning from 2010, a few case re- protocol was composed of pre-contrast deviation (SD) or median (minimum- ports suggested a link between CNO T1W three plane imaging, coronal maximum) for continuous variables and FMF/MEFV gene mutations and STIR, axial fat-saturated T2-weight- and with frequency (n) and percentage the use of colchicine as a treatment op- ed (T2W), axial diffusion-weighted (%) for categorical variables. The Kol- tion for CNO (13-16). After persistent single-shot echo-planar imaging, and mogorov-Smirnov test was used to ex- and multifocal episodes of CNO have post-contrast three plane imaging with amine the data for normal distribution. developed in two of our patients with fat saturation. Radiologic images were One-way analysis of variance (ANO- FMF, we aimed to evaluate clinical evaluated by only one paediatric radi- VA) was used for homogeneity of the characteristics, treatment modalities, ologist (SF) experienced in CNO. variables, Student’s T-test was used for and response to therapies in a cohort of To classify patients, the clinical scoring parametric data. The Mann-Whitney CNO patients within the context of its system by Jansson et al. was used that U, ANOVA, and Spearman’s correla- relationship with FMF and MEFV gene had a positive predictive value over tion were used for non-parametric data. mutations. 97% for the diagnosis of CNO if the The correlation was considered mean- clinical CNO score was ≥39 (5). Treat- ingful if the correlation coefficient (rs) Materials and methods ment responses were evaluated accord- was >0.40. The statistical significance Patients with a diagnosis of CNO fol- ing to the clinical symptoms and imag- level was accepted as a p-value <0.05. lowed-up at the Department of Paedi- ing findings on MRI. Patients with only atric Rheumatology of Ankara Univer- one episode during the follow-up were Results sity School of Medicine were included accepted as “nonrecurrent” whereas Patient characteristics, laboratory in the study. Demographic and clinical those with relapses as “recurrent”. findings, and treatment modalities findings, results of blood tests, bone Patients who did not experience clini- A total number of 18 patients with CNO biopsies, bone marrow aspirations, and cal and radiological remission despite were included in the study. The demo- microbiological cultures, radiological therapies for 6 months were classified graphic, clinical, and laboratory char- findings, and treatment modalities were as “persistent”. Solitary lesions on acteristics of the patients with CNO are recorded from the electronic medical WBMRI were categorised as “unifo- presented in Table I. All patients had records of patients. The diagnosis of cal” and multiple lesions as “multifo- bone pain with a median diagnostic de- CNO was based on clinical symptoms cal”. Clinical remission was defined as lay time of 11.00 (2.00-48.00) months. and imaging features after the exclu- not having any symptoms for the last One patient had been treated with a sion of CNO-mimicking diseases, such 6 months and radiological remission as diagnosis of JIA three years before as infection and malignancy. Patients without any active lesions on WBMRI. the onset of CNO. Two patients had a with a possible diagnosis of CNO or Patients with a previous diagnosis of previous diagnosis of FMF and one of with a follow-up less than 6 months FMF according to Yalçınkaya criteria them also had IBD. None had a fam- were excluded. had already had the MEFV gene analy- ily history of CNO or CNO-associated Regional magnetic resonance imaging sis before the diagnosis of CNO (17). diseases whereas two patients had a (MRI), whole-body MRI (WBMRI), For others, the MEFV gene analysis family history of FMF. and bone scintigraphy, if WBMRI was performed. At least six mutations Four patients had persisting anaemia was not available, were used to assess in the MEFV gene including p.M694V, compatible with anaemia of chronic bone lesions. Whole-body MRI was p.M694I, p.M680I, p.V726A, disease. Fourteen patients had in- performed with 1.5 Tesla MR system p.E148Q, and p.K695R were analysed creased C-reactive protein (CRP) and (Achieva, Philips Healthcare, Best, by direct sequencing of the PCR-am- 10 had increased erythrocyte sedimen- The Netherlands). The coronal plane plified fragments for exon 10 muta- tation rate (ESR) at the time of diagno- was the principal plane by its extensive tions and by PCR-restriction fragment sis.
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