RBP4
RBP4 has recently been linked to autosomal dominant form of anophthalmia. This form of anophthalmia has variable penetrance and a unique maternal inheritance effect that is rooted in pregnancy. Specifically, the disease only occurs when a mother and fetus both carry a RBP4 mutation which predisposes the fetus to vitamin A deficiency (a known environmental risk factor for anophthalmia) during pregnancy. If Vitamin A deficiency occurs during the first several months when the eye is developing, it may lead to anophthalmia. This form of anophthalmia is the first that may be intervened upon with vitamin A supplementation of retinyl esters during the first several months of pregnancy. This strategy exploits an RBP-independent pathway. Clinical research is underway. See RBP4 for more information. Other influential genes
SOX2 and RBP4 are not the only genes that can cause anophthalmia. Other important genes include OTX2, CHX10 and RAX. Each of these genes are an important in retinal expression. Mutations in these genes can cause a failure of retinal differentiation. OTX2 is dominantly inherited. Mutation effects vary in severity, and can include microphthalmia. BMP4 is also linked to anophthalmia, as well as causing myopia and microphthalmia. It is dominantly inherited. BMP4 interacts with the Sonic hedgehog (SHH) pathway and can cause anophthalmia. Environmental influence
Many environmental conditions have also been known to cause anophthalmia. The strongest support for environmental causes has been studies where children have had gestational-acquired infections. These infections are typically viral. A few known pathogens that can cause anophthalmia are Toxoplasma, rubella, and certain strains of the influenza virus.
Epidemiology
Anophthalmia has been reported to be present in 3 out of every 100,000 births. Many instances of anophthalmia also occur with microphthalmia. A recent study in the UK indicated that anophthalmia and microphthalmia had a combined average of 1 in every 10,000 births. The annual rate of occurrence of anophthalmia/microphthalmia in the United States is about 780 children born/year. 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 incidence of congenital anophthalmia ranged from 2.4 (95% CI 1.3 to 4.0) per 100 000 infants in 1999 to 0.4 (0 to 1.3) in 2011. Parents that already have a child who suffers from anophthalmia has a 1 in 8 chance of having another child with anophthalmia. Approximately 2/3 of all cases of anophthalmia are determined to be of genetic basis. Anophthalmia is one of the leading causes of congenital blindness and accounts for 3-11% of blindness in children. Anophthalmia and microphthalmia together make up 1.7-1.8% of reconstructive surgical cases in laboratory of plastic surgery and ocular prostheses.