What is the likely cause of a smaller‑appearing eye in a 4‑year‑old with one‑year progressive unilateral facial asymmetry and a normal contrast‑enhanced MRI of the brain and orbits?

Progressive Facial Asymmetry with Smaller-Appearing Eye in a 4-Year-Old

The smaller-appearing eye in this child with progressive unilateral facial asymmetry and normal MRI most likely represents enophthalmos (posterior globe displacement) from an underlying developmental condition—specifically microphthalmia (small globe), anophthalmia (absent globe), or hemifacial microsomia—rather than true proptosis of the contralateral eye. 1, 2

Understanding the Clinical Presentation

The key distinction here is whether one eye appears smaller because:

• The affected eye is truly posteriorly displaced or underdeveloped (enophthalmos), or
• The contralateral eye is protruding forward (proptosis) 1

Given the normal contrast-enhanced MRI of brain and orbits, mass lesions, orbital tumors, vascular malformations, and inflammatory conditions causing proptosis have been effectively excluded. 1, 3 This negative imaging shifts the diagnostic focus toward developmental orbital and globe abnormalities that may not be readily apparent on standard MRI sequences. 1

Most Likely Diagnoses

Microphthalmia or Anophthalmia

• Microphthalmia (small globe) or anophthalmia (absent globe) are developmental conditions that cause enophthalmos and create the appearance of a smaller eye. 1, 2, 4
• These conditions affect 3-30 per 100,000 live births and are reported in 3.2-11.2% of blind children. 4, 5
• Progressive facial asymmetry occurs because the underdeveloped globe fails to stimulate normal orbital bone growth during childhood, leading to micro-orbitism (small bony orbit), microblepharism (small eyelids), and potentially hemifacial microsomia. 2, 6, 4
• The 1-year progressive nature reflects ongoing differential growth between the normal and affected sides as the child develops. 6, 7

Hemifacial Microsomia

• Microphthalmia may be associated with hemifacial microsomia, where the entire hemifacial skeleton is underdeveloped. 6
• This would explain the progressive facial asymmetry beyond just the orbital region. 6

Critical Diagnostic Steps

Clinical Examination Details

• Measure globe size directly using ophthalmoscopy and ocular ultrasound to detect microphthalmia that may not be obvious on MRI. 1, 2
• Assess for leukocoria (white pupillary reflex), which would indicate globe pathology including tumors, developmental processes, or infection requiring urgent evaluation. 1
• Examine for coloboma (iris, retinal, or optic nerve defects), as anophthalmia/microphthalmia and coloboma represent a phenotypic continuum sharing common genetic basis. 4, 5
• Evaluate visual acuity and potential in the affected eye, as this determines management priorities. 4

Additional Imaging Considerations

• Ophthalmology-directed ultrasound is superior to MRI for measuring globe dimensions and detecting subtle microphthalmia. 1, 2
• CT orbits with contrast may be complementary to assess bony orbital volume asymmetry and osseous anatomy if surgical intervention is considered. 1
• MRI head and orbits without contrast can detect associated developmental brain abnormalities (present in 15.5% of children with ocular developmental anomalies), including white matter abnormalities, Chiari malformations, and optic pathway gliomas. 1, 8

Genetic and Syndromic Evaluation

• Over 90 genes are associated with anophthalmia/microphthalmia, including SOX2 (major causative gene), PAX6, OTX2, CHX10, RAX, and FOXE3. 4, 5
• One-third of cases occur as part of a syndrome (e.g., CHARGE syndrome), requiring multidisciplinary pediatric assessment. 2, 4
• Genetic counseling and testing should be offered, as familial cases follow all Mendelian inheritance patterns, though most arise from de novo mutations. 4, 5

Management Approach

Immediate Priorities

• Refer to pediatric ophthalmology for comprehensive examination including ophthalmoscopy and ocular ultrasound to confirm globe size. 1, 2
• Coordinate with pediatrics to evaluate for associated systemic conditions and syndromes. 2, 4
• Maximize existing vision in the affected eye if any visual potential exists. 4

Orbital Expansion Strategy

• Early intervention is critical because loss of an eye affects maturation of soft tissues and bony orbital structures. 7, 4
• Serial conformers during the neonatal/early childhood period are the primary intervention for mild-to-moderate microphthalmia to stimulate orbital growth. 7, 4
• Severe microphthalmia and anophthalmia require additional volume replacement using serial solid implants in the growing orbit, with orbital osteotomies reserved for late referral or insufficient volume in older children. 6, 7
• Newer technologies including hydrogel implants and saline-filled tissue expanders allow more rapid expansion, though traditional conformer therapy remains primary. 7

Long-Term Considerations

• Close interaction between ophthalmologist and ocularist with motivated family involvement is essential for good cosmetic outcome. 7
• Conjunctival sac reconstruction may be needed using serial conformers, buccal mucosa grafts, or full-thickness skin grafts. 6
• Eyelid reconstruction and cranial bone grafts may be necessary to augment deficient orbital contours. 6

Common Pitfalls to Avoid

• Do not assume normal MRI excludes all pathology—developmental globe abnormalities require direct measurement via ultrasound. 1, 2
• Do not delay ophthalmology referral—early orbital expansion intervention is time-sensitive for optimal bone growth stimulation. 6, 7, 4
• Do not overlook environmental factors in history, including maternal vitamin A deficiency, gestational infections, X-ray exposure, solvent misuse, or thalidomide exposure. 4, 5
• Do not miss syndromic associations—comprehensive pediatric evaluation is mandatory given the 33% syndromic rate. 2, 4