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Human craniofacial development is a complex and highly regulated process. It can be split into 6 stages, the formation of the pharyngeal apparatus, the tongue, the skull, face and palate.
Diagram 1:- Image of the four pharyngeal pouches that lie in between the 5 pharyngeal arches. image taken from: https://web.duke.edu/anatomy/embryology/craniofacial/craniofacial.html
The pharyngeal apparatus is a major part of craniofacial development alongside the development of the tongue, face, skull and palate. Firstly the pharyngeal apparatus contains structures such as paired pharyngeal arches, pouches, membranes and clefts). There are five pharyngeal arches (1, 2, 3, 4, and 6) each of which are formed during the fourth week of embryonic development. All five arches are supplied with their own cranial nerves. The bone, cartilage and connective tissue of each pharyngeal arch is formed from the mesenchyme of the neural crest whilst the skeletal muscle and the artery develops from the somatic mesoderm.
There are four pharyngeal pouches that lie between the pharyngeal arches. They are formed by a layer of endoderm that lines the inner pharyngeal apparatus. Also, there is a layer of Ectoderm that lines the outer pharyngeal apparatus that then form the four pharyngeal clefts. The first pharyngeal cleft later develops as the external auditory meatus; this is the only pharyngeal cleft that remains through adulthood.
Development of the Tongue is split into two stages, the formation of the anterior two-thirds of the tongue, followed by the fusion of the posterior third of the tongue. When the anterior and posterior parts fuse, it can be represented by the Terminal Sulcus. The anterior of the tongue is formed from the first pharyngeal arch, which then develops in the median and lateral tongue buds. The posterior of the tongue develops from the third and fourth pharyngeal arches. The muscles of tongue are derived from Occipital myoblasts.
The skull is formed overall by the fusion of many bones, but this process doesn't occur until after birth. Reason being, loose bones at this stage in the skull allows the baby's head to fit though the birth canal without causing damage to the brain of the newborn. The anterior skull bones and the hyoid bones are ossified from the mesenchyme of the neural crest whilst the bones on the base of the skull and the flat bones of the skull are ossified from the paraxial mesoderm.
The facial development occurs between weeks 5-10 of fetal development. It is primarily formed from right and left Maxillary prominences and Mandibular prominences (in which they fuse together during fetal development) a Frontonasal prominence and paired nasomedial prominences. The Frononasal prominence is formed from the mesenchymal neural crest. Numerous events occur at the stage, for example, the maxillary prominence fuse with the lateral nasal prominence at the midline which creates a naslactrimal groove. Most of the groove disappears aside from the superior portion of the groove where the nasolactrimal ducts and lacrimal sacs form. As the nasal prominences fuse, it forms two structures which include the philtrum of the upper lip, and also creates the midline of the nose.
Finally the palate undergoes two stages, firstly there's the primary palate, which is then followed by the secondary palate. The primary palate is formed when the two medial nasal prominences fuse together. The secondary palate is formed when the maxillary prominences grow further (Palatine Shelves). The palatine shelves then
2) Overview Of The Alx Homeobox genes.
The Homeobox gene family are a group of similar genes which are involved in directing the arrangement of many structures of the body that takes place during embryonic development. In every human genome there are Homeobox genes present that cluster together. They take part in many activities during this period such as arranging and developing the formation of the limbs and organs along the anterior-posterior axis. Some homeobox genes function as tumour suppressers and they also regulate cellular differentiation. The Homeobox genes have a notable trait and this is; that they have a specific DNA sequence which encodes a particular protein domain. 
The ANTP and PRD classes are the two main types of groups of Homeobox genes. Both groups participate in cellular differentiation or developmental patterning.  The PRD (Paired Gene of Drosophila) class is the second largest group of Homeobox genes, and within the PRD group are the three notable Alx Homeobox genes; Alx1, Alx3 and Alx4. Both humans and mice have these three Alx Homeobox genes in their genome and they participate in the closure of the neural tube, formation of the limbs and craniofacial development .
It has been discovered  that the three alx genes in mouse; Alx1, alx3 and alx4, have related expression patterns in the development in the cranial region of a human embryo. During early embryonic development, these genes are firstly expressed in the frontonasal mesenchyme followed by expression in the first and second pharyngeal arches. The causes of congenital craniofacial malformation are connected to mutations within the three alx genes.
In order to discover the functional roles of the Alx gene family, experiments have been conducted using Zebrafish. The reason behind this is because there are similarities in craniofacial development in zebrafish and mammals. For example the way the palate develops in both Zebrafish is very comparable to what occurs in mammals in cellular and genetic aspect  . Also the Frontonasal and maxillary aspects of the mesenchyme are formed from the Cranial Neural Crest (CNC) the same in mammals.
2.1) The three Alx Homeobox genes; Alx1, Alx3 and Alx4
The three Homeobox genes are a family belonging to the Arisaless- Like homebox genes. The are "characterised by a paried type domain and a conserved C-terminal paired tail domain" according to work of Kayseili et al  . Their main function is to express a distinct transcription during the development of the embryo. All three have a common source of being expressed in the mesenchyme of mammals during embryogenesis, especially during weeks 4-8 of development.
The location of the Alx1 gene in humans is at the position of 21.31 on the long arm of Chromosome 12.  The functional role of Alx1 in humans is not currently fully understood, but because there is information about the effects of homozygous mutations in the gene causes (such as Frontonasal dysplasia type 3), it is established that Alx1 must have a profound effect during facial development. It has been discovered that out of the three Alx genes, Alx-1 alone is expressed through Cranial neural crest development. This then explains why that the Phenotype caused by depletion of Alx1 in zebrafish caused extreme malformation of the eyes, palate and lack of facial cartilage. Alx1 has a fundamental role in the function of the Cranial Neural crest, thus, defects in the gene can cause notable malformations such as cleft palate of oblique facial clefting.
Alx3 gene acts as a transcriptional regulator because it encodes a nuclear protein. This nuclear protein then becomes a binding site for the strands of homebox DNA. Alx3 is important for cellular differentiation and development; it is also a possibility that Alx3 is involved in the patterning of mesoderm at early embryonic development . Defects in this gene can be associated with advanced-stage neuroblastoma tumors as well as Frontonasal dysplasia type 1 (FND1) and is associated with midfacial dysraphia. The Alx3 lies on the short arm of chromosome 1 at the position of 13.3.
The ALX4 gene is produces a transcription factor; Alx4 protein which is essential for complete development of the skull. The gene is located at the position of 11.2 on the short arm of chromosome 11. There are two significant conditions associated with mutations within the Alx4 gene; Enlarged Parietal foramina and Potocki-Shaffer syndrome [5 It has been discovered that Alx4 has an important in the development of human hair follicles and the skin.  It is thought that because Alx4 is expressed in the mesenchyme during embryonic development, it could also participates in the signalling between the mesenchyme and the epithelium of the skin. In mice defects in the Alx4 gene lead to dorsal alopecia and genital abnormalities which produces a similar effect of a mutated Alx4 gene in humans. Also as there would then be dysfunction of the hair follicle development, the little hair that was present was weak and fragile. It is therefore known that Alx4 has a role not only confined to the craniofacial region, but also in bone and limb development and as mentioned, hair follicle development.
Diagram 2 :- The location of the three Alx genes, Alx1, Alx3, Alx4 within the human genome.
2.2) The evolution of the Homeobox genes.
According to research (McGonnell et al, 2011), "the branch lengths for all Alx3 proteins are longer than those of other Alx proteins, suggesting that Alx3 genes may have rapidly evolved in comparison with Alx1 and Alx4". This could be linked as to why Alx3 gene had repeated independent loss through evolution. During early vertebrate evolution, the three alx genes underwent two complete genome duplications (2R-WGD). In which Alx 1 and Alx3 where produced from the same genome duplication and Alx2 and Alx4 where also paired. This then explains why Alx1 and Alx3 share more similarities in comparison to Alx4. Alx 2 has been lost from evolution but unknown when, whilst Alx1, Alx3 and Alx4 still remain in the vertebrate genomes . Following two whole gene duplications, Alx2 is lost quickly from the Alx Homeobox gene family tree. Whilst Alx3 is lost independently from the genome at three different species of vertebrates; "The Amphibian X tropicallis, the Squamate reptile A.carolinensi, and the bird G.Gallus" (McGonnell et al 2011) 
Both Alx1 and Alx3 are comparable in their role of neural tube closure and because they're more similar to each other as they share the same whole gene duplication. If either Alx1 or Alx3 where to be lost, they can be compensated for by the other gene due to their functional similarities. Alx4 is the only member Alx Homeobox gene that participated in axial patterning of the limbs (Takahashi et al 1997). Therefore losing Alx4 from the genome would be more consequential in comparison to losing either Alx1 or Alx3. 
Diagram 3; Two Round Whole Gene Duplication. Both Alx 1 and Alx3 are derived from the same duplication. Whilst Alx 2 and Alx4 are stemmed from a different duplication.
2.3 Alx Related Frontonasal Dysplasia.
Alx1, Alx3 and Alx4 genes are critical for craniofacial development during the early stages of embryogenesis by encoding a homeodomain protein. Severe frontonasal dysplasia phenotypes occurs when homozygous mutations are present within the Homeobox transcription factors of either Alx1, Alx3 and Alx4
Frontonasal Dysplasia 
During embryogenesis, the facial growth after week 4 of development is governed by mesenchymal-ectodermal communications. For this to occur, a number of of genes that encode transcription factors are needed in order for the epithelium to control the communication between both the mesenchyme and the ectoderm It is though that the Alx gene family are contributors to this process. Therefore an alterations in the signalling, such as mutations in the Alx genes, can cause severe disfigurement of frontofacionasal features, such as cleft palate. Frontonasal dysplasia describes a series of facial malformations, conswquently due to disrubtive median facial development. Hypertelorism is common characteristic of this disorder due to improper migration. The only genetic cause of frontonasal dysplasia that has been proven, are mutations in a ligand of Ephrine receptors tyrosine kinases. Also, most cases of Frontonasal dysplasia are sporadic without any known reason.
Alx1 related frontonasal dysplasia
Mutations in the Alx1 gene are known to cause Frontonasal Dysplaisa type 3 (FND3), which is the most severe form of Fronotnasal Dysplasia. Regardless of its severity it is possible for the individulal with FND3 to survive into childhood and sometimes even longer than that. In compartison to Alx3 and Alx4, the mutations within the Alx1 gene creates a far worse impact within the frontonasal area. , Frontonasal dysplasia is inherited as an autosomal recessive disorder. Microdeletions as well as point mutations of the Alx1 gene produce phenotypes for Frontonasal dysplasia type 3. Thus, when both parents are normal, the child will have a 25% percent chance of developing alx-related dysplasia from parents who are both carriers. It affects the face by causing frontonasal dysplasia, bilateral oblique facial cleft, hypertelorism and extreme bilateral microphthalmia. The ears will be low set and posteriorly rotated. There could be lack of upper lip, macrostomia and a complete cleft palate. A wide nasal bridge would be seen alongside hypoplasia of the alae nasi. Other affects could be mild mental retardation and caudal appendage .
Alx3 related Fronotnasal Dysplasia.
Mutations such as splicesite, framshift and missense within the Alx3 gene can cause the gene to patially lose its function or even lead to complete loss of function. Frontonasal Dysplasia type 1 (FND1) (also known as Frontorhiny) is a major disorder arising from mutations within this gene. This FND1 phenotype is a milder form in comparison to Alx1 and Alx3 related FND. Similar to Alx1 FND, it is inherited as an autosomal recessive disorder, which causes frontonasal dysplasia to the face. It will cause hypertelorism in the eyes and sometimes it can cause ptosis, iris coloboma and oribital dystopia. The mouth will generally have a long philtrum with bilateral swellings. Prominent philtral ridges can be a physical diagnosis for Alx3- related Frontonasal Dysplasia. Also FND1 can cause columella of the nose, a bifid nasal tip, a wide nasal bridge and a short nasal ridge. During FND1, it is known  that during fetal development, the fusion between the nasomedial and frontonasal prominences do not finish completion and therefore accounting for facial disfigurements such as the distinctive bifid nasal tip and a broad nasal bridge.
Alx4-related Frontonasal dysplasia.
Mutations in the Alx4 gene is the cause Frontonasal Dysplasia type 2 (FND2). In comparison to Alx1 and Alx3 - related FND, the Alx4-related FND has affects that are not confined to that facial area. For example, the individual can have total alopecia, and also genital abnormalities  such as Hypogonadism.
The mutations within the Alx4 gene can either be Homozygous or heterozygous each of which produces different phenotypes. Point mutations are likely to occur if the mutations were heterozygous; an example of this would be in the Potocki-Shaffer syndrome, where there deletions are present on chromosome 11 in the location where the Alx4 gene is located (short arm of at point 11.2) the chromosome where the Alx4 gene is present (Chromosome 11p11.2). Also in heterozygous mutaions, frame-shift and missense mutations can occur that result in a defective alx4 protein, In contrast homozygous mutations normally present with nonsense mutation a truncating affect resulting in a defective protein thus, changing its homeodomain, essential for its function.  of the protein produced following transcription of the mutated Alx4 gene. in the same location of the Alx4 gene to cause the malfunction.
The defects in the Alx4 gene have a more severe impact on the eyes. It can cause extreme hypertelorism  as well as blepharopmiosis and rotatory nustagmus. The nose in Type 2 frontonasal dysplasia can cause a depressed nasal bridge and nasal ridge, and a bifid nasal tip which can be compared with that of Alx3-related Frontonasal dysplasia. FND2 has a profound impact on the development of the skull which can lead to disorders such as Brachycephaly.
Diagram 3:- Physical appearances due to mutations within the Alx gene family, Alx1, Alx3 and Alx4. Each of which causing a type of Frononasal Dysplasia (FND)
Image take from http://www.cranirare.eu/phenotypes/alx_frontonasal_dysplasias/index.php