Clinical and genetic characteristics of Chinese patients with piebaldism accompanied by Café-au-lait macules

Abstract Background Piebaldism is a rare autosomal dominant pigmentary disorder characterized by congenital depigmented patches and a white forelock, primarily caused by pathogenic variants in KIT . A subset of patients additionally exhibit Café-au-lait macules (CALMs) and intertriginous freckling, resulting in considerable phenotypic overlap with neurofibromatosis type 1 (NF1) and complicating diagnosis. However, the clinical and molecular characteristics of Chinese patients with this uncommon phenotype remain poorly defined. Methods We retrospectively analyzed five unrelated Chinese patients with piebaldism accompanied by CALMs from Beijing Children’s Hospital and systematically reviewed ten previously reported Chinese cases. Clinical manifestations, family history, and genetic findings were evaluated. Whole-exome sequencing followed by Sanger sequencing validation was performed in newly recruited patients. Variants were interpreted according to the ACMG/AMP guidelines. Phenotypic severity was classified based on depigmentation extent. Genotype-phenotype correlations were analyzed by integrating the present cohort with published Chinese cases. Results Fifteen patients were included. All exhibited congenitial depigmentation and multiple CALMs, while six (40.0%) also presented with axillary and/or inguinal freckling. Eleven patients (73.3%) showed severe phenotypes. Heterozygous KIT variants were identified in all patients, including five previously unreported variants detected in our cohort. Notably, 80% of variants were located within the tyrosine kinase (TK) domain, with significant enrichment in TK1 subdomain (66.7%). Patients with freckling exclusively carried TK domain variants. No pathogenic variants in NF1 or SPRED1 were detected. Although one patient carring an extracellular-domain variant also exhibited CALMs, TK domain variants were strongly associated with hyperpigmented manifestations. Conclusion This study expands the clinical and mutational spectrum of Chinese patients with piebladism accompanied by CALMS. Our findings further support an association between KIT TK-domain variants and complex pigmentary characrized by CALMs and freckling, while also indicating that this correlation is not absolute. Recognition of this phenotype is essential for distinguishing KIT- related pigmentary disorders from NF1 and avoiding unnecessary surveillance and genetic conseling.