The Muenke syndrome mutation (FgfR3^P244R) causes cranial base shortening associated with growth plate dysfunction and premature perichondrial ossification in murine basicranial synchondroses

Abstract

Muenke syndrome caused by the FGFR3 P250R 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 (FgfR3 P244R) 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,

Osteophyte formation and matrix mineralization in a TMJ osteoarthritis mouse model are associated with ectopic hedgehog signaling

“…Binary images were generated using a threshold of 280. Virtual 3D models were then constructed and analyzed for morphological abnormalities (Laurita et al, 2011). …”

The formation of the foramen magnum and its role in developing ventriculomegaly and Chiari I malformation in children with craniosynostosis syndromes

“…In addition to the cranial sutures, the synchondroses of the skull base also tend to be involved (Kreiborg et al, 1993;Laurita et al, 2011;Morriss-Kay and Wilkie, 2005). The timing of fusion of the skull base synchondroses varies, and a unique pattern for each synchondrosis exists; for example, the spheno-occipital synchondrosis (SOS) normally closes during adolescence (Madeline and Elster, 1995a), while the intra-occipital synchondroses (IOS) fuse in early childhood (Furuya et al, 1984;Madeline and Elster, 1995a).…”

Differential Closure of the Spheno-occipital Synchondrosis in Syndromic Craniosynostosis

“…3 Generally, the midface hypoplasia seen in Muenke syndrome is milder than that in Apert syndrome, and the cause for this difference is unclear. 4 The cranial base acts as a supporting platform for development of the brain, provides unique physical spaces for specialized organs such as the pituitary, and contains multiple growth centers that drive both cranial and upper facial growth. 5 It contains at least 25 different ossification centers that undergo a series of morphologic changes as they become assimilated into the mature basicranium.…”