Myogenic dysregulation underlies tongue overgrowth in Beckwith-Wiedemann syndrome

Summary Macroglossia is a clinically significant feature of Beckwith-Wiedemann syndrome (BWS), but the cellular basis of tongue overgrowth remains poorly defined. Here, 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 prospectively isolated tongue satellite cells do not exhibit enhanced proliferation under growth conditions in vitro . Instead, BWS progenitors adopt distinct differentiation-associated regulatory states. IC2 loss of methylation cells sustain proliferative activity during differentiation and form enlarged myotubes, consistent with a cell-autonomous hypertrophic program. In contrast, pUPD11 cells display activation of NOTCH signaling and progenitor-associated programs, together with attenuated progression toward terminal myogenic differentiation. These findings identify skeletal muscle hypertrophy as a core tissue-level feature of BWS macroglossia and reveal that epigenetically defined BWS subtypes engage divergent myogenic programs that converge on a shared hypertrophic tissue phenotype. Together, these data define subtype-specific myogenic states in a rare human disease tissue and provide a framework for understanding how distinct epigenetic changes can produce a common overgrowth phenotype. Highlights BWS macroglossia is associated with skeletal muscle fiber hypertrophy, not fiber hyperplasia Tongue satellite cell abundance and proliferation are not increased in situ in BWS IC2 loss of methylation cells sustain proliferation during differentiation and form enlarged myotubes pUPD11 cells show enhanced NOTCH signaling and a constrained myogenic state In brief Tichy et al. show that Beckwith-Wiedemann syndrome macroglossia is driven by skeletal muscle hypertrophy and that distinct BWS molecular subtypes engage different myogenic regulatory programs. IC2 loss of methylation cells sustain proliferation during differentiation, whereas pUPD11 cells exhibit NOTCH-associated restraint of myogenic progression.