{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T03:24:25Z","timestamp":1783826665352,"version":"3.55.0"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T00:00:00Z","timestamp":1772841600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T00:00:00Z","timestamp":1776124800000},"content-version":"vor","delay-in-days":38,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Orphanet J Rare Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory disorder that may arise secondary to rheumatic diseases such as Still\u2019s disease, where macrophage activation syndrome (MAS) represents its clinical counterpart. The pathogenic significance of the PRF1 A91V variant remains uncertain, although functional data suggest partial perforin dysfunction and a possible contribution to late-onset or atypical HLH. This study aimed to clarify the clinical implications of the PRF1 A91V variant through a systematic review of published HLH and MAS cases and a comparative analysis with a single-center Still\u2019s disease cohort.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 20 studies, including 38 individual HLH or MAS cases carrying the PRF1 A91V variant, were identified. The median age at diagnosis was 22\u2009years, and 18.4% of patients were homozygous. Fever (82.6%), splenomegaly (57.9%), and hepatomegaly (36.8%) were the most frequent clinical findings. Anemia (57.1%) and thrombocytopenia (85.7%) were the predominant laboratory abnormalities, accompanied by marked hyperferritinemia (median 9319\u2009ng\/mL). Compared with 43 active Still\u2019s disease cases, PRF1-mutated HLH patients showed significantly higher rates of cytopenias, hepatomegaly, and central nervous system involvement, together with substantially elevated ferritin levels (9,193 vs 800\u2009ng\/mL,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0023), whereas C-reactive protein levels were comparable. Receiver-operating characteristic analysis identified a ferritin cutoff of 7000\u2009ng\/mL (sensitivity 63.2%, specificity 84.6%) as the optimal discriminator for PRF1 A91V positivity. In multivariate regression, ferritin\u2009\u2265\u20097,000\u2009ng\/mL remained the only independent predictor (OR 17.3, 95% CI 2.0\u2013146.3,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.009).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Patients carrying the PRF1 A91V variant represent a distinct subgroup within the spectrum of hyperinflammatory syndromes. Extreme hyperferritinemia combined with cytopenias should raise suspicion for perforin-related HLH rather than cytokine-driven MAS or classic Still\u2019s disease. Recognition of this variant as a risk-modifying allele may guide early genetic testing and therapeutic decisions, including consideration of advanced interventions in selected cases.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13023-026-04296-4","type":"journal-article","created":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T08:45:31Z","timestamp":1772873131000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Is a variant of uncertain significance always \u2018insignificant\u2019? A systematic review on PRF1 A91V in Hemophagocytic Lymphohistocytosis and comparative analysis with Still\u2019s disease"],"prefix":"10.1186","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0790-9519","authenticated-orcid":false,"given":"\u0130brahim Yahya","family":"\u00c7ak\u0131r","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8084-2018","authenticated-orcid":false,"given":"Abdulsamet","family":"Erden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3886-2813","authenticated-orcid":false,"given":"Ertu\u011frul \u00c7a\u011fr\u0131","family":"B\u00f6lek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3716-2989","authenticated-orcid":false,"given":"M. Fatih","family":"Mulayim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4100-8485","authenticated-orcid":false,"given":"Rahime","family":"Duran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4639-7464","authenticated-orcid":false,"given":"\u0130brahim","family":"Karaduman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7020-3511","authenticated-orcid":false,"given":"Esma","family":"Esero\u011flu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6184-7876","authenticated-orcid":false,"given":"Burak","family":"Karakaya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1139-5232","authenticated-orcid":false,"given":"B\u00fc\u015fra","family":"K\u00f6ksoy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4473-3932","authenticated-orcid":false,"given":"Ali","family":"Babazade","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4286-243X","authenticated-orcid":false,"given":"Gulsum","family":"Kayhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1206-4725","authenticated-orcid":false,"given":"Hamit","family":"K\u00fc\u00e7\u00fck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9696-0433","authenticated-orcid":false,"given":"Mehmet Ali","family":"Ergun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6244-9362","authenticated-orcid":false,"given":"Abdurrahman","family":"Tufan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7203-3934","authenticated-orcid":false,"given":"Mehmet Akif","family":"\u00d6zt\u00fcrk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,7]]},"reference":[{"issue":"3","key":"4296_CR1","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1038\/s41435-020-0098-4","volume":"21","author":"GS Schulert","year":"2020","unstructured":"Schulert GS, Cron RQ. The genetics of macrophage activation syndrome. Genes Immun. 2020, May;21(3):169\u201381.","journal-title":"Genes Immun"},{"issue":"2","key":"4296_CR2","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1002\/pbc.21039","volume":"48","author":"JI Henter","year":"2007","unstructured":"Henter JI, Horne A, Aric\u00f3 M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124\u201331.","journal-title":"Pediatr Blood Cancer"},{"issue":"4","key":"4296_CR3","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.blre.2014.03.002","volume":"28","author":"GE Janka","year":"2014","unstructured":"Janka GE, Lehmberg K. Hemophagocytic syndromes-an update. Blood Rev. 2014, Jul;28(4):135\u201342.","journal-title":"Blood Rev"},{"issue":"5","key":"4296_CR4","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1016\/j.hoc.2015.06.010","volume":"29","author":"A Ravelli","year":"2015","unstructured":"Ravelli A, Dav\u00ec S, Minoia F, Martini A, Cron RQ. Macrophage activation syndrome. Hematol Oncol Clin N Am. 2015, Oct;29(5):927\u201341.","journal-title":"Hematol Oncol Clin N Am"},{"issue":"5","key":"4296_CR5","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1093\/intimm\/dxy012","volume":"30","author":"GS Schulert","year":"2018","unstructured":"Schulert GS, Canna SW. Convergent pathways of the hyperferritinemic syndromes. Int Immunol. 2018, Apr, 25;30(5):195\u2013203.","journal-title":"Int Immunol"},{"issue":"5446","key":"4296_CR6","doi-asserted-by":"publisher","first-page":"1957","DOI":"10.1126\/science.286.5446.1957","volume":"286","author":"SE Stepp","year":"1999","unstructured":"Stepp SE, Dufourcq-Lagelouse R, Le Deist F, Bhawan S, Certain S, Mathew PA, et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science. 1999, Dec, 3;286(5446):1957\u201359.","journal-title":"Science"},{"issue":"12","key":"4296_CR7","doi-asserted-by":"publisher","first-page":"4700","DOI":"10.1182\/blood-2004-12-4935","volume":"105","author":"I Voskoboinik","year":"2005","unstructured":"Voskoboinik I, Thia MC, Trapani JA. A functional analysis of the putative polymorphisms A91V and N252S and 22 missense perforin mutations associated with familial hemophagocytic lymphohistiocytosis. Blood. 2005, Jun, 15;105(12):4700\u201306.","journal-title":"Blood"},{"issue":"6","key":"4296_CR8","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1038\/nri3839","volume":"15","author":"I Voskoboinik","year":"2015","unstructured":"Voskoboinik I, Whisstock JC, Trapani JA. Perforin and granzymes: function, dysfunction and human pathology. Nat Rev Immunol. 2015, Jun;15(6):388\u2013400.","journal-title":"Nat Rev Immunol"},{"issue":"3","key":"4296_CR9","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1093\/rheumatology\/kep418","volume":"49","author":"SJ Vastert","year":"2010","unstructured":"Vastert SJ, van Wijk R, D\u2019Urbano LE, de Vooght KMK, de Jager W, Ravelli A, et al. Mutations in the perforin gene can be linked to macrophage activation syndrome in patients with systemic onset juvenile idiopathic arthritis. Rheumatol Oxf Engl. 2010, Mar;49(3):441\u201349.","journal-title":"Rheumatol Oxf Engl"},{"key":"4296_CR10","doi-asserted-by":"crossref","unstructured":"Haddaway NR, Page MJ, Pritchard CC, McGuinness LA. PRISMA2020: an R package and shiny app for producing PRISMA 2020-compliant flow diagrams, with interactivity for optimised digital transparency and open synthesis. Campbell Syst Rev. 2022, Jun;18(2):e 1230.","DOI":"10.1002\/cl2.1230"},{"issue":"3","key":"4296_CR11","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1097\/00005792-200205000-00003","volume":"81","author":"B Fautrel","year":"2002","unstructured":"Fautrel B, Zing E, Golmard JL, Le Moel G, Bissery A, Rioux C, et al. Proposal for a new set of classification criteria for adult-onset still disease. Med (Baltim). 2002, May;81(3):194\u2013200.","journal-title":"Med (Baltim)"},{"issue":"3","key":"4296_CR12","first-page":"424","volume":"19","author":"M Yamaguchi","year":"1992","unstructured":"Yamaguchi M, Ohta A, Tsunematsu T, Kasukawa R, Mizushima Y, Kashiwagi H, et al. Preliminary criteria for classification of adult Still\u2019s disease. J Rheumatol. 1992, Mar;19(3):424\u201330.","journal-title":"J Rheumatol"},{"key":"4296_CR13","unstructured":"WMA - The world medical association-declaration of Helsinki [Internet]. [cited 2025 Oct 12]. Available from. https:\/\/www.wma.net\/what-we-do\/medical-ethics\/declaration-of-helsinki\/.\u00a0"},{"issue":"3","key":"4296_CR14","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1002\/art.39332","volume":"68","author":"A Ravelli","year":"2016","unstructured":"Ravelli A, Minoia F, Dav\u00ec S, Horne A, Bovis F, Pistorio A, et al. 2016 classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a European league against Rheumatism\/American college of Rheumatology\/Paediatric Rheumatology International trials organisation collaborative initiative. Arthritis Rheumatol. 2016, Mar;68(3):566\u201376.","journal-title":"Arthritis Rheumatol"},{"issue":"5","key":"4296_CR15","doi-asserted-by":"publisher","first-page":"129","DOI":"10.55563\/clinexprheumatol\/k7ri2l","volume":"39 Suppl 132","author":"H Yao","year":"2021","unstructured":"Yao H, Wang Y, Wang Z, Zhao J, Deng X, Zhang Z, et al. The performance of the diagnostic scoring system or criteria for macrophage activation syndrome in systemic juvenile idiopathic arthritis for adult-onset Still\u2019s disease. A multicentre case-control study in China. Clin Exp Rheumatol. 2021;39 Suppl 132(5):129\u201334.","journal-title":"Clin Exp Rheumatol"},{"key":"4296_CR16","unstructured":"Zhang K, Astigarraga I, Bryceson Y, Lehmberg K, Machowicz R, Marsh R, et al. Familial hemophagocytic lymphohistiocytosis. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews\u00ae [internet]. Seattle (WA), Seattle: University of Washington; 1993 [cited 2025 Oct 12]. Available from: http:\/\/www.ncbi.nlm.nih.gov\/books\/NBK1444\/."},{"issue":"5","key":"4296_CR17","doi-asserted-by":"publisher","first-page":"906","DOI":"10.1136\/annrheumdis-2016-210324","volume":"76","author":"MJ Ombrello","year":"2017","unstructured":"Ombrello MJ, Arthur VL, Remmers EF, Hinks A, Tachmazidou I, Grom AA, et al. Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: clinical and therapeutic implications. Ann Rheum Dis. 2017, May;76(5):906\u201313.","journal-title":"Ann Rheum Dis"},{"issue":"1","key":"4296_CR18","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1136\/annrheumdis-2019-215239","volume":"79","author":"Z Li","year":"2020","unstructured":"Li Z, Liu HL, Chen J, Zeng T, He L, Li M, et al. Both HLA class I and II regions identified as genome-wide significant susceptibility loci for adult-onset Still\u2019s disease in Chinese individuals. Ann Rheum Dis. 2020, Jan;79(1):161\u201363.","journal-title":"Ann Rheum Dis"},{"key":"4296_CR19","unstructured":"gnomAD [Internet]. [cited 2025 Oct 12]. Available from. https:\/\/gnomad.broadinstitute.org\/.\u00a0"},{"issue":"25","key":"4296_CR20","doi-asserted-by":"publisher","first-page":"2992","DOI":"10.1182\/blood.2024027954","volume":"145","author":"O Wegehaupt","year":"2025","unstructured":"Wegehaupt O, Borisov O, Sieni E, Oyen F, Mann J, Coniglio ML, et al. Beyond genotype: challenges in predicting disease risk for carriers of biallelic perforin variants. Blood. 2025, Jun, 19;145(25):2992\u20133006.","journal-title":"Blood"},{"issue":"6","key":"4296_CR21","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1038\/icb.2015.1","volume":"93","author":"IG House","year":"2015","unstructured":"House IG, Thia K, Brennan AJ, Tothill R, Dobrovic A, Yeh WZ, et al. Heterozygosity for the common perforin mutation, p.A91V, impairs the cytotoxicity of primary natural killer cells from healthy individuals. Immunol Cell Biol. 2015, Jul;93(6):575\u201380.","journal-title":"Immunol Cell Biol"},{"issue":"2","key":"4296_CR22","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1136\/jmg.2003.011528","volume":"41","author":"S Molleran Lee","year":"2004","unstructured":"Molleran Lee S, Villanueva J, Sumegi J, Zhang K, Kogawa K, Davis J, et al. Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis. J Med Genet. 2004, Feb;41(2):137\u201344.","journal-title":"J Med Genet"},{"issue":"3","key":"4296_CR23","doi-asserted-by":"publisher","first-page":"932","DOI":"10.1182\/blood-2004-09-3713","volume":"106","author":"C Trambas","year":"2005","unstructured":"Trambas C, Gallo F, Pende D, Marcenaro S, Moretta L, De Fusco C, et al. A single amino acid change, A91V, leads to conformational changes that can impair processing to the active form of perforin. Blood. 2005, Aug, 1;106(3):932\u201337.","journal-title":"Blood"},{"issue":"6","key":"4296_CR24","doi-asserted-by":"publisher","first-page":"1909","DOI":"10.1182\/blood-2004-02-0733","volume":"104","author":"U Zur Stadt","year":"2004","unstructured":"Zur Stadt U, Beutel K, Weber B, Kabisch H, Schneppenheim R, Janka G. A91V is a polymorphism in the perforin gene not causative of an FHLH phenotype. Blood. 2004, Sep, 15;104(6):1909; author reply 1910.","journal-title":"Blood"},{"key":"4296_CR25","unstructured":"Santoro A, Cannella S, Trizzino A, Lo Nigro L, Corsello G, Aric\u00f2 M. A single amino acid change A91V in perforin: a novel, frequent predisposing factor to childhood acute lymphoblastic leukemia? Haematologica. 2005 May;90(5):697\u201398. - Google\u2019da Ara [Internet]. [cited 2025 Oct 12]. Available from. https:\/\/www.google.com\/search?q=Santoro+A%2C+Cannella+S%2C+Trizzino+A%2C+Lo+Nigro+L%2C+Corsello+G%2C+Aric%C3%B2+M.+A+single+amino+acid+change+A91V+in+perforin%3A+a+novel%2C+frequent+predisposing+factor+to+childhood+acute+lymphoblastic+leukemia%3F+Haematologica.+2005+May%3B90(5)%3A697%E2%80%938.&oq=Santoro+A%2C+Cannella+S%2C+Trizzino+A%2C+Lo+Nigro+L%2C+Corsello+G%2C+Aric%C3%B2+M.+A+single+amino+acid+change+A91V+in+perforin%3A+a+novel%2C+frequent+predisposing+factor+to+childhood+acute+lymphoblastic+leukemia%3F+Haematologica.+2005+May%3B90(5)%3A697%E2%80%938.&gs_lcrp=EgZjaHJvbWUyBggAEEUYOdIBBzQ4NmowajSoAgCwAgE&sourceid=chrome&ie=UTF-8."},{"issue":"6","key":"4296_CR26","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1002\/pro.2265","volume":"22","author":"O An","year":"2013","unstructured":"An O, Gursoy A, Gurgey A, Keskin O. Structural and functional analysis of perforin mutations in association with clinical data of familial hemophagocytic lymphohistiocytosis type 2 (FHL2) patients. Protein Sci Publ Protein Soc. 2013, Jun;22(6):823\u201339.","journal-title":"Protein Sci Publ Protein Soc"},{"issue":"5","key":"4296_CR27","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1177\/00045632231186076","volume":"60","author":"P Sienes Bailo","year":"2023","unstructured":"Sienes Bailo P, Go\u00f1i Ros, Men\u00e9ndez J\u00e1ndula B, \u00c1lvarez Alegret R, Gonz\u00e1lez G\u00f3mez E, Gonz\u00e1lez Taranc\u00f3n R, et al. First case of very late-onset FHL2 in Spain with two variants in the PRF1 gene. Ann Clin Biochem. 2023, Sep;60(5):356\u201364.","journal-title":"Ann Clin Biochem"},{"issue":"22","key":"4296_CR28","doi-asserted-by":"publisher","first-page":"5794","DOI":"10.1182\/blood-2011-07-370148","volume":"118","author":"K Zhang","year":"2011","unstructured":"Zhang K, Jordan MB, Marsh RA, Johnson JA, Kissell D, Meller J, et al. Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood. 2011, Nov, 24;118(22):5794\u201398.","journal-title":"Blood"},{"issue":"6","key":"4296_CR29","doi-asserted-by":"publisher","first-page":"2266","DOI":"10.1182\/blood-2002-04-1030","volume":"100","author":"R Clementi","year":"2002","unstructured":"Clementi R, Emmi L, Maccario R, Liotta F, Moretta L, Danesino C, et al. Adult onset and atypical presentation of hemophagocytic lymphohistiocytosis in siblings carrying PRF1 mutations. Blood. 2002, Sep, 15;100(6):2266\u201367.","journal-title":"Blood"},{"issue":"5","key":"4296_CR30","doi-asserted-by":"publisher","first-page":"2762","DOI":"10.3390\/ijms25052762","volume":"25","author":"A Stadermann","year":"2024","unstructured":"Stadermann A, Haar M, Riecke A, Mayer T, Neumann C, Bauer A, et al. Late onset of primary hemophagocytic lymphohistiocytosis (HLH) with a novel constellation of compound Heterozygosity involving two missense variants in the PRF1 gene. Int J Mol Sci. 2024, Feb, 27;25(5):2762.","journal-title":"Int J Mol Sci"},{"issue":"6","key":"4296_CR31","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1002\/ajh.20878","volume":"82","author":"I Ueda","year":"2007","unstructured":"Ueda I, Kurokawa Y, Koike K, Ito S, Sakata A, Matsumora T, et al. Late-onset cases of familial hemophagocytic lymphohistiocytosis with missense perforin gene mutations. Am J Hematol. 2007, Jun;82(6):427\u201332.","journal-title":"Am J Hematol"},{"issue":"2","key":"4296_CR32","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1111\/j.1744-313X.2006.00582.x","volume":"33","author":"R Busiello","year":"2006","unstructured":"Busiello R, Fimiani G, Miano MG, Aric\u00f2 M, Santoro A, Ursini MV, et al. A91V perforin variation in healthy subjects and FHLH patients. Int J Immunogenet. 2006, Apr;33(2):123\u201325.","journal-title":"Int J Immunogenet"},{"issue":"3","key":"4296_CR33","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1111\/bjh.16660","volume":"190","author":"HS Jang","year":"2020","unstructured":"Jang HS, Flinsenberg TWH, Lacaze P, Thia KYT, Noori T, Fernando SL, et al. Recovery of natural killer cell cytotoxicity in a p.A91V perforin homozygous patient following severe haemophagocytic lymphohistiocytosis. Br J Haematol. 2020, Aug;190(3):458\u201361.","journal-title":"Br J Haematol"},{"key":"4296_CR34","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.jneuroim.2017.08.003","volume":"311","author":"B Palterer","year":"2017","unstructured":"Palterer B, Brugnolo F, Sieni E, Barilaro A, Parronchi P. Neuromyelitis optica, atypical hemophagocytic lymphohistiocytosis and heterozygous perforin A91V mutation. J Neuroimmunol. 2017, Oct, 15;311:10\u201313.","journal-title":"J Neuroimmunol"},{"issue":"2","key":"4296_CR35","doi-asserted-by":"publisher","first-page":"904","DOI":"10.3892\/etm.2021.10336","volume":"22","author":"A Bojan","year":"2021","unstructured":"Bojan A, Parvu A, Zsoldos IA, Torok T, Farcas AD. Macrophage activation syndrome: a diagnostic challenge (review). Exp Ther Med. 2021, Aug;22(2):904.","journal-title":"Exp Ther Med"},{"key":"4296_CR36","doi-asserted-by":"publisher","first-page":"1088525","DOI":"10.3389\/fped.2023.1088525","volume":"11","author":"HY Zhang","year":"2023","unstructured":"Zhang HY, Xiao M, Zhou D, Yan F, Zhang Y. Platelet and ferritin as early predictive factors for the development of macrophage activation syndrome in children with Kawasaki disease: a retrospective case-control study. Front Pediatr. 2023;11:1088525.","journal-title":"Front Pediatr"},{"issue":"1","key":"4296_CR37","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1093\/rheumatology\/keac247","volume":"62","author":"P Ruscitti","year":"2022","unstructured":"Ruscitti P, Ursini F, Berardicurti O, Masedu F, Bozzalla Cassione E, Naldi S, et al. Cytokine profile, ferritin and multi-visceral involvement characterize macrophage activation syndrome during adult-onset still\u2019s disease. Rheumatol Oxf Engl. 2022, Dec, 23;62(1):321\u201329.","journal-title":"Rheumatol Oxf Engl"},{"key":"4296_CR38","doi-asserted-by":"publisher","first-page":"750114","DOI":"10.3389\/fimmu.2021.750114","volume":"12","author":"T Shiga","year":"2021","unstructured":"Shiga T, Nozaki Y, Tomita D, Kishimoto K, Hirooka Y, Kinoshita K, et al. Usefulness of Interleukin-18 as a diagnostic biomarker to differentiate adult-onset Still\u2019s disease With\/Without macrophage activation syndrome from other secondary hemophagocytic lymphohistiocytosis in adults. Front Immunol. 2021;12:750114.","journal-title":"Front Immunol"}],"container-title":["Orphanet Journal of Rare Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13023-026-04296-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-026-04296-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-026-04296-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T19:33:22Z","timestamp":1781638402000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s13023-026-04296-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,7]]},"references-count":38,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["4296"],"URL":"https:\/\/doi.org\/10.1186\/s13023-026-04296-4","relation":{},"ISSN":["1750-1172"],"issn-type":[{"value":"1750-1172","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,7]]},"assertion":[{"value":"21 October 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 February 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 March 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was conducted in accordance with the principles of the Declaration of Helsinki. Ethical approval for the use of the Still\u2019s disease cohort was obtained from the Ankara University Faculty of Medicine Human Research Ethics Committee on October 25, 2024 (Application number: 2,024,000,624-1, Decision No: 2024\/624). Written informed consent was obtained from the patient included in the case presentation.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Written informed consent for publication of the clinical data was obtained from the individual patient described in this manuscript.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"150"}}