Encephalocraniocutaneous lipomatosis (ECCL) is a sporadic condition characterized by ocular, cutaneous, and central nervous system anomalies. Key clinical features include a well-demarcated hairless fatty nevus on the scalp, benign ocular tumors, and central nervous system lipomas. Seizures, spasticity, and intellectual disability can be present, although affected individuals without seizures and with normal intellect have also been reported. Given the patchy and asymmetric nature of the malformations, ECCL has been hypothesized to be due to a post-zygotic, mosaic mutation. Despite phenotypic overlap with several other disorders associated with mutations in the RAS-MAPK and PI3K-AKT pathways, the molecular etiology of ECCL remains unknown. Using exome sequencing of DNA from multiple affected tissues from five unrelated individuals with ECCL, we identified two mosaic mutations, c.1638C>A (p.Asn546Lys) and c.1966A>G (p.Lys656Glu) within the tyrosine kinase domain of FGFR1, in two affected individuals each. These two residues are the most commonly mutated residues in FGFR1 in human cancers and are associated primarily with CNS tumors. Targeted resequencing of FGFR1 in multiple tissues from an independent cohort of individuals with ECCL identified one additional individual with a c.1638C>A (p.Asn546Lys) mutation in FGFR1. Functional studies of ECCL fibroblast cell lines show increased levels of phosphorylated FGFRs and phosphorylated FRS2, a direct substrate of FGFR1, as well as constitutive activation of RAS-MAPK signaling. In addition to identifying the molecular etiology of ECCL, our results support the emerging overlap between mosaic developmental disorders and tumorigenesis.
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We are grateful to the individuals and families who participated in this study. Research reported in this publication was supported by the Care4Rare Canada Consortium (Enhanced Care for Rare Genetic Diseases in Canada) funded by Genome Canada, the Canadian Institutes of Health Research, the Ontario Genomics Institute, Ontario Research Fund, Genome Quebec, and Children’s Hospital of Eastern Ontario Foundation; and by the National Institute of Neurological Disorders and Stroke (NINDS) under award numbers 1R01NS092772 (W.B.D.) and the National Human Genome Research Institute of the National Institutes of Health. Some sequencing in this study was provided by the University of Washington Center for Mendelian Genomics (UW-CMG) and was funded by the National Human Genome Research Institute and the National Heart, Lung and Blood Institute grant U54HG006493 to Drs. Debbie Nickerson, Jay Shendure, and Michael Bamshad. M.J.L. and L.G.B. are supported by the Intramural Research Program of the National Human Genome Research Institute. We also acknowledge the contributions of the high-throughput sequencing platform of the McGill University and Genome Quebec Innovation Centre, Montreal, Canada. M.T. received a post-doctoral fellowship from the Reseau de Medecine Genique Appliquee. L.M.M. is supported by a scholarship from the (CIHR) and Consortium National de Formation en Santé. T.Y.T. was supported by an Australian National Health and Medical Research Council Postdoctoral Overseas Training Scholarship (#607431). D.A. and M.O’D. are supported by Cancer Research UK. None of the authors have any conflicts of interest to declare.