Sensitive detection of FGFR1 N546K mosaic mutation in patient with encephalocraniocutaneous lipomatosis and pilocytic astrocytoma

Abstract

Encephalocraniocutaneous lipomatosis (ECCL) is a rare neurocutaneous disorder, with only about 100 cases reported worldwide. It is characterized by congenital lesions of the eye, skin, and central nervous system. Only recently, potential causative FGFR1 point mutations have been identified in brain tumors and cultured skin biopsies from patients with this condition. Here, we analyzed the molecular status of a patient with ECCL and a coexisting pilocytic astrocytoma with detected FGFR1 N546K mutation.The presence of the alteration in both affected and unaffected tissues has been evaluated using Sanger sequencing and droplet digital polymerase chain reaction (ddPCR) technique. The ddPCR analysis showed differential distribution of the alteration in all specimens, including unaffected and untreated samples. Therefore, we confirm that FGFR1 N546K is a plausible causative mutation of ECCL patients and could be associated with a risk of brain tumor development. We also show the usefulness of sensitive ddPCR method for detection of low levels of autosomal mosaic mutation in blood or swabs. We suggest that utilization of this method may improve the diagnostic process, especially when targeted therapies are considered.

<p>Fibrous Meningioma in a Patient with Encephalocraniocutaneous Lipomatosis: A Rare Case with Unique Features</p>

“…These tumors may be explained by the occurrence of the same FGFR1 mutations recently demonstrated in ECCL in subgroups of sporadic low-grade gliomas. 3,10 On the other hand, our case is the first case of ECCL to present with meningioma. Until this presentation is corroborated by similar cases in the future, a coincidental sporadic…”

“…Gliomas of different types were reported in 11 different patients (about 10% of reported cases). All of these cases 3,10,11 were reported after Moog's paper was published and hence, they were not included in the cases on which he based his revised criteria. The tumors were mostly low-grade (10/11), and they include: pilomyxoid/pilocytic astrocytoma (5 cases), low-grade astrocytoma (3 cases), glioblastoma (1 case), dysembryoplastic neuroepithelial tumor (1 case), and papillary glioneuronal tumor (1 case).…”

“…2 The condition remains rare, with about 100 cases reported in the literature. 3 In spite of attempts by Hunter 4 and later by Moog 2 to establish diagnostic criteria for ECCL, the condition remains heterogenous and clinical presentations in the literature represent a spectrum of manifestations and severity. Here we report the first case of ECCL in association with fibrous meningioma and nevus sebaceous of Jadassohn.…”

FGFR1 is a Potential Therapeutic Target in Neuroblastoma

“…FGFR1 clone selection for rare resistant has been also reported in lung and colorectal resistant tumors, thus revealing a change in variant allele frequency of FGFR1 somatic variants 55;56 . Of note, N546K mutation was also found in Ewing sarcoma and brain tumors [27][28][29][30][31] .…”

“…Moreover, in addition to the already reported single relapsed NB case 15 , N546K mutation has also been recently reported in 6 patients 25 . Speci cally, N546K represents an activating mutation that alters FGFR1 auto-phosphorylation 26 , resulting in an increase of kinase activity and malignant transformation in Ewing sarcoma and brain tumors [27][28][29][30][31] .…”