Craniofrontonasal dysplasia is a very rare genetic condition. As such there is little information and no consensus in the published literature regarding the epidemiological statistics.

The incidence values that were reported ranged from 1:100,000 to 1:120,000.

There is still some discussion on whether FND is sporadic or genetic. The majority of FND cases are sporadic. Yet, some studies describe families with multiple members with FND. Gene mutations are likely to play an important role in the cause. Unfortunately, the genetic cause for most types of FND remains undetermined.

OAFNS is a combination of FND and oculo-auriculo-vertebral spectrum (OAVS).

The diagnosis of OAVS is based on the following facial characteristics: microtia (underdeveloped external ear), preauricular tags, facial asymmetry, mandibular hypoplasia and epibulbar lipodermoids (benign tumor of the eye which consists of adipose and fibrous tissue).

There still remains discussion about the classification and the minimal amount of characteristics. When someone presents with FND and the characteristics of OAVS, the diagnosis OAFNS may be made.

As the incidence of OAFNS is unknown, there are probably a lot of children with mild phenotypes that aren’t being diagnosed as being OAFNS.

The cause of OAFNS is unknown, but there are some theories about the genesis. Autosomal recessive inheritance is suggested because of a case with two affected siblings and a case with consanguineous parents. However, another study shows that it is more plausible that OAFNS is sporadic.

It is known that maternal diabetes plays a role in developing malformations of craniofacial structures and in OAVS. Therefore, it is suggested as a cause of OAFNS. Folate deficiency is also suggested as possible mechanism.

Low-dose CT protocols should be considered in diagnosing children with OAFNS.

CFND is a very rare X-linked malformation syndrome caused by mutations in the ephrin-B1 gene (EFNB1). The EFNB1 gene codes for a membrane-anchored ligand which can bind to an ephrin tyrosine-kinase receptor. This ephrin receptor is, amongst other things, responsible for the regulation of embryonic tissue-border formation, and is important for skeletal and craniofacial development. As the ephrin receptor and its EFNB1 ligand are both bound to the (trans)membrane of the cell its cascade is activated through cell-cell interactions. These cell-cell interactions are disturbed due to the presence of cells with the mutant EFNB1 gene, as a result causing incomplete tissue-border formation.

Paradoxical to other X-linked conditions, with CFND the females are more severely affected than males. This is due to the process of X-inactivation in females, where at random either the maternal or paternal X-chromosome is inactivated in a cell. Due to this process the body’s tissues contain either cells with normal EFNB1 or the mutated EFNB1. This is called a mosaic pattern. This mosaic pattern of cells 'interferes' with the functionality of the cell-cell interactions, as a result causing the severe physical malformations in females.

As with all X-linked conditions CFND has a preset chance of being passed down from parents to their offspring. Females have two X-chromosomes and males have one X-chromosome. When a mother is a carrier of CFND, there is a 50% chance of her passing down the X-chromosome containing the mutated EFNB1 gene to her offspring, regardless if the child is a boy or girl. If the father is a carrier there is a 100% chance of him passing down his X-chromosome with the EFNB1 mutation to a daughter, and 0% chance of him passing it down to a son.