Cranial Sutures and Skull Development PDF

Cranial Sutures and Skull Development Phrenology? Karen Liu Centre for Craniofacial and Regenerative Biology [email protected] Disproportionate growth of the skull The newborn face is only about 1/8th of the head. This changes to about 1/2 by adulthood. Questions: Which part of the skull is closes...

Cranial Sutures and Skull Development Phrenology? Karen Liu Centre for Craniofacial and Regenerative Biology [email protected] Disproportionate growth of the skull The newborn face is only about 1/8th of the head. This changes to about 1/2 by adulthood. Questions: Which part of the skull is closest to adult size? Which part of the skull grows the most? What drives this growth? Figures from http://www.hopkinsmedicine.org/craniofacial/LynmProject/#TOC How does the infant skull grow? Anterior fontanelle ‘soft spot’ Bones: P = parietal F = frontal P Sutures are fibrous joints between the skull bones. P Sutures: Sagittal suture They provide some elasticity and movement. Coronal suture F F Interfrontal or Metopic suture At birth, they are generally unfused. Doctors feel the skull and fontanelles to assess development of the baby. Meikle, Figure 7.4 Fontanelles Fontanelles are the membrane covered spots in the calvaria where three or more bones converge. Fontanelles are larger than sutures at birth but rapidly diminish in size as calvarial bones grow. Fontanelles (time of closure) F1: Anterior fontanelle (2 years) F2: Posterior fontanelle (first few months) F3: Sphenoidal fontanelle (first few months) F4: Mastoid fontanelle (first few months) Like sutures, they are flexible. Doctors feel the skull and fontanelles to assess health and development of the baby. ‘Straight’ sutures in young humans Sutures: Coronal suture Parietal bone Frontal bone ls: lambdoid suture ls Occipital bone Squamosal suture Temporal bone Sutures are sites of bone growth articulations to provide some elasticity and movement. mechanical stress absorbers Continuous growth of the skull relies on sutures remaining patent (open and unfused). Premature fusion of cranial sutures leads to craniosynostosis. What processes cause this convoluted zig-zag shape in older skulls? Sutures: cs: coronal suture ss: squamosal suture ls: lambdoid suture Frontal bone Parietal bone ls Occipital bone Temporal bone Sutures are ‘tension adapted’ Growth of the brain pushes the skull bones out; this results in tension at the sutures. This tension induces new bone growth. Deposition and resorption of bone are ongoing processes. Growth factor signaling controls bone formation - cellular & tissues Facial sutures: Are these sutures driving the growth of the face? newborn adult F fms fzs N E Figure from http://www.hopkinsmedicine.org/craniofacial/LynmProject/#TOC Facial Sutures fns: Frontonasal fms: Frontomaxillary fzs: Frontozygomatic nms: Nasomaxillary ims: Intermaxillary (median palatine) zts: zygotemporal zms: zygomaxillary zts Z fns zms L M nms ims Figure courtesy Dr. David Rice Facial Bones (in picture) F: Frontal (really a cranial bone) N: Nasal L: Lacrimal E: Ethmoid (another cranial bone) M: Maxilla Z: Zygomatic Facial sutures: orientation of suture determines direction of facial growth Facial sutures are active into adolescence. Zygomaticofrontal suture The four sutures marked in red are more or less parallel to each other. Maxillary growth could be due to growth at these sutures, resulting in downward/ forward movement of face. How does this theory compare with what we know about ‘tension adapted’ growth at the cranial sutures? Could anything be providing ‘tension’ in the facial sutures? Meikle, Figure 8.14 Mature suture structure from Ten Cate, Figure 6.34 Suture - strong tie/ joint site for new bone formation Cambian layer – osteogenic Capsular central zone – relatively inert Growth can occur independently at the bony margins. Site of osteogenesis Intramembranous ossification No cartilage anlagen 3. Mature osteoblast Bone Bone Dura mater 2. Osteoprogenitor Growth factors 1. Undifferentiated mesenchymal cell Suture morphology (mouse metopic suture) Fig 1C, Warren et al, Nature 2003 Which of these sutures meets end-on in a butt joint? overlaps to form a beveled joint? Sutures of the palate seven year old human zms M Sutures zms: zygomaxillary mps: median palatine (intermaxillary) tps: transverse palatine ips: interpalatine M zms mps tps P tps ips P Figure courtesy Dr. David Rice Bones M: Maxilla P: Palate What kind of suture is this? Why is it still patent? Palatal suture 5-6 yrs 6-7 yrs Figures courtesy Dr. David Rice Palatal suture Median palatine suture Transverse palatine suture Adult: fused 9-10 yrs Figures courtesy Dr. David Rice Palatal expansion Tension adaptation Suture patent Figures courtesy Dr. David Rice Can you do this if the suture is fused? Palatal expansion using distraction osteogenesis Tension adaptation Force applied using an expansion screw can separate the two halves of the maxillary complex. Tension induced bone growth and deposition at the intermaxillary/palatine suture results in maxillary expansion. from Meikle, Figure 8.17 Palatal expansion Tension adaptation Movement of maxilla versus movement of teeth Notice the gap in the front teeth when using the expander. Why is there no gap in the teeth after the procedure? 5 weeks 8-9 weeks http://embryology.med.unsw.edu.au/wwwhuman/Hum12wk/Hum12wk.htm#12weekHead Calvarial bone development is synchronized with brain development suture parietal bone brain cranial base parietal bone What happens when a cranial suture fuses prematurely? Craniosynostosis 1:2500 live births Growth of the skull is restricted. The expansion of the underlying brain is now accommodated by growth at other sutures. Incidence: 1:3500 Asymmetry Raised eyebrow Treatment: surgery Craniosynostosis: Unicoronal plagiocephaly p p f f Courtesy of Jyri Hukki and David Rice Single suture craniosynostosis Incidence: 1:2500 - 3500 Ridged forehead Incidence: 1:2000 Most common form of craniosynostosis Treatment: surgery Craniosynostosis: premature suture fusion Bicoronal Metopic Sagittal www.muhealth.org Craniosynostosis – facial growth Pictures courtesy Dr. David Rice Genes Causing Craniosynostosis Syndromic Craniosynostosis Fibroblast growth factor receptors: FGFR1 (Pfeiffer) FGFR2 (Crouzon, Apert, Pfeiffer) FGFR3 (Non Syndromic, Crouzon) Transcription Factors: TWIST (Saethre-Chotzen) MSX2 (Boston Type) Apert syndrome FGFR2 Craniosynostosis Midface malformations Teeth - malocclusion, delayed eruption Palate - narrow, lateral swellings cleft soft palate, uvula Gorlin, Cohen & Hennekam 2001 Apert Syndrome Severe syndactyly (bony and cutaneous fusion of hand and feet) and other unique phenotypes including visceral and skin manifestations D2-D3 FGFR2 linker mutations responsible for AS ~67% Ser252Trp 32% Pro253Arg Mutations are manifested in both FGFR2 splice forms Crouzon syndrome FGFR2 or 3 Craniosynostosis Midface - hypoplasia Eyes - shallow orbits, proptosis Dental – crowding, X bites, ectopic eruption of 6’s Normal hands 1:64,5000 live births Autosomal dominant FGFR2 mutations Courtesy of Prof M Meikle synostosis of the coronal suture often in combination with sagittal or lambdoid sutures thin calvarial bones Locations of Point Mutations in FGFR1, FGFR2, and FGFR3 Giving Rise to Cranial Deformities Mouse models of suture development Why study human diseases in mice? Mouse remains the premier mammalian animal model Examine function by observing consequences of disrupting a gene in a mammalian system Make mutations that mimic human genetic mutations Easy to do experiments: small, easy to grow Mutant mouse serves as a reagent for both basic studies and pharmaceutical applications Fgfr2C342Y/+ mice are a model for Crouzon Syndrome 3-D CT scans of infants a. normal b. Crouzon Mouse mutant: Fgfr2C342Y/+ 3D CT scan of 6 wk old mouse showing craniosynostosis of coronal and sagittal sutures Reference: Figure 1 “A model for the pharmacological treatment of Crouzon Syndrome” Perlyn, C.A., Morriss-Kay, G., Darvann, T., Tenenbaum, M., Ornitz, D.M., Neurosurgery 59:210-215 2006 Fgfr2C342Y/+ mice are a model for Crouzon Syndrome Reference: Figure 2 Perlyn, et al., 2006 Fgfr2C342Y/+ mice are a model for Crouzon Syndrome Reference: Figure 4 Perlyn, et al., 2006 Reference: Figure 5 Perlyn, et al., 2006 Site of osteogenesis Intramembranous ossification No cartilage anlagen 3. Mature osteoblast Bone Bone Dura mater FGFR? 2. Osteoprogenitor Fibroblast Growth Factor? 1. Undifferentiated mesenchymal cell FGF ligand Hypothesis: FGF signaling induces Twist FGFR receptor Cell surface Proliferation? Differentiation? Rice e Nucleus TRANSCRIPTION TWIST In vitro culture of calvaria A B Grid Bead D Bone Filter Explant C Bone Figure courtesy Dr. David Rice FGF2 bead induces Twist expression B A Whole mount Sectioned tissue Kim and Rice et al 1998 FGF signaling induces Twist during bone formation FGF ligand FGFR receptor Cell surface Proliferation? Differentiation? Rice e Nucleus TRANSCRIPTION TWIST Rice et al. 2003 Dev Biol Rice et al. 2000 Development Kim et al. 1998 Development Sagittal suture synostosis Coronal suture Pre operation Age: 4 months Lambdoidal suture Operation Age: 6 months Courtesy of Jyri Hukki and David Rice Sagittal suture synostosis Targeted therapeutics 1 year post operation Age: 20 months Reossification Courtesy of Jyri Hukki and David Rice Understand molecular pathology Understand normal development/growth Treat deformity Any Questions? Karen Liu Centre for Craniofacial and Regenerative Biology [email protected]