The Role of KRAS Mutations in Cortical Malformation and Epilepsy Surgery: A Novel Report of Nevus Sebaceous Syndrome and Review of the Literature

Abstract

The rare nevus sebaceous (NS) syndrome (NSS) includes cortical malformations and drug-resistant epilepsy. Somatic RAS-pathway genetic variants are pathogenetic in NS, but not yet described within the brain of patients with NSS. We report on a 5-year-old boy with mild psychomotor delay. A brown-yellow linear skin lesion suggestive of NS in the left temporo-occipital area was evident at birth. Epileptic spasms presented at aged six months. EEG showed continuous left temporo-occipital epileptiform abnormalities. Brain MRI revealed a similarly located diffuse cortical malformation with temporal pole volume reduction and a small hippocampus. We performed a left temporo-occipital resection with histopathological diagnosis of focal cortical dysplasia type Ia in the occipital region and hippocampal sclerosis type 1. Three years after surgery, he is seizure-and drug-free (Engel class Ia) and showed cognitive improvement. Genetic examination of brain and skin specimens revealed the c.35G > T (p.Gly12Val) KRAS somatic missense mutation. Literature review suggests epilepsy surgery in patients with NSS is highly efficacious, with 73% probability of seizure freedom. The few histological analyses reported evidenced disorganized cortex, occasionally with cytomegalic neurons. This is the first reported association of a KRAS genetic variant with cortical malformations associated with epilepsy, and suggests a possible genetic substrate for hippocampal sclerosis.

Keywords: KRAS genetic variants; RAS pathway; focal cortical dysplasia; hippocampal sclerosis; nevus sebaceous syndrome; pediatric epilepsy surgery.

Figure 1

Linear alopecic sebaceous skin lesion in the left temporo-occipital area.

Figure 2

Magnetic resonance imaging T1-weighted images demonstrating left temporal pole volumetric reduction associated with blurring of the cortico-subcortical region (a, arrow) and hyperintensity of the white matter on T2-weighted sequences (b, arrow). There is incomplete hippocampal inversion on the left (c) associated with increased T2 signal (d). (e) EEG during Wakefulness shows continuous left temporo-occipital slow and epileptiform abnormalities, with sporadic contralateral expression. (f) Periodic complexes of slow waves after awakening associated with subtle eyes elevation, recorded in 60 s.

Figure 3

Histopathologic findings. (A) Hippocampal sclerosis type 1: pronounced neuronal cell loss along the whole Ammon’s horn (CA); preserved neuronal cellularity of the dentate gyrus (DG). (Neu-N immunostain, 2.5×). (B) Occipital lobe focal cortical dysplasia type I: mildly hypercellular cortex harboring small-diameter neurons arranged in distinct microcolumns. Note the cortex–white matter blurring. (Neu-N immunostain, 2.5×). (C) Occipital lobe focal cortical dysplasia type I: higher magnification of red insert in (B), highlighting the cortex microcolumnar arrangement. (Neu-N immunostain, 20×).

Figure 4

Next-generation sequencing data from brain, skin, and blood samples showing the presence of the c.35G > T (p.Gly12Val) KRAS mutation with a ~25% mosaicism rate both in brain and skin tissue, but absence of the variation in the blood sample, thereby demonstrating the somatic origin of the mutation.