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The primary retention of molars observed in clinic corresponds to a still-unexplained absence of molar eruption despite the presence of an eruption pathway, resembling the experimental transient inhibition of RANKL signaling in mice. The aim of the present study was to confront the hypothesis according to which the primary retention of molars is associated with transitory perturbations to RANKL signaling during growth as part of a wider craniofacial skeleton pattern. The experimental strategy was based on combining a clinical study and