Anophthalmia and Microphthalmia

Journal Pre-proof Anophthalmia and Microphthalmia Beryl R. Benacerraf, MD, Bryann S. Bromley, MD, Angie C. Jelin, MD PII:

S0002-9378(19)31018-X

DOI:

https://doi.org/10.1016/j.ajog.2019.08.016

Reference:

YMOB 12838

To appear in:

American Journal of Obstetrics and Gynecology

Please cite this article as: Benacerraf BR, Bromley BS, Jelin AC, Anophthalmia and Microphthalmia, American Journal of Obstetrics and Gynecology (2019), doi: https://doi.org/10.1016/j.ajog.2019.08.016. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.

SMFM Fetal Anomalies Consult Series #1: Facial Anomalies smfm.org 1

Anophthalmia and Microphthalmia

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Beryl R. Benacerraf, MD; Bryann S. Bromley, MD; Angie C. Jelin, MD

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Introduction

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Anophthalmia and microphthalmia are characterized by the complete or almost complete lack of

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the primary optic vesicle, resulting in an absent or very small malformed orbital globe.

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Definition

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Anophthalmia is the complete absence of the orbital globe. Microphthalmia refers to a small

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typically malformed orbital globe. These abnormalities can be unilateral or bilateral. The birth

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prevalence of these two malformations combined is approximately 1 per 10,000 births (1).

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Ultrasound Findings

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The fetal orbits are typically detectable by 11–12 weeks’ gestation, and the lens is seen as a thin,

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walled circle within each orbit by 13–14 weeks gestation (2). The diagnosis of anophthalmia or

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microphthalmia is typically a subjective one, although orbital measurements at each gestational

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age are available (3). The coronal view of the fetal face is the best way to evaluate the orbits.

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This view can show the size and shape of the orbits, their positioning on the fetal face, spacing

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between the two orbits, and associated facial abnormalities. The sagittal view of each orbit is

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also helpful when measuring the size of the orbit. The lens is seen as a small, thin-walled,

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circular structure and is normally visible in the anterior aspect of the globe in both the axial and

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sagittal views. The hyaloid artery is visible traversing the middle of the eye from anterior to

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posterior usually by 14 weeks and should disappear by 29 weeks (4). Most often, the detection of

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SMFM Fetal Anomalies Consult Series #1: Facial Anomalies smfm.org 24

these rare but severe ocular anomalies is made because other fetal anomalies are present and the

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orbital findings are part of a syndrome. Orbital defects are rarely discovered prenatally as

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isolated findings(see Figure 1)

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Associated Abnormalities

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The associated anomalies vary with the fetal syndrome involved; therefore, it is crucial to

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perform a thorough sonographic anatomic evaluation. Triploidy and trisomies 9 and 13 are

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among the aneuploidies most likely to feature microphthalmia. Triploidy has early asymmetric

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fetal growth restriction associated with anomalies of the heart, brain, and face (hypertelorism).

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Trisomy 13 is associated with midline facial and brain defects as well as cardiac anomalies and

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polydactyly. Trisomy 9 results in early pregnancy loss; survival generally only occurs in mosaic

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cases. Features of mosaic trisomy 9 include abnormalities of the heart, face, and skull.

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Nonsyndromic conditions that can feature microphthalmia include holoprosencephaly spectrum,

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congenital viral infections (particularly rubella), and CHARGE association (Coloboma, Heart

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defects, Atresia choanae (choanal atresia), growth Restriction, Genital anomalies, and Ear

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anomalies). Other syndromes associated with eye anomalies include Aicardi syndrome (female

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fetus, arachnoid cyst); Fraser syndrome (genitourinary and tracheal anomalies); Fryns syndrome

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(congenital diaphragmatic hernia); Goldenhar syndrome (ear tags, cleft lip and/or palate,

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asymmetry of face); Gorlin syndrome (ventriculomegaly); Lenz syndrome (microcephaly);

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Walker-Warburg syndrome (lissencephaly, ventriculomegaly, cataracts); fetal alcohol syndrome;

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and others (5).

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Differential Diagnosis

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SMFM Fetal Anomalies Consult Series #1: Facial Anomalies smfm.org 47

Anomalies of the fetal eye may be bilateral or unilateral and asymmetrical. Anophthalmia and

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microphthalmia refer to the size of the globe and orbit. Congenital cataracts should not be

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confused with microphthalmia, although both conditions may be present in the same fetus. The

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orbit may be distorted by masses such as intracranial teratomas (associated with intracranial

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component), gliomas (usually medial aspect of orbit), or retinoblastomas (rarely seen in utero).

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Genetic Evaluation

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Diagnostic testing (amniocentesis or chorionic villus sampling) with chromosomal microarray

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analysis (CMA) should be offered when anophthalmia is detected. If screening or other

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ultrasound features are suggestive of a common aneuploidy, it is reasonable to initially perform

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karyotype or fluorescence in situ hybridization, with reflex to CMA if these test results are

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normal. Many syndromes are associated with anophthalmia; they can be sporadic, autosomal

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dominant, autosomal recessive, or X-linked. If there are additional anomalies, consanguinity, or

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a family history of a specific condition, gene panel testing or exome sequencing may be useful,

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as CMA does not detect single-gene (Mendelian) disorders. If exome sequencing is pursued,

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appropriate pretest and posttest genetic counseling by a provider experienced in the complexities

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of genomic sequencing is recommended (6). Maternal infections (rubella), vitamin A deficiency,

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and teratogenic exposures (thalidomide) have also been associated with anophthalmia; therefore,

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obtaining a history of maternal exposures and a family history is important. After appropriate

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counseling, cell-free DNA screening is an option for patients who decline diagnostic evaluation

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if a common aneuploidy is suspected.

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Pregnancy and Delivery Management

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A detailed ultrasound examination should be performed and should include comprehensive

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imaging of the intracranial structures (e.g., a neurosonogram) and the fetal heart. A fetal

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echocardiogram, as well as fetal magnetic resonance imaging to assess for intracranial

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abnormalities, should be considered. Referrals to pediatric ophthalmology, craniofacial clinic,

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plastic surgery, or other subspecialty services should be based on additional sonographic

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findings. Pregnancy termination is an option that should be discussed with all patients in whom a

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fetal anomaly is detected. Shared patient decision-making requires a thorough evaluation and

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multidisciplinary counseling regarding prognosis. The specific finding of anophthalmia or

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microphthalmia does not generally affect delivery management, although delivery at a tertiary

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care center with pediatric genetic, craniofacial, and ophthalmology consultation should be

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considered, as appropriate for the clinical findings.

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Prognosis

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The prognosis is variable and dependent upon the severity, associated anomalies, and underlying

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genetic etiology. Unilateral microphthalmia can have a favorable prognosis other than possible

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blindness in the affected eye. Mild to moderate microphthalmia can be managed with

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conformers, whereas severe cases may require surgical remodeling. Bilateral microphthalmia is

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often associated with intellectual disability, and vision is dependent upon retinal development.

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Reported cases of anophthalmia typically represent severe microphthalmia, as true, primary

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anophthalmia is rarely compatible with life secondary to associated cerebral anomalies.

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Summary

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Microphthalmia is a rare abnormality of the eye that generally occurs due to a genetic syndrome,

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maternal infection, teratogenic exposure, or vitamin deficiency. Diagnostic testing is

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recommended with CMA and/or molecular genetic testing based on associated anomalies.

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Prognostic counseling is dependent on the severity of microphthalmia, associated findings, and

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the underlying diagnosis.

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Figure <02->1. Axial view of the fetal head and face showing the small and asymmetrical size of the orbits (calipers). This fetus has multiple other anomalies.

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References 1. Busby A, Dolk H, Collin R, Jones RB, Winter R. Compiling a national register of babies born

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with anophthalmia/microphthalmia in England 1988-94. Arch Dis Child Fetal Neonatal Ed 1998

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Nov;79(3):F168-73.

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2. Mashiach R, Vardimon D, Kaplan B, Shalev J, Meizner I. Early sonographic detection of

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recurrent fetal eye anomalies. Ultrasound Obstet Gynecol 2004 Nov;24(6):640-3.

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3. Feldman N, Melcer Y, Levinsohn-Tavor O, Orenstein A, Svirsky R, Herman A, et al. Prenatal

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ultrasound charts of orbital total axial length measurement (TAL): a valuable data for correct

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fetal eye malformation assessment. Prenat Diagn 2015 Jun;35(6):558-63.

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4. Abuhamad A, Charoui R. First Trimester Ultrasound Diagnosis of Fetal Abnormalities.

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Philadelphia: Wolters Kluwer; 2018.

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5. Benacerraf B. Ultrasound Diagnosis of Fetal Syndromes. Second ed. London: Churchill

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Livingstone; 2008.

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6. International Society for Prenatal Diagnosis, Society for Maternal Fetal Medicine, Perinatal

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Quality Foundation. Joint Position Statement from the International Society for Prenatal

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Diagnosis (ISPD), the Society for Maternal Fetal Medicine (SMFM), and the Perinatal Quality

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Foundation (PQF) on the use of genome-wide sequencing for fetal diagnosis. Prenat Diagn 2018

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Jan;38(1):6-9.

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