Environmental influences may also cause, or interact with genetics to produce, orofacial clefting. An example of how environmental factors might be linked to genetics comes from research on mutations in the gene "PHF8" that cause cleft lip/palate (see above). It was found that PHF8 encodes for a histone lysine demethylase, and is involved in epigenetic regulation. The catalytic activity of PHF8 depends on molecular oxygen, a fact considered important with respect to reports on increased incidence of cleft lip/palate in mice that have been exposed to hypoxia early during pregnancy. In humans, fetal cleft lip and other congenital abnormalities have also been linked to maternal hypoxia, as caused by e.g. maternal smoking, maternal alcohol abuse or some forms of maternal hypertension treatment. Other environmental factors that have been studied include: seasonal causes (such as pesticide exposure); maternal diet and vitamin intake; retinoids — which are members of the vitamin A family; anticonvulsant drugs; nitrate compounds; organic solvents; parental exposure to lead; alcohol; cigarette use; and a number of other psychoactive drugs (e.g. cocaine, crack cocaine, heroin).

Current research continues to investigate the extent to which folic acid can reduce the incidence of clefting.

The prevalence has been estimated at 1 in 10,000 births, but exact values are hard to know because some that have the symptoms rarely have Pierre-Robin sequence (without any other associated malformation).

Genetic counseling for VWS involves discussion of disease transmission in the autosomal dominant manner and possibilities for penetrance and expression in offspring. Autosomal dominance means affected parents have a 50% chance of passing on their mutated "IRF6" allele to a their child. Furthermore, if a cleft patient has lip pits, he or she has a ten times greater risk of having a child with cleft lip with or without cleft palate than a cleft patient who does not have lip pits. Types of clefting between parents and affected children are significantly associated; however, different types of clefts may occur horizontally and vertically within the same pedigree. In cases where clefting is the only symptom, a complete family history must be taken to ensure the patient does not have non-syndromic clefting.

Cleft lip and palate occurs in about 1 to 2 per 1000 births in the developed world.

Rates for cleft lip with or without cleft palate and cleft palate alone varies within different ethnic groups.

The highest prevalence rates for (CL ± P) are reported for Native Americans and Asians. Africans have the lowest prevalence rates.

- Native Americans: 3.74/1000

- Japanese: 0.82/1000 to 3.36/1000

- Chinese: 1.45/1000 to 4.04/1000

- Caucasians: 1.43/1000 to 1.86/1000

- Latin Americans: 1.04/1000

- Africans: 0.18/1000 to 1.67/1000

Rate of occurrence of CPO is similar for Caucasians, Africans, North American natives, Japanese and Chinese. The trait is dominant.

It caused about 4,000 deaths globally in 2010 down from 8,400 in 1990.

Prevalence of "cleft uvula" has varied from .02% to 18.8% with the highest numbers found among Chippewa and Navajo and the lowest generally in Africans.

Lip pits may be surgically removed either for aesthetic reasons or discomfort due to inflammation caused by bacterial infections or chronic saliva excretion, though spontaneous shrinkage of the lip pits has occurred in some rare cases. Chronic inflammation has also been reported to cause squamous-cell carcinoma. It is essential to completely remove the entire lip pit canal, as mucoid cysts can develop if mucous glands are not removed. A possible side effect of removing the lip pits is a loose lip muscle. Other conditions associated with VWS, including CL, CP, congenital heart defects, etc. are surgically corrected or otherwise treated as they would be if they were non-syndromic.

These lesions usually present in neonates, although they may not come to clinical attention until adulthood (for cosmetic reasons). There is no gender predilection. They are present in approximately 3-6 per 1000 live births.

Twenty to 27% of individuals with a laryngeal cleft also have a tracheoesophageal fistula and approximately 6% of individuals with a fistula also have a cleft. Other congenital anomalies commonly associated with laryngeal cleft are gastro-oesophageal reflux, tracheobronchomalacia, congenital heart defect, dextrocardia and situs inversus. Laryngeal cleft can also be a component of other genetic syndromes, including Pallister-Hall syndrome and G syndrome (Opitz-Friaz syndrome).

Children affected with PRS usually reach full development and size. However, it has been found internationally that children with PRS are often slightly below average size, raising concerns of incomplete development due to chronic hypoxia related to upper airway obstruction as well as lack of nutrition due to early feeding difficulties or the development of an oral aversion. However, the general prognosis is quite good once the initial breathing and feeding difficulties are overcome in infancy. Most PRS babies grow to lead a healthy and normal adult life.

The most important medical problems are difficulties in breathing and feeding. Affected infants very often need assistance with feeding, for example needing to stay in a lateral(on the side) or prone(on the tummy) position which helps bring the tongue forward and opens up the airway. Babies with a cleft palate will need a special cleft feeding device (such as the Haberman Feeder). Infants who are unable to take in enough calories by mouth to ensure growth may need supplementation with a nasogastric tube. This is related to the difficulty in forming a vacuum in the oral cavity related to the cleft palate, as well as to breathing difficulty related to the posterior position of the tongue. Given the breathing difficulties that some babies with PRS face, they may require more calories to grow (as working of breathing is somewhat like exercising for an infant). Infants, when moderately to severely affected, may occasionally need nasopharyngeal cannulation, or placement of a nasopharyngeal tube to bypass the airway obstruction at the base of the tongue. in some places, children are discharged home with a nasopharyngeal tube for a period of time, and parents are taught how to maintain the tube. Sometimes endotracheal intubation or tracheostomy may be indicated to overcome upper respiratory obstruction. In some centers, a tongue lip adhesion is performed to bring the tongue forward, effectively opening up the airway. Mandibular distraction can be effective by moving the jaw forward to overcome the upper airway obstruction caused by the posterior positioning of the tongue.

Given that a proportion of children with Robin sequence will have Stickler syndrome, it is important that a child with PRS have an evaluation by an optometrist or ophthalmologist in the first year of life looking for myopia that can be seen in Stickler syndrome. Because retinal detachment that can occur in Stickler syndrome is a leading cause of blindness in children, it is very important to recognize and be thoughtful of this diagnosis.

Because the cause of facial clefts still is unclear, it is difficult to say what may prevent children being born with facial clefts. It seems that folic acid contributes to lowering the risk of a child being born with a facial cleft.

A common method to treat Velopharyngeal insufficiency is pharyngeal flap surgery, where tissue from the back of the mouth is used to close part of the gap. Other ways of treating velopharyngeal insufficiency is by placing a posterior nasopharyngeal wall implant (commonly cartilage or collagen) or type of soft palate lengthening procedure (i.e. VY palatoplasty).

A laryngeal cleft or laryngotracheoesophageal cleft is a rare congenital abnormality in the posterior laryngo-tracheal wall. It occurs in approximately 1 in 10,000 to 20,000 births. It means there is a communication between the oesophagus and the trachea, which allows food or fluid to pass into the airway.

Opitz G/BBB Syndrome is a rare genetic condition caused by one of two major types of mutations: MID1 mutation on the short (p) arm of the X chromosome or a mutation of the 22q11.2 gene on the 22nd chromosome. Since it is a genetic disease, it is an inherited condition. However, there is an extremely wide variability in how the disease presents itself.

In terms of prevention, several researchers strongly suggest prenatal testing for at-risk pregnancies if a MID1 mutation has been identified in a family member. Doctors can perform a fetal sex test through chromosome analysis and then screen the DNA for any mutations causing the disease. Knowing that a child may be born with Opitz G/BBB syndrome could help physicians prepare for the child’s needs and the family prepare emotionally. Furthermore, genetic counseling for young adults that are affected, are carriers or are at risk of carrying is strongly suggested, as well (Meroni, Opitz G/BBB syndrome, 2012). Current research suggests that the cause is genetic and no known environmental risk factors have been documented. The only education for prevention suggested is genetic testing for at-risk young adults when a mutation is found or suspected in a family member.

A large number of human gene defects can cause ectrodactyly. The most common mode of inheritance is autosomal dominant with reduced penetrance, while autosomal recessive and X-linked forms occur more rarely. Ectrodactyly can also be caused by a duplication on 10q24. Detailed studies of a number of mouse models for ectrodactyly have also revealed that a failure to maintain median apical ectodermal ridge (AER) signalling can be the main pathogenic mechanism in triggering this abnormality.

A number of factors make the identification of the genetic defects underlying human ectrodactyly a complicated process: the limited number of families linked to each split hand/foot malformation (SHFM) locus, the large number of morphogens involved in limb development, the complex interactions between these morphogens, the involvement of modifier genes, and the presumed involvement of multiple gene or long-range regulatory elements in some cases of ectrodactyly. In the clinical setting these genetic characteristics can become problematic and making predictions of carrier status and severity of the disease impossible to predict.

In 2011, a novel mutation in DLX5 was found to be involved in SHFM.

Ectrodactyly is frequently seen with other congenital anomalies. Syndromes in which ectrodactyly is associated with other abnormalities can occur when two or more genes are affected by a chromosomal rearrangement. Disorders associated with ectrodactyly include Ectrodactyly-Ectodermal Dysplasia-Clefting (EEC) syndrome, which is closely correlated to the ADULT syndrome and Limb-mammary (LMS) syndrome, Ectrodactyly-Cleft Palate (ECP) syndrome, Ectrodactyly-Ectodermal Dysplasia-Macular Dystrophy syndrome, Ectrodactyly-Fibular Aplasia/Hypoplasia (EFA) syndrome, and Ectrodactyly-Polydactyly. More than 50 syndromes and associations involving ectrodactyly are distinguished in the London Dysmorphology Database.

While cleft is the most common cause of VPI, other significant etiologies exist. These other causes are outlined in the chart below:

Davis and Barry 1977 tested allele frequencies in domestic cats. Among the 265 cats observed, there were 101 males and 164 females. Only one cat was recorded to have the ectrodactyly abnormality, illustrating this rare disease.

According to M.P. Ferreira, a case of ectrodactyly was found in a two-month-old male mixed Terrier dog. In another study, Carrig and co-workers also reported a series of 14 dogs with this abnormality proving that although ectrodactyly is an uncommon occurrence for dogs, it is not entirely unheard of.

Although this is a congenital lesion, airway sounds typically begin at age 4–6 weeks. Until that age, inspiratory flow rates may not be high enough to generate the sounds. Symptoms typically peak at age 6–8 months and remit by age 2 years.

Late-onset laryngomalacia may be a distinct entity, which can present after age of 2 years

An accessory auricle is considered a developmental anomaly resulting from the persistence of a structure which variably recapitulates the normal external ear.

A facial cleft is an opening or gap in the face, or a malformation of a part of the face. Facial clefts is a collective term for all sorts of clefts. All structures like bone, soft tissue, skin etc. can be affected. Facial clefts are extremely rare congenital anomalies. There are many variations of a type of clefting and classifications are needed to describe and classify all types of clefting. Facial clefts hardly ever occur isolated; most of the time there is an overlap of adjacent facial clefts.

Although laryngomalacia is not associated with a specific gene, there is evidence that some cases may be inherited. Relaxation or a lack of muscle tone in the upper airway may be a factor. It is often worse when the infant is on his or her back, because the floppy tissues can fall over the airway opening more easily in this position.

There has been a great deal of research to understand the cause of PHACE Syndrome. The abnormalities associated with this syndrome are thought to be due to errors that occur very early during development. Unfortunately, why the errors occur, or the exact cause is still unknown. PHACE has a shared biology of other vascular anomalies. There may be a genetic component involved and studies are underway to investigate this idea. No familial cases have been identified to date. Research is ongoing to find the cause of all vascular anomalies including PHACE Syndrome.

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.

Velopharyngeal insufficiency (VPI) is a failure of the body's ability to temporarily close the communication between the nasal cavity and the mouth, because of an anatomic dysfunction of the soft palate or of the lateral or posterior wall of the pharynx.

The effect of such a dysfunction leads to functional problems with speech (hypernasality), eating (chewing and swallowing), and breathing. This gap can be treated surgically, although the choice of operational technique is still controversial.

The terms velopharyngeal "incompetence", "inadequacy" and "insufficiency" historically have often been used interchangeably, although they do not necessarily mean the same thing (sense distinctions can be made but sometimes are not). Velopharyngeal insufficiency includes any structural defect of the velum or pharyngeal walls at the level of the nasopharynx with insufficient tissue to accomplish closure, or there is some kind of mechanical interference with closure. It is important that the term insufficiency is used if it is an anatomical defect and not a neurological problem.

Velopharyngeal insufficiency (VPI) can be caused by a variety of disorders (structural, genetic, functional or acquired) and is very often associated with a cleft palate. Abnormal physiological separation of the oropharynx from the nasopharynx can lead to VPI and hypernasality.

Macrostomia, (from the Greek prefix "makro-" meaning "large" and from Greek , "mouth") refers to a mouth that is unusually wide.

Macrostomia is characterized as a physical abnormality that causes clefts to form on the face of affected individuals. These clefts can form on either or both sides of the face, but they are most commonly seen on the right cheek and have a higher rate of occurrence in males. Macrostomia is very irregular and on average occurs only once in every 150,000 to 300,000 live births. It's unusual for macrostomia to occur on its own and it is included as a symptom for many diseases including craniofacial microsomia. The clefts result from improper development and fusion of the mandibular and maxillary processes. The clefts cause problems with facial muscle development. The origin of macrostomia is not yet fully understood it could have multiple causes.

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.

The inheritance of Impossible syndrome is suspected to be autosomal recessive, which means the affected gene is located on an autosome, and two copies of the gene - one from each parent - are required to have an infant with the disorder.