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.

Identification of a recurrent mosaic KRAS variant in brain tissue from an individual with nevus sebaceous syndrome

“…Here, we extend the molecular pathology with the identification of a recurrent postzygotic mosaic KRAS variant within extracutaneous tissues in the CNS in an individual with NSS. Our findings in this individual are consistent with a recent individual ( Pepi et al 2021 ), confirming the hypothesis that NSS is caused by mosaic variants distributed across multiple systems; in contrast to the localized mosaic variants found in isolated sebaceous nevi ( Groesser et al 2012 ). These results suggest that mosaic variants in NSS are likely to arise earlier in development in common progenitor cells that give rise to multiple tissue lineages.…”

“…Nevus sebaceous syndrome (NSS) refers to a rare multisystem disorder in which the nevus sebaceous occurs in association with cerebral, ocular, or skeletal abnormalities. In individuals with NSS, the most frequently reported central nervous system (CNS) finding is of hemimegalencephaly, which is typically ipsilateral to the nevus ( Pavlidis et al 2012 ), with more localized malformations in some individuals ( Pascual-Castroviejo and Ruggieri 2008 ; Pepi et al 2021 ). Hippocampal sclerosis and focal cortical dysplasia type Ia have also been described in one individual ( Pepi et al 2021 ).…”

“…In individuals with NSS, the most frequently reported central nervous system (CNS) finding is of hemimegalencephaly, which is typically ipsilateral to the nevus ( Pavlidis et al 2012 ), with more localized malformations in some individuals ( Pascual-Castroviejo and Ruggieri 2008 ; Pepi et al 2021 ). Hippocampal sclerosis and focal cortical dysplasia type Ia have also been described in one individual ( Pepi et al 2021 ). The term nevus sebaceous syndrome has been associated with a variety of eponyms and synonyms including Schimmelpenning syndrome, Jadassohn sebaceous nevus syndrome, linear sebaceous nevus syndrome, Schimmelpenning–Feuerstein–Mims syndrome, and epidermal nevus syndrome ( Schimmelpenning 1957 ).…”

“…Conversely, in the rarer individuals with NSS, KRAS appears to be more common in 13 reported individuals in whom the molecular basis has been determined with the identification of postzygotic variants. Of those 13 reported individuals with NSS, KRAS variants account for nine, with HRAS variants in three and NRAS in one ( Groesser et al 2012 ; Sun et al 2013 ; Kuroda et al 2015 ; Igawa et al 2016 ; Jiang et al 2017 ; Mitchell et al 2018 ; Chacon-Camacho et al 2019 ; Nagatsuma et al 2019 ; De los Santos-La Torre et al 2020 ; Pan et al 2020 ; Pepi et al 2021 ). Pathogenic variants tend to be recurrent affecting residues functionally conserved across all RAS proteins ( Groesser et al 2012 ).…”

The genomic landscape across 474 surgically accessible epileptogenic human brain lesions

“…5,21,22 There is also emerging evidence for somatic variants in the RAS-RAF-MAPK pathway underlying MCD, with recent case studies reporting variants in KRAS associated with epilepsy-associated tumors and malformations. 23–25…”