Generalized Nevus Lipomatosus Cutaneous Superficialis: A Case Report with Comprehensive Genetic Analysis.

Background: Nevus lipomatosus superficialis (NLS) is a rare cutaneous hamartoma characterized by ectopic adipose tissue in the dermis. Its genetic basis remains largely unknown. Methods: We conducted a comprehensive clinical, histopathological, and genetic investigation of a 17-year-old female with an exceptionally extensive distribution of lesions (involving trunk, buttocks, lower extremities, and vulva) that was atypical due to the presence of significant pain and recurrent infections. Whole exome sequencing (WES) was performed on the proband and both parents (trio-WES), and whole genome sequencing (WGS) was performed on fresh lesional tissue. Low-level mosaicism or regulatory mechanisms may remain undetected. Results: Physical examination revealed widespread hyperpigmented plaques. Histopathology confirmed mature adipocytes within the superficial to mid-dermis, consistent with NLS. Under our detection thresholds, we did not identify any pathogenic or likely pathogenic variants from WES or WGS. WES revealed 24 variants of uncertain significance, none of which were compelling for phenotype/pathway relevance. WGS did not identify pathogenic coding or non-coding variants, structural variations, copy number variations, or mitochondrial mutations. No pathogenic mutation was detected, suggesting alternative genetic mechanisms may be involved. Conclusion: This case represents a rare presentation of extensive NLS with associated pain. Comprehensive genetic analysis did not identify pathogenic variants under our detection thresholds, while suggesting possible somatic mosaicism, recessive inheritance, or non-coding region variations.