Eyes Anomalies

Anomalies of the orbits and eyes entail abnormal orbital position with respect to each other, fusion of the orbits and hypoplasia or aplasia of the orbits and ocular bulbi. 

Q11.1 Anophthalmos, Q11.2 Microphthalmos

The prevalence rate of congenital eye malformations is 7.5 per 10,000 birth with microphthalmia accounting for 1.8, anophthalmia for 0.3, cataract for 2.3 and coloboma for 0.7, respectively.¹

Every  prenatal ultrasound diagnosis of eye/orbital anomaly corresponds to an interruption or disturbance in the normal embryologic chain of events. 
Human eye development occurs between week 3 and 10 of gestation. On day 23, the optic pit forms on the embryonic plate. Two optic vesicles are created from anterolateral outpouchings on either side of the primitive brain stem. These evaginate on day 25 to eventually become the globes and then make contact with the surface ectoderm, which induces the lens placode (precursor of the lens). This in turn invaginates to become a lens pit and then differentiates into the lens vesicle. After formation of the lens vesicle, the optic vesicle invaginates to form a double-layered optic cup (which will eventually become the retina/retinal pigment epithelium). Connections between the optic vesicle and the forebrain develop and will eventually become the optic nerves. Their myelination begins at the optic chiasm at approximately 7 months fetal life and stops at the lamina cribrosa 1 month after birth. On the underside of the optic cup there is the embryonic fissure that closes at approximately gestational age day 33. If the fissure does not completely close, a coloboma occurs.²
The formation of the orbits is the result of complex processes regulated by multiple interactions and signals that also influence the development of the optic vesicles from neuroectoderm, cranial neural crest cells and mesoderm.³

Eye anomalies resulting from developmental aberrations in early intrauterine life are among the most frequent abnormalities encountered in pediatric practice and some of them are amenable to prenatal detection.² Malformations of the orbit and of the eyes can be classified grossly into two major categories: 1) isolated malformations, limited to the facial region, and 2) abnormalities associated with genetic syndromes, some of which involve an abnormal karyotype. Example of these are the various degrees of hypotelorism-cyclopia encountered in fetuses with trisomy 13 or the opacity or loss of transparency of the lens (cataract) causing visual impairment, seen as feature is various genetic syndromes. Infections (rubella, toxoplasmosis) can also affect eye development.

Anomalies of the orbits can be classified as: anomalies of the position of the eyes/orbits (hypo and hypertelorism, synophthalmia, cyclopia) and anomalies of the size or presence of the orbit (microphthalmia/anophthalmia or macrophthalmia). These anomalies originate from an abnormal development and growth of the midface cranial bones with reduction or increased distance between the orbits.⁴

Microphthalmia and anophthalmia are rare congenital abnormalities, occurring on a spectrum of congenital ocular disorders including congenital cataracts, cryptophthalmos, cyclopia/synophthalmia, congenital cystic eye, and coloboma. Microphthalmia and anophthalmia have both genetic and non-genetic causes, may be unilateral or bilateral, and may be found in isolation or as component of a syndrome.⁵
Otocephaly is a rare (1:70.000 births) and lethal genetic syndrome occurring commonly in association with severe midline defects including holoprosencephaly, cyclopia, proboscis and other cerebral malformations. Besides the single orbit and absence of nose, mouth and mandible, there is fusion of the ears on the midline, inferiorly to the single eye.⁶

The increased globe size or macrophthalmia can be found in a number of conditions such as: congenital glaucoma(buphtalmos) and connective tissue disorders such (Marfan syndrome, Ehlers-Danlos syndrome). The fetal orbit and eye size can also be enlarged due to an intracranial malignancy, usually a teratoma, protruding through the eye(s).⁷

In case of hypotelorism/microphthalmia/anophthalmia,cyclopia,  commonly associated anomalies are other facial anomalies (proboscis, arrhinia, oro-facial cleft), intracranial anomalies (holoprosencephaly) and all anomalies commonly found in association with trisomy 13. 
In case of hypertelorism stigmata of genetic syndromes such as Apert syndrome (cranial anomalies, syndactyly) or other syndromes should be searched for.

This depends on the specific diagnosis. Genetic syndromes with familiar recurrence entail a higher recurrence risk. 

The orbits can be visualized on prenatal ultrasound from 12 weeks’ gestation.
Assessment of the eyes is part of the ISUOG second trimester scan guideline. This recommends checking that both orbits and bulbi are present and that there is a normal position and separation of the eyes.⁸ The orbits are best visualized in an axial plane. As a general rule, the size of one orbit can fit between the other two orbits. Normative tables have been established for the size of the orbits as well as the distance between the inner and outer orbits throughout gestation⁹ and more recently for the distance between the center of the lenses.¹⁰ The interorbital distance (inner to inner) is the most sensitive to detect pathological variations.

Hypotelorism refers to when the infraorbital distance is reduced. This can range from a slight reduction to both orbits being in contact with each other to complete fusion of the orbits, as in synophthalmia/cyclopia. The orbits can also be reduced in size. This condition is typical of trisomy 13.
Hypertelorism refers to an increased infraorbital distance (distance between the medial orbital walls) and/or binocular distances (distance between lateral orbital walls) greater than the 95th percentile of normal distance. Hypertelorism is the most common orbital manifestation of some genetic syndromes, therefore its prenatal identification can lead to earlier suspicion and diagnosis of these conditions.

Microphthalmia is suspected when the axial length of the orbit is 2 standard deviations below that of the population age–adjusted mean. For example, the mean maximum axial length in the neonatal and adult human eye is approximately 17 and 23.8 mm, respectively. In general, for an adult eye to be classified as microphthalmic, the corneal diameter is less than 10 mm, and the anteroposterior diameter of the globe is less than 20 mm. Anophthalmia refers to the total absence of the globe in the presence of normal ocular adnexae, and it is the extreme spectrum of microphthalmia. It can be unilateral or bilateral. In fetal life the lens can be absent and the size and appearance of the orbits diminished. Microphthalmia can also rarely develop and become evident later in pregnancy.¹⁰ Intracranial masses bulging through the orbit usually give the false impression of macrophthalmia. ⁴ 
Proptosis or exophthalmos refers to an increased antero-posterior diameter of the ocular bulbus which protrudes more than usual from the orbit. (See Visuog Chapter on Exophthalmos).⁴

This will depend on the specific presentation. Orbital position anomalies can be found in different chromosomal or genetic syndromes. The same holds for micro/anophthalmia. 

The prognosis of eye and orbital anomalies associated with chromosomal anomalies or genetic syndromes is usually unfavourable and depends on the specific diagnosis. Anophthalmia is associated with blindness and variable degrees of mental retardation.

If an ocular anomaly is detected, a detailed fetal anatomic ultrasound should be performed to determine if there are associated anomalies. The fetal brain should always be evaluated in detail. Suspected cases should be referred to a tertiary care center for confirmation, additional genetic investigations, consultation with other specialists and where indicated MRI can be used in case ultrasound diagnosis of eye/brain anomalies is not definitive. The presence of other anomalies seen on ultrasound may also lead to the diagnosis of specific genetic syndromes. 

Prenatal screening for chromosomal anomalies and early transvaginal scans from the late first trimester can be useful for early exclusion or detection of recurrence. Genetic counselling will determine the diagnostic conduct in case of familiar cases. 

1. C. Stoll, Y. Alembik, B. Dott & M. P. Roth (1992) Epidemiology of congenital eye malformations in 131,760 consecutive births, Ophthalmic Paediatrics and Genetics, 13:3, 179-186, 
2. C. L. Ondeck, D. Pretorius, J. McCaulley, M. Kinori, T. Maloney, A. Hull, S. L. Robbins, Ultrasonographic prenatal imaging of fetal ocular and orbital abnormalities. Survey of Ophthalmology. 2018; 63 (6), 745-753.
3. Tawfik, H. & Dutton, J. (2018). Embryologic and Fetal Development of the Human Orbit. Ophthalmic Plastic and Reconstructive Surgery, 34 (5), 405-421. 
4. Burns NS, Iyer RS, Robinson AJ, Chapman T. Diagnostic imaging of fetal and pediatric orbital abnormalities. American Journal of Roentgenology. 2013 Dec;201(6):W797-808.
5. Searle A, Shetty P, Melov SJ, Alahakoon TI. Prenatal diagnosis and implications of microphthalmia and anophthalmia with a review of current ultrasound guidelines: two case reports. J Med Case Rep. 2018;12(1):250. 
6. Chaoui R, Heling KS, Thiel G, Karl K. Agnathia-otocephaly with holoprosencephaly on prenatal three-dimensional ultrasound. Ultrasound Obstet Gynecol. 2011;37(6):745-748. doi:10.1002/uog.9009
7. Xi Chen, Jiaxiang Yang, Guannan He, Chunlan Cheng, Chunguo Zhang, Hongli Wang, Lihong He, Zhirong Yang, Li Chen, Jing Zhao, Orbital teratoma in the foetus: a rare case without proptosis, BMC Ophthalmology, 10.1186/s12886-020-01681-w, 20, 1, (2020).
8. Salomon LJ, Alfirevic Z, Berghella V, Bilardo CM, Chalouhi GE, Da Silva Costa F, Hernandez-Andrade E, Malinger G, Munoz H, Paladini D, Prefumo F, Sotiriadis A, Toi A, Lee W, on behalf of the ISUOG Clinical Standards Committee. ISUOG Practice Guidelines (updated): performance of the routine mid-trimester fetal ultrasound scan. Ultrasound Obstet Gynecol 2022; 59: 840–856.
9. Feldman, N, Melcer, Y, Levinsohn-Tavor, O, Orenstein, A, Svirsky, R, Herman, A, and Maymon, R (2015), Prenatal ultrasound charts of orbital total axial length measurement (TAL): a valuable data for correct fetal eye malformation assessment. Prenat Diagn, 35, 558– 563. doi: 10.1002/pd.4572.
10. Kivilevitch, Z., Salomon, L.J., Benoit, B. and Achiron, R. (2010), Fetal interlens distance: normal values during pregnancy. Ultrasound Obstet Gynecol, 36: 186-190. https://doi-org.vu-nl.idm.oclc.org/10.1002/uog.7531
11. S. Blazer, E. Z. Zimmer, E. Mezer, M. Bronshtein, Early and late onset fetal microphthalmia, AmJOG. 2006.11.010, 194, 5, (1354-1359).
12. Massica R, Vardimon D, Kaplan B, Shalev J, Meizner I. Early sonographic detection of recurrent fetal eye anomalies. Ultrasound Obstet Gynecol 2004; 24(6): 640–3

Please note that the maximum upload size is 5MB, and larger images and video clips can be sent to [email protected].