Further Evidence of Early-Onset Osteoporosis and Bone Fractures as a New FGFR2-Related Phenotype

Area of Science:

• Genetics
• Pediatrics
• Orthopedics

Background:

• Primary osteoporosis in pediatric populations often indicates an underlying monogenic disorder affecting bone density and structure.
• While Osteogenesis Imperfecta is a well-known genetic cause, other genes influencing bone metabolism are implicated.
• Fibroblast Growth Factor Receptor 2 (FGFR2) is crucial for bone development, regulating osteoblast and chondrogenesis.

Observation:

• Germline pathogenic FGFR2 variants are typically linked to syndromic craniosynostosis, not bone fragility.
• A previous report suggested FGFR2 variants as a cause of dominant early-onset osteoporosis.
• This study details a child with severe osteoporosis and multiple fractures.

Findings:

• Clinical exome sequencing in a trio identified a likely mosaic pathogenic FGFR2 variant in the affected child.
• The identified variant was absent in both parental samples, suggesting a de novo occurrence.
• This case provides further evidence for FGFR2 variants causing a non-syndromic bone mineralization disorder.

Implications:

• FGFR2 pathogenic variants can lead to early-onset osteoporosis and bone fractures, independent of craniosynostosis.
• This expands the genetic spectrum of pediatric osteoporosis and bone fragility disorders.
• Understanding FGFR2's role in bone pathogenesis is critical for diagnosing and potentially treating these conditions.