Anophthalmia and microphthalmia are rare congenital conditions that originate during fetal development. Anophthalmia is the complete absence of the eye globe from the orbit, while microphthalmia describes an eye that is significantly smaller and underdeveloped than normal. These two conditions represent a spectrum of developmental failure, often occurring together, and affect up to 30 out of every 100,000 newborns.
Genetic Foundations of Eye Development Failure
Eye development is governed by complex instructions encoded in DNA. Hundreds of genes are involved, and mutations can result in anophthalmia or microphthalmia by disrupting the signaling pathways that direct cells to form the optic cup and other necessary ocular structures.
Single gene mutations are a significant cause, often affecting master regulatory genes responsible for starting the eye formation cascade. For instance, the SOX2 gene is a major cause, accounting for approximately 10 to 15 percent of cases involving bilateral, severe eye absence or smallness. The SOX2 protein regulates the activity of other genes needed for tissue formation, and its absence disrupts the development of the eyes, brain, and other structures.
Another important gene is PAX6, described as a master control gene for eye development, initiating the earliest steps of the process. Mutations in PAX6 can lead to a range of ocular malformations, including microphthalmia and aniridia (the complete absence of the iris). These single gene mutations can arise sporadically as a new change in the developing embryo, or they may be inherited from a parent, sometimes following an autosomal dominant pattern.
Beyond single gene errors, these conditions can also be a feature of broader chromosomal abnormalities or genetic syndromes. When anophthalmia or microphthalmia is part of a larger syndrome, other organ systems are typically affected, such as in Trisomy 13 (Patau syndrome) or CHARGE syndrome. These syndromic cases involve changes to the structure or number of entire chromosomes, affecting the expression of many genes simultaneously.
Environmental Factors and Teratogenic Exposure
External influences, known as teratogens, can interfere with fetal development and contribute to these conditions. These agents cause birth defects when a pregnant person is exposed to them. Exposure to certain medications during the first trimester represents a clear risk for eye malformations.
Specific pharmaceutical agents, such as the acne medication isotretinoin (a retinoid) and the drug thalidomide, are known teratogens linked to these eye defects. These substances disrupt the complex cellular signaling required for normal eye formation and are strictly contraindicated during pregnancy.
Maternal infections acquired during gestation are another recognized environmental factor that can damage the developing ocular tissues. The group of infections collectively known as TORCH pathogens—Toxoplasmosis, Rubella, Cytomegalovirus, and Herpes Simplex—are capable of crossing the placenta. Rubella, in particular, when contracted early in pregnancy, is linked to an increased risk of microphthalmia and other birth defects.
Underlying maternal health conditions can also play a role in altering the fetal environment. For example, poorly controlled pre-existing diabetes in the pregnant person has been associated with an increased risk of various birth defects, including those affecting the eye. These environmental factors can sometimes interact with a baby’s underlying genetic predisposition to cause the malformation.
Critical Periods of Development and Idiopathic Cases
The timing of any disruption is highly significant because the eye develops extremely early in the pregnancy. Eye development begins around the third week of gestation when the optic grooves first appear as outgrowths of the developing brain. By the fourth week, these structures have folded to form the optic vesicles, which are precursors to the main eye structures.
The most profound malformations, such as complete anophthalmia, occur when a genetic or environmental insult completely arrests this process between the third and eighth week of gestation. This period is when the optic vesicle must successfully transform into the optic cup. Any severe interruption at this stage results in a missing or severely underdeveloped eye, explaining why these conditions are present at birth.
Despite thorough investigation into genetics and environmental history, a definitive cause remains unknown in a significant number of cases. These are referred to as idiopathic cases, where no clear genetic mutation, chromosomal anomaly, or environmental exposure can be identified.
The difficulty in finding a cause may be due to the vast number of genes potentially involved, unknown environmental triggers, or the limitations of current testing technologies. Researchers estimate that a causative gene is only identified in about 60 to 70 percent of severe bilateral cases, and the detection rate is much lower for those affecting only one eye.