Researchers at Children’s Hospital of Philadelphia (CHOP) identified new clues to why some children with Beckwith-Wiedemann syndrome (BWS), a rare genetic condition that causes overgrowth and increases the risk of certain childhood cancers, develop unusually large tongues. The study, published in iScience, found that tongue enlargement, known as macroglossia, is driven by enlarged tongue muscle fibers rather than an increased number of muscle fibers.
BWS is linked to changes that control growth on chromosome 11. Macroglossia is one of the condition’s most common and clinically noteworthy features. Severe cases can interfere with breathing, feeding and speech, affect dental and jaw development, and require tongue-reduction surgery in early childhood.
The CHOP team studied tongue tissue from children with genetically confirmed BWS who underwent tongue-reduction surgery. They compared tissue from children with the two most common BWS subtypes with samples from similarly aged children without BWS. Researchers examined muscle structure and studied muscle stem cells in the laboratory. They found that BWS subtypes had significantly larger skeletal muscle fibers in the tongue.
“Our findings help answer a longstanding question about macroglossia in BWS,” said Jennifer M. Kalish, MD, PhD, the study’s corresponding author, a pediatric geneticist at CHOP, and Director of the CHOP Beckwith-Wiedemann syndrome program. “The tongue appears to grow because individual muscle fibers become oversized, a process called hypertrophy, rather than because the tongue produces more muscle fibers.”
Researchers also examined satellite cells, the muscle stem cells responsible for growth and repair. Children with BWS had no increase in the number of satellite cells in tongue tissue, and these cells did not typically grow faster in the laboratory. The researchers suggest tongue enlargement may result from earlier developmental changes and altered muscle-cell maturation rather than ongoing stem-cell expansion.
Cells from children with pUPD11 – a genetic change in which part of the paternal chromosome 11p15 replaces part of the maternal copy – behaved differently. They showed increased activity in the NOTCH signaling pathway, which helps regulate cell development and can keep muscle stem cells in a less mature state. Although these cells appeared less likely to complete normal muscle development under laboratory conditions, children with pUPD11 still had enlarged tongue muscle fibers.
The researchers suggest that signals from surrounding cells and tissues may contribute to abnormal tongue-muscle growth in this subtype. Future research will examine the earliest stages of tongue-muscle development and the role of surrounding cells, and work towards development of possible treatment targets.
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Researchers at Children’s Hospital of Philadelphia (CHOP) identified new clues to why some children with Beckwith-Wiedemann syndrome (BWS), a rare genetic condition that causes overgrowth and increases the risk of certain childhood cancers, develop unusually large tongues. The study, published in iScience, found that tongue enlargement, known as macroglossia, is driven by enlarged tongue muscle fibers rather than an increased number of muscle fibers.
BWS is linked to changes that control growth on chromosome 11. Macroglossia is one of the condition’s most common and clinically noteworthy features. Severe cases can interfere with breathing, feeding and speech, affect dental and jaw development, and require tongue-reduction surgery in early childhood.
The CHOP team studied tongue tissue from children with genetically confirmed BWS who underwent tongue-reduction surgery. They compared tissue from children with the two most common BWS subtypes with samples from similarly aged children without BWS. Researchers examined muscle structure and studied muscle stem cells in the laboratory. They found that BWS subtypes had significantly larger skeletal muscle fibers in the tongue.
“Our findings help answer a longstanding question about macroglossia in BWS,” said Jennifer M. Kalish, MD, PhD, the study’s corresponding author, a pediatric geneticist at CHOP, and Director of the CHOP Beckwith-Wiedemann syndrome program. “The tongue appears to grow because individual muscle fibers become oversized, a process called hypertrophy, rather than because the tongue produces more muscle fibers.”
Researchers also examined satellite cells, the muscle stem cells responsible for growth and repair. Children with BWS had no increase in the number of satellite cells in tongue tissue, and these cells did not typically grow faster in the laboratory. The researchers suggest tongue enlargement may result from earlier developmental changes and altered muscle-cell maturation rather than ongoing stem-cell expansion.
Cells from children with pUPD11 – a genetic change in which part of the paternal chromosome 11p15 replaces part of the maternal copy – behaved differently. They showed increased activity in the NOTCH signaling pathway, which helps regulate cell development and can keep muscle stem cells in a less mature state. Although these cells appeared less likely to complete normal muscle development under laboratory conditions, children with pUPD11 still had enlarged tongue muscle fibers.
The researchers suggest that signals from surrounding cells and tissues may contribute to abnormal tongue-muscle growth in this subtype. Future research will examine the earliest stages of tongue-muscle development and the role of surrounding cells, and work towards development of possible treatment targets.
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Beckwith-Wiedemann Syndrome and Overgrowth Genetics Clinic