Case report: MEK inhibitor as treatment for multi-lineage mosaic KRAS G12D-associated epidermal nevus syndrome in a pediatric patient

Abstract

The RASopathies, collectively, are a spectrum of genetic syndromes caused by mutations in genes involved in the RAS/ mitogen-activated protein kinase (MAPK) pathway, including but not limited to PTPN11, NRAS, KRAS, HRAS, BRAF, and MAP2K1. Recognized RASopathy conditions include neurofibromatosis type 1 (NF1), Noonan syndrome, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, cardiofacio-cutaneous (CFC) syndrome, LEOPARD syndrome and Legius syndrome. The RASopathies often display overlapping clinical features, presumably owing to common RAS-MAPK signaling pathway activation driving dysregulated cell proliferation. Epidermal nevus syndromes (ENS) are described as the presence of epidermal nevi, in individuals also affected by extra-cutaneous organ system involvement, and there is recent recognition of mosaic RAS mutations as molecular drivers of ENS. Currently, no curative treatments exist for RASopathy driven conditions, but rather symptom-directed management is the currently accepted standard. Here, we detail a unique case of a child exhibiting diffuse spinal nerve root hypertrophy in the context of epidermal nevus syndrome driven by molecularly confirmed KRAS G12D mosaicism, treated with the MEK 1/2 inhibitor selumetinib. Herein, we report the response of this patient to targeted therapy of more than two years' duration, including stabilization of multilevel nerve root hypertrophy as well as significant improvement in epidermal nevi. While the effectiveness of MEK inhibitors such as selumetinib is established in NF1-associated inoperable plexiform neurofibromas, their use in managing hyperactive KRAS-driven epidermal nevi and hypertrophic neuropathy remains unproven, and this case, to our knowledge, is the first such case to be reported. Shared molecular dysregulation and overlapping clinical features between these conditions suggest potential for effective therapeutic application of MEK directed therapy to address a range of conditions resulting from germline and/ or mosaic expression of aberrantly regulated RAS signaling.

Keywords: KRAS G12D; RASopathy; epidermal nevus syndrome; hypertrophic neuropathy; selumetinib.

Figure 1

Timeline of the clinical history, including significant clinical and diagnostic findings, and key findings identified on MRI of the spine.

Figure 2

Epidermal nevi along the lines of Blaschko before (A,B) and during treatment with selumetinib (C,D). The linear nevus primarily affects the left side of the patient’s torso (A,B) and the left upper extremity. There are also significant stigmata of epidermal nevus on her scalp (not shown) and deformities of the left ear helix and lobule due to the nevus. After 12 months of treatment, there is notable improvement in the affected areas, with the lesions appearing less pigmented, flatter, and smaller (C,D).

Figure 3

Histopathologic slides of the scalp lesion diagnosed as epidermal nevus. (A) Low power (2×) shows papillary epidermal hyperplasia that is both exophytic and endophytic with downward elongation of the rete into the dermis. There are aberrantly formed follicles and disorganization of the superficial connective tissue. Overall, the lesion resembles a papillomatous seborrheic keratosis. (B) At high power (10×) one can appreciate the papillary epidermal hyperplasia with hyperkeratosis and hypergranulosis, as well as disorganized superficial dermis.

Figure 4

Axial T2-weighted MRI Images pre- and post-treatment. Pre-treatment (A–F) and post-treatment (G–L) images of the cervical spine (C1-C2), superior mediastinum (SM), and lumbar spine (L3-L4), Taken at 14 months (G,I,K) and 28 months (H,J,L) after initiating selumetinib. Cervical spine (C1-C2): Progressive bilateral foraminal nerve root thickening (solid arrow, (A,B)) with post-treatment reduction in intra-spinal thickening (dashed arrow, (G,H)). Superior mediastinum: Bilateral extraforaminal nerve thickening (arrows) shows initial growth before treatment (C,D) and stabilization post-treatment (I,J). Lumbar spine (L3-L4): Persistent bilateral nerve root thickening at the neural foramina (arrows, (E,F)), with no significant change post-treatment (K,L). Measurements of nerve root hypertrophy over time (M). The graph displays the width (cm) of nerve roots at the left cervical spine (C1-C2, red), superior mediastinum (SM, blue), and left lumbar spine (L3-L4, green). The arrow marks the initiation of selumetinib treatment.