This is a mechanism module, not a disease. The key conformance target is "ocular_morphogenesis_failure#Disrupted Optic Cup and Globe Morphogenesis". The trigger is sign-agnostic (`modifier: ABNORMAL`): disorder-specific Hedgehog nodes may specialize the perturbation to INCREASED (SOX11 loss or PTCH1 loss) or DECREASED (SHH/GLI loss). The optic-stalk/optic-cup boundary shift is the experimentally resolved Hedgehog route; other drivers may join at the downstream optic-cup/globe or fissure-closure nodes rather than claim that exact intermediate. The central node has two outcome routes on purpose: early globe morphogenesis failure directly yields anophthalmia or microphthalmia, whereas the correctly ordered later fissure-closure arm yields coloboma. Open GitHub issue 3974 means Pathophysiology currently has no HP/MONDO binding slots. To avoid a synthetic shadow node or a schema exception, the consequence node points to three top-level HP-bound phenotypes; MONDO:0016764 is recorded as a close mapping because its exact synonym is "microphthalmia-anophthalmia-coloboma spectrum", while its preferred label is narrower (isolated disease) than this mechanism, which also recurs in syndromic disorders. Wave-2 phenotype-only entries remain unwired until GitHub issue 3974 is resolved.
Eye Field Specification and Optic Vesicle Patterning Perturbation
trigger
The initiating lesion changes the dosage, timing, or spatial activity of a conserved early-eye regulator. The substitutable driver may be a transcription factor or enhancer (SOX2, OTX2, PAX6, RAX, MAB21L2), the STRA6/RARB/ALDH1A3 retinoid axis, WNT/FZD5 signaling, or Hedgehog signaling. Hedgehog is explicitly bidirectional: either excess or deficient pathway output can disrupt eye-field separation and optic-vesicle patterning, so the generic module records abnormal rather than increased or decreased activity.
Downstream
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Optic Stalk–Optic Cup Proximodistal Boundary Shift
In the experimentally resolved Hedgehog arm, disturbed early patterning shifts proximal optic-stalk identity into distal retinal territory.
Optic Stalk–Optic Cup Proximodistal Boundary Shift
amplifier
Abnormal proximal-distal patterning expands PAX2-positive optic-stalk tissue at the expense of the distal PAX6-positive optic-vesicle/retinal domain. In the Patched1-deficient model, the ectopic stalk extends into the retina and physically prevents the opposing fissure margins from meeting. This node is the resolved Hedgehog intermediate; non-Hedgehog conformers should normally join the module at a downstream node rather than assert this boundary shift.
Downstream
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Disrupted Optic Cup and Globe Morphogenesis
Misallocated optic-stalk and retinal territories disrupt the geometry of the developing optic cup and its fissure-bearing ventral margin.
Disrupted Optic Cup and Globe Morphogenesis
central effector
Early-eye regulatory failure impairs optic-vesicle outgrowth, optic-cup invagination, tissue growth, and spatial patterning. Severe failure can prevent formation of the globe (anophthalmia); partial growth failure produces a small globe (microphthalmia). Because the ventral fissure is created during optic-cup invagination, the same upstream morphogenetic disturbance can also predispose its margins to fail to appose and fuse.
Used by disorders
Frias syndrome
as OTX2 and SIX-region ocular-pituitary developmental disruption
Downstream
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Failure of Optic Fissure Closure
Optic-cup invagination and ventral patterning occur before fissure apposition and fusion; disturbed cup geometry can therefore compromise the later closure step.
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Anophthalmia–Microphthalmia–Coloboma Spectrum Outcome
Severe or partial early globe morphogenesis failure supplies the anophthalmia and microphthalmia arms of the terminal spectrum directly.
Failure of Optic Fissure Closure
effector
After optic-cup invagination creates the ventral optic fissure, its opposing margins must appose, remove intervening basement membrane, and fuse. Failure or delay of this later step leaves an inferonasal gap affecting iris, ciliary body, retina/choroid, or optic nerve and produces ocular coloboma. This node is downstream of optic-cup morphogenesis; it is not modeled as the cause of anophthalmia or microphthalmia.
Downstream
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Anophthalmia–Microphthalmia–Coloboma Spectrum Outcome
Fissure non-closure supplies the coloboma arm of the terminal spectrum.
Anophthalmia–Microphthalmia–Coloboma Spectrum Outcome
consequence
The convergent developmental outcome is a severity spectrum comprising absent globe formation (anophthalmia), reduced globe size (microphthalmia), and/or a persistent tissue cleft (coloboma). The three can occur alone or in combination because early globe-growth failure and later fissure-closure failure are related but separable outputs of disturbed ocular morphogenesis.
Downstream
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Anophthalmia
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Microphthalmia
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Coloboma