Understanding craniosynostosis as a growth disorder

Abstract

Craniosynostosis is a condition of complex etiology that always involves the premature fusion of one or multiple cranial sutures and includes various anomalies of the soft and hard tissues of the head. Steady progress in the field has resulted in identifying gene mutations that recurrently cause craniosynostosis. There are now scores of mutations on many genes causally related to craniosynostosis syndromes, though the genetic basis for the majority of nonsyndromic cases is unknown. Identification of these genetic mutations has allowed significant progress in understanding the intrinsic properties of cranial sutures, including mechanisms responsible for normal suture patency and for pathogenesis of premature suture closure. An understanding of morphogenesis of cranial vault sutures is critical to understanding the pathophysiology of craniosynostosis conditions, but the field is now poised to recognize the repeated changes in additional skeletal and soft tissues of the head that typically accompany premature suture closure. We review the research that has brought an understanding of premature suture closure within our reach. We then enumerate the less well-studied, but equally challenging, nonsutural phenotypes of craniosynostosis conditions that are well characterized in available mouse models. We consider craniosynostosis as a complex growth disorder of multiple tissues of the developing head, whose growth is also targeted by identified mutations in ways that are poorly understood. Knowledge gained from studies of humans and mouse models for these conditions underscores the diverse, associated developmental anomalies of the head that contribute to the complex phenotypes of craniosynostosis conditions presenting novel challenges for future research. WIREs Dev Biol 2016, 5:429-459. doi: 10.1002/wdev.227 For further resources related to this article, please visit the WIREs website.

Figure 1

Three-dimensional (3D) reconstructions of computed tomography (CT) images of human infants depicting different types of single-suture isolated craniosynostoses. Views are superior (left) and inferior (right) with face towards the top and occiput towards the bottom. (A) unaffected individual; (B) two examples of metopic craniosynostosis; (C) bicoronal craniosynostosis (top), right unicoronal craniosynostosis (center), left unicoronal craniosynostosis (bottom); (D) two examples of sagittal craniosynostosis; (E) bilateral lambdoid craniosynostosis (top), Right unilateral lambdoid craniosynostosis (center), and left unilateral lambdoid craniosynostosis (bottom). Images from our craniofacial database modified from .

Figure 2

Coronal section showing layers from dermal epithelium to brain during osteogenesis (A) before bone formation and (B) corresponding layers after bone formation.

Figure 3

3D reconstructions of CT images of a neonatal human cranium (A & B) and newborn mouse cranium (C & D) illustrating corresponding cranial bones and sutures of the two species. In panels A and C, an oblique lateral view is shown at left and a superior view at right with face to towards top and occiput towards bottom of page. The human sagittal and metopic sutures (A) correspond to the murine interparietal and interfrontal sutures (C), respectively. Selected corresponding cranial bones in the neonatal human (B) and mouse (D) skull are shown. Labels for the various facial bones in these species can be found elsewhere^,263. The interparietal bone in mice is analogous to the most superior segment of the squamosal portion of the occipital bone in humans. The premaxilla is a separate bone in mice but is fused with the maxilla prior to birth in humans.

Figure 4

3D reconstruction of CT images of a human neonatal cranium. Left lateral view at top, superior view at middle, bones of the cranial vault removed to show endocranial surface at bottom. Face to the left, occiput to the right in all views. Crania are labelled according to A) cellular origin of cranial bones: neural crest in orange, mesoderm in blue; B) ossification type: intramembranous ossification in green, endochondral ossification in yellow; and C) cellular origin of cranial suture mesenchyme; neural crest in orange, mixed neural crest and mesoderm origin in fuchsia.

Figure 5

Stages of bone and cartilage lineage cell differentiation. A patent suture represents a gradient of bone lineage cells that become more differentiated moving from mesenchymal progenitor cells of the mid-suture to the osteogenic front. Once osteoblasts become encased in bone matrix they can either differentiate into osteocytes that become enveloped into the forming bone or undergo apoptosis. Though the differentiation of osteoblast lineage cells (top row) are diagrammed according to their role in cranial vault bone development, similar paths are taken by these cells during endochondral ossification. Cells on the bottom row show the chondrocyte lineage, which is involved in endochondral ossification. Recent research shows that hypertrophic chondrocytes retain the potential to differentiate into osteoblast precursors, osteoblasts, and osteocytes^,. Dashed lines show differentiation relationships that have not been confirmed in vivo. Diagram adapted from .

Figure 6

Suture anatomy. A) Two-photon laser scanning microscopy (2PLSM) image of a murine inter parietal suture; bone labeled fluorescently with calcein, two days postnatal (P2), coronal section. B) 2PLSM image of a murine coronal suture at P2 with bone labeled fluorescently with calcein; para sagittal section, frontal at left, parietal at right. Note that the interparietal (sagittal) suture is an abutting suture and the coronal an overlapping suture. C) Cell composition of interparietal suture, with meningeal layers below (pink - dura mater, gray - arachnoid mater, and black - pia mater). D) Cell composition of coronal suture with dura mater below (pink).

Figure 7

3D reconstruction of CT images of a human neonatal cranium (anterior/facial view at top and superior/cranial vault view at bottom with face towards top and occiput towards bottom of page) of a typically developing infant (far left) and infants with different craniosynostosis syndromes. The common cranial features associated with the syndromes shown here include: bicoronal synostosis (Apert, Crouzon, Pfeiffer, Saethre-Chotzen and Muenke), metopic synostosis (Saethre-Chotzen), orbital dysmorphology (either hypertelorism or Harlequin deformity: Apert, Crouzon, Pfeiffer, Saethre-Chotzen, Muenke), and midfacial retrusion (Apert, Crouzon, Pfeiffer, Saethre-Chotzen and Muenke syndromes).

Figure 8

Mutations of many genes of the FGF/FGFR pathway can cause craniosynostosis conditions. Red X’s indicate genes with identified mutations that cause craniosynostosis^,,,,–. Genes are colored according to function: FGF ligands (green), FGF receptor (blue), cell membrane (orange), downstream effectors of FGFR (purple). The end result of each of these mutations is to activate Runx2, which is necessary and sufficient for osteoblast differentiation. Additional unknown downstream contributors to craniosynostosis are indicated by the unlabeled hexahedron. Adapted from a figure presented by .

Figure 9

Diagram of gene interactions in the suture showing the approximate relative locations of gene expression involved in maintaining undifferentiated state of suture mesenchyme cells and causing differentiation of osteoblast lineage cells along the osteogenic front^{,,,,–,,,–}. A model proposed by Connerney et al., shows how TWIST1 heterodimers (T/E) and homodimers (T/T) regulate and are regulated by FGFR2 and BMP expression (blue lines)^,. A second model proposed by Merrill et al., shows how TWIST1 regulation of MSX2 is responsible for EPH/EPHRIN regulation of the boundary between suture mesenchyme and the osteogenic front (red lines)^,. Craniosynostosis is ultimately regulated by activation of RUNX2 and its downstream effectors. Genes known to cause craniosynostosis are colored green. Additional genes contribute to the processes diagrammed and other relationships among those genes included in the figure are possible.

Figure 10

Cellular origins of components of the coronal suture. A) Frontal bone (left) and parietal bone (right) border the mesoderm-derived mesenchymal cells of the coronal suture. B) Invasion of neural crest-derived osteogenic cells into mesoderm-derived mesenchymal cell population as a result of improper cellular boundary formation that leads to premature fusion of the suture.