{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T02:20:46Z","timestamp":1789352446318,"version":"build-2803163510"},"reference-count":56,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2015,11,6]],"date-time":"2015-11-06T00:00:00Z","timestamp":1446768000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes Chromosomes &amp; Cancer"],"published-print":{"date-parts":[[2016,2]]},"abstract":"<jats:p>A 4\u2010month\u2010old male infant presented with severe developmental delay, cerebellar, brainstem, and cutaneous hemangiomas, bilateral tumors (vestibular, hypoglossal, cervical, and lumbar spinal), and few caf\u00e9\u2010au\u2010lait macules. Cerebellar and lumbar tumor biopsies revealed venous telangiectasia and intraneural perineuroma, respectively. Sequencing <jats:italic>NF1, NF2<\/jats:italic>, and <jats:italic>RASA1<\/jats:italic> (blood), and <jats:italic>NF2<\/jats:italic> and <jats:italic>SMARCB1<\/jats:italic> (lumbar biopsy) was negative for pathogenic mutations. Clinical exome sequencing (CES), requested for tumor syndrome diagnosis, revealed two heterozygous missense variants, c.359T&gt;C;p.Phe120Ser and c.3344G&gt;A;p.Arg1115Gln, in <jats:italic>MLH3<\/jats:italic> (NM_001040108.1), a DNA mismatch repair (MMR) gene, Polyphen\u2010predicted as probably damaging, and benign, respectively. Sanger sequencing confirmed both variants in the proband, and their absence in the mother; biological father unavailable. Both biopsied tissues were negative for microsatellite instability, and expressed MLH1, MSH2, PMS2, MSH6, and MLH3 immunohistochemically. Chromosomal microarray showed a 133 kb segment copy number duplication of 14q12 region encompassing <jats:italic>FOXG1<\/jats:italic>, possibly explaining the developmental delay, but not the tumors. The presence of <jats:italic>MLH3<\/jats:italic> variants with multiple benign neural and vascular tumors was intriguing for their possible role in the pathogenesis of these neoplasms, which were suspicious for, but not diagnostic of, constitutional MMR deficiency. However, functional assays of non\u2010neoplastic patient\u2010derived cells showed intact base\u2010base MMR function. Also, no previous <jats:italic>FOXG1\u2010<\/jats:italic>aberrant patient was reported with tumors. We now report a 3\u2010year\u2010old <jats:italic>FOXG1<\/jats:italic>\u2010duplicated patient with a yet undescribed tumor syndrome with clinical features of neurofibromatosis types I and II, where several validation studies could not ascertain the significance of CES findings; further studies may elucidate precise mechanisms and diagnosis for clinical management, including tumor surveillance. \u00a9 2015 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/gcc.22319","type":"journal-article","created":{"date-parts":[[2015,11,6]],"date-time":"2015-11-06T10:52:40Z","timestamp":1446807160000},"page":"131-142","source":"Crossref","is-referenced-by-count":4,"title":["An infant with <scp><i>MLH<\/i><\/scp><i>3<\/i> variants, <scp><i>FOXG<\/i><\/scp><i>1<\/i>\u2010duplication and multiple, benign cranial and spinal tumors: A clinical exome sequencing study"],"prefix":"10.1002","volume":"55","author":[{"given":"Rina","family":"Kansal","sequence":"first","affiliation":[{"name":"Pathology and Laboratory Medicine University of California at Los Angeles, David Geffen School of Medicine Los Angeles CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinmin","family":"Li","sequence":"additional","affiliation":[{"name":"Pathology and Laboratory Medicine University of California at Los Angeles, David Geffen School of Medicine Los Angeles CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Shen","sequence":"additional","affiliation":[{"name":"Medical Genetics and Metabolism Valley Children's Hospital Madera CA 93636"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Samuel","sequence":"additional","affiliation":[{"name":"Hematology\/Oncology, Valley Children's Hospital Madera CA 93636"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fred","family":"Laningham","sequence":"additional","affiliation":[{"name":"Department of Radiology Valley Children's Hospital Madera CA 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David Geffen School of Medicine Los Angeles CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua L.","family":"Deignan","sequence":"additional","affiliation":[{"name":"Pathology and Laboratory Medicine University of California at Los Angeles, David Geffen School of Medicine Los Angeles CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel P.","family":"Strom","sequence":"additional","affiliation":[{"name":"Pathology and Laboratory Medicine University of California at Los Angeles, David Geffen School of Medicine Los Angeles CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher E.","family":"Pearson","sequence":"additional","affiliation":[{"name":"Program of Genetics &amp; Genome Biology The Hospital for Sick Children, Peter Gilgan Center for Research and Learning Toronto Ontario MSG 0A4 Canada"},{"name":"Program of Molecular Genetics, University of Toronto Toronto, Ontario  M5S 1A1 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