{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:11:55Z","timestamp":1753891915682,"version":"3.41.2"},"reference-count":24,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,18]],"date-time":"2021-03-18T00:00:00Z","timestamp":1616025600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100001245","name":"Jeffrey Modell Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001245","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:p>Autoimmune Lymphoproliferative Syndrome (ALPS), commonly caused by mutations in the <jats:italic>FAS<\/jats:italic> gene, is a disease with variable penetrance. Subjects may be asymptomatic, or they may present with lymphadenopathy, splenomegaly, cytopenias, or malignancy. Prompt recognition of ALPS is needed for optimal management. We describe a multi-generational cohort presenting with clinical manifestations of ALPS, and a previously unreported heterozygous missense variant of uncertain significance in <jats:italic>FAS<\/jats:italic> (c.758G &amp;gt;T, p.G253V), located in exon 9. Knowledge of the underlying genetic defect permitted prompt targeted therapy to treat acute episodes of cytopenia. This cohort underscores the importance of genetic testing in subjects with clinical features of ALPS and should facilitate the reclassification of this variant as pathogenic.<\/jats:p>","DOI":"10.3389\/fped.2021.624116","type":"journal-article","created":{"date-parts":[[2021,3,18]],"date-time":"2021-03-18T05:40:20Z","timestamp":1616046020000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Case Report: A Novel Pathogenic Missense Mutation in FAS: A Multi-Generational Case Series of Autoimmune Lymphoproliferative Syndrome"],"prefix":"10.3389","volume":"9","author":[{"given":"Claudia L.","family":"Gaefke","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"Metts","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donya","family":"Imanirad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daime","family":"Nieves","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paola","family":"Terranova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gianluca","family":"Dell'Orso","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eleonora","family":"Gambineri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maurizio","family":"Miano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard F.","family":"Lockey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jolan Eszter","family":"Walter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma","family":"Westermann-Clark","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,18]]},"reference":[{"volume-title":"Case Studies in Immunology: A Clinical Companion. 7th Edition edn","year":"2016","author":"Geha","key":"B1"},{"key":"B2","doi-asserted-by":"publisher","first-page":"e35","DOI":"10.1182\/blood-2010-04-280347","article-title":"Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop","volume":"116","author":"Oliveira","year":"2010","journal-title":"Blood."},{"key":"B3","doi-asserted-by":"publisher","first-page":"4798","DOI":"10.1182\/blood-2011-04-347641","article-title":"A survey of 90 patients with autoimmune lymphoproliferative syndrome related to TNFRSF6 mutation","volume":"118","author":"Neven","year":"2011","journal-title":"Blood."},{"key":"B4","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1097\/MOP.0000000000000833","article-title":"Autoimmunity as a continuum in primary immunodeficiency","volume":"31","author":"Walter","year":"2019","journal-title":"Curr Opin Pediatr."},{"key":"B5","doi-asserted-by":"publisher","first-page":"E175","DOI":"10.1002\/ajh.25119","article-title":"Sirolimus as a rescue therapy in children with immune thrombocytopenia refractory to mycophenolate mofetil","volume":"93","author":"Miano","year":"2018","journal-title":"Am J Hematol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1111\/bjh.13533","article-title":"Mycophenolate mofetil and Sirolimus as second or further line treatment in children with chronic refractory Primitive or Secondary Autoimmune Cytopenias: a single centre experience","volume":"171","author":"Miano","year":"2015","journal-title":"Br J Haematol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"3908","DOI":"10.1182\/blood.V116.21.3908.3908","article-title":"Causes and Consequences of Splenectomy In ALPS-FAS","volume":"116","author":"Price","year":"2010","journal-title":"Blood."},{"key":"B8","doi-asserted-by":"publisher","first-page":"119","DOI":"10.2214\/ajr.157.1.2048509","article-title":"Normal splenic size in infants and children: sonographic measurements","volume":"157","author":"Rosenberg","year":"1991","journal-title":"AJR Am J Roentgenol."},{"key":"B9","unstructured":"Mayo Foundation for Medical Education ResearchMayo Clinic Laboratories Pediatric Catalog Immunoglobulins Serum2020"},{"key":"B10","unstructured":"Mayo Medical LaboratoriesComplete Blood Count Normal Pediatric Values2020"},{"key":"B11","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1016\/j.jaci.2003.07.003","article-title":"Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study","volume":"112","author":"Shearer","year":"2003","journal-title":"J Allergy Clin Immunol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1002\/cyto.a.22520","article-title":"Lymphocytes subsets reference values in childhood","volume":"87","author":"Tosato","year":"2015","journal-title":"Cytometry A."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1097\/MOP.0b013e32834ea739","article-title":"New advances in the diagnosis and treatment of autoimmune lymphoproliferative syndrome","volume":"24","author":"Teachey","year":"2012","journal-title":"Curr Opin Pediatr."},{"key":"B14","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1182\/blood.v98.1.194","article-title":"The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis","volume":"98","author":"Straus","year":"2001","journal-title":"Blood."},{"key":"B15","first-page":"2575","article-title":"Lymphoproliferative syndrome with autoimmunity: A possible genetic basis for dominant expression of the clinical manifestations","volume":"94","author":"Rieux-Laucat","year":"1999","journal-title":"Blood."},{"key":"B16","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1016\/s0022-3476(98)70102-7","article-title":"The clinical spectrum in a large kindred with autoimmune lymphoproliferative syndrome caused by a Fas mutation that impairs lymphocyte apoptosis","volume":"133","author":"Infante","year":"1998","journal-title":"J Pediatr."},{"key":"B17","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med."},{"key":"B18","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1007\/s40272-016-0175-3","article-title":"Optimal management of autoimmune lymphoproliferative syndrome in children","volume":"18","author":"George","year":"2016","journal-title":"Paediatr Drugs."},{"key":"B19","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1182\/blood-2015-07-657981","article-title":"Sirolimus is effective in relapsed\/refractory autoimmune cytopenias: results of a prospective multi-institutional trial","volume":"127","author":"Bride","year":"2016","journal-title":"Blood."},{"key":"B20","doi-asserted-by":"publisher","first-page":"534","DOI":"10.1111\/j.1365-2141.2005.05496.x","article-title":"Use of mycophenolate mofetil for chronic, refractory immune cytopenias in children with autoimmune lymphoproliferative syndrome","volume":"129","author":"Rao","year":"2005","journal-title":"Br J Haematol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"2110","DOI":"10.1016\/s0041-1345(01)01965-0","article-title":"Mycophenolate mofetil interferes with interferon gamma production in T-cell activation models","volume":"33","author":"Izeradjene","year":"2001","journal-title":"Transplant Proc."},{"key":"B22","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1038\/sj.clpt.6100317","article-title":"Rapamycin: something old, something new, sometimes borrowed and now renewed","volume":"82","author":"Hartford","year":"2007","journal-title":"Clin Pharmacol Ther."},{"key":"B23","doi-asserted-by":"publisher","first-page":"e52","DOI":"10.3324\/haematol.2016.153411","article-title":"Evolution of disease activity and biomarkers on and off rapamycin in 28 patients with autoimmune lymphoproliferative syndrome","volume":"102","author":"Klemann","year":"2017","journal-title":"Haematologica."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1948","DOI":"10.3324\/haematol.2012.081901","article-title":"Sequential decisions on FAS sequencing guided by biomarkers in patients with lymphoproliferation and autoimmune cytopenia","volume":"98","author":"Rensing-Ehl","year":"2013","journal-title":"Haematologica."}],"container-title":["Frontiers in Pediatrics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2021.624116\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,18]],"date-time":"2021-03-18T05:40:24Z","timestamp":1616046024000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2021.624116\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,18]]},"references-count":24,"alternative-id":["10.3389\/fped.2021.624116"],"URL":"https:\/\/doi.org\/10.3389\/fped.2021.624116","relation":{},"ISSN":["2296-2360"],"issn-type":[{"type":"electronic","value":"2296-2360"}],"subject":[],"published":{"date-parts":[[2021,3,18]]},"article-number":"624116"}}