Nova varijanta NLRP12 u bolesnika s autoinflamatornom bolešću izazvanom hladnoćom

Daniel Victor Šimac, Srđan Novak

The pathogenesis and genetics of systemic autoinflammatory diseases (SAIDs) are becoming clearer and more descriptive with time. When it comes to these diseases, it must be noted that familial Mediterranean fever (FMF) is still known as one of the most common and well-known diseases of this group. Strides have been made in the family of cryopyrin-associated periodic syndromes (CAPS), among others, including familial cold-induced autoinflammatory syndrome (FCAS ), in which the NLRP3 gene variants have been shown to be causative by disrupting interleukin (IL)- 1β secretion. In a subset of CAPS patients without causative NLRP3 variants, the NLRP12 gene, with its anti- and proinflammatory roles, has been shown to be causative in such patients. Common symptoms include fever, musculoskeletal and abdominal symptoms, and urticaria induced by the cold. Treatment includes non-steroidal anti- inflammatory drugs, antihistamines, and glucocorticoids. The case of a 40-year-old man with recurring fever and elevated Creactive
protein during winter months without any other clear cause after extensive work up is presented. Genetic testing was ordered under suspicion of SAID, and an NLRP12 gene variant, c.850C>G, was found, which was not described in any databases or reports to date. In silico testing did not show changes to the protein, but functional studies are unavailable. Despite this, we diagnosed our patient with NLRP12-associated SAID or FCAS 2. Acquired SAID, given the age, was considered, but unlikely given the clinical presentation, and the NLRP12 gene variant. Considering that the patient lives in a region that has mild winters, and the fact that the temperatures rarely go below 0 °C in this region, it is possible that this, in combination with an aging immune system, may explain why the patient did not manifest symptoms earlier. This case report presents a patient with a clinical presentation suggestive of CAPS or FCAS 2, with a
novel NLRP12 variant, c.850C>G, which is possibly causative. This case report also shows that novel variants are still being discovered, and that they should be researched if they are suspected in certain cases.

Patogeneza i genetika sustavnih autoinflamatornih bolesti (SAIB) danas postaje sve jasnija i opsežnija. Obiteljska mediteranska groznica je među najčešćim i najpoznatijim SAIB-ovima. Otkrićem varijanti gena NLRP3 koje dovode do poremećaja sekrecije interleukina (IL)-1β prati se napredak u razumijevanju obitelji periodičnih sindroma povezanih s kriopirinom (CAPS, prema engl. Cryopyrin-associated periodic syndrome), uključujući i obiteljski autoinflamatorni sindrom izazvan hladnoćom (FCAS , prema engl. Familial cold-induced autoinflammatory syndrome). U podskupini CAPS-a bez uzročnih varijanta NLRP3, pokazalo se da važnu ulogu ima gen NLRP12, koji ima protuupalnu i proupalnu ulogu. Uobičajeni simptomi uključuju vrućicu, mišićno-koštane i trbušne simptome te urtikariju izazvanu hladnoćom. Liječenje uključuje nesteroidne protuupalne lijekove, antihistaminike i glukokortikoide. Prikazan je slučaj muškarca u dobi od 40 godina s rekurentnim vrućicama i povišenim C-reaktivnim proteinom tijekom zimskih mjeseci bez drugoga jasnog uzroka nakon proširene obrade. Učinjeno je genetsko testiranje pod sumnjom na SAIB, koje je otkrilo novu varijantu u genu NLRP12, c.850C>G, koja do danas nije opisana ni u jednoj bazi podataka niti u literaturi. In silico ispitivanje nije dokazalo oštećenje proteina, te funkcijske studije nisu dostupne. Unatoč tomu postavili smo dijagnozu SAIB-a povezanu s NLRP12 ili FCAS 2. Zbog dobi pacijenta razmatrala se i stečena SAIB, ali s obzirom na kliničku sliku i na varijantu gena NLRP12, smatramo da je ona manje vjerojatna. Moguće objašnjenje zašto pacijent nije ranije razvio simptome jest blaže vrijeme u regiji u kojoj pacijent živi, gdje temperatura rijetko pada ispod 0°C, u kombinaciji sa „starenjem” imunološkog sustava. Prikaz slučaja opisuje pacijenta s kliničkom slikom koja je karakteristična za CAPS ili FCAS 2, uz novu varijantu gena NLRP12, c.850C>G, koja je mogući uzročnik bolesti. Nove varijante stalno se otkrivaju te kod karakteristične kliničke slike treba na njih posumnjati i istražiti ih.