ICCBH2019 Poster Presentations (1) (226 abstracts)
Next-generation sequence and biomarker levels in the patients with early-onset chronic non-bacterial osteomyelitis from North Caucasian region of Russia
Mikhail Kostik 1 , Maria Makhova 1 , Evgeny Suspitsin 1, , Anna Sokolenko 1, , Vyacheslav Zorin 3 , Eugenia Isupova 1 , Shamai Magomedova 4, , Inna Kostik 6 , Hiroshi Takayanagi 7 , Alexander Mushkin 3 & Evgeny Imyanitov 1,
1Saint-Petersburg State Pediatric Medical University, Saint-Petersburg, Saint-Petersburg, Russian Federation; 2N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia; 3Science research Institute of Phthisiopulmonology, Saint-Petersburg, Russia; 4Republican Children’s Clinical Hospital, Makhachkala, Russia; 5Dagestan State Medical Academy, Makhachkala, Russia; 6Children’s Rehabilitation Center Detskye Duny, Saint-Petersburg, Russia; 7The University of Tokyo, Tokyo, Japan.
Objectives: Chronic non-bacterial osteomyelitis (CNO) is a heterogenic group of immune-mediated inflammatory bone diseases with unclear pathogenesis. Only a few genes associated with this condition have identified. The aim of the study was to evaluate the spectrum of mutations in genes associated with primary immunodeficiency syndromes (PIDs) and autoinflammatory diseases (AIDs) in the cohort of patients with early-onset CNO from North Caucasus (Dagestan and Chechnya) and assessment of new biomarkers.
Methods: We selected a subgroup of the CNO patients (n=22) having the following features: 1) early disease onset (<5 years); 2) all children were initially diagnosed as having tuberculosis (TB) due to bone morphology findings (granulomatosis, e.g. tuberculosis-like inflammation), but had negative TB culture test; 3) initial treatment with a combination of 3–4 anti-MBT drugs during 1–2 years was ineffective, and the patient continued to develop new inflammatory bone foci; 4) all patients were from areas with traditionally high prevalence of consanguinity. Targeted next-generation sequencing analysis of 302 genes related to PIDs and AIDs was performed. In each patient, we evaluated calprotectin, interleukin-6, and 14-3-3 protein level. Control group were five healthy children.
Results: Rare variants of PID genes were detected in 7/22 (32%) patients. Mutations affecting the genes previously associated with CNO were found only in two patients: one of them carried heterozygous variant IL1RN c.170G>T (p.C57F), and another had IL1RN c.512T>C (p.V171A). No mutation of LPIN2 was revealed. Other detected variants included one pathogenic MEFV p.M694V mutation in the heterozygous state and some VUS in CD40LG, NLRP12, CR2, NLRP3, IL12B, PLCG2, SH3BP2, CARD14, IRF8, CASP10, and NFKB1A genes. In CNO patients levels of calprotectin was 5.9 (5.2–6.7) vs 0.75 (0.68–0.84) ng/ml, P=0.000003; interleukin-6 – 45.5 (40.0–51.0) vs 4.0 (3.2–4.9) ng/ml, P=0.000003; 14-3-3 protein – 19.9 (18.3–27.1) vs 2.4 (1.5–5.1) ng/ml, P=0.000003 compare to controls.
Conclusion: Mutations in known genes were detected only in a minor fraction of CNO patients from Dagestan and Chechnya. Further investigations required for biomarkers validation.
This work supported by the Russian Foundation for Basic Research (grant Nº 18-515-57001) and by Japan Medical Research Foundation (grant Nº 18jmrf001).
Disclosure: The authors declared no competing interests.
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