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 effects of paternal age on offspring are not yet well understood and are studied far less extensively than the effects of maternal age. Fathers contribute proportionally more DNA mutations to their offspring via their germ cells than the mother, with the paternal age governing how many mutations are passed on. This is because, as humans age, male germ cells acquire mutations at a much faster rate than female germ cells.

Around a 5% increase in the incidence of ventricular septal defects, atrial septal defects, and patent ductus arteriosus in offspring has been found to be correlated with advanced paternal age. Advanced paternal age has also been linked to increased risk of achondroplasia and Apert syndrome. Offspring born to fathers under the age of 20 show increased risk of being affected by patent ductus arteriosus, ventricular septal defects, and the tetralogy of Fallot. It is hypothesized that this may be due to environmental exposures or lifestyle choices.

Research has found that there is a correlation between advanced paternal age and risk of birth defects such as limb anomalies, syndromes involving multiple systems, and Down's syndrome. Recent studies have concluded that 5-9% of Down's syndrome cases are due to paternal effects, but these findings are controversial.

There is concrete evidence that advanced paternal age is associated with the increased likelihood that a mother will suffer from a miscarriage or that fetal death will occur.

A low socioeconomic status in a deprived neighborhood may include exposure to “environmental stressors and risk factors.” Socioeconomic inequalities are commonly measured by the Cartairs-Morris score, Index of Multiple Deprivation, Townsend deprivation index, and the Jarman score. The Jarman score, for example, considers “unemployment, overcrowding, single parents, under-fives, elderly living alone, ethnicity, low social class and residential mobility.” In Vos’ meta-analysis these indices are used to view the effect of low SES neighborhoods on maternal health. In the meta-analysis, data from individual studies were collected from 1985 up until 2008. Vos concludes that a correlation exists between prenatal adversities and deprived neighborhoods. Other studies have shown that low SES is closely associated with the development of the fetus in utero and growth retardation. Studies also suggest that children born in low SES families are “likely to be born prematurely, at low birth weight, or with asphyxia, a birth defect, a disability, fetal alcohol syndrome, or AIDS.” Bradley and Corwyn also suggest that congenital disorders arise from the mother’s lack of nutrition, a poor lifestyle, maternal substance abuse and “living in a neighborhood that contains hazards affecting fetal development (toxic waste dumps).” In a meta-analysis that viewed how inequalities influenced maternal health, it was suggested that deprived neighborhoods often promoted behaviors such as smoking, drug and alcohol use. After controlling for socioeconomic factors and ethnicity, several individual studies demonstrated an association with outcomes such as perinatal mortality and preterm birth.

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.

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.

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.

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.

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.

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.

Craniofrontonasal dysplasia (CFND) is a rare type of FND with X linked inheritance. Multiple features are characteristic for CFND such as craniosynostosis of the coronal sutures (prematurely closed cranial sutures), dry frizzy curled hair, splitting of the nails and facial asymmetry.

There is a large variety in phenotype. Women present with a more severe phenotype than men. Females characteristically have FND, craniosynostosis and additional small malformations. Males are usually more mildly affected, presenting with only hypertelorism. The gene that causes CFND is called EFNB1 and is located on the X chromosome. A hypothesis for the more severe outcome in females is based on X-inactivation, which leads to mosaicism. As a result, patients have less functional cells, generating abnormal tissue boundaries, termed "cellular interference". This process almost never occurs in males, as they have less mutagenic material in their genes. EFBN1 also has an important function in males. As the syndrome has an X-linked inheritance pattern, there is no man-to-man inheritance.

See→ Craniofrontonasal dysplasia for more information

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".

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

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).

The occurrence of ectopia cordis is 8 per million births. It is typically classified according to location of the ectopic heart, which includes:

- Cervical

- Thoracic

- Thoracoabdominal

- Abdominal

Thoracic and thoraco-abdominal ectopia cordis constitute the vast majority of known cases.

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.

Due to the rarity and rapid postpartum mortality of ectopia cordis, limited treatment options have been developed. Only one successful surgery has been performed as of now, and the mortality rate remains high.

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.

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).

3C syndrome, also known as CCC dysplasia, Craniocerebellocardiac dysplasia or Ritscher–Schinzel syndrome, is a rare condition, whose symptoms include heart defects, cerebellar hypoplasia, and cranial dysmorphism. It was first described in the medical literature in 1987 by Ritscher and Schinzel, for whom the disorder is sometimes named.

The treatment of pentalogy of Cantrell is directed toward the specific symptoms that are apparent in each individual. Surgical intervention for cardiac, diaphragmatic and other associated defects is necessary. Affected infants will require complex medical care and may require surgical intervention. In most cases, pentalogy of Cantrell is fatal without surgical intervention. However, in some cases, the defects are so severe that the individual dies regardless of the medical or surgical interventions received.

The specific treatment strategy will vary from one infant to another based upon various factors, including the size and type of abdominal wall defect, the specific cardiac anomalies that are present, and the particular type of ectopia cordis. Surgical procedures that may be required shortly after birth include repair of an omphalocele. At this time, physicians may also attempt to repair certain other defects including defects of the sternum, diaphragm and the pericardium.

In severe cases, some physicians advocate for a staged repair of the defects associated with pentalogy of Cantrell. The initial operation immediately after birth provides separation of the peritoneal and pericardial cavities, coverage of the midline defect and repair of the omphalocele. After appropriate growth of the thoracic cavity and lungs, the second stage consists of the repair of cardiac defects and return of the heart to the chest. Eventually, usually by age 2 or 3, reconstruction of the lower sternum or epigastrium may be necessary.

Other treatment of pentalogy of Cantrell is symptomatic and supportive.

Pentalogy of Cantrell (or thoraco-abdominal syndrome) is a rare syndrome that causes defects involving the diaphragm, abdominal wall, pericardium, heart and lower sternum.

Its prevalence is less than 1 in 1000000.

It was characterized in 1958.

A locus at Xq25-26 has been described.

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.

The complete absence of an arm or leg in amelia occurs as a result of the limb formation process being either prevented or interrupted very early in the developing embryo: between 24 and 36 days following fertilization. Tetra-amelia syndrome appears to have an autosomal recessive pattern of inheritance - that is, the parents of an individual with tetra-amelia syndrome each carry one copy of the mutated gene, but do not show signs and symptoms of the condition. In a few cases, amelia may be attributed to health complications during the early stages of pregnancy, including infection, failed abortion or complications associated with removal of an IUD after pregnancy, or use of teratogenic drugs, such as thalidomide.