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

Chiara Pepi; Luca de Palma; Marina Trivisano; Nicola Pietrafusa; Francesca Romana Lepri; Andrea Diociaiuti; Francesca Diomedi Camassei; Giusy Carfi-Pavia; Alessandro De Benedictis; Camilla Rossi-Espagnet; Federico Vigevano; Carlo Efisio Marras; Antonio Novelli; Ingmar Bluemcke; Nicola Specchio

doi:10.3390/brainsci11060793

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

Brain Sci. 2021 Jun 16;11(6):793. doi: 10.3390/brainsci11060793.

Authors

Chiara Pepi¹, Luca de Palma¹, Marina Trivisano¹, Nicola Pietrafusa¹, Francesca Romana Lepri², Andrea Diociaiuti³, Francesca Diomedi Camassei⁴, Giusy Carfi-Pavia¹, Alessandro De Benedictis⁵, Camilla Rossi-Espagnet^{6

7}, Federico Vigevano⁸, Carlo Efisio Marras⁵, Antonio Novelli², Ingmar Bluemcke⁹, Nicola Specchio¹

Affiliations

¹ Rare and Complex Epilepsy Unit, Department of Neuroscience, Bambino Gesù Children's Hospital IRCCS, Member of European Reference Network EpiCARE, 00165 Rome, Italy.
² Translational Cytogenomics Research Unit, Laboratory of Medical Genetics, Bambino Gesù Children Hospital, IRCCS, 00165 Rome, Italy.
³ Genodermatosis Unit, Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Member of European Reference Network SKIN, 00165 Rome, Italy.
⁴ Department of Laboratories-Pathology Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy.
⁵ Neurosurgery Unit, Department of Neurosciences, Bambino Gesù Children's Hospital, IRCCS, Member of European Reference Network EpiCARE, 00165 Rome, Italy.
⁶ Neuroradiology Unit, Imaging Department, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy.
⁷ Neuroradiology Unit, NESMOS Department, Sapienza University, 00165 Rome, Italy.
⁸ Department of Neuroscience, Bambino Gesù Children's Hospital IRCCS, Member of European Reference Network EpiCARE, 00165 Rome, Italy.
⁹ Institute of Neuropathology, Member of European Reference Network EpiCARE, University Hospitals Erlangen, 91054 Erlangen, Germany.

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.

Publication types

Review