Myogenic dysregulation underlies human tongue overgrowth in Beckwith-Wiedemann syndrome

Abstract

Summary Macroglossia is a clinically significant feature of Beckwith-Wiedemann syndrome (BWS), but the cellular basis of tongue overgrowth remains poorly defined. Using pediatric tongue specimens from molecularly defined BWS subtypes and age-matched nonBWS controls, we show that BWS macroglossia is characterized by skeletal muscle fiber hypertrophy rather than increased fiber number. This phenotype is not explained by expansion or increased proliferation of satellite cells in situ, and isolated tongue satellite cells do not exhibit enhanced proliferation under growth conditions in vitro. Instead, BWS progenitors adopt distinct differentiation-associated regulatory states. Imprinting control region 2 (IC2) loss-of-methylation cells sustain proliferative activity during differentiation and form enlarged myotubes, consistent with a cell-autonomous hypertrophic program. In contrast, paternal uniparental disomy of chromosome 11 (pUPD11) cells display NOTCH pathway activation and progenitor-associated programs, with attenuated progression toward terminal myogenic differentiation. Together, these findings identify subtype-specific myogenic states that converge on a shared hypertrophic tissue phenotype in BWS macroglossia.