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.

Keywords: KRAS; RASopathy; didymosis; encephalocraniocutaneous syndrome; epibulbar dermoid; epidermal nevus; nevus psiloliparus; non-allelic twin spotting; oculoectodermal syndrome.

Figure 1

(A–E) Clinical features. (A,B) Eyelid coloboma, epibulbar dermoid and segmental areas of hyperpigmentation following a Blaschkoid distribution on the right upper half of the body and extending to the right arm in patient 1. (C) The same patient also presents with three areas of focal alopecia with yellow skin colour. (D,E) Palpable verrucous hyperpigmentation following Blaschko lines on the chin, extending to the neck in patient 2 ((D) age 2, (E) age 4).

Figure 2

(A–D) Histopathology. (A) A skin biopsy from the slightly palpable Blaschkoid hyperpigmentation on the right arm in individual 1 shows features suggestive of epidermal nevus, including discrete acanthosis, hyperkeratosis and pigmentation of the basal layer (magnification ×100). (B) Similarly, epithelial hyperplasia and papillomatosis confirm the diagnosis of epidermal nevus on the chin of individual 2 (magnification ×400). (C,D) A skin biopsy taken in the focal region of alopecia in individual 1 shows the presence of fat in the dermis, tissue fibrosis and an anagen arrest of hair follicles, indicative of nevus psiloliparus (magnification ×100).

Figure 2

(A–D) Histopathology. (A) A skin biopsy from the slightly palpable Blaschkoid hyperpigmentation on the right arm in individual 1 shows features suggestive of epidermal nevus, including discrete acanthosis, hyperkeratosis and pigmentation of the basal layer (magnification ×100). (B) Similarly, epithelial hyperplasia and papillomatosis confirm the diagnosis of epidermal nevus on the chin of individual 2 (magnification ×400). (C,D) A skin biopsy taken in the focal region of alopecia in individual 1 shows the presence of fat in the dermis, tissue fibrosis and an anagen arrest of hair follicles, indicative of nevus psiloliparus (magnification ×100).

Figure 3

Molecular genetic testing. Left panel: Next-generation sequencing on DNA extracted from a skin biopsy in the epidermal nevus of patient 1 identified a mosaic missense variant (c.436G > A, (p.Ala146Thr)) in the KRAS gene with variant frequencies of 60% in cells of the epidermis and 22% in the dermis/hypodermis. DNA extracted from the nevus psiloliparus identifies the same KRAS variant with a frequency of 54% in the epidermis and 5% in the dermis/hypodermis. DNA from peripheral leukocytes does not contain the KRAS variant. Right panel: Identically, in patient 2, the p.(Ala146Thr) variant was identified in the DNA extracted from the epidermal nevus with a frequency of 58% and 10% in the epidermis and dermis/hypodermis, respectively (green color: reference sequence, blue and brown color: sample sequence, red: aberration from the reference sequence).