Coloboma

A tissue defect of the eye that results from failure of the embryonic optic (choroidal) fissure to close during the fifth to seventh week of gestation. Because the fissure runs along the inferonasal aspect of the developing eye, colobomas are characteristically inferonasal: a notched or keyhole-shaped pupil if the iris is involved, a wedge-shaped retinal defect if the choroid and retina are involved, or a hollow excavation if the optic nerve is involved. The fundamental question for the geneticist is whether this is isolated or syndromic, because the syndromic associations carry organ-system risk that the ocular finding alone does not predict.

Three questions sort the differential:

1. Which tissue is involved? Iris alone vs chorioretinal vs optic nerve vs full globe (microphthalmia with coloboma). The deeper the involvement, the more likely the visual impairment, and the more likely a syndromic cause.
2. Unilateral or bilateral? Bilateral colobomas skew strongly syndromic. Isolated unilateral iris coloboma in a healthy infant with a family history is often mendelian and isolated.
3. What else is going on? A coloboma plus a heart murmur plus choanal atresia is CHARGE until proven otherwise. The pattern recognition is most of the diagnostic work.

CHARGE syndrome (the must-know association)

• CHARGE syndrome (CHD7, AD, mostly de novo): Coloboma + Heart defect + choanal Atresia + Retardation of growth/development + Genital anomalies + Ear anomalies (and characteristic external ear shape + sensorineural deafness + semicircular canal hypoplasia). Coloboma is the most common ocular finding; it is often chorioretinal and bilateral. CHD7 sequencing identifies the cause in the majority. This is the single highest-yield syndrome to know for any patient with a coloboma.

Cat-eye syndrome

• Cat-eye syndrome (chromosome 22q11.2 inverted duplication, supernumerary marker chromosome): iris coloboma + anal atresia + preauricular tags/pits + cardiac defects (often TAPVR) + renal anomalies. The "cat eye" name comes from the slit-like pupil produced by a vertically-oriented iris coloboma. A small marker chromosome is the cytogenetic finding; karyotype catches it where microarray may report it as an unusual gain.

Aicardi syndrome

• Aicardi syndrome (X-linked dominant, male-lethal, females only): chorioretinal lacunae + agenesis of the corpus callosum + infantile spasms. The chorioretinal lacunae are pathognomonic on dilated fundoscopy. Affected children are essentially all female. Brain MRI clinches it.

Trisomy 13 and other chromosomal

• Trisomy 13 (Patau syndrome): microphthalmia with coloboma + holoprosencephaly spectrum + midline facial clefting + polydactyly + cutis aplasia + severe cardiac defects. The constellation is unmistakable in a viable neonate.

MIDAS / MLS syndrome

• MIDAS / Microphthalmia with linear skin defects (MLS) (HCCS, COX7B, NDUFB11; X-linked dominant, male-lethal): microphthalmia with coloboma + linear hyperpigmented or aplastic skin lesions on the face and neck. Affected individuals are essentially all female; the skin lesions are the bedside tell.

Joubert syndrome and related ciliopathies

• Joubert syndrome: coloboma in some subtypes, especially those with retinal dystrophy. The defining MRI finding is the "molar tooth sign" (thickened, horizontally oriented superior cerebellar peduncles plus deepened interpeduncular fossa). Episodic tachypnea and hypotonia complete the picture.

Renal coloboma syndrome

• Renal coloboma syndrome / papillorenal syndrome (PAX2, AD): optic nerve coloboma (often described as "morning glory" appearance) + renal hypoplasia/dysplasia. Variable expressivity is striking; family members may present with isolated renal disease or isolated optic findings.

Branchio-oculo-facial

• Branchio-oculo-facial syndrome (TFAP2A, AD): coloboma + branchial cleft sinus/cyst + characteristic facies + lacrimal duct obstruction.

Microphthalmia / anophthalmia spectrum

• SOX2, OTX2, PAX6, RAX, VSX2: the genes that recurrently cause microphthalmia with or without coloboma, often syndromic with growth-hormone deficiency or pituitary abnormalities (SOX2, OTX2).

1. Complete ophthalmologic exam: which structures are involved, unilateral vs bilateral, presence of microphthalmia. Photograph the fundus.
2. Look for the syndromic constellation:
   • Heart: echocardiogram (CHARGE, cat-eye).
   • Choanal patency: pass a catheter (CHARGE).
   • Ears: external shape and hearing (CHARGE).
   • Anus: patency and position (cat-eye).
   • Kidneys: renal ultrasound (CHARGE, renal coloboma, cat-eye).
   • Brain: MRI for callosal agenesis (Aicardi), molar tooth sign (Joubert), pituitary anomalies (SOX2/OTX2).
   • Skin: linear defects on the face (MIDAS).
3. Family history: especially of unilateral colobomas, renal disease, deafness, or unexplained eye anomalies. Examine a parent at the slit lamp if available.
4. Cytogenetics: karyotype (catches the cat-eye supernumerary marker) + chromosomal microarray (catches the recurrent submicroscopic lesions).
5. Targeted gene testing: CHD7 for CHARGE features; PAX2 if renal involvement; PAX6/SOX2/OTX2 if microphthalmia. Microphthalmia/coloboma gene panel or exome when the picture is atypical.