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.
Highlights
Nevus sebaceous syndrome (NSS; known as Schimmelpenning–Feuerstein–Mims syndrome) is a rare neurocutaneous disorder in which nevus sebaceous (NS) is found in association with congenital abnormalities of the brain, eye, and/or skeleton [1]
Mutational analysis of HRAS, NRAS, and KRAS genes performed by a custom nextgeneration sequencing (NGS) panel on DNA extracted from specimens from brain, nevus sebaceous, and blood revealed in the KRAS gene the somatic mutation c.35G > T (p.Gly12Val), already reported and associated with a similar clinical picture, with a ~25% mosaicism rate both in brain- and skin-tissue-derived DNA, but absent in blood-derived DNA (Figure 4)
This case demonstrated that mosaic KRAS genetic variants can be associated with cortical malformation in the context of NSS
Summary
Nevus sebaceous syndrome (NSS; known as Schimmelpenning–Feuerstein–Mims syndrome) is a rare neurocutaneous disorder in which nevus sebaceous (NS) is found in association with congenital abnormalities of the brain, eye, and/or skeleton [1]. The phenotypic expression is pleomorphic, ranging from solely cutaneous involvement to severe epilepsy due to hemispheric malformation in association with alteration in bone size [2,5,6]. Epilepsy occurs in anywhere from 38% to 96% of patients with NSS and neurological involvement [10,11,12]. We report the first evidence of c.35G > T KRAS genetic variant found in both the skin lesion and a brain specimen in a patient with focal cortical dysplasia (FCD) type Ia, hippocampal sclerosis (HS), and NSS. As the syndrome is extremely rare, we performed a literature review on surgically treated cases with NSS and drug-resistant epilepsy to better delineate the association of NSS with a specific cortical malformation
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