Identification of Codon 146 KRAS Variants in Isolated Epidermal Nevus and Multiple Lesions in Oculoectodermal Syndrome: Confirmation of the Phenotypic Continuum of Mosaic RASopathies

Abstract

Mosaic RASopathies are a molecularly heterogeneous group of (neuro)cutaneous syndromes with high phenotypical variability. Postzygotic variants in KRAS have been described in oculoectodermal syndrome (OES), encephalocraniocutaneous lipomatosis (ECCL) and epidermal nevus syndrome (ENS). This study confirms the continuum of mosaic neurocutaneous RASopathies showing codon 146 KRAS variants in an individual with OES and, for the first time, in an individual with (isolated) epidermal nevus. The presence of a nevus psiloliparus in individuals with OES indicates that this finding is not specific for ECCL and highlights the phenotypical overlap between ECCL and OES. The presence of the somatic KRAS variant in the nevus psiloliparus resolves the underlying molecular etiology of this fatty-tissue nevus. In addition, this finding refutes the theory of non-allelic twin-spotting as an underlying hypothesis to explain the concurrent presence of two different mosaicisms in one individual. The identification of codon 146 KRAS variants in isolated epidermal nevus introduces a new hot spot for this condition, which is useful for increasing molecular genetic testing using targeted gene sequencing panels.

Encephalocraniocutaneous Lipomatosis

“…Importance of surveillance should be emphasized to families, as patients with ECCL are at increased risk of developing many forms of neoplasms including extranasopharyngeal angiofibroma of gingiva, papillary glioneuronal tumor, and low-grade gliomas 7 …”

Nevus Sebaceous Syndrome: A Case Report and Literature Review of the Associated Neurological Complications

“…Seizures: Biçer et al [39], Garg et al [40]. Developmental Delays: Beyens et al [8], Farschtschi et al [41], Garg et al [40]. "Other" includes a patient with cerebral palsy [40], and another patient with progressive transversal spinal cord syndrome as well as spasticity, paraparesis, pain, talipes equinovarus, positive Babinski reflex, and missing cremasteric and anal sphincter reflexes [41].…”

Mosaic RASopathies: A review of disorders caused by somatic pathogenic variants in the genes of the RAS/MAPK pathway

“…They include, so far: (1) Mosaic forms of germline RASopathies (e.g., mosaic [segmental] neurofibromatosis type 1); (2) Isolated malformations (vascular, lymphatic, cutaneous, hematologic, and osseous); (3) True mosaic RASopathies, characterized by a variable association of cutaneous and systemic congenital anomalies, mostly involving the skeletal and ocular tissues and the central nervous system. The latter include a plethora of complex malformation syndromes reported and labeled, over time, as unique entities, which in turn are part of an overlapping and continuous spectrum of mosaic phenotypes: for example, epidermal nevus syndromes (ENSs) (Hafner & Groesser, 2013; Happle, 2010; Waldman, Garzon, & Morel, 2022) including Schimmelpenning‐Feuerstein‐Mims syndrome (SFMS) or linear sebaceous nevus syndrome (MIM # 163200), keratinocytic epidermal nevus syndrome (KENS) (Farschtschi et al, 2015), and phacomatosis pigmentokeratotica (PPK) (Huang et al, 2022); oculoectodermal syndrome (OES) (Beyens et al, 2022; Peacock et al, 2015); cutaneous skeletal hypophosphatemia syndrome (CSHS) (Lim et al, 2016); encephalocraniocutaneous lipomatosis (ECCL) (Boppudi et al, 2016; Bennett et al, 2016), and Gorham‐Stout disease (Nozawa et al, 2020) (Table 1).…”

“…Features of the ECCL have been described in some individuals affected by OES. It is caused by somatic KRAS variant (Beyens et al, 2022; Peacock et al, 2015).…”