Embryogenesis Midline facial clefts are one of the symptoms in<unk> . These defects develop in the early stages of embryological development. This is around the 19th to 21st day of pregnancy. The cause of the defect is failure of the mesodermal migration. The mesoderm is one of the germ layers (a collection of cells that have the same embryological origin). As a result of this failure, a midline facial cleft is formed. Another symptom of<unk>  is the V-shaped hairline. In the normal situation, hair growth surrounding the eyes is inhibited. However, in<unk>  this suppression is prevented in the midline by the increased inter-ocular distance. This causes the so-called widow’s peak (a V-shaped hairline) in<unk>  patients. Very early in embryogenesis, the face and neck develop. This development continues until adolescence. Organs develop out of primordia (tissue in its earliest recognizable stage of development). The developmental processes of the face and jaw structures originate from different primordia: * Unpaired frontonasal process * Paired nasomedial and nasolateral processes * Paired maxillary processes and mandibular processes The head of a human embryo of about twenty-nine days old. The formation of the frontonasal process is the result of a complex signaling system which begins with the synthesis of retinoic acid (a vitamin A metabolite). This is needed to set up the facial ectodermal zone. This zone makes signaling molecules that stimulate the cell proliferation of the frontonasal process. A midfacial defect will occur if this signaling pathway is disrupted. It is suggested that the absence of this pathway will lead to the formation of a gap, and that when the pathway is working too hard, excessive tissue will be formed.<unk>  consists of various nasal malformations that result from excessive tissue in the frontonasal process, which results in hypertelorism and a broad nasal bridge. Between the 4th and 8th week of pregnancy, the nasomedial and maxillary processes will fuse to form the upper lip and jaw. A failure of the fusion between the maxillary and nasomedial processes results in a cleft lip. A median cleft lip is the result of a failed fusion between the two nasomedial processes. The palate is formed between the 6th and 10th week of pregnancy. The primordia of the palate are the lateral palatine processes and median palatine processes. A failure of the fusion between the median and lateral palatine processes results in a cleft palate. Genetics There is still some discussion on whether<unk>  is sporadic or genetic. The majority of<unk>  cases are sporadic. Yet, some studies describe families with multiple members with<unk> . Gene mutations are likely to play an important role in the cause. Unfortunately, the genetic cause for most types of<unk>  remains undetermined. Frontorhiny The cause of frontorhiny is a mutation in the ALX3 gene. ALX3 is essential for normal facial development. Different mutations can occur in the ALX3 gene, but they all lead to the same effect: severe or complete loss of protein functionality. The ALX3 mutation never occurs in a person without frontorhiny. Acromelic frontonasal dysostosis Acromelic frontonasal dysostosis is caused by a heterozygous mutation in the ZSWIM6 gene. It is thought that acromelic frontonasal dysostosis occurs due to an abnormality in the Sonic Hedgehog (SSH) signaling pathway. This pathway plays an important role in developing the midline central nervous system/craniofrontofacial region and the limbs. Hence, it is plausible that an error in the SSH pathway causes acromelic frontonasal dysostosis, because this syndrome not only shows abnormalities in the midfacial region, but also in the limbs and CNS.
Frontonasal dysplasia
Craniofrontonasal dysplasia
Oral submucous fibrosis
Hereditary mucoepithelial dysplasia
Nevoid basal-cell carcinoma syndrome
Genodermatosis
Neurofibromatosis
Neurofibromatosis type I