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SECTION

Growth of Face and Craniofacial Complex

Chapter 7 Prenatal development of the foetus with reference to craniofacial regionChapter 8 Concepts of growth and developmentChapter 9 Postnatal growth of face and craniofacial regionChapter 10 Altered orofacial functions and development of face and occlusion

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Prenatal development of the foetus with reference to

craniofacial regionNeeraj Wadhawan, Ram S Nanda, OP Kharbanda

Introduction

The human foetus develops from the fertilisation of an oocyte by a sperm to form zygote. The event usually occurs while the oocyte is still in the fallopian tube

(Fig. 7.1). Following fertilisation, a series of important changes occur in the zygote giving rise to an embryo. The sequence of events can be summarised as shown in Figure 7.2.

Broadly speaking, the intrauterine period can be divided into:1,2

1. Pre-implantation period. The fi rst 7 days following fertili-sation.

2. Embryonic period. From 7th day to 8th week after fertili-sation.

3. Foetal period. Ninth week to term—characterised by growth and expansion of the already established body structures with little differentiation or new organ for-mation. A highlight of the foetal period is the establish-ment of the ossifi cation centres and the starting of the foetal movements.1

The embryonic phase can be further divided into:1–3

1. Pre-somite phase. Encompasses the 2nd and 3rd weeks after fertilisation; characterised by the differentiation of the three germ layers and the formation of the embryonic adnexa (foetal membranes) from the inner cell mass.

◗ Introduction ◗ Pre-implantation period ◗ Pre-somite period ◗ Somite period

➧ Neurulation ➧ Development of the neural crest ➧ Development of the skeleton ➧ Pharyngeal apparatus ➧ Pharyngeal arches

◗ Post-somite period ◗ Foetal stage ◗ Development of craniofacial structures

➧ Development of face

➧ Formation of eyes ➧ Formation of ears ➧ Formation of nasal cavity ➧ Formation of nasolacrimal duct ➧ Development of palate ➧ Development of tongue

◗ Genetic regulation of craniofacial development ◗ Clinical implications

➧ Craniofacial syndromes due to defective genetic control

➧ Branchial arch syndromes ➧ Synostosis syndromes

◗ Summary

2. Somite phase. Lasts from 21st to 31st day; approximately 4th week and early 5th week; characterised by the for-mation of the dorsal metameric segments of the body (neural tube, somites, etc.), establishment of the basic body plan, polarity and patterns of the major organ systems.

3. Post-somite phase. Lasts from 32nd to 56th day; late 5th–8th week; characterised by the development of the external body features and the further development and differentiation of the basic structure.2

Weeks 4 through 8 are especially important because major-ity of tissues and organ systems differentiate during the period from the original three germ layers (Table 7.1).1–3

The embryonic period can also be divided, on the basis of morphogenetic development of the embryo, into 23 stages starting from fertilisation (Fig. 7.3). These are popularly known as Carnegie stages,4 named after Carnegie Institute of Washington, USA, and are based on the work of Streeter (1942)5 and O’Rahilly and Müller (1987).6

Pre-implantation period1−3

During the fi rst 2–3 days, the single celled zygote, 140 μm in size, divides progressively to form a 16-celled cluster called morula. With further cell division, the morula forms a

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Table 7.1 Chronological sequence of events during the embryonic period

Time from conception Signifi cant events in craniofacial region

14 days Primitive streak appears; formation of oropharyngeal membrane

17 days Neural plate formation commences

20 days Appearance of neural folds; formation of neural crest. Otic placodes appear

21 days Neural folds fuse; migration of neural crest cells starts

24 days Frontonasal process and mandibular arch appear; optic vesicles and olfactory placodes appear

26 days 2nd arch forms; maxillary process starts to differentiate; adenohypophyseal pouch appears

28 days 3rd and 4th arches develop; dental lamina appears; oropharyngeal membrane disintegrates

32 days Lateral nasal process appears; otic and lens vesicles form

33 days Medial nasal process develops; nasal pits form, are wide apart and face laterally

37 days Nasal pits face ventrally; formation of upper lip starts; nasolacrimal groove appears

41 days Medial nasal and maxillary processes fusion starts; nasal cavity separates from oral cavity; upper lip continuity established

44 days Primary palate formation ensues; nose tip forms; eyelids start to form; nasal pits migrate medially; nasal septum forms

47–48 days Nasal fi n disintegrates (failure to disintegrate predisposes to cleft lip); rima oris reduces in width; mandible ossifi cation starts

50–51 days Lidless eyes and nasal pits move medially

54 days Eyelids develop; nostrils take fi nal position; auricle of ear develops

56–57 days Eyelid closure commences; eyes still wide apart; face assumes human appearance; head elevated off the thorax; mouth opens; palatal shelves elevate; maxillary ossifi cation starts

60 days Palatal shelves fuse; tooth buds form

Source: Adapted from Sperber GH, Sperber SM, Guttmann GD. Craniofacial Embryogenetics and Development, 2nd ed. Peoples Medical Publishing House, USA, 2010, p. 21

100-celled structure called blastocyst, which implants in the uterus at around 7th day post-conception. Within the blastocyst a fl uid-fi lled cavity develops which divides the cells into the outer sphere of cells and an inner cell mass. The outer sphere of cells forms trophoblast while the inner cell mass forms the embryo. The trophoblast is responsible for the development of the chorionic villi and thus, is impor-tant for the nutrition of the developing embryo.

Zygote 2 cells stage(30 hours) Morula

(day 3)

Blastocyst(day 4–5)

Trophectoderm or trophoblast

EndometriumUterine wall

Syncytiotrophoblast

Secondary oocyte at metaphase

Ampulla

Fertilisation (day 0)

Implantation(day 6)

Blastocele

Figure 7.1 Initial stages of embryonic development from the time of fertilisation to implantation in the uterine mucosa. It is the blastocyst stage at which implantation occurs within the uterine wall approximately 6 days after fertilisation

First 3 months 3–6 6–9 months

Figure 7.2 Stages of foetal development. Most signifi cant events of life occur during the fi rst trimester and it is hence designated for a larger distance than the 2nd and 3rd trimesters


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Pre-somite period (14–21 days)1−3

During the second week, two important events occur: (i) the trophoblast layer starts to differentiate into bilaminar struc-ture which contributes to the formation of the chrionic villi, (ii) the inner cell mass divides to form a bilaminar structure (Fig. 7.4A–D). The bilaminar structure is made of the epi-blast (ectoderm), which consists of columnar cells and forms the fl oor of the amniotic cavity, and the hypoblast (endo-derm), which consists of squamous or cuboidal cells form-ing the roof of the yolk sac. Meanwhile, the coelomic cavity develops in the extraembryonic mesoderm (loose tissue adjacent to the embryo) which enlarges progressively to sur-round the embryo completely except at the stalk where the trophoblastic cells form the chorionic plate. This is the site where later the chorion would develop. By the end of the 2nd week, the axis of the embryo starts to develop with the appearance of the node at the rostral end (Fig. 7.5A, B).

The node develops under the signalling infl uence of the genes Nodal, Hedgehog, FGF (fi broblast growth factor), Wnt, and BMP (bone morphogenic protein). The activity of the node, through the ciliary movement of the cells, contributes to leftward fl uid fl ow which causes development of left–right asymmetry in the developing embryo. At the same time, localised thickening of the endoderm at the midcephalic region gives rise to the pre-chordal plate under the infl uence of the Sonic Hedgehog (SHH). This pre-chordal plate has been shown to have a head-organising or molecular organising function producing signals that pattern the forebrain and help in differentiation of the eye fi elds. Defects of signalling in this region are known to cause holoprosencephaly or agene-sis of the corpus callosum. The pre-chordal layer also con-tributes the endodermal layer to the oropharyngeal membrane (a membrane which separates the oronasal cav-ity from the pharyngeal cavity during early development).

Early in the 3rd week, the epiblast proliferates and differ-entiates to give rise to the third layer of cells called the meso-derm through a process called gastrulation, thus establishing the trilaminar structure of the embryo. The proliferation of the epiblast starts at the caudal end of the embryo leading to formation of a caudocranial groove starting at the caudal end. This groove is called the primitive streak. The cranial limit of the primitive streak is marked by the primitive node. From the primitive streak, rapid proliferation of cells leads to the formation of the intraembryonic mesoderm which pro-liferates in all directions between the ectoderm and the endoderm. By the end of the 3rd week, the mesoderm layer is well established and separates the ectoderm and endo-derm throughout the embryo except two places: the cloacal membrane in the caudal region and the pre-chordal plate at the cranial midline area, where the endoderm and ectoderm are tightly adherent. The formation of the three germ layers is a critical landmark during the early development of the embryo. The pre-chordal plate is the future region of the buccopharyngeal membrane. From henceforth, the further development of the embryo occurs through the growth and differentiation of the three basic germ layers, namely, ecto-derm (1st layer), mesoderm (2nd layer) and endoderm (3rd layer) (Fig. 7.6). Neural crest layer, considered by some as the 4th germ layer, is essentially a derivative of the ectoder-mal layer. The various derivatives of the three germ layers are summarised in the Table 7.2.

Meanwhile, cells of the primitive streak proliferate fur-ther in a cranial direction and contact the pre-chordal plate (Fig. 7.5B). These cells further invaginate the underlying tissue to form a structure called the notochord. Notochord represents the early midline axis of the embryo helping to establish the axial skeleton. It also induces the formation of the neural plate in the overlying ectoderm which later gives rise to the neural ectoderm.

13 (28 days) 14 (32 days) 15 (33 days) 16 (37 days) 17 (41 days) 18 (44 days)

19 (47 days) 20 (50 days) 21 (52 days) 22 (54 days) 23 (56 days)

Carnegie stages (approximate post-ovulatory days)

10 mm

Figure 7.3 Selected Carnegie stages of human embryonic development from 28th to 56th day. Carnegie stages divide the human embryonic period into 23 stages from the time of fertilisation to beginning of the foetal period on the basis of important embryonic events


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Cut edge of amnion

Cloacal membrane

Pre-notochordalcells

Primitive node

Primitive streak

BPre-chordal plate

Primitive(Hensen’s) node

Primitive streak

Cut edge of amnion

APre-chordal plate

Figure 7.5 A. Cut section through the amniotic cavity of a third week embryo showing the dorsal surface of the embryo proper. The formation of the primitive node and the primitive streak defi nes the axis and the poles of the embryo. B. Dorsal migration of the surface epiblast cells along the primitive streak towards the rostral end of the embryo (arrows). Subsequently, cells derived from the epiblast also invaginate between the epiblast and the hypoblast laterally to form the intraembryonic mesoderm (lines)

Figure 7.4 Early stages of development of the human embryo. A. Seven-day-old human blastocyst showing the trophoblastic and amniotic layers. A small amniotic cavity is developing. B. Nine-day-old human blastocyst. The hypoblast layer extends to enclose a cavity called exocoelomic cavity (primary yolk sac). C. Twelve-day-old blastocyst. The exocoelomic cavity and the amniotic cavity increase in size. The extraembryonic mesoderm fi lls the gap between the cytotrophoblast layer and the exocoelomic cavity. D. Thirteen-day-old blastocyst. Formation of extraembryonic coelom occurs by the breakdown and coalescence of the fl uid fi lled spaces in the extraembryonic mesoderm. Cells from the hypoblast migrate to displace the exocoelomic cavity away from the embryo proper and encase a new space called the secondary yolk sac. The exocoelomic cavity is reduced into a remnant called the exocoelomic cyst

Endometrialstroma

Blood vessels

Blastocyst cavityHypoblast

Amniotic cavity

Epiblast

Endometrialepithelium

Cytotrophoblast

Syncytiotrophoblast

Epiblast

Hypoblast

Exocoelomic cavity

Exocoelomic cavity(primitive yolk sac)

Exocoelomicmembrane

Cytotrophoblast

Hypoblast

Syncytiotrophoblast

Trophoblastic lacunae

Extraembryonicmesoderm

Amniotic cavity

Secondary yolk sac

Exocoelomic cyst

Extraembryonic coelom(chorionic cavity)

Connectingstalk

A B

CD

Bilaminar embryonicdisc

Exocoelomic (Heuser’s)membrane

Somite period (21–31 days)1−3

The somite period is characterised by establishment of the primordia of most of the important organ systems like the gut, kidneys, adrenals, heart, lungs and others. Between the 21st and 31st days the embryo changes its form from a fl at disc to a tubular structure. Simultaneously, rapid growth

of the developing central nervous system on the dorsal aspect leads to the folding of the embryo over its ventral aspect thus forming a C-shaped structure at around 4 weeks (Fig. 7.7A, B). The folding leads to incorporation of the sec-ondary yolk sac into the embryonic structure. The secondary yolk sac contributes to the formation of the gut.


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Table 7.2 Derivatives of the three germ layers

Layer Derivatives

Ectoderm

Surface ectoderm Epidermis, hair, nails, glands of skin, tooth enamel, mammary glands, adenohypophysis, placodal derivatives (inner ear, lens)

Neural tube ectoderm CNS (brain and spinal cord), retina, neurohypophysis, pineal body

Neural crest Neurons and glia of peripheral nervous system (sensory, sympathetic, parasympathetic systems), Schwann cells, chromaffi n cells of adrenal medulla, melanocytes, pharyngeal arch cartilage, most of facial skeleton and facial connective tissue (from ectomesenchyme), dentin and cementum, middle ear bones

Mesoderm (head)

Pre-chordal plate Several eye muscles

Paraxial mesoderm Several eye muscles, skull bones, head muscles, some connective tissue

Cardiogenic mesoderm Heart

Mesoderm (trunk)

Notochord Inter-vertebral discs (nuclei pulposi)

Paraxial Most of the body skeleton, muscles of trunk and limbs, dorsal dermis and connective tissue

Intermediate mesoderm Kidneys, ureters, somatic gonad, adrenal cortex, blood and blood vessels

Lateral plate (somatic and splanchnic)

Connective tissue and muscles of viscera, serosa, primitive heart, blood and lymph cells, smooth muscle, spleen, and adrenal cortex

Endoderm

Endoderm Epithelial lining of respiratory tract, lungs, gut, bladder, part of urethra; parenchymal cells of tonsils, thymus, thyroid, parathyroid, liver, pancreas; epithelial lining of tympanic cavity and auditory tube

Source: Adapted from http://conlonlab.org/courses/materials/medsmats/adultderivatives.htm; Finkelstein MW. Overview of general embryology and head and neck development. In: Textbook of Orthodontics, Bishara SE (ed.), Philadelphia, Saunders, 2001

Notochordal plate

Mesoderm(intraembryonic)

Endoderm

Ectoderm

C

Amniotic cavity

Epiblast

Prochordal plate

Wall of yolk sac

Developing notochord

Primitive pit

Yolk sac

Cloacalmembrane

A B Notochordal plate

Mesoderm(intraembryonic)

Endoderm

Ectoderm

Primitive nodeEpiblast Primitive streak

Amnioblasts

Hypoblast Newly forming mesodermal cells

D

Figure 7.6 Sections through developing embryo in the third week. A. Mid-sagittal section of embryo shows the development of the embryonal axis and the primitive notochord. B, C. Transverse section shows the formation of the third germ layer and the developing notochord. D. Transverse section through the cranial end of the primitive streak in a third week embryo showing gastrulation (at the plane marked in Fig. 7.6A). Cells from the epiblast layer differentiate and migrate extensively between the epiblast and the hypoblast to form the intraembryonic mesoderm (the third germ layer)


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A BR

A BR

C

Greatestlength

Figure 7.7 Schematic diagram showing the folding of the embryo over its ventral aspect due to exaggerated growth on the dorsal aspect*c = caudal; r = rostral

NeurulationNeurulation is the process of development of the neural plate, neuroectoderm and the neural tube. During the 3rd week of development the notochord induces the overlying ectoderm to thicken and differentiate into the neural plate. Experiments have shown that chordamesoderm (a median strip of mesodermal cells extending through the length of the embryo) and pre-chordal plate (in the anterior region) also play a signifi cant role in inducing neural plate formation. In addition, the chordamesoderm may be responsible for devel-oping the organisational plan of the head. The neural plate grows caudally towards the primitive streak (Fig. 7.8). At around the 20th day post conception, the lateral edges of the neural plate elevate to form the neural folds which enclose a neural groove in the midline (Fig. 7.9A–D).

At the 22nd day post-conception, the neural folds start to fuse with the counterpart of the other side over the neural groove. The fusion occurs fi rst in the region of the future occipital area (area of 3rd to 5th somites) and proceeds both cranially and caudally to produce the neural tube. The neural

tube is the primordium of the central nervous system and its anterior end enlarges to form the three segments of the brain, forebrain, midbrain and hindbrain. Around the same time, the lens and otic placodes begin to form as outgrowths from ectoderm at the cranial end of the embryo. These later give rise to the eye and the inner ear respectively.

Development of the neural crestNeural crest refers to a special collection of cells which arise in the crest of the neural folds during the process of neurulation (Fig. 7.10). It consists of pleuripotential cells, ectomesenchymal in origin, induced by interaction WNT activation and BMP inhibition signal pathways. These cells are characterised by their tendency to extensively migrate along the natural cleavage planes between the three germ layers, usually beginning at about the time of closure of neural tube (Fig. 7.11). They divide as they migrate, giving rise to cell masses which are much bigger at the destination than at their origin. Once they reach their pre-determined location they differentiate into specifi c tissues according to the morphogenetic fi elds and give rise to many important tissues both in the head and neck (Fig. 7.12) as well as in the trunk region. In the head and neck region, they form the complete mesenchyme of the upper facial region and sur-round the mesodermal cores of the lower facial region. Cells that migrate ventrally and caudally encounter pharyngeal endoderm that induces the formation of the pharyngeal arches. Those which migrate to the trunk region give rise to neural, endocrine and pigment cells (Table 7.3).

Development of the skeleton1−3

Following the formation of the neural plate and the noto-chord, the intraembryonic mesoderm differentiates into three types of cell masses depending upon the:

1. Lateral plate mesoderm 2. Intermediate mesoderm 3. Paraxial mesoderm.

18th day

Neural plate

Pre-chordalplate

Notochordalprocess

19th day

Neural plate

Pre-chordalplate

Rostral end

Caudal end

Neuralgroove

20th day

Figure 7.8 Schematic diagram of a horizontal section through the dorsal surface shows the growth of the neural plate. The primitive streak shortens only marginally while the embryo and the neural plate continue to grow. This reduces the relative size of the primitive streak (Redrawn from Human Embryology. Larsen WJ, Sherman LS, Potter SS eds. Churchill Livingstone pub. UK, 2001, Fig 2.13)


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The lateral plate mesoderm and the intermediate mesoderm give rise to a variety of tissues and organs throughout the body, the description of which is beyond the scope of this text. The paraxial mesoderm is of greater concern to dental professionals as it is intimately associated with the develop-ment of the cranial structures.

Paraxial mesoderm develops adjacent to the notochord along the dorsal surface of the embryo. On further differen-tiation, its rostral end gives rise to certain elevated masses of tissues in the cranial region called the somitomeres. These somitomeres are situated in the paraxial region of the noto-chord. The caudal paraxial mesoderm gives rise to similar structures in the more caudal part of the embryo which are called somites. Each somite has three basic parts differing in location each of which gives rise to different tissues:

1. Sclerotome: Ventromedial part; gives rise to the verte-bral region except in occipital region.

2. Dermatome: Lateral part; gives rise to the dermis of skin. 3. Myotome: Intermediate portion; gives rise to the mus-

cles of trunk and limbs and some craniofacial muscles.

Approximately 42–44 paired somites are known in human embryo, of which four are occipital and eight are cervical (somitomeres in the craniofacial region) (Fig. 7.13).

Pharyngeal apparatusThe pharyngeal apparatus consists of a series of bilaterally paired arches, pouches (clefts), grooves and membranes. The pharyngeal arches are seen as paired tubal elevations on the ventral surface of the embryo on either side of the midline. They are partially separated on the external surface of the embryo by fi ssures called pharyngeal grooves or clefts while the pharyngeal pouches partially separate the arches on the internal aspect. The pharyngeal membranes represent the tissue interposed between pouches and clefts and connect adjacent arches.7

Neural crest

Ectoderm

MesodermEndoderm

Neural crestNeural plate

Neural groove

Neural crest

Neural tube

Paraxialmesoderm

Neural crest

Lateral platemesoderm

A B

C D

Dorsal end

Ventral end

Paraxialmesoderm

Developingnotochord

Endoderm

Somite

Notochord

Figure 7.9 A–D. Transverse section through the developing embryo showing the folding of the neural plate to form the neural tube. (Adapted from Kandel E, Schwartz JH, Jessel TM (eds). Principles of Neuroscience, 4th edn., McGraw-Hill Publication, 2002)

Neural groove

Neural fold

Median hingepoint

Neural crest

Developing neural crest

Neural crest

A

B

C

D

Figure 7.10 Schematic diagram of transverse section through the dorsal end of embryo showing the formation of the neural crest cells (neurulation) in the lateral aspect of the neural folds


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Ant.

Post.

Somite

Rostral

Path 1 cells travel ventrallythrough the anterior sclerotome

Path 2 cells travel a dorsolateralroute between the epidermis andthe dermamyotome

Caudal

Epidermis

Neutral tube

Dermamyotome

Sclerotome

Notochord

Aorta

Figure 7.11 Schematic diagram showing neural crest cell migration in the trunk region of chick embryo. Path I cells travel ventrally through the anterior portion of the sclerotome. Path II cells travel along a dorsolateral route below the surface ectoderm (Reproduced with permission from Gilbert SF, Sunderland MA (eds). Developmental Biology, 6th edn., Sinauer Associates, 2000, Fig. 13.2)

Pharyngeal archesDevelopment of the tissues of the neck and the major part of the face is largely dependent on the cranial somitomeric mesoderm. The cells of the somitomeric mesoderm migrate into the ventral region of the embryo at the rostral end, and with a minor contribution from the lateral plate mesoderm, to form the future pharyngeal arches. The pharyngeal arches arise as outgrowths on the ventral surface of the embryo rostral to the foregut in relation to the ventral sur-face of the rhombencephalon during the 4th week of intra-uterine (IU) life. Embryologically, the arches are derived from the cranial neural crest cells which migrate from spe-cifi c segments of the hindbrain (rhombomeres) with minor overlap between segments.

Neural crest cells from rhombomeres 1 and 2 together with caudal midbrain derived crest cells, populate the fi rst

Table 7.3 Major neural crest derivatives

Organ system Cranial neural crest Trunk neural crest

Nervous system Sensory ganglia of cranial nerves: V, VII, IX, X; satellite cells of sensory ganglia, parasympathetic ganglia of cranial region; oligodendroglia

Sensory spinal ganglia; satellite cells of these ganglia; parasympathetic ganglia of trunk region; Schwann cells of peripheral neurons

Pigment cells Melanophores, xanthophores, erythrophores, iridophores Melanophores, xanthophores, erythrophores, iridophores

Endocrine system Calcitonin producing cells, carotid body (type I cells); parafollicular cells of thyroid

Adrenal medulla; neurosecretory cells of heart and lungs

Mesodermal cells (skeleton)

Cranial vault; nose and orbit skeleton; otic capsule; maxilla, minor part of sphenoid

Nil

Mesodermal cells (connective tissue)

Dermis, fat, smooth muscles of skin, ciliary muscles of eye, cornea, connective tissue of glands of head and neck; odontoblasts, part of prosencephalon and mesencephalon; semilunar valves of heart and connective tissue in aorta

Nil

Muscles Ciliary, dermal smooth muscles, vascular smooth muscles Nil

Source: Adapted from Carlson BM. Foundations of Embryology, 6th ed, Tata McGraw Hill, India, 2007, p. 474

Branchial arches

Developing head

Arrows show path ofmigration of cranialneural crest cells inthe head and neckregion of thedevelopingembryo

Figure 7.12 Migration of the cranial neural crest cells into the head and the branchial arches to form structures of face and neck including bones and cartilages. They also produce pigment cells and cranial nerves (Adapted from Gilbert SF, Sunderland MA (eds). Developmental Biology, 6th edn, Sinauer Associates, 2000, Fig. 4.16)


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arch. Crest cells from rhombomere 4 populate the 2nd arch, while rhombomeres 6 and 7 contribute to 3rd, 4th and 6th pharyngeal arches. It should be noted that rhombomeres 3 and 5 are depleted of neural crest production and whatever little cells they produce die by apoptosis under the infl uence of gene BMP4.8

Each pharyngeal arch has its specifi c apparatus: a spe-cifi c cartilage that forms the skeleton of the arch, a nerve that supplies the muscles and mucosa derived from the arch, and an artery (called the aortic arch) (Fig. 7.14).7,8 All these components are well developed in the 1st and 2nd arches except for the arteries.7,8 Pharyngeal arches play a major role in the formation of face, oral cavity, teeth, nasal cavity, pharynx, larynx and neck (Tables 7.4, 7.5).

Post-somite period (32–56 days)

The post-somite period is characterised by the growth and morphodifferentiation of the previously established organ systems. The head becomes large and predominates over the small body. The somites become less conspicuous on the external surface. Face starts to show development of the eye, ear, and nose, which start to resemble the human form.

Buccopharyngealmembrane

Somites

Cloacal membrane

Notochord

Figure 7.13 Schematic representation of a 29-day-old embryo from the dorsal aspect showing the somites

Table 7.4 Derivatives of pharyngeal arches

Arch Cartilage; Derivatives Bone Muscles Nerve

1st Meckel’s cartilage; Derivatives: Sphenomandibular ligament, anterior ligament of malleus

Maxilla, mandible, malleus, incus

Masticatory muscles: temporalis, masseter and the pterygoids, tensor palatini, tensor tympani, anterior belly of digastric

Trigeminal (V)

2nd Reichert’s cartilage: Derivatives: Stylohyoid ligament

Lesser cornu and body of hyoid

Muscles of facial expression, stapedius, posterior belly of digastric, stylohyoid

Facial (VII)

3rd – Greater cornu and body of hyoid

Stylopharyngeus Glossopharyngeal (IX)

4th and 6th

Thyroid cartilage, laryngeal cartilages

– Pharyngeal and laryngeal muscles

Recurrent laryngeal n. (Br. of CN X), spinal accessory (XI) via the pharyngeal br. of CN X

Source: Modifi ed from Hiatt JL, Gartner LP. Textbook of Head and Neck Anatomy, 3rd ed. Baltimore, Lippincott Williams & Wilkins, 2001Br. = branch; n. = nerve; CN = cranial nerve

Pharyngeal pouch

Artery

Endodermal epithelium

Nerve

Cartilage

Ectodermalepithelium

Mesenchymaltissue in 4th arch

1st pharyngeal arch

Pharyngeal cleft

2nd arch with nerve,artery and cartilage

3rd arch

4th–6th arch

Laryngeal orifice

Figure 7.14 Cut section through the branchial arches in a developing embryo. Each arch has its own neural, vascular supply and cartilage. The arches are grooved on the external surface by pharyngeal clefts and on the internal surface by pharyngeal pouches. The arches are lined externally by ectoderm and internally by endoderm between which lies each arch’s mesodermal core. The 5th arch disappears during development


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Meanwhile, limb buds start to grow and the fi rst foetal mus-cular movement may occur at later end of the stage.

Foetal stage

The foetal period is characterised by the rapid growth of the organ systems previously established. Little differentiation of new tissue systems is seen and the main emphasis remains in the differential growth of various systems. With the growth of the body the head, which occupies approximately half of the body length initially, gets reduced to about one-fourth at birth. Establishment of primary ossifi cation centres also occurs during this period.

Development of craniofacial structures

Development of faceDevelopment of the head depends to a large extent upon the prior development of the brain. As discussed earlier, the brain starts to develop at the rostral end of the neural tube as a series of three vesicles: prosencephalon (forebrain), mesencephalon (midbrain) and rhombencephalon (hind-brain; rhombomeres 2–7).

The differentiation of human face takes place between the 4th and 7th weeks of intrauterine life (Fig. 7.15A–F).

In the 4th week, the future face and neck region becomes segmented and located under the forebrain of the embryo. The brain tissue exerts an organising infl uence on the devel-oping face. The prosencephalic centre, a mass of specialised mesodermal tissue derived from the pre-chordal mesoderm of the primitive streak, induces the differentiation of the visual apparatus, inner ear part of the auditory apparatus

and the upper one-third of the face. Similarly, the rhomben-cephalic centre induces the differentiation of the middle and lower third of the face, including the external and middle ears.

The frontonasal process (FNP) develops under the infl u-ence of the forebrain. The forebrain establishes multiple sig-nalling centres in the ectoderm that covers the future FNP region under the control of the gene SHH. This signalling ensures proper descent of the FNP and its differentiation into midline organ structures. By the end of the 4th week, the face and the forebrain are made by frontonasal process (middle and front), maxillary processes (laterally placed) and mandibular process (caudally placed), hyoid arch and glossopharyngeal arch.

By the 5th week, nasal placodes appear along the inferior and lateral portion of the FNP. Further development of the nasal placodes in a medial direction in a horse-shoe manner leads to the formation of medial and lateral nasal processes. The area between the two processes gets progressively depressed to form the nasal pits. These later invaginate to form the nasal cavities. Later in the 5th week, the continued medial movement of the maxillary prominences pushes the widely separated nasal prominences more medially into the position of the future nostrils. The fusion between median nasal and maxillary processes, which occurs between 7 and 8 weeks, contributes to the central part of the nose and the philtrum of the lip. The lateral nasal processes form the outer parts of the nose while the maxillary processes form the bulk of upper lip and cheeks. The maxillary processes also fuse with the respective mandibular processes at 7–8 weeks forming the angle of mouth.

Formation of eyesThe eyes develop from a single median set of cells, the optic primordium, originating in the neural plate in the ventral anterior region of the diencephalon. Under genetic control from Cyclops gene, cells from the lateral parts of the optic primordium differentiate into bilateral lens placodes while the central part is suppressed. The lens placodes initially are located on the lateral sides of the developing face but migrate medially with growth of the cerebral hemispheres during 5th–9th week, after which, little movement is seen. Simultaneous invagination of the lens placodes occurs, and with the formation of optic vesicles, the eye balls start to take their fi nal shape.

Formation of earsThe ear has three parts which have different origins. The external ear develops in the neck region as auricular hill-ocks surrounding the fi rst pharyngeal groove. The internal ear forms from the otic placodes which develop on the lateral aspect of the developing head under the infl uence of the rhombencephalon. The placode later invaginates into the underlying tissue to form a vesicle which later differenti-ates into the inner ear. The middle ear originates from the fi rst pharyngeal pouch.

Formation of nasal cavityThe nose arises from the frontonasal process and its deri-vatives, the median and lateral nasal processes, and the

Table 7.5 Derivatives of pharyngeal pouches

Pouch Derivatives

1st pouch Tympanic cavity and lining of tympanic drumMastoid air cellsAuditory tubeAnterior two-thirds of tongueForamen caecum

2nd pouch Pharyngeal tonsilsPalatine tonsils Posterior one-third of tongueLingual tonsil

3rd pouch Inferior parathyroidThymusBase of tongue

4th pouch Superior parathyroidThymusBase of tongueEpiglottis

5th pouch Ultimobranchial bodyParafollicular cells of thyroid

Source: Adapted from Development of the nervous system. In: A Textbook of Neuroanatomy. Patestas MA, Gartner LP (eds.), Blackwell Publishing, USA, 2006, p. 15


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A

Nasal placode

Oral plate

Frontonasalprominence

Maxillary process

Mandibular arch

Hyoid arch

B

Nasal pit

Oral plate

Frontonasalprominence

Maxillary process

Mandibular arch

Hyoid arch

C D

Nasomedial process

Nasolateral process

Nasolacrimal groove

Maxillary process

MandibleHyomandibular cleft

E

Nasolateral process

Nasomedialprocess fusing to

form philtrum of lip

External ear

Ear tubercles aroundhyomandibular cleft

Hyoid bone

Laryngeal cartilages

F

Figure 7.15 Schematic view of embryonal face development between 4th and 8th weeks. A. Four-week-old embryo. Note the prominent swellings of the developing mandibular processes of both sides. The mandibular processes have fused in the midline. The maxillary processes are starting to bud from the 1st arch. The frontonasal process is yet to descend in the midline. Primitive nasal placodes and optic vesicles (not visible in the picture) are starting to form. B. Five-week-old embryo. The maxillary processes are established and are migrating towards the midline. The descent of the frontonasal process is evident. The frontonasal process divides to give rise to lateral and median nasal processes which surround the nasal pit of each side. The nasal pits are beginning to deepen and are placed wide laterally. The lens placodes are developing on the lateral aspects of developing face. C. Five-and-a-half week embryo. The hyomandibular cleft divides the mandible from the neck region. The nasal pits start to face ventrally. The nasolacrimal groove starts to form. The upper lip starts to form by fusion of the lateral nasal process with the maxillary process. D. Six-week-old embryo. The primitive eye is well established on the lateral aspects of face. Nasolacrimal groove is forming. The descent of the frontonasal process and the medial movement of the maxillary processes continue. The median nasal process and the maxillary process start to fuse separating the nasal and oral cavities. E. Seven-week-old embryo. The MNP fuses with the maxillary process of respective side to complete the upper lip. The maxillary process also fuses with the mandibular process at the lateral margins to form the rima oris. The eye is well formed but lidless and is moving medially to its future position. The ear tubercles establish around the hyomandibular cleft on the lateral aspect. F. Eight-week-old embryo. Facial structure is well recognisable. Eye closure commences and they continue to migrate medially. The nasal pits also migrate medially. Rima oris reduces signifi cantly in size laterally. The external ears are developing


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cartilaginous nasal septum. Early in the development, the nasal pits become separated from the oral cavity on the external surface by the fusion of the median and lateral nasal processes with the maxillary process (Fig. 7.16A–D). The nasal pits invaginate the underlying mesenchyme to form the anterior nares. Posteriorly, the nasal cavity is sepa-rated from the stomodeaum by the oronasal membrane. The nasal pits continue to deepen, and with the disintegration of the oronasal membrane around the 7th week, the posterior nares (primary choanae) are established. Although the nos-trils become patent early in life, they remain plugged with solid structure of epithelial tissue till late in development.

Meanwhile, the mesenchyme of the frontonasal process at the site of the future nasal septum develops thickenings, from which originates the nasal capsule. Mesoethmoid, the medial mesenchymal thickenings, are the precursor of the nasal septal cartilage. The two lateral mesodermal thicken-ings, the ectethmoid, give rise to the paired ethmoidal (chonchal) and the nasal alar cartilages. The tissue from the mesoethmoid develops downwards in the median plane to meet the palatal shelves in the midline dividing the nasal cavity into two halves while the ectethmoid forms the lateral superior, middle and inferior conchae.

Formation of nasolacrimal duct3

The nasolacrimal ducts are bilateral epithelial lined tubes which form at the line of fusion of the lateral nasal process and the maxillary process (Fig. 7.17). The ducts connect the nasolacrimal sac to the nasal cavity and function to drain the lacrimal secretions from the eye. The duct originates from the embryonic nasolacrimal groove which runs from the medial end of the eye to the nasal pits. This groove sepa-rates the lateral nasal process from the maxillary process.

During the initial stages of formation, the epithelium over the groove proliferates and invaginates the underlying mes-enchyme as a solid cord of cells. Soon, the epithelia of the lateral nasal process and the maxillary process grow over the invaginated epithelium and fuse with each other. The invaginated epithelium subsequently breaks down to form the hollow lacrimal duct and the lacrimal sac. The ducts become completely patent only after birth. Aberrations in the formation of the nasolacrimal duct lead to formation of oblique facial clefts.

Frontonasalprocess

Primitive palate

Developingtongue

Nasalcavity

Nasal cavity

Mandible

Lower lipUpper lip

Maxilla

Olfactory nerve

Secondarypalate

Oral cavity

Oral cavity Nasalcavity

C D

A B

Primary palate

Developing cribriform plateand olfactory nerve

Nasal pit

Oronasalmembrane

Breakdown of oronasal membrane

Figure 7.16 Development of the nasal cavity. A. The primitive nasal pit is separated from the oral cavity by the oronasal membrane. B. Breakdown of the oronasal membrane leads to free communication between the oral and nasal cavity. C. Deepening of the nasal pits leads to increase in size of nasal cavity. The olfactory bulb also starts to establish. The primary palate starts to form. D. The formation of the palate divides the nasal cavity from the oral cavity. The development of the nasal conchae divides the nasal cavity into superior, middle and inferior meatus

1 mm

Nasolacrimalgroove

Medial nasal processesLateral nasal processes

Maxillary prominences

Figure 7.17 The nasolacrimal duct originates as the nasolacrimal groove around 6 weeks after fertilisation. It extends from the medial end of the developing eye to the primitive stomodeum and grooves between the lateral nasal process and the maxillary process on each side


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Development of palate9

The primitive stomodeum initially is a small chamber with no barrier between the oral and the nasal cavities. It is lim-ited posteriorly by the oropharyngeal membrane. At about the 28th day, the oropharyngeal membrane disintegrates to provide continuity between the stomodeum and the gut. The stomodeum is now called the ‘oronasopharyngeal chamber’.

The palate starts to form during the 5th and 6th weeks. It is derived from the following structures: (i) two median nasal processes (derivatives of the frontonasal process) and (ii) two maxillary processes.

The primary palate forms fi rst. During the 5th week of IU life, the median nasal processes (MNPs) of the two sides extend backward into the oral cavity for a short distance and fuse in the midline to give rise to the primary palate. Around the 7th week, two palatal processes evolve as out-growths from the maxillary processes, one on each side, and

develop downwards on either side of the developing tongue. Later, with the expansion and growth of stomodeaum, the tongue descends downwards allowing for the vertically devel-oping palatal shelves to elevate and approach each other in the midline (Fig. 7.18). In the anterior region, the shelves ele-vate and approximate by a rotational (hinge-like) motion while in the posterior regions remodelling occurs along with rotation. It must be noted that the shelves are incapable of rotation and elevation until the tongue withdraws from between them. The two shelves coalesce in the midline by dis-solution of the overlying epithelium and subsequent fusion of the underlying mesenchyme. The fusion starts fi rst in the anterior region of the palate at around 9 weeks and then pro-gresses posteriorly (Fig. 7.19A–F). The complete fusion of pal-ate occurs between 10th and 12th weeks.

Failure of fusion of the palatal processes leads to forma-tion of cleft lip and/or palate. The exact nature of the defect depends upon the timing and severity of the insult and the place of nonfusion of the processes. Understanding the

Nasal septum

Tongue

Nasal cavity

Palatal shelf

Oral cavity

A B

Figure 7.18 Coronal section through the palate showing elevation of palatal shelves. A. The palatal shelves initially develop in a downward direction alongside the tongue. The tongue occupies a major part of the oronasal cavity. B. With the downward descent of the tongue, space is created and the shelves elevate and move medially towards the midline. The descent of tongue is critical for elevation of the palatal shelves. Palatal shelves meet in the midline and fuse with each other

A C

D F

B

E

Figure 7.19 Axial section at level of palate showing the fusion of palatal shelves. A–C. The primary palate grows posteriorly while the palatal shelves grow medially to approximate in the midline. D–F. The fusion starts anteriorly and proceeds posteriorly. Uvula is the last structure to form


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Secondary palate

Upper lip

Primary palate

Alveolus

Hard palate

Soft palate

1

Nose

Lateral nasal process Medial nasal process Maxillary process Frontonasal process

Figure 7.20 A, B. Embryonic origin of the various structures of the palate and face as seen from the occlusal aspect

Lateral lingualswellings

Tuberculumimpar

ForamencaecumCopulaGlottis

Tongue

Vallate papilla

Sulcus terminalisLingual tonsil

Base of tonsil

Epiglottis

Lateral lingualswellings

erculumimpar

A B C D

Figure 7.21 Development of the tongue. A, B. During the 5th and 6th week, two lateral lingual swellings develop in the mucosa of the 1st pharyngeal arch in the paraxial plane. Simultaneously, a median swelling arises in the midline alongside the lingual swellings anterior to the copula. C. Seventh week post-fertilisation. The lateral swellings and tuberculum impar fuse to from structure of tongue. Further growth and differentiation of tissues leads to formation of the adult structure. D. Adult tongue

mesenchyme from the third arch which grows over the mucosa of the 2nd arch to eliminate it from the tongue. The line of demarcation between the body and base is called the terminal sulcus, and the foramen caecum is found in the midline of this structure. The taste buds develop in the 7th week from the interaction between the special visceral affer-ent nerves (8th and 9th) and the tongue epithelium.

The innervation of the tongue refl ects its embryologic origin: sensory anterior two-thirds by the trigeminal nerve (1st arch), posterior one-third by the glossopharyngeal nerve (2nd arch) while the posterior most part may be innervated by the vagus nerve (4th arch). The motor supply is by hypo-glossal nerve. Interestingly, it has been suggested that the foetus may have the ability to taste and that it is used by the foetus to monitor its intra-amniotic environment.10

Genetic regulation of craniofacial development

The differentiation of the single-celled zygote into a highly complex organism is a nature’s marvel. The development and differentiation of the cell into multiple cells which are committed to the development of different organs and tissues is a complex process which is controlled to a large extent by gene expression. ‘It is well understood that the mechanisms of craniofacial development are under genetic control. It is helpful to consider those genes involved in embryogenesis as

embryological basis of the development of the palate is essen-tial in understanding the pathogenesis, location and extent of the clefts (Fig. 7.20A, B).

Development of tongueEmbryologically, the tongue develops from contributions by the 1st and 3rd pharyngeal arches, with a minor con-tribution from the 4th arch. The anterior two-thirds of the tongue develops from the fi rst pharyngeal arch, whereas posterior one-third develops from the 3rd arch (Fig. 7.21). The posterior-most part of the tongue may have infl uences of the 4th arch as well. The skeletal muscles of the tongue develop from the occipital somites which are derivatives of the paraxial mesoderm.

During the late 4th week or early 5th week, two lateral swellings arise in the epithelium of the fl oor of the primitive pharynx anterior to the foramen caecum, due to division of the underlying mesenchyme. Simultaneously, a medial swelling arises in between them called tuberculum impar. The foramen caecum marks the boundary of fusion between the 1st and the 2nd arches. It also represents the remnant of the tissues of pharyngeal mesenchyme which descend to form the thyroid gland. The anterior two-thirds of the tongue is formed by the rapid enlargement of the lateral lingual swellings which fuse in the midline covering the tuberculum impar. The posterior third of the tongue develops from the hypobranchial eminence distal to the foramen caecum. The hypobranchial eminence is comprised primarily of


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encoding a set of instructions or rules of assembly. Imple-mentation of these one-dimensional rules, via gene expres-sion and protein interaction, produces the three-dimensional embryo’.11

Genetic fi elds: Different genes regulate the various cellular processes of the embryo. Each gene has its own genetic fi eld (area) of infl uence and the various genetic fi elds overlap with each other to regulate growth and development. The genetic control of craniofacial embryogenesis is via Hox genes which are responsible for controlling morphogenesis of the head and neck region. However, the neural crest cells destined for the 1st branchial arch do not express the Hox genes related to the homeotic homeobox.11 It is subfamilies of the homeobox genes, which are more diverged from the ancestral Hox genes, that are expressed in spatially restricted patterns within the 1st branchial arch.12,13 Other homeo-box-containing genes which are expressed in the maxillary and mandibular arches, and developing facial primordia, are the Msx-1, Msx-2, Dlx1-6, and Barx-1 (Fig. 7.22). Members of the Msx gene family, especially Msx-1 and Msx-2 are prominently expressed in the neural crest-derived mesenchyme of the developing facial prominences, and there is now a strong evidence for the role of these genes in speci-fi cation of the skull and face.14 Similarly, neural crest cell migration into the pharyngeal arches is under strict control of genes. Wnt gene is necessary for the induction of neural crest cells while ErbB4 gene, produced in the neural ecto-derm,1 is necessary for the neural crest cell migration.

Members of the multi-gene Dlx (distal-less) family are expressed in a complex pattern within the embryonic ecto-derm and mesenchyme of the maxillary and mandibular

processes.15 Other important genes in craniofacial develop-ment are goosecoid (Gsc), orthodontical (Otx), sonic hedgehog (SHH) and Indian hedgehog (Ihh) genes.15 These homeobox genes act by exerting control on growth factor family and the steroid/thyroid/retinoic acid super-family. The regulatory molecules in the mesenchyme, such as, fi broblast growth factor (FGF), epidermal growth factor (EGF), transforming growth factor-alpha (TGF-α), transforming growth factor-beta (TGF-β), and bone morphogenetic proteins (BMPs), are the vehicles through which homeobox gene information is expressed in the coordination of cell migration and subse-quent cell interactions which regulate growth (Table 7.6).16,17

Clinical implications

Craniofacial syndromes due to defective genetic controlSeveral syndromes of craniofacial region have their origin in mutations in FGF receptor genes, the transcription fac-tors, MSX2, core binding factor 1 gene (CBFA1), etc. For example, in cleidocranial dysplasia, mutations in CBFA1 causes defects in the membranous bones of the cranial vault and the clavicles. This is attributed to defective signalling between the periosteum and the chondrocytes. Similarly, Treacher Collins syndrome (TCS) locus has been mapped to the long arm of chromosome 5. Mutations of this part of the chromosome affect the production of ‘treacle protein’ which results in the anomaly.14 Apert, Crouzon and Pfeiffer syndromes result due to mutations in the FGF receptor gene

Default state of Hox code

r1 r2 r3 r4 r5 r7

Hindbrain

Midbrain

Forebrain

Proximal (dorsal)

Anterior

Distal (ventral)

Mx

Otx-2 Hoxa

Hoxb

HoxdDlx-3-5-6

Dlx-1-2

Md B2

1 2 3 4

B3

r6

Figure 7.22 Schematic representation of homeobox gene expression in the branchial arches. The maxillary (Mx) and mandibular (Md) processes of the fi rst branchial arch are populated by the neural crest cells from the distal midbrain and rhombomeres r1 and r2. The hindbrain contributes to the proximal region (represented by the Dlx genes) and the midbrain crest to the distal region (Otx-2); in other words, crest cells populating the mandibular arch have different axial origins. Neural crest cells expressing classical Hox genes from the r3 populate the 2nd branchial arch and so on. (Reproduced with permission from Meikle MC. Early craniofacial development. In: Craniofacial Development, Growth and Evolution. Bateson Publishing, Bressingham, 2002.; Diagram taken from Northcroft Memorial Lecture 2007; Meikle MC. A century of progress: advances in orthodontics since the foundation of the British Society for the Study of Orthodontics. J Orthod 2008;35:176–90, Fig. 6)


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which is known to affect sutural development in mice and humans.

Although the genetic regulation of tissue growth is under strong check mechanisms, anomalies of cell migra-tion, differentiation or replication do occur. These anomalies occur either due to mutation of selective genes or due to environmental factors which lead to the failure of check mechanisms or an interplay between the two. Since, during embryogenesis, a small population of cells gives rise to mul-tiple structures, problems occurring early in life lead to

widespread manifestations, many of which are so charac-teristic that they can be grouped into syndromes.

Environmental factors, usually grouped as teratogens, do not act continuously but only during the time of exposure causing insult to the developing foetus. Since specifi c events occur during specifi c periods of gestation, the type of anom-aly depends upon the specifi c time during which the expo-sure to teratogen occurred (Fig. 7.23).

One of the most common congenital anomaly is the cleft lip and palate. Cleft lip occurs due to nonfusion of the

Table 7.6 Genetic regulation of cellular function

Genes Functions

CartilageMarker genes Type II collagen

IIA isoformIIB isoform

Type IX collagenAggrecan

Marker for chondroprogenitor cellsMarker for differentiated chondrocytesInteract with proteoglycansMarker for hypertrophic chondrocytesCartilage-specifi c proteoglycan

Regulatory genesTranscription factors 5

Growth factor/receptorsSox 9

Indian hedgehog (Ihh)

Fibroblast growth factors/receptors (FGF/FGFR)Transforming growth factors/ receptors (TGFb/TGFbR)Bone morphogenetic proteins/ receptors (BMP/BMPR)Parathyroid hormone related peptide/receptors (PTHrP/PTHrPR)Retinoic acid receptors (RAR)

Signals chondrocyte differentiation

Stimulates chondrocyte proliferation and PTHrPInhibits chondrocyte proliferation and hypertrophyStimulates chondrocyte differentiation and hypertrophyStimulates chondrocyte hypertrophy

Stimulates chondrocyte proliferation

Stimulates chondrocyte hypertrophy

BoneMarker genes Alkaline phosphatase

Type I collagenBone sialoproteinOsteopontin

OsteocalcinOsteonectin

Potential Ca2+ carrier, hydrolyse inhibitors of mineral deposition such as pyrophosphatesServes as scaffold of mineralisationNucleator of mineralisationInhibits mineralisation and promote bone resorptionInhibits mineralisationMay mediate deposition of hydroxyapatite

Regulatory genesTranscription factors Cbfal/Runx2

OsterixTwist

Msx2

Required for osteogenic commitment and differentiationRequired for osteogenic differentiationPositive regulator of osteoblast differentiationInhibits osteoblast differentiation

Growth factor/receptors Fibroblast growth factors/receptors (FGF/FGFR)Transforming growth factors/ receptors (TGFb/TGFbR)Bone morphogenic proteins/ receptors (BMP/BMPR) Insulin like growth factor (IGF)

Platelet derived growth factor (PDGF)

Stimulates proliferation and differentiationGenerates survival signallingModulates bone remodelling

Increases Cbfal/Runx2 expression and stimulates differentiationStimulates cell proliferation, differentiation and matrix productionSignals cell proliferation and recruit progenitor cells by stimulating chemotactic migration

Source: Cited with permission from Mao JJ, Nah HD. Growth and development: hereditary and mechanical modulations. Am J Orthod Dentofacial Orthop 2004;125:676–89


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median nasal process with the maxillary process while cleft palate occurs due to nonfusion either between the two pala-tal processes or between the palatal process and the fronto-nasal process (primary palate). In addition, in very rare circumstances, the two MNPs may fail to fuse to give rise to atypical midline clefts. Such clefts are usually associated with other anomalies related to midline structures, and, in many cases, may not be compatible with life.

Depending on the location, clefts may be classifi ed broadly into: (i) cleft lip, (ii) cleft lip and alveolus, (iii) cleft lip and palate, and (iv) isolated cleft palate. The exact nature and extent of the defect depends upon the time, location, duration, and the nature of insult. However, the nature of the defect is in synchrony with the embryologic sequence of palatal development. As discussed earlier, the critical time for the formation of upper lip is between the 5th and 8th

Table 7.7 Some branchial arch syndromes

Disease Defects of the 1st and 2nd arches Other defects Inheritance and cause

Oculo-auriculo-vertebral syndrome

Ocular and auricular anomalies, hemifacial microsomia, dermoids, upper eyelid colobomas, macrostomia, facial clefts, ear malformations

Vertebral malformations, cardiac and renal defects

Mostly sporadic; some are autosomal dominant/recessiveCause: Chromosomal alterations of 5,18,22, X

Treacher Collins syndrome

Hypoplasia of zygoma, maxilla, downslanting palpebral fi ssures, coloboma of lower eyelid, microtia, cleft palate, ear anomalies

– Autosomal dominant; haploinsuffi ciency of treacle (derivative of gene TCOF1)

Auriculo-condylar syndrome

Prominent and malformed ears, microstomia, abnormal temporomandibular joint, mandibular condyle hypoplasia; facial asymmetry

Developmental delay in few cases

Autosomal dominant; heterogeneity, ACS1: 1p21–q23

Oculo-auriculo-frontonasal syndrome

Ocular hypertelorism, wide nasal bridge, microtia, epibulbar dermoids, cleft lip, macrostomia

Congenital heart anomalies, encephaloceles, fusion C2–C3

Sporadic and autosomal dominant

Acrofacial dysostosis type Nager

Hypoplasia of the zygoma, maxilla, mandible, cup-shaped ears, cleft palate

Asymmetric thumb hypoplasia or aplasia, radial hypoplasia or aplasia with radioulnar synostosis, missing phalanges and syndactyly

Mostly sporadic; some are autosomal dominant/recessive; alterations in chromosomes 1q, 3p and 9q

Branchio-otorenal syndrome

Long, narrow, asymmetric face; facial palsy, aplasia/stenosis of lacrimal duct, ear defects, pre-auricular pits

Renal disturbance, branchial clefts, cysts/fi stulae

Autosomal dominant; haploinsuffi ciency of EYA1 and SIX5

Wildervanck syndrome

Abducens nerve palsy, retraction of eye ball, facial asymmetry, hearing loss

Fusion of cervical vertebra, short neck, spina bifi da, rib anomalies

Multifactorial

Townes–Brocks syndrome

Malformed ears, hearing defects, pre-auricular skin tags

Triphalangeal thumbs, renal, cardiac defects

Autosomal dominant; mutations in SALL1

Moebius syndrome Palsies of the 6th and 7th cranial nerves, hypoplasia/absence of the facial muscles, mask-like facies, micrognathia, ocular problems, ptosis, nystagmus or strabismus

Reductive limb anomalies, defects of the chest wall, mental retardation

Most cases sporadic; some are autosomal dominant/recessive heterogeneity; chromosomes 1, 2 and 13q12.2–q13

Orofacial digital syndrome (I-IX)

Minor facial anomalies, cleft palate, cleft tongue

Digital anomalies: brachydactyly, syndactyly, clinodactyly and polydactyly

X linked recessive, autosomal recessive/dominant X-linked semidominant

Otopalatodigital syndrome type I

Overhanging brow, prominent supraorbital ridge, wide nasal bridge, downslanting palpebral fi ssures, hypertelorism, cleft palate (only in affected males), conductive hearing loss

Retarded skeletal growth, small trunk, syndactyly, clinodactyly, short/big toes), mushroom-like appearance of the skull

X-linked semidominant

Otopalatodigital syndrome type II

Hypertelorism, frontal bossing, midface hypoplasia, broad nasal bridge, downslanting palpebral fi ssures, low set ears, microstomia, mandibular micrognathia

Thin and wavy clavicles, narrow thorax, malformed ribs, fl attened vertebrae, scoliosis, bowed humerus, radii, femora, and tibiae, digital anomalies, rocker-bottom feet

X-linked semidominant

Source: Adapted from Passos-Bueno MR, Ornelas CC, Fanganiello RD. Syndromes of the fi rst and second pharyngeal arches: a review. Am J Med Genet A 2009;149A:1853–9


99

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apter 7: P

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evelop

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e foetu

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week while for the palate it is between 7th and 10th week. Hence, processes acting during early phases lead to forma-tion of cleft lip while those acting later contribute to palatal clefts. Interestingly, although cases of cleft lip can occur in isolation, they are usually associated with some form of pal-atal cleft. Also, isolated cleft palate is usually considered a separate entity as its incidence, aetiology and genesis are different from other types of clefts.

Many of the craniofacial defects are related to problems with the differentiation or migration of the neural crest cells. Neural crest cells are particularly prone to insult due to their long paths of migration. The defects range from complete disruption in the development of the neurocra-nium (anencephaly) which usually are incompatible with life to milder defects like single-tissue malformations (mal-formations of the external ear). Usually, disruption of neu-ral crest cell activity leads to development of craniofacial syndromes, like branchial arch syndromes and craniosynos-tosis syndromes, etc.

Branchial arch syndromes18

Defects in the development of branchial arches lead to bran-chial arch syndromes (Table 7.7). These may be of both genetic and environmental origin. Since the formation of face is primarily concerned with the 1st and 2nd branchial arches, syndromes of the 1st and 2nd arches hold the maximum importance for dental professionals. The most common and important syndromes include the TCS (Treacher Collins syndrome), oculo-auriculo-vertebral syn-drome (OAVS) and auriculo-condylar syndrome (ACS; ques-tion mark ear syndrome). TCS and ACS are autosomal dominant with nearly complete penetrance and wide spec-trum of clinical variability. The phenotype of the latter has several overlapping features with OAVS, but OAVS may exist in both sporadic and autosomal dominant forms.

Synostosis syndromes19

Premature fusion of the cranial sutures leads to develop-ment of craniosynostosis. Craniosynostosis is a relatively common condition with a prevalence of 1 in 3000. More than 100 synostosis syndromes have been defi ned and many are associated with limb deformities suggesting a common pathway of development. The common craniofacial cranio-synostosis syndromes include Apert, Pfeiffer, Crouzon, Muenke, and Saethre–Chotzen syndromes (Table 7.8). Major-ity of these syndromes, in contrast to branchial arch syn-dromes, are nongenetic in origin. The sagittal suture is the most commonly affected followed by the coronal suture.

Crouzon syndrome, which occurs due to prenatal fusion of the superior and posterior sutures of the maxilla along the wall of the orbit, is the most frequently occurring synos-tosis syndrome. Due to growth cessation at the sutures, the mid face remains underdeveloped with characteristic bulg-ing eyes. The fusion may extend posteriorly into the cra-nium, producing distortions of the cranial vault.

Synostosis leads to reduced space for the growing brain—increased intracranial pressure may develop which would necessitate surgical intervention. Surgical decompression at the sutures is frequently required.

Summary

Development of foetus from an embryo is a very complicated process which occurs during the 9 months of gestation. Life originates as a single-celled zygote and differentiates rapidly into cell masses forming the embryo proper which further develops and differentiates into the foetus. The critical period of organogenesis lasts from the 4th to 8th week during which time the imprints of various organ systems are cre-ated. After the embryonic phase, there is very little new tissue

Table 7.8 Common synostosis syndromes

Syndrome Clinical fi ndings

Synostosis and skull defects Facial defects Head and foot abnormalities Others Gene defect

Apert Bicoronal; irregular with ossifi cation defects

Hypertelorism, downslanting palpebral fi ssures, cleft palate

Syndactyly of hands and feet Mental retardation, cardiac defects

FGFR2 Ser252Trp or Pro253Arg

Crouzon Bicoronal Proptosis, hypertelorism, beaked nose

None None FGFR2

Pfeiffer Bicoronal; cloverleaf in type III

Proptosis, hypertelorism, downslanting palpebral fi ssures

Broad, medially deviated thumbs and halluces

Multiple malformations in type II and III

FGFR1 and FGFR2

Muenke Uni- or bicoronal Mild facial fi ndings, downslanting palpebral fi ssures

Mild brachydactyly Learning disability

FGFR3

Saethre–Chotzen

Uni- or bicoronal Ptosis, small ears, facial asymmetry

Hallux valgus, partial duplication of 1st hallux, brachydactyly, mild syndactyly

Mental retardation

TWIST mutation

Source: Adapted from Cassidy SB, Allanson JE (eds). Management of Genetic Syndromes, 3rd ed, New Jersey, Wiley–Blackwell, 2010, p. 228


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differentiation and growth of the already formed tissues pre-dominates to give an increasingly large size to the foetus.

The complex process of foetal developmental is under strong genetic regulation. The migration of the cell popu lations, differentiation of tissues, timing of cell divi-sion, programmed cell death and many other processes are controlled by genes. Any malfunction of gene, which may be inherent or occurs due to disruptive environmental infl uences, may result in a variety of congenital malfor-mations which may or may not be compatible with life. Orthodontists should be familiar with intrauterine normal development and abnormal development of face which has obvious clinical implications in orthodontic practice.

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Embryogenetics and Development, 2nd ed, Peoples Medical Publishing House, USA, 2010.

2. Cummins MR. A survey of human development from fer-tilization to birth. In: Cummings MR, ed. Human Heredity: Principles and Issues, 9th ed, Brooks/Cole Cengage, Belmont, USA, 2010:157.

3. Carlson BM. Foundations of Embryology, 6th ed, Tata McGraw Hill, India, 2007:519.

4. Drews U. Human development. In: Colour Atlas of Embryology. Drews U, ed. Thieme, Stuttgart, 1995:40.

5. Streeter GL. Development horizons in human embryos. Description of age group XI, 13 to 20 somites, and age group XII, 21–29 somites. Carnegie Contrib Embryol 1942;30:211–45.

6. O’Rahilly R, Müller F. Developmental Stages in Human Embryos. Carnegie Institute, Washington, 1987.

7. Moore KL, Persaud TVN. The developing human. In: Clinically Oriented Embryology, 6th ed, Philadelphia, Saunders, 1998.

8. Cobourne MT. Construction for the modern head: Current concepts in craniofacial development. J Orthod 2000;27:307–14.

9. http://www.indiana.edu/∼anat550/hnanim/face/face.html. 10. Bradley RM, Mistretta CM. Fetal sensory receptors. Physiol Rev

1975;55:352–82.11. Ferguson MW. A hole in the head. Nat Gent 2000;24:330–1.12. Bulfone A, Kim HJ, Puelles L, Porteus MH, Grippo JF,

Rubenstein JL. The mouse Dlx-2 (Tes-1) gene is expressed in spatially restricted domains of the forebrain, face and limbs in mid-gestation mouse embryos, Mechanics Develop 1993;40:129–40.

13. Rivera-Pérez JA, Mallo M, Gendron-Maguire M, Gridley T, Behringer RR. Goosecoid is not an essential component of the mouse gastrula organizer but is required for craniofacial and rib development. Development 1995;121:3005–12.

14. Johnston MC, Bronsky PT. Prenatal craniofacial development: New insights on normal and abnormal mechanisms. Crit Rev Oral Biol Med 1995;6:368–422.

15. Mossey PA. The heritability of malocclusion: Part 1—Genetics, principles and terminology. Br J Orthod 1999;26:103–13.

16. Bannister LH, Berry MM, Collins P, et al. Gray’s Anatomy, 38th ed. Edinburgh Churchill Livingstone, Edinburgh, 1995:426–42.

17. Sarnat BG. Effects and noneffects of personal environmental experimentation on postnatal craniofacial growth. J Craniofac Surg 2001;12:205–17.

18. Passos-Bueno MR, Ornelas CC, Fanganiello RD. Syndromes of the fi rst and second pharyngeal arches: a review. Am J Med Genet A 2009;149A:1853–9.

19. Gripp KW, Zackai EH. Craniosynostosis syndromes. In: Management of Genetic Syndromes, 3rd ed. Cassidy SB, Allanson JE (eds.), New Jersey, Wiley–Blackwell, 2010:228.


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