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Genetske značilnosti otrok s periodičnim vročinskim sindromom z aftami, tonzilitisom in adenitisom
Perko, Daša (Avtor), Avčin, Tadej (Mentor) Več o mentorju... Povezava se odpre v novem oknu, Debeljak, Maruša (Komentor)

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Izvleček
Avtoinflamatorne bolezni so heterogena skupina bolezni, za katere je značilno sterilno in kronično vnetje v odsotnosti specifičnih avtoprotiteles in antigen-specifičnih T celic. Periodični vročinski sindrom z aftami, faringitisom in adenitisom (PFAPA) je najpogostejša avtoinflamatorna bolezen pri otrocih. Na Pediatrični kliniki v Ljubljani je bilo od leta 2006 do konca leta 2016 diagnosticiranih 130 bolnikov. Za sindrom so značilni ponavljajoči se zagoni visoke vročine, afte, vnetje žrela in vratnih bezgavk. Simptomi se začnejo pojavljati v zgodnjem otroštvu, trajajo 2 do 7 dni in se periodično ponavljajo vsakih nekaj tednov. V času med zagoni otroci nimajo težav in v krvi nimajo prisotnih laboratorijskih znakov vnetja. Bolezen je dolgotrajna, vendar pa pri večini bolnikov izzveni pred puberteto brez posledic. PFAPA še vedno velja za sporadičen sindrom. Patogeneza bolezni do zdaj še ni bila pojasnjena, domnevajo pa, da je v patogenezo bolezni lahko vključena signalna pot preko inflamasoma AIM2. Hkrati vedno več študij govori v korist genetskemu ozadju bolezni. Namen naše raziskave je bila klinična opredelitev bolnikov s PFAPA, ki se vodijo na Pediatrični kliniki v Ljubljani, in dodatna pojasnitev patogeneze sindroma PFAPA na osnovi ugotovljenih genetskih značilnosti. Zaradi prekrivajoče klinične slike smo analizirali gene, ki so povezani z nastankom ostalih, dednih periodičnih vročinskih sindromov (MEFV, NLRP3, MVK, TNFRSF1A), ter gene, ki so se nam zaradi svojega delovanja in povišanega proteinskega nivoja pri bolnikih s PFAPA zdeli možni kandidatni geni (AIM2, PYCARD, SPAG7, SAA1, SAA2, CXCL10, CXCL9 in CXCR3). V raziskavo o kliničnih značilnostih smo vključili 114 bolnikov s sindromom PFAPA, 66 fantov in 48 deklet. Podatke smo pridobili iz razpoložljive medicinske dokumentacije. Pomemben del naše raziskave je bila tudi opredelitev pojavljanja bolezni PFAPA pri družinskih članih, kjer so rezultati pokazali, da ima 70 % bolnikov pozitivno družinsko anamnezo, pri čemer je imela polovica bolnikov več kot enega družinskega člana z anamnezo PFAPA. Ta ugotovitev govori v korist genetskemu ozadju bolezni. V raziskavo o genetskih značilnostih smo vključili 80 bolnikov, kjer smo z metodama PCR in sekvenčno reakcijo opredelili spremembe v preiskovanih genih, z metodo alelne diskriminacije pa smo določene spremembe opredelili tudi pri zdravih preiskovancih ter pri dodatnih 19 bolnikih s PFAPA. Skupno smo v 12 genih opredelili 83 različnih sprememb. Spremembe z možnim vplivom na vnetni proces so bile odkrite v genih MEFV, NLRP3, TNFRSF1A in CXCL10 pri 23 bolnikih. Sedem od teh bolnikov je imelo po dve različni spremembi. Večinoma so to spremembe, ki so bile odkrite pri bolnikih z drugimi dednimi periodičnimi vročinskimi sindromi oziroma bolnikih z drugimi imunsko pogojenimi boleznimi. Najbolj zanimiva je bila novoodkrita sprememba v genu NLRP3, p.Pro200Thr, odkrita pri dveh bolnikih, ki po analizi in silico s spletnim orodjem CADD velja za patološko. Domnevamo, da imajo te spremembe večinoma nizko penetranco in same niso zadostne za pojav tipične slike drugih avtoinflamatornih bolezni, zelo verjetno pa imajo vpliv na povečano dovzetnost za sprožitev vnetnega procesa in tako lahko prispevajo k patogenezi sindroma PFAPA. Na osnovi izsledkov raziskave sklepamo, da je PFAPA rezultat delovanja različnih sprememb z nizko penetranco in variabilno ekspresivnostjo v različnih genih v kombinaciji z epigenetskimi dejavniki in dejavniki iz okolja, ki skupaj vodijo v razvoj enotne klinične slike sindroma PFAPA.

Jezik:Slovenski jezik
Ključne besede:PFAPA, avtoinflamatorne bolezni, periodični vročinski sindrom, ponavljajoče vročine, afte, tonzilitis, adenitis, klinične značilnosti, genetske značilnosti, genetsko ozadje, inflamasom, spremembe z nizko penetranco, variabilna ekspresivnost
Vrsta gradiva:Doktorsko delo/naloga (mb31)
Organizacija:MF - Medicinska fakulteta
Leto izida:2019
Število ogledov:1014
Število prenosov:357
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Sekundarni jezik

Jezik:Angleški jezik
Naslov:Genetic characteristics of children with periodic fever, aphatous stomatitis, pharyngitis and adenitis
Izvleček:
Autoinflammatory diseases are a heterogeneous group of disorders, characterized by sterile and chronic inflammation in the absence of specific autoantibodies formation and antigen-specific T cells. Periodic fever syndrome with aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) represents the most common autoinflammatory disease of childhood. At the University Children’s Hospital Ljubljana, 130 patients were diagnosed with PFAPA from year 2006 to the end of year 2016. This clinical entity is characterized by recurrent episodes of high fever, aphthous stomatitis, pharyngitis and cervical adenitis. Symptoms begin in early childhood, lasting two to seven days and periodically repeat every few weeks. Patients are asymptomatic with normalization of laboratory markers during the remission. The disease is long-lasting, however, it generally resolves before puberty with no consequences for the patient. PFAPA is still considered as a sporadic disease. The pathogenesis of the disease has not yet been clarified, but it is presumed that the pathogenesis of the disease may include a signal pathway via AIM2 inflammasome. At the same time, more and more studies are in favor of the genetic background of the disease. The aim of our study was clinical evaluation of PFAPA patients from University Children’s Hospital Ljubljana and further clarification of pathogenesis of PFAPA syndrome based on established genetic characteristics. Due to the overlapping clinical picture, we analyzed genes associated with other hereditary periodic fever syndromes (MEFV, NLRP3, MVK, TNFRSF1A) and genes that, due to their action and elevated protein level in patients with PFAPA, could be potential candidate genes for PFAPA syndrome (AIM2, PYCARD, SPAG7, SAA1, SAA2, CXCL10, CXCL9 and CXCR3). 114 patients with PFAPA syndrome (66 boys and 48 girls), were included in the study on clinical characteristics. We obtained data from the available medical documentation. An important part of our study was the determination of the occurrence of PFAPA in family members of our patients, where the results showed that 70 % of our patients had positive family history. Furthermore, half of PFAPA patients had more than one family member with a history of PFAPA. This finding speaks in favor of the genetic background of the disease. In the study of genetic characteristics, 80 patients were included, where variants in the investigated genes were determined by the PCR method and Sanger sequencing. Allelic discrimination method was also used to determine certain genetic variants in healthy subjects and in additional 19 patients with PFAPA. In total, 83 genetic variants were identified in 12 genes. Variants with a possible effect on inflammatory process were detected in MEFV, NLRP3, TNFRSF1A and CXCL10 genes in 23 patients. Seven of these patients carried two different variants. These are mostly variants that have also been detected in patients with other hereditary periodic fever syndromes or patients with other immune diseases. The most interesting gene variant was the novel variant in the NLRP3 gene, p.Pro200Thr, found in two PFAPA patients, which was considered to be pathological after the in silica analysis with CADD online tool. We assume that these are all probably low-penetrant variants which are usually not sufficient for the appearance of a typical clinical picture of other autoinflammatory diseases. However, they are likely to have an impact on the increased susceptibility to inflammatory process and thus contribute to the pathogenesis of PFAPA syndrome. Based on the results of our study, we conclude that PFAPA syndrome is the result of the multiple low-penetrant gene variants with variable expressivity in different genes in combination with epigenetic factors and environmental factors leading to uniform clinical picture of PFAPA syndrome.

Ključne besede:PFAPA, autoinflammatory diseases, periodic fever syndrome, recurrent fever, aphthae, pharyngitis, adenitis, clinical characteristics, genetic characteristics, genetic background, inflammasome, low-penetrant variants, variable expressivity

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