Molecular Basis and Clinical Spectrum of WNT10A-Related Oligodontia

WNT10A mutations, a major genetic determinant of dental agenesis and ectodermal dysplasia, exert profound effects on craniofacial development. Although classified as rare disorders, these mutations account for more than half of oligodontia cases, reflecting their critical role. The associated phenotypes span a broad clinical spectrum, ranging from isolated tooth agenesis to complex multisystem disorders, including hypodontia, enamel and root defects, palmoplantar keratoderma, alopecia, nail dystrophy, skin xerosis, hypohidrosis, eyelid cysts, and skin cancer, skeletal abnormalities and impaired bone homeostasis, underscoring their systemic impact. This review synthesizes current biological and clinical knowledge by linking phenotypes of WNT10A mutations to disruptions in Wnt/β-catenin signaling and its interactions with BMP, SMAD, RANK/RANKL/OPG, VEGF, and other regulatory pathways. Altered pathway activity affects key processes in tooth morphogenesis, osteogenesis, cellular proliferation, and tissue maintenance, offering mechanistic explanations for the heterogeneity and severity of patient presentations. A clearer understanding of these pathways is essential for improving diagnosis and management of WNT10A-associated oligodontia, particularly in treatment planning for growth-dependent interventions, regenerative strategies, and implant rehabilitation. Despite significant progress, critical gaps remain in defining the molecular basis of variable expressivity and genotype-phenotype relationships. Elucidating these mechanisms will be pivotal for advancing precision approaches in dental and craniofacial care.