Microphthalmia and anophthalmia

A newborn with a small globe (microphthalmia, axial length below age-matched norms) or an absent globe (anophthalmia, no ocular tissue on imaging). Both sit on a spectrum and often coexist with coloboma. The clinical reflex is the same in either case: ophthalmology for orbital imaging and globe characterization, plus a syndrome work-up before the family is told it is "just the eye."

Three organizing questions before any test is ordered:

1. Unilateral vs bilateral. Bilateral disease (especially symmetric) skews strongly syndromic and genetic. Unilateral disease still warrants a work-up but is more often sporadic or local.
2. Syndromic features. Coloboma, cleft, heart defect, ear anomaly, choanal atresia, genital anomaly, midline skin defect, agenesis of the corpus callosum, growth failure. Any of these flips the work-up toward a recognizable syndrome.
3. Family history. Affected parent or sibling, consanguinity, prior pregnancy with anomalies, or maternal infection during the first trimester.

Single-gene / dominant (highest yield)

• SOX2 anophthalmia syndrome (SOX2, AD, mostly de novo): the most common identifiable genetic cause of bilateral anophthalmia/microphthalmia. Often with esophageal atresia, genital anomalies, hypothalamic-pituitary disease, and seizures. The AEG (anophthalmia-esophageal-genital) phenotype is SOX2.
• OTX2-related microphthalmia (OTX2, AD): bilateral micro/anophthalmia with pituitary involvement; phenotypic overlap with SOX2.
• RAX, VSX2, PAX6 (large deletions), SIX6: rare AD microphthalmia genes; usually on a panel.

Multisystem syndromes

• CHARGE syndrome (CHD7, AD): coloboma + heart + choanal atresia + retardation + GU + ear anomalies. Coloboma is the eye finding; true micro/anophthalmia is part of the spectrum when severe.
• Lenz microphthalmia syndrome (BCOR-related, X-linked recessive): microphthalmia in males plus skeletal, dental, and genitourinary anomalies; carrier females may have minor eye findings.
• MIDAS / MLS (microphthalmia with linear skin defects) (HCCS, X-linked dominant, lethal in males): micro/anophthalmia plus linear skin defects on the face and neck plus agenesis of the corpus callosum. Almost only seen in girls; severe X-skewing or 47,XXY in surviving males.
• Walker-Warburg syndrome (α-dystroglycanopathy): microphthalmia plus cobblestone lissencephaly plus congenital muscular dystrophy. Lethal in infancy.
• Fraser syndrome (FRAS1, FREM2, GRIP1, AR): cryptophthalmos (skin covers the eye), syndactyly, laryngeal atresia, renal agenesis.
• Matthew-Wood / PDAC syndrome (STRA6): micro/anophthalmia + pulmonary hypoplasia + cardiac + diaphragmatic hernia.

Chromosomal

• Trisomy 13 (Patau): micro/anophthalmia + holoprosencephaly + cleft + polydactyly + cardiac defect. Often diagnosed prenatally; lethal in infancy.
• Other: Wolf-Hirschhorn (4p-) and various microdeletions identifiable on CMA.

Acquired / teratogenic

• Congenital infections: rubella, CMV, toxoplasmosis, Zika can cause microphthalmia.
• Vitamin A excess in pregnancy, thalidomide, alcohol.

1. Pediatric ophthalmology for axial length, anterior segment exam, and to characterize coloboma.
2. Orbital MRI to confirm anophthalmia vs severe microphthalmia and to assess the optic nerves and CNS.
3. Chromosomal microarray as the first-tier genetic test in any infant with bilateral disease or extraocular features.
4. Single-gene or panel testing for SOX2, OTX2, CHD7, HCCS, STRA6 based on phenotype; exome if the picture is non-specific.
5. Pituitary work-up (TSH, ACTH, growth hormone, prolactin) when SOX2 or OTX2 is suspected.
6. Cardiac echo, renal ultrasound, hearing test for any multisystem suspicion.
7. TORCH titers if a prenatal exposure or infection is plausible.