Expanding the clinical phenotype of FGFR1 internal tandem duplication
- Esko A. Kautto1,12,
- Kathleen M. Schieffer1,2,12,
- Sean McGrath1,
- Anthony R. Miller1,
- Maria Elena Hernandez-Gonzalez1,
- Samantha Choi1,
- Miriam R. Conces2,3,
- Esteban Fernandez-Faith4,5,
- Mai-Lan Ho6,7,
- Kristy Lee1,2,4,
- Anna P. Lillis6,7,
- Gregory D. Pearson8,
- Stephen G. Kaler4,9,
- Richard K. Wilson1,4,
- Elaine R. Mardis1,4,10,
- Vincent Magrini1,3,
- Jeffrey Leonard10,11 and
- Catherine E. Cottrell1,2,4
- 1The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA;
- 2Department of Pathology, The Ohio State University, Columbus, Ohio 43210, USA;
- 3Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA;
- 4Department of Pediatrics, The Ohio State University, Columbus, Ohio 43210, USA;
- 5Division of Dermatology, Nationwide Children's Hospital Columbus, Ohio 43205, USA;
- 6Department of Radiology, Nationwide Children's Hospital Columbus, Ohio 43205, USA;
- 7Department of Radiology, The Ohio State University, Columbus, Ohio 43210, USA;
- 8Department of Pediatric Plastic and Reconstructive Surgery, Nationwide Children's Hospital, Columbus, Ohio 43205, USA;
- 9Division of Genetic and Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA;
- 10Department of Neurosurgery, The Ohio State University College of Medicine, Columbus, Ohio 43210, USA;
- 11Division of Neurosurgery, Nationwide Children's Hospital, Columbus, Ohio 43205, USA
- Corresponding author: Kathleen.Schieffer{at}nationwidechildrens.org
-
↵12 These authors contributed equally to this work.
Abstract
Closed spinal dysraphism (SD) is a type of neural tube defect originating during early embryonic development whereby the neural tissue of the spinal defect remains covered by skin, often coinciding with markers of cutaneous stigmata. It is hypothesized that these events are caused by multifactorial processes, including genetic and environmental causes. We present an infant with a unique congenital midline lesion associated with a closed SD. Through comprehensive molecular profiling of the intraspinal lesion and contiguous skin lesion, an internal tandem duplication (ITD) of the kinase domain of the fibroblast growth factor receptor 1 (FGFR1) gene was found. This ITD variant is somatic mosaic in nature as supported by a diminished variant allele frequency in the lesional tissue and by its absence in peripheral blood. FGFR1 ITD results in constitutive activation of the receptor tyrosine kinase to promote cell growth, differentiation, and survival through RAS/MAPK signaling. Identification of FGFR1 ITD outside of central nervous system tumors is exceedingly rare, and this report broadens the phenotypic spectrum of somatic mosaic FGFR1-related disease.
Footnotes
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[Supplemental material is available for this article.]
- Received December 7, 2021.
- Accepted January 27, 2022.
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