{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T17:27:41Z","timestamp":1774459661200,"version":"3.50.1"},"reference-count":25,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2016,3,21]],"date-time":"2016-03-21T00:00:00Z","timestamp":1458518400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"NIH","award":["R01CA080175"],"award-info":[{"award-number":["R01CA080175"]}]},{"name":"LLS","award":["SCOR 7372-07"],"award-info":[{"award-number":["SCOR 7372-07"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pediatric Blood &amp; Cancer"],"published-print":{"date-parts":[[2016,7]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Infant acute lymphoblastic leukemia (ALL) has never occurred in families except for the \u223c100% concordant cases in monozygous twins attributed to twin\u2010to\u2010twin metastases. We report the first kindred with infant ALL in non\u2010twin siblings. The siblings were diagnosed with <jats:italic>MLL<\/jats:italic>\u2010rearranged (<jats:italic>MLL\u2010<\/jats:italic>R) ALL 26 months apart. The second affected sibling had an unaffected dichorionic monozygous co\u2010twin. Both had fatal outcomes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Procedures<\/jats:title><jats:p>Translocations were characterized by karyotype, FISH, multiplex FISH, and <jats:italic>MLL<\/jats:italic> breakpoint cluster region (bcr) Southern blot analysis. Breakpoint junctions and fusion transcripts were cloned by PCR. <jats:italic>TP53<\/jats:italic> mutation and NADPH quinone oxidorecuctase 1 (<jats:italic>NQO1<\/jats:italic>) C609T analyses were performed, and pedigree history and parental occupations were ascertained. The likelihood of chance occurrence of infant ALL in non\u2010twin siblings was computed based on a binomial distribution. Zygosity was determined by single nucleotide polymorphism (SNP) array.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The translocations were not related or vertically transmitted. The complex karyotype of the proband's ALL had chromosome 2, 3, 4, and 11 abnormalities causing a 5\u2032\u2010<jats:italic>MLL<\/jats:italic>\u2010<jats:italic>AFF1<\/jats:italic>\u20103\u2032 fusion and a non\u2010productive rearrangement of 3\u2032<jats:italic>MLL<\/jats:italic> with a chromosome 3q intergenic region. The affected twin's ALL exhibited a simple t(4;11). The complex karyotype of the proband's ALL suggested a genotoxic insult, but no exposure was identified. There was no germline <jats:italic>TP53<\/jats:italic> mutation. The <jats:italic>NQO1<\/jats:italic> C609T risk allele was absent. The likelihood of infant ALL occurring in non\u2010twin siblings by chance alone is one in 1.198 \u00d7 10<jats:sup>9<\/jats:sup> families.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Whether because of a deleterious transplacental exposure, novel predisposition syndrome, or exceedingly rare chance occurrence, <jats:italic>MLL<\/jats:italic>\u2010R infant ALL can occur in non\u2010twin siblings. The discordant occurrence of infant ALL in the monozygous twins was likely because they were dichorionic.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pbc.25957","type":"journal-article","created":{"date-parts":[[2016,3,22]],"date-time":"2016-03-22T02:47:25Z","timestamp":1458614845000},"page":"1175-1180","source":"Crossref","is-referenced-by-count":6,"title":["Unique Familial <i>MLL(KMT2A)\u2010<\/i>Rearranged Precursor B\u2010Cell Infant Acute Lymphoblastic Leukemia in Non\u2010twin Siblings"],"prefix":"10.1002","volume":"63","author":[{"given":"Karen A.","family":"Urtishak","sequence":"first","affiliation":[{"name":"Division of Oncology The Children's Hospital of Philadelphia  Philadelphia Pennsylvania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Blaine W.","family":"Robinson","sequence":"additional","affiliation":[{"name":"Division of Oncology The Children's Hospital of Philadelphia  Philadelphia Pennsylvania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric F.","family":"Rappaport","sequence":"additional","affiliation":[{"name":"Nucleic Acids &amp; Protein Core Facility The Children's Hospital of Philadelphia  Philadelphia Pennsylvania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margaret D.","family":"Sarezky","sequence":"additional","affiliation":[{"name":"Department of Pediatrics The Children's Hospital of Philadelphia  Philadelphia Pennsylvania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaclyn A.","family":"Biegel","sequence":"additional","affiliation":[{"name":"Division of Human Genetics The Children's Hospital of Philadelphia  Philadelphia Pennsylvania"},{"name":"Department of Pediatrics Perelman School of Medicine, University of Pennsylvania  Philadelphia Pennsylvania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kim E.","family":"Nichols","sequence":"additional","affiliation":[{"name":"Division of Oncology The Children's Hospital of Philadelphia  Philadelphia Pennsylvania"},{"name":"Department of Pediatrics Perelman School of Medicine, University of Pennsylvania  Philadelphia Pennsylvania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donna M.","family":"Wilmoth","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine The Children's Hospital of Philadelphia  Philadelphia Pennsylvania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li\u2010San","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Perelman School of Medicine, University of Pennsylvania  Philadelphia Pennsylvania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie W.","family":"Stern","sequence":"additional","affiliation":[{"name":"Division of Oncology The Children's Hospital of Philadelphia  Philadelphia Pennsylvania"},{"name":"Department of Pediatrics Perelman School of Medicine, University of Pennsylvania  Philadelphia Pennsylvania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carolyn A.","family":"Felix","sequence":"additional","affiliation":[{"name":"Division of Oncology The Children's Hospital of Philadelphia  Philadelphia Pennsylvania"},{"name":"Department of Pediatrics Perelman School of Medicine, University of Pennsylvania  Philadelphia Pennsylvania"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2016,3,21]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/363358a0"},{"key":"e_1_2_7_3_1","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1182\/blood.V83.3.641.641","article-title":"Clonal, nonconstitutional rearrangements of the MLL gene in infant twins with acute lymphoblastic leukemia: In utero chromosome rearrangement of 11q23","volume":"83","author":"Gill Super HJ","year":"1994","journal-title":"Blood"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.432"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.430"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.24417"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2013.367"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-02-0570"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.061408298"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2001-12-0264"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.22090"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3230"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-13-55"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2401981"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi049756r"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.293.10.1212"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1158\/1055-9965.EPI-04-0602"},{"key":"e_1_2_7_18_1","first-page":"2542","article-title":"Transplacental chemical exposure and risk of infant leukemia with MLL gene fusion","volume":"61","author":"Alexander FE","year":"2001","journal-title":"Cancer Res"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-59745-418-6_6"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gnf056"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.25322"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-911X(200005)34:5<313::AID-MPO1>3.0.CO;2-Q"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2141.1997.1522966.x"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-10-382861"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-01-202259"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1164"}],"container-title":["Pediatric Blood &amp; 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