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CLP paper overview
- The cleft is ultimately caused by interference with shelf elevation, attachment, or fusion.
- Shelf elevation is brought about by mesenchymal proliferation and changes in the ECM induced by growth factors such as TGF-βs.
- Crucial ECM molecules are collagens, proteoglycans, and glycosaminoglycans.
- Shelf attachment depends on specific differentiation of the epithelium involving TGF-β3, sonic hedgehog, and WNT signaling, and correct expression of epithelial adhesion molecules
- such as E-cadherin.
- The final fusion requires epithelial apoptosis and epithelium-to-mesenchyme transformation regulated by TGF-β and WNT proteins.
TGFβ-3 and FGFs
The inactivation of these genes consistently causes cleft palate because of abnormal cell proliferation, impaired adhesion of the opposing palatal shelves, and/or aberrant fusion with other structures
Variations in WNT or TGFβ genes could result in deficient expression and contribute to palatal clefting
- The nose and the mouth area of pictures of faces with a unilateral
- cleft lip and palate were looked at significantly longer by both groups.
IRF6 gene environment CL/P
- Evidence of G x E interaction was found for both maternal exposures, multivitamin supplementation and environmental tobacco smoke (ETS)
- suggest IRF6 gene may infuence risk of CL/P through interaction with multivitamin supplementation
- and ETS in the Chinese population
BMP4 and environment
Associations between offspring polymorphism of BMP4, paternal smoking, paternal high-risk drinking, maternal passive smoking, and maternal multivitamin supplement with nsCL/P were analyzed
BMP4 could be used as a genetic susceptibility marker for nsCL/P;
- maternal passive smoking exposure is a risk factor for nsCL/P;
- maternal multivitamin supplements are a protective factor;
- nsCL/P is determined by genetic and environmental factors.
- Parents identiﬁed crucial factors including
- the early need for support (including parent support groups),
- for credible information,
- and for advice for daily life.
- Surgery was a major factor affecting satisfaction and quality of life,
- and satisfaction depended not only on surgical results but importantly on communication, empathy, expectations, postsurgical care, and discharge management.
- Combining these crucial issues with a life-stage approach provides a framework for intervention that focuses on drivers of quality of life at selected milestones in the life of children with oral clefts.
BMP2 and CL/P
- Despite a signiﬁcant role for the BMPs in orofacial development, heterozygous loss of BMP2 has not been
- previously reported in patients with syndromic clefting defects.
- Haploinsufﬁciency for BMP2 is a crucial event that predisposes to cleft palate and additional anomalies (variable expressivity for phenotype)
CBCT (cone beam) and Cleidocranial Dysplasia (CCD)
- CBCT exam in the dental evaluation of patients with Cleidocranial Dysplasia (CCD), an autosomal dominant(RUNX2) skeletal dysplasia with delayed exfoliation of deciduous and eruption of permanent teeth and multiple supernumeraries, often impacted.
- useful both in the diagnostic process and in the ortho treatment planning, with an important reduction in the radiation dose absorbed by the patient
Treacher collins & body ramus angle relations
- The purpose of this study was to objectively analyze the body-ramus relation in Treacher Collins compared with control subjects and to investigate the effect of age
- mandibular plane angle (MPA)
- ramus body angle (RBA)
- The mean RBAs and MPAs for the Treacher Collins were higher than comparison groups.
- The clockwise relation of the mandibular body relative to the ramus is objectively documented in Treacher Collins subjects.
- This relation persists despite increasing age, in distinction to control subjects where the mandibular plane ﬂattens in adolescence.
FGFR2 mutations and craniosynostosis
- mutations described in FGFR2 resulting in syndromic craniosynostosis including Apert, Crouzon, or Pfeiffer syndromes.
- FGFR2 mutations were present in 9.8% of patients with craniosynostosis who were included in a prospectively ascertained sample, but no mutations were found in association with isolated fusion of the metopic or
- sagittal sutures.
- The spectrum of FGFR2 mutations causing craniosynostosis is wider than previously recognized but that, nevertheless, the IgIIIa/IIIc region represents a genuine mutation hotspot.
- only type of patient that can survive some syndromes
- don’t have full phenotype of the disease
Pre-implantation period (WEEK 1)
- (from fertilization to implantation: 0-6 days)
- Zygote, 2 cells, 4 cells, 8 cells, ~16 cells, blastocyst, implantation
- Bilaminar (2 layers) disc- epiblast and hypoblast (WEEK 2)
- Trilaminar (3 layers) disc- middle cell layer from migratory cells of dividing epiblast layer (WEEK 3)
PRIMARY GERM LAYERS:
- Ectoderm (from epiblast cells) Epidermis, oral mucosa, enamel
- Mesoderm (from migrating epiblast cells) Skeletal muscle
- Endoderm (from hypoblast cells) Gut lining
- [Neural crest cells (from migrating neuroectoderm)] CT, cartilage, bone, dentin, cementum, pulp, periodontal ligament
POLARITY of disc
- -cephalic end (head)
- -oropharyngeal membrane (mouth)
- -caudal end (tail)
Neuralation (WEEK 3)
- ○ Notochord forms from mesoderm layer- support, midline for future, induces neuralation
- ○ Ectodermal cells (neural fold making neural groove) divide faster and pinch off to form neural tube (brain and spinal cord)
- ○ *folic acid supplementation BEFORE pregnancy to prevent neural tube defects
- ○ neural crest cells migrate from ectoderm into mesoderm, to form ectomesenchyme (connective tissue for craniofacial development). Failure of migration can lead to underdeveloped mandible (treacher collins), fusion failure, etc.
Embryonic Folding (WEEK 4)
- Lateral axis folding- epidermis surrounds body
- Head/Tail folding- mouth on proper surface
- Post folding-FASTER head growth
increase in complexity (1st trimester)
prominence due to differential growth
localized thickenings (lens and nasal)
from separate to fused
groove levels out
agents that cause developmental defects (eg-drugs, xrays, alcohol)
Craniofacial development (WEEK 4-12)
- Branchial (pharyngeal) arch formation:
- -1st (mandibular) arch:
- ○ Mandibular processes fuse at midline - true fusion
- ○ Maxillary processes grow on sides of stomodeum
- ○ Frontonasal process grows (along with underlying brain)
- ○ Medial nasal processes fuse with each other (apparent fusion)
- ○ Medial nasal processes fuse with maxillary process (true fusion)
- ○ *CLEFT LIP- fusion failure of maxillary and medial nasal process
- ○ *CLEFT PALATE-fusion failure of frontonasal processes
- -Palate formation:
- ○ Palatal shelves grow vertically
- ○ Palatal shelf elevation- Mandible lowers, tongue lowers, palatal shelves move horizontally closer to each other
- ○ Anterior fusion: primary palate (intermaxillary segment) to secondary palates
- Posterior fusion: secondary palates to each other
- a. De novo (from nucleus)
- b. Bone matrix
- c. Ossification in ectomesenchyme
- d. EG-AT 7 WKS LATERAL TO MECKELS CARTILAGE
- Bone replaces cartilage
- EG- AT 12 WKS IN MANDIBLE
- - Articulation between mandibular condyle AND mandibular fossa of temporal bone
- - Synovial joint but with exceptions...
- ○ articular disc divides space into upper and lower cavities , NOT one big space (like knee)
- ○ made of fibrous cartilage, NOT hyaline cartilage (NOT CALCIFIED)
- - Late embryogenesis
- - Movement: Rotation (open ~1 inch) and Translation (fully open)
- - Joint spaces formed from selective cell death:
- ○ Hyaline cartilage grows superiorly
- ○ Cartilage cells die and condyle bone fills in (endochondral)
- ○ Hyaline cartilage gets COVERED by fibrous CT
- 7 weeks intramembranous bone forms lateral to meckels cartilage
- 12 weeks Endochondral bone formation (condyle)
- 14 weeks Mandible muscles form
- 17 weeks complete
- - Neural crest cells
- - From neural folds of neural plate (neuroectoderm)
- - From signals (BMP, notch, Wnt, FGF)
- - Ectomesenchyme is site of orofacial development
- - Anterior Cranial NC cells migrate into frontonasal skeleton
- Posterior Cranial NC cells migrate into branchial arches
- - Branchial (pharyngeal) arches
- - underneath frontal prominence
- - 6 pairs: 1-2 for most of middle/lower face, 4-6 for neck
- - Branchial grooves outside, pharyngeal grooves inside
- - ARCH 1: maxillary and mandibular processes, meckels cartilage
- ARCH 2: hyoid bone, temporal bone, reicharts cartilage
- ARCH 3: tongue
- ARCH 4 (5): tongue, laryngeal cartilage
- ARCH 6: laryngeal cartilage
- - primordia (ectodermal swellings):
- ○ Frontonasal prominence=middle nose, upper lip, maxilla, primary palate
- Maxillary prominence
- Mandibular prominence
- - MAJOR EVENT: mesenchyme proliferation=medial and lateral nasal processes, medial nasal processes fuse internally (intermaxillary segment)to make primary palate, medial nasal processes and maxillary process contact, lateral nasal process gets pushed OUT
- - Primary palate (outgrowth and fusion of intermaxillary segment) formation-Medial nasal processes fuse internally
- - Primary palate now separates Nasal cavities (separated by nasal septum medially) above and primitive oral cavity below
- - Behind primary palate is oronasal cavity
- - Beginning of palatal shelves (from maxillary processes) forming behind primary palate
- [WEEK 6/7 GROWTHS: SECONDARY NASAL SEPTUM & PALTINE SHELVES]
- - Tongue and palate shelves continue to form
- - Shelves now lie vertically and grow superiorly (elevation)
- - 2 DNA synthesis peaks during initial shelf outgrowth and vertical elongation
- - Tongue drops
- - Shelves now lie horizontally and grow medially (main elevation)*
- - Stomodeum enlargens
- - Shelves begin to fuse with each other-secondary palate is formed
- - Shelves fuse with primary palate-full seperation of oral and nasal cavities
- - Fusion is between medial edge epithelia (epithelial cells at medial edges)
- - 2 mee's adhere* at midline epithelium seam!
- - Complete palatal process fusion
- - OSSIFICATION
- ○ 4 intramembranous ossification centers (2 maxilla, 2 palatine)
- ○ Incomplete ossification=transverse & medial palatine sutures
- - Type of GAG
- - Increases just before elevation (opposite of most GAGs)
- - HA synthesizing enzmes and HA binding protiens are found in shelves
- - HA digestion and reduced weight HA prevent normal elevation
- (mesenchymal cells)
*MEE adherence (fusion)
- - Seam forms and then degenerates for fusion to occur fully:
- ○ Seam apoptosis?
- ○ Epithelial cells migrate away from seam?
- ○ Epithelial cells TURN INTO mesenchymal cells?
- - CRITICAL epithelial-mesenchymal interaction (this possibly occurs due to paracrine signalling to each other because of loss of basement membrane!!!)
- - Differentiation of mesenchymal cells produce different palatal processes
- - Adherence Via sticky glycoprotiens and seam formation via desmosomes
- - shelf epithelia adhere ONLY to each other!
- - TGFB3
- ○ Critical for MEE initial palatal fusion
- ○ TGFB3 signalling results in MMPs in MEE or mesenchymal cells
- ○ TGFBR2 inactivation in NC cells=cranial abnormalities
- ○ TGFBR ALK5 inactivation=cleft lip
- - BMP2
- ○ Overexpression=cleft lip
- - FGF's
- ○ Stimulates PROLIFERATION
- ○ FGFR1 inactivation=Kallman syndrome=CL/P
- ○ FGFR2 associated with craniosynostosis
- - Hedgehog
- ○ In frontonasal and maxillary prominences
- ○ Mutation=holoprosencephaly (cyclops)
- ○ Also expressed in tooth development
CLEFT LIP with or without PALATE
- - Nonsyndromic (%70) and syndromic
- - Multifactorial (genetic and environmental factors)
- - Environmental:
- ○ Maternal smoking, drinking, obesity, exposure to teratogens
- - Genetic
- ○ TGFB3
- ○ IRF6
- ○ FGFR1 (FGFR1 and FGFR8)
- ○ Msx1 signaling
- ○ BMP4 signaling
- ○ Wnt/B- catenin signaling
- - Muscle
- - posterior cranial base, appendicular skeleton
Neuroectoderm (neural crest cells)
- - bone, cartilage
- - Anterior cranial base, cranium, facial skeleton
- - Mesenchyme condensation via signalling
- - New cells secrete osteoids, which secrete minerals
- - Osteoblasts and osteocytes (trapped in bone) and osteoclasts
- - 4th week
- - Much more bone marrow seen in mandible than normal long bones!
- Osteoporosis-disease of osteoclast (seen less in mandible!)
- - Eg: flat bones, maxilla, inferior mandible
- - Also start with mesenchyme condensation
- - New cells transform into cartilage!
- - Differentiate into layers/zones (chondrocytes)
- ○ Hypertrophic zone (inferior)
- ○ Proliferating zone
- ○ Resting zone (superior)
- - Proliferating cells ELONGATE at epiphyseal plates
- - End of ossification: Primary and secondary ossification centers fuse
- - Eg: long bones, superior mandible
- Cortical bone
- - External, thick
- - Mechanical and protective function
- - Units are the osteons formed by osteoblasts (osteocytes trapped inside). Haversian canal houses
- neurovascular bundle
- - Periosteum on outside, can become osteoblasts when needed (during healing)
- - Thin
- - Houses bone marrow
- - Metabolic function
- - Disease seen here first (trabeculum structure no longer present!
- - From mesenchymal stem cells
- - Give rise to bone
- - Mononuclear
- - Secrete collagen and protien-PS complex for bone matrix (later becomes mineralized)
- - After osteoclasts resorb bone, osteoblasts FILL IN SPACE
- - Cbfa1:
- ○ CRUCIAL growth factor for mesenchymal->osteoblast differentiation! Prevents ossification
- ○ Regulates transcription & post-transcription
- ○ Unfolds histone nucleosomes
- ○ Cbfa1 heterozygous display Cleidocranial displasia: missing clavicles, open fontanelles, supernumerary teeth
- ○ Osterix gene is similar to Cbfa1
- - RANKL secreted (this means there's osteoblastic activity!)
- - When resting they are lining cells OR they differentiate into osteocytes..
- - Most numerous
- - Caniliculi allow for cell-cell communication
- - Mechanoreceptors
- - Secrete molecules such as
- ○ sclerostin (regulates activity: force sensed by osteocyte-> sclerostin sent out->RANKL activated->osteoclast resorbs)
- ○ DMP1 (downregulate)
- ○ FGF23 (regulates calcium phosphate homeostasis)
- - ONLY OSTEOCYTES DO NOT have beta-catenin signalling (which would downregulate sclerostin, causing more bone loss)
- - Autophagy (eat themselves) and apoptosis possible
- - Activate osteoclasts..
- - From hematopoetic stem cells (NOT mesenchymal!!)
- - Resorb bone
- - Multi-nucleated
- - Sealing zones at border where it contacts bone
- - pH gets lowered and Proteases are secreted to dissolve matrix
- - Activate osteoblasts!
- - RANKL (from osteoblast) activates RANK on preosteclast cells
- ○ CRUCIAL for differentiation
- - Osteopetrosis: absent osteoclasts (more bone formation, less resorption)
- - Osteoporosis: EXCESS osteoclastic activity (thin, brittle bone)
BONE REMODOLING UNIT (BRU)!!
- - All individual cells work together!
- - Osteoclasts- resorb bone and secrete protiens
- - Activate osteoblasts- deposit osteoids which mineralize new bone
- premature fusion of sutures
- a. Growth restriction
- b. Skull overgrowth in unrestricted area
- c. Increased intra-cranial pressure
component of craniofacial syndrome OR genetic mutation
from systemic or metabolic disorder
- surrounds brain
- skull vault (dermatocranium-membranous formation)
- skull base (chondrocranium-endochondral formation)
- surrounds face
- maxilla and mandible (membranous)
- Intramembranous- no cartilage
- a. Primary cartilage-meckels (before bone formation)
- b. Secondary cartilage- condylar,coronoid,symphyseal,zygomatic (after bone formation)
Skull is made of many "pieces" connected with articulations:
- 1. Sutures (from mesoderm)
- 2. Synchondroses
- 3. Synovial joints
Skull ~8 weeks
- 5 ossification centers on skull
- Gaps in between them are the sutures
- 2 bone plates separated by soft tissue (sutural ligament)
# of suture fusions involved
- 1. Simple CS: 1 suture
- 2. Compound CS: 2+ sutures
- 1. Syndromic CS: associated with other anomolies
- 2. Non-syndromic CS: only skull deformity
- (Earlier=more severe)
SUTURES PREMATURE FUSION (appearance)
- Metopic - 2 frontal bones Trigonocephaly
- (triangular forehead)
- Coronal- frontal and parietal Bilateral: brachycephaly
- (short and wide head)
- Unilateral: plagiocephaly
- Sagittal- 2 parietals Dolichocephaly
- (anterior-posterior growth)
- Coronal & Sagittal oxycephaly
- Lambdoid- parietal and occipital Bilateral: Turrecephaly
- (flat occipital)
- Unilateral: plagiocephaly
- Squamosal-parietal and temporal
- Synchondroses-in cranial base
- Deformational/positional plagiocephaly- no sutures fused(?)
- (CF) FGFR2
- bilateral coronal fusion
- large fontanels
- gaping frontal midline defect
- cervical vert. fusion
- (CF) FGFR2
- coronal fusion
- midfacial hypoplasia
- Wide-set eyes (hypertelorism)
- Brain swelling (Hydrocephalus)
- partial syndactyly
- Type I-hearing loss FGFR1
- Type II-cloverleaf skull, severe proptosis FGFR2
- Type III- (type I and II +) mental retardation FGFR3
- Coronal fusion TWIST
- Fused digits
- Tower shaped skull
- Fused digits
- MOST mutation in FGFRs (1,2,3) growth factor
- chotzen LOF of TWIST growth factor
- CS boston type GOF in MSX2
- NS CS GOF in FGFR and NELL1
CRITICAL for bone formation
- 1. Conservative
- 2. Surgical management
- a. strip craniectomy
- b. Suturectomy (minimally invasive)
- 3. Inhibition of FGFR- via PLOX052
[MOST ARE AUTOSOMAL DOMINANT]
- - Holoprosencephaly (brian defect)
- - Small eyes, broad nasal bridge
- - Extra digits
- - CL/P
- - Holoprosencephaly
- - Malformed ears
- - Micrognathia (small jaw)
- - Clenched hands
- - MOST COMMON
- - Short stature, fingers
- - Brachiocephaly (coronal fusion)
- TRISOMY 13,18,21 CAN HAVE CLEFT PALATE ALONE
- Van der woude (variable in families) and popliteal syndromes (LOWER lip pitting)
Ectrodactyly-ectodermal dysplasia (EEC)
- - Claw-like hands
- - Abnormal Hair, teeth, nails, sweat glands
22q11 deletion (VCF) syndrome
- - Heart defects
- - Long tubular nose/long face
- - Mandibular hypoplasia!
- - Tongue falls back
- - Bone defects
- - Droopy lower eyelid, no eyelashes there
- - Eyes slanted downward
- - Small cheek bones
- - Treacle protien IMPORTANT in branchial arch 1 development
- - Variability in family
- External ear abnormality (anotia-no ear)
- - One side of face is smaller
- - Facial nerve palsy
- - Aperts: fingers toes are fused
- - Crouzon: normal hands and feet
- - Pfeiffer: abnormal thumbs, big toes
FETAL ALCOHOL SYNDROME
- Short palpebral fissures (small eye slits)
- Indistinct philtrum (the groove under the nose)
- Thin upper lip
Place the following events in chronological order from earliest to latest during development:
- correct order:
- Formation of the trilaminar embryo
- Neural tube formation
- Embryonic folding
- Branchial arch formation
- Fusion of the mandibular processes
- Palatal shelf elevation
- Closure of the cranial sutures
Identify the primary germ layer of origin for each of the following structures/tissues:
- Muscles of mastication – Brachial arch 1
- Lining of the pharynx - endoderm
- Enamel - ectoderm
- Lining of ear canal - ectoderm
- Oral mucosa - ectoderm
- a rod-shaped body that is composed of cells derived from the mesoderm;
- its function is to provide support for the embryo and to induce the overlying ectoderm to specialize and undergo neurulation (so that the neural tube can be formed)
Compare and contrast the TMJ with other synovial joints.
Both have fiberous joint capsule, but TMJ has fibrocartilage not hyline cartilage. Also, TMJ articular disk to divide capsule into inferior and superior joint space. TMJ allows gliding and rotation.
Distinguish endochondral and intramembranous bone formation and identify where each occurs in the development of the mandible.
- Endochondral – from cartilage
- Intramembranous – denovo osstification of ectomesnchyme
- Intramembranous ossification occurs in the body of the mandible, lateral to Meckel‟s cartilage, in the facial bones, and in the inferior condylar process. Endochondral ossification occurs in the superior condylar process, through the condylar cartilage.
Describe the role of the medial edge epithelium in palatal suture formation.
- 2 palatal shelves come from maxillar process, they elevate and then fuse.
- The fusion of the palatal shelves requires the adhesion of the medial edge epithelium (MEE) of each shelf and the degeneration of the reuslting medial epithelial seam (MES) through MEE apoptosis.
Discuss the ideal treatment of a patient with a cleft lip/palate, from the time of birth through young adulthood.
- 1. First surgery – 6 months (10 weeks, 10 weight points, 10 g hemoglobin) – lip and soft palate repair
- 2. Second surgery – 1 year – hard palate closure
- 3. Third – 6-7 years – aveolar graft following orthodontic expansion of palate
- 4. Fourth – teens – maxillary advancement
Describe the zones of the growth plate and their importance in bone growth.
- As shown in the above picture, the epiphyseal/ growth plate is a hyaline cartilage plate found at each end of long bones and divided into several zones.
- This plate allows longitudinal growth of bones: the plate‟s chondrocytes are undergoing constant division by mitosis so that these daughter cells stack facing the epiphysis while the older cells are pushed towards the diaphysis; as the older chondrocytes degenerate, osteoblasts ossify the remains to form new bone.
- The relatively inactive resting zone is found at the epiphyseal end.
- More distally, proliferative and then hypertrophic zones are found, ending with a band of ossifying cartilage called the metaphysis.
- The resting zone is the germinal layer that supplies the developing cartilage cells; injury to this layer results in cessation of growth. The proliferative zone is the location in which bone length is created by the active growth of cartilage cells. Here, chondrocytes assume a flattened appearance, begin to divide, and become organized into columns. In the hypertrophic zone, there is no cellular division but the chondrocytes begin to terminally differentiate. In the metaphysic, dead chondrocytes become calcified, which then serves as a template for osteoblastic bone formation
•Describe the cycle of bone remodeling and its importance in bone homeostasis.
Bone continually undergoes remodeling (i.e. replacement of old bone with new bone) in response to microscopic cracks in the bone and changes in mechanical forces. This is accomplished through bone remodeling units, which are local groups of osteoclasts and osteoblasts responsible for remodeling
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