Case Report: Melanocyte-associated mTORC1-related molecular features in an atypical large congenital melanocytic naevus

Abstract

Congenital melanocytic naevi (CMN) are usually associated with activating alterations in NRAS or BRAF , but some extensive lesions lack detectable canonical hotspot variants. We report a 9-year-old boy with a large craniofacial CMN involving the face, scalp, upper eyelid and bulbar conjunctiva, with deep extension, mechanical ptosis and secondary amblyopia. Histology showed benign dermal melanocytic proliferation, and magnetic resonance imaging showed no neurocutaneous melanosis. High-depth whole-exome sequencing detected no canonical NRAS or BRAF hotspot variant at or above the prespecified reporting threshold. A maternally inherited TSC2 c.1307C>T (p.Pro436Leu) variant was classified as a variant of uncertain significance. Multiplex immunofluorescence showed greater p -S6 positivity among SOX10-positive cells in lesional tissue than in marginal normal skin. Single-cell RNA sequencing showed cell-type-specific variation in mechanistic target of rapamycin complex 1 (mTORC1) scores within the lesion; naevus cells had higher scores than fibroblasts and pericytes but not endothelial or hair follicle cells. These single-patient findings provide descriptive evidence of lesion-associated mTORC1-related molecular features and support pathway-level profiling in atypical CMN, without establishing disease-specific mTORC1 hyperactivation or causality for the TSC2 variant.