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.

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.

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.

Many genes associated with syndromic cases of cleft lip/palate (see above) have been identified to contribute to the incidence of isolated cases of cleft lip/palate. This includes in particular sequence variants in the genes "IRF6", "PVRL1" and "MSX1". The understanding of the genetic complexities involved in the morphogenesis of the midface, including molecular and cellular processes, has been greatly aided by research on animal models, including of the genes "BMP4", "SHH", "SHOX2", "FGF10" and "MSX1".

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.

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).

The cause of Goldenhar syndrome is largely unknown. However, it is thought to be multifactorial, although there may be a genetic component, which would account for certain familial patterns. It has been suggested that there is a branchial arch development issue late in the first trimester.

An increase in Goldenhar syndrome in the children of Gulf War veterans has been suggested, but the difference was shown to be statistically insignificant.

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.

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.

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.

Prevalence ranges from 1 in 3500 to 5600 live births. Male-female ratio is found to be 3:2.

It is not known how this abnormality occurs in infants, but one theory is that, at some time during the stage of the formation of the bones of the fetus, the tip of the jaw (mandible) becomes 'stuck' in the point where each of the collar bones (clavicle) meet (the sternum), effectively preventing the jaw bones from growing. It is thought that, at about 12 to 14 weeks gestation, when the fetus begins to move, the movement of the head causes the jaw to "pop out' of the collar bones. From this time on, the jaw of the fetus grows as it would normally, with the result that, when born, the jaw of the baby is much smaller (micrognathia) than it would have been with normal development, although it does continue to grow at a normal rate until the child reaches maturity.

However, association with gene loci 2q24.1-33.3, 4q32-qter, 11q21-23.1, and 17q21-24.3 has been found. Recent studies have indicated that genetic dysregulation of SOX9 gene prevents the SOX9 protein from properly controlling the development of facial structures, which leads to isolated PRS. Similarly, KCNJ2 gene also has a role to play. Overlap with certain other genetic syndromes like Patau syndrome has also been found.

PRS may occur in isolation, but it is often part of an underlying disorder or syndrome. The most common is Stickler Syndrome. Other disorders causing PRS, according to Dr. Robert J. Sphrintzen Ph.D. of the Center for Craniofacial Disorders Montefiore Medical Center, are Velocardiofacial syndrome, Fetal Alcohol Syndrome and Treacher Collins Syndrome. For more disorders associated with PRS see Dr. Sphrintzen's article entitled "The Implications of the Diagnosis of Robin Sequence".

There are several options for treatment of mouth anomalies like Tessier cleft number 2-3-7 . These clefts are also seen in various syndromes like Treacher Collins syndrome and hemifacial microsomia, which makes the treatment much more complicated. In this case, treatment of mouth anomalies is a part of the treatment of the syndrome.

In a newborn boy thought to have Fryns syndrome, Clark and Fenner-Gonzales (1989) found mosaicism for a tandem duplication of 1q24-q31.2. They suggested that the gene for this disorder is located in that region. However, de Jong et al. (1989), Krassikoff and Sekhon (1990), and Dean et al. (1991) found possible Fryns syndrome associated with anomalies of chromosome 15, chromosome 6, chromosome 8(human)and chromosome 22, respectively. Thus, these cases may all represent mimics of the mendelian syndrome and have no significance as to the location of the gene for the recessive disorder.

By array CGH, Slavotinek et al. (2005) screened patients with DIH and additional phenotypic anomalies consistent with Fryns syndrome for cryptic chromosomal aberrations. They identified submicroscopic chromosome deletions in 3 probands who had previously been diagnosed with Fryns syndrome and had normal karyotyping with G-banded chromosome analysis. Two female infants were found to have microdeletions involving 15q26.2 (see 142340), and 1 male infant had a deletion in band 8p23.1 (see 222400).

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.

Lip pits are harmless and do not usually require any treatment, although in some reported cases surgical excision has been used.

The condition develops in the fetus at approximately 4 weeks gestational age, when some form of vascular problem such as blood clotting leads to insufficient blood supply to the face. This can be caused by physical trauma, though there is some evidence of it being hereditary . This restricts the developmental ability of that area of the face. Currently there are no definitive reasons for the development of the condition.

Roberts syndrome is an extremely rare condition that only affects about 150 reported individuals. Although there have been only about 150 reported cases, the affected group is quite diverse and spread worldwide. Parental consanguinity (parents are closely related) is common with this genetic disorder. The frequency of Roberts syndrome carriers is unknown.

In France, Aymé, "et al." (1989) estimated the prevalence of Fryns syndrome to be 0.7 per 10,000 births based on the diagnosis of 6 cases in a series of 112,276 consecutive births (live births and perinatal deaths).

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

A congenital lip pit or lip sinus is a congenital disorder characterized by the presence of pits and possibly associated fistulas in the lips. They are often hereditary, and may occur alone or in association with cleft lip and palate, termed Van der Woude syndrome.

Ethmocephaly is a type of cephalic disorder caused by holoprosencephaly. Ethmocephaly is the least common facial anomaly. It consists of a proboscis separating narrow-set eyes with an absent nose and microphthalmia (abnormal smallness of one or both eyes). Cebocephaly, another facial anomaly, is characterized by a small, flattened nose with a single nostril situated below incomplete or underdeveloped closely set eyes.

The least severe in the spectrum of facial anomalies is the median cleft lip, also called premaxillary agenesis.

Although the causes of most cases of holoprosencephaly remain unknown, some may be due to dominant or chromosome causes. Such chromosomal anomalies as trisomy 13 and trisomy 18 have been found in association with holoprosencephaly, or other neural tube defects. Genetic counseling and genetic testing, such as amniocentesis, is usually offered during a pregnancy if holoprosencephaly is detected. The recurrence risk depends on the underlying cause. If no cause is identified and the fetal chromosomes are normal, the chance to have another pregnancy affected with holoprosencephaly is about 6%.

There is no treatment for holoprosencephaly and the prognosis for individuals with the disorder is poor. Most of those who survive show no significant developmental gains. For children who survive, treatment is symptomatic. It is possible that improved management of diabetic pregnancies may help prevent holoprosencephaly, however there is no means of primary prevention.

The condition is also known by various other names:

- Lateral facial dysplasia

- First and second branchial arch syndrome

- Oral-mandibular-auricular syndrome

- Otomandibular dysostosis

- Craniofacial microsomia

3C syndrome is very rare, occurring in less than 1 birth per million. Because of consanguinity due to a founder effect, it is much more common in a remote First Nations village in Manitoba, where 1 in 9 people carries the recessive gene.

Malpuech facial clefting syndrome, also called Malpuech syndrome or Gypsy type facial clefting syndrome, is a rare congenital syndrome. It is characterized by facial clefting (any type of cleft in the bones and tissues of the face, including a cleft lip and palate), a appendage (a "human tail"), growth deficiency, intellectual and developmental disability, and abnormalities of the renal system (kidneys) and the male genitalia. Abnormalities of the heart, and other skeletal malformations may also be present. The syndrome was initially described by Guilliaume Malpuech and associates in 1983. It is thought to be genetically related to Juberg-Hayward syndrome. Malpuech syndrome has also been considered as part of a spectrum of congenital genetic disorders associated with similar facial, urogenital and skeletal anomalies. Termed "3MC syndrome", this proposed spectrum includes Malpuech, Michels and Mingarelli-Carnevale (OSA) syndromes. Mutations in the "COLLEC11" and "MASP1" genes are believed to be a cause of these syndromes. The incidence of Malpuech syndrome is unknown. The pattern of inheritance is autosomal recessive, which means a defective (mutated) gene associated with the syndrome is located on an autosome, and the syndrome occurs when two copies of this defective gene are inherited.