Congenital Craniofacial Malformations

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This e book describes the various congenital craniofacial malformations, their mode of inheritance and classification.

Text of Congenital Craniofacial Malformations


Congenital craniofacial malformationsDr. T. Balasubramanian M.S. D.L.O.This e book describes various craniopharyngeal malformations, their mode of inheritance and their classification. An attempt is also made to discuss the variations which are possible in these patients

drtbalu Drtbalus otolaryngology resources 2/21/2010


Congenital craniofacial malformations


Dr. T. Balasubramanian


Introduction: Craniofacial malformations are usually caused by misregulation of normal tissue patterning. These malformations are usually defined by their effect on the gross anatomy of the area and the phenotypic abnormalities documented. Work is in progress to elucidate the molecular basis for these phenotypic abnormalities. Inside the uterus signals for growth and differentiation of the fetus are usually relayed from outside the cell, through the plasma membrane and cytoplasm, into the nucleus. These signals regulate and co-ordinate genetic expression and tissue differentiation, similarly from the nucleus information passes outwards to alter the Cytoplasmic structures, modulating the cellular response to the incoming signals, and also serves to coordinate the activities of other cells nearby as well as distant ones. These signals are also known as Ligands. Ligands are of two types: Diffusible Ligands: Growth factors classically belong to this group. Ligands belonging to this group are highly diffusible in the lipid matrix. They help in signal transmission from the outside. These Ligands begin signal transduction process by binding to specific receptors present over the cell membrane.


These receptors are known as transmembrane receptors. These receptors have three portions: a. Extracellular domain: This is present over the exterior of cell membrane. This is where the diffusible ligand is supposed to get attached. b. Transmembrane domain: This portion of the receptor spans the whole thickness of the cell membrane. It is in physical contact with the extracellular domain present outside. c. Intracellular domain: This domain is present within the cell and is responsible for changes that occur within the cell. This domain is in physical contact with the transmembrane domain. Binding of a ligand to the extracellular domain will cause phosphorylation of the intracellular domain leading on to phosphorylation of intracellular substrates and also alters the activity of other intracellular proteins.

Stationary Ligands: This in comparison to the diffuse Ligands doesnt usually diffuse into the cell. Examples of these Ligands include matrix associated proteins. Classic matrix associated proteins include the fibroblast growth factors (which are responsible for the growth and differentiation of fibroblasts),


Bone morphogenic factor (causing tissues to differentiate into bones). These Ligands thus cause changes in protein activity, controls cell proliferation, migration, differentiation, symmetry and sometimes even apoptosis. Co-ordination of all these cellular process is a must for development of facial skeleton. Derangements of this co-ordinated signaling process can lead to craniofacial malformations.


Diagram showing cell signaling process

Embryology of face and jaws: Tissues giving rise to face and jaws are derived from three sources:


a. The ectodermal layer that provides the surface cover. This layer also interacts with mesodermal layer helping to pattern the developing structures. b. Neural crest layer that provides for most of the facial mesenchyme. c. The paraxial / prechordal mesenchyme contribute to the development of craniofacial musculature. The first sign of development of face is the formation of a small pit called as stomodeum. Stomodeum lies just below the developing brain. The ectoderm that overlies the developing forebrain extends into the stomodeum. At the stomodeum it lies adjacent to the developing foregut. The junction between the ectoderm and the adjacent endoderm is known as the oropharyngeal membrane. The line of attachment of the oropharyngeal membrane corresponds to the future Waldayers ring.


Figure showing development of nasal placodes This oropharyngeal membrane undergoes spontaneous dissolution during the 4th week of gestation. This dissolution permits communication between the mouth and foregut. The Waldayers ring connects the nasopharyngeal tonsil, lingual tonsil and the palatine tonsils. It is during this 4th week of intrauterine gestation the neural crest cells start to migrate to the developing face from


lower portion of forebrain and upper midbrain areas. These neural crest cells are a vital source for facial connective tissue (which includes cartilage, bone and ligaments). Since these migrating neural crest cells arise from different portions of the developing brain they carry with them different developmental programmes according to their site of origin. Mutations involving these migrating neural crest cells may cause various anamolies involving the facial structures. This 4th week of gestation is really crucial in the development of facial structures. It is during this period that 5 processes develop to surround the developing stomodeum. A single unpaired frontonasal process lies in the midline just above the stomodeum (future mouth). Embryologically this process arises from the forebrain. Paired maxillary prominences lie on either side of stomodeum superiorly and paired mandibular prominences lie on either side of stomodeum inferiorly. These two paired processes arise from the first branchial arch. It is during the embryological window spanning between 4 8 weeks, the median frontonasal process give rise to median facial structures, and the paired maxillary and mandibular arches / processes give rise to lateral facial structures. Hence it should be borne in mind that malformations usually involve either median or lateral structures separately or the junctional areas.


Development of nose and nasal cavity: At the end of the 4th week paired ectodermal thickenings appear on the surface of the frontonasal process, just superolateral to the stomodeum at 1 oclock and 11 oclock positions. These thickenings known as nasal placodes gives rise to the future nose and nasal cavity. Lens placodes also develop during the same embryological window. Developments of nasal and lens placodes are dependent on the paired Box gene Pax 6. In the absence of this gene neither the nasal nor the lens placode can develop. During the 5th week of gestation the mesenchyme present over the margins of nasal placodes begins to proliferate to form horse shoe shaped projections. The medial limbs of the horse shoe projections are known as nasomedial process, and the lateral limbs are designated as nasolateral process. The nasomedial processes are larger than nasolateral processes. Tissues surrounding the optic and nasal placodes enlarge causing the nasal pit area to form recess known as nasal pits. These nasal pits give rise to future nose and nasal cavities.


Figure showing nasomedial and nasolateral processes

Figure showing development of maxillary process

Figure showing branchial arches


During the 4th and 5th weeks of gestation the mandibular processes begin to enlarge on both sides, merging with each other in the midline. This merger takes place between 6th to 8 weeks forming the mental area of the lower jaw. Incomplete fusion of this area leads to the formation of the dimple in the chin area. The paired maxillary processes grow towards each other and towards the paired nasomedial processes. The maxillary processes eventually give rise to lateral 2/3 of upper jaw. It also gives rise to the upper dentition except for the incisors. The nasolateral processes at the 6th week merges with the maxillary process to form the ala of the nose. At the junction between the maxillary and the lateral nasal process lies the nasolacrimal groove. These grooves extend between the developing nose and eyes. The ectodermal lining of this groove give rise to nasolacrimal ducts and nasolacrimal sacs. The nasolacrimal ducts extends from the medial corners of the eye up to the inferior meatus in the lateral nasal wall. Cheeks and corners of the mouth develop from fusion of maxillary and mandibular processes. Development of upper lip is usually complete by the 8th week of intrauterine life. The nasomedial processes merge with the superficial regions of maxillary processes. This line of merger is known as the lines of fusion. These areas are represented as furrows / folds after completion of development. The nasomedial processes also


merge with each other across midline to form the intermaxillary segment. This fusion displaces the frontonasal prominence posteriorly. Hence the frontonasal prominence doesnt contribute to the definitive upper lip, jaw or nasal tip. During the 7th week Pinna begins to develop. It develops from 6 mesenchymal hillocks which form around the first pharyngeal groove. Three of these hillocks (auricular) develop from the first pharyngeal arch and the other three develop from the second pharyngeal arch. These 6 auricular hillocks merge with each other to form the pinna. The groove between these hillocks gives rise to the external auditory canal. After the formation of facial structures is completed, mesodermal tissue from the first and second arches begin to invade to give rise to the muscles of facial expression and muscles of mastication. The relative size of these facial structur