KDF1 (keratinocyte differentiation factor 1) is a developmental regulator essential for ectodermal derivative formation, particularly dental and epithelial development. Functionally, KDF1 acts as a negative regulator of epithelial cell proliferation while promoting differentiation, maintaining the critical balance between these processes 1. At the molecular level, KDF1 modulates dental epithelial cell proliferation through the PI3K/AKT/mTOR signaling pathway 2, and suppresses canonical Wnt signaling activation 3. Clinically, KDF1 variants cause two distinct phenotypes: non-syndromic tooth agenesis (NSTA), characterized by missing teeth averaging 15 per individual 4, and hypohidrotic ectodermal dysplasia with broader ectodermal involvement affecting hair, nails, and teeth 1. Genotype-phenotype correlations reveal that variants clustered in the DUF4656 domain (amino acids 251-275) associate with ectodermal dysplasia, while variants in amino- or carboxy-terminal regions cause isolated tooth agenesis 4. Beyond tooth number, KDF1 mutations produce specific dental morphological defects including abnormal enamel structure with reduced mineralization, altered crystal ordering, and blunted molar cusps 52, alongside oral epithelial dyskeratosis 3. These findings establish KDF1 as a critical regulator of human dental development and ectodermal differentiation.