Abstract: To report an 18-year-old male who presented with diffuse dark macules of the skin and was diagnosed with LEOPARD syndrome, and to perform genetic mutation analysis and a literature review to summarize the genetic mutation sites and clinical characteristics of this disorder. Methods: We performed whole-exome sequencing to identify genetic mutations in the patient. We conducted a systematic literature search in the PubMed and Web of Science databases using the following search strategy: (“LEOPARD syndrome” OR “Noonan syndrome with multiple lentigines” OR “NSML”) AND (PTPN11 OR RAF1 OR BRAF OR MAP2K1). We included publications from 1964 to October 2025 that reported cases or case series with clearly defined genetic mutation sites and corresponding clinical phenotypes to characterize the mutational spectrum of LEOPARD syndrome. Results: Genetic analysis identified a heterozygous mutation in exon 7 of the PTPN11 gene (c.836A>G), which met the ACMG criteria for pathogenicity. The literature review included a total of 81 publications comprising 154 patients. Most patients presented with multiple lentigines, frequently accompanied by varying degrees of cardiac involvement and sensorineural hearing impairment. PTPN11 was the most common causative gene, accounting for 93.51% of all cases (144/154), whereas other less frequent pathogenic genes included RAF1, BRAF, and MAP2K1. Notably, mutations in RAF1 showed a strong association with the development of hypertrophic cardiomyopathy. Conclusion: Although LEOPARD syndrome is rare, it shows distinctive cutaneous manifestations. Early genetic testing, together with systematic evaluations of the cardiovascular and auditory systems, facilitates timely diagnosis and comprehensive management.

Key words: LEOPARD syndrome, PTPN11 gene, multiple lentigines