The Muenke syndrome mutation (FgfR3P244R) causes cranial base shortening associated with growth plate dysfunction and premature perichondrial ossification in murine basicranial synchondroses

Authors

  • Jason Laurita,

    1. Division of Plastic and Reconstructive Surgery, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
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  • Eiki Koyama,

    1. Division of Orthopedic Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
    2. Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
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  • Bianca Chin,

    1. Division of Plastic and Reconstructive Surgery, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
    2. Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
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  • Jesse A. Taylor,

    1. Division of Plastic and Reconstructive Surgery, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
    2. Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
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  • Gregory E. Lakin,

    1. Division of Plastic and Reconstructive Surgery, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
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  • Kurt D. Hankenson,

    1. Department of Animal Biology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania
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  • Scott P. Bartlett,

    1. Division of Plastic and Reconstructive Surgery, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
    2. Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
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  • Hyun-Duck Nah

    Corresponding author
    1. Division of Plastic and Reconstructive Surgery, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
    2. Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
    • 1116G/ARC, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd., Philadelphia, PA 19104

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Abstract

Muenke syndrome caused by the FGFR3P250R mutation is an autosomal dominant disorder mostly identified with coronal suture synostosis, but it also presents with other craniofacial phenotypes that include mild to moderate midface hypoplasia. The Muenke syndrome mutation is thought to dysregulate intramembranous ossification at the cranial suture without disturbing endochondral bone formation in the skull. We show in this study that knock-in mice harboring the mutation responsible for the Muenke syndrome (FgfR3P244R) display postnatal shortening of the cranial base along with synchondrosis growth plate dysfunction characterized by loss of resting, proliferating and hypertrophic chondrocyte zones and decreased Ihh expression. Furthermore, premature conversion of resting chondrocytes along the perichondrium into prehypertrophic chondrocytes leads to perichondrial bony bridge formation, effectively terminating the postnatal growth of the cranial base. Thus, we conclude that the Muenke syndrome mutation disturbs endochondral and perichondrial ossification in the cranial base, explaining the midface hypoplasia in patients. Developmental Dynamics 240:2584–2596, 2011. © 2011 Wiley Periodicals, Inc.

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