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Genes Chromosomes Cancer. 2016 Feb;55(2):131-42. doi: 10.1002/gcc.22319. Epub 2015 Nov 6.

An infant with MLH3 variants, FOXG1-duplication and multiple, benign cranial and spinal tumors: A clinical exome sequencing study.

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Pathology and Laboratory Medicine, University of California at Los Angeles, David Geffen School of Medicine, Los Angeles, CA, 90095.
Medical Genetics and Metabolism, Valley Children's Hospital, Madera, CA, 93636.
Hematology/Oncology, Valley Children's Hospital, Madera, CA, 93636.
Department of Radiology, Valley Children's Hospital, Madera, CA, 93636.
Program of Genetics & Genome Biology, The Hospital for Sick Children, Peter Gilgan Center for Research and Learning, Toronto, Ontario, MSG 0A4, Canada.
Program of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 1A1, Canada.
Pediatrics, University of California at Los Angeles, David Geffen School of Medicine, Los Angeles, CA, 90095.
Human Genetics, University of California at Los Angeles, David Geffen School of Medicine, Los Angeles, CA, 90095.


A 4-month-old male infant presented with severe developmental delay, cerebellar, brainstem, and cutaneous hemangiomas, bilateral tumors (vestibular, hypoglossal, cervical, and lumbar spinal), and few café-au-lait macules. Cerebellar and lumbar tumor biopsies revealed venous telangiectasia and intraneural perineuroma, respectively. Sequencing NF1, NF2, and RASA1 (blood), and NF2 and SMARCB1 (lumbar biopsy) was negative for pathogenic mutations. Clinical exome sequencing (CES), requested for tumor syndrome diagnosis, revealed two heterozygous missense variants, c.359T>C;p.Phe120Ser and c.3344G>A;p.Arg1115Gln, in MLH3 (NM_001040108.1), a DNA mismatch repair (MMR) gene, Polyphen-predicted 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 FOXG1, possibly explaining the developmental delay, but not the tumors. The presence of MLH3 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-neoplastic patient-derived cells showed intact base-base MMR function. Also, no previous FOXG1-aberrant patient was reported with tumors. We now report a 3-year-old FOXG1-duplicated 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.

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