The most extensive epidemiological survey on this congenital malformation has been carried out by Dharmasena et al and using English National Hospital Episode Statistics, they calculated the annual incidence of anophthalmia, microphthalmia and congenital malformations of orbit/lacrimal apparatus from 1999 to 2011. According to this study the annual incidence of congenital microphthalmia in the United Kingdom was 10.8 (8.2 to 13.5) in 1999 and 10.0 (7.6 to 12.4) in 2011.

The number of cases is around 0.5 to 0.7 per 10,000 births, making it a relatively rare condition.

Colobomas can be associated with a mutation in the "PAX2" gene.

Eye abnormalities have been shown to occur in over 90% of children with fetal alcohol syndrome.

Microphthalmia in newborns is sometimes associated with fetal alcohol syndrome or infections during pregnancy, particularly herpes simplex virus, rubella and cytomegalovirus (CMV), but the evidence is inconclusive. Genetic causes of microphthalmia include chromosomal abnormalities (Trisomy 13 (Patau syndrome), Triploid Syndrome, 13q deletion syndrome, and Wolf-Hirschhorn Syndrome) or monogenetic Mendelian disorders. The latter may be autosomal dominant, autosomal recessive or X linked.

The following genes have been implicated in microphthamia, many of which are transcription and regulatory factors:

How these genes result in the eye disorder is unknown but it has been postulated that interference with the process of eye growth after birth may be involved in contrast to anophthalmia (absence of eyeball) which originates much earlier during foetal development. SOX2 has been implicated in a substantial number (10-15%) of cases and in many other cases failure to develop the ocular lens often results in microphthamia. Microphthalmia-associated transcription factor (MITF) located on chromosome 14q32 is associated with one form of isolated microphthalmia (MCOP1. In mammals the failure of expression of the transcription factor, MITF (microphthalmia-associated transcription factor), in the pigmented retina prevents this structure from fully differentiating. This in turn causes a malformation of the choroid fissure of the eye, resulting in the drainage of vitreous humor fluid. Without this fluid, the eye fails to enlarge, thus the name microphthalmia.The gene encoding the microphthalmia-associated transcription factor (MITF) is a member of the basic helix-loop-helix-leucine zipper (bHLH-ZIP) family. Waardenburg syndrome type 2 (WS type 2) in humans is also a type of microphthalmia syndrome. Mutations in MITF gene are thought to be responsible for this syndrome. The human MITF gene is homologous to the mouse MITF gene (aka mouse mi or microphthalmia gene); mouse with mutations in this gene are hypopigmented in their fur. The identification of the genetics of WS type 2 owes a lot to observations of phenotypes of MITF mutant mice.

In utero exposure to cocaine and other street drugs can lead to septo-optic dysplasia.

Aniridia is the absence of the iris, usually involving both eyes. It can be congenital or caused by a penetrant injury. Isolated aniridia is a congenital disorder which is not limited to a defect in iris development, but is a panocular condition with macular and optic nerve hypoplasia, cataract, and corneal changes. Vision may be severely compromised and the disorder is frequently associated with a number of ocular complications: nystagmus, amblyopia, buphthalmos, and cataract. Aniridia in some individuals occurs as part of a syndrome, such as WAGR syndrome (kidney nephroblastoma (Wilms tumour), genitourinary anomalies and intellectual disability), or Gillespie syndrome (cerebellar ataxia).

Rare familial recurrence has been reported, suggesting at least one genetic form (HESX1). In addition to HESX1, mutations in OTX2, SOX2 and PAX6 have been implicated in de Morsier syndrome, but in most cases SOD is a sporadic birth defect of unknown cause and does not recur with subsequent pregnancies.

Aniridia may be broadly divided into hereditary and sporadic forms. Hereditary aniridia is usually transmitted in an autosomal dominant manner (each offspring has a 50% chance of being affected), although rare autosomal recessive forms (such as Gillespie syndrome) have also been reported. Sporadic aniridia mutations may affect the WT1 region adjacent to the AN2 aniridia region, causing a kidney cancer called nephroblastoma (Wilms tumor). These patients often also have genitourinary abnormalities and intellectual disability (WAGR syndrome).

Several different mutations may affect the PAX6 gene. Some mutations appear to inhibit gene function more than others, with subsequent variability in the severity of the disease. Thus, some aniridic individuals are only missing a relatively small amount of iris, do not have foveal hypoplasia, and retain relatively normal vision. Presumably, the genetic defect in these individuals causes less "heterozygous insufficiency," meaning they retain enough gene function to yield a milder phenotype.

- AN

- Aniridia and absent patella

- Aniridia, microcornea, and spontaneously reabsorbed cataract

- Aniridia, cerebellar ataxia, and mental deficiency (Gillespie syndrome)

Optic nerve hypoplasia (ONH) is a congenital condition in which the optic nerve is underdeveloped (small).

Many times, de Morsier’s Syndrome or septo-optic dysplasia (SOD) is associated with ONH, however, it is possible to have ONH without any additional issues like SOD. SOD is a condition that can involve multiple problems in the midline structures of the brain, stemming from miswiring of the brain and central nervous system. Besides having small optic nerves, persons with ONH can have agenesis of the corpus callosum, absence of the septum pellucidum, maldevelopment of the anterior and posterior pituitary gland, and anomalies of the hypothalamus. Because of this, all children with ONH are at risk for developmental delays and hormonal deficiencies, regardless of severity of ONH, or whether abnormalities are visible by MRI.

ONH is the single leading cause of permanent legal blindness in children in the western world. The incidence of ONH is increasing, although it is difficult to estimate the true prevalence. Between 1980 and 1999, the occurrences of ONH in Sweden increased four-fold to 7.2 per 100,000, while all other causes of childhood blindness had declined. In 1997, ONH overtook retinopathy of prematurity as the single leading cause of infant blindness in Sweden, with 6.3 in every 100,000 births diagnosed with ONH. The most recent prevalence report out of England in 2006 is 10.9 per 100,000.

Although many perinatal and prenatal risk factors for ONH have been suggested, the predominant, enduring, most frequent risk factors are young maternal age and primiparity (the affected child being the first child born to the mother). Increased frequency of delivery by caesarean section and fetal/neonatal complications, preterm labor, gestational vaginal bleeding, low maternal weight gain, and weight loss during pregnancy are also associated with ONH.

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.

Persistent hyperplastic primary vitreous (PHPV), also known as Persistent Fetal Vasculature (PFV), is a rare congenital developmental anomaly of the eye that results

following failure of the embryological, primary vitreous and hyaloid vasculature to regress. It can be present in three forms: purely anterior (persistent tunica vasculosa lentis and persistent posterior fetal fibrovascular sheath of the lens), purely posterior (falciform retinal septum and ablatio falcicormis congenita) and a combination of both. Most examples of PHPV are unilateral and non-hereditary. When bilateral, PHPV may follow an autosomal recessive or autosomal dominant inheritance pattern.

The incidence is estimated to range from 0.1–1.2 per 10,000 live births, though the true incidence is unknown. As of 2005, the highest prevalence was found in Canada and estimated at 1 in 8,500 live births.

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.

Causes a ‘white reflex’ in the affected eye (leukocoria), prompting further investigation.

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.

Environmental factors refer for example to maternal smoking and the maternal exposure to amine-containing drugs. Several research groups have found evidence that these environmental factors are responsible for an increase in the risk of craniosynostosis, likely through effects on fibroblast growth factor receptor genes.

On the other hand, a recent evaluation of valproic acid (an anti-epilepticum), which has been implicated as a causative agent, has shown no association with craniosynostosis.

Certain medication (like amine-containing drugs) can increase the risk of craniosynostosis when taken during pregnancy, these are so-called teratogenic factors.

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.

Genetic defects or toxins can misdirect the embryonic forebrain-dividing process. One highly teratogenic alkaloid toxin that can cause cyclopia is cyclopamine or 2-deoxyjervine, found in the plant "Veratrum californicum" (also known as "corn lily" or "false hellebore"). Grazing animals are most likely to ingest this plant and induce cyclopia in offspring. The mistake of humans ingesting "Veratrum californicum" while pregnant is often due to hellebore, an unrelated plant with the same name, being recommended as a "natural" treatment for vomiting, cramps, and poor circulation, three conditions which may be present in the early stages of pregnancy. Cyclopia occurs when certain proteins are inappropriately expressed, causing the brain to stay whole, rather than developing two distinct hemispheres. This leads to the fetus having one optic lobe and one olfactory lobe, resulting in the eye and nose malformations of cyclopia.

The sonic hedgehog (SHH) gene regulator is involved in the separation of the single eye field into two bilateral fields. Although not proven, it is thought that SHH emitted from the prechordal plate suppresses Pax6, which causes the eye field to divide into two. If the SHH gene is mutated, the result is cyclopia, a single eye in the center of the face (Gilbert, 2000).

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.

Muenke syndrome is caused by a specific gene mutation in the FGFR3 gene. The mutation arises randomly; there is no full understanding for what causes this mutation. This mutation causes the FGFR3 protein to be overly active; it interferes with normal bone growth, and allows skull bones to fuse prematurely. There is no connection between anything mother did (or did not do) to activate the syndrome. If neither of the parents have Muenke syndrome, chances of having another child with the syndrome are minimal.

This condition is inherited in an autosomal dominant pattern. This means if a parent has Muenke syndrome, every newborn has a 50% chance of inheriting the syndrome.

Coloboma of optic nerve, is a rare defect of the optic nerve that causes moderate to severe visual field defects.

Coloboma of the optic nerve is a congenital anomaly of the optic disc in which there is a defect of the inferior aspect of the optic nerve. The issue stems from incomplete closure of the embryonic fissure while in utero. A varying amount of glial tissue typically fills the defect, manifests as a white mass.

Cyclopia (also cyclocephaly or synophthalmia) is a rare form of holoprosencephaly and is a congenital disorder (birth defect) characterized by the failure of the embryonic prosencephalon to properly divide the orbits of the eye into two cavities. Its incidence is 1 in 16,000 in born animals and 1 in 200 in miscarried fetuses.

Current research is focusing on clearly defining the phenotype associated with tetrasomy 18p and identifying which genes cause medical and developmental problems when present in four copies.

Muenke syndrome is inherited in an autosomal dominant pattern. In some cases, an affected person inherits the mutation from one affected parent. If a patient is shown to have Muenke, they have a 50/50 chance of passing it on to their children. Not all cases of Muenke however is obvious. Other cases may result from new mutations in the gene. These cases occur in people with no history of the disorder in their family.

A single mutation in the FGFR3 gene cause this syndrome. The FGFR3 gene provides instructions for making a protein that is involved in the development and maintenance of bone and brain tissue. This mutation causes the FGFR3 protein to be overly active, which interferes with normal bone growth and allows the bones of the skull to fuse before they should.

As stated by researchers at the University of Washington, Muenke syndrome is inherited in an autosomal dominant manner with incomplete penetrance and variable expressivity.” Prenatal diagnosis for pregnancies at increased risk is possible if the defining mutation has been identified in the family (Agochukwu et.al. 2006). According to the article "Craniosynostosis: Molecular Genetics," penetrance is higher in females (87%) than in males (76%). Muenke syndrome is estimated to account for 25%-30% of all genetic causes of craniosynostosis according to the Journal of Anatomy.