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PubMed This is a summary of 14 peer-reviewed journal articles Updated
Ophthalmology

The Biology of Eye Development: How MAC Happens

At a Glance

Microphthalmia, anophthalmia, and coloboma (MAC) are caused by early genetic disruptions during weeks 3-8 of fetal development. Genes like SOX2 and OTX2 fail to signal properly, preventing the eye from growing or fully closing. MAC is genetic and not caused by a parent's actions during pregnancy.

The development of the human eye is one of the most complex processes in early life. Understanding the biological “why” behind a MAC diagnosis can help shift the focus from self-blame to a clearer understanding of the unique journey ahead.

The Genetic “Master Switches”

Think of early eye development like a highly coordinated construction project. There are certain genes that act as master switches or “foremen,” giving orders to thousands of other cells to build the eye. In many cases of MAC, one of these master switches simply “misfired” [1][2].

  • SOX2 and OTX2: These are the primary architects. They tell the early embryo where the “eye field” should be and ensure the eye grows to the correct size [3][4].
  • SHH (Sonic Hedgehog) and BMP4: These genes act as signaling pathways, helping the eye divide into two separate globes and ensuring different parts of the eye (like the retina and the iris) develop in the right places [5].

When one of these switches does not turn on or off at the exact right moment, the “construction” of the eye is disrupted. It is vital to understand that these genetic events are not caused by anything a parent did, ate, or was exposed to during pregnancy [6][2].

The Fetal Timeline: The Optic Fissure

The most critical window for MAC conditions occurs very early in the first trimester.

  1. Weeks 3-4: The brain begins to push out two small pouches called optic vesicles [7].
  2. Weeks 5-6: These pouches fold inward to form a cup (the optic cup). At the bottom of this cup is a temporary gap called the optic fissure [8][9].
  3. Weeks 7-8: This fissure must “zip up” perfectly to create a solid eye. If it fails to close, the result is a Coloboma—a gap in the eye’s structure [10][9].

The timing of this “misfire” determines the phenotype (the physical appearance):

  • Anophthalmia: The process stopped before the pouches even began to form [11].
  • Microphthalmia: The eye began to form but stopped growing too soon [4].
  • Coloboma: The eye formed and grew, but failed to “zip up” the final seam, often resulting in a “keyhole” shaped pupil or a gap in the internal retina [10].

Why Families Look Different: Penetrance and Expressivity

If a genetic cause is found, you may wonder why one family member is affected while another is not. This is due to two important medical concepts:

  • Incomplete Penetrance: This occurs when a person carries the “misfired” gene but shows no symptoms at all. They have the genetic blueprint for MAC, but their eyes formed perfectly [12][13].
  • Variable Expressivity: This means the same genetic change can affect people differently. In the same family, one person might have a tiny, nearly invisible coloboma, while another might have a small eye (microphthalmia) [14][13].

These variations are why a thorough genetic workup and eye exams for immediate family members are often recommended, even if their eyes appear perfectly healthy [1].

Common questions in this guide

What causes microphthalmia, anophthalmia, and coloboma (MAC)?
MAC conditions are generally caused by changes in genetic 'master switches' like SOX2, OTX2, SHH, or BMP4. These genes give essential instructions during early fetal development, and a misfire in these instructions interrupts typical eye growth.
Did something I do during pregnancy cause my baby's MAC diagnosis?
No. It is vital to understand that MAC genetic events are spontaneous or inherited biological changes. They are not caused by anything a parent did, ate, or was exposed to during pregnancy.
What is the difference between anophthalmia, microphthalmia, and coloboma?
The specific condition depends on exactly when the eye's development was interrupted. Anophthalmia means the eye failed to form at all, microphthalmia means the eye started forming but stopped growing too soon, and a coloboma means the eye grew but failed to 'zip up' its final seam.
Why do family members with the exact same MAC gene have different eye features?
This is due to concepts called incomplete penetrance and variable expressivity. The exact same genetic variation can cause severe symptoms in one relative, a tiny, nearly invisible coloboma in another, or even skip symptoms entirely in a family member whose eyes formed perfectly.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.What specific genetic variant was identified, and is it known to be a 'master switch' gene like SOX2 or OTX2?
  2. 2.Given the diagnosis, what is the likelihood that other family members carry the same variant but show no symptoms (incomplete penetrance)?
  3. 3.At what precise week of development did the optic fissure fail to close in this case?
  4. 4.Does this specific mutation typically show 'variable expressivity' within families?
  5. 5.Can you explain how this genetic 'misfire' led to the specific phenotype (Anophthalmia vs. Microphthalmia vs. Coloboma)?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (14)
  1. 1

    Evaluation of somatic and/or germline mosaicism in congenital malformation of the eye.

    Chesneau B, Ivashchenko V, Habib C, et al.

    European journal of human genetics : EJHG 2023; (31(5)):526-530 doi:10.1038/s41431-022-01234-3.

    PMID: 36404347
  2. 2

    Conserved genetic pathways associated with microphthalmia, anophthalmia, and coloboma.

    Reis LM, Semina EV

    Birth defects research. Part C, Embryo today : reviews 2015; (105(2)):96-113 doi:10.1002/bdrc.21097.

    PMID: 26046913
  3. 3

    Analysis of OTX2, PAX6, and SOX2 Gene and Protein Expression Patterns in Ocular Development of Human and Rat Embryos.

    Junga A, Pilmane M, Fedirko P

    International journal of molecular sciences 2025; (26(22)) doi:10.3390/ijms262210845.

    PMID: 41303332
  4. 4

    Heterozygous mutations in SOX2 may cause idiopathic hypogonadotropic hypogonadism via dominant-negative mechanisms.

    Cassin J, Stamou MI, Keefe KW, et al.

    JCI insight 2023; (8(3)).

    PMID: 36602867
  5. 5

    Targeted resequencing identifies PTCH1 as a major contributor to ocular developmental anomalies and extends the SOX2 regulatory network.

    Chassaing N, Davis EE, McKnight KL, et al.

    Genome research 2016; (26(4)):474-85 doi:10.1101/gr.196048.115.

    PMID: 26893459
  6. 6

    [Clinical and Genetic Characteristics of Ocular Developmental Disorders: MAC-Spectrum, Anterior Segment Dysgenesis].

    Käsmann-Kellner B, Moslemani K, Seitz B

    Klinische Monatsblatter fur Augenheilkunde 2019; (236(3)):269-285 doi:10.1055/a-0809-5523.

    PMID: 30736081
  7. 7

    An Eye Organoid Approach Identifies Six3 Suppression of R-spondin 2 as a Critical Step in Mouse Neuroretina Differentiation.

    Takata N, Abbey D, Fiore L, et al.

    Cell reports 2017; (21(6)):1534-1549 doi:10.1016/j.celrep.2017.10.041.

    PMID: 29117559
  8. 8

    Retinoic Acid-Regulated Epigenetic Marks Identify Alx1 as a Direct Target Gene Required for Optic Cup Formation.

    Berenguer M, Duester G

    Genes 2025; (16(9)) doi:10.3390/genes16091071.

    PMID: 41010016
  9. 9

    Loss of Cdc42 causes abnormal optic cup morphogenesis and microphthalmia in mouse.

    Hofstetter KS, Haas PM, Kuntz JP, et al.

    bioRxiv : the preprint server for biology 2024; doi:10.1101/2024.10.20.619331.

    PMID: 39484575
  10. 10

    Genes and pathways in optic fissure closure.

    Patel A, Sowden JC

    Seminars in cell & developmental biology 2019; (91()):55-65 doi:10.1016/j.semcdb.2017.10.010.

    PMID: 29198497
  11. 11

    Identification of novel homozygous variants in FOXE3 and AP4M1 underlying congenital syndromic anophthalmia and microphthalmia.

    Akbar W, Ullah A, Haider N, et al.

    The journal of gene medicine 2024; (26(1)):e3601 doi:10.1002/jgm.3601.

    PMID: 37758467
  12. 12

    Clinical, genetic and biochemical signatures of RBP4-related ocular malformations.

    Plaisancié J, Martinovic J, Chesneau B, et al.

    Journal of medical genetics 2023; (61(1)):84-92 doi:10.1136/jmg-2023-109331.

    PMID: 37586836
  13. 13

    Intrafamilial variability in syndromic microphthalmia type 5 caused by a novel variation in OTX2.

    Somashekar PH, Shukla A, Girisha KM

    Ophthalmic genetics 2017; (38(6)):533-536 doi:10.1080/13816810.2017.1301967.

    PMID: 28388256
  14. 14

    A 300-kb microduplication of 7q36.3 in a patient with triphalangeal thumb-polysyndactyly syndrome combined with congenital heart disease and optic disc coloboma: a case report.

    Zlotina A, Melnik O, Fomicheva Y, et al.

    BMC medical genomics 2020; (13(1)):175 doi:10.1186/s12920-020-00821-x.

    PMID: 33218365

This page explains the biology and genetics of MAC eye conditions for educational purposes only. Always consult a genetic counselor, pediatric ophthalmologist, or your primary healthcare provider regarding your specific family history and diagnosis.

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