{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T05:48:16Z","timestamp":1790056096090,"version":"4.0.1"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"8","license":[{"start":{"date-parts":[[2017,9,21]],"date-time":"2017-09-21T00:00:00Z","timestamp":1505952000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["EH 145\/5-1"],"award-info":[{"award-number":["EH 145\/5-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SFB1160"],"award-info":[{"award-number":["SFB1160"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["TP1"],"award-info":[{"award-number":["TP1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["HE 3119\/10-1"],"award-info":[{"award-number":["HE 3119\/10-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["1 EO 0803"],"award-info":[{"award-number":["1 EO 0803"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Clin Immunol"],"published-print":{"date-parts":[[2017,11]]},"DOI":"10.1007\/s10875-017-0443-1","type":"journal-article","created":{"date-parts":[[2017,9,21]],"date-time":"2017-09-21T02:36:07Z","timestamp":1505961367000},"page":"770-780","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Effective Immunological Guidance of Genetic Analyses Including Exome Sequencing in Patients Evaluated for Hemophagocytic Lymphohistiocytosis"],"prefix":"10.1007","volume":"37","author":[{"name":"the HLH study of the GPOH","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0385-1890","authenticated-orcid":false,"given":"Sandra","family":"Ammann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Lehmberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Udo","family":"zur Stadt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Klemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian F. N.","family":"Bode","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten","family":"Speckmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gritta","family":"Janka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Wustrau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirzokhid","family":"Rakhmanov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilka","family":"Fuchs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans C.","family":"Hennies","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Ehl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,9,21]]},"reference":[{"key":"443_CR1","doi-asserted-by":"crossref","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;28:135\u201342.","journal-title":"Blood Rev"},{"key":"443_CR2","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1186\/1750-1172-8-168","volume":"8","author":"L Dotta","year":"2013","unstructured":"Dotta L, Parolini S, Prandini A, Tabellini G, Antolini M, Kingsmore SF, et al. Clinical, laboratory and molecular signs of immunodeficiency in patients with partial oculo-cutaneous albinism. Orphanet J Rare Dis. 2013;8:168.","journal-title":"Orphanet J Rare Dis"},{"key":"443_CR3","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1182\/blood-2010-07-298372","volume":"117","author":"J Pachlopnik Schmid","year":"2011","unstructured":"Pachlopnik Schmid J, Canioni D, Moshous D, et al. Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1\/SAP deficiency) versus type 2 (XLP-2\/XIAP deficiency). Blood. 2011;117:1522\u20139.","journal-title":"Blood"},{"key":"443_CR4","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.blre.2007.05.001","volume":"21","author":"GE Janka","year":"2007","unstructured":"Janka GE. Hemophagocytic syndromes. Blood Rev. 2007;21:245\u201353.","journal-title":"Blood Rev"},{"key":"443_CR5","doi-asserted-by":"crossref","first-page":"538","DOI":"10.3324\/haematol.2009.019562","volume":"95","author":"V Cetica","year":"2010","unstructured":"Cetica V, Pende D, Griffiths GM, Arico M. Molecular basis of familial hemophagocytic lymphohistiocytosis. Haematologica. 2010;95:538\u201341.","journal-title":"Haematologica"},{"key":"443_CR6","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1146\/annurev-med-041610-134208","volume":"63","author":"GE Janka","year":"2012","unstructured":"Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Annu Rev Med. 2012;63:233\u201346.","journal-title":"Annu Rev Med"},{"key":"443_CR7","doi-asserted-by":"crossref","first-page":"978","DOI":"10.3324\/haematol.2014.121608","volume":"100","author":"SF Bode","year":"2015","unstructured":"Bode SF, Ammann S, Al-Herz W, et al. The syndrome of hemophagocytic lymphohistiocytosis in primary immunodeficiencies: implications for differential diagnosis and pathogenesis. Haematologica. 2015;100:978\u201388.","journal-title":"Haematologica"},{"key":"443_CR8","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1182\/asheducation-2013.1.605","volume":"2013","author":"GE Janka","year":"2013","unstructured":"Janka GE, Lehmberg K. Hemophagocytic lymphohistiocytosis: pathogenesis and treatment. Hematol Am Soc Hematol Educ Progr. 2013;2013:605\u201311.","journal-title":"Hematol Am Soc Hematol Educ Progr"},{"key":"443_CR9","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1002\/pbc.21039","volume":"48","author":"JI Henter","year":"2007","unstructured":"Henter JI, Horne A, Arico M, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124\u201331.","journal-title":"Pediatr Blood Cancer"},{"key":"443_CR10","doi-asserted-by":"crossref","first-page":"e743","DOI":"10.1542\/peds.2005-1789","volume":"117","author":"M Ouachee-Chardin","year":"2006","unstructured":"Ouachee-Chardin M, Elie C, de Saint BG, et al. Hematopoietic stem cell transplantation in hemophagocytic lymphohistiocytosis: a single-center report of 48 patients. Pediatrics. 2006;117:e743\u201350.","journal-title":"Pediatrics"},{"key":"443_CR11","doi-asserted-by":"crossref","first-page":"1694","DOI":"10.3324\/haematol.13142","volume":"93","author":"S Cesaro","year":"2008","unstructured":"Cesaro S, Locatelli F, Lanino E, et al. Hematopoietic stem cell transplantation for hemophagocytic lymphohistiocytosis: a retrospective analysis of data from the Italian Association of Pediatric Hematology Oncology (AIEOP). Haematologica. 2008;93:1694\u2013701.","journal-title":"Haematologica"},{"key":"443_CR12","doi-asserted-by":"crossref","first-page":"2754","DOI":"10.1182\/blood-2011-08-374199","volume":"119","author":"YT Bryceson","year":"2012","unstructured":"Bryceson YT, Pende D, Maul-Pavicic A, et al. A prospective evaluation of degranulation assays in the rapid diagnosis of familial hemophagocytic syndromes. Blood. 2012;119:2754\u201363.","journal-title":"Blood"},{"key":"443_CR13","doi-asserted-by":"crossref","first-page":"1858","DOI":"10.1182\/blood-2015-06-648659","volume":"126","author":"M Abdalgani","year":"2015","unstructured":"Abdalgani M, Filipovich AH, Choo S, Zhang K, Gifford C, Villanueva J, et al. Accuracy of flow cytometric perforin screening for detecting patients with FHL due to PRF1 mutations. Blood. 2015;126:1858\u201360.","journal-title":"Blood"},{"key":"443_CR14","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1002\/cytob.21166","volume":"86","author":"CE Gifford","year":"2014","unstructured":"Gifford CE, Weingartner E, Villanueva J, Johnson J, Zhang K, Filipovich AH, et al. Clinical flow cytometric screening of SAP and XIAP expression accurately identifies patients with SH2D1A and XIAP\/BIRC4 mutations. Cytometry B Clin Cytom. 2014;86:263\u201371.","journal-title":"Cytometry B Clin Cytom"},{"key":"443_CR15","doi-asserted-by":"publisher","unstructured":"Rubin TS, Zhang K, Gifford C, Lane A, Bleesing JJ, Marsh RA. Perforin and CD107a testing are superior to NK cell function testing for screening patients for genetic HLH. Blood. 2017. https:\/\/doi.org\/10.1182\/blood-2016-12-753830 .","DOI":"10.1182\/blood-2016-12-753830"},{"key":"443_CR16","doi-asserted-by":"publisher","unstructured":"Cetica V, Sieni E, Pende D, et al. Genetic predisposition to hemophagocytic lymphohistiocytosis: report on 500 patients from the Italian registry. J Allergy Clin Immunol. 2015; https:\/\/doi.org\/10.1016\/j.jaci.2015.06.048 .","DOI":"10.1016\/j.jaci.2015.06.048"},{"key":"443_CR17","doi-asserted-by":"crossref","first-page":"5783","DOI":"10.1182\/blood-2011-07-369090","volume":"118","author":"M Meeths","year":"2011","unstructured":"Meeths M, Chiang SC, Wood SM, et al. Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) caused by deep intronic mutation and inversion in UNC13D. Blood. 2011;118:5783\u201393.","journal-title":"Blood"},{"key":"443_CR18","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1111\/bjh.12371","volume":"162","author":"M Entesarian","year":"2013","unstructured":"Entesarian M, Chiang SC, Schlums H, Meeths M, Chan MY, Mya SN, et al. Novel deep intronic and missense UNC13D mutations in familial haemophagocytic lymphohistiocytosis type 3. Br J Haematol. 2013;162:415\u20138.","journal-title":"Br J Haematol"},{"key":"443_CR19","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1093\/hmg\/ddi076","volume":"14","author":"U Stadt zur","year":"2005","unstructured":"zur Stadt U. Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. Hum Mol Genet. 2005;14:827\u201334.","journal-title":"Hum Mol Genet"},{"key":"443_CR20","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.1016\/j.jaci.2014.08.039","volume":"135","author":"V Cetica","year":"2015","unstructured":"Cetica V, Hackmann Y, Grieve S, et al. Patients with Griscelli syndrome and normal pigmentation identify RAB27A mutations that selectively disrupt MUNC13-4 binding. J Allergy Clin Immunol. 2015;135:1310\u20138.e1.","journal-title":"J Allergy Clin Immunol"},{"key":"443_CR21","doi-asserted-by":"publisher","unstructured":"Ammann S, Schulz A, Kr\u00e4geloh-Mann I, et al. Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome. Blood. 2016; https:\/\/doi.org\/10.1182\/blood-2015-09-671636 .","DOI":"10.1182\/blood-2015-09-671636"},{"key":"443_CR22","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/sj.bmt.1705727","volume":"40","author":"L Scrucca","year":"2007","unstructured":"Scrucca L, Santucci A, Aversa F. Competing risk analysis using R: an easy guide for clinicians. Bone Marrow Transplant. 2007;40:381\u20137.","journal-title":"Bone Marrow Transplant"},{"key":"443_CR23","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1007\/s00431-014-2338-y","volume":"173","author":"R Taurisano","year":"2014","unstructured":"Taurisano R, Maiorana A, De Benedetti F, Dionisi-Vici C, Boldrini R, Deodato F. Wolman disease associated with hemophagocytic lymphohistiocytosis: attempts for an explanation. Eur J Pediatr. 2014;173:1391\u20134.","journal-title":"Eur J Pediatr"},{"key":"443_CR24","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1111\/bjh.12138","volume":"160","author":"K Lehmberg","year":"2013","unstructured":"Lehmberg K, Ehl S. Diagnostic evaluation of patients with suspected haemophagocytic lymphohistiocytosis. Br J Haematol. 2013;160:275\u201387.","journal-title":"Br J Haematol"},{"key":"443_CR25","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1016\/j.ajhg.2009.09.005","volume":"85","author":"U Stadt zur","year":"2009","unstructured":"zur Stadt U, Rohr J, Seifert W, et al. Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11. Am J Hum Genet. 2009;85:482\u201392.","journal-title":"Am J Hum Genet"},{"key":"443_CR26","doi-asserted-by":"crossref","first-page":"3765","DOI":"10.1172\/JCI40732","volume":"119","author":"M Cote","year":"2009","unstructured":"Cote M, Menager MM, Burgess A, et al. Munc18-2 Deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells. J Clin Invest. 2009;119:3765\u201373.","journal-title":"J Clin Invest"},{"key":"443_CR27","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/joim.12399","volume":"279","author":"H Stranneheim","year":"2016","unstructured":"Stranneheim H, Wedell A. Exome and genome sequencing: a revolution for the discovery and diagnosis of monogenic disorders. J Intern Med. 2016;279:3\u201315.","journal-title":"J Intern Med"},{"key":"443_CR28","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1038\/nm1189","volume":"11","author":"KE Nichols","year":"2005","unstructured":"Nichols KE, Hom J, Gong S-Y, Ganguly A, Ma CS, Cannons JL, et al. Regulation of NKT cell development by SAP, the protein defective in XLP. Nat Med. 2005;11:340\u20135.","journal-title":"Nat Med"},{"key":"443_CR29","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1111\/cei.12306","volume":"176","author":"S Ammann","year":"2014","unstructured":"Ammann S, Elling R, Gyrd-Hansen M, et al. A new functional assay for the diagnosis of X-linked inhibitor of apoptosis (XIAP) deficiency. Clin Exp Immunol. 2014;176:394\u2013400.","journal-title":"Clin Exp Immunol"},{"key":"443_CR30","doi-asserted-by":"publisher","unstructured":"Meeths M, Horne A, Sabel M, Bryceson YT, Henter JI. Incidence and clinical presentation of primary hemophagocytic lymphohistiocytosis in Sweden. Pediatr Blood Cancer. 2014; https:\/\/doi.org\/10.1002\/pbc.25308 .","DOI":"10.1002\/pbc.25308"},{"key":"443_CR31","doi-asserted-by":"crossref","first-page":"e536","DOI":"10.1016\/S2352-3026(15)00223-9","volume":"2","author":"A Lofstedt","year":"2015","unstructured":"Lofstedt A, Chiang SC, Onelov E, Bryceson YT, Meeths M, Henter JI. Cancer risk in relatives of patients with a primary disorder of lymphocyte cytotoxicity: a retrospective cohort study. Lancet Haematol. 2015;2:e536\u201342.","journal-title":"Lancet Haematol"},{"key":"443_CR32","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1182\/blood-2014-11-610816","volume":"125","author":"WA Spessott","year":"2015","unstructured":"Spessott WA, Sanmillan ML, McCormick ME, Patel N, Villanueva J, Zhang K, et al. Hemophagocytic lymphohistiocytosis caused by dominant-negative mutations in STXBP2 that inhibit SNARE-mediated membrane fusion. Blood. 2015;125:1566\u201377.","journal-title":"Blood"},{"key":"443_CR33","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.1182\/blood-2007-02-072850","volume":"110","author":"I Voskoboinik","year":"2007","unstructured":"Voskoboinik I, Sutton VR, Ciccone A, House CM, Chia J, Darcy PK, et al. Perforin activity and immune homeostasis: the common A91V polymorphism in perforin results in both presynaptic and postsynaptic defects in function. Blood. 2007;110:1184\u201390.","journal-title":"Blood"},{"key":"443_CR34","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.humimm.2012.10.011","volume":"74","author":"N Martinez-Pomar","year":"2013","unstructured":"Martinez-Pomar N, Lanio N, Romo N, Lopez-Botet M, Matamoros N. Functional impact of A91V mutation of the PRF1 perforin gene. Hum Immunol. 2013;74:14\u20137.","journal-title":"Hum Immunol"},{"key":"443_CR35","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1097\/ACI.0b013e3283588ca6","volume":"12","author":"J Chou","year":"2012","unstructured":"Chou J, Ohsumi TK, Geha RS. Use of whole exome and genome sequencing in the identification of genetic causes of primary immunodeficiencies. Curr Opin Allergy Clin Immunol. 2012;12:623\u20138.","journal-title":"Curr Opin Allergy Clin Immunol"}],"container-title":["Journal of Clinical Immunology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/article\/10.1007\/s10875-017-0443-1\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s10875-017-0443-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s10875-017-0443-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,10,3]],"date-time":"2019-10-03T15:48:33Z","timestamp":1570117713000},"score":1,"resource":{"primary":{"URL":"http:\/\/link.springer.com\/10.1007\/s10875-017-0443-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,9,21]]},"references-count":35,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2017,11]]}},"alternative-id":["443"],"URL":"https:\/\/doi.org\/10.1007\/s10875-017-0443-1","relation":{},"ISSN":["0271-9142","1573-2592"],"issn-type":[{"value":"0271-9142","type":"print"},{"value":"1573-2592","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,9,21]]}}}