Oncogenic codon 13 NRAS mutation in a primary mesenchymal brain neoplasm and nevus of a child with neurocutaneous melanosis

Abstract

A 28-month female with a clinical diagnosis of neurocutaneous melanosis and numerous intracranial abnormalities (including a right choroid plexus tumor and left hemimegalencephaly) presented with a rapidly expanding tumor in the left occipital cerebrum. Microscopic examination of the resected specimen revealed a myxoid mesenchymal neoplasm consisting of fusiform cells that were immunoreactive for vimentin, CD34, and P53 but no melanocyte markers. Focused amplicon deep sequencing on DNA extracted from the brain tumor and a cutaneous nevus revealed a heterozygous (c.37G > C; p.G13R) substitution in the NRAS gene. DNA sequencing of “normal” skin and buccal swab showed the identical NRAS change albeit at lower allelic frequency. Her parents did not harbor the NRAS mutation. The skin lesion, but not the brain tumor, had a BRAF mutation (c.1397G > T; p.G466V). A germline single nucleotide polymorphism in MET was found in the child and her father (c.3209C > T; p.T1010I). The findings suggest NRAS mosaicism that occurred sometime after conception and imply an oncogenic role of the activating NRAS mutation in both the brain and skin lesions in this child.

Genetic Abnormalities in Large to Giant Congenital Nevi: Beyond NRAS Mutations

“…A previous NRAS G13R spilus-type CMN patient presented neurocutaneous melanosis and mesenchymal brain tumor (Shih et al, 2014). Although in our series none of the NRAS G13R spilus-type CMN patients presented neurocutaneous melanosis or developed melanoma, all patients who developed melanoma had a spilus-type CMN.…”

“…We have characterized many patients with spilus-type CMN and confirm that NRAS alterations are found in a subset of lesions. However, NRAS mutations detected in this subgroup of lesions included less frequently reported alterations such as p.Q61L, p.Q61H, or p.G13R, which have been previously described in three CMN patients (Dessars et al, 2009;Kinsler et al, 2014;Shih et al, 2014). Among previously reported NRAS G13R CMNs, two patients also presented a spilus-type phenotype (Shih et al, 2014).…”

“…However, NRAS mutations detected in this subgroup of lesions included less frequently reported alterations such as p.Q61L, p.Q61H, or p.G13R, which have been previously described in three CMN patients (Dessars et al, 2009;Kinsler et al, 2014;Shih et al, 2014). Among previously reported NRAS G13R CMNs, two patients also presented a spilus-type phenotype (Shih et al, 2014). Unfortunately, a detailed description of the lesion was not presented in the third case (Dessars et al, 2009).…”

“…These speckled spots can exhibit a wide variety of colors and sizes (Kinsler et al, 2014;Schaffer et al, 2001). Less recurrent NRAS mutations have been observed in this subtype of lesions (Dessars et al, 2009;Kinsler et al, 2014;Krengel et al, 2016;Shih et al, 2014).…”

Oncogenic codon 13 NRAS mutation in a primary mesenchymal brain neoplasm and nevus of a child with neurocutaneous melanosis

“…Hemimegalencephaly has been associated with other neurocutaneous syndromes including epidermal nevus syndrome, proteus syndrome, hypomelanosis of Ito, and neurofibromatosis-1 [48,49]. Recently, de novo somatic mutations with mosaicism in the PI3K-AKT3-mTOR pathway were shown to cause hemimegalencephaly [50]. NRAS is known to have direct interaction with PI3K [21].…”