Mosaic Activating Mutations in FGFR1 Cause Encephalocraniocutaneous Lipomatosis

Abstract

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.

Activating mutations in the MAP‐kinase pathway define non‐ossifying fibroma of bone

“…Our data in NOF add another benign tumour to the spectrum of KRAS ‐ and MAP‐kinase signalling‐driven neoplasms, by identifying bona fide pathogenic KRAS and FGFR1 mutations that have been reported in a variety of carcinomas, sarcomas and haematological malignancies. Interestingly, FGFR1 mutations have recently been shown to occur in (sporadic) phaeochromocytomas (that can also harbour NF1 mutations), and in rare brain tumour subtypes .…”

Expansion of the phenotypic spectrum and description of molecular findings in a cohort of patients with oculocutaneous mosaic RASopathies

“…These entities are the oculoectodermal (OES, OMIM %600268) and Schimmelpenning‐Feuerstein‐Mims syndromes (SFMS, OMIM #163200), as well as encephalocraniocutaneous lipomatosis (ECCL, OMIM #613001), oculocutaneous disorders exhibiting pleiotropic anomalies that include scalp lesions, epilepsy, epibulbar dermoids, cloudy cornea, eyelid coloboma, coarctation of the aorta, and skin pigmentation abnormalities (Boppudi et al, ; Groesser et al, ; Kuroda et al, ; Peacock et al, ). Somatic mutations causing oculocutaneous mosaic RASopathies are recurrent and have been identified at KRAS codons 13, 19, and 146 in OES patients (4 subjects reported to date) (Boppudi et al, ; Peacock et al, ), KRAS codon 146 and FGFR1 codons 546 and 656 in ECCL (six reported patients) (Bennett et al, ; Boppudi et al, ), and HRAS codon 13 (2 patients), KRAS codon 12 (3 subjects), and NRAS codon 61 (1 subject) in individuals with a SFMS diagnosis (Groesser et al, ; Igawa et al, ; Kuroda et al, ; Lihua, Feng, Shanshan, Jialu, & Kewen, ; Sun et al, ; Wang, Qian, Zhang, & Zhou, ). Such pathogenic mutations also confer an elevated risk for developing a variety of tumors commonly associated with these oculocutaneos disorders (Aslan et al, ; Eisen & Michael; ; Kocak, Yarar, & Carman, ; Moog, ; Peacock et al, ; Toriello et al, ; Valera et al, ).…”

Encephalocraniocutaneous lipomatosis with Wilms' tumor

“…In a recent study the mosaic activating mutations of fibroblast growth factor receptor gene‐1 ( FGFR1 ) were found to be related to ECCL . In the present patient, no mutations were detected in FGFR or WT1 on Sanger analysis of the peripheral blood.…”