Congenital Langerhans Cell Histiocytosis With Novel KCL1::RAF1 Gene Fusion Identified Through Routine Whole-Genome Sequencing.

Langerhans cells (LC) are antigen presenting cells (APCs) of the immune system that are most commonly found in skin epidermis, oral and genital mucosa, bone marrow, and lymph nodes.(1) Langerhans cell histiocytosis (LCH) is characterized by a clonal expansion of myeloid precursors that differentiate into CD1a+/CD207+ cells in lesions, leading to neoplastic LC-like cells.(2) LCH can present at all ages and whilst typically underrecognized, the overall incidence rate of LCH in infancy (<1 year of age), has been reported to be 9-10 cases/million/year.(3),(4) Based on organ systems affected, LCH is classified as ‘single-system, single-site’, ‘single-system multi-site’, and ‘multi-system multi-site’.(5) This classification reflects the spectrum of natural history of the disease from spontaneously resolving through to aggressive multi-system disease, the latter historically requiring intensive conventional chemotherapy for cure. Through molecular analyses, disruption of the RAS-RAF-MEK-ERK signalling pathway has been identified in LCH. For example, pathogenic BRAF V600E variants are widely reported in LCH, alongside MAP2K1 variants.(6-10) Of note, such variants have frequently been identified in LCH cells from children with skin lesions and multi-system disease, and seven of 12 children with congenital multifocal single-system skin LCH.(11) However, overall there is a scarcity of molecular data linking genotype-phenotype relationships in congenital, skin isolated LCH,(12) suggesting possible alternative pathogenic drivers in the latter form. Identifying such drivers is critical to facilitate a full understanding of the molecular heterogeneity of LCH disease and allowing delivery of the most appropriate management options for patients. Accordingly, we describe a case of congenital, self-resolving isolated skin LCH, in which a novel gene fusion was identified through the routine use of whole genome sequencing (WGS).