Table 1.
Neural Crest Mechanisms Underlying Coronal Craniosynostosis.
| Human Syndrome | Associated Mouse Model Genetic Mutation | Human Craniofacial Phenotype |
Proposed Mechanism(s) of Anomaly |
|---|---|---|---|
| Craniofrontonasal Syndrome (OMIM #304110) |
Efnb1−/− | anterior-posteriorly shortened skull, facial dysmorphologies, coronal suture fusion * | Neural crest-specific disruption of Efnb1 disrupts lineage-based boundary formation of coronal suture [137,142]. |
| Apert Syndrome (OMIM #101200) |
Fgfr2 S252W/+ | Coronal, sagittal, lambdoid suture fusion; proptosis, hypertelorism, midface hypoplasia | Enhanced osteogenic differentiation along osteogenic front of parietal bone enhanced by neural crest-derived frontal bone [91,93,126]. |
| Crouzon Syndrome (OMIM #123500) |
Fgfr2 C342Y/+ | Coronal suture fusion, proptosis, hypertelorism, midface hypoplasia | Embryonic dysregulation of Sox9 expression causing mesenchymal condensation defects, symptoms of neural tube defects, plus decreased craniofacial osteogenesis and increased chondrogenesis; postnatal enhanced osteogenic differentiation within osteogenic fronts; [84,87,130]. |
| Muenke Syndrome (OMIM #602849) |
Fgfr3P250R/+ | Coronal suture fusion; pansynostosis; hearing loss; midface hypoplasia | Hearing loss due to embryonic fate switch of neural crest derived cochlear Deiters’ cells to pillar cells [143,144]. |
| Bent Bone Dysplasia (OMIM #614592) |
FGFR2C1172T Φ | Coronal suture fusion; midface hypoplasia; prenatal teeth; low set ears; micrognathia; diminished bone mineralization; bent long bones | Mutations promote ribosomal transcription within the nucleus leading to enhanced osteoprogenitor cell proliferation with diminished differentiation [145,146]. |
| Saethre-Chotzen Syndrome (OMIM #101400) |
Twist1 +/− | Coronal suture fusion, low hairline, hypertelorism, ptosis, broad nasal bridge, digit fusions | Disruption of lineage-based boundary formation of coronal suture and cell lineage mixing. Enhanced osteogenic potential of parietal vs. frontal bones [10,90,135,147]. |
| TCF12 (OMIM # 600480) |
Tcf12+/−/Twist+/− | Described as a milder form of Saethre-Chotzen syndrome. Coronal suture fusion, facial dysmorphologies, minor limb abnormalites | TCF12 is dimerization partner for TWIST1. Double mutant mice show accelerated parietal and/or frontal bone growth plus diminished pool of osteoprogenitors in coronal suture [147,148]. |
| Non-Syndromic Coronal Synostosis | EphA4−/− and Twist1+//EphA4+/− | Coronal suture fusion | Disruption of boundary formation and neural crest/mesoderm cell lineage mixing due to lack of Twist1 and its effector EphA4 [85]. |
| Infantile Hypophosphatasia (OMIM #241500) | Alpl −/− | Coronal or sagittal suture fusion #, hypomineralization, midface hypoplasia. | Hypomineralization and cell proliferation defects more severe in cells of neural crest derived craniofacial bones; enhanced FGFR2 signaling in osteoprogenitors; [149,150]. |
* The Efnb1−/− mouse craniofacial phenotype does not correspond to the human craniofacial phenotype. The Efnb1−/− mouse has an anterior-posteriorly shortened skull but does not have craniosynostosis, as is seen in individuals with Craniofrontonasal Syndrome. # The Alpl−/− mouse model of hypophosphatasia develops coronal but not sagittal suture fusion, while fusion of coronal or other cranial sutures may be evident in infants with this metabolic disorder. Φ The Bent Bone Dysplasia mutation in FGFR2 is a human mutation that has been studied in vitro (to our knowledge, no mouse model has yet been developed).